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1.
Curcumin induces endoplasmic reticulum stress-associated apoptosis in human papillary thyroid carcinoma BCPAP cells via disruption of intracellular calcium homeostasis.
Zhang, L, Cheng, X, Xu, S, Bao, J, Yu, H
Medicine. 2018;(24):e11095
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Abstract
BACKGROUND Thyroid cancer is the most common endocrine tumor. Our previous studies have demonstrated that curcumin can induce apoptosis in human papillary thyroid carcinoma BCPAP cells. However, the underlined mechanism has not been clearly elucidated. Endoplasmic reticulum (ER) is a major organelle for synthesis, maturation, and folding proteins as well as a large store for Ca. Overcoming chronically activated ER stress by triggering pro-apoptotic pathways of the unfolded protein response (UPR) is a novel strategy for cancer therapeutics. Our study aimed to uncover the ER stress pathway involved in the apoptosis caused by curcumin. METHODS BCPAP cells were treated with different doses of curcumin (12.5-50 μM). Annexin V/PI double staining was used to determine cell apoptosis. Rhod-2/AM calcium fluorescence probe assay was performed to measure the calcium level of endoplasmic reticulum. Western blot was used to examine the expression of ER stress marker C/EBP homologous protein 10 (CHOP) and glucose-regulated protein 78 (GRP78). X-box binding protein1 (XBP-1) spliced form was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS Curcumin significantly inhibited anchorage-independent cell growth and induced apoptosis in BCPAP cells. Curcumin induced ER stress and UPR responses in a dose- and time-dependent manner, and the chemical chaperone 4-phenylbutyrate (4-PBA) partially reversed the antigrowth activity of curcumin. Moreover, curcumin significantly increased inositol-requiring enzyme 1α (IRE1α) phosphorylation and XBP-1 mRNA splicing to induce a subsets of ER chaperones. Increased cleavage of activating transcription factor 6 (ATF6), which enhances expression of its downstream target CHOP was also observed. Furthermore, curcumin induced intracellular Ca influx through inhibition of the sarco-endoplasmic reticulum ATPase 2A (SERCA2) pump. The increased cytosolic Ca then bound to calmodulin to activate calcium/calmodulin-dependent protein kinase II (CaMKII) signaling, leading to mitochondrial apoptosis pathway activation. Ca chelator BAPTA partially reversed curcumin-induced ER stress and growth suppression, confirming the possible involvement of calcium homeostasis disruption in this response. CONCLUSIONS Curcumin inhibits thyroid cancer cell growth, at least partially, through ER stress-associated apoptosis. Our observations provoked that ER stress activation may be a promising therapeutic target for thyroid cancer treatment.(Figure is included in full-text article.).
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Smokeless tobacco consumption impedes metabolic, cellular, apoptotic and systemic stress pattern: A study on Government employees in Kolkata, India.
Biswas, S, Manna, K, Das, U, Khan, A, Pradhan, A, Sengupta, A, Bose, S, Ghosh, S, Dey, S
Scientific reports. 2015;:18284
Abstract
Smokeless tobacco (SLT) remains a threat amongst a large population across the globe and particularly in India. The oral use of tobacco has been implicated to cause physiological stress leading to extreme toxicological challenge. The study included 47 SLT-users and 44 non-users providing a spectrum of pathophysiological, clinico-biochemical, antioxidant parameters, cell cycle progression study of PBMC and morphological changes of red blood cells (RBC). The expressions of p53, p21, Bax, Bcl-2, IL-6, TNF- α, Cox-2, iNOS were analyzed from thirteen representative SLT-users and twelve non-users. Difference in CRP, random glucose, serum cholesterol, TG, HLDL-C, LDL-C, VLDL-C, neutrophil count, monocyte count, ESR, SOD (PBMC) and TBARS (RBC membrane) were found to be statistically significant (p < 0.05) between the studied groups. The current study confers crucial insight into SLT mediated effects on systemic toxicity and stress. This has challenged the metabolic condition leading to a rise in the inflammatory status, increased apoptosis and RBC membrane damage. The above findings were substantiated with metabolic, clinical and biochemical parameters. This is possibly the first ever in-depth report and remains an invaluable document on the fatal effects of SLT.
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Biological effects of leukotriene E4 on eosinophils.
Steinke, JW, Negri, J, Payne, SC, Borish, L
Prostaglandins, leukotrienes, and essential fatty acids. 2014;(3):105-10
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Abstract
Studies demonstrate the existence of novel receptors for cysteinyl leukotrienes (CysLTs) that are responsive to leukotriene (LT) E4 and might be pathogenic in asthma. Given the eosinophilic infiltration in this disorder, we investigated eosinophil expression of P2Y12 and gpr99 and their capacity to respond to LTE4. Receptor transcript expression was investigated via quantitative PCR and surface protein expression via flow cytometry. We investigated LTE4 influences on eosinophils including Ca(+2) flux, cAMP induction, modulation of adhesion molecule expression, apoptosis and degranulation. Eosinophils displayed both transcript and surface protein expression of P2Y12 and gpr99. We could not find evidence of LTE4 activation of eosinophils, however, LTE4 induced cAMP expression, and preincubation of eosinophils with LTE4 inhibited degranulation. Even though eosinophils are an important source of CysLTs in AERD, eosinophils are not themselves the pro-inflammatory biological target and, in contrast, LTE4 via cAMP primarily elicits anti-inflammatory responses.
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Baicalin from the extract of Scutellaria baicalensis affects the innate immunity and apoptosis in leukocytes of children with acute lymphocytic leukemia.
Orzechowska, B, Chaber, R, Wiśniewska, A, Pajtasz-Piasecka, E, Jatczak, B, Siemieniec, I, Gulanowski, B, Chybicka, A, Błach-Olszewska, Z
International immunopharmacology. 2014;(2):558-67
Abstract
Scutellariae Radix (root of Scutellaria baicalensis) has a long history of application in traditional and in modern herbal medications. The major components of Scutellariae Radix are baicalin, baicalein, wogonoside and wogonin. Accumulating evidence demonstrates that Scutellaria has immunomodulatory effects and possesses compelling anticancer potential. Treatment of peripheral blood leukocytes (PBLs) with Scutellaria extract (SBE) enriched in baicalin, reduced viability of PBLs obtained from patients with acute lymphoblastic leukemia (ALL). SBE had no impact on the survival of healthy, control leukocytes. The immune system modulation by SBE resulted in increased production of IFNγ in PBLs, and reduced TNFα and IL-10 production in bone marrow cells (BMC), in ALL patients. SBE stimulated the nonspecific antiviral immunity, assessed by resistance of PBLs and BMC to vesicular stomatitis virus (VSV) infection. SBE showed pro-apoptotic activity in NALM-6 cell line (B-type human leukemia). The number of cells expressing annexin V increased from 6% in control cultures to 29% and 52% after treatment with 100 μg/ml and 200 μg/ml respectively. Increased percentage of apoptotic cells was observed when cells were treated with corresponding concentration of baicalin. SBE enhanced apoptosis of PBLs in BMC of leukemic children. The percentage of PBLs that underwent apoptosis and mean annexin V expression increased from 11% in the control to 17% and 24% for the doses of 100 μg/ml and 200 μg/ml respectively. Importantly, SBE did not induce apoptosis of PBLs in the healthy, control group.
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Crocin prevents sesamol-induced oxidative stress and apoptosis in human platelets.
Thushara, RM, Hemshekhar, M, Paul, M, Shanmuga Sundaram, M, Shankar, RL, Kemparaju, K, Girish, KS
Journal of thrombosis and thrombolysis. 2014;(3):321-30
Abstract
Recent studies have reported the platelet proapoptotic propensity of plant-derived molecules such as, resveratrol, thymoquinone, andrographolide and gossypol. Meanwhile, there were also reports of phytochemicals such as cinnamtannin B1, which shows antiapoptotic effect towards platelets. Platelets are mainly involved in hemostasis, thrombosis and wound healing. However, altered platelet functions can have serious pathological outcomes that include cardiovascular diseases. Platelets are sensitive to external and internal stimuli including therapeutic and dietary components. The anuclear platelets do undergo apoptosis via mitochondrial pathway. However, exaggerated rate of platelet apoptosis could lead to thrombocytopenia and other bleeding disorders. The present study deals with ameliorative efficacy of crocin on sesamol-induced platelet apoptosis. The antiapoptotic property of crocin and the proapoptotic tendency of sesamol in platelets were previously demonstrated. Therefore, it was interesting to see how these two compounds would interact and wield their effects on human platelets. Crocin effectively inhibited sesamol-induced oxidative stress on platelets, which was evidenced by the measurement of endogenously generated reactive oxygen species, particularly hydrogen peroxide, and changes in thiol levels. Further, crocin abrogated sesamol-induced biochemical events of apoptosis in platelets, which include intracellular calcium mobilization, changes in mitochondrial membrane integrity, cytochrome c release, caspase activity and phosphatidylserine externalization. Even though sesamol has proapoptotic effects on platelets, its anti-platelet activity cannot be neglected. Thus, the study proposes that sesamol could be supplemented with crocin, an approach that could not only abolish the toxic effects of sesamol on platelets, but also enhance the quality of treatment due to their synergistic action.
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Glutathione protects human nucleus pulposus cells from cell apoptosis and inhibition of matrix synthesis.
Yang, D, Wang, D, Shimer, A, Shen, FH, Li, X, Yang, X
Connective tissue research. 2014;(2):132-9
Abstract
Abstract Cell death (apoptosis and necrosis) and extracellular matrix destruction induced by oxidative stress have been suggested to be closely involved in the process of disc degeneration. Glutathione, a natural peptide as a powerful antioxidant in human cytoplasm, plays an important role in protecting living cells. This study is to investigate whether glutathione could retard degenerated phenotypes in cultured disc cells. Human nucleus pulposus cells were isolated and cultured in alginate beads and subsequently treated with a pro-oxidant H2O2 alone or a pro-inflammatory cytokine IL-1β alone or either of them together with glutathione. It was shown that H2O2 dose-dependently promoted nucleus pulposus cell apoptosis detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and decreased mRNA levels of matrix proteins aggrecan and type II collagen determined by quantitative reverse transcription-polymerase chain reaction (RT-PCR). IL-1β could induce production of nitric oxide and decrease of proteoglycan, detected by the Griess reagent and the dimethyl methylene blue, respectively. The deleterious effects of either H2O2 or IL-1β could be efficiently prevented by glutathione. These results indicated that glutathione might be considered as an option for intervention of disc degeneration.
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Radioiodine therapy accelerates apoptosis in peripheral blood lymphocytes of patients with differentiated thyroid cancer.
Vrndic, O, Milosevic-Djordjevic, O, Djurdjevic, P, Jovanovic, D, Mijatovic, L, Jeftic, I, Simonovic, SZ
Neoplasma. 2013;(5):568-75
Abstract
Both apoptosis and micronuclei formation reflect cytogenetic damage in cells and could contribute to cell homeostasis. The aim of this study was to evaluate apoptosis in peripheral blood lymphocytes (PBLs) of patients with differentiated thyroid cancer (DTC) before and after 131-iodine (131-I)-therapy and its correlation with micronuclei (MN) frequency. The study population included 18 DTC patients and 18 healthy donors. Apoptotic cells were detected using the Annexin V-FITC/7-AAD kit and MN frequency by cytokinesis-block MN assay. The difference between early apoptosis in PBLs of DTC patients before therapy and controls (9.88 ± 4.99% vs. 6.64 ± 2.07%, p = 0.003) was significant, as well as between early apoptosis in PBLs of DTC patients before and after 131-I-therapy (9.88 ± 4.99% vs. 13.53 ± 6.57%, p = 0.008). The MN frequency and early apoptosis in PBLs of DTC patients was positively correlated before (r = 0.540, p= 0.021) and after 131-I-therapy (r = 0.585, p= 0.014). Thyroid cancer patients had a significantly increased early apoptosis in PBLs, which further increased after 131-I-therapy in association with MN frequency.
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MiR-21 is overexpressed in response to high glucose and protects endothelial cells from apoptosis.
Zeng, J, Xiong, Y, Li, G, Liu, M, He, T, Tang, Y, Chen, Y, Cai, L, Jiang, R, Tao, J
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2013;(7):425-30
Abstract
Diabetes was an increasing public health problem nowadays. Accumulating evidences had shed a light on the involvement of endothelial cell dysfunction in the pathogenesis of diabetes-associated vascular diseases. MiR-21, a multiple-functional miRNA, was evidenced to be involved in endothelial dysfunction, however, the underlying molecular mechanisms were still unknown. In current study, we investigated the intrinsic link between miR-21 and high glucose-induced endothelial dysfunction. We demonstrated that expression of miR-21 was elevated in circulating endothelial progenitor cells from diabetes patients. Further, inhibition of miR-21 markedly enhanced high glucose-induced endothelial cytotoxicity. Furthermore, proteomic profiling was applied to analyze the downstream effectors involved in miR-21-meidated protection of endothelial cells. A total of 31 proteins were positively identified, including Annexin A2, S100A4, SOD2, Thioredoxin and DAXX. Altered expression of these proteins was validated by immunoblot. Finally, mechanistic study showed that miR-21 protected endothelial cell against high glucose-induced endothelial cytotoxicity probably by inhibiting the expression of DAXX. Our findings were considered as a significant step toward a better understanding of diabetes-associated vascular diseases.
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The antiparasitic clioquinol induces apoptosis in leukemia and myeloma cells by inhibiting histone deacetylase activity.
Cao, B, Li, J, Zhu, J, Shen, M, Han, K, Zhang, Z, Yu, Y, Wang, Y, Wu, D, Chen, S, et al
The Journal of biological chemistry. 2013;(47):34181-34189
Abstract
The antiparasitic clioquinol (CQ) represents a class of novel anticancer drugs by interfering with proteasome activity. In the present study, we found that CQ induced blood cancer cell apoptosis by inhibiting histone deacetylases (HDACs). CQ accumulated the acetylation levels of several key proteins including histone H3 (H3), p53, HSP90, and α-tubulin. In the mechanistic study, CQ was found to down-regulate HDAC1, -3, -4, and -5 in both myeloma and leukemia cells. Computer modeling analysis revealed that CQ was well docked into the active pocket of the enzyme, where the oxygen and nitrogen atoms in CQ formed stable coordinate bonds with the zinc ion, and the hydroxyl group from CQ formed an effective hydrogen bond with Asp-267. Moreover, co-treatment with CQ and zinc/copper chloride led to decreased Ac-H3. Furthermore, CQ inhibited the activity of Class I and IIa HDACs in the cell-free assays, demonstrating that CQ interfered with HDAC activity. By inhibiting HDAC activity, CQ induced expression of p21, p27, and p53, cell cycle arrest at G1 phase, and cell apoptosis. This study suggested that the HDAC enzymes are targets of CQ, which provided a novel insight into the molecular mechanism of CQ in the treatment of hematological malignancies.
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Mediterranean diet reduces senescence-associated stress in endothelial cells.
Marin, C, Delgado-Lista, J, Ramirez, R, Carracedo, J, Caballero, J, Perez-Martinez, P, Gutierrez-Mariscal, FM, Garcia-Rios, A, Delgado-Casado, N, Cruz-Teno, C, et al
Age (Dordrecht, Netherlands). 2012;(6):1309-16
Abstract
This paper aims to study the effects of the oxidative stress induced by quality and quantity of dietary fat on cellular senescence. Twenty elderly subjects consumed three diets, each for 4 weeks: a saturated fatty acid diet (SFA), a low-fat and high-carbohydrate diet (CHO-ALA), and a Mediterranean diet (MedDiet) enriched in monounsaturated fatty acid following a randomized crossover design. For each diet, we investigated intracellular reactive oxidative species (ROS), cellular apoptosis and telomere length in human umbilical endothelial cells incubated with serum from each patient. MedDiet induced lower intracellular ROS production, cellular apoptosis, and percentage of cell with telomere shortening, compared with the baseline and with SFA and CHO-ALA diets. Dietary fat modulates the oxidative stress in human endothelial cells. MedDiet protects these cells from oxidative stress, prevents cellular senescence and reduces cellular apoptosis.