GSTT1/GSTM1 deficiency aggravated cisplatin-induced acute kidney injury via ROS-triggered ferroptosis.

Introduction: Cisplatin is a widely used chemotherapeutic agent prescribed to treat solid tumors. However, its clinical application is limited because of cisplatin- induced nephrotoxicity. A known complication of cisplatin is acute kidney injury (AKI). Deletion polymorphisms of GSTM1 and GSTT1, members of the glutathione S-transferase family, are common in humans and are presumed to be associated with various kidney diseases. However, the specific roles and mechanisms of GSTM1 and GSTT1 in cisplatin induced AKI remain unclear. Methods: To investigate the roles of GSTM1 and GSTT1 in cisplatin-induced AKI, we generated GSTM1 and GSTT1 knockout mice using CRISPR-Cas9 technology and assessed their kidney function under normal physiological conditions and cisplatin treatment. Using ELISA kits, we measured the levels of oxidative DNA and protein damage, along with MDA, SOD, GSH, and the GSH/GSSG ratio in wild-type and GSTM1/GSTT1 knockout mice following cisplatin treatment. Additionally, oxidative stress levels and the expression of ferroptosis-related proteins in kidney tissues were examined through Western blotting, qPCR, immunohistochemistry, and immunofluorescence techniques. Results: Here, we found that GSTT1 and GSTM1 were downregulated in the renal tubular cells of AKI patients and cisplatin-treated mice. Compared with WT mice, Gstm1/Gstt1-DKO mice were phenotypically normal but developed more severe kidney dysfunction and exhibited increased ROS levels and severe ferroptosis after injecting cisplatin. Discussion: Our study revealed that GSTM1 and GSTT1 can protect renal tubular cells against cisplatin-induced nephrotoxicity and ferroptosis, and genetic screening for GSTM1 and GSTT1 polymorphisms can help determine a standard cisplatin dose for cancer patients undergoing chemotherapy.

Recognition of differently expressed genes and DNA methylation markers in patients with Lupus nephritis.

Background and Objectives: Systemic lupus erythematosus (SLE) is distinguished by dysregulated immune system activity, resulting in a spectrum of clinical manifestations, with lupus nephritis being particularly prominent. This study endeavors to discern novel targets as potential therapeutic markers for this condition. Methods: Weighted correlation network analysis (WGCNA) was used to construct the network and select the key hub genes in the co-expression module based on the gene expression dataset GSE81622. Subsequently, functional enrichment and pathway analysis were performed for SLE and lupus nephritis. In addition, also identify genes and differences in SLE with lupus nephritis and methylation site. Finally, qRT-PCR and western blot were used to verify the up-regulated expression levels of the selected key genes. Results: Within the co-expression modules constructed by WGCNA, the MElightcyan module exhibited the strongest positive correlation with lupus nephritis (0.4, P = 0.003), while showing a weaker correlation with the control group SLE (0.058) and a negative correlation with the control group (-0.41, P = 0.002). Additionally, the MEgreenyellow module displayed the highest positive correlation with SLE (0.25), but its P value was 0.06, which did not reach statistical significance(P > 0.05). Furthermore, it had a negative correlation with the control group was (-0.38, P = 0.004). The module associated with lupus nephritis was characterized by processes such as neutrophil activation (neutrophil_activation), neutrophil degranulation (neutrophil_degranulation), neutrophil activation involved in immune response (neutrophil_activation_involved_in_immune_response), neutrophils mediated immune (neutrophil_mediated_immunity) and white blood cells degranulation (leukocyte_degranulation) and so on the adjustment of the process. Secondly, in the analysis of SLE samples, the identification of differentially expressed genes revealed 125 genes, with 49 being up-regulated and 76 down-regulated. In the case of lupus nephritis samples, 156 differentially expressed genes were discerned, include in 70 up-regulated and 86 down-regulated genes. When examining differential methylation sites, we observed 12432 such sites in the SLE sample analysis, encompassing 2260 hypermethylation sites and 10172 hypomethylation sites. In the lupus nephritis samples analysis, 9613 differential methylation sites were identified, comprising 4542 hypermethylation sites and 5071 hypomethylation sites. Substantiating our findings, experimental validation of the up-regulated genes in lupus nephritis confirmed increased levels of gene expression and protein expression for CEACAM1 and SLC2A5. Conclusions: We have identified several genes, notably CEACAM1 and SLC2A5, as potential markers for lupus nephritis. Their elevated expression levels and reduced DNA methylation in lupus nephritis contribute to a more comprehensive understanding of the aberrant epigenetic regulation of expression in this condition. These findings hold significant implications for the diagnosis and therapeutic strategies of lupus nephritis.

Metabolomic profiling reveals the step-wise alteration of bile acid metabolism in patients with diabetic kidney disease.

BACKGROUND: Diabetic kidney disease (DKD) is the major complication of diabetes concomitant with gut dysbiosis and glycometabolic disorder, which are strongly associated with bile acid (BA) metabolism. Yet studies investigating the BA metabolism involving in DKD pathogenesis are limited. This study aimed to explore the metabolomic profiling of BAs in DKD and analyze its association with DKD progression. METHODS: An ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established to quantify BAs in the plasma, fecal and urine samples of patients with DKD or T2DM and healthy individuals (n = 30 for each group). The key BAs associated with DKD were identified by orthogonal partial least-squares discriminant analysis (OPLS-DA) and receiver-operating characteristic (ROC) curve. Polynomial regression and Pearson's correlation analyses were performed to assess the correlation between the key BAs and the clinical indicators reflecting DKD progression. RESULTS: Metabolomic profiling of 50 kinds of BAs presented the markedly step-wise alterations of BAs in plasma and feces as well as the little in urine of patients with DKD. Eight kinds of BAs in the plasma, eight kinds in the feces and three kinds in the urine were abnormally expressed, accompanying with the increased conjugated/unconjugated ratios of cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid and hyocholic acid in the plasma, and of cholic acid, chenodeoxycholic acid and lithocholic acid in the feces. Moreover, the increased plasma level of glycochenodeoxycholic acid, and the increased fecal levels of glycolithocholic acid, 7-ketodeoxycholic acid and chenodeoxycholic acid-3-ß-D-glucuronide are strongly correlated with the clinical indicators reflecting DKD progression, including eGFR, 24 h urinary protein and 24 h urinary microalbumin. CONCLUSIONS: Our study for the first time disclosed the specific alterations of BA metabolism reflecting the step-wise progression of DKD, providing the basis for early identification and therapeutical strategies for DKD.

A 10-year retrospective cohort of diabetic patients in a large medical institution: Utilizing multiple machine learning models for diabetic kidney disease prediction.

Objective: As the prevalence of diabetes steadily increases, the burden of diabetic kidney disease (DKD) is also intensifying. In response, we have utilized a 10-year diabetes cohort from our medical center to train machine learning-based models for predicting DKD and interpreting relevant factors. Methods: Employing a large dataset from 73,101 hospitalized type 2 diabetes patients at The First Affiliated Hospital of Zhengzhou University, we analyzed demographic and medication data. Machine learning models, including XGBoost, CatBoost, LightGBM, Random Forest, AdaBoost, GBDT (gradient boosting decision tree), and SGD (stochastic gradient descent), were trained on these data, focusing on interpretability by SHAP. SHAP explains the output of the models by assigning an importance value to each feature for a particular prediction, enabling a clear understanding of how individual features influence the prediction outcomes. Results: The XGBoost model achieved an area under the curve (AUC) of 0.95 and an area under the precision-recall curve (AUPR) of 0.76, while CatBoost recorded an AUC of 0.97 and an AUPR of 0.84. These results underscore the effectiveness of these models in predicting DKD in patients with type 2 diabetes. Conclusions: This study provides a comprehensive approach for predicting DKD in patients with type 2 diabetes, employing machine learning techniques. The findings are crucial for the early detection and intervention of DKD, offering a roadmap for future research and healthcare strategies in diabetes management. Additionally, the presence of non-diabetic kidney diseases and diabetes with complications was identified as significant factors in the development of DKD.

The anabolism of volatile compounds during the pasteurization process of sea buckthorn (Hippophae rhamnoides) pulp.

Pasteurization (PS) causes the abnormal changes in volatiles and off-flavors in juices and limit the commercial production of juices. Herein, the first study on the biochemical reaction of volatile and nonvolatile compounds in response to PS factors during the process of sea buckthorn pulp (SBP) was evaluated. Processing conditions (mainly 80 °C for 20 min) had significant effects on the volatile and nonvolatile compounds. The restricted unsaturated fatty acid metabolism led to the greatest decrease of 20.25% in esters with fruity odor, and furans, smelling like caramel and toast, exhibited the highest increase of 136.40% because of the enhancement of the Maillard reaction. Dimethyl sulfide and dimethyl trisulfide elicited a cooked onion-like off-flavor, generated mainly from Strecker degradation of sulfur-containing amino acids, strengthened by the high pH and sufficient substrates due to the highest consumption rates of 4.66% and 12.01% for organic acids and sugars. Reasonable temperature and time control are crucial to the improvement of the process for PS for the SBP industry. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-024-05943-z.

RNA 5-Methylcytosine Modification: Regulatory Molecules, Biological Functions, and Human Diseases.

RNA methylation modifications influence gene expression, and disruptions of these processes are often associated with various human diseases. The common RNA methylation modification 5-methylcytosine (m5C), which is dynamically regulated by writers, erasers, and readers, widely occurs in transfer RNAs (tRNAs), messenger RNAs (mRNAs), ribosomal RNAs (rRNAs), enhancer RNAs (eRNAs), and other non-coding RNAs (ncRNAs). RNA m5C modification regulates metabolism, stability, nuclear export, and translation of RNA molecules. An increasing number of studies have revealed the critical roles of the m5C RNA modification and its regulators in the development, diagnosis, prognosis, and treatment of various human diseases. In this review, we summarized the recent studies on RNA m5C modification and discussed the advances in its detection methodologies, distribution, and regulators. Furthermore, we addressed the significance of RNAs modified with m5C marks in essential biological processes as well as in the development of various human disorders, from neurological diseases to cancers. This review provides a new perspective on the diagnosis, treatment, and monitoring of human diseases by elucidating the complex regulatory network of the epigenetic m5C modification.

Identification of amino acids metabolomic profiling in human plasma distinguishes lupus nephritis from systemic lupus erythematosus.

Lupus nephritis (LN) is an immunoinflammatory glomerulonephritis associated with renal involvement in systemic lupus erythematosus (SLE). Given the close relationship between plasma amino acids (AAs) and renal function, this study aimed to elucidate the plasma AA profiles in LN patients and identify key AAs and diagnostic patterns that distinguish LN patients from those with SLE and healthy controls. Participants were categorized into three groups: normal controls (NC), SLE, and LN. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to quantify AA levels in human plasma. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were utilized to identify key AAs. The diagnostic capacity of the models was assessed using receiver operating characteristic (ROC) curve analysis and area under the ROC curve (AUC) values. Significant alterations in plasma AA profiles were observed in LN patients compared to the SLE and NC groups. The OPLS-DA model effectively separated LN patients from the SLE and NC groups. A joint model using histidine (His), lysine (Lys), and tryptophan (Trp) demonstrated exceptional diagnostic performance, achieving an AUC of 1.0 with 100% sensitivity, specificity, and accuracy in predicting LN. Another joint model comprising arginine (Arg), valine (Val), and Trp also exhibited robust predictive performance, with an AUC of 0.998, sensitivity of 93.80%, specificity of 100%, and accuracy of 95.78% in distinguishing between SLE and LN. The joint forecasting models showed excellent predictive capabilities in identifying LN and categorizing lupus disease status. This approach provides a novel perspective for the early identification, prevention, treatment, and management of LN based on variations in plasma AA levels.

Liquiritigenin, an Active Ingredient of Liquorice, Alleviates Acute Kidney Injury by VKORC1-Mediated Ferroptosis Inhibition.

Acute kidney injury (AKI) is a major public health problem worldwide that still lacks effective treatments. Recent studies have suggested that ferroptosis is a key mediator of AKI due to its activation of lipid peroxidation. Therefore, we hypothesized that antiferroptosis agents might be a novel potential therapeutic strategy for AKI. Herein, we demonstrated that liquiritigenin (LG), an active ingredient of liquorice, improves renal function by inhibiting vitamin K epoxide reductase complex subunit 1 (VKORC1)-mediated ferroptosis, both in vivo and in vitro. In a folic acid-induced murine AKI model, after a single pre-treatment intravenous injection, LG markedly alleviated the loss of renal function through suppressing ferroptosis induced by iron accumulation. LG prevented mitochondrial morphological changes and upregulated glutathione and glutathione peroxidase 4 levels, while downregulating malonaldehyde and divalent iron levels. An in vitro RNA-sequence analysis suggested that the protective role of LG may involve upregulation of VKORC1. Moreover, knockdown of VKORC1 diminished the renal protective and antiferroptosis roles of LG. Collectively, our findings demonstrated that LG protected against AKI by inhibiting VKORC1-mediated ferroptosis. This suggests that inhibiting ferroptosis might be a novel therapeutic approach in the future.

Pharmacokinetic profiling of ZCL-278, a cdc42 inhibitor, and its effectiveness against chronic kidney disease.

ZCL-278 is a selective small molecule specifically inhibiting the Cdc42-intersectin interaction, yet its in-vivo pharmacokinetic and pharmacodynamic properties against renal diseases had not been determined. Thus, our study explored the absorption, distribution and excretion of ZCL-278 as well as its pharmacological efficacy against chronic kidney disease (CKD). With the optimized detection method, absolute oral bioavailability of ZCL-278 was determined as 10.99 % in male and 17.34 % in female rats. ZCL-278 was rapidly and abundantly distributed in various tissues, especially the kidney and heart, while few excreted through urine and feces. In the adenine-induced CKD mice, the increased plasma creatinine and urea, the decreased body weight as well as the renal pathological alterations, including vacuolization of renal tubular epithelial cells, granular degeneration, cell flattening, luminal dilation, and cylindruria, were significantly ameliorated after ZCL-278 administration. Moreover, ZCL-278 could also reverse the increased intensities of renal inflammation and fibrosis in the CKD mice. These results clarified the pharmacokinetics of ZCL-278 in rats and preliminarily indicated that ZCL-278 has favorable pharmacodynamic properties for CKD primed for lead development and optimization, warranting further drug development.

Perspectives on the involvement of the gut microbiota in salt-sensitive hypertension.

Salt-sensitivity hypertension (SSH) is an independent predictor of cardiovascular event-related death. Despite the extensiveness of research on hypertension, which covers areas such as the sympathetic nervous system, the renin-angiotensin system, the vascular system, and the immune system, its pathogenesis remains elusive, with sub-optimal blood pressure control in patients. The gut microbiota is an important component of nutritional support and constitutes a barrier in the host. Long-term high salt intake can lead to gut microbiota dysbiosis and cause significant changes in the expression of gut microbiota-related metabolites. Of these metabolites, short chain fatty acids (SCFAs), trimethylamine oxide, amino acids, bile acids, and lipopolysaccharide are essential mediators of microbe-host crosstalk. These metabolites may contribute to the incidence and development of SSH via inflammatory, immune, vascular, and nervous pathways, among others. In addition, recent studies, including those on the histone deacetylase inhibitory mechanism of SCFAs and the blood pressure-decreasing effects of H2S via vascular activation, suggest that several proteins and factors in the classical pathway elicit their effects through multiple non-classical pathways. This review summarizes changes in the gut microbiota and its related metabolites in high-salt environments, as well as corresponding treatment methods for SSH, such as diet management, probiotic and prebiotic use, antibiotic use, and fecal transplantation, to provide new insights and perspectives for understanding SSH pathogenesis and the development of strategies for its treatment.

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.

Defective natriuresis contributes to hyperkalemia in db/db mice during potassium supplementation.

OBJECTIVES: Potassium supplementation reduces blood pressure and the occurrence of cardiovascular diseases, with K + -induced natriuresis playing a potential key role in this process. However, whether these beneficial effects occur in diabetes remains unknown. METHODS: In this study, we examined the impact of high-K + intake on renal Na + /K + transport by determining the expression of major apical Na + transporters, diuretics responses (as a proxy for specific Na + transporter function), urinary Na + /K + excretion, and plasma Na + /K + concentrations in db/db mice, a model of type 2 diabetes mellitus. RESULTS: Although db/m mice exhibited increased fractional excretion of sodium (FE Na ) and fractional excretion of potassium (FE K ) under high-K + intake, these responses were largely blunted in db/db mice, suggesting impaired K + -induced natriuresis and kaliuresis in diabetes. Consequently, high-K + intake increased plasma K + levels in db/db mice, which could be attributed to the abnormal activity of sodium-hydrogen exchanger 3 (NHE3), sodium-chloride cotransporter (NCC), and epithelial Na + channel (ENaC), as high-K + intake could not effectively decrease NHE3 and NCC and increase ENaC expression and activity in the diabetic group. Inhibition of NCC by hydrochlorothiazide could correct the hyperkalemia in db/db mice fed a high-K + diet, indicating a key role for NCC in K + -loaded diabetic mice. Treatment with metformin enhanced urinary Na + /K + excretion and normalized plasma K + levels in db/db mice with a high-K + diet, at least partially, by suppressing NCC activity. CONCLUSION: Collectively, the impaired K + -induced natriuresis in diabetic mice under high-K + intake may be primarily attributed to impaired NCC-mediated renal K + excretion, despite the role of NHE3.

Ferroptosis: a potential bridge linking gut microbiota and chronic kidney disease.

Ferroptosis is a novel form of lipid peroxidation-driven, iron-dependent programmed cell death. Various metabolic pathways, including those involved in lipid and iron metabolism, contribute to ferroptosis regulation. The gut microbiota not only supplies nutrients and energy to the host, but also plays a crucial role in immune modulation and metabolic balance. In this review, we explore the metabolic pathways associated with ferroptosis and the impact of the gut microbiota on host metabolism. We subsequently summarize recent studies on the influence and regulation of ferroptosis by the gut microbiota and discuss potential mechanisms through which the gut microbiota affects ferroptosis. Additionally, we conduct a bibliometric analysis of the relationship between the gut microbiota and ferroptosis in the context of chronic kidney disease. This analysis can provide new insights into the current research status and future of ferroptosis and the gut microbiota.

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.

Exploring Physical Activity in Children and Adolescents with Disabilities: A Bibliometric Review of Current Status, Guidelines, Perceived Barriers, and Facilitators and Future Directions.

BACKGROUND: Physical activity contributes to both physiological and psychosocial benefits for children and adolescents with disabilities. However, the prevalence of physical inactivity is notably higher among disabled young people compared to their healthy peers. Despite this, there is a lack of constructed knowledge structure, evolutionary path, research hotspots, and frontiers in studies related to physical activity in young people with disabilities. METHODS: The literature related to the research of physical activity in children and adolescents with disabilities was retrieved from the core collection of the Web of Science. The annual publication numbers and the timing, frequency, and centrality of the co-occurrence network with respect to journals, countries, institutions, authors, references, and keywords were analyzed. Additionally, clustering analysis and burst analysis were performed on the references and keywords. All analyses were conducted using CiteSpace. RESULTS: A total of 1308 related articles were included. The knowledge structure of research on the physical activity of disabled children and adolescents, including annual publication numbers, influencing journals, countries, institutions, authors, references, and keywords along with their respective collaborative networks, has been constructed. Furthermore, the research foundation, current hot topics, and research frontiers have been identified by analyzing references and keywords. CONCLUSIONS: Current research hotspots include interventions, therapies, and programs aimed at enhancing specific skills, as well as addressing the satisfaction of competence to improve motivation and the effectiveness of physical activity. There is also a focus on the development of scales for quantitative studies. Future directions may be toward personalized interventions or programs to enhance physical activity levels among youth with disabilities.

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.

Evidence and causes of recent decreases in nitrogen deposition in temperate forests in Northeast China.

High reactive nitrogen (N) emissions due to anthropogenic activities in China have led to an increase in N deposition and ecosystem degradation. The Chinese government has strictly regulated reactive N emissions since 2010, however, determining whether N deposition has reduced requires long-term monitoring. Here, we report the patterns of N deposition at a rural forest site (Qingyuan) in northeastern China over the last decade. We collected 456 daily precipitation samples from 2014 to 2022 and analysed the temporal dynamics of N deposition. NH4+-N, NO3--N, and total inorganic N (TIN) deposition ranged from 10.5 ± 3.5 (mean ± SD), 6.1 ± 1.6, and 16.6 ± 4.7 kg N ha-1 year-1, respectively. Over the measurement period, TIN deposition at Qingyuan decreased by 55 %, whereas that in comparable sites in East Asia declined by 14-34 %. We used a random forest model to determine factors influencing the deposition of NH4+-N, NO3--N, and TIN during the study period. NH4+-N deposition decreased by 60 % because of decreased agricultural NH3 emissions. Furthermore, NO3--N deposition decreased by 42 %, due to reduced NOx emissions from agricultural soil and fossil fuel combustion. The steep decline in N deposition in northeastern China was attributed to reduced coal consumption, improved emission controls on automobiles, and shifts in agricultural practices. Long-term monitoring is needed to assess regional air quality and the impact of N emission control regulations.

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.

Emerging role of antidiabetic drugs in cardiorenal protection.

The global prevalence of diabetes mellitus (DM) has led to widespread multi-system damage, especially in cardiovascular and renal functions, heightening morbidity and mortality. Emerging antidiabetic drugs sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) have demonstrated efficacy in preserving cardiac and renal function, both in type 2 diabetic and non-diabetic individuals. To understand the exact impact of these drugs on cardiorenal protection and underlying mechanisms, we conducted a comprehensive review of recent large-scale clinical trials and basic research focusing on SGLT2i, GLP-1RAs, and DPP-4i. Accumulating evidence highlights the diverse mechanisms including glucose-dependent and independent pathways, and revealing their potential cardiorenal protection in diabetic and non-diabetic cardiorenal disease. This review provides critical insights into the cardiorenal protective effects of SGLT2i, GLP-1RAs, and DPP-4i and underscores the importance of these medications in mitigating the progression of cardiovascular and renal complications, and their broader clinical implications beyond glycemic management.

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.