Effects of low-dose bufalin combined with hydroxycamptothecin on human castration-resistant prostate cancer xenografts in nude mice

xlomafota13 shared this article with you from Inoreader Effects of low-dose bufalin combined with hydroxycamptothecin on human castration-resistant prostate cancer xenografts in nude mice Via Experimental and therapeutic medicine Exp Ther Med. 2021 Sep;22(3):1015. doi: 10.3892/etm.2021.10447. Epub 2021 Jul 15. ABSTRACT Prostate cancer is the most prevalent tumor found in men worldwide. Despite the efficiency of primary endocrine prostate cancer therapies, more efficient drugs are needed to tackle the most advanced and resistant forms of this condition. The present study investigated the antitumor effects of low-dose bufalin combined with hydroxycamptothecin on castration-resistant prostate cancer (CRPC) in mice, as well as the possible mechanisms of apoptosis induction. CRPC xenograft tumors were generated in mice and, subsequently, mice received appropriate doses of bufalin, hydroxycamptothecin or a combination of the two drugs. Tumors from each treatment group were removed, and the tumor volume, weight and inhibition rate of each group was determined. Hematoxylin and eosin staining was performed for pathological analysis and TUNEL staining was used to assess the level of apoptosis in the xenografts. Immunohistochemistry was used for the analysis of proliferating cell nuclear antigen expression and the expression of Bax, Bcl-XL, p53, programmed cell death 4 (PDCD4), phosphorylated (p)-AKT and glycogen synthase kinase (GSK)-3β was determined by western blotting. Treatment with bufalin significantly (P<0.05) reduced tumor volumes compared with the negative control group, reducing tumor volumes to lower levels when combined with hydroxycampothecin. The combination of bufalin (0.6 or 0.8 mg/kg) and hydroxycampothecin significantly (P<0.05) induced higher levels of cell apoptosis compared with the administration of bufalin or hydroxycampothecin alone. The combination of bufalin and hydroxycampothecin also increased the expression of apoptosis-related proteins Bax, p53, PDCD4 and GSK-3β, and decreased the expression of Bcl-XL and p-AKT compared with a single drug treatment. The present study suggested that the combination of bufalin an d hydroxycampothecin improved the inhibitory effects of both drugs on CRPC tumors in vivo, potentially via the regulation of the PI3K/AKT/GSK-3β and p53-dependent apoptosis signaling pathways. PMID:34373701 | PMC:PMC8343571 | DOI:10.3892/etm.2021.10447 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Repetitive transcranial magnetic stimulation increases neurological function and endogenous neural stem cell migration via the SDF-1α/CXCR4 axis after cerebral infarction in rats

xlomafota13 shared this article with you from Inoreader Repetitive transcranial magnetic stimulation increases neurological function and endogenous neural stem cell migration via the SDF-1α/CXCR4 axis after cerebral infarction in rats Via Experimental and therapeutic medicine Exp Ther Med. 2021 Sep;22(3):1037. doi: 10.3892/etm.2021.10469. Epub 2021 Jul 19. ABSTRACT Neural stem cell (NSC) migration is closely associated with brain development and is reportedly involved during recovery from ischaemic stroke. Chemokine signalling mediated by stromal cell-derived factor 1α (SDF-1α) and its receptor CXC chemokine receptor 4 (CXCR4) has been previously documented to guide the migration of NSCs. Although repetitive transcranial magnetic stimulation (rTMS) can increase neurological function in a rat stroke model, its effects on the migration of NSCs and associated underlying mechanism remain unclear. Therefore, the present study investigated the effects of rTMS on ischaemic stroke following middle cerebral artery occlusion (MCAO). All rats underwent rTMS treatment 24 h after MCAO. Neurological function, using modified Neurological Severity Scores and grip strength test and NSC migration, which were measured using immunofluorescence staining, were analysed at 7 and 14 days after MCAO, before the protein expression levels of the SDF-1α/CXCR4 axis was evaluated using western blot analysis. AMD3100, a CXCR4 inhibitor, was used to assess the effects of SDF-1α/CXCR4 signalling. In addition, neuronal survival was investigated using Nissl staining at 14 days after MCAO. It was revealed that rTMS increased the neurological recovery of rats with MCAO, facilitated the migration of NSC, augmented the expression levels of the SDF-1α/CXCR4 axis and decreased neuronal loss. Furthermore, the rTMS-induced positive responses were significantly abolished by AMD3100. Overall, these results indicated that rTMS conferred therapeutic neuroprotective properties, which can restore neurological function after ischaemic stroke, in a manner that may be associated with the activation of the SDF-1α/CXCR4 axis. PMID:34373723 | PMC:PMC8343462 | DOI:10.3892/etm.2021.10469 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Aging reduces kisspeptin receptor (GPR54) expression levels in the hypothalamus and extra-hypothalamic brain regions

xlomafota13 shared this article with you from Inoreader Aging reduces kisspeptin receptor (GPR54) expression levels in the hypothalamus and extra-hypothalamic brain regions Via Experimental and therapeutic medicine Exp Ther Med. 2021 Sep;22(3):1019. doi: 10.3892/etm.2021.10451. Epub 2021 Jul 15. ABSTRACT Aging leads to the diminished pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH). Kisspeptin (Kp), the upstream regulator of the hypothalamic-pituitary-gonadal (HPG) axis, regulates GnRH synthesis and release through its cognate receptor, G-protein coupled receptor 54 (GPR54). In turn, GnRH regulates GPR54 expression. GnRH administration into the third ventricle has been shown to induce neurogenesis in different brain regions in old age. However, aging-associated changes in hypothalamic and extra-hypothalamic GPR54 expression were unclear. Therefore, the expression levels of GPR54 were evaluated in various brain regions of adult (age, 3-4 months) and old (age, 20-24 months) male Wistar rats in the present study. In the hypothalamus, mRNA and protein levels of Kp and GPR54 were identified to be significantly decreased in old age. Furthermore, GnRH1 expression in the hypothalamus was analyzed to observe the functional consequence of a reduced Kp-GPR54 system in the hypothalamus. It was found that hypothalamic GnRH1 levels were significantly decreased in old age. As GnRH regulates GPR54 levels, GPR54 was examined in extra-hypothalamic regions. GPR54 levels were found to be significantly decreased in the hippocampus and medulla and pons in old-age rats when compared to adult rats. Notably, GPR54 expression was observed in the frontal lobe, cortex, midbrain and cerebellum of adult and old-age rats; however, the difference between the two groups was not statistically significant. To the best of our knowledge, this is the first study that provides the quantitative distribution of GPR54 in different brain regions during aging. Thus, the reduced levels of Kp and its receptor, GPR54 in the hypothalamus could be cumulatively responsible for reduced levels of GnRH observed in old age. PMID:34373705 | PMC:PMC8343700 | DOI:10.3892/etm.2021.10451 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Dexmedetomidine facilitates the expression of nNOS in the hippocampus to alleviate surgery-induced neuroinflammation and cognitive dysfunction in aged rats

xlomafota13 shared this article with you from Inoreader Dexmedetomidine facilitates the expression of nNOS in the hippocampus to alleviate surgery-induced neuroinflammation and cognitive dysfunction in aged rats Via Experimental and therapeutic medicine Exp Ther Med. 2021 Sep;22(3):1038. doi: 10.3892/etm.2021.10470. Epub 2021 Jul 20. ABSTRACT Postoperative cognitive dysfunction (POCD) is a common complication in the postoperative nervous system of elderly patients. Surgery-induced hippocampal neuroinflammation is closely associated with POCD. Dexmedetomidine (DEX) is an effective α2-adrenergic receptor agonist, which can reduce inflammation and has neuroprotective effects, thereby improving postoperative cognitive dysfunction. However, the mechanism by which DEX improves POCD is currently unclear. The purpose of the present study was therefore to identify how DEX acted on POCD. Male Sprague Dawley rats with exposed carotid arteries were used to mimic POCD. Locomotor activity was accessed by the open field test and the Morris water maze was performed to estimate spatial learning, memory and cognitive flexibility. Following animal sacrifice, the hippocampus was collected and cell apopt osis was determined by terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling staining. Subsequently, the expression of apoptosis-related proteins Bax, Bcl-2, cleaved caspase-3 and cleaved caspase-9 was determined by western blotting and the concentrations of TNF-α, IL-6, IL-1β and IL-10 were measured in serum using ELISA. Nitric oxide synthase and neuronal nitric oxide synthase activities in the hippocampus were also measured. The T lymphocyte subsets were analyzed by flow cytometry to evaluate the immune function in each group. Compared with the surgery group, DEX ameliorated POCD by improving cognitive dysfunctions and immune function loss, and attenuated neuroinflammation and neuronal apoptosis. PMID:343 73724 | PMC:PMC8343769 | DOI:10.3892/etm.2021.10470 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

mRNA expression level of CDH2, LEP, POSTN, TIMP1 and VEGFC modulates 5-fluorouracil resistance in colon cancer cells

xlomafota13 shared this article with you from Inoreader mRNA expression level of <em>CDH2</em>, <em>LEP</em>, <em>POSTN</em>, <em>TIMP1</em> and <em>VEGFC</em> modulates 5-fluorouracil resistance in colon cancer cells Via Experimental and therapeutic medicine Exp Ther Med. 2021 Sep;22(3):1023. doi: 10.3892/etm.2021.10455. Epub 2021 Jul 15. ABSTRACT Drug resistance severely affects the clinical efficacy of therapeutic agents in patients with colon cancer. The aim of the present study was to identify genes involved in drug resistance in colon cancer using bioinformatics analysis and to identify the underlying mechanisms in vitro. Genes associated with cancer recurrence and chemotherapy resistance were identified using data mining. Immunohistochemistry was performed to analyze the protein expression level of genes of interest in human colon cancer tissues. Reverse transcription-quantitative PCR analysis was performed to analyze the gene expression level in patient samples and in colon cancer cell lines (HCT116 and LoVo). Cell viability was evaluated using the Cell Counting Kit-8 assay in the colon cancer cell lines. Apoptosis was measured using PI staining. The results from the present study revealed 602 genes using both 'cancer recurrence' and 'chemoresistance' terms on the GenCLiP3 website. Gene functional annotation was performed using the Database for Annotation, Visualization and Integrated Discovery then, the protein-protein interaction networks of the 602 genes were analyzed using STRING analysis. Further, in the GEPIA database, 14 genes (ATM, CDH2, CDKN2A, EPO, LEP, TGFB1, TIMP1, PGR, VEGFC, POSTN, BCL6, CYP19A1, NOTCH3 and XPA) were found to be upregulated in colon cancer tissue and were associated with poor prognosis in patients with colon cancer. Further analysis of 33 paired human colon cancer tissues revealed that 8 genes (ATM, CDH2, CDKN2A, LEP, PGR, TIMP1, POSTN and VEGFC) were significantly upregulated, which was consistent with the results obtained from the earlier analysis and 5 genes (CDH2, LEP, POSTN, TIMP1 and VEGFC) were associated with patient prognosis. Silencing of these 5 genes using small interfering RNAs significantly enhanced the sensitivity of colon cancer cells to the chemotherapeutic agent, 5-fluorouracil (5-FU). Taken together, the results suggested that CDH2, LEP, POSTN, TIMP1 and VEGFC might play a role in chemotherapeutic resistance in colon cancer and represent potential targets for overcoming 5-FU resistance in colon cancer. PMID:34373709 | PMC:PMC8343572 | DOI:10.3892/etm.2021.10455 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

COVID-19 pandemic and reasons to prioritize the needs of the health care system to ensure its sustainability: A scoping review from January to October 2020 (Review)

xlomafota13 shared this article with you from Inoreader COVID-19 pandemic and reasons to prioritize the needs of the health care system to ensure its sustainability: A scoping review from January to October 2020 (Review) Via Experimental and therapeutic medicine Exp Ther Med. 2021 Sep;22(3):1039. doi: 10.3892/etm.2021.10471. Epub 2021 Jul 21. ABSTRACT The worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led the World Health Organization to characterize the pandemic as a public health emergency of international concern. National health care systems in countries during the initial surge of the pandemic were unable to handle the sanitarian crisis that had emerged. Thus, the prevention and control of future global health emergencies must be a priority. The present scoping review aimed to retrieve articles that summarize the current experience on issues related to historical knowledge, and epidemiology, clinical features and overall burden of SARS-CoV-2 on health care services. In summary, a comprehensive overview of the information that has been learnt during this period is presented in the current review. Furthermore, taking into account the global experience, the need for planning cohesive and functional health services before similar pandemic events occur in the future is highlighted. The next public health issue should be prevented rather than treated. In spite of the vaccination benefits, a number of sporadic cases of SARS-CoV-2infections will persist. Information collected remains relevant for appraising how similar threats can be faced in the future. Overall, collaborative health care plans need to be rethought to increase preparedness. PMID:34373725 | PMC:PMC8343896 | DOI:10.3892/etm.2021.10471 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Musculoskeletal adverse reactions after immunotherapy for cancer: A case series

xlomafota13 shared this article with you from Inoreader Musculoskeletal adverse reactions after immunotherapy for cancer: A case series Via Experimental and therapeutic medicine Exp Ther Med. 2021 Sep;22(3):1027. doi: 10.3892/etm.2021.10459. Epub 2021 Jul 16. ABSTRACT Immunotherapy has revolutionized cancer treatment. Immune checkpoint inhibitors (ICIs) including antibodies targeting cytotoxic T lymphocyte associated antigen-4 and programmed cell death 1 have been shown to be effective in the treatment of certain types of cancer. The benefit of these therapies is to prolong life expectancy in the case of metastatic malignancies. Rheumatic adverse events are not very common. In the present study, 9 patients were monitored between November 2018 and January 2020. The oncologist, who identified the occurrence of rheumatic toxicities after the treatment with ICIs, evaluated the patients. Only oncological patients with rheumatic manifestations after the start of immunotherapy were included. Toxicity grading was performed by both the oncologist and the rheumatologist, on a scale from 1 to 5 (1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, death related to toxicity). The results showed that rheumatoid factor, which was sampled in each patient, was negative in all cases. Patients were treated with nonsteroidal anti-inflammatory drugs or prednisone depending on the severity of the adverse events. The results varied with the severity of the adverse events. In conclusion, as the number of patients treated with ICIs increases, so will the number of patients presenting with immune-related adverse events (irAEs). The collaboration between oncologists and rheumatologists should be intimate to provide optimal treatment to patients. Musculoskeletal manifestations secondary to ICIs are slightly different from other rheumatologically conditions making diagnosis, treatment and monitoring difficult. Thus, irAEs are new and challenging for oncologists, thus understanding of the pathogenesis and clinical characteristics must be improved for better treatment guidelines. PMID:34373713 | PMC:PMC8343871 | DOI:10.3892/etm.2021.10459 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Autonomic regulation of imbalance-induced myocardial fibrosis and its mechanism in rats with cirrhosis

xlomafota13 shared this article with you from Inoreader Autonomic regulation of imbalance-induced myocardial fibrosis and its mechanism in rats with cirrhosis Via Experimental and therapeutic medicine Exp Ther Med. 2021 Sep;22(3):1040. doi: 10.3892/etm.2021.10472. Epub 2021 Jul 21. ABSTRACT The aim of the present study was to investigate the changes in cardiac function and myocardial damage in rats with cirrhosis. In addition, a secondary aim was to explore any potential changes in the expression levels of β1-adrenergic (β1) and muscarinic acetylcholine (M2) receptors . A cirrhotic cardiomyopathy (CCM) rat model was established by CCL4-oil solution for subcutaneous injection into the neck. Pathological changes in the liver and myocardial tissues were detecting by H&E staining and Masson trichrome staining. Furthermore, changes in the levels of myocardial enzymes lactate dehydrogenase (LDH), creatine kinase isoenzyme (CK-MB) and troponin in serum were measured by ELISA. The myocardial samples were homogenized and centrifuged. Subsequently, the supernatant was collected for detecting the expression of interleukins in myocardial tissue. Changes in the levels of inflammatory factors, IL-1, IL-2 and IL-6 both in the serum and myocardial tissue were determined by ELISA. Changes in echocardiographic measurements were evaluated using high-frequency ultrasound and the expression levels of β1 and M2 receptors in myocardial tissues were determined by western blotting. The normal lobular structure in liver tissues was found to be disappeared 8 weeks after modeling, which was replaced by pseudolobules in the rats in the CCM group. In addition, the myocardial cells were observed to be swollen and disorderly arranged. Compared with those in the control group, the left ventricular end-systolic and end-diastolic dimensions, interventricular septal dimension and LAD in rats in the CCM8 group were found to be significantly increased. The levels of myocardial enzymes LDH, CK-MB and cardiac troponin in the serum were also revealed to be significantly increased in the CCM8 group. Additionally, the levels of IL-1 and IL-6 in both serum and myocardial tissues were significantly increased in rats in the CCM8 group. However, the levels of IL-2 in both serum and myocardial tissues were decreased, which were observed alongside reductions in myocardial β1 and M2 receptor protein expression in the myocardial tissues. Taken together, these results indicate that inflammatory factors may be involved in mediating damage to the myocardium in rats with cirrhosis. During cirrhosis-induced cardiac dysfunction, there may exist a mechanism for downregulation of autonomic nerve system. PMID:34373726 | PMC:PMC8343770 | DOI:10.3892/etm.2021.10472 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Ellagic acid inhibits high glucose-induced injury in rat mesangial cells via the PI3K/Akt/FOXO3a signaling pathway

xlomafota13 shared this article with you from Inoreader Ellagic acid inhibits high glucose-induced injury in rat mesangial cells via the PI3K/Akt/FOXO3a signaling pathway Via Experimental and therapeutic medicine Exp Ther Med. 2021 Sep;22(3):1017. doi: 10.3892/etm.2021.10449. Epub 2021 Jul 15. ABSTRACT The pathological damage of mesangial cells serves an important role in the occurrence and development of diabetic nephropathy. Ellagic acid has been reported to possess antioxidant, antitumor, antiviral and anti-inflammatory properties in several diseases, but the roles of ellagic acid in diabetic nephropathy are unclear. The main aim of the present study was to investigate the effect of ellagic acid on high glucose-induced mesangial cell damage. The results revealed that high glucose could induce the hyperproliferation of mesangial cells, decrease the activity of superoxide dismutase, increase the malondialdehyde content, the level of reactive oxygen species, the secretion of inflammatory factors (TNF-α, IL-1β and IL-6) and the synthesis of extracellular matrix (Fibronectin, MMP-9 and TIMP-1) and activate the PI3K/Akt/FOXO3a signaling pathway. Ellagic acid could attenuate the injury of mesangial cells induced by high glucose in a concentration-dependent manner and its effect was consistent with that of a PI3K inhibitor (LY294002). Moreover, a PI3K agonist (740Y-P) reversed the protective effect of ellagic acid on mesangial cells induced by high glucose. In conclusion, ellagic acid protected mesangial cells from high glucose-induced injury in a concentration-dependent manner. The mechanism may be associated with ellagic acid inhibiting the activation of the PI3K/Akt signaling pathway and reducing the expression levels of downstream transcription factor FOXO3a. PMID:34373703 | PMC:PMC8343806 | DOI:10.3892/etm.2021.10449 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

MicroRNA-934 promotes colorectal cancer cell proliferation by directly targeting Dickkopf-related protein 2

xlomafota13 shared this article with you from Inoreader MicroRNA-934 promotes colorectal cancer cell proliferation by directly targeting Dickkopf-related protein 2 Via Experimental and therapeutic medicine Exp Ther Med. 2021 Sep;22(3):1041. doi: 10.3892/etm.2021.10473. Epub 2021 Jul 21. ABSTRACT Increasing evidence demonstrates that dysregulation of microRNAs (miRNAs/miRs) is implicated in the development of colorectal cancer. However, the biological functions of several differentially expressed miRNAs remain unknown. In the present study, a bioinformatic analysis of a previously published microarray data and reverse transcription-quantitative PCR analysis demonstrated that miR-934 expression was upregulated in colorectal cancer samples collected from patients. Mechanistically, Dickkopf-related protein 2 (DDK2) was identified as a novel target gene of miR-934 in colorectal cancer cells. Knockdown of DDK2 reversed the inactivation of Wnt signaling pathway induced using miR-934 inhibitor in colorectal cancer cells. In addition, DDK2 silencing reversed miR-934 inhibitor-induced cell proliferation inhibition and elevation of cell apoptosis. The results demonstrated that DDK2 mRNA expression was negatively associated with miR-934 expression in colorectal tumors. Collectively, the results of the present study demonstrated that the miR-934/DDK2 axis regulated colorectal cancer cell proliferation, suggesting that miR-934 may be a biomarker for patients with colorectal cancer. PMID:34373727 | PMC:PMC8343583 | DOI:10.3892/etm.2021.10473 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.