Constructing a predictive model for live birth following fresh embryo transfer in antagonist protocol for polycystic ovary syndrome.

OBJECTIVE: The present research aims to assess the factors that influence live birth outcomes following fresh embryo transfers using antagonist protocols in individuals diagnosed with polycystic ovary syndrome (PCOS). Furthermore, it seeks to develop a predictive nomogram model to facilitate clinical decision-making and provide personalized treatment strategies. METHODS: This retrospective cohort research analyzed the clinical data of 1242 individuals having PCOS who went through fresh embryo transfers employing antagonist protocols and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) at Fujian Provincial Maternal and Child Health Hospital between January 2018 and December 2022. Individuals were assigned randomly to a modeling group (869 cases) and a validation group (373 cases) in a 7:3 ratio. The Boruta algorithm and multivariable logistic regression were utilized to identify independent risk factors linked to live births after transfer. A predictive nomogram was subsequently developed. The discriminatory power of the model and its accuracy were monitored by utilizing receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis. RESULTS: Multivariable logistic regression analysis identified several independent factors that influence live birth rates in fresh embryo transfer cycles for individuals having PCOS using antagonist protocols, including female age, body mass index (BMI), infertility duration, serum testosterone levels, progesterone levels at the time of human chorionic gonadotropin (hCG) injection, number of high-quality cleavage-stage embryos, type of embryo transferred, and the total number of embryos transferred. Based on these findings, a predictive nomogram was developed. The area under the ROC curve stood at 0.804 (95% confidence interval (CI), 0.775-0.833) for the modeling group and 0.807 (95% CI, 0.762-0.851) for the validation group. Calibration curves confirmed that the predictions of the nomogram closely matched the actual live birth outcomes. Decision curve analysis highlighted that the model provides significant net benefits for predicting live birth rates, with optimal performance across a probability range of 16.5 to 88.6%. CONCLUSION: Independent factors, including female age, infertility duration, BMI, serum testosterone levels, progesterone levels on the day of hCG injection, and the number and type of high-quality cleavage-stage embryos transferred are pivotal in influencing live birth outcomes in fresh embryo transfer cycles under antagonist protocols in individuals with PCOS undergoing IVF/ICSI treatments. The predictive nomogram developed from these factors offers substantial predictive accuracy and clinical utility, providing a reliable basis for clinical prognosis, targeted interventions, and the development of personalized treatment plans.

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.

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.

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.

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.

Exploratory metabolomic analysis based on UHPLC-Q-TOF-MS/MS to study hypoxia-reoxygenation energy metabolic alterations in HK-2 cells.

PURPOSE: Renal ischemia-reperfusion injury(IRI)is a major cause of acute kidney injury(AKI), the injury and repair of renal tubular epithelial cells play an important role in the pathological process of IR-AKI. Metabolomics was used to detect cell metabolism alterations and metabolic reprogramming in the initial injury, peak injury, and recovery stage of human renal proximal tubular cells (HK-2 cells) to provide insights into clinical prevention and treatment of IRI-induced AKI. METHODS: An in vitro ischemia-reperfusion (H/R) injury and the recovery model of HK-2 cells were established at different times of hypoxia/reoxygenation. Comprehensive detection of metabolic alterations in HK-2 cells after H/R induction by nontarget metabolomics. Interconversion of glycolysis and fatty acid oxidation (FAO) in HK-2 cells after H/R induction was examined by western blotting and qRT-PCR. RESULTS: Multivariate data analysis found significant differences among the groups, with significant changes in metabolites such as glutamate, malate, aspartate, and L-palmitoylcarnitine. Hypoxia-reoxygenated HK-2 cells are accompanied by altered metabolisms such as disturbance of amino acid and nucleotide metabolism, dysregulation of lipid metabolism, increased glycolysis, and metabolic reprogramming, which manifests as a shift in energy metabolism from FAO to glycolysis. CONCLUSION: The development of IRI-induced AKI in HK-2 cells is accompanied by the disturbance of amino acid, nucleotide, and tricarboxylic acid cycle metabolism and specifically metabolic reprogramming of FAO to glycolytic conversion. The timely recovery of energy metabolism in HK-2 cells is of great significance for treating and prognosis IRI-induced AKI.

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.

Recent Progresses in Non-Dialysis Chronic Kidney Disease Patients with Hyperkalemia: Outcomes and Therapeutic Strategies.

Chronic kidney disease (CKD) affects about 10% of the world's population. Hyperkalemia is a life-threatening complication in patients with CKD, as it is associated with adverse cardiovascular and kidney outcomes. There are still many challenges and questions to address to improve the currently available therapeutic strategies to treat hyperkalemia, such as how to approach the emergency management of hyperkalemia. In recent years, in addition to novel oral potassium binders, great progress has been made in the application of novel kidney protective strategies, such as mineralocorticoid receptor antagonists and sodium-glucose cotransporter 2 inhibitors (SGLT2i) in hyperkalemia therapy. This review will discuss the recent advances from clinical trials in the effective management of hyperkalemia in non-dialysis CKD patients, enhancing the knowledge of physicians and internists concerning these newer agents and providing a helpful reference for clinical practice.

Bidirectional crosstalk between dysbiotic gut microbiota and systemic lupus erythematosus: What is new in therapeutic approaches?

Systemic lupus erythematosus is an autoimmune disease characterized by chronic inflammation and multiple organs damage. Its pathogenesis is complex and involves multiple factors including gut microbiota. Accumulating evidence indicates the interaction of microbial communities with the host immune system to maintain a state of homeostasis. Imbalances within the gut microbial composition and function may contribute to the development of many autoimmune diseases including SLE. In this review, we aim to highlight the dysregulation of commensal bacteria and their metabolites in the gastrointestinal tract and the resulting autoimmune responses in lupus and to decrypt the cross-link between the altered gut microbiota and the immune system in the SLE condition. We also provide new insights into targeting gut microbiota as a promising therapeutic approach to treat and manage SLE.

Plasma metabolomics-based reveals the treatment mechanism of ShenGui capsule for application to coronary heart disease in a rat model.

Shen Gui capsule (SGC) has been demonstrated to have a significant treatment effect for coronary heart disease (CHD). Nevertheless, the holistic therapeutic mechanism of SGC in vivo remain poorly interpreted. We aimed to systematically explore the preventive effect and mechanism of SGC on CHD rats using plasma metabolomics strategy. Rat CHD model was established by left anterior descending coronary artery ligation (LAD). Echocardiography, histological analyses of the myocardium and biochemical assays on serum were used to confirm the successful establishment of the CHD model and therapeutic effects of SGC. Then, UHPLC-MS/MS-based plasma metabolomics was combined with multivariate data analysis to screen potential pharmaco biomarkers associated with SGC treatment in the LAD-induced rat CHD model. After SGC treatment, 12 abnormal metabolites considered as potiential pharmaco biomarkers recovered to near normal levels. These biomarkers were involved in several metabolic pathways, including fat and protein metabolism, phenylalanine metabolism, neuroactive ligand-receptor interaction, androgen receptor signaling pathway, and estrone metabolism.These results suggested that SGC achieves therapeutic action on CHD via regulating various aspects of the body such as energy metabolism, neurological disturbances and inflammation, and thus plays a significant role in the treatment of CHD and its complications. The study is useful to systematically understand and analyze the mechanism of SGC's "multipie pathways, multiple levels, multiple targets" prevention and treatment of CHD.

Randomized Control Study on Hemoperfusion Combined with Hemodialysis versus Standard Hemodialysis: Effects on Middle-Molecular-Weight Toxins and Uremic Pruritus.

INTRODUCTION: Classic hemodialysis schedules present inadequate middle-molecular-weight toxin clearance due to limitations of membrane-based separation processes. Accumulation of uremic retention solutes may result in specific symptoms (e.g., pruritus) and may affect clinical outcome and patient's quality of life. Hemoperfusion (HP) is a blood purification modality based on adsorption that can overcome such limitations, and thus, it may be interesting to test the efficacy of at least one session per week of HP combined with hemodialysis. This is a randomized, open-label trial, controlled, multicenter clinical study to investigate the effect of long-term HP combined with hemodialysis on middle-molecular-weight toxins and uremic pruritus in maintenance hemodialysis (MHD) patients. METHODS: 438 MHD patients from 37 HD centers in China with end-stage kidney disease (63.9% males, mean age 51 years) suffering from chronic intractable pruritus were enrolled in the study. Eligible patients were randomized into four groups: low-flux hemodialysis (LFHD), high-flux hemodialysis (HFHD), HP + LFHD, and HP + HFHD at a 1:1:1:1 ratio. Beta-2 microglobulin (ß2M) and parathyroid hormone (PTH) were measured at baseline, 3-6, and 12 months. At the same time points, the pruritus score was evaluated. The primary outcome was the reduction of ß2M and PTH, while the secondary outcome was the reduction of the pruritus score. RESULTS: In the two groups HP + LFHD and HP + HFHD, there was a significant decrease of ß2M and PTH levels after 12 months compared to the control groups. No significant differences were noted between HP + LFHD and HP + HFHD. Pruritus score reduction was 63% in the HP + LFHD group and 51% in the HP + HFHD group, respectively. CONCLUSION: The long-term HP + HD can reduce ß2M and PTH levels and improve pruritus in MHD patients independently on the use of high- or low-flux dialyzers, showing that the results are linked to the effect of adsorption.

Relationships between social capital, patient empowerment, and self-management of patients undergoing hemodialysis: a cross-sectional study.

BACKGROUND: Hemodialysis is the most common treatment of end-stage renal disease. However, it is associated with a range of symptoms affecting patients' daily activities and quality of life. Effective self-management has proven crucial for the alleviation of symptoms. According to Social Cognitive Theory, social capital and patient empowerment may be important variables for predicting self-management. To date, few studies have explored the mechanisms underlying these results. The study aimed to verify whether patient empowerment mediated the effect of social capital on the self-management of hemodialysis patients. METHODS: The study was performed with 245 hemodialysis patients from January 2021 to April 2021 in Taiyuan, China. Demographic and clinical characteristics, social capital, patient empowerment, and self-management of patients undergoing hemodialysis were measured with a self-reported questionnaire. Descriptive statistics were used to summarize the participants' demographic and clinical characteristics, and bootstrapping tests were used to verify whether patient empowerment mediated the association of social capital with self-management in patients undergoing hemodialysis. RESULTS: Mediation analysis indicated that social capital and patient empowerment significantly predicted self-management. Patient empowerment partially mediated the relationship between social capital and self-management in hemodialysis patients. CONCLUSIONS: The results suggest that hemodialysis patients show relatively poor self-management and that patient empowerment mediates both social capital and self-management. Strategies to mobilize patients' social networks and help them identify and utilize effective social resources may provide useful information regarding the implementation of optimal health management for their disease.

Urinary Exosomal MicroRNAs as New Noninvasive Biomarkers of IgA Nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis. It is very important to find new noninvasive biomarkers for the diagnosis and treatment of IgAN. The purpose of this study was to explore the clinical value of urinary exosomal miRNAs in IgAN. In this study, urinary exosomes were isolated from 29 IgAN patients and 29 healthy controls. The miRNA was analyzed by high-throughput sequencing. The expression of hsa-miR-451a and hsa-let-7d-3p was examined by real-time quantitative polymerase chain reaction (RT-qPCR). The diagnostic value of miRNAs was evaluated using receiver operating characteristic (ROC) curves. Here, hsa-miR-451a and hsa-let-7d-3p were upregulated in IgAN patients compared with healthy controls. We evaluated the diagnostic value of hsa-miR-451a and hsa-let-7d-3p using ROC curves; hsa-miR-451a (AUC = 0.805, p = 0.001), hsa-mir-7d-3p (AUC = 0.76, p = 0.0049), and the combination of hsa-miR-451a and hsa-let-7d-3p (AUC = 0.8125, p = 0.0007). Hsa-miR-451a has correlations with Lee's grades (r = 0.511, p = 0.021), and 24-h urinary protein excretion (UPE; r = 0.557, p = 0.011). Hsa-let-7d-3p showed correlations with Lee's grades (r = 0.6, p = 0.005), UPE (r = 0.518, p = 0.019), serum creatinine (r = 0.564, p = 0.01), and estimated glomerular filtration rate (r = -0.532, p = 0.016). According to the Oxford classification, for hsa-miR-451a, S0 had lower levels than S1 (p = 0.016); for hsa-mir-7d-3p, M0 had lower levels than M1 (p = 0.05). These findings suggest that hsa-miR-451a and hsa-let-7d-3p may serve as noninvasive biomarkers for the evaluation of IgAN.

Differential Expression of Urinary Exosomal miRNA in Idiopathic Membranous Nephropathy and Evaluation of its Diagnostic Value.

Urinary exosomal miRNA is an ideal non-invasive biomarker of renal disease, but little is known about its ability to diagnose idiopathic membranous nephropathy (IMN). The purpose of this study was to explore the clinical value of urinary exosomal miRNAs in IMN. Urine samples were collected from 36 IMN patients and 36 healthy subjects. Some samples were used to analyze the miRNA profiles of urinary exosomes by high-throughput sequencing. The remaining cases were verified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Additionally, the serum of the patients and healthy people was collected, and the clinical parameters were detected. Through high-throughput sequencing of samples, it was found that 20 miRNAs were markedly down-regulated. MiR-9-5p and miR-30b-5p were selected for verification, and the results were consistent with those of high-throughput sequencing. MiR-9-5p was correlated with the level of triglyceride and estimated glomerular filtration rate. MiR-30b-5p was related to the levels of anti-phospholipase A2 receptor antibody, serum albumin, ß 2-microglobulin and the ratio of global sclerosis/observed glomeruli number. The analysis of Receiver Operating Characteristic curves revealed that miR-30b-5p and miR-9-5p showed a potential diagnostic value for IMN. This study showed that there were significant differences in urinary exosome miRNA profiles between IMN patients and healthy persons. MiR-30b-5p and miR-9-5p may become new non-invasive biomarkers of IMN.

Leucine-rich repeat kinase 2 is protective during acute kidney injury through its activation of autophagy in podocytes.

Leucine-rich repeat kinase 2 (LRRK2) is a known regulator of autophagy in a range of cell types. Here, we investigated the role of LRRK2-associated autophagy during acute kidney injury (AKI) and its underlying mechanism(s) of action. Male mice aged 8-weeks were treated with the LRRK2 inhibitor MLi-2 and exposed to lipopolysaccharide (LPS) through intraperitoneal injection or ischemia-reperfusion (IR) surgery. Mice were sacrificed 12 or 24 h post-LPS injection or IR operation and blood was collected for serum creatinine measurements. Kidney cortical tissues were collected for western blot analysis of podocyte-specific markers and autophagy-associated proteins. Renal histopathology was observed through hematoxylin-eosin staining. For cell-based assays, immortalized mouse podocytes were silenced for LRRK2 through siRNA transfection and exposed to LPS or cobalt chloride. Changes in cell viability were investigated using cell counting kit-8, flow cytometry and MTT assays. Expression of podocyte-specific markers and autophagy-associated proteins were analyzed by western blotting. We observed an increase in LRRK2 expression at 12 h post-LPS injection and IR surgery that was accompanied by enhanced autophagy. At 24 h post-treatment, both LRRK2 expression and autophagy declined. Kidney injury was most pronounced in mice treated with MLi-2. Podocytes silenced for LRRK2 showed a loss of cell viability, decreased levels of podocyte-specific protein expression and a suppression of autophagy. Together, these data reveal the protective effects of LRRK2 during AKI through enhanced podocyte autophagy and cell viability.

Rapamycin relieves lupus nephritis by regulating TIM-3 and CD4+CD25+Foxp3+ Treg cells in an MRL/lpr mouse model.

Lupus nephritis (LN) is a severe consequence of systemic lupus erythematosus (SLE) and is an important driver of morbidity and mortality in SLE. Treg cells and TIM-3 play an important role in the pathogenesis of LN. The beneficial effect of rapamycin on LN has been confirmed in both mouse models and patients, but the effect of rapamycin on Treg cells and TIM-3 is not yet completely understood. In this study, rapamycin treatment attenuated proteinuria, histological damage, and renal deposition of C3, and improved renal function. Spleen and renal draining lymph node weight and serum levels of anti-dsDNA antibodies were also improved by rapamycin. Furthermore, the frequency of Treg cells and Treg functional molecules, such as cytotoxic T cell antigen 4 (CTLA-4), interleukin 10 (IL-10), and transforming growth factor ß1 (TGF-ß1), increased significantly after treatment with rapamycin in MRL/lpr mice. We also found that expression of TIM-3 was significantly decreased in CD4+ T cells and Treg cells in mice treated with rapamycin. In summary, the study demonstrated that rapamycin treatment induced preferential expansion of CD4+CD25+Foxp3+ Tregs with increased expression of CTLA-4, IL-10, and TGF-ß1, and decreased TIM-3 expression, thereby ameliorating lupus nephritis in the MRL/lpr mouse model.

Circular RNA circVMA21 ameliorates lipopolysaccharide (LPS)-induced acute kidney injury by targeting the miR-199a-5p/NRP1 axis in sepsis.

BACKGROUND: Sepsis is a serious and elusive syndrome caused by infection, with high mortality worldwide. Circular RNAs vacuolar ATPase assembly factor (circVMA21) has been reported to be related to the inflammatory damages in sepsis. This study is designed to explore the role and mechanism of circVMA21 in the lipopolysaccharide (LPS)-induced cell injury in sepsis. METHODS: Cell viability and apoptosis were detected by CCK-8, and flow cytometry assays. CircVMA21, microRNA-199a-5p (miR-199a-5p), and Neuropilin-1 (NRP1) level were determined by RT-qPCR. Protein levels of Bcl-2, Bax, cleaved-caspase 3, and NRP1 were examined by Western blot assay. IL-1ß, IL-6, and TNF-α were detected using ELISA. Superoxide Dismutase (SOD) and glutathione (GSH) were measured by the special kits. The binding relationship between miR-199a-5p and circVMA21 or NRP1 was predicted by Starbase 3.0 and then verified by a dual-luciferase reporter and RIP assays. RESULTS: CircVMA21 and NRP1 were decreased, and miR-199a-5p was increased in LPS-induced THP-1 cells. Moreover, circVMA21 overexpression could repress LPS-mediated cell viability, apoptosis, inflammation, and oxidative stress in THP-1 cells. The mechanical analysis suggested that circVMA21 regulated NRP1 expression through sponging miR-199a-5p. CONCLUSION: CircVMA21 upregulation could attenuate LPS-triggered THP-1 cell injury through modulating the miR-199a-5p/NRP1 axis, hinting an underlying therapeutic strategy for sepsis patients.

Outcome of simultaneous thulium laser enucleation of bladder tumor and prostate in patients with non-muscle invasive bladder tumor and benign prostatic hyperplasia: a matched-pair comparison with a long-term follow-up.

OBJECTIVE: To access the surgical and oncological outcomes of simultaneous thulium laser enucleation of bladder tumor (ThuLEBT) and thulium laser enucleation of prostate (ThuLEP) in patients with non-muscle invasive bladder tumor (NMIBC) and benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Between June 2009 and June 2017, 118 men with NMIBC who underwent simultaneous ThuLEBT and ThuLEP and fulfilled the inclusion criteria were matched with 118 patients who received ThuLEBT alone. Clinicopathological parameters, surgical outcome data and oncological outcomes were retrospectively analyzed and compared. RESULTS: The patients who underwent simultaneous ThuLEBT and ThuLEP experienced a longer length of operation time (70.4 vs. 25.5 min; p < 0.001), but there were no statistically significant differences in catheterization period, hospital stay and complication between the two groups. At a mean follow-up of 58.7 and 55.8 months in ThuLEBT/ThuLEP group and ThuLEBT group, no significant differences in overall recurrence rates, progression rates, recurrence in the bladder neck/prostatic fossa and mean elapsed time to recurrence were detected. The 5-year recurrence-free probability was 73.2% for ThuLEBT/ThuLEP and 69.2% for ThuLEBT (p = 0.361). CONCLUSIONS: Our results indicate that simultaneous ThuLEBT and ThuLEP can be safely performed without increasing the surgical risk and the risk of tumor recurrence and progression in patients with NMIBC and BPH, and it may be preferred alternative for select patients.

Causal effect between total cholesterol and HDL cholesterol as risk factors for chronic kidney disease: a mendelian randomization study.

BACKGROUND: While observational studies show an association between serum lipid levels and cardiovascular disease (CVD), intervention studies that examine the preventive effects of serum lipid levels on the development of CKD are lacking. METHODS: To estimate the role of serum lipid levels in the etiology of CKD, we conducted a two-sample mendelian randomization (MR) study on serum lipid levels. Single nucleotide polymorphisms (SNPs), which were significantly associated genome-wide with serum lipid levels from the GLGC and CKDGen consortium genome-wide association study (GWAS), including total cholesterol (TC, n = 187,365), triglyceride (TG, n = 177,861), HDL cholesterol (HDL-C, n = 187,167), LDL cholesterol (LDL-C, n = 173,082), apolipoprotein A1 (ApoA1, n = 20,687), apolipoprotein B (ApoB, n = 20,690) and CKD (n = 117,165), were used as instrumental variables. None of the lipid-related SNPs was associated with CKD (all P > 0.05). RESULTS: MR analysis genetically predicted the causal effect between TC/HDL-C and CKD. The odds ratio (OR) and 95% confidence interval (CI) of TC within CKD was 0.756 (0.579 to 0.933) (P = 0.002), and HDL-C was 0.85 (0.687 to 1.012) (P = 0.049). No causal effects between TG, LDL-C- ApoA1, ApoB and CKD were observed. Sensitivity analyses confirmed that TC and HDL-C were significantly associated with CKD. CONCLUSIONS: The findings from this MR study indicate causal effects between TC, HDL-C and CKD. Decreased TC and elevated HDL-C may reduce the incidence of CKD but need to be further confirmed by using a genetic and environmental approach.

Experimental observation of the sequence of tibial plateau chondrocyte and matrix degeneration in spontaneous osteoarthritis in Guinea pigs.

BACKGROUND: To observe the sequence of chondrocyte degeneration and matrix degradation in the superficial surface cartilage of the tibial plateau in guinea pigs with spontaneous knee osteoarthritis (OA). METHODS: Sixty guinea pigs were euthanized at the ages of 8 months (n = 20),10 months (n = 20) and 12 months (n = 20) respectively. The degree of degeneration of the tibial plateau cartilage was evaluated by Osteoarthritis Research Society International (OARSI) score. The levels of Aggrecan,CollagenX,MMP-13 and Caspase-3 in the chondrocytes were detected by immunohistochemistry (IHC). The serum concentration of CTX-II was measured and compared. Western blot analysis was used to detect the levels of Aggrecan,CollagenX,MMP-13 and Caspase-3 in the cartilage tissue. RESULTS: The OARSI scores both in 8-month-old group and 10-month-old group were lower than that in the 12-month-old group. The levels of Aggrecan in articular chondrocyte were higher both in 8-month-old group and 10-month-old group than that in 12-month-old group. The level of Collagen X increased with the age of guinea pigs. And the levels of MMP-13 and caspase-3 both in 10-month-old group and 12-month-old group were higher than those in 8-month-old group. The concentration of CTX-II in serum increased significantly in 12 months old group. CONCLUSION: The superficial chondrocytes of the tibial plateau first appeared to be hypertrophic and then apoptotic, and the matrix was further degraded when spontaneous knee osteoarthritis occurred in guinea pigs. Changes in the physiological state of chondrocytes are the initiating factors in the pathogenesis of knee OA.