Effects of Mineralocorticoid Receptor Antagonists for Chronic Kidney Disease: A Systemic Review and Meta-Analysis.

BACKGROUND: Mineralocorticoid receptor blockade could be a potential approach for the inhibition of chronic kidney disease (CKD) progression. The benefits and harms of different mineralocorticoid receptor antagonists (MRAs) in CKD are inconsistent. OBJECTIVES: The aim of the study was to summarize the benefits and harms of MRAs for CKD patients. METHODS: We searched MEDLINE, EMBASE, and the Cochrane databases for trials assessing the effects of MRAs on non-dialysis-dependent CKD populations. Treatment and adverse effects were summarized using meta-analysis. RESULTS: Fifty-three trials with 6 different MRAs involving 22,792 participants were included. Compared with the control group, MRAs reduced urinary albumin-to-creatinine ratio (weighted mean difference [WMD], -90.90 mg/g, 95% CI, -140.17 to -41.64 mg/g), 24-h urinary protein excretion (WMD, -0.20 g, 95% CI, -0.28 to -0.12 g), estimated glomerular filtration rate (eGFR) (WMD, -1.99 mL/min/1.73 m2, 95% CI, -3.28 to -0.70 mL/min/1.73 m2), chronic renal failure events (RR, 0.86, 95% CI, 0.79-0.93), and cardiovascular events (RR, 0.84, 95% CI, 0.77-0.92). MRAs increased the incidence of hyperkalemia (RR, 2.04, 95% CI, 1.73-2.40) and hypotension (RR, 1.80, 95% CI, 1.41-2.31). MRAs reduced the incidence of peripheral edema (RR, 0.65, 95% CI, 0.56-0.75) but not the risk of acute kidney injury (RR, 0.94, 95% CI, 0.79-1.13). Nonsteroidal MRAs (RR, 0.66, 95% CI, 0.57-0.75) but not steroidal MRAs (RR, 0.20, 95% CI, 0.02-1.68) significantly reduced the risk of peripheral edema. Steroidal MRAs (RR, 5.68, 95% CI, 1.26-25.67) but not nonsteroidal MRAs (RR, 0.52, 95% CI, 0.22-1.22) increased the risk of breast disorders. CONCLUSIONS: In the CKD patients, MRAs, particularly in combination with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, reduced albuminuria/proteinuria, eGFR, and the incidence of chronic renal failure, cardiovascular and peripheral edema events, whereas increasing the incidence of hyperkalemia and hypotension, without the augment of acute kidney injury events. Nonsteroidal MRAs were superior in the reduction of more albuminuria with fewer peripheral edema events and without the augment of breast disorder events.

Lung Ultrasound and Bioelectrical Impedance Analysis for Fluid Status Assessing Patients Undergoing Maintenance Hemodialysis.

Background: Volume overload is a fatal complication for people undergoing hemodialysis. Therefore, regulating a patient's "dry weight" based on their fluid status is imperative. Clinical experiences are too subjective to accurately judge a patient's fluid status, but techniques have emerged for improved fluid control in the two decades. Specifically, lung ultrasonography (LUS) uses a unique aspect of ultrasound images, the B-lines, to evaluate extravascular lung water, which has increasingly attracted attention. However, the role of B-line quantification in predicting short-mid-term death and/or cardiovascular complications is unclear. Methods: Patients undergoing MHD at the hemodialysis center of Zhejiang Provincial People's Hospital from October 1, 2020, to February 28, 2021, were examined using LUS and a bioelectrical impedance analysis before and after dialysis, and related clinical data were collected. All patients were followed up for one year after the examination, and deaths and first cardiovascular events (e.g., stroke, myocardial infarction, and heart failure) during this period were recorded. Results: 98 patients were enrolled and divided into three groups in relation to their mild (<16 B-lines), moderate (16-30 B-lines), or severe (>30 B-lines) hypervolemia, defined by the number of B-lines. The long-term survival rate was significantly lower in the severe group than in the mild and moderate groups. LUS and bioelectrical impedance-related parameters (e.g., extracellular water-to-water ratio) were closely related to cardiac ultrasound parameters (left ventricular ejection fraction) (P < 0.001). The optimal B-line cutoff value on LUS for predicting fluid overload (defined clinically) in patients on hemodialysis was 11.5 lines (AUC = 0.840, 95% confidence interval 0.735-0.945, P < 0.001), and the diagnostic sensitivity and specificity were both 76.5%. During the one-year follow-up period, ten deaths and six cardiovascular events occurred. The survival rate was significantly lower in the severe group than in the mild group (log-rank test χ2 = 10.050, P=0.002) but did not differ between the severe and moderate groups (χ2 = 2.629, P=0.105). Conclusion: LUS is a cheap, noninvasive, simple, and repeatable volume-monitoring method that can assist with individualized fluid volume management in patients undergoing MHD. LUS results may also help to predict the short-mid-term survival rate of patients to a certain extent.

Plasma D-dimer levels are associated with disease progression in diabetic nephropathy: a two-center cohort study.

BACKGROUND: This study aimed to investigate the relationship between plasma D-dimer levels, clinicopathological features, and clinical outcomes in patients with biopsy-proven diabetic nephropathy (DN). METHODS: A total of 137 patients with biopsy-proven DN were enrolled in this two-center cohort study. Patients were stratified into tertiles based on plasma D-dimer levels. We investigated the relationship between plasma D-dimer levels and clinical outcomes, including a composite of death, a 40% decline in estimated glomerular filtration rate (e-GFR) from baseline, or end-stage renal disease (ESRD) (defined as e-GFR < 15 mL/min/1.73 m2 or need for renal replacement therapy including hemodialysis, peritoneal dialysis, or kidney transplantation), assessed using Cox regression models with adjustment for confounders. RESULTS: At baseline, the mean age was 52.61 ± 11.63 years, and the mean e-GFR was 58.02 ± 28.77 mL/min/1.73 m2. During a median 26-month follow-up period, 65 (47% of patients) achieved clinical outcomes. Compared with the low plasma D-dimer level group, those with higher plasma D-dimer levels were more likely to have higher 24-h proteinuria (p = .002), lower e-GFR (p = .001), lower hemoglobin (p = .001), a higher glomerular lesion class (p = .03), and higher interstitial fibrosis and tubular atrophy (IFTA) scores (p = .002). After adjustment for demographic, DN-specific covariates, and treatments, it was observed that a higher tertile of plasma D-dimer was nonlinearly associated with an increased risk of the clinical outcomes (Hazard Ratio (HR) for tertile 2 vs. 1, 1.7; 95% Confidence Interval (CI), 0.80-3.75; HR for tertile 3 vs. 1, 2.2; 95% CI, 0.93-5.27; p for trend = .001) in the Cox proportional hazards models. CONCLUSION: In this study, DN patients with higher levels of plasma D-dimer had higher 24-h proteinuria, lower e-GFR, a higher glomerular lesion class, and higher IFTA scores. Furthermore, a high level of plasma D-dimer was nonlinearly associated with DN progression.

LASSO-derived nomogram predicting new-onset diabetes mellitus in patients with kidney disease receiving immunosuppressive drugs.

WHAT IS KNOWN AND OBJECTIVE: Patients with kidney disease receiving immunosuppressive drugs (ISDs) (tacrolimus, cyclosporine and glucocorticoids) have a high risk of developing new-onset diabetes mellitus (NODM). We aimed to establish a precise and convenient model for predicting NODM in patients receiving immunosuppressive drugs. METHODS: This retrospective study recruited 1883 patients receiving ISDs between January 2010 and October 2018. The occurrence of NODM was the primary endpoint. The patients were randomly divided into training (n = 1318) and validation cohorts (n = 565) at a 7:3 ratio. A nomogram was established based on a least absolute shrinkage and selection operator (LASSO)-derived logistic regression model. The nomogram's discrimination and calibration abilities were evaluated in both cohorts using the Hosmer-Lemeshow test and calibration curves. Decision curve analysis (DCA) was used to evaluate the net benefit of the predictive efficacy. RESULTS AND DISCUSSION: Amongst the 1883 patients with kidney disease receiving immunosuppressive drugs, 375 (28.5%) and 169 (29.9%) developed NODM in the training (n = 1318) and validation cohorts (n = 565), respectively. Nine clinic predictors were included in this LASSO-derived nomogram, which is easy to be operated clinically. The discriminative ability, determined by the area under the receiver operating characteristic curve (AUC), was 0.816 (95% confidence interval [CI] 0.790-0.841) and 0.831 (95%CI 0.796-0.867) in the training and validation cohorts, respectively. Calibration was confirmed with the Hosmer-Lemeshow test in the training and validation cohorts (p = 0.238, p = 0.751, respectively). WHAT IS NEW AND CONCLUSION: Nearly one-third of patients with kidney disease receiving immunosuppressive drugs developed NODM. The nomogram established in this study may aid in predicting the occurrence of NODM in patients with kidney disease receiving immunosuppressive drugs.

Aspirin relieves the calcification of aortic smooth muscle cells by enhancing the heat shock response.

CONTEXT: Vascular calcification is a major complication of chronic renal failure, which has been identified as an active process partly driven by osteogenic transition of vascular smooth muscle cells (VSMCs). Aspirin could prevent cardiomyocyte damage by inducing heat shock response. OBJECTIVE: This study investigates the effect of aspirin on alleviating VSMC calcification. MATERIALS AND METHODS: An in vitro VSMC calcification model was established by 10-day calcification induction in osteogenic medium. VSMCs were grouped as following: control group (normal medium), calcified group (osteogenic medium) and treated group (osteogenic medium with 1 or 4 mmol/L aspirin). VSMC calcification was evaluated by calcified nodules formation, intracellular calcium concentration and osteoblastic marker (OPN and Runx2) expression. RESULTS: After 10-day culture, the intracellular calcium concentration in calcified group was significantly higher than that in control group (1.16 ± 0.04 vs. 0.14 ± 0.01 µg/mg, p < 0.01), but significantly reduced in 1 mmol/L aspirin treated group (0.74 ± 0.05 µg/mg, p < 0.01), and 4 mmol/L aspirin treated group (0.93 ± 0.03 µg/mg, p < 0.01). The elevated expression of OPN and Runx2 induced by osteogenic medium was significantly relieved after 1 or 4 mmol/L aspirin treatment. The expression of HSF1, HSP70 and HSP90 was decreased in calcification-induced VSMCs, but significantly increased after treatment of aspirin. Furthermore, inhibition of HSP70 (or HSP90) by small-molecule inhibitor or small interfering RNA could partially abolish the anti-calcification effect of aspirin, proved by the changes of intracellular calcium concentration and osteoblastic marker expression. DISCUSSION AND CONCLUSIONS: Aspirin could relieve the calcification of VSMCs partially through HSP70- or HSP90-mediated heat shock response. These findings expanded the understanding of aspirin pharmacology, and imply that local induction expression of HSPs might be a potential therapeutic strategy for the prevention and therapy of vascular calcification.

Genetic reduction of cilium length by targeting intraflagellar transport 88 protein impedes kidney and liver cyst formation in mouse models of autosomal polycystic kidney disease.

Polycystin-1 (PC1) and -2 (PC2), products of the PKD1 and PKD2 genes, are mutated in autosomal dominant polycystic kidney disease (ADPKD). They localize to the primary cilia; however, their ciliary function is in dispute. Loss of either the primary cilia or PC1 or PC2 causes cyst formation. However, loss of both cilia and PC1 or PC2 inhibits cyst growth via an unknown pathway. To help define a pathway, we studied cilium length in human and mouse kidneys. We found cilia are elongated in kidneys from patients with ADPKD and from both Pkd1 and Pkd2 knockout mice. Cilia elongate following polycystin inactivation. The role of intraflagellar transport proteins in Pkd1-deficient mice is also unknown. We found that inactivation of Ift88 (a gene expressing a core component of intraflagellar transport) in Pkd1 knockout mice, as well as in a new Pkd2 knockout mouse, shortened the elongated cilia, impeded kidney and liver cystogenesis, and reduced cell proliferation. Multi-stage in vivo analysis of signaling pathways revealed ß-catenin activation as a prominent, early, and sustained event in disease onset and progression in Pkd2 single knockout but not in Pkd2.Ift88 double knockout mouse kidneys. Additionally, AMPK, mTOR and ERK pathways were altered in Pkd2 single knockout mice but only AMPK and mTOR pathway alteration were rescued in Pkd2.Ift88 double knockout mice. Thus, our findings advocate an essential role of polycystins in the structure and function of the primary cilia and implicate ß-catenin as a key inducer of cystogenesis downstream of the primary cilia. Our data suggest that modulating cilium length and/or its associated signaling events may offer novel therapeutic approaches for ADPKD.

Laparoscopic preperitoneal tunneling technique using a novel device for peritoneal dialysis catheter placement.

BACKGROUND: We aimed to introduce the puncture technique based on a novel device for preperitoneal tunneling in laparoscopic PD catheter placement and to evaluate the safety and efficacy of this technique. METHODS: This novel device was used in our center from May 2016. We conducted a retrospective analysis of patients undergoing laparoscopic PD catheter placement. The traditional method was performed in 20 patients and the novel procedure in 18 patients. A straight Tenckhoff PD catheter was placed in all patients. RESULTS: No intraoperative complications were encountered in both groups. Compared the traditional technique group, the procedure based on the novel device had a shorter operative time (49.2 ± 11.8 vs 53.9 ± 12.5). One patient in the traditional tunneling group underwent catheter obstruction. There were no pericatheter leakage, exit site and subcutaneous infection, hernia and peritonitis in the early postoperative days. No mortality was observed in these patients. The 6-month survival rate of the catheter was 100%. CONCLUSIONS: Laparoscopic preperitoneal tunneling technique is an effective way to implant intra-abdominal catheter. Our method based on a novel puncture device for preperitoneal tunneling is safe and efficient.

In-Hospital Outcomes of Patients on Maintenance Dialysis With Frailty: 10-year Results From the US National Inpatient Sample Database.

OBJECTIVE: The in-hospital mortality rate of patients with end-stage renal disease (ESRD) is 6-8 times greater than that of the general population. A large fraction of patients with ESRD are frail, which further exacerbates this poor outcome. This study aimed to determine the impact of frailty on in-hospital outcomes of patients with ESRD. DESIGN AND METHODS: This population-based, retrospective study used data from the Nationwide Inpatient Sample (NIS), the largest all-payer US inpatient care database. Data of 1,424,026 hospitalized patients on maintenance dialysis between 2005 and 2014 were included. Patients were classified with respect to frailty status. Primary endpoints were all-cause in-hospital mortality, discharge disposition, length of hospital stay, and hospital costs. Patient characteristics included age, sex, race, income, insurance status, and Charlson's comorbidity index. Logistic regression and linear regression analyses were conducted to evaluate the associations between frailty and clinical outcomes. RESULTS: After adjustment for the confounders, hospitalized patients with frailty on maintenance dialysis were at double the risk of in-hospital mortality, 3 times the risk of discharge to long-term facilities, had hospital stays 5 days longer, and incurred $40,000 more in-hospital costs than those without frailty. The impact of frailty on all these in-hospital outcomes was greater among patients aged <65 years than among older adults. CONCLUSION: For hospitalized patients on maintenance dialysis, frailty independently predicts worse in-hospital outcomes, with stronger effects on younger patients. The development of adequate interventions for frailty in patients with ESRD and vigilance in treating this subgroup during hospitalization are highly warranted.

LncRNA NEAT1 promotes hypoxia-induced renal tubular epithelial apoptosis through downregulating miR-27a-3p.

Acute kidney injury (AKI) is a common kidney disorder that affects public health and the incidence of AKI. Sepsis, acute ischemia or hypoxia is the main reason for the occurrence of AKI. Recently, noncoding RNA that include microRNA and long noncoding RNA (lncRNAs) were reported to play important roles in AKI as well as have the potential to serve as a biomarker or therapeutic target for the development of the diagnostic and prognostic strategies of AKI. In the current study, we aimed to investigate the expression and biological function of lncRNA nuclear enriched abundant transcript 1 (NEAT1) in ischemia-induced AKI in patients' sample and in vitro. The expressions of NEAT1 and miR-27a-3p in ischemia/reperfusion-induced AKI patients were examined by quantitative reverse transcription polymerase chain reaction. Cell injury was induced by treatment of human kidney tubular cells (HK-2) with CoCl2 . After treatment, the influences of NEAT1 and miR-27a-3p on the cell apoptosis in the CoCl2 -stimulated HK-2 were tested by flow cytometry. The flow analysis results showed that the expression of NEAT1 was markedly higher in the ischemia-induced AKI patients compared with normal control. Moreover, repression the expression of NEAT1 decreased CoCl2 -induced injury in HK-2. The expression of miR-27a-3p was negatively regulated by NEAT1. Inhibition the expression of NEAT1 attenuated overexpression of miR-27a-3p enhanced CoCl2 -induced injury. In summary, an ischemia-induced injury may be enhanced by a high level of NEAT1 through targeting miR-27a-3p. Thus, NEAT1 has the potential to be explored as a biomarker for diagnosis and target for therapeutic strategies in ischemia-induced AKI.

Retinoic Acid-Induced Protein 14 (RAI14) Promotes mTOR-Mediated Inflammation Under Inflammatory Stress and Chemical Hypoxia in a U87 Glioblastoma Cell Line.

Retinoic acid-induced 14 is a developmentally regulated gene induced by retinoic acid and is closely associated with NIK/NF-κB signaling. In the present study, we examined the effect of RAI14 on mTOR-mediated glial inflammation in response to inflammatory factors and chemical ischemia. A U87 cell model of LPS- and TNF-α-induced inflammation was used to investigate the role of RAI14 in glial inflammation. U87 cells were treated with siR-RAI14 or everolimus to detect the correlation between mTOR, RAI14, and NF-κB. CoCl2-stimulated U87 cells were used to analyze the effect of RAI14 on mTOR-mediated NF-κB inflammatory signaling under chemical hypoxia. LPS and TNF-α stimulation resulted in the upregulation of RAI14 mRNA and protein levels in a dose- and time-dependent manner. RAI14 knockdown significantly attenuated the level of pro-inflammatory cytokine via inhibiting the IKK/NF-κB pathway. Treatment with an mTOR inhibitor (everolimus) ameliorated NF-κB activity and IKKα/ß phosphorylation via RAI14 signaling. Notably, RAI14 also enhanced mTOR-mediated NF-κB activation under conditions of chemical hypoxia. These findings provide significant insight into the role of RAI14 in mTOR-induced glial inflammation, which is closely associated with infection and ischemia stimuli. Thus, RAI14 may be a potential drug target for the treatment of inflammatory diseases.

Inhibition of microRNA-21-3p suppresses proliferation as well as invasion and induces apoptosis by targeting RNA-binding protein with multiple splicing through Smad4/extra cellular signal-regulated protein kinase signalling pathway in human colorectal cancer HCT116 cells.

MicroRNA-21-3p (miR-21-3p), the passenger strand of pre-mir-21, has been found to be high-expressing in various cancers and to be associated with tumour malignancy, which is proposed as a novel focus in malignant tumours. Colorectal cancer (CRC), currently known as one of the most prevalent malignancy, is a leading cause of cancer death. This study aimed to investigate the key role of miR-21-3p in CRC by inhibiting its expression using transfection with miR-21-3p inhibitors into human CRC HCT116 cells. Results showed that the expression of miR-21-3p was higher than other CRC cells used in the study including Lovo, HT29, Colo320 and SW480 cells, inhibition of which suppressed the proliferation and induced cell cycle arrest in HCT116 cells. Besides, transfection with miR-21-3p inhibitors also attenuated cell migration and invasion, and induced apoptosis as well. Moreover, luciferase assay confirmed RBPMS as a direct target of miR-21-3p in HCT116 cells. Further, miR-21-3p inhibitors increased the nuclear accumulation of Smad4 and reduced phosphorylation of ERK. Interestingly, we found that silence of RBPMS using RNA interference (siRNA) not only elevated the cell viability but also increased the phosphorylation of ERK and reversed the nuclear accumulation of Smad4 induced by miR-21-3p inhibitors in HCT116 cells. Data suggest that inhibition of miR-21-3p suppresses cell proliferation, invasion as well as migration and induces apoptosis by directly targeting RBPMS through Smad4/ERK signalling pathway in HCT116 cells. Our study demonstrates miR-21-3p as a potent target for suppressing tumour progression of CRC which may have implications in CRC therapy in the future.

Immunosuppressive therapy for steroid-resistant nephrotic syndrome: a Bayesian network meta-analysis of randomized controlled studies.

BACKGROUND: The purpose of this study was to conduct a meta-analysis examining the efficacy of cyclophosphamide, cyclosporin, and tacrolimus in treating steroid resistant nephrotic syndrome. METHODS: Medline, Cochrane, EMBASE, and Google Scholar were searched until May 02, 2017 using the keywords: immunosuppressive therapy, steroid-resistant nephrotic syndrome, cyclophosphamide, cyclosporine A, and tacrolimus. Inclusion criteria were randomized controlled trials (RCTs) including patients with SRNS treated with an immunosuppressive therapy or placebo. RESULTS: Seven RCTs were included, and the number of patients ranged from 30 to 131. Conventional pair-wise meta-analysis indicated a higher odds of complete or partial remission with tacrolimus as compared to cyclophosphamide [odds ratio (OR) 4.908, 95% confidence interval (CI) 2.278-10.576, P < 0.001], and cyclophosphamide (OR 0.143, 95% CI 0.028-0.721, P = 0.019) and placebo (OR 0.043, 95% CI 0.012-0.157, P < 0.001) were associated with a lower likelihood of complete or partial remission than cyclosporine. Bayesian analysis indicated that tacrolimus and cyclosporine were the best and the second-best agents for inducing a complete or partial remission (rank probability = 0.53 for tacrolimus and 0.46 for cyclosporine). CONCLUSION: As compared to cyclophosphamide and cyclosporin, tacrolimus is more effective at inducing remission in patients with SRNS.

Upregulation of lncRNA BANCR associated with the lymph node metastasis and poor prognosis in colorectal cancer.

BACKGROUND: Growing evidence has supported that long non-coding RNAs (lncRNAs) could play vital roles in the development, progression, and prognosis of colorectal cancer (CRC). However, little is known about the clinical significance of BRAF-activated non-coding RNA (BANCR) in CRC. The aim of this study is to explore the clinical value of lncRNA BANCR in CRC patients. METHODS: The expression of lncRNA BANCR was measured in 106 CRC tissues and 65 adjacent normal tissues using the quantitative real-time PCR. RESULTS: The study showed that lncRNA BANCR was highly expressed in CRC tissues compared with adjacent normal tissues (P < 0.001). In addition, high expression of lncRNA BANCR was positively correlated with the lymph node metastasis (P < 0.001). Kaplan-Meier analysis showed that patients with high lncRNA BANCR expression had a shorter overall survival (OS) compared with the low lncRNA BANCR expression group (P = 0.001). Interestingly, for the group of patients with the lymph node metastasis, we found the similar result that high lncRNA BANCR expression was related to poor OS (P = 0.004). Furthermore, the multivariate Cox regression model analysis indicated that high expression of lncRNA BANCR was an independent poor prognostic factor in CRC patients (HR 2.24, 95% CI 1.22-4.16, P = 0.009). CONCLUSIONS: Upregulation of lncRNA BANCR may be associated with the lymph node metastasis and poor survival of CRC. LncRNA BANCR could be served as a novel and useful biomarker for CRC lymph node metastasis and prognosis.

Bazi Bushen ameliorates age-related energy metabolism dysregulation by targeting the IL-17/TNF inflammatory pathway associated with SASP.

BACKGROUND: Chronic inflammation and metabolic dysfunction are key features of systemic aging, closely associated with the development and progression of age-related metabolic diseases. Bazi Bushen (BZBS), a traditional Chinese medicine used to alleviate frailty, delays biological aging by modulating DNA methylation levels. However, the precise mechanism of its anti-aging effect remains unclear. In this study, we developed the Energy Expenditure Aging Index (EEAI) to estimate biological age. By integrating the EEAI with transcriptome analysis, we aimed to explore the impact of BZBS on age-related metabolic dysregulation and inflammation in naturally aging mice. METHODS: We conducted indirect calorimetry analysis on five groups of mice with different ages and utilized the data to construct EEAI. 12 -month-old C57BL/6 J mice were treated with BZBS or ß-Nicotinamide Mononucleotide (NMN) for 8 months. Micro-CT, Oil Red O staining, indirect calorimetry, RNA sequencing, bioinformatics analysis, and qRT-PCR were performed to investigate the regulatory effects of BZBS on energy metabolism, glycolipid metabolism, and inflammaging. RESULTS: The results revealed that BZBS treatment effectively reversed the age-related decline in energy expenditure and enhanced overall metabolism, as indicated by the aging index of energy expenditure derived from energy metabolism parameters across various ages. Subsequent investigations showed that BZBS reduced age-induced visceral fat accumulation and hepatic lipid droplet aggregation. Transcriptomic analysis of perirenal fat and liver indicated that BZBS effectively enhanced lipid metabolism pathways, such as the PPAR signaling pathway, fatty acid oxidation, and cholesterol metabolism, and improved glycolysis and mitochondrial respiration. Additionally, there was a significant improvement in inhibiting the inflammation-related arachidonic acid-linoleic acid metabolism pathway and restraining the IL-17 and TNF inflammatory pathways activated via senescence associated secretory phenotype (SASP). CONCLUSIONS: BZBS has the potential to alleviate inflammation in metabolic organs of naturally aged mice and maintain metabolic homeostasis. This study presents novel clinical therapeutic approaches for the prevention and treatment of age-related metabolic diseases.

Integrating machine learning and single-cell trajectories to analyze T-cell exhaustion to predict prognosis and immunotherapy in colon cancer patients.

Introduction: The incidence of colon adenocarcinoma (COAD) has recently increased, and patients with advanced COAD have a poor prognosis due to treatment resistance. Combining conventional treatment with targeted therapy and immunotherapy has shown unexpectedly positive results in improving the prognosis of patients with COAD. More study is needed to determine the prognosis for patients with COAD and establish the appropriate course of treatment. Methods: This study aimed to explore the trajectory of T-cell exhaustion in COAD to predict the overall survival and treatment outcome of COAD patients. Clinical data were derived from the TCGA-COAD cohort through "UCSC", as well as the whole genome data. Prognostic genes driving T-cell trajectory differentiation were identified on the basis of single-cell trajectories and univariate Cox regression. Subsequently, T-cell exhaustion score (TES) was created by iterative LASSO regression. The potential biological logic associated with TES was explored through functional analysis, immune microenvironment assessment, immunotherapy response prediction, and in vitro experiments. Results: Data showed that patients with significant TES had fewer favorable outcomes. Expression, proliferation, and invasion of COAD cells treated with TXK siRNA were also examined by cellular experiments. Both univariate and multivariate Cox regression indicated that TES was an independent prognostic factor in patients with COAD; in addition, subgroup analysis supported this finding. Functional assay revealed that immune response and cytotoxicity pathways are associated with TES, as the subgroup with low TES has an active immune microenvironment. Furthermore, patients with low TES responded better to chemotherapy and immunotherapy. Conclusion: In this study, we systematically explored the T-cell exhaustion trajectory in COAD and developed a TES model to assess prognosis and provide guidelines for the treatment decision. This discovery gave rise to a fresh concept for novel therapeutic procedures for the clinical treatment of COAD.

The zinc figure protein ZNF575 impairs colorectal cancer growth via promoting p53 transcription.

Zinc-finger proteins play different roles in cancer; however, the function of zinc-finger protein ZNF575 in cancer remains unclear. In the present study, we aimed to determine the function and expression of ZNF575 in colorectal cancer. Proliferation assay, colony formation assay, and tumor model in mice were used to investigate the function of ZNF575 after ectopic expression of ZNF575 in colorectal cancer (CRC) cells. RNA sequencing, ChIP, and luciferase assays were used to investigate the mechanism behind ZNF575 regulation of CRC cell growth. The expression of ZNF575 was determined by IHC staining in 150 pairs of malignant CRC tissues, followed by prognosis analysis. We indicated that ectopic expression of ZNF575 inhibited CRC cell proliferation, colony formation and promoted cell apoptosis in vitro. Tumor growth in CRC was also impaired by ZNF575 in mice. RNA sequencing, follow-up western blotting, and qPCR results demonstrated the increase of p53, BAK, and PUMA in ZNF575-expressing CRC cells. Further results indicated that ZNF575 directly targeted the p53 promoter and promoted the transcription of p53. Downregulation of ZNF575 was confirmed in malignant tissues, and ZNF575 expression was positively correlated with the prognosis of CRC patients. The present study demonstrated the function, underlying mechanism, expression, and the prognosis-predicting role of ZNF575 in CRC, which indicated that ZNF575 would be a potential prognostic predictor and therapeutic target for CRC and other cancers.

Bazi Bushen mitigates epigenetic aging and extends healthspan in naturally aging mice.

Bazi Bushen (BZBS), a traditional Chinese medicine, has been proven effective in the treatment of age-related disease in mouse models. However, whether its therapeutic effects are due to antiaging mechanism has not yet been explored. In the present study, we investigated the antiaging effects of BZBS in naturally aging mice by using behavioral tests, liver DNA methylome sequencing, methylation age estimation, and frailty index assessment. The methylome analysis revealed a decrease of mCpG levels in the aged mouse liver. BZBS treatment tended to restore age-associated methylation decline and prune the methylation pattern toward that of young mice. More importantly, BZBS significantly rejuvenated methylation age of the aged mice, which was computed by an upgraded DNA methylation clock. These results were consistent with enhanced memory and muscular endurance, as well as decreased frailty score and liver pathological changes. KEGG analysis together with aging-related database screening identified methylation-targeted pathways upon BZBS treatment, including oxidative stress, DNA repair, MAPK signaling, and inflammation. Upregulation of key effectors and their downstream effects on elevating Sod2 expression and diminishing DNA damage were further investigated. Finally, in vitro experiments with senescent HUVECs proved a direct effect of BZBS extracts on the regulation of methylation enzymes during cellular aging. In summary, our work has revealed for the first time the antiaging effects of BZBS by slowing the methylation aging. These results suggest that BZBS might have great potential to extend healthspan and also explored the mechanism of BZBS action in the treatment of age-related diseases.

Excess selenium intake is associated with microalbuminuria in female but not in male among adults with obesity: Results from NHANES 2009-2018.

Introduction: Selenium is a critical trace element with antioxidant activities that has been related to the preservation of kidney function. Few studies, however, have looked at the effects of excess selenium on kidneys. The purpose of the present study was performed to investigate the relationship between dietary selenium intake and the prevalence of microalbuminuria in American adults with obesity. Methods: A total of 8,547 participants with obesity in the National Health and Nutrition Examination Survey (NHANES) with the age of 19 years or older were included in the present study. Multivariable regression and subgroup analyses were performed to examine the association between dietary selenium and microalbuminuria in the two genders, separately. A selenium intake above the median was defined as high selenium intake. Results: Dietary selenium intake was significantly higher in men compared to women (139.49 µg/day vs. 101.06 µg/day; P < 0.0001). Among female participants, the prevalence of microalbuminuria was significantly higher in participants with a high selenium intake compared with those without a high selenium intake (13.82 vs. 9.96%; P = 0.008), whereas this difference did not exist in male participants (10.79 vs. 11.97%; P = 0.40). Dietary selenium is not significantly correlated with microalbuminuria (P = 0.68) in the male population, whereas each 1 µg/day of increase in selenium consumption was independently associated with a 6h higher risk of microalbuminuria (OR = 1.006; 95% CI, 1.001-1.011, P = 0.01) in females. Conclusion: According to our research, excessive selenium consumption is positively correlated with microalbuminuria in females with obesity, but not in males with obesity.

Comparative biotic and abiotic effects on greenhouse gas emissions from agricultural ecosystems: application of straw or biochar?

Farmland has become a significant contributor to greenhouse gas (GHG) emissions, and research has shown that the addition of straw or biochar may be a viable method for mitigating these emissions. However, there is a lack of understanding regarding the comparative biotic and abiotic effects of straw and biochar amendments on GHG emissions. To address this knowledge gap, we conducted a meta-analysis of 100 published papers to quantify the impact of straw and biochar application on GHG emissions. Our findings indicate that straw application significantly increased CO2 and CH4 emissions from agricultural ecosystems by 46.2% and 113.5%, respectively, but did not have a significant effect on N2O emissions. Conversely, biochar amendment significantly reduced CO2, CH4, and N2O emissions by an average of 11.0%, 31.7%, and 22.8%, respectively. We also found that straw and biochar amendments increased soil pH, soil organic carbon (SOC), and C/N ratio, and there were significant differences between them. Moreover, straw application significantly increased the microbial biomass carbon (MBC) content and microbial quotient by 37.1% and 20.1%, respectively, while biochar application increased the MBC content by 25.0% without a significant effect on the microbial quotient. Furthermore, both straw and biochar applications promoted the nitrification process and increased the abundance of ammonia-oxidizing bacteria (AOB) by 50.7% with straw and by 57.5% and 75.1% with biochar for ammonia-oxidizing archaea (AOA) and AOB, respectively. The denitrification process was also stimulated by straw or biochar amendment, resulting in an increase in the abundance of nirK by 22.9% and 16.8%, respectively. Biochar amendment additionally increased the abundance of nosZ by 29.4%, indicating that the main reason for reducing N2O emissions through biochar application is the conversion of NO3--N to N2. Thus, compared to straw application, biochar application is a more effective method for reducing greenhouse gas emissions.