pregna-4-17-diene-3-16-dione and Disease-Models--Animal

Guggulsterone is a plant sterol derived from gum resin of Commiphora wightii. The gum resin from guggul plants has been used for thousand years in Ayurveda to treat various disorders, including internal tumors, obesity, liver disorders, malignant sores and ulcers, urinary complaints, intestinal worms, leucoderma, sinuses, edema, and sudden paralytic seizures. Guggulsterone has been identified a bioactive components of this gum resin. This plant steroid has been reported to work as an antagonist of certain nuclear receptors, especially farnesoid X receptor, which regulates bile acids and cholesterol metabolism. Guggulsterone also mediates gene expression through the regulation of transcription factors, including nuclear factor-kappa B and signal transducer and activator of transcription 3, which plays important roles in the development of inflammation and tumorigenesis. Guggulsterone has been shown to downregulate the expression of proteins involved in anti-apoptotic, cell survival, cell proliferation, angiogenic, metastatic, and chemoresistant activities in tumor cells. This review aimed to clarify the cell signal pathways targeted by guggulsterone and the bioactivities of guggulsterone in animal models and humans.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Chronic Disease; Commiphora; Disease Models, Animal; Humans; Hypolipidemic Agents; Molecular Structure; Phytotherapy; Plants, Medicinal; Pregnenediones; Signal Transduction

Autism spectrum disorder is a neurodevelopmental disorder marked by repetitive behaviour, challenges in verbal and non-verbal communication, poor socio-emotional health, and cognitive impairment. An increased level of signal transducer and activator of transcription 3 (STAT3) and a decreased level of peroxisome proliferator-activated receptor (PPAR) gamma have been linked to autism pathogenesis. Guggulsterone (GST) has a neuroprotective effect on autistic conditions by modulating these signalling pathways. Consequently, the primary objective of this study was to examine potential neuroprotective properties of GST by modulating JAK/STAT and PPAR-gamma levels in intracerebroventricular propionic acid (ICV PPA) induced experimental model of autism in adult rats. In this study, the first 11 days of ICV-PPA injections in rats resulted in autism-like behavioural, neurochemical, morphological, and histopathological changes. The above modifications were also observed in various biological samples, including brain homogenate, CSF, and blood plasma. GST was also observed to improve autism-like behavioural impairments in autistic rats treated with PPA, including locomotion, neuromuscular coordination, depression-like behaviour, spatial memory, cognition, and body weight. Prolonged GST treatment also restored neurochemical deficits in a dose-dependent manner. Chronic PPA administration increased STAT3 and decreased PPAR gamma in autistic rat brain, CSF, and blood plasma samples, which were reversed by GST. GST also restored the gross and histopathological alterations in PPA-treated rat brains. Our results indicate the neuroprotective effects of GST in preventing autism-related behavioural and neurochemical alterations.

Topics: Animals; Autism Spectrum Disorder; Disease Models, Animal; Female; Janus Kinases; Male; Neuroprotective Agents; PPAR gamma; Pregnenediones; Propionates; Rats, Wistar; Signal Transduction; STAT Transcription Factors

Growing evidence indicates that inflammatory damage is implicated in the pathogenesis of Alzheimer's disease (AD). Z-Guggulsterone (Z-GS) is a natural steroid, which is extracted from Commiphora mukul and has anti-inflammatory effects in vivo and in vitro. In the present study, we investigated the disease-modifying effects of chronic Z-GS administration on the cognitive and neuropathological impairments in the transgenic mouse models of AD. We found that chronic Z-GS administration prevented learning and memory deficits in the APPswe/PS1dE9 mice. In addition, Z-GS treatment significantly decreased cerebral amyloid-β (Aβ) levels and plaque burden via inhibiting amyloid precursor protein (APP) processing by reducing beta-site APP cleaving enzyme 1 (BACE1) expression in the APPswe/PS1dE9 mice. We also found that Z-GS treatment markedly alleviated neuroinflammation and reduced synaptic defects in the APPswe/PS1dE9 mice. Furthermore, the activated TLR4/NF-κB signaling pathways in APPswe/PS1dE9 mice were remarkably inhibited by Z-GS treatment, which was achieved via suppressing the phosphorylation of JNK. Collectively, our data demonstrate that chronic Z-GS treatment restores cognitive defects and reverses multiple neuropathological impairments in the APPswe/PS1dE9 mice. This study provides novel insights into the neuroprotective effects and neurobiological mechanisms of Z-GS on AD, indicating that Z-GS is a promising disease-modifying agent for the treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cognition; Disease Models, Animal; Mice; Mice, Transgenic; Neuroinflammatory Diseases; Pregnenediones; Presenilin-1; Signal Transduction; Toll-Like Receptor 4

Multiple Sclerosis (MS) is a progressive neurodegenerative disease with clinical signs of neuroinflammation and the central nervous system's demyelination. Numerous studies have identified the role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) overexpression and the low level of peroxisome proliferator-activated receptor-gamma (PPAR-γ) in MS pathogenesis. Guggulsterone (GST), an active component derived from 'Commiphora Mukul,' has been used to treat various diseases. Traditional uses indicate that GST is a suitable agent for anti-inflammatory action. Therefore, we assessed the therapeutic potential of GST (30 and 60 mg/kg) in ethidium bromide (EB) induced demyelination in experimental rats and investigated the molecular mechanism by modulating the JAK/STAT and PPAR-γ receptor signaling. Wistar rats were randomly divided into six groups (n = 6). EB (0.1%/10 μl) was injected selectively in the intracerebropeduncle (ICP) region for seven days to cause MS-like manifestations. The present study reveals that long-term administration of GST for 28 days has a neuroprotective effect by improving behavioral deficits (spatial cognition memory, grip, and motor coordination) associated with lower STAT-3 levels. While elevating PPAR-γ and myelin basic protein levels in rat brains are consistent with the functioning of both signaling pathways. Also, GST modulates the neurotransmitter level by increasing Ach, dopamine, serotonin and by reducing glutamate. Moreover, GST ameliorates inflammatory cytokines (TNF, IL-1β), and oxidative stress markers (AchE, SOD, catalase, MDA, GSH, nitrite). In addition, GST prevented apoptosis, as demonstrated by the reduction of caspase-3 and Bax. Simultaneously, Bcl-2 elevation and the restoration of gross morphology alterations are also recovered by long-term GST treatment. Therefore, it can be concluded that GST may be a potential alternative drug candidate for MS-related motor neuron dysfunctions.

Topics: Acetylcholinesterase; Animals; Brain; Disease Models, Animal; Dopamine; Ethidium; Female; Glutamic Acid; Male; Maze Learning; Multiple Sclerosis; Neuroprotective Agents; Oxidative Stress; PPAR gamma; Pregnenediones; Rats; Rats, Wistar; STAT3 Transcription Factor

Ischemic stroke is a serious and life-threatening cerebrovascular thrombotic disease; however, the therapeutic strategy is limited for the complicated mechanism and narrow therapeutic window. Our previous study suggested that Z-Guggulsterone (Z-GS), an active component derived from myrrh, is a good candidate for cerebral injury. The object of this study is to investigate the exact mechanisms of Z-GS in cerebral ischemic stroke. Rats were used to conduct middle cerebral artery occlusion (MCAO) model and were treated with different dosage of Z-GS. Morphological results showed that Z-GS significantly alleviated neurological deficits, infarct volume and histopathological damage in MCAO rats. A total of 8276 differentially expressed genes were identified based on microarray analysis. Oxidation-reduction process and inflammatory response were enriched as the significant gene ontology items. TXNIP and NLRP3 were screened as the potential target genes by Series Test of Cluster (STC) analysis. The results were validated by immunohistochemistry and immunofluorescence staining. Besides, Z-GS successfully inhibited oxidative stress and inflammatory response in oxygen-glucose deprivation (OGD) treated neurons. Knockdown of TXNIP significantly decreased the expression of NLRP3 in OGD-induced neurons. In addition, Z-GS treatment scarcely changed the expressions of NLRP3 in siRNA-TXNIP pretreated cells compared with the siRNA-TXNIP alone treatment group, suggesting that the neuroprotective effect of Z-GS was dependent on TXNIP-NLRP3 axis. Taken together, this study revealed that Z-GS exerted neuroprotective property through alleviated oxidative stress and inflammation via inhibiting the TXNIP/NLRP3 axis. Z-GS could be considered as a promising candidate for the treatment of ischemic stroke.

Topics: Animals; Brain; Brain Injuries; Cell Cycle Proteins; Disease Models, Animal; Gene Expression Regulation; Gene Knockdown Techniques; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intraperitoneal; Ischemic Stroke; Male; Neurons; Neuroprotective Agents; NLR Family, Pyrin Domain-Containing 3 Protein; NLR Proteins; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Pregnenediones; Primary Cell Culture; Rats, Sprague-Dawley

Z-guggulsterone, an active compound extracted from the gum resin of the tree Commiphora mukul, has been shown to improve animal memory deficits via activating the brain-derived neurotrophic factor signaling pathway. Here, we investigated the antidepressant-like effect of Z-guggulsterone in a chronic unpredictable stress mouse model of depression.. The effects of Z-guggulsterone were assessed in mice with the tail suspension test and forced swimming test. Z-guggulsterone was also investigated in the chronic unpredictable stress model of depression with fluoxetine as the positive control. Changes in hippocampal neurogenesis as well as the brain-derived neurotrophic factor signaling pathway after chronic unpredictable stress/Z-guggulsterone treatment were investigated. The tryptophan hydroxylase inhibitor and the tyrosine kinase B inhibitor were also used to explore the antidepressant-like mechanisms of Z-guggulsterone.. Z-guggulsterone (10, 30 mg/kg) administration protected the mice against the chronic unpredictable stress-induced increases in the immobile time in the tail suspension test and forced swimming test and also reversed the reduction in sucrose intake in sucrose preference experiment. Z-guggulsterone (10, 30 mg/kg) administration prevented the reductions in brain-derived neurotrophic factor protein expression levels as well as the phosphorylation levels of cAMP response element binding protein, extracellular signal-regulated kinase 1/2, and protein kinase B in the hippocampus and cortex induced by chronic unpredictable stress. Z-guggulsterone (10, 30 mg/kg) treatment also improved hippocampal neurogenesis in chronic unpredictable stress-treated mice. Blockade of the brain-derived neurotrophic factor signal, but not the monoaminergic system, attenuated the antidepressant-like effects of Z-guggulsterone.. Z-guggulsterone exhibits antidepressant activity via activation of the brain-derived neurotrophic factor signaling pathway and upregulation of hippocampal neurogenesis.

Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Cyclic AMP Response Element-Binding Protein; Depressive Disorder; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Fluoxetine; Hippocampus; Male; Mice, Inbred C57BL; Neurogenesis; Pregnenediones; Proto-Oncogene Proteins c-akt; Signal Transduction

Guggulsterone (GS), a plant steroid and a compound found at high levels in Commiphora myrrha, exhibits anti-inflammatory, anti-cancer, and cholesterol-lowering effects. However, the potential of GS to ameliorate acute pancreatitis (AP) is unknown. The aim of this study was to evaluate the effects of GS on cerulein-induced AP. AP was induced by intraperitoneally injecting supramaximal concentrations of the stable cholecystokinin analog cerulein (50 μg/kg) hourly for 6 h. In the GS-treated group, GS was administered intraperitoneally (10, 25, or 50mg/kg) 1 h before the first cerulein injection. Mice were sacrificed 6 h after the final cerulein injection. Blood samples were collected to measure serum lipase levels and evaluate cytokine production. The pancreas and lung were rapidly removed for morphologic and histological examinations, flow cytometry analysis, myeloperoxidase (MPO) assay, and real-time reverse transcription-polymerase chain reaction analysis. Pre-treatment with GS attenuated cerulein-induced histological damage, reduced pancreas weight/body weight ratio, decreased serum lipase levels, inhibited infiltrations of macrophages and neutrophils, and suppressed cytokine production. Additionally, GS treatment suppressed the activation of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) in the pancreas in cerulein-induced pancreatitis. In conclusion, our results suggest that GS attenuates AP via deactivation of ERK and JNK.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Blotting, Western; Ceruletide; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Extracellular Signal-Regulated MAP Kinases; Female; Injections, Intraperitoneal; JNK Mitogen-Activated Protein Kinases; Lipase; Mice, Inbred C57BL; Pancreas; Pancreatitis; Pregnenediones

To investigate the effect of farnesoid-X-receptor (FXR) antagonist Z-guggulsterone in an in vivo high-fat fed apolipoprotein E knockout (ApoE(-/-)) mice model of myocardial ischemia/reperfusion (I/R).. Male ApoE(-/-) mice were randomly divided into three groups: standard ApoE(-/-) group (fed with standard mouse diet for 12 weeks before myocardial I/R procedure, n = 18), high-fat ApoE(-/-) group (fed with high-fat mouse diet for 12 weeks before myocardial I/R procedure, n = 22), and high-fat ApoE(-/-) + FXR antagonist group(fed with high-fat mouse diet for 12 weeks and received FXR antagonist Z-Guggulsterone 30 minutes before myocardial I/R procedure, n = 17). The expression of FXR was detected by real-time quantitative-PCR. Myocardial infarct size was determined by Evans blue/TTC double staining methods. Myocardial apoptosis was determined by in situ TUNEL technique. Markers of the mitochondrial-mediated apoptotic pathway (cytochrome c release, caspase-9 activity, and BAX and BCL-2 levels), endoplasmic reticulum stress apoptotic pathway (caspase-12 activity and CHOP level), and death receptor apoptotic pathway (caspase-8 activity, and Fas and FasL levels) were also measured.. FXR expression (3.7-fold higher, P < 0.01), myocardial infarct size [(62.1 ± 7.0)% vs. (33.8 ± 5.8)%, P < 0.01] and myocardial apoptosis index[ (36.8 ± 5.7)% vs. (17.2 ± 3.8)%, P < 0.01]were all significantly higher in high-fat ApoE(-/-) group than those in standard ApoE(-/-) group. Compared with high-fat ApoE(-/-) group, myocardial infarct size [(24.4 ± 4.7)% vs. (62.1 ± 7.0)%, P < 0.01] and myocardial apoptosis index [(13.8 ± 2.7)% vs. (36.8 ± 5.7)%, P < 0.01] were significantly reduced in high-fat ApoE(-/-) + FXR antagonist group. Moreover, levels of mitochondrial-mediated apoptotic pathway markers (cytochrome c release, caspase-9 activity, and BAX/BCL-2 levels) and endoplasmic reticulum stress apoptotic pathway markers (caspase-12 activity and CHOP level) were significantly lower in high-fat ApoE(-/-) + FXR antagonist group than those in high-fat ApoE(-/-) group (all P < 0.01). Levels of death receptor apoptotic pathway markers (caspase-8 activity, and Fas and FasL levels) were similar between high-fat ApoE(-/-) group and high-fat ApoE(-/-) + FXR antagonist group.. FXR antagonist alleviates myocardial reperfusion injury in cholesterol-fed ApoE(-/-) mice via inhibition of the mitochondrial-mediated and endoplasmic-reticulum stress pathway.

Topics: Animals; Apolipoproteins E; Apoptosis; bcl-2-Associated X Protein; Caspase 9; Cholesterol, Dietary; Cytochromes c; Disease Models, Animal; Endoplasmic Reticulum Stress; Male; Mice; Mice, Knockout; Myocardial Reperfusion Injury; Pregnenediones; Proto-Oncogene Proteins c-bcl-2; Receptors, Cytoplasmic and Nuclear

To investigate the anti-inflammatory effects of guggulsterone, an antioxidant and antitumor agent, in endotoxin-induced uveitis (EIU) in rats and to elucidate the underlying molecular mechanism or mechanisms related to ocular inflammation.. EIU was induced by subcutaneous injection of lipopolysaccharide (LPS; 150 μg) into Lewis rats treated with guggulsterone (30 mg/kg body weight, intraperitoneally) or its carrier. After 24 hours the rats were killed, eyes were enucleated, and aqueous humor (AqH) was collected. Numbers of infiltrating cells and levels of matrix metalloproteinase-2 (MMP-2), nitric oxide (NO), and prostaglandin E(2) (PGE(2)) were determined in AqH by specific ELISAs. An antibody array was used to measure the expression of various inflammatory cytokines in AqH. The expression of MMP-2, iNOS, Cox-2, phospho-IκB, and phospho-NF-κB was determined immunohistochemically. Human primary nonpigment ciliary epithelial cells (HNPECs) were used to determine the in vitro efficacy of guggulsterone on the LPS-induced inflammatory response.. Compared with control, the EIU rat eye AqH had a significantly higher number of infiltrating cells, total protein, and inflammatory markers, such as MMP-2, NO, and PGE(2), and the treatment of guggulsterone prevented EIU-induced increases. Guggulsterone also prevented the expression of MMP-2, iNOS, and Cox-2 proteins and of IκB and NF-κB in various eye tissues. Moreover, in cultured HNPECs, guggulsterone inhibited LPS-induced expression of inflammatory proteins.. These results for the first time demonstrate that the plant sterol guggulsterone suppresses ocular inflammation in EIU, suggesting that the supplementation of guggulsterone could be a novel approach for the treatment of ocular inflammation.

Topics: Animals; Antineoplastic Agents; Antioxidants; Aqueous Humor; Blotting, Western; Cells, Cultured; Ciliary Body; Commiphora; Cytokines; Dinoprostone; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Humans; I-kappa B Proteins; Injections, Intraperitoneal; Lipopolysaccharides; Male; Matrix Metalloproteinase 2; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Pregnenediones; Rats; Rats, Inbred Lew; Uveitis

Inflammatory bowel diseases (IBD) are chronic inflammatory and relapsing diseases of the gut that may manifest as either Crohn's disease (CD) or ulcerative colitis (UC). CD and UC are immunologically different diseases characterized by exacerbated Th1 and Th2 response. T-cell resistance against apoptosis contributes to inappropriate T-cell accumulation and the perpetuation of chronic mucosal inflammation. In the present study we have investigated the effect exerted by guggulsterone (GS) a plant derived steroid isolated from the gum resin of the Commiphora mukul tree, in two models of intestinal inflammation induced in mice by trinitro-benzene sulfonic acid (TNBS) and oxazolone. We provided evidence that E-GS protects mice against development of sign and symptoms of colon inflammation. E-GS effectively attenuated the severity of wasting disease and the fecal score and colon inflammation as assessed by measuring the macroscopic- and microscopic-damage scores. Administration Z-GS failed to ameliorate colon inflammation in TNBS-induced colitis and had a partial effect in oxazolone-induced colitis. In vitro, mechanistic studies carried out using CD4+ cells isolated from the intestinal lamina propria demonstrate that GS effectively regulates the function of effector T cells by modulating cell signaling activation pathway caused by CD3/CD28. The net biological effects resulting from exposure to GS includes attenuation of generation of interleukin-2 and -4 and interferon-gamma as well as T cell proliferation. In conclusion, GS is an anti-inflammatory compound with the capacity to prevent and ameliorate T-cell-induced colitis. These data ground the use of GS, a natural cholesterol-lowering agent, in the treatment of chronic inflammatory diseases.

Topics: Animals; Base Sequence; Colitis; Disease Models, Animal; DNA Primers; Immunity, Innate; Inflammatory Bowel Diseases; Mice; Mice, Inbred BALB C; Mice, SCID; Plants; Polymerase Chain Reaction; Pregnenediones