Neuroprotection of exercise: P2X4R and P2X7R regulate BDNF actions.

The neurotrophin brain-derived neurotrophic factor (BDNF), which acts as a transducer, is responsible for improving cerebral stroke, neuropathic pain, and depression. Exercise can alter extracellular nucleotide levels and purinergic receptors in central nervous system (CNS) structures. This inevitably activates or inhibits the expression of BDNF via purinergic receptors, particularly the P2X receptor (P2XR), to alleviate pathological progression. In addition, the significant involvement of sensitive P2X4R in mediating increased BDNF and p38-MAPK for intracerebral hemorrhage and pain hypersensitivity has been reported. Moreover, archetypal P2X7R blockade induces mouse antidepressant-like behavior and analgesia by BDNF release. This review summarizes BDNF-mediated neural effects via purinergic receptors, speculates that P2X4R and P2X7R could be priming molecules in exercise-mediated changes in BDNF, and provides strategies for the protective mechanism of exercise in neurogenic disease.

Combination radiotherapy and cantharidin inhibits lung cancer growth through altering tumor infiltrating lymphocytes.

This study aimed to detect the effect of combination radiotherapy and cantharidin on lung cancer growth. We found that combination therapy with radiotherapy and cantharidin was more effective in inhibiting the tumor growth than radiotherapy or cantharidin alone. It decreased the percentage of CD4+ Tregs and enhanced the percentage of CD8+ T cells, CD4+ Teff cells when comparing to that of single treatment. Combination therapy promoted a great increase in double producing CD8+ T cells and CD4+ Teff cells in tumor infiltrating lymphocytes. Overexpression of CTLA4 reversed the inhibitory action of combination treatment on cancer growth. Our data suggest that combining radiotherapy and cantharidin may have synergistic effects in driving tumor rejection by increasing T-cell infiltration, proliferation and cytokine production.

Nutrient weight against sarcopenia: regulation of the IGF-1/PI3K/Akt/FOXO pathway in quinoa metabolites.

Sarcopenia is characterized by the loss of muscle mass and strength, and one of its major molecular mechanisms is muscle protein turnover. Quinoa, the grain-like food crop, is a health nutrient used to treat diseases that predispose individuals to muscle wasting, including cardiovascular disorders, diabetes mellitus, and cancer. Quinoa secondary metabolites have recently been demonstrated to regulate protein turnover (including protein synthesis and degradation), a main biological process within muscle cells, through diverse signals (such as the p38 MAPK, TNF-α, and IGF-1/PI3K/Akt/FOXO pathways). Here, we describe how quinoa functions in the main pathway of protein synthesis and degradation, screen promising pharmacological components in nutritional applications, and provide guidance for the effects of quinoa products in sarcopenia.

Overexpression of HOTAIR leads to radioresistance of human cervical cancer via promoting HIF-1α expression.

BACKGROUND: HOTAIR was known to enhance radioresistance in several cancers. However, the function of HOTAIR on radioresistance involving the regulation of HIF-1α in cervical cancer has not been reported. METHODS: BALB/c nude mice were injected subcutaneously with HeLa cells and irradiated by X-ray. The tumor volume was measured and the expression of HOTAIR in tumors was detected by quantitative real-time PCR. Western blot was performed to detect the protein level of HIF-1α. MTT (3-(4,5-Dimethylthiazol-2-yl) 22,5-diphenyltetrazolium bromide) assay and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to examine the cell viability and cell apoptosis of HeLa cells and C33A cells exposed to radiation. RESULTS: Radiotherapy inhibited the tumor growth in mice bearing HeLa cells. Radiotherapy reduced the expression of HOTAIR and HIF-1α in tumor tissues and HeLa cells or C33A cells. HOTAIR overexpression abrogated the effect of radiation on the cell viability and cell apoptosis of HeLa and C33A cells. HOTAIR also upregulated the expression of HIF-1α in HeLa and C33A cell exposed to radiation. HIF-1α knockdown reversed increasing cell viability and reducing apoptosis of HeLa and C33A cell induced by HOTAIR overexpression. HOTAIR overexpression promoted tumor growth in mice bearing HeLa and exposed to radiation. CONCLUSION: Radiotherapy might inhibit cervical cancer cell growth through HOTAIR/HIF-1α pathway.

Efficacy and safety of lapatinib and trastuzumab for HER2-positive breast cancer: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVES: The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour actively in models of HER2-positive breast cancer. However, the efficacy of trastuzumab in combination with lapatinib remains controversial. Therefore, we conducted this meta-analysis to compare combination treatment with lapatinib and trastuzumab to trastuzumab or lapatinib alone in the treatment of HER2-positive breast cancer. METHODS: Randomised controlled trials (RCTs), published in PubMed, Embase and Web of Science, were systematically reviewed to assess the survival benefits and toxicity profile of HER2-positive patients with breast cancer who were treated with lapatinib and trastuzumab. Outcomes included pathological complete response (pCR), event-free survival (EFS), overall survival (OS) and toxicities. Results were expressed as the risk ratio (RR) or HR with 95% CIs. Pooled estimates were calculated by using a fixed-effects model or a randomised-effects model. RESULTS: A total of 7 RCTs involving 2084 patients met the inclusion criteria and were included in this meta-analysis. The combination of lapatinib and trastuzumab significantly improved pCR (RR=1.43, 95% CI 1.23 to 1.67; p<0.001), EFS (HR=0.75, 95% CI 0.60 to 0.93; p=0.009) and OS (HR=0.72, 95% CI 0.56 to 0.93; p=0.011) in the treatment of HER2-positive breast cancer compared with trastuzumab or lapatinib alone. The combination treatment also increased the pCR irrespective of hormone receptor status and tumour size. More frequent grade 3 or 4 adverse events, including diarrhoea, rash or erythema, neutropenia and hepatic adverse events, were found in the combination group than in the trastuzumab or lapatinib group. CONCLUSIONS: On the basis of the current evidence, our results reveal that the addition of lapatinib to trastuzumab can significantly improve pCR, EFS and OS with a tolerated toxicity in patients with HER2-positive breast cancer. Further well-conducted, large-scale trials are needed to validate these findings.

Effects of down-regulation of HDAC6 expression on proliferation, cell cycling and migration of esophageal squamous cell carcinoma cells and related molecular mechanisms.

OBJECTIVE: To study the effects of down-regulation of HDAC6 expression on proliferation, cell cycling and migration of esophageal squamous cell carcinoma (ESCC) cells and related molecular mechanisms. METHODS: ESCC cell line EC9706 cells were randomly divided into untreated (with no transfection), control siRNA (transfected with control siRNA) and HDAC6 siRNA (transfected with HDAC6 small interfering RNA) groups. Effects of HDAC6 siRNA interference on expression of HDAC6 mRNA and protein in EC9706 cells were investigated by semi-quantitative RT-PCR, Western blotting and immunocytochemistry methods. Effects of down-regulation of HDAC6 expression on cell proliferation, cell cycle, and cell migration were studied using a CCK-8 kit, flow cytometry and Boyden chambers, respectively. Changes of mRNA and protein expression levels of cell cycle related factor (p21) and cell migration related factor (E-cadherin) were investigated by semi- quantitative RT-PCR and Western blotting methods. RESULTS: After transfection of HDAC6 siRNA, the expression of HDAC6 mRNA and protein in EC9706 cells was significantly downregulated. In the HDAC6 siRNA group, cell proliferation was markedly inhibited, the percentage of cells in G0/G1 phase evidently increased and the percentage of cells in S phase decreased, and the number of migrating cells significantly and obviously decreased. The mRNA and protein expression levels of p21 and E-cadherin in the HDAC6 siRNA group were significantly higher than those in the untreated group and the control siRNA group, respectively. CONCLUSIONS: HDAC6 siRNA can effectively downregulate the expression of HDAC6 mRNA and protein in EC9706 cells. Down-regulation of HDAC6 expression can obviously inhibit cell proliferation, arrest cell cycling in the G0/G1 phase and reduce cell migration. The latter two functions may be closely related with the elevation of mRNA and protein expression of p21 and E-cadherin.