Liver X receptors agonist T0901317 exerts ferroptosis sensitization in cancer.

Numerous studies have confirmed the anticancer effects of ferroptosis on a wide range of tumors, specifically in providing new perspectives for tackling drug resistance and treating refractory tumors. Notably, mechanisms of improving tumor susceptibility to ferroptosis have been a focus of current research. This study discovered that co-treatment of LXRS agonist T0901317 and ferroptosis inducers (FINs) significantly inhibited the proliferation of cancer cells, this inhibition effect could be reversed by specific inhibitors of ferroptosis and accompanied by elevated lipid peroxides. Glutathione peroxidase 4 (GPX4) regulates T0901317 induced ferroptotic sensitization, and its overexpression dramatically reverses the joint anticancer effect of T0901317 and FINs. Furthermore, xenograft model results highly confirmed the ferroptotic sensitization effect of T0901317 in vivo. In summary, our findings indicate that drug combination and ferroptosis induction strategies provide novel options for cancer therapy.

Pharmacological actions of the bioactive compounds of Epimedium on the male reproductive system: current status and future perspective.

ABSTRACT: Compounds isolated from Epimedium include the total flavonoids of Epimedium, icariin, and its metabolites (icaritin, icariside I, and icariside II), which have similar molecular structures. Modern pharmacological research and clinical practice have proved that Epimedium and its active components have a wide range of pharmacological effects, especially in improving sexual function, hormone regulation, anti-osteoporosis, immune function regulation, anti-oxidation, and anti-tumor activity. To date, we still need a comprehensive source of knowledge about the pharmacological effects of Epimedium and its bioactive compounds on the male reproductive system. However, their actions in other tissues have been reviewed in recent years. This review critically focuses on the Epimedium, its bioactive compounds, and the biochemical and molecular mechanisms that modulate vital pathways associated with the male reproductive system. Such intrinsic knowledge will significantly further studies on the Epimedium and its bioactive compounds that protect the male reproductive system and provide some guidances for clinical treatment of related male reproductive disorders.

Complete genome sequence of a novel porcine parvovirus in China.

The porcine parvovirus JT strain (PPV-JT) was isolated from a piglet showing nonsuppurative myocarditis in Shandong, China, in 2010. The complete genomic sequence of PPV-JT, 4,941 bp long, was determined from clones made from replicative form (RF) DNA. The genomic analysis demonstrated that the PPV-JT might be involved in a recombination event, which will help us understand the molecular characteristics and evolutionary of PPV in China.

The emerging role of exosomes in the development of testicular.

The mechanisms of testicular development in mammals are complex. Testis is an organ that produces sperm and secretes androgens. It is rich in exosomes and cytokines that mediate signal transduction between tubule germ cells and distal cells, promoting testicular development and spermatogenesis. Exosomes are nanoscale extracellular vesicles that transmit information between cells. By transmitting information, exosomes play an important role in male infertility diseases such as azoospermia, varicocele, and testicular torsion. However, due to the wide range of sources of exosomes, extraction methods are numerous and complex. Therefore, there are many difficulties in studying the mechanisms of exosomal effects on normal development and male infertility. Therefore, in this review, first, we introduce the formation of exosomes and methods for culturing testis and sperm. Then, we introduce the effects of exosomes on different stages of testicular development. Finally, we summarize the prospects and shortcomings of exosomes when used in clinical applications. We lay the theoretical foundation for the mechanism of the influence of exosomes on normal development and male infertility.

Hypoxia-induced autophagy confers resistance of breast cancer cells to ionizing radiation.

Hypoxia is a hallmark of solid tumors, which presents a major obstacle to the effectiveness of radiation therapy. However, the function and the importance of molecular response have not been well defined. In the present study, hypoxia-induced autophagy and its effect on the response of breast cancer cells to ionizing radiation were examined. Results showed that hypoxic exposure induced a marked accumulation of autophagosomes accompanied by mRNA induction of the autophagy-related genes Beclin-1, Atg5, Atg7, and Atg12. The elevated autophagic activity was associated with increased radioresistance of tumor cells. Accordingly, blockade of autophagy by pharmacological inhibition or Beclin-1 small interfering RNA (siRNA) contributed to retardation of DNA double-strand breaks (DSB) repair and significant radiosensitization. Our data indicate that strategies designed to suppress autophagic activity may represent promising new therapies for sensitizing hypoxic breast cancer cells to ionizing radiation (IR).

[Value of recombinant human thrombopoietin in the treatment of chemotherapy-induced thrombocytopenia in patients with solid tumor].

OBJECTIVE: To evaluate the efficacy and safety of domestically manufactured recombinant human thrombopoietin (rhTPO) in the treatment for chemotherapy-induced thrombocytopenia in patients with solid tumors. METHODS: A non-randomized controlled study was conducted. Seventy-two patients with platelet count < 75 x 10(9)/L after chemotherapy were enrolled into this study according to the standard criteria of NCI-CTC toxicity stratification. Thirty-five patients in the treatment-group received subcutaneous injection of rhTPO at a dose of 15,000 U/d, another 37 patients in the control group received subcutaneous injection of rhIL-11a at a dose of 3 mg/d as the paralleled control. RESULTS: The mean minimal platelet count after rhTPO treatment was (46.2 +/- 20.3) x 10(9)/L in the treatment-group versus (37.2 +/- 16.7) x 10(9)/L in the control-group (P < 0.05), while the mean maximal platelet count was (250.2 +/- 159.0) x 10(9)/L versus (160.5 +/- 96.4) x 10(9)/L (P < 0.05). The incidence rate of adverse effects and duration of grade III and IV thrombocytopenia in the treatment-group was also significantly lower than those in the control-group. Furthermore, the patients receiving platelet transfusion were 4/35 in the treatment-group versus 11/37 in the control-group (P > 0.05). The side-effect rate in the treatment-group was significantly lower than that in the control-group (11.4% versus 78.4%, P < 0.01). CONCLUSION: Compared with rhIL-11, administration of rhTPO after chemotherapy is safe and effective with mild adverse effects in reducing the degree and duration of thrombocytopenia.

HOXC6 predicts invasion and poor survival in hepatocellular carcinoma by driving epithelial-mesenchymal transition.

Aberrant expression of HOXC6 has been reported in several malignant tumors, yet little is known about the value of HOXC6 in invasion and prognosis of hepatocellular carcinoma (HCC). HOXC6 expression was positively correlated with high AFP level, liver cirrhosis, larger tumor, vascular invasion and BCLC stage. Kaplan-Meier analysis revealed that HOXC6 was an independent predictor for overall survival (OS) and time to recurrence (TTR). In addition, HOXC6 status could act as prognostic predictor in different risk subgroups. Moreover, HOXC6 maintained its prognostic value in different ability of invasiveness. Furthermore, combination of HOXC6 and serum AFP could be a potential predictor for survival in HCC patients. Additionally, further study showed that HOXC6 may promote invasion of HCC by driving epithelial-mesenchymal transition (EMT). Knockdown of HOXC6 significantly decreased the migration and invasion of HCC cells and changed the expression pattern of EMT markers. An opposite expression pattern of EMT markers was observed in HOXC6-transfected cells. In addition, immunohistochemistry and RT-PCR results further confirmed this correlation. In conclusion, HOXC6 contributes to invasion by inducing EMT pathway and predicts poor prognosis of HCC. HOXC6/AFP expression may help to distinguish the different risks of HCC patients after hepatectomy.

[Study on the controlling effect of Shenqi Fuzheng injection on plasma cytokine network in patients with thoracic tumor undergoing radiotherapy].

OBJECTIVE: To investigate the effect of Shenqi Fuzheng Injection (SFI) in radiation pneumonitis and its influence on the levels of plasma transforming growth factor beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) at various stages (pre-, mid- and post-radiation) of radiotherapy (RT). METHODS: Fifty-eight patients enrolled in this study were randomized into two groups, all received conventional radio therapy, but the treatment group was intravenously dripped with SFI additionally, once daily, starting 3 days before radiotherapy to 1 week after the end of it. Levels of TGF-beta, TNF-alpha and IL-10 in blood samples collected and frozen at different time point of RT, before radiotherapy (Pre-RT), after received 40-50 Gy radiation (Mid-RT) and in time of terminating RT (Post-RT), were measured with enzyme linked immunosorbent assay (ELISA). And the occurrence of radiation pneumonitis was analyzed according to RTOG acute radiation pneumonitis criteria. RESULTS: Level of TGF-beta increased in both groups after RT, either Mid- or Post-RT, but in comparing with that at Pre-RT, statistical significant (P < 0.05) only showed in the control group at Post-RT time when it raised to peak, while in inter-group comparing insignificance was shown. Level of TNF-alpha also increased in both groups, but statistical significance only showed in the control groups as compared with that of Pre-RT, accordingly, it was lower in the treatment group than that in the control group at corresponding time points (P < 0.05). Level of IL-10 decreased gradually in the process of RT, as compared with that at Pre-RT, significant difference was shown in both groups at Post-RT but not at Mid-RT, as compared between groups, no significance (P < 0.05) was shown, though the treatment group showed a high tendency. As for the ratio of IL-10/TNF-alpha, significant difference of lowering in the control group after RT was shown as compared with that at Pre-RT (P < 0.05), and also as compared with that in the treatment group at corresponding time point (P < 0.05). The occurrence of radiation pneumonia > or = grade 2 in the treatment group was significantly lower than that in the control group (chi2 = 8.7133, P < 0.01). CONCLUSION: Plasma level of TNF-alpha and ratio of IL-10/ TNF-a could be the practicable indexes for estimating the susceptibility of acute radiation pneumonia; SFI can regulate the network of cytokine, and thus be effective in preventing and treating radiation pneumonitis.

Redox-dependent modulation of metformin contributes to enhanced sensitivity of esophageal squamous cell carcinoma to cisplatin.

Glutathione is the major intracellular anti-oxidant against reactive oxygen species and serves as a detoxification essential. The anti-diabetic drug metformin has been showed to exert anti-tumor activity via modulation of redox homeostasis. In this study, we provided evidence that metformin inhibits proliferation and induces apoptosis of esophageal squamous cancer cells. Importantly, we found that metformin acts as pro-oxidant via depletion of intracellular glutathione. Co-treatment with metformin reversed the elevated intracellular glutathione induced by cisplatin and therefore enhanced the sensitivity to cisplatin in vitro and in vivo. Taken together, our data indicate that combination of metformin with cisplatin may represent a novel therapeutic strategy for esophageal squamous cell carcinoma treatment.

Acute oral mucositis in nasopharyngeal carcinoma patients treated with radiotherapy: association with genetic polymorphism in DNA DSB repair genes.

PURPOSE: The aim of this study was to investigate the association between polymorphic variants of DNA repair genes with the susceptibility of acute oral mucositis (OM) in nasopharyngeal carcinoma (NPC) patients treated with radiotherapy. MATERIALS AND METHODS: The study population consisted of 120 NPC patients treated with intensity-modulated radiation therapy (IMRT). Among them 70 patients also received concurrent chemotherapy. Genotypes in DNA repair genes Ku70 c.-1310C>G (rs2267437), Ku70 c.1781G> T (rs132788), Ku80 c.2099-2408G> A (rs3835), Ku80 c.*841G> A (rs2440) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) c.2888 + 713C> T (rs2213178) were determined by polymerase chain reaction combined with the restriction fragment length polymorphism (PCR-RFLP) technique. Mucositis was scored using the Common Terminology Criteria (CTC) for Adverse Events v.3.0 scale. The population was divided into the CTC0-2 group (CTC toxicity grade 0, 1 and 2) and the CTC3 + group (CTC toxicity grade 3 and above). Odd ratios (OR) and 95% confidence intervals (CI) were calculated using the multivariate logistic regression analysis. RESULTS: A significant difference in Ku70 c.1781G> T genotype distribution was observed between the CTC0-2 and CTC3 + groups for the 120 patients analyzed. The GG carriers were at higher risks for severe OM (CTC3+) compared with the TT homozygotes (OR = 3.000, 95% CI = 1.287-6.994, p = 0.011). No association was found between Ku70 (c.-1310C> G), Ku80 (c.2099-2408G> A, c.*841G> A), DNA-PKcs (c.2888 + 713 C > T) and the development of severe oral mucositis. Stratification analyses for the 50 patients treated with radiation alone further confirmed the association between the variant genotype of GG and severe OM (OR = 5.128, 95% CI = 1.183-22.238, p = 0.029). Concurrent radiochemotherapy increased the risk of severe OM for both the TT homozygotes and GG genotypes. CONCLUSIONS: Our study suggests that the Ku70 c.1781G> T polymorphism may be a susceptibility factor for radiation-induced oral mucositis in Chinese nasopharyngeal carcinoma patients.

Radiosensitivity enhancement of human hepatocellular carcinoma cell line SMMC-7721 by sorafenib through the MEK/ERK signal pathway.

PURPOSE: Sorafenib, an oral multikinase inhibitor, is the first agent that has demonstrated an improved overall survival benefit in advanced hepatocellular carcinoma, setting a new standard for first-line treatment. However, the association between radiosensitivity and sorafenib remains unclear. The purpose of this study was to investigate whether sorafenib could enhance radiosensitivity and the possible mechanisms of sorafenib-mediated radiosensitization in human hepatocellular carcinoma cell line SMMC-7721. EXPERIMENTAL DESIGN: The cell viability of human hepatocellular carcinoma cell line SMMC-7721 was determined by the 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. The radiosensitization of sorafenib in SMMC-7721 cells was evaluated by clonogenic assays, and immunofluorescence for DNA double-strand break detection, and Western blotting for protein detection. RESULTS: The MTT results clearly showed that sorafenib affected cell viability in human hepatocellular cell line SMMC-7721. Sorafenib administered 1 h before the radiation treatment resulted in radiosensitization with a sensitivity enhancement ratio (SER) of 1.65 as shown by clonogenic assays. Furthermore, sorafenib pretreatment led to decreased phosphorylation levels of extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) in SMMC-7721 cells. Interestingly, pretreatment of mitogen-activated protein kinase kinases/extracellular signal-regulated kinase (MEK/ERK) signaling inhibitor U0126 had a similar effect as that of sorafenib pretreatment in hepatocellular carcinoma cells, whereas pretreatment of phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling inhibitor LY294002 in the same cells had no effect on radiosensitization. The group treated with sorafenib and radiation was more sensitive to irradiation alone as demonstrated by the results of the DNA double-strand break detection. CONCLUSIONS: The combination of sorafenib and radiation affected cell viability more effectively than radiation alone. Sorafenib significantly enhanced the sensitivity of SMMC-7721 cells to radiation showing significantly reduced repair of DNA double-strand breaks. The MEK/ERK signaling pathway may be a pathway responsible for the radiosensitivity enhancement of sorafenib. Our data provided experimental support for the possible combination of sorafenib with radiation for the treatment of hepatocellular carcinoma and other cancers.