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Πέμπτη 25 Ιουλίου 2019

Histone deacetylases in stroke,

Mei-Han Kao, Teng-Nan Lin

Chinese Journal of Physiology 2019 62(3):95-107

Stroke is the second leading cause of death and the leading cause of adult disability worldwide. Despite an impressive amount of neuroprotective agents that has been identified in experimental stroke, none of them proved efficient in clinical trials. There is a general consensus that an effective treatment requires the ability to interact with not one, but multiple pathophysiological cascades at different levels that induced by the insult – cocktail therapy. Luckily, recent progress in the field of epigenetics revealed that epigenetic modifications had influence on many known pathways involved in the complex course of ischemic disease development. The fact that epigenetic molecules, by altering transcriptional regulation, may simultaneously act on different levels of ischemic brain injury makes them promising candidates for clinical use. These modifications arise typically owing to deoxyribonucleic acid methylation and histone acetylation. The aim of this review is to give a comprehensive overview of current advances in stroke epigenetics, in particular, the physiological and pathological functions of the 11 classical histone deacetylases. 

Additive and nonadditive effects of salmon calcitonin and omega-3 fatty acids on antioxidant, hematological and bone and cartilage markers in experimental diabetic-osteoarthritic rats
Wale J Adeyemi, Luqman A Olayaki

Chinese Journal of Physiology 2019 62(3):108-116

Reports on the coexistence of diabetes mellitus and osteoarthritis in human subjects dated back to the 1960s. However, there is no account in literature on the co-manifestation of these disease conditions in experimental animals. In our previous study, we reported for the first time, the effects of pharmacological agents on glucoregulatory indices, lipid profile, and inflammatory markers in experimental diabetic-knee osteoarthritic rat. However, in the present study, the effects of salmon calcitonin (Sct), and/or omega-3 fatty acids (N-3) were further investigated on other biomarkers. Forty-nine rats of seven animals per group were used for this study. Diabetes was induced by the administration of streptozotocin (65 mg/kg) and nicotinamide (110 mg/kg). Thereafter, knee osteoarthritis was induced by the intra-articular injection of 4 mg of sodium monoiodoacetate in 40 μl of saline. Nine days after the inductions, treatments started, and they lasted for 4 weeks. N-3 was administered at 200 mg/kg/day, while Sct was administered at 2.5 and 5.0 IU/kg/day. The results of the study indicated that the induced diabetes-knee osteoarthritis caused significant alterations in all the observed biomarkers. Sct showed a dose-specific effect and an additive action with N-3 in reducing malondialdehyde and lactate dehydrogenase, and in elevating total bilirubin and total antioxidant capacity. However, it largely demonstrated a nondose-specific effect and nonadditive action with N-3 on superoxide dismutase, catalase, glutathione peroxidase, total alkaline phosphatase, c-telopeptide of type-I collagen, collagen type-2 alpha 1, and hematological indices. In conclusion, the combined administration of Sct and N-3 proffer better therapeutic effects than the single therapy; therefore, they could be used in the management of diabetic-osteoarthritic condition. 

Altered expression of vascular endothelial growth factor, vascular endothelial growth factor receptor-1, vascular endothelial growth factor receptor-2, and Soluble Fms-like Tyrosine Kinase-1 in peripheral blood mononuclear cells from normal and preeclamptic pregnancies
Zaima Ali, Saba Khaliq, Saima Zaki, Hafiz Usman Ahmad, Khalid Pervaiz Lone

Chinese Journal of Physiology 2019 62(3):117-122

Preeclampsia (PE) is the leading cause of maternal and fetal morbidity and mortality. It complicates around 2%–10% pregnancies worldwide due to imbalance between proangiogenic and anti-angiogenic factors, leading to incomplete placentation, ischemia, and endothelial dysfunction. The study was aimed to analyze the mRNA expression of vascular endothelial growth factor (VEGF) and its receptors, i.e., VEGF receptor-1 (VEGFR-1), VEGF receptor-2 (VEGFR-2), and soluble Fms-like tyrosine kinase-1 (sFlt-1) from maternal peripheral blood mononuclear cells (PBMCs) of PE patients. This was a cross-sectional comparative study comprising 18 normotensive and 18 PE patients; the patients were further divided as early-onset preeclampsia (EOP) and late-onset preeclampsia (LOP). The expression level of VEGF, its receptors (VEGFR-1 and VEGFR-2), and sFlt-1 was investigated using real-time polymerase chain reaction. There was a significant change in the mRNA expression with a decrease in VEGF, VEGFR-1, and VEGFR-2 and an increase in sFlt-1 in PBMCs of PE and normal pregnancies (P < 0.001). sFlt-1 mRNA expression was increased by 2.95-fold in the PE group with an inverse correlation with expression of VEGFR-2 (Spearman's rho = 0.68). Based on these findings, we conclude that PE is associated with decrease in the mRNA expression of VEGF, VEGFR-1, and VEGFR-2 as compared to an increase in sFlt-1 in PBMCs. 

Action of chlorzoxazone on Ca2+movement and viability in human oral cancer cells
Ti Lu, Wei-Zhe Liang, Lyh-Jyh Hao, Chun-Chi Kuo, Pochuen Shieh, Chiang-Ting Chou, Chung-Ren Jan

Chinese Journal of Physiology 2019 62(3):123-130

Chlorzoxazone is a skeletal muscle relaxant. However, the effect of chlorzoxazone on intracellular Ca2+ concentrations ([Ca2+]i) in oral cancer cells is unclear. This study examined whether chlorzoxazone altered Ca2+ signaling and cell viability in OC2 human oral cancer cells. [Ca2+]iin suspended cells was measured using the fluorescent Ca2+-sensitive dye fura-2. Cell viability was examined by water-soluble tetrazolium-1 assay. Chlorzoxazone (250–1000 μM) induced [Ca2+]irises in a concentration-dependent manner. Ca2+ removal reduced the signal by approximately 50%. Mn2+ has been shown to enter cells through similar mechanisms as Ca2+ but quenches fura-2 fluorescence at all excitation wavelengths. Chlorzoxazone (1000 μM) induced Mn2+ influx, suggesting that Ca2+ entry occurred. Chlorzoxazone-induced Ca2+ entry was inhibited by 20% by inhibitors of store-operated Ca2+ channels and protein kinase C (PKC) modulators. In Ca2+-free medium, treatment with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin (TG) inhibited chlorzoxazone-evoked [Ca2+]irises by 88%. Conversely, treatment with chlorzoxazone-suppressed TG-evoked [Ca2+]irises 75%. Chlorzoxazone induced [Ca2+]irises by exclusively releasing Ca2+ from the endoplasmic reticulum. Inhibition of phospholipase C (PLC) with U73122 did not alter chlorzoxazone-induced [Ca2+]irises. PLC activity was not involved in chlorzoxazone-evoked [Ca2+]irises. Chlorzoxazone at 200–700 μM decreased cell viability, which was not reversed by pretreatment with Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/acetoxy methyl. In sum, in OC2 cells, chlorzoxazone induced [Ca2+]irises by evoking PLC-independent Ca2+ release from the endoplasmic reticulum and Ca2+ entry via PKC-sensitive store-operated Ca2+ entry. Chlorzoxazone also caused Ca2+-independent cell death. Since [Ca2+]irises play a triggering or modulatory role in numerous cellular phenomena, the effect of chlorzoxazone on [Ca2+]iand cell viability should be taken into account in other in vitro studies. 

Can royal jelly protect against renal ischemia/reperfusion injury in rats?
Mohammad Reza Salahshoor, Cyrus Jalili, Shiva Roshankhah

Chinese Journal of Physiology 2019 62(3):131-137

Royal jelly (RJ) is a honeybee secretion, has numerous medicinal properties in particular antioxidant activities. Ischemia/reperfusion (I/R) is one of the main challenges in acute kidney damage. This study was designed to assess the anti-inflammatory and protective effects of RJ against I/R-induced renal disorders. Forty male rats were randomly divided into four groups (n = 10) as sham (0.9% saline) group, I/R group, RJ group (treated for 15 consecutive days by gavage with 300 mg/kg/day RJ), and I/R + RJ group that were pretreated for 15 consecutive days by gavage with 300 mg/kg/day of RJ. The I/R-induced renal inflammation was evaluated by determining leukocyte infiltration and mRNA expression level of intercellular adhesion molecule-1 and tumor necrotic factor-alpha (TNF-α). Antioxidant capacity of kidneys and thiobarbituric acid reactive species was measured in kidneys for the evaluation of oxidative stress. In addition, the diameter of renal glomeruli, kidney function indicators, and serum nitrite oxide (NO) levels was determined. The I/R increased the completely measured parameters, except the tissue ferric reducing/antioxidant power (FRAP) level, which was decreased compared to the sham group (P < 0.05). However, pretreatment with RJ reduced significantly blood urea nitrogen, kidney malondialdehyde, creatinine, glomerular diameter, leukocyte infiltration, levels of TNF-α, adhesion molecule-1 expression, and NO and increased tissue FRAP compared to the I/R group (P < 0.05). It seems that RJ administration improved I/R-induced acute kidney injury. 

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