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Introduction: Hepatic steatosis is a hepatic pathological change closely associated with metabolic disorders, commonly observed in various metabolic diseases such as metabolic syndrome (MetS), with a high global prevalence. Dai-Zong-Fang (DZF), a traditional Chinese herbal formula, is widely used in clinical treatment for MetS, exhibiting multifaceted effects in reducing obesity and regulating blood glucose and lipids. This study aims to explore the mechanism by which DZF modulates the gut microbiota and reduces hepatic steatosis based on the gut-liver axis. Methods: This study utilized db/db mice as a disease model for drug intervention. Body weight and fasting blood glucose were monitored. Serum lipid and transaminase levels were measured. Insulin tolerance test was conducted to assess insulin sensitivity. Hematoxylin and eosin (HE) staining was employed to observe morphological changes in the liver and intestine. The degree of hepatic steatosis was evaluated through Oil Red O staining and hepatic lipid determination. Changes in gut microbiota were assessed using 16S rRNA gene sequencing. Serum lipopolysaccharide (LPS) levels were measured by ELISA. The expression levels of intestinal tight junction proteins, intestinal lipid absorption-related proteins, and key proteins in hepatic lipid metabolism were examined through Western blot and RT-qPCR. Results: After DZF intervention, there was a decrease in body weight, alleviation of glucose and lipid metabolism disorders, reduction in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and mitigation of insulin resistance in mice. DZF significantly modulated the diversity of the gut microbiota, with a notable increase in the abundance of the Bacteroidetes phylum. PICRUSt indicated that DZF influenced various functions in gut microbiota, including carbohydrate and amino acid metabolism. Following DZF intervention, serum LPS levels decreased, intestinal pathological damage was reduced, and the expression of intestinal tight junction protein occludin was increased, while the expression of intestinal lipid absorption-related proteins cluster of differentiation 36 (CD36) and apolipoprotein B48 (ApoB48) were decreased. In the liver, DZF intervention resulted in a reduction in hepatic steatosis and lipid droplets, accompanied by a decrease fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1) and fatty acid transport protein 2 (FATP2). Conversely, there was an increase in the expression of the fatty acid oxidation-related enzyme carnitine palmitoyltransferase-1ð (CPT-1ð). Conclusion: DZF can regulate the structure and function of the intestinal microbiota in db/db mice. This ameliorates intestinal barrier damage and the detrimental effects of endotoxemia on hepatic metabolism. DZF not only inhibits intestinal lipid absorption but also improves hepatic lipid metabolism from various aspects, including de novo lipogenesis, fatty acid uptake, and fatty acid oxidation. This suggests that DZF may act on the liver and intestine as target organs, exerting its effects by improving the intestinal microbiota and related barrier and lipid absorption functions, ultimately ameliorating hepatic steatosis and enhancing overall glucose and lipid metabolism.
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ETHNOPHARMACOLOGICAL RELEVANCE: Atherosclerosis (AS), a lipid-induced inflammatory condition of the arteries, is a primary contributor to atherosclerotic cardiovascular diseases including stroke. Arctium lappa L. leaf (ALL), an edible and medicinal herb in China, has been documented and commonly used for treating stroke since the ancient times. However, the elucidations on its anti-AS effects and molecular mechanism remain insufficient. AIM OF THE STUDY: To investigate the AS-ameliorating effects and the underlying mechanism of action of an ethanolic extract of leaves of Arctium lappa L. (ALLE). MATERIALS AND METHODS: ALLE was reflux extracted using with 70% ethanol. An HPLC method was established to monitor the quality of ALLE. High fat diet (HFD) and vitamin D3-induced experimental AS in rats were used to determine the in vivo effects; and oxidized low-density lipoprotein-induced RAW264.7 macrophage foam cells were used for in vitro assays. Simvatatin was used as positive control. Biochemical assays were implemented to ascertain the secretions of lipids and pro-inflammatory mediators. Haematoxylin-eosin (H&E) and Oil red O stains were employed to assess histopathological alterations and lipid accumulation conditions, respectively. CCK-8 assays were used to measure cytotoxicity. Immunoblotting assay was conducted to measure protein levels. RESULTS: ALLE treatment significantly ameliorated lipid deposition and histological abnormalities of aortas and livers in AS rats; improved the imbalances of serum lipids including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C); notably attenuated serum concentrations of inflammation-associated cytokines/molecules including TNF-α, IL-6, IL-1ß, VCAM-1, ICAM-1and MMP-9. Mechanistic studies demonstrated that ALLE suppressed the phosphorylation/activation of PI3K, Akt and NF-κB in AS rat aortas and in cultured foam cells. Additionally, the PI3K agonist 740Y-P notably reversed the in vitro inhibitory effects of ALLE on lipid deposition, productions of TC, TNF-α and IL-6, and protein levels of molecules of PI3K/Akt and NF-κB singnaling pathways. CONCLUSIONS: ALLE ameliorates HFD- and vitamin D3-induced experimental AS by modulating lipid metabolism and inflammatory responses, and underlying mechanisms involves inhibition of the PI3K/Akt and NF-κB singnaling pathways. The findings of this study provide scientific justifications for the traditional application of ALL in managing atherosclerotic diseases.
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Arctium , Aterosclerosis , Fragmentos de Péptidos , Receptores del Factor de Crecimiento Derivado de Plaquetas , Accidente Cerebrovascular , Ratas , Animales , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Fosfatidilinositol 3-Quinasas/metabolismo , Metabolismo de los Lípidos , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Aterosclerosis/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Extractos Vegetales/química , Lípidos , Colesterol/farmacología , Etanol/farmacología , Lipoproteínas LDL/metabolismo , Colecalciferol/farmacología , Colecalciferol/uso terapéuticoRESUMEN
AIM: To evaluate the clinical application value of the artificial intelligence assisted pathologic myopia (PM-AI) diagnosis model based on deep learning. METHODS: A total of 1156 readable color fundus photographs were collected and annotated based on the diagnostic criteria of Meta-pathologic myopia (PM) (2015). The PM-AI system and four eye doctors (retinal specialists 1 and 2, and ophthalmologists 1 and 2) independently evaluated the color fundus photographs to determine whether they were indicative of PM or not and the presence of myopic choroidal neovascularization (mCNV). The performance of identification for PM and mCNV by the PM-AI system and the eye doctors was compared and evaluated via the relevant statistical analysis. RESULTS: For PM identification, the sensitivity of the PM-AI system was 98.17%, which was comparable to specialist 1 (P=0.307), but was higher than specialist 2 and ophthalmologists 1 and 2 (P<0.001). The specificity of the PM-AI system was 93.06%, which was lower than specialists 1 and 2, but was higher than ophthalmologists 1 and 2. The PM-AI system showed the Kappa value of 0.904, while the Kappa values of specialists 1, 2 and ophthalmologists 1, 2 were 0.968, 0.916, 0.772 and 0.730, respectively. For mCNV identification, the AI system showed the sensitivity of 84.06%, which was comparable to specialists 1, 2 and ophthalmologist 2 (P>0.05), and was higher than ophthalmologist 1. The specificity of the PM-AI system was 95.31%, which was lower than specialists 1 and 2, but higher than ophthalmologists 1 and 2. The PM-AI system gave the Kappa value of 0.624, while the Kappa values of specialists 1, 2 and ophthalmologists 1 and 2 were 0.864, 0.732, 0.304 and 0.238, respectively. CONCLUSION: In comparison to the senior ophthalmologists, the PM-AI system based on deep learning exhibits excellent performance in PM and mCNV identification. The effectiveness of PM-AI system is an auxiliary diagnosis tool for clinical screening of PM and mCNV.
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Dactylogyrus is one of the most common parasitic diseases in fish and causes huge losses to the aquaculture industry. With the advantages of safety, low toxicity and easy degradation, plant-derived drugs are ideal for the creation of green aquatic ingredients. The use of plant-derived drugs in aquaculture is limited by their low content and high processing costs, which is a challenge that can be solved by the chemical synthesis of plant-derived drugs. Eleven new coumarin derivatives were synthesized and assessed for their anthelmintic activity in this study. Among them, the derivative 7-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (N11) has good anthelmintic activity and its mean anthelmintic efficacy against D. intermedius at a concentration of 10 µM reached 99.84%, which is even better than the anthelmintic activity of the positive control mebendazole. Further studies showed that N11 had concentration values of 3.31 and 1.94 µM for 50% maximal effect (EC50 ) against D. intermedius at 24 and 48 h, respectively. Furthermore, scanning electron microscopy revealed that N11 caused damage to D. intermedius. What is more noteworthy is that a substantial reduction in the ATP content of the parasite was observed following in vitro and in vivo administration of N11. Moreover, it was also found that N11 was able to inhibit the horizontal transmission of D. intermedius. Furthermore, real-time quantitative PCR analysis was utilized to determine the expression profile of genes associated with anti-inflammatory cytokines (IL-10, TGF-ß and IL-4) in goldfish. In all examined organs, it was observed that the expression of anti-inflammatory cytokines increased subsequent to treatment with N11, according to the results. Thus, these results all suggest that N11 possesses good anthelmintic activity and is a potentially effective agent for the control of D. intermedius.
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Antihelmínticos , Enfermedades de los Peces , Parásitos , Trematodos , Animales , Enfermedades de los Peces/tratamiento farmacológico , Enfermedades de los Peces/parasitología , Antihelmínticos/farmacología , Antihelmínticos/uso terapéutico , Citocinas , Cumarinas/farmacología , Cumarinas/uso terapéuticoRESUMEN
Diabetes is generally accompanied by difficult-to-heal wounds, which often lead to permanent disability and even death of patients. Because of the abundance of a variety of growth factors, platelet rich plasma (PRP) has been proven to have great clinical potential for diabetic wound treatment. However, how to suppress the explosive release of its active components while realizing adaptability to different wounds remains important for PRP therapy. Here, an injectable, self-healing, and non-specific tissue-adhesive hydrogel formed by oxidized chondroitin sulfate and carboxymethyl chitosan was designed as an encapsulation and delivery platform for PRP. With a dynamic cross-linking structural design, the hydrogel can meet the clinical demands of irregular wounds with controllable gelation and viscoelasticity. Inhibition of PRP enzymolysis as well as sustained release of its growth factors is realized with the hydrogel, enhancing cell proliferation and migration in vitro. Notably, greatly accelerated healing of full thickness wounds of diabetic skins is enabled by promoting the formation of granulation tissues, collagen deposition and angiogenesis as well as reducing inflammation in vivo. This self-healing and extracellular matrix-mimicking hydrogel provides powerful assistance to PRP therapy, enabling its promising applications for the repair and regeneration of diabetic wounds.
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Diabetes Mellitus , Plasma Rico en Plaquetas , Humanos , Hidrogeles/farmacología , Hidrogeles/química , Cicatrización de Heridas , Piel , Péptidos y Proteínas de Señalización Intercelular , Plasma Rico en Plaquetas/químicaRESUMEN
Objective: Mucosal immunization was an effective defender against pathogens. Nasal vaccines could activate both systemic and mucosal immunity to trigger protective immune responses. However, due to the weak immunogenicity of nasal vaccines and the lack of appropriate antigen carriers, very few nasal vaccines have been clinically approved for human use, which was a major barrier to the development of nasal vaccines. Plant-derived adjuvants are promising candidates for vaccine delivery systems due to their relatively safe immunogenic properties. In particular, the distinctive structure of pollen was beneficial to the stability and retention of antigen in the nasal mucosa. Methods: Herein, a novel wild-type chrysanthemum sporopollenin vaccine delivery system loaded with a w/o/w emulsion containing squalane and protein antigen was fabricated. The unique internal cavities and the rigid external walls within the sporopollenin skeleton construction could preserve and stabilize the inner proteins. The external morphological characteristics were suitable for nasal mucosal administration with high adhesion and retention. Results: Secretory IgA antibodies in the nasal mucosa can be induced by the w/o/w emulsion with the chrysanthemum sporopollenin vaccine delivery system. Moreover, the nasal adjuvants produce a stronger humoral response (IgA and IgG) compared to squalene emulsion adjuvant. Mucosal adjuvant benefited primarily from prolongation of antigens in the nasal cavity, improvement of antigen penetration in the submucosa and promotion of CD8+ T cells in spleen. Disccusion: Based on effective delivering both the adjuvant and the antigen, the increase of protein antigen stability and the realization of mucosal retention, the chrysanthemum sporopollenin vaccine delivery system has the potential to be a promising adjuvant platform. This work provide a novel idea for the fabrication of protein-mucosal delivery vaccine.
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Inmunidad Mucosa , Vacunas , Humanos , Emulsiones/farmacología , Mucosa Nasal , Adyuvantes Inmunológicos/farmacología , AntígenosRESUMEN
Polydopamine (PDA) is a good adhesion agent for lots of gels inspired by the mussel, whereas hybrid organic-inorganic perovskites (HOIPs) usually exhibit extraordinary optoelectronic performance. Herein, mussel-inspired chemistry has been integrated with two-dimensional HOIPs first, leading to the preparation of new crystal (HDA)2PbBr4 (1) (DA = dopamine). The organic cation dopamine can be introduced into PDA resulting in a thin film of (HPDA)2PbBr4 (PDA-1). The dissolved inorganic components of layered perovskite in DMF solution together with H2O2 addition can facilitate DA polymerization greatly. More importantly, PDA-1 can inherit an excellent semiconductor property of HOIPs and robust adhesion of the PDA hydrogel resulting in a self-adhesive photoelectric coating on various interfaces.
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Adhesivos , Dopamina , Dopamina/química , Cementos de Resina , Polimerizacion , Peróxido de HidrógenoRESUMEN
BACKGROUND: Tourniquet pain, described as a dull, tight, poorly localized aching sensation, is common in conscious patients. Although various pain-reduction methods have been implemented, none are completely effective. Femoral periarterial block (FAB) has been shown to attenuate tourniquet-induced hypertension in patients undergoing general anesthesia. We aimed to test the feasibility of FAB in inhibiting thigh tourniquet pain in orthopedic patients under conscious sedation. METHODS: Forty-two patients (aged 18-64 years and ASA I-II) scheduled for below-knee orthopedic surgeries with an anticipated tourniquet duration of more than 40 min were recruited and received FAB (Group 1) or not (Group 2). The primary outcome was the occurrence of tourniquet pain. The onset time and severity of the tourniquet pain were recorded. Total doses of sedatives and analgesics administered intraoperatively and hemodynamic changes were documented. The occurrence of local anesthetic systemic toxicity was recorded. RESULTS: Kaplan-Meier time-to-event curves indicated an improved tourniquet tolerance and delayed pain onset. Tourniquet pain occurrence was lower in Group 1 than in Group 2 (30% vs. 95.5%, P=0.02). Tourniquet pain onset was delayed in Group 1 (80[67,84] min vs. 58[51.5,60] min, P<0.01). Fewer patients in Group 1 experienced severe pain (3(15%) vs. 18(81.8%), P<0.01), and less hemodynamic changes (2(10%) vs. 12(54.5%), P<0.01). Local anesthetic systemic toxicity was absent. CONCLUSIONS: FAB, applied with regional anesthesia in patients undergoing below-knee orthopedic surgeries, could reduce thigh tourniquet pain, stabilize blood pressure and heart rate, and prolong tourniquet duration.
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Anestésicos Locales , Lidocaína , Humanos , Muslo , Torniquetes , Dolor , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & control , Dolor Postoperatorio/epidemiologíaRESUMEN
Muscone is the main active compound of Moschus. In this paper, the cardioprotective effect of Muscone on acute myocardial ischemia (AMI) rats and its potential mechanisms were investigated. AMI rat models were established to evaluate the protective effect and antioxidative function of Muscone on the hearts. Moreover, Western blot analysis was conducted to quantify the phosphorylated PI3K and AKT levels in PI3K/Akt pathway for further investigating the mechanism of Muscone. Results showed that Muscone could markedly lessen the infarct size and myocardial injury, improve cardiac function, inhibit cardiomyocyte apoptosis and down-regulate serum reactive oxygen species level as indicated by the decreased MDA, BNP and c-TnI activities and the increased SOD, GSH-px, CAT activities and the expression of Bax protein. In addition, it was revealed that Muscone notably promoted the phosphorylation of PI3K and AKT. These findings denote that Muscone exerts a protective effect in heart via inhibition of oxidative stress and apoptosis, offering new insights into the treatment of CHD and the clinical application of Muscone.
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Cicloparafinas , Isquemia Miocárdica , Transducción de Señal , Animales , Cicloparafinas/farmacología , Isquemia Miocárdica/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Proteína X Asociada a bcl-2/farmacologíaRESUMEN
Herein, N2-selective ß-thioalkylation of benzotriazoles with unactivated alkenes and styrenes is reported. The N2-selective ß-thioalkylation of benzotriazoles is highly stereospecific and works under simple and mild conditions, exhibiting excellent functional group tolerance. The high N2-selectivity is a consequence of the combination of hydrogen bonding and Lewis acid/base activation, which reverses the N2-position to be favored for alkylation.
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Ambient air quality forecasting evaluation plays an important role in improving forecasting capability. In order to provide better support for refined air quality management, with reference to the UK air quality forecasting evaluation method, this study divided six air quality index (AQI) levels into 12 half-levels and explored AQI, PM2.5, and O3-8h concentration forecasting evaluation based on the half-level method in "2+26" cities during 2020. Comparison with the AQI range forecasting and AQI level range forecasting evaluation showed that the half-level forecasting evaluation method could combine these two indicators into one, providing feasibility and application value in operational air quality forecasting evaluation. Specific half-level forecasting evaluation showed that the forecasting effect of AQI and O3-8h concentration at the low and high levels was significantly worse than that of the middle levels in "2+26" cities. The forecasting effect of the PM2.5 concentration was relatively stable in different half-levels. The monthly variation curves of AQI, PM2.5, and O3-8h concentration forecasting accuracy exhibited a bimodal pattern, first rising and then falling and a flat pattern, respectively. The overestimate of PM2.5 concentration forecasting was significant in each month. The accuracy gaps of AQI and O3-8h concentration forecasting in different cities was relatively small; however, the PM2.5 concentration forecasting accuracy fluctuated greatly. The AQI forecasting accuracies of Beijing and Tianjin were higher than that of neighboring provinces. Additionally, the PM2.5 and O3-8h concentration forecasting effects in Beijing and Henan province were relatively the best.
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Contaminación del Aire , Monitoreo del Ambiente , Ciudades , Monitoreo del Ambiente/métodos , Material Particulado/análisisRESUMEN
BACKGROUND: Early enteral nutrition (EN) after abdominal surgery can improve the prognosis of patients. However, the high feeding intolerance (FI) rate is the primary factor impeding postoperative EN. METHODS: Sixty-seven patients who underwent radical subtotal or total gastrectomy for gastric cancer (GC) were randomly allocated to the preoperative oral nutritional supplement group (ONS group) or dietary advice alone (DA group). Both groups were fed via nasojejunal tubes (NJs) from the first day after surgery to the fifth day. The primary endpoint is the FI rate. RESULTS: Of the patients, 66 completed the trial (31 in the ONS group, 35 in the DA group). The FI rate in the ONS group was lower than that in the DA group (25.8% vs. 31.4%, p = 0.249). The postoperative five-day 50% energy compliance rate in the ONS group was higher than that in the DA group (54.8% vs. 48.6%, p = 0.465). The main gastrointestinal intolerance symptoms were distension (ONS vs. DA: 45.2% vs. 62.9, p = 0.150) and abdominal pain (ONS vs. DA: 29.0% vs. 45.7%, p = 0.226). Postoperative nausea/vomiting rate and heartburn/reflux rate were similar between the two groups. We noted no difference in perioperative serum indices, short-term prognosis or postoperative complication rates between the two groups. CONCLUSIONS: The study shows that short-term preoperative ONS cannot significantly improve FI and the energy compliance rate in the early stage after radical gastrectomy.
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Nutrición Enteral , Neoplasias Gástricas , Humanos , Recién Nacido , Pronóstico , Estudios Prospectivos , Método Simple Ciego , Neoplasias Gástricas/cirugíaRESUMEN
OBJECTIVE: The present study aimed to investigate whether the drug nicorandil can improve cardiac remodeling after myocardial infarction (MI) and the underlying mechanisms. METHODS: Mouse MI was established by the ligation of the left anterior descending coronary artery and H9C2 cells were cultured to investigate the underlying molecular mechanisms. The degree of myocardial collagen (Col) deposition was evaluated by Masson's staining. The expressions of nucleolin, autophagy and myocardial remodeling-associated genes were measured by Western blotting, qPCR, and immunofluorescence. The apoptosis of myocardial tissue cells and H9C2 cells were detected by TUNEL staining and flow cytometry, respectively. Autophagosomes were observed by transmission electron microscopy. RESULTS: Treatment with nicorandil mitigated left ventricular enlargement, improved the capacity of myocardial diastolic-contractility, decreased cardiomyocyte apoptosis, and inhibited myocardial fibrosis development post-MI. Nicorandil up-regulated the expression of nucleolin, promoted autophagic flux, and decreased the expressions of TGF-ß1 and phosphorylated Smad2/3, while enhanced the expression of BMP-7 and phosphorylated Smad1 in myocardium. Nicorandil decreased apoptosis and promoted autophagic flux in H2O2-treated H9C2 cells. Autophagy inhibitors 3-methyladenine (3MA) and chloroquine diphosphate salt (CDS) alleviated the effects of nicorandil on apoptosis. Knockdown of nucleolin decreased the effects of nicorandil on apoptosis and nicorandil-promoted autophagic flux of cardiomyocytes treated with H2O2. CONCLUSIONS: Treatment with nicorandil alleviated myocardial remodeling post-MI through up-regulating the expression of nucleolin, and subsequently promoting autophagy, followed by regulating TGF-ß/Smad signaling pathway.
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Infarto del Miocardio , Nicorandil , Animales , Apoptosis , Autofagia , Peróxido de Hidrógeno/farmacología , Ratones , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Nicorandil/farmacología , Nicorandil/uso terapéutico , Fosfoproteínas , Proteínas de Unión al ARN , Remodelación Ventricular , NucleolinaRESUMEN
The PM2.5 forecast models of 95 cities in Beijing-Tianjin-Hebei and its surrounding cities (BTH); the Fenwei Plain (FWP); the border area of Jiangsu, Anhui, Shandong, and Henan (JASH); and the Yangtze River Delta (YRD) regions were established using BP neural network models, and the forecast was carried out for the next seven days in the autumn and winter in 2020. By comparing the forecast results of the BP neural network models, numerical model, and artificial correction, the PM2.5 forecast effects of the three methods were analyzed and evaluated. The results showed:â The performance of the short-term forecast based on the BP neural network was relatively good but was reduced in the medium and long term and systematically overestimated in four regions. The numerical model effects were lower than those of the BP neural network models. â¡ The accuracy rates of the PM2.5 forecast concentration by the three methods were generally low in the four regions, with an average of less than 50%, and the accuracy values in order from high to low were the BP neural network models, artificial correction, and the numerical model. The accuracy rates of IAQI levels of PM2.5 were significantly improved by the three methods, and the averages were above 65% in the first four days. The effects of the BP neural network models and artificial correction were similar, which were generally higher than those of the numerical model. ⢠The numerical model had good effects in the BTH, JASH, and YRD regions, whereas it was the worst when forecasting moderately and above-polluted days in the FWP region. The BP neural network model had a good performance when forecasting short-term PM2.5 in the BTH, JASH, and FWP regions, whereas it was poor in the YRD region. In general, the performance of artificial correction was relatively good when forecasting moderate-level days and was close to the BP neural network model when forecasting heavily polluted days.
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Contaminantes Atmosféricos , Contaminación del Aire , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , China , Monitoreo del Ambiente , Redes Neurales de la Computación , Material Particulado/análisisRESUMEN
The COVID-19, caused by SARS-CoV-2, is threatening public health, and there is no effective treatment. In this study, we have implemented a multi-targeted anti-viral drug design strategy to discover highly potent SARS-CoV-2 inhibitors, which simultaneously act on the host ribosome, viral RNA as well as RNA-dependent RNA polymerases, and nucleocapsid protein of the virus, to impair viral translation, frameshifting, replication, and assembly. Driven by this strategy, three alkaloids, including lycorine, emetine, and cephaeline, were discovered to inhibit SARS-CoV-2 with EC50 values of low nanomolar levels potently. The findings in this work demonstrate the feasibility of this multi-targeting drug design strategy and provide a rationale for designing more potent anti-virus drugs.
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Antivirales/farmacología , Diseño de Fármacos , SARS-CoV-2/efectos de los fármacos , Animales , Antivirales/síntesis química , Antivirales/química , Línea Celular , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
An epidemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. SARS-CoV-2 relies on its spike protein to invade host cells by interacting with the human receptor protein Angiotensin-Converting Enzymes 2 (ACE2). Therefore, designing an antibody or small-molecular entry blockers is of great significance for virus prevention and treatment. This study identified five potential small molecular anti-virus blockers via targeting SARS-CoV-2 spike protein by combining in silico technologies with in vitro experimental methods. The five molecules were natural products that binding to the RBD domain of SARS-CoV-2 was qualitatively and quantitively validated by both native Mass Spectrometry (MS) and Surface Plasmon Resonance (SPR). Anti-viral activity assays showed that the optimal molecule, H69C2, had a strong binding affinity (dissociation constant KD) of 0.0947 µM and anti-virus IC50 of 85.75 µM.
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Tratamiento Farmacológico de COVID-19 , Glicoproteína de la Espiga del Coronavirus , Humanos , Unión Proteica , SARS-CoV-2RESUMEN
Reverse prediction and molecular docking techniques were employed to evaluate the feasibility of reniformin A(RA) as an anti-tumor leading compound. Based on the reverse prediction, network pharmacology was used to construct a "disease-compound-target-pathway" network. Thirty-nine tumor-related targets of RA were predicted, which participated in the regulation of multiple cellular activities such as apoptosis, cell cycle, and tumor metastasis, and regulated estrogen signal transduction and inflammatory response. Discovery Studio 2020 was adopted for molecular docking and toxicity prediction(TOPKAT). As revealed by the results, the binding affinity of RA with the tumor-related targets ABL1, ESR1, SRC and BCL-XL was stronger than that of oridonin(OD), while its mutagenicity, rodent carcinogenesis, and oral LD_(50) in rats were all inferior to that of OD. Furthermore, in vitro experiments were performed to confirm the anti-tumor activity of RA, and the mechanism was preliminarily discussed. The results demonstrated that RA was superior to OD in cytotoxicity, inhibition of cell colony formation, and induction of apoptosis. RA, possessing potent anti-tumor activity, is expected to be a new anti-tumor leading compound.
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Medicamentos Herbarios Chinos , Neoplasias , Animales , Medicamentos Herbarios Chinos/farmacología , Plomo , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Ratas , Transducción de SeñalRESUMEN
OBJECTIVE: To evaluate the clinical efficacy and long-term outcomes associated with the treatment of hepatic vein (HV)-type Budd-Chiari syndrome (BCS) via accessory HV (AHV) recanalization. METHODS: In total, 26 HV-type BCS patients underwent AHV recanalization between July 2014 and December 2019 at our hospital, while 73 HV-type BCS patients without compensatory AHV underwent main HV (MHV) recanalization and served as controls in the present study. Short- and long-term clinical outcomes were compared. RESULTS: AHV and MHV recanalization approaches were both associated with 100% technical success rates, with one recanalization procedure being performed per patient. Respective clinical success rates for the AHV and MHV recanalization approaches were 96.2% and 94.5% (P = 0.744). Re-obstruction rates were comparable between these two approaches at 20% and 34.8%, respectively (P = 0.17). Primary cumulative 1-, 2-, and 5-year patency rates in the AHV group were 96.0%, 91.6%, and 76.3%, respectively, whereas in the MHV group, these three respective rates were 87.0%, 78.6%, and 58.6% (P = 0.048). Secondary cumulative 1-, 2-, and 5-year patency rates in the AHV group were 96.0%, 96.0%, and 96.0%, respectively, whereas in the MHV group, they were 97.1%, 97.1%, and 81.8%, respectively (P = 0.289). Cumulative 1-, 2-, and 5-year survival rates for AHV group patients were 96.0%, 96.0%, and 96.0%, respectively, while for the MHV group, these respective rates were 98.6%, 95.2%, and 89.7% (P = 0.462). CONCLUSION: HV-type BCS can be safely and effectively treated via AHV recanalization, which may achieve longer patency relative to MHV recanalization.