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Πέμπτη 3 Δεκεμβρίου 2020

Interleukin-6 signaling blockade treatment for cytokine release syndrome in COVID-19 (Review).

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Interleukin-6 signaling blockade treatment for cytokine release syndrome in COVID-19 (Review).

Exp Ther Med. 2021 Jan;21(1):24

Authors: Chen JJ, Zhang LN, Hou H, Xu L, Ji K

Abstract
A severe immune response in patients with coronavirus disease 2019 (COVID-19) can cause a potentially lethal unconstrained inflammatory cytokine storm, known as cytokine release syndrome (CRS). The present study provides an overview of the biology underlying CRS and how targeted inhibition of interleukin (IL)-6 signaling may improve outcomes and the survival of patients suffering from COVID-19. Preliminary clinical results have indicated that antagonism of the IL-6 receptor (IL-6R), including with the FDA-approved humanized monoclonal antibody tocilizumab, can improve the outcomes of patients with severe or critical COVID-19 while maintaining a good safety profile. The available clinical data support the expansion of clinical trials using IL-6R targeting inhibitors for severe and critical COVID-19 treatment.

PMID: 33262810 [PubMed]

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Fisetin ameliorates atherosclerosis by regulating PCSK9 and LOX-1 in apoE-/- mice.

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Fisetin ameliorates atherosclerosis by regulating PCSK9 and LOX-1 in apoE-/- mice.

Exp Ther Med. 2021 Jan;21(1):25

Authors: Yan L, Jia Q, Cao H, Chen C, Xing S, Huang Y, Shen D

Abstract
The purpose of the current study was to investigate the mechanism by which fisetin improves atherosclerosis (AS) by regulating lipid metabolism and senescence in apolipoprotein E-deficient (apoE-/-) mice. An AS model was established by feeding apoE-/- mice a high-fat diet. Mice were randomly divided into the model group (n=18), the fisetin group (n=18) and the atorvastatin group (n=18). The control group (n=18) was composed of wild-type C57BL/6 mice of the same age and genetic background. The fisetin and atorvastatin groups were respectively treated with aqueous solutions of fisetin (12.5 mg/kg) and atorvastatin (2 mg/kg) via oral gavage daily for 12 weeks. The pathological morphology, lipid accumulation, collagen deposition of the aortic sinus were observed, serum lipids, superoxide dismutase (SOD) and malondialdehyde (MDA) levels and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were measured in the peripheral blood serum. Additionally, the expressions of proprotein convertase subtilisin/kexin type 9 (PCSK9), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), tumor suppressor protein p53 (p53), cyclin-dependent kinase inhibitor 1A (p21) and multiple tumor suppressor-1 (p16) were analyzed in the aorta. The results of the current study indicated that compared with the control group, a large area of AS plaque in the aortic sinus that contained a large amount of red-stained lipids and decreased collagen fiber content were found in the model group, which exhibited higher total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), oxidized low-density lipoprotein (ox-LDL) and MDA levels; higher ALT and AST activities, lower high-density lipoprotein cholesterol (HDL-C) and SOD levels and increased expression levels of PCSK9, LOX-1, p53, p21 and p16. Fisetin is a phytochemical and bioflavonoid that serves a potential role in chronic diseases including AS , obesity, diabetes and cancer due to its wide biological activities, such as regulating lipid metabolism and anti-aging, anti-oxidation and anti-inflammatory. Atorvastatin is recognized as a first-line treatment drug for AS; therefore it was used as a positive control in the current study. Following fisetin and atorvastatin treatment, both the AS plaque and the lipid accumulation in the aortic sinus were significantly reduced, and the expressions of PCSK9, LOX-1 and aging markers, including p53, p21 and p16 were downregulated.

PMID: 33262811 [PubMed]

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Assessment of acute pancreatitis severity via determination of serum levels of hsa-miR-126-5p and IL-6.

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Assessment of acute pancreatitis severity via determination of serum levels of hsa-miR-126-5p and IL-6.

Exp Ther Med. 2021 Jan;21(1):26

Authors: Chen YJ, Lin TL, Cai Z, Yan CH, Gou SR, Zhuang YD

Abstract
Early assessment of acute pancreatitis (AP) severity is key to its treatment. The present study aimed to explore the role of microRNAs (miRNAs/miRs) combined with inflammatory factors in determining AP severity. For this, serum pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-8 and IL-10)] and miRNAs [Homo sapiens (hsa)-miR-548d-5p, hsa-miR-126-5p and hsa-miR-130b-5p] were detected in patients with mild AP (MAP), severe AP (SAP) and recurrent AP (RAP). High expression of IL-10, TNF-α, hsa-miR-126-5p, hsa-miR-548d-5p and hsa-miR-130b-5p was able to distinguish SAP from MAP and RAP (P<0.05). Multifactorial binary logistic regression analysis indicated that IL-1/IL-6 combined with hsa-miR-126-5p/hsa-miR-548d-5p had a significant influence on AP and AP severity (P<0.05). Receiver operating characteristic analysis revealed that IL-1 combined with hsa-miR-126-5p [area under the curve (AUC), 0.926; sensitivity, 90.0%; specificity, 86.7% , P<0.001] and IL-6 combined with hsa-miR-126-5p (AUC, 0.952; sensitivity, 93.3%; specificity, 90.0%; P<0.001) were able to better distinguish MAP from SAP than IL-1/IL-6 combined with hsa-miR-548d-5p, lipase, and amylase. IL-1 or IL-6 combined with hsa-miR-548d-5p (AUC, 0.924; sensitivity, 83.3%; specificity, 93.3%; P<0.001) were able to better distinguish SAP from RAP than IL-1/IL-6 combined with hsa-miR-126-5p, lipase, and amylase. IL-1 combined with hsa-miR-126-5p (AUC, 0.926; sensitivity, 90.0%; specificity, 86.7%; P<0.001) and IL-6 combined with hsa-miR-126-5p (AUC, 0.952; sensitivity, 93.3%; specificity, 90.0%; P<0.001) were able to better differentiate between MAP and RAP than IL-1/IL-6 combined with hsa-miR-548d-5p, lipase, and amylase. These results demonstrated that the combined detection of serum IL-6 and hsa-miR-126-5p may be useful for the early prediction of AP classification.

PMID: 33262812 [PubMed]

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Investigation of the relationship between chronic montelukast treatment, asthma and depression-like behavior in mice.

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Investigation of the relationship between chronic montelukast treatment, asthma and depression-like behavior in mice.

Exp Ther Med. 2021 Jan;21(1):27

Authors: Tel BC, Telli G, Onder S, Nemutlu E, Bozkurt TE

Abstract
In 2008, the Food and Drug Administration of the US issued a warning about the neuropsychiatric side effects of montelukast. Previous clinical studies on montelukast have reported conflicting results and, to the best of our knowledge, no experimental studies concerning these side effects had been conducted. In the current study, the effect of montelukast on depression-like behavior in an ovalbumin (OVA)-induced mouse model was investigated. A total of 3 OVA challenges were applied at 2 week intervals for the persistence of asthma. Depression-like behavior was assessed using forced swim tests following each challenge and locomotor activities were evaluated using open field tests. At the end of the current study, plasma montelukast concentrations were measured and the development of asthma and effect of montelukast treatment were histopathologically examined. Inflammation scores that were increased in the OVA mice following all challenges were indicated to be reduced by montelu kast treatment. The immobility time of mice increased beginning with the first challenge and this was also reduced by montelukast treatment. Montelukast administration to the control mice did not alter immobility times. Moreover, motor activity of the OVA and montelukast-treated mice were not altered. The results indicated there was no association between chronic montelukast treatment and depression. Furthermore, the chronic administration of montelukast to non-asthmatic mice did not increase immobility. However, depressive behavior increased at all time points in the OVA mice. These results indicated that chronic montelukast treatment is not associated with depression-like behavior and confirmed the association between asthma and depression. Further studies are required to provide an improved understanding of the neuropsychiatric side effects of montelukast.

PMID: 33262813 [PubMed]

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Shikonin reduces hepatic fibrosis by inducing apoptosis and inhibiting autophagy via the platelet-activating factor-mitogen-activated protein kinase axis.

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Shikonin reduces hepatic fibrosis by inducing apoptosis and inhibiting autophagy via the platelet-activating factor-mitogen-activated protein kinase axis.

Exp Ther Med. 2021 Jan;21(1):28

Authors: Song M, Zhang H, Chen Z, Yang J, Li J, Shao S, Liu J

Abstract
Liver fibrosis is a tissue repair process that occurs following various types of chronic liver injury and can develop into liver cirrhosis, portal hypertension or liver cancer without effective treatment. Shikonin has anti-inflammatory, antiviral and antitumor properties. Furthermore, shikonin has an additional effect of antagonizing tissue and organ fibrosis. The aim of the present study was to evaluate the mechanisms of action underlying shikonin against liver fibrosis. Cell viability was assessed using the Cell Counting Kit-8 and EdU incorporation assays. Protein and mRNA expression levels were measured via western blotting and immunofluorescence assays, respectively. Apoptosis was examined via flow cytometry and autophagy via transmission electron microscopy. Compared with the control group, shikonin did not significantly alter LX-2 cell viability at 0.2 µmol/ml, which was used as the intervention concentration. However, shikonin significantly inhibited fibrosis, as indi cated by a decrease in the expression of α-smooth muscle actin and collagen-I in the TGF-β + shikonin group compared with the TGF-β group. The results indicated that shikonin potentially inhibited fibrosis via promoting cell apoptosis and inhibiting autophagy. Additionally, the results of the present study indicated that shikonin downregulated the expression levels of platelet-activating factor (PAF) in TGF-β-treated cells, which subsequently activated the MAPK signaling pathway, leading to enhanced cell apoptosis and reduced autophagy. Collectively, the present study indicated that shikonin promoted cell apoptosis and suppressed autophagy via the PAF-MAPK axis in LX-2 cells, thus blocking the development of fibrosis. The results of the present study may provide a potential therapeutic strategy for liver fibrosis.

PMID: 33262814 [PubMed]

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MicroRNA-329-3p alleviates high glucose-induced endothelial cell injury via inhibition of the TLR4/TRAF6/NF-κB signaling pathway.

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MicroRNA-329-3p alleviates high glucose-induced endothelial cell injury via inhibition of the TLR4/TRAF6/NF-κB signaling pathway.

Exp Ther Med. 2021 Jan;21(1):29

Authors: Song G, Li L, Yang Y

Abstract
The aim of the current study was to determine the expression of microRNA (miRNA/miR)-329-3p in patients with type 2 diabetes mellitus (T2DM) and to investigate the effect of miR-329-3p on vascular endothelial cell function under high-glucose conditions. A total of 33 healthy individuals and 31 patients with T2DM were enrolled in the present study. Peripheral blood was collected from all participants. Human umbilical vein endothelial cells (HUVECs) were transfected with a miR-329-3p mimic or miR-329-3p inhibitor. Following treatment with 25 mmol/l glucose, a Cell Counting Kit-8 assay and flow cytometry analysis were used to assess cell viability and apoptosis levels, respectively. A dual luciferase reporter assay, western blot analysis and reverse transcription-quantitative PCR were used to assess molecular mechanism of miR-329-3p in HUVECs. The results revealed that plasma miR-329-3p expression was decreased patients with T2DM compared with healthy controls, and in HUVECs tre ated with high glucose concentrations. In addition, miR-329-3p reduced high glucose-induced damage to HUVEC cells. miR-329-3p directly bound to toll like receptor (TLR)-4 and regulated its expression at the transcriptional and post-transcriptional levels. miR-329-3p was also demonstrated to be involved in the regulation of the TLR4/tumor necrosis factor receptor associated factor 6 (TRAF6)/nuclear factor (NF)-κB signaling pathway and the nuclear translocation of NF-κB under a high glucose environment. In conclusion, the results indicated that miR-329-3p may protect endothelial cells from high glucose-induced apoptosis via inhibition of the TLR4/TRAF6/NF-κB signaling pathway. The present study also demonstrated that miR-329-3p expression in the plasma of patients with T2DM was reduced, suggesting that upregulation of miR-329-3p may alleviate high glucose-induced endothelial cell injury via inhibition of the TLR4/TRAF6/NF-κB signaling pathway.

PMID: 33262815 [PubMed]

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Ascites symptom inventory-7 is a valuable tool for evaluating the effectiveness of tolvaptan in patients with cirrhotic ascites.

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Ascites symptom inventory-7 is a valuable tool for evaluating the effectiveness of tolvaptan in patients with cirrhotic ascites.

Exp Ther Med. 2021 Jan;21(1):30

Authors: Kawaratani H, Moriya K, Namisaki T, Shimozato N, Kaji K, Takaya H, Fujinaga Y, Sawada Y, Sato S, Saikawa S, Kubo T, Akahane T, Fukui H, Yoshiji H

Abstract
Patients with liver cirrhosis frequently experience non-specific symptoms and report severe reductions in their quality of life (QOL). The underlying mechanisms of the disease are multifactorial that may be specific to the disease or directly related to the liver. The major concern of liver cirrhosis with ascites, however, is the decreased QOL. Therefore, in the present study, the Ascites Symptom Inventory-7 (ASI-7) questionnaire was applied to subjectively evaluate the symptoms in patients with cirrhotic ascites following tolvaptan administration. In total, 69 patients with liver cirrhosis with ascites hospitalized to Nara Medical University were evaluated after being treated with tolvaptan (3.75-7.5 mg/day) and conventional diuretics between December 2013 and April 2018. A follow-up assessment was conducted 7 days after tolvaptan treatment, whilst ASI-7 was used on days 1 and 8 of the study. After an uneventful 7-day tolvaptan treatment regimens, 49 patients (71.0%) lost &g t;1.5 kg of their body weight, who were referred to as responders, with the change in the ASI-7 score being found to correlate with the body weight change. By contrast, changes in urine volume did not correlate with those in the ASI-7 score. The responders experienced a greater reduction in the ASI-7 score after 7 days compared with those in the non-responders (P<0.01). ASI-7 scores were also found to correlate with body weight after tolvaptan administration. In conclusion, ASI-7 accurately reflected changes in body weight but not urine volume and results of the study highlighted the value of ASI-7 in the evaluation of ascitic volume and effectiveness of tolvaptan in cirrhotic ascites. The present clinical trial was registered onto the UMIN-Clinical Trial Registry on 1st March 2014 (registration no. UMIN000013095).

PMID: 33262816 [PubMed]

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Androgen receptor gene mutations in 258 Han Chinese patients with polycystic ovary syndrome.

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Androgen receptor gene mutations in 258 Han Chinese patients with polycystic ovary syndrome.

Exp Ther Med. 2021 Jan;21(1):31

Authors: Tian L, Zou Y, Tan J, Wang Y, Chen J, Xia L, Xu L, Chen G, Wu Q, Huang O

Abstract
Polycystic ovary syndrome (PCOS) affects 8-13% of reproductive-age females worldwide and mutations or aberrant expression of androgen receptor (AR) may cause the onset of this disease. In the present study, 258 samples from Han Chinese patients with PCOS were analyzed for the presence of AR mutations via sequencing of all coding exons of the AR gene. A total of five heterozygous missense mutations, namely p.V3M, p.Q72R, p.S158L, p.S176R and p.G396R, were identified in five of the patients. Among these, p.S158L was a novel mutation that, to the best of our knowledge, has not been reported previously. Although the remaining four mutations have been reported previously, they existed at low frequencies or were absent in the control subjects and in the Exome Aggregation Consortium database. The results of evolutionary conservation and in silico analysis revealed that the p.V3M, p.S158L and p.S176R mutations were pathogenic, whereas the p.Q72R and p.G396R mutations were benign. Com pared with the patients with PCOS without AR mutations or with benign AR mutations, markedly lower estrogen levels on the day of human chorionic gonadotropin injection were observed in the three patients with PCOS with potentially pathogenic mutations. In addition, patients with PCOS with pathogenic mutations had lower numbers of oocytes; however, the difference was not statistically significant. Of note, these observations should be interpreted with caution due to the relatively small sample size in the present study. Therefore, a larger number of samples should be collected to validate the results of the present study in future studies. In summary, the present study identified three potential pathogenic mutations in 258 Han Chinese patients with PCOS and these mutations may have an implication in the pathogenesis of PCOS.

PMID: 33262817 [PubMed]

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Transrectal ultrasound-guided seminal vesicle catheterization with continuous antibiotic infusion for the treatment of refractory hematospermia.

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Transrectal ultrasound-guided seminal vesicle catheterization with continuous antibiotic infusion for the treatment of refractory hematospermia.

Exp Ther Med. 2021 Jan;21(1):32

Authors: Wang R, Chen L, Bai X, Li T, Wu D, Chen J

Abstract
The aim of the present study was to describe transrectal ultrasound (TRUS)-guided seminal vesicle catheterizations with continuous antibiotic infusion in patients with persistent hematospermia. A retrospective record review of 45 patients with refractory hematospermia treated with TRUS-guided seminal vesicle catheterization between 2010 and 2017 was performed. Seminal vesicle puncture and catheterization was performed under TRUS guidance for all patients. Antibiotic irrigation was used to rinse the seminal vesicle until the outflow fluid was clear. The trocar sleeve was left in situ and fixed on the skin of the perineum at the end of the procedure. All patients underwent a 24-h continuous infusion of antibiotic solution through the catheter. The patients were followed up to 3 years for the presence of hematospermia. The duration of refractory hematospermia was between 6 months and 9 years. A total of 14 patients exhibited consecutive hematospermia, while the remaining patient s exhibited intermittent episodes. On TRUS, 15 cases of ejaculatory duct cyst, 7 cases of ejaculatory duct expansion, 3 cases of ejaculatory duct stones, 6 cases of seminal vesicle expansion, 8 cases of seminal vesicle stones and 5 cases of seminal vesicle wall or ejaculation wall calcification were diagnosed. A total of 41 patients completed the scheduled treatment plan; however, the catheter was dissociated on the 3rd or 4th day of catheterization in 4 patients. After a 1-3 year follow-up, hematospermia was not observed in 42 patients (93.33%) with recurrence in the remaining 3 patients. In conclusion, TRUS-guided seminal vesicle catheterization with continuous antibiotic infusion appeared to be a safe and effective method for the treatment of hematospermia.

PMID: 33262818 [PubMed]

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Towards a more effective strategy for COVID-19 prevention (Review).

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Towards a more effective strategy for COVID-19 prevention (Review).

Exp Ther Med. 2021 Jan;21(1):33

Authors: Szkaradkiewicz-Karpińska AK, Szkaradkiewicz A

Abstract
At the end of 2019, a new disease, similar to severe acute respiratory syndrome (SARS) associated with SARS-CoV was reported in Wuhan, China. It was quickly discovered that the etiological factor of the new disease (COVID-19) was a previously unknown SARS coronavirus 2 (SARS-CoV-2). The global spread of of COVID-19 has lead to the declaration of a pandemic status in 2019-2020 as declared by the World Health Organization and Public Health Emergency of International Concern. SARS-CoV-2 characterizes with high epidemic potential and is effectively disseminated between humans. SARS-CoV and SARS-CoV-2 are closely related pathogens. Their prime route of distribution is air-droplet transmission. Combating infectious diseases disseminated by inhalation is very difficult, and mainly relies on the use of vaccines. However, despite the lack of an effective anti-SARS-CoV vaccine and specific antiviral drugs, the strict sanitary procedures proved to be sufficient to stop the SARS epidemic in June 2003. However, epidemic research has indicated that SARS-CoV-2 is transmitted in humans significantly more effectively than SARS-CoV; therefore, the COVID-19 pandemic continues to expand. This indicates that the so far anti-epidemic activities to control COVID-19 are insufficient. In the current review, the possibility of using interferon α (IFN-α) as a preventive agent of COVID-19 is discussed. The current data concerning anti-COVID-19 vaccines and specific drugs against SARS-CoV-2 are also discussed. The aim of the current review is to contribute to the introduction of a more efficient strategy in the protection of the human population against COVID-19.

PMID: 33262819 [PubMed]

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Clinical implications of perivascular fat stranding surrounding spontaneous isolated superior mesenteric artery dissection on computed tomography.

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Clinical implications of perivascular fat stranding surrounding spontaneous isolated superior mesenteric artery dissection on computed tomography.

Exp Ther Med. 2021 Jan;21(1):34

Authors: Tan Z, Jin Q, Fan W, Han P, Li X

Abstract
Patients with spontaneous isolated superior mesenteric artery (SMA) dissection (SISMAD) usually present with acute or chronic abdominal pain and are admitted to the emergency or digestive diseases department to undergo auxiliary examinations, typically abdominal plain CT or contrast-enhanced CT (CECT). Plain CT is the most crucial examination in emergency radiology. An enlarged SMA diameter and perivascular fat stranding (PFS) on plain CT, though non-specific, may be the only indications for SISMAD. These results may be easily overlooked and the diagnosis of SISMAD may be missed. However, PFS around the SMA on CT may be the only indicator of the possible presence of SISMAD, particularly during the early stage when there are no massive changes in the vascular wall. The present study aimed to determine whether PFS surrounding the SMA on CT may help with the diagnosis of SISMAD by indicating the requirement for further examination. The data of 161 consecutive patients with SMA d issection who underwent abdominal CECT or underwent SMA CT angiography (CTA) after abdominal plain CT between February 2015 and February 2018 were retrospectively reviewed. SMA diameter, classification, PFS, complications, comorbidities and treatments were analyzed. The results demonstrated that SISMAD with PFS was significantly associated with admission type (emergency), clinical manifestations (abdominal pain), diagnostic modality and dissection subtype. On plain CT, PFS surrounding the SMA may be a marker for SISMAD, particularly in the emergency setting, and indicates the requirement for CTA examination.

PMID: 33262820 [PubMed]

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