Berberine exerts antidepressant effects in vivo and in vitro through the PI3K/AKT/CREB/BDNF signaling pathway.

BACKGROUND: Depression, a global neuropsychiatric disorder, brings a serious burden to patients and society as its incidence continues to rise. Berberine is one of the main compounds of a variety of Chinese herbal medicines and has been shown to have multiple pharmacological effects. However, whether berberine can exert antidepressant effects in vivo and in vitro and its related mechanisms remain to be explored. METHODS: The chronic restraint stress (CRS) method and corticosterone (CORT) were applied to simulate depression-like behavior in vivo and neuronal apoptosis in vitro, respectively. The antidepressant effects of berberine were evaluated by behavioral tests and changes in the content of monoamine neurotransmitters. Inflammatory cytokines were detected and immunofluorescence staining was used to observe the expression levels of apoptosis-related proteins. RT-qPCR and Western blot were used to examine the mRNA and protein expression (or phosphorylation) levels of biomarkers of the PI3K/AKT/CREB/BDNF signaling pathways. RESULTS: Behavioral tests and levels of neurotransmitters proved that berberine could effectively ameliorate depression-like symptoms in CRS mice. Meanwhile, the results of ELISA and immunofluorescence staining showed that berberine could alleviate inflammatory status and reduce cell apoptosis in vivo and in vitro. Moreover, the changes of the PI3K/AKT/CREB/BDNF signaling pathway induced by CRS or CORT in mouse hippocampus or HT-22 cells were significantly reversed by berberine. CONCLUSION: Our current study suggested that berberine could exert antidepressant effects in vitro and in vivo, which may be associated with the PI3K/AKT/CREB/BDNF signaling pathway.

Modified Hu-lu-ba-wan protects diabetic glomerular podocytes via promoting PKM2-mediated mitochondrial dynamic homeostasis.

BACKGROUND: Mitochondrial dysfunction is implicated in the progression of diabetic kidney disease (DKD). Damaged mitochondria produce excessive reactive oxygen species (ROS) that can cause apoptosis. Mitochondrial dynamics control the quality and function of mitochondria. Targeting mitochondrial dynamics may reduce ROS-induced apoptosis and improve renal injury in DKD. Modified Hu-lu-ba-wan (MHLBW) shows distinct clinical effects on DKD patients, which are related to its role in antioxidant stress modulation. However, the relevant mechanisms of MHLBW have not been clearly explored. PURPOSE: This study was aimed to evaluate the therapeutic effects of MHLBW on spontaneous DKD mice and clarify the potential mechanisms. METHODS: The main components of MHLBW were identified by HPLC. Using db/db mice as DKD models, we evaluated the therapeutic effects of MHLBW on mice after an 8-week administration. We investigated the molecular mechanism of MHLBW in regulating mitochondrial dynamic homeostasis, podocyte apoptosis, and glomerular damage. After that, computational docking analysis and in vitro experiments were conducted for further mechanism verification. RESULTS: Intragastric administration of MHLBW for 8 weeks in db/db mice significantly improved glucose metabolism, basement membrane thickening, mesangial expansion, glomerular fibrosis, and podocyte injury. MHLBW can reverse podocyte apoptosis via promoting mitochondrial dynamic homeostasis, which was related to regulating the PKM2/ PGC-1α/Opa1 pathway. Berberine (BBR), one of the components of MHLBW, exhibited preeminent affinity with PKM2 as reflected by computational docking analysis. In cultured podocytes, BBR can also prevent apoptosis by promoting PKM2-mediated mitochondrial dynamic homeostasis. CONCLUSION: Our study demonstrates that MHLBW can treat DKD by inhibiting glomerular damage and podocyte apoptosis through positive regulation of PKM2-mediated mitochondrial dynamic homeostasis. These results may provide a potential strategy against DKD.

Diosgenin attenuates non-alcoholic fatty liver disease in type 2 diabetes through regulating SIRT6-related fatty acid uptake.

BACKGROUND: More than 70% of patients with type 2 diabetes (T2DM) concomitantly suffer from Non-alcoholic fatty liver disease (NAFLD), and the coexistence and interaction of them increases the intractability of NAFLD. With the protective effect against hepatic steatosis and liver fibrosis, SIRT6 is becoming a notable target of NAFLD. Diosgenin, an active monomer from Chinese herbs, has been reported to protect against NAFLD. PURPOSE: This study aims to figure out the mechanism how diosgenin alleviate NAFLD in T2DM and the relationship with SIRT6. METHODS: In vivo studies used spontaneous diabetic db/db mice and divided them into two parts. The first part included four groups consisting of control (Con) group, model (Mod) group, low dose of diosgenin (DL) group and high dose of diosgenin (DH) group. The second part included four groups consisting of Con group, Mod group, DH+OSS (OSS_128167, inhibitor of SIRT6) group, MDL (MDL800, agonist of SIRT6) group. HepG2 cell line was selected in study in vitro, which was mainly composed of six groups including Con group, palmitic acid (PA) group, PA+DL group, PA+DH group, PA+DH+OSS group, PA+MDL group. OGTT, Biochemical biomarker (including TG, TC, AST, ALT), inflammatory biomarker (including IL-6 and TNF-α) were measured. HE, Oil Red O, and DHE staining were conducted. Immunohistochemistry, immunofluorescence, mRNA-seq, and qPCR were used to explore the mechanism. RESULTS: Results in the first part of study in vivo indicated that diosgenin protected against lipid accumulation, oxidative stress, cell injury, and light inflammatory of liver in db/db mice and regulated the expression of SIRT6 and fatty acid transporter including CD36, FATP2, FABP1. The effect of diosgenin could be reversed in DH+OSS group and the same effect was observed in MDL group in the second part of study in vivo. The same results were also noted in followed study in vitro. Diosgenin inhibited the fatty acids uptake and regulated the expression of SIRT6 and fatty acid transporter including CD36, FATP2, and FABP1 in PA-induced hepG2 cells, and which was reversed in DH+OSS group and resembled in MDL group. CONCLUSIONS: Diosgenin could attenuate non-alcoholic fatty liver disease in type 2 diabetes through regulating SIRT6-related fatty acid uptake.

Ban-xia-xie-xin-tang ameliorates hepatic steatosis by regulating Cidea and Cidec expression in HFD-fed mice.

BACKGROUND: Ban-xia-xie-xin-tang (BXXXT) has been applied in treating metabolic diseases, such as nonalcohol fatty liver disease, diabetes mellitus, and obesity. However, the underlying molecular mechanism of BXXXT in treating diabetes mellitus is unknown. PURPOSE: To clarify the underlying molecular mechanism of BXXXT in alleviating hepatic steatosis in high-fat diet (HFD)-fed mice. METHODS: After 12 weeks of HFD treatment, mice were administered BXXXT for 4 weeks. The main chemical components of BXXXT were identified by UPLC-TQ-MS/MS. Indicators associated with insulin resistance and lipid metabolism were detected. The effect of improving glucose and lipid metabolism between BXXXT and the different components was compared. Differentially expressed genes (DEGs) were identified by hepatic transcriptomics. Key DEGs and proteins were further detected by real-time quantitative polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence staining. LDs and mitochondria were detected by transmission electron microscopy. RESULTS: First of all, our data demonstrated that the capacity to improve glucose and lipid metabolism for BXXXT was significantly superior to different components of BXXXT. BXXXT was found to improve HFD-induced insulin resistance. Moreover, BXXXT decreased weight, serum/hepatic triglycerides, total cholesterol, and FFAs to alleviate HFD-induced hepatic steatosis. According to the results of the hepatic transcription, Cidea and Cidec were identified as critical DEGs for promoting LD fusion and reducing FFAs ß-oxidation in mitochondria and peroxisome resulting in hepatic steatosis, which was reversed by BXXXT. CONCLUSION: BXXXT ameliorates HFD-induced hepatic steatosis and insulin resistance by increasing Cidea and Cidec-mediated mitochondrial and peroxisomal fatty acid oxidation, which may provide a potential strategy for therapy of NAFLD and T2DM.

Trigonella foenum-graecum L. and Psoralea corylifolia L. Improve Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats through Suppression of Oxidative Stress.

Background: Diabetes mellitus-induced erectile dysfunction (DMED) is one of the most common complications of diabetes and is mainly attributed to oxidative stress. Hu-Lu-Ba-Wan (HLBW) is a classic Chinese formulation consisting of Trigonella foenum-graecum L. (TFG) and Psoralea corylifolia L. (PC). HLBW has been used not only for the treatment of diabetes but also for the treatment of erectile dysfunction in clinics. This study aimed to explore the efficacy and underlying mechanism of HLBW in ameliorating erectile function in streptozotocin-induced diabetic rats. Methods: The diabetic model was established by tail vein injection of streptozotocin (26 mg/kg), and then DMED rats screened by the apomorphine test were randomly divided into two groups: the model group and the HLBW group. The rats in the HLBW group were administered HLBW granules daily for 12 weeks. Fasting blood glucose and fasting insulin were tested by a commercial kit. Intracavernous pressure (ICP) and mean arterial pressure (MAP) were measured by cavernous nerve electrostimulation before the rats were killed. Erectile function was evaluated with ICP/MAP. The markers of oxidative stress in the corpus cavernosum (CC) were assayed by assay kits. Apoptosis in cavernosal tissue was detected by Western blotting (WB). The expression levels of vascular endothelial marker (vWF), α-smooth muscle actin (α-SMA), endothelial nitric oxide synthase (eNOS), and NADPH oxidase subunit P47phox were determined by WB and PCR. Furthermore, the structure of the CC was further confirmed by Masson's trichrome staining. Results: The results showed that HLBW significantly reduced blood glucose and increased insulin sensitivity. HLBW reduced oxidative stress and apoptosis. In addition, we observed that the expression levels of vWF, α-SMA, and eNOS as well as the ratio of smooth muscle to collagen increased in the HLBW group. Conclusions: Our results demonstrated that HLBW could reduce oxidative stress damage in CC to improve diabetes mellitus-induced erectile dysfunction in rats by inhibiting NADPH oxidase.

Traditional herbal formula Jiao-tai-wan improves chronic restrain stress-induced depression-like behaviors in mice.

OBJECTIVES: Jiao-tai-wan (JTW) has been often used to treat insomnia and diabetes mellitus. Recent studies found its antidepressant activity, but the related mechanism is not clear. This study is to evaluate the therapeutic effects of JTW on chronic restraint stress (CRS)-induced depression mice and explore the potential mechanisms. METHODS: CRS was used to set up a depression model. Mice in different groups were treated with 0.9 % saline, JTW and fluoxetine. After the last day of CRS, the behavioral tests were conducted. The levels of neurotransmitters, inflammatory cytokines and HPA axis index were detected and the protein expressions of NLRP3 inflammasome complex were determined. H&E, NISSL, TUNEL and immunofluorescence staining were used to observe histopathological changes and the activation of microglia and astrocytes. The potential mechanisms were explored via network pharmacology and verified by Western blot. RESULTS: The assessment of liver and kidney function showed that JTW was non-toxic. Behavioral tests proved that JTW can effectively ameliorate depression-like symptoms in CRS mice, which may be related to the inhibition of NLRP3 inflammasome activation. JTW can also improve the inflammatory state and HPA axis hyperactivity in mice, and has a protective effect on CRS-induced hippocampal neurons damage. The network pharmacology analysis and the results of Western blot suggested that the antidepressant effects of JTW may be related to the MAPK signaling pathway. CONCLUSION: Our findings indicated that JTW may exert antidepressant effects in CRS-induced mice by inhibiting NLRP3 inflammasome activation and improving inflammatory state, and MAPK signaling pathway may also be involved.

New Therapeutic Horizon of Graves' Hyperthyroidism: Treatment Regimens Based on Immunology and Ingredients From Traditional Chinese Medicine.

Graves' disease is an autoimmune disease characterized by goiter and hyperthyroidism, and 25% patients develop GO. Traditional treatment options, such as antithyroid drugs, radioiodine or thyroidectomy, have remained largely unchanged over the past 70 years. For many patients, there is a high rate of recurrence after antithyroid drugs and lifelong hypothyroidism after ablation and thyroidectomy. The symptoms and quality of life of some patients have not been effectively improved. The clinical demand for new therapeutic regimens, coupled with a deeper understanding of the pathophysiology and immunobiology of Graves' disease, has led to the emergence of several new therapeutic ideas, including biologics, small molecule peptides, immunomodulators and teprotumumab, a specific antibody targeting IGF-1R. Besides, the elements of TCM have attracted more and more interests in modern medicine, because some effective components have been successfully used in the treatment of autoimmune diseases. Based on the pathophysiology and efficacy of clinical management and treatment in Graves' hyperthyroidism, here we review the new strategies under investigation and summarize the effective components of traditional Chinese medicine used for Graves' hyperthyroidism, and explore their mechanisms. These therapies have opened a new window for the treatment of Graves' disease, but the exact mechanism and the research direction still need to be further explored.

Antidepressant Potential of Quercetin and its Glycoside Derivatives: A Comprehensive Review and Update.

Depression is a global health problem with growing prevalence rates and serious impacts on the daily life of patients. However, the side effects of currently used antidepressants greatly reduce the compliance of patients. Quercetin is a flavonol present in fruits, vegetables, and Traditional Chinese medicine (TCM) that has been proved to have various pharmacological effects such as anti-depressant, anti-cancer, antibacterial, antioxidant, anti-inflammatory, and neuroprotective. This review summarizes the evidence for the pharmacological application of quercetin to treat depression. We clarified the mechanisms of quercetin regulating the levels of neurotransmitters, promoting the regeneration of hippocampal neurons, improving hypothalamic-pituitary-adrenal (HPA) axis dysfunction, and reducing inflammatory states and anti-oxidative stress. We also summarized the antidepressant effects of some quercetin glycoside derivatives to provide a reference for further research and clinical application.

Berberine Ameliorates Glucose Metabolism in Diabetic Rats through the alpha7 Nicotinic Acetylcholine Receptor-Related Cholinergic Anti-Inflammatory Pathway.

Berberine is an isoquinoline derivative alkaloid extracted from Chinese herbs. Recent studies have demonstrated the therapeutic effect of berberine on glucose metabolic disorders. However, its specific mechanism is still unclear. Our study aimed to research the glucose-lowering effect of berberine in diabetic rats and to reveal the possible role of the cholinergic anti-inflammatory pathway. Diabetic rats induced by administration of a high-calorie diet and streptozocin tail vein injection were assessed by the oral glucose tolerance test. Then, the diabetic rats were divided into two groups, those with or without the alpha7 nicotinic acetylcholine receptor gene downregulated, respectively, followed by treatment including berberine for 6 weeks. Results of this study show that the administration of berberine downregulated levels of fasting blood glucose and fasting insulin, and ameliorated insulin resistance in diabetic rats. Treatment with berberine inhibited acetylcholinesterase activity, and upregulated acetylcholine levels in the serum and alpha7 nicotinic acetylcholine receptor gene expression in the liver tissue. Meanwhile, berberine reversed elevated expression of cytokines interleukin-1ß and TNF-α in the serum and downregulated nuclear factor κB expression. However, berberine administration showed no glucose-lowering or anti-inflammatory effect in diabetic rats in which alpha7 nicotinic acetylcholine receptor gene expression was downregulated, and acetylcholinesterase activity was also significantly inhibited. In conclusion, berberine may ameliorate glucose metabolism by activating the alpha7 nicotinic acetylcholine receptor-mediated cholinergic anti-inflammatory pathway.

The effect and mechanism of Jiao-tai-wan in the treatment of diabetes mellitus with depression based on network pharmacology and experimental analysis.

BACKGROUND: The incidence of diabetes mellitus (DM) and depression is increasing year by year around the world, bringing a serious burden to patients and their families. Jiao-tai-wan (JTW), a well-known traditional Chinese medicine (TCM), has been approved to have hypoglycemic and antidepressant effects, respectively, but whether JTW has such dual effects and its potential mechanisms is still unknown. This study is to evaluate the dual therapeutic effects of JTW on chronic restraint stress (CRS)-induced DM combined with depression mice, and to explore the underlying mechanisms through network pharmacology. METHODS: CRS was used on db/db mice for 21 days to induce depression-like behaviors, so as to obtain the DM combined with depression mouse model. Mice were treated with 0.9% saline (0.1 ml/10 g), JTW (3.2 mg/kg) and Fluoxetine (2.0 mg/kg), respectively. The effect of JTW was accessed by measuring fasting blood glucose (FBG) levels, conducting behavioral tests and observing histopathological change. The ELISA assay was used to evaluate the levels of inflammatory cytokines and the UHPLC-MS/MS method was used to determine the depression-related neurotransmitters levels in serum. The mechanism exploration of JTW against DM and depression were performed via a network pharmacological method. RESULTS: The results of blood glucose measurement showed that JTW has a therapeutic effect on db/db mice. Behavioral tests and the levels of depression-related neurotransmitters proved that JTW can effectively ameliorate depression-like symptoms in mice induced by CRS. In addition, JTW can also improve the inflammatory state and reduce the number of apoptotic cells in the hippocampus. According to network pharmacology, 28 active compounds and 484 corresponding targets of JTW, 1407 DM targets and 1842 depression targets were collected by screening the databases, and a total of 117 targets were obtained after taking the intersection. JTW plays a role in reducing blood glucose level and antidepressant mainly through active compounds such as quercetin, styrene, cinnamic acid, ethyl cinnamate, (R)-Canadine, palmatine and berberine, etc., the key targets of its therapeutic effect include INS, AKT1, IL-6, VEGF-A, TNF and so on, mainly involved in HIF-1 signal pathway, pathways in cancer, Hepatitis B, TNF signal pathway, PI3K-Akt signal pathway and MAPK signaling pathway, etc. CONCLUSION: Our experimental study showed that JTW has hypoglycemic and antidepressant effects. The possible mechanism was explored by network pharmacology, reflecting the characteristics of multi-component, multi-target and multi-pathway, which provides a theoretical basis for the experimental research and clinical application of JTW in the future.

Traditional herbal formula Wu-Mei-Wan alleviates TNBS-induced colitis in mice by inhibiting necroptosis through increasing RIPK3 O-GlcNAcylation.

BACKGROUND: Accumulating evidence indicated that necroptosis plays an essential role in the pathogenesis of inflammatory bowel disease (IBD). The O-linked ß-N-acetylglucosaminylation (O-GlcNAcylation) of necroptotic signal molecule receptor-interacting serine-threonine kinase 3 (RIPK3) was reported to exert a protective effect in gut inflammation. Our recent study suggested traditional Chinese herbal formula Wu-Mei-Wan (WMW) as an effective prescription in mouse colitis. However, the potential mechanisms are not fully understood. Considering the crucial role of necroptosis in the pathogenesis of IBD, therefore, this study was designed to explain whether the anti-colitis effect of WMW is mediated by modulating necroptosis and its related mechanisms. METHODS: The protective effects of WMW on colitis have been determined by detecting colitis mice body weight, disease activity index (DAI), survival rate and colon length. Colonic inflammation was examined by inflammatory cells infiltration and local cytokines levels. After then, we measured the levels of necroptosis and O-GlcNAcylation. C O-immunoprecipitation experiments were used to address whether elevated O-GlcNAcylation can inhibit necroptotic signal transduction in the treatment of WMW. Finally, the key enzymes in O-GlcNAcylation: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) were examined and molecular docking analysis was used to determine effective natural compounds in the regulation on OGT and OGA activities. RESULTS: Our results showed that WMW significantly improved mice body weight, survival rate and colon length, decreased DAI in TNBS-induced colitis. WMW obviously alleviated colonic inflammatory responses with reduced macrophages, neutrophils infiltration and local IL-1ß, IL-6, TNF-α and IFN-γ levels. It was found that WMW increased colonic O-GlcNAcylation level and inhibited the activation of RIPK1, RIPK3 and MLKL. Then, further experiments revealed that WMW enhanced OGT activity and suppressed OGA activity, thereby increasing RIPK3 O-GlcNAcylation and inhibiting the binding of RIPK3 and MLKL, which led to the inhibition of necroptosis. Additionally, docking analysis demonstrated that hesperidin, coptisine and ginsenoside Rb1 may exert a major role in the regulation on OGT and OGA activities by WMW. CONCLUSION: Our work demonstrated that WMW can alleviate TNBS-induced colitis in mice by inhibiting necroptosis through increasing RIPK3 O-GlcNAcylation.

A bioinformatics and transcriptomics based investigation reveals an inhibitory role of Huanglian-Renshen-Decoction on hepatic glucose production of T2DM mice via PI3K/Akt/FoxO1 signaling pathway.

BACKGROUND: Excessive hepatic glucose production (HGP) largely promotes the development of type 2 diabetes mellitus (T2DM), and the inhibition of HGP significantly ameliorates T2DM. Huanglian-Renshen-Decoction (HRD), a classic traditional Chinese herb medicine, is widely used for the treatment of diabetes in clinic for centuries and proved effective. However, the relevant mechanisms of HRD are not fully understood. PURPOSE: Based on that, this study was designed to identify the potential effects and underlying mechanisms of HRD on HGP by a comprehensive investigation that integrated in vivo functional experiments, network pharmacology, molecular docking, transcriptomics and molecular biology. METHODS: After confirming the therapeutic effects of HRD on T2DM mice, the inhibitory role of HRD on HGP was evaluated by pyruvate and glucagon tolerance tests, liver positron emission tomography (PET) imaging and the detection of gluconeogenic key enzymes. Then, network pharmacology and transcriptomics approaches were used to clarify the underlying mechanisms. Molecular biology, computational docking analysis and in vitro experiments were applied for final mechanism verification. RESULTS: Here, our results showed that HRD can decrease weight gain and blood glucose, increase fasting insulin, glucose clearance and insulin sensitivity in T2DM mice. Dysregulated lipid profile was also corrected by HRD administration. Pyruvate, glucagon tolerance tests and liver PET imaging all indicated that HRD inhibited the abnormal HGP of T2DM, and the expressions of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) were significantly suppressed by HRD as expected. Network pharmacology and transcriptomics approaches illustrated that PI3K/Akt/FoxO1 signaling pathway may be responsible for the inhibitory effect of HRD on HGP. Afterward, further western blot and immunoprecipitation found that HRD did activate PI3K/Akt/FoxO1 signaling pathway in T2DM mice, which confirmed previous results. Additionally, the conclusion was further supported by molecular docking and in vitro experiments, in which identified HRD compound, oxyberberine, was proven to exert an obvious effect on Akt. CONCLUSION: Our data demonstrated that HRD can treat T2DM by inhibiting hepatic glucose production, the underlying mechanisms were associated with the activation of PI3K/Akt/FoxO1 signaling pathway.

The Effect of Momordica charantia in the Treatment of Diabetes Mellitus: A Review.

In recent years, many studies of Momordica charantia (MC) in the treatment of diabetes mellitus (DM) and its complications have been reported. This article reviewed the effect and mechanism of MC against diabetes, including the results from in vitro and in vivo experiments and clinical trials. The common side effects of MC were also summarized. We hope that it might open up new ideas for further mechanism exploration and clinical application as well as provide a scientific theoretical basis for the development of drugs or foods derived from MC.

Protective Effects of Hu-Lu-Ba-Wan () against Oxidative Stress in Testis of Diabetic Rats through PKCα/NAPDH Oxidase Signaling Pathway.

OBJECTIVE: To explore the protective effect and the underlying mechanism of Hu-Lu-Ba-Wan (, HLBW) on the testis of diabetic rats. METHODS: Twenty-four male Wistar rats (160-180 g) were randomly divided into 3 groups according to a random number table, including a control group (n=8), diabetic group (n=8), and HLBW group (n=8). Diabetic rat model was established by high-fat-diet administration and single intravenous injection of streptozotocin (26 mg/kg). Then HLBW granule was administrated for 12 weeks. Fasting blood glucose and insulin levels as well as serum total testosterone level and testicular testosterone content were examined. Oxidative stress markers in both serum and testis were tested. Meanwhile, testicular morphology was observed under hematoxylin and eosin (HE) and the ultrastructure of Leydig cell was observed by electron microscope. The superoxide anion level was detected by DHE, and TUNEL-positive cells of testis was evaluated by TUNEL assay. The gene and protein expression of protein kinase C (PKCα), phosphorylated PKCα (P-PKCα) and P47phox in testicular tissues were determined by quantitative RT-PCR analysis and Western bolt analysis. RESULTS: Compared with the diabetic group, HLBW treatment significantly reduced the fasting glucose levels and increased the levels of fasting insulin and testosterone in serum (P<0.01). HLBW administration also reduced the levels of reactive oxygen species (ROS) in plasma and alleviated the damage of oxidative stress in the testis of diabetic rats. Additionally, HLBW down-regulated the protein and mRNA levels of PKCα, P-PKCα and P47phox in testicular tissues. CONCLUSION: HLBW may attenuate the oxidative stress in the testis of diabetic rats via PKCα /NAPDH oxidase signaling pathway.

Celastrol alleviates metabolic disturbance in high-fat diet-induced obese mice through increasing energy expenditure by ameliorating metabolic inflammation.

Celastrol, a natural triterpene, has been shown to treat obesity and its related metabolic disorders. In this study, we first assessed the relationship between the antiobesity effects of celastrol and its antiinflammatory activities. Our results showed that celastrol can reduce weight gain, ameliorate glucose intolerance, insulin resistance, and dyslipidemia without affecting food intake in high-fat diet-induced obese mice. A CLAMS was used to clarify the improvement of metabolic profiles was attribute to increased adipose thermogenesis after celastrol treatment. Further studies found that celastrol decreased the infiltration of macrophage as well as its inflammatory products (IL-1ß, IL-18, MCP-1α, and TNF-α) in liver and adipose tissues, which also displayed an obvious inhibition of TLR3/NLRP3 inflammasome molecules. This study demonstrated that celastrol could be a potential drug for treating metabolic disorders, the underlying mechanism is related to ameliorating metabolic inflammation, thus increasing body energy expenditure.

Effects of aromatherapy on anxiety: A meta-analysis of randomized controlled trials.

SCOPE: The effects of aromatherapy on relieving anxiety were controversial. The purpose of this meta-analysis was to evaluate the effects of aromatherapy on anxiety in patients. METHODS AND RESULTS: We searched randomized controlled trials (RCTs) about aromatherapy on decreasing anxiety on PUBMED, WEB OF SCIENCE (January 1990 to October 2019), COCHRANE LIBRARY, EMBASE (updated to October 2019), and the Chinese databases CNKI, WanFang and CBMD. Twenty-five articles (Thirty-two trials) were included in this meta-analysis. The data of scale scores of Spielberger State-Trait Anxiety Inventory (STAI) were extracted. The pooled results demonstrated that inhalation and massage aromatherapy significantly decreased anxiety levels in different conditions. The weighted mean difference was -5.16 for State Anxiety Inventory (SAI) (95%CI: -5.78, -4.55, p<0.001) and -2.85 for Trait Anxiety Inventory (TAI) (95%CI: -3.95, -1.75, p<0.001). No side effects were mentioned in all of studies. CONCLUSION: The meta-analysis suggested that aromatherapy with different essential oils could alleviate anxiety significantly no matter the reason of anxiety. However, the proper dosage of essential oils needs further research.

Wu-Mei-Wan prevents high-fat diet-induced obesity by reducing white adipose tissue and enhancing brown adipose tissue function.

BACKGROUND: Wu-Mei-Wan, a classic traditional Chinese herb medicine, is one of the most important formulations to treat digestive diseases from ancient times to the present. Our previous study showed that WMW treatment can prevent T2DM in db/db mice, which motivating the application of WMW on metabolic disorders. PURPOSE: Obesity and its comorbid diseases have increased dramatically and are now a worldwide health problem. There is still a lack of satisfactory treatment strategies for obesity. This work was designed to assess the effect and related mechanism of WMW on high fat diet (HFD)-induced obese mice model. METHODS: Obese mice were induced by HFD. Thetherapeutic effect of WMW were analyzed by examining body and adipose tissue weight, metabolic profile and energy expenditure. Adipose tissue phenotype was determined by histological staining and the mitochondrial content was examined by transmission electron microscopy (TEM). Immunohistochemical and immunofluorescence staining, RT-qPCR and Western blot analysis were used to evaluate expression of key molecules in adipose tissue. RESULTS: WMW treatment significantly protects HFD-induced obesity. Here we showed that WMW limits weight gain, improves metabolic profile and increases energy expenditure. WMW inhibits the hypertrophy and hyperplasia of white adipocytes, the mechanism involving the inhibition of TLR3/IL-6/JAK1/STAT3 pathway. In brown adipose tissue (BAT), WMW promotes thermogenicprogramme without affecting cell proliferation. The activated BMP7/ Smad1/5/9 pathway is considered to be one of the explanations for the effect of WMW on BAT. CONCLUSION: Our results suggested that WMW can prevent obesity and its underlying mechanisms are associated with reducing white adipose tissue and enhancing brown adipose tissue function.

Wu-Mei-Wan ameliorates chronic colitis-associated intestinal fibrosis through inhibiting fibroblast activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Wu-Mei-Wan (WMW), a classic traditional Chinese herb medicine, is one of the most important formulations to treat digestive diseases from ancient times to the present. Previous study showed that WMW has satisfactory curative effects on experimental colitis, which motivating the application of WMW on colitis-associated complications. AIM OF THE STUDY: Intestinal fibrosis is usually considered to be a common complication of inflammatory bowel disease (IBD), particularly Crohn's disease (CD). Currently, no effective preventive measures or medical therapies are available for that. This work was designed to evaluate the effect and related mechanism of WMW on chronic colitis-associated intestinal fibrosis mice model. MATERIALS AND METHODS: The chronic colitis-associated intestinal fibrosis mice model was established by weekly intrarectal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS). The mice survival rate, disease activity index (DAI), colon length and histological score were examined to assess the therapeutic effect of WMW. Masson's trichrome staining, hydroxyproline assay, immunohistochemical staining and western blot analysis were used to evaluate fibrosis level. Colon inflammation was determined by ELISA and immunofluorescence staining. Immunofluorescence staining was used to evaluate fibroblasts proliferation and epithelial to mesenchymal transition (EMT), and the expression of key molecules in fibrosis was analyzed by western blot. RESULTS: Here we showed that WMW alleviates chronic colitis with improved survival rate, DAI, colon length and histological score. WMW inhibited the progression of intestinal fibrosis, decreased the expression of various fibrosis markers, such as α-SMA, collagen I, MMP-9 and fibronectin. In addition, WMW treatment reduced cytokines IL-6 and IFN-γ, and downregulated proinflammatory NF-κBp65 and STAT3 signaling pathways. Importantly, administration of WMW led to the inhibition of colon fibroblast proliferation and EMT, which are important mediators during fibrosis. Several key profibrotic pathways, including TGF-ß/Smad and Wnt/ß-catenin pathways, were downregulated by WMW treatment. CONCLUSION: Our work demonstrated that WMW can prevent intestinal fibrosis and the mechanisms involved may be related to the inhibition of colon fibroblasts activation.

Jiao-tai-wan inhibits inflammation of the gut-brain-axis and attenuates cognitive impairment in insomnic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiao-tai-wan is a well-known traditional Chinese herbal medicine formula that is used to treat insomnia and systemic inflammation. Studies indicate chronic insomnia might contribute to the prevalence of cognitive impairment. The role of systemic inflammation and intestinal permeability in the progression of neurodegenerative diseases attracts much attention. AIM OF THE STUDY: This study aimed to investigate if Jiao-tai-wan plays a role in promoting the repair of the intestinal epithelial barrier to suppress systemic inflammation and cognitive impairment in sleep-deprived (SD) rats. MATERIALS AND METHODS: Male obesity-resistant SD rats were partially sleep-deprived for 16 weeks. During the last 8 weeks, they were treated with Jiao-tai-wan. A Morris water maze was used to analyze their cognitive ability. Aß42 and proinflammation cytokines in the cerebrospinal fluid, tissue, or serum were determined using enzyme-linked immunosorbent assay or polymerase chain reaction. Intestinal permeability was detected using the fluorescein isothiocyanate-dextran perfusion assay method. Plasma lipopolysaccharide (LPS) levels were detected with Tachypleus Amebocyte Lysate. Western bolt was used in the signaling pathway analysis. RESULTS: Sleep deprivation deteriorated the performance of rats in the Morris water maze and increased the Aß42, caspase3, IL-6, and TNF-α levels in their brains. The intestinal TLR4/NF-κB pathway was activated with an increase in the expression of IL-6 and TNF-α. The expression of tight junction proteins was also decreased in the intestinal tissue. This increased the intestinal permeability and circulation of LPS, LPS binding protein, IL-6, and TNF-α. Treatment with Jiao-tai-wan could partly reverse these changes. CONCLUSION: Jiao-tai-wan has the potential to attenuate systemic inflammation and cognitive impairment in partially sleep-deprived rats. The possible underlying mechanism is by preventing an inflammation trigger being transferred through the gut-brain-axis.

Berberine protects against diabetic kidney disease via promoting PGC-1α-regulated mitochondrial energy homeostasis.

BACKGROUND AND PURPOSE: Disordered lipid metabolism and disturbed mitochondrial bioenergetics play pivotal roles in the initiation and development of diabetic kidney disease (DKD). Berberine is a plant alkaloid, used in Chinese herbal medicine. It has multiple therapeutic actions on diabetes mellitus and its complications, including regulation of glucose and lipid metabolism, improvement of insulin sensitivity, and alleviation of oxidative damage. Here, we investigated the reno-protective effects of berberine. EXPERIMENTAL APPROACH: We used samples from DKD patients and experiments with models of DKD (db/db mice) and cultured podocytes, to characterize energy metabolism profiles using metabolomics. Molecular targets and mechanisms involved in the regulation of mitochondrial function and bioenergetics by berberine were investigated, along with its effects on metabolic alterations in DKD mice. KEY RESULTS: Metabolomic analysis suggested altered mitochondrial fuel usage and generalized mitochondrial dysfunction in patients with DKD. In db/db mice, berberine treatment reversed the disordered metabolism, podocyte damage and glomerulosclerosis. Lipid accumulation, excessive generation of mitochondrial ROS, mitochondrial dysfunction, and deficient fatty acid oxidation in DKD mouse models and in cultured podocytes were suppressed by berberine. These protective effects of berberine were accompanied by activation of the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling pathway, which promoted mitochondrial energy homeostasis and fatty acid oxidation in podocytes. CONCLUSION AND IMPLICATIONS: PGC-1α-mediated mitochondrial bioenergetics could play a key role in lipid disorder-induced podocyte damage and development of DKD in mice. Restoration of PGC-1α activity and the energy homeostasis by berberine might be a potential therapeutic strategy against DKD.