Structure Based Discovery of Inhibitors of CYP125 and CYP142 from Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) was responsible for approximately 1.6 million deaths in 2021. With the emergence of extensive drug resistance, novel therapeutic agents are urgently needed, and continued drug discovery efforts required. Host-derived lipids such as cholesterol not only support Mtb growth, but are also suspected to function in immunomodulation, with links to persistence and immune evasion. Mtb cytochrome P450 (CYP) enzymes facilitate key steps in lipid catabolism and thus present potential targets for inhibition. Here we present a series of compounds based on an ethyl 5-(pyridin-4-yl)-1H-indole-2-carboxylate pharmacophore which bind strongly to both Mtb cholesterol oxidases CYP125 and CYP142. Using a structure-guided approach, combined with biophysical characterization, compounds with micromolar range in-cell activity against clinically relevant drug-resistant isolates were obtained. These will incite further development of much-needed additional treatment options and provide routes to probe the role of CYP125 and CYP142 in Mtb pathogenesis.

Dietary interventions for autism spectrum disorder: An updated systematic review of human studies.

Autism is a complex spectrum of disorders with genetic, epigenetic, autoimmune, oxidative stress, and environmental etiologies. Treatment of ASD using dietary approach is a promising strategy, especially owing to its safety and availability. Our study critically analysed the roles and efficacy of antioxidants, probiotics, prebiotics, camel milk and vitamin D. This systematic review provides an updated synopsis of human studies that investigated therapeutic benefits of these dietary interventions in autism. A total of 943 papers were identified out of which 21 articles were included in the systematic review. The selected studies investigated the impact of 5 different dietary supplementations in ASD symptom and behaviours. These agents include; antioxidants/polyphenolic compounds, probiotics, prebiotics, camel milk and vitamin D. From the results of the present review, antioxidants/polyphenolic compounds decreased the levels of inflammatory cytokines and improved behavioural symptoms. Probiotics improved behavioural and GI symptoms as well as restored gut microbiota equilibrium. Prebiotics decreased levels of inflammatory cytokines, improved behavioural and GI symptoms and improved gut microbiota. Vitamin D improved behavioural symptoms and offered protective effects against neurotoxicity. Camel milk reduced inflammatory responses and oxidative stress. Given the chronic nature as well as early onset of ASD, dietary supplements become useful to complement nutritional deficiencies in children with ASD. Key benefits of these agents stem from their ability to target multiple physiological areas via the gut brain-axis and are devoid of potential harmful or aggravating effects on ASD patients. The evidence collated in this review propose that dietary intervention may provide a new platform for the management of autism.

Association of autism with toxic metals: A systematic review of case-control studies.

Environmental factors have been associated with the etiology of autism spectrum disorder ASD in recent times. The involvement of toxic metals in the generation of reactive oxygen species and their epigenetics effects have been implicated in ASD. This systemic review examines the association of toxic metals with autism in children. A systematic literature search was performed in scientific databases such as PubMed, Google scholar, and Scopus. Case-control studies evaluating toxic metal levels in different tissues of ASD children and comparing them to healthy children (control group) were identified. The Newcastle-Ottawa Scale was used to evaluate the risk of bias of the included studies. Six case-control studies with 425 study subjects met our inclusion criteria. A total of four studies indicated higher levels of As, Pb, Hg, Cd, Al, Sn, Sb, Ba, TI, W, and Zr in whole blood, RBC, in whole blood, RBC, and hair samples of children with autism compared with control suggestive of a greater toxic metal exposure (immediate and long-term). Three studies identified significantly higher concentrations of Cd, Pb and Hg in urine and hair samples of autistic children compared to control suggesting decreased excretion and possible high body burden of these metals. The findings from this review demonstrate that high levels of toxic metals are associated with ASD, therefore, critical care is necessary to reduce body burden of these metals in children with ASD as a major therapeutic strategy.

Emerging pollutants in Nigeria: A systematic review.

Emerging pollutants represent a group of synthetic or naturally occurring compounds that are not normally monitored within the environment but can enter into the environment and cause different adverse ecological and health effects. This systematic review identified the various emerging pollutants in Nigeria. The following databases, ScienceDirect, PubMed, Google Scholar, and African Journals OnLine (AJOL) were searched to identify studies on pollutants of emerging concerns in Nigeria. A total of 933 articles were identified out of which 30 articles were selected to be eligible for the study. Over 250 emerging pollutants were identified and divided into 9 major groups which are personal care products, pharmaceuticals, industrial chemicals, polycyclic aromatic hydrocarbons, volatile organic compounds, pesticides, mycotoxins, radionuclides and electromagnetic radiations (Gamma radiation) and other pollutants of emerging concerns such as microbes, microplastics, and particulate matter. These pollutants are found in water bodies and underground waters, soils and sediments, biological systems, and ambient air at different concentrations with seasonal variations. Some of these pollutants act as endocrine disruptors, ß-adrenergic receptors agonist blockers, oxidative stress inducers and can cause genetic alterations in DNA and epigenetic reprogramming through global DNA methylation, gene-specific CpG methylation and microRNA expression. Emerging pollutants of public health concern in Nigeria are on the increase and are threat to both ecological and human health.

Selected Food/Herb-Drug Interactions: Mechanisms and Clinical Relevance.

BACKGROUND: Food/Herb-drug interactions have become a major problem in health care. These interactions can lead to loss of therapeutic efficacy or toxic effects of drugs. AREAS OF UNCERTAINTY: To probe the clinical relevance of such interactions, the impact of food/herb intake on the clinical effects of drug administration has to be evaluated. Failure to identify and efficiently manage food-drug interactions can lead to serious consequences. A comprehensive knowledge of the mechanisms that underpin variability in disposition will help optimize therapy. DATA SOURCES: Electronic search of literatures from relevant databases were conducted. A total of 58 original scientific reports/review articles were obtained with the search strategy; of which 25 were found eligible to be included in the present review. Required data were extracted from these studies, and their methodologies were assessed. RESULTS AND CONCLUSIONS: This review updates our knowledge on clinical food-drug interactions with emphasis on mechanism and clinical implications. Results obtained from literature search identified interactions with selected foods/herbs generated from in vivo and in vitro studies. For example, interaction studies in humans revealed a reduction in the bioavailability of mercaptopurine when taken concurrently with substances containing xanthine oxidase (eg, cow milk); a reduction in the bioavailability of quinine with Garcinia kola; increased bioavailability/toxicity of felodipine, nifedipine, saquinavir, sildenafil with grape juice; increased bioavailability of felodipine, cisapride with red wine and diminished bioavailability of fexofenadine with apple. Pharmacokinetic and/or pharmacodynamic mechanisms are implicated in many of these interactions. By evaluating the dietary patterns of patients and use of prescribed medications, health professionals will be well informed of potential interactions and associated adverse effects.