Oxysterol Sensing Through GPR183 Triggers Endothelial Senescence in Hypertension.

BACKGROUND: Despite endothelial dysfunction being an initial step in the development of hypertension and associated cardiovascular/renal injuries, effective therapeutic strategies to prevent endothelial dysfunction are still lacking. GPR183 (G protein-coupled receptor 183), a recently identified G protein-coupled receptor for oxysterols and hydroxylated metabolites of cholesterol, has pleiotropic roles in lipid metabolism and immune responses. However, the role of GPR183 in the regulation of endothelial function remains unknown. METHODS: Endothelial-specific GPR183 knockout mice were generated and used to examine the role of GPR183 in endothelial senescence by establishing 2 independent hypertension models: desoxycorticosterone acetate/salt-induced and Ang II (angiotensin II)-induced hypertensive mice. Echocardiography, transmission electron microscopy, blood pressure measurement, vasorelaxation response experiments, flow cytometry analysis, and chromatin immunoprecipitation analysis were performed in this study. RESULTS: Endothelial GPR183 was significantly induced in hypertensive mice, which was further confirmed in renal biopsies from subjects with hypertensive nephropathy. Endothelial-specific deficiency of GPR183 markedly alleviated cardiovascular and renal injuries in hypertensive mice. Moreover, we found that GPR183 regulated endothelial senescence in both hypertensive mice and aged mice. Mechanistically, GPR183 disrupted circadian signaling by inhibiting PER1 (period 1) expression, thereby facilitating endothelial senescence and dysfunction through the cAMP/PKA (protein kinase A)/CREB (cAMP-response element binding protein) signaling pathway. Importantly, pharmacological inhibition of the oxysterol-GPR183 axis by NIBR189 or clotrimazole ameliorated endothelial senescence and cardiovascular/renal injuries in hypertensive mice. CONCLUSIONS: This study discovers a previously unrecognized role of GPR183 in promoting endothelial senescence. Pharmacological targeting of GPR183 may be an innovative therapeutic strategy for hypertension and its associated complications.

GhROP6 GTPase modulates auxin accumulation in cotton fibers by regulating cell-specific GhPIN3a localization.

PIN-FORMED- (PIN) mediated polar auxin transport plays a predominant role in most auxin-triggered organogenesis in plants. Global control of PIN polarity at the plasma membrane contributes to the essential establishment of auxin maxima in most multicellular tissues. However, establishment of auxin maxima in single cells is poorly understood. Cotton fibers, derived from ovule epidermal cells by auxin-triggered cell protrusion, provide an ideal model to explore the underlying mechanism. Here, we report that cell-specific degradation of GhPIN3a, which guides the establishment of the auxin gradient in cotton ovule epidermal cells, is associated with the preferential expression of GhROP6 GTPase in fiber cells. In turn, GhROP6 reduces GhPIN3a abundance at the plasma membrane and facilitates intracellular proteolysis of GhPIN3a. Overexpression and activation of GhROP6 promote cell elongation, resulting in a substantial improvement in cotton fiber length.

A thematic review on therapeutic toys and games for the elderly with Alzheimer's disease.

PURPOSE: Alzheimer's disease (AD) is a common and devastating neurological ailment that affects millions of the elderly worldwide. Therapeutic toys and games have emerged as potential non-pharmacological interventions for AD. However, despite a growing number of documents on the subject, research on the future direction of therapeutic toys and games for AD remains scarce. To address this gap, this study aims to (1) map the future trends of therapeutic toys and games for AD and (2) identify the categories and design characteristics. MATERIALS AND METHODS: Using a thematic review framework, a systematic literature search was conducted in two electronic databases (Scopus and WoS) using established criteria. Thematic analysis was done using ATLAS.ti 23 to identify prominent themes, patterns and trends. RESULTS: A total of 180 documents were found. Twenty-five articles met the inclusion criteria. A thematic review of these 25 articles identified 13 initial codes, which were been clustered into four themes: detection and evaluation; intervention; toy/game category; and design characteristics. The word "Cognitive" appears most frequently in documents according to word cloud. CONCLUSIONS: Therapeutic toys and games are used to detect and as an intervention for AD. Most of the current studies focused on specific cognitive functions. More research is needed about play therapy for neuropsychiatric symptoms. This thematic review also proposed a conceptual framework for designing toys and games tailored to the needs of the elderly with AD, offering valuable insights to future researchers focusing on this domain.

Most studies focused on cognitive function among Alzheimer's patients.More research is needed about the rehabilitation of neuropsychiatric symptoms among Alzheimer's patients.Games and toys have been evaluated as beneficial for detecting and as an intervention for Alzheimer's disease (AD). More research is needed about how to design games or toys tailored to the needs of the elderly with AD.

Identification of m6A Regulator-Associated Methylation Modification Clusters and Immune Profiles in Melanoma.

RNA N6-methyladenosine (m6A) modification in tumorigenesis and progression has been highlighted and discovered in recent years. However, the molecular and clinical implications of m6A modification in melanoma tumor microenvironment (TME) and immune infiltration remain largely unknown. Here, we utilized consensus molecular clustering with nonnegative matrix factorization based on the melanoma transcriptomic profiles of 23 m6A regulators to determine the m6A modification clusters and m6A-related gene signature. Three distinct m6A modification patterns (m6A-C1, C2, and C3), which are characterized by specific m6A regulator expression, survival outcomes, and biological pathways, were identified in more than 1,000 melanoma samples. The immune profile analyses showed that these three m6A modification subtypes were highly consistent with the three known immune phenotypes: immune-desert (C1), immune-excluded (C2), and immune-inflamed (C3). Tumor digital cytometry (CIBERSORT, ssGSEA) algorithm revealed an upregulated infiltration of CD8+ T cell and NK cell in m6A-C3 subtype. An m6A scoring scheme calculated by principal component of m6A signatures stratified melanoma patients into high- and low-m6sig score subgroups; a high score was significantly associated with prolonged survival and enhanced immune infiltration. Furthermore, fewer somatic copy number alternations (SCNA) and PD-L1 expression were found in patients with high m6Sig score. In addition, patients with high m6Sig score demonstrated marked immune responses and durable clinical benefits in two independent immunotherapy cohorts. Overall, this study indicated that m6A modification is involved in melanoma tumor microenvironment immune regulation and contributes to formation of tumor immunogenicity. Comprehensive evaluation of the m6A modification pattern of individual tumors will provide more insights into molecular mechanisms of TME characterization and promote more effective personalized biotherapy strategies.

A potential role for zinc transporter 7 in testosterone synthesis in mouse Leydig tumor cells.

Previous studies have demonstrated that zinc (Zn) is an essential trace element which is involved in male reproduction. The zinc transporter (ZnT) family, SLC30a, is involved in the maintenance of Zn homeostasis and in mediating intracellular signaling events; however, relatively little is known regarding the effect of ZnTs on testosterone synthesis. Thus, in the present study, we aimed to determine the effect of Zn transporter 7 (ZnT7) on testosterone synthesis in male CD-1 mice and mouse Leydig cells. The findings of the present study revealed that the concentrations of Zn in the testes and Leydig cells were significantly lower in mice fed a Zn-deficient diet compared with the control mice fed a Zn-adequate diet. In addition, ZnT7 was principally expressed and colocalized with steroidogenic acute regulatory protein (StAR) in the Leydig cells of male CD-1 mice. ZnT7 expression was downregulated in the mice fed a Zn-deficient diet, which led to decreases in the expression of the enzymes involved in testosterone synthesis namely cholesterol side­chain cleavage enzyme (P450scc) and 3ß-hydroxysteroid dehydrogenase/D5-D4 isomerase (3ß-HSD) as well as decreased serum testosterone levels. These results suggested that Znt7 may be involved in testosterone synthesis in the mouse testes. To examine this hypothesis, we used the mouse Leydig tumor cell line (MLTC-1 cell line) in which the ZnT7 gene had been silenced, in order to gauge the impact of changes in ZnT7 expression on testosterone secretion and the enzymes involved in testosterone synthesis. The results demonstrated that ZnT7 gene silencing downregulated the expression of StAR, P450scc and 3ß-HSD as well as progesterone concentrations in the human chorionic gonadotrophin (hCG)-stimulated MLTC-1 cells. Taken together, these findings reveal that ZnT7 may play an important role in the regulation of testosterone synthesis by modulating steroidogenic enzymes, and may represent a therapeutic target in testosterone deficiency.

Effect of zinc on high glucose-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells.

Zinc (Zn) as an essential dietary element has been indicated in a number of protein functions in the prevention of numerous types of epithelial-to-mesenchymal transition (EMT)-driven fibrosis in vivo. However, relatively little is known regarding its effect in the EMT of the renal tubular epithelial cells, which play an important role in renal tubulointerstitial fibrosis and is an important component of the renal injury that is associated with diabetic nephropathy. The present study investigated the effect of Zn on the high glucose (HG)-induced EMT in a normal rat kidney tubular epithelial cell line (NRK-52E cells) and the underlying molecular mechanisms by immunofluorescence staining and western blot analysis. The present study identified that 10 µM of Zn supplementation prevented EMT changes, such as the loss of E-cadherin and the increase in α-smooth muscle actin and vimentin expression. Conversely, depletion of Zn with N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine in these cells aggravated changes in HG-induced EMT markers. Additionally, 10 µM Zn supplementation inhibited HG-induced transforming growth factor-ß1 overexpression and reactive oxygen species production. Of note, HG increased phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase (MAPK) pathways activation and Zn reversed HG-induced expression of PI3K/Akt, extracellular-signal-regulated kinase (ERK) and p38 MAPK, as well as EMT proteins. Finally, inhibitors of PI3K/Akt, ERK and p38 MAPK, and Zn supplementation blocked the HG-induced EMT in NRK-52E cells. These results indicate that physiologically optimal levels of Zn can inhibit HG-induced EMT of the NRK-52E cells possibly through several mechanisms, including abrogation of HG-induced oxidative stress, and PI3K/Akt, p38 MAPK and ERK activation in NRK-52E cells.

Zinc modulates high glucose-induced apoptosis by suppressing oxidative stress in renal tubular epithelial cells.

Hyperglycemia is a characteristic of diabetic nephropathy, inducing renal tubular cell apoptosis by eliciting oxidative stress and inflammation. Zinc (Zn) is known as an essential trace element in many enzymes and proteins involved in antioxidant defenses, electron transport, and exerting antiapoptotic or cytoprotective effects. In this study, the underlying mechanisms involved in the protective effects of Zn on high glucose-induced cytotoxicity were explored using cultured renal tubular epithelial cells (NRK-52E). The authors discovered that Zn supplementation inhibited high glucose (HG)-induced NRK-52E cell apoptosis by attenuating reactive oxygen species production, inhibiting HG-induced caspase-3 and caspase-9 activation, and inhibiting the release of cytochrome c from mitochondria to the cytosol. Further analysis revealed that Zn supplementation facilitated cell survival through increasing nuclear translocation of NF-E2-related factor 2 (Nrf2), leading to increased regulation of levels of two antioxidant enzymes, hemeoxygenase-1 and glutamate cysteine ligase, which provided an adaptive survival response against the HG-induced oxidative cytotoxicity. Moreover, the Zn-mediated increases in Nrf2 activity were suppressed by the pharmacological inhibition of Akt or extracellular signal-regulated kinase 1/2. Taken together, these findings suggest that Zn antiapoptosis capacity through the activation of Akt and ERK signal pathways leads to Nrf2 activation and, subsequently, Nrf2 target gene induction, thereby protecting the NRK-52E cells from HG-induced apoptosis.