The protective role of selenium against high-fructose corn syrup-induced kidney damage: a histopathological and molecular analysis.

With the growth of the food industry, fructose, the intake of which increases with food, causes obesity and metabolic syndrome. Kidney damage may develop from metabolic syndrome. Selenium (Se) participates in the structure of antioxidant enzymes and has a medicinal effect. In this work, the protective impact of Se on kidney damage produced by high-fructose corn syrup (HFCS) via endoplasmic reticulum (ER) stress was examined. The study comprised four groups, each consisting of ten experimental animals: control, HFCS (20%-HFCS), HFCS (20%-HFCS), + Se (0.3 mg/kg/day/po), and Se (0.3 mg/kg/day/po) alone. The duration of the experiment was 6 weeks. Kidney tissues were stained with hematoxylin and eosin for histological examination. Immunohistochemical analysis was conducted to assess TNF-α and caspase-3 levels. The spectrophotometric evaluation was performed to measure TOS (total oxidant status), TAS (total antioxidant status), and OSI (oxidative stress index) levels. The PERK, ATF4, CHOP, BCL-2, and caspase-9 gene expression levels were assessed by the RT-qPCR method. After Se treatment, histopathological abnormalities and TNF-α and caspase-3 levels in the HFCS+Se group decreased (p < 0.001). While TOS and OSI levels increased dramatically in the HFCS group, TAS values decreased significantly but improved after Se application (p < 0.001). The expression levels of the genes PERK, ATF4, CHOP, and caspase-9 were significantly lower in the HFCS group when compared to the HFCS+Se group (p < 0.05). Our findings suggest that Se may protect against ER stress, oxidative stress, apoptosis, and kidney damage caused by high-dose fructose consumption.

Potential Hepatoprotective Effects of Irbesartan, an Accessible Angiotensin II Receptor Blocker, Against Cisplatin-Induced Liver Injury in a Rat Model.

Objectives: Drug-induced liver injury is a common adverse reaction that frequently occurs with chemotherapeutic agents, such as cisplatin (CIS). This study seeks to enhance our understanding of drug actions and their associated adverse effects by examining the toxicity of CIS on rat liver tissue. We aimed to investigate the potential hepatoprotective effects of irbesartan (IRB), an easily accessible angiotensin II receptor blocker, in mitigating CIS-induced hepatotoxicity. Materials and Methods: Wistar albino rats were divided into four groups. These groups included a control group [saline, per oral (p.o.)] for seven days, and 1 mL saline intraperitoneal [(i.p.) on the fourth day]; a CIS group (1 mL saline for seven days and 7.5 mg/kg CIS i.p. on the fourth day); a CIS + IRB group (IRB: 50 mg/kg p.o. for seven days and 7.5 mg/kg CIS i.p. on the fourth day), and an IRB group (50 mg/kg IRB p.o. for seven days). The effect of IRB on interleukin-1 beta (IL-1ß) and caspase 3 levels was evaluated by immunohistochemical analysis, and its effects on mRNA expression levels of CCAAT/enhancer-binding protein homologous protein (CHOP) and immunoglobulin-heavy-chain-binding protein (BiP) were tested by quantitative real-time polymerase chain reaction. Results: IRB administration mitigated CIS-induced liver toxicity by inhibiting endoplasmic reticulum (ER) stress. Specifically, this drug reduced the mRNA expression of ER stress markers, including CHOP and BiP. In addition, IRB treatment decreased oxidative stress, inflammatory responses, and apoptotic markers. Conclusion: These findings suggest that IRB is a promising therapeutic option for preventing CIS-induced liver injury, potentially by modulating ER stress-related pathways.

The effects of cannabidiol against Methotrexate-induced lung damage.

Methotrexate (MTX) is a widely used medication for various cancers, yet its use is associated with adverse effects on organs, notably the lungs. Cannabidiol (CBD), known for its antioxidant and anti-inflammatory properties, was investigated for its potential protective effects against MTX-induced lung injury. Thirty-two female Wistar Albino rats were divided into four groups: control, MTX (single 20 mg/kg intraperitoneal dose), MTX + CBD (single 20 mg/kg MTX with 0.1 ml of 5 mg/kg CBD for 7 days intraperitoneally) and CBD only (for 7 days). Lung tissues were analysed using histopathological, immunohistochemical and PCR methods after the study. Histopathological assessment of the MTX group revealed lung lesions like hyperemia, edema, inflammatory cell infiltration and epithelial cell loss. Immunohistochemical examination showed significant increases in Cas-3, tumour necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-κB) expressions. PCR analysis indicated elevated expressions of apoptotic peptidase activating factor 1 (Apaf 1), glucose-regulated protein 78 (GRP 78), CCAAT-enhancer-binding protein homologous protein (CHOP) and cytochrome C (Cyt C), along with reduced B-cell lymphoma-2 (BCL 2) expressions in the MTX group, though not statistically significant. Remarkably, CBD treatment reversed these findings. This study highlights CBD's potential in mitigating MTX-induced lung damage, suggesting its therapeutic promise.

Dexpanthenol ameliorates lipopolysaccharide-induced cardiovascular toxicity by regulating the IL-6/HIF1α/VEGF pathway.

Introduction: Lipopolysaccharide (Lps) is an essential component responsible for the virulence of gram-negative bacteria. Lps can cause damage to many organs, including the heart, kidneys, and lungs. Dexpanthenol (Dex) is an agent that exhibits anti-oxidative and anti-inflammatory effects and stimulates epithelialization. In this study, we aimed to investigate the effects of Dex on Lps-induced cardiovascular toxicity. Methods: Rats were divided into four groups: control, Lps (5 mg/kg, intraperitoneal), Dex (500 mg/kg, intraperitoneal), and Lps + Dex. The control group received saline intraperitoneally (i.p.) once daily for three days. The Lps group received saline i.p. once daily for three days and a single dose of Lps i.p. was administered on the third day. The Dex group received Dex i.p. once daily for three days and saline on the third day. The Lps + Dex group received Dex i.p. once daily for three days and a single dose of Lps i.p. on the third day. Heart and aortic tissues were taken for biochemical, histopathological, immunohistochemical, and genetic analysis. Results: Lps injection caused histopathological changes in both heart and aortic tissues and significantly increased total oxidant status and oxidative stress index levels. Interleukin-6, and Tumor necrosis factor-α mRNA expressions were significantly altered in heart and aorta, likely do to the anti-inflammatory and antioxidative effects of Dex. Furthermore, Dex affected Caspase-3 and Hypoxia-inducible factor 1-α staining patterns. Conclusions: Our results show that Dex treatment has a protective effect on Lps-induced cardiac and endothelial damage in rats by reducing inflammation, oxidative stress, and apoptosis.

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.

Investigation of cardioprotective effect of lercanidipine on doxorubicin-induced cardiotoxicity.

Although doxorubicin (DOX) is an effective anti-neoplastic drug for many types of cancer, particularly dose-related cardiotoxicity limits the use of the drug. In this study, it was aimed to investigate the protective effect of lercanidipine (LRD) against DOX-induced cardiotoxicity. In our study, 40 Wistar albino female rats were randomly divided into 5 groups as control, DOX, LRD 0.5 (DOX + 0.5 mg/kg LRD), LRD 1 (DOX + 1 mg/kg LRD), and LRD 2 (DOX + 2 mg/kg LRD). At the end of the experiment, the rats were sacrificed, and their blood, heart, and endothelial tissues were examined biochemically, histopathologically, immunohistochemically, and genetically. According to our findings, necrosis, tumor necrosis factor alpha activity, vascular endothelial growth factor activity, and oxidative stress were increased in the heart tissues of the DOX group. In addition, DOX treatment caused the deteriorations in biochemical parameters, and levels of autophagy-related proteins, Atg5, Beclin1, and LC3-I/II were detected. Significant dose-related improvements in these findings were observed with LRD treatment. Besides, Atg5, LC3-I/II, and Beclin1 levels evaluated by western blot revealed that LRD exerts a tissue protective effect by regulating autophagy in endothelial tissue. LRD treatment, which is a new-generation calcium channel blocker, showed antioxidant, anti-inflammatory, and anti-apoptotic properties in heart and endothelial tissue in a dose-dependent manner and also showed protective activity by regulating autophagy in endothelial tissue. With studies evaluating these mechanisms in more detail, the protective effects of LRD will be revealed more clearly.

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 .

Effect of adalimumab on experimental corneal neovascularization model.

PURPOSE: To evaluate the efficacy of adalimumab (ADA) on inhibition of experimental corneal neovascularization (CNV) and compare the outcomes with bevacizumab (BEVA). METHODS: Twenty-four female Winstar rats (48 eyes) were used. Silver/Potassium Nitrate sticks were used for creating CNV. Forty-eight eyes of the rats were separated into 6 groups. The eyes which only NaCl was injected subconjunctivally (SC) formed Group-1. The eyes which CNV was created and NaCl, BEVA (2.5 mg/0.05 mL), ADA (2.5 mg/0.05 mL), respectively, were injected SC formed group-2, 3 and 4. The eyes which only BEVA and ADA, respectively, were injected SC formed group-5 and 6. Five days later the animals were sacrificed. Hematoxylin and eosin staining, Masson trichrome staining, Vascular endothelial growth factor (VEGF), and Platelet-derived growth factor (PDGF) antibodies were performed. RESULTS: Histochemical results showed that there was no histopathological finding in group-1, 5, and 6. Collagen fiber irregularity was observed in group-2 and there was a significant improvement in collagen fiber irregularity in group-3 and 4. Collagen fiber proliferation was higher in group-2 than in group-3 and 4. VEGF and PDGF stainings were not observed in group-1, 5, and 6. VEGF and PDGF stainings were observed in group-2 and significantly decreased in group-3 and 4 compared to group-2. ADA was found to be superior to BEVA in terms of decreasing VEGF staining. CONCLUSION: Both BEVA and ADA were effective in inhibiting CNV. Subconjunctival ADA seems to be more effective than BEVA in terms of inhibiting VEGF expression. Further experimental studies about ADA and BEVA are needed.

The ß1 Adrenergic Blocker Nebivolol Ameliorates Development of Endotoxic Acute Lung Injury.

Acute lung injury (ALI) is a disease, with no effective treatment, which might result in death. Formations of excessive inflammation and oxidative stress are responsible for the pathophysiology of ALI. Nebivolol (NBL), a third-generation selective ß1 adrenoceptor antagonist, has protective pharmacological properties, such as anti-inflammatory, anti-apoptotic, and antioxidant functions. Consequently, we sought to assess the efficacy of NBL on a lipopolysaccharide (LPS)-induced ALI model via intercellular adhesion molecule-1 (ICAM-1) expression and the tissue inhibitor of metalloproteinases-1 (TIMP-1)/matrix metalloproteinases-2 (MMP-2) signaling. Thirty-two rats were split into four categories: control, LPS (5 mg/kg, intraperitoneally [IP], single dose), LPS (5 mg/kg, IP, one dosage 30 min after last NBL treatment), + NBL (10 mg/kg oral gavage for three days), and NBL (10 mg/kg oral gavage for three days). Six hours after the administration of LPS, the lung tissues of the rats were removed for histopathological, biochemical, gene expression, and immunohistochemical analyses. Oxidative stress markers such as total oxidant status and oxidative stress index levels, leukocyte transendothelial migration markers such as MMP-2, TIMP-1, and ICAM-1 expressions in the case of inflammation, and caspase-3 as an apoptotic marker, significantly increased in the LPS group. NBL therapy reversed all these changes. The results of this study suggest that NBL has utility as a potential therapeutic agent to dampen inflammation in other lung and tissue injury models.

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.

Ameliorating effects of ramelteon on oxidative stress, inflammation, apoptosis, and autophagy markers in methotrexate-induced cerebral toxicity.

Objectives: Methotrexate (MTX) is a widely used chemotherapeutic agent that, however, is known to have serious side effects such as neurotoxicity. In the present study, we aimed to evaluate the possible favorable effects of ramelteon (RMLT) on MTX-induced cerebral toxicity. Materials and Methods: Thirty-two male Wistar albino rats were divided into four groups: Control group, MTX group (20 mg/kg MTX, IP, single dose), MTX+RMLT group (20 mg/kg MTX, IP, single dose + 10 mg/kg RMLT, by gavage, 7 days), and RMLT group (10 mg/kg RMLT, by gavage, 7 days). Results: In the MTX group, increased levels of total oxidant status (TOS) and oxidative stress index (OSI) levels and decreased levels of total antioxidant status (TAS) level were observed. RMLT significantly reversed oxidative stress parameters. Real-time PCR analysis revealed that MTX increased the expressions of Beclin-1 and autophagy-related gene 12 (ATG12). These expressions were significantly decreased by RMLT. Vacuolar changes, apoptotic cells, and inflammatory cell infiltration induced by MTX were ameliorated by RMLT treatment. Increased tumor necrosis factor-α (TNF- α) and Caspase-3 activities induced by MTX were returned to their normal levels by RMLT. Conclusion: All our results demonstrate that RMLT alleviates the harmful effects of MTX on the cerebral cortex tissue. Therefore, RMLT may be considered for supportive therapy for preventing side effects of MTX in patients needing MTX therapy.

Melatonin receptor agonist ramelteon alleviates experimental acute ocular inflammation via HIF-1Α/VEGF/E-NOS signaling.

PURPOSE: Ramelteon (RML) is a potent, selective agonist of the high-affinity melatonin receptor 1 and 2 receptors. In addition, RML is known to have antioxidant and anti-inflammatory effects. In this study, we aimed to investigate the effects of RML on HIF-1α, VEGF and e-NOS signaling pathway in a rat model of endotoxin-induced uveitis (EIU). METHODS: Twenty-eight Wistar albino rats were divided into 4 groups as controls, lypopolysaccharide (LPS) group (5 mg/kg i.p.), LPS + RML group (5 mg/kg i.p and 8 mg/kg orally, respectively) and RML group (8 mg/kg orally). EIU was induced by a single intraperitoneal LPS injection. Histopathological and genetical analyses were performed. RESULTS: In histopathological analysis, LPS caused mild anterior uveitis characterized by increased surface area of iris leaflets and ciliary body due to edema, mild to moderate congestion, and inflammatory infiltrate 6 h following the injection. The pathological findings were reduced by RML. Higher inflammation levels seen in LPS group were significantly reduced in LPS + RML group. Also, HIF-1 α, eNOS and VEGF expressions increased in LPS and decreased in LPS + RML group. CONCLUSION: RML treatment reversed the changes in the HIF-1α /eNOS/ VEGF signaling pathway in LPS-induced uveitis in rats, preventing the progression of the damage and showed positive effects.

"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.

The Possible Protective Effect of Boric Acid in an Alkaline-Induced Corneal Neovascularization Rat Model.

It is known that boric acid (BA) exerts it antioxidant and anti-inflammatory effects by activating the activating transcription factor 4 (ATF4) and nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. This pathway has been reported to control antioxidant status in the eye. The aim of this study was to investigate the possible preventive effects of boric acid administration on oxidative damage and corneal neovascularization (CNV). Sixteen adult female Wistar albino rats were divided into two groups: (I) control (n = 8); the CNV model was applied to the right eye of the rats, and the left eyes were used as healthy controls. (II) CNV + BA (n = 8): After the CNV model was applied to the right eyes, a single subconjunctival dose (0.05 mL) of 0,018 g/mL BA was injected into the right and left eyes of the rats. Biochemical, histopathological, and immunohistochemical analyses were performed. Moderate VEGF positivity was observed in the vessels of the CNV group, a decrease in vessel proliferation, and weak VEGF positivity in the CNV + BA group. The TAS level in the CNV + BA group was significantly higher than that in the other groups. The TOS level was significantly higher in all groups than it is in the control group. The OSI value was increased in all groups when compared to the control group, but only the CNV and BA groups were statistically significant. BA not only reduced alkaline-induced corneal damage histologically but also showed a protective effect on oxidative stress biochemically.

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.

Modulation of Salubrinal-Mediated Endoplasmic Reticulum Stress in an Experimental Subarachnoid Hemorrhage Model.

BACKGROUND: Perfusion abnormalities due to vasospasm remain a major cause of morbidity and mortality in subarachnoid hemorrhage (SAH). Despite a large number of clinical trials, therapeutic options with strong evidence for prevention and treatment of cerebral vasospasm are rare. In this study, we aimed to evaluate the neuroprotective effect of salubrinal (SLB) in endoplasmic reticulum stress-induced apoptosis, a catastrophic consequence of vasospasm. METHODS: Thirty-two Wistar albino rats were divided into 4 groups of 8 rats each: control group, SAH, SAH+SLB, and SAH+nimodipine (NMN). In the SAH+SLB group, intraperitoneal SLB (1 mg/kg dose) administered 30 minutes after establishment of SAH, and in the SAH+NMN group, intraperitoneal NMN (0.1 mg/kg dose) was also administered 30 minutes after SAH. RESULTS: Higher total antioxidant status level, lower oxidative stress index, and significantly higher vascular endothelial growth factor-A (VEGF-A) level were detected in the SAH+SLB and SAH+NMN groups compared with the SAH group. There was a significant increase in eukaryotic translation initiation factor-2 alpha (elF2α) level in the SAH+SLB group compared with the SAH group. Histopathological evaluation revealed decrease in the subarachnoid hemorrhagic area, as well as in cortical edema and apoptotic bodies in the SAH+SLB and SAH+NMN groups. There was a significant decrease in caspase-3 staining in the SAH+SLB group, and the levels were significantly less in the SAH+NMN group than the SAH and SAH+SLB groups. CONCLUSIONS: SLB, selective inhibitor of eIF2α dephosphorylation, and NMN, a calcium channel blocker, can ameliorate SAH-induced damage. Inhibition of eIF2α dephosphorylation and enhanced VEGF-A production with SLB may protect brain tissue from apoptosis.

Pregabalin Protects Brain Tissue from Subarachnoid Hemorrhage by Enhancing HIF-1α/eNOS Signaling and VEGF Production.

OBJECTIVE: We investigated the effects of different doses of pregabalin on the pathophysiologic changes in early brain injury after subarachnoid hemorrhage (SAH) in rats. METHODS: Thirty-eight Wistar albino rats were divided into 4 groups: control (n = 8), SAH (n = 10), SAH plus 30 mg/kg/day of pregabalin (n = 10), and SAH plus 60 mg/kg/day of pregabalin (n = 10). SAH was induced with 0.3 mL of autologous blood injected to the cisterna magna of rats. Pregabalin was administered intraperitoneally. Oxidative stress markers, mRNA expression of endothelial nitric oxide synthase, hypoxia-inducible factor-1α, and vascular endothelial growth factor, and histopathological changes were evaluated. RESULTS: Pregabalin increased mRNA expression of endothelial nitric oxide synthase, hypoxia-inducible factor-1α, and vascular endothelial growth factor in a dose-dependent manner. Significant improvement in the histopathological parameters was observed at 60 mg/kg, including a decrease in diffuse hemorrhagic areas, edema and apoptotic bodies in the associated cortical area, evident vacuolization in the hippocampal area, and apoptotic bodies. However, these improvements were not observed with the lower dose (30 mg/kg). In contrast, the antioxidant effect was greater with 30 mg/kg of pregabalin than with 60 mg/kg. CONCLUSIONS: Although the antioxidant effect was significant with the lower dose of pregabalin, the anti-inflammatory effects via vasodilatation were more marked with the higher dose. Significant improvements in the histopathological changes were observed with the higher dose of pregabalin. The dose-dependent effects of pregabalin on SAH should be evaluated in animal studies as a function of time and in the acute and chronic phases.

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.