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Breakthrough discovery of a "Cocktail" involving Potential SARS-COV-2 Primary Protease Inhibitors by means of Electronic Screening process of Known Chemical substance Aspects of Vitex negundo L. ("Lagundi").
The serine protease inhibitor UAMC-00050 ameliorated both the inflammatory parameters and the intestinal barrier function. Furthermore, a decrease in colonic mRNA expression of Tbet and PAR4 was observed in colitis mice after UAMC-00050 treatment. Conclusion The beneficial effect of UAMC-00050 on inflammation was apparent via a reduction of Tbet, IFN-γ, TNF-α, IL-1β and IL-6. Based on these results, we hypothesize a pivotal effect of serine protease inhibition on the Th1 inflammatory profile potentially mediated via PAR4.Allergic asthma is a typical chronic inflammatory disease of respiratory tract. Clinical data shows that patients with allergic asthma have different degrees of cognitive dysfunction. The molecular mechanism underlying the pathogenesis of asthma-induced cognitive disorder is not yet well defined. Dexamethasone (DEX), one of the first-line drugs being widely used in the treatment of asthma, has not been reported to have an effect on cognitive dysfunction in mice model. To investigate the effect of asthma on cognitive impairment as well as the effect of DEX on asthma-caused morphological and behavioral changes, C57BL/6J mice received treatment with house dust mites (HDM) for 60 days to become allergic asthma model mice, and a group of HDM-treated asthma model mice were treated with DEX. HDM-treated asthma model mice exhibited increased airway hyperresponsiveness (AHR) and inflammatory infiltration in lung tissue. An elevated level of IL-4, IL-5, and TNF-α was detected in bronchoalveolar lavage fluid (BALF) by Luminex liquid suspension chip. Asthma model mice also presented memory deficits accompanied with morphological changes at the synaptic levels in the cortex and hippocampus. Meanwhile, vascular edema and increased expression of HIF-1α and HIF-2α were found in the brain of asthma model mice. Interestingly, DEX treatment could reverse the inflammatory changes in asthma model mice airway, rescue the cognitive impairment and improve the synaptic plasticity. Besides, DEX significantly decreased the expression of HIF-1α and HIF-2α in mice brain and lung. These processes may be used to decipher the complex interplay and pathological changes between asthma and cognition. NSC-724772 This study provides laboratory evidence for the prevention and treatment of cognitive malfunction induced by asthma.Ethnopharmacological Relevance Pepper essential oils have potential immunomodulatory, anti-tumor, and anti-cancer activities. Pepper exhibits the potential to prevent or attenuate carcinogenesis as therapeutic tools. However, the related mechanism remains unelucidated. Aim of the Study The present study aims to provide reasonable information for the explanation of the dissimilarity of the essential oils from white (WPEO) and black pepper (BPEO). Materials and Methods WPEO, BPEO, and their single active component, as well as synthetic antioxidants, were compared by the cell model methods and chemical methods, including intracellular antioxidant activity (CAA), total antioxidant activities (TAA), superoxide radical (SR), hydroxyl radical (HR), DPPH radical (DR) scavenging activities and inhibition ability of lipoprotein lipid peroxidation (ILLP). Results The median effective concentration (EC50) values (mg/mL) of the WPEO and BPEO of SR, HR, DR, and ILLP were 0.437 and 0.327, 0.486 and 0.204, 7.332 and 6.348, 0.688, and 0.624 mg/mL, respectively. The CAA units of WPEO and BPEO were 50.644 and 54.806, respectively. CAA, DR, and TAA of BPEO were significantly higher than those of WPEO (p less then 0.05). The BPEO and WPEO can be differentiated as the former have higher correlations with 3-carene, α-pinene, β-pinene, and limonene while the latter has a higher caryophyllene correlation. The WPEO and BPEO show a good intracellular scavenging ability of reactive oxygen species in HeLa cells. Conclusion Generally, pepper oil has stronger activities than single components, indicating that pepper is a broad-spectrum natural antioxidant.Cardiac hypertrophy is a common pathological process of various cardiovascular diseases, which is often accompanied with structural and electrical remodeling, and can even lead to sudden cardiac death. However, its molecular mechanism still remains largely unknown. Here, we induced cardiomyocyte hypertrophy by angiotensin II (Ang II), and found that miR-27a-3p and hypertrophy-related genes were up-regulated. Further studies showed that miR-27a-3p-inhibitor can alleviate myocardial hypertrophy and electrical remodeling. Moreover, luciferase assay confirmed that miR-27a-3p could regulate the expression of downstream Hoxa10 at the transcriptional level by targeting at its 3'UTR. At the same time, the protein expression of Hoxa10 was significantly reduced in Ang II-treated cardiomyocytes. Furthermore, overexpression of Hoxa10 can reverse myocardial hypertrophy and electrical remodeling induced by Ang II in cardiomyocytes. Finally, we found that Hoxa10 positively regulated the expression of potassium channel protein Kv4.3 which was down-regulated in hypertrophic cardiomyocytes. Taken together, our results revealed miR-27a-3p/Hoxa10/Kv4.3 axis as a new mechanism of Ang II-induced cardiomyocyte hypertrophy, which provided a new target for clinical prevention and treatment of cardiac hypertrophy and heart failure.Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure, but therapeutic options for nephroprotection are limited. Oxidative stress plays a key role in the pathogenesis of DKD. Our previous studies demonstrated that tetramethylpyrazine nitrone (TBN), a novel nitrone derivative of tetramethylpyrazine with potent free radical-scavenging activity, exerted multifunctional neuroprotection in neurological diseases. However, the effect of TBN on DKD and its underlying mechanisms of action are not yet clear. Herein, we performed streptozotocin-induced rat models of DKD and found that TBN administrated orally twice daily for 6 weeks significantly lowered urinary albumin, N-acetyl-β-D-glycosaminidase, cystatin C, malonaldehyde, and 8-hydroxy-2'-deoxyguanosine levels. TBN also ameliorated renal histopathological changes. More importantly, in a nonhuman primate model of spontaneous stage III DKD, TBN increased the estimated glomerular filtration rate, decreased serum 3-nitrotyrosine, malonaldehyde and 8-hydroxy-2'-deoxyguanosine levels, and improved metabolic abnormalities. In HK-2 cells, TBN increased glycolytic and mitochondrial functions. The protective mechanism of TBN might involve the activation of AMPK/PGC-1α-mediated downstream signaling pathways, thereby improving mitochondrial function and reducing oxidative stress in the kidneys of DKD rodent models. These results support the clinical development of TBN for the treatment of DKD.Cancer has the highest mortality in humans worldwide, and the development of effective drugs remains a key issue. Traditional Chinese medicine Saussurea involucrata (SI) exhibits a series of effects, such as anti-cancer, but the action mechanisms are still unclear. Here, systems pharmacology was applied to reveal its anti-cancer mechanism. First, we screened the active compounds of SI. Then, the compound-target network, target-disease network, and target-pathway network were constructed. DAVID was applied for GOBP analysis and KEGG pathway enrichment analysis on cancer-related targets. Seven potential compounds and 187 targets were identified. The target-disease classification network showed that compounds mainly regulated proteins related to cancer, nervous system diseases, and cardiovascular system diseases. Also, SI anti-tumor effect mainly associated with the regulation of NO production, angiogenesis, MAPK, and PKB from GOBP enrichment. Additionally, KEGG pathway enrichment indicated that targets involved in anti-inflammatory action, inhibiting angiogenesis and anti-proliferation or inducing apoptosis. Experimental validation showed that four active compounds could inhibit cell proliferation and promote apoptosis in A549 (except for kaempferol), PC-3, and C6 cells. This study not only provides experimental evidence for further research on SI in cancer treatment but also promotes the development of potential drugs of SI in modern medicine.Tongxinluo (TXL), a traditional Chinese medication, plays a key role in the formation and progression of plaques in atherosclerosis. The formation of foam cells by macrophages accelerates the destabilisation of plaques. In previous research, we had found that TXL significantly inhibits ox-LDL-induced apoptosis in macrophages in vitro by improving the dissociation of the Beclin-1-Bcl-2 complex. Therefore, here, we explored the effect of TXL on lipid metabolism in macrophages and the mechanism involved. To evaluate the role of TXL in atherosclerotic plaques, we construct the atherosclerotic animal model with lentiviral injection and performed immunofluorescence staining analysis in vivo. Western blot, immunofluorescence staining and microscopy were performed to elucidate the mechanism underlying TXL-mediated regulation of autophagy in THP-1 macrophages in vitro. Immunofluorescence assay revealed that TXL treatment inhibited lipid deposition in advanced atherosclerotic plaques. In vitro TXL treatment inhibited lipid deposition in THP-1 macrophages by enhancing autophagy via Beclin-1. TXL reversed the high expression of class I histone deacetylases (HDACs) induced by ox-LDL (p less then 0.05). Compared with the TXL + ox-LDL group, TXL failed to promote intracellular lipid droplet decomposition after the addition of the histone deacetylase agonist. We found that TXL attenuates the accumulation of lipids in macrophage by enhancing Beclin-1-induced autophagy, and additionally, it inhibits the inhibitory effect of class I HDAC on the expression of Beclin-1.The uncontrolled proliferation and migration of vascular smooth muscle cells is a critical step in the pathological process of restenosis caused by vascular intimal hyperplasia. Jujuboside B (JB) is one of the main biologically active ingredients extracted from the seeds of Zizyphus jujuba (SZJ), which has the properties of anti-platelet aggregation and reducing vascular tension. However, its effects on restenosis after vascular intervention caused by VSMCs proliferation and migration remain still unknown. Herein, we present novel data showing that JB treatment could significantly reduce the neointimal hyperplasia of balloon-damaged blood vessels in Sprague-Dawley (SD) rats. In cultured VSMCs, JB pretreatment significantly reduced cell dedifferentiation, proliferation, and migration induced by platelet-derived growth factor-BB (PDGF-BB). JB attenuated autophagy and reactive oxygen species (ROS) production stimulated by PDGF-BB. Besides, JB promoted the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). Notably, inhibition of AMPK and PPAR-γ partially reversed the ability of JB to resist the proliferation and migration of VSMCs. Taken as a whole, our findings reveal for the first time the anti-restenosis properties of JB in vivo and in vitro after the endovascular intervention. JB antagonizes PDGF-BB-induced phenotypic switch, proliferation, and migration of vascular smooth muscle cells partly through AMPK/PPAR-γ pathway. These results indicate that JB might be a promising clinical candidate drug against in-stent restenosis, which provides a reference for further research on the prevention and treatment of vascular-related diseases.
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