Naringin corrects renal failure related to Lesch-Nyhan disease in a rat model via NOS-cAMP-PKA and BDNF/TrkB pathways.

This study explored the effect of naringin (NAR) on HGPRT1 deficiency and hyperuricemia through NOS-cAMP-PKA and BDNF/TrkB signaling pathways induced by caffeine (CAF) and KBrO3 in a rat model. Sixty-three adult male albino rats were randomly assigned into nine (n = 7) groups. Group I: control animals, Group II was treated with 100 mg/kg KBrO3 , Group III was treated with 250 mg/kg CAF, Group IV was treated with 100 mg/kg KBrO3 + 250 mg/kg CAF, Group V was administered with 100 mg/kg KBrO3 + 100 mg/kg haloperidol, Group VI was administered with 100 mg/kg KBrO3 + 50 mg/kg NAR, Group VII was administered with 500 mg/kg CAF + 50 mg/kg NAR, and Group VIII was administered with 100 mg/kg KBrO3 + 250 mg/kg CAF + 50 mg/kg NAR. Finally, group IX was treated with 50 mg/kg NAR. The exposure of rats to KBrO3 and CAF for 21 days induced renal dysfunction linked with Lesch-Nyhan disease. NAR obliterated renal dysfunction linked with Lesch-Nyhan disease by decreasing uric acid, renal malondialdehyde level, inhibiting the activities of arginase, and phosphodiesterase-51 (PDE-51) with corresponding upregulation of brain derived-neurotrophic factor and its receptor (BDNF-TrkB), Bcl11b, HGPRT1, and DARPP-32. Additionally, renal failure related to Lesch-Nyhan disease was remarkably corrected by NAR as shown by the reduced activities of AChE and enzymes of ATP hydrolysis (ATPase, AMPase, and ADA) with affiliated increase in the NO level. This study therefore validates NAR as nontoxic and effective chemotherapy against kidney-related Lesch-Nyhan disease by mitigating effects of toxic food additives and enzymes of ATP-hydrolysis via NOS-cAMP-PKA and BDNF/TrkB signaling pathways.

Pre-puberty cannabichromene exposure modulates reproductive function via alteration of spermatogenesis, steroidogenesis, and eNOS pathway metabolites.

Background: Cannabis and cannabinoids affect almost every system of the body and exert systemic effects such as alterations in memory and cognitive functions, neurotransmission impediment, as well as obstruction of endocrine and reproductive system functions. Reproduction is a complicated phenomenon that integrates biological, psychological and behavioural aspects, hence susceptible to intracellular and extracellular modulations by numerous chemicals and toxicants like cannabis. Aim: The effects of early-life exposure to cannabis on reproductive function biomarkers and genes were investigated in male and female Wistar rats in this study. Method: An initial computational analysis (molecular docking and induced fit docking) of some cannabinoids with reproductive enzymes; androgen and follicle stimulating hormone receptors was conducted. Overall, cannabichromene (CBC) had the best IFD scores and binding free energies for the two proteins studied and it interacted with notable amino acids within their active sites. Subsequently, forty (40) Wistar rats, 20 male and 20 female (24-28 days old, weighing 20-28 ± 2 g) were divided into two groups each and orally administered CBC for 21 days. Penile tissues, testes and ovaries, were collected for biochemical analysis (hormonal assays, enzyme activities, and metabolite concentrations), gene expressions, and histological evaluations. Results: Activities of arginase and phosphodiesterase-5 in the penile tissue were significantly increased, while nitric oxide and calcium levels were significantly (p < 0.05) decreased in the CBC-exposed groups relative to the control group. Semen analysis showed significantly more abnormalities and decreased concentration of spermatozoa in the CBC-exposed group compared to the control. Activities of 17ß-hydroxysteroid dehydrogenase and cholesterol level were decreased in both testes and ovaries of CBC-exposed groups. Furthermore, levels of testosterone, progesterone, luteinizing, and follicle-stimulating hormones were reduced in the serum of CBC rats. Moreover, relative expressions of androgen receptor and follicle-stimulating hormone receptor genes were significantly downregulated in the CBC-exposed groups. Histological evaluations revealed lesions, tubular necrosis, and cellular congestions in both the testes and ovaries. Conclusion: This study suggests that pre-puberty exposure to cannabis modulates reproductive functions via cannabichromene inhibition of steroidogenesis, stimulation of erectile dysfunction (modulation of intermediates and enzymes of the endothelial nitric oxide synthase (eNOS) pathway in the penile tissue), and downregulation of the expressions of genes associated with reproduction.

Lycopene abolishes palmitate-mediated myocardial inflammation in female Wistar rats via modulation of lipid metabolism, NF-κB signalling pathway, and augmenting the antioxidant systems.

BACKGROUND AND AIMS: Obesity-related heart failure is exacerbated by excessive intake of saturated fats such as palmitate (PA). Lycopene (LYC) possesses anti-lipidemic, antioxidant, cytoprotective, and anti-inflammatory effects. This study, therefore, evaluated the impact of LYC against PA-invoked cardiotoxicity. METHODS AND RESULTS: Thirty-six female rats were equally divided into six groups: control; PA (5 mM); PA + LYC (24 mg/kg); PA + LYC (48 mg/kg); LYC (24 mg/kg); and LYC (48 mg/kg). The PA was administered five times weekly for seven weeks, while the LYC was given for the last two weeks. Lipids in the blood and the heart were estimated, as were oxidative stress and antioxidant indices, cardiac function, inflammation, and histology. Palmitate overload occasioned a significant (p < 0.05) increase in cardiac cholesterol (50%), phospholipids (19%), and non-esterified fatty acids (40%). However, triglyceride levels decreased (38%). Furthermore, malondialdehyde (45%), hydrogen peroxide (33%) levels and myeloperoxidase activity increased (79%). Also, cardiac gamma-glutamyl transferase (50%), serum creatine kinase activities (1.34 folds), NF-kB, interleukin1ß, and interleukin-6 mRNA expression increased in the PA group relative to the control. In contrast, reduced glutathione (13%) and nitric oxide levels (22%), interleukin-10 mRNA expression, cardiac creatine kinase (35%), lactate dehydrogenase (33%), aspartate, and alanine transaminase activities decreased markedly (15- and 10%, respectively). Also, PA caused hyperemia, congestion of the cardiac interstitium, and infiltration of inflammatory cells. However, treatment with LYC reversed the features of cardiotoxicity and histological complications caused by PA. These observations are likely because LYC has anti-inflammatory, antioxidant, and cytoprotective properties. CONCLUSION: Thus, LYC might be an appropriate remedy to manage PA-induced cardiotoxicity in female rats.

Lycopene alleviates Western diet-induced elevations in anthropometrical indices of obesity, adipose lipids, and other nutritional parameters.

Objective: Given the unrelenting surge in the prevalence of obesity and the intensified efforts aimed at elucidating underlying mechanisms and proffering effective treatments, this study investigated the effects of lycopene on various anthropometrical indices of obesity. Methods: Thirty female Wistar rats were equally divided into two groups and fed either control diet or Western diet. After eight weeks, obese rats (fed Western diet) were divided into three groups (n=5); obese control received the vehicle, while the other two received lycopene (0.2 and 0.4 mg/kg body weight, respectively). Normal rats were grouped into three (n=5) and treated similarly. This treatment lasted for another two weeks, in addition to their respective diets. Afterwards, anthropometrical indices were taken. Results: The weight gain, adiposity index, abdominal and thoracic circumference, body mass index, and Lee index were significantly increased (p<0.05) in the obese rats compared to the normal control, by 108.3%, 102.1%, 81.5%, 97.6%, 47.4%, and 13.9%, respectively. The obese rats had significantly (p<0.05) higher adipose tissue lipid contents, daily feed (37.4%) and energy intake (66.0%), daily weight gain (108.3%), and feed efficiency (25.5%) compared to control. However, the treatment of obese rats with lycopene occasioned a dose-dependent reduction in the elevated anthropometrical and nutritional parameters. In addition, lycopene elicited significant reductions (p<0.05), ranging from 16-54%, in the adipose lipid contents. Conclusion: The data presented here illustrate the positive effects of lycopene on indices of obesity and other anthropometric parameters in obese female rats.

Morin Augmented Myocardial eNOS/cGMP/PKG Signaling Pathway and Abated Oxidative and Inflammo-apoptotic Responses in Diethyl Phthalate and Bisphenol-S Co-Exposed Male Albino Rats.

Cardiac failure accounts for many deaths worldwide. Increasing experimental evidence suggests that exposure to chemicals such as bisphenol-S (BPS) and diethyl phthalate (DEP) exacerbate cardiac injuries. Morin is a flavonoid with reported cardioprotective activity. This study evaluated the modulation of pathways relevant to cardiac endothelial function in rats exposed to BPS and DEP mixture (Mix). Thirty male albino rats were distributed across five groups (n = 6): control received dimethyl sulfoxide (DMSO) as vehicle, Mix dissolved in DMSO, Mix + morin (25 mg/kg), Mix + morin (50 mg/kg), and morin (50 mg/kg). After 21 days of oral exposure at 1 ml/kg bodyweight of the Mix and treatment with morin, the animals were sacrificed, and their hearts were excised for biochemical, histological, immunohistochemical, and gene expression analyses. Exposure to the Mix caused a significant increase in oxidative stress indices (H2O2, malondialdehyde, DNA fragmentation, and advanced oxidation protein products). Also, arginase, phosphodiesterase 5', and the relative expression of TNF-α, interleukin-1ß, Bax, androgen receptor, and vascular endothelial growth factor were markedly increased. In contrast, nitric oxide, reduced glutathione, interleukin-10 levels, superoxide dismutase, catalase, and glutathione peroxidase activities decreased significantly. Furthermore, p-NF-kB-p65 expression increased markedly in the Mix-exposed group. Morin treatment significantly reversed these perturbations in a dose-dependent manner in most instances. This study concludes that morin might offer a cardioprotective effect by enhancing the cardiac endothelial system and attenuating oxidative stress, inflammation, and apoptosis elicited by BPS and DEP co-exposure in male Wistar rats.

Morin attenuates neurobehavioural deficits, hippocampal oxidative stress, inflammation, and apoptosis in rats co-exposed to bisphenol S and diethyl phthalate.

Endocrine-disrupting pollutants (EDPs) remain pervasive in the environment. Bisphenol S (BPS) and diethyl phthalates (DEP) are commonly used to replace the more toxic EDPs. However, it is unclear if they induce neurotoxicity, like their predecessors. Morin possesses relevant neuro-pharmacological activities. Hence, we sought to evaluate the protective effects of morin against the neurotoxic effects previously reported for EDPs. Male Wistar rats were exposed to a mixture of BPS and DEP (MBD) and treated with morin for 21 days. Behavioural assessments were conducted, and the hippocampal tissues were processed for analysis. Rats exposed to MBD presented anxiety-like behaviours, impaired cognitive and motor functions compared to the control group. MBD exposure induced hyperactivity of neurosignalling enzymes (AChE, ADA, MAO-A) and depleted hippocampal antioxidants (SOD, CAT, GPx, and GSH). MBD exposure increased calcium levels and inhibited total Ca2+-ATPase activity. Levels of reactive species (NO and H2O2) and oxidative damage markers (MDA and AOPP) were significantly (P < 0.05) elevated compared to control. The hippocampal expressions of IL-1ß, TNFα, BAX, and APAF-1 in the MBD-exposed rats were significantly higher compared to control. Correspondingly, NF-κB and caspase-3 pathways were activated in the hippocampus of MBD-exposed rats, while the expressions of IL-10 and BDNF were repressed. However, co-treatment with morin improved the neurobehavioral outcomes, alleviated the hyperactivity of neurosignalling enzymes, while suppressing hippocampal oxidative stress, inflammation, and apoptosis. Histological and stereological evaluations supported these findings. In conclusion, co-exposure to BPS and DEP elicit similar neurotoxic outcomes as their predecessors, while morin confers marked protection against these outcomes.

Inhibition of fat accumulation, lipid dysmetabolism, cardiac inflammation, and improved nitric oxide signalling mediate the protective effects of lycopene against cardio-metabolic disorder in obese female rats.

Obesity, hallmarked by excessive lipid accumulation and dysregulation, continues to escalate the prevalence of cardiometabolic diseases, and is a foremost cause of deaths globally. Alternative therapeutic agents are urgently needed. This study hypothesized that lycopene could proffer beneficial effects against obesity-induced cardiometabolic changes. Obesity was induced using a Western-style diet. Female albino rats (n = 36) were randomized into 6 groups of 6 rats each: normal control, obese control, obese + lycopene (20 mg/kg body weight [b.wt.]), obese + lycopene (40 mg/kg b.wt.), lycopene (20 mg/kg b.wt.), and lycopene (40 mg/kg b.wt.). The study was 10 weeks. Obese rats had significantly higher (P< .05) body weight and total body fat. Lipids (triacylglycerol, cholesterol [CHOL], and free fatty acids), cardiac injury markers (troponin-T, creatine kinase-myocardial band, and malondialdehyde), and cardiovascular risk markers (low-density lipoprotein-CHOL, atherogenic and coronary risk indices) were significantly (P< .05) elevated in obese rats compared with control groups. However, obesity significantly reduced high-density lipoprotein-CHOL and impaired cardiac nitric oxide signalling. Pro-inflammatory mediators (nuclear factor-κB-p65, interleukin-1ß [IL-1ß], and IL-6) transcripts were increased in the heart of obese rats, whereas cardiac IL-10 expression was repressed. Treatment with lycopene reduced lipid concentrations, normalized lipid and lipoprotein metabolism, augmented nitric oxide concentration and IL-10 messenger RNA transcripts, and attenuated the expression of pro-inflammatory mediators. These findings delineate the role of lycopene in the attenuation of cardiometabolic disorders potentiated by obesity.

Lycopene suppresses palmitic acid-induced brain oxidative stress, hyperactivity of some neuro-signalling enzymes, and inflammation in female Wistar rat.

Neuroinflammation can be triggered by certain high caloric nutrients such as palmitic acid (PA). The effect of lycopene against PA-induced neuroinflammation in female rats has not been as explored. In the present study, thirty rats (weighing 150-200) g were randomly allotted into six groups (n = 5) comprising normal control, PA control, PA + lycopene (0.24 mg/kg), PA + lycopene (0.48 mg/kg), lycopene (0.24 mg/kg), and lycopene (0.48 mg/kg), respectively. After seven weeks of PA challenge (5 mM) including two weeks of lycopene treatment, the brain was excised for analyses. Palmitic acid overload caused significant (p < 0.05) increases in adenosine deaminase, monoamine oxidase-A, nucleotides tri-phosphatase, 5'-nucleotidase, acetylcholine esterase, and myeloperoxidase activities, and malondialdehyde (MDA) levels which were reduced significantly in the lycopene-treated groups. Conversely, catalase and glutathione peroxidase activities, and reduced glutathione levels concentration decreased by 43%, 34%, and 12%, respectively in the PA control groups compared with the Control. Also, PA triggered a decrease in the brain phospholipids (11.43%) and cholesterol (11.11%), but increased triacylglycerol level (50%). Furthermore, upregulated expressions of Interleukin-1ß, Interleukin-6, and NF-ĸB-p65 in the PA control were attenuated, while decreased Interleukine-10 expression was upregulated due to lycopene treatment. Severe brain vacuolation observed in the histology of the PA control rats was normalized by lycopene. This study concludes that lycopene ameliorated PA-induced neuroinflammation, probably via attenuation of oxidative stress, and downregulation of TLR4/ NF-κB -p65 axis.

Lycopene abrogates obesity-provoked hyperactivity of neurosignalling enzymes, oxidative stress and hypothalamic inflammation in female Wistar rats.

Obesity, a global epidemic, has been strongly associated with impairment of brain function. Lycopene has several therapeutic properties and can cross the blood-brain barrier. However, its effects on obesity-provoked brain dysfunction remain unexplored. This study evaluated the potential remediating effects of lycopene on obesity-induced neurological derangements. Thirty-six female Wistar rats (150-200g) were distributed in six groups (n = 6); normal control, obese control, obese + lycopene (20 mg/kg), obese + lycopene (40 mg/kg), normal + lycopene (20 mg/kg), and normal + lycopene (40 mg/kg). Obesity was induced by feeding rats with the Western diet for eight weeks, while normal rats received the control diet. Afterwards, the brain was excised and processed for biochemical, gene expression analyses, and histological evaluations. Obesity-induced brain dysfunction was hallmarked by reduced brain organosomatic index, accumulation of lipids in the cerebrum, and hyperactivity of neurotransmitters-metabolizing enzymes (AChE, ADA, MAO-A, 5'-nucleotidase, and NTPdase). Also, obese rats had decreased antioxidant capacity, with increased oxidative damage, while the expressions of NF-κß p65 and pro-inflammatory cytokines (IL-1ß and IL-6) were elevated in the hypothalamus. These observations were validated by histomorphological evaluations, which showed vacuolation in the brain of obese rats. Treatment with lycopene significantly (p < 0.05) reduced the elevated lipid contents and activities of neuronal enzymes, alleviated oxidative stress and inflammation, while improving the histology of the brain, in a dose-dependent manner. Thus, lycopene abrogates obesity-provoked brain dysfunction and may present a safe and viable therapeutic option for the management of neurological perturbations associated with obesity.

A time course study on dose-response relationship between alcohol exposure and its effects on lipid profile and biomarkers of tissue damage.

This present research investigated variations in lipid profiles and important biomarkers of tissue damage in response to graded concentrations of alcohol administration in male Wistar rats. Group A (control) received distilled water while group B, C and D received 30%, 40% and 50% (v/v) alcohol respectively. Five rats each from groups A-D were sacrificed after day(s) 1, 7, 14, 21 and 28 of administration. A significant increase was observed at day 28 for serum cholesterol by 79% (group B), 78% (group C) and 47% (group D) together with serum phospholipid 58% (group B), 50% (group C) and 92% (group D). Serum triacylglycerol increased by 71% (group B), 43% (group C) and 16% (group D) at day 21, while concentration of serum albumin decreased at day 28 by 40.9% (group B), 50.2% (group C), 53.3% (group D) respectively when compared with control (group A). Serum aminotransferases and alkaline phosphatase specific activities, as well as creatinine and uric acid concentration increased in a concentration-dependent manner, following alcohol administration. Though most of these effects induced by alcohol were time- and concentration-dependent, 40% alcohol appear to be more stable, giving results consistent with alcohol-induced damages, with minimal mortality. This study therefore further validated dyslipidemia and imbalance in clinical biomarkers as hallmarks of tissue damage induced by excessive alcohol consumption with an insight on the time- and concentration-response relationship between alcohol consumption and its toxicity.

Sub-acute exposure to Sudan IV-adulterated palm oil induces oxidative stress and represses the expression of Nrf2 and antioxidant genes in male albino rats.

This study investigated the effects of Sudan IV dye (S4D) on antioxidant biomarkers using palm oil adulterated with S4D. Thirty male albino rats were grouped into five (n = 6); Normal control, palm oil (PO), PO + S4D (100 mg/kg), PO + S4D (250 mg/kg), and S4D (250 mg/kg) for 21 days. Oxidative stress biomarkers were assessed in the serum, liver, and kidneys. Exposure to S4D (alone and in adulterated PO) occasioned significant depletions in the activities of SOD, CAT, and GPx, as well as GSH levels in the assessed compartments. Contrastingly, the levels of NO and MDA were significantly (p < 0.05) increased in the serum, liver, and kidney of rats exposed to PO + S4D (both doses) and S4D (250 mg/kg) when compared to control rats. Further, the expressions of the genes coding for CAT, GPx-1, GSR, and Nrf-2 were significantly (p < 0.05) down-regulated, relative to ß-actin, in groups exposed to S4D compared to the control. Interestingly, these parameters were not significantly different (p > 0.05) in the unadulterated PO-exposed rats compared to the control. These results show that S4D depleted the antioxidant capacities, while potentiating the generation of reactive species and oxidative damage. This study provides useful information on the oxidative mechanisms associated with consumption of S4D-containing consumer products.

Probiotics consortium synergistically ameliorates aflatoxin B1-induced disruptions in lipid metabolism of female albino rats.

To investigate the effects of oral administration of probiotics consortium on lipid metabolism in aflatoxin B1 (AFB1) exposed rats, ninety female albino rats were first grouped into two: NC (control fed standard feed) and AF (fed AFB1-contaminated feed at 40 ppb). After eight weeks, baseline animals were sacrificed from both groups while the others further divided into four groups - NC treated with and without the probiotics consortium, aflatoxin treated with and without the probiotics consortium (NCT, NCC, AFT, and AFC respectively). Five animals from each group were sacrificed weekly for four weeks, with the collection of blood, liver, brain, and the small intestine. Administration of probiotics instigated significant (p < 0.05) reductions in the elevated plasma and organ lipids as well as HDL-TAG and VLDL + LDL CHO concentrations of animals exposed to AF. AF-induced hepatic lipogenesis and up-regulation of 3-hydroxy-3-methylglutaryl-CoA reductase activity were also significantly (p < 0.05) attenuated following treatment with probiotics in a time-dependent manner. Moreover, neither AF nor probiotics had any effect on glycerol-3-phosphate acyltransferase. Lipid peroxidation was significantly (p < 0.05) reduced in probiotics-treated AF groups, compared to the AF-control groups. This study indicates that the probiotic consortium used synergistically ameliorated the AFB1-induced disruptions in lipid metabolism.