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Background: Temozolomide (TMZ)-based chemotherapy represents an effective way for treating human glioma. However, its clinical application is limited because of its side effects and resistance to standard chemotherapy. Hence, the search for novel chemosensitizers to augment their anticancer efficiency has attracted much attention. Natural borneol (NB) has been identified as a potential chemosensitizer in treating human cancers. However, the synergistic effect and mechanism of NB and TMZ in human glioma have not been investigated yet. Materials and methods: U251 human glioma cells were cultured, and the cytotoxicity and apoptosis of NB and/or TMZ were examined by MTT assay, flow cytometric analysis and Western blot. Nude mice tumor model was also employed to evaluate the in vivo anticancer effect and mechanism. Results: The results showed that the combined treatment of NB and TMZ more effectively inhibited human glioma growth via triggering mitochondria-mediated apoptosis in vitro, accompanied by the caspase activation. Combined treatment of NB and TMZ also caused mitochondrial dysfunction through disturbing Bcl-2 family expression. Further investigation revealed that NB enhanced TMZ-induced DNA damage through inducing reactive oxide species (ROS) overproduction. Moreover, glioma tumor xenograft growth in vivo was more effectively inhibited by the combined treatment with NB and TMZ through triggering apoptosis and anti-angiogenesis. Conclusion: Taken together, our findings validated that the strategy of using NB and TMZ could be a highly efficient way to achieve anticancer synergism. [ABSTRACT FROM AUTHOR]

This present study is performed to figure out the role of microRNA-136 (miR-136) in radiosensitivity of esophageal squamous cell carcinoma (ESCC) cells through the regulation of MUC1. Seventy-four ESCC patients were divided into radiotherapy sensitive group and radiotherapy resistance group. Colony formation assay and flow cytometry were used to test the radiosensitivity of radiotherapy resistant strain and parent strain. The expression of miR-136 between radiotherapy resistant strain and parent strain was detected by RT-qPCR, and the expression of miR-136 in Eca109 and TE-1 cells as well as Eca109-R and TE-1-R cells was detected after different doses of X-ray irradiation. Eca109 and TE-1 cells as well as Eca109-R and TE-1-R cells with overexpression of miR-136 or co-overexpression of miR-136 and MUC1 were constructed. Cell proliferation, colony formation and apoptosis was detected by CCK-8 assay, colony formation assay, and flow cytometry, respectively. The expression of miR-136 in ESCC tissues was lower and MUC1 mRNA and protein expression was higher than that in adjacent normal tissues. The expression of miR-136 was negatively correlated with the expression of MUC1 mRNA in ESCC. Low expression of miR-136 and high expression of MUC1 were associated with tumor size, lymph node metastasis and distant metastasis. The expression of miR-136 increased while the expression of MUC1 decreased in the radiotherapy sensitive group of ESCC patients relative to the radiotherapy resistant group. The colony formation ability of radiation resistant cell line was stronger than that of parent cell line, and the apoptosis rate showed an opposite trend. Up-regulation of miR-136 reduced the survival rate, suppressed colony formation ability and induced apoptosis of ESCC cells under irradiation, which was reversed by upregulated MUC1. This study demonstrates that up-regulation of miR-136 induces apoptosis and radiosensitivity of ESCC cells by inhibiting the expression of MUC1. [ABSTRACT FROM AUTHOR]

Aims: SUMOylation is a posttranslational modification related to multiple human diseases. SUMOylation can be reversed by classes of proteases known as the sentrin/SUMO‐specific proteases (SENPs). In the present study, we investigate the potential role of SENP1 in pericytes in the brain ischemia. Methods: Pericyte‐specific deletion of senp1 mice (Cspg4‐Cre; senp1f/f) were used for brain function and neuronal damage evaluation following brain ischemia. The cerebral blood vessels of diameter, velocity, and flux were performed in living mice by two‐photon laser scanning microscopy (TPLSM). Biochemical analysis and immunohistochemistry methods were used to address the role and mechanism of pericyte‐specific SENP1 in the pathological process of brain ischemia. A coculture model of HBVPs and HBMECs mimicked the BBB in vitro and was used to evaluate BBB integrity after glucose deprivation. Results: Our results showed that senp1‐specific deletion in pericytes did not affect the motor function and cognitive function of mice. However, the pericyte‐specific deletion of senp1 aggravated the infarct size and motor deficit following focal brain ischemia. Consistently, the TPLSM data demonstrated that SENP1 deletion in pericytes accelerated thrombosis formation in brain microvessels. We also found that pericyte‐specific deletion of senp1 exaggerated the neuronal damage significantly following brain ischemia in mice. Moreover, SENP1 knockdown in pericytes could activate the apoptosis signaling and disrupt the barrier integrity in vitro coculture model. Conclusions: Our findings revealed that targeting SENP1 in pericytes may represent a novel therapeutic strategy for neurovascular protection in stroke. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) influences individual health worldwide with high morbidity and mortality. Melatonin, which shows multiple physiological functions (e.g., circadian rhythm, immune modulation, and antioncogenic action), can be present in almost all organisms and found in various tissues including gastrointestinal tract. Notably, melatonin disruption is closely associated with the elevation of CRC incidence, indicating that melatonin is effective in suppressing CRC development and progression. Mechanistically, melatonin favors in activating apoptosis and colon cancer immunity, while reducing proliferation, autophagy, metastasis, and angiogenesis, thereby exerting its anticarcinogenic effects. This review highlights that melatonin can be an adjuvant therapy and be beneficial in treating patients suffering from CRC. [ABSTRACT FROM AUTHOR]

Ligustilide is widely thought to be the most potent bioactive constituent of Angelica sinensis . We have previously reported the role of ligustilide in preventing TNF-α-induced apoptosis and identified the presence of autophagosome clusters. Then, we hypothesised that autophagy may contribute to muscle loss and that ligustilide could protect cell fibres by regulating the autophagic process. The aim of this study was to identify the effects of ligustilide on autophagy regulation during cell differentiation in the presence of TNF-α. We then observed intracellular morphologic changes and autophagosome formation using transmission electron microscopy. LC3B expression was assessed by immunofluorescence and Atg-7, Atg-5, Atg-12 and LC3B expression levels were detected by western blot. The results revealed a reduction in the number of TNF-α-induced autophagosomes after ligustilide treatment accompanied by a decrease in Atg-7, Atg-5, Atg-12 and LC3B expression, as well as a reduction of the LC3BII/I ratio in a concentration-dependent manner. Our findings provide evidence supporting a protective effect of ligustilide against TNF-α-induced autophagy during myotubes formation. [ABSTRACT FROM AUTHOR]

Abstract: This study is the first to investigate isokotomolide A (IKA), a butanolide compound isolated from the leaves of Cinnamomum kotoense Kanehira & Sasaki (Lauraceaee), which exhibits an anti-proliferative activity in human non-small cell lung cancer A549 cells. The results show that IKA inhibits the proliferation of A549 by blocking cell cycle progression in the G0/G1 phase and inducing apoptosis. Blockade of cell cycle was associated with increased p21/WAF1 levels and reduced amounts of cyclin D1, cyclin E, Cdk2, Cdk4, and Cdk6 in a p53-mediated manner. IKA treatment also increased p53 phosphorylation (Ser15) and decreased the interaction of p53–MDM2. IKA treatment triggered the mitochondrial apoptotic pathway, indicated by changing Bax/Bcl-2 ratios, cytochrome c release and caspase-9 activation. In addition, pre-treatment of cells with caspase-9 inhibitor inhibited IKA-induced apoptosis, indicating that caspase-9 activation was involved in A549 cells'' apoptosis induced by IKA. Our study reports here for the first time that the induction of p53/p21 and the initiation of the mitochondrial apoptotic system may participate in the anti-proliferative activity of IKA in human non-small cell lung cancer cells. [Copyright &y& Elsevier]

Corrigendum to "CCT128930 induces G1-phase arrest and apoptosis and synergistically enhances the anticancer efficiency of VS5584 in human osteosarcoma cells" [Biomed. Caspase-3 expression was repeated, and the correct caspase-3 expression appears below. 3B appears below: Graph The correct caspase-3 expression in Fig. [Extracted from the article]

Osteosarcoma is a highly invasive primary malignant bone tumor. PI3K/mTOR pathway plays a key role in tumor progression, and inhibition of PI3K/mTOR pathway represents a novel strategy in therapy of osteosarcoma. CCT128930 and VS5584 are both inhibitors of PI3K/mTOR, but the anticancer mechanism of CCT128930 or/and VS5584 against human osteosarcoma cells remains unclear. Herein, U2OS and MG63 human osteosarcoma cells were cultured, and the anticancer effects of CCT128930 alone and the combined effect of CCT128930 and VS5584 against human osteosarcoma cells were explored. The results showed that CCT128930 as PI3K/mTOR inhibitor effectively inhibited p-p70 and p-AKT expression and dose-dependently inhibited U2OS cells and MG63 human osteosarcoma cells growth. Further studies found that CCT128930 triggered significant G-1 phase arrest and apoptosis, as convinced by the dysfunction of p27, Cyclin B1, Cyclin D1 and Cdc2, and PARP cleavage and caspase-3 activation. Moreover, CCT128930 treatment obviously enhanced VS5584-induced growth inhibition and apoptosis in human osteosarcoma cells, followed by enhanced PARP cleavage and caspase-3 activation. Taken together, CCT128930 alone or combined treatment with CCT128930 and VS5584 both effectively inhibited human osteosarcoma cells growth by induction of G1-phase arrest and apoptosis through regulating PI3K/mTOR and MAPKs pathways. [ABSTRACT FROM AUTHOR]

Abstract Cisplatin is a widely used chemotherapeutic drug that often causes acute kidney injury (AKI) in cancer patients. The contribution of miRNAs to the cisplatin-induced renal tubular epithelial cell injury remains largely unknown. Here we performed an integrative network analysis of miRNA and mRNA expression profiles to shed light into the underlying mechanism of cisplatin-induced renal tubular epithelial cell injury. Microarray analysis identified 47 differentially expressed miRNAs, among them 26 were upregulated and 21 were downregulated. Moreover, integrating dysregulated miRNAs target prediction and altered mRNA expression enabled us to identify 1181 putative target genes for further bioinformatics analysis. Gene ontology (GO) analysis revealed that the putative target genes were involved in apoptosis process and regulation of transcription. Pathway analysis indicated that the top upregulated pathways included MAPK and p53 signaling pathway, while the top downregulated pathways were PI3K-Akt and Wnt signaling pathway. Further network analysis showed that MAPK signaling pathway and apoptosis with the highest degree were identified as core pathways, hsa-miR-9-3p and hsa-miR-371b-5p as the most critical miRNAs, and CASK, ASH1L, CDK6 etc. as hub target genes. In addition, the expression level change of selected five microRNAs (hsa-miR-4299, hsa-miR-297, hsa-miR-3135b, hsa-miR-9-3p, and hsa-miR-371b-5p) and two mRNAs(CASK and CDK6) were validated in cisplatin-induced HK-2 cells. Furthermore, a similar trend of expression level change was observed in NRK-52E cells by cisplatin treatment. Overall, our results provide the molecular basis and potential targets for the treatment of cisplatin-induced renal tubular cell injury. [ABSTRACT FROM AUTHOR]

Abstract: Ligustilide, the major component of Angelica sinensis, is also thought to be the most potent bioactive constituent of this plant. Ligustilide has been reported to markedly protect neural tissue against apoptosis. However, little is known regarding ligustilide's anti-apoptosis effect in muscle tissue. The aim of the study was to investigate the anti-apoptosis effects of ligustilide on TNF-α-induced C2C12 cells during differentiation. It was revealed that ligustilide at various concentrations significantly prevented the apoptosis of C2C12 cells incubated in TNF-α as assessed by apoptosis index and DNA fragmentation. Moreover, ligustilide-treated groups exhibited a significant increase in the bcl-2/bax ratio, pro-caspase 3 and pro-caspase 8 compared with the TNF-α-control group in a dose-dependent manner. Meanwhile, ligustilide-treated groups presented a significantly increased level of phosphorylated Akt and suppressed expression of the myogenin protein. Therefore, the findings derived suggested that ligustilide protected C2C12 cells from TNF-α-induced apoptosis during differentiation by reducing apoptosis and inducing cell proliferation. [Copyright &y& Elsevier]

Abstract: Astragalus polysaccharide (APS) is an important bioactive component of Astragalus membranaceus Bunge (Leguminosae) that has been used in traditional Chinese medicine for treating muscle wasting, a serious complication with complex mechanism manifested as myofibers atrophy and satellite cells apoptosis. In this study, the anti-atrophy and anti-apoptotic activity of Astragalus polysaccharide (APS) was characterized in C2C12 skeletal muscle myotubes and myoblasts. APS inhibited dexamethasone-induced atrophy by restoring phosphorylation of Akt, m-TOR, P70s6k, rpS6 and FoxO3A/FoxO1. The targets that protected C2C12 myoblasts from damage by H2O2 were promoting cells proliferation and inhibiting cells apoptosis. The protective mechanisms involved mitochondrial pathway and death receptor pathway. Moreover, Antioxidant effect of APS was also detected in this work. Our findings suggested that APS could be explored as a protective and perhaps as a therapeutic agent in the management of muscle wasting. [Copyright &y& Elsevier]

Abstract: In this study, we first report the chemopreventive effect of rugosin E in human breast cancer cell line, MDA-MB-231. Treatment with rugosin E decreased the cell proliferation of MDA-MB-231 cells in a dose-dependent manner. Rugosin E treatment arrested MDA-MB-231 cells at G0/G1 phase. This effect was strongly associated with concomitant decrease in the level of cyclin D1, cyclin D2, cyclin E, cdk2, cdk4, and cdk6, and increase of p21/WAF1. In addition, rugosin E also induced apoptotic cell death. Rugosin E increased in the expression of Bax, Bak, and Bcl-Xs, but decreased the levels of Bcl-2 and Bcl-XL, and subsequently triggered mitochondria apoptotic pathway (release of cytochrome c, activation of caspase-9, and caspase-3). In addition, pre-treatment of cells with caspase-9 inhibitor blocked rugosin E-induced cell proliferation and apoptosis, indicating caspase-9 activation was involved in rugosin E-mediated MDA-MB-231 cells apoptosis. Rugosin E inhibited the constitutively activated and inducible NF-κB in both its DNA-binding activity and transcriptional activity. Furthermore, rugosin E also inhibited the TNF-α-activated NF-κB-dependent reporter gene expression of cyclin D1, c-Myc, XIAP, Bcl-2, and Bcl-XL were all downregulated by rugosin E. Our results indicated that rugosin E inhibits the activation of NF-κB, and this may provide a molecular basis for drug development in the prevention and treatment of cancer by rugosin E. [Copyright &y& Elsevier]