Mitochondrial oxidative damage reprograms lipid metabolism of renal tubular epithelial cells in the diabetic kidney.

The functional and structural changes in the proximal tubule play an important role in the occurrence and development of diabetic kidney disease (DKD). Diabetes-induced metabolic changes, including lipid metabolism reprogramming, are reported to lead to changes in the state of tubular epithelial cells (TECs), and among all the disturbances in metabolism, mitochondria serve as central regulators. Mitochondrial dysfunction, accompanied by increased production of mitochondrial reactive oxygen species (mtROS), is considered one of the primary factors causing diabetic tubular injury. Most studies have discussed how altered metabolic flux drives mitochondrial oxidative stress during DKD. In the present study, we focused on targeting mitochondrial damage as an upstream factor in metabolic abnormalities under diabetic conditions in TECs. Using SS31, a tetrapeptide that protects the mitochondrial cristae structure, we demonstrated that mitochondrial oxidative damage contributes to TEC injury and lipid peroxidation caused by lipid accumulation. Mitochondria protected using SS31 significantly reversed the decreased expression of key enzymes and regulators of fatty acid oxidation (FAO), but had no obvious effect on major glucose metabolic rate-limiting enzymes. Mitochondrial oxidative stress facilitated renal Sphingosine-1-phosphate (S1P) deposition and SS31 limited the elevated Acer1, S1pr1 and SPHK1 activity, and the decreased Spns2 expression. These data suggest a role of mitochondrial oxidative damage in unbalanced lipid metabolism, including lipid droplet (LD) formulation, lipid peroxidation, and impaired FAO and sphingolipid homeostasis in DKD. An in vitro study demonstrated that high glucose drove elevated expression of cytosolic phospholipase A2 (cPLA2), which, in turn, was responsible for the altered lipid metabolism, including LD generation and S1P accumulation, in HK-2 cells. A mitochondria-targeted antioxidant inhibited the activation of cPLA2f isoforms. Taken together, these findings identify mechanistic links between mitochondrial oxidative metabolism and reprogrammed lipid metabolism in diabetic TECs, and provide further evidence for the nephroprotective effects of SS31 via influencing metabolic pathways.

Clinical features and risk factors for Sjogren's syndrome patients suffering from oral candidiasis in Shanxi, China.

OBJECTIVES: To investigate the clinical features and risk factors of Sjogren's Syndrome (SS) patients suffering from oral candidiasis and to provide a foundation for the prevention and treatment of oral candidiasis in SS patients. METHODS: The medical records of 479 SS patients admitted to the Second Hospital of Shanxi Medical University from 2018 to 2020 were analysed to determine the clinical characteristics and risk factors that influence the occurrence of oral candidiasis infection in SS patients. RESULTS: Patients with oral candidiasis were older than those without oral candidiasis (P < 0.05). Male SS patients had greater oral candidiasis rates (P < 0.05). Unstimulated whole saliva (UWS) and stimulated whole saliva (SWS) were both shown to be adversely associated with oral Candida infections (P < 0.001). Logistic regression revealed that a low UWS was an independent risk factor for oral Candida infections in SS patients (OR: 0.004, P = 0.023). Greater WBC counts (OR: 1.22, P < 0.001), lower haemoglobin levels (OR: 0.97, P = 0.007), lower serum albumin levels (OR: 0.88, P < 0.001), lower IgG levels (OR: 0.91, P = 0.011), lower IgA levels (OR: 0.75, P = 0.011), and lower IgM levels (OR: 0.91, P = 0.015) were found in patients with oral Candida infections. Patients on immunosuppressive medications (OR: 0.32, P = 0.011), particularly rapamycin (P < 0.001), had a decreased rate of oral Candida infections. CONCLUSIONS: Patients with oral candidiasis were older than those without oral candidiasis. Male SS patients are more likely to have oral candidiasis. Individuals with lower UWS and SWS are more susceptible to oral Candida infection. Oral Candida infections in SS patients depend on their immunological status. Rapamycin may increase the abundance of Treg cells to reduce oral Candida infection in SS patients.

Dynamic Evolution of Palladium Single Atoms on Anatase Titania Support Determines the Reverse Water-Gas Shift Activity.

Research interest in single-atom catalysts (SACs) has been continuously increasing. However, the lack of understanding of the dynamic behaviors of SACs during applications hinders catalyst development and mechanistic understanding. Herein, we report on the evolution of active sites over Pd/TiO2-anatase SAC (Pd1/TiO2) in the reverse water-gas shift (rWGS) reaction. Combining kinetics, in situ characterization, and theory, we show that at T ≥ 350 °C, the reduction of TiO2 by H2 alters the coordination environment of Pd, creating Pd sites with partially cleaved Pd-O interfacial bonds and a unique electronic structure that exhibit high intrinsic rWGS activity through the carboxyl pathway. The activation by H2 is accompanied by the partial sintering of single Pd atoms (Pd1) into disordered, flat, ∼1 nm diameter clusters (Pdn). The highly active Pd sites in the new coordination environment under H2 are eliminated by oxidation, which, when performed at a high temperature, also redisperses Pdn and facilitates the reduction of TiO2. In contrast, Pd1 sinters into crystalline, ∼5 nm particles (PdNP) during CO treatment, deactivating Pd1/TiO2. During the rWGS reaction, the two Pd evolution pathways coexist. The activation by H2 dominates, leading to the increasing rate with time-on-stream, and steady-state Pd active sites similar to the ones formed under H2. This work demonstrates how the coordination environment and nuclearity of metal sites on a SAC evolve during catalysis and pretreatments and how their activity is modulated by these behaviors. These insights on SAC dynamics and the structure-function relationship are valuable to mechanistic understanding and catalyst design.

CD36 deletion ameliorates diabetic kidney disease by restoring fatty acid oxidation and improving mitochondrial function.

Renal tubular epithelial cells (TECs) are vulnerable to mitochondrial dysregulation, which is an integral part of diabetic kidney disease (DKD). We found that CD36 knockout ameliorated mitochondrial dysfunction and diabetic kidney injury in mice, improved renal function, glomerular hypertrophy, tubular injury, tubulointerstitial fibrosis, and kidney cell apoptosis. Furthermore, CD36 knockout conferred protection against diabetes-induced mitochondrial dysfunction and restored renal tubular cells and mitochondrial morphology. CD36 knockout also restored mitochondrial fatty acid oxidation (FAO) and enhanced FAO-associated respiration in diabetic TECs. CD36 was found to alter cellular metabolic pathways in diabetic kidneys partly via PDK4 the -AMPK axis inactivation. Because CD36 protects against DKD by improving mitochondrial function and restoring FAO, it can serve as a potential therapeutic target.

Effects of oral alkali drug therapy on clinical outcomes in pre-dialysis chronic kidney disease patients: a systematic review and meta-analysis.

BACKGROUND: Metabolic acidosis accelerates the progression of chronic kidney disease (CKD) and increases the mortality rate. Whether oral alkali drug therapy benefits pre-dialysis CKD patients is controversial. We performed a meta-analysis of the effects of oral alkali drug therapy on major clinical outcomes in pre-dialysis CKD patients. METHODS: We systematically searched MEDLINE using the Ovid, EMBASE, and Cochrane Library databases without language restriction. We included all eligible clinical studies that involved pre-dialysis CKD adults and compared those who received oral alkali drug therapy with controls. RESULTS: A total of 18 eligible studies, including 14 randomized controlled trials and 4 cohort studies reported in 19 publications with 3695 participants, were included. Oral alkali drug therapy led to a 55% reduction in renal failure events (relative risk [RR]: 0.45; 95% confidence interval [CI]: 0.25-0.82), a rate of decline in the estimated glomerular filtration rate (eGFR) of 2.59 mL/min/1.73 m2 per year (95% CI, 0.88-4.31). There was no significant effect on decline in eGFR events (RR: 0.34; 95% CI: 0.09-1.23), proteinuria (standardized mean difference: -0.32; 95% CI: -1.08 to 0.43), all-cause mortality events (RR: 0.90; 95% CI: 0.40-2.02) and cardiovascular (CV) events (RR: 1.03; 95% CI: 0.32-3.37) compared with the control groups. CONCLUSION: Based on the available and low-to-moderate certainty evidence, oral alkali drug therapy might potentially reduce the risk of kidney failure events, but no benefit in reducing all-cause mortality events, CV events, decline in eGFR and porteninuria.

Mechanism of action of Tripterygium wilfordii for treatment of idiopathic membranous nephropathy based on network pharmacology.

BACKGROUND: Although thunder god vine (Tripterygium wilfordii) has been widely used for treatment of idiopathic membranous nephropathy (IMN), the pharmacological mechanisms underlying its effects are still unclear. This study investigated potential therapeutic targets and the pharmacological mechanism of T. wilfordii for the treatment of IMN based on network pharmacology. METHODS: Active components of T. wilfordii were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. IMN-associated target genes were collected from the GeneCards, DisGeNET, and OMIM databases. VENNY 2.1 was used to identify the overlapping genes between active compounds of T. wilfordii and IMN target genes. The STRING database and Cytoscape 3.7.2 software were used to analyze interactions among overlapping genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the targets were performed using Rx64 4.0.2 software, colorspace, stringi, DOSE, clusterProfiler, and enrichplot packages. RESULTS: A total of 153 compound-related genes and 1485 IMN-related genes were obtained, and 45 core genes that overlapped between both categories were identified. The protein-protein interaction network and MCODE results indicated that the targets TP53, MAPK8, MAPK14, STAT3, IFNG, ICAM1, IL4, TGFB1, PPARG, and MMP1 play important roles in the treatment of T. wilfordii on IMN. Enrichment analysis showed that the main pathways of targets were the AGE signaling pathway, IL-17 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway. CONCLUSION: This study revealed potential multi-component and multi-target mechanisms of T. wilfordii for the treatment of IMN based on network pharmacological, and provided a scientific basis for further experimental studies.

Berberine ameliorates renal interstitial inflammation and fibrosis in mice with unilateral ureteral obstruction.

Berberine acts via multiple pathways to alleviate fibrosis in various tissues and shows renoprotective effects. However, its role and underlying mechanisms in renal fibrosis remain unclear. Herein, we aimed to investigate the protective effects and molecular mechanisms of berberine against unilateral ureteric obstruction-induced renal fibrosis. The results indicated that berberine treatment (50 mg/kg/day) markedly alleviated histopathological alterations, collagen deposition and inflammatory cell infiltration in kidney tissue and restored mouse renal function. Mechanistically, berberine intervention inhibited NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and the levels of the inflammatory cytokine IL-1ß in the kidneys of unilateral ureteric obstruction mice. In addition, berberine relieved unilateral ureteric obstruction-induced renal injury by activating adenosine monophosphate-activated protein kinase (AMPK) signalling and promoting fatty acid ß-oxidation. In vitro models showed that berberine treatment prevented the TGF-ß1-induced profibrotic phenotype of hexokinase 2 (HK-2) cells, characterized by loss of an epithelial phenotype (alpha smooth muscle actin [α-SMA]) and acquisition of mesenchymal marker expression (E-cadherin), by restoring abnormal fatty acid ß-oxidation and upregulating the expression of the fatty acid ß-oxidation related-key enzymes or regulators (phosphorylated-AMPK, peroxisome proliferator activated receptor alpha [PPARα] and carnitine palmitoyltransferase 1A [CPT1A]). Collectively, berberine alleviated renal fibrosis by inhibiting NLRP3 inflammasome activation and protected tubular epithelial cells by reversing defective fatty acid ß-oxidation. Our findings might be exploited clinically to provide a potential novel therapeutic strategy for renal fibrosis.

Effect of a low-salt diet on chronic kidney disease outcomes: a systematic review and meta-analysis.

OBJECTIVE: The benefits of a low-salt diet for patients with chronic kidney disease (CKD) are controversial. We conducted a systematic review and meta-analysis of the effect of a low-salt diet on major clinical outcomes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE by Ovid, EMBASE and the Cochrane Library databases. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included randomised controlled trials (RCTs) and cohort studies that assessed the effect of a low-salt diet on the renal composite outcomes (more than 50% decline in estimated glomerular filtration rate (eGFR) during follow-up, doubling of serum creatinine or end-stage renal disease), rate of eGFR decline, change in proteinuria, all-cause mortality events, cardiovascular (CV) events, and changes in systolic blood pressure and diastolic blood pressure. DATA EXTRACTION AND SYNTHESIS: Two independent researchers extracted data and evaluated their quality. Relative risks (RRs) with 95% CIs were used for dichotomous data. Differences in means (MDs) or standardised mean differences (SMDs) with 95% CIs were used to pool continuous data. We used the Cochrane Collaboration risk-of-bias tool to evaluate the quality of RCTs, and Newcastle-Ottawa Scale to evaluate the quality of cohort studies. RESULTS: We found 9948 potential research records. After removing duplicates, we reviewed the titles and abstracts, and screened the full text of 230 publications. Thirty-three studies with 101 077 participants were included. A low-salt diet produced a 28% reduction in renal composite outcome events (RR: 0.72; 95% CI: 0.58 to 0.89). No significant effects were found in terms of changes in proteinuria (SMD: -0.71; 95% CI: -1.66 to 0.24), rate of eGFR (decline MD: 1.16; 95% CI: -2.02 to 4.33), risk of all-cause mortality (RR: 0.92; 95% CI: 0.58 to 1.46) and CV events (RR: 1.01; 95% CI: 0.46 to 2.22). CONCLUSION: A low-salt diet seems to reduce the risk for renal composite outcome events in patients with CKD. However, no compelling evidence indicated that such a diet would reduce the eGFR decline rate, proteinuria, incidence of all-cause mortality and CV events. Further, more definitive studies are needed. PROSPERO REGISTRATION NUMBER: CRD42017072395.

Selective ozone activation of phenanthrene in liquid CO2.

We demonstrate liquid CO2 (8 °C, 4.4 MPa) as a benign medium to perform safe ozonolysis of phenanthrene at near-ambient temperatures. The ozonolysis products consist of several monomeric oxidation products such as diphenaldehyde, diphenic acid and phenanthrenequinone as well as polymeric structures up to 1130 Da. The observed chemical shifts (1H-6.03 ppm, 13C-104.38 ppm) in 2D-NMR spectra of the products confirm the formation of secondary ozonide. Based on the range of observed products, a Criegee-type mechanism is proposed. The ability to deconstruct phenanthrene and produce oxygenated precursors via this technique is particularly of interest in creating new materials from aromatic moieties.

Performance assessment of extensive green roof runoff flow and quality control capacity based on pilot experiments.

Green roof is an important measure in "Sponge Cities" to reduce the runoff and improve the runoff quality. The runoff quantity and quality control capacity of five types of extensive green roofs (EGRs) were analyzed in Beijing for 51 nature rainfall events and 6 simulated events from July 2017 to October 2018. Different module scales (sizes) and substrate depths were examined to study their correlation to runoff retention, peak flow reduction, pollutant event mean concentration (EMC) and load reduction performance of EGRs. In general, both the single-field rainfall events and the long-term monitoring showed that as the module scale and substrate thickness increased, the retention capacity of the EGRs increased. As the module scale increased, the peak flow reduction rate (Pfrr) of the EGR modules increased, while the thickness of the substrate appeared to have less of an effect on Pfrr. When water quality effect was considered, compared with module scale, the substrate thickness had a more obvious effect on the average EMC of different pollutants. As the substrate thickness increased, the EMC of pollutants decreased. Under six simulated design rainfalls, EMC reduction rate of suspended solid (SS) of all types of EGRs ranged from 64.3%-73.1% while no reduction was found in the EMC of chemical oxygen demand (COD). The EMC trends of ammonia nitrogen (NH4+-N), nitrate nitrogen (NO3--N), total nitrogen (TN) and total phosphorus (TP) were almost the same, and their EMCs decreased with increasing total rainfall depth. When the pollutant load was considered, the EGRs in this study were a sink of NH4+-N, NO3--N, TN, and TP but a source of COD.

Characterization, thermochemical conversion studies, and heating value modeling of municipal solid waste.

A study was carried out to examine the characteristics of municipal solid waste (MSW) from the City of Red Deer, Alberta, Canada. Experiments were performed for determining the moisture content, proximate and ultimate compositions, heating value of fourteen wastes in different categories. Their thermal weight loss behaviors under pyrolysis/torrefaction conditions were also investigated in a thermogravimetric analyzer (TGA). An empirical model was developed for the high heating value (HHV) estimation of MSW. A total of 193 experimental data were collected from this study and those in the literature, of which 161 data were used for model derivation; and, 32 additional data were used for model validation. The model was developed using multiple regression analysis and a stepwise regression method: HHV (MJ/kg)=0.350C+1.01H-0.0826O, which is expressed in terms of weight percentages on a dry basis of carbon (C), hydrogen (H) and oxygen (O). The validation results suggest that this model was effective in producing accurate outputs that were close to the experimental values. In addition, it had the lowest error level in comparison with seven other models from the literature.