Cuproptosis associated cytoskeletal destruction contributes to podocyte injury in chronic kidney disease.

The podocyte cytoskeleton determines the stability of podocyte structure and function, and their imbalance plays a pathogenic role in podocyte diseases. However, the underlying mechanism of podocyte cytoskeleton damage is not fully understood. Here, we investigate the specific role of cuproptosis in inducing podocyte cytoskeleton injury. In vitro and in vivo studies, exposure to high levels of copper and adriamycin (ADR) caused significant increases in copper concentration in intracellular and renal tissue. Moreover, excessive accumulation of copper induced cuproptosis, resulting in the destruction of the podocyte cytoskeleton. However, inhibition of copper accumulation to reduce cuproptosis also significantly alleviated the damage of podocyte cytoskeleton. In addition, inhibition of cuproptosis mitigated ADR-induced mitochondrial damage as well as the production of reactive oxygen species and depolarization of mitochondrial membrane potential, and restored ATP synthesis. Among the transcriptome sequencing data, the difference of CXCL5 was the most significant. Both high copper and ADR exposure can cause up-regulation of CXCL5, and CXCL5 deletion inhibits the occurrence of cuproptosis, thereby alleviating the podocyte cytoskeleton damage. This suggests that CXCL5 may act upstream of cuproptosis that mediates podocyte cytoskeleton damage. In conclusion, cuproptosis induced by excessive copper accumulation may induce podocyte cytoskeleton damage by promoting mitochondrial dysfunction, thereby causing podocyte injury. This indicates that cuproptosis plays an important role in the pathogenesis of podocyte injury and provides a basis for seeking potential targets for the treatment of chronic kidney disease.

Mitochondrial dysfunction in the pathophysiology of renal diseases.

Mitochondria are essential organelles in the human body, serving as the metabolic factory of the whole organism. When mitochondria are dysfunctional, it can affect all organs of the body. The kidney is rich in mitochondria, and its function is closely related to the development of kidney diseases. Studying the relationship between mitochondria and kidney disease progression is of great interest. In the past decade, scientists have made inspiring progress in investigating the role of mitochondria in the pathophysiology of renal diseases. This article discusses various mechanisms for maintaining mitochondrial quality, including mitochondrial energetics, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial DNA repair, mitochondrial proteolysis and the unfolded protein response, mitochondrial autophagy, mitochondria-derived vesicles, and mitocytosis. The article also highlights the cross talk between mitochondria and other organelles, with a focus on kidney diseases. Finally, the article concludes with an overview of mitochondria-related clinical research.

Inhibition of RAC attenuates Adriamycin-induced podocyte injury.

Minimal Change Disease (MCD), which is associated with podocyte injury, is the leading cause of nephrotic syndrome in children. A considerable number of patients experience relapses and require prolonged use of prednisone and immunosuppressants. Multi-drug resistance and frequent relapses can lead to disease progression to focal and segmental glomerulosclerosis (FSGS). To identify potential targets for therapy of podocyte injury, we examined microarray data of mRNAs in glomerular samples from both MCD patients and healthy donors, obtained from the GEO database. Differentially expressed genes (DEGs) were used to construct the protein-protein interactions (PPI) network through the application of the search tool for the retrieval of interacting genes (STRING) tool. The most connected genes in the network were ranked using cytoHubba. 16 hub genes were selected and validated by qRT-PCR. RAC2 was identified as a potential therapeutic target for further investigation. By downregulating RAC2, Adriamycin (ADR)-induced human podocytes (HPCs) injury was attenuated. EHT-1864, a small molecule inhibitor that targets the RAC (RAC1, RAC2, RAC3) family, proved to be more effective than RAC2 silencing in reducing HPCs injury. In conclusion, our research suggests that EHT-1864 may be a promising new molecular drug candidate for patients with MCD and FSGS.

How to Stabilize the Current of Efficient Inverted Flexible Perovskite Solar Cells at the Maximum Power Point.

Inverted flexible perovskite cells (fPSCs) have attracted much attention for their high efficiency and power per weight. Still, the steady-state output is one of the critical factors for their commercialization. In this paper, it is found that the steady-state current of inverted fPSCs based on nickel oxide nanoparticles (n-NiOx) continuously decreases under light illumination. Conversely, those based on magnetron-sputtered NiOx (sp-NiOx) exhibit the opposite result. Based on visualization of ion migration in the photoluminescence (PL) imaging microscopy tests, the discrepancies in the buried surfaces lead to the differences in ion migration in perovskite films, which triggers the temporary instability of the output current of devices during operation. The DFT theoretical calculation and experimental results reveal that NiOx films with different contents of Ni vacancies can modulate the crystallization of the perovskite films on the NiOx surfaces. Tuning the crystallization of the perovskite films is essential to stabilize the output current of fPSCs at a steady state. To demonstrate that, capsaicin is doped into the perovskite solutions to improve the quality of the perovskite buried interface. Finally, the corresponding fPSCs exhibit outstanding efficiency and stability during operation. These results provide valuable scientific guidance for fabricating fPSCs with stable operation under illumination conditions.

Copy number variants at 4q31.3 affecting the regulatory region of FBXW7 associated with neurodevelopmental delay.

Emerging research has demonstrated that genomic alterations disrupting topologically associated domains (TADs) and chromatin interactions underlie the pathogenic mechanisms of specific copy number variants (CNVs) in neurodevelopmental disorders. We report two patients with a de novo deletion and a duplication in chromosome 4q31, potentially causing FBX-related neurodevelopmental syndrome by affecting the regulatory region of FBXW7. High-throughput chromosome conformation capture (Hi-C) analysis using available capture data in neural progenitor cells revealed the rewiring of the TAD boundary close to FBXW7. Both patients exhibited facial dysmorphisms, cardiac and limb abnormalities, and neurodevelopmental delays, showing significant clinical overlap with previously reported FBXW7-related features. We also included an additional 10 patients with CNVs in the 4q31 region from the literature and the DECIPHER database for Hi-C analysis, which confirmed that disruption of the regulatory region of FBXW7 likely contributes to the developmental defects observed in these patients.

Arsenite-induced drug-drug interactions in rats.

Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute exposure of arsenite on activities of cytochrome P450 enzymes and pharmacokinetic behaviors of drugs in rats. Midazolam, tolbutamide, metoprolol, omeprazole, caffeine, and chlorzoxazone, the probe substrates for CYPs3A2, 2C6, 2D2, 2C11, 1A2, and 2E1, were selected as model drugs for the pharmacokinetic study. Significant decreases in AUCs of probe substrates were observed in rats after consecutive 30 day exposure to As at 12 mg/kg. Microsomal incubation study showed that the subacute exposure to arsenite resulted in little changes in effects on the activities of P450 enzymes examined. However, everted gut sac study demonstrated that such exposure induced significant decreases in intestinal absorption of these drugs by both passive diffusion and carrier-mediated transport. In addition, in vivo study showed that the arsenite exposure decreased the rate of peristaltic propulsion. The decreases in intestinal permeability of the probe drugs and peristaltic propulsion rate most likely resulted in the observed decreases in the internal exposure of the probe drugs. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents co-administered resulting from the observed drug-drug interactions. Significance Statement Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents co-administered resulting from the observed drug-drug interactions. In this study, we found that P450 enzyme probe drug exposure was reduced in arsenic-exposed animals (AUCs) and the intestinal absorption of the drug was reduced in the animals. Subacute arsenic exposure tends to cause damage to intestinal function, which leads to reduced drug absorption.

DY131 activates ERRγ/TFAM axis to protect against metabolic disorders and acute kidney injury.

Renal tubular injury is considered as the main pathological feature of acute kidney injury (AKI), and mitochondrial dysfunction in renal tubular cells is implicated in the pathogenesis of AKI. The estrogen-related receptor γ (ERRγ) is a member of orphan nuclear receptors which plays a regulatory role in mitochondrial biosynthesis, energy metabolism and many metabolic pathways. Online datasets showed a dominant expression of ERRγ in renal tubules, but the role of ERRγ in AKI is still unknown. In the present study, we investigated the role of ERRγ in the pathogenesis of AKI and the therapeutic efficacy of ERRγ agonist DY131 in several murine models of AKI. ERRγ expression was reduced in kidneys of AKI patients and AKI murine models along with a negative correlation to the severity of AKI. Consistently, silencing ERRγ in vitro enhanced cisplatin-induced tubular cells apoptosis, while ERRγ overexpression in vivo utilizing hydrodynamic-based tail vein plasmid delivery approach alleviated cisplatin-induced AKI. ERRγ agonist DY131 could enhance the transcriptional activity of ERRγ and ameliorate AKI in various murine models. Moreover, DY131 attenuated the mitochondrial dysfunction of renal tubular cells and metabolic disorders of kidneys in AKI, and promoted the expression of the mitochondrial transcriptional factor A (TFAM). Further investigation showed that TFAM could be a target gene of ERRγ and DY131 might ameliorate AKI by enhancing ERRγ-mediated TFAM expression protecting mitochondria. These findings highlighted the protective effect of DY131 on AKI, thus providing a promising therapeutic strategy for AKI.

Relationship between Serum Irisin Level, All-Cause Mortality, and Cardiovascular Mortality in Peritoneal Dialysis Patients.

INTRODUCTION: This study aimed to investigate the prospective role of serum irisin - a novel adipo-myokine - in all-cause mortality and cardiovascular (CV) mortality in patients on peritoneal dialysis (PD). METHODS: A prospectively observational study was conducted with 154 PD patients. Baseline clinical data were collected from the medical records. Serum irisin concentrations were determined using enzyme-linked immunosorbent assay. Patients were divided into the high irisin group (serum irisin ≥113.5 ng/mL) and the low irisin group (serum irisin <113.5 ng/mL) based on the median value of serum irisin. A body composition monitor was used to monitor body composition. Cox regression analysis was utilized to find the independent risk factors of all-cause and CV mortality in PD patients. RESULTS: The median serum irisin concentration was 113.5 ng/mL (interquartile range, 106.2-119.8 ng/mL). Patients in the high irisin group had significantly higher muscle mass and carbon dioxide combining power (CO2CP) than those in the low irisin group (p < 0.05). Serum irisin was positively correlated with pulse pressure, CO2CP, and muscle mass, while negatively correlated with body fat percentage (p < 0.05). During a median of follow-up for 60.0 months, there were 55 all-cause deaths and 26 CV deaths. Patients in the high irisin group demonstrated a higher CV survival rate than those in the low irisin group (p = 0.016). Multivariate Cox regression analysis showed that high irisin level (hazard ratio [HR], 0.341; 95% confidence interval [CI], 0.135-0.858; p = 0.022), age, and diabetic mellitus were independently associated with CV mortality in PD patients. However, serum irisin level failed to demonstrate a statistically significant relationship with all-cause mortality. CONCLUSION: Low serum irisin levels at baseline were independently predictive of CV mortality but not all-cause mortality in PD patients. Therefore, serum irisin could be a potential target for monitoring CV outcomes in PD patients.

Decoding active compounds and molecular targets of herbal medicine by high-throughput metabolomics technology: A systematic review.

Clinical experiences of herbal medicine (HM) have been used to treat a variety of human intractable diseases. As the treatment of diseases using HM is characterized by multi-components and multi-targets, it is difficult to determine the bio-active components, explore the molecular targets and reveal the mechanisms of action. Metabolomics is frequently used to characterize the effect of external disturbances on organisms because of its unique advantages on detecting changes in endogenous small-molecule metabolites. Its systematicity and integrity are consistent with the effective characteristics of HM. After HM intervention, metabolomics can accurately capture and describe the behavior of endogenous metabolites under the disturbance of functional compounds, which will be used to decode the bioactive ingredients of HM and expound the molecular targets. Metabolomics can provide an approach for explaining HM, addressing unclear clinical efficacy and undefined mechanisms of action. In this review, the metabolomics strategy and its applications in HM are systematically introduced, which offers valuable insights for metabolomics methods to characterizing the pharmacological effects and molecular targets of HM.

Increased serum methylmalonic acid levels were associated with the presence of cognitive dysfunction in older chronic kidney disease patients with albuminuria.

BACKGROUND: This study aimed to evaluate the correlation between serum methylmalonic acid (MMA) levels and cognition function in patients with chronic kidney disease (CKD). METHODS: In this cross-sectional study, we included 537 CKD individuals aged ≥ 60-year-old with albuminuria from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Four cognitive tests including the Digit Symbol Substitution Test (DSST), the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Delayed Recall and Word Learning tests, and the Animal Fluency test (AF) were performed. Associations between MMA and cognition scores were assessed with linear regression models. RESULTS: MMA level was negatively associated with residual renal function and nutrition status. After multivariate adjustment, elevated serum MMA levels were independently correlated with decline of cognition in CKD patients with albuminuria. CONCLUSION: Our study showed that higher serum MMA levels were independently associated with the presence of cognition dysfunction in CKD patients. The exact pathogenesis of MMA and cognition needs further research.

Changes in tuberculosis burden and its associated risk factors in Guizhou Province of China during 2006-2020: an observational study.

BACKGROUND: Understanding the trends of tuberculosis (TB) burden and its risk factors at the provincial level in the context of global End TB targets is crucial to identify the progress and challenges in TB control. We aimed to estimate the burden of TB and risk factors for death from 2006 to 2020 for the first time in Guizhou Province, China. METHODS: Data were collected from the national TB surveillance system. Four indicators of TB burden and their corresponding age-standardized rates (ASRs), including incidence (ASIR), prevalence (ASPR), mortality (ASMR) and disability-adjusted life years (DALYs) (ASDR), were estimated and stratified by year, age, gender and prefecture. Temporal trends of ASRs were presented by locally weighted regression, and the annual percentage change was calculated. The correlation between gross domestic product (GDP) per capita and ASRs was evaluated by Pearson correlation analysis. The associated risk factors for death in PTB patients were determined using logistic regression models. RESULTS: A total of 557,476 pulmonary TB (PTB) cases and 11,234 deaths were reported, including 2233 (19.9%) TB specific deaths and 9001 (80.1%) deaths from other causes. The 15-year average incidence, prevalence and mortality rates were 94.6, 102.6 and 2.1 per 100,000 population, respectively. The average DALY rate was 0.60 per 1000 population. The ASIR and ASPR have shown downward trends since 2012, with the largest percentage decrease in 2020 (ASIR: -29.8%; ASPR: -30.5%). The number in TB specific deaths consistently decreased during the study period (P<0.001), while the increase in deaths from other causes drove the overall upward trend in ASMR and ASDR. Four ASRs remained high in males and 5 prefectures. GDP per capita was negatively associated with the ASIR, ASPR and ASDR (P<0.05). Among PTB patients, men, patients with no fixed job, those with a low GDP level, patients with increasing age, those previously treated, those with severe symptoms, those transferred in and those receiving directly observed treatment were more likely to suffer death. CONCLUSION: Guizhou has made progress in reducing PTB cases and TB specific deaths over the last 15 years. Targeted interventions are needed to address these risk factors for death in PTB patients and high-risk areas.

Maximizing Polysaccharides and Phycoerythrin in Porphyridium purpureum via the Addition of Exogenous Compounds: A Response-Surface-Methodology Approach.

Phycoerythrin and polysaccharides have significant commercial value in medicine, cosmetics, and food industries due to their excellent bioactive functions. To maximize the production of biomass, phycoerythrin, and polysaccharides in Porphyridium purpureum, culture media were supplemented with calcium gluconate (CG), magnesium gluconate (MG) and polypeptides (BT), and their optimal amounts were determined using the response surface methodology (RSM) based on three single-factor experiments. The optimal concentrations of CG, MG, and BT were determined to be 4, 12, and 2 g L-1, respectively. The RSM-based models indicated that biomass and phycoerythrin production were significantly affected only by MG and BT, respectively. However, polysaccharide production was significantly affected by the interactions between CG and BT and those between MG and BT, with no significant effect from BT alone. Using the optimized culture conditions, the maximum biomass (5.97 g L-1), phycoerythrin (102.95 mg L-1), and polysaccharide (1.42 g L-1) concentrations met and even surpassed the model-predicted maximums. After optimization, biomass, phycoerythrin, and polysaccharides concentrations increased by 132.3%, 27.97%, and 136.67%, respectively, compared to the control. Overall, this study establishes a strong foundation for the highly efficient production of phycoerythrin and polysaccharides using P. purpureum.

Toxicity of the sunscreen UV filter benzophenone-3 (OBZ) to the microalga Selenastrum capricornutum: An insight into OBZ's damage to photosynthesis and respiration.

Oxybenzone (OBZ; benzophenone-3, CAS# 131-57-7), as a new pollutant and ultraviolet absorbent, shows a significant threat to the survival of phytoplankton. This study aims to explore the acute toxic effects of OBZ on the growth of the microalga Selenastrum capricornutum, as well as the mechanisms for its damage to the primary metabolic pathways of photosynthesis and respiration. The results demonstrated that the concentrations for 50 % of maximal effect (EC50) of OBZ for S. capricornutum were 9.07 mg L-1 and 8.54 mg L-1 at 72 h and 96 h, respectively. A dosage of 4.56 mg L-1 OBZ significantly lowered the photosynthetic oxygen evolution rate of S. capricornutum in both light and dark conditions for a duration of 2 h, while it had no effect on the respiratory oxygen consumption rate under darkness. OBZ caused a significant decline in the efficiency of photosynthetic electron transport due to its damage to photosystem II (PSII), thereby decreasing the photosynthetic oxygen evolution rate. Over-accumulated H2O2 was produced under light due to the damage caused by OBZ to the donor and acceptor sides of PSII, resulting in increased peroxidation of cytomembranes and inhibition of algal respiration. OBZ's damage to photosynthesis and respiration will hinder the conversion and reuse of energy in algal cells, which is an important reason that OBZ has toxic effects on S. capricornutum. The present study indicated that OBZ has an acute toxic effect on the microalga S. capricornutum. In the two most important primary metabolic pathways in algae, photosynthesis is more sensitive to the toxicity of OBZ than respiration, especially in the dark.

Molecular crosstalk and putative mechanisms underlying mitochondrial quality control: The hidden link with methylmercury-induced cognitive impairment.

Methylmercury (MeHg) is a neurotoxin associated with foetal neurodevelopmental and adult cognitive deficits. Neurons are highly dependent on the tricarboxylic acid cycle and oxidative phosphorylation to produce ATP and meet their high energy demands. Therefore, mitochondrial quality control (MQC) is critical for neuronal homeostasis. While existing studies have generated a wealth of data on the toxicity of MeHg, the complex cascades and molecular pathways governing the mitochondrial network remain to be elucidated. Here, 0.6, 1.2 and 2.4 mg/kg body weight of MeHg were administered intragastrically to pregnant Sprague Dawley rats to model maternal MeHg exposure. The results of the in vivo study revealed that MeHg-treated rats tended to perform more directionless repetitive strategies in the Morris Water Maze and fewer target-orientation strategies than control offspring. Moreover, pathological injury and synaptic toxicity were observed in the hippocampus. Transmission electron microscopy (TEM) demonstrated that the autophagosomes encapsulated damaged mitochondria, while showing a typical mitochondrial fission phenotype, which was supported by the activation of PINK1-dependent key regulators of mitophagy. Moreover, there was upregulation of DRP1 and FIS1. Additionally, MeHg compensation promoted mitochondrial biogenesis, as evidenced by the activation of the mitochondrial PGC1-α-NRF1-TFAM signalling pathway. Notably, SIRT3/AMPK was activated by MeHg, and the expression and activity of p-AMPK, p-LKB1 and SIRT3 were consistently coordinated. Collectively, these findings provide new insights into the potential molecular mechanisms regulating MeHg-induced cognitive deficits through SIRT3/AMPK MQC network coordination.

LC-MS based untargeted metabolomics studies of the metabolic response of Ginkgo biloba extract on arsenism patients.

Arsenic is an environmentally ubiquitous toxic metalloid. Chronic exposure to arsenic may lead to arsenicosis, while no specific therapeutic strategies are available for the arsenism patients. And Ginkgo biloba extract (GBE) exhibited protective effect in our previous study. However, the mechanisms by which GBE protects the arsenism patients remain poorly understood. A liquid chromatography-mass spectrometry (LC-MS) based untargeted metabolomics analysis was used to study metabolic response in arsenism patients upon GBE intervention. In total, 39 coal-burning type of arsenism patients and 50 healthy residents were enrolled from Guizhou province of China. The intervention group (n = 39) were arsenism patients orally administered with GBE (three times per day) for continuous 90 days. Plasma samples from 50 healthy controls (HC) and 39 arsenism patients before and after GBE intervention were collected and analyzed by established LC-MS method. Statistical analysis was performed by MetaboAnalyst 5.0 to identify differential metabolites. Multivariate analysis revealed a separation in arsenism patients between before (BG) and after GBE intervention (AG) group. It was observed that 35 differential metabolites were identified between BG and AG group, and 30 of them were completely or partially reversed by GBE intervention, with 14 differential metabolites significantly up-regulated and 16 differential metabolites considerably down-regulated. These metabolites were involved in promoting immune response and anti-inflammatory functions, and alleviating oxidative stress. Taken together, these findings indicate that the GBE intervention could probably exert its protective effects by reversing disordered metabolites modulating these functions in arsenism patients, and provide insights into further exploration of mechanistic studies.

Assessing the mechanisms and adjunctive therapy for arsenic-induced liver injury in rats.

Environmental arsenic exposure is a significant global public health concern. Previous studies have demonstrated the association between arsenic-induced liver injury and oxidative stress as well as ferroptosis. However, the knowledge of the interactions among these mechanisms remains limited. Moreover, there is a lack of research on potential therapeutic interventions for liver injury resulting from arsenic exposure. To address these limitations, we established a rat model with liver injury caused by arsenic exposure and investigated the impact of the nuclear factor E2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPx4) signaling pathway and ferroptosis on arsenic-induced liver injury. Our findings revealed that arsenic increased Nrf2 expression and decreased GPx4 expression in the rat liver. This was accompanied by a substantial generation of reactive oxygen species and disruption of the antioxidant defense system, ultimately promoting liver injury through ferroptosis. Subsequently, we conducted intervention experiments using Rosa roxburghii Tratt (RRT) in rats exposed to arsenic. The results showed that the detrimental effects mentioned earlier were partially alleviated following RRT intervention. This study offers preliminary evidence that persistent activation of Nrf2 by arsenic triggers an adaptive antioxidant response, leading to liver injury through the promotion of ferroptosis. Additionally, we discovered that RRT inhibits Nrf2-mediated adaptive antioxidant responses by reducing hepatic ferroptosis, thereby mitigating liver injury caused by arsenic exposure in rats. Our study contributes to a deeper understanding of the molecular mechanisms underlying liver injury resulting from arsenic exposure. Furthermore, our findings may facilitate the identification of a potential edible and medicinal plant extracts that could be utilized to develop a more effective adjunctive treatment approach.

Resveratrol alleviates perinatal methylmercury-induced neurobehavioral impairments by modulating the gut microbiota composition and neurotransmitter disturbances.

Methylmercury (MeHg), a potent neurotoxic substance, causes adverse health outcomes by modulating metabolites through altered gut microbiota patterns. Among the many metabolites, neurotransmitters play a particularly important role in the nervous system and behavior. Resveratrol (RSV) has been investigated as an antiaging, antioxidant, anti-inflammatory, and neuroprotective agent. The current study evaluated that RSV is protective of neurodevelopmental toxicity induced by MeHg and further explored the underlying mechanisms. Sprague-Dawley rats were treated with 1.2 mg/kg/d of MeHg, and the effects were evaluated after supplementation with RSV (20 mg/kg/d). The results indicated that MeHg had adverse effects on early neurodevelopmental indicators in the experimental group offspring as compared to control pups. Interestingly, RSV significantly improved the MeHg-induced delays in the neurobehavioral reflexes and reduced the total mercury (THg) concentration in the colons of the offspring rats. In agreement, RSV administration improved the gut microbiota diversity and structure by increasing the abundance of probiotics and upregulating the expression of tight junction proteins. It also ameliorated the MeHg-induced abnormalities in the expression profiles of neurotransmitters. Furthermore, eight key bacteria that were strongly linked with the neurotransmitters and neuroreflex parameters were identified. Taken together, these results demonstrate that RSV treatment effectively reduces the occurrence of neurodevelopmental toxicity caused by perinatal MeHg exposure by modulating the intestinal flora and neurotransmitter metabolism. These findings provide a new therapeutic approach for treating MeHg-induced neurotoxicity. The cover image is based on the Research Article Resveratrol alleviates perinatal methylmercury-induced neurobehavioral impairments by modulating the gut microbiota composition and neurotransmitter disturbances by Fang Chen et al., https://doi.org/10.1002/tox.23973.

Chronic arsenite exposure induced skeletal muscle atrophy by disrupting angiotensin II-melatonin axis in rats.

Arsenic is a well-known environmental toxicant and emerging evidence suggests that arsenic exposure has potential skeletal muscle toxicity; however, the underlying mechanism has not yet been clarified. The aim of this study was to investigate the correlation among adverse effects of subchronic and chronic environmental arsenic exposure on skeletal muscle as well as specific myokines secretion and angiotensin II (AngII)-melatonin (MT) axis in rats. Four-week-old rats were exposed to arsenite (iAs) in drinking water at environmental relevant concentration of 10 ppm for 3 or 9 months. Results indicated that the gastrocnemius muscle had atrophied and its mass was decreased in rats exposed to arsenite for 9 months, whereas, they had no significant changes in rats exposed to arsenite for 3 months. The levels of serum-specific myokine irisin and gastrocnemius muscle insulin-like growth factor-1 (IGF-1) were increased in 3-month exposure group and decreased in 9-month exposure group, while serum myostatin (MSTN) was increased significantly in 9-month exposure group. In addition, serum AngII level increased both in 3- and 9-month exposure groups, while serum MT level increased in 3-month exposure group and decreased in 9-month exposure group. Importantly, the ratio of AngII to MT level in serum increased gradually with the prolongation of arsenite exposure. It showed a certain correlation between AngII-MT axis and gastrocnemius muscle mass, gastrocnemius muscle level of IGF-1 or serum levels of irisin and MSTN. In conclusion, the disruption of AngII-MT axis balance may be a significant factor for skeletal muscle atrophy induced by chronic environmental arsenic exposure.

Metabolomics for Clinical Biomarker Discovery and Therapeutic Target Identification.

As links between genotype and phenotype, small-molecule metabolites are attractive biomarkers for disease diagnosis, prognosis, classification, drug screening and treatment, insight into understanding disease pathology and identifying potential targets. Metabolomics technology is crucial for discovering targets of small-molecule metabolites involved in disease phenotype. Mass spectrometry-based metabolomics has implemented in applications in various fields including target discovery, explanation of disease mechanisms and compound screening. It is used to analyze the physiological or pathological states of the organism by investigating the changes in endogenous small-molecule metabolites and associated metabolism from complex metabolic pathways in biological samples. The present review provides a critical update of high-throughput functional metabolomics techniques and diverse applications, and recommends the use of mass spectrometry-based metabolomics for discovering small-molecule metabolite signatures that provide valuable insights into metabolic targets. We also recommend using mass spectrometry-based metabolomics as a powerful tool for identifying and understanding metabolic patterns, metabolic targets and for efficacy evaluation of herbal medicine.

Yi-Shen-Hua-Shi regulates intestinal microbiota dysbiosis and protects against proteinuria in patients with chronic kidney disease: a randomized controlled study.

CONTEXT: Yi-Shen-Hua-Shi (YSHS) is a traditional Chinese medicine that treats chronic kidney disease (CKD). However, its efficacy in reducing proteinuria and underlying mechanisms is unknown. OBJECTIVE: This single-center randomized controlled trial explored whether YSHS could improve proteinuria and modulate the gut microbiota. MATERIALS AND METHODS: 120 CKD patients were enrolled and randomized to receive the renin-angiotensin-aldosterone system (RAAS) inhibitor plus YSHS (n = 56) or RAAS inhibitor (n = 47) alone for 4 months, and 103 patients completed the study. We collected baseline and follow-up fecal samples and clinical outcomes from participants. Total bacterial DNA was extracted, and the fecal microbiome was analyzed using bioinformatics. RESULTS: Patients in the intervention group had a significantly higher decrease in 24-h proteinuria. After 4 months of the YSHS intervention, the relative abundance of bacteria that have beneficial effects on the body, such as Faecalibacterium, Lachnospiraceae, Lachnoclostridium, and Sutterella increased significantly, while pathogenic bacteria such as the Eggerthella and Clostridium innocuum group decreased. However, we could not find these changes in the control group. Redundancy analysis showed that the decline in 24-h proteinuria during follow-up was significantly correlated with various taxa of gut bacteria, such as Lachnospiraceae and the Lachnoclostridium genus in the YSHS group. KEGG analysis also showed the potential role of YSHS in regulating glycan, lipid, and vitamin metabolism. DISCUSSION AND CONCLUSION: The YSHS granule reduced proteinuria associated with mitigating intestinal microbiota dysbiosis in CKD patients. The definite mechanisms of YSHS to improve proteinuria need to be further explored. TRIAL REGISTRATION: ChiCTR2300076136, retrospectively registered.