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1.
A proteomic glimpse into the effect of antimalarial drugs on Plasmodium falciparum proteome towards highlighting possible therapeutic targets.
Dousti, M, Manzano-Román, R, Rashidi, S, Barzegar, G, Ahmadpour, NB, Mohammadi, A, Hatam, G
Pathogens and disease. 2021;(1)
Abstract
There is no effective vaccine against malaria; therefore, chemotherapy is to date the only choice to fight against this infectious disease. However, there is growing evidences of drug-resistance mechanisms in malaria treatments. Therefore, the identification of new drug targets is an urgent need for the clinical management of the disease. Proteomic approaches offer the chance of determining the effects of antimalarial drugs on the proteome of Plasmodium parasites. Accordingly, we reviewed the effects of antimalarial drugs on the Plasmodium falciparum proteome pointing out the relevance of several proteins as possible drug targets in malaria treatment. In addition, some of the P. falciparum stage-specific altered proteins and parasite-host interactions might play important roles in pathogenicity, survival, invasion and metabolic pathways and thus serve as potential sources of drug targets. In this review, we have identified several proteins, including thioredoxin reductase, helicases, peptidyl-prolyl cis-trans isomerase, endoplasmic reticulum-resident calcium-binding protein, choline/ethanolamine phosphotransferase, purine nucleoside phosphorylase, apical membrane antigen 1, glutamate dehydrogenase, hypoxanthine guanine phosphoribosyl transferase, heat shock protein 70x, knob-associated histidine-rich protein and erythrocyte membrane protein 1, as promising antimalarial drugs targets. Overall, proteomic approaches are able to partially facilitate finding possible drug targets. However, the integration of other 'omics' and specific pharmaceutical techniques with proteomics may increase the therapeutic properties of the critical proteins identified in the P. falciparum proteome.
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2.
Thiamine, Ascorbic Acid, and Hydrocortisone As a Metabolic Resuscitation Cocktail in Sepsis: A Meta-Analysis of Randomized Controlled Trials With Trial Sequential Analysis.
Assouline, B, Faivre, A, Verissimo, T, Sangla, F, Berchtold, L, Giraud, R, Bendjelid, K, Sgardello, S, Elia, N, Pugin, J, et al
Critical care medicine. 2021;(12):2112-2120
Abstract
OBJECTIVES Sepsis is a common condition in the ICU. Despite much research, its prognosis remains poor. In 2017, a retrospective before/after study reported promising results using a combination of thiamine, ascorbic acid, and hydrocortisone called "metabolic resuscitation cocktail" and several randomized controlled trials assessing its effectiveness were performed. DESIGN We conducted a systematic review and meta-analysis of randomized controlled trials in septic ICU patients to assess the effects of this combination therapy. SETTING PubMed, Embase, and the Cochrane library databases were searched from inception to March of 2021. Data were extracted independently by two authors. The main outcome was the change in Sequential Organ Failure Assessment score within 72 hours. Secondary outcomes included renal composite endpoints (acute kidney injury) Kidney Disease - Improving Global Outcome organization stage 3 or need for renal replacement therapy, vasopressor duration, and 28-day mortality. SUBJECTS We included randomized controlled trials with patients admitted to the ICU with sepsis or septic shock. INTERVENTION The trials compared a combination of thiamine, ascorbic acid, and hydrocortisone to standard care or placebo in patients admitted to ICU with sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS We included eight randomized controlled trials (n = 1,335 patients). Within 72 hours, the median of mean improvement was -1.8 and -3.2 in the control and intervention groups, respectively (eight randomized controlled trials, n = 1,253 patients); weighted mean difference -0.82 (95% CI, -1.15 to -0.48). Data were homogeneous and the funnel plot did not suggest any publication bias. Duration of vasopressor requirement was significantly reduced in the intervention group (six randomized controlled trials). There was no evidence of a difference regarding the ICU mortality and the renal composite outcome (acute kidney injury KDIGO 3 or need for renal replacement therapy, seven randomized controlled trials). CONCLUSIONS Metabolic resuscitation cocktail administrated in ICU septic patients improves change in Sequential Organ Failure Assessment score within 72 hours. However, this improvement is modest and its clinical relevance is questionable. The impact on renal failure and mortality remains unclear.
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3.
Time-restricted feeding improves markers of cardiometabolic health in physically active college-age men: a 4-week randomized pre-post pilot study.
McAllister, MJ, Pigg, BL, Renteria, LI, Waldman, HS
Nutrition research (New York, N.Y.). 2020;:32-43
Abstract
Time-restricted feeding (TRF) has been shown to improve body composition, blood lipids, and reduce markers of inflammation and oxidative stress. However, most of these studies come from rodent models and small human samples, and it is not clear if the benefits are dependent upon a caloric deficit, or the time restriction nature of TRF. Based off of previous research, we hypothesized that humans following an ad libitum TRF protocol would reduce caloric intake and this caloric deficit would be associated with greater improvements in cardiometabolic health including blood pressure, body composition, blood lipids, and markers of inflammation and antioxidant status compared to an isocaloric TRF protocol. The purpose of this study was to: (1) examine the impact of TRF on markers of cardio-metabolic health and antioxidant status and (2) determine if the adaptations from TRF would differ under ad libitum compared to isocaloric conditions. Twenty-three healthy men were randomized to either an ad libitum or isocaloric 16:8 (fasting: feeding) TRF protocol. A total of 22 men completed the 28-day TRF protocol (mean ± SD; age: 22 ± 2.5 yrs.; height: 178.4 ± 6.9 cm; weight: 90.3 ± 24 kg; BMI: 28.5 ± 8.3 kg/m2). Fasting blood samples were analyzed for glucose, lipids, as well as adiponectin, human growth hormone, insulin, cortisol, C-reactive protein, superoxide dismutase, total nitrate/nitrite, and glutathione. Time-restricted feeding in both groups was associated with significant (P < .05) reductions in body fat, blood pressure, and significant increases in adiponectin and HDL-c. No changes in caloric intake were detected. In summary, the results from this pilot study in metabolically healthy, active young men, suggest that TRF can improve markers of cardiometabolic health.
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Caffeine effects on systemic metabolism, oxidative-inflammatory pathways, and exercise performance.
Barcelos, RP, Lima, FD, Carvalho, NR, Bresciani, G, Royes, LF
Nutrition research (New York, N.Y.). 2020;:1-17
Abstract
Caffeine, a xanthine alkaloid compound, is consumed widely and daily by humans, as it is present in several regular beverages such as tea, coffee, soda beverages, and some drugs. Its consumption triggers arousal and alertness, improves mood, and causes the release of catecholamines, which induce beneficial effects on human behavior. Nonetheless, caffeine has been related to other beneficial effects such as antioxidant and anti-inflammatory actions that are extremely important to human health, altering the cellular redox and inflammatory status in a dose-dependent manner. Caffeine intake has also shown ergogenic effects, which are attributed to different factors, such as enhanced substrate utilization, fatigue delay, and alertness. As such, caffeine has been consumed by athletes from different sports modalities, with positive and negative effects declared. Although peripheral tissues such as the heart, skeletal muscle, and adipocytes are also impacted, there is a deficit of recognized mechanisms in systemic metabolism when compared to caffeine action in the central nervous system. This review summarizes the most relevant classical and current literature available regarding the use of caffeine in different metabolic situations, such as oxidative and inflammatory status, as well as anaerobic and aerobic physical exercises. Here, we identified the non-central nervous system caffeine mechanisms modulation, as most are still unknown or controversial, highlighting its influence in the peripheral system and its essential and crucial impacts on the human's organism adaptation.
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5.
Dancing for Healthy Aging: Functional and Metabolic Perspectives.
Rodrigues-Krause, J, Krause, M, Reischak-Oliveira, A
Alternative therapies in health and medicine. 2019;(1):44-63
Abstract
CONTEXT Dancing has been used as a form of exercise to improve functional and metabolic outcomes during aging. The field lacks randomized, clinical trials (RCTs) evaluating metabolic outcomes related to dance interventions, but dancing may be a form of exercise that could induce positive effects on the metabolic health of older adults. However, primary studies seem very heterogonous regarding the trial designs, characteristics of the interventions, the methods for outcomes assessments, statistical powers, and methodological quality. OBJECTIVE The current research team intended to review the literature on the use of dance as a form of intervention to promote functional and metabolic health in older adults. Specifically, the research team aimed to identify and describe the characteristics of a large range of studies using dance as an intervention, summarizing them and putting them into perspective for further analysis. DESIGN The research team searched the following data sources-MEDLINE, Cochrane Wiley, Clinical Trials.gov, the Physiotherapy Evidence Database (PEDRO), and the Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS)-for RCTs, quasi-experimental studies, and observational trials that compared the benefits of any style of dancing, combined with other exercises or alone, to nonexercising controls and/or controls practicing other types of exercise. SETTING The study took place at the Federal University of Rio Grande do Sul (Porto Alegre, Brazil). PARTICIPANTS Participants were aging individuals, >55 y, both with or without health conditions. INTERVENTIONS Interventions should be supervised, taking form as group classes, in a dance setting environment. Dance styles were divided into 5 categories for the review: (1) cultural dances developed by groups of people to reflect the roots of a certain region, such as Greek dance; (2) ballroom dance (ie, dances with partners performed socially or competitively in a ballroom, such as foxtrot); (3) aerobic dance with no partner required, which mixes aerobic moves with dance moves; (4) dance therapies, whichare special dance programs including emotional and physical aspects; and (5) classical dances, which are dances with a unique tradition and technique, such as ballet or jazz dance. OUTCOME MEASURES Studies needed to have evaluated functional and/or metabolic outcomes. Functional outcomes included (1) static and/or dynamic balance, (2) gait ability, (3) upper and/or lower muscle strength or power, (4) cardiorespiratory fitness, (5) flexibility, (6) risk of falls, and (7) quality of life. Metabolic outcomes included (1) lipid and glycemic profile; (2) systolic and diastolic blood pressure; (3) body composition; and (4) other specific cardiovascular risk factors or inflammatory or oxidative stress markers. RESULTS The research team retrieved 1042 articles, with 88 full texts assessed for eligibility, and 50 articles included in the analysis. Of the analyzed studies, 22 were RCTs evaluating dancing vs controls, and 3 were RCTs evaluating dancing vs other exercise. Regarding the participants of the reviewed studies: (1) 31 evaluated healthy individuals, (2) 7 evaluated patients suffering from Parkinson's disease, (3) 4 evaluated postmenopausal women, (4) 2 evaluated obese women, (5) 2 evaluated patients with chronic heart failure, (6) 1 evaluated frail older adults, (7) 1 evaluated individuals with visual impairments, (8) 1 evaluated persons with metabolic syndrome, and (9) 1 evaluated individuals with severe pain in the lower extremities. Regarding the interventions, most interventions were 12 wk long, 3 ×/wk, for 60 min each session. The dance styles most used were ballroom and cultural dances. Regarding the outcomes, functional and metabolic benefits were described in most of the included studies. Balance was the functional outcome most often assessed. CONCLUSIONS Any dance style can induce positive functional adaptations in older adults, especially related to balance. Metabolic improvements may also be a result of dancing; however, more RCTs are needed. Dancing may be a potential exercise intervention to promote health-related benefits for aging individuals.
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Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.
Kraja, AT, Liu, C, Fetterman, JL, Graff, M, Have, CT, Gu, C, Yanek, LR, Feitosa, MF, Arking, DE, Chasman, DI, et al
American journal of human genetics. 2019;(1):112-138
Abstract
Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.
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7.
Molecular logic of mTORC1 signalling as a metabolic rheostat.
Valvezan, AJ, Manning, BD
Nature metabolism. 2019;(3):321-333
Abstract
The protein kinase complex mechanistic target of rapamycin complex 1 (mTORC1) serves as a key conduit between growth signals and the metabolic processes underlying cell growth. The activation state of mTORC1 is controlled by intracellular nutrients and energy, as well as exogenous hormones and growth factors, thereby integrating local and systemic growth signals. Here we discuss the molecular logic of the mTORC1 signalling network and its importance in coupling growth signals to the control of cellular metabolism. After activation, mTORC1 promotes the conversion of available nutrients and energy into the major macromolecular species contributing to cellular mass, including proteins, nucleic acids and lipids, while suppressing the autophagic recycling of these macromolecules back into their nutrient constituents. Given that uncoupling of mTORC1 from its normal regulatory inputs contributes to many diseases-including cancer, genetic tumour syndromes, metabolic diseases, autoimmune diseases and neurological disorders-understanding the molecular logic of the mTORC1 network and how to modulate it may present therapeutic opportunities for treatment of a broad range of diseases and potentially even for the extension of lifespan.
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Leptin trajectories from birth to mid-childhood and cardio-metabolic health in early adolescence.
Li, LJ, Rifas-Shiman, SL, Aris, IM, Mantzoros, C, Hivert, MF, Oken, E
Metabolism: clinical and experimental. 2019;:30-38
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Abstract
OBJECTIVES Leptin is a hormone produced by adipose tissue that promotes satiety, and some evidence suggests that greater early life leptin exposure prevents excessive adiposity gain in later life. However, few studies have analyzed dynamic changes in leptin throughout childhood in relation to later cardio-metabolic health. Our study aims to identify distinct leptin trajectories in childhood, and to examine their associations with cardio-metabolic outcomes in adolescence. METHODS Among children in the Project Viva cohort born 1999-2002 in Massachusetts, we used latent class growth models to identify leptin trajectories independent of maternal BMI, child sex, race/ethnicity, size at birth and current age and size among 1360 children with leptin measured at least once at birth, early childhood (mean 3.3 ± SD 0.3 years), or mid-childhood (7.9 ± 0.8 years). At research visits in early adolescence (13.2 ± 0.9 years), we assessed cardio-metabolic outcomes including adiposity measures, fasting biomarkers, and blood pressure among 855 children. We then applied multiple regression models to examine associations of the leptin trajectories with these cardio-metabolic outcomes in early adolescence, adjusting for child age at outcome, maternal age, education, prenatal smoking and glucose, total gestational weight gain and paternal BMI. RESULTS The latent class growth model identified 3 distinct leptin trajectories: "low stable" (n = 1031, 75.8%), "high-decreasing" (n = 219, 16.1%) and "intermediate-increasing" (n = 110, 8.1%). In adjusted models, the intermediate-increasing leptin trajectory was associated with higher early adolescence adiposity measures (e.g. BMI z-score: 0.62 units; 95% confidence interval: 0.28, 0.96 and odds of obesity: 2.84: 1.17, 6.94), but lower systolic blood pressure (-0.46 z-score units; -0.74, -0.18), compared to the low-stable group. CONCLUSIONS Our findings on leptin trajectories in childhood suggest important differences and associations with later metabolic outcomes.
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Effects of Boxing Matches on Metabolic, Hormonal, and Inflammatory Parameters in Male Elite Boxers.
Kılıc, Y, Cetin, HN, Sumlu, E, Pektas, MB, Koca, HB, Akar, F
Medicina (Kaunas, Lithuania). 2019;(6)
Abstract
Background and objectives: Boxing is a popular combat sport that requires high intensity and cooperation. However, there are limited data about the influence of boxing matches on blood parameters. The purpose of the present study was to investigate the match-induced changes in the metabolic, hormonal, and inflammatory status in male elite boxers. Materials and methods: High-level 20 male boxers with more than 5 years experience in boxing voluntarily participated in this study. Venous blood samples of the boxers, before and after combat, were taken for determination of the plasma parameters. Results: Our results indicated that a 9-min boxing match caused significant increases in plasma energy fuels (glucose and lactate), metabolic hormones (insulin, adrenocorticotropic hormone (ACTH), cortisol, and growth hormone), inflammatory markers (interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α)), muscle damage indicators (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), and oxidative stress marker (SOD). A decrease in total oxidant status (TOS) was also considered. However, there were no significant alterations in the plasma levels of androgenic hormone (free and total testosterone), anabolic hormone (IGF-1), lipids (total cholesterol, triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL)), kidney function markers (creatinine and urea), and minerals (iron (Fe) and magnesium (Mg)). Conclusion: Elevations in the level of energy fuels and metabolic hormones of the boxers could be taken as a reflection of high-energy turnover during combat performance. The increases in inflammatory and tissue damage indicators may possibly be an indication of traumatic injury. Understanding the biochemical changes that occur during boxing match could be valuable to optimize the performance improvement of the athletes.
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10.
Phthalate exposure and metabolic effects: a systematic review of the human epidemiological evidence.
Radke, EG, Galizia, A, Thayer, KA, Cooper, GS
Environment international. 2019;:104768
Abstract
OBJECTIVE We performed a systematic review of the epidemiology literature to identify the metabolic effects associated with phthalate exposure. DATA SOURCES AND STUDY ELIGIBILITY CRITERIA Six phthalates were included in the review: di(2‑ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), butyl benzyl phthalate (BBP), and diethyl phthalate (DEP). The initial literature search (of PubMed, Web of Science, and Toxline) included all studies of metabolic effects in humans, and outcomes were selected for full systematic review based on data availability. STUDY EVALUATION AND SYNTHESIS METHODS Studies of diabetes and insulin resistance were evaluated using criteria defined a priori for risk of bias and sensitivity by two reviewers using a domain-based approach; studies identified with a pre-defined critical deficiency were excluded. Evidence was synthesized by outcome and phthalate and strength of evidence was summarized using a structured framework. Studies of obesity and renal effects received "screening level" reviews to determine whether full systematic review was warranted. RESULTS The primary outcomes reviewed here are (number of included/excluded studies in parentheses): type 2 diabetes (1/3), insulin resistance (13/3), and impaired glucose tolerance and blood glucose in pregnancy (4/2). For DEHP exposure, there was consistency among studies of insulin resistance and coherence with the single included study of diabetes, as well as an observed exposure-response gradient observed in a study of insulin resistance. This evidence is considered moderate. Similarly, for DBP and DIBP exposure, the evidence is considered moderate due to strong positive associations in the diabetes study and coherent results for insulin resistance. For DINP, BBP, and DEP, the evidence is considered slight. No association was reported in the single study of diabetes with BBP and DEP exposure (DINP was not investigated). The available evidence does indicate an association between exposure to these phthalates and insulin resistance, but the small number of studies and the lack of coherence with diabetes decreases confidence. The screening level reviews for obesity and renal effects determined that the currently available evidence is inadequate to assess the associations between these outcomes and phthalate exposure. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS Overall, these results support that phthalate exposure at levels seen in human populations may have metabolic effects. Given the mechanistic support, the large effect sizes for incident diabetes in the single available study, and the coherence with insulin resistance, the association between phthalate exposure and diabetes risk should be considered when assessing the risks and costs of exposure to specific phthalates in humans. The views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.