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1.
Biomark Med ; 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35543030

RESUMO

Aim: To investigate the clinical role of transmembrane protease serine 3 (TMPRSS3) in radioresistance and prognosis of colorectal cancer (CRC). Methods: Standardized mean difference (SMD) and summary area under the curve (AUC) of TMPRSS3 were calculated by combining all available high-throughput data globally. The prognostic significance of TMPRSS3 was determined by Kaplan-Meier and Cox regression analyses. Results: TMPRSS3 was remarkably upregulated in 198 CRC radioresistant cases compared with nonradioresistance (SMD = 0.38, AUC = 0.71). Overexpression of TMPRSS3 was observed in 1601 CRC patients compared with control subjects without CRC. TMPRSS3 was a risk factor for disease-free survival of CRC with the summarized hazard ratio 1.28. Conclusion: TMPRSS3 contributes to the radioresistance and unfavorable prognosis of CRC.

2.
Polymers (Basel) ; 14(9)2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35566938

RESUMO

Enzymatic preparation of low-molecular-weight chondroitin sulfate (LMWCS) has received increasing attention. In this work, a chondroitin sulfate lyase ABC (Chon-ABC) was successfully cloned, expressed, and characterized. The Km and Vmax of the Chon-ABC were 0.54 mM and 541.3 U mg-1, respectively. The maximal activity was assayed as 500.4 U mg-1 at 37 °C in pH 8.0 phosphate buffer saline. The half-lives of the Chon-ABC were 133 d and 127 min at 4 °C and 37 °C, respectively. Enzymatic preparation of LMWCS was performed at room temperature for 30 min. The changes between the substrate and product were analyzed with mass spectrometry (MS), high-performance liquid chromatography (HPLC), gel permeation chromatography (GPC), and nuclear magnetic resonance (NMR). Overall, the Chon-ABC from Bacteroides thetaiotaomicron is competitive in large-scale enzymatic preparation of LMWCS for its high activity, stability, and substrate specificity.

3.
Front Pharmacol ; 13: 902796, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35571137

RESUMO

The small molecule DAPT inhibits the Notch signaling pathway by blocking γ-secretase mediated Notch cleavage. Given the critical role of the Notch signaling axis in inflammation, we asked whether DAPT could block Notch-mediated inflammation and thus exert neuronal protection. We established a mouse model of chronic exposure to cadmium (Cd)-induced toxicity and treated it with DAPT. DAPT was effective in ameliorating Cd-induced multi-organ damage and cognitive impairment in mice, as DAPT restored abnormal performance in the Y-maze, forced swimming and Morris water maze (MWM) tests. DAPT also reversed Cd-induced neuronal loss and glial cell activation to normal as observed by immunofluorescence and immunohistochemistry of brain tissue sections. In addition, Cd-intoxicated mice showed significantly increased levels of the Notch/HES-1 signaling axis and NF-κB, as well as decreased levels of the inflammatory inhibitors C/EBPß and COP1. However, DAPT down regulated the elevated Notch/HES-1 signaling axis to normal, eliminating inflammation and thus protecting the nervous system. Thus, DAPT effectively eliminated the neurotoxicity of Cd, and blocking γ-secretase as well as Notch signaling axis may be a potential target for the development of neuronal protective drugs.

4.
Inj Prev ; 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35508365

RESUMO

BACKGROUND: Alcohol and other drug (AOD) use is a key preventable risk factor for serious injuries. Prevention strategies to date have largely focused on transport injuries, despite AOD use being a significant risk factor for other injury causes, including falls. This systematic review aimed to report the prevalence of AOD use in patients presenting to hospital for fall-related injuries. METHODS: This systematic review includes studies published in English after the year 2010 that objectively measured the prevalence of AOD use in patients presenting to hospital for a fall-related injury. Screening, data extraction and risk of bias assessments were completed by two independent reviewers. Data were presented using narrative synthesis and, where appropriate, meta-analyses. RESULTS: A total of 12 707 records were screened. Full texts were retrieved for 2042 records, of which 29 were included. Four studies reported the combined prevalence of any alcohol and/or drug use, generating a pooled prevalence estimate of 37% (95% CI 25% to 49%). Twenty-two records reported on the prevalence of acute alcohol use alone and nine reported specifically on the prevalence of drugs other than alcohol, with prevalence ranging from 2% to 57% and 7% to 46%, respectively. The variation in prevalence estimates likely resulted from differences in toxicology testing methods across studies. CONCLUSIONS: AOD exposure was common in hospitalised fall-related injuries. However, research addressing prevalence across different types of falls and the use of drugs other than alcohol was limited. Future research should address these areas to improve our understanding of which populations should be targeted in AOD and injury prevention strategies . PROSPERO REGISTRATION NUMBER: CRD42020188746.

5.
Langmuir ; 38(19): 6209-6216, 2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35508432

RESUMO

Probing the adlayer structures on an electrode/electrolyte interface is one of the most important tasks in modern electrochemistry for clarifying the electrochemical processes. Herein, we have combined cyclic voltammetry and electrochemical shell-isolated nanoparticle-enhanced Raman spectroscopy techniques to explore the potential-dependent adlayer structures on Au(111) in a room-temperature ionic liquid of 1-butyl-3-methylimidazolium hexafluorophosphate (BMIPF6) without or with pyridine (Py). It is clearly found that the BMI+ cations strongly adsorb on the negatively charged surface with a flat-lying orientation, leaving a little space for Py adsorption. Upon increasing the potentials of the electrode, the variations of Raman band intensities and frequencies reveal that the interaction between the BMI+ cations and the Au surface becomes weak; meanwhile, the Py adsorption becomes strong, and its geometry turns from flat, tilted to vertical. Finally, BMI+ cations desorb and leave plenty of surface sites for Py adsorption in bulk solution, and a N-bonded compact Py adlayer is formed on the very positively charged surface. This causes obvious anodic peaks in cyclic voltammograms, and the peak currents increase with the square root of the scanning rate. The present work provides a fair molecular-level understanding of electrochemical interfaces and molecular adsorption of Py in ionic liquids.

6.
Front Physiol ; 13: 799183, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35600309

RESUMO

Objective: The present study aims to explore the protective effect of nalbuphine combined with dexmedetomidine on the lungs of children with atelectasis who have a foreign body in a bronchus during the perioperative period. Methods: A total of 180 patients whose computed tomography scan showed atelectasis and a foreign body in a bronchus were randomly divided into three groups: group C (conventional anesthesia group), group D (dexmedetomidine group), and group N + D (nalbuphine combined with the dexmedetomidine group). The following indicators were recorded: 1) heart rate (HR) and mean arterial pressure (MAP) prior to induction (T0), at bronchoscope placement (T1), at intubation after surgery (T2), at tube removal (T3), 10 min after tube removal (T4), 20 min after tube removal (T5), and at awaking (T6); 2) monocyte toll-like receptors (TLRs) TLR⁃2, TLR⁃4, tumor necrosis factor α, interleukin 6, oxygenation index, and the B-line sum at T0, T3, 2 h (T7), and 24 h (T8) after tube removal; and 3) hospital stay after surgery. Results: Compared with group C, in group D and group N + D, 1) the HR and MAP at T1∼T6 were lower; 2) the inflammatory factor indicator and B-line sum were lower, and the oxygenation index was higher at T7 and T8; 3) the agitation and cough scores were decreased during tube removal; and 4) the Ramsay sedation score was higher, and ventilator weaning time was shortened at T4∼T6 (p < 0.05). Compared with group D, in group N + D, 1) the inflammatory factor indicator and B-line sum were lower at T8; 2) the oxygenation index was higher (p < 0.05). Compared with groups C and D, in group N + D, the length of hospital stay was decreased (p < 0.05). Conclusion: In patients with atelectasis and a foreign body in a bronchus during the perioperative period, nalbuphine combined with dexmedetomidine may be capable of reducing the oxidative stress response, improving the oxygenation index, decreasing the pulmonary fluid content, protecting the lung, and facilitating postoperative recovery.

7.
J Ginseng Res ; 46(3): 418-425, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35600776

RESUMO

Background: Sorafenib is effective in treating hepatoma, but most patients develop resistance to it. STAT3 signaling has been implicated in sorafenib resistance. Artesunate (ART) and 20(R)-ginsenoside Rg3 (Rg3) have anti-hepatoma effects and can inhibit STAT3 signaling in cancer cells. This study aimed to evaluate the effects of Rg3 in combination with ART (Rg3-plus-ART) in overcoming sorafenib resistance, and to examine the involvement of STAT3 signaling in these effects. Methods: Sorafenib-resistant HepG2 cells (HepG2-SR) were used to evaluate the in vitro anti-hepatoma effects of Rg3-plus-ART. A HepG2-SR hepatoma-bearing BALB/c-nu/nu mouse model was used to assess the in vivo anti-hepatoma effects of Rg3-plus-ART. CCK-8 assays and Annexin V-FITC/PI double staining were used to examine cell proliferation and apoptosis, respectively. Immunoblotting was employed to examine protein levels. ROS generation was examined by measuring DCF-DA fluorescence. Results: Rg3-plus-ART synergistically reduced viability of, and evoked apoptosis in HepG2-SR cells, and suppressed HepG2-SR tumor growth in mice. Mechanistic studies revealed that Rg3-plus-ART inhibited activation/phosphorylation of Src and STAT3 in HepG2-SR cultures and tumors. The combination also decreased the STAT3 nuclear level and induced ROS production in HepG2-SR cultures. Furthermore, over-activation of STAT3 or removal of ROS diminished the anti-proliferative effects of Rg3-plus-ART, and removal of ROS diminished Rg3-plus-ART's inhibitory effects on STAT3 activation in HepG2-SR cells. Conclusions: Rg3-plus-ART overcomes sorafenib resistance in experimental models, and inhibition of Src/STAT3 signaling and modulation of ROS/STAT3 signaling contribute to the underlying mechanisms. This study provides a pharmacological basis for developing Rg3-plus-ART into a novel modality for treating sorafenib-resistant hepatoma.

8.
J Ethnopharmacol ; 293: 115251, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35381310

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Gastritis can lead to ulcers and the development of gastric cancer. The rhizome of Atractylodes macrocephala Koidz. (Asteraceae), a traditional Chinese medicinal herb, is prescribed for the treatment of gastric disorders, hepatitis and rheumatism. Its bio-active compounds are considered to be particularly effective in this regard. However, the molecular processes of the herb's anti-inflammatory activity remain obscure. This study elucidates a mechanism upon which an ethanolic extract of this herb (Am-EE) exerts anti-inflammation effects in RAW264.7 macrophage cells (RAW cells) stimulated by lipopolysaccharide (LPS) treatment and HCl Ethanol-stimulated gastritis rats. AIM OF THE STUDY: To investigate the anti-gastritis activities of Am-EE and explore the mode of action. MATERIALS AND METHODS: Ethanol (95%) was used to prepare Am-EE. The quality of the extract was monitored by HPLC analysis. The in vivo effects of this extract were examined in an HCl Ethanol-stimulated gastritis rat model, while LPS-stimulated RAW cells were used for in vitro assays. Cell viability and nitric oxide (NO) production were observed by MTT and Griess assays. Real-time PCR was used to examine mRNA expression. The PGE2 ELISA kit was employed to detect prostaglandin E2 (PGE2). Enzyme activities and protein contents were examined by immunoblotting. Luciferase reporter gene assays (LRA) were employed to observe nuclear transcription factor (NF)-κB activity. The SPSS (SPSS Inc., Chicago, Illinois, United States) application was used for statistical examination. RESULTS: HPLC analysis indicates that Am-EE contains atractylenolide-1 (AT-1, 1.33%, w/w) and atractylenolide-2 (AT-2, 1.25%, w/w) (Additional Figure. A1). Gastric tissue damage (induced by HCl Ethanol) was significantly decreased in SD rats following intra-gastric application of 35 mg/kg Am-EE. Indistinguishable to the anti-inflammation effects of 35 mg/kg ranitidine (gastric medication). Am-EE treatment also reduced LPS-mediated nitric oxide (NO) and prostaglandin E2 (PGE2) production. The mRNA and protein synthesis of inducible cyclooxygenase (COX)-2 and NO synthase (iNOS) was down-regulated following treatment in RAW cells. Am-EE decreased NF-κB (p50) nuclear protein levels and inhibited NF-κB-stimulated LRA activity in RAW cells. Lastly, Am-EE decreased the up-regulated levels of phosphorylated IκBα and Akt proteins in rat stomach lysates and in LPS challenged RAW cell samples. CONCLUSION: Our study illustrates that Am-EE suppresses the Akt/IκBα/NF-κB pathway and exerts an anti-inflammatory effect. These novel conclusions provide a pharmacological basis for the clinical use of the A. macrocephala rhizome in the treatment and prevention of gastritis and gastric cancer.

9.
J Ethnopharmacol ; 293: 115282, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35405254

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The prescription of Wei-Tong-Xin (WTX) is improved based on the prescription "Wanyingyuan", a famous decoction documented in the book of Huatuozhongzangjing in the Han dynasty. Many years of clinical verification have demonstrated that WTX can be used to treat gastrointestinal diseases, especially gastric ulcer (GU). However, the potential pharmacological mechanism is undefined. AIM OF THE STUDY: This research was conducted to explore the pharmacological mechanisms under the consideration of the therapeutical effect of WTX against GU by combining the network pharmacology strategy and in-vivo verified experiments. MATERIALS AND METHODS: A prediction network describing the relationship between WTX and GU was established based on information collected from multiple databases. Then, the intersecting protein-protein interaction (PPI) network of the drug-disease overlapping gene targets was constructed, and several key targets related to both WTX and GU were obtained. Besides, the Gene Ontology (GO) biological enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to investigate the key target genes and pathways of WTX against GU. Then, the candidate targets and signaling pathways of network pharmacology were validated in a rat model of GU induced by indomethacin following the results and available proof. RESULTS: There are 243 targets obtained from the 65 active ingredients in WTX, and 1362 disease targets related to GU were identified. Then, 6 key targets were determined with the PPI interaction network, which was structured from 126 overlapping gene targets. GO and KEGG analyses revealed that the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) signaling pathway might play a crucial role in the therapeutic mechanism of GU. In vivo verified experiments, WTX significantly reduced the ulcer area and improved the histopathological appearance of gastric tissues. Moreover, down-regulated the protein levels of IL6, TNF-α, and Caspase 3 in the gastric tissues while up-regulating the expression of p-PI3K, p-AKT, p-P53, and VEGFA compared to the model group. CONCLUSION: WTX, an ancient traditional Chinese medicine (TCM) compound prescription, may affect the inflammatory response and apoptosis process by regulating PI3K/AKT signaling pathway and related gene targets. Therefore, it is an effective drug candidate for the modern treatment of GU.

10.
Small ; 18(19): e2107881, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35417059

RESUMO

In contrast to the 2D organic-inorganic hybrid Ruddlesden-Popper halide perovskites (RPP), a new class of 2D all inorganic RPP (IRPP) has been recently proposed by substituting the organic spacers with an optimal inorganic alternative of cesium cations (Cs+ ). Nevertheless, the synthesis of high-membered 2D IRPPs (n > 1) has been a very challenging task because the Cs+ need to act as both spacers and A-site cations simultaneously. This work presents the successful synthesis of stable phase-pure high-membered 2D IRPPs of Csn+1 Pbn Br3n+1 nanosheets (NSs) with n = 3 and 4 by employing the strategy of using additional strong binding bidentate ligands. The structures of the 2D IRPPs (n = 3 and 4) NSs are confirmed by powder X-ray diffraction and high-resolution aberration-corrected scanning transmission electron microscope measurements. These 2D IRPPs NSs exhibit a strong quantum confinement effect with tunable absorption and emission in the visible light range by varying their n values, attributed to their inherent 2D quantum-well structure. The superior structural and optical stability of the phase-pure high-membered 2D IRPPs make them a promising candidate as photocatalysts in CO2 reduction reactions with outstanding photocatalytic performance and long-term stability.

12.
World J Clin Cases ; 10(8): 2529-2536, 2022 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-35434049

RESUMO

BACKGROUND: Due to the rarity of mesenchymal-epithelial transition factor (MET) fusions, the clinical efficacy of crizotinib has only been described in a few patients with MET fusions involving various fusion partners. Herein, we report the clinical response to crizotinib of a patient with advanced poorly differentiated non-small cell carcinoma (NSCLC) having concurrent MET fusions. CASE SUMMARY: A 46-year-old woman was diagnosed with poorly differentiated NSCLC (T4N3M1). With no classic driver mutations, she was treated with two cycles of gemcitabine and cisplatin without clinical benefit. Targeted sequencing revealed the detection of two concurrent MET fusions, KIF5B-MET and novel MET-CDR2. Crizotinib was initiated at a dose of 250 mg twice daily. Within 4 wk of crizotinib therapy, repeat computed chromatography revealed a dramatic reduction in primary and metastatic lesions, assessed as partial response. She continued to benefit from crizotinib for 3 mo until disease progression and died within 1 mo despite receiving nivolumab therapy. CONCLUSION: Crizotinib sensitivity was observed in an advanced poorly differentiated NSCLC patient with concurrent MET fusions KIF5B-MET and MET-CDR2. Crizotinib can serve as a therapeutic option for patients with MET fusions. In addition, our case also highlights the importance of comprehensive genomic profiling particularly in patients with no classic driver mutation for guiding alternative therapeutic decisions.

13.
BMC Health Serv Res ; 22(1): 560, 2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35473928

RESUMO

INTRODUCTION: The burden of chronic kidney disease (CKD) is rising globally including in Singapore. Primary care is the first point of contact for most patients with early stages of CKD. However, several barriers to optimal CKD management exist. Knowing healthcare professionals' (HCPs) perspectives is important to understand how best to strengthen CKD services in the primary care setting. Integrating a theory-based framework, we explored HCPs' perspectives on the facilitators of and barriers to CKD management in primary care clinics in Singapore. METHODS: In-depth interviews were conducted on a purposive sample of 20 HCPs including 13 physicians, 2 nurses and 1 pharmacist from three public primary care polyclinics, and 4 nephrologists from one referral hospital. Interviews were audio recorded, transcribed verbatim and thematically analyzed underpinned by the Theoretical Domains Framework (TDF) version 2. RESULTS: Numerous facilitators of and barriers to CKD management identified. HCPs perceived insufficient attention is given to CKD in primary care and highlighted several barriers including knowledge and practice gaps, ineffective CKD diagnosis disclosure, limitations in decision-making for nephrology referrals, consultation time, suboptimal care coordination, and lack of CKD awareness and self-management skills among patients. Nevertheless, intensive CKD training of primary care physicians, structured CKD-care pathways, multidisciplinary team-based care, and prioritizing nephrology referrals with risk-based assessment were key facilitators. Participants underscored the importance of improving awareness and self-management skills among patients. Primary care providers expressed willingness to manage early-stage CKD as a collaborative care model with nephrologists. Our findings provide valuable insights to design targeted interventions to enhance CKD management in primary care in Singapore that may be relevant to other countries. CONCLUSIONS: The are several roadblocks to improving CKD management in primary care settings warranting urgent attention. Foremost, CKD deserves greater priority from HCPs and health planners. Multipronged approaches should urgently address gaps in care coordination, patient-physician communication, and knowledge. Strategies could focus on intensive CKD-oriented training for primary care physicians and building novel team-based care models integrating structured CKD management, risk-based nephrology referrals coupled with education and motivational counseling for patients. Such concerted efforts are likely to improve outcomes of patients with CKD and reduce the ESKD burden.


Assuntos
Insuficiência Renal Crônica , Atitude do Pessoal de Saúde , Feminino , Humanos , Masculino , Atenção Primária à Saúde , Pesquisa Qualitativa , Insuficiência Renal Crônica/terapia , Singapura
14.
J Inflamm Res ; 15: 2491-2507, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35479834

RESUMO

Purpose: Emphysema is the main cause of the progression of chronic obstructive pulmonary disease (COPD). This study aimed to identify the key genes involved in COPD-related emphysema. Patients and Methods: GSE76925 was downloaded from Gene Expression Omnibus database. Protein-protein interaction networks of differentially expressed genes (DEGs) between control and COPD groups were constructed to identify hub genes using Cytoscape. Diagnostic performance of hub genes was evaluated using receiver operating characteristic analysis. Correlation analysis was performed to identify the key genes by analyzing the relationship between the hub genes and lung function and computed tomography (CT) indexes of emphysema. COPD patients were then divided into two groups based on the median expression of key genes and DEGs between these two groups were identified. Enrichment analysis of DEGs and correlation analysis between key genes and the infiltration of the immune cells were also analyzed. Finally, the role of key genes was evaluated in a lung tissues dataset (GSE47460) and a blood dataset (GSE76705). Additionally, the expression of key genes was validated by quantitative real-time polymerase chain reaction and immunohistochemistry. Results: CD19 and POU2AF1 had diagnostic efficacy for COPD and were significantly correlated with lung function and CT indexes of emphysema. Enrichment and immune analyses revealed that CD19 and POU2AF1 were correlated with the B cells in COPD. These results were consistent in GSE47460. The expression of CD19 and POU2AF1 in blood was the opposite of that in lung tissues, and CD19 and POU2AF1 were both significantly upregulated in COPD lung tissues at both the mRNA and protein levels. Conclusion: CD19 and POU2AF1 may serve as key regulators of emphysema and contribute to the progression of COPD by regulating the B-cell immunology. Targeting B cells may be a promising strategy for treating COPD.

15.
Nutr Res ; 103: 47-58, 2022 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-35477124

RESUMO

Lactoferrin (Lf) is an iron-binding glycoprotein with potentially beneficial biological functions. However, the interaction between Lf and type 2 diabetes mellitus (T2DM) remains unclear. We hypothesized that Lf would improve hepatic insulin resistance and pancreatic dysfunction in diabetic mice. Male C57BL/6J mice were fed a high-fat diet for 15 weeks and injected with streptozotocin (STZ) for 5 consecutive days to establish a T2DM model. One week after STZ injection, mice with ≥11.1 mmol/L fasting blood glucose concentration were considered T2DM mice. These mice received 0.5% or 2% Lf solution for another 12 weeks. Biochemical parameters were measured, and histopathological examination of the pancreas and liver was performed. Hepatic protein expression related to the insulin signalling pathway was also assessed. Diabetic mice showed insulin resistance and abnormal glucolipid metabolism. Lf decreased serum concentrations of glycated serum protein, fasting insulin, cholesterol, and triglyceride and increased liver insulin sensitivity. Hematoxylin-eosin staining showed that Lf reversed the abnormal pancreatic islets of diabetic mice. Lf improved pancreatic dysfunction by reducing oxidative stress and inflammation responses. Furthermore, Lf upregulated the protein expression of insulin receptor, insulin receptor substrate-1, glucose transporter 4, phosphor phosphatidylinositol 3-kinase/phosphatidylinositol 3-kinase (PI3K), and phosphor protein kinase B/protein kinase B (AKT) in the liver. This study indicated that Lf supplementation improved hepatic insulin resistance and pancreatic dysfunction, possibly by regulating the PI3K/AKT signaling pathway in T2DM mice.

16.
Int Immunopharmacol ; 109: 108782, 2022 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-35468366

RESUMO

Acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) is featured by intensive inflammatory responses and oxidative stress, which lead to cytokine storms and pyroptosis. Here, we aimed to investigate whether melatonin was capable of alleviating LPS-induced ALI via activating the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling axis and inhibiting pyroptosis. Mice were injected with melatonin (30 mg/kg) intraperitoneally for consecutive five days before LPS instillation intratracheally, and human alveolar epithelial cell (AECⅡ) A549 cell lines and murine macrophages Raw264.7 cell lines were pretreated with melatonin (400 µM) before LPS (10 µg/ml) stimulation. The result demonstrated that LPS induced obvious lung injury characterized by alveolar damage, neutrophil infiltration and lung edema as well as the reduction of the survival rate of mice, which were totally reversed by melatonin pretreatment. Mechanistically, melatonin pretreatment activated nuclear factor erythroid2-related factor (Nrf) 2 signaling, subsequently, drove antioxidant pathways including significant increases in the expression of Nrf2, HO-1, NQO1, Mn-SOD and Catalase in vivo and in vitro. Simultaneously, melatonin inhibited ROS and MDA overproduction, iNOS expression as well as TNF-α and IL-1ß expression and release. Furthermore, melatonin inhibited LPS-induced pyroptosis by reversing the overexpression of NLRP3, Caspase-1, IL-1ß, IL-18 and GSDMD-N, as well as LDH release and TUNEL-positive cells in A549 cells and Raw264.7 cells. Overall, the current study suggests that melatonin exerts protective roles on LPS-induced ALI and pyroptosis by inhibiting NLRP3-GSDMD pathway via activating Nrf2/HO-1 signaling axis.

17.
Thorac Cancer ; 13(9): 1333-1341, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35394115

RESUMO

BACKGROUND: Starting with low metastatic capability, T4N0M0 (diameter ≥ 7 cm) non-small cell lung cancers (NSCLCs) constitute a unique tumor subset, as with a large tumor size but no regional or distant metastases. We systematically investigated intratumoral heterogeneity, clonal structure, chromosomal instability (CIN), and immune microenvironment in T4N0M0 (≥7 cm) NSCLCs. METHODS: Whole-exome sequencing, RNA sequencing, and multiplex immunohistochemistry (mIHC) staining were conducted to analyze 24 spatially segregated tumor samples from eight patients who were pathologically diagnosed with T4N0M0 (diameter ≥ 7 cm) NSCLCs. The adjacent normal tissues and peripheral blood served as controls. RESULTS: In total, 35.2% of mutations and 91.1% of somatic copy number alterations were classified as subclonal events, which exhibited widespread genetic intratumoral heterogeneity. In contrast, a low degree of CIN was observed. None of the patients had genome doubling. The burden of loss of heterozygosity, aneuploidy, and the genome instability index of these tumors were significantly lower than those in the TRACERx cohort. Expression profiles revealed significantly upregulated expression of cell division-related signals and the G2/M checkpoint pathway. In addition, a similar expression pattern of the immune microenvironment was observed in different regions of the tumor, which was confirmed by mIHC profiles. CONCLUSIONS: Our study indicates the presence of intratumoral genetic heterogeneity and immune microenvironmental heterogeneity features in T4N0M0 NSCLCs, and the low degree of CIN may be related to the low metastatic capability.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/genética , Variações do Número de Cópias de DNA , Heterogeneidade Genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Microambiente Tumoral/genética , Sequenciamento Completo do Exoma
18.
BMJ Open ; 12(4): e054111, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35396285

RESUMO

OBJECTIVE: To investigate the prevalence, incidence and relating factors that are associated with hereditary retinal dystrophy (HRD) in Taiwan from 2000 to 2013. DESIGN, SETTING AND PARTICIPANTS: This is a nationwide, population-based, retrospective case-control study using National Health Insurance Database. Study groups are patients with HRD as case group; age-matched patients without any diagnosis of HRD as control group. We enrolled 2418 study subjects, of which 403 were HRD patients. Important relating factors such as hypertension, diabetes, coronary artery disease, autoimmune disease, cancer, liver cirrhosis, chronic kidney disease, stroke, hyperlipidaemia, asthma, depression and dementia are also included. EXPOSURE: Patients diagnosed with HRD were retrieved from National Health Insurance Database. MAIN OUTCOMES AND MEASURES: OR calculated between the relating factors and HRD for objects and stratified by age and sex group between 2000 and 2013. RESULTS: Four hundred and three patients were included in the study group and 2015 in the control group. The incidence of HRD was 3.29/100 000, and the prevalence of HRD was 40.5/100 000 persons. The tendency of study group to have more cataract, cystoid macula oedema (CME) as compared with the control group. Among the subgroup with comorbidities, the relating factors such as hypertension, diabetes and chronic kidney disease was significantly higher among HRD patients with age 55 and above. CONCLUSIONS: 74% of the diagnosed HRD are retinitis pigmentosa. Population-based data suggested an increased incidence of cataract in younger patients, whereas older HRD patients are more susceptible to develop CME. Further work is needed to elucidate the mechanism between these ophthalmological disorders and HRD.


Assuntos
Catarata , Diabetes Mellitus , Hipertensão , Edema Macular , Insuficiência Renal Crônica , Distrofias Retinianas , Estudos de Casos e Controles , Catarata/epidemiologia , Comorbidade , Diabetes Mellitus/epidemiologia , Humanos , Hipertensão/epidemiologia , Incidência , Edema Macular/epidemiologia , Pessoa de Meia-Idade , Prevalência , Insuficiência Renal Crônica/epidemiologia , Distrofias Retinianas/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia
19.
Int J Mol Sci ; 23(7)2022 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-35409009

RESUMO

Given the popularity of ketogenic diets, their potential long-term consequences deserve to be more carefully monitored. Mitochondrially derived formate has a critical role in mammalian one-carbon (1C) metabolism and development. The glycine cleavage system (GCS) accounts for another substantial source for mitochondrially derived 1C units. OBJECTIVE: We investigated how the ketogenic state modulates mitochondrial formate generation and partitioning of 1C metabolic fluxes. DESIGN: HepG2 cells treated with physiological doses (1 mM and 10 mM) of ß-hydroxybutyrate (ßHB) were utilized as the in vitro ketogenic model. Eight-week male C57BL/6JNarl mice received either a medium-chain fatty-acid-enriched ketogenic diet (MCT-KD) or a control diet AIN 93M for 8 weeks. Stable isotopic labeling experiments were conducted. RESULTS AND CONCLUSIONS: MCT-KD is effective in weight and fat loss. Deoxythymidine (dTMP) synthesis from the mitochondrial GCS-derived formate was significantly suppressed by ßHB and consumption of MCT-KD. Consistently, plasma formate concentrations, as well as the metabolic fluxes from serine and glycine, were suppressed by MCT-KD. MCT-KD also decreased the fractional contribution of mitochondrially derived formate in methionine synthesis from serine. With the worldwide application, people and medical professionals should be more aware of the potential metabolic perturbations when practicing a long-term ketogenic diet.


Assuntos
Dieta Cetogênica , Ácido 3-Hidroxibutírico/metabolismo , Animais , Carbono/metabolismo , Dieta Cetogênica/métodos , Humanos , Corpos Cetônicos/metabolismo , Masculino , Mamíferos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Serina/metabolismo , Triglicerídeos/metabolismo
20.
Animals (Basel) ; 12(7)2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-35405859

RESUMO

Intestinal microbiota functions such as an endocrine organ to regulate host physiological homeostasis and behavioral exhibition in stress responses via regulating the gut-brain axis in humans and other mammals. In humans, stress-induced dysbiosis of the gut microbiota leads to intestinal permeability, subsequently affecting the clinical course of neuropsychiatric disorders, increasing the frequency of aggression and related violent behaviors. Probiotics, as direct-fed microorganism, have been used as dietary supplements or functional foods to target gut microbiota (microbiome) for the prevention or therapeutic treatment of mental diseases including social stress-induced psychiatric disorders such as depression, anxiety, impulsivity, and schizophrenia. Similar function of the probiotics may present in laying hens due to the intestinal microbiota having a similar function between avian and mammals. In laying hens, some management practices such as hens reared in conventional cages or at a high stocking density may cause stress, leading to injurious behaviors such as aggressive pecking, severe feather pecking, and cannibalism, which is a critical issue facing the poultry industry due to negative effects on hen health and welfare with devastating economic consequences. We discuss the current development of using probiotic Bacillus subtilis to prevent or reduce injurious behavior in laying hens.

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