morin and Inflammation

The valuable effects of metformin (MET) and morin (MOR) in the improvement of NAFLD have been proposed, nevertheless, their combination impacts were not investigated so far. We determined the therapeutic effects of combined MET and MOR treatment in high-fat diet (HFD)-induced Non-alcoholic fatty liver disease (NAFLD) mice.. C57BL/6 mice were fed on an HFD for 15 weeks. Animals were allotted into various groups and supplemented with MET (230 mg/kg), MOR (100 mg/kg), and MET + MOR (230 mg/kg + 100 mg/kg).. MET in combination with MOR reduced body and liver weight in HFD-fed mice. A significant decrease in fasting blood glucose and improvement in glucose tolerance was observed in HFD mice treated with MET + MOR. Supplementation with MET + MOR led to a decline in hepatic triglyceride levels and this impact was associated with diminished expression of fatty-acid synthase (FAS) and elevated expression of carnitine palmitoyl transferase 1 (CPT1) and phospho-Acetyl-CoA Carboxylase (p-ACC). Moreover, MET combined with MOR alleviates hepatic inflammation through the polarization of macrophages to the M2 phenotype, decreasing the infiltration of macrophages and lowering the protein level of NF-kB. MET and MOR in combination reduce the size and weight of epididymal white adipose tissue (eWAT), and subcutaneous WAT (sWAT), whereas improves cold tolerance, BAT activity, and mitochondrial biogenesis. Combination therapy results in stimulating brown-like adipocyte (beige) formation in the sWAT of HFD mice.. These results suggest that the combination of MET and MOR has a protective effect on hepatic steatosis, which may use as a candidate therapeutic for the improvement of NAFLD.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Diet, High-Fat; Inflammation; Lipid Metabolism; Metformin; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Thermogenesis

Polycystic Ovary Syndrome (PCOS) is a gynecologic disorder with unsatisfactory treatment options. Hyperandrogenism and insulin resistance (IR) are two symptoms of PCOS. The majority of PCOS patients (approximately 50% to 70%) have IR and moderate diffuse inflammation of varying degrees. We investigated in-vitro and in-vivo effects of naringenin, morin and their combination on PCOS induced endometrial hyperplasia by interfering with the mTORC1 and mTORC2 signaling pathways. The vaginal smear test ensured the regular oestrous cycles in female rats. Serum cytokines (TNF-α and IL-6) were assessed using the ELISA test, followed by in-vivo and in-vitro determination of prominent gene expressions (mTORC1and C2, p62, LC3-II, and Caspase-3 involved in the inflammatory signaling mechanisms through RT-PCR, western bloting, or immunohistochemical analysis. In addition, the viability of naringenin or morin treated cells was determined using flow cytometry analysis. The abnormal oestrous cycle and vaginal keratosis indicated that PCOS was induced successfully. The recovery rate of the oestrous cycle with treatments was increased significantly (P<0.01) when compared to the PCOS model. Narigenin, morin, or a combination of the two drugs substantially decreased serum insulin, TNF-α, IL-6 levels with improved total anti-oxidant capacity and SOD levels (P<0.01). Treatments showed suppression of HEC-1-A cells proliferation with increased apoptosis (P<0.01) by the upregulation of Caspase-3 expression, followed by downregulation of mTORC, mTORC1, and p62 (P<0.01) expressions with improved LC3-II expressions (P<0.05) respectively. The histological findings showed a substantial increase in the thickness of granulose layers with improved corpora lutea and declined the number of cysts. Our findings noticed improved inflammatory and oxidative microenvironment of ovarian tissues in PCOS treated rats involving the autophagic and apoptotic mechanisms demonstrating synergistic in-vitro and in-vivo therapeutic effects of treatments on PCOS-induced endometrial hyperplasia.

Topics: Animals; Antioxidants; Apoptosis; Autophagy; Cell Line, Tumor; Cytokines; Drug Therapy, Combination; Endometrial Hyperplasia; Female; Flavanones; Flavonoids; Humans; Inflammation; Insulin Resistance; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Polycystic Ovary Syndrome; Rats; Signal Transduction

Acrylamide (ACR) has genotoxic, neurotoxic, and carcinogenic effects. From past to present, various plants or their products have been used for therapeutic purposes such as morin. It was aimed to detect possible protective effects of morin vs ACR-induced lung toxicity. The rats, treated with ACR alone or with morin for 10 consecutive days, were included in the study. A broad variety of biomarkers related to oxidative stress, apoptosis, autophagy, and inflammatory responses were evaluated. ACR increased malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), nuclear factor kappa-B (NF-κB), Beclin-1, IL-1β, bcl-2 associated X protein (Bax), caspase-3, light chain 3-A (LC3-A), and light chain 3-B (LC3-B) levels but reduced mammalian target of rapamycin (mTOR), b-cell lymphoma-2 (Bcl-2), catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione (GSH) in lung tissues. The morin had effects on the level of these molecules in a way that is opposite to ACR. While ACR-induced oxidative stress, apoptotic, autophagic, inflammatory responses, and may cause pulmonary dysfunction, the morin reduced ACR-induced lung damage. PRACTICAL APPLICATIONS: ACR is a toxic chemical produced by frying, baking, roasting, or grilling foods with high starch content and has genotoxic, neurotoxic, and carcinogenic effects. As an antioxidant compound, the morin is obtained from plants or their products. It was aimed to detect possible protective effects of morin against ACR-induced lung toxicity. It was detected that ACR-induced oxidative stress, apoptotic, autophagic, inflammatory responses, and may cause pulmonary dysfunction, but the morin reduced ACR-induced lung damage.

Topics: Acrylamide; Animals; Apoptosis; Autophagy; Biomarkers; Flavonoids; Glutathione; Inflammation; Lung; Mammals; Oxidative Stress; Rats

The side effects of doxorubicin (Dox) may influence the long-term survival of patients with malignancies. Therefore, it is necessary to clarify the mechanisms generating these side effects induced by Dox and identify effective therapeutic strategies. Here, we found that interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) levels were significantly increased in vascular tissues of Dox-treated mice and Dox-treated vascular smooth muscle cells (VSMCs). Furthermore, we revealed that Dox downregulated the phosphatase and tension homology deleted on chromosome 10 (PTEN) level while upregulated p-AKT and p65 level in VSMCs in vitro. Overexpression of PTEN in VSMCs partly reversed Dox-induced inflammation. Importantly, we demonstrated that Morin could inhibit Dox-induced inflammation by facilitating an increase of PTEN, thus inhibiting the activation of protein kinase B (AKT)/nuclear factor kappa B (NF-κB)/pathway. Additionally, we showed that Morin could reduce the miR-188-5p level, which was increased in Dox-treated VSMCs. Inhibition of miR-188-5p suppressed Dox-induced vascular inflammation in vitro. In conclusion, Morin reduced the Dox-induced vascular inflammatory by moderating the miR-188-5p/PTEN/AKT/NF-κB pathway, indicating that Morin might be a therapeutic agent for overcoming the Dox-induced vascular inflammation.

Topics: Animals; Doxorubicin; Inflammation; Mice; MicroRNAs; NF-kappa B; Proto-Oncogene Proteins c-akt; Signal Transduction

Endocrine-disrupting pollutants (EDPs) remain pervasive in the environment. Bisphenol S (BPS) and diethyl phthalates (DEP) are commonly used to replace the more toxic EDPs. However, it is unclear if they induce neurotoxicity, like their predecessors. Morin possesses relevant neuro-pharmacological activities. Hence, we sought to evaluate the protective effects of morin against the neurotoxic effects previously reported for EDPs. Male Wistar rats were exposed to a mixture of BPS and DEP (MBD) and treated with morin for 21 days. Behavioural assessments were conducted, and the hippocampal tissues were processed for analysis. Rats exposed to MBD presented anxiety-like behaviours, impaired cognitive and motor functions compared to the control group. MBD exposure induced hyperactivity of neurosignalling enzymes (AChE, ADA, MAO-A) and depleted hippocampal antioxidants (SOD, CAT, GPx, and GSH). MBD exposure increased calcium levels and inhibited total Ca

Topics: Animals; Antioxidants; Apoptosis; Flavones; Flavonoids; Hippocampus; Hydrogen Peroxide; Inflammation; Male; Oxidative Stress; Phenols; Phthalic Acids; Rats; Rats, Wistar; Sulfones

Methotrexate (MT) is a broadly used chemotherapeutic drug however its clinical use is confronted with several forms of toxicities containing testicular damage. The current study assessed the ameliorative effects of morin on MT-induced testicular damage with the investigation of its mechanism and the potential involvement of oxidative stress, inflammation, apoptosis and endoplasmic reticulum stress in such protection.. The animals were divided into 5 distinct groups (7 rats in each group). Group 1 was control group, group 2 received MT-only (20 mg/kg bw), group 3 received orally morin-only (100 mg/kg bw), group 4 received MT (20 mg/kg bw) + morin (50 mg/kg bw) and group 5 received MT (20 mg/kg bw) + morin (100 mg/kg). In this study, morin was administered orally for 10 days, while MT was administered intraperitoneally on the 5th day.. MT intoxication was linked with augmented MDA while decreased GSH levels, the enzyme activities of glutathione peroxidase, superoxide dismutase, and catalase and mRNA levels of HO-1 and Nrf2 in the testis tissues. MT injection caused inflammation in the testicular tissue via up-regulation of MAPK14, NFκB, TNF-α and IL-1β. MT application also caused apoptosis and endoplasmic reticulum stress in the testis tissue via increasing mRNA transcript levels of Bax, caspase-3, PERK, IRE1, ATF-6, GRP78 and down-regulation of Bcl-2.. Treatment with morin at a dose of 50 and 100 mg/kg considerably mitigated oxidative stress, inflammation, apoptosis and endoplasmic reticulum stress in the testicular tissue indicating that testicular damage related to MT toxicity could be modulated by morin administration.

Topics: Activating Transcription Factor 6; Animals; Antioxidants; bcl-2-Associated X Protein; Caspase 3; Catalase; Endoplasmic Reticulum Chaperone BiP; Flavones; Glutathione Peroxidase; Inflammation; Male; Methotrexate; Mitogen-Activated Protein Kinase 14; NF-E2-Related Factor 2; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Rats; RNA, Messenger; Signal Transduction; Superoxide Dismutase; Testis; Tumor Necrosis Factor-alpha

Morin is a flavonoid and broadly found in white berry and cranberry branch. Ifosfamide (IFOS) is known as an anticancer and cytotoxic drug especially on the liver. This study aimed to explore the potential protective effects of Morin against IFOS-induced liver toxicity in rats. The model group of rats received a single injection of IFOS (500 mg/kg; i.p.) at day 2, whereas the protective groups of rats were given two different doses of Morin (100 and 200 mg/kg; given by gavage) at days 1 and 2. All animals were then culled 24 h post-IFOS injection. We observed that IFOS caused liver injury, oxidative stress, inflammation, DNA damage, and apoptosis. However, Morin decreased the levels of aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT) (

Topics: Animals; Antioxidants; Apoptosis; Chemical and Drug Induced Liver Injury; DNA Damage; Flavonoids; Glutathione; Ifosfamide; Inflammation; Liver; Oxidative Stress; Rats; Superoxide Dismutase

The slightly available data about the pathogenesis process of mild repetitive traumatic brain injury (mRTBI) indicates to the necessity of further exploration of mRTBI consequences. Several cellular changes are believed to contribute to the cognitive disabilities, and neurodegenerative changes observed later in persons subjected to mRTBI. We investigated glial fibrillary acidic protein (GFAP), the important severity related biomarker, where it showed further increase after multiple trauma compared to single one. To authenticate our aim, Morin (10 mg/kg loading dose, then twice daily 5 mg/kg for 7 days), MK-801 (1 mg/kg; i.p) and their combination were used. The results obtained has shown that all the chosen regimens opposed the upregulated dementia markers (Aβ1-40,p(Thr231)Tau) and inflammatory protein contents/expression of p(Ser53s6)NF-κBp65, TNF-α, IL-6,and IL-1β and the elevated GFAP in immune stained cortex sections. Additionally, they exerted anti-apoptotic activity by decreasing caspase-3 activity and increasing Bcl-2 contents. Saving brain tissues was evident after these therapeutic agents via upregulating the non-canonical Wnt-1/PKC-α cue and IL-10/p(Tyr(1007/1008))JAK-2/p(Tyr705)STAT-3 signaling pathway to confirm enhancement of survival pathways on the molecular level. Such results were imitated by correcting the injury dependent deviated behavior, where Morin alone or in combination enhanced behavior outcome. On one side, our study refers to the implication of two survival signaling pathways; viz.,the non-canonical Wnt-1/PKC-α and p(Tyr(1007/1008))JAK-2/p(Tyr705)STAT-3 in single and repetitive mRTBI along with distorted dementia markers, inflammation and apoptotic process that finally disrupted behavior. On the other side, intervention through affecting all these targets by Morin alone or with MK-801 affords a promising neuroprotective effect.

Topics: Amyloid beta-Peptides; Animals; Apoptosis; Brain Injuries, Traumatic; Cerebral Cortex; Conditioning, Psychological; Dizocilpine Maleate; Fear; Flavonoids; Inflammation; Janus Kinase 2; Oligopeptides; Phosphopeptides; Protein Kinase C-alpha; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor; tau Proteins; Wnt1 Protein

The presented study investigates the effects of morin against toxicity induced by acrylamide (ACR) in the brains of Sprague Dawley rats. In this study, neurotoxicity was induced by orally administering 38.27 mg/kg/b.w ACR to rats through gastric gavage for 10 days. Morin was administered at the same time and at different doses (50 and 100 mg/kg/b.w) with ACR. Biochemical and Western blot analyses showed that ACR increased malondialdehyde (MDA), p38α mitogen-activated protein kinase (p38α MAPK), nuclear factor kappa-B (NF-κB), tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), p53, caspase-3, bcl-2 associated X protein (Bax), Beclin-1, light chain 3A (LC3A), and light chain 3B (LC3B) levels and decreased those of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), b-cell lymphoma-2 (Bcl-2), mammalian target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt) in brain tissue and therefore induced neurotoxicity by causing oxidative stress, inflammation, apoptosis, and autophagy. On the other hand, it was determined that morin positively affected the levels of these markers by displaying antioxidant, anti-inflammatory, anti-apoptotic, and anti-autophagic properties and had a protective effect on ACR-induced neurotoxicity. As a result, morin is an effective substance against brain damage caused by ACR, yet further studies are needed to use it effectively.

Topics: Acrylamide; Animals; Antioxidants; Apoptosis; Flavonoids; Inflammation; Oxidative Stress; Phosphatidylinositol 3-Kinases; Rats; Rats, Sprague-Dawley; Signal Transduction

The glyoxalase pathway (GP) is an antioxidant defense system that detoxifies metabolic byproduct methylglyoxal (MG). Through sequential reactions, reduced glutathione (GSH), glyoxalase I (glo-1), and glyoxalase II (glo-2) convert MG into d-lactate. Spontaneous reactions involving MG alter the structure and function of cellular macromolecules through the formation of inflammatory advanced glycation endproducts (AGEs). Accumulation of MG and AGEs in neural cells contributes to oxidative stress (OS), a state of elevated inflammation commonly found in neurodegenerative diseases including Alzheimer's disease (AD). Morin is a common plant-produced flavonoid polyphenol that exhibits the ability to enhance the GP-mediated detoxification of MG. We hypothesize that structural modifications to morin will improve its inherent GP enhancing ability. Here we synthesized a morin derivative, dibromo-morin (DBM), formulated a morin encapsulated nanoparticle (MNP), and examined their efficacy in enhancing neural GP activity. Cultured mouse primary cerebellar neurons and

Topics: Alzheimer Disease; Animals; Antioxidants; Flavonoids; Inflammation; Lactoylglutathione Lyase; Mice, Inbred C57BL; Neural Pathways; Neurons; Oxidative Stress; Pyruvaldehyde

Psychosocial stress and biological predispositions are linked to mood and personality disorders related to psychiatric behaviors. Targeting neuroinflammation and oxidative stress has been recognized as a potential strategy for the prevention of psychosocial stress-induced psychiatric disorders. Morin, a bioactive compound isolated from mulberry leaf has been shown to produce antiamnesic, antipsychotic and anti-inflammatory effects relative to ginseng, a well-known adaptogen. Hence, the present study investigated the effect of morin on social-defeat stress (SDS)-induced behavioral, neurochemical, neuroimmune and neurooxidative changes in mice using intruder-resident paradigm. The intruder male mice were distributed into 6 groups (n = 10). Groups 1 (normal-control) and 2 (SDS-control) received normal saline, groups 3-5 had morin (25-100 mg/kg) while group 6 received ginseng (50 mg/kg) intraperitoneally daily for 14 days. Thirty minutes after treatment from days 7-14 onwards, mice in groups 2-6 were exposed to SDS for 10 min physical and psychological confrontations respectively with aggressive-resident mice. Neurobehavioral effects (locomotor activity, cognitive performance, anxiety- and depressive-like behavior) were assessed on day 14. Biomarkers of oxidative/nitrergic stress and neuroinflammation; acetylcholinesterase (AChE) and glutamic-acid decarboxylase-67 (GAD

Topics: Animals; Antioxidants; Brain; Flavonoids; Glutamate Decarboxylase; Inflammation; Inflammation Mediators; Male; Mice; NADPH Oxidases; Oxidative Stress; Stress, Psychological

Morin hydrate (MH) is the major flavonoid constituent of Morus alba acclaimed to have antioxidant, anti-inflammatory, anti-stress and neuroprotective properties. However, report on the effect of MH on memory performance and the underlying mechanism following chronic stress exposure is lacking. The current study aimed at investigating the neuroprotective effect of MH on chronic unpredictable stress (CUS)-induced memory impairment in mice using the Y maze test. Mice were subjected to unpredicted stress for 14 days, during which MH (5, 10 and 20 mg/kg i.p) or 25 mg/kg Ginseng was administered to them. On the 14th day, 1 h after treatment, learning and memory deficit was evaluated using the Y maze test and thereafter brains were harvested for the estimation of glutathione (GSH), lipid peroxidation product; malondialdehyde (MDA) and nitrite. Levels of inflammatory mediators tumor necrosis factor-alpha (TNF-α) and interleukin1-beta (IL-1β), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-кB) expressions were also determined. The hippocampus was stained with hematoxylin-eosin (H&E) to examine any morphological changes in the neurons. Mice exposed to CUS showed evidence of impaired memory and increase levels of MDA, nitrite, TNF-α and IL-1β. Furthermore, CUS reduced GSH level, increased the expressions of iNOS and NFкB immune-positive cells and produced loss of neuronal cells in the hippocampus. The MH treatment however improved memory, reduced MDA and nitrite levels, and enhanced brain GSH levels in CUS-mice. Besides, MH reduced brain levels of TNF-α and IL-1β levels, down regulated the expressions of iNOS and NF-кB and rescue neurons in the hippocampal CA3 region of mice exposed to CUS. The results of the study indicate that MH improved CUS-induced memory impairment, which may be related to its ability to boost antioxidant defense system and suppress neuroinflammatory pathways.

Topics: Animals; Cytokines; Flavonoids; Hippocampus; Inflammation; Male; Maze Learning; Memory; Memory Disorders; Mice; Nerve Degeneration; Neurons; Neuroprotective Agents; Oxidative Stress; Reactive Oxygen Species

This study aimed to investigate the effects of morin on cerebral damage and blood-brain barrier (BBB) integrity in a middle cerebral artery occlusion (MCAO) and reperfusion model. Wistar rats were exposed to MCAO for 2 h, followed by reperfusion. Thirty mg/kg of morin was administered via intraperitoneal injection at the different time points: before ischemia, during ischemia, and at reperfusion. The rats were divided into five groups, including sham, vehicle, and three groups of morin. Twenty-four hours after reperfusion, the rats were tested for neurological deficits, and the brains were harvested to assess brain damage. In addition, brains were harvested 72 h to determine BBB disruption. We found that morin significantly reduced reactive oxygen species production and lipid peroxidation. It also decreased inflammation via reducing the expression of Toll-like receptor 4, nuclear factor kappa-beta. Morin ameliorated cerebral damage and reduced apoptosis through decreasing the cerebral infarct size, including apoptotic cell death. Moreover, morin decreased the BBB damage via reducing Evans blue extravasation, neutrophil infiltration, and increasing tight junction protein expression. Therefore, morin protected against cerebral and BBB damage by attenuating oxidative stress, inflammation, and apoptosis in MCAO and reperfusion models.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Blood-Brain Barrier; Brain Ischemia; Disease Models, Animal; Flavonoids; Inflammation; Injections, Intraperitoneal; Lipid Peroxidation; Male; Neutrophil Infiltration; NF-kappa B; Oxidative Stress; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Toll-Like Receptor 4

Morin (MO), a natural bioflavinoid, exists in many herbs. Previous studies have acclaimed MO's anti-inflammatory, antidiabetic, antioxidant, antifibrotic, anticancer, and antihyperglycemic biological effects. This study aimed to assess the molecular mechanism of MO involved in the oleic acid (OA)-induced inflammatory damage and lipid accumulation in HepG2 cell and tyloxapol (Ty)-induced hyperlipidemia in mice. We found that MO can efficaciously mitigate reactive tumor necrosis factor-α (TNF-α) level and triglyceride (TG) accumulation in OA-induced HepG2 cell and in tyloxapol-induced mice. Next, the study testified that MO apparently suppressed OA-excited nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways in HepG2 cell. In addition, MO distinctly upregulated the expression of peroxisome proliferator-activated receptor α (PPARα) and decreased the expression of sterol regulatory element-binding protein 1c (SREBP-1c) in OA-induced HepG2 cell and in tyloxapol-induced mice, both of which are dependent upon the phosphorylation of acetyl-CoA carboxylase (ACC), adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and protein kinase B (AKT). In conclusion, these results suggest that MO has protective potential against hyperlipidemia and steatosis, and the potential mechanism may have a close relation with activation of PPARα and inhibition of SREBP-1c.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinase Kinases; Animals; Flavonoids; Hep G2 Cells; Hepatocytes; Humans; Hyperlipidemias; Inflammation; Lipid Metabolism; Mice; Non-alcoholic Fatty Liver Disease; Oleic Acid; Phosphorylation; Polyethylene Glycols; PPAR alpha; Protein Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Triglycerides

Vincristine is a toxic chemotherapeutic agent which often triggers neuropathic pain through inflammation. Morin isolated from figs (Ficus carica) exerts anti-inflammatory and neuroprotective activities. We investigated whether morin ameliorates vincristine-induced neuropathic pain and the underlying mechanism. Vincristine was injected i.p. for 10 days (day 1-5 and day 8-12). Morin was orally administered every other day from day 1 to 21. The pain behaviors were determined by measuring paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The axons of sciatic nerves were stained with toluidine blue to study the histological abnormality. Function deficit of sciatic nerves was evaluated by sciatic functional index and the sciatic nerve conduction velocity. Neuronal excitability was assessed electrophysiologically and inflammatory mediators were detected using western blotting in dorsal root ganglia. The vincristine-induced reduction in PWT, PWL, and body weight gain was attenuated by morin. Morin restored the sciatic nerve deficits both histologically and functionally in vincristine-injected rats. The vincristine-induced neuronal hyperexcitability and increase in the expression of IL-6, NF-κB, and pNF-κB were abolished after morin administration. This study suggests that morin treatment suppressed vincristine-induced neuropathic pain by protecting the sciatic nerve and inhibiting inflammation through NF-κB pathway.

Topics: Animals; Flavonoids; Ganglia, Spinal; Inflammation; Inflammation Mediators; Male; Neuralgia; Neuroprotective Agents; NF-kappa B; Rats, Sprague-Dawley; Sciatic Nerve; Signal Transduction; Vincristine

Morin, a flavonoid isolated from various medicinal herbal plants, has an anti-inflammatory effect. This study aimed to elucidate the anticatabolic effects and cellular mechanism of morin against interleukin-1β (IL-1β) in rat primary chondrocytes. Morin at 10-100 μM did not affect the viability of rat primary chondrocytes. Treatment with morin for 21 days ameliorated the IL-1β-induced decrease in extracellular matrix. Furthermore, treatment with morin attenuated IL-1β-induced proteoglycan loss in the articular cartilage through suppression of catabolic factors, such as matrix metalloproteinases, inflammatory mediators, and pro-inflammatory cytokines. These data indicated that morin exerted anticatabolic effects that can prevent and reduce progressive degeneration of the articular cartilage, and thus may be a potential candidate treatment for osteoarthritis.

Topics: Animals; Cartilage, Articular; Cell Survival; Cells, Cultured; Chondrocytes; Cytokines; Extracellular Matrix; Flavonoids; Inflammation; Inflammation Mediators; Interleukin-1beta; Matrix Metalloproteinases; Proteoglycans; Rats, Sprague-Dawley

Morin, a bioflavonoid with diverse pharmacological effects against various diseases; in most cases morin protective effects were attributed to its detoxifying effect against reactive oxygen species (ROS). Diabetic neuropathy (DN) is a chronic, debilitating neuronal pain associated with intense generation of free radicals and proinflammatory cytokine accumulation in peripheral neurons. We investigated the pharmacological effect of morin against metabolic excess mediated mitochondrial ROS generation and corresponding effect on Nrf2, NF-κB pathways in Streptozotocin (STZ)-induced diabetic rats and in high glucose insulted Mouse neuroblastoma cell line, Neuro 2A (N2A). Animals were evaluated for nerve function parameters, motor and sensory nerve conduction velocities (MNCV and SNCV) and nerve blood flow (NBF) followed by TUNEL and immunoblot analysis. Mitochondrial function was evaluated by performing JC-1 and MitoSOX assays in high glucose (30 mM) incubated N2A cells. Diabetic animals showed significant impairment in MNCV, SNCV, and NBF as well as increased pain hypersensitivity. However, oral administration of morin at 50 and 100 mg/kg improved SNCV, MNCV, and NBF and reduced sensorimotor alterations (hyperalgesia and allodynia) in diabetic animals. Studies in N2A cells have revealed that morin ameliorated the high glucose-induced mitochondrial superoxide production, membrane depolarization, and total ROS generation. Morin effectively counteracted NF-κB-mediated neuroinflammation by reducing ROS mediated IKK activation and increased Nrf2-mediated antioxidant defenses in high glucose-induced N2A cells. The results of our study suggest that morin has exquisite role in offering neuroprotection in experimental DN and further clinical investigation may reward in finding better alternative for the management of DN. © 2017 BioFactors, 44(2):109-122, 2018.

Topics: Animals; Antioxidants; Blood Glucose; Cell Line; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Flavonoids; Glutathione; Hyperalgesia; Inflammation; Lipid Peroxidation; Male; Neurons; Neuroprotection; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Streptozocin

Topics: Acute Kidney Injury; AMP-Activated Protein Kinase Kinases; Animals; Anti-Inflammatory Agents; Autophagy; Cisplatin; Creatinine; Cytokines; Endoplasmic Reticulum Stress; Flavonoids; HEK293 Cells; Humans; Inflammation; Inflammation Mediators; Kidney; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Poly (ADP-Ribose) Polymerase-1; Protein Kinases

Adenosine deaminase (ADA) is one of the major enzymes involved in purin metabolism, it has a significant role in cell growth and differentiation. Over-activity of ADA has been noticed in some pathology, like malignancy and inflammation and makes it an attractive target for the development of drugs for such diseases. In the present study, ADA inhibitory activity of morin, a bioactive flavonoid, was assessed through computational and biophysical methods. The enzyme kinetics data showed that morin is a competitive inhibitor of ADA. Binding energy calculated from ITC analysis was -7.11 kcal/mol. Interaction of morin with ADA was also studied using fluorescence quenching method. Molecular docking studies revealed the structural details of the interaction. Molecular dynamics study in explicit solvent was also conducted to assess the structural stability of protein ligand complex.

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Binding Sites; Flavonoids; Humans; Inflammation; Kinetics; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Multiprotein Complexes

Doxorubicin (DOX) is an effective antineoplastic agent of the anthracycline group. However, as with most anticancer drugs, they cause some toxic effects, including major cardiotoxicity and cognitive impairment. In this study, protective effects of morin against DOX-induced cardiotoxicity and neurotoxicity in rats were investigated. Morin was orally administered to rats at a dose of 50 and 100 mg/kg body weight for 10 days. DOX was administered 40 mg/kg body weight by single dose intraperitoneal injection on the 8th day of the study. Both the levels of glutathione (GSH) and malondialdehyde (MDA) were assessed and enzyme activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were assessed to determine the protective effect of morin against oxidative stress. To determine the anti-inflammatory effect, the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), nuclear factor kappa B (NF-κB) were assessed in the heart and brain tissues. Lactate dehydrogenase (LDH) and creatine kinase isoenzyme-MB (CKMB) activities, which are cardiac function markers, and cardiac troponin-I (cTn-I) levels were also determined. Anti-apoptotic effect was determined by anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) and pro-apoptotic protein cysteine aspartate specific protease-3 (caspase-3) changes. The regulatory role of morin in signal transduction in the brain tissue was assigned with the determination of amount of acetylcholinesterase (AChE), and its healing effect on the central nervous system was determined with imuinohistochemical detection of glial fibrillar acidic protein (GFAP) level. Histopathological evaluation of heart and brain tissues was performed in all groups.

Topics: Acetylcholinesterase; Animals; Anti-Infective Agents; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers; Brain; Brain Diseases; Cardiotoxicity; Cytokines; Cytoprotection; Disease Models, Animal; Doxorubicin; Flavonoids; Glial Fibrillary Acidic Protein; GPI-Linked Proteins; Heart Diseases; Inflammation; Inflammation Mediators; Male; Myocardium; Oxidative Stress; Rats, Wistar; Signal Transduction

The purpose of the study was to develop a liposomal drug delivery system for morin, a dietary polyphenol, in order to target the synovial macrophages and investigate the remission of disease severity in the adjuvant-induced arthritic (AIA) rats. To do so, mannose decorated liposomal morin (ML-Morin) was prepared using the thin film hydration method and the physicochemical properties were characterized. The particle size and zeta potential of liposomal morin (L-Morin) was found to be 127.9nm±2.6 and -24.5mV±0.76, whereas ML-Morin showed an increased value of 132.5nm±5.2 and -54.8mV±0.67 respectively. Further, the drug entrapment efficiency (% EE) of ML-Morin was found 86.7±3.8%. To understand the efficacy of L-Morin, ML-Morin over free-Morin; cellular uptake, production and expression of pro-inflammatory mediators, osteoclastogenic factors, and transcription factors were evaluated in primarily isolated synovial and spleen macrophages. Interestingly, confocal microscopic images showed an increased uptake of ML-Morin in the synovial and spleen macrophages than L-morin. In addition, ML-Morin significantly suppressed the production and mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-17), angiogenic factors (VEGF), an inflammatory enzyme (iNOS), and transcription factor (NF-κB-p65). Furthermore, the protein expression of TNF-α, IL-1β, IL-6, IL-17, RANKL, STAT-3, and p-STAT-3 was found to decrease with increased osteoprotegerin (OPG) expression in the ML-Morin targeted macrophages. Thus, our findings endorsed that, ML-Morin preferential internalization into the macrophages of arthritic rats effectively inhibited the inflammatory immune response and osteoclastogenesis better than the dexamethasone palmitate encapsulated mannosylated liposomes (ML-DP), a reference drug as evidenced by clinical and histological analysis.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cytokines; Diet; Female; Flavonoids; Inflammation; Inflammation Mediators; Liposomes; Macrophages; Male; Mannose; Osteogenesis; Rats; Rats, Wistar; Transcription Factor RelA; Vascular Endothelial Growth Factor A

Morin is a flavanoid which exhibits potent antioxidant activity in various oxidative stress related diseases. The current study was attempted to scrutinize the preclinical bio-efficacy of morin on focal ischemia.. The animal model of focal cerebral ischemic injury was done by midbrain carotid artery occlusion (MCAO) method, followed by Morin (30mg/kg) administration for seven days.. The outcome of the study showed that treatment with morin displayed positive effects in reducing the focal cerebral ischemia. This effect was evident with the improvements in neurological deficits, reduction in MDA content and elevation of antioxidant levels (SOD, GSH and Gpx). Furthermore, protein expression of Bax and caspase-3 were effectively down-regulated, whilst the expression of Bcl-2 was significantly elevated. On the other hand, the mRNA expression of proinflammatory cytokines was significantly reduced in focal cerebral ischemic rats upon morin intervention.. Thus, the beneficial effects of morin on cerebral ischemia assault may result from the reduction of oxidative stress, inhibition of apoptosis and inflammation. The neuroprotective effects of morin supplement may serve as potent adjuvant in the amelioration of ischemic stroke.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Brain Ischemia; Cytokines; Disease Models, Animal; Flavonoids; Inflammation; Male; Oxidative Stress; Phytotherapy; Plant Extracts; Rats, Sprague-Dawley; RNA, Messenger; Stroke

As inflammatory and immune responses are involved in pathophysiology of debilitating neuropathic pain, reagents that can modulate these two responses may have therapeutic potential. Morin, derived from the moraceae family of plants, benefits inflammation-related diseases, but its antinociceptive effects on cancer pain remain elusive. In the present study, we investigated antinociceptive effects of morin on bone cancer pain using a rat model, where rats were subject to implantation of Walker 256 mammary gland carcinoma cells into the tibia. Morin (5-20 mg/kg) dose-dependently attenuated behavioral hypersensitivities, including mechanical allodynia and free movement pain, which was accompanied by downregulation of astrocyte marker glial fibrillary acidic protein in the spinal cord in cancer-bearing rats. Treatment with morin also induced reduction of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 and upregulation of an antiinflammatory cytokine IL-10. Furthermore, intrathecal injection of AM630 (an antagonist of cannabinoid receptor 2, CB

Topics: Animals; Astrocytes; Bone Neoplasms; Cancer Pain; Cytokines; Female; Flavonoids; Glial Fibrillary Acidic Protein; Hyperalgesia; Indoles; Inflammation; Injections, Spinal; Interleukin-10; Interleukin-1beta; Interleukin-6; Neoplasm Transplantation; Neuralgia; Pain Measurement; Rats; Rats, Sprague-Dawley; Spinal Cord; Tumor Necrosis Factor-alpha

Morin is a flavonoid isolated from certain fruits and Chinese herbs and is known to possess various medicinal properties. In this study, we investigated the anti-inflammatory effects of morin on lipopolysaccharide (LPS)-induced microglial activation, both in vitro and in vivo. We found that morin inhibited inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines in LPS-stimulated BV2 microglial cells. Furthermore, morin suppressed the microglial activation and cytokine expression in the brains of LPS-stimulated mice. Subsequent mechanistic studies revealed that morin inhibited the action of LPS-activated mitogen-activated protein kinases (MAPKs), protein kinase B (Akt) phosphorylation, nuclear factor-κB (NF-κB), and activating protein-1 (AP-1). Further, the phosphorylation and DNA binding activity of cAMP responsive element binding protein (CREB) was enhanced by morin. Moreover, morin suppressed the LPS-induced expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, while it increased heme oxygenase-1 (HO-1) expression and nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Therefore, our data suggest that morin exerts anti-inflammatory effects in LPS-stimulated microglia by downregulating MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways while upregulating protein kinase A (PKA)/CREB and Nrf2/HO-1 signaling pathways.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclic AMP-Dependent Protein Kinases; Cytokines; Flavonoids; Heme Oxygenase-1; Inflammation; Lipopolysaccharides; Membrane Proteins; Mice, Inbred ICR; Microglia; Mitogen-Activated Protein Kinases; Neuroprotective Agents; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Sepsis; Signal Transduction

Asthma is one of the most common inflammatory diseases characterized by airway hyperresponsiveness, inflammation, and remodeling. Morin, an active ingredient obtained from Moraceae plants, has been demonstrated to have promising anti-inflammatory activities in a range of disorders. However, its impacts on pulmonary diseases, particularly on asthma, have not been clarified. This study was designed to investigate whether morin alleviates airway inflammation in chronic asthma with an emphasis on oxidative stress modulation. In vivo, ovalbumin- (OVA-) sensitized mice were administered with morin or dexamethasone before challenge. Bronchoalveolar lavage fluid (BALF) and lung tissues were obtained to perform cell counts, histological analysis, and enzyme-linked immunosorbent assay. In vitro, human bronchial epithelial cells (BECs) were challenged by tumor necrosis factor alpha (TNF-α). The supernatant was collected for the detection of the proinflammatory proteins, and the cells were collected for reactive oxygen species (ROS)/mitogen-activated protein kinase (MAPK) evaluations. Severe inflammatory responses and remodeling were observed in the airways of the OVA-sensitized mice. Treatment with morin dramatically attenuated the extensive trafficking of inflammatory cells into the BALF and inhibited their infiltration around the respiratory tracts and vessels. Morin administration also significantly suppressed goblet cell hyperplasia and collagen deposition/fibrosis and dose-dependently inhibited the OVA-induced increases in IgE, TNF-α, interleukin- (IL-) 4, IL-13, matrix metalloproteinase-9, and malondialdehyde. In human BECs challenged by TNF-α, the levels of proteins such as eotaxin-1, monocyte chemoattractant protein-1, IL-8 and intercellular adhesion molecule-1, were consistently significantly decreased by morin. Western blotting and the 2',7'-dichlorofluorescein assay revealed that the increases in intracellular ROS and MAPK phosphorylation were abolished by morin, implying that ROS/MAPK signaling contributes to the relief of airway inflammation. Our findings indicate for the first time that morin alleviates airway inflammation in chronic asthma, which probably occurs via the oxidative stress-responsive MAPK pathway, highlighting a novel profile of morin as a potent agent for asthma management.

Topics: Animals; Bronchi; Bronchoalveolar Lavage Fluid; Collagen; Cytokines; Epithelial Cells; Fibrosis; Flavonoids; Goblet Cells; Humans; Hyperplasia; Immunization; Immunoglobulin E; Inflammation; Malondialdehyde; MAP Kinase Signaling System; Matrix Metalloproteinase 9; Mice, Inbred BALB C; Ovalbumin; Oxidative Stress; Pneumonia; Reactive Oxygen Species; Th2 Cells; Tumor Necrosis Factor-alpha

Morin, a flavonoid isolated from Chinese herbs of the Moraceae family, has been reported to possess antiinflammatory activity. However, the effects of morin on mastitis have not been investigated. The present study was conducted to elucidate the antiinflammatory properties of morin on lipopolysaccharide (LPS)-stimulated primary bovine mammary epithelial cells (bMEC). The viability of bMEC was analyzed by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium] assay. Subsequently, bMEC were stimulated with LPS in the presence or absence of morin. Gene expression of proinflammatory cytokines was determined by quantitative real-time PCR (qRT-PCR). Nuclear factor-κB (NF-κB), inhibitory kappa B (IκBα) protein, extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) were detected by Western blotting. The results showed that cell viability was not affected by morin. Moreover, morin inhibited the gene expression of tumor necrosis factor-α (TNF-α), IL-6, and IL-1β in LPS-stimulated bMEC in a dose-dependent manner. Western blot analysis showed that morin suppressed the phosphorylation of IκBα, NF-κB unit p65, ERK, p38, and JNK in LPS-stimulated bMEC. In conclusion, the protective effects of morin on LPS-induced inflammatory response in bMEC may be due to its ability to suppress NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways. These findings suggest that morin may be used as antiinflammatory drug for mastitis.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cattle; Cytokines; Down-Regulation; Epithelial Cells; Female; Flavonoids; Gene Expression Regulation; Inflammation; Interleukin-1beta; Interleukin-6; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; MAP Kinase Signaling System; Mastitis, Bovine; NF-kappa B; Signal Transduction; Tumor Necrosis Factor-alpha

Neuropathic pain is initiated or caused due to the primary lesion or dysfunction in the nervous system and is proposed to be linked to a cascade of events including excitotoxicity, oxidative stress, neuroinflammation and apoptosis. Oxidative/nitrosative stress aggravates the neuroinflammation and neurodegeneration through poly (ADP) ribose polymerase (PARP) overactivation. Hence, the present study investigated the antioxidant and anti-inflammatory effects of the phytoconstituent; morin in chronic constriction injury (CCI) induced neuropathy. Neuropathic pain was induced by chronic constriction of the left sciatic nerve in rats, and the effect of morin (15 and 30 mg/kg, p.o.) was evaluated by measuring behavioural and biochemical changes. Mechanical, chemical and thermal stimuli confirmed the CCI-induced neuropathic pain and treatment with morin significantly improved these behavioural deficits and improved the sciatic functional index by the 14th day after CCI induction. After 14 days of CCI induction, oxidative/nitrosative stress and inflammatory markers were elevated in rat lumbar spinal cord. Oxidative stress induced PARP overactivation resulted in depleted levels of ATP and elevated levels of poly (ADP) ribose (PAR). Treatment with morin reduced the levels of nitrites, restored glutathione levels and abrogated the oxidant induced DNA damage. It also mitigated the increased levels of TNF-α and IL-6. Protein expression studies confirmed the PARP inhibition and anti-inflammatory activity of morin. Findings of this study suggest that morin, by virtue of its antioxidant properties, limited PARP overactivation and neuroinflammation and protected against CCI induced functional, behavioural and biochemical deficits.

Topics: Animals; Antioxidants; Constriction; Flavonoids; Inflammation; Inflammation Mediators; Male; Neuralgia; Oxidative Stress; Poly(ADP-ribose) Polymerases; Random Allocation; Rats; Rats, Sprague-Dawley; Sciatic Neuropathy

Cisplatin is a widely used chemotherapeutic drug; however, it induces damage on kidney and liver at clinically effective higher doses. Morin hydrate possesses antioxidant, anti-inflammatory, and anticancer properties. Therefore, we aimed to investigate the effects of morin hydrate (50 and 100 mg/kg, orally) against the renohepatic toxicity induced by a high dose of cisplatin (20 mg/kg, intraperitoneally). Renal and hepatic function, oxidative/nitrosative stress, and inflammatory markers along with histopathology were evaluated. Morin hydrate ameliorated cisplatin-induced renohepatic toxicity significantly at 100 mg/kg as evidenced from the significant reversal of cisplatin-induced body weight loss, mortality, functional and structural alterations of kidney, and liver. The protective role offered by morin hydrate against cisplatin-induced renohepatic toxicity is by virtue of its free radical scavenging property, thereby abating the depletion of cellular antioxidant defense components and through modulation of inflammatory cytokines. We speculate morin hydrate as a protective candidate against renohepatic toxicity of cisplatin.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Cisplatin; Drug Administration Schedule; Female; Flavonoids; Inflammation; Interleukin-6; Kidney; Liver; Mice; Nitrosation; Oxidative Stress; Treatment Outcome; Tumor Necrosis Factor-alpha; Weight Loss

Using an experimental model of allergic asthma, we evaluated the anti-asthmatic potential of polyphenol flavonol derivate morin after either acute or long-term treatment of male OVA-sensitised guinea pigs.. The following methods were used in experiments: the in-vitro tracheal smooth muscle contraction induced by histamine; the changes in specific airway resistance (sRaw) to histamine and the sensitivity of a chemically induced cough reflex both via an in-vivo method; the serum and BALF concentrations' analysis of the inflammatory cytokines interleukin IL-4, IL-5, IL-13; and lung tissue infiltration by eosinophils and mastocytes.. Our data show that acute morin (30 mg/kg) and chronic 21-day morin (30 mg/kg/day) administration had a comparable antitussive efficiency with opioid antitussive codeine. Acute morin bronchodilatory activity defined by in-vivo sRaw decline did not reach SABA salbutamol effect. However, bronchodilatory efficiency of morin after long-term administration was by 34% higher as effect of LABA salmeterol. The 21-day morin treatment of OVA-sensitised guinea pigs reduced the serum, BALF levels of IL-4 and IL-13, lung tissue eosinophil and mastocyte infiltration comparable with corticosteroid budesonide.. In summary, morin represents very rational target for additional studies as potential substance for control as well as prevention of asthma inflammation and symptoms.

Topics: Airway Resistance; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Antitussive Agents; Asthma; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Cough; Cytokines; Eosinophils; Flavonoids; Guinea Pigs; Histamine; Hypersensitivity; Inflammation; Lung; Male; Ovalbumin; Phytotherapy; Plant Extracts; Trachea

Vaccine reactions are described in cytology textbooks as having eosinophilic to magenta colored globules within and admixed with inflammatory cells. Recently, we have seen increased numbers of inflammatory lesions containing blue to blue-gray globular material, with historical information suggesting an association with rabies vaccination.. The purpose of the study was to confirm the blue-gray and the eosinophilic material observed microscopically in some inflammatory lesions as being vaccine-derived.. Three different vaccines were cytocentrifuged and Wright stained. Vaccine aliquots were also added to the culture media of canine-derived macrophages for 24 hours and the cells subsequently harvested, cytocentrifuged, and Wright stained. The globular material present in both preparations was compared to that observed in vaccine-induced inflammatory lesions. Morin staining was used to identify metal within vaccine material in both in vitro- and in vivo-derived cytology samples.. Vaccine-derived material has a characteristic color and appearance. Appearance of the material was consistent in cytologic samples, in cells incubated with the vaccine, and in cytocentrifuged preparations of the vaccine vial contents. The blue-gray globules stained positively for Morin stain, while the eosinophilic material did not stain.. Vaccine-induced inflammatory lesions may contain blue to blue-gray or magenta stained globular material. Blue-gray material was associated with administration of rabies vaccine Imrab 3 TF and the observed material may be metal-containing adjuvant. Magenta material was associated with other vaccines and negative for Morin stain, suggesting a metal-free adjuvant.

Topics: Adjuvants, Immunologic; Animals; Cytodiagnosis; Dogs; Flavonoids; Indicators and Reagents; Inflammation; Macrophages; Rosaniline Dyes; Staining and Labeling; Vaccines

Acetaminophen (APAP) is frequently taken to relieve pain. Staggered APAP overdoses have been reported to cause acetaminophen-induced liver injury (AILI). Identification of efficacious therapeutic modalities to address complications imposed by accidental/intentional long-term APAP ingestion is needed. Morin, a plant-derived phytochemical, possesses a multitude of pharmacological properties including hepatoprotective action; however, the underlying mechanisms have been inadequately explored. Our present report demonstrates significant attenuation of APAP-mediated liver injury by morin supplementation in vivo as indicated by reduction in histological and serum markers of hepatotoxicity. Morin not only limited necroinflammation as revealed by reduced HMGB1 release, NALP3 and caspase-1 maturation, but also suppressed oxidative stress and mitochondrial dysfunction. This suggests that morin may have exerted its cytoprotective role by way of early intervention in the pathway leading to perpetuation of AILI. Morin reinforced cellular defenses by suppressing Nrf2 ubiquitination and promoting nuclear Nrf2 retention as well as ARE-Nrf2 binding affinity. The effects were observed to be a result of molecular intervention in the activity of PHLPP2, a phosphatase previously reported by us to subdue cellular Nrf2 responses via Fyn kinase activation. Morin was observed to inhibit APAP-induced increase in PHLPP2 activity ex vivo as well as its association with cellular target Akt1. As a result, morin prevented oxidative stress induced deactivation of Akt (Ser473) leading to suppression in GSK3β and Fyn kinase activation. The study supports the inhibitory action of morin against PHLPP2-regulated Nrf2-suppression and hence indentifies Nrf2-potentiating property of morin that may be exploited in developing novel therapeutic strategy to address AILI.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Flavonoids; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Inflammation; Liver; Male; Mitochondria; NF-E2-Related Factor 2; Oxidative Stress; Phosphoprotein Phosphatases; Plant Extracts; Proto-Oncogene Proteins c-akt; Rats, Wistar; Signal Transduction

Our previous studies had reported that morin, a bioflavanoid exhibited potent anti-inflammatory effect against adjuvant-induced arthritic rats. In this current study, we investigated the anti-inflammatory mechanism of morin against monosodium urate crystal (MSU)-induced inflammation in RAW 264.7 macrophage cells, an in vitro model for acute gouty arthritis. For comparison purpose, colchicine was used as a reference drug. We have observed that morin (100-300 μM) treatment significantly suppressed the levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, MCP-1 and VEGF), inflammatory mediators (NO and PEG2), and lysosomal enzymes (acid phosphatase, β-galactosidase, N-acetyl glucosamindase and cathepsin D) in MSU-crystals stimulated macrophage cells. The mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and MCP-1), inflammatory enzymes (iNOS and COX-2), and NF-κBp65 was found downregulated in MSU crystal stimulated macrophage cells by morin treatment, however, the mRNA expression of hypoxanthine phospho ribosyl transferse (HPRT) was found to be increased. The flow cytometry analysis revealed that morin treatment decreased intracellular reactive oxygen species levels in MSU crystal stimulated macrophage cells. The western blot analysis clearly showed that morin mainly exerts its anti-inflammatory effects by inhibiting the MSU crystal-induced COX-2 and TNF-α protein expression through the inactivation of NF-κB signaling pathway in RAW 264.7 macrophage cells similar to that of BAY 11-7082 (IκB kinase inhibitor). Our results collectively suggest that morin can be a potential therapeutic agent for inflammatory disorders like acute gouty arthritis.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Gouty; Cell Line; Chemokine CCL2; Colchicine; Cyclooxygenase 2; Flavonoids; Gout Suppressants; Hypoxanthine Phosphoribosyltransferase; Inflammation; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Macrophages; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; Polyethylene Glycols; Reactive Oxygen Species; Signal Transduction; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Uric Acid; Vascular Endothelial Growth Factor A

Diabetes-induced damages in brain are known as diabetic encephalopathy, which is well characterized by cellular, molecular and functional changes in the brain of diabetic subjects and rodents. However, little is known about the mechanism of damages and the therapeutic strategies in ameliorating those damages in the diabetic brain. In this study, we utilized a flavonoid, morin which is emerging as a potent drug against a wide range of free radical-mediated as well as neurodegenerative diseases. Morin (15 and 30 mg/kg body weight/day) was orally administered to two different groups of rats after 1 week of diabetes induction, and continued for five consecutive weeks. Two other untreated groups of diabetic and non-diabetic rats were used to compare with drug-treated groups. After drug treatments, cerebral cortex of the brain harvested and analyzed for different factors. Morin supplementation especially at high dose increased the levels of insulin, reduced glutathione, superoxide dismutase and catalase activities, and decreased fasting glucose and thiobarbituric acid reactive substances in the diabetic brain compared to untreated diabetic rats (P < 0.05). Morin also significantly decreased the level of inflammatory markers (TNFα, IL1β, IL-6) in the diabetic brain compared to untreated diabetic rats. Furthermore, the drug influenced an increase in the level of neurotrophic factors (BDNF, NGF and IGF-1) in the diabetic brain compared to untreated diabetic rats (P < 0.05). Thus, our results indicate a beneficial effect of morin by decreasing oxidative stress, inflammation and increasing the neurotrophic support in the diabetic brain, which may ameliorate diabetic encephalopathy.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Brain; Catalase; Cytokines; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Flavonoids; Glutathione; Inflammation; Male; Nerve Growth Factors; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

SphK1/S1P signaling pathway is involved in the development of hepatic inflammation and injury. But its role in high fructose-induced NAFLD has not yet been reported. The aim of this study was to elucidate the crucial role of SphK1/S1P signaling pathway in high fructose-induced hepatic inflammation and lipid accumulation in rats. Moreover, the hepatoprotective effects of morin, a flavonoid with anti-inflammatory and anti-hyperlipedimic activities, on these hepatic changes in rats were investigated. High fructose-fed rats were orally treated with morin (30 and 60mg/kg) and pioglitazone (4mg/kg) for 8 weeks, respectively. Fructose feeding induced hyperlipidemia, and activated SphK1/S1P signaling pathway characterized by the elevation of SphK1 activity, S1P production as well as SphK1, S1PR1 and S1PR3 protein levels, which in turn caused NF-κB signaling activation to produce IL-1β, IL-6 and TNF-α and inflammation in the liver of rats. Subsequently, hepatic insulin and leptin signaling impairment and lipid metabolic disorder were observed in this animal model, resulting in liver lipid accumulation. Morin restored high fructose-induced the activation of hepatic SphK1/S1P signaling pathway in rats. Subsequently, the reduced NF-κB signaling activation by morin decreased inflammatory cytokine production, recovered insulin and leptin signaling impairment to reduce lipid accumulation and injury in the rat liver. These effects of morin were confirmed in Buffalo rat liver (BRL3A) cell model stimulated with 5mM fructose. Thus, the inhibition of hepatic SphK1/S1P signaling pathway may be a novel mechanism by which morin exerts hepatoprotection in high fructose-fed rats, possibly involving liver inflammation inhibition and lipid accumulation recovery.

Topics: Animals; Dietary Carbohydrates; Flavonoids; Fructose; Inflammation; Lipid Metabolism; Liver; Lysophospholipids; Male; Phosphotransferases (Alcohol Group Acceptor); Rats; Rats, Sprague-Dawley; Signal Transduction; Sphingosine

Morin displayed significant inhibition of chick chorioallantoic membrane (CAM) angiogenesis and was able to increase the endostatin level in human umbilical vein endothelial cells (HUVECs). Morin was shown to contain an in vivo anti-inflammatory activity using a carrageenan-induced air pouch model in mice. Antinociceptive activity of morin was also assessed using an acetic acid-induced writhing test in mice. Collectively, morin possesses antiangiogenic, in vivo anti-inflammatory, and antinociceptive activities.

Topics: Acetic Acid; Analgesics; Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Behavior, Animal; Carrageenan; Cell Line; Chick Embryo; Chorioallantoic Membrane; Disease Models, Animal; Endostatins; Endothelial Cells; Flavonoids; Humans; Inflammation; Maclura; Male; Mice; Mice, Inbred ICR; Pain; Phytotherapy; Plant Extracts; Psidium; Umbilical Veins

The purpose of this study was to investigate possible beneficial effects of morin on CCl(4)-induced acute hepatotoxicity in rats. Rats received a single dose of CCl(4) (150 microL/100 g 1:1 in corn oil). Morin treatment (20 mg/kg) was given at 48, 24, and 2 h before CCl(4) administration. CCl(4) challenge elevated serum alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) levels, but these effects were prevented by the pretreatment of rats with morin. To identify the mechanism of protective activity of morin in CCl(4)-induced hepatotoxicity in rats, we investigated expressions of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and inducible nitric oxide (iNOS). The expressions of TNF-alpha, IL-1beta, IL-6, and iNOS were increased by CCl(4) treatment and increased expressions of those were decreased by morin. These findings suggest that morin prevents acute liver damage by inhibiting the production of TNF-alpha, IL-1beta, IL-6, and iNOS.

Topics: Acute Disease; Animals; Antioxidants; Body Weight; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Enzyme Inhibitors; Flavonoids; Inflammation; Interleukin-1beta; Interleukin-6; Liver; Male; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA; Tumor Necrosis Factor-alpha

Morin is a flavone that exhibits antiproliferative, antitumor, and anti-inflammatory effects through a mechanism that is not well understood. Because of the role of transcription factor nuclear factor-kappaB (NF-kappaB) in the control of cell survival, proliferation, tumorigenesis, and inflammation, we postulated that morin mediates its effects by modulating NF-kappaB activation.. We investigated the effect of morin on NF-kappaB pathway activated by inflammatory agents, carcinogens, and tumor promoters. The effect of this flavone on expression of NF-kappaB-regulated gene products involved in cell survival, proliferation, and invasion was also examined.. We showed by DNA-binding assay that NF-kappaB activation induced by tumor necrosis factor (TNF), phorbol 12-myristate 13-acetate, lipopolysaccharide, ceramide, interleukin-1, and H(2)O(2) was suppressed by morin; the suppression was not cell type specific. The suppression of NF-kappaB by morin was mediated through inhibition of IkappaBalpha (inhibitory subunit of NF-kappaB) kinase, leading to suppression of phosphorylation and degradation of IkappaBalpha and consequent p65 nuclear translocation. Morin also inhibited the NF-kappaB-dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR1-associated death domain, TNFR-associated factor 2, NF-kappaB-inducing kinase, IkappaB kinase, and the p65 subunit of NF-kappaB. NF-kappaB-regulated gene products involved in cell survival [inhibitor of apoptosis (IAP) 1, IAP2, X chromosome-linked IAP, Bcl-xL, and survivin], proliferation (cyclin D1 and cyclooxygenase-2), and invasion (matrix metalloproteinase-9) were down-regulated by morin. These effects correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents.. Overall, our results indicate that morin suppresses the activation of NF-kappaB and NF-kappaB-regulated gene expression, leading to enhancement of apoptosis. This may provide the molecular basis for the ability of morin to act as an anticancer and anti-inflammatory agent.

Topics: Antioxidants; Apoptosis; Blotting, Western; Carcinogens; Cell Proliferation; Cells, Cultured; Electrophoretic Mobility Shift Assay; Enzyme Activation; Flavonoids; Gene Expression; Humans; Inflammation; Neoplasm Invasiveness; NF-kappa B; Up-Regulation

The anti-inflammatory activities of flavonols (quercetin, rutin and morin) and flavanones (hesperetin and hesperidin) were investigated in animal models of acute and chronic inflammation. Rutin was only effective in the chronic process, principally in adjuvant arthritis. On neurogenic inflammation induced by xylene, only the flavanones were effective; besides, these compounds were the most effective on subchronic process. The most important compound in reducing paw oedema induced by carrageenan was quercetin.

Topics: Animals; Arthritis, Experimental; Carrageenan; Disease Models, Animal; Ear; Edema; Flavonoids; Hesperidin; Hindlimb; Inflammation; Mice; Molecular Structure; Quercetin; Random Allocation; Rats; Rats, Wistar; Rutin; Xylenes