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1.
Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d9-methadone.The pharmacokinetic profiles of d9-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.7- and 4.4-fold increase in the area under the time-concentration curve and maximum concentration in plasma, respectively, as well as reduction in clearance (0.9 ± 0.3 L/h/kg vs 4.7 ± 0.8 L/h/kg). The lower brain-to-plasma ratio of d9-methadone compared to that of methadone (0.35 ± 0.12 vs 2.05 ± 0.62) suggested that deuteration decreases the transfer of the drug across the blood-brain barrier. The estimated LD50 value for a single intravenous dose of d9-methadone was 2.1-fold higher than that for methadone. Moreover, d9-methadone outperformed methadone in the efficacy against postoperative pain by primarily activating peripheral opioid receptors. Collectively, these data suggest that the replacement of three hydrogen atoms in three methyl groups of methadone altered its pharmacokinetic properties, improved safety, and enhanced its analgesic efficacy.  相似文献   
2.
间歇性禁食是一种新的饮食干预策略,其可能改善恶性肿瘤治疗的疗效并减少并发症。 限时进食是间歇性禁食的 一种特殊形式,通常仅限制每天的进食时间窗而不限制热量,除了和其他间歇性禁食手段一样能够控制体重并改善代谢紊乱 以外,限时进食还能调节昼夜节律并影响自噬水平,具有潜在的抗衰作用,相关研究已经表明了它预防肿瘤发生以及减缓肿 瘤发展的潜力。 同时,由于实施方案便利、不良反应轻微,限时进食有着不错的依从性及安全性,有可能成为一种适合肿瘤患 者长期实施的辅助治疗方案乃至健康生活方式。 本文从改善肥胖和代谢紊乱、调节昼夜节律和自噬水平以及目前与肿瘤相 关的研究进展这三个方面阐述了限时进食对恶性肿瘤的潜在作用,旨在为将来的相关研究提供理论依据和探索方向,探讨限 时进食作为一种营养干预手段对恶性肿瘤发生的潜在预防作用以及对恶性肿瘤的治疗或辅助治疗作用,以期可以完善对肿 瘤患者的营养干预策略,改善患者的生活质量及预后。  相似文献   
3.
The melanocortin 4 receptor (MC4R) plays a critical role in the long-term regulation of energy homeostasis, and mutations in the MC4R are the most common cause of monogenic obesity. However, the precise molecular and cellular mechanisms underlying the maintenance of energy balance within MC4R-expressing neurons are unknown. We recently reported that the MC4R localizes to the primary cilium, a cellular organelle that allows for partitioning of incoming cellular signals, raising the question of whether the MC4R functions in this organelle. Here, using mouse genetic approaches, we found that cilia were required specifically on MC4R-expressing neurons for the control of energy homeostasis. Moreover, these cilia were critical for pharmacological activators of the MC4R to exert an anorexigenic effect. The MC4R is expressed in multiple brain regions. Using targeted deletion of primary cilia, we found that cilia in the paraventricular nucleus of the hypothalamus (PVN) were essential to restrict food intake. MC4R activation increased adenylyl cyclase (AC) activity. As with the removal of cilia, inhibition of AC activity in the cilia of MC4R-expressing neurons of the PVN caused hyperphagia and obesity. Thus, the MC4R signaled via PVN neuron cilia to control food intake and body weight. We propose that defects in ciliary localization of the MC4R cause obesity in human inherited obesity syndromes and ciliopathies.  相似文献   
4.
Aging is a natural biological event that has some downsides such as increased frailty, decline in cognitive and physical functions leading to chronical diseases, and lower quality of life. There is therefore a pressing need of reliable biomarkers to identify populations at risk of developing age-associated syndromes in order to improve their quality of life, promote healthy ageing and a more appropriate clinical management, when needed. Here we discuss the importance of hippuric acid, an endogenous co-metabolite, as a possible hallmark of human aging and age-related diseases, summarizing the scientific literature over the last years. Hippuric acid, the glycine conjugate of benzoic acid, derives from the catabolism by means of intestinal microflora of dietary polyphenols found in plant-based foods (e.g. fruits, vegetables, tea and coffee). In healthy conditions hippuric acid levels in blood and/or urine rise significantly during aging while its excretion drops in conditions related with aging, including cognitive impairments, rheumatic diseases, sarcopenia and hypomobility. This literature highlights the utility of hippuric acid in urine and plasma as a plausible hallmark of frailty, related to low fruit and vegetable intake and changes in gut microflora.  相似文献   
5.
《Cirugía espa?ola》2021,99(9):635-647
IntroductionBariatric surgery is a relatively safe surgical procedure with a high success rate. However, recent reports indicate a higher prevalence of alcohol or substance abuse disorder in this patient group. The purpose of this study was to review the related evidence to serve as a reference for multidisciplinary teams who treat these patients.MethodsWe searched the PubMed and CENTRAL databases. The odds ratios were extracted from the different articles, comparing the prevalence of the abuse of alcohol or other substances in the postoperative period versus preoperative levels. We also compared the prevalence of alcohol use disorder after different types of bariatric surgery.ResultsA total of 49 121 bariatric patients (80.8% female) were evaluated for alcohol use disorder. In general, bariatric surgery was found to be associated with an increase in the prevalence of alcohol abuse (4.58±5.3 vs. 1.58±10.7% in the preoperative period). We also found that the population of patients who underwent RYGB procedures had a higher prevalence of alcohol use disorder than patients who underwent another type of surgery (OR: 1.83; 95% CI: 1.51-2.21). The prevalence of substance abuse disorder (other than alcohol) after this procedure is less studied, although there appears to be an increased risk of abuse of certain substances.ConclusionsBariatric surgery is the best treatment for obesity and its complications. The evidence reviewed suggests that it correlates with a modest but consistent increase in the prevalence of abuse of alcohol and other substances. Medical teams who treat bariatric patients must be informed about this eventuality for its timely prevention, diagnosis and treatment.  相似文献   
6.
Background:It is well-known that insulin resistance and hyperglycemia are important pathological causes for the development of diabetic cardiomyopathy (DCM). However, its precise molecular mechanisms in the pathogenesis of DCM remain unclear.Objectives:Recent studies reveal that microRNAs (miRNA) play essential roles in the pathogenesis of DCM. This project aimed to determine the roles of miR-34a and miR-125b in hyperglycemia-induced cardiomyocyte cell death.Methods:Rat primary cardiomyocytes were isolated and exposed to normal and high concentrations of glucose. Cell viability was measured using MTT assay. Expressions of miR-34a and miR-125b were detected by qRT-PCR. Potential targets of miR-34a and miR-125b were predicted from www.Targetscan.org and validated from human heart tissues. A statistical significance of p<0.05 was considered.Results:The present study shows that miR-34a and miR-125b are downregulated in a human diabetic heart. Moreover, in vitro data from rat primary cardiomyocytes showed that short-term high glucose treatment stimulates miR-34a and miR-125b expressions. Under high glucose, it was found that rat cardiomyocytes displayed increased intracellular glucose metabolism, and glucose uptake and lactate production were significantly increased. It was also found that the key glucose metabolic enzymes, Hexokinase 2 (HK2) and Lactate dehydrogenase-A (LDHA), were direct targets of miR-125b and miR-34a, respectively. Overexpression of miR-125b and miR-34a could prevent hyperglycemia-induced cardiomyocyte cell death. Finally, the restoration of HK2 and LDHA in miR-125b and miR-34a overexpressed cardiomyocytes recovered the cardiomyocytes’ sensitivity to hyperglycemia.Conclusion:Our results proposed a molecular mechanism for the microRNA-mediated diabetic cardiovascular protection and will contribute to developing treatment strategies for diabetes-associated cardiovascular dysfunction.  相似文献   
7.
There is increasing evidence highlighting the potential role of the gut-brain axis in the pathogenesis of Parkinson’s disease (PD) and on the use of probiotics as a therapeutic strategy for this neurodegenerative disorder. While several studies have been published on the topic in recent years, there is still a lack of a comprehensive understanding of the effects of probiotics in PD and their possible underlying mechanisms. Through this systematic review, we collected a total of 17 articles, consisting of preclinical and clinical models of PD investigating the effect of probiotics on (1) energy metabolism, (2) inflammation and oxidative stress, (3) neurodegeneration, as well as (4) motor and (5) non-motor function. Articles were obtained from PubMed/Medline, Scopus, Web of Science and Embase databases. Findings from preclinical studies suggest that treatment with probiotics increases glucose metabolism (increased secretion of glucagon-like peptide-1), reduces peripheral and central inflammation (reduced interleukin-6 and tumor necrosis factor-α (TNF-α)), reduces peripheral and central oxidative stress (reduced peripheral superoxide anion levels and increased central antioxidant glutathione levels), decreases neurodegeneration (increased numbers of tyrosine hydroxylase dopaminergic neurons and levels of brain-derived neurotrophic factor), increases motor function (increased motor agility) and non-motor function (decreased memory deficits). Similarly, findings from clinical studies suggest that probiotics increase glucose metabolism (reduced insulin resistance), reduce peripheral inflammation (reduced peripheral TNF-α expression and C-reactive protein levels), and increase motor and non-motor function (decreased overall PD symptomatology and constipation); however, findings on oxidative stress were inconclusive across studies. Overall, this review is the first one to systematically report evidence for the putative beneficial effects of probiotics on molecular and cellular mechanisms, as well as behavioural phenotypes, in either preclinical or clinical studies in PD. However, additional and more robust studies are still needed to confirm these outcomes, and should aim to focus more on bench-to-bedside approaches, in order to address the existing gaps between preclinical and clinical findings in this field.  相似文献   
8.
Background: Acne is a common and chronic inflammatory dermatosis of sebaceous gland units of the human hair follicle. Acne is closely related to immune cytokines and cells including T helper 17cells (Th17 cells). Mis-regulated glycolipid metabolism also plays a vital role in the process. Objective: This investigation aimed to explore the role of IL-17 in signaling pathways controlling sebaceous gland lipoprotein metabolism in a rat model of acne. Methods: We generated the rat ear acne model, and investigated the pathological changes of acne skin tissue by histological analysis and the changes in the critical factors including DEFB1, GPR65, FADS1, and FADS2 by Western Blot in this model. Results: There were more Th17 cells in the rat ear acne model than in the control mice. The expression levels of DEFB1, GPR65, FADS1, FADS2 and MOGAT1 were significantly upregulated in serum and tissue from rat acne model, which could be concluded that the Th17 cells play a major role in the pathogenesis of acne based. Conclusion: Although acne is associated with immune effects and glycolipid metabolism, inhibition of IL-17 signaling pathway might be a novel way for acne therapy. Our findings also suggest a new strategy for targeted therapy of acne.  相似文献   
9.
Nonalcoholic fatty liver disease(NAFLD)is a broad-spectrum disease,ranging from simple hepatic steatosis to nonalcoholic steatohepatitis,which can progress to cirrhosis and liver cancer.Abnormal hepatic lipid accumulation is the major manifestation of this disease,and lipotoxicity promotes NAFLD progression.In addition,intermediate metabolites such as succinate can stimulate the activation of hepatic stellate cells to produce extracellular matrix proteins,resulting in progression of NAFLD to fibrosis and even cirrhosis.G protein-coupled receptors(GPCRs)have been shown to play essential roles in metabolic disorders,such as NAFLD and obesity,through their function as receptors for bile acids and free fatty acids.In addition,GPCRs link gut microbiota-mediated connections in a variety of diseases,such as intestinal diseases,hepatic steatosis,diabetes,and cardiovascular diseases.The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids.GPCR agonists,including peptides and natural products like docosahexaenoic acid,have been applied to investigate their role in liver diseases.Therapies such as probiotics and GPCR agonists may be applied to modulate GPCR function to ameliorate liver metabolism syndrome.This review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD and describes some preclinical and clinical studies of GPCR-mediated treatment.Overall,understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD.  相似文献   
10.
目的探讨硒补充剂对妊娠期糖尿病患者血糖、血脂代谢和妊娠结局的影响。方法将2018年7月-2019年6月盘锦市中心医院收治的45例妊娠期糖尿病患者随机分为对照组21例和硒酵母组24例。两组患者均给予健康教育、饮食指导、运动指导等常规治疗,硒酵母组在常规治疗基础上给予硒酵母片治疗。比较两组治疗前后空腹血糖、胰岛素抵抗指数、总胆固醇、甘油三酯、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇水平及妊娠结局。结果治疗后两组空腹血糖和胰岛素抵抗指数均较治疗前下降,且硒酵母组两项指标均低于对照组,差异均具有统计学意义(P<0.05)。治疗后两组孕妇总胆固醇、甘油三酯、低密度脂蛋白胆固醇水平较治疗前下降,且硒酵母组三项指标水平低于对照组,差异均具有统计学意义(P<0.05)。治疗后硒酵母组高密度脂蛋白胆固醇水平高于治疗前,差异具有统计学意义(P<0.05)。对照组治疗前后以及两组治疗后高密度脂蛋白胆固醇水平差异均无统计学意义(P>0.05)。硒酵母组新生儿高胆红素血症发生率和新生儿住院率均低于对照组,差异均具有统计学意义(P<0.05)。两组其他不良妊娠结局差异均无统计学意义(P>0.05)。结论硒补充剂能够进一步改善妊娠期糖尿病患者的血糖和血脂代谢,同时,也能降低新生儿高胆红素血症发生率和住院率,值得推广使用。  相似文献   
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