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In this study, 10 metabolites were obtained by collecting and extracting fecal samples after oral administration of panaxadiol (PD). Of these 10 metabolites, M7 (3β,21β,22α-hydroxy-24-norolean-12-ene), M8 (21β,22α-hydroxy-24-norolean-12-ene-3-one), M9 (3β,30α-hydroxy-24-norolean-22,30-epoxy-12-ene), and M10 (3β,21β-hydroxy-24-norolean-12-ene) were new compounds. MTT screening of the isolated compounds revealed that the inhibitions of cancer cells by M2, M4, M7, M8, and M10 were significantly stronger than that by the mother drug M0, with the activity of M2 being the most significant. Further, we investigated the anticancer mechanism of M2. The results showed that M2 significantly increased the level of ROS in cells; regulated the expressions of Bax, Bcl-2, and Cyt-C through the mitochondrial pathway; triggered the caspase cascade; and induced apoptosis. M2 could also induce G1 phase arrest and significantly regulate cell cycle-related proteins. In conclusion, the experimental results provide data for further study on the metabolic mechanism of PD in vivo and the potential of developing new anti-cancer drugs.

Spag6 encodes an axoneme central apparatus protein that is required for normal flagellar and cilia motility. Recent findings suggest that Spag6 plays a role in hearing and planar cell polarity (PCP) in the cochlea of the inner ear. However, a role for Spag6 in the vestibule has not yet been explored. In the present study, the function of Spag6 in the vestibule of the inner ear was examined using Spag6-deficient mice. Our results demonstrate a vestibular disorder in the Spag6 mutants, associated with abnormal ultrastructures of vestibular hair cells and Scarpa's ganglion cells, including swollen stereocilia, decreased crista in mitochondria and swollen Scarpa's ganglion cells. Immunostaining data suggests existence of caspase-dependent apoptosis in vestibular sensory epithelium and Scarpa's ganglion cells. Our observations reveal new functions for Spag6 in vestibular function and apoptosis in the mouse vestibule., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Cantharidin (CTD), an important active compound derived from the traditional Chinese medicine Mylabris (also called Banmao), has been used in the treatment of diseases such as tumors and dermatosis. However, Mylabris has been shown to induce hepatotoxicity in clinical practice and animal experiments, limiting its use. Further, a detailed mechanism underlying CTD-induced hepatotoxicity has not been determined. In the present study, we aimed to explore the effect of endoplasmic reticulum stress (ERS), autophagy, and apoptosis on CTD-induced hepatotoxicity. We found that CTD could inhibit the proliferation of LO2 cells; increase alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and malondialdehyde levels; and reduce glutathione peroxidase and superoxide dismutase activities. Western blotting showed that low concentrations of CTD induced the expressions of ERS-related proteins [GRP78, ATF4, PERK, p-PERK, XBP1-1 s, and CHOP], but high concentrations of CTD inhibited their expressions. Furthermore, high concentrations of CTD activated autophagy (LC3, Beclin-1, Atg3, Atg4A, Atg4B, and Atg7), induced the expressions of apoptotic proteins (Bax/Bcl-2 and caspase-3), and increased LO2 toxicity. Taken together, these results indicated that CTD can induce LO2 cytotoxicity by inhibiting ERS and inducing autophagy and apoptosis, which provides a scientific basis for CTD-induced hepatotoxicity., (© 2020 John Wiley & Sons, Ltd.)

Cocoa tea (Camellia ptilophylla), a natural gallocatechin gallate (GCG)-rich and low caffeine-containing tea species, has been recently reported to possess various bioactivities. However, the anti-colon cancer effects of Cocoa tea and its underlying mechanisms remain virtually unknown. This study aimed to assess the anti-proliferative and pro-apoptotic effects of water extract of Cocoa tea (CWE) on human colon cancer HCT116 cells compared with Yunnan Daye tea (YWE). Primarily, CWE showed stronger anti-proliferation and apoptosis induction than YWE. Moreover, reduction of mitochondrial membrane potential (MMP), up-regulation of Bax/Bcl-2 ratio, release of cytochrome c, activation of caspase-9 and -3, and cleavage of poly (ADP-ribose) polymerase (PARP) were observed, suggesting that mitochondrial apoptotic pathway was activated by CWE. Furthermore, CWE-induced apoptosis in HCT116 cells was dependent on the generation of intracellular reactive oxygen species (ROS) and down-regulation of phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Pretreatment with ROS scavenger N-acetyl cysteine (NAC) attenuated the impact of CWE on mitochondria-related apoptosis proteins, and partially recovered the inhibition of Akt phosphorylation. These results indicated that ROS generation mediated mitochondrial dysfunction and inactivation of PI3K/Akt pathway in CWE-induced HCT116 cell apoptosis. Additionally, CWE significantly inhibited tumor growth in HCT116 tumor-bearing mice, suggesting that Cocoa tea could act as a potential functional beverage to prevent or treat colorectal cancer., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Histone deacetylase 9 functions as an oncogene in a variety of cancers, but its role on non-small cell lung cancer (NSCLC) has not been reported. Melatonin was proven to possess anticancer actions, whereas its effect on NSCLC and underlying mechanisms remains poorly understood. In this study, 337 patients with complete clinicopathologic characteristics who underwent NSCLC surgery were recruited for the study. We found that NSCLC patients with high HDAC9 expression were correlated with worse overall survival and poor prognosis. HDAC9 knockdown significantly reduced NSCLC cell growth and induced apoptosis both in vivo and in vitro. Melatonin application also markedly inhibited cell proliferation, metastasis, and invasion and promoted apoptosis in NSCLC cells. Moreover, RNA-seq, real-time quantitative polymerase chain reaction, and western blot analyses showed that melatonin treatment decreased the HDAC9 level in NSCLC cells. A mechanistic study revealed that HDAC9 knockdown further enhanced the anticancer activities of melatonin treatment, whereas HDAC9 overexpression partially reversed the melatonin's anticancer effects. Additionally, the in vivo study found melatonin exerted anti-proliferative and pro-apoptotic effects on xenograft tumors which were also strengthened by HDAC9 knockdown. These results indicated that HDAC9 downregulation mediated the anti-NSCLC actions of melatonin, and targeting HDAC9 may be the novel therapeutic strategy for NSCLC., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cisplatin is an anti-cancer drug that causes oxotoxic side effects such as impairment of inner ear function and hearing loss. We aimed to investigate the effects of allicin against cisplatin-induced stria vascularis damage in mice, and to clarify the mechanism underlying the protective effects of allicin against ototoxicity. Stria vascularis injury was induced in mice by intraperitoneal injection of cisplatin, which was significantly prevented by pretreatment with allicin. Allicin not only reduced cisplatin-activated expression of cleaved caspase-3 in marginal cells, PVM/Ms (perivascular resident macrophage-like melanocytes), and basal cells of the stria vascularis, but also decreased the expression of poly(ADP-ribose) polymerase-1 (PARP-1) and apoptosis-inducing factor (AIF) nuclear translocation in the stria vascularis cells. Our results demonstrate that allicin plays an effective role in protecting stria vascularis injury induced by cisplatin by inhibiting caspase-dependent, as well as caspase-independent PARP-1-AIF-mediated apoptotic pathways. Therefore, allicin may be useful in preventing cisplatin-induced ototoxicity., (© 2019 S. Karger AG, Basel.)

Mammalian Sperm Associated Antigen 6 (SPAG6) is the orthologue of Chlamydomonas PF16, a protein localized in the axoneme central apparatus. Recent studies showed that Spag6 has a role in brain neuronal proliferation and differentiation. The mammalian spiral ganglion neurons (SGNs) are specialzed bipolar neurons in the inner ear. However, the role of SPAG6 in SGN has not been elucidated. Therefore, We hypothesized that a Spag6 knockout would affect the development and function of SGNs. We utilized Spag6-deficient mice and SGN explants to define the role of SPAG6. On postnatal day 30 (P30) mutant mice had lower SGN density compared to their wild-type littermates, and more apoptosis was evident in the mutants. Increased Bax expression, a disturbed distribution of cytochrome c, and cleaved caspase-3 positive staining indicated that increased apoptosis involved a mitochondrial pathway. Transmission electron microscopy revealed abnormalities in the ultrastructure of mutant SGNs as early as P7. In vitro, lack of SPAG6 affected the growth of neurites and growth cones. Additionally, SPAG6 deficiency decreased synapse density in SGN explants. Finally, Spag6 mutant SGNs were more sensitive to the microtubule stabilizing agent, paclitaxel. These findings suggest that Spag6 plays a crucial role in SGN development and function.

Cisplatin is an anticancer drug that causes the impairment of inner ear function as side effects, including hearing loss and balance dysfunction. The purpose of this study was to investigate the effects of allicin against cisplatin-induced vestibular dysfunction in mice and to make clear the mechanism underlying the protective effects of allicin on oto-vestibulotoxicity. Mice intraperitoneally injected with cisplatin exhibited vestibular dysfunction in swimming test, which agreed with impairment in vestibule. However, these impairments were significantly prevented by pre-treatment with allicin. Allicin markedly reduced cisplatin-activated expression of cleaved-caspase-3 in hair cells and vascular layer cells of utricule, saccule and ampulla, but also decreased AIF nuclear translocation of hair cells in utricule, saccule and ampulla. These results showed that allicin played an effective role in protecting vestibular dysfunction induced by cisplatin via inhibiting caspase-dependent and caspase-independent apoptotic pathways. Therefore, allicin may be useful in preventing oto-vestibulotoxicity mediated by cisplatin., (Copyright © 2017. Published by Elsevier B.V.)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent for esophageal squamous cell carcinoma (ESCC). Forced expression of CHOP, one of the key downstream transcription factors during endoplasmic reticulum (ER) stress, upregulates the death receptor 5 (DR5) levels and promotes oxidative stress and cell death. In this study, we show that ER stress mediated by thapsigargin promoted CHOP and DR5 synthesis thus sensitizing TRAIL treatment, which induced ESCC cells apoptosis. These effects were reversed by DR5 siRNA in vitro and CHOP siRNA both in vitro and in vivo. Besides, chemically inhibition of AMPK by Compound C and AMPK siRNA weakened the anti-cancer effect of thapsigargin and TRAIL co-treatment. Therefore, our findings suggest ER stress effectively sensitizes human ESCC to TRAIL-mediated apoptosis via the TRAIL-DR5-AMPK signaling pathway, and that activation of ER stress may be beneficial for improving the efficacy of TRAIL-based anti-cancer therapy.

In this study, we investigated the antitumor activity of icariin (ICA) in human esophageal squamous cell carcinoma (ESCC) in vitro and in vivo and explored the role of endoplasmic reticulum stress (ERS) signaling in this activity. ICA treatment resulted in a dose- and time-dependent decrease in the viability of human EC109 and TE1 ESCCs. Additionally, ICA exhibited strong antitumor activity, as evidenced by reductions in cell migration, adhesion, and intracellular glutathione (GSH) levels and by increases in the EC109 and TE1 cell apoptotic index, Caspase 9 activity, reactive oxygen species (ROS) level, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Furthermore, ICA treatments upregulated the levels of ERS-related molecules (p-PERK, GRP78, ATF4, p-eIF2α, and CHOP) and a pro-apoptotic protein (PUMA) and simultaneously downregulated an anti-apoptotic protein (Bcl2) in the two ESCC cell lines. The downregulation of ERS signaling using eIF2α siRNA desensitized EC109 and TE1 cells to ICA treatment, and the upregulation of ERS signaling using thapsigargin sensitized EC109 and TE1 cells to ICA treatment. In summary, ERS activation may represent a mechanism of action for the anticancer activity of ICA in ESCCs, and the activation of ERS signaling may represent a novel therapeutic intervention for human esophageal cancer.

The overexpression of metastasis‑associated in colon cancer 1 (MACC1) has been demonstrated not only in colon cancer, but also in various other types of cancer. Gliomas are the most common type of intracranial tumors, and recent studies have reported MACC1 to be involved in human glioma progression. The present study aimed to investigate the effects of MACC1 expression silencing in glioma cells using RNA interference, in order to determine the underlying biological mechanisms of glioma progression, including proliferation, apoptosis, invasion and metastasis. The expression levels of MACC1 were determined in various types of U251 glioma cells using western blot analyses. MACC1‑specific short hairpin RNA (shRNA) was used to silence the expression of MACC1 in the U251 cells. The results obtained following MACC1 silencing demonstrated a significant inhibition of cell proliferation, invasion and migration, as well as a marked enhancement of apoptosis. MACC1 shRNA‑induced inhibition of cell proliferation was observed by colony forming and MTT assays, and cell apoptosis was measured using flow cytometry and Hoechst staining. In addition, inhibition of cell invasion and migration was assessed using wound healing and transwell assays. Western blotting and fluorescence‑activated cell sorting (FACS) revealed a G0/G1 phase cell cycle arrest regulated by cyclins D1 and E; cell apoptosis regulated by caspase‑3; and cell invasion and migration regulated by matrix metalloproteinases 2 and 9, respectively. The present study demonstrated that the expression levels of MACC1 were significantly correlated with the biological processes underlying glioma cell proliferation, invasion and metastasis. Therefore, MACC1 may serve as a promising novel therapeutic target in human glioma. Notably, the inhibition of MACC1 expression by shRNA may prove to be an effective genetic therapeutic strategy for glioma treatment.

The Crosstalk between a tumor and its hypoxic microenvironment has become increasingly important. However, the exact role of UCP2 function in cancer cells under hypoxia remains unknown. In this study, UCP2 showed anti-apoptotic properties in A549 cells under hypoxic conditions. Over-expression of UCP2 in A549 cells inhibited reactive oxygen species (ROS) accumulation (P<0.001) and apoptosis (P<0.001) compared to the controls when the cells were exposed to hypoxia. Moreover, over-expression of UCP2 inhibited the release of cytochrome C and reduced the activation of caspase-9. Conversely, suppression of UCP2 resulted in the ROS generation (P = 0.006), the induction of apoptosis (P<0.001), and the release of cytochrome C from mitochondria to the cytosolic fraction, thus activating caspase-9. These data suggest that over-expression of UCP2 has anti-apoptotic properties by inhibiting ROS-mediated apoptosis in A549 cells under hypoxic conditions.

Asterosaponin 1, a new cytostatic agent from starfish, possesses several bioactivities including an antitumor effect. The aim of this study was to investigate the potential anti-proliferative and pro-apoptotic activity of asterosaponin 1 in A549 human lung cancer cells, as well as the potential mechanisms. The results showed that asterosaponin 1 inhibited the proliferation of A549 cells in a dose-dependent manner, and the cytostatic activity resulted from the induction of apoptotic cell death. Asterosaponin 1 increased ER dilation and cytosolic Ca2+ concentration, and enhanced the expression of the ER molecular chaperones GRP78 and GRP94 in a dose- and time-dependent manner. In addition, asterosaponin 1 treated A549 cells exerted increased expression and activity of CHOP, caspase-4 and JNK, three essential ER-associated apoptotic molecules. In summary, these results demonstrated that asterosaponin 1 inhibits the proliferation of A549 cells through induction of ER stress-associated apoptosis, making asterosaponin 1 a candidate new anticancer drug for lung cancer therapy.

Background: Silymarin, the main flavonoid constituent element extracted from Silybum marianum possessing antioxidant activity, is already known to be able to block the NF-κB activation process and result in cell apoptosis, implicating silymarin's potential to control cancer cell growth., Materials and Methods: In this study, based upon the above assumption, silymarin was administered to a highly metastatic lung cancer cell line Anip973 to test silymarin's role in cancer cell proliferation., Results: Silymarin had significant inhibitory effects on the proliferation of Anip973 cells in a dose-dependent and time-response manner within 48 hours. Silymarin can induce Anip973 apoptosis., Conclusions: Silymarin may in vitro inhibit the proliferation of the human lung adenocarcinoma cell line Anip973 and induce apoptosis via the mitochondria-dependent caspase cascade pathway.

Objective To investigate the effect of CA3(CIL56) on the proliferation and apoptosis of hepatocellular carcinoma HepG2 cells and its mechanism. Methods HepG2 cells were cultured in vitro and treated with different concentrations of CA3 (0, 0.25, 0.5, 1.0, 2.0, 4.0 mmol/L) for 24 and 48 hours, respectively. Enhanced CCK-8 reagent was used to detect the effect of CA3 on cell proliferation. Flow cytometry was utilized to detect cell apoptosis rate. We detected the changes of intracellular reactive oxygen species (ROS). Western blot was utilized to analyze the expression of YAP1, Bcl-2, Bax and Caspase-3 protein. Results The enhanced CCK-8 reagent test results showed that after 0.25, 0.5, 1.0, 2.0, 4.0 mmol/L CA3 treatment for 24 and 48 hours, the cell proliferation rates were (80.5±0.3)%, (79.4±0.2)%, (76.2±0.2)%, (76.4±0.1)%, (49.3±0.4)% and (75.3±0.2)%, (64.8±0.3)%, (48.4±0.2)%, (32.2±0.4)%, (31.9±0.2)%, respectively. Flow cytometry results showed that when CA3 concentration was increased to 2 mmol/L, the apoptosis rate was increased to 58.48%. CA3 could significantly increase the content of reactive oxygen species in HepG2 cells, reduce the expression of YAP1 and Bcl-2 protein, and increase the expression of Bax and Caspase-3. Conclusion CA3 could inhibit the proliferation and induce the apoptosis of HepG2 cells. The mechanism may be related to the increase of intracellular reactive oxygen species production and the regulation of YAP1, Bcl-2, Bax and Caspase-3 protein expression.

miRNAs have been pointed to play critical role in the development of congenital heart disease (CHD). miRNA-375-3p (miR-375-3p) was involved in cardiac dysfunction and cardiogenesis. However, no prior study had established a therapeutic role of miR-375-3p in CHD. We intended to investigate the effect and mechanism of miR-375-3p on apoptosis in hypoxic cardiomyocytes in vitro. Expression of miR-375-3p, forkhead box P1 (FOXP1) and Bcl2 like protein 2 (Bcl2l2) was detected using real-time quantitative PCR and western blot. Apoptosis was measured with MTT assay, flow cytometry and caspase-3 activity assay. The potential target binding between miR-375-3p and FOXP1/Bcl2l2 was predicted on DianaTools, and was validated by luciferase reporter assay and RNA pull-down assay. As a result, miR-375-3p was upregulated and FOXP1/Bcl2l2 was downregulated in maternal serum of women with fetal CHD and hypoxia-induced rat cardiomyocyte h9c2 cells. Hypoxia induced apoptosis rate elevation, caspase-3 activity promotion and viability inhibition in h9c2 cells; overexpression of miR-375-3p promoted, whereas knockdown of miR-375-3p antagonized hypoxia-induced effects in h9c2 cells. In addition, miR-375-3p was validated to negatively regulate FOXP1 and Bcl2l2 expression through target binding, and silencing of FOXP1 and Bcl2l2 could independently abate the anti-apoptosis role of miR-375-3p knockdown in hypoxic h9c2 cells. Collectively, blocking miR-375-3p suppressed hypoxia-evoked apoptosis of cardiomyocytes by targeting and upregulating FOXP1 and Bcl2l2. Our results might suggest maternal serum miR-375-3p as a potential biomarker for prenatal detection of fetal CHD. [ABSTRACT FROM AUTHOR]

Selenium nanoparticles (SeNPs), a novel selenium form, have attracted worldwide attention due to their bioactivities and low toxicity. This study aimed to assess the physicochemical characterization, storage stability, and anti-proliferative activities of SeNPs stabilized by Polyporus umbellatus polysaccharide (PUP). Results showed that orange-red, zero-valent, amorphous and spherical SeNPs with mean diameter of approximately 82.5 nm were successfully prepared by using PUP as a capping agent. PUP-SeNPs solution stored at 4 °C in dark condition could be stable for at least 84 days. Moreover, PUP-SeNPs treatment inhibited four cancer cell lines proliferation in a dose-dependent manner, while no significant cytotoxicity towards three normal cell lines was observed. Comparing with the other cancer cell lines (HepG2, Hela, and HT29), PUP-SeNPs displayed the most sensitive towards MDA-MB-231 cells with an IC 50 value of 6.27 μM. Furthermore, PUP-SeNPs significantly up-regulated Bax/Bcl-2 ratio, promoted cytochrome c release, increased caspase-9, -8 and -3 activities, and poly (ADP-ribose) polymerase cleavage, suggesting that mitochondria-mediated and death receptor-mediated apoptotic pathways were activated in MDA-MB-231 cells. Besides, PUP-SeNPs possessed better anti-proliferative activity than selenomethionine as well as lower cytotoxicity than sodium selenite. Taken together, PUP-SeNPs have strong potential as a dietary supplement for application in cancer chemoprevention, especially breast cancer. [ABSTRACT FROM AUTHOR]

Novel therapeutic strategies are still urgently expected for leukemia despite undisputed success of various targeted therapeutics. The antileukemia activity of Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on human leukemia cells was investigated. Atorvastatin inhibited K562 and HL60 cell proliferation, induced G2/M cell cycle arrest in K562 cells by down-regulating cyclinB1 and cdc2, but G0/G1 arrest in HL60 cells by up-regulating p27 and down-regulating cyclinD1 and p-pRb. Atorvastatin also induced apoptosis in both cell lines, in which the reactive oxygen species (ROS)-related mitochondrial apoptotic signaling might be involved, with increase of ROS and Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (MMP), release of cytochrome C into cytosol, and activation of Bax/Caspase-9/Caspase-3/PARP pathway. Inhibition of YAP nuclear localization and activation by Atorvastatin was reversed by the addition of mevalonate, GGPP, or FPP. Further, the effects on cell cycle arrest- and apoptosis- related proteins by Atorvastatin were alleviated by addition of mevalonate, suggesting the antileukemia effect of Atorvastatin might be through mevalonate-YAP axis in K562 and HL60 cells. Our results suggest that Atorvastatin might be used for leukemia therapy while evidence of clinical efficacy is required. [ABSTRACT FROM AUTHOR]

The present study examined the effects of procyanidin B2 (PB2) on L-NAME (nitric oxide synthase inhibitor)-induced hypertensive nephropathy. After 4 weeks of treatment with daily PB2 supplementation, lower blood pressure levels were observed in rats. The potential mechanisms were combined with amelioration of renal function impairment. The L-NAME–induced renal histological damage were reduced by PB2 treatment, which showed similar protective tendency in kidney injury molecule–1, nephrin, fibronectin and α–smooth muscle actin protein expression. This appears to be due to PB2 inducing a less pronounced generation of renal reactive oxygen species and inflammatory mediators than in the model group. Downregulation of Ang II type 1 receptor and NADPH oxidase subunit (NOX4, gp91phox and p47phox) played a critical role in the effect of PB2 reducing oxidative stress production. These activities could further support the use of PB2 commercially in food for the prevention of hypertension and its complications. [ABSTRACT FROM AUTHOR]

Cisplatin is a broad-spectrum anticancer drug that is commonly used in the clinic. Ototoxicity is one of the major side effects of this drug, which caused irreversible sensorineural hearing loss. Allicin, the main biologically active compound derived from garlic, has been shown to exert various anti-apoptotic and anti-oxidative activities in vitro and in vivo studies. We took advantage of C57 mice intraperitoneally injected with cisplatin alone or with cisplatin and allicin combined, to investigate whether allicin plays a protective role in vivo against cisplatin ototoxicity. The result showed that C57 mice in cisplatin group exhibited increased shift in auditory brainstem response, whereas the auditory fuction of mice in allicin + cisplatin group was protected in most frequencies, which was accordance with observed damages of outer hair cells (OHCs) and spiral ganglion neurons (SGNs) in the cochlea. Allicin markedly protected SGN mitochondria from damage and releasing cytochrome c, and significantly reduced pro-apoptosis factor expressions activated by cisplatin, including Bax, cleaved-caspase-9, cleaved-caspase-3and p53. Furthermore, allicin reduced the level of Malondialdehyde (MDA), but increased the level of superoxide dismutase (SOD). All data suggested that allicin could prevent hearing loss induced by cisplatin effectively, of which allicin protected SGNs from apoptosis via mitochondrial pathway while protected OHCs and supporting cells (SCs) from apoptosis through p53 pathway. [ABSTRACT FROM AUTHOR]

Background: As radioresistance of non-small cell lung cancers ( NSCLC) is one of the main causes of failure in radiotherapy, we examined whether micro ribonucleic acid (mi R-451) could function as a potential radiosensitizer of NSCLC and the related mechanism. Methods: Radioresistant NSCLC cell line A549 was transfected with pre-mi R-451 or a scrambled control. The mi R-451 messenger RNA level, colony-forming ability, apoptosis, and phosphatase and tensin homolog ( PTEN) protein level of 549 cells were examined by real-time polymerase chain reaction, clonogenic assay, flow cytometry analysis, and Western blot. Results: Upregulation of mi R-451 enhanced the suppressive effects of irradiation on the colony-forming ability of A549 cells. The apoptosis and PTEN expression of A549 cells post-irradiation were also enhanced by upregulation of mi R-451. Conclusions: Upregulation of miR-451 sensitized radioresistant NSCLC A549 cells to irradiation through the enhancement of apoptosis. The activation of PTEN post-irradiation was possibly correlated with the radiosensitization of A549 cells induced by mi R-451 overexpression. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) affects millions of people worldwide. MI causes massive cardiac cell death and heart function decrease. However, heart tissue cannot effectively regenerate by itself. While stem cell therapy has been considered an effective approach for regeneration, the efficacy of cardiac stem cell therapy remains low due to inferior cell engraftment in the infarcted region. This is mainly a result of low cell retention in the tissue and poor cell survival under ischemic, immune rejection and inflammatory conditions. Various approaches have been explored to improve cell engraftment: increase of cell retention using biomaterials as cell carriers; augmentation of cell survival under ischemic conditions by preconditioning cells, genetic modification of cells, and controlled release of growth factors and oxygen; and enhancement of cell survival by protecting cells from excessive inflammation and immune surveillance. In this paper, we review current progress, advantages, disadvantages, and potential solutions of these approaches. [ABSTRACT FROM AUTHOR]

Highlights: [•] Novel combination therapy using aspirin and valproic acid (VPA). [•] Combination of aspirin and VPA elicits synergistic cytotoxic effects. [•] Combination of aspirin and VPA significantly reduces the drug dosage required alone. [•] Combination of aspirin and VPA significantly inhibit tumor growth. [•] Lower dose of aspirin in combination therapy will minimize side effects of aspirin. [ABSTRACT FROM AUTHOR]

Aim To study the rate of apoptotic cell death in the process of thrombus evolution after plaque rupture in myocardial infarction. Methods Paraffin embedded thrombosuction aspirates of 63 patients were stained with haematoxylin & eosin (H&E) to assess histologically the age of the thrombi: fresh (intact blood cells; < 1 day old), lytic (necrosis; 1–5 days old) or organized (ingrowth of cells; > 5 days old). Presence of plaque constituents (atheroma including foam cells, cholesterol crystals calcifications and fibrous cap tissue) was also recorded. Immunohistochemical (double) stains with anti-caspase-3-antibody were used to visualize apoptosis and the cells involved. For the latter caspase-3 antibody was combined with cell-specific markers MPO (granulocytes), CD68 (macrophages), CD34 (endothelial cells), SMA-1 (smooth muscle cells) and a Feulgen stain (DNA). Second, the rate of apoptosis was evaluated in relation to the age of the thrombi. Platelet apoptosis was further evaluated with the use of TEM. Results From a total of 63 aspirates, plaque constituents were found in 33 of the aspirates, and in 15 of them lipid rich plaque tissue was the sole component. Age classification of all thrombus containing aspirates (n = 48) resulted in 12 fresh (25%), 18 lytic (37.5%) and 18 organized (37.5%) thrombi. Apoptosis was more extensive in lytic thrombi than in fresh or organized thrombi (P < 0.0001). Plaque-containing aspirates showed more apoptosis than aspirates without plaque (P < 0.05). Immuno staining with caspase-3 antibody in combination with cell-specific markers showed that apoptosis was most extensive in MPO + granulocytes. Caspase-3-positive platelets (CD61 + anucleate particles) were most abundant in lytic thrombi. Apoptosis in platelets was confirmed by ultrastructure. Conclusion This study demonstrated a significant association between thrombus age and occurrence of apoptosis of granulocytes and also platelets, with highest rates in (fragile) lytic thrombi. We propose that apoptotic cell death in athero thrombosis could potentially serve as a biomarker for thrombus instability. [ABSTRACT FROM AUTHOR]

Mylabris , as a natural product of traditional Chinese medicine (TCM), exhibiting typical antitumor activity, and cantharidin (CTD) is the major bioactive component. However, drug-induced nephrotoxicity (DIN) extremely limited its clinical application. In this study, we proved that activation of the endoplasmic reticulum (ER) stress-dependent PERK/CHOP pathway exerts a toxic role in rats and HK-2 cells through inducing autophagy and apoptosis. Results showed that CTD could cause renal function damage, cytotoxicity, and apoptosis. The ER dilatation and autolysosomes were observed after CTD treatment. Furthermore, the distribution of LC3, ATF4, and CHOP proteins was observed in the nucleus and cytoplasm. In addition, the mRNA levels of ER stress-regulated genes (PERK , eIF2α , CHOP , and ATF4) were increased, and the expression levels of GRP78, ATF4, CHOP, LC3, Beclin-1, Atg3, Atg7, Caspase 3, and Bax/Bcl-2 proteins were increased both in vitro and in vivo. Consistently, this upregulation could be inhibited by an ER stress inhibitor 4-Phenylbutyric acid (4-PBA), indicating that ER stress is partly responsible for activation of autophagy and apoptosis in CTD-induced DIN. In conclusion, CTD could induce DIN by triggering ER stress, further activating autophagy and apoptosis both in vivo and in vitro. • Cantharidin (CTD) caused renal injury and apoptosis in a dose-time-dependent manner in vivo and in vitro. • CTD could trigger endoplasmic reticulum stress, which in turn activates autophagy and apoptosis in nephrotoxicity. • Apoptosis and autophagy could be mitigated by inhibition of the PERK/CHOP pathway in CTD-induced nephrotoxicity. [ABSTRACT FROM AUTHOR]