Diosmin ameliorates renal fibrosis through inhibition of inflammation by regulating SIRT3-mediated NF-κB p65 nuclear translocation.

BACKGROUND: Renal fibrosis is considered an irreversible pathological process and the ultimate common pathway for the development of all types of chronic kidney diseases and renal failure. Diosmin is a natural flavonoid glycoside that has antioxidant, anti-inflammatory, and antifibrotic activities. However, whether Diosmin protects kidneys by inhibiting renal fibrosis is unknown. We aimed to investigate the role of Diosmin in renal interstitial fibrosis and to explore the underlying mechanisms. METHODS: The UUO mouse model was established and gavaged with Diosmin (50 mg/kg·d and 100 mg/kg·d) for 14 days. HE staining, Masson staining, immunohistochemistry, western blotting and PCR were used to assess renal tissue injury and fibrosis. Elisa kits were used to detect the expression levels of IL-1ß, IL-6, and TNF-α and the activity of SIRT3 in renal tissues. In addition, enrichment maps of RNA sequencing analyzed changes in signaling pathways. In vitro, human renal tubular epithelial cells (HK-2) were stimulated with TGF-ß1 and then treated with diosmin (75 µM). The protein and mRNA expression levels of SIRT3 were detected in the cells. In addition, 3-TYP (selective inhibitor of SIRT3) and SIRT3 small interfering RNA (siRNA) were used to reduce SIRT3 levels in HK-2. RESULTS: Diosmin attenuated UUO-induced renal fibrosis and TGF-ß1-induced HK-2 fibrosis. In addition, Diosmin reduced IL-1ß, IL-6, and TNF-α levels in kidney tissues and supernatants of HK-2 medium. Interestingly, Diosmin administration increased the enzymatic activity of SIRT3 in UUO kidneys. In addition, Diosmin significantly increased mRNA and protein expression of SIRT3 in vitro and in vivo. Inhibition of SIRT3 expression using 3-TYP or SIRT3 siRNA abolished the anti-inflammatory effects of diosmin in HK-2 cells. Enrichment map analysis by RNA sequencing indicates that the nuclear factor-kappa B (NF-κB) signaling pathway was inhibited in the Diosmin intervention group. Furthermore, we found that TGF-ß1 increased the nuclear expression of nuclear NF-κB p65 but had little significant effect on the total intracellular expression of NF-κB p65. Additionally, Diosmin reduced TGF-ß1-caused NF-κB p65 nuclear translocation. Knockdown of SIRT3 expression by SIRT3 siRNA increased the nuclear expression of NF-κB p65 and abolished the inhibition effect of Diosmin in NF-κB p65 expression. CONCLUSIONS: Diosmin reduces renal inflammation and fibrosis, which is contributed by inhibiting nuclear translocation of NF-κB P65 through activating SIRT3.

Global, Regional, and National Burden of CKD in Children and Adolescents from 1990 to 2019.

BACKGROUND AND AIMS: CKD is one of the most prevalent non-communicable health concerns in children and adolescents worldwide; however, data on its incidence, prevalence, disability-adjusted life years (DALYs), and trends in the population are limited. We aimed to assess the global, regional, and national trends in CKD burden in children and adolescents. METHODS: In this trend analysis based on the 2019 Global Diseases, Injuries, and Risk Factors Study, CKD incidence, prevalence, and DALYs rates per 100,000 population for children and adolescents were reported at the global, regional, and national levels, as well as the average annual percentage change (AAPC). These global trends were analyzed by age, sex, region, and socio-demographic index (SDI). RESULTS: Globally, the overall incidence of CKD (all stages including KRT) in children and adolescents showed an increasing trend (AAPC 0.44 [95% CI 0.36-0.52]) between 1990 and 2019. Similarly, the overall prevalence of CKD also showed an upward trend (AAPC 0.46 [95% CI 0.42-0.51]). However, the DALYs of CKD showed a continuous decreasing trend (AAPC -1.18[-1.37- -0.99]). The population aged 15-19 years had the largest CKD incidence increase during this period. The largest increase in age-standardized incidence rate (ASIR) was in middle SDI countries (AAPC 0.56 [0.45-0.67]). The relationship between the ASIR and SDI showed an inverse U-shaped correlation while the relationship between the age-standardized DALYs rate (ASDR) and SDI showed an inverse trend with SDI. Among adolescents (15-19 years), the ASIR continued to increase for five causes of CKD, owing to type 2 diabetes mellitus and hypertension. Most of the disease burden was concentrated in countries with a lower SDI. Andean Latin America and Central Latin America showed the largest increases in CKD ASIR between 1990 and 2019. CONCLUSION: The burden of CKD in children and adolescents has increased worldwide, especially in regions and countries with a lower SDI.

Machine learning algorithms assist early evaluation of enteral nutrition in ICU patients.

Background: This study applied machine learning (ML) algorithms to construct a model for predicting EN initiation for patients in the intensive care unit (ICU) and identifying populations in need of EN at an early stage. Methods: This study collected patient information from the Medical Information Mart for Intensive Care IV database. All patients enrolled were split randomly into a training set and a validation set. Six ML models were established to evaluate the initiation of EN, and the best model was determined according to the area under curve (AUC) and accuracy. The best model was interpreted using the Local Interpretable Model-Agnostic Explanations (LIME) algorithm and SHapley Additive exPlanation (SHAP) values. Results: A total of 53,150 patients participated in the study. They were divided into a training set (42,520, 80%) and a validation set (10,630, 20%). In the validation set, XGBoost had the optimal prediction performance with an AUC of 0.895. The SHAP values revealed that sepsis, sequential organ failure assessment score, and acute kidney injury were the three most important factors affecting EN initiation. The individualized forecasts were displayed using the LIME algorithm. Conclusion: The XGBoost model was established and validated for early prediction of EN initiation in ICU patients.

Analysis of the potential biological mechanisms of diosmin against renal fibrosis based on network pharmacology and molecular docking approach.

BACKGROUND: Interstitial fibrosis is involved in the progression of various chronic kidney diseases and renal failure. Diosmin is a naturally occurring flavonoid glycoside that has antioxidant, anti-inflammatory, and antifibrotic activities. However, whether diosmin protects kidneys by inhibiting renal fibrosis is unknown. METHODS: The molecular formula of diosmin was obtained, targets related to diosmin and renal fibrosis were screened, and interactions among overlapping genes were analyzed. Overlapping genes were used for gene function and KEGG pathway enrichment analysis. TGF-ß1 was used to induce fibrosis in HK-2 cells, and diosmin treatment was administered. The expression levels of relevant mRNA were then detected. RESULTS: Network analysis identified 295 potential target genes for diosmin, 6828 for renal fibrosis, and 150 hub genes. Protein-protein interaction network results showed that CASP3, SRC, ANXA5, MMP9, HSP90AA1, IGF1, RHOA, ESR1, EGFR, and CDC42 were identified as key therapeutic targets. GO analysis revealed that these key targets may be involved in the negative regulation of apoptosis and protein phosphorylation. KEGG indicated that pathways in cancer, MAPK signaling pathway, Ras signaling pathway, PI3K-Akt signaling pathway, and HIF-1 signaling pathway were key pathways for renal fibrosis treatment. Molecular docking results showed that CASP3, ANXA5, MMP9, and HSP90AA1 stably bind to diosmin. Diosmin treatment inhibited the protein and mRNA levels of CASP3, MMP9, ANXA5, and HSP90AA1. Network pharmacology analysis and experimental results suggest that diosmin ameliorates renal fibrosis by decreasing the expression of CASP3, ANXA5, MMP9, and HSP90AA1. CONCLUSIONS: Diosmin has a potential multi-component, multi-target, and multi-pathway molecular mechanism of action in the treatment of renal fibrosis. CASP3, MMP9, ANXA5, and HSP90AA1 might be the most important direct targets of diosmin.

Dialysis vintage is associated with a high prevalence and severity of unpleasant symptoms in patients on hemodialysis.

Background: The burden of physical and emotional symptoms caused by somatic illness is present in most dialysis patients. However, it's unclear how symptom burden varies among patients with different dialysis vintages. We sought to examine differences in the prevalence and severity of unpleasant symptoms in hemodialysis patients with diverse dialysis vintage cohorts.Methods: This cross-sectional study included patients on maintenance hemodialysis at the Second Hospital of Anhui Medical University. We used the Dialysis Symptom Index (DSI) to determine the associated unpleasant symptoms, which is a validated survey to assess symptom burden/severity (higher scores indicate more severe symptoms), over June 2022 - September 2022.Results: We studied 146 patients: 35 (24%) had a dialysis vintage of ≤12 months (group 1) and 111 (76%) had a dialysis vintage of >12 months (group 2). Concerning Group 1 patients, the prevalence and severity of unpleasant symptoms were significantly higher in Group 2, the most common individual symptoms included feeling tired or lack of energy and trouble falling asleep (i.e., 75-85% of patients in each group), with dialysis vintage being an independent influencing factor (adjusted OR, 0.19; 95% CI, 0.16 to 0.23). Lower hemoglobin levels, iron stores, and dialysis adequacy levels are correlated with longer dialysis vintage.Conclusion: We observed a high prevalence of unpleasant symptoms and symptom clusters in a diverse dialysis vintages hemodialysis cohort. Further studies are needed to accurately and routinely define the symptom burden of chronic patients with chronic kidney disease (CKD).