Month: July 2020

But the recruitment strategy of selecting loyal patients is likely to reduce this chance. Fourth, the compliance of insulin medication was not examined. In conclusion, no cancer signal with insulin glargine was found in this carefully characterized clinical cohort with diabetes. While our study is limited in size, we avoided potential for major distortions by implementing a new user, active comparator study design. Our study thus adds to the evidence that insulin glargine does not increase the risk for any cancer outcomes when compared with its main treatment alternative, NPH insulin. Chemotherapy is still the main clinical treatment for cancer. Most of the chemotherapeutic drugs induce serious multi-drug resistance and a series of side effects, e.g., fatigue, muscle and joint pain, impaired immune responses, anemia, neutropenia and thrombocytopenia. Therefore, searching for novel anti-tumor agents from natural products with fewer adverse effects is highly important. The use of medicinal mushrooms in the fight against cancer has been known for a very long time in Korea, China, Japan, Russia, USA and Crizotinib 877399-52-5 Canada. Mushrooms produce a variety of complex, lowmolecular-weight compounds with diverse chemical compositions, such as phenolic compounds, polyketides, triterpenoids and steroids. Many have shown direct beneficial effects on cancer development by interfering with specific transduction pathways. Mushroom Pyropolyporus fomentarius Teng, also called Fomes fomentarius, is a fungus of the Polyporaceae family that acts a parasite on beech and birch trees ; it has worldwide distribution. P. fomentarius has wideranging uses, including medicinal use. Many bioactive substances were isolated from the P. fomentarius petroleum ether fraction, such as b-sitosterol, 5a,8a-epidioxy-ergosta-6,22-dien-3bol, ergosta-7,22-dien-3b-ol, ergosta-7,22-dien-3-palmitate, Stearic acid, Palmitic acid, Ergosta-7,22-dien-3-one, ergosta7,22-dien-3-one, dimethyl acetal and sterols. However, there no studies have demonstrated its anti-tumor activities and the underlying mechanism. Many traditional herbal medicines have shown antiproliferative effects on the S180 cell line or cytotoxic activities on the S180-bearing mouse model, alone or combined with cyclophosphamide. The present work has demonstrated the significant anti-tumor activity of the PFPE both in vitro and in vivo. One of the anti-tumor activity chemotherapeutic targets is cytotoxicity. Most clinically used anti-tumor agents possess significant cytotoxic activity in cell culture systems. In our paper, PFPE was toxic to S180 cells at 240 and 480 mg/ml in time-dosedependent manners. However, at the concentration of 120 mg/ml, there was no proliferation inhibition effect with the prolonged incubation time. The dose response phenomenon and low dose stimulation have been previously reported for other drugs. The lower concentration might have other functions, such as anti-inflammation, anti-virus, etc., and the underlying mechanisms require further exploration. Moreover, PFPE had no or little cytotoxicity in HEK-293 cells. Thus, the present study suggests that PFPE has a potential application as a natural anti-tumor agent. Defects in apoptosis are the critical step in the resistance to therapy in many types of cancers. Thus, apoptotic pathways are relevant targets in cancer therapies. Previous studies have shown that apoptosis is an important mechanism through which various anticancer agents exert anticancer effects. In the present study, we aimed to determine whether apoptosis was induced in S180 cells along with the PFPE exposure. As evidenced by Annexin V-FITC/PI double staining, we found that the proportion of early and late apoptotic cells increased significantly after the PFPE treatment.

As shown in Figure 4, PFPE caused obvious DNA fragmentation in S180 cells, which is also a typical biochemical feature of apoptosis. The data in this study suggest that the PFPE could induce apoptosis in S180 cells, and the cytotoxic effects were associated with apoptosis, implying that the extract has great potential in anti-cancer drug screening. Mitochondria play a critical role in cell apoptosis triggered by many stimuli. Loss of MMP is an early event in apoptosis. The MMP, as detected by flow cytometry with Rh123, significantly decreased immediately after 24 h PFPE treatment. Electron leakage from the mitochondrial respiratory chain may react with molecular oxygen, resulting in the formation of superoxide, which is subsequently converted to ROS. Moreover, excessive ROS may cause oxidative damage to lipids, proteins, and DNA, leading to cell death. As seen from Figure 6, compared with the control group, the generation of intracellular ROS dramatically increased in S180 cells. These results suggest that the decreased MMP and elevated ROS may both related to cell apoptosis after the PFPE treatment, and the PFPE-induced cell apoptosis might be mitochondria dependent. Consistent with in vitro findings, the in vivo study provides information that the PFPE significantly reduced the S180 sarcoma weight at the indicated dose, showing its specific role in anticancer therapy. In tumor immunotherapy, the occurrence, growth of tumor and immune state has a very important relationship. Spleen and thymus are important immunological organs. The spleen index and thymus index could reflect the immune Adriamycin function of spleen and thymus. According to other reports, CTX caused atrophy of spleen and thymus and influenced the spleen. We got similar results in the in vivo experiment in CTX treated group. However, at low concentration group, PFPE did not induce such changes. As illustrated in our work, PFPE could efficiently inhibit tumor growth and also has lower immune organ toxicity. Via GC–MS analysis, various possible chemical components were detected in PFPE. n-Hexadecanoic acid has antitumor activity to human leukemic cells as well as murine cells. Hexadecanoic acid has been reported to induce NF-kB activation in HaCaT keratinocytes, which is an important pathway involved in cancer development. Moreover, fatty acids exhibit cytotoxicity against HeLa cells and retard tumor growth. The essential oil, with n-Hexadecanoic acid and octadecanoic acid as the main components, showed significant cytotoxicity against oral cancer, breast cancer and small cell lung cancer. Steroidal compounds had a potent inhibition effect against various cancer cells. Therefore, the anti-tumor effect of PFPE both in vitro and vivo may be closely related to the specific efficacy of such components, functioning either alone or together, which needs further confirmation. In conclusion, this work provided evidence that the PFPE inhibits the proliferation of S180 cells in vitro through inducing apoptosis, while the PFPE significantly reduced the weight of S180 sarcoma in vivo. Apoptosis induction has become a new therapeutic target in cancer research, and the results in our paper indicate that the PFPE may have a potential application as a natural anti-tumor agent. Future research should investigate the specific bioactive compounds and then try to explore the molecular mechanisms of the PFPE in cancer therapy. The cyclic nucleotides, cyclic adenosine monophosphate and cyclic guanosine monophosphate are intracellular second messengers with diverse regulatory functions in both unicellular and multicellular organisms. Hence there are an extreme variety and large number of isoforms of these nucleotidyl cyclases.

First, in line with previous reports in SLE patients,, our data indicate that ApoCell-phagocytosis is deficient in several MDM preparations that were derived from SS and SLE patients by cultivation in the absence of patients’ sera, a fact that may at least partly support a model of intrinsically defective monocyte in these disorders. Alternatively, the impaired capacity of phagocytes of SS and SLE patients for uptake of prey may be viewed as a result of cellular activation taking place in vivo, a notion probably also implied by the significant correlation between the findings in the various phagocytosis assays and the activity indices of these diseases. Finally, the notably low capacity of SS and SLE patients for phagocytosis of particulate targets by blood-borne monocytes and MDM that was observed may reflect an overall dysfunction of phagocytes in the proper engulfment of certain preys in these disorders. Interestingly, deficient phagocytosis of particulate targets is also reported in primary biliary cirrhosis, a disease with striking clinicopathologic similarities to SS. On the other hand, it should be noticed that in sharp contrast to the above deficient phagocytic capacities, the bloodborne monocytes of SS and SLE were found remarkably hyperfunctional in the phagocytosis of necrotic cell debris. The addition of healthy serum was found to facilitate significantly the ingestion of apoptotic cells by blood-borne monocytes derived from healthy individuals, as well as from SLE or SS patients. These findings are in good agreement with the previously observed capacity of sera from healthy individuals to restore the phagocytic ability of macrophages from SLE patients. In addition, ApoCell-phagocytosis by healthy monocytes was presently shown to be severely impaired following the substitution of HBD sera by sera derived from SS and SLE patients. Consistent with previous observations, the sera from approximately 80% of SLE patients studied were not as efficient as healthy sera in supporting of ApoCell-phagocytosis by normal blood-borne monocytes. In this study, we present first evidence that such incapacity is also manifested by the vast majority of sera from SS patients studied. The precise nature of this aberration in SS and SLE patients is unclear. Normally, several serum proteins attach to apoptotic cells and induce the deposition of C3 and its degradation products C3b and iC3b, thus enhancing efferocytosis by phagocytes via recognition by complement receptors CR3 and CR4. In this context, mice lacking such bridging molecules, such as MFG-e8, Mer or C1q are reported to develop lupus-like manifestations GW-572016 associated with inefficient removal of apoptotic cells. In line to these observations, several quantitative and functional aberrations of the above opsonins have been described in SLE and SS patients, including hypocomplementemia, which is considered as one of the major immunological markers and of key clinical importance for both disorders.

MMT, nanosilicate platelets were isolated in water to produce high surface areas and multiple ionic charges per platelets. After using these unique characteristics to bind to the surface of microorganism, it was demonstrated that the AB1010 790299-79-5 growth of various strains of bacteria was completely inhibited at 0.3% NSP by nonspecific binding. Furthermore, the surface of NSP modified by silver nanoparticles could improve the antibacterial activity but merely elicit slight immune response. The low cytotoxicity and genotoxicity of NSP have been verified by several methods, including comet assay, micronucleus test, and Salmonella gene mutation assay. A high lethal dose greater than 5,700 mg/kg body weight was also observed in rats with acute oral administration of NSP. Based on the strong binding ability and the low toxicity of NSP, we expect that NSP will act as a good mycotoxin adsorption agent when used as a feed additive. However, the effect of NSP on the development of embryos has not yet been reported. In this study, we evaluate the influences of NSP on the pre-implantation development of mouse embryos and the adsorption of FB1 by NSP via both in vitro and in vivo assays. Corn and soybean meal are major ingredients in animal feed. Corn is also the best medium to support Fusarium verticillioides growth. Almost all of the hog, broiler, and layer feed in Taiwan is reported to be contaminated by FB1 at up to 1.3 mg/kg on average. Therefore, how to prevent and reduce the deteriorated effects caused by FB1 is an important problem. Ceramide synthase can use sphinganine or sphingosine with fatty acyl-CoA to synthesize ceramide. Ceramide is a critical intermediate product during sphingolipid metabolism, producing sphingomyelin, sphingosine, or glycosphingolipid. However, due its chemical similarities with sphinganine and sphingosine, FB1 may inhibit the activity of ceramide synthase localized at the endoplasmic reticulum and disturb the metabolism of the sphingolipids that are important for stabilizing the structure and function of the cell membrane. In addition, free sphingoid bases were accumulated because of inhibition of ceramide synthase. The inhibition of ceramide synthase can promote free sphingoid base-induced cell death but inhibit cell death triggered by ceramide. Cells that are sensitive to sphingoid base-induced cell death will die and insensitive cells will survive. It has been hypothesized that FB1 can decrease the production of glycosphingolipids and thus lead to impaired function of the folate transporters on the cell membrane, and the intake of folate decreases after exposure to FB1. The low folate intake is responsible for the increased incidence of neural tube defects and the failure of neurulation during embryogenesis, particularly the exencephaly. However, a recent study held the opposite opinion which demonstrated that folate deficiency does not exacerbate NTD induction by FB1 in LM/Bc mice.

In line, therapeutic administration of this antibody in experimental chronic metabolic injury attenuated hepatic macrophage infiltration, pro-inflammatory cytokine levels and steatosis development in mice. On the one hand, our experiments using aCXCL16 revealed that blocking this chemokine pathway almost completely abolished the rapid accumulation of hepatic NKT cells in response to an acute injury. This is well in line with a prior in vitro experiment from our group, demonstrating that CXCR6 is specifically required by NKT, but not other CXCR6-expressing lymphocytes, to migrate towards CXCL16. Moreover, it had been reported that CXCL16 neutralization reduced accumulation of mature NK1.1+, but not immature NK1.12 NKT cell recent thymic emigrants in the liver in homeostatic conditions in vivo. NKT cells display a unique population of unconventional T cells that express both a T cell receptor and NK1.1 receptor from NK cells. There are different types of NKT cell subsets that are defined by the ability of recognizing a-galactosylceramide presented by the non-classical MHC-like molecule CD1d, termed type-I classical, type-II non classical and CD1d-independent NK1.1+ NKT cells. Especially the type-I NKT cells, which the by far largest subset in the liver, have the ability to secrete various types of cytokines within a very short time period after activation, including IL-4 and IFNc. In line, mice that are deficient for the CXCL16 chemokine displayed a reduced number of liver NKT cells, decreased production of IFNc and IL-4 by administration of a-GalCeramide and impaired inflammatory responses against Propionibacterium MK-1775 acnes-infections in vivo. On the other hand, our experiments indicate that aCXCL16 could be an interesting therapeutic strategy in hepatic inflammation and steatohepatitis. Importantly, the same aCXCL16 antibody had been tested as an interventional approach for severe inflammatory conditions before. In a murine immunological liver injury induced by Bacille Calmette-Guerin and lipopolysaccharide, mice treated with aCXCL16 showed reduced liver injury, inflammation and improved survival. Administration of aCXCL16 also reduced colonic inflammation in mouse models of on dextran sodium sulfate- and trinitrobenzene sulfonic acidinduced colitis. In our hands, therapeutic administration of aCXCL16 during the last three weeks of a 6-weeks course of MCD diet in mice significantly reduced the number of hepatic macrophages, alongside minor reductions in intrahepatic levels of pro-inflammatory cytokines, and steatosis development. The link between macrophages and progression of fatty liver degeneration is well established, as macrophages release many inflammatory mediators that not only attract additional immune cells, but also drive oxidative stress and intrahepatocytic lipid accumulation. Our experiments now indicate that blocking CXCL16 effectively reduces pro-inflammatory macrophages in experimental steatohepatitis.