GSK3ß: A ray of hope for the treatment of diabetic kidney disease.

Diabetic kidney disease (DKD), a major microvascular complication of diabetes, is characterized by its complex pathogenesis, high risk of chronic renal failure, and lack of effective diagnosis and treatment methods. GSK3ß (glycogen synthase kinase 3ß), a highly conserved threonine/serine kinase, was found to activate glycogen synthase. As a key molecule of the glucose metabolism pathway, GSK3ß participates in a variety of cellular activities and plays a pivotal role in multiple diseases. However, these effects are not only mediated by affecting glucose metabolism. This review elaborates on the role of GSK3ß in DKD and its damage mechanism in different intrinsic renal cells. GSK3ß is also a biomarker indicating the progression of DKD. Finally, the protective effects of GSK3ß inhibitors on DKD are also discussed.

c-Cbl induced podocin ubiquitination contributes to the podocytes injury in diabetic nephropathy.

The ubiquitination function in diabetic nephropathy (DN) has attracted much attention, but there is a lack of information on its ubiquitylome profile. To examine the differences in protein content and ubiquitination in the kidney between db/db mice and db/m mice, we deployed liquid chromatography-mass spectrometry (LC-MS/MS) to conduct analysis. We determined 145 sites in 86 upregulated modified proteins and 66 sites in 49 downregulated modified proteins at the ubiquitinated level. Moreover, 347 sites among the 319 modified proteins were present only in the db/db mouse kidneys, while 213 sites among the 199 modified proteins were present only in the db/m mouse kidneys. The subcellular localization study indicated that the cytoplasm had the highest proportion of ubiquitinated proteins (31.87%), followed by the nucleus (30.24%) and the plasma membrane (20.33%). The enrichment analysis revealed that the ubiquitinated proteins are mostly linked to tight junctions, oxidative phosphorylation, and thermogenesis. Podocin, as a typical protein of slit diaphragm, whose loss is a crucial cause of proteinuria in DN. Consistent with the results of ubiquitination omics, the K261R mutant of podocin induced the weakest ubiquitination compared with the K301R and K370R mutants. As an E3 ligase, c-Cbl binds to podocin, and the regulation of c-Cbl can impact the ubiquitination of podocin. In conclusion, in DN, podocin ubiquitination contributes to podocyte injury, and K261R is the most significant site. c-Cbl participates in podocin ubiquitination and may be a direct target for preserving the integrity of the slit diaphragm structure, hence reducing proteinuria in DN.

ACSF2 and lysine lactylation contribute to renal tubule injury in diabetes.

AIMS: Lactate accumulation is reported to be a biomarker for diabetic nephropathy progression. Lactate drives lysine lactylation, a newly discovered post-translational modification that is involved in the pathogenesis of cancers and metabolic and inflammatory disease. Here, we aimed to determine whether lysine lactylation is involved in the pathogenesis of diabetic nephropathy. METHODS: Renal biopsy samples from individuals with diabetic nephropathy (n=22) and control samples from individuals without diabetes and kidney disease (n=9) were obtained from the First Affiliated Hospital of Zhengzhou University for immunohistochemical staining. In addition, we carried out global lactylome profiling of kidney tissues from db/m and db/db mice using LC-MS/MS. Furthermore, we assessed the role of lysine lactylation and acyl-CoA synthetase family member 2 (ACSF2) in mitochondrial function in human proximal tubular epithelial cells (HK-2). RESULTS: The expression level of lysine lactylation was significantly increased in the kidneys of individuals with diabetes as well as in kidneys from db/db mice. Integrative lactylome analysis of the kidneys of db/db and db/m mice identified 165 upregulated proteins and 17 downregulated proteins, with an increase in 356 lysine lactylation sites and a decrease in 22 lysine lactylation sites decreased. Subcellular localisation analysis revealed that most lactylated proteins were found in the mitochondria (115 proteins, 269 sites). We further found that lactylation of the K182 site in ACSF2 contributes to mitochondrial dysfunction. Finally, the expression of ACSF2 was notably increased in the kidneys of db/db mice and individuals with diabetic nephropathy. CONCLUSIONS: Our study strongly suggests that lysine lactylation and ACSF2 are mediators of mitochondrial dysfunction and may contribute to the progression of diabetic nephropathy. DATA AVAILABILITY: The LC-MS/MS proteomics data have been deposited in the ProteomeXchange Consortium database ( https://proteomecentral.proteomexchange.org ) via the iProX partner repository with the dataset identifier PXD050070.

Impaired distal renal potassium handling in streptozotocin-induced diabetic mice.

Diabetes is closely associated with K+ disturbances during disease progression and treatment. However, it remains unclear whether K+ imbalance occurs in diabetes with normal kidney function. In this study, we examined the effects of dietary K+ intake on systemic K+ balance and renal K+ handling in streptozotocin (STZ)-induced diabetic mice. The control and STZ mice were fed low or high K+ diet for 7 days to investigate the role of dietary K+ intake in renal K+ excretion and K+ homeostasis and to explore the underlying mechanism by evaluating K+ secretion-related transport proteins in distal nephrons. K+-deficient diet caused excessive urinary K+ loss, decreased daily K+ balance, and led to severe hypokalemia in STZ mice compared with control mice. In contrast, STZ mice showed an increased daily K+ balance and elevated plasma K+ level under K+-loading conditions. Dysregulation of the NaCl cotransporter (NCC), epithelial Na+ channel (ENaC), and renal outer medullary K+ channel (ROMK) was observed in diabetic mice fed either low or high K+ diet. Moreover, amiloride treatment reduced urinary K+ excretion and corrected hypokalemia in K+-restricted STZ mice. On the other hand, inhibition of SGLT2 by dapagliflozin promoted urinary K+ excretion and normalized plasma K+ levels in K+-supplemented STZ mice, at least partly by increasing ENaC activity. We conclude that STZ mice exhibited abnormal K+ balance and impaired renal K+ handling under either low or high K+ diet, which could be primarily attributed to the dysfunction of ENaC-dependent renal K+ excretion pathway, despite the possible role of NCC.NEW & NOTEWORTHY Neither low dietary K+ intake nor high dietary K+ intake effectively modulates renal K+ excretion and K+ homeostasis in STZ mice, which is closely related to the abnormality of ENaC expression and activity. SGLT2 inhibitor increases urinary K+ excretion and reduces plasma K+ level in STZ mice under high dietary K+ intake, an effect that may be partly due to the upregulation of ENaC activity.

Integrated analysis of RNA methylation regulators crosstalk and immune infiltration for predictive and personalized therapy of diabetic nephropathy.

BACKGROUND: RNA methylation is a widely known post-transcriptional regulation which exists in many cancer and immune system diseases. However, the potential role and crosstalk of five types RNA methylation regulators in diabetic nephropathy (DN) and immune microenvironment remain unclear. METHODS: The mRNA expression of 37 RNA modification regulators and RNA modification regulators related genes were identified in 112 samples from 5 Gene Expression Omnibus datasets. Nonnegative Matrix Factorization clustering method was performed to determine RNA modification patterns. The ssGSEA algorithms and the expression of human leukocyte antigen were employed to assess the immune microenvironment characteristics. Risk model based on differentially expression genes responsible for the modification regulators was constructed to evaluate its predictive capability in DN patients. Furthermore, the results were validated by using immunofluorescence co-localizations and protein experiments in vitro. RESULTS: We found 24 RNA methylation regulators were significant differently expressed in glomeruli in DN group compared with control group. Four methylation-related genes and six RNA regulators were introduced into riskScore model using univariate Logistic regression and integrated LASSO regression, which could precisely distinguish the DN and healthy individuals. Group with high-risk score was associated with high immune infiltration. Three distinct RNA modification patterns were identified, which has significant differences in immune microenvironment, biological pathway and eGFR. Validation analyses showed the METTL3, ADAR1, DNMT1 were upregulated whereas YTHDC1 was downregulated in DN podocyte cell lines comparing with cells cultured by the normal glucose. CONCLUSION: Our study reveals that RNA methylation regulators and immune infiltration regulation play critical roles in the pathogenesis of DN. The bioinformatic analyses combine with verification in vitro could provide robust evidence for identification of predictive RNA methylation regulators in DN.

Role of ferroptosis in chronic kidney disease.

Chronic kidney disease (CKD) has historically been a significant global health concern, profoundly impacting both life and well-being. In the process of CKD, with the gradual loss of renal function, the incidence of various life-threatening complications, such as cardiovascular diseases, cerebrovascular accident, infection and stroke, is also increasing rapidly. Unfortunately, existing treatments exhibit limited ability to halt the progression of kidney injury in CKD, emphasizing the urgent need to delve into the precise molecular mechanisms governing the occurrence and development of CKD while identifying novel therapeutic targets. Renal fibrosis, a typical pathological feature of CKD, plays a pivotal role in disrupting normal renal structures and the loss of renal function. Ferroptosis is a recently discovered iron-dependent form of cell death characterized by lipid peroxide accumulation. Ferroptosis has emerged as a potential key player in various diseases and the initiation of organ fibrosis. Substantial evidence suggests that ferroptosis may significantly contribute to the intricate interplay between CKD and its progression. This review comprehensively outlines the intricate relationship between CKD and ferroptosis in terms of iron metabolism and lipid peroxidation, and discusses the current landscape of pharmacological research on ferroptosis, shedding light on promising avenues for intervention. It further illustrates recent breakthroughs in ferroptosis-related regulatory mechanisms implicated in the progression of CKD, thereby providing new insights for CKD treatment. Video Abstract.

Novel immune cross-talk between inflammatory bowel disease and IgA nephropathy.

The mechanisms underlying the complex correlation between immunoglobulin A nephropathy (IgAN) and inflammatory bowel disease (IBD) remain unclear. This study aimed to identify the optimal cross-talk genes, potential pathways, and mutual immune-infiltrating microenvironments between IBD and IgAN to elucidate the linkage between patients with IBD and IgAN. The IgAN and IBD datasets were obtained from the Gene Expression Omnibus (GEO). Three algorithms, CIBERSORTx, ssGSEA, and xCell, were used to evaluate the similarities in the infiltrating microenvironment between the two diseases. Weighted gene co-expression network analysis (WGCNA) was implemented in the IBD dataset to identify the major immune infiltration modules, and the Boruta algorithm, RFE algorithm, and LASSO regression were applied to filter the cross-talk genes. Next, multiple machine learning models were applied to confirm the optimal cross-talk genes. Finally, the relevant findings were validated using histology and immunohistochemistry analysis of IBD mice. Immune infiltration analysis showed no significant differences between IBD and IgAN samples in most immune cells. The three algorithms identified 10 diagnostic genes, MAPK3, NFKB1, FDX1, EPHX2, SYNPO, KDF1, METTL7A, RIDA, HSDL2, and RIPK2; FDX1 and NFKB1 were enhanced in the kidney of IBD mice. Kyoto Encyclopedia of Genes and Genomes analysis showed 15 mutual pathways between the two diseases, with lipid metabolism playing a vital role in the cross-talk. Our findings offer insights into the shared immune mechanisms of IgAN and IBD. These common pathways, diagnostic cross-talk genes, and cell-mediated abnormal immunity may inform further experimental studies.

Novel Insight into Ferroptosis in Kidney Diseases.

BACKGROUND: Various kidney diseases such as acute kidney injury, chronic kidney disease, polycystic kidney disease, renal cancer, and kidney stones, are an important part of the global burden, bringing a huge economic burden to people around the world. Ferroptosis is a type of nonapoptotic iron-dependent cell death caused by the excess of iron-dependent lipid peroxides and accompanied by abnormal iron metabolism and oxidative stress. Over the past few decades, several studies have shown that ferroptosis is associated with many types of kidney diseases. Studying the mechanism of ferroptosis and related agonists and inhibitors may provide new ideas and directions for the treatment of various kidney diseases. SUMMARY: In this review, we discuss the differences between ferroptosis and other types of cell death such as apoptosis, necroptosis, pyroptosis, cuprotosis, pathophysiological features of the kidney, and ferroptosis-induced kidney injury. We also provide an overview of the molecular mechanisms involved in ferroptosis and events that lead to ferroptosis. Furthermore, we summarize the possible clinical applications of this mechanism among various kidney diseases. KEY MESSAGE: The current research suggests that future therapeutic efforts to treat kidney ailments would benefit from a focus on ferroptosis.

Population total and unbound pharmacokinetics and pharmacodynamics of ciprofol and M4 in subjects with various renal functions.

AIMS: The aim of this study was to develop a population pharmacokinetic (PK) model to simultaneously describe both total and unbound concentrations of ciprofol and its major glucuronide metabolite, M4, and to link it to the population pharmacodynamics (PD) model in subjects with various renal functions. METHODS: A total of 401 and 459 pairs of total and unbound plasma concentrations of ciprofol and M4, respectively, as well as 2190 bispectral index (BIS) data from 24 Chinese subjects with various renal functions were available. Covariates that may potentially contribute to the PK and PD variability of ciprofol were screened using a stepwise procedure. The optimal ciprofol induction dosing regimen was determined by model-based simulations. RESULTS: The PK of unbound ciprofol could best be described by a three-compartment model, while a two-compartment model could adequately describe unbound M4 PK. The concentrations of total and unbound ciprofol and M4 were linked using a linear protein binding model. The relationship between plasma concentrations of ciprofol and BIS data was best described by an inhibitory sigmoidal Emax model with a two-compartment biophase distribution compartment. Hemoglobin was the identified covariate determining the central compartment clearance of ciprofol; uric acid was a covariate affecting the central compartment clearance of M4 and protein binding rate, kB . The included covariates had no effect on the PD of ciprofol. Simulation results indicated that the label-recommended dose regimen was adequate for anaesthesia induction. CONCLUSIONS: The developed model fully characterized the population PK and PD profiles of ciprofol. No dose adjustment is required in patients with mild and moderate renal impairment.

3D asymmetric expectation-maximization attention network for brain tumor segmentation.

Automatic brain tumor segmentation on MRI is a prerequisite to provide a quantitative and intuitive assistance for clinical diagnosis and treatment. Meanwhile, 3D deep neural network related brain tumor segmentation models have demonstrated considerable accuracy improvement over corresponding 2D methodologies. However, 3D brain tumor segmentation models generally suffer from high computation cost. Motivated by a recently proposed 3D dilated multi-fiber network (DMF-Net) architecture that pays more attention to reduction of computation cost, we present in this work a novel encoder-decoder neural network, ie a 3D asymmetric expectation-maximization attention network (AEMA-Net), to automatically segment brain tumors. We modify DMF-Net by introducing an asymmetric convolution block into a multi-fiber unit and a dilated multi-fiber unit to capture more powerful deep features for the brain tumor segmentation. In addition, AEMA-Net further incorporates an expectation-maximization attention (EMA) module into the DMF-Net by embedding the EMA block in the third stage of skip connection, which focuses on capturing the long-range dependence of context. We extensively evaluate AEMA-Net on three MRI brain tumor segmentation benchmarks of BraTS 2018, 2019 and 2020 datasets. Experimental results demonstrate that AEMA-Net outperforms both 3D U-Net and DMF-Net, and it achieves competitive performance compared with the state-of-the-art brain tumor segmentation methods.

Inhibition of the glycogen synthase kinase 3ß-hypoxia-inducible factor 1α pathway alleviates NLRP3-mediated pyroptosis induced by high glucose in renal tubular epithelial cells.

NEW FINDINGS: What is the central question of this study? Activation of the glycogen synthase kinase 3 ß (GSK-3ß)-hypoxia-inducible factor 1 α (HIF-1α) pathway results in stimulation of pyroptosis under high glucose, and exerts actions in a number renal diseases: does this pathway have a role in renal tubular epithelial cells? What is the main finding and its importance? Down-regulation of GSK-3ß can inhibit pyroptosis of renal tubular epithelial cells induced by high glucose and this may be related to down-regulation of HIF-1α. This role of the GSK-3ß-HIF-1α pathway has not previously been reported and identifies a potential new therapeutic target in diabetic nephropathy. ABSTRACT: Diabetic nephropathy (DN) is not only one of the main complications of diabetes, but also has a high incidence rate and a high mortality rate. Glycogen synthase kinase 3 ß (GSK-3ß) and hypoxia-inducible factor 1 α (HIF-1α) have been demonstrated to influence DN by regulating pyroptosis. This study aimed to investigate the effect of the GSK-3ß-HIF-1α pathway on pyroptosis of high-glucose (HG)-induced renal tubular cells. Mouse renal proximal tubular epithelial cells (TKPT cells) were induced by HG to simulate DN cell and we transfected TKPT cells with GSK-3ß knockdown lentivirus. Western blot analysis confirmed the transfection effects and detected the expression of GSK-3ß, HIF-1α, Nod-like receptor protein 3 (NLRP3), cleaved-caspase-1, pro-caspase-1, gasdermin D (GSDMD) and GSDMD-N. The expression of GSDMD-N and HIF-1α were also verified by immunofluorescence. The levels of interleukin (IL)-1ß and IL-18 were measured by enzyme linked immunosorbent assay. Flow cytometric analysis determined the apoptosis rate. Results showed that HIF-1α expression was increased in HG-induced TKPT cells, and GSK-3ß knockdown could decrease the levels of NLRP3, cleaved-caspase-1, GSDMD-N and HIF-1α, verified by immunofluorescence. Moreover, GSK-3ß knockdown suppressed the expression of IL-1ß and IL-18, and reduced the apoptosis rate. Lithium chloride (LiCl) interference could cause the same changes as GSK-3ß knockdown for HG-induced TKPT cells, and dimethyloxallyl glycine could reverse the effect of GSK-3ß-knockdown interference. Our studies definitively demonstrate that the GSK-3ß-HIF-1α signalling pathway mediates HG-stimulated pyroptosis in renal tubular epithelial cells and that down-regulation of GSK-3ß inhibited HG-induced pyroptosis by inhibiting the expression of HIF-1α. These findings suggest a new potential target for the treatment of DN.

A Megabirnavirus Alleviates the Pathogenicity of Fusarium pseudograminearum to Wheat.

Fusarium pseudograminearum is a phytopathogen that causes wheat crown rot disease worldwide. Fusarium pseudograminearum megabirnavirus 1 (FpgMBV1) was isolated from the hypovirulent strain FC136-2A of F. pseudograminearum as a novel double-stranded RNA mycovirus belonging to the family Megabirnaviridae. Here we examined the effects of FpgMBV1 on colony morphology and pathogenicity of F. pseudograminearum. Through hyphal tip culture, we obtained virus-free progeny of strain FC136-2A, referred to as FC136-2A-V-. FpgMBV1 was transferred horizontally to another virus-free strain, WZ-8A-HygR-V-. The progeny obtained through horizontal transfer was referred to as WZ-8A-HygR-V+. Colony morphology was similar between the FpgMBV1-positive and -negative strains. The ability to penetrate cellophane in vitro was lost, and pathogenicity on wheat plants was reduced significantly in the FpgMBV1-positive strains relative to the FpgMBV1-negative strains. Microscopic observations showed a 6-h delay in the formation of appressoria-like structures in FC136-2A relative to FC136-2A-V-. Mycelium extension was significantly longer in wheat coleoptiles infected by WZ-8A-HygR-V- than in that infected by WZ-8A-HygR-V+ at 12 and 20 h after inoculation (hai). In addition, expression of five genes that encode cell wall-degrading enzymes differed significantly between FpgMBV1-positive and -negative strains at 12 and 20 hai during early infection of wheat cells by conidia. This study provides evidence for the hypovirulence effect of FpgMBV1 on F. pseudograminearum and suggests that the underlying mechanism involves unsuccessful early infection and perhaps cell wall degradation.

The first report of Lasiodiplodia theobromae causing leaf spot on Illicium verum in China.

Star anise (Illicium verum) production is an important industry in parts of southern China (Wang et al. 2011). The production of star anise (cultivar Dahong) was seriously affected by a leaf spot disease during the summer of 2020 in Rong County, Guangxi province, China. Approximately 20% to 30% of the trees (n = 200, 15-16 years old) had obvious leaf spots on more than 80% of the leaves. Local growers had to cut down the seriously diseased trees. Symptomatic samples were collected and sent to us at the end of August 2021. A single brown-edged round gray spot appeared on each leaf. The spot was ~20 mm in diameter. The margin was cut into 5 mm pieces, then disinfested with 3% NaOCl for 30 s, 75% ethanol for 30 s and sterile deionized water for 1 min before dried and placed on potato dextrose agar (PDA) medium at 25°C in the dark. A total of 25 fungal isolates were obtained (isolation rate 82%). Genomic DNAs was extracted from the mycelia of these isolates and three diagnostic regions including ITS1/ITS4 (White et al. 1990), EF1-728F/EF1-986R (Carbone and Kohn 1999) and Bt2a/Bt2b (Glass and Donaldson 1995) were amplified. The colony morphology on PDA and the sequences of the five isolates BJ20-1, BJ20-4, BJ20-5, BJ20-7, BJ20-8 were identical. Fungal colonies had light gray mycelium and black pigment on PDA. The average colony growth rate was 4.25±0.31 cm per day and no spores were produced. Sequences of the representative isolate BJ20-1 were deposited in GenBank (Accession nos. OK483326, OL547596 and OL547597). BLASTn search indicated high identity 99.6%, 98.58% and 100% to ITS (AY640255), EF1-α (AY640258), and ß-tubulin (KU887532) of Lasiodiplodia theobromae, respectively. Combined phylogenetic analysis using MEGAX (Kumar et al. 2018) clustered BJ20-1 and L. theobromae CBS164.96 in one clade. To test pathogenicity, 2-years-old healthy I. verum trees (cultivar Dahong) maintained in a greenhouse were inoculated. Leaves were surface sterilized with 70% ethanol. One PDA plug (5mm in diameter) was placed on each wound acupunctured with a sterile needle pick. Ten PDA plugs with mycelial of BJ20-1 growing 7 days on it were inoculated on five leaves. Four sterile PDA plugs placed on two leaves served as controls. All the plugs were removed from the leaves the day after inoculation. The experiment was repeated three times. At 1 day post-inoculation (DPI), brown expanding lesions were observed on the inoculated leaves. At 7 DPI, a mature ellipse of necrosis formed with 18±4 mm in diameter with black pycnidia in the center. Conidia were observed in the pycnidia. The immature conidia were thick-walled, hyaline, aseptate and ellipsoid, measuring 20 - 25.2 × 11 - 13 µm (n = 25). The mature conidia were dark brown with one central septum, measuring 24.3 - 27 × 13 - 14 µm (n = 25). At 10 DPI, the control leaves remained asymptomatic. Re-isolation was successful from the spot on the inoculated leaves. The colony morphology and molecular identification of the re-isolations were all the same as that of BJ20-1. In conclusion, the morphological and molecular evidence consistently indicated these isolates were L. theobromae. Koch's postulates were fulfilled that L. theobromae was pathogenic on star anise. Although L. theobromae has been reported to cause leaf spot disease on Camellia sinensis (Bao et al, 2021), Kadsura longipedunculata (Fan et al, 2020) and Broussonetia papyrifera (Luo et al, 2020), etc., this is the first report of L. theobromae causing leaf spot on I. verum in China. Due to the leaf spot disease resulting in serious yield reduction on star anise, accurate pathogen identification in this study would significantly improve the control of the leaf spot disease on star anise.

Comparison Between Radial Forearm Free Flap and Pectora is Major Myocutaneous Flap for Reconstruction in Oral Cavity Cancer Patients: Assessment of the Quality of Life.

ABSTRACT: We aimed to evaluate the quality of life of Chinese patients after immediate reconstruction surgery on individuals with oral cavity cancer. In addition, we compared the differences between radial forearm free flap and pectoralis major myocuta- neous flap. Using the University of Washington quality of life v4 questionnaire, 1:1 matched research was performed on patients received PMM or RFF flap. Chi-square test was used to analyze the variables. One hundred twenty four of 179 questionnaires were returned (69.3%). Age, N stage, and postoperative radiotherapy were similar for both groups. However, there were significant differences between two groups in gender, T stage, operation duration, and complication rate. Oral cavity cancer patients reconstructed with radial forearm free flap had better shoulder and speech functions but worse appearance domains. The results of our research provide important information for patients and physicians during their discussion of treatment programs for oral cavity cancers.

Screening and Mechanism of Novel Angiotensin-I-Converting Enzyme Inhibitory Peptides in X. sorbifolia Seed Meal: A Computer-Assisted Experimental Study Method.

Angiotensin-I-converting enzyme (ACE) inhibitors are used extensively to control hypertension. In this study, a computer-assisted experimental approach was used to screen ACE-inhibiting peptides from X. sorbifolum seed meal (XSM). The process conditions for XSM hydrolysis were optimized through the orthogonal experimental method combined with a database. The optimal conditions for ACE inhibition included an alkaline protease dose of 5%, 45 °C, 15 min and pH 9.5. The hydrolysate was analyzed by LC-MS/MS, and 10 optimal peptides were screened. Molecular docking results revealed four peptides (GGLPGFDPA, IMAVLAIVL, ETYFIVR, and INPILLPK) with ACE inhibitory potential. At 0.1 mg/mL, the synthetic peptides GGLPGFDPA, ETYFIVR, and INPILLPK provided ACE inhibition rates of 24.89%, 67.02%, and 4.19%, respectively. GGLPGFDPA and ETYFIVR maintained high inhibitory activities during in vitro digestions. Therefore, the XSM protein may be a suitable material for preparing ACE inhibitory peptides, and computer-assisted experimental screening is an effective, accurate and promising method for discovering new active peptides.

MiR-138 plays an important role in diabetic nephropathy through SIRT1-p38-TTP regulatory axis.

Diabetic nephropathy (DN) is the main cause of chronic kidney disease (CKD) and is one of the most common and serious complications of diabetes mellitus (DM). Sirtuin 1 (SIRT1) and tristetraprolin (TTP) are two important protective factors in DN; however, the regulatory relationship between SIRT1 and TTP, and the underneath mechanism are interesting but still unclear. Identifying the key factors that regulate SIRT1 or TTP may be of great value to the understanding and treatment of the DN. In this study, through systematic experimental methods, we found that the expression of miR-138 was significantly upregulated in DN clinical patient samples, and our experimental results suggested that miR-138 could bind the 3'-UTR of SIRT1 and inhibit its expression in both cultured podocytes and db/db mice kidney tissues. Furthermore, our in vitro and in vivo experiments also indicated miR-138 could target SIRT1 and affect TTP through p38 pathway. And downregulation of miR-138 attenuated podocyte injury and showed some extent of therapeutic effects in DN mice models. Our findings revealed that the regulatory axis of miR-138-SIRT1-p38-TTP might play a key role in DN. We believe that these findings may be of some value for deepening the understanding of DN and may serve as a reference for future treatment of this disease.

Large-scale importance of microbial carbon use efficiency and necromass to soil organic carbon.

Optimal methods for incorporating soil microbial mechanisms of carbon (C) cycling into Earth system models (ESMs) are still under debate. Specifically, whether soil microbial physiology parameters and residual materials are important to soil organic C (SOC) content is still unclear. Here, we explored the effects of biotic and abiotic factors on SOC content based on a survey of soils from 16 locations along a ~4000 km forest transect in eastern China, spanning a wide range of climate, soil conditions, and microbial communities. We found that SOC was highly correlated with soil microbial biomass C (MBC) and amino sugar (AS) concentration, an index of microbial necromass. Microbial C use efficiency (CUE) was significantly related to the variations in SOC along this national-scale transect. Furthermore, the effect of climatic and edaphic factors on SOC was mainly via their regulation on microbial physiological properties (CUE and MBC). We also found that regression models on explanation of SOC variations with microbial physiological parameters and AS performed better than the models without them. Our results provide the empirical linkages among climate, microbial characteristics, and SOC content at large scale and confirm the necessity of incorporating microbial biomass and necromass pools in ESMs under global change scenarios.

Fine Particulate Matter (PM2.5) and Chronic Kidney Disease.

The impact of ambient particulate matter (PM) on public health has become a great global concern, which is especially prominent in developing countries. For health purposes, PM is typically defined by size, with the smaller particles having more health impacts. Particles with a diameter <2.5 µm are called PM2.5. Initial research studies have focused on the impact of PM2.5 on respiratory and cardiovascular diseases; nevertheless, an increasing number of data suggested that PM2.5 may affect every organ system in the human body, and the kidney is of no exception. The kidney is vulnerable to particulate matter because most environmental toxins are concentrated by the kidney during filtration. According to the high morbidity and mortality related to chronic kidney disease, it is necessary to determine the effect of PM2.5 on kidney disease and its mechanism that needs to be identified. To understand the current status of PM2.5 in the atmosphere and their potential harmful kidney effects in different regions of the world this review article was prepared based on peer-reviewed scientific papers, scientific reports, and database from government organizations published after the year 1998. In this review, we focus on the worldwide epidemiological evidence linking PM2.5 with chronic kidney disease and the effect of PM2.5 on the chronic kidney disease (CKD) progression. At the same time, we also discuss the possible mechanisms of PM2.5 exposure leading to kidney damage, in order to emphasize the contribution of PM2.5 to kidney damage. A global database on PM2.5 and kidney disease should be developed to provide new ideas for the prevention and treatment of kidney disease.

Bacterially mediated release and mobilization of As/Fe coupled to nitrate reduction in a sediment environment.

Metal-reducing bacteria play an important role in the release and mobilization of arsenic from sediments into groundwater. This study aimed to investigate the influence of nitrate on arsenic bio-release. Microcosm experiments consisting of high arsenic sediments and indigenous bacterium Bacillus sp. D2201 were conducted and the effects of nitrate on the mobilization of As/Fe determined. The results show arsenic release is triggered by iron reduction, which is regulated by nitrate. Increasing the nitrate concentration from 0 to 1 and 3 mM decreased Fe(III) reduction by 62.5% and 16.9% and decreased As(V) bio-release by 41.5% and 85.5%, respectively. Moreover, the results of step-wise Wenzel sequential extractions indicate nitrate addition prevents the transformation of poorly crystalline iron oxides to well crystalline iron oxides. Overall, nitrate appears to have a dual effect, inhibiting both iron reduction and arsenic release by incubation strain D2201. This study offers new insights regarding the biogeochemistry of arsenic in groundwater systems.

Mediation and moderation analyses: exploring the complex pathways between hope and quality of life among patients with schizophrenia.

BACKGROUND: The underlying mechanism between hope and quality of life is as yet unknown. We aim to examine the potential mediating effect of depression and resilience and the moderated effect of sex in this well-established association. METHODS: Two hundred seven patients diagnosed with schizophrenia were administered a questionnaire battery that measured hope, depression, resilience and QOL. A multiple mediation model was used to examine the mediating effect of resilience and depression on the association between hope and QOL. A subgroup analysis was performed and a moderated mediation model was examined to find and test the moderated effect of sex on the mediation model. We used Mplus to perform moderation and mediation analyses so that the mediators and moderator could function together in the same model. RESULT: Sex was the moderator on the direct path between hope and QOL. The relationship between hope and QOL was mediated by resilience and depression in both sexes. When compared with female patients, the effect of hope on QOL was completely mediated by resilience and depression in males. In female patients, the model was partially mediated, and the direct effect of hope on QOL was significantly negatively correlated with the level of hope. CONCLUSION: We present a conceptual model containing the mediated effects of resilience and depression and the moderated effect of sex between hope and QOL, which we believe facilitates the understanding of these associations. This model should be useful in the formulation of strategies to improve QOL.