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The field of orthodontics has seen a recent increase in the number of patients over the age of 50 seeking treatment and also an increase in the use of cone beam technology. Similar to other joints in the body, the temporomandibular joint (TMJ) is associated with age-related degeneration. However, unlike other joints, degeneration of the TMJ is rarely symptomatic and when there is pain, it is usually self-limiting. In this article, we will review: a) the incidence and prevalence of TMJ degenerative diseases, b) similarities and differences of TMJ vs knee degenerative diseases, and c) current treatment recommendations for TMJ degenerative diseases. In the vast majority of people, radiographic evidence of TMJ degeneration is an incidental finding. Future longitudinal research is needed to follow the natural course of TMJ degenerative patients.
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Background: COVID-19 disease is characterized by a spectrum of disease phases (mild, moderate, and severe). Each disease phase is marked by changes in omics profiles with corresponding changes in the expression of features (biosignatures). However, integrative analysis of multiple omics data from different experiments across studies to investigate biosignatures at various disease phases is limited. Exploring an integrative multi-omics profile analysis through a network approach could be used to determine biosignatures associated with specific disease phases and enable the examination of the relationships between the biosignatures. Aim: To identify and characterize biosignatures underlying various COVID-19 disease phases in an integrative multi-omics data analysis. Method: We leveraged a multi-omics network-based approach to integrate transcriptomics, metabolomics, proteomics, and lipidomics data. The World Health Organization Ordinal Scale WHO Ordinal Scale was used as a disease severity reference to harmonize COVID-19 patient metadata across two studies with independent data. A unified COVID-19 knowledge graph was constructed by assembling a disease-specific interactome from the literature and databases. Disease-state specific omics-graphs were constructed by integrating multi-omics data with the unified COVID-19 knowledge graph. We expanded on the network layers of multiXrank, a random walk with restart on multilayer network algorithm, to explore disease state omics-specific graphs and perform enrichment analysis. Results: Network analysis revealed the biosignatures involved in inducing chemokines and inflammatory responses as hubs in the severe and moderate disease phases. We observed distinct biosignatures between severe and moderate disease phases as compared to mild-moderate and mild-severe disease phases. Mild COVID-19 cases were characterized by a unique biosignature comprising C-C Motif Chemokine Ligand 4 (CCL4), and Interferon Regulatory Factor 1 (IRF1). Hepatocyte Growth Factor (HGF), Matrix Metallopeptidase 12 (MMP12), Interleukin 10 (IL10), Nuclear Factor Kappa B Subunit 1 (NFKB1), and suberoylcarnitine form hubs in the omics network that characterizes the moderate disease state. The severe cases were marked by biosignatures such as Signal Transducer and Activator of Transcription 1 (STAT1), Superoxide Dismutase 2 (SOD2), HGF, taurine, lysophosphatidylcholine, diacylglycerol, triglycerides, and sphingomyelin that characterize the disease state. Conclusion: This study identified both biosignatures of different omics types enriched in disease-related pathways and their associated interactions (such as protein-protein, protein-transcript, protein-metabolite, transcript-metabolite, and lipid-lipid interactions) that are unique to mild, moderate, and severe COVID-19 disease states. These biosignatures include molecular features that underlie the observed clinical heterogeneity of COVID-19 and emphasize the need for disease-phase-specific treatment strategies. The approach implemented here can be used to find associations between transcripts, proteins, lipids, and metabolites in other diseases.
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Background: Periodontal health in men with HIV remains understudied, despite suggestions of associations between HIV infection and gingival pocketing, periodontal attachment loss, and gingival inflammation. As antiretroviral therapy (ART) has improved the quality of life for people living with HIV (PLWH), aging-related risk factors and comorbidities, including periodontitis, have emerged. This study aims to assess alveolar bone height, gingival crevicular fluid (GCF) cytokines, and periodontal disease activity in men with and without HIV. Methods: Ninety-three men (50 HIV+, 43 HIVâ) aged 35-70 years were recruited from Columbia University Irving Medical Center clinics. Periodontal examination, GCF collection, and intraoral radiographs were conducted. Results: While no significant differences were observed in bleeding on probing, clinical attachment loss and pocket depths, men with HIV exhibited significantly greater alveolar crestal height on radiographs compared to men without HIV (HIV + 3.41+/-1.35 mm, HIV- 2.64+/-1.01 mm; p = 0.004), reflecting greater alveolar bone loss. GCF IL6 levels showed a trend towards elevation in men with HIV (HIV + 0.349+/-0.407 pg/ml, HIV- 0.220+/-0.228 pg/ml; p = 0.059). Conclusions: Men with HIV demonstrate increased alveolar bone loss compared to those without HIV, possibly mediated by elevated IL6 levels. These results underscore the importance of comprehensive oral health management in PLWH and highlight the need for further research understanding the mechanisms linking HIV infection, cytokine dysregulation, and periodontal health.
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In July 2020, the H3Africa Ethics and Community Engagement (E&CE) Working Group organised a webinar with ethics committee members and biomedical researchers from various African institutions throughout the Continent to discuss the issue of whether and how biological samples for scientific research may be accessed by commercial entities when broad consents obtained for the samples are silent. 128 people including Research Ethics Committee members (10), H3Africa researchers (46) including members of the E&CE working group, biomedical researchers not associated with H3Africa (27), representatives from the National Institutes of Health (16) and 10 other participants attended the webinar and shared their views. Several major themes emerged during the webinar, with the topics of broad versus explicit informed consent, defining commercial use, legacy samples and benefit sharing prevailing in the discussion. This report describes the consensus concerns and recommendations raised during the meeting and will be informative for future research on ethical considerations for genomic research in the African research context.
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Genómica , Consentimiento Informado , Humanos , Ética en Investigación , Comités de Ética en InvestigaciónRESUMEN
Advances in omics technologies allow for holistic studies into biological systems. These studies rely on integrative data analysis techniques to obtain a comprehensive view of the dynamics of cellular processes, and molecular mechanisms. Network-based integrative approaches have revolutionized multi-omics analysis by providing the framework to represent interactions between multiple different omics-layers in a graph, which may faithfully reflect the molecular wiring in a cell. Here we review network-based multi-omics/multi-modal integrative analytical approaches. We classify these approaches according to the type of omics data supported, the methods and/or algorithms implemented, their node and/or edge weighting components, and their ability to identify key nodes and subnetworks. We show how these approaches can be used to identify biomarkers, disease subtypes, crosstalk, causality, and molecular drivers of physiological and pathological mechanisms. We provide insight into the most appropriate methods and tools for research questions as showcased around the aetiology and treatment of COVID-19 that can be informed by multi-omics data integration. We conclude with an overview of challenges associated with multi-omics network-based analysis, such as reproducibility, heterogeneity, (biological) interpretability of the results, and we highlight some future directions for network-based integration.
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Background: The need for competent research managers and administrators (RMAs) has increased due to the complexity in managing research projects between disparate and international partners. To facilitate the creation of robust training and professional development programmes it is essential to first understand the status quo. A collaborative project, Sustainable Management and Administration for Research: Training across the project Lifecycle (SMARTLife), made up of RMAs from South Africa, Zimbabwe and the United Kingdom (UK) developed a set of competencies to conduct an RMA competency-based training needs assessment scoping tool. Method: Nine areas were identified: Equitable partnership; Finance Management; Project Management; Monitoring and Evaluation; Reporting and Communications; Equity, Diversity & Inclusion; Training and Capacity Development; Impact a& Sustainability; and Ethical, Social, Legal a& Social Implications. Tasks for each competency area were identified to develop an scoping tool that had 168 data collection points. The tool was advertised through press releases, mailing lists and social media. Results: 108 responses were obtained: with 49% from 15 Africa countries/the remainder from the UK. The UK (71%) had more permanent RMA staff members compared to Africa (39%). There were more respondents in Africa with the title of Research Manager/Coordinator(p=0.0132) compared to the UK where most of the RMAs were employed as Finance/Contract officers. 60% of respondents from the UK had more than three years experience while only 35% from Africa had experience. While most RMAs had formal higher education qualifications, their training was not in research management and administration, which requires a diverse range of skills. Confidence in specific tasks varied between the UK and Africa whereas collaborative partnerships challenges and enablers were similar. Conclusion This work highlights differences in RMA training and experience RMA between Africa and UK, this work could inform much needed competency-based training for RMAs and partnership strategies that aid mutual-learning.
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BACKGROUND: The emergence and spread of malaria drug resistance have resulted in the need to understand disease mechanisms and importantly identify essential targets and potential drug candidates. Malaria infection involves the complex interaction between the host and pathogen, thus, functional interactions between human and Plasmodium falciparum is essential to obtain a holistic view of the genetic architecture of malaria. Several functional interaction studies have extended the understanding of malaria disease and integrating such datasets would provide further insights towards understanding drug resistance and/or genetic resistance/susceptibility, disease pathogenesis, and drug discovery. METHODS: This study curated and analysed data including pathogen and host selective genes, host and pathogen protein sequence data, protein-protein interaction datasets, and drug data from literature and databases to perform human-host and P. falciparum network-based analysis. An integrative computational framework is presented that was developed and found to be reasonably accurate based on various evaluations, applications, and experimental evidence of outputs produced, from data-driven analysis. RESULTS: This approach revealed 8 hub protein targets essential for parasite and human host-directed malaria drug therapy. In a semantic similarity approach, 26 potential repurposable drugs involved in regulating host immune response to inflammatory-driven disorders and/or inhibiting residual malaria infection that can be appropriated for malaria treatment. Further analysis of host-pathogen network shortest paths enabled the prediction of immune-related biological processes and pathways subverted by P. falciparum to increase its within-host survival. CONCLUSIONS: Host-pathogen network analysis reveals potential drug targets and biological processes and pathways subverted by P. falciparum to enhance its within malaria host survival. The results presented have implications for drug discovery and will inform experimental studies.
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Descubrimiento de Drogas , Resistencia a Medicamentos/genética , Malaria Falciparum/prevención & control , Plasmodium falciparum/genética , Mapeo de Interacción de Proteínas , Proteínas Protozoarias/genética , Antimaláricos/uso terapéutico , Simulación por Computador , Humanos , Plasmodium falciparum/efectos de los fármacosRESUMEN
BACKGROUND: Orthodontic tooth movement (OTM) has been shown to induce osteocyte apoptosis in alveolar bone shortly after force application. However, how osteocyte apoptosis affects orthodontic tooth movement is unknown. The goal of this study was to assess the effect of inhibition of osteocyte apoptosis on osteoclastogenesis, changes in the alveolar bone density, and the magnitude of OTM using a bisphosphonate analog (IG9402), a drug that affects osteocyte and osteoblast apoptosis but does not affect osteoclasts. MATERIAL AND METHODS: Two sets of experiments were performed. Experiment 1 was used to specifically evaluate the effect of IG9402 on osteocyte apoptosis in the alveolar bone during 24 h of OTM. For this experiment, twelve mice were divided into two groups: group 1, saline administration + OTM24-h (n=6), and group 2, IG9402 administration + OTM24-h (n=6). The contralateral unloaded sides served as the control. The goal of experiment 2 was to evaluate the role of osteocyte apoptosis on OTM magnitude and osteoclastogenesis 10 days after OTM. Twenty mice were divided into 4 groups: group 1, saline administration without OTM (n=5); group 2, IG9402 administration without OTM (n=5); group 3, saline + OTM10-day (n=6); and group 4, IG9402 + OTM10-day (n=4). For both experiments, tooth movement was achieved using Ultra Light (25g) Sentalloy Closed Coil Springs attached between the first maxillary molar and the central incisor. Linear measurements of tooth movement and alveolar bone density (BVF) were assessed by MicroCT analysis. Cell death (or apoptosis) was assessed by terminal dUTP nick-end labeling (TUNEL) assay, while osteoclast and macrophage formation were assessed by tartrate-resistant acid phosphatase (TRAP) staining and F4/80+ immunostaining. RESULTS: We found that IG9402 significantly blocked osteocyte apoptosis in alveolar bone (AB) at 24 h of OTM. At 10 days, IG9402 prevented OTM-induced loss of alveolar bone density and changed the morphology and quality of osteoclasts and macrophages, but did not significantly affect the amount of tooth movement. CONCLUSION: Our study demonstrates that osteocyte apoptosis may play a significant role in osteoclast and macrophage formation during OTM, but does not seem to play a role in the magnitude of orthodontic tooth movement.
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Osteocitos , Técnicas de Movimiento Dental , Animales , Apoptosis , Remodelación Ósea , Ratones , Proyectos PilotoRESUMEN
Introduction Multiple primary malignancies (MPMs) are seen in ~5% of all tumors. The aim of this study was to determine the quantitative impact on overall survival (OS) and treatment choices in patients with MPMs. Methods A retrospective analysis to determine patients with MPMs was conducted over a six-year period. Patients were defined as simultaneous MPMs if the second malignancy was discovered within 60 days of the first, and as sequential MPMs if discovered after 60 days of the first. Results Fifty-six patients with MPMs as defined above were identified, 38 (68%) simultaneous and 18 (32%) sequential. Development of second malignancy did not affect treatment in 47 (84%) of patients. Median OS after diagnosis of first malignancy was 13.0 months (95% confidence interval (CI) 10.3-15.8 months), compared to 10.6 months (95% CI 7.1-13.9 months) after the diagnosis of second malignancy. Median OS for the simultaneous MPM group was 13.5 months (95% CI 7.1-19.9 months), compared to 3.2 months (95% CI 0.0-9.8 months) for the sequential MPM group. Conclusions The development of a second malignancy impacts OS and treatment decisions. Patients who developed sequential MPM performed poorer than those who developed simultaneous MPM. This was likely in part due to effects of existing treatment on performance status as well as treatment preferences when second MPM is diagnosed (as many patients opted for supportive care after second MPM). Further analysis with larger patient cohorts is necessary to ascertain the aforementioned effects of OS and treatment options with respect to tumor pathology, stage, and performance status.
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Precision medicine is being enabled in high-income countries by the growing availability of health data, increasing knowledge of the genetic determinants of disease and variation in response to treatment (pharmacogenomics), and the decreasing costs of data generation, which promote routine application of genomic technologies in the health sector. However, there is uncertainty about the feasibility of applying precision medicine approaches in low- and middle-income countries, due to the lack of population-specific knowledge, skills, and resources. The Human Heredity and Health in Africa (H3Africa) initiative was established to drive new research into the genetic and environmental basis for human diseases of relevance to Africans as well as to build capacity for genomic research on the continent. Precision medicine requires this capacity, in addition to reference data on local populations, and skills to analyze and interpret genomic data from the bedside. The H3Africa consortium is collectively processing samples and data for over 70,000 participants across the continent, accompanied in most cases by rich clinical information on a variety of non-communicable and infectious diseases. These projects are increasingly providing novel insights into the genetic basis of diseases in indigenous populations, insights that have the potential to drive the development of new diagnostics and treatments. The consortium has also invested significant resources into establishing high-quality biorepositories in Africa, a bioinformatic network, and a strong training program that has developed skills in genomic data analysis and interpretation among bioinformaticians, wet-lab researchers, and health-care professionals. Here, we describe the current perspectives of the H3Africa consortium and how it can contribute to making precision medicine in Africa a reality.
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Coronary artery disease (CAD) is a major cause of cardiovascular death worldwide. Prevalence of CAD is highly variable among different races. Asian Indians have been noted to have the highest CAD rates and the conventional risk factors fail to explain this difference completely. Asian Indians constitute a fifth of the global population, and the higher rates of CAD in this population constitute a major health challenge. There have been studies in the early 2000s that investigate the risk factors in this population; however, very few studies have been done since then that explore the higher CAD rates in Asian Indians. This is a comprehensive and current review of the known risk factors for CAD in Asian Indians and strategies physicians should consider relieving this burden.
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Atrial flutter (AF) is the second most common supraventricular tachyarrhythmia following atrial fibrillation. We present an interesting case of a diagnostic challenge manifested as an electrocardiogram (ECG) recording mimicking AF in a patient with Parkinson's disease (PD). A 72-year-old African-American female with history of PD presented to our Emergency Department with a one day history of chest pain. Her vital signs were within normal limits. Physical exam was remarkable for bilateral resting hand tremors at a frequency of 6-8 hertz and mild cogwheel rigidity in both upper extremities. Initial ECG was interpreted as AF prompting admission. After careful review of her ECG by a cardiologist, several features such as, sharply contoured upright p waves in all leads, different flutter wave morphologies in the same leads, more prominence of "pseudo-flutter" waves in the limb leads compared to the precordial leads, and return to isoelectric baseline after sharp peaked p waves, questioned the diagnosis of AF. A repeat 12 lead ECG clearly demonstrated normal sinus rhythm, and the patient remained completely asymptomatic throughout the stay. A 48-hour Holter monitoring in the clinic later confirmed consistent sinus rhythm with no evidence of any arrhythmias Tremor induced artifacts can be mistaken for arrhythmias. Correct and accurate diagnosis is critically important, in order to avoid wrong treatment and unnecessary interventions. Our case illustrates the importance of recognizing artifact related ECG changes to prevent unnecessary treatment and hospital admissions.
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Peripheral arterial disease (PAD) is a common disorder associated with a high risk of cardiovascular mortality and continues to be under-recognized. The major risk factors for PAD are similar to those for coronary and cerebrovascular disease. Management includes exercise program, pharmacologic therapy and revascularization including endovascular and surgical approach. The optimal revascularization strategy, endovascular or surgical intervention, is often debated due to the paucity of head to head randomized controlled studies. Despite significant advances in endovascular interventions resulting in increased utilization over surgical bypass, significant challenges still remain. Platelet activation and aggregation after percutaneous transluminal angioplasty of atherosclerotic arteries are important risk factors for re-occlusion/restenosis and life-threatening thrombosis following endovascular procedures. Antiplatelet agents are commonly prescribed to reduce the risk of myocardial infarction, stroke and death from cardiovascular causes in patients with PAD. Despite an abundance of data demonstrating efficacy of antiplatelet therapy in coronary artery disease and cerebrovascular disease, there is a paucity of clinical information, clinical guidelines and randomized controlled studies in the PAD population. Hence, data on antiplatelet therapy in coronary interventions is frequently extrapolated to peripheral interventions. The aim of this review article is to elucidate the current data on revascularization and the role and duration of antiplatelet and anticoagulant therapy in re-vascularized lower limb PAD patients.
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Medicinal plants are part of the healthcare systems worldwide, especially in low- and middle-income countries. African lettuce (Launaea taraxacifolia) is cultivated extensively in Africa, from Senegal in the west to Ethiopia and Tanzania in the east, and in Southern Africa. Potential anticancer effects of L. taraxacifolia have been suggested, but little is known about putative molecular mechanisms or potential for herb-drug interactions through inhibition or induction of drug-metabolizing enzymes. We investigated the effects of crude aqueous extracts of L. taraxacifolia on growth kinetics and cell cycle progression of the WHC01 esophageal cancer cells. Antiproliferative and apoptotic effects were evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and flow cytometry, while examining, in parallel, the genes regulating apoptosis and cell cycle in this cell culture model. In addition, we tested the inhibitory and enzyme kinetic effects of the aqueous L. taraxacifolia using recombinant human CYP450 isozyme model systems (CYP1A2, CYP2C9, and CYP2C19). L. taraxacifolia exhibited a significant growth inhibitory effect on the WHC01 cancer cells. Most cell cycle genes were downregulated. Cell cycle analysis showed a G0-G1 cell cycle arrest in WHC01 cells in the presence of L. taraxacifolia extract, accompanied by morphological changes. L. taraxacifolia extract treatment resulted in downregulation of expression levels of CYP1A2 (p < 0.0005) and CYP2C19 (p < 0.003) by 50-70%. L. taraxacifolia extract caused reversible and time-dependent inhibition of the recombinant CYP1A2, CYP2C9, and CYP2C19. This study provides new insights on possible anticancer effects of L. taraxacifolia, a widely used medicinal plant in parts of Africa and across the world especially by patients with cancer. Further mechanistic studies expanding on these observations would be timely and contribute to the field of global precision medicine that requires solid understanding of drug and herb molecular mechanisms of action and drug-herb interaction potentials, given the worldwide use of medicinal plants.
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Antineoplásicos/farmacología , Citocromo P-450 CYP1A2/efectos de los fármacos , Citocromo P-450 CYP2C19/efectos de los fármacos , Citocromo P-450 CYP2C9/efectos de los fármacos , Interacciones de Hierba-Droga , Lactuca/química , Extractos Vegetales/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Isoenzimas , Pruebas de Farmacogenómica , Extractos Vegetales/química , Plantas Medicinales , Proteínas RecombinantesRESUMEN
INTRODUCTION: Variability in lopinavir (LPV) plasma concentration among patients could be due to genetic polymorphisms. This study set to evaluate significance of variants in CYP3A4/5, SLCO1B1 and ABCC2 on LPV plasma concentration among African HIV-positive patients. MATERIALS & METHODS: Eighty-six HIV-positive participants on ritonavir (LPV/r) were genetically characterized and LPV plasma concentration determined. RESULTS & DISCUSSION: LPV plasma concentrations differed >188-fold (range 0.0206-38.6 µg/ml). Both CYP3A4*22 and SLCO1B1 rs4149056G (c.521C) were not observed in this cohort. CYP3A4*1B, CYP3A5*3, CYP3A5*6 and ABCC2 c.1249G>A which have been associated with LPV plasma concentration, showed no significant association. CONCLUSION: These findings highlight the need to include African groups in genomics research to identify variants of pharmacogenomics significance.
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Fármacos Anti-VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Lopinavir/sangre , Variantes Farmacogenómicas , Adulto , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Población Negra/genética , Estudios Transversales , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Etnicidad/genética , Femenino , Infecciones por VIH/metabolismo , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Lopinavir/farmacocinética , Lopinavir/uso terapéutico , Masculino , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
Highly active antiretroviral therapy (HAART) has greatly improved health parameters of HIV infected individuals. However, there are several challenges associated with the chronic nature of HAART administration. For populations in health transition, dual use of medicinal plant extracts and conventional medicine poses a significant challenge. There is need to evaluate interactions between commonly used medicinal plant extracts and antiretroviral drugs used against HIV/AIDS. Efavirenz (EFV) and nevirapine (NVP) are the major components of HAART both metabolized by CYP2B6, an enzyme that can potentially be inhibited or induced by compounds found in medicinal plant extracts. The purpose of this study was to evaluate the effects of extracts of selected commonly used medicinal plants on CYP2B6 enzyme activity. Recombinant human CYP2B6 was used to evaluate inhibition, allowing the assessment of herb-drug interactions (HDI) of medicinal plants Hyptis suaveolens, Myrothamnus flabellifolius, Launaea taraxacifolia, Boerhavia diffusa and Newbouldia laevis. The potential of these medicinal extracts to cause HDI was ranked accordingly for reversible inhibition and also classified as potential time-dependent inhibitor (TDI) candidates. The most potent inhibitor for CYP2B6 was Hyptis suaveolens extract (IC50 = 19.09 ± 1.16 µg/mL), followed by Myrothamnus flabellifolius extract (IC50 = 23.66 ± 4.86 µg/mL), Launaea taraxacifolia extract (IC50 = 33.87 ± 1.54 µg/mL), and Boerhavia diffusa extract (IC50 = 34.93 ± 1.06 µg/mL). Newbouldia laevis extract, however, exhibited weak inhibitory effects (IC50 = 100 ± 8.71 µg/mL) on CYP2B6. Launaea taraxacifolia exhibited a TDI (3.17) effect on CYP2B6 and showed a high concentration of known CYP450 inhibitory phenolic compounds, chlorogenic acid and caffeic acid. The implication for these observations is that drugs that are metabolized by CYP2B6 when co-administered with these herbal medicines and when adequate amounts of the extracts reach the liver, there is a high likelihood of standard doses affecting drug plasma concentrations which could lead to toxicity.
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Extractos Vegetales/química , Extractos Vegetales/farmacología , Plantas Medicinales/química , Alquinos , Terapia Antirretroviral Altamente Activa , Benzoxazinas/farmacología , Ciclopropanos , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2B6/metabolismo , Inhibidores del Citocromo P-450 CYP2B6/química , Inhibidores del Citocromo P-450 CYP2B6/farmacología , Interacciones de Hierba-Droga , Humanos , Magnoliopsida/química , Nevirapina/farmacologíaRESUMEN
The most accessible points of call for most African populations with respect to primary health care are traditional health systems that include spiritual, religious, and herbal medicine. This review focusses only on the use of herbal medicines. Most African people accept herbal medicines as generally safe with no serious adverse effects. However, the overlap between conventional medicine and herbal medicine is a reality among countries in health systems transition. Patients often simultaneously seek treatment from both conventional and traditional health systems for the same condition. Commonly encountered conditions/diseases include malaria, HIV/AIDS, hypertension, tuberculosis, and bleeding disorders. It is therefore imperative to understand the modes of interaction between different drugs from conventional and traditional health care systems when used in treatment combinations. Both conventional and traditional drug entities are metabolized by the same enzyme systems in the human body, resulting in both pharmacokinetics and pharmacodynamics interactions, whose properties remain unknown/unquantified. Thus, it is important that profiles of interaction between different herbal and conventional medicines be evaluated. This review evaluates herbal and conventional drugs in a few African countries and their potential interaction at the pharmacogenomics level.
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INTRODUCTION: Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor prescribed as part of first-line highly active antiretroviral therapy (HAART) in South Africa. Despite administration of fixed doses of EFV, inter-individual variability in plasma concentrations has been reported. Poor treatment outcomes such as development of adverse drug reactions or treatment failure have been linked to EFV plasma concentrations outside the therapeutic range (1-4 µg/mL) in some studies. The drug metabolizing enzyme (DME), CYP2B6, is primarily responsible for EFV metabolism with minor contributions by CYP1A2, CYP2A6, CYP3A4, CYP3A5, and UGT2B7. DME coding genes are also regulated by microRNAs through targeting the 3'-untranslated region. Expanded analysis of 30 single nucleotide polymorphisms (SNPs), including those in the 3'-UTR, was performed to identify pharmacogenetics determinants of EFV plasma concentrations in addition to CYP2B6 c.516G>T and c.983T>C SNPs. METHODS: SNPs in CYP1A2, CYP2B6, UGT2B7, and NR1I2 (PXR) were selected for genotyping among 222 Bantu-speaking South African HIV-infected patients receiving EFV-containing HAART. This study is a continuation of earlier pharmacogenetics studies emphasizing the role of genetic variation in the 3'-UTR of genes which products are either pharmacokinetic or pharmacodynamic targets of EFV. RESULTS: Despite evaluating thirty SNPs, CYP2B6 c.516G>T and c.983T>C SNPs remain the most prominent predictors of EFV plasma concentration. CONCLUSION: We have shown that CYP2B6 c.516G>T and c.983T>C SNPs are the most important predictors of EFV plasma concentration after taking into account all other SNPs, including genetic variation in the 3'-UTR, and variables affecting EFV metabolism.
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The present study reports promoter variants in four sub-Saharan African populations that may affect BST-2 gene regulation. Recently, an in/del within the BST-2 promoter has been associated with HIV-1 disease progression in a Spanish cohort. Hence, we sequenced the proximal promoter region of the BST-2 gene in 581 individuals from South Africa, Zimbabwe, Malawi, and Cameroon. Seven SNPs were identified: rs28413176 (+26i6/Δ6); rs28413175 (-160i1/Δ1), -187A>G (nucleotide position -17516614); rs28413174 (-193G>A); rs73921425 (-199G>A); rs12609479 (-201C>T); and rs112492472 (-225C>T). The -199A and -225T alleles showed interesting trends across the sub-Saharan continent. Using predictive bioinformatics tools, we show that allelic variation at -199 and -201 potentially affect key transcription factor binding sites including bHLH, c-Myb, and E47. Importantly, data available from the ENCODE study gave further credence to our hypothesis of transcriptional regulation of BST-2 by a bHLH TF such as Mxi1. The possible repressive transcriptional effect of Mxi1 combined with the allelic frequency trend seen at -199 between African populations overlays well with current HIV-1 prevalence data, and may be a contributing factor to this phenomenon. The differences in HIV-1 prevalence in African countries could be, in part, due to distribution of genetic variants that affect susceptibility to HIV-1. Our findings therefore have substantive value for the design of future diagnostics for global health oriented diagnostics for HIV-1 susceptibility, and rational therapeutics on the critical path to personalized medicine in the African continent. As HIV-1 epidemiology vastly impacts human populations around the world, the population genomics strategy we have utilized herein can have value for other global regions as well.