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1.
IUBMB Life ; 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35514074

RESUMO

Acetaminophen (APAP), one of the most widely used antipyretics and analgesics, principally results in acute liver injury (ALI) in developed countries when taken overdose. Ferulic acid (FA) is a natural polyphenol compound existing in many plants that has free radical scavenging, anti-inflammatory and liver-protective properties. However, the effect and underlying mechanism of FA in treating APAP-induced ALI have not been fully elucidated. Herein, we established a mouse model of APAP-induced ALI and used APAP-stimulated mouse primary hepatocytes for biochemical assessment of molecular parameters. After constructing networks and obtaining predicted targets from public databases, we further verified the putative pathways using immune-blotting assays both in vivo and in vitro. The reign of liver necrosis, serum levels of ALT and AST and oxidative stress in livers significantly elevated after APAP treatment, which were almost recovered back to normal levels by FA administration. In addition, FA significantly upregulated the APAP-induced downregulation of hepatic specific markers, including HNF4a, Foxa2 and ALB. Then, the results of functional enrichment indicated the possible signaling pathways of FA against APAP challenge, mainly including AMPK, autophagy, apoptosis and other metabolic process. Furthermore, FA markedly reversed the APAP-induced decline of mitochondria membrane potential, increased ratio of BAX/BCL2 and CASPASE 3 expression, and promoted autophagy flux of hepatocytes by upregulating AMPK phosphorylation, which were abrogated by a specific AMPK inhibitor, compound C. Overall, the hepatoprotective effect of FA on APAP-induced ALI might be associated with anti-oxidant and anti-apoptosis, which were at least partly attributed to AMPK-mediated protective autophagy.

2.
Artigo em Inglês | MEDLINE | ID: mdl-35526796

RESUMO

BACKGROUND & AIMS: Excessive acetaminophen (APAP) intake causes oxidative stress and inflammation, leading to fatal hepatotoxicity, however, the mechanism remains unclear. This study aims to explore the protective effects and detailed mechanisms of sirtuin 6 (SIRT6) in the defense against APAP-induced hepatotoxicity. METHODS: Hepatocyte-specific SIRT6 knockout (SIRT6-LKO) mice,farnesoid X receptor (FXR) knockout mice, and mice with genetic or pharmacological activation of SIRT6 were subjected to APAP to evaluate the critical role of SIRT6 in the pathogenesis of acute liver injury (ALI). RNA sequences were used to investigate molecular mechanisms underlying this process. RESULTS: Hepatic SIRT6 expression was substantially reduced in the ALI patients and mice. The deletion of SIRT6 in mice and mice primary hepatocytes (MPHs) led to high NAPQI and low glutathione (GSH) levels in the liver, thereby enhancing APAP overdose-induced liver injury, manifested as increased hepatic centrilobular necrosis, oxidative stress, and inflammation. Conversely, overexpression or pharmacological activation of SIRT6 enhanced GSH and decreased NAPQI, thus alleviating APAP-induced hepatotoxicity via normalization of liver damage, inflammatory infiltration and oxidative stress. Our molecular analysis revealed that FXR is regulated by SIRT6, which is associated with the pathological progression of ALI. Mechanistically, SIRT6 deacetylates FXR, and elevates FXR transcriptional activity. FXR ablation in mice and MPHs prominently blunted SIRT6 overexpression and activation-mediated ameliorative effects. Conversely, pharmacological activation of FXR mitigated APAP-induced hepatotoxicity in SIRT6-LKO mice. CONCLUSIONS: Our current study suggests that SIRT6 plays a crucial role in APAP-induced hepatotoxicity, and pharmacological activation of SIRT6 may represent a novel therapeutic strategy for APAP overdose-induced liver injury.

3.
Zhongguo Zhong Yao Za Zhi ; 47(7): 1705-1729, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-35534243

RESUMO

The traditional Chinese medicine(TCM) contains very complex constituents. Besides the major constituents, there are a large number of unclear trace constituents with novel skeletons and potent bioactivities, which have been regarded as one of the important therapeutic substances and the great resources of innovative drugs derived from TCM. The present review highlighted that the development of the trace therapeutic substances of TCM is closely depends on the advanced technologies for their identification, isolation, structure elucidation, and bioactivity evaluation. Additionally, this paper reviewed the novel trace compounds derived from Chinese herbal medicines which have been published in Organic Letters during 2001-2021, and summarized the important licensed drugs originated from the trace therapeutic substances and the discovery and development of trace therapeutic substances of 8 kinds of Chinese herbal medicines. This review provides references for the research and development of TCM therapeutic substances and innovative drugs.


Assuntos
Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico
4.
Sci China Life Sci ; 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35508791

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by a strong production of inflammatory cytokines such as TNF and IL-6, which underlie the severity of the disease. However, the molecular mechanisms responsible for such a strong immune response remains unclear. Here, utilizing targeted tandem mass spectrometry to analyze serum metabolome and lipidome in COVID-19 patients at different temporal stages, we identified that 611 metabolites (of 1,039) were significantly altered in COVID-19 patients. Among them, two metabolites, agmatine and putrescine, were prominently elevated in the serum of patients; and 2-quinolinecarboxylate was changed in a biphasic manner, elevated during early COVID-19 infection but levelled off. When tested in mouse embryonic fibroblasts (MEFs) and macrophages, these 3 metabolites were found to activate the NF-κB pathway that plays a pivotal role in governing cytokine production. Importantly, these metabolites were each able to cause strong increase of TNF and IL-6 levels when administered to wildtype mice, but not in the mice lacking NF-κB. Intriguingly, these metabolites have little effects on the activation of interferon regulatory factors (IRFs) for the production of type I interferons (IFNs) for antiviral defenses. These data suggest that circulating metabolites resulting from COVID-19 infection may act as effectors to elicit the peculiar systemic inflammatory responses, exhibiting severely strong proinflammatory cytokine production with limited induction of the interferons. Our study may provide a rationale for development of drugs to alleviate inflammation in COVID-19 patients.

5.
Environ Monit Assess ; 194(6): 405, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35522350

RESUMO

When performing a landslide susceptibility analysis, a model is usually established on the basis of a multi-temporal or event-triggered landslide inventory. Because multi-temporal landslide inventories for most areas are rarely available, an event-triggered landslide inventory is often used, but the result depends on the selection of single event. In order to establish a landslide susceptibility model with a good prediction performance, the present study tried to find out how to select a single event-triggered landslide inventory, and investigated the effect of various combinations of event inventories. We selected Shihmen reservoir watershed as the research area, conducted a logistic regression analysis to build 23 event-based landslide susceptibility models and one multi-year landslide susceptibility model, and estimated the performance of these models. In addition, this study further assessed the influence of event characteristics on the model prediction performance, used the above results to merge two different events, and then established models based on these combinations. The results indicated that when establishing an event-based landslide susceptibility model, selecting events with suitable rainfall return periods and landslide density can yield robust models with relatively high predictive ability. Furthermore, the combination of two events which negatively correlate with each other in rainfall spatial distributions can enhance a model's predictive ability and modeling efficiency.


Assuntos
Deslizamentos de Terra , Monitoramento Ambiental/métodos , Taiwan
6.
Am J Cancer Res ; 12(4): 1465-1483, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35530295

RESUMO

To evaluate the potential anticancer effects of 1175 FDA-approved drugs, cell viability screening was performed using 25 human cancer cell lines covering 14 human cancer types. Here, we focus on the action of paroxetine, which demonstrated greater toxicity toward human gastric adenocarcinoma cell-line AGS cells compared with the other FDA-approved drugs, exhibiting an IC50 value lower than 10 µM. Evaluation of the underlying novel mechanisms revealed that paroxetine can enhance DNA damage in gastric cancer cells and involves downregulation of Rad51, HR23B and ERCC1 expression and function, as well as nucleotide shortage. Enhancement of autophagy counteracted paroxetine-induced apoptosis but did not affect paroxetine-induced DNA damage. Paroxetine also enhanced ROS generation in AGS cells, but a ROS scavenger did not improve paroxetine-mediated DNA damage, apoptosis, or autophagy, suggesting ROS might play a minor role in paroxetine-induced cell toxicity. In contrast, paroxetine did not enhance DNA damage, apoptosis, or autophagy in another insensitive gastric adenocarcinoma cell-line MKN-45 cells. Interestingly, co-administration of paroxetine with conventional anticancer agents sensitized MKN-45 cells to these agents: co-treated cells showed increased apoptosis relative to MKN-45 cells treated with the anticancer agent alone. Unequivocally, these data suggest that for the first time that paroxetine triggers cytotoxicity and DNA damage in AGS cells at least partly by reducing the gene expression of Rad51, HR23B, and ERCC1. Our findings also suggest that paroxetine is a promising candidate anticancer agent and/or chemosensitizing agent for use in combination with other anticancer drugs in cancer therapy. The molecular mechanisms underlying the anticancer activity of co-treatment with paroxetine and chemotherapy appear to be complex and are worthy of further investigation.

7.
Phytomedicine ; 102: 154148, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35576742

RESUMO

BACKGROUND: Non-alcoholic steatohepatitis (NASH) can develop into cirrhosis, liver failure, or hepatocellular carcinoma without effective treatment. However, there are currently no drugs for NASH treatment, and the development of new therapeutics has remained a major challenge in NASH research. Advances in traditional Chinese medicine to treat liver disease inspired us to search for new NASH candidates from Chi-Shao, a widely used traditional Chinese medicine. PURPOSE: In this research, we aimed to clarify the anti-NASH effect and the underlying mechanism of isopropylidenyl anemosapogenin (IA, 1), which was a new lead compound isolated from Chi-Shao. STUDY DESIGN AND METHODS: Isopropylidenyl anemosapogenin (IA, 1) was first discovered by collagen type I α 1 promoter luciferase bioassay-guided isolation and then characterized by single crystal X-ray diffraction analysis and enriched by semi-synthesis. Using various molecular biology techniques, the multiple anti-NASH efficacies and mechanisms of IA were clarified based on in vitro LX-2 and Huh7 cell models, along with the in vivo choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced mouse model and bile duct ligation (BDL)-induced rat model. The UPLC-MS/MS method was used to assess the plasma concentration of IA. RESULTS: A new lead compound IA was isolated from the traditional Chinese medicine Chi-Shao, which showed significant anti-liver fibrosis activity in TGF-ß1-treated LX-2 cells and anti-liver steatosis activity in oleic acid-treated Huh7 cells. Furthermore, IA could significantly ameliorate in vivo CDAHFD-induced liver injury by activating the farnesoid X receptor pathway, including its targets Nr0b2, Abcb11, and Slc10a2. Simultaneously, IA activated the autophagy pathway by activating the TFEB factor, thereby promoting lipid degradation. Its liver-protective and anti-fibrosis activities were verified by the BDL-induced rat model. Finally, with an oral administration of 100 mg/kg, IA achieved the maximum plasma concentration of 1.23 ± 0.18 µg/ml at 2.67 ± 0.58 h. CONCLUSION: IA, an unreported lupine-type triterpenoid isolated from Chi-shao, can significantly alleviate liver injury and fibrosis via farnesoid X receptor activation and TFEB-mediated autophagy, which indicates that IA could serve as a novel therapeutic candidate against NASH.

9.
J Clin Med ; 11(9)2022 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-35566498

RESUMO

PURPOSE: According to previous studies, the prevalence rate of cataracts has increased in recent years. This study aims to investigate and analyze the risk factors of early-onset cataracts in Taiwan. METHODS: A total of 71 subjects aged between 20 and 55 were diagnosed with cataracts in a medical center. Participants were divided into three groups: control, early-onset cataract (EOC), and combined (EOC combined with dry eye) groups. Eye examinations including autorefraction, best-corrected visual acuity (BCVA), subjective refraction, axial length, fundus, slit lamp, and reactive oxygen species (ROS, including total antioxidative capacity, TAC; C-reactive protein, CRP; and glutathione peroxidase, GPx) were performed. In addition, a questionnaire on patient information, history, habits, family history, and Depression Anxiety Stress Scales (DASS) was completed before the examination. RESULTS: 27 non-EOC (control group), 20 EOC, and 24 combined patients participated in the study. Compared with the control group, Body Mass Index (BMI), gender, educational level, hypertension, diabetes, hyperlipidemia, chronic pain, and body-related diseases were significantly different between the three groups. Family history was also significantly different: family heart disease, hypertension, asthma, allergies, stroke, and immune system were also significantly different. In addition, subjects who took hypertensive drugs, antihistamines, and other medications were also significantly different. Statistical analysis indicated that best corrective visual acuity and the spherical equivalent were significantly different between the three groups. Similar results were found in CRP blood analysis. DISCUSSION AND CONCLUSION: According to the results, EOC may result from systemic diseases. The risk corresponded to an increase in ROS blood analysis. Furthermore, eye drops and medicine intake significantly influenced EOC patients. To prevent or defer early-onset cataracts, monitoring physical health, CRP, and GPx analysis may be worth considering in the future.

10.
Stat Med ; 41(10): 1797-1814, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35403735

RESUMO

Effect decomposition is a critical technique for mechanism investigation in settings with multiple causally ordered mediators. Causal mediation analysis is a standard method for effect decomposition, but the assumptions required for the identification process are extremely strong. Moreover, mediation analysis focuses on addressing mediating mechanisms rather than interacting mechanisms. Mediation and interaction for mediators both contribute to the occurrence of disease, and therefore unifying mediation and interaction in effect decomposition is important to causal mechanism investigation. By extending the framework of controlled direct effects, this study proposes the effect attributable to mediators (EAM) as a novel measure for effect decomposition. For policymaking, EAM represents how much an effect can be eliminated by setting mediators to certain values. From the perspective of mechanism investigation, EAM contains information about how much a particular mediator or set of mediators is involved in the causal mechanism through mediation, interaction, or both. EAM is more appropriate than the conventional path-specific effect for application in clinical or medical studies. The assumptions of EAM for identification are considerably weaker than those of causal mediation analysis. We develop a semiparametric estimator of EAM with robustness to model misspecification. The asymptotic property is fully realized. We applied EAM to assess the magnitude of the effect of hepatitis C virus infection on mortality, which was eliminated by controlling alanine aminotransferase and treating hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Complexo Mediador/fisiologia , Carcinoma Hepatocelular/etiologia , Causalidade , Coleta de Dados , Humanos , Neoplasias Hepáticas/etiologia , Modelos Estatísticos
11.
PLoS One ; 17(4): e0266876, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35443009

RESUMO

BACKGROUND: Norovirus (NoV) infection is common in pediatric patients with immunodeficiency and is more likely to cause severe disease. Objective Our study aims to figure out the clinical differences and distribution of intestinal microbiota in immunocompromised children with NoV gastroenteritis. METHODS: Pediatric patients admitted to Shang-Ho Hospital with diagnosis of acute gastroenteritis including different immune status were enrolled and their medical records were reviewed. NoV gastroenteritis was validated using RT-PCR molecular methods. Viral shedding period was determined by real-time RT-PCR assays. Intestinal microbiota enrichment analysis was carried out by next generation sequencing after fecal DNA extraction and subsequent Linear Discriminant Analysis (LDA) Effect Size (LEfSe) method. RESULTS: Significantly higher frequency of diarrhea [mean, (IQR), 3.8 (3-5) /day] and longer viral shedding time [mean, IQR, 8.5 (5-13) days] was found in immunocompromised NoV infections than in immunocompetent patients without NoV infections (p = 0.013*) and immunocompetent patients with NoV infections (p = 0.030**). The fever prevalence was significantly lower in immunocompromised NoV infections than in different immune or infection status. Intestinal microbiota metagenomics analysis showed no significant community richness difference while the LEfSe analysis showed a significant difference in commensal richness at the phylum level, the family level, and the genus level in patients under different immune status. CONCLUSION: We evaluated the clinical significances and microbiota composition in immunocompromised children with norovirus gastroenteritis. This will further facilitate studies of the interaction between the intestinal microbiota in such patients with precise determination of their bacterial infection control and probiotic supplements strategy.


Assuntos
Infecções por Caliciviridae , Gastroenterite , Microbioma Gastrointestinal , Norovirus , Infecções por Caliciviridae/epidemiologia , Criança , Fezes , Microbioma Gastrointestinal/genética , Genótipo , Humanos , Lactente , Norovirus/genética , RNA Viral
12.
Front Oncol ; 12: 870914, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35444934

RESUMO

Objectives: Triple-negative breast cancer (TNBC) is defined as a highly aggressive type of breast cancer which lacks specific biomarkers and drug targets. Damage-associated molecular pattern (DAMP)-induced immunogenic cell death (ICD) may influence the outcome of immunotherapy for TNBC patients. This study aims to develop a DAMPs gene signature to classify TNBC patients and to further predict their prognosis and immunotherapy outcome. Methods: We identified the DAMPs-associated subtypes of 330 TNBCs using K-means analysis. Differences in immune status, genomic alterations, and predicted immunotherapy outcome were compared among each subtype. Results: A total of 330 TNBCs were divided into three subtypes according to DAMPs gene expression: the nuclear DAMPs subtype, featuring the upregulation of nuclear DAMPs; the inflammatory DAMPs subtype, characterized by the gene set enrichment of the adaptive immune system and cytokine signaling in the immune system; and the DAMPs-suppressed subtype, having the lowest level of ICD-associated DAMPs. Among them, the inflammatory subtype patients had the most favorable survival, while the DAMPs-suppressed subtype was associated with the worst prognosis. The DAMPs subtyping system was successfully validated in the TCGA cohort. Furthermore, we systemically revealed the genomic alterations among the three DAMPs subtypes. The inflammatory DAMPs subtype was predicted to have the highest response rate to immunotherapy, suggesting that the constructed DAMPs clustering had potential for immunotherapy efficacy prediction. Conclusion: We established a novel ICD-associated DAMPs subtyping system in TNBC, and DAMPs expression might be a valuable biomarker for immunotherapy strategies. Our work could be helpful to the development of new immunomodulators and may contribute to the development of precision immunotherapy for TNBC.

13.
J Clin Med ; 11(7)2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-35407532

RESUMO

Variable techniques in periacetabular osteotomy have been formulated for the treatment of acetabular dysplasia. However, few studies have compared the radiographic outcomes between different osteotomy types. This study compared modified triple innominate (MTI) osteotomy and Ganz osteotomy with respect to radiographic outcomes. Patients receiving MTI osteotomies and Ganz osteotomies at any time between 2006 and 2018 in a tertiary medical centre were recruited. Only patients with unilateral osteotomies were recruited to eliminate potential influence from the contralateral hip following periacetabular osteotomy. Patients having hip-joint dislocation, receiving simultaneous proximal femoral osteotomy, or having fewer than 2 years of follow-up were excluded. The radiographic parameters of preoperative and postoperative anteroposterior radiographs of the pelvis were measured, and Sharp's angle (SA), the lateral centre-edge angle (CE angle), the femoral head extrusion index (FHEI), and the centre-head distance discrepancy (CHDD) were included for comparison. Among 55 participants, 23 received MTI osteotomies and 32 received Ganz osteotomies. The mean age at which patients underwent surgery was 21.9 years in the Ganz osteotomy group and 21.1 years in the MTI group. The mean follow-up length was 2.5 years. The preoperative radiographic parameters between groups differed only slightly and nonsignificantly. Both groups exhibited significantly improved SA, LCEA, and FHEI after surgery. The Ganz osteotomy group exhibited more favourable postoperative FHEI (13.5 vs. 24.3, p < 0.0001), CHDD (3.7 vs. 11.5, p < 0.0001), Sharp angle (45.0 vs. 41.8, p = 0.0489) and CE angles (28.3 vs. 21.1, p = 0.029) compared with the MTI osteotomy group. Notably, CHDD became better and worse following Ganz and MTI osteotomies, respectively; this suggests that the femoral head is pushed laterally in modified triple osteotomy. With respect to femoral head coverage and the medialization of the femoral head, Ganz osteotomy exhibits more favourable corrections in postoperative radiographic parameters than does MTI osteotomy.

14.
PLoS One ; 17(4): e0266771, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35404960

RESUMO

PURPOSE: Gonadotropin-releasing hormone (GnRH) analogues reduce testosterone levels to castration levels in patients with prostate cancer. However, the role of testosterone in atopic diseases has remained undefined. We aimed to investigate this role. MATERIALS AND METHODS: This retrospective cohort study was conducted using the National Health Insurance Research Database (NHIRD). Patients with prostate cancer were categorized into two groups according to whether they received GnRH analogue treatment (study group I) or not (study group II), and men without prostate cancer and with no GnRH analogue use were defined to comprise the comparison group after their ages and index years were matched with group II. Cox proportional hazard models were used to assess the hazard ratio (HR) of atopic diseases. RESULTS: Group I, group II, and the comparison group comprised 663, 2,172, and 8,688 individuals, respectively. Group I had a significantly lower risk of atopic diseases (adjusted HR: 0.66, 95% CI, 0.49-0.89, p < 0.01) than did group II. A reduced risk of atopic diseases was found when GnRH analogues were prescribed for 2 months (adjusted HR 0.53, 95% CI, 0.29-0.97, p = 0.04) and 2-14 months (adjusted HR 0.66, 95% CI, 0.49-0.89, p = 0.007). No significant difference in the risk of atopic diseases between group II and the comparison group was observed. CONCLUSIONS: A decreased risk of atopic diseases was observed in patients with prostate cancer treated with GnRH analogues. Further studies are warranted to verify the association between testosterone levels and atopic diseases.


Assuntos
Hormônio Liberador de Gonadotropina , Neoplasias da Próstata , Estudos de Coortes , Hormônio Liberador de Gonadotropina/análogos & derivados , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/epidemiologia , Estudos Retrospectivos , Testosterona
15.
Cell Death Dis ; 13(4): 414, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35487917

RESUMO

Midkine (MDK), a secreted growth factor, regulates signal transduction and cancer progression by interacting with receptors, and it can be internalized into the cytoplasm by endocytosis. However, its intracellular function and signaling regulation remain unclear. Here, we show that intracellular MDK interacts with LKB1 and STRAD to disrupt the LKB1-STRAD-Mo25 complex. Consequently, MDK decreases the activity of LKB1 to dampen both the basal and stress-induced activation of AMPK by glucose starvation or treatment of 2-DG. We also found that MDK accelerates cancer cell proliferation by inhibiting the activation of the LKB1-AMPK axis. In human cancers, compared to other well-known growth factors, MDK expression is most significantly upregulated in cancers, especially in liver, kidney and breast cancers, correlating with clinical outcomes and inversely correlating with phosphorylated AMPK levels. Our study elucidates an inhibitory mechanism for AMPK activation, which is mediated by the intracellular MDK through disrupting the LKB1-STRAD-Mo25 complex.


Assuntos
Proteínas Quinases Ativadas por AMP , Neoplasias , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Humanos , Midkina , Transdução de Sinais
16.
Pathogens ; 11(4)2022 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-35456126

RESUMO

Noroviruses (NoVs) are one of the emerging and rapidly spreading groups of pathogens threatening human health. A reduction in sporadic NoV infections was noted following the start of the COVID-19 pandemic, but the return of NoV gastroenteritis during the COVID-19 pandemic has been noted recently. Research in recent years has shown that different virus strains are associated with different clinical characteristics; moreover, there is a paucity of research into extraintestinal or unusual complications that may be associated with NoV. The genomic diversity of circulating NoVs is also complex and may vary significantly. Therefore, this short narrative review focuses on sharing the Taiwan experience of NoV infection including epidemiology, clinical features, and complications following suboptimal rotavirus immunization in Taiwan (after October 2006). We also highlight the unusual complications associated with NoV infections and the impacts of NoV infection during the COVID-19 pandemic in the literature for possible future research directions. To conclude, further research is needed to quantify the burden of NoV across the spectrum of disease severity in Taiwan. The evidence of the connection between NoV and the unusual complications is still lacking.

17.
Eur J Med Chem ; 237: 114406, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35486994

RESUMO

Mutation-induced resistance to targeted drug treatment poses a serious threat to successful chemotherapy. Multiple mutations underlying drug resistance remain a largely unsolved scientific issue. Tropomyosin receptor kinases (TRKs) are promising therapeutic targets for several malignant human cancers, but they have become less effective due to multiple resistance mutations. Thus, TRKs are representative cases to explore the problem of multiple resistance mutations. Here, we proposed a conformational adjustment strategy of drug design to overcome multiple resistance mutations in cancer treatments. A representative inhibitor, TIY-7, exhibited remarkable inhibitory activity against five TRK mutants, showing an IC50 value of 1.1 nM against the most severe mutant TRKA-G595R. Moreover, it displayed superior tumor growth inhibitory activity compared with the clinically used drug selitrectinib. These results validated our strategy to design a new inhibitor structure to overcome multiple resistance mutations.

18.
Int Immunopharmacol ; 109: 108732, 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35468364

RESUMO

Programmed death-1 (PD-1) blockade promoted the combination therapy of advanced non-small cell lung cancer (NSCLC), induces changes in peripheral memory T cell subsets. Neuropilin-1 (NRP1) is a new T cell memory checkpoint, its association with the clinical prognosis of NSCLC is less reported. Here, we detected the expression of NRP1 and the depletion-associated factor thymocyte selection-associated HMG box protein (TOX) in peripheral T cell subsets with responders treated with hypofractionated radiotherapy (HFRT) combined with PD-1 blockade and chemoimmunotherapy, aimed to explore their association with the prognosis of advanced NSCLC. NRP1 and TOX expression was localized on tissue-infiltrating T cells by immunofluorescence assay in nine patients who had undergone surgery. Flow cytometry was used to detect the expression of NRP1 and TOX in peripheral circulating T cells in patients with advanced NSCLC before and after HFRT combined with PD-1 blockade (HFRT+PD-1) and chemoimmunotherapy in thirty-nine patients. NSCLC patients showed an increase in NRP1 and TOX in peripheral T cells as compared to that in healthy controls. The expression of NRP1 and TOX in CD8+ T cells was higher in tumor tissues than in uninvolved tissues. Patients who responded to HFRT+PD-1 blockade showed a reduction in NRP1+CD8+, TOX+CD4+, and TOX+CD8+ levels, chemoimmunotherapy responders showed decreased expression of NRP1 in the CD4+ T cell subpopulation. In conclusion, lower expression levels of NRP1 and TOX in peripheral circulating CD8+ T cells were associated with a better prognosis for advanced NSCLC patients treated with HFRT+PD-1 blockade.

20.
Front Surg ; 9: 818591, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35402497

RESUMO

Purpose: To determine whether treatment with uvulopalatopharyngoplasty (UPPP) or continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) prevents hypertension, compared to those not receiving any treatment. Methods: A retrospective cohort study was conducted among 413 patients with OSA (age ≥ 35 years) at the Shuang Ho Hospital between 2009 and 2016. The patients were divided into three groups: UPPP, CPAP, and non-treatment groups. Data about the personal characteristics, history of comorbidities, and polysomnography (PSG) reports were collected at baseline. A Cox model with inverse probability of treatment weighting was used to adjust for confounders and baseline diversity. Results: After multivariate adjustment and weighting for incident hypertension, patients in both the CPAP and UPPP groups showed a significant preventive effect on hypertension than in the non-treatment group. Moreover, patients in the CPAP group had lower event rates than those in the UPPP group. Conclusion: UPPP can prevent the development of new-onset hypertension in patients with OSA. CPAP had a better preventive effect than UPPP. UPPP might be a good alternative for reducing the risk of the onset of hypertension when compliance to CPAP is poor.

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