Whole-exome sequencing of Nigerian benign prostatic hyperplasia reveals increased alterations in apoptotic pathways.

BACKGROUND: Through whole-exome sequencing of 60 formalin-fixed paraffin-embedded Nigerian (NGRn) benign prostatic hyperplasia (BPH) samples, we identified germline and somatic alterations in apoptotic pathways impacting BPH development and progression. Prostate enlargement is a common occurrence in male aging; however, this enlargement can lead to lower urinary tract symptoms that negatively impact quality of life. This impact is disproportionately present in men of African ancestry. BPH pathophysiology is poorly understood and studies examining non-European populations are lacking. METHODS: In this study, NGRn BPH, normal prostate, and prostate cancer (PCa) tumor samples were sequenced and compared to characterize genetic alterations in NGRn BPH. RESULTS: Two hundred and two nonbenign, ClinVar-annotated germline variants were present in NGRn BPH samples. Six genes [BRCA1 (92%), HSD3B1 (85%), TP53 (37%), PMS2 (23%), BARD1 (20%), and BRCA2 (17%)] were altered in at least 10% of samples; however, compared to NGRn normal and tumor, the frequency of alterations in BPH samples showed no significant differences at the gene or variant level. BRCA2_rs11571831 and TP53_rs1042522 germline alterations had a statistically significant co-occurrence interaction in BPH samples. In at least two BPH samples, 173 genes harbored somatic variants known to be clinically actionable. Three genes (COL18A1, KIF16B, and LRP1) showed a statistically significant (p < 0.05) higher frequency in BPH. NGRn BPH also had five gene pairs (PKD1/KIAA0100, PKHD1/PKD1, DNAH9/LRP1B, NWD1/DCHS2, and TCERG1/LMTK2) with statistically significant co-occurring interactions. Two hundred and seventy-nine genes contained novel somatic variants in NGRn BPH. Three genes (CABP1, FKBP1C, and RP11-595B24.2) had a statistically significant (p < 0.05) higher alteration frequency in NGRn BPH and three were significantly higher in NGRn tumor (CACNA1A, DMKN, and CACNA2D2). Pairwise Fisher's exact tests showed 14 gene pairs with statistically significant (p < 0.05) interactions and four interactions approaching significance (p < 0.10). Mutational patterns in NGRn BPH were similar to COSMIC (Catalog of Somatic Mutations in Cancer) signatures associated with aging and dysfunctional DNA damage repair. CONCLUSIONS: NGRn BPH contained significant germline alteration interactions (BRCA2_rs11571831 and TP53_rs1042522) and increased somatic alteration frequencies (LMTK2, LRP1, COL18A1, CABP1, and FKBP1C) that impact apoptosis. Normal prostate development is maintained by balancing apoptotic and proliferative activity. Dysfunction in either mechanism can lead to abnormal prostate growth. This work is the first to examine genomic sequencing in NGRn BPH and provides data that fill known gaps in the understanding BPH and how it impacts men of African ancestry.

Breast Cancer Phenotypes in Africa: A Scoping Review and Meta-Analysis.

PURPOSE: Africans have been associated with more aggressive forms of breast cancer (BC). However, there is a lack of data regarding the incidence and distribution of different subtypes on the basis of phenotypic classification. This scoping review and meta-analysis was undertaken to determine the distribution pattern of BC phenotypes (luminal, human epidermal growth factor receptor 2 [HER2]+, and triple-negative breast cancer [TNBC]) across the African region. METHODS: Four online databases (PubMed, Scopus, ProQuest, and EBSCOhost) were accessed to identify studies published between 2000 and 2022 reporting the representation of receptor status (estrogen receptor, progesterone receptor, and HER2) in African patients with BC. Furthermore, the meta-analysis was carried out using a random-effects model and pooled using the inverse variance method and logit transformation. 95% CI and I2 statistics were calculated using the Clopper-Pearson method to estimate between-study heterogeneity. RESULTS: A total of 2,734 records were retrieved, of which 2,133 were retained for further screening. After the screening, 63 studies were finally selected for the scoping review and meta-analysis. The pooled frequency of luminal, HER2-positive (HER2+), and TNBC was estimated at 56.30%, 12.61%, and 28.10%, respectively. Northern Africa had the highest frequency of the luminal subtype, while West Africa showed higher frequencies of HER2+ and TNBC subtypes. The review also had a representation of only 24 countries in Africa. CONCLUSION: Our results highlight the disparity in the representation of molecular subtypes among the people in different regions of Africa. There is a need to incorporate routine molecular subtyping into the management of African patients with BC.

Detection of Cancer-Associated Gene Mutations in Urinary Cell-Free DNA among Prostate Cancer Patients in South Africa.

Prostate cancer (PCa) is the most common cause of cancer death among African men. The presence of tumor-specific variations in cell-free DNA (cfDNA), such as mutations, microsatellite instability, and DNA methylation, has been explored as a source of biomarkers for cancer diagnosis. In this study, we investigated the diagnostic role of cfDNA among South African PCa patients. We performed whole exome sequencing (WES) of urinary cfDNA. We identified a novel panel of 31 significantly deregulated somatic mutated genes between PCa and benign prostatic hyperplasia (BPH). Additionally, we performed whole-genome sequencing (WGS) on matching PCa and normal prostate tissue in an independent PCa cohort from South Africa. Our results suggest that the mutations are of germline origin as they were also found in the normal prostate tissue. In conclusion, our study contributes to the knowledge of cfDNA as a biomarker for diagnosing PCa in the South African population.

African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A.

African American (AA) prostate cancer associates with vitamin D3 deficiency, but vitamin D receptor (VDR) genomic actions have not been investigated in this context. We undertook VDR proteogenomic analyses in European American (EA) and AA prostate cell lines and four clinical cohorts. Rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) analyses revealed that nonmalignant AA RC43N prostate cells displayed the greatest dynamic protein content in the VDR complex. Likewise, in AA cells, Assay for Transposase-Accessible Chromatin using sequencing established greater 1α,25(OH)2D3-regulated chromatin accessibility, chromatin immunoprecipitation sequencing revealed significant enhancer-enriched VDR cistrome, and RNA sequencing identified the largest 1α,25(OH)2D3-dependent transcriptome. These VDR functions were significantly corrupted in the isogenic AA RC43T prostate cancer cells, and significantly distinct from EA cell models. We identified reduced expression of the chromatin remodeler, BAZ1A, in three AA prostate cancer cohorts as well as RC43T compared with RC43N. Restored BAZ1A expression significantly increased 1α,25(OH)2D3-regulated VDR-dependent gene expression in RC43T, but not HPr1AR or LNCaP cells. The clinical impact of VDR cistrome-transcriptome relationships were tested in three different clinical prostate cancer cohorts. Strikingly, only in AA patients with prostate cancer, the genes bound by VDR and/or associated with 1α,25(OH)2D3-dependent open chromatin (i) predicted progression from high-grade prostatic intraepithelial neoplasia to prostate cancer; (ii) responded to vitamin D3 supplementation in prostate cancer tumors; (iii) differentially responded to 25(OH)D3 serum levels. Finally, partial correlation analyses established that BAZ1A and components of the VDR complex identified by RIME significantly strengthened the correlation between VDR and target genes in AA prostate cancer only. Therefore, VDR transcriptional control is most potent in AA prostate cells and distorted through a BAZ1A-dependent control of VDR function. Significance: Our study identified that genomic ancestry drives the VDR complex composition, genomic distribution, and transcriptional function, and is disrupted by BAZ1A and illustrates a novel driver for AA prostate cancer.

Early-life AFB1 exposure: DNA methylation and hormone alterations.

Aflatoxins are secondary metabolites of mold that contaminate food and feedstuff. They are found in various food including grains, nuts, milk and eggs. Aflatoxin B1 (AFB1) is the most poisonous and commonly found of the various types of aflatoxins. Exposures to AFB1 start early in life viz. in utero, during breastfeeding, and during weaning through the waning foods which are mainly grain based. Several studies have shown that early-life exposures to various contaminants may have various biological effects. In this chapter, we reviewed the effects of early-life AFB1 exposures on changes in hormone and DNA methylation. In utero AFB1 exposure results in alterations in steroid and growth hormones. Specifically, the exposure results in a reduction in testosterone levels later in life. The exposure also affects the methylation of various genes that are significant in growth, immune, inflammation, and signaling pathways.

Evaluation of Efflux-Mediated Resistance and Biofilm formation in Virulent Pseudomonas aeruginosa Associated with Healthcare Infections.

Pseudomonas aeruginosa is a significant pathogen identified with healthcare-associated infections. The present study evaluates the role of biofilm and efflux pump activities in influencing high-level resistance in virulent P. aeruginosa strains in clinical infection. Phenotypic resistance in biotyped Pseudomonas aeruginosa (n = 147) from diagnosed disease conditions was classified based on multiple antibiotic resistance (MAR) indices and analysed with logistic regression for risk factors. Efflux pump activity, biofilm formation, and virulence factors were analysed for optimal association in Pseudomonas infection using receiver operation characteristics (ROC). Age-specificity (OR [CI] = 0.986 [0.946-1.027]), gender (OR [CI] = 1.44 [0.211-9.827]) and infection sources (OR [CI] = 0.860 [0.438-1.688]) were risk variables for multidrug resistance (MDR)-P. aeruginosa infection (p < 0.05). Biofilm formers caused 48.2% and 18.5% otorrhea and wound infections (95% CI = 0.820-1.032; p = 0.001) respectively and more than 30% multidrug resistance (MDR) strains demonstrated high-level efflux pump activity (95% CI = 0.762-1.016; p = 0.001), protease (95% CI = 0.112-0.480; p = 0.003), lipase (95% CI = 0.143-0.523; p = 0.001), and hemolysin (95% CI = 1.109-1.780; p = 0.001). Resistance relatedness of more than 80% and 60% to cell wall biosynthesis inhibitors (ceftazidime, ceffproxil, augumentin, ampicillin) and, DNA translational and transcriptional inhibitors (gentamicin, ciprofloxacin, ofloxacin, nitrofurantoin) were observed (p < 0.05). Strong efflux correlation (r = 0.85, p = 0.034) with MDR strains, with high predictive performances in efflux pump activity (ROC-AUC 0.78), biofilm formation (ROC-AUC 0.520), and virulence hierarchical-clustering. Combine activities of the expressed efflux pump and biofilm formation in MDR-P. aeruginosa pose risk to clinical management and infection control.

Haptoglobin genotypes and malaria comorbidity in breast cancer and healthy Nigerian women.

Background: Breast cancer is the leading cause of mortality among women, with over a million cases recorded globally. Haptoglobin (Hp) protein and genotypes play important roles in cancer predisposition and progression, but studies have reported varying outcomes in populations. Aim: The association of Hp genotypes in breast cancer patients with malaria has not been investigated in Nigerians, which is the aim of our study. In healthy women (control; n = 279) and clinically diagnosed breast cancer patients (breast cancer; n = 70). Methods: Haptoglobin genotypes and Plasmodium falciparum cyclooxygenase III genes were detected by polymerase chain reaction (PCR). Proportions were compared, and the test of association was carried out with a significance level set at P < 0.05. Results: Overall, 311 of 349 (89%) individuals had malaria infection with similar proportions in breast cancer (63 of 70) and healthy control group (248 of 279); malaria incidence was, however, lower in Hp 2-2 breast cancer patients (P = 0.04). The prevalence of Hp genotypes was Hp 1-1 (78.2%), Hp 2-1 (7.2%), and 2-2 (14.6%). In breast cancer groups, Hp 2-2 genotype was significantly lower with 3 (4.2%) of 70 vs. 48 (17.2%) of 279 in control group (P = 0.006). Conclusions: The results of the study show low Hp 2-2 genotype relative to other genotypes in breast cancer patients; we conclude that low Hp 2-2 genotype is associated with lower malaria risk in breast cancer Nigerian women. It is important to further understand the roles malaria, Hp, and other genotypes play in the pathogenesis of aggressive breast cancer commonly seen in Nigerian women.

Résumé Contexte: Le cancer du sein est la principale cause de mortalité chez les femmes, avec plus d'un million de cas enregistrés dans le monde. La protéine et les génotypes de l'haptoglobine (Hp) jouent un rôle important dans la prédisposition et la progression du cancer, mais des études ont rapporté des résultats variables dans les populations. Objectif: L'association des génotypes d'haptoglobine chez les patientes atteintes d'un cancer du sein et atteintes de paludisme n'a pas été étudiée chez les Nigérians, ce qui est l'objectif de notre étude. Chez les femmes en bonne santé (témoin ; nombre = 279) et les patientes atteintes d'un cancer du sein diagnostiqué cliniquement (cancer du sein ; nombre = 70). Méthodologie: Les génotypes de l'haptoglobine et les gènes de la cyclooxygénase-III de Plasmodium falciparum ont été détectés par PCR. Les proportions ont été comparées et le test d'association a été réalisé avec un seuil de signification fixé à P < 0,05. Résultats: Dans l'ensemble, 311 personnes sur 349 (89 %) avaient une infection palustre avec des proportions similaires dans le groupe du cancer du sein (63 sur 70) et dans le groupe témoin sain (248 sur 279); l'incidence du paludisme était cependant plus faible chez les patientes atteintes d'un cancer du sein Hp 2-2 (p = 0,04). La prévalence des génotypes Hp était : Hp 1-1 (78,2 %), Hp 2-1 (7,2 %) et 2-2 (14,6 %). Dans les groupes de cancer du sein, le génotype Hp 2-2 était significativement plus faible avec 3 (4,2 %) sur 70 contre 48 (17,2 %) sur 279 dans le groupe témoin (p = 0,006). Conclusions: Les résultats de l'étude montrent un faible génotype Hp 2-2 par rapport aux autres génotypes chez les patientes atteintes d'un cancer du sein; nous concluons qu'un faible génotype Hp 2-2 est associé à un risque de paludisme plus faible chez les femmes nigérianes atteintes d'un cancer du sein. Il est important de mieux comprendre les rôles que jouent le paludisme, l'haptoglobine et d'autres génotypes dans la pathogenèse du cancer du sein agressif couramment observé chez les femmes nigérianes. Mots-clés: Cancer du sein, génotypes, haptoglobine, paludisme, Nigeria.

Whole-exome Sequencing of Nigerian Prostate Tumors from the Prostate Cancer Transatlantic Consortium (CaPTC) Reveals DNA Repair Genes Associated with African Ancestry.

In this study, we used whole-exome sequencing of a cohort of 45 advanced-stage, treatment-naïve Nigerian (NG) primary prostate cancer tumors and 11 unmatched nontumor tissues to compare genomic mutations with African American (AA) and European American (EA) The Cancer Genome Atlas (TCGA) prostate cancer. NG samples were collected from six sites in central and southwest Nigeria. After whole-exome sequencing, samples were processed using GATK best practices. BRCA1 (100%), BARD1 (45%), BRCA2 (27%), and PMS2(18%) had germline alterations in at least two NG nontumor samples. Across 111 germline variants, the AA cohort reflected a pattern [BRCA1 (68%), BARD1 (34%), BRCA2 (28%), and PMS2 (16%)] similar to NG samples. Of the most frequently mutated genes, BRCA1 showed a statistically (P ≤ 0.05) higher germline mutation frequency in men of African ancestry (MAA) and increasing variant frequency with increased African ancestry. Disaggregating gene-level mutation frequencies by variants revealed both ancestry-linked and NG-specific germline variant patterns. Driven by rs799917 (T>C), BRCA1 showed an increasing mutation frequency as African ancestry increased. BRCA2_rs11571831 was present only in MAA, and BRCA2_rs766173 was elevated in NG men. A total of 133 somatic variants were present in 26 prostate cancer-associated genes within the NG tumor cohort. BRCA2 (27%), APC (20%), ATM (20%), BRCA1 (13%), DNAJC6 (13%), EGFR (13%), MAD1L1 (13%), MLH1 (11%), and PMS2 (11%) showed mutation frequencies >10%. Compared with TCGA cohorts, NG tumors showed statistically significant elevated frequencies of BRCA2, APC, and BRCA1. The NG cohort variant pattern shared similarities (cosign similarities ≥0.734) with Catalogue of Somatic Mutations in Cancer signatures 5 and 6, and mutated genes showed significant (q < 0.001) gene ontology (GO) and functional enrichment in mismatch repair and non-homologous repair deficiency pathways. Here, we showed that mutations in DNA damage response genes were higher in NG prostate cancer samples and that a portion of those mutations correlate with African ancestry. Moreover, we identified variants of unknown significance that may contribute to population-specific routes of tumorigenesis and treatment. These results present the most comprehensive characterization of the NG prostate cancer exome to date and highlight the need to increase diversity of study populations. Significance: MAA have higher rates of prostate cancer incidence and mortality, however, are severely underrepresented in genomic studies. This is the first study utilizing whole-exome sequencing in NG men to identify West African ancestry-linked variant patterns that impact DNA damage repair pathways.

Report of the Premier African Organisation for Research and Training in Cancer Virtual Genomics Conference held from 18-20 February 2021.

The rapidly rising cancer burden and mortality rate in Africa are in contrast to the increase in cancer survivorship in Europe and North America. Genomic medicine has contributed to the rise in survival and has facilitated precision cancer control. However, there is a shortage of African representation in genomic databases, even for cancers that disproportionately affect Africans. To improve this outlook and address research in genomics and genetics relevant to Africa and people of African descent, the African Organisation for Research and Training in Cancer (AORTIC), under the Research Committee's auspices, organised the Cancer Genomic Conference. The conference aimed to develop a roadmap for cancer genomics research to control the continent's increasing cancer burden. Presentations at the conference revealed that: (1) Africa is made up of a highly heterogeneous group of people with diverse ethnic groups, (2) Very few African countries have been the focus of cancer genomics research, (3) Cancer exacts a heavy burden on global populations across the African diaspora with obvious genetic variants and cancer disparities and (4) There are differences in the contribution of genetics by race or ancestry and these differences are likely due to evolutionary genetics, contextual factors and genomic architecture. The importance of data security, ethics and integrity of the African genomics data was emphasised. The implementation of the conference highlights will provide the bedrock for pharmacogenomics to guide treatment decisions for cancer in Africa. The conference concluded with the formation of an AORTIC Special Interest Group on cancer genomics. It is the goal of this group to drive the implementation of this Conference's outcomes.

Vitamin D: Possible Therapeutic Roles in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a unique type of liver cancer instigated by underlying liver diseases. Pre-clinical evidence suggests that HCC progression, like other cancers, could be aided by vitamin D deficiency. Vitamin D is a lipid-soluble hormone usually obtained through sunlight. Vitamin D elucidates its biological responses by binding the vitamin D receptor; thus, promoting skeletal mineralization, and maintain calcium homeostasis. Other reported Vitamin D functions include specific roles in proliferation, angiogenesis, apoptosis, inflammation, and cell differentiation. This review highlighted studies on vitamin D's functional roles in HCC and discussed the specific therapeutic targets from various in vivo, in vitro and clinical studies over the years. Furthermore, it described recent advancements in vitamin D's anticancer effects and its metabolizing enzymes' roles in HCC development. In summary, the review elucidated specific vitamin D-associated target genes that play critical functions in the inhibition of tumorigenesis through inflammation, oxidative stress, invasion, and apoptosis in HCC progression.

Authorship Patterns in Cancer Genomics Publications Across Africa.

PURPOSE: Authorship is a proxy indicator of research capacity. Understanding the research capacity is imperative for developing population-specific cancer control strategies. This is particularly apropos for African nations, where mortality from cancer is projected to surpass that from infectious disease and the populations are critically under-represented in cancer and genomics studies. Here, we present an analysis and discussion of the patterns of authorship in Africa as they pertain to cancer genomics research across African countries. METHODS: PubMed metadata of relevant cancer genomics peer-reviewed publications on African populations, published between January 1, 1990, and December 31, 2019, were retrieved and analyzed for patterns of authorship affiliation using R packages, RISmed, and Pubmed.mineR. RESULTS: The data showed that only 0.016% (n = 375) of cancer publications globally were on cancer genomics of African people. More than 50% of the first and last authors of these publications originated from the North African countries of Tunisia, Morocco, Egypt, and Algeria. South Africa (13.6% and 12.7%) and Nigeria (2.2% and 1.9%) were the Sub-Saharan African countries most represented by first and last authorship positions, respectively. The United States contributed 12.6% of first and last authored papers, and nearly 50% of all African countries had no contributing author for the publications we reviewed. CONCLUSION: This study highlights and brings awareness to the paucity of cancer genomics research on African populations and by African authors and identifies a need for concerted efforts to encourage and enable more research in Africa, needed for achieving global equity in cancer outcomes.

Naringin prevents cyclophosphamide-induced hepatotoxicity in rats by attenuating oxidative stress, fibrosis, and inflammation.

Cyclophosphamide (CYCP), a synthetic alkylating antineoplastic, disrupts both cancerous and non-cancerous cells to cause cancer regression and multi organotoxicity respectively. CYCP-induced hepatotoxicity is rare but possible. Evidence has shown that naringin has several beneficial potentials against oxidative stress, inflammation, and fibrosis. This study examined the chemoprotective potentials of naringin on exited radical scavenging, hepatic integrity, oxidative stress, fibrosis, and inflammation in CYCP-mediated hepatotoxicity. Rats were pre-treated orally by gavage for fourteen consecutive days with three doses (50, 100, and 200 mg/kg) of naringin before single CYCP (200 mg/kg, i.p.) administration. Subsequently, the rats were euthanized; blood and liver were removed, and assessed for serum and hepatic enzymes, oxidative stress, inflammation, and gene expression dynamics. Naringin concentrations required for 50% scavenging hydroxyl radical and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonic acid) radical cation were 0.32 mg/mL and 0.39 mg/mL, respectively. Pretreatment with naringin significantly (p < 0.05) abolish CYCP-induced changes in the activities of serum and hepatic ALT, AST, GGT, ALP, and LDH. Pretreatment with naringin remarkably (p < 0.05) reversed CYCP-mediated increases in hepatic levels of malondialdehyde, hydroperoxide, and nitric oxide; reverse CYCP-induced decreases in the hepatic glutathione levels, activities of catalase, glutathione peroxidase, and glutathione reductase; and also attenuated CYCP-induced upregulation of expression of hepatic chemokine (C-C motif) ligand 2 (CCL2), interferon alpha1 (IFN-α1), interleukine-1ß, interleukine-1 receptor, and transforming growth factor beta 1 (TGF-ß1). Taken together, different doses of naringin can prevent CYCP-induced oxidants generation, hepatocytes dysfunctions, oxidative stress as well as inflammatory perturbations in rats when pre-administered for as few as 14 days.

Early Life Exposure to Aflatoxin B1 in Rats: Alterations in Lipids, Hormones, and DNA Methylation among the Offspring.

Aflatoxins are toxic compounds produced by molds of the Aspergillus species that contaminate food primarily in tropical countries. The most toxic aflatoxin, aflatoxin B1 (AFB1), is a major cause of hepatocellular carcinoma (HCC) in these countries. In sub-Saharan Africa, aflatoxin contamination is common, and perinatal AFB1 exposure has been linked to the early onset of HCC. Epigenetic programming, including changes to DNA methylation, is one mechanism by which early life exposures can lead to adult disease. This study aims to elucidate whether perinatal AFB1 exposure alters markers of offspring health including weight, lipid, and hormone profiles as well as epigenetic regulation that may later influence cancer risk. Pregnant rats were exposed to two doses of AFB1 (low 0.5 and high 5 mg/kg) before conception, throughout pregnancy, and while weaning and compared to an unexposed group. Offspring from each group were followed to 3 weeks or 3 months of age, and their blood and liver samples were collected. Body weights and lipids were assessed at 3 weeks and 3 months while reproductive, gonadotropic, and thyroid hormones were assessed at 3 months. Prenatal AFB1 (high dose) exposure resulted in significant 16.3%, 31.6%, and 7.5% decreases in weight of the offspring at birth, 3 weeks, and 3 months, respectively. Both doses of exposure altered lipid and hormone profiles. Pyrosequencing was used to quantify percent DNA methylation at tumor suppressor gene Tp53 and growth-regulator H19 in DNA from liver and blood. Results were compared between the control and AFB1 exposure groups in 3-week liver samples and 3-week and 3-month blood samples. Relative to controls, Tp53 DNA methylation in both low- and high-dose exposed rats was significantly decreased in liver samples and increased in the blood (p < 0.05 in linear mixed models). H19 methylation was higher in the liver from low- and high-exposed rats and decreased in 3-month blood samples from the high exposure group (p < 0.05). Further research is warranted to determine whether such hormone, lipid, and epigenetic alterations from AFB1 exposure early in life play a role in the development of early-onset HCC.

Bisphenol A in Africa: A review of environmental and biological levels.

Bisphenol A (BPA) is a synthetic ubiquitous environmental toxicant present in many industrial and consumer products. BPA is recognized as an endocrine-disrupting chemical (EDC), and its mechanisms of perturbation of the physiological process include interference with hormone pathways and epigenetic modifications. An increase in industrial productions and food packaging across Africa has resulted in increased utilization of BPA-containing products with a concomitant increase in environmental bioaccumulation and human exposure. In order to assess the extent of this bioaccumulation, we identified, collated, and summarized the levels of BPA that have been reported across Africa. To achieve this aim, we performed a systematic search of four indexing databases to identify articles and extracted the necessary data from the selected articles. Of the 42 publications we retrieved, 42% were on water samples, 22% on food, 20% on human biological fluids, 10% on sediments, soils, and sludge and 6% on consumer and personal care products (PCPs). The highest level of BPA reported in literature across Africa was 251 ng/mL, 384.8 ng/mL, 937.49 ng/g, 208.55 ng/mL, 3,590 µg/g, and 154,820 µg/g for water, wastewater, food, biological fluids, consumer and PCPs, and semisolids, respectively. This review presented a comparative perspective of these levels relative to regulatory limits and levels reported from other continents. Finally, this review highlighted critical needs for the regulation of BPA across Africa in order to stem its environmental and toxicological impact. We hope that this review will stimulate further research in understanding the impact of BPA on health outcomes and wellbeing across Africa.

The Impact of Diet on the Involvement of Non-Coding RNAs, Extracellular Vesicles, and Gut Microbiome-Virome in Colorectal Cancer Initiation and Progression.

Cancer is the major cause of morbidity and mortality in the world today. The third most common cancer and which is most diet related is colorectal cancer (CRC). Although there is complexity and limited understanding in the link between diet and CRC, the advancement in research methods have demonstrated the involvement of non-coding RNAs (ncRNAs) as key regulators of gene expression. MicroRNAs (miRNAs) which are a class of ncRNAs are key players in cancer related pathways in the context of dietary modulation. The involvement of ncRNA in cancer progression has recently been clarified throughout the last decade. ncRNAs are involved in biological processes relating to tumor onset and progression. The advances in research have given insights into cell to cell communication, by highlighting the pivotal involvement of extracellular vesicle (EV) associated-ncRNAs in tumorigenesis. The abundance and stability of EV associated ncRNAs act as a new diagnostic and therapeutic target for cancer. The understanding of the deranging of these molecules in cancer can give access to modulating the expression of the ncRNAs, thereby influencing the cancer phenotype. Food derived exosomes/vesicles (FDE) are gaining interest in the implication of exosomes in cell-cell communication with little or no understanding to date on the role FDE plays. There are resident microbiota in the colon; to which the imbalance in the normal intestinal occurrence leads to chronic inflammation and the production of carcinogenic metabolites that lead to neoplasm. Limited studies have shown the implication of various types of microbiome in CRC incidence, without particular emphasis on fungi and protozoa. This review discusses important dietary factors in relation to the expression of EV-associated ncRNAs in CRC, the impact of diet on the colon ecosystem with particular emphasis on molecular mechanisms of interactions in the ecosystem, the influence of homeostasis regulators such as glutathione, and its conjugating enzyme-glutathione S-transferase (GST) polymorphism on intestinal ecosystem, oxidative stress response, and its relationship to DNA adduct fighting enzyme-0-6-methylguanine-DNA methyltransferase. The understanding of the molecular mechanisms and interaction in the intestinal ecosystem will inform on the diagnostic, preventive and prognosis as well as treatment of CRC.

Effects of vitamin K dietary supplementation in pulmonary dysfunction induced by 7,12-dimethylbenz[a]anthracene in rat.

One of the well-known toxicants of the mammary tissue is 7,12-dimethylbenz[a]anthracene (DMBA). This study was carried out to investigate the possible prophylactic's role of increased dietary intake of vitamin K on the induction of toxicity in the lung tissue. Twenty-eight Wistar albino rats (120-150 g) were randomly divided into different groups. Group 1 served as the control and were fed with a normal diet (containing the recommended daily allowance of vitamin K (0.0075%)). Groups 2 and 3 received a single dose of DMBA (80 mg/kg body weight) intragastically. In addition, group 3 rats were maintained on surplus vitamin K diet (0.075% diet) as against the group 2 animals that were on a normal diet. Group 4 rats were on surplus vitamin K diet (0.075% diet) throughout the experimental period of 16 weeks. Our results revealed that supplementation of diet with surplus vitamin K significantly increased the activities of catalase. Superoxide dismutase, glutathione-S-transferase, and glutathione peroxidase were significantly increased in the serum and lungs when compared with the DMBA-treated group, which was maintained on a normal diet. Significant alterations in malondialdehyde, nitric oxide, granulocyte-macrophage colony-stimulating factor, and interleukin 17F were observed in rats challenged with DMBA-fed normal diets but were normalized in rats with surplus vitamin K. These alterations and reversal were confirmed by histopathology studies. This suggests the prophylactic benefit of increased dietary intake of vitamin K without any observed deleterious effect on DMBA-induced pulmonary toxicity.

A Review of Cancer Genetics and Genomics Studies in Africa.

Cancer is the second leading cause of death globally and is projected to overtake infectious disease as the leading cause of mortality in Africa within the next two decades. Cancer is a group of genomic diseases that presents with intra- and inter-population unique phenotypes, with Black populations having the burden of morbidity and mortality for most types. At large, the prevention and treatment of cancers have been propelled by the understanding of the genetic make-up of the disease of mostly non-African populations. By the same token, there is a wide knowledge gap in understanding the underlying genetic causes of, and genomic alterations associated with, cancer among black Africans. Accordingly, we performed a review of the literature to survey existing studies on cancer genetics/genomics and curated findings pertaining to publications across multiple cancer types conducted on African populations. We used PubMed MeSH terms to retrieve the relevant publications from 1990 to December 2019. The metadata of these publications were extracted using R text mining packages: RISmed and Pubmed.mineR. The data showed that only 0.329% of cancer publications globally were on Africa, and only 0.016% were on cancer genetics/genomics from Africa. Although the most prevalent cancers in Africa are cancers of the breast, cervix, uterus, and prostate, publications representing breast, colorectal, liver, and blood cancers were the most frequent in our review. The most frequently reported cancer genes were BRCA1, BRCA2, and TP53. Next, the genes reported in the reviewed publications' abstracts were extracted and annotated into three gene ontology classes. Genes in the cellular component class were mostly associated with cell part and organelle part, while those in biological process and molecular function classes were mainly associated with cell process, biological regulation, and binding, and catalytic activity, respectively. Overall, this review highlights the paucity of research on cancer genomics on African populations, identified gaps, and discussed the need for concerted efforts to encourage more research on cancer genomics in Africa.

African Walnuts (Tetracarpidium conophorum) Modulate Hepatic Lipid Accumulation in Obesity via Reciprocal Actions on HMG-CoA Reductase and Paraoxonase.

BACKGROUND: Obesity is characterized by increased body fat and involves an imbalance between the synthesis and degradation of lipids. OBJECTIVE: The study aimed to investigate the effect of African walnuts (Tetracarpidium conophorum) on lipids storage and the regulatory enzymes of hepatic lipid metabolism in obese rats. METHODS: Nuts were extracted in ethanol (WE) and further separated to obtain the ethyl-acetate fraction (ET) and the residue (RES). These were administered orally to 3 groups of monosodium glutamate- obese rats (n = 6), respectively, for 6 weeks. Other groups in the study were: normal (NC), obese control (OC) and standard control (SC) which received orlistat. Hepatic total lipids, total phospholipids, triacylglycerol (TG), total cholesterol (TCHOL), 3-hydroxyl-3-methylglutaryl-CoA (HMG-CoA) reductase and paraoxonase were studied. RESULTS: Total lipids, TG and TCHOL which increased in OC compared to NC group, decreased. HMG-CoA reductase activity decreased in the 3 study groups relative to OC. Paraoxonase activity which decreased in OC was up-regulated, while the magnitude of hepatic cholesterol decreased from 94.32 % in OC to 52.19, 65.43 and 47.04 % with WE, ET and RES, respectively. Flavonoids, alkaloids, glycosides, tannins and saponins were detected in the nut. GC-MS analysis revealed 16, 18 and 10 volatile components in WE, ET and RES, respectively. Unsaturated fatty acids (linolenic acids: 33.33, 47.95 and 50.93 %, and α-linolenic acids: 25, 19.66 and 26.63 %) in WE, ET and RES, respectively, are the most abundant, and likely to be responsible for the observed activity. CONCLUSION: African walnuts can prevent hepatic lipid accumulation through reciprocal actions on HMG-CoA reductase and paraoxonase in obesity.

Time-Course Effects of Acute Aflatoxin B1 Exposure on Hepatic Mitochondrial Lipids and Oxidative Stress in Rats.

Aflatoxins are secondary metabolites of certain Aspergillus species, that contaminate staple foods, particularly in developing countries. Aflatoxin B1 (AFB1) is the most toxic and common of the major types of aflatoxins. AFB1 is hepatotoxic and has been implicated in increasing the risk of hepatocellular carcinoma (HCC). We have previously shown that subacute exposure to AFB1 for 7 days disrupts hepatic lipids; therefore, this study determined the time-course effects of acute aflatoxin exposure on hepatic mitochondrial lipids and oxidative stress. To achieve this, thirty male albino rats were randomly assigned to six groups. The groups received an oral dose of 1 mg/kg body weight AFB1 or vehicle only (controls) for one, four, or seven days, respectively. Twenty-four hours after the last dose, the animals were sacrificed and liver excised. Mitochondria and cytosolic fractions were obtained from the liver after which lipids (cholesterol, triacylglycerols) were determined in the mitochondria while biomarkers of oxidative stress (glutathione, glutathione transferase (GST), glutathione peroxidase (GPx), glutathione reductase, nitric oxide (NO), malonaldehyde (MDA), thioredoxin reductase (TR), and superoxide dismutase (SOD) were determined spectrophotometrically in the mitochondria and cytosolic fractions. The expression of genes (Nrf2, Acc, Nqo1, and HmgCoa) were determined using quantitative RT-PCR. Results showed that AFB1 significantly increased mitochondrial cholesterol at day seven (treatment vs. control, p = 0.016). It also increased the concentrations of NO and MDA at day one and day seven while the activity of GPx and concentration of GSH were increased at day seven (p = 0.030) and day one (p = 0.025) alone, respectively, compared to control. The activities of cytosolic GR (p = 0.014), TR (p = 0.046) and GST (p = 0.044) were increased at day seven. AFB1 significantly increased the expression of Nrf2 (p = 0.029) and decreased the expression of Acc (p = 0.005) at day one. This study revealed that AFB1 disrupts hepatic mitochondrial lipids and antioxidant capacity. These changes were dependent on the timing of exposure and did not follow a linear time-course trend. These alterations could be part of the hepatic mitochondria response mechanism to acute AFB1 toxicity.

Oxidative Stress in Extrahepatic Tissues of Rats Co-Exposed to Aflatoxin B1 and Low Protein Diet.

Early life exposure to aflatoxin B1 (AFB1) and low protein diet through complementary foods during weaning is common in parts of Africa and Asia. This study evaluated the effect of co-exposure to AFB1 and low protein diet on the extrahepatic tissues of rats. Twenty-four three-week old weanling male albino rats were used for this study and were randomly assigned into four groups: group 1 served as control and was fed normal protein diet (20% protein), group 2 was fed low protein diet (5% protein), group 3 was fed normal protein diet + 40 ppb AFB1 while group 4 received low protein diet + 40 ppb AFB1, all for eight weeks. Afterward, biomarkers of anemia (packed cell volume (PCV), hemoglobin) and kidney function (urea, uric acid, and creatinine) were determined in the blood while biomarkers of oxidative stress were determined in the tissues spectrophotometrically. Co-exposure to AFB1 and low protein diet significantly (p < 0.05) decreased body weight gain and PCV, increased biomarkers of kidney functions and induced oxidative stress in the tissues studied. There was significant (p < 0.05) reduction in glutathione concentration while TBARS was significantly increased in the tissues. Co-exposure to AFB1 and low protein diet had additive effects on decreasing the weight gain and potentiation effect of kidney dysfunction in the rats. The co-exposure also decreased antioxidant enzymes and increased oxidant status in the tissues. Our results demonstrate that this co-exposure has deleterious health effects on extrahepatic tissues and should be a public health concern especially in developing countries where AFB1 contamination is common.