Epigenetic Biomarkers and the Wnt/ß-Catenin Pathway in Opisthorchis viverrini-associated Cholangiocarcinoma: A Scoping Review on Therapeutic Opportunities.

BACKGROUND: Epigenetic modifications, such as DNA methylation and histone modifications, are pivotal in regulating gene expression pathways related to inflammation and cancer. While there is substantial research on epigenetic markers in cholangiocarcinoma (CCA), Opisthorchis viverrini-induced cholangiocarcinoma (Ov-CCA) is overlooked as a neglected tropical disease (NTD) with limited representation in the literature. Considering the distinct etiological agent, pathogenic mechanisms, and pathological manifestations, epigenetic research plays a pivotal role in uncovering markers and potential targets related to the cancer-promoting and morbidity-inducing liver fluke parasite prevalent in the Great Mekong Subregion (GMS). Emerging studies highlight a predominant hypermethylation phenotype in Opisthorchis viverrini (O. viverrini) tumor tissues, underscoring the significance of abnormal DNA methylation and histone modifications in genes and their promoters as reliable targets for Ov-CCA. PRINCIPAL FINDINGS: Relevant published literature was identified by searching major electronic databases using targeted search queries. This process retrieved a total of 81 peer-reviewed research articles deemed eligible for inclusion, as they partially or fully met the pre-defined selection criteria. These eligible articles underwent a qualitative synthesis and were included in the scoping review. Within these, 11 studies specifically explored Ov-CCA tissues to investigate potential epigenetic biomarkers and therapeutic targets. This subset of 11 articles provided a foundation for exploring the applications of epigenetics-based therapies and biomarkers for Ov-CCA. These articles delved into various epigenetic modifications, including DNA methylation and histone modifications, and examined genes with aberrant epigenetic changes linked to deregulated signalling pathways in Ov-CCA progression. CONCLUSIONS: This review identified epigenetic changes and Wnt/ß-catenin pathway deregulation as key drivers in Ov-CCA pathogenesis. Promoter hypermethylation of specific genes suggests potential diagnostic biomarkers and dysregulation of Wnt/ß-catenin-modulating genes contributes to pathway activation in Ov-CCA progression. Reversible epigenetic changes offer opportunities for dynamic disease monitoring and targeted interventions. Therefore, this study underscores the importance of these epigenetic modifications in Ov-CCA development, suggesting novel therapeutic targets within disrupted signalling networks. However, additional validation is crucial for translating these novel insights into clinically applicable strategies, enhancing personalised Ov-CCA management approaches.

Exploration of Gut Microbiome Research in Africa: A Scoping Review.

The crucial role of the gut microbiome in various diseases has led to increased interest in interventions and therapeutics targeting the human microbiome. Accordingly, the current scoping review analyzed the diseases and interventions involved in gut microbiome research in Africa. The electronic databases of PubMed, Google Scholar, and Scopus were searched from inception to October 2021. This study identified 48 studies involving 7073 study participants. Of the 48 studies, 20 (42%) used interventions to modulate gut microbiota, whereas the remaining 28 (58%) did not. Out of the total African countries, only 13% were involved in intervention-based gut microbiome research, whereas a larger proportion of 67% were not involved in any gut microbiome research. The interventions used in gut microbiome research in Africa include supplements, natural products, educational approaches, associated pathogens, albendazole, fresh daily yogurt, iron-containing lipid-based nutrient supplements, fecal microbiota transplant, and prophylactic cotrimoxazole. This scoping review highlights the current state of gut microbiome research in Africa. The findings of this review can inform the design of future studies and interventions aimed at improving gut health in African populations.

Microbiota-gut-brain axis impairment in the pathogenesis of stroke: implication as a potent therapeutic target.

The human microbiota-gut-brain axis has an enormous role in the maintenance of homeostasis and health. Over the last two decades, it has received concerted research attention and focus due to a rapidly emerging volume of evidence that has established that impairment within the microbiota-gut-brain axis contributes to the development and progression of various diseases. Stroke is one of the entities identified to be associated with microbiota-gut-brain axis impairment. Currently, there are still limitations in the clinical treatment of stroke, and the presence of a non-nervous factor from gut microbiota that can alter the course of stroke presents a novel strategy towards the search for a therapeutic silver bullet against stroke. Hence, the aim herein, was to focus on the involvement of microbiota-gut-brain axis impairment in the pathogenesis stroke as well as elucidate its implications as a potent therapeutic target against stroke. The findings of studies to date have revealed and extended the role microbiota-gut-brain axis impairment in the pathogenesis of stroke, and studies have identified from both clinical and pre-clinical perspectives targets within the microbiota-gut-brain axis and successfully modulated the outcome of stroke. It was concluded that the microbiota-gut-brain axis stands as potent target to salvage the neurons in the ischemic penumbra for the treatment of stroke. Assessment of the microbiota profile and its metabolites status holds enormous clinical potentials as a non-invasive indicator for the early diagnosis and prognosis of stroke.

Exploring NFκB pathway as a potent strategy to mitigate COVID-19 severe morbidity and mortality.

The pandemic of coronavirus disease 2019 (COVID-19), for which there does not appear to be an approved cure, the primary treatment options consist of non-pharmacological preventive measures and supportive treatment that are aimed at halting the progression of the disease. Nuclear factor kappa B (NFkB) presents a promising therapeutic opportunity to mitigate COVID-19-induced cytokine storm and reduce the risk of severe morbidity and mortality resulting from the disease. However, the effective clinical application of NFkB modulators in COVID-19 is hampered by a number of factors that must be taken into consideration. This paper therefore explored the modulation of the NFB pathway as a potential strategy to mitigate the severe morbidity and mortality caused by COVID-19. The paper also discusses the factors that form the barrier, and it offers potential solutions to the various limitations that may impede the clinical use of NFkB modulators against COVID-19. This paper revealed and identified three key potential solutions for the future clinical use of NFkB modulators against COVID-19. These solutions are pulmonary tissue-specific NFkB blockade, agents that target common regulatory proteins of both canonical and non-canonical NFkB pathways, and monitoring clinical indicators of hyperinflammation and cytokine storm in COVID-19 prior to using NFkB modulators.

A REVIEW ON EMERGING PATHOGENESIS OF COVID-19 AND POINTS OF CONCERN FOR RESEARCH COMMUNITIES IN NIGERIA.

BACKGROUND: COVID-19 remains an emerging pandemic that continuously poses an alarming threat and challenge to economic, social and well-being of the people throughout the world. It also remains an evolving disease which complete pathogenesis that translates into clinical features is only just emerging by each second of the day. There have been observations about the emerging trends of the disease in Nigeria like in any other country in the world where there is outbreak. This study examined from evidence-based literature the emerging pathogenesis of COVID-19 and important points of concern of the disease in Nigeria. MATERIALS AND METHODS: The paper reviewed published articles in PubMed and Google Scholar using search terms 'COVID-19" and "SARS-CoV-2", as well as searched for general COVID-19 information on internet. RESULTS: The result summarized literature on emerging pathogenesis of COVID-19 and important points of concern as well as research questions as to the peculiar trends of the disease in Nigeria. CONCLUSION: Pathogenesis of COVID-19 remains an emerging knowledge and there are many important research questions that need to be scientifically answered for a successful containment of COVID-19 in Nigeria. It is recommended that all members of intellectual research communities should join the fight against COVID-19 pandemic.

Pleiotropic ameliorative effects of ellagitannin geraniin against metabolic syndrome induced by high-fat diet in rats.

OBJECTIVES: Metabolic syndrome (MetS), a multiplex risk factor for cardiovascular disease and type 2 diabetes, is increasingly prevalent worldwide. Ellagitannin geraniin, a polyphenol found in the rind of rambutan (Nephelium lappaceum), has demonstrated therapeutic effects against metabolism dysfunction. The aim of this study was to characterize the metabolic effects and possible mechanism of geraniin in rats with MetS induced by a high-fat diet (HFD). METHODS: MetS was induced in Sprague Dawley rats on an HFD, followed by a daily oral gavage of geraniin (25 mg/kg) for 4 wk. The outcomes of geraniin-treated rats were compared with those of untreated rats on either a control diet or an HFD and with rats with MetS treated with metformin on a daily basis (200 mg/kg). RESULTS: The supplementation of geraniin ameliorated multiple metabolic abnormalities caused by HFD, including hypertension, impaired glucose and lipid metabolism, ectopic fat deposition in the visceral fat and liver, and disturbed antioxidant mechanism and inflammatory response. The benefits conferred by geraniin were comparable to metformin. Transcriptomic analysis revealed a profound influence of geraniin on the hepatic expression profiles. The lipid and steroid metabolic processes that were aberrantly activated by HFD were suppressed by geraniin. Based on the differential transcriptomes, geraniin also exerted a significant modulatory effect on the expression of mitochondrial genes, potentially influencing the mitochondrial activity and leading to the observed beneficial effects. CONCLUSION: Geraniin supplementation mitigated metabolic anomalies of MetS in rats, making it an attractive drug candidate for further investigation.

Effect of Caffeine on Serum Tumour Necrosis Factor Alpha and Lactate Dehydrogenase in Wistar Rats Exposed to Cerebral Ischaemia-reperfusion Injury.

Caffeine is known to confer neuro-protection via A1 and A2A adenosine receptor antagonism in which adenosine neuro-modulates excitotoxic release of glutamate. Currently, it is unclear whether caffeine modulates inflammation in ischaemic stroke model. The present study examined effects of caffeine following ischaemia-reperfusion injury on neuro-inflammatory tumour necrosis alpha (TNF-α), lactate dehydrogenase (LDH), as well as effect of caffeine against brain ischaemic damage on histology. Thirty three adult male Wistar rats (180-300 g) were used in this study. They were randomly divided into four groups (n=5 each): Group I (Control) that received neither the operation nor any treatment; Group II (Sham/Water) received a pseudo-ischaemic-reperfusion and 1ml water for injection; Group III (BCCO/Water) that received complete bilateral common carotid occlusion (BCCO) and 1ml water for injection; Group IV (BCCO/Caffeine) that received complete BCCO and caffeine solution intraperitoneally at a dose of 50% LD50 value (144mg/kg); and thirteen rats were used for LD50 assessment. Sensory and motor functions significantly (p<0.05) decreased in the rat following ischaemia-reperfusion injury when compared to pre-injury state on Garcia neurological score. Caffeine reduced brain ischaemic injury and significantly reduced (p<0.05) TNF-α activity. While no significant effects (p>0.05) of caffeine was observed on LDH activity. This study has shown neuro-protective roles of caffeine against ischaemia-reperfusion damage to brain tissue, inflammatory TNF-α activity, but not on LDH activity.

Effect of a CNS-Sensitive Anticholinesterase Methane Sulfonyl Fluoride on Hippocampal Acetylcholine Release in Freely Moving Rats.

Anticholinesterases (antiChEs) are used to treat Alzheimer's disease. The comparative effects of two antiChEs, methanesulfonyl fluoride (MSF) and donepezil, on the extracellular levels of ACh in the hippocampus were investigated by in vivo microdialysis in freely moving rats. MSF at 1 and 2 mg/kg produced a dose-dependent increase in ACh efflux from 10 min to at least 3 hrs after injection. At 2 mg/kg, the increase was still present at 24 hr. Donepezil at 1 mg/kg showed a similar but smaller effect, and, paradoxically, 2 mg/kg showed no consistent effect. MSF at 1 and 2 mg/kg decreased acetylcholinesterase activity in the hippocampus to 54.8 and 20.1% of control, respectively. These results suggest that MSF is a suitable candidate for the treatment of Alzheimer's disease.

Tributyltin-induced Ca(2+) mobilization via L-type voltage-dependent Ca(2+) channels in PC12 cells.

The effects of tributyltin (TBT) on cytosolic Ca(2+) concentration ([Ca(2+)](c)) and cell viability were investigated in nerve growth factor-differentiated PC12 cells. TBT concentration dependently increased [Ca(2+)](c) with an EC(50) value of 0.07µM. This effect was markedly reduced by removal of the extracellular Ca(2+) or membrane depolarization with a high K(+) medium, but unaffected by thapsigargin causing depletion of intracellular Ca(2+) stores. The L-type voltage-dependent Ca(2+) channel (VDCC) blocker nicardipine blocked the effect of TBT, but the N-type VDCC blocker ω-conotoxin did not. TBT decreased the number of viable cells with an EC(50) value of 0.09µM. The TBT-induced cell death was prevented by nicardipine or by chelating the cytosolic Ca(2+) with BAPTA-AM, but not by ω-conotoxin. The results show that TBT causes an increase in [Ca(2+)](c) via activating L-type VDCCs, and support the idea that the organotin-induced cell death arises through Ca(2+) mobilization via L-type VDCCs.

Differential presynaptic actions of pyrethroid insecticides on glutamatergic and GABAergic neurons in the hippocampus.

This study was designed to investigate the effects of several pyrethroids on the extracellular level of glutamate and gamma-aminobutyric acid (GABA) in the hippocampus of rats measured using microdialysis following systemic (i.p.) administration. Pyrethroids, allethrin (type I), cyhalothrin (type II) and deltamethrin (type II), were found to have differential effects on glutamatergic and GABAergic neurons in the hippocampus. Allethrin had an interesting dual effect, increasing glutamate release with low doses (10 and 20mg/kg) to about 175-150% and decreasing glutamate release with high dose (60 mg/kg) to about 50% of baseline. Cyhalothrin (10, 20 and 60 mg/kg) inhibited the release of glutamate dose-dependently to about 60-30% of baseline. The extracellular level of GABA was decreased to about 50% of baseline by 10 and 20mg/kg allethrin. The high dose of allethrin (60 mg/kg) and all doses of cyhalothrin (10, 20 and 60 mg/kg) increased the extracellular level of GABA while decreasing the level of glutamate. Deltamethrin dose-dependently increased extracellular glutamate levels to about 190-275% of baseline while decreasing the level of GABA. Local infusion of TTX (1 microM), a Na(+) channel blocker, completely prevented the effect of allethrin (10, 20 and 60 mg/kg), cyhalothrin (20 and 60 mg/kg) and deltamethrin (20mg/kg) on glutamate and GABA release, but only partially blocked the effects of 60 mg/kg deltamethrin. The effect of deltamethrin (60 mg/kg) on glutamate release was completely prevented by local infusion of nimodipine (10 microM), an L-type Ca(2+) channel blocker. Collectively, results from this study suggest that the excitatory glutamatergic neurons in the hippocampus are modulated by inhibitory GABA-releasing interneurons and that other mechanisms, beside sodium channels, may be involved with the neurotoxic action of pyrethroids.

Neuromechanical effects of pyrethroids, allethrin, cyhalothrin and deltamethrin on the cholinergic processes in rat brain.

Our previous microdialysis study of freely moving rats demonstrated that 3 pyrethroids, allethrin (type I), cyhalothrin (type II) and deltamethrin (type II) differentially modulate acetylcholine (ACh) release in the hippocampus. To better understand the mechanisms of their modulatory effects and also other effects on the cholinergic system in the brain, the activities of ACh hydrolyzing enzyme acetylcholinesterase (AChE), ACh synthesizing enzyme choline acetyltransferase (ChAT) and ACh synthesizing rate-limiting step, high-affinity choline uptake (HACU) were examined in the present study. The pyrethroids studied had no effect on AChE activity in the cortex, hippocampus and striatum. These pyrethroids had no significant effect on ChAT in the cortex and hippocampus, but striatal ChAT was increased at higher dosage (60 mg/kg) by all three compounds. Lineweaver-Burk analysis of hippocampal HACU revealed that the pyrethroids did not alter the Michaelis-Menten constant (Km) value but caused alteration of maximal velocity (Vmax). Allethrin (60 mg/kg) and cyhalothrin (20 and 60 mg/kg) decreased while deltamethrin (60 mg/kg) increased the Vmax for HACU. In vitro study showed that at higher concentrations (> or = 10(-) (6) M) allethrin and cyhalothrin reduced the hippocampal HACU but deltamethrin increased it. These results suggest that mechanisms of ACh synthesis are involved in the modulatory effects of the pyrethroids on ACh release and other cholinergic activities.

The modulatory effect of pyrethroids on acetylcholine release in the hippocampus of freely moving rats.

The peripheral effects of pyrethroids on Na(+) channels are well known but the effects on CNS neurotransmission are less known. In the present study, type I and II pyrethroids were found to affect the release of acetylcholine (ACh) from hippocampus in freely moving rats as measured by in vivo microdialysis. The basal release of ACh from the hippocampus of untreated rats was 6.6 pmol/10 microl/10 min. Allethrin had an interesting dual effect on ACh release, increasing ACh efflux (to about 300% of baseline) at the lower dose of 20 mg/kg i.p. with a peak time of 60 min and decreasing the efflux (to about 40% of baseline) at the higher dose of 60 mg/kg i.p. up to 3 h after administration. Cyhalothrin 20 and 60 mg/kg i.p. inhibited the release (to about 30% of baseline) dose-dependently, with a peak time of 50-60 min after administration. Deltamethrin 20 mg/kg i.p. increased the efflux (to about 250% of baseline) with a peak time of 30 min after administration and 60 mg/kg i.p. increased the efflux (to about 450% of baseline) and remained at a steady level during the rest of the 3 h experiment. Control vehicle injections had no effect on the efflux of ACh in any of the experiments. This is the first report, using in vivo microdialysis, that pyrethroids modulate the ACh release in the hippocampus of rat brain.