Identification and validation of diagnostic markers related to immunogenic cell death and infiltration of immune cells in diabetic nephropathy.

INTRODUCTION: Immunogenic cell death (ICD) is a unique cell death triggered by chemotherapy. However, studies elucidating the potential therapeutic role of ICD and the underlying mechanism in diabetic nephropathy (DN) are limited. METHODS: WGCNA was conducted on the human kidney biopsy data linked to DN, analyzing gene sets associated with ICD. Gene Set Enrichment Analysis and Gene Set Variation Analysis were utilized to examine the discrepancy in biological function. We used Gene Ontology, the Kyoto Encyclopedia of Genes and Genomes, and the GeneMANIA database to investigate the function of the signature genes. An analysis using the receiver operating characteristic (ROC) was conducted to validate the diagnostic value of hub genes. Additionally, immune infiltration-related analyses were also performed. In conclusion, we examined the association between the glomerular filtration rate, serum creatinine, and hub genes. Hub genes were validated by immunohistochemistry using db/db mice kidneys. RESULTS: WGCNA revealed that the targets in the turquoise unit (1674 genes) exhibited the highest positive correlation with ICD. Furthermore, 4222 statistically significant DEGs were identified when comparing the DN and healthy control groups. Significantly, the KEGG pathway enrichment analysis indicated a connection between ICD and the nuclear factor-kappa B signaling pathway and the synthesis of cytokines (tumor necrosis factor superfamily). ROC analysis revealed that 16 hub genes exhibited strong discriminatory potential as biomarkers for DN. Therefore, immunohistochemical validation, with the potential involvement of chemokines (CCL11, CCR2, CCR7, CX3CR1, CXCL10, CXCL12, and CXCR5) and immune cells (CD3G, CD5, and CD247) may be crucial for the diagnosis and therapy of DN. CONCLUSIONS: DKK3, NR4A1, NR4A2, VEGFA, and DUSP1 may be associated with the development of DN. The pathogenesis of DN may specifically involve chemokines (CCL11, CCR2, CCR7, CX3CR1, CXCL10, CXCL12, and CXCR5) and immune cells (CD3G, CD5, and CD247), with LCP2 playing a significant role.

Dynamic landscape of m6A modifications and related post-transcriptional events in muscle-invasive bladder cancer.

BACKGROUND: Muscle-invasive bladder carcinoma (MIBC) is a serious and more advanced stage of bladder carcinoma. N6-Methyladenosine (m6A) is a dynamic and reversible modifications that primarily affects RNA stability and alternative splicing. The dysregulation of m6A in MIBC can be potential target for clinical interventions, but there have been limited studies on m6A modifications in MIBC and their associations with post-transcriptional regulatory processes. METHODS: Paired tumor and adjacent-normal tissues were obtained from three patients with MIBC following radical cystectomy. The additional paired tissues for validation were obtained from patients underwent transurethral resection. Utilizing Nanopore direct-RNA sequencing, we characterized the m6A RNA methylation landscape in MIBC, with a focus on identifying post-transcriptional events potentially affected by changes in m6A sites. This included an examination of differential transcript usage, polyadenylation signal sites, and variations in poly(A) tail length, providing insights into the broader impact of m6A alterations on RNA processing in MIBC. RESULTS: The prognostic-related m6A genes and m6A-risk model constructed by machine learning enables the stratification of high and low-risk patients with precision. A novel m6A modification site in the 3' untranslated region (3'UTR) of IGLL5 gene were identified, characterized by a lower m6A methylation ratio, elongated poly(A) tails, and a notable bias in transcript usage. Furthermore, we discovered two particular transcripts, VWA1-203 and CEBPB-201. VWA1-203 displayed diminished m6A methylation levels, a truncated 3'UTR, and an elongated poly(A) tail, whereas CEBPB-201 showed opposite trends, highlighting the complex interplay between m6A modifications and RNA processing. Source code was provided on GitHub ( https://github.com/lelelililele/Nanopore-m6A-analysis ). CONCLUSIONS: The state-of-the-art Nanopore direct-RNA sequencing and machine learning techniques enables comprehensive identification of m6A modification and provided insights into the potential post-transcriptional regulation mechanisms on the development and progression in MIBC.

Huperzine A targets Apolipoprotein E: A potential therapeutic drug for diabetic nephropathy based on omics analysis.

AIMS: Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM) without curative interventions currently. Huperzine A (Hup A), a natural alkaloid, has demonstrated significant hypoglycemic and anti-inflammatory effects. We aim to investigate the protective effects of Hup A on DN and explore the underlying mechanisms METHODS: We applied STZ induced diabetic rats as DN model and leveraged combination analysis of the transcriptome, metabolome, microbiome, and network pharmacology (NP). The total effect of Hup A on DN was detected (i.e. urine protein, renal tissue structure) and the differential genes were further verified at the level of diabetic patients, db/db mice and cells. Clinical data and small interfering RNA (siRNA)-Apoe were adopted. RESULTS: Hup A alleviated kidney injury in DN rats. Transcriptomics data and Western blot indicated that the improvement in DN was primarily associated with Apoe and Apoc2. Additionally, metabolomics data demonstrated that DN-induced lipid metabolism disruption was regulated by Hup A, potentially involving sphingosine. Hup A also enriched microbial diversity and ameliorated DN-induced microbiota imbalance. Spearman's correlation analysis demonstrated significant associations among the transcriptome, metabolome, and microbiome. Apoe level was positively correlated with clinical biomarkers in DN patients. Si-Apoe also played protective role in podocytes. NP analysis also suggested that Hup A may treat DN by modulating lipid metabolism, microbial homeostasis, and apoptosis, further validating our findings. CONCLUSIONS: Collectively, we provide the first evidence of the therapeutic effect of Hup A on DN, indicating that Hup A is a potential drug for the prevention and treatment of DN.

19Fluorine-MRI Based Longitudinal Immuno-Microenvironment-Monitoring for Pancreatic Cancer.

BACKGROUND: Pancreatic cancer has a poor prognosis. Targeting Kirsten Rat Sarcoma (KRAS) mutation and its related pathways may enhance immunotherapy efficacy. While in vivo monitoring of therapeutic response and immune cell migration remains challenging, Fluorine-19 MRI (19F MRI) may allow noninvasive longitudinal imaging of immune cells. PURPOSE: Evaluating the potential of 19F MRI for monitoring changes in the tumor immune microenvironment, in response to combined SHP2/MEK inhibition. STUDY TYPE: Pre-clinical animal study. ANIMAL MODEL: Murine genetically engineered pancreatic cancer model (N = 20, both sexes). FIELD STRENGTH/SEQUENCE: 9.4-T, two-dimensional multi-slice Rapid Acquisition with Relaxation Enhancement sequence. Intravenous injection of 19F-perfluorocarbon (PFC) nanoparticles. ASSESSMENT: Upon tumor detection by conventional 1H MRI screening, 19F MRI was performed in mice 24 hours after PFC nanoparticle administration. Animals were randomly assigned to four treatment groups: allosteric Src-homology-2-containing protein tyrosine phosphatase 2 (SHP2) inhibitor SHP099, the mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) inhibitor Trametinib, the combination of both, or a vehicle control (4 to 6 mice each group), administered every other day per oral gavage. 1H and 19F MRI was repeated 7 days and 14 days later. Pancreatic immune cell infiltrates were analyzed by flow cytometry and multiplex immunohistofluorescence (mIHF) upon sacrifice. STATISTICAL TESTS: Independent t-tests and one-way analysis of variance. RESULTS: 19F MRI revealed continuous decrease of PFC-signals in tumors from vehicle controls (100%, 80%, and 74% on days 0, 7, and 14, respectively), contrasting with stable or increasing signals under KRAS-pathway-directed treatment. MEK inhibition showed 100%, 152%, and 84% and dual SHP2/MEK1/2 inhibition demonstrated signals of 100%, 134%, and 100% on days 0, 7, 14, respectively. mIHF analyses indicated CD11b+ macrophages/monocytes as primary contributors to the observed 19F MRI signal differences. DATA CONCLUSION: 19F MRI might provide non-invasive longitudinal estimates for abundance and spatial distribution of CD11b+ macrophages/monocytes in pancreatic cancer. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Can good neighbourhood perception magnify the positive effect of favourable built environment on recreational walking in China?

BACKGROUND: It remains unknown whether good neighbourhood perception can enhance the benefits of favourable built environment to physical activity. Moreover, the moderation pattern is less understood in developing countries. OBJECTIVES: This work aims to examine the moderation effects of perceived neighbourhood safety and aesthetics on the relationship between built environment and time for recreational walking. METHODS: We performed the examination using a sample of 760 residents in Fuzhou City, China. The Negative Binomial Regression Model was developed to examine the moderation roles of neighbourhood safety and aesthetics on the impact of built environment, adjusting for the effects of location, socioeconomic, personal preferences and social environment factors. Moreover, two sensitivity analyses were performed to test whether the moderators found are robust to the control of residential self-selection, and differential measures of conceptually-comparable aspects of built environment. RESULTS: We found stronger associations of time for recreational walking with road density and proportion of parks and squares POIs for residents with high perception of neighbourhood safety, compared to those with low perception of neighbourhood safety. There was a greater effect of the proportion of parks and squares POIs, when perceived aesthetics was high than when perceived aesthetics was low. The findings of neighbourhood safety and aesthetics as moderator, were robust in the two sensitivity analyses. No significant moderation effect was found for land use diversity. CONCLUSIONS: High perceived neighbourhood safety can magnify the positive effects of road connectivity and accessibility to parks and squares. Neighbourhood aesthetics positively moderates the association of time for recreational walking with accessibility to parks and squares. The findings emphasize the need to consider safety- and aesthetics-specific differences in estimates of built environment effects. Improvements in neighbourhood safety and aesthetics are key to effective interventions in built environment to better promote physical activity.

Impact of COVID-19 Vaccination on Mortality and Clinical Outcomes in Hemodialysis Patients.

This study analyzed 550 hemodialysis patients, 469 unvaccinated and 81 vaccinated against COVID-19, to assess the impact on infection rates, mortality, and clinical/laboratory parameters. Gender distribution was similar (p = 0.209), but the vaccinated group's median age was significantly lower (p = 0.005). Hospitalization rates showed no significant difference (p = 0.987), while mortality was lower in the vaccinated group (p = 0.041). Only uric acid levels were significantly higher in the vaccinated group (p = 0.009); other parameters, including creatinine and B-type natriuretic peptide, showed no significant differences. Age was an independent predictor of mortality (HR = 1.07, p < 0.001). Peak mortality occurred in December 2022 and January 2023, predominantly among unvaccinated patients. Although vaccination lowered mortality, it did not significantly affect long-term survival rates (p = 0.308). Logistic regression identified age and dialysis duration as significant mortality factors. Monthly death counts indicated higher mortality among unvaccinated patients during peak pandemic months, suggesting that vaccination provides some protection, though no significant long-term survival benefit was found.

Association of weight-adjusted waist index and diabetic kidney disease in type 2 diabetes mellitus.

Objective: The aim of this study was to investigate the relationship between weight-adjusted-waist index (WWI) and diabetic kidney disease in individuals afflicted with type 2 diabetes. Methods: Comprehensive data were ascertained from the National Health and Nutrition Examination Survey in 2013-March 2020. Weighted univariate, multivariate logistic regression models, subgroup analyses and tests for interaction were performed. Additionally, we employed smooth curve fitting to assess linear correlations and the threshold effects were calculated by applying a binary linear regression model. Breakpoints are identified by a model with maximum likelihood ratio and a two-step recursive approach. Receiver operating characteristic curve (ROC) along with the area under the curve (AUC) value predict the capability of WWI and body mass index for diabetic kidney disease. Results: A total of 10,661 individuals diagnosed with type 2 diabetes were included, and the overall prevalence of diabetic kidney disease was 20.74%. WWI exhibited a positive correlation with the likelihood of diabetic kidney disease in type 2 diabetes patients (OR: 1.17, 95% CI: 1.03-1.33). The results of subgroup analysis showed significant interaction for gender (P < 0.05). Among female patients, U-shaped correlations were observed with a breakpoint at 11.48. Additionally, weight-adjusted waist index (AUC = 0.664) proved to be a more effective predictor of diabetic kidney disease compared to body mass index (AUC = 0.555). Conclusion: In patients with type 2 diabetes, increased weight-adjusted-waist index is implicated with an increased risk of diabetic kidney disease. WWI can be used as a new anthropometric index to predict diabetic kidney disease, and its predictive ability is stronger than body mass index.

Direct and indirect photodegradation of bisphenol A in the presence of natural water components.

The impacts and mechanisms of natural water constituents, such as humic acid (HA), nitrates, iron and chloride ions, to the photodegradation of bisphenol A (BPA) were investigated in aqueous media under UV light irradiation. Due to the contributions of ·OH, 1O2, O2- and BPA* to BPA photodegradation in pure water in 13.4, 7.7, 22.9 and 47.9%, respectively, BPA was attenuated through the reaction pathway of direct photodegradation more than self-sensitized photodegradation. About indirect photodegradation, BPA photolysis through inhibitory effect from HA was mainly by light screening effect and quenching effect was insignificant. NO- 3 and NO- 2 both showed inhibitory effect but due to different reactive oxidization species (ROS). The photodegradation of BPA was significantly enhanced by the addition of iron from the formation of ·OH and H2O2, due to iron-assisted indirect photolysis for the degradation process. A dual effect of chloride depending on the different concentration levels involved quenching and promotion effect on reactive photo-induced species (RPS). A simple linear model revealed that BPA photodegradation was significantly impacted by the interaction of the above factors. In natural water, the decreased photolytic rate of BPA was mainly attributed to triple-excited dissolved organic matter (3DOM*), indicating that indirect photolysis was the primary transformation pathway of BPA. The detected photolysis products, such as nitrate and chlorinated products, suggest that there might be potential ecological risk of BPA photodegradation.

Association between weight-adjusted-waist index and the risk of hyperuricemia in adults: a population-based investigation.

Objective: This investigation sought to elucidate the potential correlation between a recently characterized adiposity metric, termed the Weight-Adjusted-Waist Index (WWI) and hyperuricemia. Methods: A cross-sectional design was employed in this study, featuring both hyperuricemic and non-hyperuricemic subjects with complete WWI data, sourced from the National Health and Nutrition Examination Survey (NHANES) spanning 2017 to March 2020. WWI was calculated utilizing the formula which involves the division of waist circumference (WC) by the square root of the body weight. In order to determine the relationship between WWI and hyperuricemia, both univariate and multivariate logistic regression models, appropriately weighted, were employed in the analysis. The linearity of relationships was validated using smooth curve fitting. Additionally, subgroup evaluations and interaction assessments were conducted. Results: The study sample comprised 7437 subjects, yielding a hyperuricemia prevalence of 18.22%. Stratifying WWI into tertiles, a progressive rise in hyperuricemia prevalence was evident with increasing WWI (Tertile 1: 11.62%, Tertile 2: 17.91%, Tertile 3: 25.13%). The odds ratio (OR) demonstrated that individuals within the highest WWI tertile were significantly more prone to hyperuricemia than those in the lowest tertile (OR = 2.41, 95% CI: 1.88-3.08). Conclusion: This study provides evidence that an elevated WWI is correlated with an increased risk of hyperuricemia in the adult population of the United States. These results suggest that WWI may serve as a viable anthropometric indicator for predicting hyperuricemia.

SCM is potential resource for non-invasive preimplantation genetic testing based on human embryos single-cell sequencing.

The ongoing development of assisted reproductive technologies has provided hope to individuals struggling with infertility, promising the potential for a healthy pregnancy. One significant innovation in field of pre-implantation genetic screening (PGS) requires the biopsy of embryos or oocytes, which has potential implications for the health and development of the resultant offspring. Therefore, a non-invasive approach to preimplantation genetic screening is highly sought after. The clinical application of non-invasive preimplantation genetic testing (ni-PGT) is currently limited, with its sensitivity and specificity requiring further investigation. In this study, we used 218 human embryos for single-cell whole genome amplification (WGA), along with ni-PGT of blastocoele fluid (BF) and spent culture medium (SCM). Whole blastocyst (WB), trophectoderm biopsy (TB), and inner cell mass (ICM) from embryo biopsies were used as controls to track genomic signal alterations. Our results showed that the overall genome similarity between SCM and ICM was higher than that of BF. Apart from the Y chromosome, both SCM and ICM demonstrated numerous variant sites across other chromosomes.Further categorization of gene variants in these two sample types revealed that missense variants were the most prevalent, single nucleotide polymorphisms were more common than insertions or deletions, and C > T was the dominant single nucleotide variants in both ICM and SCM. Lastly, we found that the mutant genes in SCM and ICM had different biological functions and pathways. This study indicates that SCM provides a more effective source of embryonic DNA for preimplantation genetic screening, offering a novel reference point for genetic screening research.

Study on the relationship between lipoprotein (a) and diabetic kidney disease.

OBJECTIVE: Little is currently known about the role of lipid metabolism in diabetic kidney disease (DKD), warranting further study. The present study sought to investigate the correlation between lipid metabolism and renal function as well as renal pathological grade/score in DKD patients. METHODS: A total of 224 patients diagnosed with DKD by pathological examination were retrospectively analyzed, of which 74 patients were further evaluated by DKD pathological grade/score. ANOVA was used to investigate serum lipoprotein (a) [Lp (a)] levels in DKD patients with different chronic kidney disease (CKD) stages. Spearman correlation analysis was used to evaluate the relationship between Lp (a) and renal function-related indicators. The DKD pathological grade/score was also evaluated with this method. The receiver operating characteristic (ROC) curve was used to analyze the value of Lp (a) in assessing renal function and pathological changes. RESULTS: There were significant differences in Lp (a) levels among different CKD stages (H = 17.063, p = 0.002) and glomerular grades (H = 12.965, p = 0.005). Lp (a) levels correlated with serum creatinine (p = 0.000), blood urea nitrogen (p = 0.000), estimated glomerular filtration rate (p = 0.000), 24-h proteinuria (24hUPro, p = 0.000), urine microalbumin (p = 0.000), urine albumin creatinine ratio (p = 0.000), glomerular basement membrane thickness (p = 0.003), and glomerular grade (p = 0.039). ROC curve demonstrated good performance of Lp (a) as an indicator to assess CKD stage 4-5 (AUC = 0.684, p = 0.000), 24hUPro > 3.5 g (AUC = 0.720, p = 0.000), and glomerular grade III-IV (AUC = 0.695, p = 0.012). CONCLUSIONS: Elevated levels of Lp (a) are associated with decreased GFR, increased proteinuria, and renal pathological progression, suggesting they could be used to monitor changes in DKD patients.

Super-enhancers conserved within placental mammals maintain stem cell pluripotency.

Despite pluripotent stem cells sharing key transcription factors, their maintenance involves distinct genetic inputs. Emerging evidence suggests that super-enhancers (SEs) can function as master regulatory hubs to control cell identity and pluripotency in humans and mice. However, whether pluripotency-associated SEs share an evolutionary origin in mammals remains elusive. Here, we performed comprehensive comparative epigenomic and transcription factor binding analyses among pigs, humans, and mice to identify pluripotency-associated SEs. Like typical enhancers, SEs displayed rapid evolution in mammals. We showed that BRD4 is an essential and conserved activator for mammalian pluripotency-associated SEs. Comparative motif enrichment analysis revealed 30 shared transcription factor binding motifs among the three species. The majority of transcriptional factors that bind to identified motifs are known regulators associated with pluripotency. Further, we discovered three pluripotency-associated SEs (SE-SOX2, SE-PIM1, and SE-FGFR1) that displayed remarkable conservation in placental mammals and were sufficient to drive reporter gene expression in a pluripotency-dependent manner. Disruption of these conserved SEs through the CRISPR-Cas9 approach severely impaired stem cell pluripotency. Our study provides insights into the understanding of conserved regulatory mechanisms underlying the maintenance of pluripotency as well as species-specific modulation of the pluripotency-associated regulatory networks in mammals.

Single-cell transcriptome analysis of Bisphenol A exposure reveals the key roles of the testicular microenvironment in male reproduction.

Testicular development during juvenile is crucial for subsequent male reproductive function. However, it remains poorly understood about the contribution of the testis microenvironment to human germ cell maturation. Therefore, we systematically analyzed scRNA-seq transcriptome and found the dramatic changes in cell-type composition in human testis during puberty. Then we constructed cell-cell communication networks between germ cells and somatic cells in the juvenile testis, which may be achieved via immune-related pathways. Our results showed that maturation-promoting factors are the switches of the Sertoli cells that drive sperm maturation. Furthermore, we found that Bisphenol A(BPA) enhanced the maturation and growth of germ cells through the Sertoli cell's secretory protein. Finally, our results indicate Bisphenol A would lead to the dysregulation of secreted protein expression in Sertoli cells during spermatogenesis, which in turn has direct cytotoxicity to Sertoli cells. Bisphenol A is one of the underlying causes of non-obstructive azoospermia (NOA). In summary, our results reveal the reproductive toxicity and molecular mechanism of Bisphenol A in Sertoli cells and male reproduction. Provide a reference for the toxicity of Bisphenol A to human reproduction.

Prognostic evaluation model of diabetic nephropathy patients.

BACKGROUND: Diabetic nephropathy (DN) affects about 40% of diabetes mellitus (DM) patients and is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally, especially in advanced countries. We aimed to explore the risk factors affecting the prognosis of DN, and to establish a prognostic evaluation line map. METHODS: We analyzed 471 cases of DN from December 2011 to April 2020, and extracted the basic clinical factors, including gender, age, and history of diabetes. Analysis included that of associations between DN and hypertension, creatinine (CR), body mass index (BMI), and fundus lesions. Statistical analysis was performed using R software and the related R package. The above clinical factors were analyzed by both single- and multiple-factor Cox regression. The participants were divided into two groups, including a high risk and a low risk group. A Kaplan-Meier curve was drawn for survival analysis of the high and low risk groups, and the log-rank method was used for statistical testing. A receiver operating characteristic (ROC) curve was drawn with the area under the curve (AUC) calculated to evaluate the predictive effectiveness of the line map. RESULTS: This study initially included 471 patients; however, 33 patients (7.0%) were lost to follow-up due to inaccessibility. A total of 93 cases (21.2%) died during the follow-up. The 3-year and 5-year renal survival rates were 74.5% and 22.6%, respectively. Single factor Cox analysis showed that the course of diabetes, fundus lesions, BMI, and grade of hypertension were risk factors for renal survival, and had adverse effects on prognosis (P<0.05). Multivariate Cox regression analysis showed that BMI and grade of hypertension were independent risk factors for survival of DKD, and had adverse effects on prognosis (P<0.05). Survival analysis showed that low risk group participants had significantly better survival rates than high risk group participants (P<0.05). The AUC was 0.742, which meant that the line map could accurately predict the survival rate of DN patients. CONCLUSIONS: The influence of risk factors on prognosis can be accurately evaluated by line diagram which can provide a basis for clinical decision making.

TET2 mediated demethylation is involved in the protective effect of triptolide on podocytes.

The epithelial-mesenchymal transition (EMT) is usually considered the central mechanism of podocyte injury that eventually leads to proteinuria. We used an in vitro TGF-ß1 induced podocyte EMT model and an in vivo rat focal segmental glomerulosclerosis (FSGS) model to uncover the mechanism underlying the protective effect of triptolide (TP) on podocytes. We found that TP could reverse the podocyte EMT process and upregulate the expression of TET2 in the TGF-ß1-induced podocyte injury model. Bisulfite amplicon sequencing (BSAS) showed TP could alter the methylation status at some specific sites of the medium CpG density region in the promoters of NEPH1 and nephrin, two main markers of the podocyte slit diaphragm. Knockdown of TET2 with shRNA lentivirus (Lv) leads to high methylation of the promoters of NEPH1 and nephrin such that their expression can not return to normal levels, even after treatment with TP. In vivo, we found that TP could protect against podocyte injury in the FSGS rat and increase TET2 expression. These results suggested TET2-mediated DNA demethylation may be partly involved in podocyte injury. We believe these findings can help uncover a novel molecular mechanism of TP in alleviating podocyte-associated glomerular diseases.

FifBase: a comprehensive fertility-associated indicators factor database for domestic animals.

Fertility refers to the ability of animals to maintain reproductive function and give birth to offspring, which is an important indicator to measure the productivity of animals. Fertility is affected by many factors, among which environmental factors may also play key roles. During the past years, substantial research studies have been conducted to detect the factors related to fecundity, including genetic factors and environmental factors. However, the identified genes associated with fertility from countless previous studies are randomly dispersed in the literature, whereas some other novel fertility-related genes are needed to detect from omics-based datasets. Here, we constructed a fertility index factor database FifBase based on manually curated published literature and RNA-Seq datasets. During the construction of the literature group, we obtained 3301 articles related to fecundity for 13 species from PubMed, involving 2823 genes, which are related to 75 fecundity indicators or 47 environmental factors. Eventually, 1558 genes associated with fertility were filtered in 10 species, of which 1088 and 470 were from RNA-Seq datasets and text mining data, respectively, involving 2910 fertility-gene pairs and 58 fertility-environmental factors. All these data were cataloged into FifBase (http://www.nwsuaflmz.com/FifBase/), where the fertility-related factor information, including gene annotation and environmental factors, can be browsed, retrieved and downloaded with the user-friendly interface.

The Association of Low Hemoglobin Levels with IgA Nephropathy Progression: A Two-Center Cohort Study of 1,828 Cases.

AIM: To investigate the relationship between hemoglobin levels and the progression of IgA nephropathy (IgAN). METHODS: In a two-center cohort of 1,828 cases with biopsy-proven IgAN, we examined the association of hemoglobin levels with the primary outcome of a composite of all-cause mortality or kidney failure defined as a 40% decline in eGFR, or ESKD (defined as eGFR <15 mL/min/1.73 m2 or need for kidney replacement therapy including hemodialysis, peritoneal dialysis, or kidney transplantation), or the outcome of kidney failure, assessed using Cox and logistic regression models, respectively, with adjustment for confounders. RESULTS: At baseline, mean age, eGFR, and hemoglobin levels were 33.75 ± 11.03 years, 99.70 ± 30.40 mL/min/1.73 m2, and 123.47 ± 18.36 g/L, respectively. During a median of approximately 7-year follow-up, 183 cases reached the composite outcome. After adjustment for demographic and IgAN-specific covariates and treatments, a lower quartile of hemoglobin was nonlinearly associated with an increased risk of the primary outcome or kidney failure in the Cox proportional hazards models (primary outcome: HR for quartile 3 vs. 4, 1.37; 95% CI, 0.83-2.25; HR for quartile 2 vs. 4, 1.18; 95% CI, 0.68-2.07; HR for quartile 1 vs. 4, 1.91; 95% CI, 1.15-3.17; kidney failure: HR for quartile 3 vs. 4, 1.39; 95% CI, 0.84-2.31; HR for quartile 2 vs. 4, 1.20; 95% CI, 0.68-2.11; HR for quartile 1 vs. 4, 1.83; 95% CI, 1.09-3.07) in the fully adjusted model. Then, hemoglobin levels were transformed to a binary variable for fitting the model according to the criteria for anemia of 110 g/L in the women and 120 g/L in men in China. The participants in the anemia group had an increased risk of developing outcomes compared with the nonanemia group in both genders (primary outcome: male: HR, 1.64; 95% CI, 1.01-2.68; female: HR, 1.68; 95% CI, 1.02-2.76; kidney failure: male: HR, 1.60; 95% CI, 0.97-2.64; female: HR, 1.58; 95% CI, 0.95-2.61) in the fully adjusted model. CONCLUSIONS: A low level of hemoglobin was nonlinearly associated with IgAN progression. The anemic IgAN patients presented a higher risk of developing poor outcomes compared with the nonanemic patients.

Anti-apoptosis mechanism of triptolide based on network pharmacology in focal segmental glomerulosclerosis rats.

Triptolide (TPL), the active component of Tripterygium wilfordii, exhibits anti-cancer and antioxidant functions. We aimed to explore the anti-apoptosis mechanism of TPL based on network pharmacology and in vivo and in vitro research validation using a rat model of focal segmental glomerulosclerosis (FSGS). The chemical structures and pharmacological activities of the compounds reported in T. wilfordii were determined and used to perform the network pharmacology analysis. The Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) was then used to identify the network targets for 16 compounds from Tripterygium wilfordii. Our results showed that 47 overlapping genes obtained from the GeneCards and OMIM databases were involved in the occurrence and development of FSGS and used to construct the protein-protein interaction (PPI) network using the STRING database. Hub genes were identified via the MCODE plug-in of the Cytoscape software. IL4 was the target gene of TPL in FSGS and was mainly enriched in the cell apoptosis term and p53 signaling pathway, according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. TPL inhibited FSGS-induced cell apoptosis in rats and regulated IL4, nephrin, podocin, and p53 protein levels via using CCK8, TUNEL, and Western blot assays. The effects of IL4 overexpression, including inhibition of cell viability and promotion of apoptosis, were reversed by TPL. TPL treatment increased the expression of nephrin and podocin and decreased p53 expression in rat podocytes. In conclusion, TPL inhibited podocyte apoptosis by targeting IL4 to alleviate kidney injury in FSGS rats.