FACULTY OF BASIC MEDICAL SCIENCES
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Item Induction of aggression and anxiety-like responses by perfluorooctanoic acid is accompanied by modulation of cholinergic- and purinergic signaling-related parameters in adult zebrafish(Elsevier Inc., 2022) Adedara, I. A. || || || || || || || || || || ||; Souza, T. P.; Canzian, J.; Olabiyi, A. A.; Borba, J. V.; Biasuz, E.; Sabadin, G. R.; Goncalves, F. L. S.; Costa, F. V.; Schetinger, M. R. C.; Farombi E.O.; Rosemberg, D. B.Perfluorooctanoic acid (PFOA) is a contaminant of global concern owing to its prevalent occurrence in aquatic and terrestrial environments with potential hazardous impact on living organisms. Here, we investigated the influence of realistic environmental concentrations of PFOA (0, 0.25, 0.5, or 1.0 mg/L) on relevant behaviors of adult zebrafish (Danio rerio) (e.g., exploration to novelty, social preference, and aggression) and the possible role of PFOA in modulating cholinergic and purinergic signaling in the brain after exposure for 7 consecutive days. PFOA significantly increased geotaxis as well as reduced vertical exploration (a behavioral endpoint for anxiety), and increased the frequency and duration of aggressive episodes without affecting their social preference. Exposure to PFOA did not affect ADP hydrolysis, whereas ATP and AMP hydrolysis were significantly increased at the highest concentration tested. However, AChE activity was markedly decreased in all PFOA-exposed groups when compared with control. In conclusion, PFOA induces aggression and anxiety-like behavior in adult zebrafish and modulates both cholinergic and purinergic signaling biomarkers. These novel data can provide valuable insights into possible health threats related to human activities, demonstrating the utility of adult zebrafish to elucidate how PFOA affects neurobehavioral responses in aquatic organisms.Item Zebrafish as a potential non-traditional model organism in translational bipolar disorder research: Genetic and behavioral insights(Elsevier Ltd., 2022) Canzian, J.; Goncalves, F. L. S.; Muller, T. E.; Fransescon, F.; Santos, L. W.; Adedara, I. A.; Rosemberg, D. B.Bipolar disorder (BD) is a severe and debilitating illness that affects 1-2% of the population worldwide. BD is characterized by recurrent and extreme mood swings, including mania/hypomania and depression. Animal experimental models have been used to elucidate the mechanisms underlying BD and different strategies have been proposed to assess BD-like symptoms. The zebrafish (Danio rerio) has been considered a suitable vertebrate system for modeling BD-like responses, due to the genetic tractability, molecular/physiological conservation, and well-characterized behavioral responses. In this review, we discuss how zebrafish-based models can be suc- cessfully used to understand molecular, biochemical, and behavioral alterations paralleling those found in BD. We also outline some advantages and limitations of this aquatic species to examine BD-like phenotypes in translational neurobehavioral research. Overall, we reinforce the use of zebrafish as a promising tool to investigate the neural basis associated with BD-like behaviors, which may foster the discovery of novel pharmaco- logical therapies.Item Influence of acid-sensing ion channel blocker on behavioral responses in a zebrafish model of acute visceral pain(Elsevier B.V., 2022) Adedara, I. A.; Costa, F. V.; Biasuz, E.; Canzian, J.; Farombi, E. O.; Rosemberg, D. B.Acid-sensing ion channels (ASICs) play significant roles in numerous neurological and pathological conditions, including pain. Although acid-induced nociception has been characterized previously in zebrafish, the contri- bution of ASICs in modulating pain-like behaviors is still unknown. Here, we investigated the role of amiloride, a nonselective ASICs blocker, in the negative modulation of specific behavioral responses in a zebrafish-based model of acute visceral pain. We verified that intraperitoneal injection (i.p.) of 0.25, 0.5, 1.0, and 2.0 mg/mL amiloride alone or vehicle did not change zebrafish behavior compared to saline-treated fish. Administration of 2.5% acetic acid (i.p.) elicited writhing-like response evidenced by the abnormal body curvature and impaired locomotion and motor activity. Attenuation of acetic acid-induced pain was verified at lower amiloride doses (0.25 and 0.5 mg/mL) whereas 1.0 and 2.0 mg/mL abolished pain-like responses. The protective effect of the highest amiloride dose tested was evident in preventing writhing-like responses and impaired locomotion and vertical activity. Collectively, amiloride antagonized abdominal writhing-like phenotype and aberrant behaviors, supporting the involvement of ASICs in a zebrafish-based model of acute visceral painItem Utility of cockroach as a model organism in the assessment of toxicological impacts of environmental pollutants(Elsevier Ltd., 2022) Adedara, I. A.; Mohammed, K. A.; Da-Silva, O. F.; Salaudeen, F. A.; Goncalves, F. L. S.; Rosemberg, D. B.; Aschner, M.; Rocha, J. B. T.; Farombi, E. O.Environmental pollution is a global concern because of its associated risks to human health and ecosystem. The bio-monitoring of environmental health has attracted much attention in recent years and efforts to minimize environmental contamination as well as to delineate toxicological mechanisms related to toxic exposure are essential to improve the health conditions of both humans and animals. This review aims to substantiate the need and advantages in utilizing cockroaches as a complementary, non-mammalian model to further understand the noxious impact of environmental contaminants on humans and animals. We discuss recent advances in neuro- toxicology, immunotoxicology, reproductive and developmental toxicology, environmental forensic entomo- toxicology, and environmental toxicology that corroborate the utility of the cockroach (Periplaneta americana, Blaptica dubia, Blattella germanica and Nauphoeta cinerea) in addressing toxicological mechanisms as well as a sensor of environmental pollution. Indeed, recent improvements in behavioural assessment and the detection of potential biomarkers allow for the recognition of phenotypic alterations in cockroaches following exposure to toxic chemicals namely saxitoxin, methylmercury, polychlorinated biphenyls, electromagnetic fields, pharma- ceuticals, polycyclic aromatic hydrocarbon, chemical warfare agents and nanoparticles. The review provides a state-of-the-art update on the current utility of cockroach models in various aspects of toxicology as well as discusses the potential limitations and future perspectives.Item Indole-3-propionic acid mitigates chlorpyrifos-mediated neurotoxicity by modulating cholinergic and redox-regulatory systems, inflammatory stress, apoptotic responses and DNA damage in rats(Elsevier B.V., 2022) Owumi, S. E.; Adedara, I. A.; Oyelere, A. K.This study probed the neuroprotective influence of indole-3-propionic acid (IPA) in rats exposed to chlorpyrifos (CPF) alone at 5 mg/kg body weight or co-administered with IPA at 12.5 and 25 mg/kg for 14 days. Behavioral data indicated that IPA significantly (p < 0.05) abated CPF-mediated anxiogenic-like behaviors with concomitant improvement in the locomotor and exploratory behaviors as substantiated by track plots and heat maps data. Also, IPA mitigated CPF-mediated diminution in cholinergic and antioxidant defense systems whereas it mark- edly improved thioredoxin level and thioredoxin reductase activity in cerebral and cerebellar tissues of the animals. Co-administration of IPA significantly enhanced anti-inflammatory cytokine, interleukin-10 but sup- pressed oxidative and inflammatory stress, caspase-9 and caspase-3 activation with concomitant reduction in 8- hydroxy-2'-deoxyguanosine (8-OHdG) level and histological damage. Collectively, IPA-mediated neuro- protection involves modulation of cholinergic and redox-regulatory systems, inflammatory stress, apoptotic re- sponses and DNA damage in cerebrum and cerebellum of rats.Item Influence of Atrazine and Diclofenac Co-exposure on Hypothalamic-Pituitary-Testicular Axis Function in Rats(2021) Adedara I. A.|| || || || ||; Godswill U. S.; Amorha C. C.; Sule, J.; Mike M. A.; Farombi E.O.Humans and animals are commonly exposed to numerous chemicals through diverse sources causing unpredictable real-life health effects. This study evaluated the influence of joint exposure to the herbicide atrazine (ATZ) and the NSAID diclofenac (DCF) on the hypothalamic-pituitary-testicular axis function in pubertal rats. The animals were jointly exposed to ATZ (20 and 40 mg/kg body weight) and DCF (10 and 20 mg/kg body weight) for 42 days. In comparison with individual exposures, the current data illustrated that combined exposure to ATZ and DCF exacerbated the reductions in follicle stimulating hormone (FSH), luteinizing hormone (LH), serum and intra-testicular testosterone levels with testosterone/LH ratio. Additionally, co- exposure to ATZ and DCF worsened the sperm quality and quantity with marked disruption in the testicular function marker enzymes activities. The diminution in the epididymal, testicular and hypothalamic antioxidant defense mechanisms was intensified in animals co-exposed to ATZ and DCF. Moreover, the induction of reactive oxygen and nitrogen species, lipid peroxidation, inflammatory stress and histopathological lesions in the epididymal, testicular and hypothalamic tissues was intensified in co-exposed animals. These data accentuate the possible male reproductive dysfunction related to ATZ and DCF co-exposure in mammals and, by extension, provide useful insights into the public health threats associated with combined exposure to pesticides and pharmaceuticals.Item Kolaviron suppresses dysfunctional reproductive axis associated with multi-walled carbon nanotubes exposure in male rats(Springer-Verlag GmbH, 2021) Adedara, I. A.; Awogbindin, I. O.; Maduako, I. C.; Ajeleti, A. O.; Owumi, S. E.; Owoeye, O.; Patlola, A. K.; Farombi, E. O.Reproductive toxicity associated with excessive exposure to multi-walled carbon nanotubes (MWCNTs), which are commonly used in medicine as valuable drug delivery systems, is well documented. Kolaviron, a bioflavonoid isolated from Garcinia kola seeds, elicits numerous health beneficial effects related to its anti-inflammatory, anti-genotoxic activities, anti-apoptotic, and antioxidant properties. However, information on the role of kolaviron inMWCNTs-induced reproductive toxicity is not available in the literature. Herein, we assessed the protective effects of kolaviron onMWCNTs-induced dysfunctional reproductive axis in rats following exposure toMWCNTs (1 mg/kg) and concurrent treatment with kolaviron (50 or 100 mg/kg body weight) for 15 successive days. Results showed thatMWCNTs-induced dysfunctional reproductive axis as evidenced by deficits in pituitary and testicular hormones, marker enzymes of testicular function, and sperm functional characteristics were abrogated in rats coadministered with kolaviron. Moreover, co-administration of kolaviron-abated MWCNTs-induced inhibition of antioxidant enzyme activities increases in oxidative stress and inflammatory indices. This is evidenced by diminished levels of tumor necrosis factor-alpha, nitric oxide, lipid peroxidation, reactive oxygen, and nitrogen species as well as reduced activity of myeloperoxidase in testes, epididymis, and hypothalamus of the rats. Biochemical data on the chemoprotection of MWCNTsinduced reproductive toxicity were corroborated by histological findings. Taken together, kolaviron suppressed dysfunctional reproductive axis associated with MWCNTs exposure via abrogation of oxidative stress and inflammation in male rats.Item Neuroprotective role of gallic acid in aflatoxin Bi-induced behavioral abnormalities in rats(Wiley Periodicals LLC, 2020) Adedara, I. A.; Owumi, S. E.; Oyelere, A. K.; Farombi, E. O.The neurotoxic impact of dietary exposure to aflatoxin Bi (AFBJ is documented in experimental and epidemiological studies. Gallic acid (GA) is a triphenolic phyto- chemical with potent anticancer, anti-inflammatory, and antioxidant activities. There is a knowledge gap on thè influence of GA on AFBi-induced neurotoxicity. This study probed thè influence of GA on neurobehavioral and biochemical abnormalities in rats orally treated with AFBi per se (75pg/kg body weight) or administered together with GA (20 and 40mg/kg) for 28 uninterrupted days. Behavioral endpoints obtained with video-tracking software demonstrated sig-nificant (p<.05) abatement of AFBrinduced anxiogenic-like behaviors (increased freezing, urination, and fecal bolus discharge), motor and locomotor inadequacies, namely increased negative geotaxis and diminished grip strength, absolute turn angle, total time mobile, body rotation, maximum speed, and total distance traveled by GA. The improvement of exploratory behavior in animals that received both AFBi and GA was confirmed by track plots and heat maps appraisal. Abatement of AFBj-induced decreases in acetylcholinesterase activity, antioxidant status and glutathione level by GA was accompanied by a marked reduction in oxidative stress markers in thè cerebellum and cerebrum of rats. Additionally, GA treatment abro- gated AFBi-mediated decrease in interleukin-10 and elevation of inflammatory in- dices, namely tumor necrosis factor-a, myeloperoxidase activity, interleukin-l|3, and nitric oxide. Further, GA treatment curtailed caspase-3 activation and histological injuries in thè cerebral and cerebellar tissues. In conclusion, abatement of AFBi-induced neurobehavioral abnormalities by GA involves anti-inflammatory, antioxidant, and antiapoptotic mechanisms in rats.Item Chronic ciprofloxacin and atrazine co-exposure aggravates locomotor and exploratory deficits in non-target detritivore speckled cockroach (Nauphoeta cinerea)(Springer-Verlag GmbH, 2021) Adedara, I. A. || || || || || || ||; Godswill, U. S.; Mike. M. A.; Afolabi, B. A.; Amorha, C. C.; Sule, J.; Rocha, J. B. T.; Farombi, E. O.The global detection of ciprofloxacin and atrazine in soil is linked to intensive anthropogenic activities in agriculture and inadvertent discharge of industrial wastes to the environment. Nauphoeta cinerea is a terrestrial insect with cosmopolitan distribution and great environmental function. The current study probed the neurobehavioral and cellular responses of N. cinerea singly and jointly exposed to atrazine (1.0 and 0.5 μg g−1 feed) and ciprofloxacin (0.5 and 0.25 μg g−1 feed) for 63 days. Results demonstrated that the reductions in the body rotation, maximum speed, turn angle, path efficiency, distance traveled, episodes, and time of mobility induced by atrazine or ciprofloxacin per se was exacerbated in the co-exposure group. The altered exploratory and locomotor in insects singly and jointly exposed to ciprofloxacin and atrazine were verified by track plots and heat maps. Furthermore, we observed a decrease in acetylcholinesterase and anti-oxidative enzyme activities with concomitant elevation in the levels of lipid peroxidation, nitric oxide, and reactive oxygen and nitrogen species were significantly intensified in the midgut, hemolymph, and head of insects co-exposed to ciprofloxacin and atrazine. In conclusion, exposure to binary mixtures of ciprofloxacin and atrazine elicited greater locomotor and exploratory deficits than upon exposure to the individual compound by inhibiting acetylcholinesterase activity and induction of oxido-inflammatory stress responses in the insects. N. cinerea may be a usable model insect for checking contaminants of ecological risks.Item Immunohistochemical human epidermal growth factor receptor 2 (her2) expression pattern in gastric adenocarcinomas in a Nigerian tertiary hospital(West African College of Physicians and the West African College of Surgeons, 2024) Mashor, M. I.; Ezenkwa, U. S.; Ogun, G. O.; Ajani, M. A.; Ogunbiyi, J. O.BACKGROUND AND OBJECTIVE: The demonstration of HER2 in gastric adenocarcinoma (GA) tissues by immunohistochemistry assists in deciding whether targeted therapy would optimise the treatment of GA patients who are HER2 positive. However, this has not been extensively studied in our patients hence the need for this study. METHODS: Recipient tissue microarray blocks were constructed from donor archival formalin fixed paraffin embedded gastric tumour tissue from 80 patients seen over a period of 17 years in a retrospective descriptive study. Slides cut from these blocks were stained with anti human HER2 antibody by immunohistochemistry and scored using the trastuzumab in gastric adenocarcinomas (ToGA) trial criteria. Data on age, gender, site of lesion and histological subtype of the gastric adenocarcinomas were also retrieved and reviewed. RESULTS: Eighty cases (52 males and 28 females; male to female ratio of 1.9:1), 55.65 ±13.50 years (modal age group 60-69 years), were studied. Most tumours (91.2%) involved the distal parts (pylorus, antrum and body) with a few (8.8%) involving the proximal part (cardia and fundus) of the stomach. HER2 was overexpressed in a total of 6 (7.5%) cases only. Two of seven (28.6%) proximal tumours showed HER2 positivity whereas only 4 of 73 (5.5%) of the distal tumours showed HER2 positivity. CONCLUSION: We had only a slightly lower HER2 overexpression rate than in studies from many other parts of the world. The observed overexpression was significantly higher in proximal than distally located tumours suggesting that distal tumours are less likely to respond to Trastuzumab than proximal tumours. The known association of distal gastric tumours with Helicobacter pylori infection probably provides for a possible difference in the molecular aetiopathogenesis of GAs by site of occurrence. The exact mechanisms for proximal gastric carcinogenesis remain to be more clearly elucidated. More studies, including clinical trials with larger sample sizes, are recommended to elucidate this differential expression of HER2 in gastric adenocarcinoma.