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Lysosomes are highly dynamic organelles that maintain cellular homeostasis and regulate fundamental cellular processes by integrating multiple metabolic pathways. Lysosomal ion channels such as TRPML1-3, TPC1/2, ClC6/7, CLN7, and TMEM175 mediate the flux of Ca2+, Cl−, Na+, H+, and K+ across lysosomal membranes in response to osmotic stimulus, nutrient-dependent signals, and cellular stresses. These ion channels serve as the crucial transducers of cell signals and are essential for the regulation of lysosomal biogenesis, motility, membrane contact site formation, and lysosomal homeostasis. In terms of pathophysiology, genetic variations in these channel genes have been associated with the development of lysosomal storage diseases, neurodegenerative diseases, inflammation, and cancer. This review aims to discuss the current understanding of the role of these ion channels in the central nervous system and to assess their potential as drug targets. [ABSTRACT FROM AUTHOR]

As one of the emerging hallmarks of tumorigenesis and tumor progression, metabolic remodeling is common in the tumor microenvironment. Hepatocellular carcinoma (HCC) is the third leading cause of global tumor-related mortality, causing a series of metabolic alterations in response to nutrient availability and consumption to fulfill the demands of biosynthesis and carcinogenesis. Despite the efficacy of immunotherapy in treating HCC, the response rate remains unsatisfactory. Recently, research has focused on metabolic reprogramming and its effects on the immune state of the tumor microenvironment, and immune response rate. In this review, we delineate the metabolic reprogramming observed in HCC and its influence on the tumor immune microenvironment. We discuss strategies aimed at enhancing response rates and overcoming immune resistance through metabolic interventions, focusing on targeting glucose, lipid, or amino acid metabolism, as well as systemic regulation. [ABSTRACT FROM AUTHOR]

Uromodulin is recognized as a protective factor during AKI-to-CKD progression, but the mechanism remains unclear. We previously reported that uromodulin interacts with complement factor H (CFH) in vitro, and currently aimed to study the expression and interaction evolution of uromodulin and CFH during AKI-to-CKD transition. We successfully established a rat model of AKI-to-CKD transition induced by a four-time cisplatin treatment. The blood levels of BUN, SCR, KIM-1 and NGAL increased significantly during the acute injury phase and exhibited an uptrend in chronic progression. PAS staining showed the nephrotoxic effects of four-time cisplatin injection on renal tubules, and Sirius red highlighted the increasing collagen fiber. Protein and mRNA levels of uromodulin decreased while urine levels increased in acute renal injury on chronic background. An extremely diminished level of uromodulin correlated with severe renal fibrosis. RNA sequencing revealed an upregulation of the alternative pathway in the acute stage. Renal CFH gene expression showed an upward tendency, while blood CFH localized less, decreasing the abundance of CFH in kidney and following sustained C3 deposition. A co-IP assay detected the linkage between uromodulin and CFH. In the model of AKI-to-CKD transition, the levels of uromodulin and CFH decreased, which correlated with kidney dysfunction and fibrosis. The interaction between uromodulin and CFH might participate in AKI-to-CKD transition. [ABSTRACT FROM AUTHOR]

Alcoholic liver disease (ALD) refers to the damages to the liver and its functions due to alcohol overconsumption. It consists of fatty liver/steatosis, alcoholic hepatitis, steatohepatitis, chronic hepatitis with liver fibrosis or cirrhosis, and hepatocellular carcinoma. However, the mechanisms behind the pathogenesis of alcoholic liver disease are extremely complicated due to the involvement of immune cells, adipose tissues, and genetic diversity. Clinically, the diagnosis of ALD is not yet well developed. Therefore, the number of patients in advanced stages has increased due to the failure of proper early detection and treatment. At present, abstinence and nutritional therapy remain the conventional therapeutic interventions for ALD. Moreover, the therapies which target the TNF receptor superfamily, hormones, antioxidant signals, and MicroRNAs are used as treatments for ALD. In particular, mesenchymal stem cells (MSCs) are gaining attention as a potential therapeutic target of ALD. Therefore, in this review, we have summarized the current understandings of the pathogenesis and diagnosis of ALD. Moreover, we also discuss the various existing treatment strategies while focusing on promising therapeutic approaches for ALD.

Atorvastatin ester (Ate) is a structural trim of atorvastatin that can regulate hyperlipidemia. The purpose of this study was to evaluate the lipid-lowering effect of Ate. Male Sprague Dawley (SD) rats were fed a high-fat diet for seven months and used as a hyperlipidemia model. The lipid level and liver function of the hyperlipidemia rats were studied by the levels of TG, TC, LDL, HDL, ALT, and AST in serum after intragastric administration with different doses of Ate. HE staining was used to observe the pathological changes of the rat liver and gastrocnemius muscle. The lipid deposits in the liver of rats were observed by staining with ORO. The genes in the rat liver were sequenced by RNA-sequencing. The results of the RNA-sequencing were further examined by qRT-PCR and western blotting. Biochemical test results indicated that Ate could obviously improve the metabolic disorder and reduce both the ALT and AST levels in serum of the hyperlipidemia rats. Pathological results showed that Ate could improve HFD-induced lipid deposition and had no muscle toxicity. The RNA-sequencing results suggested that Ate affected liver lipid metabolism and cholesterol, metabolism in the hyperlipidemia-model rats may vary via the PPAR-signaling pathway. The western blotting and qRT-PCR results demonstrated the Ate-regulated lipid metabolism in the hyperlipidemia model through the PPAR-signaling pathway and HMGCR expression. In brief, Ate can significantly regulate the blood lipid level of the model rats, which may be achieved by regulating the PPAR-signaling pathway and HMGCR gene expression. [ABSTRACT FROM AUTHOR]

Grain filling is an importantly developmental process which is associated with the yield and quality of foxtail millet (Setaria italic L.). However, the molecular mechanisms of grain filling are rarely reported in foxtail millet. In our study, RNA-seq was performed to investigate the transcriptional dynamics and identify the key genes involved in grain filling in foxtail millet at five different developmental stages. A total of 11,399 differentially expressed genes (DEGs), including 902 transcription factors (TFs), were identified. Certain important genes involved in grain filling were discovered through a function annotation and temporal expression patterns analysis. These genes included genes associated with starch biosynthesis, cell-wall invertases, hormone signal transduction, and polyamine metabolism pathways. The expression levels of seven randomly selected DEGs were validated by a quantitative real-time polymerase chain reaction (qRT-PCR). This study provides the first insight into the changes in the gene expression of grain filling at different developmental stages in foxtail millet. These results could help understand the complex molecular mechanisms of the panicle formation in foxtail millet and other cereal crops. [ABSTRACT FROM AUTHOR]

Alcoholic liver disease (ALD) refers to the damages to the liver and its functions due to alcohol overconsumption. It consists of fatty liver/steatosis, alcoholic hepatitis, steatohepatitis, chronic hepatitis with liver fibrosis or cirrhosis, and hepatocellular carcinoma. However, the mechanisms behind the pathogenesis of alcoholic liver disease are extremely complicated due to the involvement of immune cells, adipose tissues, and genetic diversity. Clinically, the diagnosis of ALD is not yet well developed. Therefore, the number of patients in advanced stages has increased due to the failure of proper early detection and treatment. At present, abstinence and nutritional therapy remain the conventional therapeutic interventions for ALD. Moreover, the therapies which target the TNF receptor superfamily, hormones, antioxidant signals, and MicroRNAs are used as treatments for ALD. In particular, mesenchymal stem cells (MSCs) are gaining attention as a potential therapeutic target of ALD. Therefore, in this review, we have summarized the current understandings of the pathogenesis and diagnosis of ALD. Moreover, we also discuss the various existing treatment strategies while focusing on promising therapeutic approaches for ALD. [ABSTRACT FROM AUTHOR]

Glucocorticoid administration is the leading cause of secondary osteoporosis. In this study, we tested the hypotheses that histone deacetylase 4 (HDAC4) is associated with glucocorticoid-induced bone loss and that HDAC4 dependent bone loss can be ameliorated by miRNA-365. Our previous studies showed that miR-365 mediates mechanical stimulation of chondrocyte proliferation and differentiation by targeting HDAC4. However, it is not clear whether miR-365 has an effect on glucocorticoid-induced osteoporosis. We have shown that, in MC3T3-E1 osteoblasts, dexamethasone (DEX) treatment decreased the expression of miR-365, which is accompanied by the decrease of cell viability in a dose-dependent manner. Transfection of miR-365 ameliorated DEX-induced inhibition of MC3T3-E1 cell viability and alkaline phosphatase activity, and attenuated the suppressive effect of DEX on runt-related transcription factor 2 (Runx2), osteopontin (OPN), and collagen 1a1 (Col1a1) osteogenic gene expression. In addition, miR-365 decreased the expression of HDAC4 mRNA and protein by direct targeting the 3'-untranslated regions (3'-UTR) of HDAC4 mRNA in osteoblasts. MiR-365 increased Runx2 expression and such stimulatory effect could be reversed by HDAC4 over-expression in osteoblasts. Collectively, our findings indicate that miR-365 ameliorates DEX-induced suppression of cell viability and osteogenesis by regulating the expression of HDAC4 in osteoblasts, suggesting miR-365 might be a novel therapeutic agent for treatment of glucocorticoid-induced osteoporosis.

Bone mesenchymal stem cells (BMSCs) have multiple potentials to differentiate into osteoblasts and adipocytes, and methods to enhance their osteogenic differentiation are gaining increasing attention. MicroRNAs are critical regulation factors during the process of the osteogenic induction in BMSCs, and mir-205 has been substantiated to be involved in the osteogenic process, but the underlying mechanisms remain unclear. The purpose of this article is to investigate the role of mir-205 in the osteogenic differentiation of BMSCs. We found that mir-205 expression was down-regulated in a time-dependent manner during BMSC osteo-induction. Inhibition of mir-205 enhanced osteogenic abilities by up-regulating bone sialoprotein (BSP) and osteopontin (OPN) protein levels and increasing alkaline phosphatase (ALP) activity and osteocalcin secretion. Furthermore, we found that mir-205 could regulate protein expression of special AT-rich sequence-binding protein 2 (SATB2) and runt-related transcription factor 2 (Runx2), and over-expression of SATB2 activated Runx2 and reversed the negative effects of mir-205 on osteoblastic differentiation. Furthermore, we examined the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) pathways during osteogenic induction and our data indicates that mir-205 might exert negative functions on the osteogenic differentiation in BMSCs at least partly via altering phosphorylation of ERK and p38 MAPK. These results shed new light on the molecular mechanisms of microRNAs in governing differentiation of BMSCs.

Genistein, a major phytoestrogen of soy, is considered a potential drug for the prevention and treatment of post-menopausal osteoporosis. Mounting evidence suggested a positive correlation between genistein consumption and bone health both in vivo and in vitro. Earlier studies have revealed that genistein acted as a natural estrogen analogue which activated estrogen receptor and exerted anti-osteoporotic effect. However, it remains unclear whether PTH, the most crucial hormone that regulates mineral homeostasis, participates in the process of genistein-mediated bone protection. In the present study, we compared the therapeutic effects between genistein and nilestriol and investigated whether PTH and its specific receptor PTHR1 altered in response to genistein-containing diet in the animal model of ovariectomy. Our results showed that genistein administration significantly improved femoral mechanical properties and alleviates femoral turnover. Genistein at all doses (4.5 mg/kg, 9.0 mg/kg and 18.0 mg/kg per day, respectively) exerted improved bending strength and b-ALP limiting effects than nilestriol in the present study. However, genistein administration did not exert superior effects on bone protection than nilestriol. We also observed circulating PTH restoration in ovariectomized rats receiving genistein at the dose of 18 mg/kg per day. Meanwhile, PTHR1 abnormalities were attenuated in the presence of genistein as confirmed by RT-PCR, Western blot and immunohistochemistry. These findings strongly support the idea that besides serving as an estrogen, genistein could interact with PTH/PTHR1, causing a superior mineral restoring effect than nilestriol on certain circumstance. In conclusion, our study reported for the first time that the anti-osteoporotic effect of genistein is partly PTH/PTHR1-dependent. Genistein might be a potential option in the prevention and treatment of post-menopausal osteoporosis with good tolerance, more clinical benefits and few undesirable side effects.

Hypoxic pulmonary hypertension is a life-threatening emergency if untreated. Consistent pulmonary hypertension also leads to arteries and ventricular remodeling. The clinical therapeutic strategy for pulmonary hypertension and the corresponding remodeling mainly interacts with NO, angiotensin II (Ang II) and elevated endothelin (ET) targets. In the present study, we evaluated the effects of polydatin on hypoxia-induced pulmonary hypertension. It was observed that polydatin attenuated hypoxic pulmonary hypertension, reversed remodeling, and regulated NO, Ang II, ET contents in the serum and lung samples. However, forced activation of PKC signaling by its selective activator thymeleatoxin (THX) could abate the effects of polydatain. These results suggest that polydatin might be a promising candidate for hypoxic pulmonary treatment through interaction with PKC mechanisms.