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INTRODUCTION: Prostate cancer (PCa) located in the peripheral zone (PZ) and transitional zone (TZ) showed a different clinical and pathological characteristic. This passage aims to preliminarily evaluate the relationship between the zonal heterogeneity of PCa quantitatively assessed by bpMRI and pathological risk stratification of the primary lesion. METHODS: This prospective study was conducted from January 2019 to February 2023. A total of 113 PCa patients whose bpMRI data indicated that the lesions located in only 1 single zone of the prostate were selected. A transrectal ultrasound and MRI-targeted biopsy were performed to verify the bpMRI results, and then radical prostatectomy (RP) was performed in 3 weeks after the biopsy. The high-risk (HR) group was defined as ISUP grades ≥ 3. Binary regression was performed to evaluate if the zonal heterogeneity could be an independent predictor of the HR group. The receiver operator characteristic (ROC) curve was performed to analyze the added value of zonal location in predicting the HR group. RESULTS: PSA, T staging, and ISUP grades, incidence of positive surgical margins were significantly lower in the TZ PCa, and the ADCmin, and ADCmean values in the TZ PCa were significantly higher (all P < .01). The zonal heterogeneity could independently predict the HR group patients (OR: 5.170 [1.663-16.067], P = .005) and improve the predicting efficiency of HR patients (AUC 0.824, 95% CI, 0.741-0.889). CONCLUSIONS: BpMRI could quantitively assess the zonal heterogeneity of PCa precisely and increase the predicting efficacy of HR patients, which can provide better help for clinical individualized treatment.
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BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with an extended Tofts linear (ETL) model for tissue and tumor evaluation has been established, but its effectiveness in evaluating the pancreas remains uncertain. PURPOSE: To understand the pharmacokinetics of normal pancreas and serve as a reference for future studies of pancreatic diseases. MATERIAL AND METHODS: Pancreatic pharmacokinetic parameters of 54 volunteers were calculated using DCE-MRI with the ETL model. First, intra- and inter-observer reliability was assessed through the use of the intra-class correlation coefficient (ICC) and coefficient of variation (CoV). Second, a subgroup analysis of the pancreatic DCE-MRI pharmacokinetic parameters was carried out by dividing the 54 individuals into three groups based on the pancreatic region, three groups based on age, and two groups based on sex. RESULTS: There was excellent agreement and low variability of intra- and inter-observer to pancreatic DCE-MRI pharmacokinetic parameters. The intra- and inter-observer ICCs of Ktrans, kep, ve, and vp were 0.971, 0.952, 0.959, 0.944 and 0.947, 0.911, 0.978, 0.917, respectively. The intra- and inter-observer CoVs of Ktrans, kep, ve, vp were 9.98%, 5.99%, 6.47%, 4.76% and 10.15%, 5.22%, 6.28%, 5.40%, respectively. Only the pancreatic ve of the older group was higher than that of the young and middle-aged groups (P = 0.042, 0.001), and the vp of the pancreatic head was higher than that of the pancreatic body and tail (P = 0.014, 0.043). CONCLUSION: The application of DCE-MRI with an ETL model provides a reliable, robust, and reproducible means of non-invasively quantifying pancreatic pharmacokinetic parameters.
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Meios de Contraste , Imageamento por Ressonância Magnética , Pâncreas , Humanos , Meios de Contraste/farmacocinética , Imageamento por Ressonância Magnética/métodos , Masculino , Feminino , Pâncreas/diagnóstico por imagem , Reprodutibilidade dos Testes , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Aumento da Imagem/métodos , Variações Dependentes do ObservadorRESUMO
We report the design and synthesis of a series of proline-derived quinoline formamide compounds as human urate transporter 1 (URAT1) inhibitors via a ligand-based pharmacophore approach. Structure-activity relationship studies reveal that the replacement of the carboxyl group on the polar fragment with trifluoromethanesulfonamide and substituent modification at the 6-position of the quinoline ring greatly improve URAT1 inhibitory activity compared with lesinurad. Compounds 21c, 21e, 24b, 24c, and 23a exhibit potent activities against URAT1 with IC50 values ranging from 0.052 to 0.56 µM. Furthermore, compound 23a displays improved selectivity towards organic anion transporter 1 (OAT1), good microsomal stability, low potential for genotoxicity and no inhibition of the hERG K+ channel. Compounds 21c and 23a, which have superior pharmacokinetic properties, also demonstrate significant uric acid-lowering activities in a mouse model of hyperuricemia. Notably, 21c also exhibits moderate anti-inflammatory activity related to the gout inflammatory pathway. Compounds 21c and 23a with superior druggability are potential candidates for the treatment of hyperuricemia and gout.
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Gota , Hiperuricemia , Transportadores de Ânions Orgânicos , Quinolinas , Camundongos , Animais , Humanos , Ácido Úrico/metabolismo , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Quinolinas/farmacologiaRESUMO
AIM: Non-alcoholic fatty liver is the most common cause of chronic liver disease. GPR40 is a potential therapeutic target for energy metabolic disorders. GPR40 is a potential therapeutic target for energy metabolic disorders. SZZ15-11 is a newly synthesized GPR40 agonist. In this study, we estimate the potency of SZZ15-11 in fatty liver treatment. METHODS: In vivo, diet-induced obese (DIO) mice received SZZ15-11 (50 mg/kg) and TAK875 (50 mg/kg) for 6 weeks. Blood glucose and lipid, hepatocyte lipid and liver morphology were analysed. In vitro, HepG2 cells and GPR40-knockdown HepG2 cells induced with 0.3 mM oleic acid were treated with SZZ15-11. Triglyceride and total cholesterol of cells were measured. At the same time, the AMPK pathway regulating triglycerides and cholesterol esters synthesis was investigated via western blot and quantitative polymerase chain reaction in both liver tissue and HepG2 cells. RESULTS: SZZ15-11 was found to not only attenuate hyperglycaemia and hyperlipidaemia but also ameliorate fatty liver disease in DIO mice. At the same time, SZZ15-11 decreased triglyceride and total cholesterol content in HepG2 cells. Whether examined in the liver of DIO mice or in HepG2 cells, SZZ15-11 upregulated AMPKα phosphorylation and then downregulated the expression of the cholesterogenic key enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibited acetyl-CoA carboxylase activity. Furthermore, SZZ15-11 promotes AMPK activity via [cAMP]i accumulation. CONCLUSION: This study confirmed that SZZ15-11, a novel GPR40 agonist, improves hyperlipidaemia and fatty liver, partially via Gs signalling and the AMPK pathway in hepatocytes.
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Proteínas Quinases Ativadas por AMP , Homeostase , Hepatopatia Gordurosa não Alcoólica , Obesidade , Receptores Acoplados a Proteínas G , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Dieta Hiperlipídica , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triglicerídeos/metabolismoRESUMO
BACKGROUND: Hemodialysis holds the highest incidence and prevalence rate in Taiwan globally. However, the implementation of advance care planning (ACP), advance directives (AD), and patient self-determination acts (PSDA) remains limited. Our objective was to examine the current status of ACP, AD and PSDA and potential opportunities for enhancement. METHODS: We developed a novel questionnaire to assess individuals' knowledge, attitudes, and intentions regarding ACP, AD, and PSDA. We also collected baseline characteristics and additional inquiries for correlation analysis to identify potential factors. Student's t-test and Analysis of Variance were employed to assess significance. RESULTS: Initially, a cohort of 241 patients was initially considered for inclusion in this study. Subsequently, 135 patients agreed to participate in the questionnaire study, resulting in 129 valid questionnaires. Among these respondents, 76 were male (59.9%), and 53 were female (41.1%). Only 13.2% had signed AD. A significant portion (85.3%) indicated that they had not discussed their dialysis prognosis with healthcare providers. Additionally, a mere 14% engaged in conversations about life-threatening decisions. Ninety percent believed that healthcare providers had not furnished information about ACP, and only 30% had discussed such choices with their families. The findings revealed that the average standardized score for ACP and AD goals was 84.97, while the attitude towards PSDA received a standardized score of 69.94. The intention score stood at 69.52 in standardized terms. Potential candidates for ACP initiation included individuals aged 50 to 64, possessing at least a college education, being unmarried, and having no history of diabetes. CONCLUSION: Patients undergoing hemodialysis exhibited a significant knowledge gap concerning ACP, AD, and the PSDA. Notably, a substantial number of dialytic patients had not received adequate information on these subjects. Nevertheless, they displayed a positive attitude, and a considerable proportion expressed a willingness to sign AD. It is imperative for nephrologists to take an active role in initiating ACP discussions with patients from the very beginning.
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Planejamento Antecipado de Cuidados , Patient Self-Determination Act , Estados Unidos , Humanos , Masculino , Feminino , Intenção , Conhecimentos, Atitudes e Prática em Saúde , Diretivas Antecipadas , Diálise RenalRESUMO
BACKGROUND: Geriatric hip fractures are one of the most common fractures in elderly individuals, and prolonged hospital stays increase the risk of death and complications. Machine learning (ML) has become prevalent in clinical data processing and predictive models. This study aims to develop ML models for predicting extended length of stay (eLOS) among geriatric patients with hip fractures and to identify the associated risk factors. AIM: To develop ML models for predicting the eLOS among geriatric patients with hip fractures, identify associated risk factors, and compare the performance of each model. METHODS: A retrospective study was conducted at a single orthopaedic trauma centre, enrolling all patients who underwent hip fracture surgery between January 2018 and December 2022. The study collected various patient characteristics, encompassing demographic data, general health status, injury-related data, laboratory examinations, surgery-related data, and length of stay. Features that exhibited significant differences in univariate analysis were integrated into the ML model establishment and subsequently cross-verified. The study compared the performance of the ML models and determined the risk factors for eLOS. RESULTS: The study included 763 patients, with 380 experiencing eLOS. Among the models, the decision tree, random forest, and extreme Gradient Boosting models demonstrated the most robust performance. Notably, the artificial neural network model also exhibited impressive results. After cross-validation, the support vector machine and logistic regression models demonstrated superior performance. Predictors for eLOS included delayed surgery, D-dimer level, American Society of Anaesthesiologists (ASA) classification, type of surgery, and sex. CONCLUSION: ML proved to be highly accurate in predicting the eLOS for geriatric patients with hip fractures. The identified key risk factors were delayed surgery, D-dimer level, ASA classification, type of surgery, and sex. This valuable information can aid clinicians in allocating resources more efficiently to meet patient demand effectively.
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BACKGROUND: The prevalence of osteoporosis and low bone mass is steadily rising each year. Low body weight is commonly linked to diminished bone mass and serves as a robust predictor of osteoporosis. Nonetheless, the connection between body mass index (BMI), bone mineral density, and lipid profiles among the elderly remains elusive. AIM: To examine the association between BMI and bone mass, explore the correlation between lipid profiles and bone mass, and delve into the interplay between lipid metabolism and bone health. METHODS: The study included 520 patients aged ≥ 65 years (178 men and 342 women). Age, sex, weight, and height were recorded. Femoral neck bone mineral density and T scores were determined using a dual-energy X-ray absorptiometry scanner. Blood calcium (Ca), phosphorus (P), albumin (ALB), alkaline phosphatase (ALP), aspartate aminotransferase, alanine aminotransferase, triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels were measured. Patients were classified by sex (male and female), age (65-79 years and ≥ 80 years), and T score (normal bone mineral density, osteopenia and osteoporosis). RESULTS: Age, sex, BMI, and ALP and TG levels were independent risk factors for osteoporosis. For the 65-79- and ≥ 80-year-old groups, females presented lower T scores than males. Ca, P, ALB, ALP, TC, HDL and LDL levels were significantly different between men and women in the 65-79-year-old group. In addition, BMI and TG levels were significantly decreased in osteoporotic patients compared with patients with normal bone mass. TC levels declined in 65- to 79-year-old male and female osteoporosis patients. In the group of women aged ≥ 80 years, osteoporotic patients showed significantly increased ALP levels. Furthermore, we found positive correlations between BMI and TG levels in the male and female patient groups. However, we found no significant differences in ALB, Ca, P, HDL and LDL levels in osteoporotic patients compared to patients with normal bone mass. CONCLUSION: Osteoporotic patients showed significantly decreased BMI and TG levels compared with those with normal bone mass. BMI showed positive correlations with TG levels in male and female patients. These results indicate correlations between BMI and bone mass and between lipid profiles and bone mass.
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Background: Morus alba L. (Sangzhi) alkaloid (SZ-A) is a new antidiabetic drug approved by the China National Medical Products Administration in 2020. Diabetic nephropathy (DN) is a common diabetic complication and an important cause of morbidity and mortality in patients with diabetes. The effects of SZ-A on DN remain unknown. Purpose: This study evaluated the effects of SZ-A on DN in Zucker diabetic fatty (ZDF) rats and explored the underlying mechanisms based on nitrosative stress, inflammation, and fibrosis. Methods: Diabetic ZDF rats were orally administered 100 and 200 mg/kg of SZ-A once daily for 9 weeks. The glucose metabolism and kidney function were assayed. The pathological injury and fibrosis of the kidneys were separately evaluated using hematoxylin and eosin staining and Masson's staining. The oxidative and nitrosative stress and inflammation were assayed by determining the levels of related indices in the blood and kidneys and quantifying the related gene and protein expression. The expression of transforming growth factor ß1 (TGFß1) gene and protein were assayed by quantitative real-time PCR and immunohistochemistry, respectively. The renal transcriptomics was analyzed using RNA sequencing. Results: Repeated treatment with SZ-A significantly improved glucose metabolism, dose-dependently decreased the levels of blood urea nitrogen, urinary albumin, and ß2-microglobulin, and evidently relieved the renal injury in diabetic ZDF rats. As for the mechanisms, SZ-A remarkably ameliorated systemic nitrosative stress through lowering the levels of blood inducible nitric oxide synthase and nitric oxide, and significantly relieved systemic and renal inflammation by reducing the levels of blood interleukin-1ß and monocyte chemoattractant protein-1 (MCP-1) and decreasing the levels of renal C-reactive protein content and expression of tumor necrosis factor-α in the kidneys. SZ-A also improved renal fibrosis by lowering the expression of TGFß1 in the kidneys. Additionally, SZ-A significantly lowered the expression of stimulator of chondrogenesis 1 in the kidneys. Conclusion: Repeated treatments with SZ-A significantly ameliorates DN by regulating systemic nitrosative stress, renal inflammation, and renal fibrosis partially through inhibition of the cytokine-NO and TGF-ß1 signaling in ZDF rats, providing evidence for the additional application of SZ-A in clinical use for the treatment of DN.
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BACKGROUND: The prognosis prediction of locally advanced rectal cancer (LARC) was important to individualized treatment, we aimed to investigate the performance of ultra-high b-value DWI (UHBV-DWI) in progression risk prediction of LARC and compare with routine DWI. METHODS: This retrospective study collected patients with rectal cancer from 2016 to 2019. Routine DWI (b = 0, 1000 s/mm2) and UHBV-DWI (b = 0, 1700 ~ 3500 s/mm2) were processed with mono-exponential model to generate ADC and ADCuh, respectively. The performance of the ADCuh was compared with ADC in 3-year progression free survival (PFS) assessment using time-dependent ROC and Kaplan-Meier curve. Prognosis model was constructed with ADCuh, ADC and clinicopathologic factors using multivariate COX proportional hazard regression analysis. The prognosis model was assessed with time-dependent ROC, decision curve analysis (DCA) and calibration curve. RESULTS: A total of 112 patients with LARC (TNM-stage II-III) were evaluated. ADCuh performed better than ADC for 3-year PFS assessment (AUC = 0.754 and 0.586, respectively). Multivariate COX analysis showed that ADCuh and ADC were independent factors for 3-year PFS (P < 0.05). Prognostic model 3 (TNM-stage + extramural venous invasion (EMVI) + ADCuh) was superior than model 2 (TNM-stage + EMVI + ADC) and model 1 (TNM-stage + EMVI) for 3-year PFS prediction (AUC = 0.805, 0.719 and 0.688, respectively). DCA showed that model 3 had higher net benefit than model 2 and model 1. Calibration curve demonstrated better agreement of model 1 than model 2 and model 1. CONCLUSIONS: ADCuh from UHBV-DWI performed better than ADC from routine DWI in predicting prognosis of LARC. The model based on combination of ADCuh, TNM-stage and EMVI could help to indicate progression risk before treatment.
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Imagem de Difusão por Ressonância Magnética , Neoplasias Retais , Humanos , Estudos Retrospectivos , Análise MultivariadaRESUMO
Introduction: Limitation of pharmaceutical application of resveratrol (RSV) and piceatannol (PIC) continue to exist, there is a need to obtain the superior analogs of two stilbenes with promoted activity, stability, and bioavailability. Microbial transformation has been suggested as a common and efficient strategy to solve the above problems. Methods: In this study, Beauveria bassiana was selected to transform RSV and PIC. LC-MS and NMR spectroscopies were used to analyze the transformed products and identify their structures. The biological activities of these metabolites were evaluated in vitro with GPR119 agonist and insulin secretion assays. Single factor tests were employed to optimize the biotransformation condition. Results: Three new methylglucosylated derivatives of PIC (1-3) and two known RSV methylglucosides (4 and 5) were isolated and characterized from the fermentation broth. Among them, 1 not only showed moderate GPR119 agonistic activity with 65.9%, but also promoted insulin secretion level significantly (12.94 ng/mg protein/hour) at 1 µM. After optimization of fermentation conditions, the yield of 1 reached 45.53%, which was increased by 4.2-fold compared with the control. Discussion: Our work presents that 3-O-MG PIC (1), obtained by microbial transformation, is an effective and safer ligand targeting GPR119, which lays a foundation for the anti-diabetic drug design in the future.
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Farnesoid X receptor (FXR) is a promising target for drug discovery against nonalcoholic fatty liver disease (NAFLD). However, no FXR agonist has been approved for NAFLD so far. The R & D of FXR agonists are somewhat hindered by the lack of effective and safe chemotypes. To this end, we developed a multi-stage computational workflow to screen the Specs and ChemDiv chemical library for FXR agonists, which consisted of machine learning (ML)-based classifiers, shape-based and electrostatic-based models, a FRED-based molecular docking protocol, an ADMET prediction protocol and substructure search. As a result, we identified a novel chemotype that has never been reported before, with compound XJ02862 (ChemDiv ID: Y020-6413) as the representative. By designing an asymmetric synthesis strategy, we were able to prepare four isomers of compound XJ02862. Interestingly, one of the isomers, 2-((S)-1-((2S,4R)-2-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)-1-oxopropan-2-yl)hexahydro-1H-isoindole-1,3(2H)-dione (XJ02862-S2), showed potent FXR agonistic activity in HEK293T cells. The molecular docking, molecular dynamics simulations and site-directed mutagenesis suggested the hydrogen bond between compound XJ02862-S2 and HIS294 of FXR is essential for ligand binding. We further demonstrated that compound XJ02862-S2 had no agonistic effect on TGR5. Further biological experiments have shown that compound XJ02862-S2 could ameliorate hypercholesterolemia, hepatic steatosis, hyperglycemia, insulin resistance (IR) in high-fat-diet induced obese (DIO) mice. In term of molecular mechanism, compound XJ02862-S2 regulates the expression of FXR downstream genes involved in lipogenesis, cholesterol transport and bile acid biosynthesis and transport. Taken together, we have discovered a novel chemotype as potent FXR agonists for NAFLD by computational modeling, chemical synthesis and biological evaluation.
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Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Simulação de Acoplamento Molecular , Células HEK293 , Receptores Citoplasmáticos e Nucleares/metabolismo , Simulação de Dinâmica Molecular , Fígado/metabolismo , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: To explore the relationship between unambiguous radiologic extranodal extension (rENE) and M1 staging in patients with metastatic PCa. METHODS: A respective analysis of 1073 patients of PCa N1 staging from January 2004 to May 2022 was retrospectively enrolled. They were divided into rENE + and rENE - groups and retrospectively analyzed the M staging with nuclear medicine data. The correlation index between unambiguous rENE and M1b staging was calculated. Logistic regression was used to evaluate the predictive performance of unambiguous rENE in M1b staging. ROC curves were used to investigate the relationship between unambiguous rENE and M staging in patients who underwent 68 Ga-PSMA PET/CT. RESULTS: A total of 1073 patients were included. Seven hundred and eighty patients were classified into the rENE + group (mean age, 69.6 years ± 8.7 [standard deviation]), and 293 were classified into rENE - group (mean age, 66.7 years ± 9.4 [standard deviation]). Relationship between unambiguous rENE and M1b existed (r = 0.58, 95%CI: 0.52-0.64, P < 0.05). Unambiguous rENE could be an independent predictor for M1b (OR = 13.64, 95%CI: 9.23-20.14, P < 0.05). The AUC of unambiguous rENE in predicting M1b and M staging was 0.835 and 0.915, respectively, in patients who underwent 68 Ga-PSMA PET/CT. CONCLUSIONS: Unambiguous rENE could be a strong biomarker to predict M1b and M staging in patients with PCa. When rENE came up, patients should perform nuclear medicine immediately, and a systematic treatment should be considered.
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Extensão Extranodal , Neoplasias da Próstata , Masculino , Humanos , Idoso , Extensão Extranodal/patologia , Estudos Retrospectivos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Imageamento por Ressonância Magnética , Biomarcadores , Estadiamento de NeoplasiasRESUMO
Antioxidative and antiaging abilities of probiotic fermented ginseng (PG) were evaluated in Caenorhabditis elegans (C. elegans). Lifespan and effect on heat stress and acute oxidative stress in C. elegans were significantly enhanced by PG. Antioxidative enzymes such as T-SOD, GSH-PX, CAT were significantly up-regulated, and MDA, ROS and apoptosis levels were significantly down-regulated. At the same time, PG exerted antioxidant and anti-aging activities by reducing the expression of DAF-2 mRNA and increasing the expression of SKN-1 and SOD-3 mRNA in C. elegans. In addition, the mechanism of antioxidative and antiaging activities of PG was explored through gut microbiota sequencing and untargeted metabolomics. The results of gut microbiota indicated that PG could significantly improve the composition and structure of microbes in the gut of C. elegans, and the relative abundance of beneficial bacteria was up-regulated. Untargeted metabolomic results elucidated that PG modulated antioxidant and antiaging activities through neuroactive ligand-receptor interaction, Citrate cycle (TCA cycle), pyruvate metabolism, ascorbate and aldarate metabolism and D-Arginine and D-ornithine metabolism of C. elegans. These results indicated that PG had excellent antioxidant and anti-aging activities, providing research value for the development of functional foods and improvement of aging-related diseases.
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Proteínas de Caenorhabditis elegans , Microbioma Gastrointestinal , Panax , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/farmacologia , Envelhecimento , Estresse Oxidativo , Longevidade/fisiologia , Superóxido Dismutase/metabolismo , RNA Mensageiro , Espécies Reativas de Oxigênio/metabolismoRESUMO
Background: Two dimensional shear wave elastography (2D-SWE) is an ultrasound elastography technique based on shear waves implemented on a diagnostic ultrasound system. Transient elastography (TE) uses an ultrasound displacement M-mode and A-mode image produced by the system. So, TE mechanically induced impulse at tissue surface and difficultly across water. This paper compared the reliability and reproducibility of 2D-SWE with that of TE in patients with chronic hepatic disease. Comparisons were made in terms of the success rate, reliability, reproducibility, operation time, and influence of operator experience. Methods: A total of 170 patients were included in this study. Participants underwent 2D-SWE and TE performed by 2 different operators (a novice and veteran) on the same day. Nonparametric statistical tests were used to compare the technical success rate and reliable measurement rate, and inter-operator reproducibility was evaluated using intra-class correlation coefficients (ICCs). Results: The 2D-SWE technique showed a higher technical success rate than TE. Either 2D-SWE or TE can be utilized in patients with ascites lamella of less than 10 mm or ascites lamella plus skin-capsular distance of less than 25 mm. However, although the reliability rate of liver stiffness measurement with 2D-SWE did not significantly differ between the novice and veteran operators, for TE, there was a significant difference when body mass index (BMI) ≤25 kg/m2. When performed by the novice and veteran operators, 2D-SWE and TE both showed excellent inter-operator agreement, with ICCs of 0.968 and 0.973, respectively. Both 2D-SWE and TE displayed reliable measurement and excellent reproducibility in patients with chronic liver disease, were minimally influenced by operator experience. Conclusions: 2D-SWE may be a more reliable method for clinical application in noninvasive detecting the liver stiffness.
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Coronavirus disease-19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2 that has rapidly evolved into a pandemic to cause over 600 million infections and more than 6.6 million deaths up to Nov 25, 2022. COVID-19 carries a high mortality rate in severe cases. Co-infections and secondary infections with other micro-organisms, such as bacterial and fungus, further increases the mortality and complicates the diagnosis and management of COVID-19. The current guideline provides guidance to physicians for the management and treatment of patients with COVID-19 associated bacterial and fungal infections, including COVID-19 associated bacterial infections (CABI), pulmonary aspergillosis (CAPA), candidiasis (CAC) and mucormycosis (CAM). Recommendations were drafted by the 7th Guidelines Recommendations for Evidence-based Antimicrobial agents use Taiwan (GREAT) working group after review of the current evidence, using the grading of recommendations assessment, development, and evaluation (GRADE) methodology. A nationwide expert panel reviewed the recommendations in March 2022, and the guideline was endorsed by the Infectious Diseases Society of Taiwan (IDST). This guideline includes the epidemiology, diagnostic methods and treatment recommendations for COVID-19 associated infections. The aim of this guideline is to provide guidance to physicians who are involved in the medical care for patients with COVID-19 during the ongoing COVID-19 pandemic.
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COVID-19 , Micoses , Humanos , COVID-19/diagnóstico , COVID-19/epidemiologia , SARS-CoV-2 , Taiwan/epidemiologia , Pandemias , Micoses/diagnóstico , Micoses/tratamento farmacológico , Teste para COVID-19RESUMO
OBJECTIVES: To evaluate the potential of multi b-value DWI in predicting the prognosis of patients with locally advanced rectal cancer (LARC). METHODS: From 2015 to 2019, a total of 161 patients with LARC were enrolled and randomly sampled into a training set (n = 113) and validation set (n = 48). Multi b-value DWI (b = 0~1500 s/mm2) scans were postprocessed to generate functional parameters, including apparent diffusion coefficient (ADC), Dt, Dp, f, distributed diffusion coefficient (DDC), and α. Histogram features of each functional parameter were submitted into Least absolute shrinkage and selection operator (LASSO) and stepwise multivariate COX analysis to generate DWI_score based on the training set. The prognostic model was constructed with functional parameter, DWI_score, and clinicopathologic factors by using univariate and multivariate COX analysis on the training set and verified on the validation set. RESULTS: Multivariate COX analysis revealed that DWI_score was an independent indicator for 5-year progression-free survival (PFS, HR = 5.573, p < 0.001), but not for overall survival (OS, HR = 2.177, p = 0.051). No mean value of functional parameters was correlated with PFS or OS. Prognostic model for 5-year PFS based on DWI_score, TNM-stage, mesorectal fascia (MRF), and extramural venous invasion (EMVI) showed good performance both in the training set (AUC = 0.819) and validation set (AUC = 0.815). CONCLUSIONS: The DWI_score based on histogram features of multi b-value DWI functional parameters was an independent factor for PFS of LARC and the prognostic model with a combination of DWI_score and clinicopathologic factors could indicate the progression risk before treatment. KEY POINTS: ⢠Mean value of functional parameters obtained from multi b-value DWI might not be useful to assess the prognosis of LARC. ⢠The DWI_score based on histogram features of multi b-value DWI functional parameters was an independent prognosis factor for PFS of LARC. ⢠Prognostic model based on DWI_score and clinicopathologic factors could indicate the progression risk of LARC before treatment.
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Neoplasias Retais , Humanos , Prognóstico , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/terapia , Neoplasias Retais/patologia , Reto/patologia , Imagem de Difusão por Ressonância Magnética , Terapia Neoadjuvante , Estudos RetrospectivosRESUMO
Farnesoid X receptor (FXR) is an attractive target for drug discovery against non-alcoholic fatty liver disease (NAFLD). We previously reported an orally active, new-chemotype FXR agonist XJ034 by ensemble learning-driven drug discovery. However, its FXR agonistic activity and the efficacy in vivo remain to be improved. In this study, we designed and synthesized 52 derivatives, and preliminarily evaluated their FXR transactivation activity in HEK293T cells at the concentration of 10 µM. 12 FXR agonists were superior or comparable to compound XJ034, two of which showed over 9-fold activity of compound XJ034, and were as potent as OCA. The molecular docking and molecular dynamics simulations implied an additional hydrogen bond with TYR383 is involved in FXR transactivation for both compounds. According to EC50 determined by the confirmatory transactivation assay, we selected adamantan-1-yl(4-(2-amino-5-chlorophenyl)piperazin-1-yl)methanone (10a, EC50: 1.05 µM) as our lead compound. Interestingly, compound 10a had no agonistic effect on TGR5 or PPAR, and no cytotoxicity to HepG2 cells. In vivo bioassays with high-fat-diet induced C57BL/6J obese (DIO) mice have shown that compound 10a (100 mg/kg) is more effective than compound XJ034 (200 mg/kg) in improving hyperlipidemia, hepatic steatosis and insulin resistance. We also observed that compound 10a down-regulated the expression of genes involved in liver inflammation in vivo, implying its potential to treat hepatic inflammation. In summary, the present data have proved that our strategy for structural optimization is effective, and compound 10a is a promising lead compound with improved efficacy for NAFLD.
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Hepatopatia Gordurosa não Alcoólica , Piperazinas , Receptores Citoplasmáticos e Nucleares , Animais , Humanos , Camundongos , Células HEK293 , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Piperazinas/química , Piperazinas/farmacologiaRESUMO
Objectives: To investigated the safety and efficacy of treating patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) and elevated levels of N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) with levosimendan within 24 hours of first medical contact (FMC). Methods: This multicenter, open-label, block-randomized controlled trial (NCT03189901) investigated the safety and efficacy of levosimendan as an early management strategy of acute heart failure (EMS-AHF) for patients with NSTEMI and high NT-proBNP levels. This study included 255 patients with NSTEMI and elevated NT-proBNP levels, including 142 males and 113 females with a median age of 65 (58-70) years, and were admitted in the emergency or outpatient departments at 14 medical centers in China between October 2017 and October 2021. The patients were randomly divided into a levosimendan group (n=129) and a control group (n=126). The primary outcome measure was NT-proBNP levels on day 3 of treatment and changes in the NT-proBNP levels from baseline on day 5 after randomization. The secondary outcome measures included the proportion of patients with more than 30% reduction in NT-proBNP levels from baseline, major adverse cardiovascular events (MACE) during hospitalization and at 6 months after hospitalization, safety during the treatment, and health economics indices. The measurement data parameters between groups were compared using the t-test or the non-parametric test. The count data parameters were compared between groups using the χ² test. Results: On day 3, the NT-proBNP levels in the levosimendan group were lower than the control group but were statistically insignificant [866 (455, 1 960) vs. 1 118 (459, 2 417) ng/L, Z=-1.25,P=0.21]. However, on day 5, changes in the NT-proBNP levels from baseline in the levosimendan group were significantly higher than the control group [67.6% (33.8%,82.5%)vs.54.8% (7.3%,77.9%), Z=-2.14, P=0.03]. There were no significant differences in the proportion of patients with more than 30% reduction in the NT-proBNP levels on day 5 between the levosimendan and the control groups [77.5% (100/129) vs. 69.0% (87/126), χ²=2.34, P=0.13]. Furthermore, incidences of MACE did not show any significant differences between the two groups during hospitalization [4.7% (6/129) vs. 7.1% (9/126), χ²=0.72, P=0.40] and at 6 months [14.7% (19/129) vs. 12.7% (16/126), χ²=0.22, P=0.64]. Four cardiac deaths were reported in the control group during hospitalization [0 (0/129) vs. 3.2% (4/126), P=0.06]. However, 6-month survival rates were comparable between the two groups (log-rank test, P=0.18). Moreover, adverse events or serious adverse events such as shock, ventricular fibrillation, and ventricular tachycardia were not reported in both the groups during levosimendan treatment (days 0-1). The total cost of hospitalization [34 591.00(15 527.46,59 324.80) vs. 37 144.65(16 066.90,63 919.00)yuan, Z=-0.26, P=0.80] and the total length of hospitalization [9 (8, 12) vs. 10 (7, 13) days, Z=0.72, P=0.72] were lower for patients in the levosimendan group compared to those in the control group, but did not show statistically significant differences. Conclusions: Early administration of levosimendan reduced NT-proBNP levels in NSTEMI patients with elevated NT-proBNP and did not increase the total cost and length of hospitalization, but did not significantly improve MACE during hospitalization or at 6 months.
Assuntos
Masculino , Feminino , Humanos , Idoso , Peptídeo Natriurético Encefálico , Simendana/uso terapêutico , Infarto do Miocárdio sem Supradesnível do Segmento ST , Insuficiência Cardíaca/tratamento farmacológico , Fragmentos de Peptídeos , Arritmias Cardíacas , Biomarcadores , PrognósticoRESUMO
AIM To establish an UPLC-MS/MS method for the simultaneous content determination of chlorogenic acid,umbellifolactone,rutin,isochlorogenic acid A and isochlorogenic acid C in Artemisia sieversiana Ehrhart ex Willd.and Ajania tenuifolia(Jacquem.ex DC.)Tzvelev in Schischk.&Bobrov by HPLC,and compare the differences between them.METHODS The analysis of 50%methanol extract of both was performed on a 30℃thermostatic CAPCELL PAK-C18 column(100 mm×2.1 mm,1.7 μm),with the mobile phase comprising of acetonitrile-0.2%phosphoric acid water,flowing at 1 mL/min in a gradient elution manner,and the detection wavelengths were set at 290 nm.A t-test was used to compare the contents differences of five constituents in the two crude drugs.RESULTS Five constituents showed good linear relationships within their own ranges(r≥0.999 5),whose average recoveries were 96.03%-103.11%,with the RSDs of 0.51%-2.26%.The average contents of chlorogenic acid,umbellifolactone,rutin,isochlorogenic acid A and isochlorogenic acid C in A.sieversiana and A.tenuifolia were 3.61,0.71,1.46,8.74,1.44 mg/g and 2.60,0.26,0.79,6.31,1.22 mg/g,respectively.CONCLUSION The method is accurate,reliable and reproducible.There was no significant difference in the five chemical constituents between A.sieversiana and A.tenuifolia.
RESUMO
Voglibose is an α-glycosidase inhibitor that improves postprandial hyperglycemia and increases glucagon-like peptide-1 (GLP-1) secretion in patients with type 2 diabetes. Recently, there has been increasing interest in the anti-inflammatory effects of voglibose on the intestine, but the underlying mechanism is not clear. This study evaluated the effects and mechanisms of voglibose on glycemic control and intestinal inflammation. Type 2 diabetic KKAy mice were treated with voglibose (1 mg/kg) by oral gavage once daily. After 8 weeks, glucose metabolism, levels of short-chain fatty acids (SCFAs), systematic inflammatory factors, intestinal integrity and inflammation were evaluated using hematoxylin and eosin staining, immunohistochemistry, immunofluorescence and Western blot analysis. Voglibose ameliorated glucose metabolism by enhancing basal- and glucose-dependent GLP-1 secretion. Several beneficial SCFAs, such as acetic acid and propionic acid, were increased by voglibose in the fecal sample. Additionally, voglibose notably decreased the proportion of pro-inflammatory macrophages and the expression of nuclear factor kappa B but increased the expression of tight junction proteins in the ileum, thus markedly improving intestinal inflammatory damage and reducing the systematic inflammatory factors. Ileal genomics and protein validation suggested that voglibose attenuated inositol-requiring protein 1α-X-box binding protein 1-mediated endoplasmic reticulum stress (ERS). Together, these results showed that voglibose enhanced the secretion of GLP-1, which contributed to the glycemic control in KKAy mice at least in part by regulating intestinal inflammation and the expression of ERS factors.