Probiotic bacteria protect against indomethacin-induced gastric ulcers through modulation of oxidative stress, inflammation, and apoptosis.

BACKGROUND: Indomethacin is an anti-inflammatory drug that causes ulcers on the gastric mucosa due to its use. Probiotic bacteria are live microorganisms, and it has been stated by various studies that these bacteria have antioxidant and anti-inflammatory effects. In this study, we investigated the possible protective effect of various types of probiotic bacteria (Lactobacillus rhamnosus, Lactobacillus fermentum, and Lactobacillus brevis) against acute gastric mucosal damage caused by indomethacin. METHODS: Control group - Physiological saline was administered daily for 10 days. Indo group-Physiological saline was administered daily for 10 days. Ranitidine + Indo group 5 mg/kg ranitidine dose was administered daily for 5 days. On day 11, a single dose of 100 mg/kg of indomethacin was given to the same group. Probiotic + Indo group 1 ml/kg of oral probiotic bacteria was administered daily for 10 days. On day 11, a single 100 mg/kg dose of indomethacin was given. After the application, the rats were anesthetized with ketamine xylazine, killed under appropriate conditions, the abdominal cavity was opened and the stomach tissues were removed. The obtained gastric tissues were used in the biochemical and histopathological analyses discussed below. All data were statistically evaluated by one-way ANOVA using SPSS 20.00, followed by Duncan Post hoc test. The data were expressed as mean ± SD. P < 0.05 was considered statistically significant. RESULTS: As a result, the administration of indomethacin caused gastric damage, stimulating oxidative stress, inflammation, and apoptosis. We found that the use of probiotic bacteria reduces oxidative stress (TOC), increases the activity of antioxidant enzymes (TAC), suppresses inflammation (IL-6 and Tnf-α), and inhibits apoptosis (Bax and Bcl-2) (P < 0.05). CONCLUSION: Probiotic treatment can mitigate gastric damage and apoptosis caused by indomethacin-induced gastric damage in rats. Probiotic also enhances the restoration of biochemical oxidative enzymes as it has anti-inflammatory, antioxidant, and antiapoptotic properties.

Molecular insights into the antioxidative and anti-inflammatory effects of P-coumaric acid against bisphenol A-induced testicular injury: In vivo and in silico studies.

This study investigated the protective effects of p-coumaric acid (PCA) against bisphenol A (BPA)-induced testicular toxicity in male rats. The rats were divided into control, BPA, BPA+PCA50, BPA+PCA100, and PCA100 groups. Following a 14-day treatment period, various analyses were conducted on epididymal sperm quality and testicular tissues. PCA exhibited dose-dependent cytoprotective, antioxidant, and anti-inflammatory effects, ameliorating the decline in sperm quality induced by BPA. The treatment elevated antioxidant enzyme activities (SOD, GPx, CAT) and restored redox homeostasis by increasing cellular glutathione (GSH) and reducing malondialdehyde (MDA) levels. PCA also mitigated BPA-induced proinflammatory responses while reinstating anti-inflammatory IL-10 levels. Apoptotic parameters (p53 and p38-MAPK) were normalized by PCA in BPA-treated testicular tissue. Immunohistochemical and immunofluorescent analyses confirmed the cytoprotective and anti-inflammatory effects of PCA, evidenced by the upregulation of HO-1, Bcl-2, and Nrf-2 and the downregulation of the proapoptotic gene Bax in BPA-induced testicular intoxication. PCA corrected the disturbance in male reproductive hormone levels and reinstated testosterone biosynthetic capacity after BPA-induced testicular insult. In silico analyses suggested PCA's potential modulation of the oxidative stress KEAP1/NRF2/ARE pathway, affirming BPA's inhibitory impact on P450scc. This study elucidates BPA's molecular disruption of testosterone biosynthesis and highlights PCA's therapeutic potential in mitigating BPA's adverse effects on testicular function, showcasing its cytoprotective, anti-inflammatory, and hormone-regulating properties. The integrated in vivo and in silico approach offers a comprehensive understanding of complex mechanisms, paving the way for future research in reproductive health and toxicology, and underscores the importance of employing BPA-free plastic wares in semen handling.

Mitigation of Acute Hepatotoxicity Induced by Cadmium Through Morin: Modulation of Oxidative and Pro-apoptotic Endoplasmic Reticulum Stress and Inflammatory Responses in Rats.

Cadmium (Cd) is a toxic heavy metal with significant environmental health hazards. It enters the body through various routes with tissue accumulation. The relatively longer half-life with slow body clearance significantly results in hepatotoxicity during its liver detoxification. Therefore, researchers are exploring the potential use of herbal-derived phytocomponents to mitigate their toxicity. Here, we investigated, for the first time, the possible ameliorative effect of the phytochemical Morin (3,5,7,29,49-pentahydroxyflavone) against acute Cd-induced hepatotoxicity while resolving its underlying cellular mechanisms in a rat animal model. The study involved 50 adult male Sprague-Dawley rats weighing 200-250 g. The animals were divided into five equal groups: control, Cd, Morin100 + Cd, Morin200 + Cd, and Morin200. The 2nd, 3rd, and 4th groups were intraperitoneally treated with Cd (6.5 mg/kg), while the 3rd, 4th, and 5th groups were orally treated with Morin (100 and 200 mg/kg) for 5 consecutive days. On the 6th day, hepatic function (serum ALT, AST, ALP, LDH enzyme activities, and total bilirubin level) testing, transcriptome analysis, and immunohistochemistry were performed to elucidate the ameliorative effect of Morin on hepatotoxicity. In addition to restoring liver function and tissue injury, Morin alleviated Cd-induced hepatic oxidative/endoplasmic reticulum stress in a dose-dependent manner, as revealed by upregulating the expression of antioxidants (SOD, GSH, Gpx, CAT, and Nrf2) and decreasing the expression of ER stress markers. The expression of the proinflammatory mediators (TNF-α, IL-1-ß, and IL-6) was also downregulated while improving the anti-inflammatory (IL-10 and IL-4) expression levels. Morin further slowed the apoptotic cascades by deregulating the expression of pro-apoptotic Bax and Caspase 12 markers concomitant with an increase in anti-apoptotic Blc2 mRNA expression. Furthermore, Morin restored Cd-induced tissue damage and markedly suppressed the cytoplasmic expression of JNK and p-PERK immunostained proteins. This study demonstrated the dose-dependent antioxidant hepatoprotective effect of Morin against acute hepatic Cd intoxication. This effect is likely linked with the modulation of upstream p-GRP78/PERK/ATF6 pro-apoptotic oxidative/ER stress and the downstream JNK/BAX/caspase 12 apoptotic signaling pathways.

The role of GRP78/ATF6/IRE1 and caspase-3/Bax/Bcl2 signaling pathways in the protective effects of gallic acid against cadmium-induced liver damage in rats.

Objectives: Cadmium (CD) causes widespread and severe toxic effects on various tissues. Studies have shown that apoptosis, inflammation, and endoplasmic reticulum stress play a role in organ damage caused by CD. Phenolic compounds with strong antioxidant effects are found in various fruits and vegetables. One of these compounds is Gallic acid (GA), which is found both free and hydrolyzable in grapes, pomegranate, tea, hops, and oak bark. Result of various studies show that GA has active antioxidant, anti-inflammatory, and anti-apoptotic properties. In our study, we investigated the mechanism of the protective effect of GA on CD-induced hepatotoxicity in rats. Materials and Methods: In this study, 50 adult male Sprague Dawley rats weighing approximately 200-250 g were used and the rats were divided into 5 groups: Control, CD, GA50+CD, GA100+CD, and GA100. The rats were treated with GA (50 and 100 mg/kg body weight), and Cd (6.5 mg/kg) was administrated to the rats for 5 consecutive days. The liver enzymes, TB levels in serum samples, oxidative stress, inflammation, ER stresses, apoptosis marker, histopathology, 8-OHDG, and caspase-3 positivity were analyzed. Results: CD administration significantly increased liver enzyme levels (AST, ALT, ALP, and LDH), MDA, IL-1-ß, IFN-γ, TNF-α, IL-10, IL-6, GRP78, CHOP, ATF6, p -IRE1, sXBP, Bax mRNA expression, Caspase 3, and 8-OHdG expression (P<0.05). These values were found to be significantly lower in the Control, GA100+CD, and GA100 groups compared to the CD group (P<0.05). CD administration significantly decreased the expression levels of TB, IL-4, SOD, GSH, CAT, GPX, and Bcl-2 mRNA (P<0.05). These values were found to be significantly higher in the Control, GA100+CD, and GA100 groups compared to the CD group (P<0.05). Conclusion: The results of the present study indicated that GA prevented Cd-induced hepatic oxidative stress, inflammation, ER stress, apoptosis, and tissue damage in rats.

The protective effects of hesperidin and curcumin on 5-fluorouracil-induced nephrotoxicity in mice.

Nephrotoxicity is a very important complication of 5-fluorouracil (5-FU)-treated cancer patients. Increased oxidative stress, kidney damage, and apoptosis play an important role in the pathogenesis of nephrotoxicity caused by 5-FU. In this study, protective effects of two natural compounds, hesperidin and curcumin, on experimentally induced kidney damage in mice with 5-FU were determined. Application of 5-FU resulted in severe histopathological changes and severe renal failure with increased serum urea and creatinine levels. Also, 5-FU-induced kidney damage, increased levels of malondialdehyde (MDA), decreased superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) activity, and glutathione (GSH) level have been demonstrated. Also, where 5-FU is in the concentration of caspase-3 and 8-OHdG immune-positive cells and therefore causes apoptosis and DNA damage in kidney tissue cells. However, especially high doses of hesperidin and curcumin treatment significantly improved 5-FU-induced oxidative stress/lipid peroxidation, apoptosis/DNA damage, and renal dysfunction. Based on these data, our results suggest that hesperidin and curcumin may be used as new and promising agents against 5-FU-induced nephrotoxicity.

The Effects of Selenium in Acrylamide-Induced Nephrotoxicity in Rats: Roles of Oxidative Stress, Inflammation, Apoptosis, and DNA Damage.

We sought to determine the effects of selenium (Se) on acrylamide (ACR)-induced nephrotoxicity in rats. In our study, 50 adult male Sprague-Dawley rats weighing 200-250 g were randomly divided into five groups. The control group was given intra-gastric (i.g.) saline (1 mL) for 10 days. The ACR group was given i.g. ACR in saline (38.27 mg/kg titrated to 1 mL) for 10 days. The Se0.5 + ACR and Se1 + ACR groups were administered Se in saline (0.5 and 1 mg/kg, respectively) for 10 days and given i.g. ACR (38.27 mg/kg) one hour after the Se injections. The Se1 group was administered i.g. Se (1 mg/kg) for 10 days. On day 11, intracardiac blood samples were obtained from the rats while they were under anesthesia, after which they were euthanized by decapitation. Urea and creatinine concentrations of blood serum samples were analyzed with an autoanalyzer. Enzyme-linked immunosorbence immunosorbent assay (ELISA) was used to quantify malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT), tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB), interleukin (IL)-33, IL-6, IL-1ß, cyclooxygenase-2 (COX-2), kidney injury molecule-1 (KIM-1), mitogen-activated protein kinase-1 (MAPK-1), and caspase-3 in kidney tissues. Renal tissues were evaluated by histopathological and immunohistochemical examinations for 8-hydroxylo-2'-deoxyguanosin 8-hydroxy-2'-deoxyguanosine (8-OhDG) and Bax. Serum urea and creatinine levels were higher in the ACR group than in the control, and these ACR-induced increases were prevented by high doses of Se. Additionally, ACR induced the renal oxidative stress, inflammation, apoptosis, and damage to DNA and tissue; likewise, these were prevented by high doses of Se. Taken with ACR, Se confers protection against ACR-induced nephrotoxicity in rats by reducing oxidative stress, inflammation, apoptosis, and DNA damage.

The protective effects of naringin against 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats.

OBJECTIVES: 5-fluorouracil-induced (5-FU), an anticarcinogenic agent, is reported to have side-effects that include hepatotoxicity and nephrotoxicity. The study objective was to investigate the protective effects of naringin on 5-FU-induced hepatotoxicity and nephrotoxicity. MATERIALS AND METHODS: Thirty rodents were assigned to three groups. The control group received 1 ml of intragastric distilled water for 14 days. The 5-FU group received 1 ml of distilled water for 14 days as a placebo. On day 9, this same group received a 20 mg/kg dose of 5-FU administered intraperitoneally(IP) for a further five days. The naringin+5-FU group received a 100 mg/kg dose of naringin (IP) for 14 days. On day 9, 20 mg/kg of 5-FU was administered (IP) to this group for a further five days. On day 15, the rats were decapitated, and blood and renal and hepatic tissues were taken. RESULTS: It was determined that serum creatinine, BUN, AST, ALT, ALP, and LDH levels, as well as cytokine levels in the liver and kidney tissues were significantly elevated in the 5-FU group, compared to the control group. The comparative values were similar in the control and naringin+5-FU groups. When the liver tissue was examined histopathologically, in the control group it was found to be normal in structure. However, necrosis was observed in the hepatocytes of the pericentric region in the 5-FU group. 8-OHdG cell density was significantly elevated in the 5-FU group, compared to the control and naringin+5-FU groups. CONCLUSION: Naringin was observed to have a protective effect on 5-FU-induced liver and kidney damage.

An Investigation of Protective Effects of Litium Borate on Blood and Histopathological Parameters in Acute Cadmium-Induced Rats.

This study was carried out to determine the protective effects of lithium borate (LTB) on blood parameters and histopathological findings in experimentally induced acute cadmium (Cd) toxicity in rats. Twenty-eight male Wistar albino rats were used, weighing 200-220 g, and they were randomly divided into four groups, including one control and the following three experimental groups: a Cd group (0.025 mmol/kg), a LTB group (15 mg/kg/day orally for 5 days), and a LTB + Cd group (15 mg/kg/day orally for 5 days and Cd 0.025 mmol/kg by intraperitoneal injection on the fifth day). All the rats in the study were anesthetized with ketamine at the end of the sixth day, blood was taken from their hearts, and then the rats were decapitated. The values in the control and LTB group were usually close to each other. White blood cell (WBC), neutrophil %, and C-reactive protein (CRP) levels increased in the Cd and LTB + Cd groups while lymphocyte and monocyte levels decreased in a statistically significant manner, in comparison to the other groups. It was determined that the levels of red blood cells (RBCs), hematocrit (Htc), and hemoglobin (Hb) did not change in the groups. The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the Cd and LTB + Cd groups significantly increased, in comparison to the other groups, while the glucose, alkaline phosphatase (ALP), albumin (ALB), and total protein (TP) levels decreased. According to histopathological findings in the control and LTB groups, the liver and kidney tissues were found to have normal histological structures. In the Cd group, severe necrotic hemorrhagic hepatitis, mild steatosis, and mononuclear cell infiltration were detected in the liver. In the LTB + Cd group, degeneration and mild mononuclear cell infiltration were found in the liver. Regarding the kidney tissue in the Cd group, severe intertubular hyperemia in both kidney cortex and medulla, as well as degeneration and necrosis in the tubulus epithelium, was observed. In the LTB + Cd group, mild interstitial hyperemia and mononuclear cell infiltration was detected. Resultantly, it can be said that LTB at this dose has non-toxic effects and some beneficial effects for liver and kidney damage caused by acute Cd toxicity.

The protective effect of quercetin on cyclophosphamide-Induced lung toxicity in rats.

Cyclophosphamide (CYP) is an anticancer agent widely used in chemotherapy. It has been suggested that CYP causes toxicity in many organs, including the lungs and testes. Many studies have indicated that some antioxidants have possible protective effects against CYP's side effects. This study aimed to investigate the protective effect of quercetin (QUE) on CYP-induced lung toxicity in rats using histologic and biochemical methods. In the study, 50 male Sprague-Dawley rats weighing 220-250g were used. There were 4 experimental groups and 1 control group. Group I is the control group, which was given only intragastric (i.g.) solvent (corn oil) for 7days. Group II was given i.g. corn oil for 7days as a placebo, and a single dose of intraperitoneal (i.p.) CYP (200mg/kg) was given on day 7. Groups III and IV, respectively, were given QUE in doses of 50 and 100mg/kg, dissolved in corn oil, and administered i.g. for 7days. In addition, a single dose of CYP (200mg/kg, i.p.) was administered on the 7th day of study. In Group V, a 100mg/kg dose of QUE was given to rats i.g. for 7days. On the 8th day of the experiment, all groups of rats' blood and lung tissue samples were collected for analysis of oxidative stress parameters and histopathological examinations. In the biochemical result (although oxidative parameters were increased in favor of tissue damage) QUE administration revealed attenuated CYP toxicity in the rats 'lungs. In histologic analysis, QUE prevented the CYP-mediated tissue damage and the increase in mast-cell densities in the rats' lung tissues. The results of the present study have revealed that QUE provides a possible protective effect by inhibiting ROS and mast cell degranulation in induced lung damage.

Pomegranate seed extract attenuates chemotherapy-induced acute nephrotoxicity and hepatotoxicity in rats.

Cisplatin (CDDP), one of the most active cytotoxic agents against cancer, has adverse side effects, such as nephrotoxicity and hepatotoxicity. The present study was designed to investigate the potential protective effect of pomegranate seed extract (PSE) against oxidative stress caused by CDDP injury of the kidneys and liver by measuring tissue biochemical and antioxidant variables and immunohistochemically testing caspase-3-positive cells. Twenty-four Sprague-Dawley rats were divided into 4 groups: control; CDDP: injected intraperitoneally with CDDP (7 mg/kg body weight, single dose); PSE: treated for 15 consecutive days by gavage with PSE (300 mg/kg per day); and PSE+CDDP: treated by gavage with PSE 15 days after a single injection of CDDP. The degree of protection against CDDP injury afforded by PSE was evaluated by determining the levels of malondialdehyde as a measure of lipid peroxidation. The levels of glutathione and activities of glutathione peroxidase, glutathione S-transferase, and superoxide dismutase were estimated from liver and kidney homogenates; the liver and kidney were also histologically examined. PSE elicited a significant protective effect toward liver and kidney by decreasing the level of lipid peroxidation; elevating the levels of glutathione S-transferase; and increasing the activities of glutathione peroxidase, glutathione S-transferase, and superoxide dismutase. These biochemical observations were supported by immunohistochemical findings and suggested that PSE significantly attenuated nephrotoxicity and hepatotoxicity by the way of its antioxidant, radical-scavenging, and antiapoptotic effects. This PSE extract could be used as a dietary supplement in patients receiving chemotherapy medications.