AIM:Renal fibrosis is a major contributor to chronic kidney disease (CKD) progression and eventual organ failure. G protein-coupled bile acid receptor 1 (TGR5) was previously shown to have beneficial effects on kidney diseases. The current study aimed to investigate whether TGR5 activation prevents kidney fibrosis and to clarify the underlying mechanism. METHODS:TGR5 expression was examined in human fibrotic kidneys. Two animal models of renal fibrosis were used: unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury with contralateral nephrectomy (uIRIx) in wild-type and TGR5 knockout mice. Renal histology, extracellular matrix (ECM) deposition, and renal function were examined. In vitro studies were performed on human proximal tubular HK2 cells by treating them with transforming growth factor-β1 and TGR5 agonists/antagonists. RESULTS:TGR5 was significantly downregulated in fibrotic human kidneys. In both UUO and uIRIx models, TGR5 activation by lithocholic acid alleviated renal fibrosis, reduced ECM deposition, and improved kidney function. Conversely, Tgr5 knockout in mice exacerbated fibrotic injury. Mechanistically, TGR5 activation prevented fibrosis development, probably by enhancing NEDD4L-mediated ubiquitination and degradation of phosphorylated Smad2/3 by inhibiting the upstream PI3K-SGK1 pathway. CONCLUSION:TGR5 activation protects against renal fibrosis by inhibiting the PI3K-SGK1-NEDD4L axis and promoting p-Smad2/3 degradation.

ObjectiveGestational diabetes mellitus (GDM) is associated with gut microbiota dysbiosis and placental dysfunction. This study aimed to investigate whether gut microbiota-derived short-chain fatty acids (SCFAs) ameliorate placental injury and insulin resistance in GDM by suppressing ferroptosis, a novel form of iron-dependent cell death.MethodsA GDM rat model was induced by streptozotocin, and gut microbiota was depleted via a broad-spectrum antibiotic cocktail. Physiological parameters, gut microbiota composition, and SCFA levels were assessed. Placental and metabolic tissues were analyzed for ferroptosis markers (Fe2+, MDA, ROS), key regulatory enzymes (GPX4, ACSL4, LPCAT3), polyunsaturated fatty acid (PUFA) profiles, and inflammation. An in vitro insulin resistance model in human trophoblast cells (HTR-8/SVneo) was used to validate the causal role of SCFAs.ResultsGDM and antibiotic-induced dysbiosis led to a significant depletion of SCFA-producing bacteria and reduced colonic SCFA levels. This was concomitant with severe placental ferroptosis, characterized by iron accumulation, lipid peroxidation, and downregulation of GPX4 alongside upregulation of ACSL4 and LPCAT3. PUFA substrates were significantly consumed, and systemic inflammation was elevated. In vitro, insulin resistance induced trophoblast ferroptosis and dysfunction, which was effectively rescued by SCFA treatment. SCFAs restored GPX4 expression, suppressed ACSL4/LPCAT3, preserved PUFAs, and attenuated inflammation.ConclusionGut microbiota-derived SCFAs play a critical protective role in GDM by inhibiting the ACSL4/LPCAT3-mediated ferroptotic pathway in placental trophoblasts, thereby improving insulin sensitivity and mitigating cellular injury. Our findings highlight the gut-placenta axis as a potential therapeutic target for GDM, warranting further validation in human studies.

AIMS:Excess extracellular matrix (ECM) deposition is the characteristic of renal fibrosis, owing to the imbalance between synthesis and degradation. Fibronectin could regulate the deposition of other ECM, thus plays a crucial role in the progression of renal fibrosis. Mannose receptor C type 1 (MRC1), largely expressed on macrophages, owns an extracellular fibronectin type II domain that binds to and internalizes collagen and thus involves in fibrosis modulation. The purpose of the present study was to investigate whether MRC1 participates in the internalization of fibronectin and whether alginate oligosaccharides (AOSC), a degradation product of alginate, has beneficial effects in the resolution of renal fibrosis via MRC1. MATERIALS AND METHODS:Renal fibrosis models were constructed by unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI) in MRC1-WT and MRC1-KO mice. RAW264.7 cells were treated with TGF-β1 to induce pro-fibrotic responses. Expression of fibrotic markers and fibronectin endocytosis were examined. KEY FINDINGS:MRC1 gene knockout aggravated renal fibrosis in UUO and UIRI models. Inhibition of MRC1 exacerbated TGF-β1-induced pro-fibrotic responses in RAW264.7 cells. MRC1 regulated integrin β1-mediated fibronectin endocytosis through Arp2/3-Kindlin-2 signaling pathway. AOSC improved renal fibrosis by increasing MRC1 expression and endocytosis of fibronectin. SIGNIFICANCE:Our findings highlight the importance of MRC1 and fibronectin endocytosis in the development of renal fibrosis, suggesting that activation of MRC1 by AOSC is probably a therapeutic option to delay the progress of kidney fibrosis.

Renal ischemia-reperfusion (IR) injury is a major cause of acute kidney injury (AKI), with limited specific therapies. Recombinant human brain natriuretic peptide (rhBNP) shows potential renal protective effects, but its role and mechanism in IR-induced AKI is unclear. The present study showed rhBNP improved renal function recovery and reduced AKI progression in ICU patients. In rat IR models, rhBNP alleviated tubular injury and enhanced kidney function. Selenocysteine lyase (SCLY), an enzyme critical for selenium recycling and selenoprotein synthesis, was identified as the hub gene associated with rhBNP treatment by transcriptome sequencing. rhBNP treatment markedly upregulated the expression of SCLY in rat kidneys with elevated selenium levels. rhBNP also inhibited ferroptosis and apoptosis in the kidney, which was significantly reversed by the knockdown of SCLY. SCLY silencing blocked the protective effect of rhBNP on human HK2 cells subjected to CCCP-R (carbonyl cyanide 3-chlorophenylhydrazone induced ATP depletion-repletion), while SCLY overexpression enhanced it. rhBNP modulated SCLY expression likely through inhibiting the binding of active GTPase RhoA to SCLY protein. In conclusion, rhBNP prevented IR-induced AKI through inhibiting ferroptosis by upregulating SCLY level and promoting selenium recycling, presenting a potentially new target for AKI treatment.

Epithelial sodium channel (ENaC), located in the collecting duct principal cells of the kidney, is responsible for the reabsorption of sodium and plays a critical role in the regulation of extracellular fluid volume and consequently blood pressure. The G protein-coupled bile acid receptor (TGR5) is a membrane receptor mediating effects of bile acid and is implicated in kidney diseases. The current study aims to investigate whether TGR5 activation in the kidney regulated ENaC expression and potential mechanism. Lithocholic acid (LCA), a TGR5 agonist, markedly decreased systolic blood pressure induced by DOCA-salt in mice, which was associated with decreased ENaC expression in the kidney. DOCA-salt treatment increased renal expression of histone H3 lysine 4 trimethylation (H3K4me3) and decreased expression of lysine-specific demethylase 5A (KDM5A), a lysine demethylase, which was markedly reversed by LCA. TGR5 knockout caused further increased systolic blood pressure and ENaC expression in mice with DOCA-salt in association with increased H3K4me3 and decreased KDM5A. In immortalized mouse cortical collecting duct (mpkCCD) cells LCA markedly inhibited aldosterone-induced ENaC-mediated current. LCA treatment or TGR5 overexpression markedly inhibited ENaC and H3K4me3 protein expression in association with decreased KDM5A in mpkCCD cells treated with either aldosterone or angiotensin II. Inhibition or knockdown of KDM5A in mpkCCD cells prevented LCA-induced downregulation of ENaC expression by promoting H3K4me3 on the ENaC transcription start site. LCA upregulated KDM5A expression was likely through JNK/c-Jun signal pathway. In conclusion, LCA decreased blood pressure and ENaC protein expression in the kidney of mice with DOCA-salt, likely through activating TGR5 and upregulating KDM5A-induced H3K4me3 demethylation in ENaC promoter region.

Acute kidney injury (AKI) is a clinical syndrome that is defined as a sudden decline in renal function and characterized by inflammation and tubular injury. Alginate oligosaccharide (AOSC), a natural product obtained from alginate by acidolysis and hydrolysis, shows activities of antioxidant, immunomodulation, and anti-inflammation. In this study, we investigated the potential of AOSC in the treatment of AKI. Renal ischemia-reperfusion (I/R) was induced in male rats by clipping both the renal artery and vein for 45 min followed by reperfusion for 24 h. The rats were treated with AOSC (100 mg/kg, i.g.) before surgery. At the end of the experiments, both kidneys were collected for protein, mRNA measurement, or histological analysis. We showed that AOSC pretreatment significantly improved glomerular and tubular function in the kidney of I/R rats. AOSC markedly inhibited I/R-induced activation of TLR4/MyD88/NF-κB/IL-1β inflammatory signaling and prevented apoptosis in the kidney. In HK2 cells subjected to hypoxia/reoxygenation (H/R) stimulation, AOSC (250–1000 μg/ml) dose-dependently prevented pro-inflammatory responses and cell apoptosis. Transcriptomic analysis revealed that I/R increased the expression levels of mannose receptor type C1 (MRC1) in the kidney, which was markedly inhibited by AOSC. Molecular docking showed that AOSC interacted with E725, N727, E733, T743, S745, and N747 of MRC1 through hydrogen bonds. MRC1 gene knockout significantly improved renal function and attenuated I/R-induced kidney inflammation and apoptosis in mice. In line with this, AOSC failed to prevent I/R-induced kidney injury in MRC1 gene knockout mice. UPLC analysis showed that the protection of AOSC in HK2 cells subjected to H/R was likely attributed to MRC1-mediated intracellular endocytosis. In conclusion, AOSC prevents I/R-induced AKI, which is at least partially mediated by MRC1.

PURPOSE:To explore the associations between serum uric acid (SUA) level change and changes in the retinal neurodegenerative biomarkers in type 2 diabetes mellitus patients without retinopathy. METHODS:This is a prospective observational cohort study based on the baseline and 1-year follow-up data of the Guangzhou Diabetic Eye Study. Type 2 diabetes mellitus patients without retinopathy were recruited. Thicknesses of ganglion cell inner plexiform layer (GC-IPL) and peripapillary retinal nerve fiber layer (pRNFL) were measured via swept-source optical coherence tomography. The associations between SUA level change and the thinning rates of GC-IPL and pRNFL were analyzed using multivariate linear regression analysis. Sub-group analysis based on sex was constructed. RESULTS:A total of 1084 participants were enrolled in our study. After adjustment, both male and female patients with decreased SUA levels in higher baseline SUA level group had a significantly slower thinning rate of GC-IPL than those with non-decreased SUA levels. In higher baseline SUA level with decreased SUA level group, male patients exhibited significantly slower thinning rate of inferior GC-IPL, while female patients exhibited significantly slower thinning rate of inferior and nasal GC-IPL and inferior pRNFL, when compared to those with non-decreased SUA levels. CONCLUSION:Our findings prove that decreased SUA level is associated with a slower GC-IPL thinning rate in higher baseline SUA level group, suggesting that decreased SUA level could be constituted as a potential future control target to delay the neurodegeneration in type 2 diabetes mellitus patients.

Background:The epidemiology and severity of asthma vary by sex and age. The diagnosis, treatment, and management of asthma in female patients are quite challenging. However, there is hitherto no comprehensive and standardized guidance for female patients with asthma.Methods:Corresponding search strategies were determined based on clinical concerns regarding female asthma. Search terms included "sex hormones and lung development", "sex hormone changes and asthma", "hormones and asthma immune response", "women, asthma", "children, asthma", "puberty, asthma", "menstruation, asthma", "pregnancy, asthma", "lactation, asthma", "menopause, asthma", "obesity, asthma", and "women, refractory, severe asthma". Literature was retrieved from PubMed/Medline, Embase, Cochrane Library, China Biology Medicine disc, China National Knowledge Infrastructure, Wanfang Data with the search date of July 30, 2022 as the last day. This consensus used the Grading of Recommendations Assessment, Development, and Evaluation to evaluate the strength of recommendation and quality of evidence.Results:We collected basic research results and clinical evidence-based medical data and reviewed the effects of sex hormones, classical genetics, and epigenetics on the clinical presentation and treatment response of female patients with asthma under different environmental effects. Based on that, we formulated this expert consensus on the management of female asthma throughout the life cycle.Conclusions:This expert consensus on the management of asthma in women throughout the life cycle provides diagnosis, treatment, and research reference for clinical and basic medical practitioners.

Purpose:To investigate the association between mean ocular perfusion pressure (MOPP), estimated cerebrospinal fluid pressure (CSFP), and changes in diabetic retinopathy (DR) in a Southern Chinese population with type 2 diabetes (T2DM). Methods:A total of 1224 subjects from the Guangzhou Diabetic Eye Study were enrolled. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and intraocular pressure (IOP) were measured. MOPP was calculated with the formula: MOPP = 2/3 [DBP + 1/3 (SBP - DBP)] - IOP. CSFP was calculated using the formula: CSFP = 0.44 × body mass index (kg/m2) + 0.16 × DBP - 0.18 × age (years) - 1.91. Incidence, progression, and regression of DR were graded based on seven-field 45° conventional fundus photographs at baseline and during two-year follow-up examinations according to the United Kingdom National Diabetic Eye Screening Program guidelines. Results:Higher MOPP was associated with DR incidence in the multivariate model (per 1 mm Hg increase: relative risk, 1.05; 95% confidence interval, 1.01-1.09; P = 0.02) and was not associated with DR development and DR regression in two-year follow-up of T2DM patients. However, CSFP was not associated with DR changes (incidence, progression, or regression). Conclusions:The higher MOPP is an independent risk factor for DR incidence among T2DM patients in a Southern Chinese cohort. Monitoring MOPP and managing blood pressure can be part of a comprehensive approach to prevent or delay the onset of DR in T2DM patients. Translational Relevance:MOPP might be an indicator for the detection of DR incidence.

PurposeCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a life-threatening disease with largely unknown intraocular pathogenesis. Herein, we determined the presence of SARS-CoV-2-specific ribonucleic acid (RNA) and virus-associated antibodies in the vitreous humor of people who have recently recovered from SARS-CoV-2 infection.DesignThis cross-sectional study included 33 patients (33 eyes) who have recently recovered from SARS-CoV-2 infection. Vitreous humor and blood serum samples were tested for the SARS-CoV-2 RNA and virus-associated antibodies.ResultsAmong 33 participants, blood serum and vitreous humor were all tested negative for SARS-CoV-2 RNA. SARS-CoV-2-specific IgM was detected in 87.88% (29/33) patients in blood serum and 6.10% (2/33) in vitreous humor; SARS-CoV-2-specific IgG was detected in 96.97% (32/33) patient in blood serum and 81.82% (27/33) in vitreous humor. Statistical significance was found for IgM expression between blood serum and vitreous humor (P<0.01), while IgG was not(P=0.11). The days after recovery were statistically longer both in IgM-positive blood serum samples group and IgG-positive vitreous humor samples group compared with negative samples of each group(P<0.01). Additionally, no statistical difference could be detected in antibody expression in vitreous humor between different groups divided on the condition of the risk of blood-retina-barrier(BRB) failure (P=0.49 for IgM; P=0.37 for IgG).ConclusionAfter recovering from COVID-19, no SARS-CoV-2 RNA was detected in vitreous humor, but anti-CoV-2 IgM was detected in 6.1% and IgG in approximately 80% of vitreous humor samples of participants. We also found that the positivety rate of SARS-CoV-2-specific antibodies in the blood serum and vitreous humor were both correlated with the days after recovery since the infection.

PURPOSE:To investigate the impact of exercise and mask-wearing on retinal microvasculature using optical coherence tomography angiography (OCTA). METHODS:A total of 30 healthy volunteers were enrolled and tasked with physical exercise to reach 75-80 % maximum heart rates. Swept-source OCTA was performed on the macular region and optic nerve head (ONH) in participants with no mask, surgical mask, or N95 mask at quiescent conditions (Step 1) and 0 min, 10 min, 20 min, and 30 min post-exercise (Steps 2-5, respectively). The functional vessel density (VD), including the superficial and deep plex (SP and DP) in the macular area and the superficial plex (SP), nerve fiber plex, and small vessels in the optic nerve head, were measured. RESULTS:Under quiescent conditions, the functional VD of SP and DP exhibited significant reduction with surgical and N95 masks in the foveal area (P < 0.05). In step 2 (immediately after training) with or without masks, functional VD of SP and nerve fiber both showed significant reduction in the inside disc and peripapillary area, small functional VD of nerve fiber in the ONH showed significant reduction in peripapillary area (P < 0.05). These changes had been recovered in Step 5 (30 min post-exercise) in all groups (no-mask, surgical mask and N95 mask groups) (P > 0.05). CONCLUSIONS:Mask-wearing and physical exercise reduce retinal functional VD in macular and ONH areas. The retinal vasoconstriction induced by exercise tends to recover after rest for approximately 30 min. Our research provides insights into mask-wearing and physical exercise's immediate retinal microvasculature effects, hinting at systemic microvascular changes.

Background: Preeclampsia (PE) is a severe pregnancy complication associated with autophagy. Objective: This research sought to uncover autophagy-related genes in pre-eclampsia through bioinformatics and machine learning. Methods: GSE75010 from the GEO series was subjected to WGCNA to identify key modular genes in PE. Autophagy genes retrieved from the THANATOS overlapped with the modular genes to yield PErelated autophagy genes. Furthermore, the crucial step involved the utilization of two machine learning algorithms (LASSO and SVM-RFE) for dimensionality reduction. The candidate gene was further verified by quantitative reverse transcription polymerase chain reaction, western blot, and immunohistochemistry. Preliminary experiments were conducted on HTR-8/SVneo cell lines to explore the role of candidate genes in autophagy regulation. Results: WGCNA identified 291 genes from 5 hubs, and after overlapping with 1087 autophagy-related genes obtained from THANATOS, 42 PE-related ARGs were identified. ANXA6 was recognized as a potential target through SVM-RFE and LASSO analyses. The mRNA and protein expression of ANXA6 were verified in placenta samples. In HTR8/SVneo cells, modulating ANXA6 expression altered autophagy levels. Knocking down ANXA6 resulted in an anti-autophagy effect, which was reversed by treatment with CAL101, an inhibitor of PI3K, Akt, and mTOR. Conclusion: We observed that ANXA6 may serve as a possible PE action target and that autophagy may be crucial to the pathogenesis of PE.

Background The rates of successful vaginal birth after previous cesarean section (VBAC) have been increasing with minimal complication. Successful vaginal birth after cesarean section improves maternal and fetal outcomes by shortening the length of hospital stay, avoiding abdominal surgery, decreasing the risk of infections and hemorrhage, and decreasing injury of the bladder and bowel. Despite a few single studies stating different predictors of successful VBAC, there is a lack of nationwide data to show the determinants of successful VBAC. Thus, this meta-analysis aimed to determine the predictors of successful VBAC in Ethiopia. Methods A systematic literature search was performed from PubMed, Web of Sciences, EMBASE, CINAHL, and Google scholar until July 25, 2022. The quality of included studies was evaluated using the Joanna Briggs Institute (JBI) critical appraisal checklist. The analysis was executed using Stata 14 statistical software. Heterogeneity was evaluated statistically using Cochran’s Q-statistic and quantified by the I 2 value. A random-effects model was used to estimate the determinants of successful vaginal birth after a cesarean section if substantial heterogeneity was detected across included studies; otherwise, a fixed-effects model was used. Results Women living in rural residence (AOR: 2.14; 95% CI: 1.01, 4.52), history of previous spontaneous vaginal delivery (AOR: 2.92; 95% CI: 2.02, 4.23), previous successful vaginal birth after previous cesarean section (AOR: 5.29; 95% CI: 2.20, 12.69), history of stillbirth (AOR: 1.57; 95% CI: 1.20, 2.04), cervical dilation of ≥ 4 cm at admission (AOR: 2.14; 95% CI: 1.27, 3.61), spontaneous ruptured membranes at admission (AOR: 1.32; 95% CI: 1.17, 1.48) were independent determinants of successful vaginal birth after previous cesarean section. Conclusion The results of this meta-analysis showed that successful VBAC was influenced by past and present obstetric conditions and other predictors. Thus, it is recommended that obstetric care providers should emphasize those factors that lead to successful vaginal birth during counseling and optimal selection of women for the trial of labour after cesarean section. Systematic review and meta-analysis registration PROSPERO CRD42022329567.

Acute abdomen in pregnancy（AAP）can be due to obstetric as well as non-obstetric causes. The diagnosis and treatment of AAP are often delayed due to lack of typical symptoms and signs. AAP develops rapidly,and can endanger the life safety of mothers and fetuses in severe cases. Early identification of AAP and early warning of the severity are of great significance to maintain the health of mothers and children.

妊娠期高血糖是妊娠期最常见的并发症，可对母儿健康产生近远期的危害。规范孕前及妊娠期的管理，可降低高血糖相关的母儿并发症。本文对妊娠期高血糖的诊断、监测与预防进行阐述，以利于妊娠期高血糖的规范化诊治。

目的:本研究旨在探索自我悲悯团体干预项目对于减轻大学生应激感受的作用,以及积极情绪在其中的中介作用.方法:通过网络公开招募在校大学生68名,随机分为干预组和等待控制组,干预组接受4周的自我悲悯团体干预,等待控制组在此期间不接受干预.采用自我悲悯量表、应激感受量表、积极情绪量表对所有被试进行前后测.结果:干预组被试在后测中的自我悲悯水平显著高于前测(F(1,60)=10.66,P=0.002,η2p=0.151),应激感受水平显著低于前测(F(1,60)=23.72,P＜0.001,η2p=0.283),且积极情绪总体水平(F(1,60)=13.13,P=0.001,η2p=0.180)及其各维度水平均显著高于前测.中介分析结果显示,安全型积极情绪在自我悲悯干预与应激感受之间起部分中介作用.结论:自我悲悯团体干预可以有效缓解大学牛的应激感受,且这一效果部分是通过安全型积极情绪的提升实现的.

Nutrition therapy plays an integral role in gestational diabetes mellitus management, emphasizing a variety of nutrient-dense foods in appropriate portion sizes, low glycemic index (GI)/ glycemic load (GL) diet, and adequate calorie intake, so as to promote fetal and maternal health and achieve glycemic goals.