Celecoxib ameliorates diabetic neuropathy by decreasing apoptosis and oxidative stress in dorsal root ganglion neurons via the miR-155/COX-2 axis

xlomafota13 shared this article with you from Inoreader Celecoxib ameliorates diabetic neuropathy by decreasing apoptosis and oxidative stress in dorsal root ganglion neurons via the miR-155/COX-2 axis Via Experimental and therapeutic medicine Exp Ther Med. 2021 Aug;22(2):825. doi: 10.3892/etm.2021.10257. Epub 2021 Jun 2. ABSTRACT Celecoxib (CXB) is the only clinical cyclooxygenase-2 (COX-2) inhibitor. Oral administration of CXB in experimental diabetic mice effectively relieved the symptoms of diabetic neuropathy (DN); however, the molecular mechanism remains unclear. The present study aimed to investigate the potential molecular mechanisms of CXB in the treatment of DN. An in vitro cellular model of DN was produced by stimulating dorsal root ganglion (DRG) neurons with high glucose. Cell viability and apoptosis were assessed by Cell Counting Kit-8 assays and flow cytometry, respectively. Reactive oxygen species (ROS) kits, ELISA kits and western blotting were used to determine oxidative cellular damage. The expression level of microRNA (miR)-155 was analyzed by reverse transcription-quantitative PCR. The starBase database and dual-luciferase assays were performed to predict and determine the interaction between miR-155 and COX-2. Protein expression of neurotrophic factors, oxidative stress-related proteins and COX-2 were analyzed by western blotting. Incubation with high glucose led to a decrease in DRG neuron cell viability, facilitated apoptosis, downregulated NGF and BDNF expression, increased ROS and MDA generation and decreased SOD activity. Treatment with CXB significantly protected DRG neurons against high glucose-evoked damage. CXB promoted the expression of miR-155 and COX-2 was revealed to be a direct target of miR-155. Inhibition of COX-2 enhanced the protective effect of CXB on DRG neurons and that treatment with an miR-155 inhibitor partially rescued this effect. The present study demonstrated the involvement of the miR-155/COX-2 axis in the protective effect of CXB against high glucose-induced DN. PMID:34149871 | PMC:PMC8200812 | DOI:10.3892/etm.2021.10257 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

miR-125b-5p inhibits cell proliferation by targeting ASCT2 and regulating the PI3K/AKT/mTOR pathway in an LPS-induced intestinal mucosa cell injury model

xlomafota13 shared this article with you from Inoreader miR-125b-5p inhibits cell proliferation by targeting ASCT2 and regulating the PI3K/AKT/mTOR pathway in an LPS-induced intestinal mucosa cell injury model Via Experimental and therapeutic medicine Exp Ther Med. 2021 Aug;22(2):838. doi: 10.3892/etm.2021.10270. Epub 2021 Jun 6. ABSTRACT Intestinal barrier injury is an important cause of death in patients with acquired immune deficiency syndrome (AIDS). Therefore, it is of great significance to identify a therapeutic target for intestinal barrier injury to delay the progression of AIDS. microRNA (miRNA/miR)-125b-5p has an extensive role in cancer and controlling intestinal epithelial barrier function, but its role in human immunodeficiency virus-related intestinal mucosal damage remains unknown. The present study was designed to explore the effects of miR-125b-5p on lipopolysaccharide (LPS)-induced intestinal mucosal injury and the underlying mechanism. The expression of miR-125b-5p and ASCT2 mRNA was detected in colon biopsy samples of 10 patients with AIDS and 10 control healthy subjects. Human intestinal embryonic mucosa cells (CCC-HIE-2) were used to establish an LPS-induced in testinal mucosa cell injury model in vitro. Cell proliferation and apoptosis were determined by MTT assays and flow cytometry, respectively. miR-125b-5p levels and ASCT2 mRNA and protein expression levels in the LPS-induced intestinal mucosa cell injury model were detected by reverse transcription-quantitative PCR (RT-qPCR) and western blotting. The interaction between miR-125b-5p and ASCT2 was analyzed using a dual luciferase reporter assay. The results demonstrated that miR-125b-5p levels were increased and ASCT2 mRNA expression levels were decreased in colon samples from patients with AIDS and in LPS-induced intestinal mucosa cells. In the LPS-induced intestinal mucosa cell injury model, transfection with miR-125b-5p mimic inhibited cell proliferation and promoted cell apoptosis, while transfection with a miR-125b-5p inhibitor increased cell proliferation and attenuated cell apoptosis. Furthermore, miR-125b-5p mimic transfection resulted in a decrease of ASCT2 mRNA and pro tein expression, whereas the inhibitor increased ASCT2 mRNA and protein expression. Dual luciferase reporter assays suggested that ASCT2 was a direct target of miR-125b-5p, and its restoration weakened the effect of miR-125b-5p on LPS-induced intestinal mucosa cell injury. Transfection with the miR-125b-5p mimic also exhibited a suppressive effect on the PI3K/AKT/mTOR pathway in the LPS-induced intestinal mucosal cell injury model. Overall, the present study indicated that miR-125b-5p accelerated LPS-induced intestinal mucosa cell injury by targeting ASCT2 and upregulating the PI3K/AKT/mTOR pathway. The current findings may provide novel targets for the treatment of intestinal barrier injury in patients with AIDS. PMID:34149884 | PMC:PMC8210225 | DOI:10.3892/etm.2021.10270 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

STK10 knockout inhibits cell migration and promotes cell proliferation via modulating the activity of ERM and p38 MAPK in prostate cancer cells

xlomafota13 shared this article with you from Inoreader STK10 knockout inhibits cell migration and promotes cell proliferation via modulating the activity of ERM and p38 MAPK in prostate cancer cells Via Experimental and therapeutic medicine Exp Ther Med. 2021 Aug;22(2):851. doi: 10.3892/etm.2021.10283. Epub 2021 Jun 8. ABSTRACT Prostate cancer (PCa) is one of the most common types of cancer and is a serious threat to men's health due to the high rate of incidence and metastasis. However, the exact underlying pathology of this malignant disease has yet to be fully elucidated. The ezrin-radixin-moesin (ERM) family of proteins are associated with the development and metastasis of various types of cancer. Serine threonine kinase 10 (STK10) is an ERM kinase that is involved in the activation of ERM proteins and serves essential roles in the aggregation and adhesion of lymphocytes. To evaluate the functional roles of STK10 in the pathogenesis of PCa, a STK10-knockout (KO) DU145 PCa cell line was generated using the CRISPR-Cas9 gene editing system, and the effects of STK10 deletion on tumor biological behaviors were further analyzed. The present data suggested that STK10 KO promoted PCa cell proliferation by inhibiting p38 MAPK activation and suppressed migration primarily via the inhibition of p38 MAPK signaling and ERM protein activation. To the best of our knowledge, this is the first study to provide evidence that STK10 plays important roles in the proliferation and migration of PCa cells, which will be useful for further investigation into the pathogenesis of this disease. PMID:34149897 | PMC:PMC8210223 | DOI:10.3892/etm.2021.10283 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Changes in bone density, intraosseous pressure of distal femoral articular cartilage and subchondral bone after proximal femoral medullary cavity cement filling in rabbits

xlomafota13 shared this article with you from Inoreader Changes in bone density, intraosseous pressure of distal femoral articular cartilage and subchondral bone after proximal femoral medullary cavity cement filling in rabbits Via Experimental and therapeutic medicine Exp Ther Med. 2021 Aug;22(2):839. doi: 10.3892/etm.2021.10271. Epub 2021 Jun 6. ABSTRACT Bone cement is widely used, particularly in hip replacements, but the potential clinical complications of its use have been largely unrecognized. The purpose of the present study was to investigate the effects of bone cement in the proximal femoral medullary cavity (PFMC) on bone mineral density (BMD), intraosseous pressure (IOP), articular cartilage and subchondral bone in the distal femurs of rabbits. A total of 32 New Zealand white rabbits were randomly numbered and the left hind limb of the odd-numbered rabbits and the right hind limb of the even numbered rabbits were selected as the experimental side. For each rabbit, the non-experimental hind limb was labeled as the control side by the principal investigator. An intramedullary injection of polymethyl methacrylate was made into the experimental hindlimb of each rabbit and the PFMC filled with bone cement. BMD and IOP of the distal femur of the bilateral hindlimb were measured at 4 and 16 weeks after surgery, and histological and ultra-fine structural features were examined by light and transmission electron microscopy, respectively. At week 4 after the operation, IOP in the experimental limb was significantly higher and BMD lower compared with the control limb. At the 16th week after operation, the IOP in the experimental limb was lower than at the 4th week after operation, but still higher compared with controls, and the BMD was significantly higher than the controls. In the controls, IOP and BMD was not significantly different between the 4th and 16th week after operation. Compared with controls, the cartilage in the experimental group was thinner, the chondrocytes partially necrotic and the trabecular structure of the subchondral bone broken. Analysis of ultra-fine structural features in the experimental group showed chondrocytes with necrotic cytoplasm and pyknotic n uclei relative to controls. The results indicated that blockage of the PFMC with bone cement resulted in an increase in the IOP in the distal femur, a change in BMD and damage to the subchondral bone and articular cartilage. PMID:34149885 | PMC:PMC8210259 | DOI:10.3892/etm.2021.10271 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Discovery of hydroxytyrosol as thioredoxin reductase 1 inhibitor to induce apoptosis and G1/S cell cycle arrest in human colorectal cancer cells via ROS generation

xlomafota13 shared this article with you from Inoreader Discovery of hydroxytyrosol as thioredoxin reductase 1 inhibitor to induce apoptosis and G<sub>1</sub>/S cell cycle arrest in human colorectal cancer cells via ROS generation Via Experimental and therapeutic medicine Exp Ther Med. 2021 Aug;22(2):829. doi: 10.3892/etm.2021.10261. Epub 2021 Jun 3. ABSTRACT Colorectal cancer (CRC) is one of the most common cancer types and a leading cause of cancer-associated mortality in China. Increased thioredoxin reductase 1 (TrxR1) levels have been previously identified as possible target for CRC. The present study revealed that the natural product hydroxytyrosol (HT), which exhibits a polyphenol scaffold, is a potent inhibitor of TrxR1. Inhibition of TrxR1 was indicated to result in accumulation of reactive oxygen species, inhibit proliferation and induce apoptosis and G1/S cell cycle arrest of CRC cells. Using a C-terminal mutant TrxR1 enzyme activity assay, TrxR1 RNA interference assay and HT binding model assay, the present study demonstrated the core character of the selenocysteine residue in the interaction between HT and TrxR1. HT can serve as polyphenol scaffold to develop novel TrxR1 inhibitor s for CRC treatment in the future. PMID:34149875 | PMC:PMC8200807 | DOI:10.3892/etm.2021.10261 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Pharmacological activities of ginsenoside Rg5 (Review)

xlomafota13 shared this article with you from Inoreader Pharmacological activities of ginsenoside Rg5 (Review) Via Experimental and therapeutic medicine Exp Ther Med. 2021 Aug;22(2):840. doi: 10.3892/etm.2021.10272. Epub 2021 Jun 6. ABSTRACT Ginseng, a perennial plant belonging to genus Panax, has been widely used in traditional herbal medicine in East Asia and North America. Ginsenosides are the most important pharmacological component of ginseng. Variabilities in attached positions, inner and outer residues and types of sugar moieties may be associated with the specific pharmacological activities of each ginsenoside. Ginsenoside Rg5 (Rg5) is a minor ginsenoside synthesized during ginseng steaming treatment that exhibits superior pharmaceutical activity compared with major ginsenosides. With high safety and various biological functions, Rg5 may act as a potential therapeutic candidate for diverse diseases. To date, there have been no systematic studies on the activity of Rg5. Therefore, in this review, all available literature was reviewed and discussed to facilitate further re search on Rg5. PMID:34149886 | PMC:PMC8210315 | DOI:10.3892/etm.2021.10272 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Inhibition of miR-200b-3p alleviates lipid accumulation and promotes cholesterol efflux by targeting ABCA1 in macrophage-derived foam cells

xlomafota13 shared this article with you from Inoreader Inhibition of miR-200b-3p alleviates lipid accumulation and promotes cholesterol efflux by targeting ABCA1 in macrophage-derived foam cells Via Experimental and therapeutic medicine Exp Ther Med. 2021 Aug;22(2):831. doi: 10.3892/etm.2021.10263. Epub 2021 Jun 3. ABSTRACT Atherosclerosis (As) is a chronic cardiovascular disease characterized by abnormal of lipid accumulation and cholesterol efflux. The present study aimed to investigate whether the micro-RNA (miR)-200b-3p could exacerbate As by promoting lipid accumulation and inhibiting cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) in macrophage-derived foam cells. Blood samples from 30 patients with As and 30 healthy people were collected at Quanzhou First Hospital. RAW264.7 cells were used to establish foam cells using oxidized low-density lipoprotein. The expression of miR-200b-3p and ABCA1 was evaluated by reverse transcription quantitative PCR and western blotting. Lipid accumulation was analyzed by Oil Red O staining and cholesterol content was assessed by ELISA. A targeting relationship between miR-200b-3p and ABCA1 was demonstrated by l uciferase reporter assays. Compared with healthy volunteers and RAW264.7 cells, the expression level of miR-200b-3p was significantly increased whereas the expression level of ABCA1 was significantly decreased in patients with As and foam cells. Furthermore, miR-200b-3p expression was negatively correlated with ABCA1 expression in the blood of the patients with As. Lipid content was significantly decreased and cholesterol efflux was significantly increased in foam cells transfected with the miR-200b-3p inhibitor compared with inhibitor control cells. In addition, ABCA1 was shown to be targeted by miR-200b-3p. Furthermore, the lipid content in foam cells transfected with the miR-200b-3p inhibitor and small interfering-ABCA1 was significantly increased, while the cholesterol efflux was significantly decreased compared with foam cells transfected with the miR-200b-3p inhibitor. In conclusion, the findings from the present study indicated that inhibition of miR-200b-3p may alleviate lip id accumulation and promote cholesterol efflux by targeting ABCA1 in macrophage-derived foam cells. PMID:34149877 | PMC:PMC8200800 | DOI:10.3892/etm.2021.10263 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Pharmacological inhibition of EZH2 by GSK126 decreases atherosclerosis by modulating foam cell formation and monocyte adhesion in apolipoprotein E-deficient mice

xlomafota13 shared this article with you from Inoreader Pharmacological inhibition of EZH2 by GSK126 decreases atherosclerosis by modulating foam cell formation and monocyte adhesion in apolipoprotein E-deficient mice Via Experimental and therapeutic medicine Exp Ther Med. 2021 Aug;22(2):841. doi: 10.3892/etm.2021.10273. Epub 2021 Jun 6. ABSTRACT Histone modifications play an important role in the occurrence and development of atherosclerosis in human and atherosclerosis-prone mice. Histone methylation in macrophages, monocytes and endothelial cells markedly influence the progression of atherosclerosis. However, it remains unclear whether treatment with a histone methyltransferase enhancer of zeste homolog 2 (EZH2) inhibitor may suppress atherosclerosis. The present study aimed to determine the effects of the EZH2 inhibitor, GSK126, on the suppression and regression of atherosclerosis in apolipoprotein E-deficient mouse models. In vitro, it was found that pharmacological inhibition of EZH2 by GSK126 markedly reduced lipid transportation and monocyte adhesion during atherogenesis, predominantly through increasing the expression levels of ATP-binding cassette transporter A1 and suppres sing vascular cell adhesion molecule 1 in human THP-1 cells. In vivo, it was found that atherosclerotic plaques in GSK126-treated mice were significantly decreased when comparing with the vehicle-treated animals. These results indicated that the GSK126 has the ability to attenuate the progression of atherosclerosis by reducing macrophage foam cell formation and monocyte adhesion in cell and mouse models. In conclusion, the present study provided new insights into the molecular mechanism behind the action of GSK126 and suggested its therapeutic potential for the treatment of atherosclerosis. PMID:34149887 | PMC:PMC8210282 | DOI:10.3892/etm.2021.10273 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Protective role and molecular mechanism of action of Nesfatin-1 against high glucose-induced inflammation, oxidative stress and apoptosis in retinal epithelial cells

xlomafota13 shared this article with you from Inoreader Protective role and molecular mechanism of action of Nesfatin-1 against high glucose-induced inflammation, oxidative stress and apoptosis in retinal epithelial cells Via Experimental and therapeutic medicine Exp Ther Med. 2021 Aug;22(2):833. doi: 10.3892/etm.2021.10265. Epub 2021 Jun 3. ABSTRACT Diabetic retinopathy (DR) is a major complication of diabetes mellitus that may cause severe visual impairment. It has been reported that the levels of nesfatin-1 in the serum and vitreous humor were negatively correlated with DR; however, its role in DR has not been fully elucidated. Therefore, the present study was performed to investigate the effect of nesfatin-1 on high glucose-treated human retinal epithelial cells (ARPE-19) and explore the underlying mechanism. The effects of nesfatin-1 on cell viability, inflammation, oxidative stress and apoptosis were examined under high glucose conditions. The Cell Counting Kit-8 assay was used to determine cell viability. The levels of inflammatory cytokines were evaluated using ELISA kits. The reactive oxygen species and malondialdehyde content was estimated using commercial assay kits. Flow cytometry w as performed to detect apoptotic cells and western blot analysis was employed to evaluate the expression of apoptosis-associated proteins. Moreover, the levels of NF-κB, NACHT, LRR and PYD domains-containing protein 3 (NLRP3) and high-mobility group protein B1 (HMGB1) were determined via western blot analysis. The results revealed that nesfatin-1 enhanced cell viability and suppressed inflammation, oxidative stress and apoptosis in the presence of high glucose concentration. Moreover, the activation of the NF-κB/NLRP3 inflammasome signaling and the expression of HMGB1 were inhibited by nesfatin-1. Furthermore, HMGB1 overexpression partially abrogated the inactivation of the NF-κB/NLRP3 inflammasome pathway caused by nesfatin-1. Taken together, these findings demonstrated that nesfatin-1 inhibited the activation of the NF-κB/NLRP3 inflammasome signaling via modulating HMGB1 and exerted a protective effect on ARPE-19 cells against high glucose-induced inflammation, oxidative stres s and apoptosis. PMID:34149879 | PMC:PMC8200809 | DOI:10.3892/etm.2021.10265 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Inhibitory effects of quercetin and its major metabolite quercetin-3-O-β-D-glucoside on human UDP-glucuronosyltransferase 1A isoforms by liquid chromatography-tandem mass spectrometry

xlomafota13 shared this article with you from Inoreader Inhibitory effects of quercetin and its major metabolite quercetin-3-O-β-D-glucoside on human UDP-glucuronosyltransferase 1A isoforms by liquid chromatography-tandem mass spectrometry Via Experimental and therapeutic medicine Exp Ther Med. 2021 Aug;22(2):842. doi: 10.3892/etm.2021.10274. Epub 2021 Jun 6. ABSTRACT Quercetin is a flavonoid that is widely present in plant-derived food. Quercetin-3-O-β-D-glucoside (Q3GA) is a predominant metabolite of quercetin in animal and human plasma. The inhibitory effects of the UDP-glucuronosyl transferases (UGTs) caused by herbal components may be a key factor for the clinical assessment of herb-drug interactions (HDIs). The present study aimed to investigate the inhibitory profile of quercetin and Q3GA on recombinant UGT1A isoforms in vitro. The metabolism of the nonspecific substrate 4-methylumbelliferone (4-MU) by the UGT1A isoforms was assessed by liquid chromatography-tandem mass spectrometry. Preliminary screening experiments indicated that quercetin exhibited stronger inhibitory effects on UGT1A1, UGT1A3, UGT1A6 and UGT1A9 enzymes than Q3GA. Kinetic experiments were performed to characterize the type of i nhibition caused by quercetin and Q3GA towards these UGT isoforms. Quercetin exerted non-competitive inhibition on UGT1A1 and UGT1A6, with half maximal inhibitory concentration (IC50) values of 7.47 and 7.07 µM and inhibition kinetic parameter (Ki) values of 2.18 and 28.87 µM, respectively. Quercetin also exhibited competitive inhibition on UGT1A3 and UGT1A9, with IC50 values of 10.58 and 2.81 µM and Ki values of 1.60 and 0.51 µM, respectively. However, Q3GA displayed weak inhibition on UGT1A1, UGT1A3 and UGT1A6 enzymes with IC50 values of 45.21, 106.5 and 51.37 µM, respectively. In the present study, quercetin was a moderate inhibitor of UGT1A1 and UGT1A3, a weak inhibitor of UGT1A6, and a strong inhibitor on UGT1A9. The results of the present study suggested potential HDIs that may occur following quercetin co-administration with drugs that are mainly metabolized by UGT1A1, UGT1A3 and UGT1A9 enzymes. PMID:34149888 | PMC:PMC8210293 | DOI:10.3892/etm.2021.10274 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.