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Parasitology Research Jun 2024Sterol 14-demethylase (CYP51) inhibitors, encompassing new chemical entities and repurposed drugs, have emerged as promising candidates for Chagas disease treatment,... (Meta-Analysis)
Meta-Analysis Review
Sterol 14-demethylase (CYP51) inhibitors, encompassing new chemical entities and repurposed drugs, have emerged as promising candidates for Chagas disease treatment, based on preclinical studies reporting anti-Trypanosoma cruzi activity. Triazoles like ravuconazole (RAV) and posaconazole (POS) progressed to clinical trials. Unexpectedly, their efficacy was transient in chronic Chagas disease patients, and their activity was not superior to benznidazole (BZ) treatment. This paper aims to summarize evidence on the global activity of CYP51 inhibitors against T. cruzi by applying systematic review strategies, risk of bias assessment, and meta-analysis from in vivo studies. PubMed and Embase databases were searched for original articles, obtaining fifty-six relevant papers meeting inclusion criteria. Characteristics of animal models, parasite strain, treatment schemes, and cure rates were extracted. Primary outcomes such as maximum parasitaemia values, survival, and parasitological cure were recorded for meta-analysis, when possible. The risk of bias was uncertain in most studies. Animals treated with itraconazole, RAV, or POS survived significantly longer than the infected non-treated groups (RR = 4.85 [3.62, 6.49], P < 0.00001), and they showed no differences with animals treated with positive control drugs (RR = 1.01 [0.98, 1.04], P = 0.54). Furthermore, the overall analysis showed that RAV or POS was not likely to achieve parasitological cure when compared with BZ or NFX treatment (OD = 0.49 [0.31, 0.77], P = 0.002). This systematic review contributes to understanding why the azoles had failed in clinical trials and, more importantly, how to improve the animal models of T. cruzi infection by filling the gaps between basic, translational, and clinical research.
Topics: Animals; Humans; 14-alpha Demethylase Inhibitors; Chagas Disease; Disease Models, Animal; Sterol 14-Demethylase; Thiazoles; Treatment Outcome; Triazoles; Trypanocidal Agents; Trypanosoma cruzi
PubMed: 38904688
DOI: 10.1007/s00436-024-08257-3 -
Diving and Hyperbaric Medicine Jun 2024Inhalation of high concentrations of carbon dioxide (CO₂) at atmospheric pressure can be toxic with dose-dependent effects on the cardiorespiratory system or the... (Review)
Review
INTRODUCTION
Inhalation of high concentrations of carbon dioxide (CO₂) at atmospheric pressure can be toxic with dose-dependent effects on the cardiorespiratory system or the central nervous system. Exposure to both hyperbaric and hypobaric environments can result in decompression sickness (DCS). The effects of CO₂ on DCS are not well documented with conflicting results. The objective was to review the literature to clarify the effects of CO₂ inhalation on DCS in the context of hypobaric or hyperbaric exposure.
METHODS
The systematic review included experimental animal and human studies in hyper- and hypobaric conditions evaluating the effects of CO₂ on bubble formation, denitrogenation or the occurrence of DCS. The search was based on MEDLINE and PubMed articles with no language or date restrictions and also included articles from the underwater and aviation medicine literature.
RESULTS
Out of 43 articles, only 11 articles were retained and classified according to the criteria of hypo- or hyperbaric exposure, taking into account the duration of CO₂ inhalation in relation to exposure and distinguishing experimental work from studies conducted in humans.
CONCLUSIONS
Before or during a stay in hypobaric conditions, exposure to high concentrations of CO₂ favors bubble formation and the occurrence of DCS. In hyperbaric conditions, high CO₂ concentrations increase the occurrence of DCS when exposure occurs during the bottom phase at maximum pressure, whereas beneficial effects are observed when exposure occurs during decompression. These opposite effects depending on the timing of exposure could be related to 1) the physical properties of CO₂, a highly diffusible gas that can influence bubble formation, 2) vasomotor effects (vasodilation), and 3) anti-inflammatory effects (kinase-nuclear factor and heme oxygenase-1 pathways). The use of O₂-CO₂ breathing mixtures on the surface after diving may be an avenue worth exploring to prevent DCS.
Topics: Animals; Humans; Atmospheric Pressure; Carbon Dioxide; Decompression Sickness; Diving
PubMed: 38870953
DOI: 10.28920/dhm54.2.110-119 -
Nutrients Apr 2024Alcoholic Fatty Liver Disease (AFLD) is characterized by the accumulation of lipids in liver cells owing to the metabolism of ethanol. This process leads to a decrease... (Meta-Analysis)
Meta-Analysis
Alcoholic Fatty Liver Disease (AFLD) is characterized by the accumulation of lipids in liver cells owing to the metabolism of ethanol. This process leads to a decrease in the NAD/NADH ratio and the generation of reactive oxygen species. A systematic review and meta-analysis were conducted to investigate the role of oxidative stress in AFLD. A total of 201 eligible manuscripts were included, which revealed that animals with AFLD exhibited elevated expression of CYP2E1, decreased enzymatic activity of antioxidant enzymes, and reduced levels of the transcription factor Nrf2, which plays a pivotal role in the synthesis of antioxidant enzymes. Furthermore, animals with AFLD exhibited increased levels of lipid peroxidation markers and carbonylated proteins, collectively contributing to a weakened antioxidant defense and increased oxidative damage. The liver damage in AFLD was supported by significantly higher activity of alanine and aspartate aminotransferase enzymes. Moreover, animals with AFLD had increased levels of triacylglycerol in the serum and liver, likely due to reduced fatty acid metabolism caused by decreased PPAR-α expression, which is responsible for fatty acid oxidation, and increased expression of SREBP-1c, which is involved in fatty acid synthesis. With regard to inflammation, animals with AFLD exhibited elevated levels of pro-inflammatory cytokines, including TNF-a, IL-1β, and IL-6. The heightened oxidative stress, along with inflammation, led to an upregulation of cell death markers, such as caspase-3, and an increased Bax/Bcl-2 ratio. Overall, the findings of the review and meta-analysis indicate that ethanol metabolism reduces important markers of antioxidant defense while increasing inflammatory and apoptotic markers, thereby contributing to the development of AFLD.
Topics: Animals; Humans; Antioxidants; Cytochrome P-450 CYP2E1; Cytokines; Disease Models, Animal; Fatty Liver, Alcoholic; Lipid Peroxidation; Liver; NF-E2-Related Factor 2; Oxidative Stress; Reactive Oxygen Species
PubMed: 38674865
DOI: 10.3390/nu16081174 -
Biomedicines Apr 2024Hemin is clinically used in acute attacks of porphyria; however, recent evidence has also highlighted its capability to stimulate the heme oxygenase enzyme, being... (Review)
Review
BACKGROUND
Hemin is clinically used in acute attacks of porphyria; however, recent evidence has also highlighted its capability to stimulate the heme oxygenase enzyme, being associated with cytoprotective, antioxidant, and anti-inflammatory effects. Indeed, current preclinical evidence emphasizes the potential anti-inflammatory role of hemin through its use in animal models of disease. Nevertheless, there is no consensus about the underlying mechanism(s) and the most optimal therapeutic regimens. Therefore, this review aims to summarize, analyze, and discuss the current preclinical evidence concerning the pharmacological effect of hemin.
METHODS
Following the application of the search expression and the retrieval of the articles, only nonclinical studies in vivo written in English were considered, where the potential anti-inflammatory effect of hemin was evaluated.
RESULTS
Forty-nine articles were included according to the eligibility criteria established. The results obtained show the preference of using 30 to 50 mg/kg of hemin, administered intraperitoneally, in both acute and chronic contexts. This drug demonstrates significant anti-inflammatory and antioxidant activities considering its capacity for reducing the expression of proinflammatory and oxidative markers.
CONCLUSIONS
This review highlighted the significant anti-inflammatory and antioxidant effects of hemin, providing a clearer vision for the medical community about the use of this drug in several human diseases.
PubMed: 38672251
DOI: 10.3390/biomedicines12040898 -
Drug Metabolism Reviews 2024Due to legal, political, and cultural changes, the use of cannabis has rapidly increased in recent years. Research has demonstrated that the cannabinoids cannabidiol...
Due to legal, political, and cultural changes, the use of cannabis has rapidly increased in recent years. Research has demonstrated that the cannabinoids cannabidiol (CBD) and Δ-tetrahydrocannabinol (THC) inhibit and induce cytochrome P450 (CYP450) enzymes. The objective of this review is to evaluate the effect of CBD and THC on the activity of CYP450 enzymes and the implications for drug-drug interactions (DDIs) with psychotropic agents that are CYP substrates. A systematic search was conducted using PubMed, Scopus, Scientific Electronic Library Online (SciELO) and PsychINFO. Search terms included 'cannabidiol', 'tetrahydrocannabinol', and 'cytochrome P450'. A total of seven studies evaluating the interaction of THC and CBD with CYP450 enzymes and psychotropic drugs were included. Both preclinical and clinical studies were included. Results from the included studies indicate that both CBD and THC inhibit several CYP450 enzymes including, but not limited to, CYP1A2, CYP3C19, and CYP2B6. While there are a few known CYP450 enzymes that are induced by THC and CBD, the induction of CYP450 enzymes is an understudied area of research and lacks clinical data. The inhibitory effects observed by CBD and THC on CYP450 enzymes vary in magnitude and may decrease the metabolism of psychotropic agents, cause changes in plasma levels of psychotropic medications, and increase adverse effects. Our findings clearly present interactions between THC and CBD and several CYP450 enzymes, providing clinicians evidence of a high risk of DDIs for patients who consume both cannabis and psychotropic medication. However, more clinical research is necessary before results are applied to clinical settings.
Topics: Animals; Humans; Cannabidiol; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dronabinol; Drug Interactions; Psychotropic Drugs
PubMed: 38655747
DOI: 10.1080/03602532.2024.2346767 -
Journal of Psychiatric Research Jun 2024Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and... (Review)
Review
Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and risperidone are two commonly prescribed antipsychotics, metabolized primarily through CYP2D6. Here, we aimed to provide an overview of the effect of CYP2C19 and CYP2D6 on side-effects of aripiprazole and risperidone, and expand on existing literature by critically examining methodological issues associated with pharmacogenetic studies. A PRISMA compliant search of six electronic databases (Pubmed, PsychInfo, Embase, Central, Web of Science, and Google Scholar) identified pharmacogenetic studies on aripiprazole and risperidone. 2007 publications were first identified, of which 34 were included. Quality of literature was estimated using Newcastle-Ottowa Quality Assessment Scale (NOS) and revised Cochrane Risk of Bias tool. The average NOS score was 5.8 (range: 3-8) for risperidone literature and 5 for aripiprazole (range: 4-6). All RCTs on aripiprazole were rated as high risk of bias, and four out of six for risperidone literature. Study populations ranged from healthy volunteers to inpatient individuals in psychiatric units and included adult and pediatric samples. All n = 34 studies examined CYP2D6. Only one study genotyped for CYP2C19 and found a positive association with neurological side-effects of risperidone. Most studies did not report any relationship between CYP2D6 and any side-effect outcome. Heterogeneity between and within studies limited the ability to synthesize data and draw definitive conclusions. Studies lacked statistical power due to small sample size, selective genotyping methods, and study design. Large-scale randomized trials with multiple measurements, providing robust evidence on this topic, are suggested.
Topics: Humans; Aripiprazole; Cytochrome P-450 CYP2D6; Risperidone; Cytochrome P-450 CYP2C19; Antipsychotic Agents
PubMed: 38631139
DOI: 10.1016/j.jpsychires.2024.04.001 -
Nutrients Apr 2024The aim of this systematic review is to comprehensively assess the weight loss (WL) practices in different combat sports (CS). The review protocol was preregistered with... (Review)
Review
The aim of this systematic review is to comprehensively assess the weight loss (WL) practices in different combat sports (CS). The review protocol was preregistered with PROSPERO [CRD42023487196]. Three databases were searched (Web of Science, EBSCOhost, and PubMed) until 8 December 2023. Eligible studies had to meet five criteria: they must have been (a) written in English, (b) published in a peer-reviewed journal, (c) used a survey design to investigate the WL practices of CS athletes, and (d) reported the WL methods used by athletes using a five-point scale. Twenty-six studies (3994 participants from 14 CS) were included. This review found that (1) WL is highly prevalent in CS athletes; (2) many CS athletes started losing weight for competition as teenagers two to three times a year; (3) CS athletes usually lose <5% body weight in 7-14 days before competition; (4) increasing exercise and gradually dieting are the most commonly used WL methods; and (5) the influence of scientific practitioners on athletes is negligible. The habitual practices of CS athletes may be relatively harmless, but in some special cases, CS athletes also perform extreme WL practices. Scientific practitioners have little influence on their WL practices, which may form a vicious cycle of non-qualified influence.
Topics: Adolescent; Humans; Athletes; Sports; Tryptophan Oxygenase; Databases, Factual; Weight Loss
PubMed: 38613083
DOI: 10.3390/nu16071050 -
International Journal of Molecular... Mar 2024Squalene epoxidase (SQLE) is a key enzyme in the mevalonate-cholesterol pathway that plays a critical role in cellular physiological processes. It converts squalene to...
Squalene epoxidase (SQLE) is a key enzyme in the mevalonate-cholesterol pathway that plays a critical role in cellular physiological processes. It converts squalene to 2,3-epoxysqualene and catalyzes the first oxygenation step in the pathway. Recently, intensive efforts have been made to extend the current knowledge of SQLE in cancers through functional and mechanistic studies. However, the underlying mechanisms and the role of SQLE in cancers have not been fully elucidated yet. In this review, we retrospected current knowledge of SQLE as a rate-limiting enzyme in the mevalonate-cholesterol pathway, while shedding light on its potential as a diagnostic and prognostic marker, and revealed its therapeutic values in cancers. We showed that SQLE is regulated at different levels and is involved in the crosstalk with iron-dependent cell death. Particularly, we systemically reviewed the research findings on the role of SQLE in different cancers. Finally, we discussed the therapeutic implications of SQLE inhibitors and summarized their potential clinical values. Overall, this review discussed the multifaceted mechanisms that involve SQLE to present a vivid panorama of SQLE in cancers.
Topics: Humans; Cell Death; Cholesterol; Mevalonic Acid; Neoplasms; Squalene Monooxygenase
PubMed: 38612682
DOI: 10.3390/ijms25073874 -
Neural Regeneration Research Dec 2024The search for reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis, to detect neurodegeneration from the prodromal phase and...
The search for reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis, to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies. Despite the need for non-invasively accessible biomarkers, the majority of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers, which require invasive collection procedures. Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers. In the present study, after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson's disease, we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson's disease patients. A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289 articles. After screening and exclusion, 34 relevant articles were derived for systematic review. Alpha-synuclein, the histopathological hallmark of Parkinson's disease, has been the most investigated Parkinson's disease biomarker in saliva, with oligomeric alpha-synuclein consistently found increased in Parkinson's disease patients in comparison to healthy controls, while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein, and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson's disease. Beyond alpha-synuclein, other biomarkers targeting different molecular pathways have been explored in the saliva of Parkinson's disease patients: total tau, phosphorylated tau, amyloid-β1-42 (pathological protein aggregation biomarkers); DJ-1, heme-oxygenase-1, metabolites (altered energy homeostasis biomarkers); MAPLC-3beta (aberrant proteostasis biomarker); cortisol, tumor necrosis factor-alpha (inflammation biomarkers); DNA methylation, miRNA (DNA/RNA defects biomarkers); acetylcholinesterase activity (synaptic and neuronal network dysfunction biomarkers); Raman spectra, proteome, and caffeine. Despite a few studies investigating biomarkers targeting molecular pathways different from alpha-synuclein in Parkinson's disease, these results should be replicated and observed in studies on larger cohorts, considering the potential role of these biomarkers in determining the molecular variance among Parkinson's disease subtypes. Although the need for standardization in sample collection and processing, salivary-based biomarkers studies have reported encouraging results, calling for large-scale longitudinal studies and multicentric assessments, given the great molecular potentials and the non-invasive accessibility of saliva.
PubMed: 38595280
DOI: 10.4103/NRR.NRR-D-23-01677 -
Chemosphere May 2024With industrialisation and the rapidly growing agricultural demand, many organic compounds have been leaked into the environment, causing serious damage to the... (Review)
Review
With industrialisation and the rapidly growing agricultural demand, many organic compounds have been leaked into the environment, causing serious damage to the biosphere. Persistent organic pollutants (POPs) are a type of toxic chemicals that are resistant to degradation through normal chemical, biological or photolytic approaches. With their stable chemical structures, POPs can be accumulated in the environment, and transported through wind and water, causing global environmental issues. Many researches have been conducted to remediate POPs contamination using various kinds of biological methods, and significant results have been seen. Microalgae-bacteria consortium is a newly developed concept for biological technology in contamination treatment, with the synergetic effects between microalgae and bacteria, their potential for pollutants degradation can be further released. In this review, two types of POPs (polychlorinated biphenyls and polycyclic aromatic hydrocarbons) are selected as the targeted pollutants to give a systematic analysis of the biodegradation through microalgae and bacteria, including the species selection, the identification of dominant enzymes, as well as the real application performance of the consortia. In the end, some outlooks and suggestions are given to further guide the development of applying microalgae-bacteria consortia in remediating POPs contamination. In general, the coculturing of microalgae and bacteria is a novel and efficient way to fulfil the advanced treatment of POPs in soil or liquid phase, and both monooxygenase and dioxygenase belonging to oxygenase play a vital role in the biodegradation of PCBs and PAHs. This review provides a general guide in the future investigation of biological treatment of POPs.
Topics: Persistent Organic Pollutants; Biodegradation, Environmental; Microalgae; Environmental Monitoring; Polychlorinated Biphenyls; Environmental Pollutants; Polycyclic Aromatic Hydrocarbons
PubMed: 38556179
DOI: 10.1016/j.chemosphere.2024.141852