The antineoplastic drug carmofur is shown to inhibit the SARS-CoV-2 main protease (M
). Here, the X-ray crystal structure of M
in complex with carmofur reveals that the carbonyl reactive group of ...carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC
= 24.30 μM) and is a promising lead compound to develop new antiviral treatment for COVID-19.
郭松棻深情訴說著戰前戰後的「臺灣存有」，然而他卻不只是一個傳統的「說故事的人」，因為他同時使得他的小說成為一種隱跡書寫，這些故事之所以被書寫，是為了傳遞另一層更為重要的追問，「為何我要寫作？」文學成為充滿異質疊層與嵌套的地勢學，他的每一篇小說都構成具有當代文學意含的「劇中劇」（mise en ...abyme）。小說的真正主角是「寫作」，或者應該說，每一個小說主角都離不開郭松棻用以構成他的獨特敘事，這是深深蝕入文字肌理的文學思考，而且正是在此舖展著郭松棻無比重視的「寫作論」。郭松棻更以文字肌里在語言的底層重塑了一種特屬於文學的時間，而小說亦是對這種時間的無窮追問，最終形構了一種獨特的「時間－文字」。
The sudden outbreak of 2019 novel coronavirus (2019-nCoV, later named SARS-CoV-2) rapidly turned into an unprecedented pandemic of coronavirus disease 2019 (COVID-19). This global healthcare ...emergency marked the third occurrence of a deadly coronavirus (CoV) into the human society after entering the new millennium, which overwhelmed the worldwide healthcare system and affected the global economy. However, therapeutic options for COVID-19 are still very limited. Developing drugs targeting vital proteins in viral life cycle is a feasible approach to overcome this dilemma. Main protease (M
) plays a dominant role in processing CoV-encoded polyproteins which mediate the assembly of replication-transcription machinery and is thus recognized as an ideal antiviral target. Here we summarize the recent progress in the discovery of anti-SARS-CoV-2 agents against M
. Combining structural study, virtual screen, and experimental screen, numerous therapeutic candidates including repurposed drugs and
designed compounds have been proposed. Such collaborative effort from the scientific community would accelerate the pace of developing efficacious treatment for COVID-19.
A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is ...an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARSCoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 μmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substratebinding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.
Glioblastoma is the most lethal brain tumor and harbors glioma stem cells (GSCs) with potent tumorigenic capacity. The function of GSCs in tumor propagation is maintained by several core ...transcriptional regulators including c-Myc. c-Myc protein is tightly regulated by posttranslational modification. However, the posttranslational regulatory mechanisms for c-Myc in GSCs have not been defined. In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation. In contrast, overexpression of the ubiquitin E3 ligase FBXL14 induced c-Myc degradation, promoted GSC differentiation, and inhibited tumor growth. Ectopic expression of the ubiquitin-insensitive mutant T58A-c-Myc rescued the effects caused by FBXL14 overexpression or USP13 disruption. These data suggest that USP13 and FBXL14 play opposing roles in the regulation of GSCs through reversible ubiquitination of c-Myc.
To assess the effectiveness and safety of omega-3 fatty acid for patients with PCOS.
In this meta-analysis, data from randomized controlled trials were obtained to assess the effects of omega-3 fatty ...acid versus placebo or western medicine in women with PCOS. The study's registration number is CRD42017065859. The primary outcomes included the change of homeostatic model assessment (HOMA) of insulin resistance, total cholesterol (TC), triglyceride (TG) and adiponectin.
Nine trials involving 591 patients were included. Comparing with the control group, omega-3 fatty acid may improve HOMA index (WMD -0.80; 95% CI -0.89, - 0.71; P<0. 00001), decrease TC and TG level TC: (WMD -9.43; 95% CI -11.90, - 6.95; P<0. 00001); TG: (WMD -29.21; 95% CI -48.08, - 10.34; P = 0. 002), and increase adiponectin level (WMD 1.34; 95% CI 0.51, 2.17; P = 0. 002).
Based on current evidence, omega-3 fatty acid may be recommended for the treatment of PCOS with insulin resistance as well as high TC (especially LDL-C) and TG.
The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key enzyme, which extensively digests CoV replicase polyproteins essential for viral replication and ...transcription, making it an attractive target for antiviral drug development. However, the molecular mechanism of how Mpro of SARS-CoV-2 digests replicase polyproteins, releasing the nonstructural proteins (nsps), and its substrate specificity remain largely unknown. Here, we determine the high-resolution structures of SARS-CoV-2 Mpro in its resting state, precleavage state, and postcleavage state, constituting a full cycle of substrate cleavage. The structures show the delicate conformational changes that occur during polyprotein processing. Further, we solve the structures of the SARS-CoV-2 Mpro mutant (H41A) in complex with six native cleavage substrates from replicase polyproteins, and demonstrate that SARS-CoV-2 Mpro can recognize sequences as long as 10 residues but only have special selectivity for four subsites. These structural data provide a basis to develop potent new inhibitors against SARS-CoV-2.
Metabolic dysregulation drives tumor initiation in a subset of glioblastomas harboring isocitrate dehydrogenase (IDH) mutations, but metabolic alterations in glioblastomas with wild-type IDH are ...poorly understood. MYC promotes metabolic reprogramming in cancer, but targeting MYC has proven notoriously challenging. Here, we link metabolic dysregulation in patient-derived brain tumor-initiating cells (BTIC) to a nexus between MYC and mevalonate signaling, which can be inhibited by statin or 6-fluoromevalonate treatment. BTICs preferentially express mevalonate pathway enzymes, which we find regulated by novel MYC-binding sites, validating an additional transcriptional activation role of MYC in cancer metabolism. Targeting mevalonate activity attenuated RAS-ERK-dependent BTIC growth and self-renewal. In turn, mevalonate created a positive feed-forward loop to activate MYC signaling via induction of miR-33b. Collectively, our results argue that MYC mediates its oncogenic effects in part by altering mevalonate metabolism in glioma cells, suggesting a therapeutic strategy in this setting.
.
Resveratrol and quercetin have effects on polycystic ovary syndrome (PCOS). Hence, resveratrol combined with quercetin may have better effects on it. However, because of the limitations in animal and ...human experiments, the pharmacological and molecular mechanism of quercetin-resveratrol combination (QRC) remains to be clarified. In this research, a systematic pharmacological approach comprising multiple compound target collection, multiple potential target prediction, and network analysis was used for comparing the characteristic of resveratrol, quercetin and QRC, and exploring the mechanism of QRC. After that, four networks were constructed and analyzed: (1) compound-compound target network; (2) compound-potential target network; (3) QRC-PCOS PPI network; (4) QRC-PCOS-other human proteins (protein-protein interaction) PPI network. Through GO and pathway enrichment analysis, it can be found that three compounds focus on different biological processes and pathways; and it seems that QRC combines the characteristics of resveratrol and quercetin. The in-depth study of QRC further showed more PCOS-related biological processes and pathways. Hence, this research not only offers clues to the researcher who is interested in comparing the differences among resveratrol, quercetin and QRC, but also provides hints for the researcher who wants to explore QRC's various synergies and its pharmacological and molecular mechanism.
Background
Modern pharmacological research found that the chemical components of
Curcuma longa L.
are mainly curcumin and turmeric volatile oil. Several recent randomized controlled trials (RCT) have ...shown that curcumin improves symptoms and inflammation in patients with arthritis.
Methods
Pubmed, Cochran Library, CNKI, and other databases were searched to collect the randomized controlled trials (RCTs). Then, the risk of bias of RCTs were assessed and data of RCTs were extracted. Finally, RevMan 5.3 was utilized for meta-analysis.
Results
Twenty-nine (29) RCTs involving 2396 participants and 5 types of arthritis were included. The arthritis included Ankylosing Spondylitis (AS), Rheumatoid Arthritis (RA), Osteoarthritis (OA), Juvenile idiopathic arthritis (JIA) and gout/hyperuricemia. Curcumin and Curcuma longa Extract were administered in doses ranging from 120 mg to 1500 mg for a duration of 4-36 weeks. In general, Curcumin and Curcuma longa Extract showed safety in all studies and improved the severity of inflammation and pain levels in these arthritis patients. However, more RCTs are needed in the future to elucidate the effect of Curcumin and Curcuma longa Extract supplementation in patients with arthritis, including RA, OA, AS and JIA.
Conclusion
Curcumin and Curcuma longa Extract may improve symptoms and inflammation levels in people with arthritis. However, due to the low quality and small quantity of RCTs, the conclusions need to be interpreted carefully.
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