naphthoquinones and Inflammation

Shikonin, the primary active compound found in the rhizome of the traditional Chinese medicinal herb known as "ZiCao", exhibits a diverse range of pharmacological effects. This drug has a wide range of uses, including as an anti-inflammatory, antioxidant, and anti-cancer agent. It is also effective in promoting wound healing and treating autoimmune diseases such as multiple sclerosis, diabetes, asthma, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. Although shikonin has a wide range of applications, its mechanisms are still not fully understood. This review article provides a comprehensive overview of the recent advancements in the use of shikonin for the treatment of immune-related diseases. The article also delves into the anti-inflammatory and immunoregulatory mechanisms of shikonin and offers insights into the inflammation and immunopathogenesis of related diseases. Overall, this article serves as a valuable resource for researchers and clinicians working in this field. These findings not only provide significant new information on the effects and mechanisms of shikonin but also establish a foundation for the development of clinical applications in treating autoimmune diseases.

Topics: Anti-Inflammatory Agents; Autoimmune Diseases; Humans; Inflammation; Naphthoquinones

Bone metabolism is essential for maintaining bone mineral density and bone strength through a balance between bone formation and bone resorption. Bone formation is associated with osteoblast activity whereas bone resorption is linked to osteoclast differentiation. Osteoblast progenitors give rise to the formation of mature osteoblasts whereas monocytes are the precursors for multi-nucleated osteoclasts. Chronic inflammation, auto-inflammation, hormonal changes or adiposity have the potential to disturb the balance between bone formation and bone loss. Several plant-derived components are described to modulate bone metabolism and alleviate osteoporosis by enhancing bone formation and inhibiting bone resorption. The plant-derived naphthoquinone plumbagin is a bioactive compound that can be isolated from the roots of the

Topics: Bone Resorption; Cell Differentiation; Humans; Inflammation; Naphthoquinones; Osteoblasts; Osteoclasts; Phytochemicals

Shikonin is one of the primary active components extracted from the dried root of

Topics: Humans; Inflammation; Lithospermum; Naphthoquinones; Skin Diseases

Inflammation plays a significant role in the pathogenesis of chronic diseases. Inflammatory diseases such as bacterial diseases, Alzheimer's disease, rheumatoid arthritis, multiple sclerosis, and so on, impose huge costs on the health systems. On the other hand, some side effects have been reported for the classic drugs used to treat these diseases. Plants phytochemicals have revealed important prospects in the handling and controlling of human diseases. β-lapachone, is a derivative of the naturally occurring element lapachol, from Tabebuia avellanedae and its anti-inflammatory effects have been reported in several reports. This review summarized the evidence from cell and animal studies supporting the anti-inflammatory role of β-lapachone and discussed its potential mechanisms.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Bacterial Infections; Humans; Inflammation; Multiple Sclerosis; Naphthoquinones; Tabebuia

Pyruvate kinase M2 is a critical enzyme that regulates cell metabolism and growth under different physiological conditions. In its metabolic role, pyruvate kinase M2 catalyzes the last glycolytic step which converts phosphoenolpyruvate to pyruvate with the generation of ATP. Beyond this metabolic role in glycolysis, PKM2 regulates gene expression in the nucleus, phosphorylates several essential proteins that regulate major cell signaling pathways, and contribute to the redox homeostasis of cancer cells. The expression of PKM2 has been demonstrated to be significantly elevated in several types of cancer, and the overall inflammatory response. The unusual pattern of PKM2 expression inspired scientists to investigate the unrevealed functions of PKM2 and the therapeutic potential of targeting PKM2 in cancer and other disorders. Therefore, the purpose of this review is to discuss the mechanistic and therapeutic potential of targeting PKM2 with the focus on cancer metabolism, redox homeostasis, inflammation, and metabolic disorders. This review highlights and provides insight into the metabolic and non-metabolic functions of PKM2 and its relevant association with health and disease.

Topics: Adenosine Triphosphate; Atherosclerosis; Carrier Proteins; Cell Proliferation; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Glycolysis; Homeostasis; Humans; Inflammation; Inflammatory Bowel Diseases; Insulin; Kidney Diseases; Liver; Membrane Proteins; Metabolic Diseases; Naphthoquinones; Neoplasm Metastasis; Neoplasms; Neuralgia; Oxidants; Oxidation-Reduction; Protein Isoforms; Sepsis; Signal Transduction; Thyroid Hormone-Binding Proteins; Thyroid Hormones; Tissue Distribution

Oxyprenylated secondary metabolites from plants, fungi, and bacteria, and their semisynthetic derivatives have been subject of growing interest during the last decade. Such natural products in fact have been discovered as potentially novel lead compounds for a series of pharmacological activities, mainly in terms of anti-cancer and anti-inflammatory ones. Especially during the last 5 years, a wider panel of prenyloxy secondary metabolites have been investigated from chemical and biological points of view and these include benzoic acids, alcohols, aldehydes, chalcones, anthraquinones, 1,4-naphthoquinones, other than the well known oxyprenylated ferulic acid and coumarin derivatives. The aim of this comprehensive review is to focus on the anti-inflammatory properties and related mechanisms of action of selected classes of oxyprenylated naturally occurring compounds and their semisynthetic analogues covering the literature period from 2011 to 2017. In vitro and in vivo data on their pharmacological activity triggering different pathways of the overall inflammatory machinery as well as structure activity relationship acquisitions will be summarized in order to make a detailed survey of the most recent reports on the potential of the title compounds as a novel class of anti-inflammatory agents.

Topics: Animals; Anthraquinones; Anti-Inflammatory Agents; Benzoates; Biological Products; Chalcones; Cinnamates; Coumarins; Drug Discovery; Humans; Inflammation; Naphthoquinones; Prenylation; Secondary Metabolism

Species of the carnivorous genus Drosera L. have long been a source of valuable natural products. The various phytochemicals characteristic of these species, particularly 1,4-naphthoquinones and flavonoids, have contributed to the diverse utilization of sundews in traditional medicine systems worldwide. A growing number of studies have sought to investigate the comparative phytochemistry of Drosera species for improved sources of pharmaceutically important compounds. The outcomes of these studies are here collated, with emergent trends discussed in detail. Important factors which affect production of secondary metabolites in plants are critically examined, such as environmental influences and in vitro culture, and recommendations subsequently presented based on this. Explicitly, the current review aims to i) present an updated, comprehensive listing of the phytochemical constituents of the genus (including quantitative data where available), ii) summarize important factors which may influence the production of phytopharmaceuticals in plants, and iii) recommend guidelines for future research based on the above, including improved standardization and quality control. We have also included a section discussing future perspectives of research on Drosera spp. based on three different research lines i) the potential to produce much needed lead compounds for treatment of tuberculosis, ii) the potential role of anthocyanins in nitrogen transport, and iii) research into 'Natural Deep Eutectic' solvents produced by Drosera spp. in the droplets or 'dew' employed to capture insect prey.

Topics: Anthocyanins; Anti-Inflammatory Agents; Drosera; Drug Synergism; Ethnopharmacology; Flavonoids; Humans; Inflammation; Naphthoquinones; Plant Components, Aerial; Plant Extracts

Vitamin Ks (VKs) are fat-soluble quinone compounds known to have various bioactivities. This review describes the inflammatory effects of VKs and their related quinone derivatives based on DNA polymerase (pol) inhibition. VK3, but not VK1 or VK2 (=MK-4), inhibited the activity of human pol γ, which is the DNA replicative pol in mitochondria. Of the intermediate compounds between VK2 and VK3 (namely MK-3, MK-2 and MK-1), MK-2 was the strongest inhibitor of mammalian pols α, κ and λ, which belong to the B-, Y- and X-families of pols, respectively. Among the VK3 based quinone derivatives, such as 1,4-naphthoquinone (NQ), 2-dimethyl-1,4-naphthoquinone (1,2-dimethyl-NQ), 1,4-benzoquinone (BQ), 9,10-anthraquinone (AQ) and 5,12-naphthacenequinone (NCQ), NQ was the strongest inhibitor of mammalian pols α and λ, in particular, DNA repair-related pol λ. Among the all compounds tested, NQ displayed the strongest suppression of tumor necrosis factor (TNF)-α production induced by lipopolysaccharide (LPS) in a cell culture system using RAW264.7 mouse macrophages. NQ also suppressed the expression of pol λ protein in these cells, after LPS-treated RAW264.7 cells were stimulated to induce pol λ expression. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of NQ into mice suppressed TNF-α production in peritoneal macrophages and serum. In an in vivo colitis mouse model induced using dextran sulfate sodium (DSS), NQ markedly suppressed DSS-evoked colitis. The promising anti-inflammatory candidates based on the inhibition of DNA repair-related pols, such as pol λ, by VKs quinone derivatives, such as NQ, are discussed.

Topics: Animals; DNA Polymerase beta; DNA Polymerase gamma; DNA Polymerase I; DNA Repair; DNA-Directed DNA Polymerase; Humans; Inflammation; Mice; Mitochondria; Naphthoquinones; Nucleic Acid Synthesis Inhibitors; Tumor Necrosis Factor-alpha; Vitamin K

Patients undergoing an abdominal surgical procedure develop a transient episode of impaired gastrointestinal motility or postoperative ileus. Importantly, postoperative ileus is a major determinant of recovery after intestinal surgery and leads to increased morbidity and prolonged hospitalization, which is a great economic burden to health-care systems. Although a variety of strategies reduce postoperative ileus, including multimodal postoperative rehabilitation (fast-track care) and minimally invasive surgery, none of these methods have been completely successful in shortening the duration of postoperative ileus. The aetiology of postoperative ileus is multifactorial, but insights into the pathogenesis of postoperative ileus have identified intestinal inflammation, triggered by surgical handling, as the main mechanism. The importance of this inflammatory response in postoperative ileus is underscored by the beneficial effect of pharmacological interventions that block the influx of leukocytes. New insights into the pathophysiology of postoperative ileus and the involvement of the innate and the adaptive (T-helper type 1 cell-mediated immune response) immune system offer interesting and important new approaches to prevent postoperative ileus. In this Review, we discuss the latest insights into the mechanisms behind postoperative ileus and highlight new strategies to intervene in the postoperative inflammatory cascade.

Topics: Adaptive Immunity; Ghrelin; Humans; Ileus; Immunity, Innate; Inflammation; Naphthoquinones; Postoperative Complications; Serotonin 5-HT4 Receptor Agonists

The naphthoquinone pigment, shikonin, isolated from Lithospermum erythrorhizon Sieb. et Zucc.(Boraginaceae) and its derivatives are the active components isolated from the Chinese herbal therapeutic, Zicao. Historically, Zicao root extracts have been used to treat macular eruption, measles, sore-throat, carbuncles and burns. Multiple pharmacological actions have been attributed to shikonin, e.g. antiinflammatory, antigonadotropic and anti-HIV-1 activity. In this review, several therapeutic applications of shikonin will be summarized including its pleiotropic, antiinflammatory and antitumour effects. Widely diverse and sometimes conflicting activities have been attributed to shikonin, e.g. wound healing, enhanced granuloma formation, suppression of local acute inflammatory reactions, inhibition of angiogenesis, inhibition of select chemokine ligands, inhibition of DNA topoisomerase activity, inhibition of platelet activation and antimicrobial activity. Comparison of the various reported mechanisms of action for shikonin lead us to hypothesize that shikonin is an effective inhibitor of protein-protein interaction with multiple targets in both the intracellular and extracellular compartments. This general inhibitory effect can account for the broad spectrum of shikonin biological and pharmacological activities.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Granuloma; Humans; Inflammation; Lithospermum; Mast Cells; Naphthoquinones; Neoplasms; Neutrophils; Phytotherapy; Plant Extracts; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Respiratory Burst; Signal Transduction; Wound Healing

Clinical morphological efficiency of local application of a new biopolymeric film was studied. The film was based on methylcellulose derivatives and contained shikonin (preparation of plant origin) and its esters isolated from Lithospermum erythrorhizon L. cell culture. Combined therapy of 30 patients (34-72 years) with erosive ulcerative lichen planus and leukoplakia of the buccal mucosa was carried out. Local application of the new drug led to more rapid pain relief, epithelialization of the inflammatory destructive foci in the buccal mucosa, and reduced the intensity of morphological signs of lesions in the studied patient population.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Biopolymers; Drugs, Chinese Herbal; Female; Humans; Inflammation; Leukoplakia, Oral; Lichen Planus, Oral; Male; Methylcellulose; Middle Aged; Mouth Mucosa; Naphthoquinones; Oral Ulcer

P2X7 receptors (P2X7Rs) are ligand-gated ion channels that play a significant role in inflammation and are considered a potential therapeutic target for some inflammatory diseases. We have previously shown that a number of synthetic 1,4-naphthoquinones are capable of blocking P2X7Rs in neuronal and macrophage cells. In the present investigation, we have demonstrated the ability of the tetracyclic quinone-thioglucoside conjugate

Topics: Adenosine Triphosphate; Anti-Inflammatory Agents; Humans; Inflammation; Macrophages; Naphthoquinones; Receptors, Purinergic P2X7; Thioglucosides

Topics: Cartilage, Articular; Cells, Cultured; Chondrocytes; Humans; Inflammation; Naphthoquinones; Osteoarthritis

As air pollution has been paid more attention to by public in recent years, effects and mechanism in particulate matter-triggered health problems become a focus of research. Lysosomes and mitochondria play an important role in regulation of inflammation. Interleukin-33 (IL-33) has been proved to promote inflammation in our previous studies. In this research, macrophage cell line RAW264.7 was used to explore the potential mechanism of upregulation of IL-33 induced by 1,4-naphthoquinone black carbon (1,4-NQ-BC), and to explore changes of lysosomes and mitochondria during the process.. 50 μg/mL 1,4-NQ-BC exposure for 24 h dramatically increased expression of IL-33 in RAW264.7 cells. Lysosomal membrane permeability was damaged by 1,4-NQ-BC treatment, and higher mitochondrial membrane potential and ROS level were induced by 1,4-NQ-BC. The results of proteomics suggested that expression of ferritin light chain was increased after cells were challenged with 1,4-NQ-BC, and it was verified by Western blot. Meanwhile, expressions of p62 and LC3B-II were increased by 50 μg/mL 1,4-NQ-BC in RAW264.7 cells. Ultimately, expression of IL-33 could return to same level as control in cells treated with 50 μg/mL 1,4-NQ-BC and 50 μM deferoxamine combined.. 1,4-NQ-BC induces IL-33 upregulation in RAW264.7 cells, and it is responsible for higher lysosomal membrane permeability and ROS level, lower mitochondrial membrane potential, and inhibition of autophagy. Ferritin light chain possibly plays an important role in the upregulation of IL-33 evoked by 1,4-NQ-BC.

Topics: Animals; Apoferritins; Carbon; Humans; Inflammation; Interleukin-33; Mice; Naphthoquinones; RAW 264.7 Cells; Reactive Oxygen Species; Soot; Up-Regulation

Shikonin is an ointment produced from Lithospermun erythrorhizon which has been used in traditional medicine both in Europe and Asia for wound healing and is associated with anti-inflammatory properties. The goal of this work is to assess the analgesic properties of Shikonin in the CFA-induced inflammation model of pain. Rats were subjected to inflammation of the hind paw by CFA injection with a preventive injection of Shikonin and compared to either a control group or to a CFA-inflamed group with the vehicle drug solution. Inflammation of the hind paw by CFA was assessed by measurement of the dorsal to plantar diameter. Mechanical thresholds were established by means of the Von Frey filaments which are calibrated filaments that exert a defined force. Finally, the spinal cord of the studied animals was extracted to analyse the microglia population through immunohistochemistry using the specific marker Iba-1. Our results show that Shikonin reduces the paw oedema caused by CFA inflammation. Subsequently, there is a concomitant restoration of the mechanical thresholds reduced by CFA hind paw injection. Additionally, spinal microglia is activated after CFA-induced inflammation. Our results show that microglia is inhibited by Shikonin and has concomitant restoration of the mechanical thresholds. Our findings demonstrate for the first time that Shikonin inhibits microglia morphological changes and thereby ameliorates pain-like behaviour elicited by mechanical stimulation.

Topics: Animals; Disease Models, Animal; Hyperalgesia; Inflammation; Microglia; Naphthoquinones; Pain; Rats; Spinal Cord

Inflammatory bowel disease (IBD) represents a chronic inflammation of the gastrointestinal tract characterized by an overreaction of immune responses and damage at the intestinal mucosal barrier. P-glycoprotein (P-gp) plays a key role to protect the intestinal barrier from xenobiotic accumulation and suppressing excessive immune responses. Therefore, induction/activation of P-gp function could serve as a novel therapeutic target to treat IBD. This study aimed to evaluate the potential therapeutic values of naphthoquinone derivatives (NQ-1 - NQ-8) as P-gp modulators to counterbalance intestinal inflammation. The data indicate that NQ-2, NQ-3, and NQ-4 act as P-gp inducers/activators and are recognized as substrates for P-gp. The three derivatives possess anti-inflammatory effects mediated by suppression of NF-κB and HDAC6 activity in Caco2 monolayer cells. Besides, they reversed LPS-induced intestinal barrier dysfunction by enhancing the expression of P-gp and ZO-1 tight junction proteins in a Caco-2 spheroid model. NQ-2, NQ-3, and NQ-4 showed a robust inhibitory effect on IL-1β maturation in LPS-primed THP-1 cells. This effect may contribute to alleviate the inflammatory cascades associated with IBD. Distinctively, NQ-2 and NQ-3 exerted anti-NLRP3 inflammasome activity evidenced by the inhibition of CASP-1 activity and the promotion of autophagy. Both compounds induced disruptions of the microtubule network in transfected U2OS-GFP-α-tubulin cells. Treatment with NQ-2 remarkably attenuated dextran sulfate sodium (DSS)-induced colitis in rats by suppressing changes in colon length, colon mass index, and intestinal histopathology scores. Thus, 1,4-naphthoquinone derivatives such as NQ-2 may provide potential therapeutic anti-inflammatory effects for IBD patients and for other NLRP3-associated inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; ATP Binding Cassette Transporter, Subfamily B; Caco-2 Cells; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Humans; Inflammation; Inflammatory Bowel Diseases; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Naphthoquinones; Rats

Colorectal cancer (CRC) and inflammatory bowel disease (IBD) are the most common diseases of human digestive system. Nowadays, the influence of the inflammatory microenvironment on tumorigenesis has become a new direction, and the exploration of relative molecular mechanism will facilitate the discovery and identification of novel potential anti-cancer molecules.. Natural shikonin (SK) and acetyl-shikonin (acetyl-SK) was administered to azoxymethane (AOM)/dextran sodium sulphate (DSS)-induced colitis-associated colorectal cancer (CAC) mice model by gavage to investigate their therapeutic effects. Moreover, fresh feces and colon tissues were collected for determining the function of SK and acetyl-SK on the gut microbes and protein expression, respectively.. Both SK and acetyl-SK decreased AOM/DSS-induced CAC, and regulated the intestinal flora structure in CAC mouse model. They, especially SK, improved species richness, evenness and diversity of intestinal flora, recovered the upregulated ratio of Firmicutes to Bacteroidota (F/B ratio) which symbolizes gut microbiota dysbiosis. SK and its derivative increased the beneficial bacteria g__norank_f__Muribaculaceae, Lactobacillus, Lachnospiraceae_NK4A136_Group, and reduced those harmful ones including Ileibacterium and Coriobacteriaceae UCG-002. Notably, AOM/DSS caused significant increase in the abundance of Ileibaterium valens and g__norank_f__norank_o__Clostridia_UCG-014, which were not previously reported in studies of colonic inflammation or cancer, and the disorder was reversed by 20 mg/kg of SK. In our current study, the action of SK and acetyl-SK is dose-dependent, and 20 mg/kg SK exhibited the most effective functions, even better than the positive drug mesalazine. Moreover, differential proteomics and ELISA results showed that SK could recover the increase of pro-inflammatory cytokines (including IL-1β, IL-6 and TNF-α), the upregulation of pyruvate kinase isozyme type M2 (PKM2) and some other proteins (mainly concentrated in transcriptional mis-regulation in cancer and IL-17 signaling pathways), and the downregulation of Aldh1b1-Acc3-Maoa and Μgt2b34-Aldh1a1-Aldh1a7 involved in Wnt/β-catenin signaling pathway.. Our study identified SK and acetyl-SK, especially SK, as potential preventive agents for CAC through regulating both gut microbes and pathways involved in inflammation and cancer such as Wnt/β-catenin signaling pathway.

Topics: Animals; Azoxymethane; Bacteroidetes; Colitis; Colitis-Associated Neoplasms; Colorectal Neoplasms; Dextran Sulfate; Disease Models, Animal; Firmicutes; Humans; Inflammation; Mice; Mice, Inbred C57BL; Naphthoquinones; Tumor Microenvironment

Indomethacin [IND] is reported to treat colon cancer. However, continuous exposure to IND causes gastric ulceration, an adverse side effect in humans. This study implies the therapeutic effect of IND and juglone [JUG] against colon carcinogenesis, without gastric ulceration - an adverse side effect of IND.. Adult male Balb/C mice were divided into six groups randomly: control, AOM/DSS-induced, IND-treated, JUG-treated, IND + JUG-treated and drug-control. Levels of serum markers, haematoxylin & eosin staining to observe tissue architecture, toluidine blue staining to detect mast cells expression, Masson's trichrome and sirius-red staining were used to detect the collagen deposition. RT-PCR and western blot analysis were carried out to detect inflammation and apoptosis.. IND + JUG effectively decreased the levels of serum markers: CEA, AFP, LDH, AST and ALT. Although, IND restored colonic architecture by regulating the accumulation of mast cell and collagen content, it causes gastric ulceration. To address this adverse effect of IND, JUG was given along with IND and was shown to alleviate IND-induced gastric ulceration. AOM/DSS induced animals showed increased expression of inflammatory molecules - TNFα, NFκB and Cox-2, apoptosis regulator - Bcl-2 and decreased expression of pro-apoptotic molecules - Bad, Bax and caspase3; whereas, IND and JUG treated groups showed decreased inflammatory expression with increased expression of pro-apoptotic molecules.. IND and JUG reduce the inflammatory activity and induce apoptotic cell death, while JUG effectively prevents IND induced gastric ulceration. These findings establish that a combination of IND + JUG may serve as a promising treatment regimen for colon cancer.

Topics: Animals; Apoptosis; Azoxymethane; Carcinogenesis; Cell Count; Cell Line, Tumor; Collagen; Colonic Neoplasms; Dextran Sulfate; Indomethacin; Inflammation; Male; Mast Cells; Mice, Inbred BALB C; Naphthoquinones

Shikonin is the major active component in

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Bronchoalveolar Lavage Fluid; Caspase 3; Cytokines; Disease Models, Animal; DNA Fragmentation; Inflammation; Lipopolysaccharides; Male; Mice, Inbred C57BL; Myeloid Cell Leukemia Sequence 1 Protein; Naphthoquinones; Neutrophil Infiltration; Neutrophils; Poly(ADP-ribose) Polymerases; Teichoic Acids; Tumor Suppressor Protein p53

Juglone (JUG), a natural product found in walnut trees and other plants, shows potent antioxidant, antimicrobial, and immunoregulatory activities. However, it remains unknown whether JUG can alleviate ulcerative colitis. This study aims to explore the effect of JUG on dextran sulfate sodium (DSS)-induced colitis in mice. The mice were randomly assigned into three groups: the vehicle group, the DSS group, and the JUG group. The experiments lasted for 17 days; during the experiment, all mice received dimethyl sulfoxide (DMSO, 0.03% v/v)-containing water, while the mice in the JUG group received DMSO-containing water supplemented with JUG (0.04 w/v). Colitis was induced by administering DSS (3% w/v) orally for 10 consecutive days. The results showed that the JUG treatment significantly ameliorated body weight loss and disease activity index and improved the survival probability, colon length, and tissue damage. JUG reversed the DSS-induced up-regulation of proinflammatory cytokines, including interleukin (IL)-6, 12, 21, and 23, and tumor necrosis factor-alpha, and anti-inflammatory cytokines, such as IL-10 and transforming growth factor-beta, in the serum of the colitis mice. Additionally, the activation of mitochondrial uncoupling protein 2 and phospho-Nuclear Factor-kappa B p65 and the inhibition of the kelch-like ECH-associated protein 1 and NF-E2-related factor 2 induced by DSS were also reversed under JUG administration. Although the JUG group possessed a similar microbial community structure as the DSS group, JUG enriched potential beneficial microbes such as

Topics: Animals; Colitis, Ulcerative; Inflammation; Male; Mice; Mice, Inbred C57BL; Naphthoquinones; Oxidative Stress

LQB 118, a hydride molecule, has been described as an antineoplastic and antiparasitic drug. Recently, LQB118 was also shown to display anti-inflammatory properties using an LPS-induced lung inflammation model. However, LQB 118 effects on the inflammatory response induced by zymosan has not been demonstrated. In this study, swiss mice were LQB 118 intraperitoneally (i.p.) treated and zymosan was used to induce peritoneal inflammation. Peritoneal fluid was collected and used for cell counting and proinflammatory cytokines quantification (IL-1β, IL-6, and TNF-α) by immunoenzymatic assay (ELISA). For in vitro studies, peritoneal macrophages zymosan-stimulated were used. Results demonstrated that LQB 118 treatment reduced polymorphonuclear cell migration and TNF-α, IL-1β, and IL-6 levels in the peritoneal cavity. In macrophages, LQB 118 treatment display no cytotoxic effect and is also able to reduce cytokines levels. To investigate LQB 118 putative mechanism of action, TLR2, CD69, and P-p38 MAPK expression were evaluated. LQB 118 treatment reduced CD69 expression and p38 phosphorylation induced by zymosan. Furthermore, LQB 118 was able to negatively modulate TLR2 expression in the presence of inflammatory stimulus. Thus, our study provide new evidences for the mechanisms related to the anti-inflammatory effect of LQB 118 in vivo and in vitro.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Cells, Cultured; Cytokines; Disease Models, Animal; Female; Humans; Inflammation; Inflammation Mediators; Macrophages; Mice; Naphthoquinones; Peritoneum; Peritonitis; Pterocarpans; Zymosan

Zicao is the dried root of Lithospermum erythrorhizon Sieb, et Zucc, Arnebia euchroma (Royle) Johnst, or Arnebia guttata Bunge and commonly used to treat viral infection, inflammation, arthritis and cancer in China.Shikonin (SKN) is a major active chemical component isolated from zicao. Previous research showed that SKN has anti-inflammatory, immunomodulatory and analgesic effects, and inhibits the development of arthritis and the condition of collagen arthritis (CIA) mice; nevertheless, its role in the angiogenesis of rheumatoid arthritis (RA) has not been elucidated.. The purpose of this study was to investigate the antiangiogenic activity of SKN in CIA rats and various angiogenesis models.. The anti-arthritic effect of SKN on CIA rats was tested by arthritis score, arthritis incidence, radiological observation and histopathology evaluation of inflamed joints. Vessel density evaluated with CD31 immunohistochemistry/immunofluorescence in joint synovial membrane tissues of CIA rats, chick chorioallantoic membrane assay, rat aortic ring assay, and the migration, invasion, adhesion and tube formation of human umbilical vein endothelial (HUVEC) cells induced by tumor necrosis factor (TNF)-α were used to measured the antiangiogenenic activity of SKN. Moreover, the effect of SKN on the expression of angiogenic mediators, such as vascular endothelial growth factor (VEGF), VEGFR2, TNF-α, interleukin (IL)-1β, platelet derived growth factor (PDGF) and transforming growth factor (TGF)-β in sera and joint synovia of rats, and in TNF-α-induced MH7A/HUVEC cells were measured by immunohistochemistry, enzyme linked immunosorbent assay, Western blot and/or real-time polymerase chain reaction (PCR). Through the analysis of protein and mRNA levels of phosphoinositide 3-kinase (PI3K), Akt and PTEN, and the autophosphorylation of ERK1/2, JNK and p38 in joint synovia of rats and in TNF-α-induced HUVEC cells, the molecular mechanism of its inhibition was elucidated by using Western blot and/or real-time PCR.. These findings indicate for the first time that SKN has the anti-angiogenic effect in RA in vivo, ex vivo and in vitro by interrupting the PI3K/AKT and MAPKs signaling pathways.

Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Arthritis, Rheumatoid; Chick Embryo; Chorioallantoic Membrane; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Male; MAP Kinase Signaling System; Naphthoquinones; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley

Sepsis is an infection-induced aggressive and life-threatening organ dysfunction with high morbidity and mortality worldwide. Infection-associated inflammation and coagulation promote the progression of adverse outcomes in sepsis. Here, we report that phospho-Tyr705 of STAT3 (pY-STAT3), not total STAT3, contributes to systemic inflammation and coagulopathy in sepsis.. Cecal ligation and puncture (CLP)-induced septic mice were treated with BP-1-102, Napabucasin, or vehicle control respectively and then assessed for systemic inflammation, coagulation response, lung function and survival. Human pulmonary microvascular endothelial cells (HPMECs) and Raw264.7 cells were exposed to lipopolysaccharide (LPS) with pharmacological or genetic inhibition of pY-STAT3. Cells were assessed for inflammatory and coagulant factor expression, cell function and signaling.. Pharmacological inhibition of pY-STAT3 expression by BP-1-102 reduced the proinflammatory factors, suppressed coagulation activation, attenuated lung injury, alleviated vascular leakage and improved the survival rate in septic mice. Pharmacological or genetic inhibition of pY-STAT3 diminished LPS-induced cytokine production in macrophages and protected pulmonary endothelial cells via the IL-6/JAK2/STAT3, NF-κB and MAPK signaling pathways. Moreover, the increase in procoagulant indicators induced by sepsis such as tissue factor (TF), the thrombin-antithrombin complex (TAT) and D-Dimer were down-regulated by pY-STAT3 inhibition.. Our results revealed a therapeutic role of pY-STAT3 in modulating the inflammatory response and defective coagulation during sepsis. Video Abstract.

Topics: Aminosalicylic Acids; Animals; Benzofurans; Blood Coagulation; Cecum; Cell Membrane Permeability; Endothelial Cells; Humans; Inflammation; Inflammation Mediators; Ligation; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Models, Biological; Molecular Targeted Therapy; Naphthoquinones; Phosphotyrosine; Punctures; RAW 264.7 Cells; Sepsis; STAT3 Transcription Factor; Sulfonamides; Suppression, Genetic; Survival Analysis; Thromboplastin; Toll-Like Receptor 4

Topics: Animals; Cell Line; Inflammation; Interleukin-18; Interleukin-1beta; Lipopolysaccharides; Macrophages; Mice; Naphthoquinones; Nitric Oxide; NLR Family, Pyrin Domain-Containing 3 Protein; Reactive Oxygen Species

One of the most significant adverse postburn responses is abnormal scar formation, such as keloids. Despite its prolificacy, the underlying pathophysiology of keloid development is unknown. We recently demonstrated that NLRP3 inflammasome, the master regulator of inflammatory and metabolic responses (e.g., aerobic glycolysis), is essential for physiological wound healing. Therefore, burn patients who develop keloids may exhibit altered immunometabolic responses at the site of injury, which interferes with normal healing and portends keloid development. Here, we confirmed keloid NLRP3 activation (cleaved caspase-1 [P < 0.05], IL-1β [P < 0.05], IL-18 [P < 0.01]) and upregulation in Glut1 (P < 0.001) and glycolytic enzymes. Burn skin similarly displayed enhanced glycolysis and Glut1 expression (P < 0.01). However, Glut1 was significantly higher in keloid compared with nonkeloid burn patients (>2 SD above mean). Targeting aberrant glucose metabolism with shikonin, a pyruvate kinase M2 inhibitor, dampened NLRP3-mediated inflammation (cleaved caspase-1 [P < 0.05], IL-1β [P < 0.01]) and improved healing in vivo. In summary, burn skin exhibited evidence of Warburg-like metabolism, similar to keloids. Targeting this altered metabolism could change the trajectory toward normal scarring, indicating the clinical possibility of shikonin for abnormal scar prevention.

Topics: Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal; Burns; Case-Control Studies; Female; Glucose Transporter Type 1; Glycolysis; Humans; Inflammasomes; Inflammation; Inflammation Mediators; Keloid; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Naphthoquinones; NLR Family, Pyrin Domain-Containing 3 Protein; Pyruvate Kinase; Skin; Wound Healing

During inflammation, dysregulated neutrophil behaviour can play a major role in a range of chronic inflammatory diseases, for many of which current treatments are generally ineffective. Recently, specific naturally occurring tanshinones have shown promising anti-inflammatory effects by targeting neutrophils in vivo, yet such tanshinones, and moreover, their isomeric isotanshinone counterparts, are still a largely underexplored class of compounds, both in terms of synthesis and biological effects. To explore the anti-inflammatory effects of isotanshinones, and the tanshinones more generally, a series of substituted tanshinone and isotanshinone analogues was synthesised, alongside other structurally similar molecules. Evaluation of these using a transgenic zebrafish model of neutrophilic inflammation revealed differential anti-inflammatory profiles in vivo, with a number of compounds exhibiting promising effects. Several compounds reduce initial neutrophil recruitment and/or promote resolution of neutrophilic inflammation, of which two also result in increased apoptosis of human neutrophils. In particular, the methoxy-substituted tanshinone 39 specifically accelerates resolution of inflammation without affecting the recruitment of neutrophils to inflammatory sites, making this a particularly attractive candidate for potential pro-resolution therapeutics, as well as a possible lead for future development of functionalised tanshinones as molecular tools and/or chemical probes. The structurally related β-lapachones promote neutrophil recruitment but do not affect resolution. We also observed notable differences in toxicity profiles between compound classes. Overall, we provide new insights into the in vivo anti-inflammatory activities of several novel tanshinones, isotanshinones, and structurally related compounds.

Topics: Abietanes; Animals; Animals, Genetically Modified; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Humans; Inflammation; Molecular Structure; Naphthoquinones; Neutrophil Infiltration; Zebrafish

Sepsis is characterized by a dysregulated immune response to infection characterized by an early hyperinflammatory and oxidative response followed by a subsequent immunosuppression phase. Although there have been some advances in the treatment of sepsis, mortality rates remain high, urging for the search of new therapies.

Topics: Animals; Anti-Inflammatory Agents; Chemoprevention; Cytokines; Disease Models, Animal; Immunosuppression Therapy; Inflammation; Inflammation Mediators; Male; Mice; Naphthoquinones; Oxidative Stress; Sepsis; Survival Rate

Echinochrome A (Ech A), a natural pigment extracted from sea urchins, is the active ingredient of a marine-derived pharmaceutical called 'histochrome'. Since it exhibits several biological activities including anti-oxidative and anti-inflammatory effects, it has been applied to the management of cardiac injury and ocular degenerative disorders in Russia and its protective role has been studied for other pathologic conditions. In the present study, we sought to investigate the therapeutic potential of Ech A for inflammatory bowel disease (IBD) using a murine model of experimental colitis. We found that intravenous injection of Ech A significantly prevented body weight loss and subsequent lethality in colitis-induced mice. Interestingly, T cell proliferation was significantly inhibited upon Ech A treatment in vitro. During the helper T (Th) cell differentiation process, Ech A stimulated the generation regulatory T (Treg) cells that modulate the inflammatory response and immune homeostasis. Moreover, Ech A treatment suppressed the in vitro activation of pro-inflammatory M1 type macrophages, while inducing the production of M2 type macrophages that promote the resolution of inflammation and initiate tissue repair. Based on these results, we suggest that Ech A could provide a beneficial impact on IBD by correcting the imbalance in the intestinal immune system.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Cytokines; Humans; Inflammation; Leukocytes, Mononuclear; Macrophages; Mice; Naphthoquinones

Chronic consumption of fructose causes obesity and nonalcoholic fatty liver disease (NAFLD). Currently available therapies have limitations; hence there is a need to screen new molecules. Plumbagin is a naphthoquinone present in the roots of Plumbago species which has hypolipidemic and hepatoprotective activities.. Rats were divided into five groups: normal control, disease control, orlistat, plumbagin (0.5 mg/kg and 1 mg/kg body weight). The normal control group received standard diet and drinking water while the remaining groups received fructose in drinking water alongwith the standard diet for 16 weeks. Orlistat and plumbagin were administered orally from the 9. Fructose feeding resulted in a significant increase in the body weight gain, calorie intake, visceral fat, liver weight, blood glucose and insulin and caused dyslipidemia which was mitigated by plumbagin. Plumbagin exerted antioxidant, anti-inflammatory and anti-fibrotic effects in the liver and reduced the hepatic lipids. Plumbagin reduced the gene expression of SREBP-1c and increased that of PPAR-α. Plumbagin reduced the hypertrophy of adipocytes and ameliorated the degenerative changes in the liver.. Plumbagin thus seems to be a promising molecule for the management of obesity and NAFLD.

Topics: Adjuvants, Immunologic; Animals; Antioxidants; Fructose; Inflammation; Lipid Metabolism; Male; Naphthoquinones; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Random Allocation; Rats; Rats, Wistar

The present study investigates the protective effect of napabucasin on the expression of apoptosis markers and inflammatory factors in the neuronal rat cells with post-isolation damage. The level of ROS determined by the fluorescence measurement in the neuronal rat cells with post-isolation damage was 310.21 RFU compared to 21.45 RFU in sham cell cultures. Napabucasin treatment decreased ROS level in the neuronal rat cells with post-isolation damage in dose based manner. ROS level decreased to 278.67, 203.65, 163.32 and 26.87 RFU, respectively in 1, 2, 3 and 4 μM napabucasin treated cell cultures. Treatment with napabucasin increased GSH level significantly (P < 0.05) in the neuronal rat cells with post-isolation damage. Napabucasin treatment at with 1, 2, 3 and 4 μM concentrations increased SOD activity to 2.4, 3.6, 5.1 and 6.1 U/mg, respectively. Treatment with napabucasin increased the activity of catalase in dose based manner. Napabucasin treatment increased Gpx in injured brain cells of neonatal rats. A significant (P < 0.05) increase in the activity of AChE was observed in neuronal rat cells with post-isolation damage on treatment with napabucasin. Treatment with napabucasin reduced the level of TNF-α and IL-6 significantly (P < 0.05) compared to untreated group. Napabucasin treatment decreased the expression of Bax, caspase-3 and p53 proteins in the neuronal rat cells with post-isolation damage. Napabucasin treatment protects post-isolation damage in the neuronal cells of neonatal rats by suppression of apoptosis and oxidative stress. Therefore, napabucasin can be used for the treatment of brain injury.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Benzofurans; Brain; Brain Injuries; Caspase 3; Catalase; Dose-Response Relationship, Drug; Glutathione Peroxidase; Inflammation; Interleukin-6; Naphthoquinones; Neuroglia; Neurons; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53

Acetaminophen (APAP) overdose causes acute liver injury and leads to fatal liver damage. However, the therapies are quite limited. Shikonin is a natural product with antioxidant and anti-inflammatory activities. In the present study, the hepatoprotective effects and the underlying mechanisms of shikonin in APAP-induced hepatotoxicity in vivo and in vitro were investigated. APAP-induced acute liver injury and shikonin pretreatment models were established in vivo and in vitro, as evidenced by serum hepatic enzymes, histological changes, oxidative stress indicators and proinflammatory cytokines. The results revealed that shikonin pretreatment prevented the elevation of serum alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels and markedly reduced APAP-induced histological alterations in liver tissues. Additionally, shikonin restored superoxide dismutase (SOD) expression and glutathione (GSH) content in line with the blockade of oxidative stress. The changes in gene expression involved in oxidative stress including methionine sulfoxide reductase (such as MsrA and MsrB1), heme oxygenase-1 (HO-1), SOD2 and cytochrome P450 2E1 (CYP2E1), were markedly reversed after shikonin therapy. Furthermore, shikonin markedly attenuated the APAP-induced production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) and suppressed the expression of genes related to inflammation. In AML-12 cells, shikonin pretreatment decreased APAP-induced cytotoxicity as measured by CCK-8 assay and LDH release. The changes in gene expression involved in oxidative stress and the inflammatory response were consistent with those in mouse livers. This study indicated that shikonin attenuated APAP-induced acute liver injury via inhibiting oxidative stress and inflammatory responses in vivo and in vitro. These findings offer new insights into the potential therapy for APAP hepatotoxicity.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Inflammation; Male; Mice; Mice, Inbred BALB C; Naphthoquinones; Oxidative Stress

Acute lung injury (ALI) is a challenging clinical syndrome, which manifests as an acute inflammatory response. Myeloid differentiation protein 2 (MD2) has an important role in mediating LPS-induced inflammation. Currently, there are no effective molecular-based therapies for ALI or viable biomarkers for predicting the severity of disease. Recent preclinical studies have shown that shikonin, a natural naphthoquinone, prevents LPS-induced inflammation. However, little is known about the underlying mechanisms.. The binding affinity of shikonin to MD2 was analysed using computer docking, surface plasmon resonance analysis and elisa. In vitro, the anti-inflammatory effect and mechanism of shikonin were investigated through elisa, real-time quantitative reverse transcription PCR, Western blotting and immunoprecipitation assay. In vivo, lung injury was induced by intratracheal administration of LPS and assessed by changes in the histopathological and inflammatory markers. The underlying mechanisms were investigated by immunoprecipitation in lung tissue.. Shikonin directly bound to MD2 and interfered with the activation of toll-like receptor 4 (TLR4) induced by LPS. In cultured macrophages, shikonin inhibited TLR4 signalling and pro-inflammatory cytokine production. These effects were produced through suppression of key signalling proteins including the NF-κB and the MAPK pathway. We also showed that shikonin inhibits MD2-TLR4 complex formation and reduces LPS-induced inflammatory responses in a mouse model of ALI.. Our studies have uncovered the mechanism underlying the biological activity of shikonin in ALI and suggest that the targeting of MD2 may prove to be beneficial as a treatment option for this condition.

Topics: Acute Lung Injury; Animals; Cytokines; Humans; Inflammation; Lipopolysaccharides; Lymphocyte Antigen 96; MAP Kinase Signaling System; Mice; Molecular Docking Simulation; Naphthoquinones; Toll-Like Receptors

The current study was designed to investigate the protective role of alkannin (ALK) on liver injury in diabetic C57BL/KsJ-db/db mice and explore its potential mechanisms.. An oral glucose tolerance test (OGTT) was performed. The levels of insulin, alanine aminotransferase (ALT), aspartate aminotransaminase (AST), total cholesterol (TC) and triglyceride (TG) were determined by commercial kits. The pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were determined by ELISA. The levels of the ROCK/NF-κB pathway were determined by Western blotting.. The contents of pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were inhibited by ALK, metformin or fasudil in diabetic db/db mice. Further, Western blotting analysis showed that the expression of Rho, ROCK1, ROCK2, p-NF-κBp65, and p-IκBα was significantly reversed by ALK treatment. In human hepatic HepG2 cells, the hepatoprotective effects of ALK were further characterized. With response to palmitic acid-challenge, increased amounts of insulin, ALT, AST, TG, and TC were observed, whereas ALK pretreatment significantly inhibited their leakage in HepG2 cells without appreciable cytotoxic effects. The inflammation condition was recovered with ALK treatment as shown by changes of IL-1β, IL-6 and TNF-α. Further, Western blotting analysis also suggested that ALK improves hepatic inflammation in a Rho-kinase pathway.. The present study successfully investigated the role of Rho-kinase signalling in diabetic liver injury. ALK exhibited hepatoprotective effects in diabetic db/db mice, and it might act through improving hepatic inflammation through the Rho-kinase pathway.

Topics: Animals; Anti-Inflammatory Agents; Cell Survival; Cytokines; Diabetes Complications; Diabetes Mellitus; Hep G2 Cells; Humans; Inflammation; Liver; Liver Diseases; Mice, Inbred C57BL; Naphthoquinones; rho-Associated Kinases; Signal Transduction

Plumbagin, a vitamin K3 analogue is the major active constituent in several plants including root of Plumbago indica Linn. This compound has been shown to exhibit a wide spectrum of pharmacological activities. The present investigation was to evaluate the ameliorative effects of plumbagin (PL) against severe malaria pathogenesis due to involvement of oxidative stress and inflammatory response in Plasmodium berghei infected malaria in mice. Malaria pathogenesis was induced by intra-peritoneal injection of P. berghei infected red blood cells into the Swiss albino mice. PL was administered orally at doses of 3, 10 and 30 mg/kg/day following Peter's 4 day suppression test. Oral administration of PL showed significant reduction of parasitaemia and increase in mean survival time. PL treatment is also attributed to significant increase in the blood glucose and haemoglobin level when compared with vehicle-treated infected mice. Significant inhibition in level of oxidative stress and pro-inflammation related markers were observed in PL treated group. The trend of inhibition in oxidative stress markers level after oral treatment of PL was MPO > LPO > ROS in organ injury in P. berghei infected mice. This study showed that plumbagin is able to ameliorate malaria pathogenesis by augmenting anti-oxidative and anti-inflammatory mechanism apart from its effect on reducing parasitaemia and increasing mean survival time of malaria-induced mice.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antimalarials; Disease Models, Animal; Dose-Response Relationship, Drug; Inflammation; Malaria; Male; Mice; Naphthoquinones; Oxidative Stress; Plasmodium berghei; Plumbaginaceae

Topics: Animals; Antineoplastic Agents; Apoptosis; Cisplatin; Gene Expression Regulation; Inflammation; Kidney Diseases; NAD; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Oxidative Stress; Protective Agents; Rats; Rats, Wistar

Glycation and advanced glycation end products (AGE) damage skin which is compounded by AGE-induced oxidative stress and inflammation. Lip and facial skin could be susceptible to glycation damage as they are chronically stressed. As Gromwell (Lithospermum erythrorhizon) root (GR) has an extensive traditional medicine history that includes providing multiple skin benefits, our objective was to determine whether GR extract and its base naphthoquinone, shikonin, might protect skin by inhibiting glycation, increasing oxidative defenses, suppressing inflammatory responses and offering ultraviolet (UV) absorptive potential in lip and facial cosmetic matrices. We show GR extract and shikonin dose-dependently inhibited glycation and enhanced oxidative defenses through nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element activation. Inflammatory targets, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and tumor necrosis factor alpha, were suppressed by GR extract and shikonin. Glyoxalase 1 (GLO1) and glutathione synthesis genes were significantly upregulated by GR extract and shikonin. GR extract boosted higher wavelength UV absorption in select cosmetic matrices. Rationale for the use of GR extract and shikonin are supported by our research. By inhibiting glycation, modulating oxidative stress, suppressing inflammation and UV-absorptive properties, GR extract and shikonin potentially offer multiple skin benefits.

Topics: Absorption, Radiation; Anti-Inflammatory Agents, Non-Steroidal; Cosmetics; Glutathione; Glycation End Products, Advanced; Hep G2 Cells; Humans; Inflammation; Lactoylglutathione Lyase; Lithospermum; Naphthoquinones; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Plant Extracts; Plant Roots; Tumor Necrosis Factor-alpha; Ultraviolet Rays; Up-Regulation

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).\ \ This article has been retracted at the request of the Editor-in-Chief.\ \ Given the comments of Dr Elisabeth Bik regarding this article “In almost all papers, Western blot panels within the same figure, and across figures and papers, appear to share the same background, while the bands are regularly spaced, all have similar rounded edges without the usual smudges and specks, and with some bands showing a recognizable “jumping sardine” shape”, the journal requested the authors to provide the raw data. However, the authors were not able to fulfil this request and therefore the Editor-in-Chief decided to retract the article.

Topics: Apoptosis; Cell Line; Cell Survival; Cytokines; Epithelial Cells; Humans; Inflammation; Kidney Tubules, Proximal; Lipopolysaccharides; MicroRNAs; Naphthoquinones; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Protective Agents; Signal Transduction; Up-Regulation

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antipyretics; Cytokines; Fever; Inflammation; Mice; Naphthoquinones; Plant Extracts; Prostaglandins

Plumbagin is known to exhibit a broad range of biological activities including anti-cancer, antimicrobial and has been widely used traditionally. Nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) inhibitory and Nuclear factor (erythroid derived-2) like-2 (Nrf2) modulatory activities of Plumbagin have been reported already. In nerve injury model of neuropathy in rats, the role of NF-κB upregulation and declined antioxidant defence has been well recognized. So, we evaluated neuroprotective potential of Plumbagin in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in male Sprague-Dawley rats.. Animals were tested for functional, behavioural and biochemical changes. Various markers associated with oxidative stress and inflammatory changes were assessed in the sciatic nerve and dorsal root ganglion (DRG) of the animals exposed to CCI mediated nerve injury.. CCI induced nerve injury led to long-lasting mechanical hyperalgesia, loss of hind limb function and abnormal pain sensation. Plumbagin treatment (10 and 20mg/kg, po) significantly and dose-dependently reversed mechanical hyperalgesia and other functional deficits. There was a marked increase in NF-κB and reduced Nrf2 levels in sciatic nerve and DRG following nerve injury. Plumbagin strengthened the antioxidant defence by improving Nrf2 levels and checked the neuroinflammation by decreasing NF-κB levels in sciatic nerve and DRG.. Together, these results suggested that Plumbagin alleviated CCI-induced neuropathic pain via antioxidant and anti-inflammatory mechanisms. Hence, the study suggests that Plumbagin may be useful for the management of trauma-induced neuropathic pain.

Topics: Adjuvants, Immunologic; Animals; Biomarkers; Hyperalgesia; Inflammation; Male; Naphthoquinones; Neuralgia; NF-E2-Related Factor 2; NF-kappa B; Rats; Rats, Sprague-Dawley; Sciatic Neuropathy

We aimed to find candidate molecules possibly involved in the anti-inflammatory activity of shikonin (active compound of "Shikon") by analyzing its effects on gene expression of lipopolysaccharide (LPS)-treated THP-1 macrophages. Polysome-associated mRNAs (those expected to be under translation: translatome) from cells treated with LPS alone (LPS: 5 µg/mL), shikonin alone (S: 100 nM), or LPS plus shikonin (LPS&S) for 3 h were analyzed by DNA microarray followed by detection of enriched pathways/gene ontologies using the tools of the STRING database. Candidate genes in enriched pathways in the comparison of LPS&S cells vs. LPS cells were analyzed by reverse-transcription quantitative real-time PCR (RT-qPCR; 1, 2, and 3 h). DNA microarray showed shikonin significantly influences gene expression. Gene expression changes between LPS&S cells and LPS cells were compared to detect relevant proteins and/or mRNAs underlying its anti-inflammatory effects: shikonin downregulated pathways which were upregulated in LPS cells, for example, 'innate immune response'. Within changed pathways, three genes were selected for RT-qPCR analyses as key candidates influencing inflammatory responses: CYBA (component of the superoxide-generating Nox2 enzyme), GSK3B (controller of cell responses after toll-like receptor stimulation), and EIF4E (a key factor of the eukaryotic translation initiation factor 4F complex that regulates abundance of other proteins involved in immune functions). All three mRNAs were decreased at 2 h, and CYBA continued low at 3 h relative to LPS cells. Given that shikonin decreased the expression of CYBA gene of Nox2, in addition to the direct inhibition of the Nox2 activity that we have previously shown, it is suggested that one of its anti-inflammatory mechanisms could be attenuation of oxidative stress.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Differentiation; Gene Expression; Humans; Inflammation; Lipopolysaccharides; Macrophages; Naphthoquinones

We report in vitro and in vivo anti-inflammatory activities of a series of copper(II)-lawsone complexes of the general composition [Cu(Law)2(LN)x(H2O)(2-x)]·yH2O; where HLaw = 2-hydroxy-1,4-naphthoquinone, x = 1 when LN = pyridine (1) and 2-aminopyridine (3) and x = 2 when LN = imidazole (2), 3-aminopyridine (4), 4-aminopyridine (5), 3-hydroxypyridine (6), and 3,5-dimethylpyrazole (7). The compounds were thoroughly characterized by physical techniques, including single crystal X-ray analysis of complex 2. Some of the complexes showed the ability to suppress significantly the activation of nuclear factor κB (NF-κB) both by lipopolysaccharide (LPS) and TNF-alpha (complexes 3-7 at 100 nM level) in the similar manner as the reference drug prednisone (at 1 μM level). On the other hand, all the complexes 1-7 decreased significantly the levels of the secreted TNF-alpha after the LPS activation of THP-1 cells, thus showing the anti-inflammatory potential via both NF-κB moderation and by other mechanisms, such as influence on TNF-alpha transcription and/or translation and/or secretion. In addition, a strong intracellular pro-oxidative effect of all the complexes has been found at 100 nM dose in vitro. The ability to suppress the inflammatory response, caused by the subcutaneous application of λ-carrageenan, has been determined by in vivo testing in hind-paw edema model on rats. The most active complexes 1-3 (applied in a dose corresponding to 40 μmol Cu/kg), diminished the formation of edema simalarly as the reference drug indomethacine (applied in 10 mg/kg dose). The overall effect of the complexes, dominantly 1-3, shows similarity to anti-inflammatory drug benoxaprofen, known to induce intracellular pro-oxidative effects.

Topics: Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Copper; Crystallography, X-Ray; Dose-Response Relationship, Drug; Edema; Humans; Inflammation; Male; Naphthoquinones; NF-kappa B; Rats; Rats, Wistar; Spectrometry, Mass, Electrospray Ionization

Shikonin, isolated from the roots of herbal plant Lithospermum erythrorhizon, is a naphthoquinone. It has been reported to exert beneficial anti-inflammatory effects and anti-oxidant properties in various diseases. Isoproterenol (ISO) has been widely used to establish cardiac injury in vivo and in vitro. However, shikonin function in ISO-induced cardiac injury remains uncertain. In our study, we attempted to investigate the efficiency and possible molecular mechanism of shikonin in cardiac injury treatment induced by ISO. In vivo, C57BL6 mice were subcutaneously injected with 5mg/kg ISO to induce heart failure. And mice were given a gavage of shikonin (2 or 4mg/kg/d, for four weeks). Cardiac function, fibrosis indices, inflammation response, apoptosis and endoplasmic reticulum (ER) stress were calculated. Pathological alterations, fibrosis-, inflammation-, apoptosis- and ER stress-related molecules were examined. In ISO-induced cardiac injury, shikonin significantly ameliorated heart function, decreased myocardial fibrosis, suppressed inflammation, attenuated apoptosis and ER stress through impeding collagen accumulation, Toll like receptor 4/nuclear transcription factor κB (TLR4/NF-κB), Caspase-3 and glucose-regulated protein 78 (GRP78) signaling pathways activity, relieving heart failure in vivo. Also, in vitro, shikonin attenuated ISO-induced cardiac muscle cells by reducing fibrosis, inflammation, apoptosis and ER stress. Our findings indicated that shikonin treatment attenuated ISO-induced heart injury, providing an effective therapeutic strategy for heart failure treatment for future.

Topics: Animals; Apoptosis; Cardiomyopathies; Caspase 3; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Fibrosis; Gene Expression Regulation; Heart; Heart Failure; HSP70 Heat-Shock Proteins; Inflammation; Isoproterenol; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Myocardium; Myocytes, Cardiac; Naphthoquinones; NF-kappa B

Neuroinflammation plays a central role in the pathophysiology of Alzheimer's disease (AD). Compounds that suppress neuroinflammation have been identified as potential therapeutic targets for AD. Rhinacanthin C (RC), a naphthoquinone ester found in

Topics: Amyloid beta-Peptides; Animals; Inflammation; Interferon-gamma; Lipopolysaccharides; Mice; Naphthoquinones; Neuroglia; Neurons; Rats; Rats, Sprague-Dawley

Black carbon (BC) is a key component of atmospheric particles and has a significant effect on human health. BC can provide reactive sites and surfaces thus absorb quinones which were primarily generated from fossil fuel combustion and/or atmospheric photochemical conversions of PAHs. Oxidation could change the characteristics of BC and increase its toxicity. The comparison of lung damage in mice exposed to BC and 1,4-NQ-coated BC (1,4NQ-BC) particles is investigated in this study. Mice which were intratracheally instilled with particles have a higher expression of IL-1β, IL-6 and IL-33 in bronchoalveolar lavage fluid (BALF). Also, the IL-6, IL-33 mRNA expression in the lung tissue of mice instilled with 1,4NQ-BC were higher than that of mice instilled with BC. The pathology results showed that the lung tissue of mice instilled with 1,4NQ-BC particles have much more inflammatory cells infiltration than that of mice treated with BC. It is believed that the MAPK and PI3K-AKT pathway might be involved in the 1,4NQ-BC particles caused lung damage. Results indicated that 1,4NQ-BC particles in the atmosphere may cause more damage to health.

Topics: Air Pollutants; Animals; Bronchoalveolar Lavage Fluid; Carbon; Inflammation; Interleukins; Lung; Mice; Naphthoquinones; Phosphatidylinositol 3-Kinases; Soot

Inflammation and inflammatory cytokines have been reported to play vital roles in the development of osteoarthritis (OA). Plumbagin, a quinonoid compound extracted from the roots of medicinal herbs of the Plumbago genus, has been reported to have anti-inflammatory effects. However, the anti-inflammatory effects of plumbagin on OA have not been reported. This study aimed to assess the effects of plumbagin on human OA chondrocytes and in a mouse model of OA induced by destabilization of the medial meniscus (DMM). In vitro, human OA chondrocytes were pretreated with plumbagin (2, 5, 10 μM) for 2 h and subsequently stimulated with IL-1β for 24 h. Production of NO, PGE2, MMP-1, MMP-3, and MMP-13 was evaluated by the Griess reagent and ELISAs. The messenger RNA (mRNA) expression of COX-2, iNOS, MMP-1, MMP-3, MMP-13, aggrecan, and collagen-II was measured by real-time PCR. The protein expression of COX-2, iNOS, p65, p-p65, IκBα, and p-IκBα was detected by Western blot. The protein expression of collagen-II was evaluated by immunofluorescence. In vivo, the severity of OA was determined by histological analysis. We found that plumbagin significantly inhibited the IL-1β-induced production of NO and PGE2; expression of COX-2, iNOS, MMP-1, MMP-3, and MMP-13; and degradation of aggrecan and collagen-II. Furthermore, plumbagin dramatically suppressed IL-1β-stimulated NF-κB activation. In vivo, treatment of plumbagin not only prevented the destruction of cartilage and the thickening of subchondral bone but also relieved synovitis in mice OA models. Taken together, these results suggest that plumbagin may be a potential agent in the treatment of OA.

Topics: Adjuvants, Immunologic; Animals; Chondrocytes; Disease Progression; Humans; Inflammation; Interleukin-1beta; Mice; Naphthoquinones; NF-kappa B; Osteoarthritis; Signal Transduction

The aim of the present study was to investigate the protective effect exerted by bone marrow mesenchymal stem cells (BMSCs) in combination with plumbagin on spinal cord injury (SCI) and explore the mechanism behind this protective effect. Firstly, BMSCs were extracted from male Sprague-Dawley rats, cultured in vitro, and identified by hematoxylin. Sprague-Dawley rats were then randomly divided into a control group, SCI model group, BMSC-treated group, a plumbagin-treated group, and a BMSC and plumbagin-treated group. After treatment with BMSCs combined with plumbagin, a Basso, Beattie and Bresnahan (BBB) test was carried out and the spinal cord water content was examined in order to analyze the effect of BMSCs combined with plumbagin on SCI. The myeloperoxidase (MPO), superoxide dismutase (SOD), malondialdehyde (MDA), nuclear factor-κB (NF-κB) p65 unit, tumor necrosis factor-α (TNF-α) levels were also detected. Moreover, nuclear factor erythroid 2‑related factor 2 (Nrf2), phosphoinositide 3-kinase (PI3K), phosphorylated (p-)Akt, p-p38 mitogen-activated protein kinase (MAPK), and p-extracellular-signal-regulated kinase (ERK) protein expression levels were measured using western blot analysis. Treatment with BMSCs combined with plumbagin significantly improved locomotor recovery and reduced the spinal cord water content after SCI. The increased MPO, MDA, NF-κB p65 and TNF-α levels were significantly suppressed and the decreased SOD was significantly increased in SCI rats. The suppression of Nrf2, p-Akt and p-ERK, as well as the promotion of p-p38 MAPK, were reversed by treatment with BMSCs combined with plumbagin. These effects suggest that treatment with BMSCs combined with plumbagin alleviates SCI through its effects on oxidative stress, inflammation, apoptotis and activation of the Nrf2 pathway.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Inflammation; Locomotion; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Naphthoquinones; NF-E2-Related Factor 2; Oxidative Stress; Plumbaginaceae; Rats, Sprague-Dawley; Recovery of Function; Signal Transduction; Spinal Cord Injuries

Shikonin, which is derived from Lithospermum erythrorhizon, a herb used in traditional medicine, has long been considered to be a useful treatment for various diseases in traditional oriental medicine. Shikonin has recently been reported to have several pharmacological properties, e.g., it has anti-microbial, anti-tumor, and anti-inflammatory effects. The aim of this study was to examine whether shikonin is able to influence the production of interleukin (IL)-6, IL-8, and/or chemokine C-C motif ligand (CCL)20, which contribute to the pathogenesis of periodontal disease, in human periodontal ligament cells (HPDLC). The production levels of IL-6, IL-8, and CCL20 in HPDLC were determined using an ELISA. Western blot analysis was used to detect nuclear factor kappa B (NF-κB) pathway activation in HPDLC. Shikonin prevented IL-1β- or tumor necrosis factor (TNF)-α-mediated IL-6, IL-8, and CCL20 production in HPDLC. Moreover, we found that shikonin suppressed the phosphorylation and degradation of inhibitor of kappa B-alpha (IκB-α) in IL-1β- or TNF-α-stimulated HPDLC. These findings suggest that shikonin could have direct beneficial effects against periodontal disease by reducing IL-6, IL-8, and CCL20 production in periodontal lesions.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Chemokine CCL20; Cytokines; Humans; Inflammation; Interleukin-6; Interleukin-8; Naphthoquinones; Periodontal Diseases; Periodontal Ligament

Plumbagin, one of the constituents responsible for the various biological activities of Plumbago zeylanica has been demonstrated to possess antioxidant activity, which may inhibit lipid peroxidation in a dose- and time-dependent manner. In the present study, we aimed to examine the protective effects of plumbagin as well as the underlying mechansim through which plumbagin attenuates hydrogen peroxide (H2O2)-induced oxidative stress in nucleus pulposus cells (NPCs). For this purpose, the NPCs were incubated with fresh medium containing H2O2 (200 µM) at 37˚C in a humidified 5% CO2 atmosphere for 6 h, and cultured with various concentrations of plumbagin (0, 0.5, 1, 2, 5, 10 and 20 µM). Treatment with plumbagin significantly increased the viability of the H2O2-exposed NPCs in a dose‑dependent manner. Moreover, plumbagin significantly reduced the generation of reactive oxygen species, lipid peroxidation, as well as the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in the H2O2‑exposed NPCs. Glutathione (GSH) content, as well as the activity of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxdiase (GSH-Px) were increased. We found that the administration of plumbagin significantly inhibited the activity of caspase-9 and -3, and downregulated NF-κB expression and upregulated Nrf-2 expression in the H2O2-exposed NPCs. Taken together, these findings suggest that plumbagin exerts neuroprotective effects in NPCs by attenuating H2O2‑induced oxidative stress, inflammation and apoptosis through mediating the expression of NF-κB and Nrf-2.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Catalase; Chondrocytes; Dose-Response Relationship, Drug; Gene Expression Regulation; Glutathione; Glutathione Peroxidase; Hydrogen Peroxide; Inflammation; Male; Naphthoquinones; NF-E2-Related Factor 2; NF-kappa B; Nucleus Pulposus; Osteoblasts; Oxidative Stress; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Primary Cell Culture; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase

Pterocarpanquinone (+/-)-LQB-118 presents antineoplastic and antiparasitic properties and also shows great inhibitory effect on TNF-α release in vitro. Here, its anti-inflammatory activity was evaluated in a lipopolysaccharide (LPS)-induced lung inflammation model in C57BL/6 mice. LPS inhalation induced a marked neutrophil infiltration to the lungs which was reduced by intraperitoneal treatment with (+/-)-LQB-118 in a similar manner to that of dexamethasone and even better than that of acetylsalicylic acid. Moreover, (+/-)-LQB-118 administration resulted in decrease of NF-κB activation and KC level in lungs, with a pronounced inhibitory effect on TNF-α release, measured in bronchoalveolar lavage fluid. Trying to understand the anti-inflammatory mechanism by which (+/-)-LQB-118 acts, we performed a molecular modeling analysis, including docking to estrogen receptors α and β. Results suggested that (+/-)-LQB-118 may bind to both receptors, with a similar orientation to 17-β-estradiol. Together, these results showed that (+/-)-LQB-118 exhibits an anti-inflammatory effect, most likely by inhibiting TNF-α release and NF-κB activation, which may be related to the estrogen receptor binding.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Hydrogen Bonding; Inflammation; Lung Diseases; Male; Mice; Mice, Inbred C57BL; Naphthoquinones; NF-kappa B; Pterocarpans; Receptors, Estrogen; Thermodynamics

Spinal cord injury causes post-traumatic degeneration through series of biochemical events. This study aims to evaluate the possible protective mechanism of Plumbagin against Spinal cord injury induced oxidative stress and inflammation. Plumbagin is a potent antioxidant and shows anti-carcinogenic, anti-inflammatory and analgesic activities. However, its exact molecular mechanism of action has yet to be explored.. We tested the effects of Plumbagin on spinal cord injury induced ROS generation and lipid peroxidation content in wistar rats. Additionally, the expression of 2 important transcription factors NF-κB and Nrf-2 was investigated.. Plumbagin treatment significantly ameliorated oxidative stress through inhibition of ROS and lipid peroxidation with a concomitant increase in antioxidant status. Western blot analysis revealed enhanced nuclear levels of Nrf-2, while NF-κB expression was suppressed during Plumbagin administration. Enzyme linked immunosorbent assay for pro-inflammatory cytokines (TNF-α, IL-1β) showed a significant downregulation followed by Plumbagin treatment in spinal cord injury rats.. Taken together, the data suggests potential and novel role of Plumbagin in cytoprotection by modulating NF-κB and Nrf-2 levels against spinal cord injury.

Topics: Animals; Antioxidants; Inflammation; Male; Naphthoquinones; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Protective Agents; Rats; Spinal Cord Injuries; Up-Regulation

We previously found that vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase (pol) γ. In this study, we focused on plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), and chemically synthesized novel plumbagins conjugated with C2:0 to C22:6 fatty acids (5-O-acyl plumbagins). These chemically modified plumbagins displayed enhanced mammalian pol inhibition, with plumbagin conjugated to docosahexaenoic acid (C22:6-acyl plumbagin) exhibiting the strongest inhibition of pol λ among the ten 5-O-acyl plumbagins synthesized. C22:6-acyl plumbagin selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols or DNA metabolic enzymes tested. The inhibition of pol λ, a DNA repair/recombination pol, by these compounds was significantly correlated with both their suppression of lipopolysaccharide (LPS) induced tumor necrosis factor-α (TNF-α) production by mouse RAW264.7 macrophages and the reduction of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in the mouse ear. These data indicate that 5-O-acyl plumbagins act as anti-inflammatory agents by inhibiting mammalian pol λ. These results further suggest that C22:6-acyl plumbagin is a promising anti-inflammatory candidate and that acylation could be an effective chemical modification to improve the anti-inflammatory activity of vitamin K3 derivatives, such as plumbagin.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; DNA Polymerase beta; Escherichia coli Proteins; Fatty Acids; Gene Knockdown Techniques; Humans; Inflammation; Lipopolysaccharides; Macrophages; Mice; Naphthoquinones; Plant Proteins; Rats; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Juglone as a natural production mainly extracted from green walnut husks of Juglans mandshurica has been defined as the functional composition among a series of compounds. It showed powerful protective effect in various diseases by inhibiting inflammation and tumor cells growth. However, studies on its anti-inflammatory effect based on high-fat diet-induced hepatitis and neuroinflammation are still not available. In this regard, we first investigated whether juglone suppresses high-fat diet-stimulated liver injury, hypothalamus inflammation and underlying mechanisms by which they may recover them. SD rats were orally treated with or without high-fat diet, 0.25 mg/kg or 1 mg/kg juglone for 70 days. Subsequently, blood, hypothalamus and liver tissue were collected for different analysis. Also, the primary astrocytes were isolated and used to analyze the inhibitory effect of juglone in vitro. Analysis of inflammatory cytokines declared that the inhibition of TNF-α, IL-1β and IL-6 could be carried by juglone in response to high-fat diet rats. Meanwhile, TLR4 expression and NF-kappa activity also have been confirmed to be the key link in the development of hepatitis and nerve inflammation. The activation was significantly suppressed in treatment group as compared with model. These results indicated that juglone prevents high-fat diet-induced liver injury and nerve inflammation in mice through inhibition of inflammatory cytokine secretion, NF-kappa B activation and endotoxin production.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Cytokines; Diet, High-Fat; Endotoxemia; Hepatitis, Animal; Hypothalamus; Inflammation; Lipopolysaccharides; Male; Mice; Naphthoquinones; Nervous System Diseases; NF-kappa B; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Toll-Like Receptor 4

Shikonin, a natural product from Lithospermum erythrorhizon, exerts a wide range of anti-inflammatory actions both in vitro and in vivo. Matrix metalloproteinases (MMPs) have long been considered as the major catabolic enzymes involved in osteoarthritis (OA) cartilage erosion. Here, we investigated the anti-inflammatory and effects of shikonin on MMPs in both IL-1β induced rabbit chondrocytes and the experimental rabbit OA model induced by anterior cruciate ligament (ACL) transection and evaluated the potential involvement of nuclear factor kappa B (NF-κB) in the processes. In vitro, rabbit chondrocytes were cultured and pretreated with shikonin (0, 1, 5, 10μM) for 1h (h) with or without IL-1β (10ng/ml) for 24h. The expression of MMPs (MMP-1, MMP-3 and MMP-13) and tissue inhibitors of metalloproteinase-1 (TIMP-1) at mRNA and protein levels were determined by quantitative real-time PCR and ELISA respectively. NF-κB related signaling molecules were investigated by Western blotting. In vivo study, the effects of shikonin on MMPs and TIMP-1 were determined at the gene level and the cartilage damage was evaluated at the histological level after the rabbits sacrificed. We found that shikonin significantly reversed the elevated expression of MMP-1, MMP-3 and MMP-13 and the reduced expression of TIMP-1 at both gene and protein levels in IL-1β induced chondrocytes. Additionally, the reduction of IκBα and the activation of NF-κB p65 induced by IL-1β were subsided by shikonin in rabbit chondrocytes. In vivo, both the cartilage damage and the elevated expression of MMP-1, MMP-3 and MMP-13 and the decreased expression of TIMP-1 were ameliorated in shikonin intra-articular injection knees compared to vehicle knees. Our findings indicated that shikonin have anti-inflammatory and chondro-protective effects and may be a potential therapeutic agent for the treatment of OA.

Topics: Animals; Cartilage; Cell Survival; Chondrocytes; Gene Expression Regulation; I-kappa B Kinase; Inflammation; Interleukin-1beta; Male; Matrix Metalloproteinases; Naphthoquinones; NF-kappa B; Osteoarthritis; Rabbits; Tissue Inhibitor of Metalloproteinase-1

Plumbagin (PL) has been reported to exhibit anti-carcinogenic, anti-inflammatory and analgesic activities, but little is known about its mechanism. In this study, we investigated the anti-inflammatory property of PL and its mechanism of action. Although no significant cytotoxicity of PL was observed over the concentration range tested, PL (2.5-7.5 μM) significantly and dose-dependently suppressed the secretion of pro-inflammatory mediators and inhibited the expression of TNF-α, IL-1β, IL-6 and iNOS in LPS-stimulated RAW 264.7 cells. Furthermore, PL consistently suppressed the activity of iNOS in LPS-induced RAW 264.7 cells. To elucidate the mechanism underlying the anti-inflammatory activity of PL, we assessed the effects of PL on the MAPK pathway and the activity and expression of NF-κB. These experiments demonstrated that PL significantly reduced the luciferase activity of an NF-κB promoter reporter and p65 nuclear translocation. The LPS-induced phosphorylation of MAP kinases was also attenuated by PL; significant changes were observed in the levels of phosphorylated ERK1/2, JNK and p38 MAPK. Additionally, MAPK inhibitors confirmed the inhibitory effect of PL on the MAPK pathway. Taken together, these data suggest that PL exerts its anti-inflammatory effects by down-regulating the expression of pro-inflammatory mediators through inhibition of NF-κB and MAPK signaling in LPS-stimulated RAW 264.7 cells.

Topics: Animals; Base Sequence; Cell Line; DNA Primers; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Naphthoquinones; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphorylation; Tumor Necrosis Factor-alpha

This study reports the in vivo anti-inflammatory and antioxidative effects of the methanolic extract of the aerial parts of Mitracarpus frigidus (MFM) and its chemical fingerprint.. The acute anti-inflammatory activity was performed using the carrageenan-induced paw oedema and peritonitis, ear oedema induced by croton oil and ethyl phenylpropiolate methods. Total COX, COX-1 and COX-2 expression was also evaluated. Chronic activity was determined by cotton pellet granuloma model. The antioxidative activity was assessed using liver tissue malondialdehyde, catalase and myeloperoxidase activities.. M. frigidus showed an intense acute anti-inflammatory action (100 and 300 mg/kg) in a nondose-dependent manner with selective inhibition of COX-2 expression. This activity may be also related to the strong antioxidative effect observed. By the other side, the chronic anti-inflammatory activity of MFM was not expressive. Kaempferol, kaempferol-O-rutenoside, rutin, ursolic acid and psychorubrin were identified in MFM.. The anti-inflammatory activity of MFM was probably due to inhibition of COX expression in a selective manner for COX-2. Other mechanisms, such as inhibition of inflammatory mediators and of the oxidative stress were possibly involved in the effects observed. To the best of our knowledge, it is the first time those activities are reported for M. frigidus.

Topics: Animals; Antioxidants; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Edema; Female; Inflammation; Inflammation Mediators; Kaempferols; Male; Mice; Naphthoquinones; Oxidative Stress; Phytotherapy; Plant Components, Aerial; Plant Extracts; Rats, Wistar; Rubiaceae; Rutin; Triterpenes; Ursolic Acid

CD45 is a receptor-like member of the protein tyrosine phosphatase (PTP) family. We screened in silico for small molecules binding at a predicted allosteric pocket unique to the CD45 intracellular domain, and validated inhibitors by in vitro phosphatase assays. Compound 211 exhibited a CD45 IC50 value of 200 nM and had >100-fold selectivity over six related PTPs. The relevance of the allosteric pocket was verified through site-directed mutagenesis. Compound 211 has a noncompetitive mechanism of action, and it is extremely effective at preventing dephosphorylation of substrate Lck phosphotyrosine (pY)-505 versus preventing dephosphorylation of Lck pY-393. In cultured primary T cells, compound 211 prevents T-cell receptor-mediated activation of Lck, Zap-70, and mitogen-activated protein kinase, and interleukin-2 production. In a delayed-type hypersensitivity reaction in vivo, compound 211 abolished inflammation. This work demonstrates a novel approach to develop effective allosteric inhibitors that can be expanded to target the corresponding allosteric domains of other receptor PTPs.

Topics: Allosteric Regulation; Allosteric Site; Animals; Cells, Cultured; Enzyme Activation; Female; Hypersensitivity, Delayed; Immunologic Factors; Immunosuppressive Agents; Inflammation; Interleukin-2; Leukocyte Common Antigens; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Molecular Docking Simulation; Mutagenesis, Site-Directed; Naphthoquinones; Phosphorylation; Phosphotyrosine; Receptors, Antigen, T-Cell; Signal Transduction; Structure-Activity Relationship; ZAP-70 Protein-Tyrosine Kinase

Although cystic fibrosis (CF) pathophysiology is explained by a defect in CF transmembrane conductance regulator (CFTR) protein, the broad spectrum of disease severity is the consequence of environmental and genetic factors. Among them, oxidative stress has been demonstrated to play an important role in the evolution of this disease, with susceptibility to oxidative damage, decline of pulmonary function, and impaired lung antioxidant defense. Although oxidative stress has been implicated in the regulation of inflammation, its molecular outcomes in CF cells remain to be evaluated. To address the question, we compared the gene expression profile in NuLi-1 cells with wild-type CFTR and CuFi-1 cells homozygous for ΔF508 mutation cultured at air-liquid interface. We analyzed the transcriptomic response of these cell lines with microarray technology, under basal culture conditions and after 24 h oxidative stress induced by 15 μM 2,3-dimethoxy-1,4-naphtoquinone. In the absence of oxidative conditions, CuFi-1 gene profiling showed typical dysregulated inflammatory responses compared with NuLi-1. In the presence of oxidative conditions, the transcriptome of CuFi-1 cells reflected apoptotic transcript modulation. These results were confirmed in the CFBE41o- and corrCFBE41o- cell lines as well as in primary culture of human CF airway epithelial cells. Altogether, our data point to the influence of oxidative stress on cell survival functions in CF and identify several genes that could be implicated in the inflammation response observed in CF patients.

Topics: Apoptosis; Caspase 3; Caspase 7; Cell Line; Cell Survival; Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Down-Regulation; Epithelial Cells; Gene Expression Profiling; Gene Expression Regulation; Gene Ontology; Humans; Inflammation; Lung; Naphthoquinones; Oxidative Stress; Reproducibility of Results; RNA, Messenger; Up-Regulation

Microglia are important macrophages to defend against pathogens in the central nervous system (CNS); however, persistent or acute inflammation of microglia lead to CNS disorders via neuronal cell death. Therefore, we theorized that a good strategy for the treatment of CNS disorders would be to target inflammatory mediators from microglia in disease. Consequently, we investigated whether isobutyrylshikonin (IBS) attenuates the production of proinflammatory mediators, such as nitric oxide (NO) and prostaglandin E2, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Treatment with IBS inhibited the secretion of NO and prostaglandin E2 (as well as the expression of their key regulatory genes), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2). Isobutyrylshikonin also suppressed LPS-induced DNA-binding activity of nuclear transcription factor-κB (NF-κB), by inhibiting the nuclear translocation of p50 and p65 in addition to blocking the phosphorylation and degradation of IκBα. Pretreatment with pyrrolidine dithiocarbamate, a specific NF-κB inhibitor, showed the down-regulation of LPS-induced iNOS and COX-2 messenger RNA by suppressing NF-κB activity. This indirectly suggests that IBS-mediated NF-κB inhibition is the main signaling pathway involved in the inhibition of iNOS and COX-2 expression. In addition, IBS attenuated LPS-induced phosphorylation of PI3K and Akt, which are upstream molecules of NF-κB, in LPS-stimulated BV2 microglial cells. The functional aspects of the PI3K/Akt signaling pathway were analyzed with LY294002, which is a specific PI3K/Akt inhibitor that attenuated LPS-induced iNOS and COX-2 expression by suppressing NF-κB activity. These data suggest that an IBS-mediated anti-inflammatory effect may be involved in suppressing the PI3K/Akt-mediated NF-κB signaling pathway.

Topics: Antioxidants; Cell Line; Central Nervous System Diseases; Cyclooxygenase 2; Dinoprostone; Down-Regulation; Inflammation; Inflammation Mediators; Lipopolysaccharides; Lithospermum; Macrophages; Microglia; Naphthoquinones; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphatidylinositol 3-Kinases; Phosphorylation; Phytotherapy; Plant Extracts; Proto-Oncogene Proteins c-akt; Pyrrolidines; Signal Transduction; Thiocarbamates

Complex [Bi(Lp)(2)]Cl was obtained with 4-hydroxy-3-(3-methylbut-2-enyl)naphthalene-1,2-dione, "lapachol" (HLp). Lapachol, [Bi(Lp)(2)]Cl and BiCl(3) were evaluated in a murine model of inflammatory angiogenesis induced by subcutaneous implantation of polyether polyurethane sponge discs. Intraperitoneal (i.p.) administration of lapachol or [Bi(Lp)(2)]Cl reduced the hemoglobin content in the implants suggesting that reduction of neo-vascularization was caused by lapachol. In the per os treatment only [Bi(Lp)(2)]Cl decreased the hemoglobin content in the implants. Likewise, N-acetylglucosaminidase (NAG) activity decreased in the implants of the groups i.p. treated with lapachol and [Bi(Lp)(2)]Cl while in the per os treatment inhibition was observed only for [Bi(Lp)(2)]Cl. Histological analysis showed that the components of the fibro-vascular tissue (vascularization and inflammatory cell population) were decreased in lapachol- and complex-treated groups. Our results suggest that both lapachol and [Bi(Lp)(2)]Cl exhibit anti-angiogenic and anti-inflammatory activities which have been attributed to the presence of the lapachol ligand. However, coordination to bismuth(III) could be an interesting strategy for improvement of lapachol's therapeutic properties.

Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Bismuth; Implants, Experimental; Inflammation; Male; Mice; Molecular Structure; Naphthoquinones

Toxicological studies have correlated inflammatory effects of diesel exhaust particles (DEP) with its organic constituents, such as the organic electrophile 1,2-naphthoquinone (1,2-NQ).. To elucidate the mechanisms involved in 1,2-NQ-induced inflammatory responses, we examined the role of oxidant stress in 1,2-NQ-induced expression of inflammatory and adaptive genes in a human airway epithelial cell line.. We measured cytosolic redox status and hydrogen peroxide (H2O2) in living cells using the genetically encoded green fluorescent protein (GFP)-based fluorescent indicators roGFP2 and HyPer, respectively. Expression of interleukin-8 (IL-8), cyclooxygenase-2 (COX-2), and heme oxygenase-1 (HO-1) mRNA was measured in BEAS-2B cells exposed to 1,2-NQ for 1-4 hr. Catalase overexpression and metabolic inhibitors were used to determine the role of redox changes and H2O2 in 1,2-NQ-induced gene expression.. Cells expressing roGFP2 and HyPer showed a rapid loss of redox potential and an increase in H2O2 of mitochondrial origin following exposure to 1,2-NQ. Overexpression of catalase diminished the H2O2-dependent signal but not the 1,2-NQ-induced loss of reducing potential. Catalase overexpression and inhibitors of mitochondrial respiration diminished elevations in IL-8 and COX-2 induced by exposure to 1,2-NQ, but potentiated HO-1 mRNA levels in BEAS cells.. These data show that 1,2-NQ exposure induces mitochondrial production of H2O2 that mediates the expression of inflammatory genes, but not the concurrent loss of reducing redox potential in BEAS cells. 1,2-NQ exposure also causes marked expression of HO-1 that appears to be enhanced by suppression of H2O2. These findings shed light into the oxidant-dependent events that underlie cellular responses to environmental electrophiles.

Topics: Air Pollutants; Bronchi; Catalase; Cell Line; Cyclooxygenase 2; Environmental Health; Epithelial Cells; Gene Expression Regulation; Green Fluorescent Proteins; Heme Oxygenase-1; Humans; Hydrogen Peroxide; Inflammation; Interleukin-8; Naphthoquinones; Oxidation-Reduction; Oxidative Stress; Particulate Matter; Reactive Oxygen Species; RNA, Messenger; Vehicle Emissions

NADPH oxidase (NOX) is a predominant source of reactive oxygen species (ROS), and the activity of NOX, which uses NADPH as a common rate-limiting substrate, is upregulated by prolonged dietary salt intake. β-Lapachone (βL), a well-known substrate of NAD(P)H:quinone oxidoreductase 1 (NQO1), decreases the cellular NAD(P)H/NAD(P)(+) ratio via activation of NQO1. In this study, we evaluated whether NQO1 activation by βL modulates salt-induced renal injury associated with NOX-derived ROS regulation in an animal model. Dahl salt-sensitive (DS) rats fed a high-salt (HS) diet were used to investigate the renoprotective effect of NQO1 activation. βL treatment significantly lowered the cellular NAD(P)H:NAD(P)(+) ratio and dramatically reduced NOX activity in the kidneys of HS diet-fed DS rats. In accordance with this, total ROS production and expression of oxidative adducts also decreased in the βL-treated group. Furthermore, HS diet-induced proteinuria and glomerular damage were markedly suppressed, and inflammation, fibrosis, and apoptotic cell death were significantly diminished by βL treatment. This study is the first to demonstrate that activation of NQO1 has a renoprotective effect that is mediated by NOX activity via modulation of the cellular NAD(P)H:NAD(P)(+) ratio. These results provide strong evidence that NQO1 might be a new therapeutic target for the prevention of salt-induced renal injury.

Topics: Acute Kidney Injury; Animals; Apoptosis; Enzyme Activation; Enzyme Activators; Fibrosis; Inflammation; Kidney Glomerulus; Male; NAD(P)H Dehydrogenase (Quinone); NADP; NADPH Oxidases; Naphthoquinones; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Inbred Dahl; Reactive Oxygen Species; Sodium Chloride

Various shortcomings of the available methods of extraction of plumbagin from Plumbago zeylanica using non-edible organic solvents coupled with the poor aqueous solubility and low bioavailability called for extracting plumbagin in a water soluble form via a single step technique using hydrophilic lipid Gelucire 44/14.. Gelucire extract of P. zeylanica (GPZ) was prepared and evaluated for extraction efficiency, High-performance thin layer chromatography (HPTLC) and thermal analysis. In vitro intestinal absorption and bioavailability of plumbagin from GPZ in comparison with that of aqueous (APZ), ethanolic extract (EPZ) and standard plumbagin studied using non-everted rat intestinal sac model.. The GPZ showed significantly higher extraction efficiency (3.24±0.12% w/w) compared to ethanolic (EPZ) and aqueous (APZ) extraction, 2.48±0.16% w/w and 0.07±0.02% w/w respectively. GPZ displayed significantly higher Q(30min) (cumulative percentage absorption of plumbagin in 30 min) and lower t(40%) (time required for 40% w/w drug absorption). The flux and apparent permeability coefficient in duodenum and ileum were 2, 3 and 6 fold higher than EPZ, standard plumbagin and APZ respectively.. Improved therapeutic efficacy of plumbagin may be due to the micellar solubilization and consequent enhanced partitioning of plumbagin through intestinal by Gelucire which was reflected in the in vivo anti-inflammatory study conducted in rats.. Thus extraction using Gelucire can be proclaimed as an efficient, economic and solvent-free technique for extraction of plumbagin and can be utilized for various clinically important water insoluble phytoconstituents in order to improve their biopharmaceutical properties.

Topics: Animals; Carrageenan; Chemical Fractionation; Chromatography, High Pressure Liquid; Inflammation; Intestinal Absorption; Intestinal Mucosa; Intestines; Liquid-Liquid Extraction; Male; Mice; Models, Biological; Naphthoquinones; Permeability; Plant Extracts; Plumbaginaceae; Polyethylene Glycols; Rats; Toxicity Tests, Acute; Water

Although various drugs for the treatment of rheumatoid arthritis (RA) have been used in clinics, RA is not completely curable to date. Thus, to seek new drugs for the treatment of RA has been a hotspot. Hydroxynaphthoquinones are the major anti-inflammatory active constituents in Arnebia euchroma (Royle) Johnst. The present study aims to evaluate the anti-arthritic activity of a hydroxynaphthoquinone mixture (HM) of A. euchroma (Royle) Johnst, including its anti-inflammatory and analgesic effects. The anti-arthritic efficacy of HM was examined using complete Freund's adjuvant- and bovine type II collagen-induced arthritic models. The paw edema, polyarthritis index and histopathological change were evaluated. The analgesic effect was assessed using the chemical and thermal models of nociception. Results found that HM administered prophylactically and curatively showed marked anti-arthritic activity by suppressing the paw swelling and development of inflammation, lowering the levels of TNF-α and IL-1β and protecting cartilage and bone from damage. The protection of HM was superior to that of reference drugs such as prednisone acetate or etanercept, and showed no direct deleterious effect. Similarly, HM showed significant analgesic effects. In summary, HM possessed potent anti-arthritic activity. It could relieve inflammatory symptoms and protect against joint destruction. These findings indicate that HM would be a potential therapeutic agent for arthritic disease, which provide pharmacological evidence for its clinical application.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Bone Diseases; Boraginaceae; Cartilage Diseases; Cattle; Collagen Type II; Edema; Etanercept; Freund's Adjuvant; Hot Temperature; Immunoglobulin G; Inflammation; Interleukin-1beta; Joint Diseases; Male; Naphthoquinones; Phytotherapy; Plant Extracts; Prednisone; Rats; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

Previously, we reported that vitamin K(3), which consists of a quinone component, inhibits the activity of human DNA polymerase γ (pol γ). In this study, we investigated the inhibitory effects of 4 quinone derivatives (1,4-benzoquinone (BQ), 1,4-naphthoquinone (NQ), 9,10-anthraquinone (AQ) and 5,12-naphthacenequinone (NCQ)) on the activity of mammalian pols. BQ and NQ potently inhibited the activity of all the pol species: pols α, β, γ, δ, ε and λ, and NQ was a stronger pol inhibitor than BQ. Because we previously found a positive relationship between pol l inhibition and anti-inflammatory action, we examined whether these quinone derivatives could inhibit inflammatory responses. BQ and NQ caused a marked reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ear, although AQ and NCQ did not. In a cell culture system using mouse macrophages, NQ displayed the strongest suppression in the production of tumor necrosis factor (TNF)-α induced by lipopolysaccharide (LPS) among the quinone derivatives tested. Moreover, NQ was found to inhibit the action of nuclear factor (NF)-κ. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of BQ and NQ to mice led to suppression of TNF-α production in serum. These anti-inflammatory responses of NQ were more potent than those of BQ. In conclusion, this study has identified several quinone derivatives, such as NQ, that are promising anti-inflammatory candidates.

Topics: Animals; Anthraquinones; Anti-Inflammatory Agents, Non-Steroidal; Antifibrinolytic Agents; Cattle; Cell Line; DNA-Directed DNA Polymerase; Enzyme Inhibitors; Female; Genes, pol; Humans; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; Naphthoquinones; Nucleic Acid Synthesis Inhibitors; Rats; Vitamin K 3

Cipura paludosa (Iridaceae) is a plant that is distributed in the north region of Brazil. Its bulbs are used in folk medicine to treat inflammation and pain. Four naphthalene derivatives have been isolated from the bulbs of this plant. Three of them have been identified as the known naphthalene derivatives, eleutherine, iso-eleutherine, and hongkonin. The structure of the fourth and new component was determined as 11-hydroxyeleutherine by extensive NMR study. In addition, the IN VIVO effect of the two major compounds, eleutherine and iso-eleutherine, was evaluated in carrageenan-induced hypernociception and inflammation in mice. Eleutherine and iso-eleutherine (1.04-34.92 µmol/kg), dosed intraperitoneally (i.p.) or orally (p.o.), decreased the carrageenan-induced paw oedema (i.p. - inhibitions of 36 ± 7 % and 58 ± 14 %, respectively; p.o. - inhibitions of 36 ± 7 % and 58 ± 14 %, respectively). Iso-eleutherine, but not eleutherine, significantly reduced (inhibitions of 39 ± 4 %) the plasma extravasation induced by intradermal (i.d.) injection of carrageenan. Likewise, eleutherine and iso-eleutherine (1.04-34.92 µmol/kg, i.p. or p.o.) were also effective in preventing the carrageenan-induced hypernociceptive response (i.p. - inhibition of 59 ± 4 % and 63 ± 1 %, respectively; p.o. - inhibitions of 36 ± 7 % and 58 ± 14 %, respectively). It was also suggested that the anti-inflammatory and anti-hypernociceptive effects of eleutherine or iso-eleutherine partly depend on the interference with the synthesis or activity of mast cell products, kinins, cytokine, chemokines, prostanoids, or sympathetic amines. Our findings show that two major compounds of C. paludosa contain pharmacologically active constituents that possess antinociceptive and anti-inflammatory activity, justifying, at least in part, its popular therapeutic use for treating conditions associated with pain.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brazil; Carrageenan; Drug Evaluation, Preclinical; Edema; Female; Inflammation; Injections, Intraperitoneal; Iridaceae; Magnetic Resonance Spectroscopy; Male; Mice; Molecular Structure; Naphthoquinones; Pain; Plant Roots; Plants, Medicinal

Shikonin, extracted from medicinal Chinese herb (Lithospermum erythrorhizo), was reported to exert anti-inflammatory and anti-cancer effects both in vitro and in vivo. We have found that proteasome was a molecular target of shikonin in tumor cells, but whether shikonin targets macrophage proteasome needs to be investigated. In the current study, we report that shikonin inhibited inflammation in mouse models as efficiently as dexamethasone. Shikonin at 4 μM reduced the Lipopolysaccharides (LPS)-mediated TNFα release in rat primary macrophage cultures, and blocked the translocation of p65-NF-κB from the cytoplasm to the nucleus, associated with decreased proteasomal activity. Consistently, shikonin accumulated IκB-α, an inhibitor of NF-κB, and ubiquitinated proteins in rat primary macrophage cultures, demonstrating that the proteasome is a target of shikonin under inflammatory conditions. Shikonin also induced macrophage cell apoptosis and cell death. These results demonstrate for the first time that proteasome inhibition by shikonin contributes to its anti-inflammatory effect. The novel finding about macrophage proteasome as a target of shikonin suggests that this medicinal compound has great potential to be developed into an anti-inflammatory agent.

Topics: Active Transport, Cell Nucleus; Animals; Anti-Inflammatory Agents; Capillary Permeability; Cell Death; Cell Nucleus; Cytoplasm; Drugs, Chinese Herbal; Ear Auricle; Inflammation; Lithospermum; Macrophages; Mice; Naphthoquinones; NF-kappa B; Protease Inhibitors; Proteasome Inhibitors; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Previously, we reported that vitamin K₃ (menadione, 2-methyl-1,4-naphthoquinone) (compound 2) inhibits the activity of human mitochondrial DNA polymerase γ (pol γ). In this study, we investigated the inhibitory effects (IEs) of vitamin K3 and its derivatives, such as 1,4-naphthoquinone (compound 1) and 1,2-dimethyl-1,4-naphthoquinone (compound 3), on the activity of mammalian pols. Among compounds 1-3 (10 µM for each), compound 1 was the strongest inhibitor of mammalian pols α and λ, which belong to the B and X pol families, respectively, whereas compound 2 was the strongest inhibitor of human pol γ, a family A pol. However, these compounds did not affect the activity of human pol κ, a family Y pol. As we previously found a positive relationship between pol λ inhibition and anti-inflammatory action, we examined whether these vitamin K₃ derivatives are able to inhibit inflammatory responses. Among the three compounds tested, compound 1 caused the greatest reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ears. In addition, in a cell culture system using RAW264.7 mouse macrophages, compound 1 displayed the strongest suppression of tumor necrosis factor (TNF)-α production induced by lipopolysaccharide (LPS). In an in vivo mouse model of LPS-evoked acute inflammation, the intraperitoneal injection of compound 1 into mice suppressed TNF-α production in their peritoneal macrophages and serum. In an in vivo colitis mouse model induced using dextran sulfate sodium (DSS), the vitamin K₃ derivatives markedly suppressed DSS-evoked colitis. In conclusion, this study has identified several vitamin K₃ derivatives, such as compound 1, that are promising anti-inflammatory candidates.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Dextran Sulfate; DNA-Directed DNA Polymerase; Enzyme Inhibitors; Female; Humans; Inflammation; Isoenzymes; Lipopolysaccharides; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Naphthoquinones; Nucleic Acid Synthesis Inhibitors; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha; Vitamin K 3

We previously found that vitamin K(3) (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase γ (pol γ). In this study, we focused on juglone (5-hydroxy-1,4-naphthoquinone), which is a 1,4-naphthoquinone derivative, and chemically synthesized novel juglones conjugated with C2:0 to C22:6 fatty acid (5-O-acyl juglones). The chemically modified juglones enhanced mammalian pol inhibition and their cytotoxic and anti-inflammatory activities. The juglone conjugated with oleic acid (C18:1-acyl juglone) showed the strongest inhibition of DNA replicative pol α activity and human colon carcinoma (HCT116) cell growth in 10 synthesized 5-O-acyl juglones. C12:0-Acyl juglone was the strongest inhibitor of DNA repair-related pol λ, as well as the strongest suppression of the production of tumor necrosis factor (TNF)-α production induced by lipopolysaccharide (LPS) in the compounds tested. Moreover, this compound caused the greatest reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ears. C12:0- and C18:1-Acyl juglones selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols and DNA metabolic enzymes tested. These data indicate that the novel 5-O-acyl juglones target anti-cancer and/or anti-inflammatory agents based on mammalian pol inhibition. Moreover, the results suggest that acylation of juglone is an effective chemical modification to improve the anti-cancer and anti-inflammation of vitamin K(3) derivatives, such as juglone.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Cell Line, Tumor; DNA Polymerase beta; Enzyme Inhibitors; Humans; Inflammation; Lipopolysaccharides; Mice; Naphthoquinones; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

The environmental chemical 1,2-naphthoquinone (1,2-NQ) is implicated in the exacerbation of airways diseases induced by exposure to diesel exhaust particles (DEP), which involves a neurogenic-mediated mechanism. Plasma extravasation in trachea, main bronchus and lung was measured as the local (125)I-bovine albumin accumulation. RT-PCR quantification of TRPV1 and tachykinin (NK(1) and NK(2)) receptor gene expression were investigated in main bronchus. Intratracheal injection of DEP (1 and 5 mg/kg) or 1,2-NQ (35 and 100 nmol/kg) caused oedema in trachea and bronchus. 1,2-NQ markedly increased the DEP-induced responses in the rat airways in an additive rather than synergistic manner. This effect that was significantly reduced by L-732,138, an NK(1) receptor antagonist, and in a lesser extent by SR48968, an NK(2) antagonist. Neonatal capsaicin treatment also markedly reduced DEP and 1,2-NQ-induced oedema. Exposure to pollutants increased the TRPV1, NK(1) and NK(2) receptors gene expression in bronchus, an effect was partially suppressed by capsaicin treatment. In conclusion, our results are consistent with the hypothesis that DEP-induced airways oedema is highly influenced by increased ambient levels of 1,2-NQ and takes place by neurogenic mechanisms involving up-regulation of TRPV1 and tachykinin receptors.

Topics: Air Pollutants; Animals; Female; Inflammation; Male; Naphthoquinones; Neurons, Afferent; Rats; Rats, Wistar; Respiratory System; TRPV Cation Channels; Vehicle Emissions

In the present paper we studied the effect of shikonin on ear oedema induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), and determined the mechanisms through which shikonin might exert its topical anti-inflammatory action.. Acute ear oedema was induced in mice by topical application of TPA. The in vitro assays used macrophages RAW 264.7 cells stimulated with lipopolysaccharide. Cyclooxygenase-2, inducible nitric oxide synthase, protein kinase Calpha, extracellular signal-regulated protein kinase (ERK), phosphorylated ERK (pERK), c-Jun N-terminal kinase (JNK), pJNK, p38, p-p38, p65, p-p65, inhibitor protein of nuclear factor-kappaB (NF-kappaB) (IkappaBalpha) and pIkappaBalpha were measured by Western blotting, activation and binding of NF-kappaB to DNA was detected by reporter gene and electrophoretic mobility shift assay, respectively, and NF-kappaB p65 localization was detected by immunocytochemistry.. Shikonin reduced the oedema (inhibitory dose 50 = 1.0 mg per ear), the expression of cyclooxygenase-2 (70%) and of inducible nitric oxide synthase (100%) in vivo. It significantly decreased TPA-induced translocation of protein kinase Calpha, the phosphorylation and activation of ERK, the nuclear translocation of NF-kappaB and the TPA-induced NF-kappaB-DNA-binding activity in mouse skin. Moreover, in RAW 264.7 cells, shikonin significantly inhibited the binding of NF-kappaB to DNA in a dose-dependent manner and the nuclear translocation of p65.. Shikonin exerted its topical anti-inflammatory action by interfering with the degradation of IkappaBalpha, thus inhibiting the activation of NF-kappaB.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Cell Nucleus; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Female; I-kappa B Proteins; Inflammation; Inhibitory Concentration 50; Macrophages; Mice; Naphthoquinones; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Protein Transport; Tetradecanoylphorbol Acetate

Shikonin exhibits a wide range of anti-inflammatory actions. Here, we assessed its effects on maturation of murine bone marrow-derived dendritic cells (BM-DCs) and on allergic reactions in a murine model of asthma.. Cultured murine BM-DCs were used to investigate the effects of shikonin on expression of cell surface markers and their stimulation of T-cell proliferation and cytokine production. The therapeutic potential of shikonin was evaluated in a model of allergic airway disease.. Shikonin dose-dependently inhibited expression of major histocompatibility complex class II, CD80, CD86, CCR7 and OX40L on BM-DCs, induced by a mixture of ovalbumin (OVA; 100µg·mL(-1) ) and thymic stromal lymphopoietin (TSLP; 20ng·mL(-1) ). Shikonin-treated BM-DCs were poor stimulators of CD4(+) T lymphocyte and induced lower levels of interleukin (IL)-4, IL-5, IL-13 and tumour necrosis factor (TNF)-α release by responding T-cells. After intratracheal instillation of shikonin in OVA-immunized mice, OVA challenge induced lower IL-4, IL-5, IL-13, TNF-α and eotaxin release in bronchial alveolar lavage fluid, lower IL-4 and IL-5 production in lung cells and mediastinal lymph node cells and attenuated OVA-induced lung eosinophilia and airway hyperresponsiveness.. Shikonin effectively suppressed OVA + TSLP-induced BM-DC maturation in vitro and inhibited allergic inflammation and airway hyperresponsiveness in a murine model of asthma, showing good potential as a treatment for allergic asthma. Also, our model provides a novel platform for screening drugs for allergic diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Bone Marrow Cells; Bronchoalveolar Lavage Fluid; Cytokines; Dendritic Cells; Drugs, Chinese Herbal; Female; Inflammation; Interleukin-13; Interleukin-4; Interleukin-5; Lung; Mice; Mice, Inbred BALB C; Naphthoquinones; Ovalbumin; Thymic Stromal Lymphopoietin; Tumor Necrosis Factor-alpha

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) (PL) is a naturally occurring yellow pigment found in the plants of the Plumbaginaceae, Droseraceae, Ancistrocladaceae, and Dioncophyllaceae families. It has been reported that PL exhibits anticarcinogenic, anti-inflammatory, and analgesic activities. However, the mechanism underlying its anti-inflammatory action remains unknown. In the current study, we investigated and characterized the anti-inflammatory and analgesic effects of PL orally administrated in a range of dosages from 5 to 20 mg/kg. We also examined the role of nuclear factor κB (NF-κB) and proinflammatory cytokines and mediators in this effect. The results showed that PL significantly and dose-dependently suppressed the paw edema of rats induced by carrageenan and various proinflammatory mediators, including histamine, serotonin, bradykinin, and prostaglandin E(2). PL reduced the number of writhing episodes of mice induced by the intraperitoneal injection of acetic acid, but it did not reduce the writhing episode numbers induced by MgSO(4) in mice or prolong the tail-flick reaction time of rats to noxious thermal pain. Mechanistic studies showed that PL effectively decreased the production of the proinflammatory cytokines interleukin 1β, interleukin 6, and tumor necrosis factor α. It also inhibited the expression of the proinflammatory mediators inducible nitric-oxide synthase and cyclooxygenase 2, whereas it did not inhibit the expression of cyclooxygenase 1. Further studies demonstrated that PL suppressed inhibitor of κBα phosphorylation and degradation, thus inhibiting the phosphorylation of the p65 subunit of NF-κB. This study suggests that PL has a potential to be developed into an anti-inflammatory agent for treating inflammatory diseases.

Topics: Abdominal Pain; Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Carrageenan; Cyclooxygenase 2; Dinoprostone; Edema; Foot; Gene Expression; Histamine; Hot Temperature; I-kappa B Proteins; Inflammation; Interleukin-1beta; Interleukin-6; Magnesium Sulfate; Male; Mice; Mice, Inbred ICR; Naphthoquinones; NF-kappa B; NF-KappaB Inhibitor alpha; Nitric Oxide Synthase Type II; Pain Threshold; Phosphorylation; Rats; Rats, Sprague-Dawley; Serotonin; Transcription Factor RelA; Tumor Necrosis Factor-alpha

This study aimed at developing a topical formulation of lapachol, a compound isolated from various Bignoniaceae species and at evaluating its topical anti-inflammatory activity. The influence of the pharmaceutical form and different types of emulsifiers was evaluated by in-vitro release studies. The formulations showing the highest release rate were selected and assessed trough skin permeation and retention experiments. It was observed that the gel formulation provided significantly higher permeation and retained amount (3.9-fold) of lapachol as compared to the gel-cream formulation. Antinociceptive and antiedematogenic activities of the most promising formulation were also evaluated. Lapachol gel reduced the increase in hind-paw volume induced by carrageenan injection and reduced nociception produced by acetic acid (0.8% in water, i.p.) when used topically. These results suggest that topical delivery of lapachol from gel formulations may be an effective medication for both dermal and subdermal injuries.

Topics: Administration, Topical; Animals; Anti-Infective Agents; Diffusion; Drug Carriers; Drug Compounding; Drug Evaluation, Preclinical; Inflammation; Materials Testing; Naphthoquinones; Rats; Rats, Wistar

The current authors have previously demonstrated that diesel exhaust particles (DEP) enhance antigen-related airway inflammation in mice. Furthermore, a recent study has shown that organic chemicals in DEP, rather than their carbonaceous nuclei, are important contributors to the aggravating effects of airway inflammation. However, the components in DEP responsible for the enhancing effects on the model remain to be identified. The current authors investigated the effects of naphthoquinone (NQ), one of the extractable chemical compounds of DEP, on antigen-related airway inflammation, local expression of cytokine proteins, and antigen-specific immunoglobulin (Ig) production in mice. Pulmonary exposure to NQ dose-dependently aggravated antigen-related airway inflammation, as characterised by infiltration of eosinophils and lymphocytes around the airways and an increase in goblet cells in the bronchial epithelium. Combined exposure to NQ and antigen enhanced the local expression of interleukin (IL)-4, IL-5, eotaxin, macrophage chemoattractant protein-1 and keratinocyte chemoattractant, compared with exposure to antigen or NQ alone. Also, NQ exhibited adjuvant activity for the antigen-specific production of IgG(1) and IgG(2a). These results provide the first experimental evidence that naphthoquinone can enhance antigen-related airway inflammation in vivo, and that naphthoquinone can, to some extent, partly play a role in the pathogenesis of diesel exhaust particle toxicity on the condition.

Topics: Animals; Antigens; Bronchoalveolar Lavage Fluid; Cytokines; Immunoglobulin G; Inflammation; Lung; Male; Mice; Mice, Inbred ICR; Naphthoquinones; Ovalbumin; Pneumonia; Respiratory Hypersensitivity; Vehicle Emissions

Topics: Alopecia; History, 19th Century; Humans; Inflammation; Naphthoquinones; Phenylenediamines; Plant Extracts; Skin

Plumbagin, derived from the medicinal plant Plumbago zeylanica, modulates cellular proliferation, carcinogenesis, and radioresistance, all known to be regulated by the activation of the transcription factor NF-kappaB, suggesting plumbagin might affect the NF-kappaB activation pathway. We found that plumbagin inhibited NF-kappaB activation induced by TNF, and other carcinogens and inflammatory stimuli (e.g. phorbol 12-myristate 13-acetate, H2O2, cigarette smoke condensate, interleukin-1beta, lipopolysaccharide, and okadaic acid). Plumbagin also suppressed the constitutive NF-kappaB activation in certain tumor cells. The suppression of NF-kappaB activation correlated with sequential inhibition of the tumor necrosis factor (TNF)-induced activation of IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRAF2, NIK, IKK-beta, and the p65 subunit of NF-kappaB. Plumbagin also suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by dithiothreitol both in vitro and in vivo. However, plumbagin did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine 38 mutated to serine. Plumbagin down-regulated the expression of NF-kappaB-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin), proliferative (cyclin D1 and COX-2), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by TNF and paclitaxel and inhibited cell invasion. Overall, our results indicate that plumbagin is a potent inhibitor of the NF-kappaB activation pathway that leads to suppression of NF-kappaB-regulated gene products. This may explain its cell growth modulatory, anticarcinogenic, and radiosensitizing effects previously described.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cytokines; Dithiothreitol; Enzyme Activation; Humans; I-kappa B Proteins; Inflammation; Models, Chemical; Naphthoquinones; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; U937 Cells

Tumor necrosis factor alpha (TNF-alpha) contributes to the pathogenesis of both acute and chronic inflammatory diseases and has been a target for the development of new anti-inflammatory drugs. Shikonins, the naphthoquinone pigments present in the root tissues of Lithospermum erythrorhizon Sieb. et Zucc. (Boraginaceae), have been reported to exert anti-inflammatory effects both in vitro and in vivo. In this study, we evaluated the effects of shikonin and its derivatives on the transcriptional activation of human TNF-alpha promoter in a gene gun-transfected mouse skin system by using a luciferase reporter gene assay. The crude plant extract of L. erythrorhizon as well as derived individual compounds shikonin, isobutyryl shikonin, acetyl shikonin, dimethylacryl shikonin and isovaleryl shikonin showed significant dose-dependent inhibition of TNF-alpha promoter activation. Among the tested compounds, shikonin and isobutyryl shikonin exhibited the highest inhibition of TNF-alpha promoter activation and also showed significant suppression of transgenic human TNF-alpha mRNA expression and protein production. We demonstrated that shikonin-inhibitory response was retained in the core TNF-alpha promoter region containing the TATA box and a 48-bp downstream sequence relative to the transcription start site. Further our results indicated that shikonin suppressed the basal transcription and activator-regulated transcription of TNF-alpha by inhibiting the binding of transcription factor IID protein complex (TATA box-binding protein) to TATA box. These in vivo results suggest that shikonins inhibit the transcriptional activation of the human TNF-alpha promoter through interference with the basal transcription machinery. Thus, shikonins may have clinical potential as anti-inflammatory therapeutics.

Topics: Animals; Anti-Inflammatory Agents; Betamethasone; Blotting, Western; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Gene Transfer Techniques; Humans; Hydrocortisone; Inflammation; Lithospermum; Luciferases; Mice; Mice, Inbred BALB C; Models, Chemical; Naphthoquinones; NF-kappa B; Plasmids; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Skin; Time Factors; Transcription Factor RelA; Transcription, Genetic; Transcriptional Activation; Transfection; Transgenes; Tumor Necrosis Factor-alpha

beta-Lapachone, a 1,2-naphthoquinone, is a novel chemotherapeutic agent. It has been shown to be capable of suppressing inducible nitric oxide synthase expression and function in rat alveolar macrophages. The authors further performed experiments to examine the molecular mechanism of beta-lapachone on LPS-induced responses in rat alveolar macrophages and to evaluate its in vivo antiinflammatory effect. A significant increase in nitrite production and inducible nitric oxide synthase expression was elicited in macrophages treated with LPS that was inhibited by coincubation with beta-lapachone. beta-Lapachone could also inhibit the production of tumor necrosis factor-alpha induced by LPS. LPS induces protein tyrosine phosphorylation and nuclear factor-kappaB binding activity by gel mobility shift assay in macrophages. These events were significantly inhibited by beta-lapachone. Furthermore, beta-lapachone in vivo protected against the induction of lung edema, lung-inducible nitric oxide synthase protein expression and nuclear factor-kappaB activation, lethality, and increased plasma nitrite and serum tumor necrosis factor-alpha levels induced by LPS. These results indicate that beta-lapachone suppresses inducible nitric oxide synthase induction and tumor necrosis factor-alpha production mediated by the inhibition of protein tyrosine phosphorylation and nuclear factor-kappaB activation caused by LPS. This results in a beneficial effect in an animal model of sepsis.

Topics: Animals; Anti-Infective Agents; Cells, Cultured; Disease Models, Animal; Drug Evaluation, Preclinical; Endotoxins; Inflammation; Lipopolysaccharides; Macrophage Activation; Macrophages, Alveolar; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Naphthoquinones; NF-kappa B; Nitric Oxide Synthase; Phosphorylation; Pulmonary Edema; Rats; Sepsis; Signal Transduction; Tumor Necrosis Factor-alpha

We have investigated the mechanisms of action of aethiopinone, an anti-inflammatory compound from Salvia aethiopis L. roots.. Human neutrophils from healthy volunteers and murine peritoneal macrophages. Swiss mice were randomly divided into groups of six animals.. Test compounds were applied topically in the mouse ear oedema test. In the air pouch, mice received aethiopinone (0.001-0.5 pmol/pouch or 12.5-50 mg/kg p.o.).. LTB4 production was assayed in human neutrophils and COX-2 and iNOS activities in murine macrophages. Air pouches were induced subcutaneously in mice and injected with zymosan on the day six. Mouse ear oedema was induced by arachidonic acid. Dunnett's t-test was employed for statistical analysis.. We have observed potent inhibitory effects on human neutrophil LTB4 production without effects on COX or NOS activities. Aethiopinone is an in vitro inhibitor of 5-LO from human neutrophils (IC50 = 0.11 microM). In addition, aethiopinone reduced leukocyte accumulation and showed in vivo inhibitory activity on this enzyme.. Our results indicate that inhibition of 5-LO could participate in the anti-inflammatory properties of this natural product.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Ear; Edema; Humans; Inflammation; Isoenzymes; Leukotriene B4; Lipoxygenase Inhibitors; Macrophages, Peritoneal; Membrane Proteins; Mice; Naphthoquinones; Neutrophils; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phospholipases A; Prostaglandin-Endoperoxide Synthases

In the present study, the potential involvement of lipid peroxidation and disruption of lysosomal integrity in the pathogenesis of different experimental models of inflammation was examined. The chosen models were carrageenan-induced paw oedema, carrageenan granuloma pouch (acute phase) and Freund's adjuvant-induced arthritis in rats. The pharmacological and biochemical effects of naftazone, a lysosomal membrane stabilizer and indomethacin, a standard anti-inflammatory agent were evaluated with regard to paw oedema volume, serum and exudate activities of the lysosomal enzyme N-acetyl-beta-D-glucosaminidase (NAG), in addition to serum and liver lipid peroxide (LP) levels. Intraperitoneal administration of the test drugs, in rats subjected to inflammation, produced: (1) a significant inhibition of carrageenan-induced paw oedema, (2) a marked reduction of the paw oedema of the Freund's adjuvant arthritis animals, (3) a remarkable decrease of lysosomal leakage of NAG into the exudate of carrageenan granuloma pouch, (4) a slight, but significant, reduction of NAG activity in the serum of rats subjected to carrageenan inflammation, and (5) a reduction of the serum level of LP that was elevated in adjuvant-induced arthritic rats. The level of liver LP was altered by either drugs in an opposite manner; while naftazone lowered hepatic LP, indomethacin markedly elevated its level. The results of the present investigation revealed that lipid peroxidation and disruption of lysosomal integrity are implicated in the pathogenesis of inflammatory processes, and the protection against these deleterious effects imparted both drugs significant anti-inflammatory activity.

Topics: Acetylglucosaminidase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Carrageenan; Edema; Foot; Freund's Adjuvant; Granuloma; Indomethacin; Inflammation; Lipid Peroxidation; Lysosomes; Male; Naphthoquinones; Rats; Rats, Sprague-Dawley

Topics: Humans; Inflammation; Liver Glycogen; Naphthoquinones; Prednisolone; Vitamin K 3

Topics: Aniline Compounds; Coloring Agents; Genital Diseases, Female; Humans; Inflammation; Naphthoquinones; Protamines; Vitamin K

Topics: Benzoquinones; Capillaries; Carbohydrates; Humans; Inflammation; Naphthoquinones; Oxidoreductases; Pain; Patient Discharge; Quinones