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Abstract Heat stroke is a serious pathological condition with high mortality. Vascular endothelial cell injury is a key feature in the pathogenesis of heat stroke, but the specific pathophysiological process whereby this occurs is still unclear. Currently, relevant studies are primarily based upon examination of apoptosis. Recently, pyroptosis, a new form of inflammation-related programmed cell death, was also demonstrated to be involved in heat stroke pathophysiology. Herein, we present evidence that vascular endothelial cell pyroptosis can be induced by heat stress in a time- and temperature-dependent manner. Furthermore, this process can be significantly inhibited by GSDMD siRNA. These findings suggest a new therapeutic target for heat stroke. [ABSTRACT FROM AUTHOR]

The aim of the present study was to examine the effects of alisertib (ALS) on RAS signaling pathways against a panel of colorectal cancer (CRC) cell lines and engineered Flp-In stable cell lines expressing different Kirsten rat sarcoma virus (KRAS) mutants. The viability of Caco-2KRAS wild-type, Colo-678KRAS G12D, SK-CO-1KRAS G12V, HCT116KRAS G13D, CCCL-18KRAS A146T and HT29BRAF V600E cells was examined by Cell Titer-Glo assay, and that of stable cell lines was monitored by IncuCyte. The expression levels of phosphorylated (p-)Akt and p-Erk as RAS signal outputs were measured by western blotting. The results suggested that ALS exhibited different inhibitory effects on cell viability and different regulatory effects on guanosine triphosphate (GTP)-bound RAS in CRC cell lines. ALS also exhibited various regulatory effects on the PI3K/Akt and mitogen-activated protein kinase (MAPK) pathways, the two dominant RAS signaling pathways, and induced apoptosis and autophagy in a RAS allele-specific manner. Combined treatment with ALS and selumetinib enhanced the regulatory effects of ALS on apoptosis and autophagy in CRC cell lines in a RAS allele-specific manner. Notably, combined treatment exhibited a synergistic inhibitory effect on cell proliferation in Flp-In stable cell lines. The results of the present study suggested that ALS differentially regulates RAS signaling pathways. The combined approach of ALS and a MEK inhibitor may represent a new therapeutic strategy for precision therapy for CRC in a KRAS allele-specific manner; however, this effect requires further study in vivo. [ABSTRACT FROM AUTHOR]

Aim Rheumatoid arthritis is characterized by type 17 helper T cell (Th17)/regulatory T cell (Treg) imbalance. The objective of this article is to study whether insufficient apoptosis contributes to the imbalance of Th17/Treg in rheumatoid arthritis. Methods Twenty-one rheumatoid arthritis patients and eight healthy volunteers were involved in this study. The percentage of CD4+ interleukin ( IL)-17+ T cells and CD4+ transcription factor-forkhead box protein 3 (Foxp3)+ T cells were measured by flow cytometry, and active caspase-3 labeling was used to detect early apoptosis. The number of T cell subtypes in peripheral blood between the two groups was compared, as well as the apoptotic ratio. Results Neither the number of Th17 nor Treg cells was significantly different between rheumatoid arthritis patients and healthy controls. However, the number of regulatory T cells positively correlated with erythrocyte sedimentation rate, Disease Activity Score of 28 joints and rheumatoid factor. For the apoptosis of T cell subtypes, the percentage of apoptotic Th17 cells was higher in peripheral blood of rheumatoid arthritis patients compared to controls. Furthermore, peripheral Th17 cells were more sensitive to apoptosis than Treg cells, but there was no difference between rheumatoid arthritis patients and controls. Conclusion It seemed that there was no relationship between the number and apoptosis ratio of peripheral Th17/Treg cells. But the number of Treg cells positively correlated with disease activity. Furthermore, Th17 cells are more sensitive to apoptosis after freezing, especially in RA patients. This serendipitous finding may provide new areas for the further study of these two cell populations. [ABSTRACT FROM AUTHOR]

[Display omitted] • Oral bioavailability of COS was improved by nanoencapsulation. • Microfold cell-mediated route was proved to be effective for intestinal absorption of CANs. • CANs enriched in liver improved apoptosis and LSEC capillarization of liver fibrosis. • Antihepatotoxic mechanism of COS was attributed to inhibition of JNK/p38 MAPK pathway. Chitooligosaccharides (COS) significantly attenuates liver dysfunction. However, the conundrum of the oral bioavailability of COS limits their pharmacological effects. Therefore, a strategy of nanoencapsulation was employed to enhance oral bioavailability and tissue-targeted distribution of COS. In this study, nanospheres loaded with COS (CANs) were prepared, their bioavailability, biodistribution, transport mechanism and anti-liver fibrosis effects were explored. Nanoencapsulation improved the oral bioavailability of various COS monomers through microfold cell-mediated absorption route in an indiscriminate manner. CANs were more favorably enriched and protractedly accumulated in the liver. In a liver fibrosis model, CANs ameliorated the pathological state and extracellular matrix deposition. The alleviation of liver fibrosis for COS could be attributed to the inhibition of liver cell apoptosis and liver sinusoidal endothelial cell (LSEC) capillarization. Consequently, this study highlights the improved oral bioavailability of COS and proposes a novel mechanism of COS, for better understanding its hepatoprotective effect. [ABSTRACT FROM AUTHOR]

Background: Heat stress can be acutely cytotoxic, and heat stress-induced apoptosis is a prominent pathological feature of heat-related illnesses, although the precise mechanisms by which heat stress triggers apoptosis are poorly defined. Methods: The percentages of viability and cell death were assessed by WST-1 and LDH release assays. Apoptosis was assayed by DNA fragmentation and caspase activity. Expression of cleaved PARP, Apaf-1, phospho-PERK, Phospho-eIF2a, ATF4, XBP-1s, ATF6, GRP78, phospho-IP3R, RYR and SERCA was estimated by Western blot. The effect of calcium overload was determined using flow cytometric analysis with the fluorescent probe Fluo-3/AM. The generation of ROS (O2−, H2O2, NO) was labeled by confocal laser scanning microscopy images of fluorescently and flow cytometry. Results: In this study, we found that heat stress in HUVEC cells activated initiators of three major unfolded protein response (UPR) signaling transduction pathways: PERK-eIF2a-ATF4, IRE1-XBP-1S and ATF6 to protect against ER stress, although activation declined over time following cessation of heat stress. Furthermore, we show that intense heat stress may induce apoptosis in HUVEC cells through the calcium-mediated mitochondrial apoptotic pathway, as indicated by elevation of cytoplasmic Ca2+, expression of Apaf-1, activation of caspase-9 and caspase-3, PARP cleavage, and ultimately nucleosomal DNA fragmentation; Reactive oxygen species (ROS) appear to act upstream in this process. In addition, we provide evidence that IP3R upregulation may promote influx of Ca2+ into the cytoplasm after heat stress. Conclusion: Our findings describe a novel mechanism for heat stress-induced apoptosis in HUVEC cells: following elevation of cytoplasm Ca2+, activation of the mitochondrial apoptotic pathway via the IP3R upregulation, with ROS acting as an upstream regulator of the process. [ABSTRACT FROM AUTHOR]

Abstract: Dietary soy intake is associated with protection from breast cancer, but questions persist on the potential risks of the major soy isoflavone genistein (GEN) on female reproductive health. Here, we evaluated intermediate markers of cancer risk in uteri of cycling, young adult Sprague–Dawley rats lifetime exposed to one of three AIN-93G semipurified diets: casein (CAS), soy protein isolate (SPI+ with 276 mg GEN aglycone equivalents/kg) and CAS+GEN (GEN at 250 mg/kg). Postnatal day 50 (PND50) rats lifetime exposed to GEN or SPI+ had similar uterine luminal epithelium height, myometrial thickness, endometrial gland numbers, endometrial immunoreactive proliferating cell nuclear antigen (PCNA), and serum estrogen and progesterone, as CAS-fed rats. GEN-fed rats showed modestly increased apoptosis in uterine glandular epithelium, compared to those of CAS- or SPI+-fed groups. Diet had no effect on the uterine expression of genes for the tumor suppressors PTEN, p53 and p21, and the apoptotic-associated proteins Bcl2, Bax and progesterone receptor. Uterine tissue and serum concentrations of total GEN were higher in rats fed GEN than in those fed SPI+. Human Ishikawa endocarcinoma cells treated with GEN-fed rat serum tended to exhibit increased apoptotic status than those treated with CAS-fed rat serum. Exogenously added GEN (0.2 and 2 μM) increased, while estradiol-17β (0.1 μM) decreased Ishikawa cell apoptosis, relative to untreated cells. Results suggest that lifetime dietary exposure to soy foods does not alter uterine cell phenotype in young adult rats, while GEN, by enhancing uterine endometrial glandular apoptosis in vivo and in vitro, may confer protection against uterine carcinoma. Given its limited influence on uterine phenotype of young adult females, GEN, when taken as part of soy foods or as supplement, should be favorably considered for other potential health benefits. [Copyright &y& Elsevier]

Abstract: We previously demonstrated that female Sprague–Dawley rats fed AIN-93G diets containing soy protein isolate (SPI+) had lower DMBA-induced mammary tumor incidence than those fed diets containing casein (CAS), due partly to altered Phase I metabolism with soy. Here, we evaluated the tumor protective effects of these same diets to the direct-acting carcinogen N-methyl-nitrosourea (NMU). Tumor incidence was reduced and tumor latency was enhanced, in NMU-administered female rats lifetime exposed to SPI+, relative to the CAS group. Tumor multiplicity did not differ with diet, while tumor grade tended to be more advanced with SPI+. Normal mammary glands of CAS and SPI+ tumor-bearing rats had comparable proliferative and apoptotic status. However, mammary expression of HER-2/neu and progesterone receptor (PR) genes was higher for SPI+ rats. Moreover, tumored SPI+ rats had lower serum progesterone levels than those fed CAS, while serum estrogen did not differ. Serum from tumored SPI+ rats had higher apoptotic activity towards mammary epithelial MCF-7 cells, than CAS serum. Thus, dietary soy protects against mammary tumorigenesis induced by a direct-acting carcinogen and alters signaling pathways involving PR and HER-2/neu. [Copyright &y& Elsevier]

We have found that AIN-93G diets made with whey protein hydrolysate (WPH) reduce 7,12-dimethyl-benz[a]anthracene (DMBA)-induced tumor incidence in Sprague-Dawley (Harlan) rats relative to those fed a diet with casein (CAS). Herein, we replicated these findings in another Sprague-Dawley substrain (Charles River) and examined whether WPH protective effects were associated with altered mammary gland differentiation status and expression of the tumor suppressor phosphatase and tensin homolog deleted in chromosome ten (PTEN). Mammary tumor incidence was lower in DMBA-treated rats fed WPH than in those fed CAS. Mammary glands of WPH- and CAS-fed rats were isolated at weaning [postnatal day (PND) 21-28] and at an early adult stage (PND 50-53) and analyzed for proliferative (proliferating cell nuclear antigen immunoreactivity), apoptotic (terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick-end labeling), and differentiation (beta-casein) indices, as well as for PTEN mRNA and protein levels. PND 50-53 rats fed WPH showed decreased proliferation and increased apoptosis in mammary structures, coincident with increased mammary beta-casein gene expression, decreased terminal end-bud numbers, and increased ductal lengths, relative to same-age CAS-fed rats. When challenged with DMBA for 24 h, mammary glands of PND 53 CAS-fed rats had decreased cell survival in both terminal end buds and ductal epithelium, while the mammary glands of WPH-fed rats were not altered from pre-DMBA levels. At 7 d post-DMBA, mammary glands of CAS- and WPH-fed rats exhibited comparable apoptotic indices. Mammary PTEN expression was higher in WPH- than in CAS-fed rats at PND 21-28, but was not different in young adults fed either diet. Results demonstrate that dietary WPH advances mammary gland differentiation during neonatal development and suggest that the transiently increased expression of the pro-apoptotic signal PTEN during a sensitive developmental window may partly underlie the cancer protective effects of WPH. [ABSTRACT FROM AUTHOR]