PRE-084 ameliorates adenine-induced renal fibrosis in rats.

2-(4-morpholinoethyl)- 1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084) is a selective sigma 1 receptor agonist. It has been shown that PRE-084 protected various tissues from experimental injury. However, no reports are available on its effect on renal fibrosis. Rat model of adenine-induced chronic kidney disease was chosen to study this. Adenine feeding in rats caused renal dysfunction as shown by increased serum creatinine and reduced creatinine clearance along with increased high molecular weight (HMW) urine protein excretion. Further, adenine feeding induced profibrotic changes in the kidney as reflected by increased expression of alpha-smooth muscle actin (α-SMA), fibroblast specific protein-1 (FSP-1) and matrix metalloproteinase-2 (MMP-2) activity; reduced cytokeratin expression. Further, there was excess deposition of extracellular matrix in the kidney, a striking character of fibrosis. However, administration of PRE-084 to adenine fed rats led to reduction in creatinine and proteinuria parameters partly. This was accompanied by reduced expression of α-SMA, FSP-1 and MMP-2 activity and slight restoration of cytokeratin levels leading to reduced extracellular matrix deposition in the kidney. These data demonstrate that PRE-084 partly ameliorated renal dysfunction and exhibited anti-fibrotic potential in the kidney of adenine fed rats.

Fermentability of select polyphenol-rich substrates in the canine faecal inoculum and their interaction with a canine-origin probiotic: an in vitro appraisal.

BACKGROUND: This in vitro study aimed to compare the hindgut fermentability and digestibility of four different sources of polyphenols, namely orange (Citrus sinensis) peel (ORP), pomegranate (Punica granatum) peel (PMP), Indian blackberry (Syzygium cumini) pulp (IBP), and Jerusalem artichoke (Helianthus tuberosus) tuber (JAT), and their influence on the viability of a canine-origin probiotic, Lactobacillus johnsonii CPN23. RESULTS: An in vitro gas production test carried out using the four substrates for a period of 72 h with dog faecal inoculum indicated that the total gas production, dry matter, and organic matter digestibility were significantly (P < 0.001) higher with JAT, whereas they were lowest for PMP. Short-chain fatty acids production was significantly higher (P < 0.001) with ORP and JAT, with the least values recorded for PMP. The ammonia-nitrogen production was significantly (P < 0.001) higher with JAT than with ORP, IBP, and PMP, and a lower (P < 0.001) pH was evident with ORP, JAT, and IBP than with PMP. Viability of L. johnsonii CPN23 was tested in the presence of the polyphenol-rich extract from each of the four sources at varying doses (50, 500, 1000, 2500, and 5000 µg mL-1 ). PMP extract showed the highest inhibitory effect on the probiotic bacteria's growth in a dose- and time-dependent manner (P < 0.001). ORP and IBP extracts were stimulatory at the optimum dosage, whereas JAT reduced probiotic activity significantly at all doses tested. CONCLUSION: Overall, the results indicate a higher hindgut fermentability of JAT, ORP, and IBP, suggesting their potential beneficial effects for gut health application. An interaction study between polyphenol extract and L. johnsonii CPN23 showed a stimulatory effect of polyphenolic extracts from ORP and IBP on probiotic growth at optimal dosage. Consistent with the fermentation study findings, PMP extract reduced the growth of L. johnsonii CPN23 irrespective of the doses tested. © 2021 Society of Chemical Industry.

An appraisal of the gut health modulatory effects of a calf faecal-origin probiotic Lactobacillus salivarius CPN60 using Wistar rats with dextran sulfate sodium-induced colitis.

BACKGROUND: Probiotics of varied origins are being developed for augmenting the gut health of human and animals. The present study aimed to evaluate the effect of a calf-origin probiotic supplement on the gut health of Wistar rats for both healthy and colitis conditions. RESULTS: Forty-eight rats were randomly distributed into four equal groups. The 42-day study involved feeding basal diet alone (CON) or diet supplemented with the calf-origin Lactobacillus salivarius strain CPN60 (PRO). The third (CONc) and fourth (PROc) groups of rats also received the same dietary treatments (CON and PRO, respectively) but were subjected to dextran sulfate sodium (DSS)-induced colitis after 32 days of feeding. The results of a digestion trial conducted after 5 days of DSS administration revealed no influence of probiotic on the digestibility of nutrients. However, the reduced digestibility of protein and fat seen in the CONc rats was improved in the PROc group. The concentrations of lactate and acetate, propionate and butyrate, as well as total short-chain fatty acids (SCFA), were increased (P < 0.05) in the caecal and colonic digesta upon probiotic supplementation, together with significantly reduced colonic ammonia levels. Furthermore, there were reductions (P < 0.05) in acetate, butyrate and total SCFA levels in the caecal contents as a result of colitis. Probiotic supplementation increased (P < 0.05) lactobacilli and bifidobacteria counts in the colon, whereas clostridia and coliform counts were reduced (P < 0.05). These were reversed by the probiotic supplementation. CONCLUSION: Dietary supplementation of L. salivarius CPN60 had a positive effect with respect to improving the overall gut health of healthy rats, as well as that of rats exposed to experimental colitis. © 2020 Society of Chemical Industry.

Adding α-tocopherol-selenium and ascorbic acid to periparturient sow diets influences hemogram, lipid profile, leptin, oxidant/antioxidant imbalance, performance and neonatal piglet mortality.

Alpha-tocopherol-selenium (ATS) and ascorbic acid (AA) are the potent antioxidants. The present study investigated whether supplementation of ATS and AA in periparturient sows has positive effects on amelioration of oxidative stress, serum immunoglobulin G (IgG), lipid profile and sows performance. For this, twenty-four pregnant multiparous sows (landrace×indigenous) were randomly distributed into four groups (6 sows per group) 20 days before expected date of farrowing as Control (basal diet); ATS (basal diet + ATS); AA (basal diet + AA) and ATS-AA (basal diet + ATS plus AA). The results of the study revealed that the concentrations of triglyceride and cholesterol significantly reduced from day -7 to day 7 of farrowing irrespective of supplementations to sows, but the leptin concentration significantly reduced on day 7 of farrowing in ATS-AA supplemented sows (p<0.05). Moreover, sows of supplemented groups experienced decreased oxidative stress and cortisol level than control sows. The serum IgG concentration was significantly increased on day 7 post-farrowing in ATS group but it was much earlier on day 2 of farrowing in ATS-AA group (p<0.001). Supplementing sows with ATS and/or AA did not influence significantly the birth weight, weaning weight and litter size at weaning (p>0.05). Although piglet survival rate was not affected significantly by supplementation, however, piglet mortality rate was lowest in ATS-AA than any other groups. It was concluded that supplementation of ATS and/or AA to sows during late gestating and early lactating period ameliorated oxidative stress, improved lipid profile and serum IgG level without influencing reproductive performance.

Nutrient digestibility, hindgut metabolites and antioxidant status of dogs supplemented with pomegranate peel extract.

The present study assessed the effect of dietary supplementation of pomegranate peel (methanolic) extract (PPE) on the nutrient digestibility, faecal fermentative metabolites and antioxidant status of dogs. Six medium-sized dogs of mixed breeds were allocated to two groups in a replicated cross-over design and fed a basal diet with and without supplementation of PPE at 50 mg/kg body weight. Each of the experimental periods consisted of 30 d, with a 21 d washout period in between. Results indicated that PPE supplementation led to no significant changes in nutrient digestibility except a trend of improvement (P = 0·070) in crude fibre digestibility. PPE supplementation significantly (P < 0·001) influenced faecal pH, ammonia and lactate production, indicative of positive effects of PPE polyphenols. PPE supplementation further increased faecal SCFA concentration accompanied by a reduction (P < 0·01) in branched-chain fatty acids. PPE supplementation also improved (P < 0·05) indices of erythrocytic antioxidants, namely reduced glutathione, catalase, glutathione peroxidase and glutathione S-transferase together with an improvement in lipid peroxidation. Overall, it can be concluded that dietary supplementation with PPE at 50 mg/kg body weight had a positive impact on hindgut fermentation and antioxidant status in dogs, thereby demonstrating its potential as a gut health-promoting nutraceutical.

Comparative assessment of canine-origin Lactobacillus johnsonii CPN23 and dairy-origin Lactobacillus acidophillus NCDC 15 for nutrient digestibility, faecal fermentative metabolites and selected gut health indices in dogs.

The present experiment was undertaken to validate a probiotic of canine origin for its potential use in dogs. A total of fifteen adult female Labrador dogs were allocated to three equal groups and fed a basal diet without probiotic (control) or with probiotic of either canine (Lactobacillus johnsonii CPN23; cPRO) or dairy (L. acidophilus NCDC 15; dPRO) origin for 9 weeks. The digestibility of most macronutrients remained similar among the groups; however, fibre digestibility was improved (P = 0·034) in dogs receiving cPRO. The faecal fermentative metabolites ammonia (P < 0·05) and lactate (P = 0·094) were altered favourably, indicating a positive influence of both probiotics. Faecal concentrations of acetate, propionate and butyrate were increased (P < 0·01) in both probiotic groups. However, improvements were higher in cPRO v. dPRO. The delayed-type hypersensitivity reaction to intradermal inoculation of phytohaemagglutinin-P was higher (P = 0·053) in cPRO as compared with control. The antibody response to sheep erythrocytes was, however, similar across the three groups. Overall, in dogs, the canine-origin probiotic was superior when compared with the dairy-origin probiotic.

Time course pathogenesis of sulphur mustard-induced skin lesions in mouse model.

Sulphur mustard (SM) is a bifunctional alkylating agent that causes cutaneous blistering in humans and animals. In this study, we have presented closer views on pathogenesis of SM-induced skin injury in a mouse model. SM diluted in acetone was applied once dermally at a dose of 5 or 10 mg/kg to Swiss albino mice. Skin was dissected out at 0, 1, 3, 6, 12, 24, 48, 72 and 168 hours, post-SM exposure for studying histopathological changes and immunohistochemistry of inflammatory-reparative biomarkers, namely, transforming growth factor alpha (TGF-α), fibroblast growth factor (FGF), endothelial nitric oxide synthase (eNOS) and interlukin 6 (IL-6). Histopathological changes were similar to other mammalian species and basal cell damage resembled the histopathological signs observed with vesication in human skin. Inflammatory cell recruitment at the site of injury was supported by differential expressions of IL-6 at various stages. Time-dependent expressions of eNOS played pivotal roles in all the events of wound healing of SM-induced skin lesions. TGF-α and FGF were strongly associated with keratinocyte migration, re-epithelialisation, angiogenesis, fibroblast proliferation and cell differentiation. Furthermore, quantification of the tissue leukocytosis and DNA damage along with semiquantitative estimation of re-epithelialisation, fibroplasia and neovascularisation on histomorphologic scale could be efficiently used for screening the efficacy of orphan drugs against SM-induced skin injury.

Protective efficacy of 2-PAMCl, atropine and curcumin against dichlorvos induced toxicity in rats.

The effect of 2- pyridine aldoxime methyl chloride (2-PAMCl) and atropine with or without curcumin was investigated in dichlorvos (2,2-dichlorovinyl dimethyl phosphate; DDVP) induced toxicity in rats. Rats were exposed to DDVP (2 mg/kg sub-cutaneously) once daily for the period of 21 days. Post DDVP exposure, rats were further treated with 2-PAMCl (50 mg/kg intramuscular, once daily) + atropine (10 mg/kg, i.m. once daily) with or without curcumin (200 mg/kg; oral; once daily) for further 21 days. We observed a significant increase in lipid peroxidation (LPO), reactive oxygen species (ROS), oxidized glutathione (GSSG), while there was a significant decrease in antioxidant enzymes, brain acetylcholinesterase (AChE) and 5-hydroxy tryptamine (5-HT) activity on DDVP exposure of rats. These alterations were restored significantly by co-administration of 2-PAMCl + atropine in DDVP exposed rats. Curcumin when co-supplemented with 2-PAMCl + atropine also significantly protected serum aspartate aminotransferase (AST) and restored brain AChE activity and 5-HT level in animals sub-chronically exposed to DDVP. Histopathological observations along with biochemical changes in rat blood and tissues revealed significant protection offered by 2-PAMCl + atropine against DDVP. The results indicate that DDVP-induced toxicity can be significantly protected by co-administration of 2-PAMCl + atropine individually, however, curcumin co-supplementation with 2-PAMCl + atropine provides more pronounced protection, concerning particularly neurological disorders.

Designing of mouse model: a new approach for studying sulphur mustard-induced skin lesions.

This study was planned to design a mouse model for studying sulphur mustard (SM)-induced skin injury. SM was applied dermally at dose of 5 or 10 mg kg(-1) in polyethyleneglycol-300 (PEG-300) or dimethylsulphoxide (DMSO) or acetone once. The changes in body weight, organ body weight indices (OBWI) and haematological and oxidative stress parameters were investigated over a period of 3-7 days and supported by histopathological observations. Exposure to SM in PEG-300 or DMSO resulted in a significant depletion in body weight, OBWI, hepatic glutathione (GSH) and elevation in hepatic lipid peroxidation, without affecting the blood GSH and hepatic oxidised glutathione (GSSG) levels. Interestingly, no aforesaid change was observed after dermal application of SM diluted in acetone. These biochemical changes were supported by the histological observations, which revealed pronounced toxic effect and damage to liver, kidney and spleen after dermal application of SM diluted in PEG-300 or DMSO. The skin showed similar microscopic changes after dermal application of SM in all the three diluents, however; the severity of lesions was found to be time and dose dependent. It can be concluded that dermal exposure of SM diluted in acetone can be used to mimic SM-induced skin toxicity without systemic toxicity in a mouse model.