Association of the podocyte phenotype with extracapillary hypercellularity in patients with diabetic kidney disease.

BACKGROUND: Extracapillary hypercellularity was recently identified as a poor prognostic factor for diabetic kidney disease (DKD), but its nature, pathogenesis, and relationship with glomerular sclerosis are still unclear. METHODS: We retrospectively studied 107 patients with biopsy-proven DKD, recruited from January 2018 through December 2020. We compared the clinicopathologic characteristics of 25 patients with extracapillary hypercellularity lesions (the extracapillary hypercellularity group) to those of 82 patients without extracapillary hypercellularity (the control group). Multiple cell-specific markers were used for immunohistochemical staining to analyse the types of cells that exhibited extracapillary hypercellularity. Podocyte phenotype changes were evaluated via immunohistochemical staining for Synaptopodin and Nephrin, and foot process width was measured via transmission electron microscopy. RESULTS: Patients with extracapillary hypercellularity lesions had more severe clinical features than patients without extracapillary hypercellularity in DKD, as indicated by elevated proteinuria and serum creatinine levels, and decreased serum albumin. Pathologically, extracapillary hypercellularity was accompanied by increased mesangial hyperplasia and interstitial fibrosis. Severe obliterative microvascular disease was observed more frequently in the extracapillary hypercellularity group than in the control group. At cell type analysis, 25 patients in the DKD-extracapillary hypercellularity group showed that a mixture of cells expressed either Wilm's tumor-1 or paired box protein 2. Furthermore, DKD-extracapillary hypercellularity patients had significant loss of podocyte phenotype and severe foot process effacement. Cells in extracapillary hypercellularity had increased hypoxia-induced factor-1 alpha expression. CONCLUSIONS: Extracapillary hypercellularity is associated with severe renal dysfunction and renal sclerosis. Vascular damage is closely related to severe podocyte hypoxia injury and requires additional attention in future research.

Inonotus obliquus (Chaga) against HFD/STZ-induced glucolipid metabolism disorders and abnormal renal functions by regulating NOS-cGMP-PDE5 signaling pathway.

Our prior investigations have established that Inonotus obliquus (Chaga) possesses hypoglycemic effects. Persistent hyperglycemia is known to precipitate renal function abnormalities. The functionality of the kidneys is intricately linked to the levels of cyclic guanosine-3',5'-monophosphate (cGMP), which are influenced by the activities of nitric oxide synthase (NOS) and phosphodiesterase (PDE). Enhanced cGMP levels can be achieved either through the upregulation of NOS activity or the downregulation of PDE activity. The objective of the current study is to elucidate the effects of Chaga on disorders of glucolipid metabolism and renal abnormalities in rats with type 2 diabetes mellitus (T2DM), while concurrently examining the NOS-cGMP-PDE5 signaling pathway. A model of T2DM was developed in rats using a high-fat diet (HFD) combined with streptozotocin (STZ) administration, followed by treatment with Chaga extracts at doses of 50 and 100 mg·kg-1 for eight weeks. The findings revealed that Chaga not only mitigated metabolic dysfunctions, evidenced by improvements in fasting blood glucose, total cholesterol, triglycerides, and insulin resistance, but also ameliorated renal function markers, including serum creatinine, urine creatinine (UCr), blood urea nitrogen, 24-h urinary protein, and estimated creatinine clearance. Additionally, enhancements in glomerular volume, GBM thickness, podocyte foot process width (FPW), and the mRNA and protein expressions of podocyte markers, such as nephrin and wilms tumor-1, were observed. Chaga was found to elevate cGMP levels in both serum and kidney tissues by increasing mRNA and protein expressions of renal endothelial NOS and neural NOS, while simultaneously reducing the expressions of renal inducible NOS and PDE5. In summary, Chaga counteracts HFD/STZ-induced glucolipid metabolism and renal function disturbances by modulating the NOS-cGMP-PDE5 signaling pathway. This research supports the potential application of Chaga in the clinical prevention and treatment of T2DM and diabetic nephropathy (DN), with cGMP serving as a potential therapeutic target.

Nomogram to predict the probability of clinical pregnancy in women with poor ovarian response undergoing in vitro fertilization/ intracytoplasmic sperm injection cycles.

BACKGROUND: Poor ovarian response (POR) is associated with decreased clinical pregnancy rates, emphasizing the need for developing clinical prediction models. Such models can improve prognostic accuracy, personalize medical interventions, and ultimately enhance live birth rates among patients with POR. OBJECTIVE: This study aims to develop and validate a prognostic model for predicting clinical pregnancy outcomes in individuals with POR undergoing in vitro fertilization/ intracytoplasmic sperm injection (IVF/ICSI) cycles. METHODS: A retrospective cohort of 969 patients with POR undergoing fresh embryo transfer cycles at the Reproductive Center of Fujian Maternal and Child Health Center from January 2018 to January 2022 was included. The cohort was randomly divided into model (n = 678) and validation (n = 291) groups in a 7:3 ratio. A single-factor analysis was performed on the model group to identify variables influencing clinical pregnancy. Optimal variables were selected using LASSO regression, and a clinical prediction model was constructed using multivariate logistic regression analysis. The model's calibration and discrimination were assessed using receiver operating characteristic (ROC) and calibration curves, while the clinical utility was evaluated using decision curve analysis. RESULTS: Multivariate logistic regression analysis revealed that the age of the women (odds ratio [OR] 0.936, 95% confidence interval [CI] 0.898-0.976, P = 0.002), body mass index (BMI) ≤ 24 (OR 2.748, 95% CI 1.724-4.492, P < 0.001), antral follicle count (AFC) (OR 1.232, 95% CI 1.073-1.416, P = 0.003), anti-Müllerian hormone (AMH) (OR 1.67, 95% CI 1.178-2.376, P = 0.004), number of mature oocytes (OR 1.227, 95% CI 1.075-1.403, P = 0.003), number of embryos transferred (OR 1.692, 95% CI 1.132-2.545, P = 0.011), and transfer of high-quality embryos (OR 3.452, 95% CI 1.548-8.842, P = 0.005) were independent predictors of clinical pregnancy in patients with POR. According to the receiver operating characteristic (ROC) analysis, the prediction model exhibited an area under the curve (AUC) of 0.752 (0.714, 0.789) in the model group and 0.765 (0.708, 0.821) in the validation group. The clinical decision curve demonstrated that the model held maximum clinical utility in both cohorts when the threshold probability of clinical pregnancy ranged from 6-81% to 12-82%, respectively. CONCLUSION: Clinical pregnancy outcomes in patients with POR who underwent IVF/ICSI treatment were influenced by several independent factors, including the age of the women, BMI, AFC, AMH, number of mature oocytes, number of embryos transferred, and transfer of high-quality embryos. A clinical prediction model based on these factors exhibited favorable clinical predictive and applicative value. Therefore, this model can serve as a valuable tool for clinical prognosis, intervention, and facilitating personalized medical treatment.

Gut microbiota mediates the protective effects of ß-hydroxybutyrate against cisplatin-induced acute kidney injury.

The gut microbiota has been reported to be perturbed by chemotherapeutic agents and to modulate side effects. However, the critical role of ß-hydroxybutyrate (BHB) in the regulation of the gut microbiota and the pathogenesis of chemotherapeutic agents related nephrotoxicity remains unknown. We conducted a comparative analysis of the composition and function of gut microbiota in healthy, cisplatin-challenged, BHB-treated, and high-fat diet-treated mice using 16 S rDNA gene sequencing. To understand the crucial involvement of intestinal flora in BHB's regulation of cisplatin -induced nephrotoxicity, we administered antibiotics to deplete the gut microbiota and performed fecal microbiota transplantation (FMT) before cisplatin administration. 16 S rDNA gene sequencing analysis demonstrated that both endogenous and exogenous BHB restored gut microbiota dysbiosis and cisplatin-induced intestinal barrier disruption in mice. Additionally, our findings suggested that the LPS/TLR4/NF-κB pathway was responsible for triggering renal inflammation in the gut-kidney axis. Furthermore, the ablation of the gut microbiota ablation using antibiotics eliminated the renoprotective effects of BHB against cisplatin-induced acute kidney injury. FMT also confirmed that administration of BHB-treated gut microbiota provided protection against cisplatin-induced nephrotoxicity. This study elucidated the mechanism by which BHB affects the gut microbiota mediation of cisplatin-induced nephrotoxicity by inhibiting the inflammatory response, which may help develop novel therapeutic approaches that target the composition of the microbiota.

Effect of Telitacicept on Circulating Gd-IgA1 and IgA-Containing Immune Complexes in IgA Nephropathy.

Introduction: Telitacicept, a transmembrane activator and cyclophilin ligand interactor (TACI) fusion protein targeting B cell activating factor and a proliferation-inducing ligand (APRIL), has proven efficacy in treating Immunoglobulin A (IgA) nephropathy (IgAN). However, serum biomarkers that could predict the clinical response during the treatment remain unclear. Methods: Plasma samples from 24 participants in the phase 2 clinical trial were collected at baseline and after 4, 12, and 24 weeks; with 8 participants in the placebo group, 9 in the 160 mg group, and 7 in the 240 mg group. We measured the levels of galactose-deficient-IgA1 (Gd-IgA1), IgA-containing immune complexes, C3a, C5a, and sC5b-9. The association between the changes in these markers and proteinuria reduction was analyzed. Results: After 24 weeks of treatment, Gd-IgA1 decreased by 43.9% (95% confidence interval: 29.8%, 55.1%), IgG-IgA immune complex by 31.7% (14.4%, 45.5%), and poly-IgA immune complex by 41.3% (6.5%, 63.1%) in the 160 mg group; Gd-IgA1 decreased by 50.4% (38.6%, 59.9%), IgG-IgA immune complex decreased by 42.7% (29.5%, 53.4%), and poly-IgA immune complex decreased by 67.2% (48.5%,79.1%) in the 240 mg group. There were no significant changes in the circulatory C3a, C5a, or sC5b-9 levels during telitacicept treatment. Decreases in both plasma Gd-IgA1 and IgG-IgA or poly-IgA immune complexes were associated with proteinuria reduction. In turn, IgG-IgA or poly-IgA immune complexes showed a dose-dependent effect, consistent with proteinuria reduction during telitacicept treatment. Conclusion: Telitacicept lowered both circulating Gd-IgA1 and IgA-containing immune complexes, whereas IgA immune complex levels were more consistent with decreased proteinuria.

ß-Hydroxybutyrate Protects Against Cisplatin-Induced Renal Damage via Regulating Ferroptosis.

Cisplatin is a particularly potent antineoplastic drug. However, its usefulness is restricted due to the induction of nephrotoxicity. More recent research has indicated that ß-hydroxybutyrate (ß-HB) protects against acute or chronic organ damage as an efficient healing agent. Nonetheless, the therapeutic mechanisms of ß-HB in acute kidney damage caused by chemotherapeutic drugs remain unclear. Our study developed a model of cisplatin-induced acute kidney injury (AKI), which involved the administration of a ketogenic diet or ß-HB. We analyzed blood urea nitrogen (BUN) and creatinine (Cr) levels in serum, and used western blotting and immunohistochemical staining to assess ferroptosis and the calcium/calmodulin-dependent kinase kinase 2 (Camkk2)/AMPK pathway. The mitochondrial morphology and function were examined. Additionally, we conducted in vivo and in vitro experiments using selective Camkk2 inhibitor or activator to investigate the protective mechanism of ß-HB on cisplatin-induced AKI. Exogenous or endogenous ß-HB effectively alleviated cisplatin-induced abnormally elevated levels of BUN and Cr and renal tubular necrosis in vivo. Additionally, ß-HB reduced ferroptosis biomarkers and increased the levels of anti-ferroptosis biomarkers in the kidney. ß-HB also improved mitochondrial morphology and function. Moreover, ß-HB significantly attenuated cisplatin-induced cell ferroptosis and damage in vitro. Furthermore, western blotting and immunohistochemical staining indicated that ß-HB may prevent kidney injury by regulating the Camkk2-AMPK pathway. The use of the Camkk2 inhibitor or activator verified the involvement of Camkk2 in the renal protection by ß-HB. This study provided evidence of the protective effects of ß-HB against cisplatin-induced nephrotoxicity and identified inhibited ferroptosis and Camkk2 as potential molecular mechanisms.

ß-HB protects against cisplatin-induced renal damage both in vivo and in vitro.Moreover, ß-HB is effective in attenuating cisplatin-induced lipid peroxidation and ferroptosis.The regulation of energy metabolism, as well as the treatment involving ß-HB, is associated with Camkk2.

Expression and significance of SIRT6 in human peritoneal dialysis effluents and peritoneal mesothelial cells.

Sirtuin 6 (SIRT6) can inhibit the fibrosis of many organs. However, the relationship between SIRT6 and peritoneal fibrosis (PF) in peritoneal dialysis (PD) remains unclear. We collected 110 PD patients with a duration of PD for more than 3 months and studied the influence of PD duration and history of peritonitis on SIRT6 levels in PD effluents (PDEs). We also analyzed the relationship between SIRT6 levels in PDEs and transforming growth factor beta 1 (TGF-ß1), IL-6, PD duration, peritoneal function, PD ultrafiltration (UF), and glucose exposure. We extracted human peritoneal mesothelial cells (HPMCs) from PDEs and measured the protein and gene expression levels of SIRT6, E-cadherin, vimentin, and TGF-ß1 in these cells. Based on the clinical results, we used human peritoneal mesothelial cells lines (HMrSV5) to observe the changes in SIRT6 levels and mesothelial-to-mesenchymal transition (MMT) after intervention with PD fluid. By overexpressing and knocking down SIRT6 expression, we investigated the effect of SIRT6 expression on E-cadherin, vimentin, and TGF-ß1 expression to elucidate the role of SIRT6 in mesothelial-to-epithelial transition in PMCs. Results: (1) With the extension of PD duration, the influence of infection on SIRT6 levels in PDEs increased. Patients with the PD duration of more than 5 years and a history of peritonitis had the lowest SIRT6 levels. (2) SIRT6 levels in PDEs were negatively correlated with PD duration, total glucose exposure, TGF-ß1, IL-6 levels, and the dialysate-to-plasma ratio of creatinine (Cr4hD/P), but positively correlated with UF. This indicates that SIRT6 has a protective effect on the peritoneum. (3) The short-term group (PD ≤ 1 year) had higher SIRT6 and E-cadherin gene and protein levels than the mid-term group (1 year < PD ≤ 5 years) and long-term group (PD > 5 years) in PMCs, while vimentin and TGF-ß1 levels were lower in the mid-term group and long-term group. Patients with a history of peritonitis had lower SIRT6 and E-cadherin levels than those without such a history. (4) After 4.25% PD fluid intervention for HPMCs, longer intervention time resulted in lower SIRT6 levels. (5) Overexpressing SIRT6 can lead to increased E-cadherin expression and decreased vimentin and TGF-ß1 expression in HPMCs. Knocking down SIRT6 expression resulted in decreased E-cadherin expression and increased vimentin and TGF-ß1 expression in HPMCs. This indicates that SIRT6 expression can inhibit MMT in HPMCs, alleviate PF associated with PD, and have a protective effect on the peritoneum.

Integrative analysis of single-cell and bulk RNA-sequencing data revealed T cell marker genes based molecular sub-types and a prognostic signature in lung adenocarcinoma.

Immunotherapy has emerged as a promising modality for addressing advanced or conventionally drug-resistant malignancies. When it comes to lung adenocarcinoma (LUAD), T cells have demonstrated significant influence on both antitumor activity and the tumor microenvironment. However, their specific contributions remain largely unexplored. This investigation aimed to delineate molecular subtypes and prognostic indicators founded on T cell marker genes, thereby shedding light on the significance of T cells in LUAD prognosis and precision treatment. The cellular phenotypes were identified by scrutinizing the single-cell data obtained from the GEO repository. Subsequently, T cell marker genes derived from single-cell sequencing analyses were integrated with differentially expressed genes from the TCGA repository to pinpoint T cell-associated genes. Utilizing Cox analysis, molecular subtypes and prognostic signatures were established and subsequently verified using the GEO dataset. The ensuing molecular and immunological distinctions, along with therapy sensitivity between the two sub-cohorts, were examined via the ESTIMATE, CIBERSORT, and ssGSEA methodologies. Compartmentalization, somatic mutation, nomogram development, chemotherapy sensitivity prediction, and potential drug prediction analyses were also conducted according to the risk signature. Additionally, real-time qPCR and the HPA database corroborated the mRNA and protein expression patterns of signature genes in LUAD tissues. In summary, this research yielded an innovative T cell marker gene-based signature with remarkable potential to prognosis and anticipate immunotherapeutic outcomes in LUAD patients.

Energy metabolic reprogramming regulates programmed cell death of renal tubular epithelial cells and might serve as a new therapeutic target for acute kidney injury.

Acute kidney injury (AKI) induces significant energy metabolic reprogramming in renal tubular epithelial cells (TECs), thereby altering lipid, glucose, and amino acid metabolism. The changes in lipid metabolism encompass not only the downregulation of fatty acid oxidation (FAO) but also changes in cell membrane lipids and triglycerides metabolism. Regarding glucose metabolism, AKI leads to increased glycolysis, activation of the pentose phosphate pathway (PPP), inhibition of gluconeogenesis, and upregulation of the polyol pathway. Research indicates that inhibiting glycolysis, promoting the PPP, and blocking the polyol pathway exhibit a protective effect on AKI-affected kidneys. Additionally, changes in amino acid metabolism, including branched-chain amino acids, glutamine, arginine, and tryptophan, play an important role in AKI progression. These metabolic changes are closely related to the programmed cell death of renal TECs, involving autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. Notably, abnormal intracellular lipid accumulation can impede autophagic clearance, further exacerbating lipid accumulation and compromising autophagic function, forming a vicious cycle. Recent studies have demonstrated the potential of ameliorating AKI-induced kidney damage through calorie and dietary restriction. Consequently, modifying the energy metabolism of renal TECs and dietary patterns may be an effective strategy for AKI treatment.

Safety assessment, whole genome sequence, and metabolome analysis of Streptococcus thermophilus CICC 20372 for bone cement fermentation.

Bone is a kind of meat processing by-product with high nutritional value but low in calorie, which is a typical food in China and parts of East Asian countries. Microbial fermentation by lactic acid bacteria showed remarkable advantages to increase the absorption of nutrients from bone cement by human body. Streptococcus thermophilus CICC 20372 is proven to be a good starter for bone cement fermentation. No genes encoding virulence traits or virulence factors were found in the genome of S. thermophilus CICC 20372 by a thorough genomic analysis. Its notable absence of antibiotic resistance further solidifies the safety. Furthermore, the genomic analysis identified four types of gene clusters responsible for the synthesis of antimicrobial metabolites. A comparative metabolomic analysis was performed by cultivating the strain in bone cement at 37 °C for 72 h, with the culture in de Man, Rogosa, and Sharpe (MRS) medium as control. Metabolome analysis results highlighted the upregulation of pathways involved in 2-oxocarboxylic acid metabolism, ATP-binding cassette (ABC) transporters, amino acid synthesis, and nucleotide metabolism during bone cement fermentation. S. thermophilus CICC 20372 produces several metabolites with health-promoting function during bone cement fermentation, including indole-3-lactic acid, which is demonstrated ameliorative effects on intestinal inflammation, tumor growth, and gut dysbiosis. In addition, lots of nucleotide and organic acids were accumulated at higher levels, which enriched the fermented bone cement with a variety of nutrients. Collectively, these features endow S. thermophilus CICC 20372 a great potential strain for bone food processing.

Identification of Cell-Cell Communications by Single-Cell RNA Sequencing in End Stage Renal Disease Provides New Insights into Immune Cell Heterogeneity.

Objective: Impaired immune system characterized by low-grade inflammation is closely associated with kidney chronic kidney disease (CKD) progression. To reveal the alterations of the function, component, and intercellular communication of immune cells during the progression of CKD. Patients and Methods: We conducted a case-control study enrolling regular hemodialysis patients and healthy controls. Clinical data, serum and peripheral blood mononuclear cell (PBMC) samples were collected. Flow cytometry and single-cell RNA sequencing were performed to quantitatively analyze the immune cell subsets and T-cell subsets of PBMCs. scRNA data of GSE140023 containing mouse unilateral ureteral obstruction (UUO) models were analyzed the heterogeneity of immune cells. Results: Overall reduction in peripheral blood lymphocyte subsets in patients with end-stage renal disease (ESRD) was observed. A higher ratio of Th17/Treg, Th1/Treg, and b-cell/Treg in the ESRD group was associated with a decrease in eGFR, PTH, and ferritin. Among T cell subsets identified by scRNA analysis, Th17 cells were significantly increased in the ESRD and UU0 group. TFH, Th1, and Th2 cells are located at the final stage in the developmental tree, while Treg and memory CD8+ T cells are at the beginning site. Early developmental differentiation of Th17, Th1, and Tfh cells was observed in the ESRD and UUO group. Analysis of intercellular communication between t-cell subpopulations identified two major input and output signaling pathways: the CD40 and macrophage inhibitory factor (MIF) pathways. The MIF signaling pathway primarily mediates intercellular communication among th17 effects, CD8+ t-cell, and Th17-Treg in the ESRD group, the serum level of MIF showed significant upregulation, which was closely related to Th17/Treg cells. Conclusions: A global immune imbalance was closely associated with the deterioration in renal function and complication development. The MIF signaling pathway mediates Th17/Treg communication and promotes the trans-differentiation of Treg cells to Th17 cells in CKD progression.

Antimycobacterial Activities of Hydroxamic Acids and Their Iron(II/III), Nickel(II), Copper(II) and Zinc(II) Complexes.

Hydroxamic acid (HA) derivatives display antibacterial and antifungal activities. HA with various numbers of carbon atoms (C2, C6, C8, C10, C12 and C17), complexed with different metal ions, including Fe(II/III), Ni(II), Cu(II) and Zn(II), were evaluated for their antimycobacterial activities and their anti-biofilm activities. Some derivatives showed antimycobacterial activities, especially in biofilm growth conditions. For example, 20-100 µM of HA10Fe2, HA10FeCl, HA10Fe3, HA10Ni2 or HA10Cu2 inhibited Mycobacterium tuberculosis, Mycobacterium bovis BCG and Mycobacterium marinum biofilm development. HA10Fe2, HA12Fe2 and HA12FeCl could even attack pre-formed Pseudomonas aeruginosa biofilms at higher concentrations (around 300 µM). The phthiocerol dimycocerosate (PDIM)-deficient Mycobacterium tuberculosis H37Ra was more sensitive to the ion complexes of HA compared to other mycobacterial strains. Furthermore, HA10FeCl could increase the susceptibility of Mycobacterium bovis BCG to vancomycin. Proteomic profiles showed that the potential targets of HA10FeCl were mainly related to mycobacterial stress adaptation, involving cell wall lipid biosynthesis, drug resistance and tolerance and siderophore metabolism. This study provides new insights regarding the antimycobacterial activities of HA and their complexes, especially about their potential anti-biofilm activities.

Acteoside protects podocyte against apoptosis through regulating AKT/GSK-3ß signaling pathway in db/db mice.

BACKGROUND: Podocyte apoptosis is one of the important pathological mechanisms of diabetic kidney disease (DKD). Acteoside (Act), a major active component of Rehmannia glutinosa leaves total glycoside, has a strong renoprotective action. Our study aims to demonstrate Act's renoprotective actions in db/db mice. METHODS: We adopted C57BLKS/J db/db mice as DKD animal models. After 8 weeks of Act administration, the 24-hour urine albumin, renal function index, and blood lipid levels were quantified using matching kits. Renal pathology was evaluated by HE and PAS staining. The podocyte damage and apoptosis-related signaling pathway were observed by using immunohistochemistry, western blot, and TUNEL staining. RESULTS: The albuminuria of db/db mice was reduced from 391 ug/24 h to 152 ug/24 h, and renal pathology changes were alleviated after Act administration. The western blot and immunohistochemistry showed that Act treatment upregulated the synaptopodin and podocin expression compared with db/db mice, while the TUNEL staining indicated podocyte apoptosis was inhibited. The B-cell lymphoma-2 (Bcl-2) level was upregulated in the Act group, but cleaved caspase-3 and Bcl-2 associated X protein (Bax) expression declined, while the protein kinase B/glycogen synthase kinase-3ß (AKT/GSK-3ß) signaling pathway was repressed. CONCLUSIONS: By inhibiting the AKT/GSK-3ß signaling pathway, Act protected podocytes from apoptosis, decreasing the urine albumin of db/db mice and delaying the course of DKD.

Prognostic prediction of idiopathic membranous nephropathy using interpretable machine learning.

BACKGROUND: Established prognostic models of idiopathic membranous nephropathy (IMN) were limited to traditional modeling methods and did not comprehensively consider clinical and pathological patient data. Based on the electronic medical record (EMR) system, machine learning (ML) was used to construct a risk prediction model for the prognosis of IMN. METHODS: Data from 418 patients with IMN were diagnosed by renal biopsy at the Fifth Clinical Medical College of Shanxi Medical University. Fifty-nine medical features of the patients could be obtained from EMR, and prediction models were established based on five ML algorithms. The area under the curve, recall rate, accuracy, and F1 were used to evaluate and compare the performances of the models. Shapley additive explanation (SHAP) was used to explain the results of the best-performing model. RESULTS: One hundred and seventeen patients (28.0%) with IMN experienced adverse events, 28 of them had compound outcomes (ESRD or double serum creatinine (SCr)), and 89 had relapsed. The gradient boosting machine (LightGBM) model had the best performance, with the highest AUC (0.892 ± 0.052, 95% CI 0.840-0.945), accuracy (0.909 ± 0.016), recall (0.741 ± 0.092), precision (0.906 ± 0.027), and F1 (0.905 ± 0.020). Recursive feature elimination with random forest and SHAP plots based on LightGBM showed that anti-phospholipase A2 receptor (anti-PLA2R), immunohistochemical immunoglobulin G4 (IHC IgG4), D-dimer (D-DIMER), triglyceride (TG), serum albumin (ALB), aspartate transaminase (AST), ß2-microglobulin (BMG), SCr, and fasting plasma glucose (FPG) were important risk factors for the prognosis of IMN. Increased risk of adverse events in IMN patients was correlated with high anti-PLA2R and low IHC IgG4. CONCLUSIONS: This study established a risk prediction model for the prognosis of IMN using ML based on clinical and pathological patient data. The LightGBM model may become a tool for personalized management of IMN patients.

Identification and validation of a m7G-related lncRNA signature for predicting the prognosis and therapy response in hepatocellular carcinoma.

BACKGROUND: N7-methylguanosine (m7G) is one of the most common RNA posttranscriptional modifications; however, its potential role in hepatocellular carcinoma (HCC) remains unknown. We developed a prediction signature based on m7G-related long noncoding RNAs (lncRNAs) to predict HCC prognosis and provide a reference for immunotherapy and chemotherapy. METHODS: RNA-seq data from The Cancer Genome Atlas (TCGA) database and relevant clinical data were used. Univariate and multivariate Cox regression analyses were conducted to identify m7G-related lncRNAs with prognostic value to build a predictive signature. We evaluated the prognostic value and clinical relevance of this signature and explored the correlation between the predictive signature and the chemotherapy treatment response of HCC. Moreover, an in vitro study to validate the function of CASC19 was performed. RESULTS: Six m7G-related lncRNAs were identified to create a signature. This signature was considered an independent risk factor for the prognosis of patients with HCC. TIDE analyses showed that the high-risk group might be more sensitive to immunotherapy. ssGSEA indicated that the predictive signature was strongly related to the immune activities of HCC. HCC in high-risk patients was more sensitive to the common chemotherapy drugs bleomycin, doxorubicin, gemcitabine, and lenalidomide. In vitro knockdown of CASC19 inhibited the proliferation, migration and invasion of HCC cells. CONCLUSION: We established a 6 m7G-related lncRNA signature that may assist in predicting the prognosis and response to chemotherapy and immunotherapy of HCC.

Research Progress of Cordyceps sinensis and Its Fermented Mycelium Products on Ameliorating Renal Fibrosis by Reducing Epithelial-to-Mesenchymal Transition.

Renal fibrosis is a hallmark and common outcome of various chronic kidney diseases (CKDs) and manifests pathologically as accumulation and deposition of extracellular matrix (ECM) in the kidney. Epithelial-to-mesenchymal transition (EMT) has been shown to be an important mechanism involved in renal fibrosis. Cordyceps sinensis, a traditional Chinese medicine, has long been used for the treatment of renal fibrosis. As research on the mycelium of C. sinensis progressed, a variety of medicines developed from fermented mycelium were used to treat CKD. However, their efficacies and mechanisms have not been fully summarized. In this review, five medicines developed from fermented mycelium of C. sinensis are presented. The pharmacodynamic effects of C. sinensis on different animal models of renal fibrosis are summarized. The in vitro studies and related mechanisms of C. sinensis on renal cells are detailed. Finally, the application and efficacy of these five commercial medicines that meet national standards in different types of CKD are summarized. From this review, it can be concluded that C. sinensis can alleviate various causes of renal fibrosis to some extent, and its mechanism is related to TGF-ß1 dependent signaling, inhibition of inflammation, and improvement of renal function. Further research on rigorously designed, large-sample, clinically randomized controlled trial studies and detailed mechanisms should be conducted.

Nicotine promotes renal interstitial fibrosis via upregulation of XIAP in an alpha7-nAChR-dependent manner.

Renal fibrosis, characterized by excessive accumulation of the extracellular matrix in the renal tubulointerstitium, can lead to chronic kidney disease (CKD), resulting in a heavy burden on families and society. Clinical studies have shown that smoking is closely associated with CKD deterioration in patients with diabetes, hypertension, polycystic kidney disease, and kidney transplantation. However, the mechanism of action of nicotine in renal fibrosis pathogenesis remains largely unknown. X-linked inhibitor of apoptosis (XIAP), a member of the inhibitor of apoptosis protein (IAP) family, is involved in apoptosis, necroptosis, autophagy, and immune response. Here, the upregulated expression of XIAP and α7 nicotine acetylcholine receptor (α7-nAChR) was determined in the kidneys of the CKD smoking group in human and animal studies. A significant positive correlation between XIAP and cotinine was observed. In addition, the nuclear translocation and transcriptional activity of SP1 were promoted when nicotine bound to α7-nAChR, resulting in XIAP overexpression and renal interstitial fibrosis progression. This phenotype can be reversed by the nicotine receptor subtype α7-nAChR antagonists methyllycaconitine. Our results revealed the complex underlying mechanism of nicotine in promoting renal fibrosis by altering SP1 nucleocytoplasmic translocation and regulating XIAP expression. These results provide novel insights into the pathogenesis and treatment of CKD.

Alterations of gut microbiota in biopsy-proven diabetic nephropathy and a long history of diabetes without kidney damage.

The gut microbiota is closely related to parenteral noncommunicable diseases through intestinal immunity and plays an important role in the occurrence of diabetes and diabetic nephropathy. The aim of the study was to understand the gut-kidney axis by an analysis of gut microbiota composition among patients with biopsy-proven diabetic nephropathy (DN), patients with type 2 diabetes for more than 10 years without kidney damage (DM), and healthy controls (NC). Thirty-five DN patients, 40 DM patients and 40 healthy subjects matched by age and sex were enrolled between January 2022 and December 2022. Baseline information and clinical parameters were collected. 16S rDNA sequencing was performed to characterize the gut microbiome and identify gut microbes that were differentially abundant between patients and healthy controls. The relationship between the relative abundance of specific bacterial taxa in the gut and clinical phenotype and pathological indicators was evaluated. Substantial differences were found in the richness of the gut microbiota and the variation in the bacterial population among DN patients, DM patients and healthy controls. DM patients could be accurately distinguished from age- and sex-matched healthy controls by variations in g_Clostridium-XVIII (AUC = 0.929), and DN patients could be accurately distinguished from age- and sex-matched healthy controls by variations in g_Gemmiger (AUC = 0.842). DN patients could be accurately distinguished from age- and sex-matched DM patients by variations in g_Flavonifractor or g_Eisenbergiella (AUC = 0.909 and 0.886, respectively). The gut microbiota was also closely related to clinical phenotypes and pathological indicators. The study of gut microbiota composition was explored to determine its relationship to the occurrence of DN and a long history of diabetes without kidney damage. The renal pathological progression of DN may be delayed by regulating changes in the gut microbiota.

Integrated Analysis of Single-Cell RNA-Seq and Bulk RNA-Seq Combined with Multiple Machine Learning Identified a Novel Immune Signature in Diabetic Nephropathy.

Background: Increasing evidence suggests that immune modulation contributes to the pathogenesis and progression of diabetic nephropathy (DN). However, the role of immune modulation in DN has not been elucidated. The purpose of this study was to search for potential immune-related therapeutic targets and molecular mechanisms of DN. Methods: Gene expression datasets were obtained from the Gene Expression Omnibus (GEO) database. A total of 1793 immune-related genes were acquired from the Immunology Database and Analysis Portal (ImmPort). Weighted gene co-expression network analysis (WGCNA) was performed for GSE142025, and the red and turquoise co-expression modules were found to be key for DN progression. We utilized four machine learning algorithms, namely, random forest (RF), support vector machine (SVM), adaptive boosting (AdaBoost), and k-nearest neighbor (KNN), to evaluate the diagnostic value of hub genes. Immune infiltration patterns were analyzed using the CIBERSORT algorithm, and the correlation between immune cell type abundance and hub gene expression was also investigated. Results: A total of 77 immune-related genes of advanced DN were selected for subsequent analyzes. Functional enrichment analysis showed that the regulation of cytokine-cytokine receptor interactions and immune cell function play a corresponding role in the progression of DN. The final 10 hub genes were identified through multiple datasets. In addition, the expression levels of the identified hub genes were corroborated through a rat model. The RF model exhibited the highest AUC. CIBERSORT analysis and single-cell sequencing analysis revealed changes in immune infiltration patterns between control subjects and DN patients. Several potential drugs to reverse the altered hub genes were identified through the Drug-Gene Interaction database (DGIdb). Conclusion: This pioneering work provided a novel immunological perspective on the progression of DN, identifying key immune-related genes and potential drug targets, thus stimulating future mechanistic research and therapeutic target identification for DN.