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1.
Arch Esp Urol ; 77(4): 397-404, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38840283

RESUMO

OBJECTIVE: This study aimed to analyse the family resilience of patients with stress urinary incontinence (SUI) after cervical cancer surgery and its influencing factors. METHODS: Patients with cervical cancer postoperative SUI admitted to our hospital from May 2020, to May 2023, were retrospectively selected. They were divided into low-resilience group and high-resilience group in accordance with the Family Resilience Questionnaire (FaREQ). The general demographic data of the two groups were statistically analysed, and correlation and logistic regression analyses were performed. RESULTS: The FaREQ score of 222 patients was (93.61 ± 8.45). Amongst these patients, 21.62% scored less than 84 points, and 78.38% scored more than 84 points. Significant differences were found in the educational level, indwelling catheter time, family monthly income, religious belief, hope index, psychological resilience, family function and social support between the two groups (p < 0.05). A significant positive correlation was observed between family resilience and the above indicators (p < 0.05). The variance inflation coefficient values of educational level and indwelling catheter time were 15.764 and 43.766, and the tolerance values were 0.063 and 0.023, respectively. After removing them, family monthly income, religious belief, hope index, psychological resilience, family function and social support were the factors affecting the family resilience level of patients with SUI after cervical cancer surgery. CONCLUSIONS: The level of family resilience of patients with SUI after cervical cancer surgery is low. Many factors, such as family monthly income and religious belief, affect the level of resilience. Therefore, corresponding measures could be formulated in advance to improve the level of family resilience of such patients.


Assuntos
Complicações Pós-Operatórias , Resiliência Psicológica , Incontinência Urinária por Estresse , Neoplasias do Colo do Útero , Humanos , Feminino , Estudos Retrospectivos , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/psicologia , Incontinência Urinária por Estresse/psicologia , Incontinência Urinária por Estresse/cirurgia , Pessoa de Meia-Idade , Complicações Pós-Operatórias/psicologia , Complicações Pós-Operatórias/etiologia , Família/psicologia , Adulto , Idoso
2.
Int J Geriatr Psychiatry ; 39(6): e6110, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38831201

RESUMO

OBJECTIVES: To explore the association between drinking water sources and cognitive functioning among older adults residing in rural China. METHODS: Data were extracted from the 2008-2018 Chinese Longitudinal Healthy Longevity Survey. Drinking water sources were categorized according to whether purification measures were employed. The Chinese version of the Mini-Mental State Examination was used for cognitive functioning assessment, and the score of <24 was considered as having cognitive dysfunction. Cox regression analyses were conducted to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the effects of various drinking water sources, changes in such sources, and its interaction with exercise on cognition dysfunction. RESULTS: We included 2304 respondents aged 79.67 ± 10.02 years; of them, 1084 (44.49%) were men. Our adjusted model revealed that respondents consistently drinking tap water were 21% less likely to experience cognitive dysfunction compared with those drinking untreated water (HR = 0.79, 95% CI: 0.70-0.90). Respondents transitioning from natural to tap water showed were 33% less likely to experience cognitive dysfunction (HR = 0.67, 95% CI: 0.58-0.78). Moreover, the HR (95% CI) for the interaction between drinking tap water and exercising was 0.86 (0.75-1.00) when compared with that between drinking untreated water and not exercising. All results adjusted for age, occupation, exercise, and body mass index. CONCLUSIONS: Prolonged tap water consumption and switching from untreated water to tap water were associated with a decreased risk of cognitive dysfunction in older individuals. Additionally, exercising and drinking tap water was synergistically associated with the low incidence of cognitive dysfunction. These findings demonstrate the importance of prioritizing drinking water health in rural areas, indicating that purified tap water can enhance cognitive function among older adults.


Assuntos
Disfunção Cognitiva , Água Potável , População Rural , Humanos , Masculino , Idoso , Feminino , China/epidemiologia , População Rural/estatística & dados numéricos , Idoso de 80 Anos ou mais , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Estudos Longitudinais , Exercício Físico , Cognição/fisiologia , Modelos de Riscos Proporcionais , Abastecimento de Água
3.
Anim Sci J ; 95(1): e13966, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38845341

RESUMO

Prolonged exposure of bisphenol A (BPA) has adverse effects on in vitro maturation (IVM) of oocytes, but treatment with tauroursodeoxycholic acid (TUDCA) can improve the IVM and development of embryos. The purpose of this study was to investigate the effects of BPA and both BPA and TUDCA on IVM and parthenogenetic development of embryos. The results showed that BPA treatment adverse effects on the cumulus expansion index, survival rate, polar body rate, mitochondrial distribution of the oocytes after maturation culture, and that it also decreased the cleavage rate and blastocyst rate of embryos after parthenogenetic develpoment. In addition, BPA treatment upregulated expression of genes related to endoplasmic reticulum stress and apoptosis and increased the intracellular reactive oxygen species (ROS) level, while it decreased expression of genes related to cumulus expansion. However, the supplementation of TUDCA relieved these adverse effects of BPA except polar body rate, blastocyst rate, and expression of BCL2 and PTGS1. In conclusion, the supplementation of TUDCA can partly attenuate the negative effects of BPA on IVM and parthenogenetic development of embryos, possibly by modification of the expression of genes related to endoplasmic reticulum stress, apoptosis and cumulus expansion, intracellular ROS level, and mitochondrial distribution.


Assuntos
Apoptose , Compostos Benzidrílicos , Desenvolvimento Embrionário , Estresse do Retículo Endoplasmático , Técnicas de Maturação in Vitro de Oócitos , Oócitos , Partenogênese , Fenóis , Espécies Reativas de Oxigênio , Ácido Tauroquenodesoxicólico , Animais , Fenóis/toxicidade , Ácido Tauroquenodesoxicólico/farmacologia , Oócitos/efeitos dos fármacos , Partenogênese/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Suínos/embriologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Blastocisto/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos
4.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 36(5): 485-490, 2024 May.
Artigo em Chinês | MEDLINE | ID: mdl-38845494

RESUMO

OBJECTIVE: To construct a bundled therapy management and practice program for sepsis and explore its clinical application effect. METHODS: (1) Construction of sepsis bundled therapy management and practice program: a project team was established to conduct literature review, select experts, compile and distribute questionnaires, organize, analyze expert opinions, and ensure quality control throughout the research process. From October to November 2022, expert letter consultation was carried out, and questionnaires were distributed and collected by on-site filling and WeChat. The Likert 5-point scale was used to rate each item. (2) Clinical application of the protocol: ninety patients with sepsis admitted to the intensive care unit (ICU) of the First Affiliated Hospital of Xinjiang Medical University from January to July 2022 were retrospectively selected as the control group, and routine bundle treatment and nursing strategy for sepsis were adopted. Ninety patients with sepsis admitted from January to July 2023 were prospectively selected as the intervention group. Based on the treatment and nursing strategy of the control group, sepsis bundled therapy management and practice program constructed using the Delphi inquiry method was implemented. The completion rate of 1-hour, 3-hour and 6-hour bundle, the levels of inflammatory indicators at 1, 3, 7 days of treatment, and prognostic indicators were compared between the two groups. RESULTS: (1) Construction of sepsis bundled therapy management and practice program: the final plan consists of 4 primary indicators, 15 secondary indicators and 34 tertiary indicators. The response rates for both rounds of inquiry questionnaires were 100%. The coefficients of expert authority value were 0.948 and 0.940, respectively. The coefficient of variation for each item was 0-0.287 and 0-0.187, respectively. Kendall's W coefficients were 0.242 and 0.249, respectively, with statistical significances (all P < 0.05). (2) Clinical application of the protocol: there were no statistically significant differences in baseline data such as age, gender, infection site, pathogen species, duration of mechanical ventilation, sequential organ failure assessment (SOFA), acute physiology and chronic health evaluation II (APACHE II) between the two groups. The completion rate of 1-hour, 3-hour and 6-hour bundle in the intervention group were higher than those in the control group (1-hour bundle completion rate: 53.30% vs. 21.10%, 3-hour bundle completion rate: 92.20% vs. 80.00%, 6-hour bundle completion rate: 88.89% vs. 65.56%, all P < 0.05). The levels of C-reactive protein (CRP), white blood cell count (WBC), procalcitonin (PCT), and interleukin-6 (IL-6) in two groups of patients showed statistically significant differences at different time points, between groups, and in interaction effects. Compared with the control group, the length of ICU stay in the intervention group was significantly shortened [days: 7.00 (4.00, 14.00) vs. 8.00 (7.00, 20.00), P < 0.01], and the hospitalization cost of ICU was significantly reduced [ten thousand yuan: 4.63 (3.36, 6.19) vs. 6.46 (3.32, 11.34), P < 0.05]. The 28-day mortality in the intervention group was lower than that in the control group (33.33% vs. 46.67%), but the difference was not statistically significant (P > 0.05). CONCLUSIONS: The constructed bundled therapy management and practice program for sepsis can improve the completion rate of bundle treatment, shorten the length of ICU stay of sepsis patients, reduce the hospitalization cost in ICU, and have a tendency to reduce the 28-day mortality.


Assuntos
Unidades de Terapia Intensiva , Sepse , Humanos , Sepse/terapia , Inquéritos e Questionários , Unidades de Terapia Intensiva/organização & administração , Estudos Retrospectivos , Pacotes de Assistência ao Paciente/métodos
5.
Artigo em Inglês | MEDLINE | ID: mdl-38850311

RESUMO

PURPOSE: The reversibility of early liver fibrosis highlights the need for improved early detection and monitoring techniques. Fibroblast activation protein (FAP) is a promising theranostics target significantly upregulated during fibrosis. This preclinical and preliminary clinical study investigated a FAP-targeted probe, gallium-68-labeled FAP inhibitor 04 ([68Ga]Ga-DOTA-FAPI-04), for its capability to visualize liver fibrosis. METHODS: The preclinical study employed [68Ga]Ga-DOTA-FAPI-04 micro-positron emission tomography (PET)/computed tomography (CT) on carbon tetrachloride-induced mice model (n = 34) and olive oil-treated control group (n = 26), followed by validation of the probe's biodistribution. Hepatic uptake was correlated with fibrosis and inflammation levels, quantified through histology and serum assays. FAP and α-smooth muscle actin expression were determined by immunohistochemistry, as well as immunofluorescence. The subsequent clinical trial enrolled 26 patients with suspected or confirmed liver fibrosis to undergo [68Ga]Ga-DOTA-FAPI-04 PET/magnetic resonance imaging or PET/CT. Key endpoints included correlating [68Ga]Ga-DOTA-FAPI-04 uptake with histological inflammation grades and fibrosis stages, and evaluating its diagnostic and differential efficacy compared to established serum markers and liver stiffness measurement (LSM). RESULTS: [68Ga]Ga-DOTA-FAPI-04 mean uptake in mice livers was notably higher than in control mice, increasing from week 6 [0.70 ± 0.11 percentage injected dose per cubic centimeter (%ID/cc)], peaking at week 10 (0.97 ± 0.15%ID/cc) and slightly reducing at week 12 (0.89 ± 0.28%ID/cc). The hepatic biodistribution and FAP expression showed a consistent trend. In the patient cohort, hepatic [68Ga]Ga-DOTA-FAPI-04 uptake presented moderate correlations with inflammation grades (r = 0.517 to 0.584, all P < 0.05) and fibrosis stages (r = 0.653 to 0.698, all P < 0.01). The average SUVmax to background ratio in the liver showed superior discriminative ability, especially between stage 0 and stage 1, outperforming LSM (area under curve 0.984 vs. 0.865). CONCLUSION: [68Ga]Ga-DOTA-FAPI-04 PET shows significant potential for non-invasive visualization and dynamic monitoring of liver fibrosis in both preclinical experiment and preliminary clinical trial, especially outperforming other common clinical indicators in the early stage. TRIAL REGISTRATION: NCT04605939. Registered October 25, 2020, https://clinicaltrials.gov/study/NCT04605939.

6.
Front Immunol ; 15: 1403324, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38694498

RESUMO

[This corrects the article DOI: 10.3389/fimmu.2023.1254532.].

7.
Plants (Basel) ; 13(9)2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38732446

RESUMO

SCARECROW-LIKE6 (SCL6) plays a role in the formation and maintenance of the meristem. In Larix kaempferi (Lamb.) Carr., an important afforestation tree species in China, SCL6 (LaSCL6) has two alternative splicing variants-LaSCL6-var1 and LaSCL6-var2-which are regulated by microRNA171. However, their roles are still unclear. In this study, LaSCL6-var1 and LaSCL6-var2 were transformed into the Arabidopsis thaliana (L.) Heynh. genome, and the phenotypic characteristics of transgenic A. thaliana, including the germination percentage, root length, bolting time, flower and silique formation times, inflorescence axis length, and branch and silique numbers, were analyzed to reveal their functions. It was found that LaSCL6-var1 and LaSCL6-var2 overexpression shortened the root length by 41% and 31%, respectively, and increased the inflorescence axis length. Compared with the wild type, the bolting time in transgenic plants was delayed by approximately 2-3 days, the first flower and silique formation times were delayed by approximately 3-4 days, and the last flower and silique formation times were delayed by about 5 days. Overall, the life cycle in transgenic plants was prolonged by approximately 5 days. These results show that LaSCL6 overexpression inhibited the transitions from the vegetative meristem to inflorescence meristem and from the flower meristem to meristem arrest in A. thaliana, revealing the roles of LaSCL6-var1 and LaSCL6-var2 in the fate transition and maintenance of the meristem.

8.
Arch Gynecol Obstet ; 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38753205

RESUMO

PURPOSE: To evaluate the effect of intravenous infusion versus intramyometrial injection of oxytocin on hemoglobin levels in neonates with delayed umbilical cord clamping during cesarean section. METHODS: The multi-centre randomized controlled trial was performed at three hospitals from February to June 2023. Women with term singleton gestations scheduled for cesarean delivery were allocated to receive an intravenous infusion of 10 units of oxytocin or a myometrial injection of 10 units of oxytocin during the surgery. The primary outcome was neonatal hemoglobin at 48 to 96 h after birth. Secondary outcomes were side-effects of oxytocin, postpartum haemorrhage, phototherapy for jaundice, feeding at 1 month, maternal and neonatal morbidity and re-admissions. RESULTS: A total of 360 women were randomized (180 women in each group). The mean neonatal hemoglobin did not show a significant difference between the intravenous infusion group (194.3 ± 21.7 g/L) and the intramyometrial groups (195.2 ± 24.3 g/L) (p = 0.715). Secondary neonatal outcomes, involving phototherapy for jaundice, feeding at 1 month and neonatal intensive care unit admission were similar between the two groups. The maternal outcomes did not differ significantly between the two groups, except for a 200 mL higher intraoperative infusion volume observed in the intravenous group compared to the intramyometrial group. CONCLUSION: Among women undergoing elective cesarean delivery of term singleton pregnancies, there was no significant difference in neonatal hemoglobin at 48 to 96 h after birth between infants with delayed cord clamping, whether the oxytocin was administrated by intravenous infusion or intramyometrial injection. TRIAL REGISTRATION: Chinese Clinical trial registry: ChiCTR2300067953 (1 February 2023).

9.
Nat Commun ; 15(1): 3987, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38734698

RESUMO

Despite advances in active drug targeting for blood-brain barrier penetration, two key challenges persist: first, attachment of a targeting ligand to the drug or drug carrier does not enhance its brain biodistribution; and second, many brain diseases are intricately linked to microcirculation disorders that significantly impede drug accumulation within brain lesions even after they cross the barrier. Inspired by the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, we propose a molecular library design centered on this class of cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system. Our findings reveal that: (i) vinpocetine-derived ionizable-lipidoid nanoparticles efficiently breach the blood-brain barrier; (ii) they have high gene-loading capacity, facilitating endosomal escape and intracellular transport; (iii) their administration is safe with minimal immunogenicity even with prolonged use; and (iv) they have potent pharmacologic brain-protective activity and may synergize with treatments for brain disorders as demonstrated in male APP/PS1 mice.


Assuntos
Barreira Hematoencefálica , Encéfalo , Circulação Cerebrovascular , Nanopartículas , Alcaloides de Vinca , Animais , Alcaloides de Vinca/farmacologia , Alcaloides de Vinca/farmacocinética , Alcaloides de Vinca/administração & dosagem , Alcaloides de Vinca/química , Nanopartículas/química , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Camundongos , Circulação Cerebrovascular/efeitos dos fármacos , Masculino , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Humanos , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Camundongos Endogâmicos C57BL , Distribuição Tecidual , Sistemas de Liberação de Medicamentos , Camundongos Transgênicos
10.
Heliyon ; 10(9): e30759, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38765170

RESUMO

Background: Transarterial chemoembolization (TACE) is a common treatment for hepatocellular carcinoma (HCC), but the best therapeutic agent for TACE treatment has not been determined. The neutrophil/lymphocyte ratio (NLR) is a systemic immune system marker; however, the ability of the NLR to predict the prognosis of patients with HCC is unknown, and no studies have been conducted to determine the most appropriate TACE regimen for HCC patients with different NLRs. Methods: The PubMed, Embase, Web of Science, and CNKI databases were searched through May 28, 2023. Comparisons of overall survival (OS) among cohort studies with different NLRs and different TACE treatment regimens were performed with a random effects model. Findings: Thirty-five studies involving 9210 patients were included in this meta-analysis. The results showed that Group 3-4 (NLR<2.5) patients had a significantly longer OS than Group 1-2 (NLR 2.5-5.0). Among the patients, Group 1-3 (NLR 2.0-5.0) patients had the best survival after treatment with adriamycin (lnHR (95 % CI = 0.48 [0.31, 0.75] and lnHR (95 % CI = 0.41 [0.19, 0.91]). Among the Group 4 patients (NLR<2.0), the best outcome was obtained with platinum + adriamycin (lnHR (95 % CI = 0.59 [0.45, 0.78]), followed by adriamycin. A subgroup analysis of TACE combined with other treatments showed that adriamycin combined with sorafenib was the most effective and superior to the other treatment agents. Interpretation: The NLR can be used to predict the prognosis of HCC patients treated with TACE; the higher the NLR is, the worse the prognosis. Adriamycin may be the best therapeutic agent for HCC patients treated with TACE.

11.
ACS Appl Mater Interfaces ; 16(20): 26348-26359, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38728664

RESUMO

Organic solar cells (OSCs) could benefit from the ternary bulk heterojunction (BHJ), a method that allows for fine-tuning of light capture, cascade energy levels, and film shape, in order to increase their power conversion efficiency (PCE). In this work, the third components of PM6:Y6 and PM6:BTP-eC9 BHJs are a set of four star-shaped unfused ring electron acceptors (SSUFREAs), i.e., BD-IC, BFD-IC, BD-2FIC, and BFD-2FIC, that are facilely synthesized by direct C-H arylation. The four SSUFREAs all show complete complementary absorption with PM6, Y6, and BTP-eC9, which facilitates light harvesting and exciton collection. When BFD-2FIC is added as a third component, the PCEs of PM6:Y6 and PM6:BTP-eC9 binary BHJs are able to be improved from 15.31% to 16.85%, and from 16.23% to 17.23%, respectively, showing that BFD-2FIC is useful for most effective ternary OSCs in general, and increasing short circuit current (JSC) and better film morphology are two additional benefits. The ternary PM6:Y6:BFD-2FIC exhibits a 9.7% percentage of increase in PCE compared to the PM6:Y6 binary BHJ, which is one of the highest percentage increases among the reported ternary BHJs, showing the huge potential of BFD-2FIC for ternary BHJ OSCs.

12.
Am J Transl Res ; 16(4): 1062-1080, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38715839

RESUMO

BACKGROUND: ETS1, a member of the large ETS domain family of transcription factors, plays a role in the progression of many types of carcinoma. ETS1 expression has been linked to a more favorable prognosis in renal cell carcinoma. The objective of this study was to assess the predictive significance of ETS1 in individuals suffering from clear cell renal cell carcinoma (ccRCC). METHODS: The correlation between ETS1 expression and ccRCC was analyzed. Data on ETS1 and clinical information for ccRCC patients were obtained from the Cancer Genome Atlas database and analyzed using R software. Then, we presented validation results using RT-qPCR (quantitative reverse transcription PCR). The receiver operator characteristic (ROC) curves were generated using the pROC software package to determine the cutoff values for ETS1. Additionally, the ImmuneScore, StromalScore, and ESTIMATEScore were calculated using the ESTIMATES algorithm. The connection between ccRCC and ETS1 was investigated using enrichment analysis based on Gene Oncology and the Kyoto Encyclopedia of Genes and Genomes. The tumor immunity estimation resource (TIMER) and the integrated repository portal for tumor-immune system interactions (TISIDB) databases were utilized to analyze the association between ETS1 expression and immune cell infiltration in ccRCC. The impact of ETS1 on the survival of ccRCC patients was evaluated using the PrognoScan database. We evaluated the Tumor Mutation Burden (TMB) value between the two sets of samples with high and low ETS1 expression, as well as the differences in gene mutations between the two groups. RESULTS: The mRNA expression of ETS1 in ccRCC was higher compared to normal tissues. Results showed a significant positive correlation between elevated ETS1 expression levels and improved overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS), with a P < 0.05. Furthermore, high ETS1 expression levels were closely linked to early tumor stage and prolonged survival time. TMB in the ETS1-high expression group was significantly less than that in the ETS1-low expression group. CONCLUSIONS: Downregulation of ETS1 expression correlated with poor prognosis and immune infiltration in ccRCC, further suggesting that ETS1 may be a biomarker for better prognosis in ccRCC patients.

13.
Cell Metab ; 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38718793

RESUMO

Obesity alters levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, dysregulation of which leads to nonalcoholic fatty liver disease (NAFLD). However, the impact of obesity on intra-pituitary homeostasis is largely unknown. Here, we uncovered a blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice and humans. Furthermore, we found that obesity inflames the pituitary gland, leading to impaired pituitary inositol-requiring enzyme 1α (IRE1α)-X-box-binding protein 1 (XBP1) UPR branch, which is essential for protecting against pituitary endocrine defects and NAFLD progression. Intriguingly, pituitary IRE1-deletion resulted in hypothyroidism and suppressed the thyroid hormone receptor B (THRB)-mediated activation of Xbp1 in the liver. Conversely, activation of the hepatic THRB-XBP1 axis improved NAFLD in mice with pituitary UPR defect. Our study provides the first evidence and mechanism of obesity-induced intra-pituitary cellular defects and the pathophysiological role of pituitary-liver UPR communication in NAFLD progression.

14.
Redox Biol ; 73: 103139, 2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38696898

RESUMO

In this study, we observed worsening metabolic crosstalk in mouse models with concomitant metabolic disorders such as hyperhomocysteinemia (HHcy), hyperlipidemia, and hyperglycemia and in human coronary artery disease by analyzing metabolic profiles. We found that HHcy worsening is most sensitive to other metabolic disorders. To identify metabolic genes and metabolites responsible for the worsening metabolic crosstalk, we examined mRNA levels of 324 metabolic genes in Hcy, glucose-related and lipid metabolic systems. We examined Hcy-metabolites (Hcy, SAH and SAM) by LS-ESI-MS/MS in 6 organs (heart, liver, brain, lung, spleen, and kidney) from C57BL/6J mice. Through linear regression analysis of Hcy-metabolites and metabolic gene mRNA levels, we discovered that SAH-responsive genes were responsible for most metabolic changes and all metabolic crosstalk mediated by Serine, Taurine, and G3P. SAH-responsive genes worsen glucose metabolism and cause upper glycolysis activation and lower glycolysis suppression, indicative of the accumulation of glucose/glycogen and G3P, Serine synthesis inhibition, and ATP depletion. Insufficient Serine due to negative correlation of PHGDH with SAH concentration may inhibit the folate cycle and transsulfurarion pathway and consequential reduced antioxidant power, including glutathione, taurine, NADPH, and NAD+. Additionally, we identified SAH-activated pathological TG loop as the consequence of increased fatty acid (FA) uptake, FA ß-oxidation and Ac-CoA production along with lysosomal damage. We concluded that HHcy is most responsive to other metabolic changes in concomitant metabolic disorders and mediates worsening metabolic crosstalk mainly via SAH-responsive genes, that organ-specific Hcy metabolism determines organ-specific worsening metabolic reprogramming, and that SAH, acetyl-CoA, Serine and Taurine are critical metabolites mediating worsening metabolic crosstalk, redox disturbance, hypomethylation and hyperacetylation linking worsening metabolic reprogramming in metabolic syndrome.

15.
Front Cell Dev Biol ; 12: 1370042, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38694821

RESUMO

TIR domain-containing adaptor inducing IFN-ß (TRIF) is a crucial adaptor molecule downstream of toll-like receptors 3 (TLR3) and 4 (TLR4). TRIF directly binds to TLR3 through its TIR domain, while it associates with TLR4 indirectly through the bridge adaptor molecule TRIF-related adaptor molecule (TRAM). TRIF plays a pivotal role in regulating interferon beta 1 (IFN-ß) response, nuclear factor kappa B (NF-κB) signaling, apoptosis, and necroptosis signaling mediated by TLR3 and TLR4. It accomplishes these by recruiting and activating various kinases or transcription factors via its distinct domains. In this review, we comprehensively summarize the TRIF-dependent signaling pathways mediated by TLR3 and TLR4, elucidating key target molecules and downstream pathways. Furthermore, we provide an overview of TRIF's impact on several liver disorders, including drug-induced liver injury, ischemia-reperfusion liver injury, autoimmune hepatitis, viral hepatitis, alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). We also explore its effects on liver steatosis, inflammation, fibrosis, and carcinogenesis. A comprehensive understanding of the TRIF-dependent signaling pathways, as well as the intricate relationship between TRIF and liver diseases, can facilitate the identification of potential drug targets and the development of novel and effective therapeutics against hepatic disorders.

17.
Heliyon ; 10(10): e30806, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38803858

RESUMO

Platinum-based chemotherapies, historically the cornerstone of first-line treatment for small-cell lung cancer (SCLC), face a major hurdle: the frequent emergence of chemoresistance, notably to cisplatin (CDDP). Current understanding of the mechanisms driving CDDP resistance in SCLC is incomplete. Notably, Interferon inducible transmembrane protein1 (IFITM1) has been identified as a key player in the distant metastasis of SCLC. Analysis of The Cancer Genome Atlas (TCGA) database revealed that IFITM1 expression is markedly elevated in tumor tissues as compared to that from adjacent normal tissues, correlating with a worse prognosis for patients with SCLC. Our research focused on investigating the role of IFITM1 in the acquisition of cisplatin resistance in SCLC. Further clinical sample analysis highlighted a significant increase in IFITM1 levels in SCLC tissues from cisplatin-resistant patients versus those were responsive to CCDP treatment, with similar trends observed in cisplatin-resistant SCLC cells. Crucially, overexpression of IFITM1 reduced the sensitivity of SCLC cells to cisplatin, while silencing IFITM1 enhanced chemosensitivity in cisplatin-resistant strains. Our in vivo studies further confirmed that silencing IFITM1 significantly boosted the efficacy of cisplatin in inhibiting growth of subcutaneous tumors of NCI-H466/CDDP cells (cisplatin-resistant SCLC cells) in a mouse model. Mechanistically, IFITM1 appears to foster cisplatin resistance through activation of the Wnt/ß-catenin pathway. In summary, our findings suggest that targeting IFITM1, alongside cisplatin treatment, could offer a promising therapeutic strategy to overcome resistance and improve outcomes for SCLC patients.

18.
Microbiol Spectr ; : e0422823, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38814065

RESUMO

The emergence of carbapenem-resistant Escherichia coli strains poses a considerable challenge to global public health, and little is known about carbapenemase-producing E. coli strains in Tianjin, China. This study aimed to investigate the risk factors for infections with carbapenem-resistant E. coli (CREC) strains. This retrospective case-control study was conducted at a tertiary teaching hospital. A total of 134 CREC clinical isolates were collected from the General Hospital of Tianjin Medical University between 2013 and 2020. The control group was selected at a ratio of 1:1 from patients with nosocomial carbapenem-susceptible E. coli infection. Risk factors for nosocomial CREC infection and clinical outcomes were analyzed using univariate and multivariate analyses. Multivariate analysis revealed that cephalosporin exposure (odd ratio OR = 2.01), carbapenem exposure (OR = 1.96), glucocorticoid exposure (OR = 32.45), and surgical history (OR = 3.26) were independent risk factors for CREC infection. The in-hospital mortality rate in the CREC group was 29.1%, and age >65 years (OR = 3.19), carbapenem exposure (OR = 3.54), and central venous catheter insertion (OR = 4.19) were independent risk factors for in-hospital mortality in patients with CREC infections. Several factors were identified in the development of nosocomial CREC infections. The CREC isolates were resistant to most antibiotics. Reducing CREC mortality requires a comprehensive consideration of appropriate antibiotic use, underlying diseases, and invasive procedures.IMPORTANCEEscherichia coli is an opportunistic pathogen that causes severe hospital-acquired infections. The spread of carbapenem-resistant E. coli is a global threat to public health, and only a few antibiotics are effective against these infections. Consequently, these infections are usually associated with poor prognosis and high mortality. Therefore, understanding the risk factors associated with the causes and outcomes of these infections is crucial to reduce their incidence and initiate appropriate therapies. In our study, several factors were found to be involved in nosocomial carbapenem-resistant E. coli (CREC) infections, and CREC isolates were resistant to most antibiotics. Reducing CREC mortality needs a comprehensive consideration of whether antibiotics are used appropriately, underlying diseases, and invasive interventions. These findings provide valuable evidence for the development of anti-infective therapy, infection prevention, and control of CREC-positive infections.

19.
JAMA Netw Open ; 7(5): e2413708, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38809553

RESUMO

Importance: Helicobacter pylori treatment and nutrition supplementation may protect against gastric cancer (GC), but whether the beneficial effects only apply to potential genetic subgroups and whether high genetic risk may be counteracted by these chemoprevention strategies remains unknown. Objective: To examine genetic variants associated with the progression of gastric lesions and GC risk and to assess the benefits of H pylori treatment and nutrition supplementation by levels of genetic risk. Design, Setting, and Participants: This cohort study used follow-up data of the Shandong Intervention Trial (SIT, 1989-2022) and China Kadoorie Biobank (CKB, 2004-2018) in China. Based on the SIT, a longitudinal genome-wide association study was conducted to identify genetic variants for gastric lesion progression. Significant variants were examined for incident GC in a randomly sampled set of CKB participants (set 1). Polygenic risk scores (PRSs) combining independent variants were assessed for GC risk in the remaining CKB participants (set 2) and in an independent case-control study in Linqu. Exposures: H pylori treatment and nutrition supplementation. Main Outcomes and Measures: Primary outcomes were the progression of gastric lesions (in SIT only) and the risk of GC. The associations of H pylori treatment and nutrition supplementation with GC were evaluated among SIT participants with different levels of genetic risk. Results: Our analyses included 2816 participants (mean [SD] age, 46.95 [9.12] years; 1429 [50.75%] women) in SIT and 100 228 participants (mean [SD] age, 53.69 [11.00] years; 57 357 [57.23%] women) in CKB, with 147 GC cases in SIT and 825 GC cases in CKB identified during follow-up. A PRS integrating 12 genomic loci associated with gastric lesion progression and incident GC risk was derived, which was associated with GC risk in CKB (highest vs lowest decile of PRS: hazard ratio [HR], 2.54; 95% CI, 1.80-3.57) and further validated in the analysis of 702 case participants and 692 control participants (mean [SD] age, 54.54 [7.66] years; 527 [37.80%] women; odds ratio, 1.83; 95% CI, 1.11-3.05). H pylori treatment was associated with reduced GC risk only for individuals with high genetic risk (top 25% of PRS: HR, 0.45; 95% CI, 0.25-0.82) but not for those with low genetic risk (HR, 0.81; 95% CI, 0.50-1.34; P for interaction = .03). Such effect modification was not found for vitamin (P for interaction = .93) or garlic (P for interaction = .41) supplementation. Conclusions and Relevance: The findings of this cohort study indicate that a high genetic risk of GC may be counteracted by H pylori treatment, suggesting primary prevention could be tailored to genetic risk for more effective prevention.


Assuntos
Predisposição Genética para Doença , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/complicações , China/epidemiologia , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles , Adulto , Fatores de Risco , Suplementos Nutricionais , Estudos de Coortes , Idoso , Antibacterianos/uso terapêutico
20.
Lung Cancer ; 192: 107817, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38735177

RESUMO

OBJECTIVE: The aim of this study is to scrutinize the prognostic significance of inflammatory biomarkers concerning the effectiveness and safety of combining PD-1 inhibition with chemotherapy in the management of advanced NSCLC. METHODS: We conducted a retrospective analysis involving 206 NSCLC patients who received treatment at Qingdao Municipal Hospital. The study encompassed the acquisition of baseline clinical attributes and hematological parameters of these patients. The optimal threshold values for PLT and NLR were ascertained based on pre-treatment evaluations, with a particular focus on their association with PFS. Variables linked to PFS were subject to scrutiny through Kaplan-Meier analysis and logistic regression. The Receiver Operating Characteristic (ROC) curve served as the means to determine the ideal cut-off values for categorizing levels of inflammatory markers into high and low classifications. We employed Chi-square tests to evaluate the relationship between elevated and reduced baseline levels of inflammatory markers and irAE. RESULTS: Kaplan-Meier analysis disclosed that patients in the low baseline PLT group and the low NLR group exhibited a substantially more favorable prognosis in contrast to their counterparts in the high baseline PLT and high NLR groups. Multivariate analysis indicated that diminished baseline PLT and NLR levels before treatment independently foretell extended PFS. Chi-square analysis underscored a substantial correlation between baseline WBC, NEUT, LYMPH, MONO, and NLR levels and irAE. CONCLUSION: Subdued baseline PLT and NLR levels may serve as indicators of a more auspicious prognosis in patients contending with advanced NSCLC undergoing the combination of PD-1 inhibition and chemotherapy. Elevated baseline levels of inflammatory markers antedating PD-1 therapy in advanced NSCLC may be intimately interrelated with the occurrence of irAE.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Pessoa de Meia-Idade , Estudos Retrospectivos , Prognóstico , Idoso , Imunoterapia/métodos , Biomarcadores Tumorais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Inflamação , Idoso de 80 Anos ou mais
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