Clinical Science (London, England : 1979)最新文献

{"title":"DAPT, a potent Notch inhibitor regresses actively growing abdominal aortic aneurysm via divergent pathways.","authors":"Chetan P Hans,&nbsp;Neekun Sharma,&nbsp;Rishabh Dev,&nbsp;Jones M Blain,&nbsp;Jeff Tonniges,&nbsp;Gunjan Agarwal","doi":"10.1042/CS20200456","DOIUrl":"https://doi.org/10.1042/CS20200456","url":null,"abstract":"<p><p>Abdominal aortic aneurysm (AAA) is a localized pathological dilation of the aorta exceeding the normal diameter (∼20 mm) by more than 50% of its original size (≥30 mm), accounting for approximately 150000-200000 deaths worldwide per year. We previously reported that Notch inhibition does not decrease the size of pre-established AAA at late stage of the disease. Here, we examined whether a potent pharmacologic inhibitor of Notch signaling (DAPT (N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester)), regresses an actively growing AAA. In a mouse model of an aneurysm (Apoe-/- mice; n=44); DAPT (n=17) or vehicle (n=17) was randomly administered at day 14 of angiotensin II (AngII; 1 µg/min/kg), three times a week and mice were killed on day 42. Progressive increase in aortic stiffness and maximal intraluminal diameter (MILD) was observed in the AngII + vehicle group, which was significantly prevented by DAPT (P<0.01). The regression of aneurysm with DAPT was associated with reduced F4/80+Cd68+ (cluster of differentiation 68) inflammatory macrophages. DAPT improved structural integrity of aorta by reducing collagen fibrils abnormality and restoring their diameter. Mechanistically, C-C chemokine receptor type 7 (Ccr7)+F4/80- dendritic cells (DCs), implicated in the regression of aneurysm, were increased in the aorta of DAPT-treated mice. In the macrophages stimulated with AngII or lipopolysaccharide (LPS), DAPT reverted the expression of pro-inflammatory genes Il6 and Il12 back to baseline within 6 h compared with vehicle (P<0.05). DAPT also significantly increased the expression of anti-inflammatory genes, including c-Myc, Egr2, and Arg1 at 12-24 h in the LPS-stimulated macrophages (P<0.05). Overall, these regressive effects of Notch signaling inhibitor emphasize its therapeutic implications to prevent the progression of active AAAs.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"1555-1572"},"PeriodicalIF":6.0,"publicationDate":"2020-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890598/pdf/nihms-1665977.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38007124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin alleviates hyperuricaemia-induced serum FFA elevation and insulin resistance by inhibiting adipocyte hypertrophy and reversing suppressed white adipose tissue beiging.","authors":"Mengqi Su,&nbsp;Li Sun,&nbsp;Wenpeng Li,&nbsp;He Liu,&nbsp;Yang Liu,&nbsp;Ying Wei,&nbsp;Yue Yuan,&nbsp;Linqun Zheng,&nbsp;Shuangli Yin,&nbsp;Chenguang Dai,&nbsp;Chenyang Zhao,&nbsp;Zhenwei Pan,&nbsp;Yue Li","doi":"10.1042/CS20200580","DOIUrl":"https://doi.org/10.1042/CS20200580","url":null,"abstract":"<p><p>Hyperuricaemia (HUA) significantly increases the risk of metabolic syndrome and is strongly associated with the increased prevalence of high serum free fatty acids (FFAs) and insulin resistance. However, the underlying mechanisms are not well established, especially the effect of uric acid (UA) on adipose tissue, a vital organ in regulating whole-body energy and FFA homeostasis. In the present study, we noticed that adipocytes from the white adipose tissue of patients with HUA were hypertrophied and had decreased UCP1 expression. To test the effects of UA on adipose tissue, we built both in vitro and in vivo HUA models and elucidated that a high level of UA could induce hypertrophy of adipocytes, inhibit their hyperplasia and reduce their beige-like characteristics. According to mRNA-sequencing analysis, UA significantly decreased the expression of leptin in adipocytes, which was closely related to fatty acid metabolism and the AMPK signalling pathway, as indicated by KEGG pathway analysis. Moreover, lowering UA using benzbromarone (a uricosuric agent) or metformin-induced activation of AMPK expression significantly attenuated UA-induced FFA metabolism impairment and adipose beiging suppression, which subsequently alleviated serum FFA elevation and insulin resistance in HUA mice. Taken together, these observations confirm that UA is involved in the aetiology of metabolic abnormalities in adipose tissue by regulating leptin-AMPK pathway, and metformin could lessen HUA-induced serum FFA elevation and insulin resistance by improving adipose tissue function via AMPK activation. Therefore, metformin could represent a novel treatment strategy for HUA-related metabolic disorders.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"1537-1553"},"PeriodicalIF":6.0,"publicationDate":"2020-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38059269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renal functional effects of the highly selective AT2R agonist, β-Pro7 Ang III, in normotensive rats.","authors":"Lucinda M Hilliard Krause,&nbsp;Brandon A Kemp,&nbsp;Amanda Suan Jui Tan,&nbsp;Emma S Jones,&nbsp;Mark P Del Borgo,&nbsp;Marie-Isabel Aguilar,&nbsp;Kate M Denton,&nbsp;Robert M Carey,&nbsp;Robert E Widdop","doi":"10.1042/CS20200153","DOIUrl":"https://doi.org/10.1042/CS20200153","url":null,"abstract":"<p><p>Recently, we designed a group of peptides by sequential substitution of the naturally occurring α-amino acid throughout the Ang III peptide sequence with the corresponding β-amino acid. β-Amino acid substitution at the proline residue of Ang III (β-Pro7-Ang III) resulted in a highly selective AT2R ligand, demonstrating remarkable selectivity for the AT2R in both binding and functional studies. To provide additional functional evidence for the suitability of β-Pro7 Ang III as a novel AT2R agonist, we tested effects of acute systemic administration of β-Pro7-Ang III on renal hemodynamic and excretory function in anesthetized normotensive male and female rats. We also compared the natriuretic effects of acute intrarenal administration of native Ang III and β-Pro7-Ang III in the presence of systemic AT1R blockade in anesthetized female rats to allow for the differentiation of systemic versus direct intrarenal natriuretic actions of β-Pro7-Ang III. In both male and female rats, acute systemic administration of β-Pro7-Ang III elicited renal vasodilatation and natriuresis. Notably, greater renal vasodilatory effects were observed in female versus male rats at the highest dose of β-Pro7-Ang III administered. Moreover, intra-renal administration of β-Pro7-Ang III produced significant natriuretic effects in female rats and, like Ang III, evoked AT2R translocation to the apical plasma membrane in renal proximal tubular cells. Taken together, our findings support the use of β-Pro7-Ang III as a novel AT2R agonist and experimental tool for exploring AT2R function and its potential as a therapeutic target. Furthermore, our findings provide further evidence of a sex-specific influence of AT2R stimulation on renal function.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"871-884"},"PeriodicalIF":6.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f7/86/cs-134-cs20200153.PMC7158249.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37762776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclin D1 promotes secretion of pro-oncogenic immuno-miRNAs and piRNAs.","authors":"Jinhui Lü,&nbsp;Qian Zhao,&nbsp;Xin Ding,&nbsp;Yuefan Guo,&nbsp;Yuan Li,&nbsp;Zhen Xu,&nbsp;Shujun Li,&nbsp;Zhongrui Wang,&nbsp;Lei Shen,&nbsp;Huang-Wen Chen,&nbsp;Zuoren Yu,&nbsp;Richard G Pestell","doi":"10.1042/CS20191318","DOIUrl":"https://doi.org/10.1042/CS20191318","url":null,"abstract":"<p><p>The molecular mechanisms governing the secretion of the non-coding genome are poorly understood. We show herein that cyclin D1, the regulatory subunit of the cyclin-dependent kinase that drives cell-cycle progression, governs the secretion and relative proportion of secreted non-coding RNA subtypes (miRNA, rRNA, tRNA, CDBox, scRNA, HAcaBox. scaRNA, piRNA) in human breast cancer. Cyclin D1 induced the secretion of miRNA governing the tumor immune response and oncogenic miRNAs. miR-21 and miR-93, which bind Toll-Like Receptor 8 to trigger a pro-metastatic inflammatory response, represented >85% of the cyclin D1-induced secreted miRNA transcripts. Furthermore, cyclin D1 regulated secretion of the P-element Induced WImpy testis (PIWI)-interacting RNAs (piRNAs) including piR-016658 and piR-016975 that governed stem cell expansion, and increased the abundance of the PIWI member of the Argonaute family, piwil2 in ERα positive breast cancer. The cyclin D1-mediated secretion of pro-tumorigenic immuno-miRs and piRNAs may contribute to tumor initiation and progression.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"791-805"},"PeriodicalIF":6.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37777901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of circulating extracellular microvesicles from spinal cord-injured adults on endothelial cell function.","authors":"L Madden Brewster,&nbsp;Geoff B Coombs,&nbsp;Vinicius P Garcia,&nbsp;Jamie G Hijmans,&nbsp;Noah M DeSouza,&nbsp;Kelly A Stockelman,&nbsp;Otto F Barak,&nbsp;Tanja Mijacika,&nbsp;Zeljko Dujic,&nbsp;Jared J Greiner,&nbsp;Aaron A Phillips,&nbsp;Philip N Ainslie,&nbsp;Christopher A DeSouza","doi":"10.1042/CS20200047","DOIUrl":"https://doi.org/10.1042/CS20200047","url":null,"abstract":"<p><p>People with spinal cord injury (SCI) have three- to four-fold greater risk of cardiovascular disease (CVD) compared with those without SCI. Although circulating extracellular microvesicles are key effectors of vascular health and disease, how their functional phenotype might be altered with SCI is unknown. The aim of the present study was to determine the effects of microvesicles isolated from SCI adults on endothelial cell inflammation and oxidative stress as well as endothelial nitric oxide (NO) synthase (eNOS) activation and tissue-type plasminogen activator (t-PA) expression. Eighteen young and middle-aged adults were studied: 10 uninjured (7M/3F; age: 39 ± 3 years) and 8 cervical level spinal cord injured (SCI; 7M/1F; 46 ± 4 years; cervical injury: C3: n=1; C5: n=4; C6: n=3). Circulating microvesicles were isolated, enumerated and collected from plasma by flow cytometry. Human umbilical vein endothelial cells (HUVECs) were cultured and treated with microvesicles from either the uninjured or SCI adults. Microvesicles from SCI adults did not affect cellular markers or mediators of inflammation and oxidative stress. However, microvesicles from the SCI adults significantly blunted eNOS activation, NO bioavailability and t-PA production. Intercellular expression of phosphorylated eNOS at Ser1177 and Thr495 sites, specifically, were ∼65% lower and ∼85% higher, respectively, in cells treated with microvesicles from SCI compared with uninjured adults. Decreased eNOS activity and NO production as well as impaired t-PA bioavailability renders the vascular endothelium highly susceptible to atherosclerosis and thrombosis. Thus, circulating microvesicles may contribute to the increased risk of vascular disease and thrombotic events associated with SCI.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"777-789"},"PeriodicalIF":6.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37777904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local endothelial DNA repair deficiency causes aging-resembling endothelial-specific dysfunction.","authors":"Paula K Bautista-Niño,&nbsp;Eliana Portilla-Fernandez,&nbsp;Eloisa Rubio-Beltrán,&nbsp;Janette J van der Linden,&nbsp;René de Vries,&nbsp;Richard van Veghel,&nbsp;Martine de Boer,&nbsp;Matej Durik,&nbsp;Yanto Ridwan,&nbsp;Renata Brandt,&nbsp;Jeroen Essers,&nbsp;Robert I Menzies,&nbsp;Rachel Thomas,&nbsp;Alain de Bruin,&nbsp;Dirk J Duncker,&nbsp;Heleen M M van Beusekom,&nbsp;Mohsen Ghanbari,&nbsp;Jan H J Hoeijmakers,&nbsp;Radislav Sedlacek,&nbsp;Rhian M Touyz,&nbsp;Augusto C Montezano,&nbsp;Ingrid van der Pluijm,&nbsp;A H Jan Danser,&nbsp;Kristian A Haanes,&nbsp;Anton J M Roks","doi":"10.1042/CS20190124","DOIUrl":"https://doi.org/10.1042/CS20190124","url":null,"abstract":"<p><p>We previously identified genomic instability as a causative factor for vascular aging. In the present study, we determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of ERCC1 (excision repair cross-complementation group 1) DNA repair in mice (EC-knockout (EC-KO) mice). EC-KO showed a progressive decrease in microvascular dilation of the skin, increased microvascular leakage in the kidney, decreased lung perfusion, and increased aortic stiffness compared with wild-type (WT). EC-KO showed expression of DNA damage and potential senescence marker p21 exclusively in the endothelium, as demonstrated in aorta. Also the kidney showed p21-positive cells. Vasodilator responses measured in organ baths were decreased in aorta, iliac and coronary artery EC-KO compared with WT, of which coronary artery was the earliest to be affected. Nitric oxide-mediated endothelium-dependent vasodilation was abolished in aorta and coronary artery, whereas endothelium-derived hyperpolarization and responses to exogenous nitric oxide (NO) were intact. EC-KO showed increased superoxide production compared with WT, as measured in lung tissue, rich in endothelial cells (ECs). Arterial systolic blood pressure (BP) was increased at 3 months, but normal at 5 months, at which age cardiac output (CO) was decreased. Since no further signs of cardiac dysfunction were detected, this decrease might be an adaptation to prevent an increase in BP. In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived NO. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"727-746"},"PeriodicalIF":6.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37762773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Self DNA perpetuates IPF lung fibroblast senescence in a cGAS-dependent manner.","authors":"Michael Schuliga,&nbsp;Jane Read,&nbsp;Kaj E C Blokland,&nbsp;David W Waters,&nbsp;Janette Burgess,&nbsp;Cecilia Prêle,&nbsp;Steven E Mutsaers,&nbsp;Jade Jaffar,&nbsp;Glen Westall,&nbsp;Andrew Reid,&nbsp;Allen James,&nbsp;Christopher Grainge,&nbsp;Darryl A Knight","doi":"10.1042/CS20191160","DOIUrl":"https://doi.org/10.1042/CS20191160","url":null,"abstract":"<p><p>Senescence and mitochondrial stress are mutually reinforcing age-related processes that contribute to idiopathic pulmonary fibrosis (IPF); a lethal disease that manifests primarily in the elderly. Whilst evidence is accumulating that GMP-AMP synthase (cGAS) is crucial in perpetuating senescence by binding damaged DNA released into the cytosol, its role in IPF is not known. The present study examines the contributions of cGAS and self DNA to the senescence of lung fibroblasts from IPF patients (IPF-LFs) and age-matched controls (Ctrl-LFs). cGAS immunoreactivity was observed in regions of fibrosis associated with fibroblasts in lung tissue of IPF patients. Pharmacological inhibition of cGAS or its knockdown by silencing RNA (siRNA) diminished the escalation of IPF-LF senescence in culture over 7 days as measured by decreased p21 and p16 expression, histone 2AXγ phosphorylation and/or IL-6 production (P < 0.05, n = 5-8). The targeting of cGAS also attenuated etoposide-induced senescence in Ctrl-LFs (P < 0.05, n = 5-8). Levels of mitochondrial DNA (mDNA) detected by qPCR in the cytosol and medium of IPF-LFs or senescence-induced Ctrl-LFs were higher than Ctrl-LFs at baseline (P < 0.05, n = 5-7). The addition of DNAse I (100 U/ml) deaccelerated IPF-LF senescence (P < 0.05, n = 5), whereas ectopic mDNA or the induction of endogenous mDNA release augmented Ctrl-LF senescence in a cGAS-dependent manner (P < 0.05, n = 5). In conclusion, we provide evidence that cGAS reinforces lung fibroblast senescence involving damaged self DNA. The targeting of cGAS to supress senescent-like responses may have potential important therapeutic implications in the treatment of IPF.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"889-905"},"PeriodicalIF":6.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37777902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-210 transferred by lung cancer cell-derived exosomes may act as proangiogenic factor in cancer-associated fibroblasts by modulating JAK2/STAT3 pathway.","authors":"Junqiang Fan,&nbsp;Guanxin Xu,&nbsp;Zhibo Chang,&nbsp;Ling Zhu,&nbsp;Jie Yao","doi":"10.1042/CS20200039","DOIUrl":"https://doi.org/10.1042/CS20200039","url":null,"abstract":"It has been generally believed that cancer-associated fibroblasts (CAFs) have the ability to increase the process of tumor angiogenesis. However, the potential mechanisms by which cancer-derived exosomes in lung cancer (LC) remains to be investigated. LC-derived exosomes were administrated to NIH/3T3 cells. A variety of experiments were conducted to investigate the proangiogenic factors of CAFs, including Western blot, RT-PCR, Colony Formation Assay, tube formation assay, Matrigel plug assay et al. In addition, the impact of JAK2/STAT3 signaling pathway were also explored. The role of hsa-miR-210 was identified with microarray profiling and validated in-vitro & in -vivo assays. The target of miR-210 was screened by RNA pull down, RNA-sequencing and then verified. It was shown that LC- derived exosomes could induce cell reprogramming thus promoting the fibroblasts transferring into CAFs. In addition, the exosomes with over-expressed miR-210 could increase the level of angiogenesis and vice versa, which suggested the miR-210 secreted by the LC-derived exosomes may initiate the CAF proangiogenic switch. According to our analysis, the miR-210 had the ability of elevating the expression of some proangiogenic factors such as MMP9, FGF2 and VEGFa by activating the JAK2/STAT3 signaling pathway, TET2 was identified as the target of miR-210 in CAFs which has been involved in proangiogenic switch. miR-210 was overexpressed in serum exosomes of untreated NSCLC patients. We concluded that the promotion effect of exosomal miR-210 on proangiogenic switch of CAFs may be explained by the modulation of JAK2/STAT3 signaling pathway and TET2 in recipient fibroblasts.","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"807-825"},"PeriodicalIF":6.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37777962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Albendazole negatively regulates keratinocyte proliferation.","authors":"Davide Di Fusco,&nbsp;Carmine Stolfi,&nbsp;Antonio Di Grazia,&nbsp;Vincenzo Dinallo,&nbsp;Federica Laudisi,&nbsp;Irene Marafini,&nbsp;Alfredo Colantoni,&nbsp;Ivan Monteleone,&nbsp;Giovanni Monteleone","doi":"10.1042/CS20191215","DOIUrl":"https://doi.org/10.1042/CS20191215","url":null,"abstract":"<p><strong>Background: </strong>Increased keratinocyte proliferation occurs in the skin of psoriatic patients and is supposed to play a role in the pathogenesis of this disorder. Compounds interfering with keratinocyte proliferation could be useful in the management of psoriatic patients.</p><p><strong>Aim: </strong>To investigate whether albendazole, an anti-helmintic drug that regulates epithelial cell function in various systems, inhibits keratinocyte proliferation in models of psoriasis.</p><p><strong>Methods: </strong>Aldara-treated mice received daily topical application of albendazole. Keratinocyte proliferation and keratin (K) 6 and K16 expression were evaluated by immunohistochemistry and Western blotting and inflammatory cells/mediators were analysed by immunohistochemistry and real-time PCR. In human keratinocytes (HEKa and HaCaT) treated with albendazole, cell cycle and proliferation, keratins and cell cycle-associated factors were evaluated by flow cytometry, colorimetric assay and Western blotting respectively.</p><p><strong>Results: </strong>Aldara-treated mice given albendazole exhibited reduced epidermal thickness, decreased number of proliferating keratinocytes and K6/K16 expression. Reduction of CD3- and Ly6G-positive cells in the skin of albendazole-treated mice associated with inhibition of IL-6, TNF-α, IL-1β, IL-17A, IL-36, CCL17, CXCL1, CXCL2 and CXCL5 expression. Treatment of keratinocytes with albendazole reduced K6/K16 expression and reversibly inhibited cell growth by promoting accumulation of cells in S-phase. This phenomenon was accompanied by down-regulation of CDC25A, a phosphatase regulating progression of cell cycle through S-phase, and PKR-dependent hyper-phosphorylation of eIF2α, an inhibitor of CDC25 translation. In Aldara-treated mice, albendazole activated PKR, enhanced eIF2α phosphorylation and reduced CDC25A expression.</p><p><strong>Conclusions: </strong>Data show that albendazole inhibits keratinocyte proliferation and exerts therapeutic effect in a murine model of psoriasis.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"907-920"},"PeriodicalIF":6.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37793050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of microglial phenotypes improves sepsis-induced hippocampus-dependent cognitive impairments and decreases brain inflammation in an animal model of sepsis.","authors":"Monique Michels, Mariane Abatti, Andriele Vieira, Pricila Ávila, Amanda Indalécio Goulart, Heloisa Borges, Emily Córneo, Diogo Dominguini, Tatiana Barichello, Felipe Dal-Pizzol","doi":"10.1042/CS20191322","DOIUrl":"10.1042/CS20191322","url":null,"abstract":"<p><strong>Background: </strong>In order to modulate microglial phenotypes in vivo, M1 microglia were depleted by administration of gadolinium chloride and the expression of M2 microglia was induced by IL-4 administration in an animal model of sepsis to better characterize the role of microglial phenotypes in sepsis-induced brain dysfunction.</p><p><strong>Methods: </strong>Wistar rats were submitted to sham or cecal ligation and perforation (CLP) and treated with IL-4 or GdCl3. Animals were submitted to behavioral tests 10 days after surgery. In a separated cohort of animals at 24 h, 3 and 10 days after surgery, hippocampus was removed and cytokine levels, M1/M2 markers and CKIP-1 levels were determined.</p><p><strong>Results: </strong>Modulation of microglia by IL-4 and GdCl3 was associated with an improvement in long-term cognitive impairment. When treated with IL-4 and GdCl3, the reduction of pro-inflammatory cytokines was apparent in almost all analyzed time points. Additionally, CD11b and iNOS were increased after CLP at all time points, and both IL-4 and GdCl3 treatments were able to reverse this. There was a significant decrease in CD11b gene expression in the CLP+GdCl3 group. IL-4 treatment was able to decrease iNOS expression after sepsis. Furthermore, there was an increase of CKIP-1 in the hippocampus of GdCl3 and IL-4 treated animals 10 days after CLP induction.</p><p><strong>Conclusions: </strong>GdCl3 and IL-4 are able to manipulate microglial phenotype in an animal models of sepsis, by increasing the polarization toward an M2 phenotype IL-4 and GdCl3 treatment was associated with decreased brain inflammation and functional recovery.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"765-776"},"PeriodicalIF":0.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37777961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}