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Gastric cancer (GC) is a malignant tumor with global incidence and death ranking fifth and fourth, respectively. GC patients nevertheless have a poor prognosis despite the effectiveness of more advanced chemotherapy and surgical treatment options. The second most frequently mutated gene in GC is PI3Kalpha, a confirmed oncogene that results in abnormal PI3K/AKT/mTOR signaling, causing enhanced translation, proliferation, and survival, and is mutated in 7-25% of GC patients. The protein PI3Kalpha was targeted in the present study by utilizing machine learning (ML), molecular docking, and simulation. A total of 9214 molecules from the DrugBank database were chosen for the first screening. A training set for 6770 compounds tested against PI3Kalpha was assessed to create a quantitative structure-activity relationship-based machine learning model using five different classification algorithms: random forest, random tree, J48 pruned tree, decision stump, and REPTree. Furthermore, consideration was given to the random forest classifier for screening based on its performance index (Kappa statistics, ROC, and MCC). Overall, 1539 of the 9214 drug bank compounds were predicted to be active. Thereafter, three pharmacological filters, Lipinski's rule, Ghose filter, and Veber rule, were applied to test the drug-like properties of the screened compounds. Twenty-six of 1593 compounds showed excellent drug-like properties and were further considered for molecular docking. Thereafter, two compounds were screened as hits because they possessed the molecular docked position with the lowest binding energy and an excellent bonding profile. The binding stability of the selected compounds was further assessed through molecular dynamics simulations for up to 100 ns. Furthermore, compound 1-(3-(2,4-dimethylthiazol-5-YL)-4-oxo-2,4-dihydroindeno[1,2-C]pyrazol-5-YL)-3-(4-methylpiperazin-1-YL) urea was selected as a potential hit in the final screening by analyzing a number of parameters, including the Rg, RMSD, RMSF, H bonding, and SASA profile. Therefore, we conclude that compound 1-(3-(2, 4-dimethylthiazol-5-YL)-4-oxo-2,4-dihydroindeno[1,2-C]pyrazol-5-YL)-3-(4-methylpiperazin-1-YL) urea has efficient inhibitory potential against PI3Kalpha protein and could be utilized for the development of effective drugs against GC.
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BACKGROUND: Chronic diarrhea is difficult to prevent and treat due to its complex etiology and pathogenesis. It places a huge burden on patients and public healthcare. It is known that the regulation of body homeostasis relies heavily on calcium. However, in the general population, the relationship between calcium and chronic diarrhea remains uncertain. METHODS: We assessed the association between serum calcium and diarrhea using data from the 2005-2010 National Health and Nutrition Examination Survey (NHANES). Serum calcium level was measured from collected blood samples. Diarrhea was assessed using the Bristol Stool Scale (BSFS) (types 1-7). The stability of the results was assessed using logistic regression and sensitivity analysis. The dose-response association between serum calcium and the risk of diarrhea was analyzed using a restricted cubic spline plot. RESULTS: This study included 12,342 participants. In each of the five models, an increased calcium level was negatively associated with the incidence of diarrhea (OR[95%CI]:0.26 [0.13-0.53], 0.28 [0.14-0.58], 0.4 [0.19-0.82], 0.27 [0.11-0.64] and 0.24 [0.10-0.59], respectively). When serum calcium was analyzed as a categorical variable, a significant association between serum calcium and diarrhea prevalence was found. The restricted cubic spline plot showed a linear relationship between serum calcium and diarrhea. Sensitivity analysis confirmed that the results were stable. CONCLUSION: The results of our cross-sectional study suggest that a higher level of serum calcium may reduce the incidence of diarrhea. In the future, this finding should be further validated in a randomized controlled trial.
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Calcio , Diarrea , Humanos , Encuestas Nutricionales , Estudios Transversales , Incidencia , Diarrea/epidemiologíaRESUMEN
Let-7i regulates tumors primarily by binding to the 3' untranslated region (3' UTR) of mRNA, which indirectly regulates post-transcriptional gene expression. Let-7i also has an epigenetic function via modulating DNA methylation to directly regulate gene expression. Let-7i performs a dual role by inducing both the promotion and inhibition of various malignancies, depending on its target. The mechanism of Let-7i action involves cancer cell proliferation, migration, invasion, apoptosis, epithelial-mesenchymal transition, EV transmission, angiogenesis, autophagy, and drug resistance sensitization. Let-7i is closely related to cancer, and hence, is a potential biomarker for the diagnosis and prognosis of various cancers. Therapeutically, it can be used to promote an anti-cancer immune response by modifying exosomes, thus exerting a tumor-suppressive effect.
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Polycystic ovary syndrome (PCOS) is a very common chronic disease and causes reproductive disorders in women of childbearing age worldwide. The cause of metabolic dysfunction in PCOS is unknown, and there is a lack of systematic bibliometric analysis for this disease. This study included 3,972 articles on metabolic dysfunction in PCOS published from 2012 to 2021. We applied the VOSviewer and the CiteSpace scientometric analysis software to analyze the data regarding the publication of the articles, countries, authors, institutions, scientific categories, cited journals, and keywords. Through this analysis, we determined the research efforts and their developing trends and anticipated the progress in understanding PCOS-related metabolic dysfunction.
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Síndrome del Ovario Poliquístico , Humanos , Femenino , Bibliometría , Reproducción , Programas InformáticosRESUMEN
BACKGROUND: This study aimed to explore the underlying mechanism of puerarin against rotavirus (RV), based on network pharmacology analysis and experimental study in vitro. METHODS: The cytopathic effect inhibition assay with different concentrations of puerarin at different times of infection in vitro was applied to evaluate the effect of puerarin against human RV G1P[8] Wa strain (HRV Wa). Subsequently, the potential targets of puerarin and RV-related genes were obtained from online databases. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the major target genes were also performed. Furthermore, the major targets and signaling pathway related to RV infection were verified at the molecular level via Western blot, quantitative real-time reverse transcription PCR (RT-qPCR), and Enzyme-linked immunosorbent assay (ELISA) tests. RESULTS: Our results suggest that puerarin had a certain inhibitory effect on viral replication and proliferation. The network pharmacology analysis showed that a total of 436 puerarin corresponding target and 497 RV-related targets were acquired from the online databases. The core targets of puerarin against RV, such as Toll-like receptor 4 (TLR4), tumor necrosis factor (TNF), and caspase 3 (CASP3), were identified from the protein-protein interaction (PPI) network. The KEGG analysis indicated that the TLR signaling pathway was one of the crucial mechanisms of puerarin against RV. In particular, puerarin could inhibit the expression of key factors of the TLR4/nuclear factor kappa-B (NF-κB) signaling pathway in HRV-infected Caco-2 cells and regulate the levels of cellular inflammatory factors. CONCLUSIONS: Based on the network pharmacology analysis and experimental study, the study showed that puerarin not only had an anti-RV effect, but could also modulate the inflammatory response induced by RV infection via the TLR4/NF-κB signaling pathway. This study reveals the potential of puerarin in the treatment of RV infection, suggesting that it might be a promising therapeutic agent.
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BACKGROUND AND OBJECTIVES: The association between abdominal obesity and reflux esophagitis (RE) has been extensively evaluated, but the current findings are mixed and more convincing epidemiological evidence urgently needs to be established. To thoroughly explore this relationship, we summarized the latest studies, performed an updated meta-analysis, and examined the dose-response relationship. METHODS: We performed a systematic search of PubMed, Web of Science, and Embase up to 28 March 2021, using prespecified terms to identify studies investigating the association between abdominal obesity and RE. Odds ratios (ORs) with 95% confidence intervals (CIs), mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs were taken as effect-size estimates. RESULTS: Forty-two observational studies, including 11 cohort studies, were meta-analyzed. Overall, a statistically significant association was observed between abdominal obesity and RE, by both the pooled OR (adjusted OR = 1.51, 95% CI: 1.37-1.66, p < .001) and the pooled SMD (SMD = 0.36, 95% CI: 0.30-0.42, p < .001). Moreover, this significant relationship persisted with subgroup stratification. In subgroup analyses, we found that study design, abdominal obesity measurement, adjustment for covariates and sex were possible sources of between-study heterogeneity. For the dose-response analyses, the risk of RE increased with the degree of abdominal obesity, and the increasing trend accelerated when waist circumference (WC) reached 87.0 cm. CONCLUSION: This meta-analysis indicated a significant association between abdominal obesity and RE, and the risk of RE increased with abdominal obesity especially when the WC was over 87.0 cm.
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Esofagitis Péptica , Obesidad Abdominal , Índice de Masa Corporal , Esofagitis Péptica/epidemiología , Esofagitis Péptica/etiología , Humanos , Obesidad Abdominal/complicaciones , Factores de Riesgo , Circunferencia de la Cintura/fisiologíaRESUMEN
BACKGROUND: The incidence of ulcerative colitis (UC) is increasing year by year worldwide, and it is listed as one of the refractory diseases by World Health Organization. In addition to typical intestinal manifestations such as abdominal pain, diarrhea, mucus, pus, and bloody stool, it can also accompany multiorgan and multisystem extraintestinal manifestations, seriously affecting the life and work of patients. Furthermore, UC patients with a tremendous psychological pressure and affects their physical and mental health. In recent years, many complementary and alternative therapies have been used for treatment of UC, but only pair-wised drugs have been evaluated in the traditional meta-analyses and some results are inconsistent. Consequently, it is essential to propose a protocol for systematic review and meta-analysis to discuss the efficacy and safety of complementary and alternative therapies in the treatment of UC. METHODS: We will search Chinese and English databases comprehensively and systematically from the establishment of databases to May 2020, free of language or publication restrictions. All randomized controlled trials on complementary and alternative therapies for UC will be included. Two researchers will independently screen titles, abstracts, full texts, and extract data, then assess the bias risk of each study. We will conduct pairwise meta-analyses and Bayesian network meta-analyses to the relative outcomes of the efficacy and safety. Data analysis will use STATA and WinBUGs 1.4.3 software in this meta-analysis. RESULTS: This study will evaluate the efficacy and safety of complementary and alternative therapies for UC based on changes in symptoms, clinical efficacy, quality of life and adverse events. CONCLUSION: This study will provide evidence for whether complementary and alternative therapies are beneficial to the treatment of UC. In order to provide reliable evidence-based medicine for clinical practice. INPLASY REGISTRATION NUMBER: INPLASY202060015.
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Colitis Ulcerosa/terapia , Terapias Complementarias/métodos , Adulto , Teorema de Bayes , Medicamentos Herbarios Chinos/uso terapéutico , Femenino , Humanos , Masculino , Metaanálisis en Red , Proyectos de Investigación , Revisiones Sistemáticas como Asunto , Resultado del TratamientoRESUMEN
BACKGROUND: Corona Virus Disease 2019 (COVID-19) has caused a worldwide epidemic since its discovery. The outbreak of virus infection has aroused great concern of the World Health Organization (WHO). COVID-19 is highly infectious and has a high infection rate. So far, no specific drug has been found to cure it. China as one of the first countries attacked by epidemic has shown outstanding in fighting against the COVID-19. The contribution of traditional Chinese medicine can not be ignored. As a kind of representative of traditional Chinese medicine, the Chinese patent medicine injection has significant effect in reducing the clinical symptoms of patients and preventing the deterioration of the disease. However, there is no systematic review of its efficacy and safety. The purpose of this study is to evaluate the efficacy and safety of Chinese patent medicine injection in the treatment of COVID-19. METHODS: All randomized controlled trials of Chinese patent medicine injection for COVID-19 will be included. The following electronic databases will be searched: PubMed, Web of Science, the Cochrane Library, EMBASE, China National Knowledge Infrastructure, Wanfang Database, Chinese Scientific Journal Database, Chinese Biomedical Literature database and some clinical trial registration websites. Two researchers will independently screen titles, abstracts, full texts, and extract data, then assess the bias risk of each study. We will conduct meta-analyses to assess all the available evidence of the efficacy and safety. RESULTS: Systematic review of current evidence will be provided from the indexes of efficacy and safety. CONCLUSION: Evidence regarding the efficacy and safety of Chinese patent medicine injection in the treatment of COVID-19 will be provided to clinicians.PROSPERO registration number: CRD42020182725.
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Infecciones por Coronavirus/tratamiento farmacológico , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/efectos adversos , Metaanálisis como Asunto , Neumonía Viral/tratamiento farmacológico , Revisiones Sistemáticas como Asunto , Betacoronavirus , COVID-19 , Humanos , Inyecciones , Pandemias , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19RESUMEN
Chronic atrophic gastritis (CAG) is a common and possibly precancerous digestive tract disease. Development of drugs with effect of preventing precancerous lesions draws the eyes of global researchers. Qilianshupi decoction (QLSP) is a Traditional Chinese Medicine (TCM) that is commonly used to treat CAG, but few studies have explored the mechanism of QLSP on treating CAG. This study investigated the molecular targets of the component herbs of QLSP in preventing precancerous lesions based on network pharmacology. Network pharmacology analysis revealed that the 6 herbs regulated multiple CAG-related genes, among which the most important were cancer-related pathway (apoptosis, p53, and VEGF) and epithelial cell signaling in Helicobacter pylori infection. Further animal experiments showed that the expression of survivin and p53 in precancerous lesions of CAG rats was significantly increased which was suppressed by QLSP. Moreover, telomerase activity was inhibited in precancerous lesions of CAG rats, and telomere length of gastric mucosa was increased, which was reversed by QLSP. Our results suggest that the components of QLSP prevents gastric precancerous lesions through decreasing the expression of survivin and p53 and regulating telomerase activity and telomere length in CAG.
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The Nb-doped lanthanum strontium ferrite perovskite oxide La0.8 Sr0.2 Fe0.9 Nb0.1 O3-δ (LSFNb) is evaluated as an anode material in a solid oxide fuel cell (SOFC). The effects of Nb partial substitution in the crystal structure, the electrical conductivity, and the valence of Fe ions are studied. LSFNb exhibits good structural stability in a severe reducing atmosphere at 800 °C, suggesting that high-valent Nb can effectively promote the stability of the lattice structure. The concentration of Fe2+ increases after Nb doping, as confirmed by X-ray photoelectron spectroscopy. The maximum power density of a thick Sc-stabilized zirconia (ScSZ) electrolyte-supported single cell reached 241.6â mW cm-2 at 800 °C with H2 as fuel. The cell exhibited excellent stability for 100â h continuous operation without detectable degeneration. Scanning electron microscopy clearly revealed exsolution on the LSFNb surface after operation. Meanwhile, LSFNb particles agglomerated significantly during long-term stability testing. Impedance spectra suggested that both the LSFNb anode and the (La0.75 Sr0.25 )0.95 MnO3-δ /ScSZ cathode underwent an activation process during long-term testing, through which the charge transfer ability increased significantly. Meanwhile, low-frequency resistance (RL ) mainly attributed to the anode (80 %) significantly increased, probably due to the agglomeration of LSFNb particles. The LSFNb anode exhibits excellent anti-sulfuring poisoning ability and redox stability. These results demonstrate that LSFNb is a promising anode material for SOFCs.
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Suministros de Energía Eléctrica , Compuestos Férricos/química , Lantano/química , Niobio/química , Estroncio/química , Conductividad Eléctrica , Electrodos , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Oxidación-Reducción , Espectroscopía de Fotoelectrones , TermogravimetríaRESUMEN
Artemisinin and its derivatives are well-known anti-malaria drugs and in the early stages of research for cancer treatment. Dihydroartemisinin (DHA), a more water-soluble derivative of artemisinin, has demonstrated strong anti-angiogenic activity. The purpose of the present study was to investigate the underlying molecular mechanisms of the effect of DHA on angiogenesis. Human umbilical vein endothelial cells (HUVECs) treated with DHA were examined for apoptosis and activation of the c-Jun N-terminal kinase (JNK) signaling pathway, one of the major mitogen-activated protein kinase cascades. It was observed that 20 µM DHA induces transient activation of JNK in HUVECs. DHA also elevates the expression of cyclooxygenase-2 and matrix metalloproteinase-13, which is abolished by treatment with the JNK inhibitor SP600125. Although DHA persistently increases inhibitor of κB-α protein and thus inhibits nuclear factor-κB signaling, it does not affect apoptosis or caspase 3/9 activities in HUVECs. The present study provides key information for understanding the effects of DHA on endothelial cells, which is required for investigating its potential for clinic application as a chemotherapeutic agent.
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Disrupting tumor angiogenesis serves as an important strategy for cancer therapy. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has exhibited potent anti-angiogenic activity. However, the molecular mechanisms underlying this effect have not been fully understood. The present study aimed to investigate the role of DHA on endothelial cell proliferation, the essential process in angiogenesis. Human umbilical vein endothelial cells (HUVECs) treated with DHA were examined for proliferation, apoptosis and activation of the extracellular signal-regulated kinase (ERK) signaling pathway. Proliferation of HUVECs was inhibited by 20 µM DHA without induction of apoptosis. DHA also reduced the phosphorylation of ERK1/2, and downregulated the mRNA and protein expression of ERK1/2 in HUVECs. In addition, DHA suppressed the transcription and protein expression of ERK1/2 downstream effectors c-Fos and c-Myc. Electrical cell-substrate impedance sensing real-time analysis demonstrated that ERK signaling inhibitor PD98059 comprises the anti-proliferative effects of DHA. Thus, DHA inhibits endothelial cell proliferation by suppressing the ERK signaling pathway. The present study strengthened the potential of DHA as an angiogenesis inhibitor for cancer treatment.
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Artemisininas/farmacología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Endoteliales de la Vena Umbilical Humana , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , FosforilaciónRESUMEN
The anti-malarial agent dihydroartemisinin (DHA) has strong anti-angiogenic activity. This study aimed to investigate the molecular mechanism underlying this effect of DHA on angiogenesis. We found that DHA shows a dose-dependent inhibition of proliferation and migration of in HUVECs. DHA specifically down-regulates the mRNA and protein expression of VEGFR2 in endothelial cells. Treatment with DHA increases IκB-α protein and blocks nuclear translocation of NF-κB p65. In addition, DHA directly regulates VEGFR2 promoter activity through p65 binding motif, and decreases the binding activity of p65 and VEGFR2 promoter, suggesting defective NF-κB signaling may underlie the observed effects of DHA on VEGFR2 expression. In the presence of the NF-κB inhibitor PDTC, DHA could not further repress VEGFR2. Co-treatment with PDTC and DHA produced minimal changes compared to the effects of either drug alone in in vitro angiogenesis assays. Similar findings were found in vivo through a mouse retinal neovascularization model examining the effects of PDTC and DHA. Our data suggested that DHA inhibits angiogenesis largely through repression of the NF-κB pathway. DHA is well tolerated, and therefore may be an ideal candidate to use clinically as an angiogenesis inhibitor for cancer treatment.