Hexavalent Chromium Induces Neurotoxicity by Triggering Mitochondrial Dysfunction and ROS-Mediated Signals.

Hexavalent chromium (Cr (VI)), one of the most detrimental pollutants, has been ubiquitously present in the environment and causes serious toxicity to humans, such as hepatotoxicity, nephrotoxicity, pulmonary toxicity, and cardiotoxicity. However, Cr (VI)-induced neurotoxicity in primary neuron level has not been well explored yet. Herein, potassium dichromate (K2Cr2O7) was employed to examine the neurotoxicity of Cr (VI) in rat primary hippocampal neurons. MTT test was used to examine the neural viability. Mitochondrial dysfunction was assessed by the JC-1 probe and Mito-Tracker probe. DCFH-DA and Mito-SOX Red were utilized to evaluate the oxidative status. Bcl-2 family and MAPKs expression were investigated using Western blotting. The results demonstrated that Cr (VI) treatment dose- and time-dependently inhibited neural viability. Mechanism investigation found that Cr (VI) treatment causes mitochondrial dysfunction by affecting Bcl-2 family expression. Moreover, Cr (VI) treatment also induces intracellular reactive oxygen species (ROS) generation, DNA damage, and MAPKs activation in neurons. However, inhibition of ROS by glutathione (GSH) effectually balanced Bcl-2 family expression, attenuated DNA damage and the MAPKs activation, and eventually improved neural viability neurons. Collectively, these above results above suggest that Cr (VI) causes significant neurotoxicity by triggering mitochondrial dysfunction, ROS-mediated oxidative damage and MAKPs activation.

[Role of NLRP3 inflammasome in diabetic neuropathy and prevention and treatment with traditional Chinese medicine].

As one of the most frequent complications of diabetes, diabetic neuropathy often involves peripheral and central nervous systems. Neuroinflammation is the key pathogenic factor of secondary nerve injury in diabetes. NOD-like receptor pyrin domain-containing 3(NLRP3) inflammasome is a group of subcellular multiprotein complexes, including NLRP3, apoptosis associated speck-like protein(ASC), and pro-cysteinyl aspartate specific proteinase 1(pro-caspase-1). NLRP3 inflammasome is an inducer of innate immune responses. Its activation stimulates the inflammatory cascade reaction, promotes the release of inflammatory mediators, triggers cell death and uncontrolled autophagy, activates glial cells, facilitates peripheral immune cell infiltration, and initiates amyoid ß(Aß)-tau cascade reactions. As a result, it contributes to the central nerve, somatic nerve, autonomic nerve, and retinal nerve cell damage secondary to diabetes. Therefore, due to its key role in the neuroinflammation responses of the body, NLRP3 inflammasome may provide new targets for the treatment of diabetic neuropathy. With multi-target and low-toxicity advantages, traditional Chinese medicine plays a vital role in the treatment of diabetic neuropathy. Accumulating evidence has shown that traditional Chinese medicine exerts curative effects on diabetic neuropathy possibly through regulating NLRP3 inflammasome. Although the role of NLRP3 inflammasome in diabetes and related complications has been investigated in the literature, systematical studies on drugs and mechanism analysis for secondary neuropathy are still lacking. In this article, the role of NLRP3 inflammasome in diabetic neuropathy was explored, and the research progress on traditional Chinese medicine in the treatment of diabetic neuropathy through NLRP3 inflammasome was reviewed.

Gene expression and methylation profiles show the involvement of POMC in primary hyperparathyroidsm.

Primary hyperparathyroidism (PHPT) is mainly caused by parathyroid adenoma, which produces excess parathyroid hormones. Its pathogenic mechanisms have not yet been fully understood. To investigate the mechanism in the pathogenesis of PHPT, the transcriptome and genome-wide DNA methylation profiles of parathyroid adenoma were analyzed. The candidate genes that may be involved in the PHPT were verified via qRT-PCR, immunohistochemistry, western blot, and methylation-specific PCR. A total of 1650 differentially expressed genes and 2373 differentially methylated regions were identified. After the integration of its transcriptome and DNA methylation data, IL6, SYP, GNA01, and pro-opiomelanocortin (POMC) were the candidate genes that demonstrated a similar pattern between their mRNA expression and DNA methylation status. Of the 4 candidate genes, POMC, a pro-peptide which is processed to a range of bioactive peptide products like ACTH, was further confirmed to be expressed at low levels at both the mRNA and protein levels, which may be due to POMC promoter hypermethylation. Hypermethylation of the POMC promoter may contribute to its low expression, which may be involved in the pathogenesis of PHPT.

Efficacy of artemisinin and its derivatives in animal models of type 2 diabetes mellitus: A systematic review and meta-analysis.

Although current evidence suggests that artemisinin and its derivatives play a multitarget therapeutic role in type 2 diabetes mellitus (T2DM), their efficacy and safety remain under debate. This meta-analysis aimed to evaluate the effects and safety of artemisinin and its derivatives in T2DM animal models. Preclinical studies that met the inclusion criteria were retrieved from PubMed, Embase, Web of Science, Scopus, CINAHL, OpenGrey, Google Scholar, Psyclnfo, British Library Ethos, ProQuest Dissertations & Theses, China National Knowledge Internet, VIP Information Chinese Periodical Service Platform, Chinese Biomedicine Literature Database, and Wanfang Data Knowledge Service Platform. Twenty-two studies involving 526 animals were included in the meta-analysis. The RevMan 5.3 and Stata 15.0, were used to perform the statistical analyses. The overall results showed that artemisinin or its derivatives could significantly reduce fasting plasma glucose, 2-h plasma glucose (2hPG) in the intraperitoneal glucose tolerance test (IPGTT), 2hPG in the intraperitoneal insulin tolerance test (IPITT), glycated hemoglobin A1c, under the curve in the IPGTT/IPITT, total cholesterol, triglyceride, low-density lipoprotein cholesterol, free fatty acid, and urine volume. Although increase in body weight was observed due to administration of the compounds, no significant effect was observed regarding serum insulin. In terms of adverse reactions, only two of the included studies reported that high-dose artemether may cause digestive inhibition in mice. Our results suggest that artemisinins could improve several parameters related to glycolipid metabolism in T2DM animal models. However, to evaluate the antidiabetic effects and safety of artemisinins in a more accurate manner, additional preclinical studies are necessary.

Effects of cinnamon supplementation on lipid profiles among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Studies in animals and humans have reported numerous beneficial effects of cinnamon. However, its hypolipidemic efficacy in patients with metabolic syndrome (MetS) and related disorders is still controversial. This meta-analysis aimed to evaluate the lipid-regulating effects and safety of cinnamon in a population with MetS and related disorders. METHODS: Studies that met the inclusion criteria were retrieved from PubMed, Embase, Cochrane Library, and Web of Science. Randomized placebo-controlled trials of cinnamon or its extracts in the treatment of MetS and related metabolic diseases were the main eligibility criteria. The Cochrane Handbook was used to guide the study selection, quality assessment, and data analysis. All statistical analyses were performed using Stata 15.0. RESULTS: Twelve studies involving 773 subjects were included in the meta-analysis. The overall results showed that cinnamon could significantly reduce total cholesterol (weighted mean difference [WMD]: -0.19 mmol/L [-7.34 mg/dL]; 95% confidence interval [CI]: -0.24, -0.14 [-9.27, -5.41]), triglyceride (WMD: -0.10 mmol/L [-8.85 mg/dL]; 95% CI: -0.16, -0.04 [-14.16, -3.54]), and low-density lipoprotein cholesterol (WMD: -0.16 mmol/L [-6.18 mg/dL]; 95% CI: -0.20, -0.11 [-7.72, -4.25]). In the subgroup analysis, cinnamon did not exhibit a significant effect on lipid profiles in European and American patients. Larger doses of cinnamon tended to exhibit better regulation of lipid profiles and high-dose cinnamon (≥1.5 g/d) significantly increased high-density lipoprotein cholesterol (WMD: 0.07 mmol/L [2.70 mg/dL]; 95% CI: 0.03, 0.11 [1.16, 4.25]). CONCLUSION: The current evidence shows that cinnamon can regulate lipid profiles in patients with metabolic disorders.

Exploring the synergistic and complementary effects of berberine and paeoniflorin in the treatment of type 2 diabetes mellitus by network pharmacology.

Investigation of the synergistic and complementary effects is vital but difficult for Chinese herbal medicine. We explored the synergistic and complementary mechanisms of berberine (BBR) and paeoniflorin (PF) in the treatment of type 2 diabetes mellitus (T2DM) through network pharmacology and molecular docking. We identified putative targets of BBR, PF, and T2DM, and constructed a protein-protein interaction (PPI) network. Gene ontology and Kyoto encyclopedia of gene and genomes pathway enrichment analysis and molecular docking were used to predict the molecular mechanisms. A diabetes model was induced by a high-fat diet to verify the therapeutic effect. Ninety-two targets of BBR + PF in the treatment of T2DM were identified, which were considered as synergistic targets. Fifty-nine complementary targets of BBR-T2DM and 47 of PF-T2DM were identified. PPI network analysis showed that JAK2, ESR1, IFG1R, STAT3, EGFR, MAPK1, and AKT1 are closely related to T2DM. The enrichment analysis further showed that the synergistic targets mainly involved the AGE-RAGE signaling pathway in diabetic complications, FOXO, AMPK, and VEGF signaling pathways, and glycolysis/gluconeogenesis. AKT1, JAK2, and STAT3, which are common targets of the AGE-RAGE signaling pathway in diabetic complications and the FOXO signaling pathway, were chosen for docking with BBR and PF, respectively, and showed good binding activities. BBR + PF significantly reduced weight and fasting blood glucose, and alleviated insulin resistance. Moreover, BBR + PF promoted the phosphorylation of AKT1, JAK2, and STAT3. This study provides information to understand the synergistic and complementary mechanism of BBR + PF against T2DM, and may facilitate the development of new anti-T2DM drugs.

Protective Effect and Possible Mechanisms of Artemisinin and Its Derivatives for Diabetic Nephropathy: A Systematic Review and Meta-Analysis in Animal Models.

Background: Artemisinin and its derivatives have potential antidiabetic effects. There is no evaluation of reported studies in the literature on the treatment of diabetic nephropathy (DN), one of the commonest diabetic microangiopathies, with artemisinins. Here, we aimed to evaluate preclinical evidence for the efficacy and possible mechanisms of artemisinins in reducing diabetic renal injury. Methods: We conducted an electronic literature search in fourteen databases from their inception to November 2021. All animal studies assessing the efficacy and safety of artemisinins in DN were included, regardless of publication or language. Overall, 178 articles were screened according to predefined inclusion and exclusion criteria. Finally, 18 eligible articles were included in this systematic review. The SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool was used to assess the risk of bias in the included studies. The primary outcomes were kidney function, proteinuria, and renal pathology. Secondary endpoints included changes in fasting plasma glucose (FPG) levels, body weight, and relevant mechanisms. Results: Of the 18 included articles involving 418 animal models of DN, 1, 2, 6, and 9 used dihydroartemisinin, artemether, artesunate, and artemisinin, respectively. Overall, artemisinins reduced indicators of renal function, including blood urea nitrogen (P < 0.00001), serum creatinine (P < 0.00001), and kidney index (P = 0.0001) compared with control group treatment. Measurements of proteinuria (P < 0.00001), microalbuminuria (P < 0.05), and protein excretion (P = 0.0002) suggested that treatment with artemisinins reduced protein loss in animals with DN. Artemisinins may lower blood glucose levels (P = 0.01), but there is a risk of weight gain (P < 0.00001). Possible mechanisms of action of artemisinins include delaying renal fibrosis, reducing oxidative stress, and exerting antiapoptotic and anti-inflammatory effects. Conclusion: Available evidence suggests that artemisinins may be protective against renal injury secondary to diabetes in preclinical studies; however, high-quality and long-term trials are needed to reliably determine the balance of benefits and harms.

Study on the Mechanisms of Banxia Xiexin Decoction in Treating Diabetic Gastroparesis Based on Network Pharmacology.

In China, Banxia Xiexin decoction (BXD) is applied to treat diabetic gastroparesis (DGP), but its key active ingredients and mechanisms against DGP are unclear. This study is designated to reveal the molecular mechanisms of BXD in treating DGP by adopting a creative approach known as network pharmacology to explore the active ingredients and therapeutic targets of BXD. In our study, 730 differentially expressed genes of DGP were obtained, and 30 potential targets of BXD against DGP were screened out (including ADRB2, DRD1, FOS, MMP9, FOSL1, FOSL2, JUN, MAP2, DRD2, MYC, F3, CDKN1A, IL6, NFKBIA, ICAM1, CCL2, SELE, DUOX2, MGAM, THBD, SERPINE1, ALOX5, CXCL11, CXCL2, CXCL10, RUNX2, CD40LG, C1QB, MCL1, and ADCYAP1). Based on the findings, BXD contains 60 compounds with therapeutic effect on DGP, including the key active ingredients such as quercetin, wogonin, baicalein, beta-sitosterol, and kaempferol. Sixty-eight pathways including TNF signaling pathway, IL-17 signaling pathway, and AGE-RAGE signaling pathway were significantly enriched. In this study, the mechanisms of BXD in treating DGP are affirmed to be a complex network with multi-target and multi-pathway, which provides a reference for future experimental studies.

Effect of Fenugreek on vasomotor symptoms in menopausal women: A protocol for systematic review and meta-analysis.

BACKGROUND: Vasomotor symptoms (hot flashes or night sweats) are closely related to the impaired quality of life in menopausal women. Fenugreek is the ripe seed of Trigonella foenum graecum Linn. In China, this plant is used to relieve menopausal symptoms in women. Although recent studies have shown that fenugreek may have a good effect on the menopausal symptoms, there is no meta-analysis to systematically evaluate its efficacy in improving menopausal vasomotor symptoms. METHODS: Randomized controlled trials that met the inclusion criteria will be retrieved in 5 English online databases and 4 Chinese online databases. The primary outcomes are changes in frequency and intensity of vasomotor symptoms that measured by validated scales. The secondary outcomes will include quality of life, blood hormone parameters, blood biochemical parameters, and adverse events. Heterogeneity of data will be assessed by I and Cochrane Q statistics. Sensitivity analysis and subgroup analysis will be performed to explore the sources of heterogeneity. Egger test and Begg test will be used to assess the publication bias. Finally, we will evaluate the quality of evidence by the GRADE approach. All the data statistics will be performed using the STATA 15.0 software. RESULTS: All the results of will be published in a peer-reviewed journal. CONCLUSIONS: This meta-analysis will systematically evaluate the efficacy and safety of fenugreek in the treatment of menopausal vasomotor symptoms. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/3BCY8.

The efficacy and safety of acupoint injection for diabetic gastroparesis: A protocol for systematic review and meta-analysis.

BACKGROUND: Diabetic gastroparesis (DGP) is one of the common complications of diabetes. Accumulated evidences have shown that acupoint injection is beneficial for the clinical treatment of diabetic gastroparesis. However, there is currently no systematic review to assess this therapy. This program aims to evaluate the effectiveness and safety of this therapy for the patients with DGP. METHODS AND ANALYSIS: Literature search will be conducted via following electronic bibliographic databases from inception to Aug 2020: the Cochrane Library, PubMed, MEDLINE, Web of Science, EMBASE, Springer, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), Chinese Scientific Journal Database (VIP), Wan-Fang Database. All randomized controlled trials published in English or Chinese related to acupoint injection for DGP will be included. The primary outcome is the total effective rate. The secondary outcomes are the change of motilin and gastrin levels before and after the treatment. Two researchers will be responsible for the selection of study, extraction of data, and assessment of study quality independently. RevMan V5.3 Software will be used for assessing the risk of bias and synthesizing data. RESULTS: This study will provide a high-quality synthesis of current available evidence for the treatment of DGP with this therapy clinically. CONCLUSION: The conclusions of our study will provide new evidence to judge whether acupoint injection is an effective intervention for patients suffered from DGP. OSF REGISTRATION NUMBER:: osf.io/ms58j.

The efficacy and safety of Banxia-Houpo-Tang for chronic pharyngitis: A protocol for systematic review and meta analysis.

BACKGROUND: Chronic pharyngitis is a common disease with a dry throat, sore throat, pharyngeal itching, dry cough, and difficulty in swallowing, bringing inconvenience to patients' daily life. Banxia-Houpo-Tang (BHT) has proven to be effective in the treatment of chronic pharyngitis, yet its real extent is not well understood. To prove this point, we will perform a protocol for a systematic review and meta-analysis of BHT for chronic pharyngitis. METHODS/DESIGN: We will search for electronic databases both English and Chinese from inception to December 2019. Two experienced researchers select the qualified articles from: The Cochrane Library, EBM Reviews, OVID, Web of Science, PubMed, Chinese National Knowledge Infrastructure (CNKI), China Academic Journal Network Publishing Database (CAJD), China Biomedical Literature database (CBM), VIP Database for Chinese Technical Periodicals (VIP). Journal Integration Platform and WAN FANG Database. We select the appropriate searching language. The primary outcome was remission rate, and the secondary outcomes include clinical symptoms, clinical examination, adverse event. Data extraction and quality assessment will be conducted by 2 experienced researchers independently. Data analysis and the risk of bias assessment will be determined by RevMan 5.3 software. RESULTS: Based on the current proofs, we will get the exact evidence about the safety and effectiveness of BHT in the treatment of chronic pharyngitis. CONCLUSION: Our study is the first meta-analysis to evaluate the efficacy and safety of BHT in the treatment of chronic pharyngitis, and it will provide evidence for alternative treatment for the management of chronic pharyngitis. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/QNF6X.