Objective:To identify factors associated with depressive symptoms in maintenance hemodialysis patients and to examine the relationship between these symptoms and mortality.Methods:Between January and December 2019, patients who received maintenance hemodialysis in the Blood Purification Center of the Second Affiliated Hospital of Nanjing Medical University were enrolled in a prospective cohort study. Depressive symptoms were assessed using the internationally validated patient health questionnaire-8 (PHQ-8). Sleep quality and anxiety were measured with the Pittsburgh sleep quality index (PSQI) and the generalized anxiety disorder-7 (GAD-7) scale, respectively. Follow-up continued until December 31, 2022, with all-cause mortality as the primary outcome. Ordinal logistic regression was used to identify independent predictors of depression severity. Cox proportional hazards models evaluated the association between depressive symptoms and mortality.Results:A total of 532 maintenance hemodialysis (MHD) patients completed the study. Among them, 177 (33.3%) exhibited depressive symptoms. Compared with patients without depression, those with mild or moderate-to-severe depression were older [median age: 58 (50, 66) vs. 60 (55, 65) vs. 55 (46, 64)], more likely to smoke [35.9% (51/142) vs. 40.0% (14/35) vs.26.2% (93/355)], had poorer sleep quality [PSQI: 9 (6, 13) vs. 12 (9, 17) vs. 5 (3, 9)], and higher anxiety levels [GAD-7: 1 (0, 3) vs. 3 (1, 6) vs. 0 (0, 1)], the differences among the three groups were statistically significant (all P<0.05). Ordinal logistic regression identified smoking status, history of diabetes or cardiovascular disease, hemoglobin level, PSQI score, and GAD-7 score as independent predictors of depression severity ( OR=1.60, 1.80, 1.81, 0.98, 3.67, 8.67; all P<0.05). After a median follow-up of 40 (35, 44) months, 109 patients died, including 66 (60.6%) from cardio-cerebrovascular causes and 24 (22.0%) from infections. Kaplan-Meier analysis revealed significantly lower cumulative survival in the depression group compared to the non-depression group ( P<0.001). Cox regression analysis demonstrated that depressive symptoms remained independently associated with all-cause mortality after adjusting for confounders ( HR=1.06, 95% CI 1.00-1.13, P=0.048), with an even stronger association observed for patients with PHQ-8 scores≥2.9 ( HR=1.10, 95% CI 1.03-1.16, P=0.005). However, the associations between depression and cardio-cerebrovascular mortality ( P=0.111) or infection-related mortality ( P=0.509) were not statistically significant. Conclusions:Depressive symptoms are prevalent among maintenance hemodialysis patients and are independently associated with increased all-cause mortality. Smoking, comorbid diabetes or cardiovascular disease, low hemoglobin level, poor sleep quality, and anxiety are risk factors contributing to depression. Maintenance hemodialysis patients with PHQ-8 scores≥3 should be considered at heightened risk for mortality.

Objective:To identify factors associated with depressive symptoms in maintenance hemodialysis patients and to examine the relationship between these symptoms and mortality.Methods:Between January and December 2019, patients who received maintenance hemodialysis in the Blood Purification Center of the Second Affiliated Hospital of Nanjing Medical University were enrolled in a prospective cohort study. Depressive symptoms were assessed using the internationally validated patient health questionnaire-8 (PHQ-8). Sleep quality and anxiety were measured with the Pittsburgh sleep quality index (PSQI) and the generalized anxiety disorder-7 (GAD-7) scale, respectively. Follow-up continued until December 31, 2022, with all-cause mortality as the primary outcome. Ordinal logistic regression was used to identify independent predictors of depression severity. Cox proportional hazards models evaluated the association between depressive symptoms and mortality.Results:A total of 532 maintenance hemodialysis (MHD) patients completed the study. Among them, 177 (33.3%) exhibited depressive symptoms. Compared with patients without depression, those with mild or moderate-to-severe depression were older [median age: 58 (50, 66) vs. 60 (55, 65) vs. 55 (46, 64)], more likely to smoke [35.9% (51/142) vs. 40.0% (14/35) vs.26.2% (93/355)], had poorer sleep quality [PSQI: 9 (6, 13) vs. 12 (9, 17) vs. 5 (3, 9)], and higher anxiety levels [GAD-7: 1 (0, 3) vs. 3 (1, 6) vs. 0 (0, 1)], the differences among the three groups were statistically significant (all P<0.05). Ordinal logistic regression identified smoking status, history of diabetes or cardiovascular disease, hemoglobin level, PSQI score, and GAD-7 score as independent predictors of depression severity ( OR=1.60, 1.80, 1.81, 0.98, 3.67, 8.67; all P<0.05). After a median follow-up of 40 (35, 44) months, 109 patients died, including 66 (60.6%) from cardio-cerebrovascular causes and 24 (22.0%) from infections. Kaplan-Meier analysis revealed significantly lower cumulative survival in the depression group compared to the non-depression group ( P<0.001). Cox regression analysis demonstrated that depressive symptoms remained independently associated with all-cause mortality after adjusting for confounders ( HR=1.06, 95% CI 1.00-1.13, P=0.048), with an even stronger association observed for patients with PHQ-8 scores≥2.9 ( HR=1.10, 95% CI 1.03-1.16, P=0.005). However, the associations between depression and cardio-cerebrovascular mortality ( P=0.111) or infection-related mortality ( P=0.509) were not statistically significant. Conclusions:Depressive symptoms are prevalent among maintenance hemodialysis patients and are independently associated with increased all-cause mortality. Smoking, comorbid diabetes or cardiovascular disease, low hemoglobin level, poor sleep quality, and anxiety are risk factors contributing to depression. Maintenance hemodialysis patients with PHQ-8 scores≥3 should be considered at heightened risk for mortality.

AIM:This study investigates the protective effect of the selective peroxisome proliferator-activated receptor δ(PPARδ)agonist seladelpar on podocytes in a mouse model of diabetic kidney disease(DKD).METHODS:A DKD mouse model was established using streptozotocin and a high-fat diet.Mice were randomly assigned to three groups:control,DKD with vehicle treatment,and DKD with seladelpar treatment at dosages of 1,5 and 10 mg/kg(6 to 7 mice per group).After four weeks of treatment,mice were euthanized,and various parameters were measured,including urinary albumin,creatinine,blood urea nitrogen,serum triglycerides,and cholesterol using respective kits.Renal tissues were processed for histological examination through HE and PAS staining to assess glomerular pathology.The RNA from glomerular tissues was analyzed via RT-qPCR for podocyte marker(Nphs1,Nphs2,Wt1 and Synpo)expression,and the protein expression was evaluated using Western blot for PPARδ.Immunofluorescence staining of frozen renal cortical sec-tions was conducted to quantify WT1-positive cells and desmin protein levels.Transmission electron microscopy was used to observe glomerular ultrastructural changes.RESULTS:(1)PPARδ protein levels in the glomerular tissue of DKD mice were significantly lower than in controls.(2)Mice treated with 10 mg/kg of seladelpar showed reduced blood glu-cose,triglycerides,and cholesterol levels compared to the diabetic nephropathy group.(3)Both 5 mg/kg and 10 mg/kg se-ladelpar treatment groups exhibited decreased urine albumin/creatinine ratios,along with improvements in glomerular hy-pertrophy and mesangial matrix deposition.Increased mRNA expression levels of Nphs1,Nphs2,Wt1,and Synpo were also observed,alongside an increase in WT1-positive cells and a decrease in desmin expression.Additionally,there was a reduction in podocyte foot process fusion and glomerular basement membrane thickness.(4)RNA sequencing indicated that 5 mg/kg seladelpar treatment modulated PPAR signaling pathway and influenced various metabolic pathways,includ-ing bile acid metabolism,carbon metabolism,glutathione metabolism,glycerophospholipid metabolism,and fatty acid metabolism.CONCLUSION:Seladelpar,a PPARδ agonist,mitigates podocyte injury and reduces proteinuria in DKD mice.Notably,the protective effects of seladelpar are partially independent of its hypolipidemic properties.

AIM:This study investigates the protective effect of the selective peroxisome proliferator-activated receptor δ(PPARδ)agonist seladelpar on podocytes in a mouse model of diabetic kidney disease(DKD).METHODS:A DKD mouse model was established using streptozotocin and a high-fat diet.Mice were randomly assigned to three groups:control,DKD with vehicle treatment,and DKD with seladelpar treatment at dosages of 1,5 and 10 mg/kg(6 to 7 mice per group).After four weeks of treatment,mice were euthanized,and various parameters were measured,including urinary albumin,creatinine,blood urea nitrogen,serum triglycerides,and cholesterol using respective kits.Renal tissues were processed for histological examination through HE and PAS staining to assess glomerular pathology.The RNA from glomerular tissues was analyzed via RT-qPCR for podocyte marker(Nphs1,Nphs2,Wt1 and Synpo)expression,and the protein expression was evaluated using Western blot for PPARδ.Immunofluorescence staining of frozen renal cortical sec-tions was conducted to quantify WT1-positive cells and desmin protein levels.Transmission electron microscopy was used to observe glomerular ultrastructural changes.RESULTS:(1)PPARδ protein levels in the glomerular tissue of DKD mice were significantly lower than in controls.(2)Mice treated with 10 mg/kg of seladelpar showed reduced blood glu-cose,triglycerides,and cholesterol levels compared to the diabetic nephropathy group.(3)Both 5 mg/kg and 10 mg/kg se-ladelpar treatment groups exhibited decreased urine albumin/creatinine ratios,along with improvements in glomerular hy-pertrophy and mesangial matrix deposition.Increased mRNA expression levels of Nphs1,Nphs2,Wt1,and Synpo were also observed,alongside an increase in WT1-positive cells and a decrease in desmin expression.Additionally,there was a reduction in podocyte foot process fusion and glomerular basement membrane thickness.(4)RNA sequencing indicated that 5 mg/kg seladelpar treatment modulated PPAR signaling pathway and influenced various metabolic pathways,includ-ing bile acid metabolism,carbon metabolism,glutathione metabolism,glycerophospholipid metabolism,and fatty acid metabolism.CONCLUSION:Seladelpar,a PPARδ agonist,mitigates podocyte injury and reduces proteinuria in DKD mice.Notably,the protective effects of seladelpar are partially independent of its hypolipidemic properties.

One group of Bcl-2 protein family, which shares only the BH3 domain (BH3-only), is critically involved in the regulation of programmed cell death. Herein we demonstrated a novel human BH3-only protein (designated as Bop) which could induce apoptosis in a BH3 domain-dependent manner. Further analysis indicated that Bop mainly localized to mitochondria and used its BH3 domain to contact the loop regions of voltage dependent anion channel 1 (VDAC1) in the outer mitochondrial membrane. In addition, purified Bop protein induced the loss of mitochondrial transmembrane potential (Δψm) and the release of cytochrome c. Furthermore, Bop used its BH3 domain to contact pro-survival Bcl-2 family members (Bcl-2, Bcl-X(L), Mcl-1, A1 and Bcl-w), which could inhibit Bop-induced apoptosis. Bop would be constrained by pro-survival Bcl-2 proteins in resting cells, because Bop became released from phosphorylated Bcl-2 induced by microtubule-interfering agent like vincristine (VCR). Indeed, knockdown experiments indicated that Bop was partially required for VCR induced cell death. Finally, Bop might need to function through Bak and Bax, likely by releasing Bak from Bcl-X(L) sequestration. In conclusion, Bop may be a novel BH3-only factor that can engage with the regulatory network of Bcl-2 family members to process intrinsic apoptotic signaling.
Amino Acid Sequence ; Animals ; Apoptosis ; Cell Line ; Cell Survival ; Humans ; Mice ; Mitochondria ; metabolism ; Mitochondrial Membranes ; metabolism ; Molecular Sequence Data ; Protein Structure, Tertiary ; Protein Transport ; Proto-Oncogene Proteins c-bcl-2 ; chemistry ; metabolism ; Signal Transduction ; Time Factors ; Voltage-Dependent Anion Channel 1 ; metabolism ; bcl-2 Homologous Antagonist-Killer Protein ; metabolism ; bcl-2-Associated X Protein ; metabolism