Mediator subunit MED1 deficiency prevents carbon tetrachloride-induced hepatic fibrosis in mice.

Mediator subunit mediator 1 (MED1) mediates ligand-dependent binding of the mediator coactivator complex to various nuclear receptors and plays a critical role in embryonic development, lipid and glucose metabolism, liver regeneration, and tumorigenesis. However, the precise role of MED1 in the development of liver fibrosis has been unclear. Here, we showed that MED1 expression was increased in livers from nonalcoholic steatohepatitis (NASH) patients and mice and positively correlated with transforming growth factor ß (TGF-ß) signaling and profibrotic factors. Upon treatment with carbon tetrachloride (CCl4), hepatic fibrosis was much less in liver-specific MED1 deletion (MED1ΔLiv) mice than in MED1fl/fl littermates. TGF-ß/Smad2/3 signaling pathway was inhibited, and gene expression of fibrotic markers, including α-smooth muscle actin (α-SMA), collagen type 1 α 1 (Col1a1), matrix metalloproteinase-2 (Mmp2), and metallopeptidase inhibitor 1 (Timp1) were decreased in livers of MED1ΔLiv mice with CCl4 injection. Transcriptomic analysis revealed that the differentially expressed genes in livers of CCl4-administered MED1ΔLiv mice were enriched in the pathway of oxidoreductase activity, followed by robustly reduced oxidoreductase activity-related genes, such as Gm4756, Txnrd3, and Etfbkmt. More importantly, we found that the reduction of reactive oxygen species (ROS) in MED1 knockdown hepatocytes blocked the activation of TGF-ß/Smad2/3 pathway and the expression of fibrotic genes in LX2 cells. These results indicate that MED1 is a positive regulator for hepatic fibrogenesis, and MED1 may be considered as a potential therapeutic target for the regression of liver fibrosis.NEW & NOTEWORTHY In this study, we present the first evidence that liver mediator 1 (MED1) deficiency attenuated carbon tetrachloride-induced hepatic fibrosis in mouse. The underlying mechanism is that MED1 deficiency reduces reactive oxygen species (ROS) production in hepatocytes, thus restricts the activation of TGF-ß/Smad2/3 signaling pathway and fibrogenic genes expression in hepatic stellate cells (HSCs). These data suggest that MED1 is an essential regulator for hepatic fibrogenesis, and MED1 may be considered as a potential therapeutic target for liver fibrosis.

Iron-modified phosphorus- and silicon-based biochars exhibited various influences on arsenic, cadmium, and lead accumulation in rice and enzyme activities in a paddy soil.

Contamination of paddy soils with potentially toxic elements (PTEs) has become a severe environmental issue. Application of functionalized biochar for rice cultivation has been proposed as an effective means to reduce environmental risks of these PTEs in paddy soils. This work was undertaken to seek the positive effects of a rice husk-derived silicon (Si)-rich biochar (Si-BC) and a pig carcass-derived phosphorus (P)-rich biochar (P-BC), as well as their Fe-modified biochars (Fe-Si-BC and Fe-P-BC) on the enzyme activity and PTE availability in an As-Cd-Pb-contaminated soil. A rice cultivation pot trial was conducted using these functionalized biochars as soil amendments for the alleviation of PTE accumulation in rice plants. Results showed that Si-BC decreased the concentrations of As in rice grain and straw by 59.4 % and 61.4 %, respectively, while Fe-Si-BC significantly (P < 0.05) enhanced plant growth, increasing grain yield (by 38.6 %). Fe-Si-BC significantly (P < 0.05) elevated Cd and Pb accumulation in rice plants. P-BC enhanced the activities of dehydrogenase, catalase, and urease, and reduced grain-Pb and straw-Pb by 49.3 % and 43.2 %, respectively. However, Fe-P-BC reduced plant-As in rice grain and straw by 12.2 % and 51.2 %, respectively, but increased plant-Cd and plant-Pb. Thus, Fe-modified Si- and P-rich biochars could remediate paddy soils contaminated with As, and enhance the yield and quality of rice. Application of pristine P-rich biochar could also be a promising strategy to remediate the Pb-contaminated paddy soils and limit Pb accumulation in rice.

MED1 Deficiency in Macrophages Aggravates Isoproterenol-Induced Cardiac Fibrosis in Mice.

Mediator 1 (MED1), a key subunit of the mediator complex, interacts with various nuclear receptors and functions in lipid metabolism and energy homeostasis. Dilated cardiomyopathy-related ventricular dilatation and heart failure have been reported in mice with cardiomyocyte-specific Med1 deficiency. However, the contribution of macrophage-specific MED1 in cardiac remodeling remains unclear. In this study, macrophage-specific Med1 knockout (Med1ΔMac) mice were generated and exposed to isoproterenol (ISO) to induce cardiac fibrosis; these mice showed aggravated cardiac fibrosis compared with Med1fl/fl mice. The levels of expression of marker genes for myofibroblast transdifferentiation [α-smooth muscle actin (SMA)] and of profibrotic genes, including Col1a1, Col3a1, Postn, Mmp2, Timp1, and Fn1, were significantly increased in the cardiac tissues of Med1ΔMac mice with ISO-induced myocardial fibrosis. In particular, the transforming growth factor (TGF)-ß-Smad2/3 signaling pathway was activated. In bone marrow-derived and peritoneal macrophages, Med1 deficiency was also associated with elevated levels of expression of proinflammatory genes, including Il6, Tnfa, and Il1b. These findings indicate that macrophage-specific MED1 deficiency may aggravate ISO-induced cardiac fibrosis via the regulation of the TGF-ß-SMAD2/3 pathway, and the underlying mechanism may involve MED1 deficiency triggering the activation of inflammatory cytokines in macrophages, which in turn may stimulate phenotypic switch of cardiac fibroblasts and accelerate cardiac fibrosis. Thus, MED1 is a potential therapeutic target for cardiac fibrosis.

Endothelial MicroRNA-483-3p Is Hypertension-Protective.

Hypertension is a high-risk factor for developing coronary heart disease and stroke. Endothelial dysfunction and arterial remodeling can lead to increased vascular wall thickness and arterial stiffness. Previous studies showed that microRNA-483 (miR-483) enhances endothelial cell (EC) function. Here, we investigated the protective role of miR-483 in hypertension. Data collected from two patient cohorts showed that the serum miR-483-3p level was associated with the progression of hypertension and positively correlated with vascular function. In cultured ECs, miR-483 targets a number of endothelial dysfunction-related genes, such as transforming growth factor-ß (TGF-ß), connective tissue growth factor (CTGF), angiotensin-converting enzyme 1 (ACE1), and endothelin-1 (ET-1). Overexpression of miR-483-3p in ECs inhibited Ang II-induced endothelial dysfunction, revealed by the decreased expression of TGF-ß, CTGF, ACE1, and ET-1. Furthermore, miR-483-3p secreted from ECs was taken up by smooth muscle cells (SMCs) via the exosome pathway, which also decreased these genes in SMCs. Additionally, telmisartan could increase the aortic and serum levels of miR-483-3p in hypertension patients and spontaneous hypertension rats (SHR). These findings suggest that miR-483-3p exerts a protective effect on EC function during the onset of hypertension and thus may be considered a potential therapeutic target for hypertension-related cardiovascular diseases.

Small molecule selenium-containing compounds: Recent development and therapeutic applications.

Selenium (Se) is an essential micronutrient of organism and has important function. It participates in the functions of selenoprotein in several manners. In recent years, Se has attracted much attention because of its therapeutic potential against several diseases. Many natural and synthetic organic Se-containing compounds were studied and explored for the treatment of cancer and other diseases. Studies have showed that incorporation of Se atom into small molecules significantly enhanced their bioactivities. In this paper, according to different applications and structural characteristics, the research progress and therapeutic application of Se-containing compounds are reviewed, and more than 110 Se-containing compounds were selected as representatives which showed potent activities such as anticancer, antioxidant, antifibrolytic, antiparasitic, antibacterial, antiviral, antifungal and central nervous system related effects. This review is expected to provide a basis for further study of new promising Se-containing compounds.

Iron-modified biochar and water management regime-induced changes in plant growth, enzyme activities, and phytoavailability of arsenic, cadmium and lead in a paddy soil.

The aim of this study was to evaluate the effect of raw (RawBC) and iron (Fe)-modified biochar (FeBC) derived from Platanus orientalis Linn branches on the plant growth, enzyme activity, and bioavailability and uptake of As, Cd, and Pb by rice in a paddy soil with continuously flooded (CF) or alternately wet and dry (AWD) irrigation in a pot experiment. Application of RawBC (3%, w/w) significantly increased soil pH, while FeBC decreased it. The FeBC was more effective in reducing As and Pb bioavailability, particularly under the AWD water regime, while RawBC was more conducive in reducing Cd bioavailability under the CF water regime. The FeBC decreased As concentration, but increased concentrations of Cd and Pb in the straw and brown rice, as compared to the untreated soil. Soil catalase and urease activities were enhanced by RawBC, but decreased by FeBC treatment. The FeBC increased the grain yield by 60% and 32% in CF and AWD treatments, respectively. The FeBC can be recommended for immobilization of As in paddy soils, but a potential human health risk from Cd and Pb in FeBC-treated soils should be considered due to increased uptake and translocation of the metals to brown rice.

Kidney manifestations of mild, moderate and severe coronavirus disease 2019: a retrospective cohort study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a pandemic that has affected more than 3 million patients globally. Previous data from Wuhan city showed that acute kidney injury (AKI), proteinuria and hematuria occurred frequently in patients with severe COVID-19. However, the prevalence of kidney injury in milder cases remains unclear. METHODS: This retrospective study included two major consecutive cohorts of COVID-19 patients in Sichuan Province. Baseline characteristics, laboratory data including renal function, proteinuria and dipstick hematuria, and other laboratory parameters were collected. A subgroup of patients was followed up for 2-4 weeks to evaluate the short-term outcome of renal impairment. RESULTS: Overall, 168 COVID-19-positive patients were included in the study. The majority of patients (79.7%) were diagnosed with mild or moderate disease. Half of patients presented with fever; however, in The Tibetan cohort, fever only occurred in 13.4% of patients. On hospital admission, proteinuria and dipstick hematuria were noted in 18.4% and 17.4% of patients, respectively, while AKI only occurred in one patient. Further analysis showed that severe or critical COVID-19 was associated with higher risk of proteinuria [relative risk (RR) 7.37, 95% confidence interval (CI) 2.45-22.18, P = 3.8 × 10-4] and dipstick hematuria (RR 8.30, 95% CI 2.69-25.56, P = 2.3 × 10-4). Proteinuria, dipstick hematuria, or the combination of proteinuria and hematuria could significantly predict severe or critical severe COVID-19. CONCLUSIONS: Proteinuria and dipstick hematuria are not uncommon in patients with COVID-19 infection, especially in severe or critical cases.