Clinical and Experimental Pharmacology and Physiology最新文献

{"title":"Olfactory training for olfactory dysfunction in COVID-19: A promising mitigation amidst looming neurocognitive sequelae of the pandemic.","authors":"Pooja Ojha,&nbsp;Abhinav Dixit","doi":"10.1111/1440-1681.13626","DOIUrl":"https://doi.org/10.1111/1440-1681.13626","url":null,"abstract":"<p><p>Olfactory dysfunction (OD) is a recognized symptom of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is independently associated with neurodegenerative disorders. Moreover, the central nervous system manifestations in patients infected with the coronavirus-2019 (COVID-19) have demonstrated cognitive decline and neuropsychiatric manifestations. Hence, OD in COVID-19 necessitates perusal of its mechanism and available treatment options to avert possible development of neurocognitive sequelae of the pandemic. The article presents a literature review organized from the published information about olfactory training (OT) for OD during COVID-19. The methodology comprised retrieval of available literature from database searches and subsequent scrutinization of relevant information. Inferentially, injury to the sustentacular cells, possessing angiotensin-converting enzyme 2 (ACE-2) receptors, is an important mechanism causing OD in COVID-19. Olfactory dysfunction may be prolonged in severe cases of anosmia predisposing to neurodegenerative and cognitive impairment in COVID-19 infection. Olfactory training demonstrates an effective treatment for OD based on human and animal-derived evidence through recent studies. It curtails the progression of OD, besides inducing neural rearrangement and changes in functional connectivity in patients receiving OT. Additionally, contemporary reports support that the administration of OT for COVID-induced anosmia is effective and encompasses no significant adverse effects. The present review highlights the prominence of olfactory training as a recommended intervention for OD in COVID-19. This review can guide the clinicians in curbing neurological repercussions of COVID besides enhancing cognitive rehabilitation through olfactory training.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"49 4","pages":"462-473"},"PeriodicalIF":0.0,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39868357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salt loading with unilateral nephrectomy accelerates decline in glomerular filtration rate in the hypertensive, obese, type 2 diabetic SDT fatty rat model of diabetic kidney disease.","authors":"Yuichi Shinozaki,&nbsp;Yuko Katayama,&nbsp;Fuminari Yamaguchi,&nbsp;Tomohisa Suzuki,&nbsp;Kana Watanabe,&nbsp;Kinuko Uno,&nbsp;Takahiro Tsutsui,&nbsp;Miki Sugimoto,&nbsp;Masami Shinohara,&nbsp;Katsuhiro Miyajima,&nbsp;Takeshi Ohta","doi":"10.1111/1440-1681.13621","DOIUrl":"https://doi.org/10.1111/1440-1681.13621","url":null,"abstract":"<p><p>For the evaluation of novel therapeutic agents for diabetic kidney disease (DKD), it is desirable to examine their efficacy in animal models by using the glomerular filtration rate (GFR) as an index. For this purpose, animal models that demonstrate a short-term GFR decline because of disease progression are required. Therefore, we aimed to develop such an animal model of DKD by using obese type 2 diabetic spontaneously diabetic Torii (SDT) fatty rats treated with salt loading by drinking water containing sodium chloride with or without unilateral nephrectomy. As a result, we have found that 0.3% salt loading with unilateral nephrectomy or 0.8% salt loading alone caused a rapid GFR decline, hypertension and rapid development of tubulointerstitial fibrosis. Moreover, the addition of losartan to a mixed diet suppressed the GFR decline in SDT fatty rats treated with 0.3% salt loading with unilateral nephrectomy. These results suggest that the model of SDT fatty rats treated with 0.3% salt loading and unilateral nephrectomy could be used as a hypertensive DKD model for evaluating therapeutic agents based on suppression of GFR decline.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"49 4","pages":"492-500"},"PeriodicalIF":0.0,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39851619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tau and stathmin proteins in breast cancer: A potential therapeutic target.","authors":"Hanzhao Yang","doi":"10.1111/1440-1681.13622","DOIUrl":"https://doi.org/10.1111/1440-1681.13622","url":null,"abstract":"<p><p>Breast cancer is the most common malignant neoplasm among women, responsible for 30% of all malignant tumours, and the second most significant reason of cancer fatality in women. Treatment failure and tumour recurrence are common outcomes of chemotherapy when patients develop multidrug resistance (MDR). New therapeutic methods like molecularly targeted therapeutic interventions need a thorough understanding of malignant tumour's molecular processes. Numerous studies published in the last few years indicate that stathmin and tubulin-associated units (tau) are upregulated in a range of human malignant tumours, suggesting that they may enhance the incidence and progression of malignancies. By promoting cancer cell reproduction, infiltration and generating drug resistance, these proteins aid in the disease's development. Existing information on the expression of tau protein and stathmin in breast cancer, as well as their involvement in treatment methods, is summarized in this literature review.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"49 4","pages":"445-452"},"PeriodicalIF":0.0,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39851623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin and its derivative disrupt cancer stem-like phenotypes of lung cancer cells via AKT downregulation.","authors":"Preeyaporn Plaimee Phiboonchaiyanan,&nbsp;Ploenthip Puthongking,&nbsp;Verisa Chawjarean,&nbsp;Saraporn Harikarnpakdee,&nbsp;Monruedee Sukprasansap,&nbsp;Pithi Chanvorachote,&nbsp;Aroonsri Priprem,&nbsp;Piyarat Govitrapong","doi":"10.1111/1440-1681.13572","DOIUrl":"https://doi.org/10.1111/1440-1681.13572","url":null,"abstract":"<p><p>Cancer stem cells (CSCs), a small subpopulation of tumour cells, have properties of self-renewal and multipotency, which drive cancer progression and resistance to current treatments. Compounds potentially targeting CSCs have been recently developed. This study shows how melatonin, an endogenous hormone synthesised by the pineal gland, and its derivative suppress CSC-like phenotypes of human non-small cell lung cancer (NSCLC) cell lines, H460, H23, and A549. The effects of MLT and its derivative, acetyl melatonin (ACT), on CSC-like phenotypes were investigated using assays for anchorage-independent growth, three-dimensional spheroid formation, scratch wound healing ability, and CSC marker and upstream protein signalling expression. Enriched CSC spheroids were used to confirm the effect of both compounds on lung cancer cells. MLT and ACT inhibited CSC-like behaviours by suppression of colony and spheroid formation in NSCLC cell lines. Their effects on spheroid formation were confirmed in CSC-enriched H460 cells. CSC markers, CD133 and ALDH1A1, were depleted by both compounds. The behaviour and factors associated to epithelial-mesenchymal transition, as indicated by cell migration and the protein vimentin, were also decreased by MLT and ACT. Mechanistically, MLT and ACT decreased the expression of stemness proteins Oct-4, Nanog, and β-catenin by reducing active AKT (phosphorylated AKT). Suppression of the AKT pathway was not mediated through melatonin receptors. This study demonstrates a novel role, and its underlying mechanism, for MLT and its derivative ACT in suppression of CSC-like phenotypes in NSCLC cells, indicating that they are potential candidates for lung cancer treatment.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 12","pages":"1712-1723"},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13572","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39314860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Novel HCV NS5B polymerase inhibitor, 2-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]thiazin-2(4H)-yl)-N-(2-fluorobenzyl)acetamide via molecular docking and experimental approach.","authors":"Hina Khalid,&nbsp;Sana Shahid,&nbsp;Somayya Tariq,&nbsp;Bushra Ijaz,&nbsp;Usman Ali Ashfaq,&nbsp;Matloob Ahmad","doi":"10.1111/1440-1681.13571","DOIUrl":"https://doi.org/10.1111/1440-1681.13571","url":null,"abstract":"<p><p>Hepatitis C Virus (HCV) is a viral infection posing a severe global threat that left untreated progresses to end-stage liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Moreover, no prophylactic approach exists so far enabling its prevention. The NS5B polymerase holds special significance as the target of intervention against HCV infection. The current study kindles benzothiazine derivatives against HCV NS5B polymerase through in silico and experimental approaches. Following docking, the compound 2-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]thiazin-2(4H)-yl)-N-(2-fluorobenzyl)acetamide was revealed to form effective binding interaction in the proposed site of HCV NS5B with a score of -10 kcal/mol and subsequently was deciphered through molecular dynamics (MD) simulation study which indicated interaction of residues TYR_382, VAL_381 and HIS_467 through hydrophobic interaction and two residues such as GLU_202 and LYS_209 contributed in the formation of water bridges. The subsequent in silico pharmacological analysis revealed its safe drug profile. The cytotoxicity activity of compound 6c indicated to be non-toxic in HepG2 cells at concentration ranges from 0.001-1.0 µmol/L with >80% cell viability and diminished expression of the HCV NS5B to 98% at the dose of 1.0 µmol/L and 90% at 0.5µmol/L. Thus the hit compound 6c might be a potent NS5B polymerase inhibitor required to be validated further through in vivo and preclinical studies.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 12","pages":"1653-1661"},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13571","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39307043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential effects of inhibitors of PTZ-induced kindling on glutamate transporters and enzyme expression.","authors":"Numan Taspinar,&nbsp;Ahmet Hacimuftuoglu,&nbsp;Selcuk Butuner,&nbsp;Basak Togar,&nbsp;Gokhan Arslan,&nbsp;Ali Taghizadehghalehjoughi,&nbsp;Ufuk Okkay,&nbsp;Erdal Agar,&nbsp;Robert Stephens,&nbsp;Hasan Turkez,&nbsp;A M Abd El-Aty","doi":"10.1111/1440-1681.13575","DOIUrl":"https://doi.org/10.1111/1440-1681.13575","url":null,"abstract":"<p><p>Epilepsy is a neurological disorder resulting from abnormal neuronal firing in the brain. Glutamate transporters and the glutamate-glutamine cycle play crucial roles in the development of seizures. In the present study, the correlation of epilepsy with glutamate transporters and enzymes was investigated. Herein, male Wistar rats were randomly allocated into four groups (six animals/group); 35 mg/kg pentylenetetrazole (PTZ) was used to induce a kindling model of epilepsy. Once the kindling model was established, animals were treated for 15 days with either valproic acid (VPA, 350 mg/kg) or ceftriaxone (CEF, 200 mg/kg) in addition to the control group receiving saline. After treatment, electrocorticography (ECoG) was performed to record the electrical activity of the cerebral cortex. The glutamate reuptake time (T₈₀ ) was also determined in situ using an in vivo voltammetry. The expression levels of glutamate transporters and enzymes in the M1 and CA3 areas of the brain were determined using a real-time polymerase chain reaction (RT-PCR). ECoG measurements showed that the mean spike number of the PTZ + VPA and PTZ + CEF groups was significantly lower (p < 0.05) than that of the PTZ group. Compared with the PTZ group, VPA or CEF treatment decreased the glutamate reuptake time (T₈₀ ). The expression levels of EAAC1, GLT-1, GLAST, glutamine synthetase (GS), and glutaminase were increased in the PTZ group. Treatment with VPA or CEF enhanced the expression levels of GLT-1, GLAST, EAAC1, and GS, whereas the glutaminase expression level was reduced. The current results suggest that VPA or CEF decreases seizure activity by increasing glutamate reuptake by upregulating GLT-1 and GLAST expression, implying a possible mechanism for treating epilepsy. Also, we have suggested a novel mechanism for the antiepileptic activity of VPA via decreasing glutaminase expression levels. To our knowledge, this is the first study to measure the glutamate reuptake time in situ during the seizure (i.e., real-time measurement).</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 12","pages":"1662-1673"},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13575","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39324939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carrier-mediated serotonin efflux induced by pharmacological anoxia in the rat heart in vivo.","authors":"Takashi Sonobe,&nbsp;Tsuyoshi Akiyama,&nbsp;James T Pearson","doi":"10.1111/1440-1681.13576","DOIUrl":"https://doi.org/10.1111/1440-1681.13576","url":null,"abstract":"<p><p>Serotonin (5-HT) accumulates in the heart during myocardial ischaemia and induces deleterious effects on the cardiomyocytes. We aimed to investigate whether carrier-mediated 5-HT efflux contributed to the increase in interstitial 5-HT level during ischaemia. Using microdialysis technique applied to the heart of anaesthetised Wistar rats, myocardial interstitial concentration of 5-HT was measured by electro-chemical detection coupled with high-performance liquid chromatography (HPLC-ECD) while simultaneously various pharmacological agents, which create a similar condition to ischaemia, were locally administered by reverse-microdialysis. Sodium cyanide-induced chemical anoxia increased dialysate 5-HT concentration. A similar increase in dialysate 5-HT concentration was induced by ouabain, an inhibitor of sodium-potassium ATPase and reserpine, an inhibitor of vesicular monoamine transporter. Fluoxetine, a selective serotonin reuptake inhibitor raised the baseline level of 5-HT, and neither sodium cyanide nor the combination of ouabain and reserpine induced further increase in 5-HT in the presence of fluoxetine. The results indicate that reverse transport of 5-HT via SERT, which is caused by an impaired ion gradient, contributes to the rise in interstitial level of 5-HT during ischaemia suggesting carrier-mediated 5-HT efflux occurs in the heart in vivo.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 12","pages":"1685-1692"},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13576","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39327030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quercetin promotes locomotor function recovery and axonal regeneration through induction of autophagy after spinal cord injury.","authors":"Yeyang Wang,&nbsp;Man Xiong,&nbsp;Mingsen Wang,&nbsp;Hongdong Chen,&nbsp;Wenjun Li,&nbsp;Xiaozhong Zhou","doi":"10.1111/1440-1681.13573","DOIUrl":"https://doi.org/10.1111/1440-1681.13573","url":null,"abstract":"<p><p>Quercetin (Que), one of the flavonoids, exerts numerous actions on the central nervous system. However, the roles and underlying mechanism of Que in locomotor function recovery and axonal regeneration following spinal cord injury (SCI) have not been fully elucidated. A rat model of spinal cord injury (SCI) was established at T10 using the modified Allen's method. The results in our study indicated that Basso, Beattie and Bresnahan (BBB) locomotor scores were significantly higher after Que treatment. Additionally, Que administration cut down the latency of somatosensory evoked potentials (SEP) and motor evoked potentials (MEP), increased the amplitude of MEP and SEP following SCI. Hematoxylin-eosin (HE) staining demonstrated that Que administration reduced lesion size and cavity formation. Biotinylated dextran amine (BDA) anterograde tracing revealed that BDA positive fibres were increased by Que following SCI. Immunofluorescence staining revealed that Que elevated 5-hydroxytryptamine (5-HT) positive nerve fibres and neurofilament-200 (NF-200) positive neurons, reduced glial fibrillary acidic protein (GFAP) positive astrocytes. In addition, Que inhibited GFAP expression, increased both NeuN and NF-200 expression and facilitated the spinal cord energy metabolism. Moreover, Que increased ¹⁸ F-FDG uptake in a time-dependent manner. Furthermore, Que increased Beclin 1 and LC3 II expression, blocked the phosphorylation of Akt, mTOR and p70S6K. 3-methyladenine (3-MA) partly abolished the neuro-protective roles of Que following SCI. Taken together, our study suggested that Que might promote locomotor function recovery, axonal regeneration and energy metabolism through induction of autophagy via Akt/mTOR/p70S6K pathway.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 12","pages":"1642-1652"},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13573","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39335491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety profile of sitagliptin, vildagliptin, and metformin in newly diagnosed type 2 diabetic subjects.","authors":"Sahar Hossam Elhini,&nbsp;Amal K Hussien,&nbsp;Ahmed Abd Elsamie Omran,&nbsp;Asmaa A Elsayed,&nbsp;Haitham Saeed","doi":"10.1111/1440-1681.13561","DOIUrl":"https://doi.org/10.1111/1440-1681.13561","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease that requires long-term management. Thus, dipeptidyl peptidase-4 inhibitors (DPP-4) need more investigations about their efficacy and safety profile as there is still no evidence of whether DPP-4 inhibitors can be used as a first line option for T2DM drug-naïve patients. In this randomized case-controlled study, 60 drug-naïve T2DM subjects were randomized into three groups, each group comprising 20 subjects. Group 1 was given sitagliptin 100 mg once daily, Group 2 was given vildagliptin 50 mg twice daily, and Group 3 served as the control group and was given metformin 1 g twice daily. Efficacy endpoints included changes in glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), and 2-hr postprandial plasma glucose (PPG), and the secondary endpoints were related to safety profile were the assessment of liver and kidney function tests and complete blood count (CBC). All treatment regimens had comparable efficacy and safety profiles with the non-significant relative superiority of vildagliptin in lowering HbA1c more than sitagliptin but significant (p = 0.011) regarding FPG reduction, vildagliptin significantly decreased HbA1c by -1.02% (p < 0.001), sitagliptin significantly decreased HbA1c by -0.96% (p < 0.001), and control significantly decreased HbA1c by -0.90% (p < 0.001) compared with baseline. The studied drugs showed moderate efficacy in lowering HbA1c levels with the non-significant relative higher efficacy of DPP-4 inhibitors. DPP-4 inhibitors and metformin showed favourable effects on improving metabolic syndrome by decreasing blood pressure, serum triglycerides (TG), low-density lipoprotein (LDL), total cholesterol, and increasing high-density lipoprotein (HDL), plus their positive impacts on weight. As a final conclusion, the three medications are highly comparable.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 12","pages":"1589-1602"},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13561","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39263535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective effects of FK 506 against haemorrhagic shock-induced microvascular hyperpermeability.","authors":"Binu Tharakan,&nbsp;Felicia A Hunter,&nbsp;Ed W Childs","doi":"10.1111/1440-1681.13578","DOIUrl":"https://doi.org/10.1111/1440-1681.13578","url":null,"abstract":"<p><p>Microvascular hyperpermeability, the excessive leakage of fluid and proteins from the intravascular space to the interstitium, is a devastating clinical concern in haemorrhagic shock (HS), sepsis, burn and so forth. Previous studies have shown that HS-induced microvascular hyperpermeability is associated with activation of the mitochondria-mediated 'intrinsic' apoptotic signalling cascade and caspase-3 mediated disruption of the endothelial cell barrier. In this study, our objective was to test if FK506, an immunomodulator that is also known to protect mitochondria, would protect barrier functions and decrease vascular hyperpermeability following HS by acting on this pathway. FK506 (25 µM) was given 10 minutes before the shock period in a rat model of HS. The HS model was a non-traumatic/fixed pressure model of hypovolemic shock developed by withdrawing blood to reduce the mean arterial pressure to 40 mm Hg for 60 minutes. The mesenteric post-capillary venules were monitored for changes in permeability using intravital microscopic imaging. The changes in mitochondrial transmembrane potential (MTP) were determined using the cationic dye 5,5',6,6' tetrachoro-1,1',3,3' tetraethyl benzimidazolyl carbocyanine iodide (JC-1), that was superfused on the mesenteric vasculature followed by intravital imaging. The mesenteric caspase-3 activity was measured fluorometrically. Haemorrhagic shock induced a significant increase in hyperpermeability compared to the sham-control group and FK506 treatment decreased HS-induced hyperpermeability significantly (P < .05). FK506 dampened HS-induced loss of MTP and elevation of caspase-3 activity significantly (P < .05). FK506 has protective effects against HS-induced microvascular hyperpermeability. The maintenance of the MTP and protection against caspase-3 mediated endothelial cell barrier disruption are possible mechanisms by which FK506 attenuates HS-induced hyperpermeability. FK506, currently used in clinical settings as an immunomodulator, needs to be explored further for its therapeutic usefulness against HS-induced vascular hyperpermeability and associated complications.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 12","pages":"1704-1711"},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13578","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39343857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}