Baicalein analogues as prospective SARS-CoV-2 main protease (Mpro) inhibitors: A dataset of molecular docking-based virtual screening hits.

The global coronavirus disease 2019 (COVID-19) pandemic originating from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has exerted profound damage to millions of lives. Baicalein is a flavonoid that has gotten a lot of attention as a possible SARS-CoV-2 main protease (Mpro) inhibitor because it can fight off many different viruses. We prepared and screened three sets of databases, each containing 2563 baicalein analogues, against Mpro using molecular docking simulation. The data showed that several baicalein analogues exhibited stable binding energies relative to standard baicalein, indicating that they have some selectivity against Mpro. The binding properties of the top three stable analogues from each database were further analyzed with respect to their binding properties, such as binding mode, binding energy, and binding interaction of putative stable ligand confirmations at the target binding site region.

The mechanism governing the formation of intermolecular charge transfer bands: a series of polyoxomolybdates as a case study.

A series of proof-of-concept models of polyoxomolybdates with different protonated disubstituted aniline counterions and the same ß-Mo8O26 polyanion were synthesized to study the mechanism governing the formation of the intermolecular charge transfer (inter-CT) band.

Enhancing paranasal sinus disease detection with AutoML: efficient AI development and evaluation via magnetic resonance imaging.

PURPOSE: Artificial intelligence (AI) in the form of automated machine learning (AutoML) offers a new potential breakthrough to overcome the barrier of entry for non-technically trained physicians. A Clinical Decision Support System (CDSS) for screening purposes using AutoML could be beneficial to ease the clinical burden in the radiological workflow for paranasal sinus diseases. METHODS: The main target of this work was the usage of automated evaluation of model performance and the feasibility of the Vertex AI image classification model on the Google Cloud AutoML platform to be trained to automatically classify the presence or absence of sinonasal disease. The dataset is a consensus labelled Open Access Series of Imaging Studies (OASIS-3) MRI head dataset by three specialised head and neck consultant radiologists. A total of 1313 unique non-TSE T2w MRI head sessions were used from the OASIS-3 repository. RESULTS: The best-performing image classification model achieved a precision of 0.928. Demonstrating the feasibility and high performance of the Vertex AI image classification model to automatically detect the presence or absence of sinonasal disease on MRI. CONCLUSION: AutoML allows for potential deployment to optimise diagnostic radiology workflows and lay the foundation for further AI research in radiology and otolaryngology. The usage of AutoML could serve as a formal requirement for a feasibility study.

Photocatalytic Aryl Sulfide Oxidation Using 4-Nitrophenylacetylene-Modified Cu2O Crystals.

4-Nitrophenylacetylene-functionalized Cu2O rhombic dodecahedra and cubes have been used to photocatalyze aryl sulfide oxidation generating aryl sulfoxides. With an oxygen supply and light from a blue light-emitting diode (LED), the reaction can be completed in 12 h with a water and methanol mixed solution. Generally high product yields and excellent product selectivity of sulfoxides over sulfones were achieved. In particular, a thioanisole to methyl phenyl sulfoxide yield of 98% was obtained. A mechanistic study has revealed that photogenerated electrons, holes, and superoxide radicals are involved in the oxidation reaction. The benefit of simple photocatalyst preparation and molecular functionalization to boost catalytic performance shows that surface-controlled ionic solids can be very effective photocatalysts for some organic transformations.

Network Meta-analysis of oral Chinese patent medicines in treatment of acute exacerbation of chronic obstructive pulmonary disease / 中国中药杂志

This study aimed to evaluate the effectiveness and safety of eight oral Chinese patent medicines in the treatment of acute exacerbation of chronic obstructive pulmonary disease(AECOPD) by network Meta-analysis. Randomized controlled trial(RCT) on the treatment of AECOPD with eight oral Chinese patent medicines was retrieved from databases including CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, EMbase, and Cochrane Library from database inception to August 6, 2022. The information was extracted from the included literature and the quality of the included studies was evaluated using the Cochrane risk of bias assessment tool. The data were analyzed using Stata SE 15.1 and ADDIS 1.16.8 software. Finally, 53 RCTs were included, with 5 289 patients involved, including 2 652 patients in the experimental group and 2 637 patients in the control group. Network Meta-analysis showed that Lianhua Qingwen Capsules+conventional western medicine were optimal in improving clinical effective rate, Shufeng Jiedu Capsules+conventional western medicine in improving FEV1/FVC, Qingqi Huatan Pills+conventional western medicine in improving FEV1%pred, Feilike Mixture(Capsules)+conventional western medicine in improving PaO_2, Lianhua Qingwen Capsules+conventional western medicine in reducing PaCO_2, and Qingqi Huatan Pills+conventional western medicine in reducing C-reactive protein(CRP). In terms of safety, most of them were gastrointestinal symptoms, and no serious adverse reactions were reported. When the clinical effective rate was taken as the comprehensive index of efficacy evaluation, Lianhua Qingwen Capsules+conventional western medicine were the most likely to be the best treatment for AECOPD. There are some limitations in the conclusion of this study. It only provides references for clinical medication.

[Effects of RPA1 down-regulation on the invasion and migration and cell cycle of human nasopharyngeal carcinoma CNE-2R cells with radio resistance].

Objective: To investigate the effects of RPA1 silencing on the invasion, migration and cell cycle of human nasopharyngeal carcinoma CNE-2R cells. Methods: shRNA technology was used to construct CNE-2R cell lines with RPA1 low-expression, which were verified by RT-PCR and Western blotting. The following assays were performed using the three 3 groups: control group(CNE-2),negative control group(NC-shRNA) and RPA1 down-regulation group(RPA1-shRNA). The effects of RPA silence on the proliferation, invasion, migration, and cell cycle of CNE-2R cells were detected using Cell Counting Kit-8, clone formation experiment, Transwell, scratch test and flow cytometry, respectively. The expressions of Chk2, p-Chk2, Cdc 25c and p-cdc25c were tested by Western blot assay. Results: The expressions of RPA1 mRNA and protein in the RPA1-shRNA group were lower than those in the CNE-2 and NC-shRNA groups significantly (P＜0.01 and 0.05). Compared with CNE-2 and NC-shRNA groups, the abilities of proliferation, invasion and migration of RPA1-shRNA group were decreased and the cell cycle in the RPA1-shRNA group was blocked in the G2/M phase (P＜0.01). The expressions of Chk2 and Cdc25c in RPA1-shRNA group cells were lower than those in CNE-2R and NC-shRNA group cells (P＜0.05), while the expressions of p-Chk2 and p-cdc25c were higher than those in the other groups (P＜0.05). Conclusion: After RPA1 silenced, the proliferation and migration of radio resistant human nasopharyngeal carcinoma CNE-2R cells was inhibited, resulting in cell cycle arrested in the G2/M phase.

TNFAIP8 drives metabolic reprogramming to promote prostate cancer cell proliferation.

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a member of TIPE/TNFAIP8 family, has been involved in the development and progression of various human cancers. We hypothesized that TNFAIP8 promotes prostate cancer (PCa) progression via regulation of oxidative phosphorylation (OXPHOS) and glycolysis. Ectopic expression of TNFAIP8 increased PCa cell proliferation/migration/spheroid formation by enhancing cell metabolic activities. Mechanistically, TNFAIP8 activated the PI3K-AKT pathway and up-regulated PCa cell survival. TNFAIP8 was also found to regulate the expression of glucose metabolizing enzymes, enhancing glucose consumption, and endogenous ATP production. Treatment with a glycolysis inhibitor, 2-deoxyglucose (2-DG), reduced TNFAIP8 mediated glucose consumption, ATP production, spheroid formation, and PCa cell migration. By maintaining mitochondrial membrane potential, TNFAIP8 increased OXPHOS and glycolysis. Moreover, TNFAIP8 modulates the production of glycolytic metabolites in PCa cells. Collectively, our data suggest that TNFAIP8 exerts its oncogenic effects by enhancing glucose metabolism and by facilitating metabolic reprogramming in PCa cells. Therefore, TNFAIP8 may be a biomarker associated with prostate cancer and indicate a potential therapeutic target.

Interaction Between Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphisms and Environment with Susceptibility to Ischemic Stroke in Chinese Population.

AIMS: To investigate the association of several single-nucleotide polymorphisms (SNPs) within methylenetetrahydrofolate reductase (MTHFR) gene, and additional gene-environment interaction with ischemic stroke (IS) risk. METHODS: Testing for Hardy-Weinberg equilibrium in controls was conducted using SNPstats (online software: http://bioinfo.iconcologia.net/SNPstats). Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among four SNPs within MTHFR gene and smoking or alcohol drinking. RESULTS: The frequency of the rs4846049-A allele was 28.6% in IS patients and 19.1% in normal controls, in addition, the frequency of the rs3737967-T allele was 27.9% in IS patients and 20.3% in normal controls, which was also indicating a statistically significant difference. The rs4846049-A and rs3737967-T were associated with an increased risk of IS risk; adjusted odds ratios (ORs) (95% confidence interval [CI]) were 1.76 (1.28-2.13) and 1.51 (1.13-1.97), respectively. GMDR model found significant gene-alcohol drinking interaction combination, but no significant gene-tobacco smoking interaction combinations. In order to obtain the odds ratios and 95% CI for the joint effects of gene-alcohol drinking on IS, we conducted stratified analysis for interaction effect using logistic regression. We found that alcohol drinkers with rs4846049-CA/AA genotype also have the highest IS risk, compared with never drinkers with rs4846049-CC genotype, OR (95% CI) = 3.12 (1.83-4.45), after adjustment for age, smoke, and smoking status. CONCLUSIONS: The rs4846049-A and rs3737967-T, gene-environment interaction between rs1764391 and rs918592, gene-environment interaction between rs4846049 and alcohol drinking were all associated with increased IS risk.

Synthesis of Dibenzosuberones Bearing an Isoxazole Group via Palladium-Catalyzed Intramolecular C-H/C-Br Bond Cross-Coupling of Ortho-Aroylated 3,5-Diarylisoxazoles.

A facile and efficient synthetic methodology for preparing dibenzosuberones via a C-H bond activation strategy is presented. The ortho-aroylated 3,5-diarylisoxazole was employed as the starting substrate to undergo palladium-catalyzed intramolecular C-H/C-Br bond cross-coupling to produce a variety of dibenzosuberones bearing an isoxazole group in 24 to >99% 1H NMR yields. The dibenzosuberone structure was further confirmed by X-ray crystallography. The developed methodology exhibits very good functional group tolerance. In addition, a rational mechanism was presented for describing the reaction process. For the prepared dibenzosuberone, the use of Mo(CO)6 as the catalyst can easily transform the isoxazole ring into the ß-aminoenone group. Finally, the structure of the anticipated ring-opening product, dibenzosuberenone, bearing a ß-amino-α-ketone group was secured by X-ray crystallography.

Physical exercise and associated factors of rural primary and secondary school students in the north of Jiangsu Province / 中国学校卫生

Objective@#To understand the current situation and influencing factors of physical exercise participation of rural primary and secondary school students in Jiangsu Province, and to provide reference for promoting healthy development of rural youth in Northern Jiangsu.@*Methods@#A total of 3 597 rural primary and middle school students in Northern Jiangsu Province were selected to conduct a questionnaire survey on the status quo of physical exercise.@*Results@#Only 37.6% of students in Northern Jiangsu had more than 3 hours of physical education every week, 23.6% of the students participated in extracurricular physical exercise for more than 3 times a week, 14.3% of the students participated in physical exercise for more than 1 hour every day, 77.9% of the students master more than 1 sports skills, 72.0% of students participated in extracurricular activities perceived, and 27.3% of the students participated in extracurricular sports professional counseling; 35.7% of the students reported lack of parental support physical education curriculum lacks of interest, 17.0% of the students didn t like the physical education teachers or their teaching methods, 28.6% of the students reported lack of sports venues or equipment, 8.4% of the students reported that their parents do not support, 38.2% of the students reported lack of extracurricular sports professional guidance, 18.1% of the students think that the performance of physical education didn t affect the evaluation and progress of the school. Univariate Logistic regression analysis showed that gender, academic stage, dislike of physical education teaching methods and lack of physical education professional guidance were the influencing factors of physical exercise participation havior of rural students(P<0.05).@*Conclusion@#The present situation of physical exercise of rural primary and secondary school students in Northern Jiangsu Province is not optimistic. Special attention to the formation of female exercise behavior, improve the teaching quality of rural physical education and support the off campus sports training institutions.

Prognostic Value of Combined Analysis of CTLA-4 and PLR in Esophageal Squamous Cell Carcinoma (ESCC) Patients.

OBJECTIVE: The purpose of this study was to evaluate the prognostic role of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) expression level and the platelet lymphocyte ratio (PLR) level in esophageal squamous cell carcinoma (ESCC) patients. METHODS: 84 ESCC patients who received surgical treatment in our hospital were enrolled in the study. The correlation of each biomarker's level with ESCC patients' clinicopathological characteristics and overall survival (OS) was assessed. RESULTS: The elevated expression rate of T-CTLA-4 (tumor cell CTLA-4) and I-CTLA-4 (interstitial lymphocyte CTLA-4) was 48.8% and 44.0%, respectively. The number of enrolled patients with a higher PLR level (≥119) was 48. The prognostic value of T-CTLA-4, I-CTLA-4, and PLR in ESCC patients was not detected. However, patients with both a low T-CTLA-4 expression level and a low PLR level that had longer OS (p = 0.023) were found. The prognostic role of T-CTLA-4(-) +PLR (-) status in ESCC patients was also confirmed in multivariate analyses (p = 0.027). CONCLUSION: These results demonstrated the potential prognostic value of combined analysis of CTLA-4 and PLR in ESCC patients.

Tunable Moiré Superlattice of Artificially Twisted Monolayers.

Twisting between two stacked monolayers modulates periodic potentials and forms the Moiré electronic superlattices, which offers an additional degree of freedom to alter material property. Considerable unique observations, including unconventional superconductivity, coupled spin-valley states, and quantized interlayer excitons are correlated to the electronic superlattices but further study requires reliable routes to study the Moiré in real space. Scanning tunneling microscopy (STM) is ideal to precisely probe the Moiré superlattice and correlate coupled parameters among local electronic structures, strains, defects, and band alignment at atomic scale. Here, a clean route is developed to construct twisted lattices using synthesized monolayers for fundamental studies. Diverse Moiré superlattices are predicted and successfully observed with STM at room temperature. Electrical tuning of the Moiré superlattice is achieved with stacked TMD on graphite.

Cooperative impact of thiazolidinedione and fatty acid synthase on human osteogenesis.

Previous, we found that the small molecules capable of inhibiting the expression and the pro-adipogenic activity of ZNF521 might improve the osteogenic performance of aging human bone marrow MSCs (bmMSCs), and that fatty acid synthase (FASN) was a critical effector of ZNF521's pro-adipogenic activity. Here, by characterizing the netoglitazone (MCC-555), one of the thiazolidinediones known as adipogenic enhancers, as an inhibitor of ZNF521 expression, we found that MCC-555 indeed also harbored pro-osteoblastic effect. Investigation revealed that MCC-555 might function as a GSK3ß inhibitor to promote osteoblastogenesis and bone formation. Importantly, combination of MCC-555 with FASN knockdown, but not with GW9662 (a PPARγ2 antagonist), blocked the pro-adipogenic but retained the pro-osteoblastic effect of MCC-555. Using a 3-dimentional culture system, we showed that MCC-555 facilitated the FASN-knockdown of aging human bmMSCs to form cell clusters in scaffolds, and to promote osteoblastic differentiation and biomineralization in cell clusters. These data indicated that MCC-555 promoted bmMSCs to produce bone-like tissues. Our data narrate a thiazolidinedione-based novel strategy to improve the osteogenic performance of aging bmMSCs to support the application of autologous aging bmMSCs in cell therapy and in producing bone-like tissues for repairing bone injury in the elderly.

Decreased expression of nemo-like kinase in melanoma is correlated with increased vascularity and metastasis.

Melanoma is a highly metastatic cancer, and its incidence has increased over the past several decades. Angiogenesis is associated with melanoma metastasis and a poor prognosis. Many genetic and epigenetic factors affecting tumour vascularization and metastasis have been investigated, despite the heterogeneity of cancer cells and the complicated mechanisms involved in melanoma. Nemo-like kinase (NLK) is a serine/threonine kinase regulating the transcription factor by negatively regulating Wnt and downstream vascular endothelial growth factor receptor 2 (VEGFR2) signalling. This study aimed to investigate whether NLK expression in melanoma correlates with VEGFR2-related angiogenesis and melanoma metastasis. Immunohistochemistry analysis using 175 biopsied tissues of melanoma patients showed that NLK is expressed in 73.7% of melanoma tissues, whereas 26.3% of the samples showed absent expression of NLK. In metastatic melanoma, the expression of NLK was significantly lower than that in primary melanoma (P = 0.002). Furthermore, tissues with a lower expression of NLK showed a higher microvessel density as detected by VEGFR2 expression compared with tissues showing higher NLK expression. These data suggest that reduced expression of NLK in melanoma correlates with VEGFR2-related microvessel formation and melanoma metastasis. This study showed that NLK may serve as a novel prognosis marker and revealed new mechanisms in melanoma metastasis.

Thalidomide (THD) alleviates radiation induced lung fibrosis (RILF) via down-regulation of TGF-ß/Smad3 signaling pathway in an Nrf2-dependent manner.

Radiation-induced lung fibrosis (RILF) is a complication of radiotherapy in thoracic cancer patients. Thalidomide (THD) has a therapeutic effect on fibrotic and inflammatory disorders. The purpose of the current study was to investigate the therapeutic effect of THD on RILF in mice and better understand the underlying regulatory mechanisms of the therapeutic effect. We found that THD mitigated the fibrosis caused by irradiation in mice. The action of THD on RILF was related to the elevation of low levels reactive oxygen species (ROS), which inhibited the transforming growth factor­ß (TGF­ß)/Smad3 signaling pathway through activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Analysis of the therapeutic effect of THD using Nrf2-/- mouse model confirmed the role of Nrf2 in vivo. In addition, no radioprotective effect of THD on thoracic cancer cell lines was observed. In conclusion, these data showed that THD attenuated RILF in mice, which was mediated by Nrf2-dependent down-regulation of the TGF-ß/Smad3 pathway, suggesting THD as a potential novel agent for RILF prevention.

Nrf2-Mediated Metabolic Reprogramming in Cancer.

Metabolic reprogramming is one of the hallmarks of cancer. Nrf2 pathway is one of the critical signaling cascades involved in cell defense and survival against oxidative stress. The significance of Nrf2 in cancer metabolism begins to be recognized. In this minireview, we focus on the Nrf2-mediated cancer metabolic reprogramming and intend to highlight the role of Nrf2 in the regulation of malignant transformation, cancer proliferation, and the development of treatment resistance via metabolic adaptations. We hope for the development of noninvasive biomarkers and novel therapeutic approaches for cancer based on Nrf2-directed cancer metabolic reprogramming in the near future.

FTO regulates the chemo-radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting ß-catenin through mRNA demethylation.

The role of N6 -methyladenosine (m6 A) demethylase fat mass and obesity-associated protein (FTO) in the regulation of chemo-radiotherapy resistance remains largely unknown. Here, we show that the mRNA level of FTO is elevated in cervical squamous cell carcinoma (CSCC) tissues when compared with respective adjacent normal tissues. FTO enhances the chemo-radiotherapy resistance both in vitro and in vivo through regulating expression of ß-catenin by reducing m6 A levels in its mRNA transcripts and in turn increases excision repair cross-complementation group 1 (ERCC1) activity. Clinically, the prognostic value of FTO for overall survival is found to be dependent on ß-catenin expression in human CSCC samples. Taken together, these findings uncover a critical function for FTO and its substrate m6 A in the regulation of chemo-radiotherapy resistance, which may bear potential clinical implications for CSCC treatment.

Hippocampal-Sparing Whole-Brain Radiotherapy for Lung Cancer.

Brain metastases occur in 20% to 40% of lung cancer patients. Whole-brain radiotherapy (WBRT) has long been considered the treatment of choice for many patients with lung cancer, because of its wide availability, ease of delivery, and effectiveness in prolonging survival. However, WBRT is also associated with several side effects, such as decline in memory and other cognitive functions. There exists significant preclinical and clinical evidence that radiation-induced injury to the hippocampus correlates with neurocognitive decline of patients who receive WBRT. Technological advances in treatment planning and delivery facilitate the use of hippocampal-sparing (HS) WBRT as prophylactic cranial irradiation or the primary treatment modality for lung cancer patients with brain metastases. In this review, we provide a detailed and comprehensive discussion of the safety profile, techniques for hippocampus-sparing, and the clinical evidence of HS-WBRT for lung cancer patients.

Protein tyrosine phosphatase 1B is a mediator of cyclic ADP ribose-induced Ca²⁺ signaling in ventricular myocytes

Cyclic ADP-ribose (cADPR) releases Ca²⁺ from ryanodine receptor (RyR)-sensitive calcium pools in various cell types. In cardiac myocytes, the physiological levels of cADPR transiently increase the amplitude and frequency of Ca²⁺ (that is, a rapid increase and decrease of calcium within one second) during the cardiac action potential. In this study, we demonstrated that cADPR levels higher than physiological levels induce a slow and gradual increase in the resting intracellular Ca²⁺ ([Ca²⁺](i)) level over 10 min by inhibiting the sarcoendoplasmic reticulum Ca²⁺ ATPase (SERCA). Higher cADPR levels mediate the tyrosine-dephosphorylation of α-actin by protein tyrosine phosphatase 1B (PTP1B) present in the endoplasmic reticulum. The tyrosine dephosphorylation of α-actin dissociates phospholamban, the key regulator of SERCA, from α-actin and results in SERCA inhibition. The disruption of the integrity of α-actin by cytochalasin B and the inhibition of α-actin tyrosine dephosphorylation by a PTP1B inhibitor block cADPR-mediated Ca²⁺ increase. Our results suggest that levels of cADPR that are relatively higher than normal physiological levels modify calcium homeostasis through the dephosphorylation of α-actin by PTB1B and the subsequent inhibition of SERCA in cardiac myocytes.

AT-101 enhances gefitinib sensitivity in non-small cell lung cancer with EGFR T790M mutations.

BACKGROUND: Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have become the standard care of patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC), development of acquired resistance is inevitable. A secondary mutation of threonine 790 (T790M) is associated with approximately half of the cases of acquired resistance. Strategies or agents to overcome this type of resistance are still limited. In this study, enhanced antitumor effect of AT-101, a-pan-Bcl-2 inhibitor, on gefitinib was explored in NSCLC with T790M mutation. METHODS: The effect of cotreatment with AT-101 and gefitinib on the viability of NSCLC cell lines harboring acquired T790M mutation was investigated using the MTT assay. The cellular apoptosis of NSCLC cells after cotreatment with AT-101 and gefitinib was assessed by FITC-annexin V/PI assay and Western blots analysis. The potential underlying mechanisms of the enhanced therapeutic effect for AT-101 was also studied using Western blots analysis. The in vivo anti-cancer efficacy of the combination with AT-101 and gefitinib was examined in a mouse xenograft model. RESULTS: In this study, we found that treatment with AT-101 in combination with gefitinib significantly inhibited cell proliferation, as well as promoted apoptosis of EGFR TKIs resistant lung cancer cells. The apoptotic effects of the use of AT-101 was related to the blocking of antiapoptotic protein: Bcl-2, Bcl-xl, and Mcl-1 and downregrulation of the molecules in EGFR pathway. The observed enhancements of tumor growth suppression in xenografts supported the reverse effect of AT-101 in NSCLC with T790M mutation, which has been found in in vitro studies before. CONCLUSIONS: AT-101 enhances gefitinib sensitivity in NSCLC with EGFR T790M mutations. The addition of AT-101 to gefitinib is a promising strategy to overcome EGFR TKIs resistance in NSCLC with EGFR T790M mutations.