Utility of zebrafish-based models in understanding molecular mechanisms of neurotoxicity mediated by the gut-brain axis.

The gut microbes perform several beneficial functions which impact the periphery and central nervous systems of the host. Gut microbiota dysbiosis is acknowledged as a major contributor to the development of several neuropsychiatric and neurological disorders including bipolar disorder, depression, anxiety, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, and autism spectrum disorder. Thus, elucidation of how the gut microbiota-brain axis plays a role in health and disease conditions is a potential novel approach to prevent and treat brain disorders. The zebrafish (Danio rerio) is an invaluable vertebrate model that possesses conserved brain and intestinal features with those of humans, thus making zebrafish a valued model to investigate the interplay between the gut microbiota and host health. This chapter describes current findings on the utility of zebrafish in understanding molecular mechanisms of neurotoxicity mediated via the gut microbiota-brain axis. Specifically, it highlights the utility of zebrafish as a model organism for understanding how anthropogenic chemicals, pharmaceuticals and bacteria exposure affect animals and human health via the gut-brain axis.

Ferulic acid interventions ameliorate NDEA-CCl4-induced hepatocellular carcinoma via Nrf2 and p53 upregulation and Akt/PKB-NF-κB-TNF-α pathway downregulation in male Wistar rats.

Hepatocellular carcinoma is a prevalent form of liver cancer that is life threatening. Many chemically synthesized anti-cancer drugs have various degrees of side effects. Hence, this study investigated the effect of FEAC interventions on NDEA-CCl4-induced HCAR in male Wistar rats. HCAR was induced by intraperitoneal administration of 200 mg/kg of NDEA and 0.5 mL/kg CCl4 (as a promoter of HCAR). Following the induction of HCAR, rats were treated differently with two different doses (25 and 50 mg/kg) of FEAC. HCAR induction was confirmed by the significant elevation of serum levels of ALT, AST, and α-FP. Also elevated significantly were liver levels of Akt/PKB, NF-κB, TNF-α, MDA, GSH, and activities of GST, SOD, and CAT, while levels of liver p53 and Nrf2 were significantly lowered compared with normal rats. Treatment interventions with both 25 and 50 mg/kg of FEAC against the DEN-CCl4-induced HCAR gave comparable effects, marked by a significant reduction in the levels of serum ALT, AST and α-FP, as well as liver levels of MDA, GSH, Akt/PKB, NF-κB, TNF-α, GST, SOD, and CAT, while levels of liver p53 and Nrf2 were significantly elevated compared with normal rats. Put together and judging by the outcomes of this study, FEAC being a potent antioxidant may also be potent against chemical-induced HCAR via upregulation of p53 and Nrf2, as well as downregulation of the Akt/PKB-NF-κB pathway in rats.

Kolaviron modulates angiogenesis, apoptosis and inflammatory signaling in rat model of testosterone propionate-induced benign prostate hyperplasia.

Benign prostatic hyperplasia (BPH) is a non-malignant disease of the prostate characterized by uncontrolled proliferation of the prostate gland. Inflammation and oxidative stress have been reported to play a role in the development of BPH. Kolaviron, a bioflavonoid complex of Garcinia kola seed, has been shown to possess anti-inflammatory effect. In this study, we investigated the effect of Kolaviron on testosterone propionate (TP)-induced BPH in rats. Fifty male rats were assigned in 5 groups. Groups 1 and 2 were orally exposed to corn oil (2 ml/kg) and Kolaviron (200 mg/kg/day, p.o) for 28 days. Group 3 rats received TP (3 mg/kg/day, s.c) for 14 days while Groups 4 and 6 were treated with Kolaviron (200 mg/kg/day, p.o) and Finasteride (5 mg/kg/day, p.o), respectively, for 14 days prior to TP (3 mg/kg, s.c) co-exposure for the remaining 14 days. Administration of Kolaviron to TP-treated rats reverted histological alteration and significantly decreased prostate weight, prostate index, 5α-reductase, dihydrotestosterone, androgen receptor expression, tumor necrosis factor α, interleukin-1ß, cyclooxygenase-2, prostaglandin E2, 5-lipoxygenase leukotriene B4, inducible nitric oxide synthase and nitric oxide concentration. In addition, Kolaviron alleviated TP-induced oxidative stress and reduced the expression of Ki-67, VEGF, and FGF to almost control levels. Furthermore, Kolaviron promoted apoptosis in TP-treated rats through downregulation of BCL-2 and upregulation of P53 and Caspase 3 expressions. Overall, Kolaviron prevented BPH via regulation of androgen/androgen receptor signaling, anti-oxidative and anti-inflammatory mechanisms.

Syringic acid demonstrates better anti-apoptotic, anti-inflammatory and antioxidative effects than ascorbic acid via maintenance of the endogenous antioxidants and downregulation of pro-inflammatory and apoptotic markers in DMN-induced hepatotoxicity in rats.

Dimethyl nitrosamine (DMN) is a known hepatotoxin, carcinogen, and mutagen. This study is therefore carried out to investigate the therapeutic effects of syringic acid (SYRA) and ascorbic acid (ASCA) in DMN-induced hepatic injury in rats. Following DMN administrations, malondialdehyde (MDA), nitric oxide (NO) and reduced glutathione (GSH) as well as activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) were significantly increased. Also significantly increased were levels of tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Following treatment with SYRA and ASCA, the activities of ALT, AST, GPx, CAT and SOD, as well as MDA, GSH, TNF-α, IL-1ß, and NFkB levels were significantly reduced. Overall, both treatments were effective, but SYRA had a better therapeutic effect than ASCA. Therefore, this promising potential of SYRA can be taken advantage of in the treatment of DMN-induced hepatic injury.

6- shogaol suppresses AOM/DSS-mediated colorectal adenoma through its antioxidant and anti-inflammatory effects in mice.

Colorectal adenoma appears as benign lesions and is a precursor of colorectal adenocarcinoma. The effect of 6-Shogaol (6-[S]), a bioactive agent from ginger, in early colonic adenoma growth is unknown. As a result, this study examines the effect of 6-[S] in a mouse colorectal adenoma model induced by Azoxymethane (AOM) and dextran sulfate sodium (DSS). Adult male mice served as control in Group 1. Group 2 was treated orally with 6-[S] extract (20 mg/kg BW). Group 3 was exposed to AOM (25 mg/kg BW, ip) and one cycle of DSS (2.5%) in drinking water alone while Group 4 was co-treated with 6-[S] for twenty-one (21) days. The body weight gain, organ weight and length, oxidative stress indices, inflammatory markers and histological examination were estimated. Our findings show that 6-[S] co-treatment reversed AOM/DSS-induced elevation in colon weight, colon length, nitric oxide (NO), myeloperoxidase (MPO), hydrogen peroxidase (H2 O2 ), and tumor necrosis factor-alpha (TNF-α). However, the antioxidant enzyme activities measured namely catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), and glutathione-S-transferase were significantly increased in 6-[S] treated mice. Taken together, the protective effect of 6-[S] on oxidative burden, inflammation, and histological aberration observed in the colon of the AOM/DSS model of adenoma growth in mice is mediated primarily owing to its anti-inflammatory and anti-oxidative properties. Thus, this study reveals 6-[S] as a useful agent in the possible clinical intervention of colorectal adenoma. PRACTICAL APPLICATIONS: Certain spices have been reported to have numerous phytochemicals with numerous medicinal purposes. However, no studies have been conducted to investigate the role of 6-[S], a phytochemical found in ginger, in the treatment of colorectal adenoma. The study's findings show that 6-[S] is protective in early colonic cancer development, as it manages colorectal adenoma cancer models of AOM/DSS. As a result, 6-[S]'s ability to reduce oxidative stress and inflammation in the colon may be a potential nutritional therapeutic adjuvant for colorectal adenoma.

Naja nigricollis venom altered reproductive and neurological functions via modulation of pro-inflammatory cytokines and oxidative damage in male rats.

Reproductive and neurological anomalies are often characterized by malfunctioning of reproductive and nervous organs sometimes attributed to systemic toxins. However, limited information is available on the impact of snake venom toxins on male reproductive and nervous system. This study investigated the toxicological effects of Naja nigricollis venom on male reproductive and neural functions in rat model. Twenty male Wistar rats weighing between 195 and 230 g were divided randomly into two groups of ten rats each. Group 1 served as normal control while rats in group 2 were envenomed with a single intraperitoneal injection of 0.25 mg/kg-1 (LD12.5) of N. nigricollis venom on first and twenty fifth day within the period of fifty days experiment. The venom significantly decreased sperm counts, motile cells and volume combined with increased sperm abnormalities. The venom induced hormonal imbalances in the envenomed group as levels of testosterone, luteinizing and follicle stimulating hormones depreciated compared to the control. Oxidative stress biomarkers: malondialdehyde significantly increased parallels with depletion of glutathione level and catalase activities in testis, epididymis and brain of envenomed rats. Furthermore, N. nigricollis venom up-regulated tumor necrosis factor-alpha (TNF-α) and interleukin1-beta (IL-1ß) production in testis, epididymis and brain of envenomed rats compared to the control. Also, various histological alterations were noticed in tissues of testis, epididymis and brain of envenomed rats. Findings indicated that N. nigricollis venom is capable of inducing reproductive and neurological dysfunction in envenomed victims.

Syringic and ascorbic acids prevent NDMA-induced pulmonary fibrogenesis, inflammation, apoptosis, and oxidative stress through the regulation of PI3K-Akt/PKB-mTOR-PTEN signaling pathway.

Idiopathic lung fibrosis (ILF) is a severe and life threatening lung disorder that is characterized by scarring of lung tissue, leading to thickening and stiffening of affected areas. This study looked at the role played by PI3K-Akt/PKB-mToR signaling pathway in the pathogenesis of N-Nitrosodimethylamine (NDMA)-induced lung fibrotic injury, and the effects of syringic acid (SYR) and ascorbic acid (ASC) treatments in male Wistar rats. Pulmonary fibrosis was induced by intraperitoneal injection of 10 mg/kg NDMA once daily, thrice (consecutively) a week for four weeks, and this condition was treated daily with SYR (50 mg/kg) and ASC (100 mg/kg) acids orally for four weeks. Fibrogenesis, following NDMA administration was marked by a significant increase in collagen-1 and α-SMA levels, while oxidative stress was marked by a significant decrease in GSH level, GST, GPx, CAT, and SOD activities. Also, NDMA significantly increased lung Bax, p53, caspase-3, TNF-α, IL-1ß, NFkB, and decreased Bcl-2, mdm2, cyclin D1 and Nrf-2 levels. Looking at the PI3K-Akt-mTOR signaling pathway, NDMA administration significantly activated lung PI3K, Akt, and mTOR, and deactivated PTEN, FoxO1 and TSC2. Treatments with SYR and ASC significantly reduced oxidative stress by restoring the antioxidant systems via Nrf2 activation, decreased the levels of inflammatory markers through inhibition of NFkB, downregulated p53, Bax, and caspase-3 via up-regulation of mdm2 and cyclin D1. SYR and ASC also regulated the PI3K-Akt-mTOR signaling pathway via the deactivation of PI3K, Akt, and mTOR, and up-regulation of PTEN, FoxO1 and TSC2. Overall, SYR and ASC modulate the PI3K-Akt-mTOR signaling pathway via inhibition of oxidative stress, inflammation and apoptosis in NDMA-induced lung fibrosis.

Sodium benzoate induces neurobehavioral deficits and brain oxido-inflammatory stress in male Wistar rats: Ameliorative role of ascorbic acid.

BACKGROUND: Sodium benzoate (SB) is a widely used food preservative. However, excessive intake of a high dose of SB poses a risk of neurotoxicity. Ascorbic acid (AA) is a naturally occurring antioxidant found in fruits with reported neuroprotective properties. The present study investigated the neurobehavioral and biochemical alterations in SB-treated rats and the ameliorative effect of AA in rats. METHODS: Forty-two male Wistar rats were divided into six groups (n = 7). Group 1 (vehicle, 10 ml/kg), Groups 2-4 rats SB (150, 300, and 600 mg/kg), Group 5 AA (100 mg/kg) and Group 6 (SB 600 mg/kg + AA 100 mg/kg). Treatment was daily administered for 28 days by oral route. Anxiogenic behavior, locomotor, and exploratory activities were evaluated in the open field monitored with a camera, and memory performance in Y-maze. Brain oxidative stress, inflammatory, apoptosis, and cholinergic markers were determined. The cortico-hippocampal tissues were examined histologically. RESULTS: SB-treated rats showed significant anxiogenic-like behavior and impairment in locomotor, exploratory, and memory performance. This was reversed in SB (600 mg/kg)-treated rats coadministered with AA. SB-treated rats showed a decrease in antioxidant enzyme activities, increase malondialdehyde (MDA), nitrite, tumor necrosis factor-alpha, caspase-3, and acetylcholinesterase activity in the striatum, hippocampus, frontal cortex, and cerebellum. These biochemical changes were reversed in AA-treated rats. Reduced cortico-hippocampal neuronal cell count and the pyknotic index were found in SB-treated rats, which was also reversed in AA-treated rats. CONCLUSION: Conclusively, sodium-benzoate-induced neurobehavioral deficits and brain biochemical changes were ameliorated by ascorbic acid probably via antioxidant, anti-inflammatory, and apoptotic mechanisms.

Moringa oleifera leaf fractions attenuated Naje haje venom-induced cellular dysfunctions via modulation of Nrf2 and inflammatory signalling pathways in rats.

Naja haje envenoming could activate multiple pathways linked to haematotoxic, neurological, and antioxidant systems dysfunctions. Moringa oleifera has been used in the management of different snake venom-induced toxicities, but there is no scientific information on its antivenom effects against Naja haje. This study thus, investigated the antivenom activities of different extract partitions of M. oleifera leaves against N. haje envenoming. Forty five male rats were divided into nine groups (n = 5). Groups 2 to 9 were envenomed with 0.025 mg/kg (LD50) of N . haje venom while group 1 was given saline. Group 2 was left untreated, while group 3 was treated with polyvalent antivenom, groups 4, 6 and 8 were treated with 300 mg/kg-1 of N-hexane, ethylacetate and ethanol partitions of M. oleifera, respectively. Groups 5, 7 and 9 were also treated with 600 mgkg-1of the partitions, respectively. Ethanol extract and ethyl acetate partition of M. oleifera significantly improved haematological indices following acute anaemia induced by the venom. Likewise, haemorrhagic, haemolytic and anti-coagulant activities of N. haje venom were best inhibited by ethanol partition. Envenoming significantly down-regulated Nuclear factor erythroid 2-related factor 2 (Nrf2) with the consequent elevation of antioxidant enzymes activities in the serum and brain. Treatment with extract partitions however, elevated Nrf2 levels while normalising antioxidant enzyme activities. Furthermore, there were reduction in levels of pro-inflammatory cytokines (TNF-α and interleukin-1ß) in tissues of treated envenomed rats. This study concludes that ethanol partition of M. oleifera was most effective against N. haje venom and could be considered as a potential source for antivenom metabolites.

Oxidative stress-mediated induction of pulmonary oncogenes, inflammatory, and apoptotic markers following time-course exposure to ethylene glycol monomethyl ether in rats.

Ethylene glycol monomethyl ether (EGME) has been used in many products usually handled by humans including inks, paints, polishes, brake fluids and so on. This present study therefore, investigated its effect on lung, in a time-course study in male Wistar rats. Animals were orally administered 50 mg/kg body weight of EGME for a period of 7, 14, and 21 days. Following 7 days of oral exposure to EGME, activities of GPx and SOD were significantly increased, as well as levels of K-Ras, c-Myc, p53, caspase-3, TNF-α and, IL-6, while NO level and GST activity were significantly reduced compared with control. At the end of 14 days exposure, GSH level was significantly decreased, while levels of K-Ras, c-Myc, p53, caspase-3, TNF-α, IL-6, NO and the activities of SOD and GPx were significantly elevated with respect to control. After 21 days of EGME administration, levels of Bcl-2, IL-10, GSH and NO as well as GST activity were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, IL-6, IL-1ß, TNF-α, as well as GPx, CAT, and SOD activities were significantly elevated compared with control. Lung histopathology revealed chronic disseminated alveolar inflammation, bronchiolitis, severe alveolar and bronchi hyperplasia, severe disseminated inflammation, thrombosis, and thickened vessels as a result of EGME exposures. Exposures to EGME could trigger lung damage via the disorganization of the antioxidant system, eliciting the up-regulation of inflammatory, apoptotic, and oncogenic markers in rats.

Toxicological outcome of exposure to psychoactive drugs carbamazepine and diazepam on non-target insect Nauphoeta cinerea.

The continuous detection of human pharmaceuticals during environmental biomonitoring is a global concern because of the menaces they may exert on non-target organisms. Carbamazepine (CBZ) and diazepam (DZP) are commonly prescribed psychotropic drugs which have been reported to coexist in the environment globally. Nauphoeta cinerea is a common insect with high ecological impact. This study elucidated the influence of co-exposure to DZP (0.5 and 1.0 µg kg-1 diet) and CBZ (1.5 and 3.0 µg kg-1 diet) for 42 days on the behavior and biochemical responses in Nauphoeta cinerea. Results showed that DZP alone did not induce adverse effect on the behavior and antioxidant status in the exposed insects. However, exposure to CBZ alone and binary mixtures of DZP and CBZ significantly decreased locomotor and exploratory accomplishments evidenced by decreased mobile episodes, total mobile time, maximum speed, total distance traveled, absolute turn angle, body rotation and path efficiency in comparison with control. The decline observed in the exploratory activities of insects fed with CBZ alone and the mixtures was confirmed by track plots and heat maps. Further, acetylcholinesterase and antioxidant enzyme activities decreased significantly whereas reactive oxygen and nitrogen species, nitric oxide and lipid peroxidation levels increased significantly in the hemolymph, head and midgut of insects exposed to CBZ alone and the mixtures. Collectively, CBZ alone and binary mixtures of CBZ and DZP caused neurotoxicity via induction of inflammatory and oxidative stress in insects. Nauphoeta cinerea may be a potential non-target insect model for monitoring ecotoxicological hazard of pharmaceuticals.

Hepatic oxidative stress, up-regulation of pro-inflammatory cytokines, apoptotic and oncogenic markers following 2-methoxyethanol administrations in rats.

2-methoxyethanol (2-ME) is an organic solvent widely used in the manufacture of brake fluids, paints, resins, varnish, nail polish, acetate cellulose, wood coloring, and as a plasticizer in plastics manufacturing. We therefore, investigated its effect on the liver, in a time-course study in male Wistar rats. Animals were orally administered 50 mg/kg body weight of 2-ME for a period of 7, 14, and 21 days. Following 7 days of administration of 2-ME, there was a significant increase in the level of Bax, c-Myc, K-Ras, TNF-α, IL-1ß, IL-6, MDA and GPx activity, while the levels of Bcl-2, NO and GSH were significantly reduced compared with control. At the end of 14 days exposure, Bcl-2, and GSH levels, as well as GST activity, were significantly decreased, while levels of Bax, c-Myc, K-Ras, caspase-3, TNF-α, IL-1ß, IL-6, MDA and NO were significantly increased compared with control. After 21 days of 2-ME administration, Bcl-2, IL-10, and GSH levels, as well as SOD and GST activities, were significantly decreased, while levels of Bax, c-Myc, K-Ras, caspase-3, p53, TNF-α, IL-1ß, IL-6, MDA and NO were significantly increased compared with control. Lastly, liver histopathology confirmed and corroborated the biochemical findings reported above. We therefore, advised that exposures to 2-ME should be strictly avoided as it could trigger hepatic damage through the disorganization of the antioxidant system, up-regulation of inflammatory, apoptotic, and oncogenic markers in rats.

Ethylene glycol monomethyl ether-induced testicular oxidative stress and time-dependent up-regulation of apoptotic, pro-inflammatory, and oncogenic markers in rats.

Ethylene glycol monomethyl ether (EGME) is a major component of paints, lacquers, inks, and automobile brake fluids. As a result, exposures to humans are inevitable. We therefore, investigated in this study, its effect on testicular cells in a time-course manner in male Wistar rats. Animals were orally administered 50 mg/kg body weight of EGME for duration of 7, 14, and 21 days. Following 7 days of the administration, levels of NO and GSH were significantly reduced, while levels of c-Myc, K-Ras, caspase-3, IL-6, TNF-α, and IL-1ß were significantly increased compared with control. At the end of 14 days exposure, GPx, and SOD activities, as well as IL-10 level were significantly decreased, while levels of c-Myc, K-Ras, p53, Bax, caspase-3, IL-6, TNF-α, IL-1ß, and GST activity were significantly elevated compared with control. After 21 days of EGME administration, Bcl-2, IL-10, and NO levels were significantly decreased, while levels of c-Myc, K-Ras, p53, Bax, caspase-3, IL-6, TNF-α, IL-1ß, MDA and GST activity were significantly increased compared with control. After 7, 14, and 21 days of EGME administrations, testis histopathology showed severe loss of seminiferous tubules, the seminiferous epithelium revealed very few spermatocytes, spermatids, spermatogonia, spermatozoa, and Sertoli cells, while the interstitial tissue is eroded, with scanty abnormal Leydig cells, compared with the control that appeared normal. We therefore, concluded that EGME-induced testicular toxicity as a result of EGME administration could be via the disorganization of the endogenous antioxidant systems as well as up-regulation of pro-inflammatory, apoptotic and oncogenic mediators in rats.

Hazardous impact of diclofenac exposure on the behavior and antioxidant defense system in Nauphoeta cinerea.

Environmental pollution by pharmaceuticals such as diclofenac (DCF) is globally acknowledged to be a threat to the ecosystems. Nauphoeta cinerea is an important insect with valuable ecological role. The present investigation aimed to elucidate the impact of DCF on insects by assessing the behavior and antioxidant defense response in nymphs of N. cinerea exposed to DCF-contaminated food at 0, 0.5, 1.0 and 2.0 µg kg-1 feed for 42 successive days. Subsequent to exposure period, neurobehavioral analysis using video-tracking software in a novel apparatus was performed before estimation of biochemical endpoints in the head, midgut and hemolymph of the insects. Results indicated that DCF-exposed insects exhibited marked reduction in the maximum speed, total distance traveled, mobile episodes, total mobile time, body rotation, absolute turn angle and path efficiency, whereas the total freezing time was increased compared with the control. The diminution in the exploratory activities of DCF-exposed insects was substantiated by heat maps and track plots. Additionally, DCF elicited marked diminution in antioxidant enzyme and acetylcholinesterase (AChE) activities along with increase in nitric oxide (NO), reactive oxygen and nitrogen species (RONS), and lipid peroxidation (LPO) levels in the head, midgut and hemolymph of the insects. Taken together, DCF elicited neurotoxicity and oxido-inflammatory stress in exposed insects. N. cinerea may be a suitable model insect for environmental risk assessment of pharmaceuticals in non-target insect species.

Methyl cellosolve-induced renal oxidative stress and time-dependent up-regulation of pro-inflammatory cytokines, apoptotic, and oncogenic markers in rats.

Methyl cellosolve (MC) is used in production of textile, paints, stains, inks, surface coatings, and anti-icing additive in hydraulic fluids and jet fuel. Consequently, the present study investigated its effect on renal cells, in a time-course study in male Wistar rats. Animals were orally administered 50 mg/kg body weight of MC for a period of 7, 14, and 21 days. Following 7 days of administration of MC, there was a significant increase in the levels of K-Ras, c-Myc, TNF-α, IL-6 and NO, while GSH level and SOD activity were significantly reduced compared with control. At the end of 14 days exposure, RKW, GSH, NO, and Bcl-2 levels were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, TNF-α, IL-1ß, IL-6, MDA and GPx activity were significantly increased compared with control. After 21 days of MC administration, RKW, GSH, NO, IL-10 and Bcl-2 levels were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, TNF-α, IL-1ß, IL-6, MDA and GST activity were significantly increased compared with control. Exposures to MC in any way should be strictly avoided as it could trigger renal damage through the disorganization of the antioxidant system, up-regulation of inflammatory, apoptotic, and oncogenic markers in rats.

6-Gingerol delays tumorigenesis in benzo[a]pyrene and dextran sulphate sodium-induced colorectal cancer in mice.

Colorectal cancer (CRC) has been linked to dietary consumption of benzo[a]pyrene (B[a]P). 6-Gingerol (6-G), a component of ginger has been reported to possess anti-inflammatory and antioxidant activities, but little is known regarding the mechanism of 6-G in CRC chemoprevention. We therefore investigated the effect of 6-G on B[a]P. and dextran sulphate sodium (DSS) induced CRC in mice. Mice in Group I and Group II received corn oil and 6-G orally at 2 ml/kg and 100 mg/kg, respectively for 126 days. Group III were administered 125 mg/kg of B[a]P for 5 days followed by 3 cycles of 4% dextran sulphate sodium (DSS). Group IV received 6-G for 7 days followed by co-administration with 125 mg/kg of B[a]P. for 5 days and 3 cycles of 4% DSS. Tumor formation was reduced and expression of Ki-67, WNT3a, DVL-2 and ß-catenin following 6-G exposure. Also, 6-G increases expression of APC, P53, TUNEL positive nuclei and subsequently decreased the expression of TNF-α, IL-1ß, INOS, COX-2 and cyclin D1. 6-G inhibited angiogenesis by decreasing the concentration of VEGF, Angiopoietin-1, FGF and GDF-15 in the colon of B[a]P. and DSS exposed mice. Overall, 6-G attenuated B[a]P and DSS-induced CRC in mice via anti-inflammatory, anti-proliferative and apoptotic mechanisms.

Neuroprotective mechanisms of selenium against arsenic-induced behavioral impairments in rats.

Environmental pollution due to arsenic is associated with several adverse health effects including neurotoxicity in animals and humans. Selenium is a nutritionally essential trace metalloid well documented to elicit compelling pharmacological activities in vitro and in vivo. Report on the influence of selenium on arsenic-mediated behavioral derangement is lacking in literature. Hence, to fill this knowledge gap, rats were either exposed to arsenic per se in drinking water at 60 µg AsO2Na/L or co-administered with inorganic selenium at 0.25 mg/kg or organic selenium diphenyl diselenide (DPDS) at 2.5 mg/kg body weight for 45 successive days. Neurobehavioural data from rats in a new environment using video-tracking software evinced that inorganic and organic forms of selenium significantly (p < 0.05) abrogated arsenic-induced motor and locomotor insufficiencies such as increased negative geotaxis and fecal pellets numbers as well as the diminution in grip strength, body rotation, maximum speed, absolute turn angle and total distance travelled. The augmentation in the behavioral activities in rats co-administered with arsenic and both forms of selenium was substantiated using track and occupancy plots analyses. Selenium mitigated arsenic-induced decreases in glutathione level and acetylcholinesterase activity as well as the increase in oxidative stress and reactive oxygen and nitrogen species. Moreover, selenium diminished inflammatory parameters (myeloperoxidase activity, nitric oxide, tumour necrosis factor alpha and interleukin-1 beta levels), caspase-3 activity and ameliorated histological lesions in the cerebellum, cerebrum and liver of the rats. Collectively, selenium abated arsenic-induced behavioral derangements via anti-inflammation, antioxidant and anti-apoptotic mechanisms in rats.

Renal and testicular up-regulation of pro-inflammatory chemokines (RANTES and CCL2) and cytokines (TNF-α, IL-1ß, IL-6) following acute edible camphor administration is through activation of NF-kB in rats.

Camphor-induced oxidative stress and histopathological changes (in brain, lung, liver, kidney and testes) have been reported. We therefore investigated the effect of various doses of camphor in an acute study, on renal and testicular levels of some pro-inflammatory mediators in male wistar rats. Twenty rats divided into four groups of five rats each were used in this study. Group 1 served as control and was administered 6 mL/kg olive oil, the vehicle for camphor, while groups 2, 3 and 4 were orally administered 1000, 2000, and 4000 mg/kg body weight camphor, for seven days. Compared with control, levels of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß) and interleukin 6 (IL-6) were significantly increased kidney and testes by 2000 and 4000 mg/kg body weight, while interleukin 10 (IL-10) was only significantly increased by 1000 mg/kg body weight of camphor in both tissues. Also compared with control, all doses of camphor administered resulted in a significant increase in the expressions of renal and testicular nuclear factor kappa B (NFkB), cyclooxygenase 2 (COX-2), regulated upon activation normal T cell expressed and secreted (RANTES), and monocyte chemo-attractant protein 1 (MCP-1). Conclusively, use and consumption of camphor should be with caution as it could trigger renal and testicular inflammation through activation of NF-kB and up-regulation of pro-inflammatory markers.

Camphor elicits up-regulation of hepatic and pulmonary pro-inflammatory cytokines and chemokines via activation of NF-kB in rats.

Consumption of camphor infusions is widely used as an aphrodisiac in preparation for sexual intercourse, to boost performance. There is dearth of information associating or relating its consumption to liver or lung inflammation. Therefore, we investigated the effect of various doses of camphor in an acute study, on hepatic and pulmonary levels of some pro-inflammatory cytokines and chemokines in male wistar rats. Following administration, 2000 and 4000 mg/kg body weight camphor significantly increase liver and lung levels of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß) and interleukin 6 (IL-6) in a dose dependent manner compared with control, while interleukin 10 (IL-10) levels were significantly increased only by 1000 and 4000 mg/kg body weight camphor in liver and lung respectively, compared with control. Also compared with control, camphor administration resulted in a significant increase in the expressions of hepatic and pulmonary nuclear factor kappa B (NFkB), cyclooxygenase 2 (COX-2), regulated upon activation normal T cell expressed and secreted (RANTES) or CCL5, and monocyte chemo-attractant protein 1 (MCP-1) in a dose dependent manner. It is therefore advised that the use and consumption of camphor should be with caution as it could trigger liver and lung inflammation via activation of NF-kB and up-regulation of pro-inflammatory mediators.

6-Gingerol abates benzo[a]pyrene-induced colonic injury via suppression of oxido-inflammatory stress responses in BALB/c mice.

Exposure to benzo[a]pyrene (BaP), the most toxic polycyclic aromatic hydrocarbon and a procarcinogen, is a global health concern which necessitates preventive measures. [6]-Gingerol (6-G), the most pharmacologically active constituent of ginger has been reported to promote gut health in various experimental settings. This study investigated the role of 6-G in BaP-induced colonic oxidative and inflammatory stress responses in mice. Experimental mice were randomly assigned into five groups of eight mice each and were orally gavage with BaP (125 mg/kg) singly or in combination with 6-G at 50 and 100 mg/kg for 14 consecutive days. Following sacrifice, the colonic activities of superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), myeloperoxidase (MPO) as well as levels of glutathione (GSH), nitrites and lipid peroxidation (LPO) were assessed spectrophotometrically. Moreover, colonic concentration of epoxide hydrolase (EPXH), tumor necrosis factor alpha (TNF-α), interleukin-1 ß (IL-1ß), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were assessed using ELISA. Administration of 6-G augmented BaP detoxification and colonic antioxidant status by increasing the EPXH, GST, SOD and CAT activities, GSH level with concomitant decrease in MDA level when compared with BaP alone group. In addition, 6-G suppressed BaP-induced colonic inflammation by decreasing MPO activity as well as nitrites, TNF-α, IL-1ß, COX-2 and iNOS levels when compared with BaP alone group. In conclusion, 6-G protected against a decrease in colonic epoxide detoxifying enzymes and antioxidant defense mechanisms caused by BaP.