Osthole suppresses the proliferation and induces apoptosis via inhibiting the PI3K/AKT signaling pathway of endometrial cancer JEC cells

xlomafota13 shared this article with you from Inoreader Osthole suppresses the proliferation and induces apoptosis via inhibiting the PI3K/AKT signaling pathway of endometrial cancer JEC cells Via Experimental and therapeutic medicine Exp Ther Med. 2021 Oct;22(4):1171. doi: 10.3892/etm.2021.10605. Epub 2021 Aug 13. ABSTRACT Osthole, a natural product extracted mainly from fruits of Fructus Cnidii, possesses multiple pharmacological functions, including anti-inflammatory, anti-convulsant and anticancer effects. However, the effects of osthole in endometrial cancer (EC) is not fully understood. In the present study, EC cell lines, including JEC, KLE and Ishikawa cells and normal human cervical epithelial cells (HcerEpic) were applied to detect the anticancer effect of osthole. The present study demonstrated that osthole inhibited the proliferation of JEC, KLE and Ishikawa cells, but had no cytotoxic effect on HcerEpic. Furthermore, treatment of osthole induced JEC cell apoptosis, while osthole promoted the release of pro-apoptotic proteins, Bax and activated the cleaved caspase-3, caspase-9 and PARP. Additionally, osthole significantly increased the expression of PETN and decreased the phosphorylated form of PI3K and AKT in a concentration-dependent manner. Furthermore, osthole treatment suppressed the JEC tumor cell growth in a nude mouse xenograft model in vivo, and neither renal toxicity nor hepatotoxicity was induced by the indicated concentration. Taken together, the results of the present study suggested that osthole may be a novel and potential therapeutic agent of EC. PMID:34504616 | PMC:PMC8393372 | DOI:10.3892/etm.2021.10605 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

How specific molecular-targeted agents can make obsolete a 'one size fits all' approach in EGFR-mutated NSCLC treatment (Review)

xlomafota13 shared this article with you from Inoreader How specific molecular-targeted agents can make obsolete a 'one size fits all' approach in <em>EGFR</em>-mutated NSCLC treatment (Review) Via Experimental and therapeutic medicine Exp Ther Med. 2021 Oct;22(4):1150. doi: 10.3892/etm.2021.10584. Epub 2021 Aug 10. ABSTRACT Despite many advances in the latest period, lung cancer remains the cancer with the highest mortality. The latest developments concerning lung cancer treatment have changed the clinical practice by prolonging patient survival; however, unfortunately, there remains a high mortality rate firstly due to disease aggressivity and secondly through lack of early diagnosis and screening programs. Currently, researchers and clinicians are talking about personalized cancer treatment, and a complete diagnostic evaluation should consider, in addition to staging and histology, molecular aberrations, and genetics of the tumor tissue. The development of tyrosine kinase inhibitors (TKIs) has led to an improvement in survival for patients with EGFR mutations, this being the most studied driver mutation in adenocarcinoma; and at the same time an important predicti ve factor for patient outcome following the treatment with TKIs. Reseach must investigate the different TKI combination strategies in order to overcome resistance and to increase patient survival. Currently, there are ongoing clinical trials that will probably change the therapeutic approach for EGFR-mutated advanced or metastatic NSCLC patients. PMID:34504595 | PMC:PMC8393358 | DOI:10.3892/etm.2021.10584 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

MicroRNA-124-5p delays the progression of cerebral aneurysm by regulating FoxO1

xlomafota13 shared this article with you from Inoreader MicroRNA-124-5p delays the progression of cerebral aneurysm by regulating FoxO1 Via Experimental and therapeutic medicine Exp Ther Med. 2021 Oct;22(4):1172. doi: 10.3892/etm.2021.10606. Epub 2021 Aug 13. ABSTRACT Cerebral aneurysm (CA) is a common brain disease, and the development of cerebral aneurysm is driven by inflammation and hemodynamic stress. MicroRNA (miR)-124-5p is reported to be associated with inflammatory response in brain disease such as cerebral ischemia-reperfusion injury. However, the function and molecular mechanism of miR-124-5p in CA are not clear, thus, the effects of miR-124-5p on inflammatory response in CA were explored. Firstly, the expression of miR-124-5p in the peripheral blood of patients with CA and the control group was detected by reverse transcription-quantitative PCR. Then, the human umbilical vein endothelial cells (HUVECs) were used as an in vitro model system and stimulated with interleukin (IL)-1β to simulate the inflammatory environment of CA, and the expression of miR-124-5p was detected. Next, the effect o f miR-124-5p on the migration and invasion of HUVECs was detected using Transwell assays. Meanwhile, the function of miR-124-5p on various inflammatory factors was determined by western blotting and enzyme-linked immunosorbent assay (ELISA). Next, the TargetScan website was used to predict FoxO1 as a target gene of miR-124-5p, and this target association was validated by double luciferase reporter assay and western blotting. Finally, the interaction of miR-124-5p with FoxO1 in CA was measured by Transwell western blotting and ELISA assays. The results showed that the expression level of miR-124-5p in the peripheral blood of patients with CA was lower compared with that of control group, and the miR-124-5p in HUVECs stimulated by IL-1β was less compared with that in normal HUVECs. Besides, miR-124-5p could inhibit the migration and invasion abilities of HUVECs and the release of inflammatory factors. Additionally, the overexpression of miR-124-5p was able to inhibit the expression o f FoxO1. miR-124-5p-inhibitor promoted the migration and invasion of HUVECs, as well as inflammatory response, which was weakened following the introduction of FoxO1 small interfering RNA. Overall, the present study demonstrated that miR-124-5p could prevent the occurrence and development of cerebral aneurysm by downregulating the expression of FoxO1. PMID:34504617 | PMC:PMC8393823 | DOI:10.3892/etm.2021.10606 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Killer-cell immunoglobulin-like receptor/human leukocyte antigen-C combination and 'great obstetrical syndromes' (Review)

xlomafota13 shared this article with you from Inoreader Killer-cell immunoglobulin-like receptor/human leukocyte antigen-C combination and 'great obstetrical syndromes' (Review) Via Experimental and therapeutic medicine Exp Ther Med. 2021 Oct;22(4):1178. doi: 10.3892/etm.2021.10612. Epub 2021 Aug 13. ABSTRACT Recurrent pregnancy loss (RPL), pre-eclampsia (PE), fetal growth restriction (FGR), and preterm delivery are examples of 'great obstetrical syndromes' (GOS). Placental dysfunction is the most common pathogenesis of GOS. In human pregnancies, the effects of uterine natural killer cells involve angiogenesis, promoting the remodeling of uterine spiral artery, and improving the invasion of trophoblast cells. The uNK cells supply killer immunoglobulin-like receptors (KIRs), which come into contact with human leukocyte antigen-C (HLA-C) ligands expressed by extravillous trophoblast cells (EVTs). Numerous studies have investigated the association between GOS and KIR/HLA-C combination. However, the outcomes have not been conclusive. The present review aimed to reveal the association between GOS and KIR/HLA-C combination to screen out high-risk pregnancie s, strengthen the treatment of pregnancy complications, and reduce the frequency of adverse maternal and fetal outcomes. It has been reported that a female with a KIR AA genotype and a neonate with a paternal HLA-C2 molecule is more prone to develop GOS and have a small fetus since less cytokines were secreted by uNK cells. Conversely, the combination of KIR BB haplotype (including the activating KIR2DS1) and HLA-C2 can induce the production of cytokines and increase trophoblast invasion, leading to the birth of a large fetus. KIR/HLA-C combinations may be applicable in selecting third-party gametes or surrogates. Detection of maternal KIR genes and HLA-C molecules from the couple could serve as useful markers for predicting and diagnosing GOS. PMID:34504623 | PMC:PMC8394021 | DOI:10.3892/etm.2021.10612 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Clinical efficiency of combination therapy using testosterone replacement therapy, phosphodiesterase 5 inhibitors and Kampo herbal medicine for eugonadal patients with late-onset hypogonadism syndrome

xlomafota13 shared this article with you from Inoreader Clinical efficiency of combination therapy using testosterone replacement therapy, phosphodiesterase 5 inhibitors and Kampo herbal medicine for eugonadal patients with late-onset hypogonadism syndrome Via Experimental and therapeutic medicine Exp Ther Med. 2021 Oct;22(4):1173. doi: 10.3892/etm.2021.10608. Epub 2021 Aug 13. ABSTRACT In the present study, the initial treatment efficiency of combination therapy using testosterone replacement therapy (TRT), herbal medicine and phosphodiesterase 5 inhibitors (PDE5i) in male patients with late-onset hypogonadism (LOH) were assessed. A total of 21 patients were enrolled and after 12 weeks, the clinical efficacy was evaluated based on improvement of LOH symptoms via laboratory parameters and several questionnaires, including the Ageing Males' Symptoms (AMS) scale. The overall AMS scores, as well as the psychological, physical and sexual AMS factors prior to and after treatment in the TRT, testosterone enanthate (T enanthate) monotherapy and T enanthate + PDE5i treatment groups were significantly improved. In the herbal medicine group, only the AMS physiological factors were significantly improved after treatment compared with the b aseline. The improvement of the overall AMS scores, as well as the physiological and sexual AMS factors, were significantly negatively correlated with the free testosterone (FT) value prior to treatment. In conclusion, treatment with combination therapy using TRT, herbal medicine and PDE5i improved AMS scores in patients with LOH syndrome. Particularly in patients with LOH syndrome and low FT, the symptoms were significantly improved following combination therapy. PMID:34504618 | PMC:PMC8393732 | DOI:10.3892/etm.2021.10608 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Neuroplasticity and depression: Rewiring the brain's networks through pharmacological therapy (Review)

xlomafota13 shared this article with you from Inoreader Neuroplasticity and depression: Rewiring the brain's networks through pharmacological therapy (Review) Via Experimental and therapeutic medicine Exp Ther Med. 2021 Oct;22(4):1131. doi: 10.3892/etm.2021.10565. Epub 2021 Aug 5. ABSTRACT In modern society, depression is one of the most common mental illness; however, its pathophysiology is not yet fully understood. A great body of evidence suggests that depression causes changes in neuroplasticity in specific regions of the brain which are correlated to symptom severity, negative emotional rumination as well as fear learning. Depression is correlated with atrophy of neurons in the cortical and limbic brain regions that control mood and emotion. Antidepressant therapy can exhibit effects on neuroplasticity and reverse the neuroanatomical changes found in depressed patients. The investigation of fast-acting agents that reverse behavioral and neuronal deficiencies of chronic depression, especially the glutamate receptor antagonist NMDA ketamine, and the cellular mechanisms underlying the rapid antidepressant actions of ketamine and r elated agents are of real interest in current research. Actual medication such as serotonin (5-HT) selective reuptake inhibitor (SSRI) antidepressants, require weeks to months of administration before a clear therapeutic response. The current review aimed to underline the negative effects of depression on neuroplasticity and present the current findings on the effects of antidepressant medication. PMID:34504581 | PMC:PMC8383338 | DOI:10.3892/etm.2021.10565 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Gardnerella vaginalis induces NLRP3 inflammasome-mediated pyroptosis in macrophages and THP-1 monocytes

xlomafota13 shared this article with you from Inoreader Gardnerella vaginalis induces NLRP3 inflammasome-mediated pyroptosis in macrophages and THP-1 monocytes Via Experimental and therapeutic medicine Exp Ther Med. 2021 Oct;22(4):1174. doi: 10.3892/etm.2021.10609. Epub 2021 Aug 13. ABSTRACT The vagina is colonized by a variety of microbes that serve vital roles in the maintenance of vaginal health. The purpose of the present study was to explore the underlying mechanism by which Gardnerella vaginalis (GV) can induce bacterial vaginosis (BV). The viability of primary mouse macrophages and THP-1 cells was detected using a Cell Counting Kit-8 assay. Lactate dehydrogenase and caspase-1 activity in the culture medium of macrophages and THP-1 cells were measured using a colorimetric assay and a caspase-1 activity assay kit, respectively. In the macrophages and THP-1 cells, the levels of TNF-α, IL-1β and IL-18 were detected using ELISA whereas reactive oxygen species (ROS) levels were detected using flow cytometry. The pyroptosis of macrophages and THP-1 cells was detected using calcein-AM/PI double staining. Expression of protein s associated with the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing protein 3 inflammasome (NLRP3), including NLRP3, apoptosis associated speck-like protein (ASC), caspase-1 and pro-caspase-1, were measured by western blotting and reverse transcription-quantitative PCR. GV significantly inhibited cell viability and increased LDH activity in macrophages and THP-1 cells. In addition, GV markedly promoted the production of TNF-α, IL-1β, IL-18 and ROS by macrophages and THP-1 cells. GV significantly promoted caspase-1 activation-mediated pyroptosis in macrophages and THP-1 cells. Treatment with GV significantly increased the protein and mRNA expression of NLRP3, ASC and caspase-1 in macrophages and THP-1 cells. To conclude, data from the present study suggest that G. vaginalis can induce BV by promoting NLRP3 inflammasome-mediated pyroptosis, which provides one of the molecular mechanisms by which G. vaginalis can induce BV. PMID:34504619 | PMC:PMC8393845 | DOI:10.3892/etm.2021.10609 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Gadolinium chloride pre-treatment reduces the inflammatory response and preserves intestinal barrier function in a rat model of sepsis

xlomafota13 shared this article with you from Inoreader Gadolinium chloride pre-treatment reduces the inflammatory response and preserves intestinal barrier function in a rat model of sepsis Via Experimental and therapeutic medicine Exp Ther Med. 2021 Oct;22(4):1143. doi: 10.3892/etm.2021.10577. Epub 2021 Aug 9. ABSTRACT The inflammatory response is closely associated with sepsis occurrence and progression. Damage to the function of the intestinal mucosal barrier is considered to be the ῾initiation factor᾿ for the development of multiple organ dysfunction syndrome, which is the most severe progression of sepsis. The aim of the present study was to investigate whether gadolinium chloride (GdCl3) could alleviate the systemic inflammatory response and protect the function of the intestinal mucosal barrier in a rat model of sepsis. The mechanism underlying this protective effect was also explored. Sprague-Dawley rats were divided into four groups: Sham, sham + GdCl3, cecal ligation and puncture (CLP; a model of sepsis) and CLP + GdCl3. In each group, blood was collected from the abdominal aorta, and intestinal tissue was collected after 6, 12 and 24 h of successful modeling. Levels of tumor necrosis factor-α, interleukin (IL)-6 and IL-1β were determined using ELISA. Western blot analysis was used to determine levels of occludin, tight junction protein ZO-1 (ZO-1), myosin light chain kinase 3 (MLCK), NF-κB and caspase-3 in intestinal tissues. Hematoxylin-eosin staining was used to observe the degree of damage to intestinal tissue. The results indicated that in CLP sepsis model rats treated with GdCl3, the release of systemic and intestinal pro-inflammatory factors was reduced and tissue damage was alleviated when compared with untreated CLP rats. Additionally, the expression of occludin and ZO-1 was increased, while that of NF-κB, MLCK, and caspase-3 was reduced in the CLP + GdCl3 rats compared with the CLP rats. GdCl3 may alleviate systemic and intestinal inflammatory responses and reduce the expression of MLCK through inhibition of the activation of NF-kB. The results of the present study also indicated that GdCl3 promoted the expression of occludin and ZO-1. GdCl3 was also demonstrated to reduce cell apoptosis through the inhibition of caspase-3 expression. PMID:34504589 | PMC:PMC8393272 | DOI:10.3892/etm.2021.10577 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Piperazine ferulate prevents high-glucose-induced filtration barrier injury of glomerular endothelial cells

xlomafota13 shared this article with you from Inoreader Piperazine ferulate prevents high-glucose-induced filtration barrier injury of glomerular endothelial cells Via Experimental and therapeutic medicine Exp Ther Med. 2021 Oct;22(4):1175. doi: 10.3892/etm.2021.10607. Epub 2021 Aug 13. ABSTRACT Filtration barrier injury induced by high glucose (HG) levels leads to the development of diabetic nephropathy. The endothelial glycocalyx plays a critical role in glomerular barrier function. In the present study, the effects of piperazine ferulate (PF) on HG-induced filtration barrier injury of glomerular endothelial cells (GEnCs) were investigated and the underlying mechanism was assessed. Immunofluorescence was used to observe the distribution of the glycocalyx as well as the expression levels of syndecan-1 and Zonula occludens-1 (ZO-1). Endothelial permeability assays were performed to assess the effects of PF on the integrity of the filtration barrier. Protein and mRNA expression levels were measured by western blotting and reverse transcription-quantitative PCR analyses, respectively. In vitro experiments revealed that adenosine mon ophosphate-activated protein kinase (AMPK) mediated HG-induced glycocalyx degradation and endothelial barrier injury. PF inhibited the HG-induced endothelial barrier injury and restored the expression levels of heparanase-1 (Hpa-1), ZO-1 and occludin-1 by AMPK. In vivo assays demonstrated that PF reduced the expression levels of Hpa-1, increased the expression levels of ZO-1 and attenuated glycocalyx degradation in the glomerulus. These data suggested that PF attenuated HG-induced filtration barrier injury of GEnC by regulating AMPK expression. PMID:34504620 | PMC:PMC8393711 | DOI:10.3892/etm.2021.10607 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Deacetylated Sp1 improves β-glycerophosphate-induced calcification in vascular smooth muscle cells

xlomafota13 shared this article with you from Inoreader Deacetylated Sp1 improves β-glycerophosphate-induced calcification in vascular smooth muscle cells Via Experimental and therapeutic medicine Exp Ther Med. 2021 Oct;22(4):1152. doi: 10.3892/etm.2021.10586. Epub 2021 Aug 10. ABSTRACT The aging of the population has led to an annual increase in the incidence of vascular calcification (VC). Specific protein 1 (Sp1) is a transcriptional activator that serves an important role in VC. The deacetylation of transcription factors represses their binding to the promoters of downstream genes, thereby causing their downregulation. The present study aimed to investigate the role of deacetylated Sp1 in the development of VC. In the present study, western blotting and immunoprecipitation (IP) were performed to detect the protein levels of acetylated Sp1. Western blotting and immunofluorescence staining were used to analyze phenotypic switching in vascular smooth muscle cells (VSMCs). Alizarin red S, alkaline phosphatase (ALP) activity and calcium content assays were used to assess calcium deposition in VSMCs. Western blotting, flow cytomet ry, TUNEL staining and caspase3 activity assay were used to evaluate apoptosis of VSMCs. Chromatin immunoprecipitation (ChIP) assay was used to detect Sp1 binding to the BMP2 promoter. The results indicated that, in a β-glycerophosphate (β-GP)-induced VSMC calcification model, the level of acetylated Sp1 was increased. Western blotting and immunofluorescence staining results showed that, compared with the Sp1 overexpression group (Sp1-WT), deacetylated Sp1 (Sp1-K704A) downregulated the expression of osteogenic markers runt-related transcription factor 2 (Runx2) and bone morphogenetic protein 2 (BMP2), and upregulated the expression of contraction marker α-smooth muscle actin (α-SMA) and calponin 1. In addition, deacetylated Sp1 also reduced the ALP activity and calcium content of calcified VSMCs, and the Alizarin red S assay revealed that the calcium crystallization of Sp1-K704A group was markedly decreased. Western blotting, flow cytometry, TUNEL staining and caspase-3 activity assay were detected to indicate that the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein ratio was increased, and caspase-3 activity and the apoptotic rate of VSMCs were decreased, in the Sp1-K704A group, as compared with the Sp1-WT group. ChIP assay revealed that Sp1 binding to the BMP2 promoter was downregulated in the Sp1-K704A group, compared with that in theSp1-WT group. In conclusion, a deacetylated mutant of Sp1 decreased Sp1 binding to the BMP2 promoter, thus decreasing apoptosis, phenotypic switching and calcium deposition in calcified VSMCs. This finding may indicate potential therapeutic targets for VC. PMID:34504597 | PMC:PMC8394101 | DOI:10.3892/etm.2021.10586 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.