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.

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.

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.

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.

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.

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.

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.