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Aim: The study aimed to investigate the interaction effect between blood selenium levels and stroke history on all-cause mortality. Methods: In this retrospective cohort study, participant data were obtained from the National Health and Nutrition Examination Survey (NHANES) 2011-2018. The covariates were screened via the backward selection method in weighted univariate and multivariate Cox regression models. Weighted univariate and multivariate Cox regression models were conducted to investigate the association of blood selenium and stroke history with all-cause mortality. The results were expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). The synergy index (SI) was used to assess the assistive interaction. The association was further explored in different gender groups. Results: Totally, 8,989 participants were included, of whom 861 (9.57%) died. Participants with blood selenium ≥192.96 ug/L were associated with lower odds of all-cause mortality (HR = 0.70, 95% CI: 0.58-0.84), whereas those with a stroke history were associated with a higher risk of all-cause mortality (HR = 1.57, 95% CI: 1.15-2.16). Compared to participants with blood selenium ≥192.96 ug/L and non-stroke history, participants with both blood selenium < 192.96 ug/L and stroke history had a higher all-cause mortality risk (HR = 2.31, 95% CI: 1.62-3.29; SI = 0.713, 95% CI: 0.533-0.952). All participants with blood selenium < 192.96 ug/L and stroke history were related to higher all-cause mortality risk (HR = 1.61, 95% CI: 1.21-2.13). In males, the interaction effect of blood selenium and stroke history on all-cause mortality (HR = 2.27, 95% CI: 1.50-3.46; SI = 0.651, 95% CI: 0.430-0.986) increased twice. Conclusion: Blood selenium and stroke history have an interaction effect on all-cause mortality. Increasing selenium-rich food or supplement intake, especially for individuals with a stroke history, may improve poor prognosis.
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Background: Isoniazid-resistant, rifampicin-susceptible tuberculosis (Hr-TB) globally exhibits a high prevalence and serves as a potential precursor to multidrug-resistant tuberculosis (MDR-TB). Recognizing the spatial distribution of Hr-TB and identifying associated factors can provide strategic entry points for interventions aimed at early detection of Hr-TB and prevention of its progression to MDR-TB. This study aims to analyze spatial patterns and identify socioeconomic, demographic, and healthcare factors associated with Hr-TB in Shanghai at the county level. Method: We conducted a retrospective study utilizing data from TB patients with available Drug Susceptible Test (DST) results in Shanghai from 2010 to 2016. Spatial autocorrelation was explored using Global Moran's I and Getis-Ord Gi∗ statistics. A Bayesian hierarchical model with spatial effects was developed using the INLA package in R software to identify potential factors associated with Hr-TB at the county level. Results: A total of 8,865 TB patients with DST were included in this analysis. Among 758 Hr-TB patients, 622 (82.06%) were new cases without any previous treatment history. The drug-resistant rate of Hr-TB among new TB cases in Shanghai stood at 7.20% (622/8014), while for previously treated cases, the rate was 15.98% (136/851). Hotspot areas of Hr-TB were predominantly situated in southwestern Shanghai. Factors positively associated with Hr-TB included the percentage of older adult individuals (RR = 3.93, 95% Crl:1.93-8.03), the percentage of internal migrants (RR = 1.35, 95% Crl:1.15-1.35), and the number of healthcare institutions per 100 population (RR = 1.17, 95% Crl:1.02-1.34). Conclusion: We observed a spatial heterogeneity of Hr-TB in Shanghai, with hotspots in the Songjiang and Minhang districts. Based on the results of the models, the internal migrant population and older adult individuals in Shanghai may be contributing factors to the emergence of areas with high Hr-TB notification rates. Given these insights, we advocate for targeted interventions, especially in identified high-risk hotspots and high-risk areas.
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Migrantes , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Idoso , China/epidemiologia , Estudos Retrospectivos , Isoniazida/farmacologia , Isoniazida/uso terapêutico , Teorema de Bayes , Tuberculose Resistente a Múltiplos Medicamentos/diagnósticoRESUMO
[This corrects the article DOI: 10.3389/fpubh.2024.1354515.].
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Backgrounds: The diagnostic delay of tuberculosis (TB) contributes to further transmission and impedes the implementation of the End TB Strategy. Therefore, we aimed to describe the characteristics of patient delay, health system delay, and total delay among TB patients in Shanghai, identify areas at high risk for delay, and explore the potential factors of long delay at individual and spatial levels. Method: The study included TB patients among migrants and residents in Shanghai between January 2010 and December 2018. Patient and health system delays exceeding 14 days and total delays exceeding 28 days were defined as long delays. Time trends of long delays were evaluated by Joinpoint regression. Multivariable logistic regression analysis was employed to analyze influencing factors of long delays. Spatial analysis of delays was conducted using ArcGIS, and the hierarchical Bayesian spatial model was utilized to explore associated spatial factors. Results: Overall, 61,050 TB patients were notified during the study period. Median patient, health system, and total delays were 12 days (IQR: 3-26), 9 days (IQR: 4-18), and 27 days (IQR: 15-43), respectively. Migrants, females, older adults, symptomatic visits to TB-designated facilities, and pathogen-positive were associated with longer patient delays, while pathogen-negative, active case findings and symptomatic visits to non-TB-designated facilities were associated with long health system delays (LHD). Spatial analysis revealed Chongming Island was a hotspot for patient delay, while western areas of Shanghai, with a high proportion of internal migrants and industrial parks, were at high risk for LHD. The application of rapid molecular diagnostic methods was associated with reduced health system delays. Conclusion: Despite a relatively shorter diagnostic delay of TB than in the other regions in China, there was vital social-demographic and spatial heterogeneity in the occurrence of long delays in Shanghai. While the active case finding and rapid molecular diagnosis reduced the delay, novel targeted interventions are still required to address the challenges of TB diagnosis among both migrants and residents in this urban setting.
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Migrantes , Tuberculose , Feminino , Humanos , Idoso , Diagnóstico Tardio , Teorema de Bayes , China/epidemiologia , Tuberculose/diagnóstico , Tuberculose/epidemiologiaRESUMO
In this study, a novel reciprocating tribometer, in which the frictional pairs were immersed in liquid nitrogen directly, was developed to simulate the cryogenic fluid lubrication. To eliminate the negative influence of extremely low temperature on force sensors, a transfer structure of force-deformation, consisting of cantilever beams and measurement beams, was designed specially. It can transfer the structural deformations caused by the loading force and the friction force from the cryogenic zone to the room-temperature zone. The corresponding measurement principle was discussed in detail, and the linear relationship between the structural deformation and the applied force was verified theoretically. Through static calibration experiments, the fitting relationship between the deformations and the loading/friction force was acquired for the developed tribometer. In final, a preliminary investigation of graphite materials was conducted on the tribometer to compare the room-temperature and cryogenic tribological behaviors.
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Since time immemorial human beings have constantly been fighting against viral infections. The ongoing and devastating coronavirus disease 2019 pandemic represents one of the most severe and most significant public health emergencies in human history, highlighting an urgent need to develop broad-spectrum antiviral agents. Salicylamide (2-hydroxybenzamide) derivatives, represented by niclosamide and nitazoxanide, inhibit the replication of a broad range of RNA and DNA viruses such as flavivirus, influenza A virus, and coronavirus. Moreover, nitazoxanide was effective in clinical trials against different viral infections including diarrhea caused by rotavirus and norovirus, uncomplicated influenza A and B, hepatitis B, and hepatitis C. In this review, we summarize the broad antiviral activities of salicylamide derivatives, the clinical progress, and the potential targets or mechanisms against different viral infections and highlight their therapeutic potential in combating the circulating and emerging viral infections in the future.
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COVID-19 , Humanos , Tiazóis/farmacologia , Nitrocompostos/farmacologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Salicilamidas/farmacologia , Replicação ViralRESUMO
Sirt6 activation has emerged as a promising drug target for the treatment of various human diseases, while only limited Sirt6 activators have been reported. Herein, a series of novel pyrrolo[1,2-a]quinoxaline-based derivatives have been identified as potent and selective Sirt6 activators with low cytotoxicity. Sirt6-knockdown findings have validated the on-target effects of this class of Sirt6 activators. Docking studies indicate the protonated nitrogen on the side chain of 38 forms π-cation interactions with Trp188, further stabilizing it into this extended binding pocket. New compounds 35, 36, 38, 46, 47, and 50 strongly repressed LPS-induced proinflammatory cytokine/chemokine production, while 38 also significantly suppressed SARS-CoV-2 infection with an EC50 value of 9.3 µM. Moreover, compound 36 significantly inhibited the colony formation of cancer cells. These new molecules may serve as useful pharmacological tools or potential therapeutics against cancer, inflammation, and infectious diseases.
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COVID-19 , Sirtuínas , Humanos , Quinoxalinas/farmacologia , Quinoxalinas/química , SARS-CoV-2/metabolismo , Sirtuínas/metabolismoRESUMO
BACKGROUND & AIMS: Intestinal fibrosis is a significant complication of Crohn's disease (CD). Gut microbiota reactive Th17 cells are crucial in the pathogenesis of CD; however, how Th17 cells induce intestinal fibrosis is still not completely understood. METHODS: In this study, T-cell transfer model with wild-type (WT) and Areg-/- Th17 cells and dextran sulfate sodium (DSS)-induced chronic colitis model in WT and Areg-/- mice were used. CD4+ T-cell expression of AREG was determined by quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of AREG on proliferation/migration/collagen expression in human intestinal myofibroblasts was determined. AREG expression was assessed in healthy controls and patients with CD with or without intestinal fibrosis. RESULTS: Although Th1 and Th17 cells induced intestinal inflammation at similar levels when transferred into Tcrßxδ-/- mice, Th17 cells induced more severe intestinal fibrosis. Th17 cells expressed higher levels of AREG than Th1 cells. Areg-/- mice developed less severe intestinal fibrosis compared with WT mice on DSS insults. Transfer of Areg-/- Th17 cells induced less severe fibrosis in Tcrßxδ-/- mice compared with WT Th17 cells. Interleukin (IL)6 and IL21 promoted AREG expression in Th17 cells by activating Stat3. Stat3 inhibitor suppressed Th17-induced intestinal fibrosis. AREG promoted human intestinal myofibroblast proliferation, motility, and collagen I expression, which was mediated by activating mammalian target of rapamycin and MEK. AREG expression was increased in intestinal CD4+ T cells in fibrotic sites compared with nonfibrotic sites from patients with CD. CONCLUSIONS: These findings reveal that Th17-derived AREG promotes intestinal fibrotic responses in experimental colitis and human patients with CD. Thereby, AREG might serve as a potential therapeutic target for fibrosis in CD.
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Colite , Doença de Crohn , Animais , Humanos , Camundongos , Anfirregulina/genética , Anfirregulina/metabolismo , Colite/metabolismo , Colágeno/metabolismo , Doença de Crohn/patologia , Sulfato de Dextrana/efeitos adversos , Fibrose , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Miofibroblastos/patologia , Células Th17/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Objective@#To assess the effectiveness of online and offline myopia prevention and control health education interventions using wearable behavior monitoring tools for non myopic elementary school students,so as to provide evidence based medical support for public health practices.@*Methods@#From May to June in 2021, two schools were selected within the same county in Jiangsu Province. School 1 conducted online and offline parental health education ( n =111), while school 2 exclusively conducted offline health education activities, representing the traditional intervention group ( n =122). Students from both schools underwent monitoring through wearable behavior tracking tools, with feedback reports provided (eye distance, eye duration, ambient light, and outdoor exposure time). Both schools relied on activities to carry out health education interventions, and organized the distribution of promotional materials and display boards. The intervention group also established WeChat groups to conduct online "Healthy Parents Action" (answering and providing feedback on health knowledge related to myopia prevention and control, myopia prevention and control, science popularization, etc. raised by parents). Evaluation criteria included myopia rates, post dilation refractive error, and axial length, with a tracking period of two years (from 2021 to 2023). Additionally, the study collected refractive parameters from non myopic students who did not participate in wearable tool monitoring in the 12 classes across the two schools.@*Results@#The baseline results indicated that there were no significant differences between the two groups in terms of refractive parameters and wearable tool monitoring results (including screen time, viewing distance, outdoor exposure time, and homework light exposure)( t/Z/χ 2=1.94,1.17,0.58,0.40,0.80,0.69,0.32, P >0.05). After a two-year follow up, in the first and second year, the myopia rate of the online Healthy Parents Action group (11.4%, 29.7%) were lower than that of the traditional group (26.2%, 50.9%), and the degree of refractive change in the intervention group [0.63(0.38,1.19)D] was lower than that of the traditional group [0.91(0.40,1.50)D], and all the differences were statistically significant( χ 2/ Z =4.93,10.37,2.29, P <0.05). However, there were no significant differences ( P >0.05) in axial length changes between the two groups over the twoyear intervention period. Nevertheless, in the second year, the axial length change in the traditional group [0.35(0.20,0.65)mm] was lower than that in the natural observation group [0.55(0.30,0.75)mm], and this difference was statistically significant ( Z =1.92, P <0.05).@*Conclusions@#Online and offline myopia prevention and control health education can effectively reduce myopia rates. The intervention mode combining wearable behavior monitoring tools with online health education may have better effects, but further large sample and multi center studies are needed to provide additional evidence and confirmation.
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The wear-resistant superhydrophobic (SHB) surfaces with excellent water-repellency ability were prepared by constructing a microtextured armor on an aluminum surface. With the assistance of laser-induced microtextures, the SHB surface could keep a longer water-repellency ability and a lower friction coefficient even after repeated friction tests under different loads and at different speeds. The mechanism of microtexture-protecting SHB coating is revealed based on both theoretical and elemental analysis. Additionally, we explore the relationship between the three-dimensional topography parameters (ISO 25178) and variation of water contact angles under different test recycles. The results show that the rough surface with appropriate Sa and higher Sku exhibits a better wear resistance, which is mainly related to the storing ability of SHB coating inside the microtextures. Moreover, the surface with appropriate Str exhibits excellent wear resistance, which is mainly associated with better chip-removal ability. Finally, the tribological properties of the microtextured SHB surface are researched. It is worth noting that compared with the microtextured surface without SHB coating and the SHB-coated surface without microtextures, the microtextured SHB surface has the lowest friction coefficient under dry friction because the SHB coating would largely decrease the surface energy of the interface, so the adhesion friction decreases. The microtexture armor on the surfaces would protect the wear of SHB coating, so the SHB coating inside the microtexture could continuously play the role of a particle lubricant at the sliding interface and decrease the friction force of the sliding interface. We believe that the present study would contribute to the further understanding of the constructing mechanism of anti-wear SHB surfaces and provide a new strategy for topography design of engineering surfaces with friction reduction properties.
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Zika virus (ZIKV) causes significant human diseases without specific therapy. Previously we found erythrosin B, an FDA-approved food additive, inhibited viral NS2B-NS3 interactions, leading to inhibition of ZIKV infection in cell culture. In this study, we performed pharmacokinetic and in vivo studies to demonstrate the efficacy of erythrosin B against ZIKV in 3D mini-brain organoid and mouse models. Our results showed that erythrosin B is very effective in abolishing ZIKV replication in the 3D organoid model. Although pharmacokinetics studies indicated that erythrosin B had a low absorption profile, mice challenged by a lethal dose of ZIKV showed a significantly improved survival rate upon oral administration of erythrosin B, compared to vehicle control. Limited structure-activity relationship studies indicated that most analogs of erythrosin B with modifications on the xanthene ring led to loss or reduction of inhibitory activities towards viral NS2B-NS3 interactions, protease activity and antiviral efficacy. In contrast, introducing chlorine substitutions on the isobenzofuran ring led to slightly increased activities, suggesting that the isobenzofuran ring is well tolerated for modifications. Cytotoxicity studies indicated that all derivatives are nontoxic to human cells. Overall, our studies demonstrated erythrosin B is an effective antiviral against ZIKV both in vitro and in vivo.
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SARS-CoV-2 has raised the alarm to search for effective therapy for this virus. To date several vaccines have been approved but few available drugs reported recently still need approval from FDA. Remdesivir was approved for emergency use only. In this report, the SARS-CoV-2 3CLpro was expressed and purified. By using a FRET-based enzymatic assay, we have screened a library consisting of more than 300 different niclosamide derivatives and identified three molecules JMX0286, JMX0301, and JMX0941 as potent allosteric inhibitors against SARS-CoV-2 3CLpro, with IC50 values similar to that of known covalent inhibitor boceprevir. In a cell-based antiviral assay, these inhibitors can inhibit the virus growth with EC50 in the range of 2-3 µM. The mechanism of action of JMX0286, JMX0301, and JMX0941 were characterized by enzyme kinetics, affinity binding and protein-based substrate digestion. Molecular docking, molecular dynamics (MD) simulations and hydration studies suggested that JMX0286, JMX0301, JMX0941 bind specifically to an allosteric pocket of the SARS-CoV-2 3CL protease. This study provides three potent compounds for further studies.
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Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Antivirais/química , Antivirais/farmacologia , Proteases 3C de Coronavírus , Cisteína Endopeptidases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptídeo Hidrolases/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais ViraisRESUMO
In our continued SAR study efforts, a series of O-alkylamino-tethered salicylamide derivatives with various amino acid linkers has been designed, synthesized, and biologically evaluated as potent anticancer agents. Five selected compounds with different representative chemical structures were found to show broad anti-proliferative activities, effective against all tested ER-positive breast cancer (BC) and triple-negative breast cancer (TNBC) cell lines with low micromolar IC50 values. Among these compounds, compound 9a (JMX0293) maintained good potency against MDA-MB-231 cell line (IC50 = 3.38 ± 0.37 µM) while exhibiting very low toxicity against human non-tumorigenic breast epithelial cell line MCF-10A (IC50 > 60 µM). Further mechanistic studies showed that compound 9a could inhibit STAT3 phosphorylation and contribute to apoptosis in TNBC MDA-MB-231 cells. More importantly, compound 9a significantly suppressed MDA-MB-231 xenograft tumor growth in vivo without significant toxicity, indicating its great potential as a promising anticancer drug candidate for further clinical development.
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Antineoplásicos , Neoplasias de Mama Triplo Negativas , Aminoácidos/farmacologia , Aminoácidos/uso terapêutico , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Salicilamidas , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Flaviviruses cause a significant amount of mortality and morbidity, especially in regions where they are endemic. A recent example is the outbreak of Zika virus throughout the world. Development of antiviral drugs against different viral targets is as important as the development of vaccines. During viral replication, a single polyprotein precursor (PP) is produced and further cleaved into individual proteins by a viral NS2B-NS3 protease complex together with host proteases. Flavivirus protease is one of the most attractive targets for development of therapeutic antivirals because it is essential for viral PP processing, leading to active viral proteins. In this review, we have summarized recent development in drug discovery targeting the NS2B-NS3 protease of flaviviruses, especially Zika, dengue, and West Nile viruses.
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A superhydrophobic (SHB) surface with an excellent self-cleaning ability is of great significance in both human survival and industrial fields. However, it is still a challenge to achieve large-area preparation of antiabrasive SHB surfaces with great mechanical robustness for broader applications. Thus, a kind of facile SHB coating with excellent liquid repellency and antiresistance is constructed by spraying a fluorine-free suspension consisting of epoxy resin, hexadecyltrimethoxysilane (HDTMS), and silica nanoparticles on a glass sheet. The SHB coating not only shows high adhesion on various materials but also has high water repellency under various test conditions, including tape peeling after blade scraping, sandpaper abrasion, and immersing in a complex environment. Additionally, the SHB spheres coated with laser-induced microstructure armor could form a continuous gas cavity during the water entry process, which is essential to prolonging the drag reduction ability of SHB coatings in liquid. Finally, the prepared robust SHB coatings have been employed in underwater buoyancy enhancement and reducing fluid resistance, which may open new avenues for underwater drag reduction in the field of marine applications.
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Mechanical power transmission (MPT) components are almost indispensable for every engineering equipment with motions. In order to satisfy some rigorous requirements, such as contamination free and zero leakage in the mixing process of biomedical solutions, a contactless MPT mode was proposed in this study based on the high-T c superconducting flux pinning mechanism. It makes the stirring container with the driven part inside that can be totally isolated from the external environment. The physical principle of superconducting flux pinning effect was discussed firstly to explore a feasible structural scheme, which can completely restrain all the six degrees of freedom (DOFs) by the linkage of magnetic flux lines. Then, a measurement device was established to verify and investigate the proposed contactless MPT mode. The motion can be transferred synchronously from the superconducting driving part to the permanent magnet driven part since they are unified as an integrity through the pinned flux lines. The influence of driving speed, cooling clearance, and magnet arrangement on the transmitted torque was analyzed. The verified contactless MPT mode also has the advantages of self-stability and overload protection, which can avoid the drawbacks of traditional permanent magnetic transmission mode.
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Cancer is one of the diseases with high morbidity and mortality on a global scale. Chemotherapy remains the primary treatment option for most cancer patients, including patients with progressive, metastatic, and recurrent diseases. To date, hundreds of chemotherapy drugs are used to treat various cancers, however, the anti-cancer efficacy and outcomes are largely hampered by chemotherapy-associated toxicity and acquired therapeutic resistance. The natural product (NP) oridonin has been extensively studied for its anti-cancer efficacy. More recently, oridonin has been shown to overcome drug resistance through multiple mechanisms, with yet-to-be-defined bona fide targets. Hundreds of oridonin derivative analogs (oridonalogs) have been synthesized and screened for improved potency, bioavailability, and other drug properties. Particularly, many of these oridonalogs have been tested against oridonin for tumor growth inhibition, potential for overcoming therapeutic resistance, and immunity modulation. This concise review seeks to summarize the advances in this field in light of identifying clinical-trial level drug candidates with the promise for treating progressive cancers and reversing chemoresistance.
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Based on the modern anatomy and physiology, the referred pain of myofascial trigger points of each muscle is integrated; compared with the twelve meridians as well as conception vessel and governor vessel, the similarity of their position and running course is observed. With the current research progress of myofascial trigger points and fasciology, based on the running course of referred pain of trigger points, combined with fascia mechanics, nerve and vascular, the location of acupoints and meridians, as well as the relationship between acupoints and meridians, are discussed.
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Meridianos , Pontos de Acupuntura , Humanos , Músculos , Dor Referida , Pontos-GatilhoRESUMO
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in young children, and specific treatment for RSV infections remains unavailable. We herein reported a series of substituted N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent RSV inhibitors. Among them, six low cytotoxic compounds (11, 12, 15, 22, 26, and 28) have been identified and selected to study associated inhibitory mechanisms. All these compounds suppressed not only the viral replication but also RSV-induced IRF3 and NF-κB activation and associated production of cytokines/chemokines. The two most potent compounds (15 and 22) were selected for further molecular mechanism studies associated with their suppression effect on RSV-activated IRF3 and NF-κB. These two compounds decreased RSV-induced IRF3 phosphorylation at serine 396 and p65 phosphorylation at serine 536 at both early and late infection phases. In addition, compound 22 also inhibited RSV-induced p65 phosphorylation at serine 276 at the late phase of RSV infection.
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Antivirais/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Inflamação/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Células A549 , Benzamidas/uso terapêutico , Humanos , Inflamação/etiologia , Infecções por Vírus Respiratório Sincicial/complicações , Vírus Sinciciais Respiratórios/fisiologiaRESUMO
Human adenoviruses (HAdVs) display a wide range of tissue tropism and can cause an array of symptoms from mild respiratory illnesses to disseminated and life-threatening infections in immunocompromised individuals. However, no antiviral drug has been approved specifically for the treatment of HAdV infections. Herein, we report our continued efforts to optimize salicylamide derivatives and discover compound 16 (JMX0493) as a potent inhibitor of HAdV infection. Compound 16 displays submicromolar IC50 values, a higher selectivity index (SI > 100) and 2.5-fold virus yield reduction compared to our hit compound niclosamide. Moreover, unlike niclosamide, our mechanistic studies suggest that the antiviral activity of compound 16 against HAdV is achieved through the inhibition of viral particle escape from the endosome, which bars subsequent uncoating and the presentation of lytic protein VI.