Ferroptosis is a newly discovered type of cell death that differs from traditional apoptosis and necrosis and results from iron‐dependent lipid peroxide accumulation. Ferroptotic cell death is characterized by cytological changes, including cell volume shrinkage and increased mitochondrial membrane density. Ferroptosis can be induced by two classes of small‐molecule substances known as class 1 (system X c − inhibitors) and class 2 ferroptosis inducers [glutathione peroxidase 4 (GPx4) inhibitors]. In addition to these small‐molecule substances, a number of drugs (e.g. sorafenib, artemisinin and its derivatives) can induce ferroptosis. Various factors, such as the mevalonate (MVA) and sulphur‐transfer pathways, play pivotal roles in the regulation of ferroptosis. Ferroptosis plays an unneglectable role in regulating the growth and proliferation of some types of tumour cells, such as lymphocytoma, ductal cell cancer of the pancreas, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Here, we will first introduce the discovery of and research pertaining to ferroptosis; then summarize the induction mechanisms and regulatory pathways of ferroptosis; and finally, further elucidate the roles of ferroptosis in human tumourous diseases.
The gastrointestinal tract is the site of nutrient digestion and absorption and is also colonized by diverse, highly mutualistic microbes. The intestinal microbiota has diverse effects on the development and function of the gut-specific immune system, and provides some protection from infectious pathogens. However, interactions between intestinal immunity and microorganisms are very complex, and recent studies have revealed that this intimate crosstalk may depend on the production and sensing abilities of multiple bioactive small molecule metabolites originating from direct produced by the gut microbiota or by the metabolism of dietary components. Here, we review the interplay between the host immune system and the microbiota, how commensal bacteria regulate the production of metabolites, and how these microbiota-derived products influence the function of several major innate and adaptive immune cells involved in modulating host immune homeostasis.
Nicotinamide N-methyltransferase (NNMT) has been found involved in cell proliferation of several malignancies. However, the functional role of NNMT in breast cancer has not been elucidated. In the present study, we showed that NNMT was selectively expressed in some breast cancer cell lines, down-regulation of NNMT expression in Bcap-37 and MDA-MB-231 cell lines by NNMT shRNA significantly inhibited cell growth in vitro, decreased tumorigenicity in mice and induced apoptosis. The silencing reciprocal effect of NNMT was confirmed by over-expressing NNMT in the MCF-7 and SK-BR-3 breast cancer cell lines which lack constitutive expression of NNMT. In addition, down-regulation of NNMT expression resulted in reducing expression of Bcl-2 and Bcl-xL, up-regulation of Bax, Puma, cleaved caspase-9, cleaved caspase-3 and cleaved PARP, increasing reactive oxygen species production and release of cytochrome c from mitochondria, and decreasing the phosphorylation of Akt and ERK1/2. These data suggest that down-regulation of NNMT induces apoptosis via the mitochondria-mediated pathway in breast cancer cells.
Poison of intestinal induce severe health problems in human infants and young animals due to contaminating foods and feedstuffs. With the emergence of public health concerns and high-speed diffuse of drug-opposition of bacteria, the adoption of antimicrobial peptides as potential candidates in treating pathogen infections raised up. Nature Microcin J25 (MccJ25), a class of lasso peptides separated from a fecal strain of E. coli, has been replied to display powerful antimicrobial behavior. Herein, the study was to assess the usefulness of biogenic MccJ25 in the prophylaxis of ETEC K88 infection in IPEC-J2 cells. In vitro antimicrobial activity against ETEC K88 and cytotoxicity of biogenic MccJ25 were determined first. To further understand how biogenic MccJ25 mediates its impact, ETEC K88 adhesion in cells, membrane permeability [as indicated by reduced release of lactate dehydrogenase (LDH)], transepithelial electrical resistance (TEER), barrier function, and proinflammatory cytokines levels were determined in IPEC-J2 cells after treatment with biogenic MccJ25 and challenge with ETEC K88. Biogenic MccJ25 had a minimum inhibitory concentration of 0.25 μg/mL against ETEC K88, decreased ETEC K88 adhesion in cells and did not cause cytotoxicity toward cells. Furthermore, biogenic MccJ25 protects against ETEC-induced barrier dysfunction by increasing the TEER, decreasing the LDH and promoting tight junction proteins (TJPs) by promoting the assembly of occludin and claudin-1 in the tight junction complex. Biogenic MccJ25 was further found to relieve inflammation responses through modulation of interleukine-6, IL-8 and tumor necrosis factor-α levels via inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor κB activation. In summary, biogenic MccJ25 can protects against ETEC K88-induced intestinal damage and inflammatory response, recommend the hidden adoption of biogenic MccJ25 as a novel prophylactic agent to reduce pathogen infection in animals, food or humans.
Microcin J25 (MccJ25) is an antimicrobial peptide produced by a fecal strain of Escherichia coli containing 21 AA. This study was performed primarily to evaluate the effects of MccJ25 as a potential substitute for antibiotics (AB) on growth performance, nutrient digestibility, fecal microbiota, and intestinal barrier function in weaned pigs. In the present study, 180 weaned pigs (7.98 ± 0.29 kg initial BW) were randomly assigned to 1 of 5 treatments, including a basal diet (CON) and CON supplemented with AB (20 mg/kg colistin sulfate; ABD) or 0.5, 1.0, and 2.0 mg/kg MccJ25. On d 0 to 14, dietary supplementation with MccJ25 and ABD had positive effects on ADG, ADFI, diarrhea incidence, and G:F ( < 0.05). Pigs fed the 2.0 mg/kg MccJ25 diet had greater ADG ( < 0.05) and marginally greater G:F ( < 0.10) compared with pigs fed the ABD diet. Compared with the CON diet, the 2.0 mg/kg MccJ25 diet sharply improved ( < 0.05) ADG and G:F and decreased ( < 0.05) diarrhea incidence (d 15 to 28 and d 0 to 28). Apparent digestibility of nutrients in pigs fed 1.0 and 2.0 mg/kg MccJ25 was improved ( < 0.05) compared with that of pigs fed CON and ABD. The serum cytokines IL-6 and IL-1β and tumor necrosis factor-α levels in pigs fed MccJ25 were greater than in pigs fed CON ( < 0.05). Additionally, the IL-10 concentration in pigs fed MccJ25 was sharply increased ( < 0.05) compared with that of pigs fed CON. Pigs fed 1.0 and 2.0 mg/kg MccJ25 diets had remarkably decreased lactate, diamine oxidase, and endotoxin concentrations and fecal numbers ( < 0.05) and improved fecal and numbers ( < 0.05). Compared with the ABD diet, the diet containing 2.0 mg/kg MccJ25 did not increase lactate, diamine oxidase, and endotoxin (d 14) concentrations ( < 0.05) or decrease the and (d 28) numbers ( < 0.05). The diets containing 1.0 and 2.0 mg/kg MccJ25 and ABD (d 28) improved lactate concentration and short-chain fatty acid concentrations, including acetate, propionate, and butyrate, in feces ( < 0.05). Moreover, the pigs fed 2.0 mg/kg MccJ25 had greater lactate, butyrate (d 14), and propionate concentrations than the pigs fed the ABD diet ( < 0.05). In conclusion, dietary supplemented MccJ25 effectively improved performance, attenuated diarrhea and systematic inflammation, enhanced intestinal barrier function, and improved fecal microbiota composition of weaned pigs. Therefore, MccJ25 could be a potential effective alternative to AB for weaned pigs.
Drug delivery with nanocarriers relies on the interaction of individual nanocarriers with the cell surface. For lipid-based NCs, this interaction uniquely involves a process of membrane fusion between the lipid bilayer that makes up the NC and the cell membrane. Cubosomes have emerged as promising fusogenic NCs, however their individual interactions had not yet been directly observed due to difficulties in achieving adequate resolution or disentangling multiple interactions with common characterization techniques. Moreover, many studies on these interactions have been performed under static conditions which may not mimic the actual transport of NCs. Herein we have observed fusion of lipid cubosome NCs with lipid bilayers under flow. Total internal reflection microscopy has allowed visualisation of the fusion event which was sensitive to the lipid compositions and rationalized by lipid diffusion. The fusion event in supported lipid bilayers has been compared with those in cells, revealing a distinct similarity in kinetics.
Antimicrobial peptide (AMP) can be a promising alternative in various domains. However, further risk information is required. In this study, mice were orally administrated different dosages of recombinant AMP microcin J25 (4.55, 9.1, and 18.2 mg/kg; MccJ25) for 1 week, and the toxicity risk impacts were examined. We evidenced that middle-dosage administration mice had a lower inflammation, better body weight, and ameliorated mucosal morphology, accompanied by reduced intestinal permeability and tighter intestinal barrier. Fecal microbiota composition analysis in middle-or low-dosage mice revealed the Bifidobacterium count was increased and the coliform bacteria count was decreased, and increased in shortchain fatty acid levels. Unexpectedly, there was a risk that high-dosage mice increased intestinal permeability and imbalance of intestinal bacteria. Taken together, these data indicated a safe threshold for usage of MccJ25 in clinical practice. Such studies can effectively enhance the safety of various aspects such as food preservative and drug.
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