Daidzein belongs to the group of isoflavones, found in a wide variety of plant-derived foods, especially in soybeans and soy-based foods. In this study, the effect of daidzein on human gastric carcinoma cells (BGC-823) and its mechanism were investigated. MTT assay was applied in the detection of the inhibitory effects of daidzein on cell proliferation. Hoechst-propidium iodide staining and flow cytometry were used to examine the apoptosis as well as the mitochondrial transmembrane potential. Western blotting was performed to detect the expression of apoptosis-associated proteins: cleaved PARP, cleaved caspase-9, cleaved caspase-3, Bcl-2, and Bax. Daidzein significantly inhibited the growth and proliferation of human gastric carcinoma cells (BGC-823) in a concentration- and time-dependent manner. Furthermore, it was found that an insult of daidzein to BGC-823 cells caused them to die by disruption of mitochondrial transmembrane potential, demonstrated not only by staining dead cells for phosphatidylserine but also by the up-regulation (cleaved PARP, cleaved caspase-9, cleaved caspase-3, Bax) and down-regulation (Bcl-2) of proteins associated with apoptosis and survival; whereas, the pan-caspase inhibitor z-VAD-fmk could partially rescue cells against damage of daidzein. Taken together, the results of this study demonstrate that daidzein significantly induces apoptosis via a mitochondrial pathway. Specifically, daidzein induced a change in the Bax/Bcl-2 ratios and activation of caspases-3 and -9 and the cleavage of PARP. Therefore, daidzein has the potential for use as a therapeutic agent for the treatment of gastric carcinoma.
Acute pancreatitis (AP) is an inflammatory disease mediated by damage to acinar cells and pancreatic inflammation. In patients with AP, subsequent systemic inflammatory responses and multiple organs dysfunction commonly occur. Interactions between cytokines and oxidative stress greatly contribute to the amplification of uncontrolled inflammatory responses. Molecular hydrogen (H2) is a potent free radical scavenger that not only ameliorates oxidative stress but also lowers cytokine levels. The aim of the present study was to investigate the protective effects of H2 gas on AP both in vitro and in vivo. For the in vitro assessment, AR42J cells were treated with cerulein and then incubated in H2-rich or normal medium for 24 h, and for the in vivo experiment, AP was induced through a retrograde infusion of 5% sodium taurocholate into the pancreatobiliary duct (0.1 mL/100 g body weight). Wistar rats were treated with inhaled air or 2% H2 gas and sacrificed 12 h following the induction of pancreatitis. Specimens were collected and processed to measure the amylase and lipase activity levels; the myeloperoxidase activity and production levels; the cytokine mRNA expression levels; the 8-hydroxydeoxyguanosine, malondialdehyde, and glutathione levels; and the cell survival rate. Histological examinations and immunohistochemical analyses were then conducted. The results revealed significant reductions in inflammation and oxidative stress both in vitro and in vivo. Furthermore, the beneficial effects of H2 gas were associated with reductions in AR42J cell and pancreatic tissue damage. In conclusion, our results suggest that H2 gas is capable of ameliorating damage to the pancreas and AR42J cells and that H2 exerts protective effects both in vitro and in vivo on subjects with AP. Thus, the results obtained indicate that this gas may represent a novel therapy agent in the management of AP.
Diphenyl difluoroketone (EF24), a molecule having structural similarity to curcumin, was recently reported to inhibit proliferation of various cancer cells significantly. Here we try to determine the effect and mechanism of EF24 on hepatocellular carcinoma. 2 µM EF24 was found to inhibit the proliferation of PLC/PRF/5, Hep3B, HepG2, SK-HEP-1 and Huh 7 cell lines. However, even 8 µM EF24 treatment did not affect the proliferation of normal liver LO2 cells. Accordingly, 20 mg/kg/d EF24 inhibited the growth of the tumor xenografts conspicuously while causing no apparent change in liver, spleen or body weight. In addition, significant apoptosis and G2/M phase cell cycle arrest were found using flow cytometry. Besides, caspases and PARP activation and features typical of apoptosis including fragmented nuclei with condensed chromatin were also observed. Furthermore, the mechanism was targeted at the reduction of nuclear factor kappa b (NF-κB) pathway and the NF-κB–regulated gene products Bcl-2, COX-2, Cyclin B1. Our study has offered a strategy that EF24 being a therapeutic agent for hepatocellular carcinoma.
Background High mobility group box 1 (HMGB1) is increased in osteoarthritis (OA) tissue and chondrocytes stimulated with interleukin-1β (IL-1β). Suppression of HMGB1 expression is correlated with reduced inflammatory responses induced by IL-1β. This study aimed to investigate how inhibition of HMGB1 by glycyrrhizin might affect inflammatory responses and viability of OA patient–derived chondrocytes treated with IL-1β. Design The amounts of HMGB1 in the cartilage tissue and synovial fluid in patients with OA were assessed by Western blot and enzyme-linked immunosorbent assay (ELISA). Chondrocytes were extracted from OA patients and maintained in culture. The impact of glycyrrhizin on IL-1β-induced cell toxicity and inflammatory mediators and cytokines, including prostaglandin E2 (PGE2), nitric oxide (NO), proinflammatory cytokines, and metalloproteases (MMPs), were assessed by ELISA, Western blot, quantitative real-time polymerase chain reaction, and the Griess reagent assay. Results We confirmed that HMGB1 was significantly upregulated in specimens acquired from patients with OA. HMGB1 inhibition by glycyrrhizin improved cell viability of chondrocytes treated with IL-1β. Glycyrrhizin suppressed IL-1β-induced upregulation of HMGB1 and inflammatory mediators and cytokines, including PGE2, NO, proinflammatory cytokines, and MMPs. Conclusion Our results indicate that glycyrrhizin may be a potential therapy for OA patients and these promising findings warrant further study for clinical application.
Sepsis is a systemic inflammatory response caused by infection, and severe sepsis is commonly associated with the development of acute kidney injury (AKI). Accumulating evidence has revealed the implication of circular RNAs in AKI. In this study, we explored the potential engagement and the underlying mechanism of hsa_circ_010157 (circSTRN3) in sepsis-induced AKI. CircSTRN3 levels in HK2 cells and serum samples of patients were determined by RT-PCR. The protein levels of TLR4 (Toll Like Receptor 4), bax (Bcl-2-associated X protein), cleaved caspase 3 and bcl-2 (B-cell lymphoma-2) were detected by Western blotting (WB), and the levels of proinflammatory cytokines were detected by ELISA. The molecular interactions between mir-578/TLR4 and circSTRN3/miR-578 were analyzed by dual luciferase reporter assay as well as RNA pull-down experiment. Lipopolysaccharide (LPS) treated HK2 cells were used as an in vitro model to investigate the functional interaction of circSTRN3/miR-578/TLR4 axis. We found that the expression level of circSTRN3 in patients with sepsis-induced AKI and LPS-induced HK2 cells was higher. Silencing cicrSTRN3 alleviated LPS-induced cell proliferation, and suppressed the inflammatory response and apoptosis in LPS-treated HK2 cells. In contrast, the overexpression of circSTRN3 aggravated the cellular damages induced by LPS treatment. CircSTRN3 targeted miR-578/TLR4 axis to influence the damage effect induced by LPS. miR-578 inhibitor or TLR4 overexpression impaired the rescue effect of circSTRN3 knockdown. These results indicate that circSTRN3 upregulation in sepsis-induced AKI modulates miR-578/TLR4 axis to promote the pathogenesis of AKI, which could serve as future therapeutic targets for AKI treatment.
Breast carcinosarcoma is a rare and aggressive subtype of metaplastic breast cancer. Data focusing on breast carcinosarcoma is limited. The purposes of this study are to describe the clinicopathological features of breast carcinosarcoma and to evaluate post-surgical outcomes. Material and methods: All case reports about breast carcinosarcoma in China were collected from eligible papers published in Chinese core periodicals between 1990 and 2015 with key words of breast carcinosarcoma, breast cancer, carcinosarcoma, or metaplastic carcinoma. The survival rates, clinical behaviour, and pathological characteristics were analysed. Results: The mean age of the cohort of 215 patients was 53 years (range, 25-82 years). The tumour size ranged from 2.5 cm to 18 cm. The incidence of pathologically confirmed lymph node metastases was 30.81%. The epithelial component in a tumour may be composed of invasive ductal carcinoma (84.21%), squamous cell carcinoma (7.89%), lipid-rich carcinoma (6.58%), or adenocarcinoma (1.31%). Mesenchymal components may contain different elements ranging from fibrosarcoma (63.16%) to chondrosarcoma (19.73%), osteosarcoma (9.21%), liposarcoma (3.95%), or leiomyosarcoma (3.95%). The five-year survival of the breast carcinosarcoma in 149 patients is 62.6% (CI: 54.9%~0.703%). Conclusions: Breast carcinosarcoma is a rare subtype of metaplastic breast cancer. It is characterised by large tumour size, higher rates of axillary nodal involvement, higher rates of both local and distant recurrence, and is difficult to diagnose with preoperative core needle biopsies. Adjuvant treatment after surgical operation may improve the five-year OS of patients with breast carcinosarcoma.
Withaferin A, a withanolide obtained from Withania somnifera exhibits remarkable pharmacological properties. Withaferin A has been reported to exert cytotoxic effects against human multiple myeloma cells. Nevertheless, the in-depth understanding of the withaferin A induced antiproliferative effects against human myeloma cells is still unclear. The results showed that withaferin A inhibited the viability of six different myeloma cells with a lowest IC50 of 9 μM against the U266B1 and IM-9 cell lines. Withaferin A inhibited the viability and colony formation of the U266B1 and IM-9 cells in a dose and time-dependent manner. The DAPI and annexin V/PI staining assays revealed that withaferin A exerts anticancer effects against the human myeloma cells via induction of apoptosis. The induction of apoptosis in U266B1 and IM-9 cells was associated with upregulation of Bax and cytochrome c, downregulation of Bcl-2 and activation of PARP, caspase-3 and capase-9 cleavage. Additionally, withaferin A triggered the production of ROS in human myeloma cells indicative of ROS mediated apoptosis in human myeloma cells. The treatment of the U266B1 and IM-9 with ascorbic acid (antioxidant) could prevent the withaferin A mediated ROS production and the withaferin A induced antiproliferative effects. Collectively, the results show that withaferin A inhibits human myeloma cell proliferation via ROS mediated intrinsic apoptosis.
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