Cannabidiol ameliorates lipopolysaccharide-induced cardiovascular toxicity by its antioxidant and anti-inflammatory activity via regulating IL-6, Hif1α, STAT3, eNOS pathway.

BACKGROUND: Systemic inflammation causes several organ damage by activating the intracellular signaling mechanisms. Heart and aorta tissues are the structures mostly affected by this situation. By examining underlying processes, this study sought to determine whether cannabidiol (CBD) may have protective effects against the cardiovascular damage brought on by lipopolysaccharide (LPS). MATERIALS AND METHODS: A total of 32 female rats were randomly allocated to one of four groups: control, lipopolysaccharide (LPS) (5 mg/kg, i.p., single dose), LPS + CBD (5 mg/kg, i.p., single dose), and CBD groups. The rats were killed six hours after receiving LPS, and tissues from the heart and aorta were taken. Histopathological and immunohistochemical analyzes were performed. Oxidative stress was evaluated biochemically by spectrophotometric method. Expression levels of genes were studied by RT-qPCR method. RESULTS: Histopathological analysis of the LPS group showed moderate hyperemia, hemorrhages, edema, inflammation, and myocardial cell damage. There was a slight to moderate increase in Cox-1, G-CSF, and IL-3 immunoexpressions, along with enhanced expressions of IL-6, Hif1α, and STAT3 genes, and decreased expressions of eNOS genes. Additionally, there were increased levels of TOS and decreased TAS levels observed biochemically. CBD treatment effectively reversed and improved all of these observed changes. CONCLUSIONS: CBD protects the heart and aorta against systemic inflammation through its antioxidant and anti-inflammatory activity via regulating IL-6, Hif1α, STAT3, and eNOS intracellular pathways.

Lercanidipine ameliorated doxorubicin-induced neuroinflammation and maintained the expressions of choline acetyltransferase via enhancing the levels of PI3K/AKT/HIF1-α expressions.

BACKGROUND: Doxorubicin (DOX) may cause various neurological side effects in the brain. Lercanidipine (LRD) has antioxidant, anti-inflammatory, and anti-apoptotic properties. The aim of this study was to investigate the potential benefits of. METHODS AND RESULTS: Lercanidipine in reducing doxorubicin-induced neuroinflammation and maintaining the expressions of choline acetyltransferase. Thirty-two adult Wistar albino female rats were divided into four groups as Control, DOX (20 mg/kg intraperitoneally), DOX + LRD 0.5 (0.5 mg/kg orally), and DOX + LRD2(2 mg/kg orally). Twenty-four hours after the last drug administration (9th day), brain tissues were taken for histopathological, immunohistochemical (choline acetyltransferase [CHAT], interleukin-10 [IL-10], and caspase-3 [Cas-3] staining), biochemical (total antioxidant status [TAS], total oxidant status [TOS], and oxidative stress index [OSI]), and genetic analyzes (PI3K/AKT/HIF1-α and IL-6 gene expressions). Histopathological analyses revealed hyperemia, slight hemorrhage, degeneration, neuronal loss, gliosis in the cerebellum, and neuronal loss in the brain cortex and hippocampus in the DOX group. According to other analyzes, decreased CHAT, PI3K, AKT, HIF1-α and increased IL-6, IL-10, Cas-3 expression were observed in the DOX group. CONCLUSIONS: Both LRD doses reversed all these findings, but LRD2 was observed to be more effective. In conclusion, we determined that LRD has potential therapeutic effect by reducing DOX-induced neuroinflammation, oxidative stress and apoptosis in brain tissues.

The ameliorative effects of cannabidiol on methotrexate-induced neuroinflammation and neuronal apoptosis via inhibiting endoplasmic reticulum and mitochondrial stress.

Methotrexate (MTX) is an antineoplastic agent and has neurotoxic effects. It exerts its toxic effect on the brain by triggering inflammation and apoptosis. Cannabidiol (CBD) is an agent known for its antioxidant, anti-inflammatory effects in various tissues. The aim of this study is to examine the protective effects of CBD treatment in various brain structures from MTX damage and to evaluate the effect of intracellular pathways involved in apoptosis. Thirty-two adult Wistar Albino female rats were divided into four groups as control, MTX (20 mg/kg intraperitoneally [i.p.]), MTX + CBD (0.1 mL of 5 mg/kg i.p.), and CBD (for 7 days, i.p.). At the end of the experiment, brain tissues collected for biochemical analyses as total oxidant status (TOS), total antioxidant status, oxidative stress index (OSI), histopathological and immunohistochemical analyses as tumor necrosis factor-α (TNF-α), serotonin, mammalian target of rapamycin (mTOR) staining, genetic analyses as caspase-9 (Cas-9), caspase-12 (Cas-12), C/EBP homologous protein (CHOP), and cytochrome-c (Cyt-c) gene expressions. In the histopathological and immunohistochemical evaluation, hyperemia, microhemorrhage, neuronal loss, and significant decreasing expressions of seratonin were observed in the cortex, hippocampus, and cerebellum regions in the MTX group. mTOR, TNF-α, Cas-9, Cas-12, CHOP, and Cyt-c expressions with TOS and OSI levels were increased in the cortex. It was observed that these findings were reversed after CBD application in all regions. MTX triggers neuronal apoptosis via endoplasmic reticulum and mitochondrial stress while destroying serotonergic neurons. The reversal of the pathological changes with CBD treatment proves that it has anti-inflammatory and antiapoptotic activity in brain.

The Preventive Effect of Preoperative and Postoperative Selenium on the Medication-Related Osteonecrosis of the Jaw: An Animal Study in Rats.

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is a condition that can occur primarily in patients undergoing or have previously undergone therapy with bisphosphonates, particularly in the presence of risk factors, such as tooth extraction (TE). PURPOSE: This study aimed to evaluate the effect of selenium (SEL) administration on the prevention of osteonecrosis of the jaw in an MRONJ animal model. STUDY DESIGN, SETTING, AND SAMPLE: This study was a longitudinal in vivo animal study using a TE model in a sample of 48 Wistar rats. PREDICTOR VARIABLE: The predictor variables were SEL exposure, timing of SEL exposure, and zoledronic acid (ZOL) exposure. The animals were randomly assigned to 4 treatment groups (n = 12 per group): 1) saline (negative control), 2) ZOL (positive control), 3) SELpreop + ZOL, and 4) ZOL + SELpostop. The animals were administered saline (negative control) or ZOL (0.06 mg/kg, intraperitoneally) once a week for 5 weeks. All rats underwent TE at the end of the fifth week. SEL (0.3 mg/kg, intraperitoneally) was administered once daily for 15 days to the SELpreop + ZOL group before TE and to the ZOL + SELpostop group after TE. All animals were sacrificed at the end of the ninth week. MAIN OUTCOME VARIABLES: The primary outcome variables were new bone area, necrotic bone area, fibrosis, new connective tissue formation, and inflammatory cell infiltration in the histopathological analysis, as well as angiogenesis and percentage of osteoblasts in the immunohistochemical analysis. COVARIATES: There was none. ANALYSES: Statistical analysis was conducted using the Kruskal-Wallis test, followed by post hoc Bonferroni-corrected Mann-Whitney U tests, with a significance level of P ≤ .05. RESULTS: The new bone area was higher in the ZOL + SELpostop group (3.00 score) than in the saline group (0.58 ± 1.08 score, P < .001) and the ZOL group (0.82 ± 1.40 score, P = .001), while the necrotic bone area was lower in the ZOL + SELpostop group (0.08 ± 0.29 score) than in the ZOL group (2.82 ± 0.40 score, P < .001) and the SELpreop + ZOL group (1.67 ± 0.89 score, P = .007). The percentage of osteoblasts was higher in the ZOL + SELpostop group (18.73%) than in the saline group (8.63%, P < .001) and the ZOL group (0.07%, P < .001), and it was also higher in the SELpreop + ZOL group (18.49%) than in the ZOL group (0.07%, P < .001). CONCLUSION AND RELEVANCE: In conclusion SEL prevents MRONJ, with postoperative SEL demonstrating greater prevention effects. Given these findings, we hypothesize that SEL exposure may decrease the risk of MRONJ.

Agomelatine ameliorates doxorubicin-induced cortical and hippocampal brain injury via inhibition of TNF-alpha/NF-kB pathway.

Side effects of doxorubicin (DOX) are mainly due to oxidative stress, with the involvement of inflammatory and apoptotic mechanisms. Agomelatine (AGO) is a melatonin receptor agonist with antioxidant, anti-inflammatory, and anti-apoptotic features. This study aimed to evaluate the effects of AGO with different doses on DOX-induced neurotoxicity. Rats were divided into four groups as control, DOX (40 mg/kg, intraperitoneal single dose), DOX + AGO20 (20 mg/kg AGO oral gavage for 14 days), and DOX + AGO40 (40 mg/kg AGO oral gavage for 14 days). On day 14, brain tissues were collected for biochemical, histopathological, and genetic examinations. DOX significantly increased malondialdehyde and decreased superoxide dismutase and catalase (CAT) levels. CAT levels were significantly increased only in the DOX + AGO40 group compared to the DOX group (p = 0.040) while other changes in oxidant and antioxidant indicators were insignificant. DOX-induced significant increases in TNF-alpha and NF-κB were reversed following both low and high-dose AGO administration in a dose-dependent manner (p < 0.001 for both doses). Cellular shrinkage, pycnotic change, and vacuolization in apoptotic bodies were apparent in the cortical and hippocampal areas of DOX-treated samples. Both doses of AGO alleviated these histopathological changes (p = 0.01 for AGO20 and p = 0.05 for AGO40). Significantly increased apoptosis shown with caspase-3 immunostaining in the DOX group was alleviated following AGO administration, with additional improvement after high-dose treatment (p < 0.01 for DOX compared to both AGO groups and p < 0.05 for AGO40 compared to AGO20). AGO can be protective against DOX-induced neurotoxicity by antioxidant, anti-inflammatory, and anti-apoptotic mechanisms in a dose-dependent manner.

Selenium exerts protective effects on inflammatory cardiovascular damage: molecular aspects via SIRT1/p53 and Cyt-c/Cas-3 pathways.

BACKGROUND: Systemic inflammatory response could affect many systems. Cardiac dysfunction develops due to cardiovascular system damage and could be mortal. Selenium is a trace element that can be used as a dietary supplement and has antioxidant, anti-inflammatory, and anti-apoptotic properties. This study aims to evaluate the protective effects of selenium on cardiovascular damage via silenced information regulator 1 (SIRT1)/p53 and cytochrome C (Cyt-c)/ caspase-3 (Cas-3) pathways. METHODS AND RESULTS: Thirty-two rats were randomly divided into 4 groups as control, LPS (0.1 mg/kg, intraperitoneally(i.p.), 2-7 days) and LPS + Selenium (LPS-0.1 mg/kg, i.p., 2-7 days, selenium - 100 µg/kg, i.p., 1-7 days) and selenium (100 µg/kg, i.p., 1-7 days) group. On the 8th day of the experiment, rats were sacrificed. Blood samples and half of the left ventricles were collected for biochemical and genetic analysis. The remaining left ventricles and aorta were taken for histological and immunohistochemical analysis. In the LPS group myocardial hemorrhages, hyperemia, and endothelial cell loss were observed. Also, Cas-3 and vascular endothelial growth factor (VEGF) expressions; creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α), ischemia modified albumin (IMA), total oxidant status (TOS), oxidative stress index (OSI) levels; p53, Cyt-c, Cas-3 mRNA expressions increased while total antioxidant status (TAS) levels, glutathione peroxidase (GPx) activity, SIRT1 mRNA expression decreased. Selenium treatment reversed all these changes. CONCLUSION: Selenium showed protective effects on cardiovascular injury via regulating SIRT1/p53 and Cyt-c/Cas-3 pathways. This study enlightened the possible usage of selenium on cardiotoxicity.

Selenium ameliorates inflammation by decreasing autophagic flux and mitogen-activated protein kinase signalling on experimentally induced rat periapical lesions.

AIM: To reveal the molecular mechanisms that targets mitogen-activated protein kinase (MAPK) signalling and the autophagic flux and to investigate the possible effects of the systemic administration of selenium (Se) on experimentally induced rat periapical lesions. METHODOLOGY: Thirty adult Sprague-Dawley rats were divided equally into negative control, positive control and Se groups. In the positive control and Se groups, the pulp chambers of their mandibular first molars were exposed to the oral environment to induce periapical lesions The Se group received daily intraperitoneal injections of Se at a dose of 0.1 mg kg-1 . After 28 days, the amount of bone destruction; severity of inflammation; penetration of microorganisms along the root canal; collagen degradation in periodontal ligament; interleukin (IL)-6, hypoxia-inducible factor-1 (HIF-1), cyclooxygenase-2 (COX-2) and caspase-3 expression; autophagic flux; and p38 MAPK signalling were evaluated using radiographic, histopathological, Gram staining, picrosirius red stain, immunohistochemical, quantitative real-time polymerase chain (qRT-PCR) and Western blot methods, respectively. These data were analysed through the Kruskal-Wallis and Dunnett's tests (p < .05). RESULTS: The area of radiographic periapical bone loss, histopathological scores, the area of periapical bone loss and the scores for the bacteria localisation, the intensity of immunohistochemical staining for IL-6, HIF-1, COX-2 and caspase-3 in the Se group was significantly less than those of the positive control group (p < .01). The mRNA expression levels of Beclin-1, Atg3, Atg5, Atg7 and Atg16L1 were lower in the Se group than in the positive control group (p < .01). The protein expressions of Beclin-1, Atg5 and LC3-II, the phosphorylation ratio of the p38 MAPK and the ratios of LC3II/LC3I were significantly higher (p < .05) in the positive control and Se groups. On the contrary, the expression of the p62/SQSTM1 protein was significantly lower (p < .05) in the positive control and Se groups than in the negative control group. CONCLUSION: The induction of periapical lesions in rats increased autophagic flux and activated p38 MAPK signal transduction processes. Se suppressed the inflammatory process, reduced bone destruction and both the autophagic flux and p38 MAPK activation.

Combined Pulsed Magnetic Field and Radiofrequency Electromagnetic Field Enhances MMP-9, Collagen-4, VEGF Synthesis to Improve Wound Healing Via Hif-1α/eNOS Pathway.

BACKGROUND: The blood supply of the tissue is very important in the acceleration of wound healing. Radiofrequency electromagnetic field (RF) and the pulsed magnetic field (PMF) increase vasodilation to contribute wound healing. The aim of this study was to evaluate the effects of RF and PMF on wound healing via hypoxia-inducible factor-1 alpha (Hif-1α)/endothelial nitric oxide synthase (eNOS) pathway. METHODS: Forty-eight rats were divided into 4 groups as sham (wound created only), PMF (27.12 MHz, 12 times a day at 30-min intervals), RF (0.5 mT, continuously) and PMF + RF groups. Wounds were created at 1.5 × 1.5 cm size to the dorsal region, and animals were put into unit. Six animals were killed on days 4 and 7; wound tissues were collected for histopathological, immunohistochemical as collagen-4, cytokeratin, matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) staining and Hif-1α/eNOS/VEGF expressions. RESULTS: On day 4, in addition to increasing VEGF and MMP-9 stainings, connection between intact tissue and scar tissue which was stronger in the RF- and PMF-applied groups was observed. On day 7, epithelization started; inflammatory reaction decreased; collagen production, cytokeratin, VEGF and MMP-9 expression enhanced, especially in the RF + PMF applied group. eNOS, Hif-1α and VEGF expression levels were found to be significantly highest in both days of RF + PMF-applied group. CONCLUSIONS: This study revealed that both in vitro RF and PMF applications can cause notable changes in factors that are required for tissue repair on wound healing such as epithelization, connective tissue formation, collagen production and angiogenesis via vasodilatory Hif-1α/eNOS pathway and VEGF signaling. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Ramelteon and mechanism of its restorative effect in an experimental lung disease model.

Methotrexate (MTX) is an anticancer agent widely used in clinical practice for various oncological, rheumatological, autoimmune, and inflammatory diseases. However, the side effects of MTX limit its usage for treatment. In addition, diffuse alveolar damage, interstitial pneumonia, fibrosis, and pleural reactions may be encountered in MTX-induced pulmonary toxicity. Ramelteon (RML), a melatonin receptor agonist, has antioxidant, anti-inflammatory, and protective effects are shown by several studies. This study aimed to show the antioxidant, anti-inflammatory, and antiapoptotic effects of RML and its effect on the airway surface liquid volume homeostasis via aquaporins (AQP) in MTX-induced lung injury. Thirty-two female Wistar Albino rats were grouped into four groups as control, MTX (20 mg/kg, intraperitoneally, a single dose), MTX + RML, and RML (10 mg/kg, via oral gavage, for seven days) groups. Once the experiment ended, the rats' lung tissues were taken for biochemical, genetic, histopathological, and immunohistochemical examinations. MTX significantly increased oxidative stress index and total oxidative status, and decreased total antioxidant status levels by 202.0%, 141.4%, 20.2%, respectively, relative to the control (p ˂ 0.001 for all). AQP-1/5, which is an indicator of lung damage, was also found to decrease significantly (p ˂ 0.001). In addition, a significant increase was observed in interleukin-1ß, interferon-beta, and caspase-8 expressions and histopathological changes as a result of immunohistochemical and histochemical examinations (p ˂ 0.001). RML treatment ameliorated all these changes and significantly regressed lung damage. Our results suggest that RML might be used as a lung-protective agent in various models of lung and tissue injury.

Salubrinal Ameliorates Inflammation and Neovascularization via the Caspase 3/Enos Signaling in an Alkaline-Induced Rat Corneal Neovascularization Model.

Background and Objectives: Ocular alkaline burn is a clinical emergency that can cause permanent vision loss due to limbal stem cell deficiency and corneal neovascularization (CNV). Although the basic pathogenetic mechanisms are considered to be acute oxidative stress and corneal neovascularization triggered by inflammation, the underlying intracellular mechanisms have not been clearly elucidated. The aim of this study was to investigate the role of endoplasmic reticulum (ER) stress on inflammation and neovascularization, and the effect of the ER stress inhibitor salubrinal (SLB), as a novel treatment in a corneal alkaline burn model in rats. Methods: Chemical burns were created by cautery for 4 s using a rod coated with 75% silver nitrate and 25% potassium nitrate in the corneal center for the corneal neovascularization (CNV) model. Twenty-eight Wistar albino rats were divided into four groups: SHAM, CNV, CNV + SLB, and CNV + bevacizumab (BVC). After the CNV model was applied to the right eye, a single subconjunctival dose (0.05 mL) of 1 mg/kg salubrinal was injected into both eyes in the CNV + SLB group. A total of 1.25 mg/mL of subconjunctival BVC was administered to the CNV + BVC group. Fourteen days after experimental modeling and drug administration, half of the globes were placed in liquid nitrogen and stored at -20 °C until biochemical analysis. The remaining tissues were collected and fixed in 10% buffered formalin for histopathological and immunohistochemical analysis. Three qualitative agents from three different pathways were chosen: TNFR for inflammation, endothelial nitric oxide synthase (e-NOS) for vascular endothelial growth factor (VEGF)-mediated vascular permeability, and caspase-3 for cellular apoptosis. Results: Significantly lower caspase-3 and eNOS levels were detected in the CNV + SLB and CNV + BVC groups than in the CNV group. Additionally, histopathological evaluation revealed a significant decrease in neovascularization, inflammatory cell infiltration, and fibroblast activity in the CNV + SLB and CNV + BVC groups. The endoplasmic reticulum stress inhibitor, salubrinal, administered to the treatment group, attenuated apoptosis (caspase-3) and inflammation (e-NOS). In the control group (left eyes of the SLB group), salubrinal did not have a toxic effect on the healthy corneas. Conclusion: The ER stress pathway plays an important role in angiogenesis after alkaline corneal burns, and treatment with SLB modulates this pathway, reducing caspase-3 and eNOS levels. Further studies are needed to understand the molecular mechanisms altered by SLB-mediated therapy. The fact that more than one mechanism plays a role in the pathogenesis of CNV may require the use of more than one molecule in treatment. SLB has the potential to affect multiple steps in CNV pathogenesis, both in terms of reducing ER stress and regulating cellular homeostasis by inhibiting the core event of integrated stress response (ISR). Therefore, it can be used as a new treatment option and as a strengthening agent for existing treatments. Although blockade of intracellular organelle stress pathways has shown promising results in experimental studies, more in-depth research is needed before it can be used in routine practice. To the best of our knowledge, this study is the first to report the role of ER stress in corneal injury.

Protective effects of swimming exercises and metformin on cardiac and aortic damage caused by a high-fat diet in obese rats with type 2 diabetes, by regulating the Bcl2/Bax signaling pathway.

Background/aim: Due to the increasing mortality and morbidity rates in diabetes mellitus (DM), which is one of the biggest health problems of our age, many treatment modalities are still being tried. The positive effects of metformin (MET) and physical exercise (EXE) on the pathophysiology of diabetes are well known. In this study, it was aimed to detail these positive effects of MET and EXE in combination on the basis of inflammation, apoptosis mechanisms, and endogen nesfatin-1 (NES-1) synthesis. Materials and methods: Twenty-seven type 2 DM (DM-2) male Wistar Albino rats were divided into 4 groups, as the high-fat diet (HFD), MET, EXE, and MET+EXE groups. The total duration of the study was 3 months. At the end of the experiment, blood glucose and lipid profiles were measured. Histopathological evaluation was performed on the cardiac and aortic tissues and apoptotic markers were evaluated immunohistochemically. Inflammatory markers and NES-1 levels were analyzed by enzyme-linked immunosorbent assay. Results: The plasma glucose, homeostatic model evaluation-insulin resistance (HOMA-IR), low-density lipoprotein (LDL) levels increased, and high-density lipoprotein (HDL) levels decreased significantly in the HFD group. In the treatment groups, the glucose, HOMA-IR, LDL, NES-1 levels in the plasma, as well as tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß), IL-6, caspase-3 (Cas-3), Bcl-2-associated X protein (Bax), and histopathological findings of inflammation in tissues were decreased. Additionally, there was an increase in plasma insulin, HDL, and tissue B-cell lymphoma-2 and levels. Conclusion: It was observed that the MET and EXE treatments in the DM-2 model reduced cellular damage mechanisms such as inflammation and apoptosis. The decrease in NES-1 levels was thought to be secondary to this antiinflammatory effect. In conclusion, the results demonstrated the effectiveness of EXE in reducing DM-2 and the NES-1 levels. Further studies are needed to evaluate the effect in different EXE models and treatment durations.

Irbesartan decreased mitochondrial stress related apoptosis in cisplatin induced acute kidney injury via regulating BCL-2/BAX signaling.

BACKGROUND: Cisplatin (CPN) is used in the treatment of various cancers. However, the especially nephrotoxic effect is limiting its use. We aimed to evaluate the renoprotective effects of Irbesartan (IBN) on CPN-induced acute kidney injury via mitochondrial stress related apoptosis. METHODS AND RESULTS: 32 rats were divided into 4 groups as control, CPN, CPN + IBN and IBN. Water or IBN 50 mg/kg (orally) was administered for 7 days and a single dose of CPN (5 mg/kg) intraperitoneally was given CPN and CPN + IBN groups on fourth day of experiment. At the end of the experiment, serum BUN and creatinine (Cre) levels, which are the indicators of kidney function are measured. Bcl-2-associated X protein (Bax) and B-cell-lymphoma-2 (Bcl-2) mRNA levels were analyzed by using qRT-PCR from kidneys as a mitochondrial stress indicator. Also, active caspase-3(cas-3) protein and tumor necrosis factor alpha (TNF-α) expressions were examined by immunostaining of the kidney tissues. For evaluation of oxidative stress, malondialdehyde (MDA), total oxidant status (TOS) and total antioxidant status (TAS) levels of renal tissues were measured and oxidative stress index (OSI) were calculated. CPN increased serum BUN and creatinine levels. Also, MDA, TOS and OSI levels were significantly elevated and TAS levels decreased in the CPN group. Moreover, CPN elevated the levels of Bax, active cas-3 protein and TNF-α expressions and suppressed Bcl-2 levels. IBN treatment reversed all these changes. CONCLUSIONS: IBN significantly regressed kidney damage by its anti-inflammatory and antioxidant activity via inhibiting mitochondrial stress. IBN could be used as a renoprotective agent in CPN-induced kidney injury.

"Theranekron: A Novel Anti-inflammatory Candidate for Acetic Acid-Induced Colonic Inflammation in Rats".

BACKGROUND: Inflammatory bowel disease (IBD) is characterized with chronic inflammation of gastrointestinal track. In the pathogenesis of IBD, inflammation is the main mechanism. Induction of inflammation triggers the oxidative stress that subsequently leading to apoptosis. Considering the all pathological mechanisms, many therapeutic agents have been used for IBD but because of serious side effects there is still a need for new therapeutic drugs. In this study, we aim to evaluate the possible protective effects of Theranekron (TH) on acetic acid (AA)- induced colonic damage and to describe the probable effect mechanisms of TH. MATERIALS AND RESULTS: Fourty female adult Wistar albino rats were divided into 5 groups. Following 24 h fasting, colitis was induced by rectal instillation of AA. In TH group, a single dose of subcutaneous 0.2 ml TH was used. In treatment groups, 0.2 ml TH single dose or 100 mg/kg sulfasalazine (SS) for 7 days were used after colitis induction. Normal salin was used for all applications in control group. Histopathologically hemorrhage, edema and inflammatory reactions were seen in AA group. TH and SS decreased the severity of lesions. Nuclear factor kappa B, Serum amyloid A, C-reactive protein, Growth-related oncogene, and Osteopontin expressions were markedly increased in AA group and TH markedly reduced these expressions. In Western analysis, decreased NF-kB and caspase-3 levels were observed with TH. Oxidative markers did not changed significantly. CONCLUSIONS: TH has a prominent anti-inflammatory effect on AA-induced colonic inflammation via NF-kB signaling whereas antiapoptic effects seem to be independent from this pathway.

Dexpanthenol may protect the brain against lipopolysaccharide induced neuroinflammation via anti-oxidant action and regulating CREB/BDNF signaling.

BACKGROUND: Neuroinflammation plays an important role in the pathogenesis of many psychiatric and neurodegenerative diseases. Dexpanthenol (Dex) is an alcoholic analogue of pantothenic acid with antioxidant, anti-inflammatory and anti-apoptotic properties. The purpose of this study was to determine the effect of dexpanthenol on lipopolysaccharide (LPS)-induced brain injury, specifically on the CREB/BDNF pathway. METHOD: Thirty-two rats were distributed into four groups: control, LPS, LPS + Dex and Dex groups. In this study, using real-time PCR, we evaluated changes in the gene expression of BDNF and CREB in the hippocampal brain tissue. Total antioxidant status (TAS), total oxidant status (TOS) were measured spectrophotometrically in the cortical tissue. Brain and cerebellum tissues were collected for histopathological examination and immunohistochemical assessment of tumor necrosis factor alpha (TNF-α) and caspase-3 (Cas-3). RESULT AND DISCUSSION: In the LPS + Dex group, TAS levels were significantly higher while TOS and OSI levels were significantly lower than the LPS group. In the LPS + Dex and Dex group, BDNF relative mRNA expressions were significantly higher than the LPS group. The levels of CREB relative mRNA expression in LPS and LPS + Dex group were significantly lower than the control group. An increased expression of Cas-3 and TNF-α in the LPS group and a decreased expression in the LPS + Dex group were observed in the immunohistochemical examination. CONCLUSION: According to these results, it may be considered that CREB-mediated BDNF synthesis may play a role in the etiopathogenesis of neuroinflammation. By regulating these changes with dexpanthenol treatment, a positive contribution may be made to neuroinflammation treatment.

A study on Wistar Albino rats: investigating protective role of ramelteon on liver damage caused by methotrexate.

Methotrexate is an important immunosuppressive and antineoplastic drug and is widely used for treatment. However, hepatotoxicity is one of the major adverse effects of methotrexate. In this study, it was aimed to investigate whether ramelteon has a possible protective effect on hepatotoxicity induced by methotrexate. Thirty-two Wistar albino rats were equally divided into four groups: control, methotrexate, methotrexate + ramelteon, and ramelteon. Following a single dose of 20 mg/kg, methotrexate (i.p.), either saline or ramelteon 10 mg/kg (orally) was administered for 7 days. After treatment, animals were sacrificed, and histopathological analyses were evaluated with Hematoxylin-eosin (H-E), immunohistological analyses were evaluated with Interleukin-1 Beta (IL-1ß) and Caspase 3 (CAS-3), biochemical analyzes were evaluated with Total Oxidant Status (TOS), Total antioxidants status (TAS), Oxidative Stress Index (OSI), aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities, at last genetical analyses were evaluated with Sirtuin-1 (SIRT-1) - P53 gene expressions. In the control and ramelteon groups, normal histological structures were observed, while histopathological findings were observed in the methotrexate group. Increasing levels of IL-1ß staining, CAS-3 staining, p53 gene expression, TOS, OSI, AST and ALT were observed in methotrexate group while were observed decreasing levels of TAS and SIRT-1 gene expression (p < 0.05). However, ramelteon reduced the increased findings in methotrexate-induced hepatotoxicity (p < 0.05). The results of the present study showed that ramelteon protects against methotrexate induced hepatotoxicity in rats via SIRT-1 signaling by histological, immunohistological, biochemical and genetical analyses.

Nebivolol alleviates liver damage caused by methotrexate via AKT1/Hif1α/eNOS signaling.

Despite the wide clinical indications, methotrexate (MTX) use is limited because of serious side effects including liver toxicity. MTX was shown to cause tissue damage by mainly oxidative stress and also inflammation and apoptosis. Thus, Nebivolol (NEB) which has antioxidant and antiapoptotic properties were thought to be effective against MTX-induced injury. This study aimed to evaluate the effects of NEB on MTX-induced liver toxicity via AKT/Hypoxia-Inducible Factor 1 Alpha (HIF1α)/Endothelial Nitric Oxide Synthase (eNOS) signaling pathways. Rats were divided into three groups as control, MTX, and NEB. A single dose of MTX (20 mg/kg intraperitoneally) was given to the rats on the first day of the experiment and NEB (10 mg/kg, daily by oral gavage) was given to the treatment group for a week. At the end of the experiment, bloods were taken for aspartate transaminase (AST), alanine aminotransferase (ALT), and total bilirubin (T-BIL) analyses. Liver tissues were harvested for biochemical (total oxidant status (TOS) and total antioxidant status (TAS), genetic (PCR analyses for AKT1, eNOS, and HIF1a), and histological (Hemotoxylin-Eosin, Masson Trichome, Periodic Acid Schiff-Asien Blue, reticulin for histological, and CD3 for immunohistochemical staining) analyses. MTX increased the levels of TOS values, AST, ALT, T-BIL levels and decreased the expressions of AKT/HIF1α/eNOS. NEB treatment reversed all these changes markedly via decreasing inflammation by nitric oxid (NO) production. In conclusion, NEB treatment significantly preserves the liver by decreasing oxidant levels and inflammatory parameters through HIF1α/eNOS signaling. Due to the antioxidant properties of NEB, it can be used in other liver injury models sharing the same pathway.

Combined Use of Magnesium Sulfate and Fingolimod for Antenatal Neuroprotection against Inflammation-Mediated Experimental Preterm Brain Injury in a Rat Model.

BackgroundWe compared the neuroprotective effects of Fingolimod (fng), a neuroprotective and anti-inflammatory drug, with that of magnesium sulfate (MgSO4), alone and in combination, in fetal rat whose mothers were exposed to endotoxin.MethodSeven groups of pregnant rats (28 total) were evaluated at 0.8 gestation - Group1 - saline only; 2 - endotoxin only; 3 - endotoxin + MgSO4; 4 - endotoxin + fng; 5 - endotoxin + MgSO4 + fng; 6 - saline + fng; 7 - saline + MgSO4 + fng. Preterm labor was induced 4 h after intraperitoneal endotoxin administration. Fetal brain samples were examined immunohistochemically using S100ß, IL-6, and IL-10.ResultsEndotoxin caused increased expression of S100ß, IL-6, and IL-10. Compared with MgSO4 alone, combined treatment was associated with lower expression of IL-10, IL-6 and S100 ß.ConclusionFng decreases inflammatory markers after in-utero exposure to endotoxin, has a synergistic effect combined with MgSO4, and may be a candidate neuroprotective drug for inflammation-induced preterm brain injury.

Thymoquinone could be protective against valproic acid-induced testicular toxicity by antioxidant and anti-inflammatory mechanisms.

Although valproic acid (VPA) is a low-cost and effective drug, it is known to cause organ toxicity via oxidative stress and related process. In present study, we aimed to evaluate the possible protective effects of thymoquinone (TMQ) on VPA-induced testicular toxicity. Male Sprague-Dawley rats were divided into three as control, VPA (500 mg kg-1  day-1 ) for 14 days and VPA plus TMQ (50 mg kg-1  day-1 for 14 days) with seven rats in. Spermatic and interstitial degenerations induced by VPA were ameliorated with TMQ. In VPA group, increased TOS and OSI levels, and decreased TAS level were seen. TMQ reversed these oxidative stress parameters significantly. In Western analysis, VPA was found to increase the expressions of phospho-nuclear factor kappa beta (p-Nf-kB) and Caspase-3. These expressions were decreased by TMQ significantly. Intense immunostaining for p-Nf-kB, Caspase-3 and NADPH oxidase 2 induced by VPA were transformed to moderate immunostaining by TMQ. VPA-induced inflammation and apoptosis that were developed mainly by p-Nf-kB pathway were attenuated by TMQ. TMQ can be a candidate supportive treatment for patients who need long-term and high-dose VPA therapy. TMQ inhibits the Nf-kB activation, and in addition to antioxidant property, it shows anti-inflammatory feature on VPA-induced testicular toxicity.

Immunohistochemical analysis of protective effects of maternal fingolimod on the placenta and fetal lung and brain in chorioamnionitis-induced preterm birth rat model.

OBJECTIVES: Fingolimod (FIN) is used for multiple sclerosis treatment and has potential antiapoptotic and anti-inflammatory effects. We aimed at expanding our knowledge on various immunohistochemical markers for elucidating the possible mechanisms of action of fingolimod in the placenta and fetal lung and brain. METHODS: Sixteen pregnant rats were divided into four groups. On gestational day 17, lipopolysaccharide (LPS) was injected intraperitoneally to induce preterm fetal injury followed by intraperitoneal injection of fingolimod. Hysterotomy for preterm delivery was performed 6 h after fingolimod was injected. The study groups included (1) control, (2) LPS (1 mg/kg), (3) FIN (4 mg/kg), and (4) FIN + LPS. Fetal brain and lung and placenta samples were collected for histopathological examination. Moreover, fetal lungs (surfactant protein-A (SP-A), SP-B, SP-D, caspase-3, and caspase-8), fetal brains (interleukin-10, interleukin-1ß, TNF-α, caspase-8, glial fibrillary acidic protein, vimentin, myelin basic protein, and receptor activator of nuclear factor kappa), and placenta tissues (interleukin-10, interleukin-1ß, TNF-α, caspase-3, and caspase-8) were immunohistochemically evaluated. RESULTS: Maternal fingolimod treatment led to attenuation of LPS-induced fetal brain, lung, and placental injury, as indicated by lower immunoexpression of inflammatory markers compared to LPS group (p < .0001 for all comparisons). CONCLUSION: The findings of the present study confirm the neuroprotective effects of antenatally administered fingolimod, which also significantly improved preterm fetal lung injury and placental inflammation in LPS-exposed preterm pregnancies by possible antiapoptotic and anti-inflammatory effects.

Pathology of cigarettes on the reproductive system and ameliorative effects of alpha lipoic acid: A rat model study.

Cigarette smoking (CS) has some detrimental effects that occur via oxidative stress (OS). The aim of this work was to demonstrate the pathological and immunohistochemical effects of CS and the protective effects of a strong antioxidant alpha lipoic acid (ALA) on CS-induced genital system changes in a rat model. Twenty-eight female rats were randomly allocated to three groups as control, CS-exposed, and CS-exposed and ALA-treated. Reproductive tract organs were collected for biochemical and pathological examinations. In the CS group, OS markers increased in the tissues of both the ovary and fallopian tubes. Decreased follicle numbers in the ovary, marked cilial loss in the fallopian tubes, and pathologic changes in the uterus were observed in the CS group. Positive calcitonin gene-related peptide (CGRP), caspase 3α, hypoxia-inducible factor 1α (HIF-1α), tumor necrosis factor-α (TNF-α) immunoreactions were observed in uterine tissues and HIF-1α immunoreactions in tubal and uterine epithelial cells of the CS group. ALA reversed all these findings effectively. CS has negative effects on the female reproductive system via HIF-1α in tuba uterina and HIF-1α, HIF-2α, TNF-α, caspase 3, and CGRP in the uterus, and ALA could protect against the negative effects of CS on the female reproductive system.