Emodin alleviates arthritis pain through reducing spinal inflammation and oxidative stress.

Chronic pain is the predominant problem for rheumatoid arthritis patients, and negatively affects quality of life. Arthritis pain management remains largely inadequate, and developing new treatment strategies are urgently needed. Spinal inflammation and oxidative stress contribute to arthritis pain and represent ideal targets for the treatment of arthritis pain. In the present study, collagen-induced arthritis (CIA) mouse model was established by intradermally injection of type II collagen (CII) in complete Freund's adjuvant (CFA) solution, and exhibited as paw and ankle swelling, pain hypersensitivity and motor disability. In spinal cord, CIA inducement triggered spinal inflammatory reaction presenting with inflammatory cells infiltration, increased Interleukin-1ß (IL-1ß) expression, and up-regulated NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and cleaved caspase-1 levels, elevated spinal oxidative level presenting as decreased nuclear factor E2-related factor 2 (Nrf2) expression and Superoxide dismutase (SOD) activity. To explore potential therapeutic options for arthritis pain, emodin was intraperitoneally injected for 3 days on CIA mice. Emodin treatment statistically elevated mechanical pain sensitivity, suppressed spontaneous pain, recovered motor coordination, decreased spinal inflammation score and IL-1ß expression, increased spinal Nrf2 expression and SOD activity. Further, AutoDock data showed that emodin bind to Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) through two electrovalent bonds. And emodin treatment increased the phosphorylated AMPK at threonine 172. In summary, emodin treatment activates AMPK, suppresses NLRP3 inflammasome response, elevates antioxidant response, inhibits spinal inflammatory reaction and alleviates arthritis pain.

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.

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.

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.

Inhibitory effects of berberine on proinflammatory M1 macrophage polarization through interfering with the interaction between TLR4 and MyD88.

BACKGROUNDS: Inflammation is recognized as the key pathological mechanism of type 2 diabetes. The hypoglyceamic effects of berberine (BBR) are related to the inhibition of the inflammatory response, but the mechanism is not completely clear. METHODS: The inflammatory polarization of Raw264.7 cells and primary peritoneal macrophages were induced by LPS, and then effects and underlying mechanisms of BBR were explored. An inflammatory model was established by LPS treatment at different concentrations for different treatment time. An ELISA assay was used to detect the secretions of TNF-α. RT-PCR was applied to detect M1 inflammatory factors. The F4/80+ ratio and CD11c+ ratio of primary peritoneal macrophages were determined by flow cytometry. The expressions of p-AMPK and TLR4 were detected by Western blot. The cytoplasmic and nuclear distributions of NFκB p65 were observed by confocal microscopy. The binding of TLR4 to MyD88 was tested by CoIP, and the affinity of BBR for TLR4 was assessed by molecular docking. RESULTS: Upon exposure to LPS, the secretion of TNF-α and transcription of inflammatory factors in macrophages increased, cell morphology changed and protrusions appeared gradually, the proportion of F4/80+CD11c+ M1 macrophages increased, and the nuclear distribution of NFκB p65 increased. BBR pretreatment partially inhibited the changes mentioned above. However, the expression of TLR4 and p-AMPK did not change significantly after LPS intervention for 3 h. Meanwhile, CoIP showed that the interaction between TLR4 and MyD88 increased, and BBR inhibited the binding. Molecular docking suggested that BBR might interact with TLR4. CONCLUSIONS: Inflammatory changes were induced in macrophages after LPS stimulation for 3 h, and BBR pretreatment inhibited inflammatory polarization. BBR might interact with TLR4 and disturb TLR4/MyD88/NFκB signalling pathway, and it might be the mechanism by which BBR attenuated inflammation in the early phase.

A Systematic Review and Meta-analysis of Randomized Controlled Trials on the Effects of Turmeric and Curcuminoids on Blood Lipids in Adults with Metabolic Diseases.

Dyslipidemia is a global health problem and a high risk factor for atherosclerosis, which can lead to serious cardiovascular disease (CVD). Existing studies have shown inconsistent effects of turmeric and curcuminoids on blood lipids in adults. We performed this systematic review and meta-analysis to evaluate the effects of turmeric and curcuminoids on blood triglycerides (TG), total cholesterol (TC), LDL cholesterol, and HDL cholesterol. We searched the English databases of the Web of Science, PubMed, Ovid (including EMBASE and MEDLINE), Scopus, and the Cochrane Library and 2 Chinese databases, Wanfang Data and China National Knowledge Infrastructure, for randomized controlled trials (RCTs) that studied the effects of turmeric and curcuminoids on blood TG, TC, LDL cholesterol, and HDL cholesterol in subjects with metabolic diseases. With random-effects models, separate meta-analyses were conducted by using inverse-variance. The results are presented as the mean difference with 95% CIs. Evidence from 12 RCTs for TG, 14 RCTs for TC, 13 RCTs for LDL cholesterol, and 16 RCTs for HDL cholesterol showed that turmeric and curcuminoids could lower blood TG by -19.1 mg/dL (95% CI: -31.7, -6.46 mg/dL; P = 0.003), TC by -11.4 mg/dL (95% CI: -17.1, -5.74 mg/dL; P < 0.0001), and LDL cholesterol by -9.83 mg/dL (95% CI: -15.9, -3.74 mg/dL; P = 0.002), and increase HDL cholesterol by 1.9 mg/dL (95% CI: 0.31, 3.49 mg/dL; P = 0.02). In conclusion, turmeric and curcuminoids can significantly modulate blood lipids in adults with metabolic diseases. However, these findings should be interpreted cautiously because of the significant heterogeneity between included studies (I2 > 50%). There is a need for further RCTs in future.

Effects of Huanglian-Renshen-Decoction, a Fixed Mixture of Traditional Chinese Medicine, on the Improvement of Glucose Metabolism by Maintenance of Pancreatic ß Cell Identity in db/db Mice.

Huanglian-Renshen-Decoction (HRD) is widely used to treat type 2 diabetes mellitus (T2DM) in China. However, the underlying mechanism is unclear. We aimed to investigate the mechanism by which HRD regulates the glucose level. Forty 7-8-week-old db/db (BSK) mice were randomly assigned to the following four groups: model, low dose HRD (LHRD), high dose HRD (HHRD), and saxagliptin (SAX). Additionally, 10 db/m mice were assigned to control group. The experimental mice were administered 3.03g/kg/d and 6.06g/kg/d of HRD in the LHRD and HHRD groups, respectively, and 10mg/kg/d saxagliptin in the SAX group for 8 weeks. The control and model groups were supplied with distilled water. After the intervention, the pancreas and blood were collected and tested. Compared with that of model group, the fasting blood glucose (FBG) was significantly decreased in all intervention groups (p < 0.05 or 0.01), whereas fasting serum insulin (FINS) was increased significantly in both HHRD and SAX groups. The immunofluorescence images showed that the mass of insulin+ cells was increased and that of glucagon+ cells was reduced obviously in experimental groups compared to those of the model group. In addition, the coexpression of insulin, glucagon, and PDX1 was decreased in HHRD group, and the level of caspase 12 in islet was decreased significantly in all intervention groups. However, little difference was found in the number and morphology of islet, and the expression of ki67, bcl2, bax, caspase 3, and cleaved-caspase 3 in the pancreas among groups. Interestingly, the cleaved-Notch1 level was increased and the Ngn3 level in islet was decreased significantly in HHRD group. The HRD showed dose-dependent effects on glucose metabolism improvement through maintenance of ß cell identity via a mechanism that might involve the Notch1/Ngn3 signal pathway in db/db mice.

Effects of green tea on lipid metabolism in overweight or obese people: A meta-analysis of randomized controlled trials.

SCOPE: The effects of green tea on lipid metabolism were inconsistent. The objective of this meta-analysis was to evaluate the effects of green tea on lipid metabolism in overweight or obese people. METHODS AND RESULTS: We searched randomized controlled trials (RCTs) comparing green tea with a control on lipid metabolism on PUBMED and WEB OF SCIENCE (January 1990 to September 2016), COCHRANE and EMBASE (updated to October 2016), and the Chinese databases CNKI, WanFang and CBMD. Twenty-one articles studying 1704 overweight or obese subjects were selected for this meta-analysis. The pooled results demonstrated that green tea significantly decreased plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) levels in overweight or obese people. The weighted mean difference was -3.38 mg/dl for TC (95% CI: -6.42,  -0.33 mg/dL) and -5.29 mg/dL for LDL (95% CI: -7.92, -2.6 6 mg/dL), respectively. Green tea intake, however, showed no effect on plasma triglyceride (TG) and high-density lipoprotein cholesterol(HDL) levels in overweight or obese people with a relatively high heterogeneity. CONCLUSION: The meta-analysis shows that drinking green tea can lower plasma TC and LDL levels significantly. Nevertheless, green tea's effect on plasma TG and HDL must be further evaluated by additional high-quality and large-scale RCTs.

Quality of reporting of randomized clinical trials in tai chi interventions-a systematic review.

Objectives. To evaluate the reporting quality of published randomized clinical trials (RCTs) in the Tai Chi literature following the publication of the CONSORT guidelines in 2001. Data Sources. The OVID MEDLINE and PUBMED databases. Review Methods. To survey the general characteristics of Tai Chi RCTs in the literature, we included any report if (i) it was an original report of the trial; (ii) its design was RCT; (iii) one of the treatments being tested was Tai Chi; and (iv) it was in English. In addition, we assessed the reporting quality of RCTs that were published between 2002 and 2007, using a modified CONSORT checklist of 40 items. The adequate description of Tai Chi interventions in these trials was examined against a 10-item checklist adapted from previous reviews. Results. The search yielded 31 Tai Chi RCTs published from 2002 to 2007 and only 11 for 1992-2001. Among trials published during 2002-2007, the most adequately reported criteria were related to background, participant eligibility and interpretation of the study results. Nonetheless, the most poorly reported items were associated with randomization allocation concealment, implementation of randomization and the definitions of period of recruitment and follow-up. In addition, only 23% of RCTs provided adequate details of Tai Chi intervention used in the trials. Conclusion. The findings in this review indicated that the reporting quality of Tai Chi intervention trials is sub-optimal. Substantial improvement is required to meet the CONSORT guidelines and allow assessment of the quality of evidence. We believe that not only investigators, but also journal editors, reviewers and funding agencies need to follow the CONSORT guidelines to improve the standards of research and strengthen the evidence base for Tai Chi and for complementary and alternative medicine.

[Comparative study of the effects of Gypsum Fibrosum and Gypsum Fibrosum Preparatum in promoting granulation].

OBJECTIVE: To investigate the effects of Gypsum Fibrosum and Gypsum Fibrosum Preparatum in promoting granulation. METHODS: The wounds of muscle layer were produced in rats by using surgical operation. Two round wounds, with diameter about 1.5 cm, were cut at the depilatory area of two sides of the back of each rat, with an interval of 2 cm, deep to muscle layer, and the thickness of the knife wound of muscle layer was about 0.15 cm. Forty SD rats with the wounds were randomly divided into 4 groups: untreated group, beifuji-treated group, Gypsum Fibrosum-treated group and Gypsum Fibrosum Preparatum-treated group, with 10 rats in each group. Then the wounds were sprinkled with powders of Gypsum Fibrosum and Gypsum Fibrosum Preparatum, or sprayed with beifuji solution, respectively. The healing state of granulation tissues of the wounds was observed at the eighth and fourteenth day respectively. RESULTS: The number of fibroblasts, the number of capillary tubes and the area of capillary tubes in granulation tissue of wounds in the Gypsum Fibrosum Preparatum-treated group were significantly higher than those in the untreated group and Gypsum Fibrosum-treated group (P<0.01). There were no statistical differences between the Gypsum Fibrosum Preparatum-treated group and the beifuji-treated group. However, Gypsum Fibrosum-treated group showed no obvious differences compared to the untreated group (P>0.05). CONCLUSIONS: Gypsum Fibrosum Preparatum can accelerate the formation of collagenoblast and micrangium in wounds, and the proliferation of granulation tissues, thus promoting the skin wounds to healing. The effect of Gypsum Fibrosum is changed after being calcined, and Gypsum Fibrosum Preparatum has obvious effect in promoting granulation.

Modulation of isoflavones on bone-nodule formation in rat calvaria osteoblasts in vitro.

OBJECTIVE: To observe the effects of two main isoflavones, daidzein and genistein on the bone-nodule formation in rat calvaria osteoblasts in vitro. METHODS: Osteoblasts obtained from newborn Sprague-dawley rat calvaria were cultured for several generations. The second generation cells were cultured in Minimum Essential Medium supplemented with ascorbic acid and Na-beta-glycerophosphate for several days, in the presence of daidzein and genistein, with or without the estrogen receptor antagonist ICI 182780. Number of nodules was counted at the end of the incubation period (day 20) by staining with Alizarin Red S calcium stain. The release of osteocalcin, as a marker of osteoblast activity, was also determined on day 7 and day 12 during the incubation period. RESULTS: Compared with the control, the numbers of nodules were both increased by incubation with daidzein and genistein. 17 beta-estradiol was used as a positive control and proved to be a more effective inducer of the increase in bone-nodules formation that daidzein and genistein. The release of osteocalcin into culture media was also increased in the presence of daidzein and genistein, as well as 17 beta-estradiol on day 7 and day 12 (day 12 were higher). The estrogen receptor antagonist ICI 182780 completely blocked the genistein- and 17 beta-estradiol-induced increase of nodule numbers and osteocalcin release in osteoblasts. However, the effects induced by daidzein could not be inhibited by ICI 182780. CONCLUSION: These findings suggest that geinistein can stimulate bone-nodule formation and increase the release of osteocalcin in rat osteoblasts. The effects, like those induced by 17 beta-estradiol, are mediated by the estrogen receptor dependent pathway. Daidzein also can stimulate bone-nodule formation and increase the release of osteocalcin in rat osteoblasts, but it is not, at least not merely, mediated by the estrogen receptor dependent pathway.

Modulation of isoflavones on bone-nodule formation in rat calvaria osteoblasts in vitro / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To observe the effects of two main isoflavones, daidzein and genistein on the bone-nodule formation in rat calvaria osteoblasts in vitro.</p><p><b>METHODS</b>Osteoblasts obtained from newborn Sprague-dawley rat calvaria were cultured for several generations. The second generation cells were cultured in Minimum Essential Medium supplemented with ascorbic acid and Na-beta-glycerophosphate for several days, in the presence of daidzein and genistein, with or without the estrogen receptor antagonist ICI 182780. Number of nodules was counted at the end of the incubation period (day 20) by staining with Alizarin Red S calcium stain. The release of osteocalcin, as a marker of osteoblast activity, was also determined on day 7 and day 12 during the incubation period.</p><p><b>RESULTS</b>Compared with the control, the numbers of nodules were both increased by incubation with daidzein and genistein. 17 beta-estradiol was used as a positive control and proved to be a more effective inducer of the increase in bone-nodules formation that daidzein and genistein. The release of osteocalcin into culture media was also increased in the presence of daidzein and genistein, as well as 17 beta-estradiol on day 7 and day 12 (day 12 were higher). The estrogen receptor antagonist ICI 182780 completely blocked the genistein- and 17 beta-estradiol-induced increase of nodule numbers and osteocalcin release in osteoblasts. However, the effects induced by daidzein could not be inhibited by ICI 182780.</p><p><b>CONCLUSION</b>These findings suggest that geinistein can stimulate bone-nodule formation and increase the release of osteocalcin in rat osteoblasts. The effects, like those induced by 17 beta-estradiol, are mediated by the estrogen receptor dependent pathway. Daidzein also can stimulate bone-nodule formation and increase the release of osteocalcin in rat osteoblasts, but it is not, at least not merely, mediated by the estrogen receptor dependent pathway.</p>