ABSTRACT
Testicular dysfunction is distinguished by a deficiency in testosterone levels, which can be attributed to the occurrence of oxidative stress injury in Leydig cells. The empirical prescription known as Bushen Zhuanggu Tang, developed by a highly experienced traditional Chinese medicine practitioner with six decades of clinical expertize, aligns with the traditional Chinese medicine principle of "kidney governing bone". Researchers have demonstrated that the administration of BSZGT can effectively enhance testosterone production. The objective of this study is to investigate the potential anti-testicular dysfunction effects of BSZGT and elucidate its underlying mechanism in an in vitro setting. Specifically, the impact of oxidative stress induced by H2O2 on the activity and testosterone levels of Leydig cells (TM3) was examined. Furthermore, the utilization of UPLC-QE-Qrbitrap-MS enabled the identification of the involvement of BSZGT in various metabolic pathways, including arginine biosynthesis, amino acyl-tRNA biosynthesis, Alanine, aspartate and glutamine metabolism, and Citrate Cycle, through the modulation of 25 distinct metabolites. Additionally, a network pharmacological analysis was conducted to investigate the pivotal protein targets associated with the therapeutic effects of BSZGT. The findings demonstrate the identification of six key proteins (CYP19A1, CYP1B1, ALOX5, ARG1, XDH, and MPO) that play a significant role in augmenting testicular function through their involvement in the ovarian steroid production pathway. In summary, our study presents a comprehensive research methodology that combines cell metabonomics and network pharmacology to enhance the discovery of new therapeutic agents for TD.
Subject(s)
Drugs, Chinese Herbal , Network Pharmacology , Male , Humans , Hydrogen Peroxide , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Metabolomics/methods , TestosteroneABSTRACT
BACKGROUND: Asthma is a chronic inflammatory disease of the airways that seriously endangers human health. Belamcanda chinensis (BC), a traditional Chinese medicine, has been used to counteract asthma as it has been shown to possess anti-inflammatory and regulatory immunity properties. OBJECTIVE: The study aimed to investigate the mechanisms of action of BC in the treatment of asthma; a "dose-effect weighted coefficient" network pharmacology method was established to predict potential active compounds. METHODS: Information on the components and content of BC was obtained by UPLC-QEOrbitrap- MS spectrometry. Based on BC content, oral bioavailability, and molecular docking binding energy, dose-effect weighting coefficients were constructed. With the degree greater than average as the index, a protein-protein interaction (PPI) database was used to obtain the core key targets for asthma under dose-effect weighting. GO function and KEGG pathway analyses of the core targets were performed using DAVID software. Finally, MTT and ELISA assays were used to assess the effects of active components on 16HBE cell proliferation. RESULTS: The experimental results using the 16HBE model demonstrated BC to have a potential protective effect on asthma. Network pharmacology showed SYK, AKT1, and ALOX5 to be the main key targets, and Fc epsilon RI as the promising signaling pathway. Eight components, such as tectoridin, mangiferin, luteolin, and isovitexin were the main active compounds, Finally, we analyzed the LPS-induced 16HBE proliferation of each active ingredient. Based on the activity verification study, all five predicted components promoted the proliferation of 16HBE cells. These five compounds can be used as potential quality markers for asthma. CONCLUSION: This study provides a virtual and practical method for the simple and rapid screening of active ingredients in natural products.
ABSTRACT
The neuroprotective properties of ginsenosides have been found to reverse the neurological damage caused by oxidation in many neurodegenerative diseases. However, the distribution of ginsenosides in different tissues of the main root, which was regarded as the primary medicinal portion in clinical practice was different, the specific parts and specific components against neural oxidative damage were not clear. The present study aims to screen and determine the potential compounds in different parts of the main root in ginseng. Comparison of the protective effects in the main root, phloem and xylem of ginseng on hydrogen peroxide-induced cell death of SH-SY5Y neurons was investigated. UPLC-Q-Exactive-MS/MS was used to quickly and comprehensively characterize the chemical compositions of the active parts. Network pharmacology combined with a molecular docking approach was employed to virtually screen for disease-related targets and potential active compounds. By comparing the changes before and after Content-Effect weighting, the compounds with stronger anti-nerve oxidative damage activity were screened out more accurately. Finally, the activity of the selected monomer components was verified. The results suggested that the phloem of ginseng was the most effective part. There were 19 effective compounds and 14 core targets, and enriched signaling pathway and biological functions were predicted. After Content-Effect weighting, compounds Ginsenosides F1, Ginsenosides Rf, Ginsenosides Rg1 and Ginsenosides Rd were screened out as potential active compounds against neural oxidative damage. The activity verification study indicated that all four predicted ginsenosides were effective in protecting SH-SY5Y cells from oxidative injury. The four compounds can be further investigated as potential lead compounds for neurodegenerative diseases. This also provides a combined virtual and practical method for the simple and rapid screening of active ingredients in natural products.
Subject(s)
Ginsenosides , Neuroblastoma , Panax , Humans , Tandem Mass Spectrometry/methods , Ginsenosides/chemistry , Panax/chemistry , Molecular Docking Simulation , Phloem/metabolism , Oxidative Stress , Chromatography, High Pressure Liquid/methodsABSTRACT
The general consensus is that stress affects the central nervous system and can lead to cognitive problems. The root of Polygala tenuifolia (P. tenuifolia) is a well-known traditional Chinese medicine used for improving brain function. Tenuifolin (TEN) is the major constituent of P. tenuifolia and has a promising neuroprotective property. The purpose of this study was to investigate the alleviating effect of TEN on cognitive impairment induced by chronic restraint stress (CRS) and its mechanism. Our results showed that CRS exposure resulted in impaired cognitive performance in C57BL/6J mice, as indicated by decreased responses in Y-maze, novel objects recognition, and step-through passive avoidance tests. TEN treated daily orally (10 and 20 mg/kg) for 30 days reversed these behavior changes. Meanwhile, TEN could significantly regulate interleukin (IL)-6 and IL-10 levels in the hippocampus. TEN inhibited the toll-like receptor 4/nuclear factor-kappa B-mediated inflammation, as well as adrenocorticotropic hormone and corticosterone levels in serum. Most importantly, we found that TEN also upregulated the expressions of brain-derived neurotrophic factor, tropomyosin kinase B, glucocorticoid receptor, glutamate receptor 1, and synapse-associated proteins. Collectively, these data suggest that TEN has a potential improvement effect on memory loss caused by CRS.
Subject(s)
Cognitive Dysfunction , Polygala , Animals , Mice , Brain-Derived Neurotrophic Factor/metabolism , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/etiology , Hippocampus , Mice, Inbred C57BL , Polygala/metabolismABSTRACT
One new secoiridoid compound swertiamarin B (1), along with a known compound lytanthosalin (2), were isolated from ethanol extract of the aerial parts of Swertia mussotii. Their structures were elucidated by the detailed analysis of comprehensive spectroscopic data. All compounds were first isolated from the Swertia genus. Their antitumor activities were evaluated for four human tumor cell lines (HCT-116, HepG2, MGC-803 and A549). Compounds 1 and 2 showed excellent cytotoxic activities toward the MGC-803 cell lines with IC50 values 3.61 and 12.04 µM, respectively.
Subject(s)
Iridoids/isolation & purification , Iridoids/pharmacology , Plant Components, Aerial/chemistry , Swertia/chemistry , Carbon-13 Magnetic Resonance Spectroscopy , Cell Death/drug effects , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Iridoid Glucosides/chemistry , Iridoid Glucosides/isolation & purification , Iridoid Glucosides/pharmacology , Iridoids/chemistry , Plant Extracts/chemistry , Proton Magnetic Resonance Spectroscopy , Pyrones/chemistry , Pyrones/isolation & purification , Pyrones/pharmacologyABSTRACT
Exposure to chronic stress negatively affects the development of cognition, characterized by learning and memory decline. Ginsenoside Re (GRe), an active compound derived from Panax ginseng, exhibited neuroprotective activity in various neurological diseases. In this study, the protective effect of GRe on chronic restraint stress (CRS)-induced memory deficit was investigated. The mice were experienced 35 days of the CRS induction. The GRe was administered daily orally (10, 20, or 40 mg/kg) during the next 3 weeks stress session and the behavior test period. The CRS-induced memory impairment mice were subjected to behavioral tasks, such as the Y-maze, novel objects recognition, and step-through passive avoidance tests. Nissl staining was used to examine the neuron numbers. The levels of antioxidant enzymes, malondialdehyde, and proinflammatory factor were determined by kits and ELISA assays. The expressions of brain-derived neurotrophic factor (BDNF), NOD-like receptor protein 3 (NLRP3), nuclear factor erythroid-2 related factor 2 (Nrf2) and synapse-associated proteins (synaptophysin, SYP, and postsynaptic density 95, PSD95) were measured by Western blotting. Behavioral assessments indicated that GRe could ameliorate the cognitive impairment of CRS-induced mice, as indicated by increased responses in Y-maze (p < .05), novel objects recognition (p < .01), and step-through passive avoidance tests (p < .01). In addition, GRe treatment significantly decreased the neuronal loss in CRS mice in histological examination. Moreover, chronic GRe treatment significantly ameliorated the down-regulated the expressions of BDNF, Nrf2, heme oxygenase (HO)-1, SYP, and PSD95, as well as up-regulated NLRP3, the adaptor protein ASC, and Caspase-1 protein expression in the hippocampus of CRS-treated mice. Taken together, these findings suggest that GRe has a potential therapeutic effect on memory impairment in C57BL/6J mice exposed to CRS paradigm.
ABSTRACT
Depression is a common yet severe neuropsychiatric condition that causes imposes considerable personal, economic, and social burdens worldwide. Medicinal plant species (e.g., Panax ginseng and Polygala tenuifolia) demonstrate potent antidepressant-like effects with less toxicity and other side effects. Shen yuan prescription (SY), composed of Panax ginseng (GT) and Polygala tenuifolia (YT). The present study aimed to elucidate the effects of SY treatment on chronic unpredictable mild stress (CUMS) rats and study the underlying mechanism. Our results indicated that SY (67.5, 135, or 270 mg/kg) significantly reverses the depressive-like behaviors in rats with a 5-week CUMS exposure, as demonstrated by increased sucrose consumption in the sucrose preference test, and decreased immobility time in the tail suspension and forced swim test. Moreover, SY altered serum corticosterone levels, pro-inflammatory cytokines (IL-6, IL-1ß, and TNF-α), and oxidative markers (SOD, CAT, and MDA), and increased the levels of hippocampal neurotransmitters (5-HT, DA, and NE) in rats exposed to CUMS. Furthermore, rats treated with SY showed a reduction in the protein expression of BDNF, p-TrkB, p-Akt, and p-mTOR proteins induced by CUMS exposure in the hippocampus. In conclusion, SY prevented depressive-like behaviors in CUMS-exposed rats by preventing hypothalamus-pituitary-adrenal axis dysfunction, decreasing the levels of the neurotransmitters, minimizing oxidative stress, suppressing neuroinflammation, and activating the PI3K/Akt/mTOR-mediated BDNF/TrkB pathway, all of which are the key players in the pathological basis of depression.
ABSTRACT
The Shen Yuan prescription (SY) comprises Panax ginseng (GT) and Polygala tenuifolia (YT), elicited superior antidepressant activity compared with that of GT or YT alone. The aim of this paper is to elucidate the effects of SY treatment on chronic social defeat stress (CSDS)-induced depression-like symptoms and the related mechanism. Our results indicated that SY treatment reverses the depressive-like behaviors induced by CSDS as measured by the social interaction test, sucrose preference test, forced swim test, and tail suspension test. SY decreased the serum levels of CORT and increased hippocampal neurotransmitters (5-HT, DA, and NE) in CSDS mice. Meanwhile, SY upregulated the brain-derived neurotrophic factor (BDNF) signaling pathway and reversed the decreased hippocampal neurogenesis caused by CSDS. In addition, we found that the TrkB antagonist K252a fully blocked the SY effects on behavioral improvement and eliminated the promoting effects of SY on hippocampal neurogenesis and BDNF-TrkB signaling (including the downstream ERK and Akt pathways) activation, thus further demonstrating that BDNF-TrkB signaling was necessary for the SY effects. In conclusion, our study showed that SY acted as an antidepressant in mice exhibiting CSDS-induced depression-like symptoms, and its effect was facilitated by promoting hippocampal neurogenesis and BDNF signaling pathway activation.
ABSTRACT
Rh2 is a rare ginsenoside and there are few reports of its effect on cognition compared with other similar molecules. This study aimed to establish the impact of Rh2 treatment on improving scopolamine (Scop)-induced memory deficits in mice and illuminate the underlying mechanisms. First, memory-related behavior was evaluated using two approaches: object location recognition (OLR), based on spontaneous activity, and a Morris water maze (MWM) task, based on an aversive stimulus. Our results suggested that Rh2 treatment effectively increased the discrimination index of the mice in the OLR test. In addition, Rh2 elevated the crossing numbers and decreased the escape latency during the MWM task. Moreover, Rh2 markedly upregulated the phosphorylation of the extracellular signal-regulated kinase (ERK)-cAMP response element binding (CREB)-brain derived neurotrophic factor (BDNF) pathway in the hippocampus. Meanwhile, the administration of Rh2 significantly promoted the cholinergic system and dramatically suppressed oxidative stress in the hippocampus. Taken together, Rh2 exhibited neuroprotective effects against Scop-induced memory dysfunction in mice. Rh2 activity might be ascribed to several underlying mechanisms, including its effects on modulating the cholinergic transmission, inhibiting oxidative stress and activating the ERK-CREB-BDNF signaling pathway. Consequently, the ginsenoside Rh2 might serve as a promising candidate compound for Alzheimer's disease.
Subject(s)
Cholinergic Neurons/drug effects , Ginsenosides/therapeutic use , Memory Disorders/drug therapy , Oxidative Stress/drug effects , Signal Transduction/drug effects , Acetylcholinesterase/metabolism , Animals , Brain-Derived Neurotrophic Factor/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Hippocampus/drug effects , Male , Maze Learning/drug effects , Memory Disorders/chemically induced , Mice , Mice, Inbred ICR , Neuroprotective Agents/therapeutic use , Phosphorylation , Scopolamine/adverse effectsABSTRACT
ETHNOPHARMACOLOGY RELEVANCE: The water extract of Panax ginseng (GT) and Polygala tenuifolia (YT), the main constituents of the commonly used kai-xin-san formula of traditional Chinese medicine, represents SY. It possesses strong neuroprotective effects. Using behavioural tests, we have previously established that the SY formulation exerts superior antidepressant activity than that of GT or YT. AIM: To elucidate the impact of SY treatment on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviours and the prospective mechanism related to hippocampal neurogenesis and the BDNF signaling pathway. METHODS: We exposed Sprague-Dawley rats (male; 180-200 g) to CUMS for 35 days. The rats in the experimental treatment groups were daily treated with either fluoxetine (10 mg kg-1d-1) or SY (67.5, 135, or 270 mg kg-1d-1) orally until the behavioural tests (tail suspension test [TST], novelty-suppressed feeding test [NSFT], sucrose preference test [SPT], and forced swim test [FST]) were completed. We assessed the modifications in the hippocampal neurogenesis and the BDNF signaling pathway post-treatment with CUMS and SY. Additionally, K252a, a tyrosine protein kinase inhibitor, was utilized to evaluate the antidepressant mechanisms of SY. RESULT: s: The results of SPT, NSFT, FST, and TST in CUMS-exposed rats confirmed the antidepressant actions of SY. Additionally, SY treatment induced the BDNF signaling pathway and reversed the hippocampal neurogenesis caused by CUMS. Moreover, we found that the TrkB antagonist K252a blocked SY effects on behavioural improvement, inhibited the incremental effects of SY on hippocampal neurogenesis, and eliminated the impact of SY on BDNF-TrkB signaling activation. Thus, the impact of SY treatment on BDNF signaling molecules (pAkt, pERK1/2, and pCREB) were significantly inhibited by K252a. CONCLUSIONS: This study showed that SY acted as an antidepressant in rats exhibiting CUMS-induced depressive-like behaviours, and was facilitated by promoting hippocampal neurogenesis and the BDNF signaling pathway activation. Thus, SY could act as a potential novel supplement or adjuvant to prevent or treat clinical depressive disorders.
Subject(s)
Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Brain-Derived Neurotrophic Factor/metabolism , Depression/prevention & control , Hippocampus/drug effects , Neurogenesis/drug effects , Panax , Plant Extracts/pharmacology , Polygala , Receptor, trkB/metabolism , Animals , Antidepressive Agents/isolation & purification , Depression/metabolism , Depression/physiopathology , Depression/psychology , Disease Models, Animal , Exploratory Behavior/drug effects , Food Preferences/drug effects , Hippocampus/metabolism , Hippocampus/physiopathology , Male , Motor Activity/drug effects , Panax/chemistry , Plant Extracts/isolation & purification , Polygala/chemistry , Rats, Sprague-Dawley , Signal Transduction , Solvents/chemistry , Water/chemistryABSTRACT
Chronic ethanol intake can lead to dementia by activating neuroinflammation, causing oxidative stress response, reducing cholinergic function and inducing neuronal apoptosis. Soy isoflavones (SIs) exert beneficial effects in a variety of neurodegenerative disorders by acting on the anti-inflammatory, anti-oxidant, anti-apoptotic and neuro-trophic processes. However, at present, it is unknown whether SIs have a neuroprotective effect in chronic ethanol-induced dementia. The aim of the present study was to investigate the effect of SI on chronic ethanol-induced cognitive deficit in mice and explore the underlying mechanisms. The cognition-impaired mouse model was induced by ethanol (2.0 g kg-1, p.o) for 4 weeks. SIs (10, 20 or 40 mg kg-1, p.o) were delivered 1 hour after ethanol administration for 4 weeks. The Morris water maze (MWM) test and the passive avoidance (PA) task were conducted to evaluate the learning and memory abilities. After the behavioral tests, the biochemical parameter assay and western blot analysis were used to explore the underlying mechanisms of its action. SI administration significantly improved the cognitive performance in the MWM and PA tests, regulated the acetylcholinesterase (AChE) activity and acetylcholine (Ach) level, elevated the synaptic plasticity-related protein expressions and inhibited neuron apoptosis-related protein expressions in the cortex and hippocampus of mice. The results revealed that soy isoflavones may provide a possible novel candidate for the prevention and treatment of alcoholic dementia.
Subject(s)
Dementia/drug therapy , Ethanol/adverse effects , Glycine max/chemistry , Isoflavones/administration & dosage , Neuroprotective Agents/administration & dosage , Plant Extracts/administration & dosage , Acetylcholine/metabolism , Acetylcholinesterase/genetics , Acetylcholinesterase/metabolism , Animals , Dementia/etiology , Dementia/metabolism , Dementia/psychology , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/metabolism , Humans , Male , Memory/drug effects , Mice , Mice, Inbred ICRABSTRACT
Cognitive impairment has been widely recognized as a common symptom of chronic stress. Ginsenoside Rd (GRd), the major active compound in Panax ginseng, was previously reported in various neurological researches. However, little research is available regarding on the effect of GRd on cognitive improvement in mice subjected to chronic stress. In the present study, we investigated the neuroprotective effects of GRd in chronic restraint stress (CRS)-induced cognitive deficits and explored the potential mechanism in male C57BL/6J mice. Our results demonstrated that oral administration of GRd for 28 days markedly increased the spontaneous alternation in Y-maze and the relative discrimination index in novel object or location recognition tests following CRS. Additionally, GRd treatment considerably increased the antioxidant enzymes activities in the hippocampus. The expression levels of hippocampus and serum inflammation factors in the CRS groups were also counter-regulated by GRd treatment. Meanwhile, GRd treatment could reverse CRS-induced the decrease in phosphorylated phosphoinositide 3-kinase (PI3K), camp-reflecting element binding protein (CREB), brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) expression in the hippocampus. These findings provided evidences that GRd improves cognitive impairment in CRS mice by mitigating oxidative stress and inflammation, while upregulating the hippocampal BDNF-mediated CREB signaling pathway.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Ginsenosides/therapeutic use , Restraint, Physical , Signal Transduction , Stress, Psychological/drug therapy , Animals , Chronic Disease , Cognitive Dysfunction/blood , Cognitive Dysfunction/physiopathology , Disease Models, Animal , Ginsenosides/chemistry , Ginsenosides/pharmacology , Hippocampus/drug effects , Hippocampus/enzymology , Hippocampus/pathology , Hippocampus/physiopathology , Inflammation/blood , Male , Maze Learning/drug effects , Memory, Short-Term/drug effects , Mice, Inbred C57BL , Models, Biological , Motor Activity/drug effects , Oxidative Stress/drug effects , Receptor, trkB/metabolism , Signal Transduction/drug effects , Stress, Psychological/blood , Stress, Psychological/physiopathologyABSTRACT
Dammarane sapogenins (DS), an extract derived from ginseng by alkaline hydrolysis of total ginsenosides, possesses high pharmacological activity and higher bioavailability than ginsenosides. The present study was designed to investigate the anxiolytic-like effects of DS in a mouse model of chronic social defeat stress (CSDS). DS (40 and 80 mg/kg) significantly ameliorated social avoidance and anxiety-like behavior in four test models of CSDS, showing increased time in the interaction zone in the social interaction test and in the center of the field in the open field test, an increased percentage of entries and open arm time in the elevated plus maze, and reduced latency to eat in the novelty-suppressed feeding test. Biochemical analyses showed that DS significantly reduced serum corticosterone levels and increased brain concentration of neurotransmitter 5-HT and noradrenaline in CSDS mice. Treatment with DS significantly upregulated BDNF (brain-derived neurotrophic factor), p-CREB/CREB and p-ERK1/2/ERK1/2 protein expression in the hippocampus and prefrontal cortex of CSDS mice. Collectively, these results suggest that DS exerts anxiolytic-like effects in CSDS model mice and the action is mediated, at least in part, by modulating the HPA (hypothalamic-pituitary-adrenal) axis and monoamine neurotransmitter levels, and via ERK/CREB/BDNF signaling pathway.
Subject(s)
Anti-Anxiety Agents/therapeutic use , Anxiety/drug therapy , Brain-Derived Neurotrophic Factor/drug effects , Sapogenins/therapeutic use , Triterpenes/therapeutic use , Animals , Anti-Anxiety Agents/pharmacology , Disease Models, Animal , Humans , Male , Mice , Sapogenins/pharmacology , Triterpenes/pharmacology , Up-Regulation , DammaranesABSTRACT
Sleep deprivation has been widely reported to cause cognitive dysfunction, and elevation in oxidative stress and inflammation in the body, including the brain, have been suggested as the main factors. Genistein (GE) is an isoflavone widely present in leguminous plants, and it was found to exert a wide spectrum of biological activities, including antioxidant, anti-inflammatory, hepatoprotective, neuroprotective, and antimetastatic effects. In this study, the protective effect of GE on chronic sleep deprivation (CSD)-induced cognitive dysfunction was investigated. The mice were subjected to the sleep interruption apparatus and continuously sleep deprived for 25 days. GE was orally administrated (10, 20, and 40 mg/kg) during the sleep deprivation process totally for 25 days. Cognitive behavioral tests were conducted to study the learning and memory using the object location recognition (OLR) task, novel object recognition (NOR) test, and the Morris water maze (MWM) task. Additionally, the cortex and hippocampus were dissected to measure the oxidative stress markers and the antioxidant element nuclear erythroid-2-related factor 2 (Nrf2) and its downstream targets, including glutamate cysteine ligase catalytic, glutamate cysteine ligase modifier, heme oxygenase 1, and quinone oxidoreductase 1, as well as nuclear factor kappa B (NF-κB) p65, nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) protein expression. Moreover, the pro-inflammatory cytokines (TNF-α, interleukin [IL]-6, and IL-1ß) level was examined in the serum. The current results showed that GE could dose-dependently ameliorate the cognitive deficits of CSD-treated mice in the OLR, NOR, and MWM tasks. In addition, GE treatment significantly elevated the activities of total antioxidant capacity and superoxide dismutase and the level of glutathione and lowered the content of malondialdehyde in the cortex and hippocampus of CSD-treated mice. Furthermore, GE administration effectively activated the antioxidant element Nrf2 and its downstream targets in the cortex and hippocampus of CSD-treated mice. Moreover, GE treatment significantly suppressed CSD-induced NF-κB p65, iNOS, and COX-2 activation in the cortex and hippocampus, as well as inhibited CSD-induced pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) release in the serum. Taken together, all these results suggested that GE has substantial potential as a therapeutic intervention for the alleviation of CSD-induced deleterious effects.
Subject(s)
Cognitive Dysfunction/etiology , Cognitive Dysfunction/prevention & control , Genistein/pharmacology , Neuroprotective Agents/pharmacology , Sleep Deprivation/complications , Animals , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Antioxidants/therapeutic use , Behavior, Animal/drug effects , Brain/drug effects , Chronic Disease , Cognitive Dysfunction/drug therapy , Genistein/therapeutic use , Male , Maze Learning/drug effects , Mice , Mice, Inbred ICR , Neuroprotective Agents/therapeutic use , Oxidative Stress/drug effects , Sleep Deprivation/drug therapy , Sleep Deprivation/psychologyABSTRACT
Fructus Gardeniae (FG) is a common Chinese medicine and food. However, the toxicity of FG has drawn increasing concern, especially its hepatotoxicity. The purpose of this study was to screen the hepatotoxic components of FG and evaluate their effects on rat liver BRL-3A cells. The chemical composition of FG was determined by HPLC-ESI-MS. CCK-8 assay was used to evaluate the cytotoxicity of ten chemical components from FG, and then the toxic components with significant inhibitory activity were selected for further study. The results showed that geniposide, genipin, genipin-1-gentiobioside, gardenoside, and shanzhiside all suppress cells viability. Apoptosis assays further indicated that geniposide and its metabolite genipin are the main hepatotoxic components of FG. Pretreatment of cells with geniposide or genipin increased the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). The activities of superoxide dismutase (SOD) and glutathione (GSH) were decreased, while the malondialdehyde (MDA) level was increased. The cell contents of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) were also increased. Molecular docking simulations were used to investigate the mechanism of FG-induced hepatotoxicity, revealing that geniposide and genipin bind strongly to the pro-inflammatory factor TNFR1 receptor of the NF-κB and MAPK signaling pathways. The obtained results strongly indicate that the hepatotoxicity of FG is caused by iridoids compounds. Genipin had the most significant hepatotoxic effect. These toxic substances destroy the cell antioxidant defense system, increasing inflammatory injury to the liver cells and leading to apoptosis and even necrosis. Thus, this study lays a foundation for toxicology research into FG and its rational application.
Subject(s)
Gardenia/chemistry , Liver/pathology , Phytochemicals/toxicity , Animals , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line , Cell Survival/drug effects , Chromatography, High Pressure Liquid , Inflammation/pathology , Iridoids/pharmacology , Liver/drug effects , Molecular Docking Simulation , Oxidative Stress/drug effects , Plant Extracts/pharmacology , Rats , Receptors, Tumor Necrosis Factor, Type I/metabolism , Reference StandardsABSTRACT
20(S)-Protopanaxadiol (PPD) is a basic aglycone of the dammarane triterpenoid saponins and exerts antidepressant-like effects on behaviour in the forced swimming test (FST) and tail suspension test (TST) and in rat olfactory bulbectomy depression models. However, the antidepressant effects of PPD have not been studied thoroughly. The objective of the present study was first to investigate the effect of PPD on depression behaviours induced by chronic social defeat stress (CSDS) in mice. The results showed that CSDS was effective in producing depression-like behaviours in mice, as indicated by decreased responses in the social interaction test, sucrose preference test, TST, and FST, and that this effect was accompanied by noticeable alterations in the levels of oxidative markers (superoxide dismutase, catalase, and lipid peroxidation) and monoamines (5-HT and NE) in the hippocampus and serum corticosterone levels. Additionally, western blot analysis revealed that CSDS exposure significantly downregulated BDNF, p-TrkB/TrkB, p-Akt/Akt, and p-mTOR/mTOR protein expression in the hippocampus. Remarkably, chronic PPD treatment significantly ameliorated these behavioral and biochemical alterations associated withCSDS-induced depression. Our results suggest that PPD exerts antidepressant-like effects in mice with CSDS-induced depression and that this effect may be mediated by the normalization of neurotransmitter and corticosterone levels and the alleviation of oxidative stress, as well as the enhancement of the PI3K/Akt/mTOR-mediated BDNF/TrkB pathway.
Subject(s)
Antidepressive Agents/pharmacology , Depression/drug therapy , Sapogenins/pharmacology , Stress, Psychological/complications , Animals , Chronic Disease , Corticosterone/blood , Depression/etiology , Disease Models, Animal , Hippocampus/drug effects , Male , Mice , Mice, Inbred C57BL , Oxidative Stress/drug effects , Rats , Sapogenins/therapeutic useABSTRACT
Lepidium meyenii is now widely consumed as a functional food and medicinal product, which is known as an enhancer of reproductive health. However, the specific chemical composition and mechanism of action for improving sexual function are unclear. The present study aims at screening and determining the potential compounds, which promote mouse leydig cells (TM3) proliferation. The partial least squares analysis (PLS) was employed to reveal the correlation between common peaks of high performance liquid chromatography (HPLC) fingerprint of L. meyenii and the proliferation activity of TM3. The results suggested that three compounds had good activities on the proliferation of TM3 and promoting testosterone secretion, there were N-benzyl-hexadecanamide, N-benzyl-(9z,12z)-octadecadienamide and N-benzyl-(9z,12z,15z)-octadecatrienamide which might be the potential bioactive markers related to the enhancing sexual ability functions of L. meyenii. The first step in testosterone synthesis is the transport of cholesterol into the mitochondria, and the homeostasis of mitochondrial function is related to cyclophilin D (CypD). In order to expound how bioactive ingredients lead to promoting testosterone secretion, a molecular docking simulation was used for further illustration in the active sites and binding degree of the ligands on CypD. The results indicated there was a positive correlation between the binding energy absolute value and testosterone secretion activity. In addition, in this study it also provided the reference for a simple, quick method to screen the promoting leydig cell proliferation active components in traditional Chinese medicine (TCM).
Subject(s)
Lepidium/chemistry , Leydig Cells/cytology , Phytochemicals/analysis , Phytochemicals/pharmacology , Spectrometry, Mass, Electrospray Ionization , Tandem Mass Spectrometry , Animals , Cell Line , Cell Proliferation/drug effects , Chromatography, High Pressure Liquid , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Least-Squares Analysis , Leydig Cells/drug effects , Ligands , Male , Mice , Molecular Docking Simulation , Multivariate Analysis , Phytochemicals/chemistry , Testosterone/metabolismABSTRACT
OBJECTIVES: Chronic stress exposure can disrupt the balance of organisms, result in learning and memory impairments and induce oxidative stress. However, there is a lack of safe and effective long-term therapeutic agents for stress-related injuries. Fresh ginseng (FG), an unprocessed raw root of ginseng, has antioxidant and neuroprotective activities and has been used as functional health food in Asian countries for many years. The aim of this study was to verify the protective effects of FG on chronic restraint stress (CRS)-induced learning and memory impairments as well as oxidative stress damage in mice. METHODS: Animals were subjected to object location recognition test (OLRT) and novel object recognition test (NORT) to evaluate discriminative ability and spatial learning and memory, and Morris water maze test (MWMT) was used to evaluate the acquisition and retention of spatial memory. In addition, oxidative stress parameters were assessed by measuring the malondialdehyde (MDA) and total antioxidant reactivity levels in serum. RESULTS: Experimental results demonstrated that CRS-induced mice exhibited significantly decreased discrimination index (DI) in OLRT and NORT, longer escape latency and swimming distance, and decreased crossing numbers in MWMT. FG (2 and 6 g/kg) treatment markedly enhanced the discriminative ability by elevating DI in OLRT and NORT, improved the acquisition and retention of spatial memory by decreasing escape latency and swimming distance in the acquisition phase, and increased the crossing numbers in the probe phase of MWMT. Administration of FG (2 and 6 g/kg) significantly reduced the elevated MDA level caused by CRS. DISCUSSION: Our results suggest that FG treatment could improve CRS-induced learning and memory impairments and oxidative stress damage. FG is an intriguing therapeutic agent and functional health food in stress-related dementia.
Subject(s)
Antioxidants/administration & dosage , Panax , Spatial Memory/drug effects , Stress, Psychological/prevention & control , Animals , Male , Mice, Inbred ICR , Oxidative Stress/drug effects , Recognition, Psychology/drug effects , Restraint, Physical , Spatial Learning/drug effects , Stress, Psychological/metabolismABSTRACT
BACKGROUND: Ginkgo biloba extract (EGb-761) has been in use to treat variety of ailments including memory loss and emotional disorders usually experienced after ischemic stroke. However, data regarding its protective role in stroke associated motor dysfunction is scarce. PURPOSE: The present work was designed to investigate the long-term effects of EGb-761 on the motor dysfunctions associated with permanent middle cerebral artery occlusion (pMCAO) in rats. STUDY DESIGN/METHODS: Focal ischemic stroke was induced in male Sprague-Dawley rats by pMCAO. These rats were orally administered with EGb-761 (25, 50, 100â¯mg/kg) and positive control butylphthalide (50â¯mg/kg) for up to 28 consecutive days. The motor function was evaluated by assessing neurological scores, rotarod performance and gait analysis after 7, 14, 21 and 28 days. After 28 days, the histological examination of in frontal cortex and hippocampus was also carried out. RESULTS: EGb-761 treatment significantly improved motor function with better outcome in coordination and gait impairment rats. EGb-761 (25, 50, 100â¯mg/kg) treatment for 28 days significantly decreased the neurological scores. After 28 days of treatment EGb-761 (50 and 100â¯mg/kg) significantly increased the latency in rotarod test, walk speed, and the body rotation, whereas, decreased the stride time and the left posterior swing length in gait were observed. EGb-761 (50, 100â¯mg/kg). EGb-761 (50, 100â¯mg/kg) significantly improved the pathological changes related to pMCAO. CONCLUSIONS: EGb 761 could improve motor function especially gait impairments among pMCAO rat model related to the decreased neuronal damage. Therefore, it might be the potential to be explored further as an effective therapeutic drug to treat post stroke motor dysfunctions.
Subject(s)
Infarction, Middle Cerebral Artery/physiopathology , Locomotion/drug effects , Plant Extracts/pharmacology , Stroke/drug therapy , Animals , Frontal Lobe/drug effects , Frontal Lobe/pathology , Ginkgo biloba , Hippocampus/drug effects , Hippocampus/pathology , Infarction, Middle Cerebral Artery/chemically induced , Male , Neurons/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
OBJECTIVE: Riboflavin-responsive multiple acyl-coenzyme A dehydrogenation deficiency (RR-MADD) is an inherited fatty acid metabolism disorder mainly caused by genetic defects in electron transfer flavoprotein-ubiquinone oxidoreductase (ETF:QO). The variant ETF:QO protein folding deficiency, which can be corrected by therapeutic dosage of riboflavin supplement, has been identified in HEK-293 cells and is believed to be the molecular mechanism of this disease. To verify this hypothesis in vivo, we generated Etfdh (h)A84T knockin (KI) mice. METHODS: Tissues from these mice as well as muscle biopsies and fibroblasts from 7 RR-MADD patients were used to examine the flavin adenine dinucleotide (FAD) concentration and ETF:QO protein amount. RESULTS: All of the homozygous KI mice (Etfdh (h)A84T/(h)A84T , KI/KI) were initially normal. After being given a high-fat and vitamin B2 -deficient (HF-B2 D) diet for 5 weeks, they developed weight loss, movement ability defects, lipid storage in muscle and liver, and elevated serum acyl-carnitine levels, which are clinically and biochemically similar to RR-MADD patients. Both ETF:QO protein and FAD concentrations were significantly decreased in tissues of HF-B2 D-KI/KI mice and in cultured fibroblasts from RR-MADD patients. After riboflavin treatment, ETF:QO protein increased in proportion to elevated FAD concentrations, but not related to mRNA levels. These results were further confirmed in cultured fibroblasts from RR-MADD patients. INTERPRETATION: For the first time, we successfully developed a RR-MADD mice model and confirmed that FAD homeostasis disturbances played a crucial role on the pathomechanism of RR-MADD in this mouse model and culture cells from patients. Supplementation of riboflavin may stabilize variant ETF:QO protein by rebuilding FAD homeostasis. Ann Neurol 2018;84:667-681.