High glucose-induced apoptosis and necroptosis in podocytes is regulated by UCHL1 via RIPK1/RIPK3 pathway.

Diabetic nephrology (DN) is attributed largely to the depletion of podocytes, which is closely associated to apoptosis. However, the complex mechanism of podocyte loss in DN pathogenesis remains unclear. Recently, necroptosis has emerged as an important cell death model in many pathological conditions, which is regulated through RIPK1/RIPK3 pathway. In addition, necroptosis was found to share several upstream signaling pathways with apoptosis. Therefore, it was speculated that both apoptosis and necroptosis may occur in podocytes during the process of podocyte injury in DN. Herein, necroptosis and apoptosis were shown to be involved in podocyte injury induced by high glucose (HG), both in vitro and in vivo, with a high level of positive signaling markers RIPK1 (298.4 ±â€¯17.35), cleaved caspase 3 (497.1 ±â€¯23.09), RIPK3 (108.4 ±â€¯14.92), and MLKL (470.4 ±â€¯15.73) than the control groups. Scaning electron microscopy examination revealed the morphological characteristics of necroptotic and apoptotic cells, which differed remarkably. z-VAD-fmk, a pan-inhibitor of apoptosis, could block apoptosis and enhance necroptosis. Furthermore, UCHL1 was found to play a major role in promoting podocyte necroptosis by regulating the ubiquitination state of the RIPK1/RIPK3 pathway. The half-life of RIPK1 and RIPK3 proteins reduced and the expression of RIPK1, RIPK3, and MLKL decreased significantly after the knockdown of UCHL1. It was shown that UCHL1 exerted a more regulatory response to necroptosis. These data suggested that necroptosis may have more effect on the loss of podocytes than apoptosis in DN with the regulation of UCHL1. Thus, inhibiting UCHL1 to downregulate the RIPK1/RIPK3 pathway may be a novel strategy to protect the podocytes in DN patients.

Vitamin and mineral status of children with autism spectrum disorder in Hainan Province of China: associations with symptoms.

Objective: This study was designed to compare the vitamin and mineral levels of children with autism spectrum disorders (ASDs) with those of age-matched typically developing (TD) children and to investigate their effects on the symptoms of autistic children. Methods: The Autism Behavior Checklist (ABC), Social Responsiveness Scale (SRS) and Gesell Developmental Scale (GDS) were completed for 274 children diagnosed with ASD. Vitamins and minerals were compared for all ASD children and 97 age-matched TD children. Serum levels of vitamin A (VA) were detected with high-performance liquid chromatography (HPLC); those of vitamin D (VD), folate, vitamin B12 (VB12), and ferritin were measured with immunoassay methods; and those of minerals were detected using atomic absorption spectrophotometry in two groups. Results: The VD and folate levels of children with ASD were significantly lower than those of TD children. The levels of calcium (Ca), magnesium (Mg), iron (Fe), and zinc (Zn) in children with ASD were significantly lower than those in TD children, and no significant difference was found in copper (Cu) levels. Correlation analysis showed that VA and Ca levels were negatively correlated with ASD symptoms. Folate, Ca, Fe and Zn were positively correlated with the GDS scores of autistic children. There were no significant interactions among VD, VB12 and ferritin and symptoms. Conclusion: We found that children with autism had more vitamin and mineral insufficiencies than TD children, and their levels were related to ASD symptoms. Therefore, it is essential to formulate a detailed nutritional evaluation for ASD children and provide timely and intensive interventions.

Photothermionic Effect-Assisted Ultrafast Charge Transfer in NbS2/MoS2 Heterostructure.

Two-dimensional (2D) van der Waals heterostructures (vdW HSs) composed of transition metal dichalcogenides (TMDCs) have emerged as frontrunners in the optoelectronics field, owing to their exceptional optical and electrical properties. Recent research on the intrinsic interlayer charge transfer mechanism has been primarily focused on the Type II HSs, while metal-semiconductor (MS) vertical HSs, promising for advancing photodetector technology, have received comparatively less attention. Here, we reveal the first experimental observation of photothermionic effect-assisted ultrafast interlayer charge transfer in the NbS2/MoS2 heterostructure using femtosecond transient absorption technology and first-principles calculations, effectively ignoring the Schottky barrier height. We demonstrate that within 500 fs, charge transfer occurs from NbS2 to MoS2 in the heterostructure, resulting in supplementary carrier generation in the visible spectrum when excited with infrared light below the MoS2 bandgap, at wavelengths of 1030 and 1500 nm. Such promising characteristics of 2D NbS2-semiconductor heterostructures offer a potential platform for synergistically combining low contact resistance with broadband photocarrier generation, marking a significant advancement in optoelectronics and light harvesting.

Reducing Voltage Losses of Organic Solar Cells against Energetics Modifications by Thermal Stress.

Voltage losses are one of the main obstacles for further improvement in the power conversion efficiency of organic solar cells. In this work, we investigate the effect of thermal stress on voltage losses in various material systems by multiple spectroscopic measurements on both devices and thin films. The energetics of nonfullerene small molecules are more readily altered under thermal stress compared to all-polymer and fullerene-based systems, thereby strongly affecting open-circuit voltage. These energetics variations correlate with the glass transition of respective materials. While nonfullerene small molecular acceptor systems exhibit both dynamic and static disorders which can be restrained in annealed films, all-polymeric systems exhibit dominated static disorders, which are also stable against thermal stress. The much higher voltage losses in fullerene-based systems compared to the other two counterparts are mainly due to the losses from device band gap to charge transfer states and the high nonradiative recombination.

Berberine Ameliorates Prenatal Dihydrotestosterone Exposure-Induced Autism-Like Behavior by Suppression of Androgen Receptor.

Many epidemiology studies have shown that maternal polycystic ovary syndrome (PCOS) results in a greater risk of autism spectrum disorders (ASD) development, although the detailed mechanism remains unclear. In this study, we aimed to investigate the potential mechanism and provide a possible treatment for PCOS-mediated ASD through three experiments: Experiment 1: real-time PCR and western blots were employed to measure gene expression in human neurons, and the luciferase reporter assay and chromatin immunoprecipitation (ChIP) was used to map the responsive elements on related gene promoters. Experiment 2: pregnant dams were prenatally exposed to dihydrotestosterone (DHT), androgen receptor (AR) knockdown (shAR) in the amygdala, or berberine (BBR), and the subsequent male offspring were used for autism-like behavior (ALB) assay followed by biomedical analysis, including gene expression, oxidative stress, and mitochondrial function. Experiment 3: the male offspring from prenatal DHT exposed dams were postnatally treated by either shAR or BBR, and the offspring were used for ALB assay followed by biomedical analysis. Our findings showed that DHT treatment suppresses the expression of estrogen receptor ß (ERß) and superoxide dismutase 2 (SOD2) through AR-mediated hypermethylation on the ERß promoter, and BBR treatment suppresses AR expression through hypermethylation on the AR promoter. Prenatal DHT treatment induces ERß suppression, oxidative stress and mitochondria dysfunction in the amygdala with subsequent ALB behavior in male offspring, and AR knockdown partly diminishes this effect. Furthermore, both prenatal and postnatal treatment of BBR partly restores prenatal DHT exposure-mediated ALB. In conclusion, DHT suppresses ERß expression through the AR signaling pathway by hypermethylation on the ERß promoter, and BBR restores this effect through AR suppression. Prenatal DHT exposure induces ALB in offspring through AR-mediated ERß suppression, and both prenatal and postnatal treatment of BBR ameliorates this effect. We conclude that BBR ameliorates prenatal DHT exposure-induced ALB through AR suppression, this study may help elucidate the potential mechanism and identify a potential treatment through using BBR for PCOS-mediated ASD.

Betulinic Acid Inhibits Endometriosis Through Suppression of Estrogen Receptor ß Signaling Pathway.

Endometriosis is an inflammatory gynecological disorder characterized by endometrial tissue growth located outside of the uterine cavity in addition to chronic pelvic pain and infertility. In this study, we aim to develop a potential therapeutic treatment based on the pathogenesis and mechanism of Endometriosis. Our preliminary data showed that the expression of estrogen receptor ß (ERß) was significantly increased, while ERα was significantly decreased, in endometriotic cells compared to normal endometrial cells. Further investigation showed that betulinic acid (BA) treatment suppressed ERß expression through epigenetic modification on the ERß promoter, while had no effect on ERα expression. In addition, BA treatment suppresses ERß target genes, including superoxide dismutase 2 (SOD2), nuclear respiratory factor-1 (NRF1), cyclooxygenase 2 (COX2), and matrix metalloproteinase-1 (MMP1), subsequently increasing oxidative stress, triggering mitochondrial dysfunction, decreasing elevated proinflammatory cytokines, and eventually suppressing endometriotic cell proliferation, mimicking the effect of ERß knockdown. On the other hand, gain of ERß by lentivirus infection in normal endometrial cells resulted in increased cell proliferation and proinflammatory cytokine release, while BA treatment diminished this effect through ERß suppression with subsequent oxidative stress and apoptosis. Our results indicate that ERß may be a major driving force for the development of endometriosis, while BA inhibits Endometriosis through specific suppression of the ERß signaling pathway. This study provides a novel therapeutic strategy for endometriosis treatment through BA-mediated ERß suppression.

Ultrafine bimetallic phosphide nanoparticles embedded in carbon nanosheets: two-dimensional metal-organic framework-derived non-noble electrocatalysts for the highly efficient oxygen evolution reaction.

The development of noble-metal-free highly efficient oxygen evolution reaction (OER) catalysts is crucial for electrochemical energy technology but still challenging. Herein, ultrafine cobalt-iron bimetallic phosphide nanoparticles embedded in carbon nanosheets are synthesized using two-dimensional (2D) metal-organic frameworks (MOFs) as the precursor. The 2D morphology of the carbon matrix and the ultrafine character of Co1-xFexP nanoparticles make contributions to OER catalysis. By optimizing the molar ratio of Co/Fe atoms in MOFs, a series of Co1-xFexP/C catalysts are prepared. Among them, Co0.7Fe0.3P/C shows the best OER performance with an overpotential of 270 mV at a current density of 10 mA cm-2 and an ultralow Tafel slope of 27 mV dec-1 in an alkaline electrolyte. Moderate iron doping preserves the catalytically active sites and improves the ability to be oxidized of the surface of Co1-xFexP nanoparticles, and thus enhances the OER activity. Our finding paves the way to the rational design of the morphology and chemical composition of OER catalysts.

Nephrokeli, a Chinese herbal formula, may improve IgA nephropathy through regulation of the sphingosine-1-phosphate pathway.

Nephrokeli (NPKL) is a Chinese herbal formula that has been used to treat patients with IgA nephropathy (IgAN) for improvement of proteinuria and kidney injury. However, the mechanism remains unclear. Sphingosine-1-phosphate (S1P) and its receptors S1PR2 and S1PR3 are known to play an important role in kidney disease. Here, we tested whether NPKL is able to regulate the S1P pathway in the kidney of IgAN rats. Four groups of rats were included in the study: Control, IgAN, IgAN treated with losartan, and IgAN treated with NPKL. The IgAN model was generated by injection of bovine serum albumin and staphylococcus enterotoxin B. We found that IgAN rats had increased staining for proliferating cell nuclear antigen (PCNA) in the mesangial area and increased mRNA and protein levels of S1PR2 and S1PR3 in the kidney compared to control rats. Connective tissue growth factor (CTGF), a downstream growth factor in the S1P pathway, was also elevated in the kidney of IgAN rats. Treatment with either NPKL or losartan was able to reduce PCNA staining and the expression of both S1PR2 and S1PR3 in the kidney of IgAN rats. However, NPKL (but not losartan treatment) reduced the expression of CTGF in the kidney of IgAN rats. In addition, we treated rat mesangial cells with sera collected from either NPKL-treated rats or control rats and found that NPKL-serum was able to reduce S1P-induced mesangial cell proliferation and the expression of S1PR2/S1PR3 and CTGF. NPKL also attenuates expression of fibrosis, inflammation, and oxidative stress markers in the kidney of IgAN rats. Our studies provide the mechanism by which NPKL attenuates kidney injury in IgAN rats.

The Application of SILAC Mouse in Human Body Fluid Proteomics Analysis Reveals Protein Patterns Associated with IgA Nephropathy.

Body fluid proteome is the most informative proteome from a medical viewpoint. But the lack of accurate quantitation method for complicated body fluid limited its application in disease research and biomarker discovery. To address this problem, we introduced a novel strategy, in which SILAC-labeled mouse serum was used as internal standard for human serum and urine proteome analysis. The SILAC-labeled mouse serum was mixed with human serum and urine, and multidimensional separation coupled with tandem mass spectrometry (IEF-LC-MS/MS) analysis was performed. The shared peptides between two species were quantified by their SILAC pairs, and the human-only peptides were quantified by mouse peptides with coelution. The comparison for the results from two replicate experiments indicated the high repeatability of our strategy. Then the urine from Immunoglobulin A nephropathy patients treated and untreated was compared by this quantitation strategy. Fifty-three peptides were found to be significantly changed between two groups, including both known diagnostic markers for IgAN and novel candidates, such as Complement C3, Albumin, VDBP, ApoA,1 and IGFBP7. In conclusion, we have developed a practical and accurate quantitation strategy for comparison of complicated human body fluid proteome. The results from such strategy could provide potential disease-related biomarkers for evaluation of treatment.