Rheumatoid arthritis (RA) is considered an autoimmune disease distinguished by chronic synovial membrane inflammation, degraded cartilage, as well as bone destruction, which lead to joints pain and ...stiffness. The pathogenesis of RA involved at least two mechanisms: Cellular proliferation and activation of glycogen synthase kinase-3β (GSK3β) enzyme. Thus, we tested the hypothesis that the GSK3binhibitor, TDZD-8, can treat the synovial tissue toward collagen type II (COII)-mediated RA linked to apoptosis induction and biomarker suppression of inflammation. Wistar rats were immunized with COII (the model group) for 21 days. Matched immunized rats were daily injected with TDZD-8 (1 mg/kg; i.p) for three additional weeks (COII+TDZD- 8).After 42 days of post-immunization, blood and tissues were collected. Histology (H&E) and immunohistochemistry (CD45; leukocyte common antigen) images showed that COII induced RA was demonstrated by profound damage to the synovial tissue and infiltration of the inflammatory cells, which were substantially ameliorated with TDZD-8. In addition, COII immunization caused the induction of rheumatoid factor (RF), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin 1 beta (IL-1β) that were substantially (p<0.05) suppressed by TDZD-8. Whereas, TDZD-8 augmented the apoptotic biomarker, Bcl-2-associated X protein (Bax), which was significantly (p<0.05) ameliorated by RA. We also showed a substantial relationship (p<0.001) between the blood levels of RF and the synovial tissue levels of TNF-α (r = 0.759), IL-1b (r = 0.969), IL-6 (r = 0.749), and Bax (r = - 0.914). These results indicate effective treatment of the injured synovial tissue by TDZD-8 against COII-induced RA in rats, which also decreases inflammatory biomarkers and augmentation of apoptosis.
Acute renal failure induced by a toxic dose of acetaminophen (also known as paracetamol, or APAP) is common in both humans and experimental animal models. Glomerular ultrastructural alterations ...induced by APAP overdose associated with the suppression of biomarkers of kidney injury have not been investigated before. Also, we investigated whether the combined polyphenolic antioxidants and anti-inflammatory compounds, resveratrol (RES) and quercetin (QUR) can protect against APAP-induced nephrotoxicity. Rats either received a single dose of APAP (2 g/kg) before being sacrificed after 24 hours or were pretreated for 7 days with combined doses of RES (30 mg/kg) and QUR (50 mg/kg) before being given a single dose of APAP and then sacrificed 24 hours post APAP ingestion. APAP significantly (p < 0.05) increased blood levels of urea, creatinine, malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), which were effectively reduced by RES + QUR. In addition, APAP overdose induced the tissue expression of the apoptotic biomarker, p53, and caused profound kidney damage as demonstrated by substantial alterations to the glomerular basement membrane, podocytes, endothelial cells, widening of Bowman's space, and vacuolation of the cells lining the parietal layer, which were substantially protected by RES + QUR. Furthermore, a significant (p < 0.0001) positive correlation was observed between either glomerular basement membrane or podocyte foot processes and these parameters, urea, creatinine, MDA, and TNF-α. Thus, we conclude that APAP induces alterations to the glomerulus ultrastructure, which is protected by resveratrol plus quercetin, which also reduces blood levels of urea and creatinine, and biomarkers of oxidative stress and inflammation.
Cardiovascular complications are prevalent manifestations of type 2 diabetes mellitus (T2DM) and are usually the main cause of death. This study aims to show the underlying mechanisms of the ...potential therapeutic effect of mesenchymal stem cells (MSCs) on diabetic cardiac dysfunction. Twenty-four male Wistar rats were randomly assigned to one of three groups The control group received standard laboratory chow, and the groups with T2DM received a single dose of 45 mg/kg body weight of streptozotocin (STZ) after 3 weeks of pretreatment with a high-fat diet (HFD). Eight weeks after the diagnosis of T2DM, rats were divided into two groups: the T2DM model group and the T2DM + MSCs group. BM-MSCs were administered systemically at 2 × 106 cells/rat doses.
A Significant amelioration in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and dyslipidemia was noted 2 weeks post-administration of MSCs. Administration of MSCs improved dyslipidemia, the altered cardiac injury biomarkers (p ≤ 0.0001), downregulated Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)/inducible Nitric oxide synthase (iNOS) and iNOS/Apoptosis signaling pathways. This was associated with improved cardiac dysfunction (impaired left ventricular performance and decreased contractility index).
Our results show that MSCs ameliorate cardiac dysfunction associated with diabetic cardiomyopathy by lowering dyslipidemia and insulin resistance, inhibiting oxidative stress, and inflammation, downregulating JAK2/STAT3/iNOS and iNOS/Apoptosis signaling pathways.
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•Mesenchymal stem cells improved diabetic cardiomyopathy.•Ameliorate HOMA-IR and dyslipidemia.•Reduce cardiac injury biomarkers.•Downregulation of JAK2/STAT3/iNOS signaling pathways.•Suppress iNOS/Apoptosis signaling pathways.
Chronic liver injury can lead to hepatic failure and the only available method of treatment would be liver transplantation. The link between inflammation (TNF-α), nuclear factor-kappa B (NF-kB), ...nitrosative stress (iNOS) and hypoxia-inducible factor-1α (HIF-1α) in thioacetamide (TAA) induced liver fibrosis, and hypertension with and without the incorporation of the anti-inflammatory and antioxidant resveratrol (RES) has not been investigated before. Consequently, we injected rats with either 200 mg/kg TAA for 8 weeks starting at week 2 (model group) or pretreated them before TAA injections with RES (20 mg/kg) for 2 weeks and continued them on RES and TAA until being culled at week 10 (protective group). In the model group, we documented the induction of hepatic fibrosis and upregulation of tumor necrosis factor-α (TNF-α), NF-kB, inducible nitric oxide synthase (iNOS), HIF-1α and the profibrotic biomarkers alpha-smooth muscle actin (α-SMA) and matrix metalloproteinase-9 (MMP-9) that was significantly (
p
≤ 0.0014) ameliorated by RES. RES also significantly (
p
≤ 0.0232) reduced triglycerides (TG), cholesterol (CHOL), very low-density lipoprotein (vLDL-C), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure, and heart rate (HR) induction by TAA. Also, a significant (
p
< 0.0001) positive correlation between TNF-α/NF-kB/iNOS/HIF-1α axis-mediated fibrosis and hypertension and liver injury biomarkers was observed. These findings suggest that in the hepatotoxic compound, TAA is associated with TNF-α/NF-kB/iNOS/HIF-1α-mediated fibrosis and hypertension, whilst being inhibited by RES.
Pure and manganese-doped titanium dioxide nanoparticles (MnTiO2-NPs) were synthesized by the defect-oriented hydrothermal approach. The synthesized material was then characterized by X-ray ...diffraction (XRD), Scanning electron microscopy (SEM), Energy dispersive X-ray spectroscopy (EDX), and UV–visible spectroscopy (UV–Vis). The agar well diffusion method assessed the antibacterial efficiency of TiO2 and MnTiO2-NPs against E. coli and S. aureus. Zone of inhibition (ZOI) formed by pure TiO2 was observed as 12 mm and 11.5 mm against E. coli and S. aureus, while for MnTiO2-NPs it was observed as 19 mm (E. coli) and 21 mm (S. aureus). The concentration of synthesized nanoparticles (10 mg/ml, and 20 mg/ml) was used for antibacterial studies. The efficacy of the pure and MnTiO2-NPs as an active photocatalyst for the degradation of methylene blue (MB) dye was also assessed using a UV light. It was observed that the photodegradation efficiency of 1 g of MnTiO2-NPs was higher than the same amount of pure TiO2. The results suggest that the photocatalyst concentration directly impacts the photodegradation of MB dye. The pH value was found to influence the photodegradation of MB dye at higher pH values. Based on the obtained results, MnTiO2-NPs were observed as a promising agent for microbial resistance and water remediation.
•Highlights (for review).•Synthesized pure and manganese-doped TiO2-NPs via defect-oriented hydrothermal technique.•MnTiO2-NPs were found to have better antibacterial efficiency than TiO2.•MnTiO2-NPs were found as a promising agent for microbial resistance.•MnTiO2-NPs were found as an active photocatalyst for the degradation of methylene blue.
It has been reported that the gut-liver axis and intestinal microbiome contribute crucially to different liver diseases. So, targeting this hepato-intestinal connection may provide a novel treatment ...modality for hepatic disorders such as drug-induced liver injury (DILI). The present study thought to investigate the protective effect of turmeric (TUR) on metronidazole (MNZ)-induced liver damage and the possible association of the gut-liver axis and gut microbiota as a suggested underlying mechanism. In the first experiment, a MNZ-induced liver injury rat model was reproduced after 130 mg/kg oral MNZ administration for 30 days. Meanwhile, the treatment group was orally treated with 100 mg/kg turmeric daily. In the second experiment, fecal microbiome transplantation (FMT) was conducted, in which the fecal microbiome of each group in the first experiment was transplanted to a healthy corresponding group in the second experiment. The liver enzymes (aminotransferase (ALT) and aspartate aminotransferase (AST)) and histopathological examination were estimated to assess liver function. Inflammatory cytokines and oxidative markers were evaluated in the liver tissues. Histological analysis, intestinal barrier markers, and expression of tight junction proteins were measured for assessment of the intestinal injury. Changes in the gut microbial community and possible hepatic bacterial transmission were analyzed using 16S rRNA sequencing. MNZ induced intestinal and liver injuries which were significantly improved by turmeric. Increased firmicutes/bacteroidetes ratio and bacterial transmission due to gut barrier disruption were suggested. Moreover, TUR has maintained the gut microbial community by rebalancing and restoring bacterial proportions and abundance, thereby repairing the gut mucosal barrier and suppressing bacterial translocation. TUR protected against MNZ-induced gut barrier disruption. Reshaping of the intestinal bacterial composition and prohibition of the hepatic microbial translocation were suggested turmeric effects, potentially mitigating MNZ-related liver toxicity.It has been reported that the gut-liver axis and intestinal microbiome contribute crucially to different liver diseases. So, targeting this hepato-intestinal connection may provide a novel treatment modality for hepatic disorders such as drug-induced liver injury (DILI). The present study thought to investigate the protective effect of turmeric (TUR) on metronidazole (MNZ)-induced liver damage and the possible association of the gut-liver axis and gut microbiota as a suggested underlying mechanism. In the first experiment, a MNZ-induced liver injury rat model was reproduced after 130 mg/kg oral MNZ administration for 30 days. Meanwhile, the treatment group was orally treated with 100 mg/kg turmeric daily. In the second experiment, fecal microbiome transplantation (FMT) was conducted, in which the fecal microbiome of each group in the first experiment was transplanted to a healthy corresponding group in the second experiment. The liver enzymes (aminotransferase (ALT) and aspartate aminotransferase (AST)) and histopathological examination were estimated to assess liver function. Inflammatory cytokines and oxidative markers were evaluated in the liver tissues. Histological analysis, intestinal barrier markers, and expression of tight junction proteins were measured for assessment of the intestinal injury. Changes in the gut microbial community and possible hepatic bacterial transmission were analyzed using 16S rRNA sequencing. MNZ induced intestinal and liver injuries which were significantly improved by turmeric. Increased firmicutes/bacteroidetes ratio and bacterial transmission due to gut barrier disruption were suggested. Moreover, TUR has maintained the gut microbial community by rebalancing and restoring bacterial proportions and abundance, thereby repairing the gut mucosal barrier and suppressing bacterial translocation. TUR protected against MNZ-induced gut barrier disruption. Reshaping of the intestinal bacterial composition and prohibition of the hepatic microbial translocation were suggested turmeric effects, potentially mitigating MNZ-related liver toxicity.
MicroRNAs have been implicated in the pathogenesis of rheumatoid arthritis (RA) and their syntheses are modulated by glycogen synthase kinase-3β (GSK-3β). Therefore, we hypothesised that the GSK-3β ...inhibitor, TDZD-8 can protect against collagen-induced arthritis (CIA) via downregulating miR155 and miR-24 expression. Rats were randomly allocated into four groups (n = 6) as follows: Control, Control + TDZD-8 (1 mg/kg), CIA, and CIA + TDZD-8. Rats were sacrificed after 6 weeks. We observed in the model group (CIA) significant (p<.05) increase in arthritis score and serum levels of RA biomarkers, which were significantly (p < .05) inhibited by TDZD-8. TDZD-8 also significantly (p<.05) inhibited CIA-induced synovial tissue levels of miR155, miR-24, and inflammation. In addition, a significant (p<.05) modulation of biomarkers of survival (Bcl-2) and apoptosis (cleaved caspase-3) by TDZD-8 was observed. Thus, TDZD-8 protects against CIA in rats for a period of 6 weeks, which is associated with the inhibition of miR155/24 and inflammation, and apoptosis augmentation.
Background: We investigated whether the anti-inflammatory and antioxidant agent, resveratrol can inhibit type 2 diabetes mellitus (T2DM)-induced osteoarthritis (OA) in rats and whether it is ...associated with the suppression of glycaemia, dyslipidemia and inflammatory and oxidative stress biomarkers.
Materials and methods: T2DM was induced by streptozotocin (50 mg/kg body weight) and high carbohydrate and fat diet (HCFD). The protective group was put on resveratrol (30 mg/kg) 14 days prior to the induction of diabetes and continued on resveratrol and HCFD until being sacrificed at week 12.
Results: Diabetic rats showed a substantial damage to the knee joints and loss of proteoglycans from the articular cartilage, which were effectively but not completly protected by resveratrol. Resveratrol also significantly (p ≤ .0029) reduced diabetic up-regulation of HbA1c, hyperlipidaemia, inflammation and oxidative stress.
Conclusions: Resveratrol protects against T2DM-induced OA associated with the inhibition of glycated haemoglobin, dyslipidemia, and biomarkers of oxidative stress and inflammation.
The first-generation antihistamine chlorpheniramine (CPA) is believed to have both anxiolytic and antidepressant properties. The current study sought to assess the mechanisms behind the ...antidepressant and anxiolytic effects of CPA therapy concerning oxidative stress, inflammation, and nuclear factor p45 for erythroid 2-Brain-derived neurotrophic factor (Nrf2-BDNF) signaling pathway in forced swimming-induced depressive-like behavior and anxiety. Eighteen male Wistar rats (180–200 gm) rats were separated into three groups (n = 6): a stressed group (acute stress) that underwent the forced swimming test (FST) and a stressed group that received pretreatment with CPA (10 mg/kg body weight) for 3 weeks (CPA + acute stress). Animals were subsequently put through the following behavioral tests after undergoing a forced swim test (FST) for 5 min: an immobility test, open field test, and elevated plus maze test. Serum cortisol levels were measured when the rats were euthanized at the end of the experiments. Brain neurotransmitters (cortisol, serotonin, and noradrenaline), oxidative stress (SOD and MDA), inflammatory (IL-6 and IL-1) biomarkers, and the Nrf2-BDNF signaling pathway in the hippocampus and cerebral cortex tissues was determined. CPA prevented stress-induced increases in cortisol levels (p < 0.0001), decreased brain neurotransmitters, and increased oxidative stress and inflammation. CPA also upregulated the Nrf2-BDNF signaling pathway. Thus, CPA mitigates depressive-like behavior and anxiety by inhibiting oxidative stress and inflammation and upregulating the Nrf2-BDNF signaling pathway in the brain tissues.
The link between oxidative stress (ROS), apoptosis (p53) and fibrosis (collagen) in type 2 diabetes mellitus (T2DM)-induced cardiac injury in the presence and absence of the antidiabetic drug, ...metformin has not been investigated before.
T2DM was induced in rats by a combination of high carbohydrate and fat diets (HCFD) and streptozotocin (50 mg/kg) injection. The protection group started metformin (200 mg/kg) treatment 14 days prior to the induction of diabetes and continued on metformin and HCFD until being sacrificed at week 12.
Diabetes significantly induced blood levels of ROS and left ventricular p53 and collagen expression that was inhibited by metformin. Metformin also significantly reduced glycated haemoglobin and dyslipidemia induced by diabetes. In addition, a significant correlation between ROS-p53-collagen axis and glycaemia and hyperlipidaemia was observed.
These findings show that metformin provides substantial protection against diabetic cardiomyopathy-induced ROS-p53 mediated fibrosis and dyslipidemia.
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