ABSTRACT
COVID-19 has been prevalent for three years. The virulence of SARS-CoV-2 is weaken as it mutates continuously. However, elderly patients, especially those with underlying diseases, are still at high risk of developing severe infections. With the continuous study of the molecular structure and pathogenic mechanism of SARS-CoV-2, antiviral drugs for COVID-19 have been successively marketed, and these anti-SARS-CoV-2 drugs can effectively reduce the severe rate and mortality of elderly patients. This article reviews the mechanism, clinical medication regimens, drug interactions and adverse reactions of five small molecule antiviral drugs currently approved for marketing in China, so as to provide advice for the clinical rational use of anti-SARS-CoV-2 in the elderly.
ABSTRACT
Macrophages show significant heterogeneity in function and phenotype, which could shift into different populations of cells in response to exposure to various micro-environmental signals. These changes, also termed as macrophage polarization, of which play an important role in the pathogenesis of many diseases. Numerous studies have proved that Hesperidin (HDN), a traditional Chinese medicine, extracted from fruit peels of the genus citrus, play key roles in anti-inflammation, anti-tumor, anti-oxidant and so on. However, the role of HDN in macrophage polarization has never been reported. Additional, because of its poor water solubility and bioavailability. Our laboratory had synthesized many hesperidin derivatives. Among them, hesperidin derivatives-12 (HDND-12) has better water solubility and bioavailability. So, we evaluated the role of HDND-12 in macrophage polarization in the present study. The results showed that the expression of Arginase-1 (Arg-1), interleukin-10 (IL-10), transforming growth factor β (TGF-β) were up-regulated by HDND-12, whereas the expression of inducible Nitric Oxide Synthase (iNOS) was down-regulated in LPS- and IFN-γ-treated (M1) RAW264.7 cells. Moreover, the expression of p-JAK2 and p-STAT3 were significantly decreased after stimulation with HDND-12 in M1-like macrophages. More importantly, when we taken AG490 (inhibitor of JAK2/STAT3 signaling), the protein levels of iNOS were significantly reduced in AG490 stimulation group compare with control in LPS, IFN-γ and HDND-12 stimulation cells. Taken together, these findings indicated that HDND-12 could prevent polarization toward M1-like macrophages, at least in part, through modulating JAK2/STAT3 pathway.
Subject(s)
Animals , Mice , Cytokines , Genetics , Metabolism , Enzyme Inhibitors , Pharmacology , Gene Expression Regulation , Hesperidin , Chemistry , Pharmacology , Inflammation , Genetics , Metabolism , Janus Kinase 2 , Metabolism , Macrophages , Allergy and Immunology , Metabolism , Medicine, Chinese Traditional , Molecular Structure , Phosphorylation , STAT3 Transcription Factor , Metabolism , Signal TransductionABSTRACT
Transforming growth factor-β (TGF-β) is a driving force of renal fibrosis, which may lead to chronic kidney diseases and even end stage renal diseases. By activating canonical and non-canonical signaling pathways, TGF-β promotes the synthesis of extracellular matrix while preventing their degradation. In the injured kidney, TGF-β induces apoptosis, proliferation and fibrotic response of renal cells including epithelial cells, endothelial cells, podocytes, fibroblasts, pericytes and macrophages, and it also promotes transdifferentiation, activation and proliferation of myofibroblasts. Additionally, TGF-β exerts profibrotic effects by interplaying with other signaling pathways like BMP-7, Wnt/β-catenin and MAP kinase. Smad3 is the central pathological gene in renal fibrosis, and epigenetic regulation of TGF-β/Smad3 is a hot topic in kidney field. Although direct targeting TGF-β may cause side effects including tumorigenesis and immune diseases, the therapeutic strategies targeting the balance of downstream Smad3 and Smad7 may prevent or delay the progression of fibrotic kidney disease.
Subject(s)
Humans , Epigenesis, Genetic , Fibrosis , Kidney Diseases , Pathology , Signal Transduction , Smad3 Protein , Metabolism , Smad7 Protein , Metabolism , Transforming Growth Factor beta , MetabolismABSTRACT
OBJECTIVE Alcohol is mainly metabolized through liver and excreted by kidney in the body. Kidney damage has been considered as the secondary to liver injury and kidney dysfunction is common in hospitalized patients with severe alcoholic hepatitis. Both acute and chronic alcoholism accumulation can compromise kidney function, although alcoholic kidney disease has drawn much more attention recently,the methodology for establishing the in vivo and in vitro alcoholic renal fibrosis models are still lacking,and the underlying mechanisms are to be determined. METHODS and RESULTS Mice were feed with a liquid diet containing alcohol for 4 weeks, 8 weeks and 12 weeks respectively, results of Masson′s Trichrome staining showed that kidney fibrosis peaked in 8-week model group, which consistent with the results of albumin assay,Western blot,immunostaining and real-time PCR of collagen I and α-SMA.In vitro study also confirmed that ethanol upregulated the level of fibrotic index-es,including collagen I and α-SMA,in tubular epithelial cells(HK2 cells).Additionally,both in vivo and in vitro studies showed that Smad7 was decreased and Smad3 was highly activated. Then we further detected the underlying mechanisms by which alcohol induced the imbalance of Smad7 and Smad3. Results of Genome-wide methylation sequencing found DNA methylation of Smad7 in the alcoholic fibrosis kidney,which may be mainly mediated by DNA methyltransferase 1(DNMT1),because knock-down of DNMT1,but not DNMT2 and 3,largely restored Smad7 level in ethanol-treated HK2 cells.Con-sequently, we found that NADPH Oxidases (nox)-mediated oxidative stress is the major force upregu-lating DNMT1,since knockdown of Nox2 and 4 could both decrease DNMT1 while rebalancing Smad7/Smad3 axis, and thereby relieved ethanol-induced fibrotic response in HK2 cells. More importantly, intraperitoneal injection of apocynin,an inhibitor of NADPH oxidoreductase,attenuated renal fibrosis in alcoholic kidney fibrosis mouse model. CONCLUSION By establishing the novel in vivo and in vitro models,we found that through activating oxidative stress-induced DNA methylation of Smad7,alcohol induces renal fibrosis by breaking the balance between Smad7 and Smad3.Elimination of Nox-mediated oxidative stress may be a potential therapy for treatment of long-term alcohol abuse-induced kidney fibrosis.