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Chronic hypoxia is a key pathological change in patients with cyanotic congenital heart defect (CCHD). It has been demonstrated that enhanced myocardial unfolded protein response (UPR) increases the capacity to buffer endoplasmic reticulum (ER) stress and to avoid subsequent apoptosis caused by the hypoxia that underlies CCHD. The present study was performed to determine the regulatory role of microRNAs (miRNAs) in this cytoprotective UPR process. The results revealed that miR‑199a‑5p was markedly downregulated in the cardiac tissue of patients with CCHD and in human myocardial cells cultured in hypoxic conditions. The two major UPR modulators, 78 kDa glucose‑regulated protein (GRP78) and activating transcription factor 6 (ATF6), were potential target genes of miR‑199a‑5p in CCHD myocardial specimens. In addition, the miR‑199a‑5p mimic and inhibitor were evidently able to change GRP78 and ATF6 gene expression and ER stress‑associated apoptosis in hypoxia‑treated cardiomyocytes. The interaction between miR‑199a‑5p and the ATF6 and GRP78 3'‑UTR binding sites in myocardial cells was also confirmed by luciferase assay. Thus, it is concluded that myocardial downregulation of miR‑199a‑5p favors the UPR against hypoxia‑induced ER stress in CCHD, which contributes to myocardial protection.

Dilated cardiomyopathy (DCM) is associated with sudden cardiac death and heart failure, resulting in a significant medical burden. The mechanisms underlying the pathogenesis of DCM remain elusive. In the present study, human cardiac tissues from patients with DCM and healthy donors were collected and their pathology was examined. The expression levels of apoptosis regulator Bcl-2 and fibrosis-associated microRNAs were also evaluated. Extensive myocardial fibrosis and apoptosis in DCM cardiac tissues was observed. As demonstrated by western blotting, reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, the expression of Bcl‑2 was significantly increased in the apex, and the left and right ventricle of the heart in patients with DCM. In the specified locations, it was identified that miR‑21 was upregulated, while members of miR‑29 family (miR‑29a, miR‑29b and miR‑29c) and miR‑133 family (miR-133a and miR-133b) were downregulated. The present study suggested that Bcl‑2 and specific microRNAs may be involved in DCM pathogenesis, with a potential implication as therapeutic targets.

Increasing evidence suggests that microRNAs (miRNAs or miRs) serve a critical role in tumor development. However, the role of miRNAs in non-small cell lung cancer (NSCLC) progression remains largely unknown. The present study observed that miR-593 was significantly impaired in patients with NSCLC and was a novel regulator of NSCLC progression. Patients whose tumors had high expression levels of miR-593 had longer overall survival than patients whose tumors had low levels of miR-593 expression (P=0.0219). miR-593 expression levels were inversely correlated with zinc finger protein SNAI2 (SLUG) messenger RNA (mRNA) levels in 87 clinical tissue specimens of NSCLC (P

Inhibitor of DNA binding (Id)3 is a member of the Id multigene family of dominant‑negative helix‑loop-helix transcription factors, which function as oncogenes or tumor suppressors in human cancers. Its upregulation was recently shown to have inhibitory effects on lung cancer, which is the leading cause of cancer‑associated mortality worldwide. As drug resistance represents a major bottleneck of cancer therapy, the present study assessed the ability of Id3 to inhibit cisplatin‑resistant A549 lung adenocarcinoma cells (A549/DDP). A549/DPP cells were transiently transfected with enhanced green fluorescence protein overexpression plasmid (pEGFP) or Id3 overexpression plasmid (Id3/pEGFP), which was confirmed by confocal fluorescence microscopy, PCR and western blot analysis. The effects of Id3 on the viability and apoptosis of A549/DDP were determined using an MTT assay, fluorescence microscopy with Hoechst 33258 staining and flow cytometry following Annexin V/propidium iodide double staining. The results revealed that overexpression of Id3 significantly inhibited the proliferation and viability of A549/DDP cells in a time‑dependent manner. Furthermore, overexpression of Id3 significantly increased the apoptotic rate of A549/DDP cells from 2.73 to 16.92%, confirming the implication of Id3 in the negative control of tumour growth. The results of the present study revealed that overexpression of Id3 may serve as a novel strategy for inhibiting cisplatin‑sensitive lung cancer. Further experiments will be performed to determine whether Id3 overexpression could enhance the sensitivity of lung cancer cells to DDP.

The present study investigated whether grape seed proanthocyanidin extract (GSPE) can attenuate varicocele‑induced testicular oxidative injury through the nuclear factor (erythroid‑derived 2)‑like 2 (Nrf2) antioxidant pathway. A varicocele model in rats was established by partial ligation of the left renal vein. Following 4 weeks of GSPE administration, the decreased sperm count and motility and other pathological changes caused by varicocele were significantly alleviated, as indicated by the results of computer‑assisted sperm analysis and hematoxylin and eosin staining. In addition, the decreased antioxidant enzyme (superoxide dismutase and glutathione peroxidase) activity and elevated oxidative stress level were partially reversed by administration of GSPE. Furthermore, the apoptotic level of the testis induced by varicocele was decreased by the GSPE treatment, according to terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Additionally, the expression of apoptosis‑related proteins, including B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑like protein 4 and cleaved caspase‑3, were also affected by GSPE. GSPE activated Nrf2, which is a key antioxidative transcription factor, with elevation of the downstream factor hemeoxygenase‑1. These findings suggest that GSPE can ameliorate abnormal spermatogenesis and testicular injury in varicocele rats, potentially due to its antioxidative activity and ability to activate the Nrf2 pathway.

Berberine is a well‑known component of the Chinese herbal medicine Huanglian (Coptis chinensis), and is capable of inhibiting the proliferation of multiple cancer cell lines. However, information available regarding the effect of berberine on prostate cancer cell growth is limited. In the present study, LnCaP and PC‑3 human prostate cancer cell lines were selected as in vitro models in order to assess the efficacy of berberine as an anticancer agent. A cell proliferation assay demonstrated that berberine inhibited cell growth in a dose‑and time‑dependent manner. Further investigation revealed berberine significantly accumulated inside cells that were in the G1 phase of the cell cycle and enhanced apoptosis. Western blot analysis demonstrated that berberine inhibited the expression of prostate‑specific antigen and the activation of epidermal growth factor receptor (EGFR), and it attenuated EGFR activation following EGF treatment in vitro. In conclusion, the results indicate that berberine inhibits the proliferation of prostate cancer cells through apoptosis and/or cell cycle arrest by inactivation of the EGFR signaling pathway.

Triptolide (TP) exhibits numerous biological activities, including immunosuppressive, anti‑inflammatory and antitumor effects. The aim of the present study was to investigate the role of TP as a potent therapeutic drug for the treatment of lung cancer and to investigate the underlying therapeutic mechanisms. Western blot analyses and reverse transcription‑quantitative polymerase chain reaction (PCR) were performed to investigate the expression of genes at transcriptional and translational levels, respectively. Methylation‑specific PCR assays were conducted to investigate whether TP affects the Wnt inhibitory factor‑1 (WIF‑1) methylation status and subsequently affects apoptosis, migration or the invasion of lung cancer cells. The results of the present study revealed that the methylation status of WIF‑1 in lung cancer cell lines A549 and H460 was significantly enhanced compared with the human normal bronchial epithelial cell line HBE, whereas treatment with TP was revealed to induce the demethylation of WIF‑1. The present study aimed to investigate whether the biological activities of TP are regulated by inhibiting the Wnt signaling pathway via an increase in WIF‑1 expression levels. The results of the present study revealed that Wnt signaling was suppressed in cells following treatment with TP, which was concluded by the downregulation of Axin 2 and β‑catenin expression. Further investigation demonstrated that the silencing of WIF‑1 expression with small interfering RNA reversed the TP‑induced upregulation of WIF‑1 expression, upregulated Axin 2 and β‑catenin expression and enhanced the activation of Wnt signaling. Notably, an upregulation of cellular tumor antigen p53 expression, and downregulation of matrix metalloproteinase‑9 (MMP‑9) and phosphorylated‑nuclear factor‑κB (NF‑κB) P65 (p‑P65) levels was observed following TP treatment. These results suggest that the Wnt, p53 and NF‑κB signaling pathways mediate the potent antitumor effects of TP. Notably, the silencing of WIF‑1 did not completely recover the levels of p53, MMP‑9 and p‑P65 in cells treated with TP compared with the control cells, thus suggesting that TP exhibits further functions in addition to the targeting of WIF‑1.

As influencing factors of genesis and progression in several types of human tumor, microRNAs (miRs) serves roles in the regulation of tumor cell viability, migration, and apoptosis. The present research aimed to investigate the association between the function of miR‑100‑5p and renal cell carcinoma (RCC). miR‑100‑5p expression was determined in RCC tissue and paired normal tissue samples using reverse transcription‑quantitative polymerase chain reaction. To assess the effects of miR‑100‑5p on cell viability, migration and apoptosis, multiple methods were used, including scratch wound assays, MTT assays, and flow cytometry. It was demonstrated that miR‑100‑5p was significantly upregulated in RCC tissue compared with in normal adjacent tissue samples. Furthermore, the viability and migration of 786‑O and, ACHN cells tranfected with miR‑100‑5p was significantly increased compared with the negative control group. In addition, miR‑100‑5p‑transfected 786‑O and ACHN cells demonstrated significantly reduced cellular apoptotic rates compared with the negative control group. To the best of our knowledge, the present study is the first to report an association between miR‑100‑5p and RCC. The results of the current study suggest that tumor oncogene miR‑100‑5p could be used as a diagnostic biomarker for RCC.

Tetramethylpyrazine (TMP) is an effective component of the traditional Chinese medicine Chuanxiong, which has been reported to have beneficial effects in various types of cancer. However, the activity and mechanism of action of TMP in osteosarcoma (OS) have not been elucidated to date. The aim of the present study was to investigate the inhibitory effect of TMP on OS and its underlying mechanism of action. OS cells were treated with various concentrations of TMP for 48 h. BALB/c nude mice with OS were treated with an intraperitoneal injection of TMP at a dose of 100 mg/kg every other day for 28 days. Cell proliferation was evaluated using an MTT assay. Cell cycle and apoptosis were measured using flow cytometry. The protein expression of nuclear and cytosolic nuclear factor‑κB (NF-κB) p65, BCL‑2 and cyclin D1 was measured using western blot analysis. TMP inhibited the proliferation of OS cells (MG-63, SAOS-2 and U2OS) in a dose‑dependent manner. Additionally, TMP significantly induced apoptosis and G0/G1 arrest in MG-63 OS cells (P

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood malignancy, deriving from T-cell progenitors in the thymus, and comprises 10-15% of pediatric and 25% of adult primary ALL cases. Despite advances, 20% of pediatric and the majority of adult patients with T-ALL succumb to mortality from resistant or relapsed disease, and the survival rate for patients with resistant or relapsed T-ALL remains poor. Alterations in the expression of Forkhead box protein M1 (FoxM1) have been detected in several types of cancer, and the inhibition of FoxM1 has been investigated as therapeutic strategy in cancer. The present study investigated the effects of the inhibition of FoxM1 by thiostrepton in human T-ALL Jurkat cells. The cells were treated with different concentrations of thiostrepton, either alone or in combination with doxorubicin. Cell viability was measured using CCK-8 assays and the cell cycle distribution, apoptosis and cell-associated mean fluorescence intensity of intracellular doxorubicin were assessed using flow cytometric analysis. The mRNA and protein expression levels were detected by reverse transcription-quantitative polymerase chain reaction and western blot analyses. The inhibition of FoxM1 by thiostrepton significantly decreased the proliferation of the Jurkat cells proliferation in a time- and dose-dependent manner. Cell arrest at the G2/M phase, and apoptosis was significantly increased in the thiostrepton-treated Jurkat cells. Thiostrepton reduced the half maximal inhibitory concentration of doxorubicin in the Jurkat cells, and significantly enhanced the cytotoxicity of doxorubicin within the Jurkat cells by enhancing doxorubicin-induced apoptosis and increasing the accumulation of intracellular doxorubicin. Furthermore, the inhibition of FoxM1 by thiostrepton enhanced doxorubicin-induced apoptosis, possibly through a caspase-3-dependent pathway, and increased the accumulation of intracellular doxorubicin, possibly through downregulating the expression of glutathione S-transferase pi. Collectively, the results of the present study suggested that targeting FoxM1 with thiostrepton resulted in potent antileukemia activity and chemosensitizing effects in human T-ALL Jurkat cells.

The clinical application of hyperbaric oxygen therapy (HBOT) in spinal cord injury (SCI) has been reported, however the mechanism underlying its therapeutic effects remains to be elucidated. In the present study, SCI was modeled in male Sprague‑Dawley rats. A total of 120 rats were randomly divided into four groups: Sham‑operated group (SH); sham‑operated and hyperbaric oxygen group (SH+HBO); spinal cord injury group (SCI) and spinal cord injury and hyperbaric oxygen treatment group (SCI+HBO). The rats in each group were randomly divided into five smaller groups (12 h, 1, 3, 7 and 14 days after surgery). The mRNA and protein expression levels of NACHT domain‑, leucine‑rich‑repeat‑ and pyrin domain‑containing protein 3 (NALP3) inflammasome, including NALP3, adaptor molecule apoptosis‑associated speck‑like protein (ASC) and caspase‑1 were determined at several time points following injury. The results of the present study demonstrated that HBOT compromised the mRNA and protein expression levels of NALP3, ASC and caspase‑1 in the SCI model rats and HBOT mitigated SCI‑induced interleukin 1β release in the injured spinal cord tissue. It was concluded that HBOT is an effective approach, which can prevent against spinal cord injury, likely by inactivating NALP3 inflammasome.

'Secondary insult' following primary traumatic brain injury (TBI), including ischemia and edema, may aggravate brain impairments and affect the outcomes. The hippocampus is particularly sensitive to ischemia or edema due to its selective vulnerability, as neural cells of the hippocampus may be more prone to abnormal function or cell death in response to ischemia and edema. Aquaporin‑1 (AQP‑1) was reported to be associated with cerebral edema; however, the expression and role of AQP‑1 in hippocampal edema following TBI have seldom been investigated. In the current study, BALB/c mouse closed craniocerebral injury models were established and the changes of AQP‑1 expression in hippocampi of mouse models following TBI were investigated. Neurological function and edema formation of the models were evaluated and the apoptotic hippocampal cells were then stained in situ and detected, followed by determination of AQP‑1 expression in the hippocampus using immunohistochemistry and western blot analysis. As a result, the majority of mice in the TBI group were severely injured and hippocampal edema was confirmed. The apoptotic cells increased significantly in the hippocampi of mice in the TBI group compared with those in the sham group (P