Thursday, August 26, 2021

TNF‐α blockade may lead to improvement of vascular function in psoriasis patients

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Abstract

Psoriasis is one of the most common chronic inflammatory skin diseases and at the same time a risk factor for cardiovascular disease. Interleukin-17A (IL-17A)-mediated inflammation in psoriasis may lead to vascular dysfunction. This study aimed at investigating whether anti-inflammatory treatment by tumor necrosis factor (TNF)-α blockade alters vascular function in psoriasis patients. A total of 11 patients with psoriasis who underwent treatment with either adalimumab (n=8) or etanercept (n=3), 10 healthy control individuals, and 14 patients with coronary artery disease (CAD) were included in this study. Treatment response was assessed using the Psoriasis Area and Severity Index (PASI) score. Endothelial reactivity and resting endothelium-dependent vascular tone were assessed by ultrasound measurement of flow-mediated dilation (FMD) and low-flow-mediated constriction (l-FMC), respectively. FMD was slightly impaired in psoriasis patients compared to healthy controls. Anti-TNF-α t reatment did not significantly change FMD levels. Psoriasis patients showed a trend towards increased baseline vascular activity compared to healthy controls. Anti-TNF-α treatment significantly improved l-FMC in psoriasis patients. Noteworthy, both FMD and l-FMC in psoriasis patients were comparable to those in patients with CAD, however, an important influence of age differences between the groups or co-existent classical cardiovascular risk factors on FMD and l-FMC cannot be ruled out by our small study. The results suggest that anti-inflammatory treatment with TNF-α blockade improves vascular function in patients with psoriasis, mainly by altering baseline vascular tone. Further studies will be necessary to establish the potentially protective impact of anti-inflammatory therapy on vascular function in patients with chronic inflammatory diseases.

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Mechanism‐based therapeutic targets of pemphigus vulgaris: a scoping review of pathogenic intracellular pathways

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Abstract

Pemphigus Vulgaris (PV) is a potentially fatal autoimmune blistering disease characterised by cell-cell detachment or acantholysis. The mechanisms which follow antibody (Ab) binding and culminate in acantholytic changes and skin/mucosal blistering have not been fully clarified. Current treatment strategies are not specific to PV pathophysiology and although life-saving, harbour considerable side effects. We aimed to systematically assess the molecules amenable to targeted treatments that follow Ab binding and are associated with PV acantholysis. The resulting scoping review was conducted under PRISMA- ScR guidelines with clear inclusion and exclusion criteria and focused specifically on kinases, caspases, proteases, hydrolytic enzymes and other molecules of interest postulated to take part in the pathophysiology of PV. The review process resulted in the identification of 882 articles, of which 56 were eligible for qualitative synthesis. From the included articles, the majority (n= 42) used PV-IgG as the pathogenic agent, mainly via in vitro (n=16) and in vivo (n= 10) models. Twenty-five molecules were found to play a pathogenic role in PV, including uPA, ADAM10, EGFR, Src, PKC, cdk2, ERK, PLC, nNOS, calmodulin, NOS, p38MAPK and caspase-3. Selective inhibition of these molecules resulted in varying degrees of reduction in acantholysis and blistering. The pathogenic molecules identified in this review represent potential candidates for clinical translation.

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Aloperine protects against cerebral ischemia/reperfusion injury via activating the PI3K/AKT signaling pathway in rats

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Exp Ther Med. 2021 Oct;22(4):1045. doi: 10.3892/etm.2021.10478. Epub 2021 Jul 22.

ABSTRACT

Cerebral ischemia is among the leading causes of death and long-term disability worldwide. The aim of the present study was to investigate the effects of aloperine (ALO) on cerebral ischemia/reperfusion (I/R) injury in rats and elucidate the possible underlying mechanisms. Therefore, a rat model of reversible middle cerebral artery occlusion (MCAO) was established to induce cerebral I/R injury. Following pretreatment with different doses of ALO, the histopathological changes in the brain tissue were evaluated by hematoxylin and eosin staining. The degree of cerebral infarction was determined using by 2,3,5-triphenyltetrazolium chloride staining. Additionally, the levels of oxidative stress- and inflammation-related factors were measured using commercially available kits. Cell apoptosis was assessed by TUNEL staining, while the expression levels o f apoptosis- and PI3K/AKT signaling pathway-related proteins were determined by western blot analysis. The results demonstrated that ALO alleviated histopathological injury in the brain tissue and the area of cerebral infarction in a dose-dependent manner. Furthermore, significantly reduced levels of reactive oxygen species and malondialdehyde were observed in the ALO-treated rats post-MCAO/reperfusion, accompanied by increased levels of superoxide dismutase, catalase and glutathione. Consistently, treatment with ALO notably decreased the concentration of inflammatory factors, including TNF-α, IL-1β and IL-6, in a dose-dependent manner. In addition, ALO attenuated neuronal cell apoptosis, downregulated the expression of Bax and upregulated that of Bcl-2. I/R markedly reduced the expression levels of phosphorylated (p-)PI3K and p-AKT, which were dose-dependently restored by ALO intervention. Collectively, the aforementioned findings indicated that ALO could improve cerebral I/R inj ury and alleviate oxidative stress, inflammation and cell apoptosis via activating the PI3K/AKT signaling pathway, thus supporting the therapeutic potential of ALO against cerebral I/R injury in ischemic stroke.

PMID:34434259 | PMC:PMC8353632 | DOI:10.3892/etm.2021.10478

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Inhibition of miR-483-5p improves the proliferation, invasion and inflammatory response of triple-negative breast cancer cells by targeting SOCS3

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Exp Ther Med. 2021 Oct;22(4):1047. doi: 10.3892/etm.2021.10480. Epub 2021 Jul 22.

ABSTRACT

microRNAs (miRs) have been indicated to serve oncogenic or tumor suppressor roles. However, the role of miR-483-5p in breast cancer and its associated molecular mechanisms remain unclear. In the present study, compared with adjacent normal tissues and MCF-10a cells, the expression level of miR-483-5p was upregulated in triple-negative breast cancer (TNBC) tissues and TNBC cell lines. Bioinformatic analysis and luciferase reporter assay confirmed the presence of miR-483-5p binding sites in the 3'-untranslated region of suppressor of cytokine signaling 3 (SOCS3). In addition, the expression level of SOCS3 protein in TNBC tissues was markedly lower compared with in adjacent tissues, and miR-483-5p expression was negatively correlated with SOCS3 expression in TNBC tissues. Cell proliferation and flow cytometry assays indicated that knockdown of miR-4 83-5p inhibited the proliferation and promoted apoptosis in the TNBC cell line BT-549. This effect was markedly attenuated by SOCS3 small interfering (si)RNA transfection. Additionally, wound healing and Transwell assays demonstrated that SOCS3 siRNA reversed the inhibitory effects of miR-483-5p inhibitor on the migration and invasion of BT-549 cells. Moreover, the decrease in miR-483-5p expression significantly reduced the secretion of TNF-α, IL-6, IL-1β and monocyte chemoattractant protein-1 in BT-549 cells, while SOCS3 siRNA could partially reverse this effect. Additionally, SOCS3 overexpression reversed the effects of miR-483-5p mimic on the proliferation, migration, invasion and inflammation of BT-549 cells. Taken together, these data demonstrated that the inhibition of miR-483-5p could inhibit the proliferation, migration, invasion and inflammatory response, while promoting the apoptosis of TNBC cells by negatively regulating SOCS3. miR-483-5p may be a potential target for T NBC therapy.

PMID:34434261 | PMC:PMC8353637 | DOI:10.3892/etm.2021.10480

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Effects of the p16/cyclin D1/CDK4/Rb/E2F1 pathway on aberrant lung fibroblast proliferation in neonatal rats exposed to hyperoxia

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Exp Ther Med. 2021 Oct;22(4):1057. doi: 10.3892/etm.2021.10491. Epub 2021 Jul 26.

ABSTRACT

p16INK4a (p16) inhibits the vital G1 to S phase transition during cell cycle progression through the p16/cyclin D1/CDK4/retinoblastoma(Rb)/E2F1 pathway. Hyperoxia can suppress the G1/S checkpoint and induce more lung fibroblasts (LFs) to transition from the G1 phase to the S phase and undergo cell proliferation. The present study investigated the rate of p16 gene promoter methylation and the protein expression levels of p16, cyclin D1, CDK4, Rb and E2F1 in LFs from the lungs of rats exposed to hyperoxia and normoxia on postnatal days 3, 7 and 14. In the hyperoxia-exposed group, the methylation rate was 50 and 80% on days 7 and 14, respectively. Cyclin D1 and CDK4 overexpression was associated with p16 loss and Rb inactivation by phosphorylation. Rb phosphorylation induced E2F1 release in the G1 phase, which promoted cell proliferation. No methylation was observed in the normoxia-exposed group. These observations suggested that p16 loss may stimulate aberrant LF proliferation via the p16/cyclin D1/CDK4/Rb/E2F1 pathway.

PMID:34434271 | PMC:PMC8353642 | DOI:10.3892/etm.2021.10491

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Anti-inflammatory effects of miR-150 are associated with the downregulation of STAT1 in macrophages following lipopolysaccharide treatment

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Exp Ther Med. 2021 Oct;22(4):1049. doi: 10.3892/etm.2021.10483. Epub 2021 Jul 23.

ABSTRACT

Sepsis is a condition that is associated with high rates of mortality. It is characterized by serious systemic inflammatory responses induced by pathogenic invasion. Although microRNA-150 (miR-150) has been previously reported to be involved in the modulation of sepsis, the underlying molecular mechanism in sepsis remains poorly understood. In the present study, the human monocytic cell line THP-1 was treated with LPS to mimic sepsis in vitro, following which miR-150 and STAT1 expression were measured using reverse transcription-quantitative PCR or western blotting. Secretion of inflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) into the medium were measured by ELISA. The potential relationship between STAT1 and miR-150 was determined using dual-luciferase reporter and RNA immunoprecipitation assays. mi R-150 expression was found to be was downregulated by LPS treatment in THP-1 cells in both dose- and time-dependent manners. LPS treatment also induced IL-1β, IL-6 and TNF-α secretion in a manner that could be inhibited by miR-150 overexpression and enhanced by transfection with the miR-150 inhibitor. miR-150 was revealed to directly target STAT1 by negatively regulating its expression. In addition, STAT1 expression was demonstrated to be upregulated by LPS treatment. STAT1 overexpression reversed the inhibitory effects of miR-150 overexpression on IL-1β, IL-6 and TNF-α secretion whilst STAT1 knockdown attenuated IL-1β, IL-6 and TNF-α secretion induced by miR-150 inhibitor transfection. In conclusion, the present study suggested that miR-150 regulates the inflammatory response in macrophages following LPS challenge by regulating the expression of STAT1.

PMID:34434263 | PMC:PMC8353636 | DOI:10.3892/etm.2021.10483

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Establishment of incontinence-associated dermatitis rat models and assessment of the therapeutic effects of zinc oxide, painless skin protective film and silicone dressing

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Exp Ther Med. 2021 Oct;22(4):1058. doi: 10.3892/etm.2021.10492. Epub 2021 Jul 26.

ABSTRACT

The aim of the present study was to construct incontinence-associated dermatitis (IAD) rat models and observe the therapeutic effects of zinc oxide, painless skin protective film and silicone dressing on IAD. A total of 54 rats were randomly divided into nine groups: i) Control group; ii) trypsin model group; iii) model + zinc oxide group; iv) model + painless skin protective film group; v) model + silicon dressing group; vi) synthetic urine combined with trypsin model group (joint model group); vii) joint model + zinc oxide group; viii) joint model + painless skin protective film group; and ix) joint model + silicone dressing group. A total of 4 days after applying the zinc oxide, protective film or silicon dressing intervention, IAD scores and pH values in skin tissues were examined. Skin tissues and blood samples were collected. Hematoxylin an d eosin staining, immunohistochemical staining of major histocompatibility complex class II (MHC-II) and western blot analysis of MHC-II, NF-κB/p65, phosphorylated (p)-NF-κB/p65, STAT1 and p-STAT1 were carried out in skin tissue. Serum IFN-γ, IL-1β, IL-2 and TNF-α levels were determined using ELISA. The results demonstrated that IAD scores and pH values were both higher in the model groups than the control, which were significantly ameliorated by silicone dressing. The skin tissue structure of IAD rats both in trypsin model group and joint model group was severely damaged, the wounds were not covered by epidermis, and numerous inflammatory cell infiltrations were observed. After treatment, dermatitis was improved. Skin tissue from the trypsin and joint IAD models had higher MHC-II, NF-κB p65, p-NF-κB p65, STAT1 and p-STAT1 expression than controls, which was decreased by protective film and silicon dressing. Zinc oxide reduced NF-κB p65, p-NF-κB p65, STAT1 and p-STAT1 expre ssion. However, no significant differences were observed in NF-κB/p-NF-κB ratio and STAT1/p-STAT1 ratio among groups. Furthermore, serum IFN-γ, IL-1β, IL-2 and TNF-α levels were significantly elevated in trypsin and joint IAD rats. The upregulation of these cytokines was significantly inhibited after all three treatments. Among the three treatment methods, silicone dressing had the best therapeutic effect. Thus, these findings revealed that zinc oxide, painless skin protective film and silicone dressing could ameliorate the severity of IAD rat models, and that silicone dressing possessed the best therapeutic effect.

PMID:34434272 | PMC:PMC8353640 | DOI:10.3892/etm.2021.10492

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IKKε knockout alleviates angiotensin II-induced apoptosis and excessive autophagy in vascular smooth muscle cells by regulating the ERK1/2 pathway

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Exp Ther Med. 2021 Oct;22(4):1051. doi: 10.3892/etm.2021.10485. Epub 2021 Jul 23.

ABSTRACT

Inhibitor of nuclear factor-κB kinase subunit ε (IKKε) is an important signal regulator in the formation of abdominal aortic aneurysm (AAA). However, the underlying mechanism remains to be elucidated. Therefore, the present study aimed to investigate the mechanism underlying IKKε function in AAA formation by studying apoptosis and autophagy in angiotensin II (Ang II)-induced vascular smooth muscle cells (VSMCs). AngII was used to stimulate VSMCs for 24 h to simulate the process of AAA formation. VSMCs were transfected with IKKε small interfering RNA to investigate the effect of IKKε on AAA formation, cell apoptosis and autophagy. IKKε deficiency led to reduced mitochondrial damage and apoptosis in VSMCs in the early stage of apoptosis in vitro, as demonstrated using a JC-1 probe. IKKε deficiency also reduced autophagy and decreased the formation of autophagic vacuoles in VSMCs, demonstrated using transmission electron microscopy. The decrease in apoptosis caused by IKKε knockdown was reversed when the autophagic flow was blocked using bafilomycin A1. Western blot analysis further revealed that IKKε deficiency negatively regulated the ERK1/2 signaling pathway to reduce autophagy. Collectively, the results of the present study revealed that IKKε played a key role in apoptosis by inducing excessive autophagy, thereby potentially contributing to AAA formation. These findings further revealed the mechanism underlying IKKε function in the formation of AAA.

PMID:34434265 | PMC:PMC8353624 | DOI:10.3892/etm.2021.10485

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MicroRNA-139-5p improves sepsis-induced lung injury by targeting Rho-kinase1

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Exp Ther Med. 2021 Oct;22(4):1059. doi: 10.3892/etm.2021.10493. Epub 2021 Jul 26.

ABSTRACT

Sepsis-induced acute lung injury (ALI) is an inflammatory process that involves inflammatory cytokine production and cell apoptosis. In the present study, the regulatory role of microRNA (miR)-139-5p in sepsis-induced ALI was investigated using a murine model of cecal ligation puncture (CLP) and an in vitro model using lipopolysaccharide (LPS)-induced normal human bronchial epithelial cells (NHBEs). Sepsis-induced pathological changes in the lungs of ALI mice were detected using hematoxylin and eosin staining. Lung water content was determined, and the expression of proinflammatory cytokines in the bronchoalveolar lavage fluid and serum of sepsis-induced ALI mice were quantified using ELISA. The levels of oxidative stress in lung tissues were determined using commercial kits. The degree of apoptosis was determined using a TUNEL assay. The expression levels of miR-139-5p and Rho-kinase 1 (ROCK1) were determined using reverse transcription-quantitative PCR and western blot analyses. A dual-luciferase reporter assay was used to confirm the direct targeting of ROCK1 by miR-139-5p. NHBEs were co-transfected with vectors expressing ROCK1 (or empty vector) and miR-139-5p mimics or control mimics prior to LPS treatment. The transcriptional activity of caspase-3, the ratio of apoptotic cells, the expression levels of mucin 5AC, mucin 1, TNF-α, IL-1β, IL-6, NLR family pyrin domain containing 3, apoptosis-associated speck-like protein containing a CARD and caspase-1 were evaluated. Compared with the normal group, mice that underwent CLP exhibited abnormal lung morphology, enhanced production of TNF-α, IL-1β and IL-6, increased reactive oxygen species (ROS), malondialdehyde and lactate dehydrogenase levels, an increased proportion of apoptotic cells and increased ROCK1 expression. Superoxide dismutase, glutathione peroxidase and miR-139-5p levels were decreased following CLP. In the NHBEs, stimulation with LPS caused a marked increase in inflammatory cytokine levels and apoptosis compared with the untreated cells. Overexpression of miR-139-5p attenuated cell apoptosis and inflammation. Overexpression of ROCK1 in NHBEs restored the ROS levels and proinflammatory cytokine production inhibited by miR-139-5p. In conclusion, miR-139-5p alleviated sepsis-induced ALI via suppression of its downstream target, ROCK1, suggesting that miR-139-5p may hold promise in the treatment of sepsis-induced ALI.

PMID:34434273 | PMC:PMC8353635 | DOI:10.3892/etm.2021.10493

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NEIL3 contributes toward the carcinogenesis of liver cancer and regulates PI3K/Akt/mTOR signaling

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Exp Ther Med. 2021 Oct;22(4):1053. doi: 10.3892/etm.2021.10487. Epub 2021 Jul 23.

ABSTRACT

Liver cancer is one of the top three fatal types of cancer and it causes several thousands of mortalities each year. The main treatment is surgical resection which shows little benefit for patients with recurrence or metastasis. NEIL3 promotes progression and predicts survival in cancer. However, its role in liver cancer remains unclear. Based on data in the TCGA database, NEIL3 exhibited much higher expression in liver cancer tissues and was clinically correlated with tumor grade in patients with liver cancer. Furthermore, high NEIL3 expression caused shorter survival times. In liver cancer cell lines, NEIL3 showed abundant expression. When NEIL3 was knocked down in HepG2 and Huh-7 cells, cell abilities including proliferation, growth, migration and invasion, exhibited deficiency to different extents. Cell cycl e transition was blocked at the G2 phase and the cell apoptotic rate increased notably. In addition, the phosphorylation levels of Akt, PI3K and mTOR were increased following NEIL3-overexpression but decreased following NEIL3-knockdown. In conclusion, NEIL3 contributes toward development and/or progression in liver cancer and regulates PI3K/Akt/mTOR signaling.

PMID:34434267 | PMC:PMC8353638 | DOI:10.3892/etm.2021.10487

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