Apoptosis In Different Types Research Articles

Cannabis sativa L. and Nonpsychoactive Cannabinoids: Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer.

In the last decades, a lot of attention has been paid to the compounds present in medicinal Cannabis sativa L., such as Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), and their effects on inflammation and cancer-related pain. The National Cancer Institute (NCI) currently recognizes medicinal C. sativa as an effective treatment for providing relief in a number of symptoms associated with cancer, including pain, loss of appetite, nausea and vomiting, and anxiety. Several studies have described CBD as a multitarget molecule, acting as an adaptogen, and as a modulator, in different ways, depending on the type and location of disequilibrium both in the brain and in the body, mainly interacting with specific receptor proteins CB1 and CB2. CBD is present in both medicinal and fibre-type C. sativa plants, but, unlike Δ9-THC, it is completely nonpsychoactive. Fibre-type C. sativa (hemp) differs from medicinal C. sativa, since it contains only few levels of Δ9-THC and high levels of CBD and related nonpsychoactive compounds. In recent years, a number of preclinical researches have been focused on the role of CBD as an anticancer molecule, suggesting CBD (and CBD-like molecules present in the hemp extract) as a possible candidate for future clinical trials. CBD has been found to possess antioxidant activity in many studies, thus suggesting a possible role in the prevention of both neurodegenerative and cardiovascular diseases. In animal models, CBD has been shown to inhibit the progression of several cancer types. Moreover, it has been found that coadministration of CBD and Δ9-THC, followed by radiation therapy, causes an increase of autophagy and apoptosis in cancer cells. In addition, CBD is able to inhibit cell proliferation and to increase apoptosis in different types of cancer models. These activities seem to involve also alternative pathways, such as the interactions with TRPV and GRP55 receptor complexes. Moreover, the finding that the acidic precursor of CBD (cannabidiolic acid, CBDA) is able to inhibit the migration of breast cancer cells and to downregulate the proto-oncogene c-fos and the cyclooxygenase-2 (COX-2) highlights the possibility that CBDA might act on a common pathway of inflammation and cancer mechanisms, which might be responsible for its anticancer activity. In the light of all these findings, in this review we explore the effects and the molecular mechanisms of CBD on inflammation and cancer processes, highlighting also the role of minor cannabinoids and noncannabinoids constituents of Δ9-THC deprived hemp.

Lower Vitamin D Status in Patients with Differentiated Thyroid Carcinoma

Thyroid cancer (TC) has become the most rapidly increasing type of cancer representing 1-1.5% of all cancers diagnosed annually probably due to intensive screening. It is estimated that the death rate of TC has slowly increased from 0.49 to 0.51/100.000 in the last 10 years and 53.990 new cases will be diagnosed in 2018 in the United States. Therefore, efforts are being made in order to stop the increasing incidence and genetic alterations are thoroughly studied. One of the most recent incriminated factors in TC etiology and physiopathology is vitamin D deficiency. Besides the well-known role in bone metabolism, vitamin D has extra-skeletal effects exerted through the vitamin D receptor (VDR) and has been shown to interfere with many cellular functions such as inhibiting cell proliferation, stimulating differentiation and malignant cell apoptosis in different types of cancer. Cross-sectional, retrospective study which included 114 patients (71 with confirmed thyroid cancer and 43 patients in the control group with benign pathology). Preoperative levels of 25(OH)vitamin D, PTH, biochemical and thyroid panel were measured. The histopathologic features were analyzed. Mean values of vitamin D was 16.31 � 7.14 ng/mL with lower levels in patients with thyroid cancer (14.95 � 5.91 ng/mL) in comparison to patients with benign thyroid pathology (18.55 � 8.41 ng/mL), with a p value of 0.008. Majority of the cases were papillary thyroid cancer (97.18%) in stage 3 (45.07%). Vitamin D levels also correlated negatively with TNM staging. The necessity of further studies is a reality in order to establish if vitamin D deficiency is a possible risk factor for thyroid cancer and its correction can be considered an additional therapy.

Downregulation of microRNA‑21 expression inhibits proliferation, and induces G1 arrest and apoptosis via the PTEN/AKT pathway in SKM‑1 cells

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and may progress to acute myeloid leukemia (AML). MicroRNAs (miRNA/miRs) as oncogenes or tumor suppressors regulate a number of biological processes including cell proliferation, cell cycle and apoptosis in different types of cancer cells. Recently, it has been reported that miR-21 as an oncogene is overexpressed and directly targets SMAD-7 in MDS. However, little is known about the mechanism of miR-21 in the progression of MDS. In the present study, the role of miR-21 in the proliferation and apoptosis of SKM-1 cells, an acute myeloid leukemia cell line established in the AML/MDS leukemic phase was investigated. The present results demonstrated that downregulation of miR-21 inhibited proliferation, induced apoptosis and caused G1 phase cell cycle arrest of SKM-1 cells. In addition, the expression levels of apoptosis regulator Bcl-2 (bcl2), cyclinD1 and phosphorylated-protein kinase B (AKT) were significantly decreased in SKM-1 cells transfected with the miR-21 inhibitor, whilst the expression levels of phosphatase and tensin homolog (PTEN), bcl-associated protein X (bax) and cleaved caspase 3 were significantly elevated. Furthermore, knockdown of Akt by small interfering (si)RNA significantly increased the expression of bax, cleaved caspase 3 and reduced the expression of bcl2 and cyclinD1 in SKM-1 cells. Taken together, these data indicate that miR-21 targets the PTEN/AKT pathway in the pathogenesis of MDS and could be a potential target for MDS therapy.

Down-regulation of intracellular anti-apoptotic proteins, particularly c-FLIP by therapeutic agents; the novel view to overcome resistance to TRAIL.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a member of the tumor necrosis factor (TNF) superfamily that induces apoptosis in different types of cancer cells via activation of caspase cascade. TRAIL interacts with its cognate receptors that placed on cancer cells surface, including TRAIL-R1 (death receptor 4, DR4), TRAIL-R2 (death receptor 5, DR5), TRAIL-R3 (decoy receptor 1, DcR1), TRAIL-R4 (decoy receptor 2, DcR2), and osteoprotegerin (OPG). Despite high apoptosis-inducing ability of TRAIL, various cancerous cells gain resistance to TRAIL gradually, and consequently TRAIL potential for apoptosis stimulation in these cells diminishes intensely. According to diverse ranges of examinations, intracellular anti-apoptotic proteins, such as cellular-FLICE inhibitory protein (c-FLIP), apoptosis inhibitors (IAPs), myeloid cell leukemia sequence 1 (MCL-1), BCL-2, BCL-XL, and survivin play key role in cancer cells resistance to TRAIL. These proteins attenuate cancer cells sensitivity to TRAIL via various functions, importantly through caspase cascade suppression. The c-FLIP avoids from caspase 8 activation by FADD via binding to caspase 8 cleavage of FADD. Moreover, it activates signaling pathways that involved in cancer cells survival and proliferation. Intriguingly, it appears that the down-regulation of intracellular anti-apoptotic proteins, particularly c-FLIP is effectiveness goal for TRAIL-resistant cancers therapy, because their up-regulation in association with poor prognosis has been observed in various types of TRAIL-resistant cancers. In this review, we tried to collect and examine investigations that researchers have been able to sensitize cancer cells to TRAIL through targeting of c-FLIP alone or with other intracellular anti-apoptotic proteins directly or indirectly. It seems that co-treatment of resistant cells by TRAIL with other therapeutic agents with the aim of intracellular anti-apoptotic proteins inhibition is hopeful and attractive approach to overcome various TRAIL-resistant cancers.

MicroRNA-133b inhibits cell proliferation and promotes apoptosis by targeting cullin 4B in esophageal squamous cell carcinoma.

microRNAs (miRs) serve a role as modulators during carcinogenesis. It has been demonstrated that the expression of miR-133b is decreased in a variety of tumor tissues and cell lines and serves a suppressive role in the proliferation and apoptosis of different types of tumor cells. However, its effect on esophageal squamous cell carcinoma (ESCC) cells remains unclear. In the current study, the expression of mature miR-133b was measured using reverse transcription-quantitative polymerase chain reaction and the results indicated that miR-133b was significantly downregulated in ESCC tissues and various ESCC cell lines. The overexpression of miR-133b significantly inhibited the proliferation and promoted the apoptosis of KYSE150 and Eca-109 cells. Furthermore, it was demonstrated that cullin 4B (CUL4B) promotes ESCC cell proliferation and inhibits apoptosis by activating the protein kinase B/glycogen synthase kinase 3β/β-catenin pathway. Taken together, these results demonstrate that miR-133b/CUL4B serves a tumor suppressive role during ESCC progression and may therefore be used as a potential target to treat patients with ESCC.

The TRAIL: TRAILshort Axis in HIV Immunopathology.

Accelerated loss of HIV-infected and uninfected CD4 T cells is a hallmark of HIV infection that leads to severe immunodeficiency, rendering the host susceptible to opportunistic infections and malignancies. Obstacles to eradicating HIV involve the virus's ability to remain in a quiescent state as latent viral reservoirs and manipulate host defenses to benefit viral survival and persistence of the infected reservoir. Several mechanisms cause CD4 T-cell depletion and recent studies demonstrate the role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in this process. Expression of TRAIL and its receptors is upregulated in response to HIV infection. TRAIL interacts with its receptors to activate apoptotic pathways. We recently demonstrated the presence of TRAILshort, a novel splice variant of full-length TRAIL, in the serum of HIV-infected patients. A unique carboxy-terminus allows TRAILshort to bind to death receptors without inducing apoptosis and prevents TRAIL from binding to its receptors, thereby conferring resistance to TRAIL-mediated death. In this review, we describe how the TRAIL: TRAILshort receptor axis modulates apoptosis of different types of immune cells in the context of HIV infection. We also discuss how TRAIL and TRAILshort contribute to the activation of immune cells involved in host defense against HIV and mechanisms that HIV has evolved to manipulate TRAIL for its survival.

Targeting the anion exchanger 2 with specific peptides as a new therapeutic approach in B lymphoid neoplasms.

Regulatory T (Treg) cells can weaken antitumor immune responses, and inhibition of their function appears to be a promising therapeutic approach in cancer patients. Mice with targeted deletion of the gene encoding the Cl−/HCO3− anion exchanger AE2 (also termed SLC4A2), a membrane-bound carrier involved in intracellular pH regulation, showed a progressive decrease in the number of Treg cells. We therefore challenged AE2 as a potential target for tumor therapy, and generated linear peptides designed to bind the third extracellular loop of AE2, which is crucial for its exchange activity. Peptide p17AE2 exhibited optimal interaction ability and indeed promoted apoptosis in mouse and human Treg cells, while activating effector T-cell function. Interestingly, this linear peptide also induced apoptosis in different types of human leukemia, lymphoma and multiple myeloma cell lines and primary malignant samples, while it showed only moderate effects on normal B lymphocytes. Finally, a macrocyclic AE2 targeting peptide exhibiting increased stability in vivo was effective in mice xenografted with B-cell lymphoma. These data suggest that targeting the anion exchanger AE2 with specific peptides may represent an effective therapeutic approach in B-cell malignancies.

Synthesis and evaluation of haloperidol metabolite II prodrugs as anticancer agents.

The use of haloperidol metabolite II (HP-metabolite II) prodrugs is an emerging strategy in the treatment of cancer. HP-metabolite II exhibits antiproliferative properties at micromolar concentrations inducing apoptosis in different types of cancer. Thus, the application of the prodrug approach appears as a useful method leading to much more desirable pharmacokinetic and pharmacodynamic properties. Some studies have shown that the esterification of the hydroxyl group of HP-metabolite II with 4-phenylbutiric acid (4-PBA) or valproic acid enhances the anticancer therapeutic potency. The current progresses in the design, synthesis and evaluation of anticancer activity of HP metabolite II prodrugs will be discussed in this review.

RIP1 has a role in CD40-mediated apoptosis in human follicular lymphoma cells

CD40 is a cell surface receptor which belongs to tumor necrosis factor receptor (TNFR) family members. It transmits signals that regulate diverse cellular responses such as proliferation, differentiation, adhesion molecule expression and apoptosis. Unlike other TNFR family members (TRAIL-R, Fas-R and TNFR1), the CD40 cytoplasmic tail lacks death domain. However, CD40 is capable of inducing apoptosis in different types of cancer cells including lymphoma. The apoptotic effect of CD40 is linked to the involvement of Fas, TRAIL or receptor interacting protein 1 (RIP1) kinase. We have previously shown that CD40 activation has anti-apoptotic or apoptotic effect in follicular lymphoma (FL) cell lines. In this study, we investigated the mechanism by which CD40 mediates apoptosis in a follicular lymphoma cell line, HF4.9. We show here that CD40-induced apoptosis was dependent on caspase-8 activation because caspase-8 specific inhibitor, Z-IETD-FMK completely prevented apoptosis. Therefore, the involvement of TRAIL, Fas and RIP1 in caspase-8 activation was examined. The exogenous TRAIL-induced apoptosis was fully prevented by anti-TRAIL neutralizing antibody. However, the antibody had no effect on CD40-induced apoptosis indicating that CD40 did not induce the expression of endogenous TRAIL in HF4.9 cells. Moreover, the cells were not sensitive to Fas-mediated apoptosis. Interestingly, RIP1 specific inhibitor, necrostatin-1 decreased CD40-induced apoptosis, which showed that RIP1 has a role in caspase-8 activation. In conclusion, the survival or apoptotic effects of CD40-mediated signaling might be related to the differentiation stages of FL cells.

Nanotechnology: Next generation war against cancer

The applications of nanotechnology significantly benefit clinical practices in cancer diagnosis, management and treatment. This article reveals the application of nanotechnology in cancer treatment by using the different strategies for example use of nanoparticles like liposomes, dendrimers, nanoshells, carbon nanotubes, superpara-magnetic, silver/gold nanoparticles and nucleic acid based nanoparticles as well as the nanotechnology for a combination of therapeutic strategies. The advantages and challenges of these particles are also discussed. The use of different green synthesized based gold and silver nanoparticles are important for the apoptosis of different types of cancerous cells. Both size and shapes of these particles are important from the biological point of view and from the material characteristics. In present review we have also highlighted the role of some advanced nano-technologies and bio-therapeutics for diagnose and treatment of this lethal disease. Keywords: Liposomes; Gold nanoparticles; Silver nanoparticles; Super paramagnetic; Anti-tumor; Bio-therapeutics http://dx.doi.org/10.19045/bspab.2017.60034

Dietary supplementation of coenzyme Q10 plus multivitamins to hamper the ROS mediated cisplatin ototoxicity in humans: A pilot study.

Oxidative stress exerts major role in the pathogenesis of side effects of many antineoplastic drugs, including ototoxicity of cisplatin. In particular, increased levels of reactive oxygen species (ROS) represent one of the molecular mechanisms underlying the apoptosis of different types of hearing cells. Antioxidants and ROS scavengers may thus represent potential therapeutic options to prevent platinum-associated ototoxicity.The aim of this preliminary case-control study was to explore the efficacy of a dietary antioxidant supplement, in order to hamper the occurrences of ototoxicity in patients undergoing cisplatin chemotherapy.As results, a significant protection against cochlear toxic damage was demonstrated in patients who took the antioxidant supplement, which furthermore prevented the occurrence of hearing disorders and tinnitus. These clinical evidences were corroborated by the oxidative status of patients. After cisplatin chemotherapy, the plasma derivatives of reactive oxygen metabolites (d-ROMs) content rapidly increased in control patients, but it was maintained in those under dietary supplementation, likely because of a higher anti-ROMs potential. Indeed, an increment in rapid anti-ROMs was detected in supplemented patients, though no differences were highlighted in terms of slow anti-ROMs.In conclusion, in this preliminary report we demonstrated the feasibility of a dietary antioxidant supplementation in order to prevent the cisplatin induced hearing damage.

The Modulation of Apoptotic Pathways by Gammaherpesviruses.

Apoptosis or programmed cell death is a tightly regulated process fundamental for cellular development and elimination of damaged or infected cells during the maintenance of cellular homeostasis. It is also an important cellular defense mechanism against viral invasion. In many instances, abnormal regulation of apoptosis has been associated with a number of diseases, including cancer development. Following infection of host cells, persistent and oncogenic viruses such as the members of the Gammaherpesvirus family employ a number of different mechanisms to avoid the host cell’s “burglar” alarm and to alter the extrinsic and intrinsic apoptotic pathways by either deregulating the expressions of cellular signaling genes or by encoding the viral homologs of cellular genes. In this review, we summarize the recent findings on how gammaherpesviruses inhibit cellular apoptosis via virus-encoded proteins by mediating modification of numerous signal transduction pathways. We also list the key viral anti-apoptotic proteins that could be exploited as effective targets for novel antiviral therapies in order to stimulate apoptosis in different types of cancer cells.

Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice

Programmed cell death (PCD) was demonstrated in neurons and glia in normal brain development, plasticity, and aging, but also in neurodegeneration. (Macro)autophagy, characterized by cytoplasmic vacuolization and activation of lysosomal hydrolases, and apoptosis, typically entailing cell shrinkage, chromatin and nuclear condensation, are the two more common forms of PCD. Their underlying intracellular pathways are partly shared and neurons can die following both modalities, according to the type of death-triggering stimulus. Reelin is an extracellular protein necessary for proper neuronal migration and brain lamination. In the mutant Reeler mouse, its absence causes neuronal mispositioning, with a notable degree of cerebellar hypoplasia that was tentatively related to an increase in PCD. We have carried out an ultrastructural analysis on the occurrence and type of postnatal PCD affecting the cerebellar neurons in normal and Reeler mice. In the forming cerebellar cortex, PCD took the form of apoptosis or autophagy and mainly affected the cerebellar granule cells (CGCs). Densities of apoptotic CGCs were comparable in both mouse strains at P0-P10, while, in mutants, they increased to become significantly higher at P15. In WT mice the density of autophagic neurons did not display statistically significant differences in the time interval examined in this study, whereas it was reduced in Reeler in the P0-P10 interval, but increased at P15. Besides CGCs, the Purkinje neurons also displayed autophagic features in both WT and Reeler mice. Therefore, cerebellar neurons undergo different types of PCD and a Reelin deficiency affects the type and degree of neuronal death during postnatal development of the cerebellum.

Effects of EGF on apoptosis of adipose derived stem cells by regulating miRNA-21

Abstract Objective The miroRNA-21 (MiR-21) plays a vital role in the process of proliferation and apoptosis in different types of cells. EGF could increase the miR-21 primary transcript during adipose derived stem cells (ADSCs) differentiation, however, the underlying molecular mechanism is unclear. We hypothesized that EGF affects the proliferation and apoptosis of ADSCs by regulating miRNA-21. Methods Gain or loss of function strategy was used through transfecting ADSCs with chemically synthesized oligonucleotides complementary to miR-21. Profiles of post-transfection miR-21 caused by EGF were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Apoptosis of ADSCs was evaluated with flow cytometry. The expression levels of miR-21's targeted genes PTEN and FASLwere determined by Western blot assay. Results In response to miR-21 mimics or inhibitor, the apoptosis and cytoactivity of ADSCs changed correspondingly. Change of miR-21 expression level was checked and an inverse correlation of EGF was observed with PTEN and FASL expression in ADSCs. Conclusion Our results indicated that miR-21 could influence EGF expression and furtherly inhibits the apoptosis of ADSCs by downregulating PTEN and FASL. These findings may provide clues toward regulating biological activity of ADSCs with miR-21.

MiR-128 downregulation promotes growth and metastasis of bladder cancer cells and involves VEGF-C upregulation

MicroRNA-128 (miR-128) serves an important role in regulating growth, invasiveness, stem cell-like traits, differentiation and apoptosis of different types of tumor cells. Vascular endothelial growth factor-C (VEGF-C) has been associated with angiogenesis, lymphangiogenesis and regional lymph node metastasis and has previously been reported to have an anti-apoptotic and proliferative role in bladder cancer (BC). To investigate the regulation of miR-128 on VEGF-C expression and their effects on proliferation and metastasis of bladder cancer, T24 and 5637 BC cells were transfected with pre-miR-128, anti-miR-128 and their respective negative control. miR-128 was downregulated in BC tissues and cell lines, while the expression levels of VEGF-C were upregulated. The present results indicated that miR-128 negatively regulated VEGF-C expression in BC T24 and 5637 BC cells. VEGF-C is a direct target of miR-128 in BC cells. Overexpression of miR-128 inhibited cell proliferation, migration and invasion. Knockdown of miR-128 promoted proliferation, migration and invasion in BC cells. Therefore, downregulation mediated malignant progression of BC may be partly attributed to increased VEGF-C expression. Consequently, the findings of the present study provide a molecular basis for the role of miR-128/VEGF-C in the progression of human BC and indicate a novel target for treatment of BC.

The unduced effect of arsenic trioxide in different types of neuroblastoma cell lines

Objective To identify the effect of arsenic trioxide (As2O3) on the differentiation and apoptosis of different types of neuroblastoma(NB) cell lines. Methods The cell lines [SK-N-SH, SK-N-BE2, SH-SY5Y] were induced with different concentrations (0 μmol/L, 1 μmol/L, 3 μmol/L, 5 μmol/L and 7 μmol/L) of arsenic trioxide for 24 h, 48 h, 72 h under the same conditions.The expression of MYCN gene was examined by fluorescence in situ hybridization assay in SK-N-BE2, cell proliferation, cell cycle and cell apoptosis were detected with cell counting kit-8(CCK-8) assay and flow cytometry. Results 5 μmol/L of As2O3 inhibited the expression of MYCN gene in SK-N-BE2; CCK-8 assay indicated that As2O3 inhibited the proliferation of NB cell in a dose-and time-depen-dent manner, the cell proliferation was significantly suppressed compared with the low concentration (1 μmol/L) after treated with As2O3 by 1 μmol/L, 3 μmol/L, 5 μmol/L and 7 μmol/L in 24 h, 48 h and 72 h, SH-SY5Y: 24 h(chisq=9.666 7, P<0.05), 48 h(chisq=9.666 7, P<0.05), 72 h(chisq=9.512 8, P<0.05); SK-N-SH, 24 h(chisq=10.38, P<0.054 6), 48 h(chisq=8.641 0, P<0.05), 72 h(chisq=9.461 5, P<0.05); SK-N-BE2: 24 h(chisq=8.435 9, P<0.05), 48 h(chisq=8.641 0, P<0.05), 72 h(chisq=9.545 5, P<0.05); compared with the control group, the As2O3-treated cells showed increased apoptosis percentage, with the percentage of 1.6%(0 μmol/L), 3.8%(1 μmol/L), 6.1% (3 μmol/L), 10.4%(5 μmol/L), 40.2%(7 μmol/L); the cell cycle was arrested at G2/M phase, which prevented cell division. Conclusions (1)As2O3 play an important role on the NB cells proliferation, apoptosis which were dose-and time-dependent manner.(2)As2O3 can inhibit the expression of MYCN gene.(3)As2O3 also could block NB cell cycle at S and G2/M, and inhibit the cell nucleus replication and the As2O3 had different induced effect between different types of NB cell. Key words: Neuroblastoma; Arsenic trioxide; Cell cycle; MYCN gene

Neuronal cell death: an overview of its different forms in central and peripheral neurons.

The discovery of neuronal cell death dates back to the nineteenth century. Nowadays, after a very long period of conceptual difficulties, the notion that cell death is a phenomenon occurring during the entire life course of the nervous system, from neurogenesis to adulthood and senescence, is fully established. The dichotomy between apoptosis, as the prototype of programmed cell death (PCD ), and necrosis, as the prototype of death caused by an external insult, must be carefully reconsidered, as different types of PCD: apoptosis, autophagy, pyroptosis, and oncosis have all been demonstrated in neurons (and glia ). These modes of PCD may be triggered by different stimuli, but share some intracellular pathways such that different types of cell death may affect the same population of neurons according to several intrinsic and extrinsic factors. Therefore, a mixed morphology is often observed also depending on degrees of differentiation, activity, and injury. The main histological and ultrastructural features of the different types of cell death in neurons are described and related to the cellular pathways that are specifically activated in any of these types of PCD.

EOLA1 protects lipopolysaccharide induced IL-6 production and apoptosis by regulation of MT2A in human umbilical vein endothelial cells.

Endothelial cell (EC) injury or dysfunction is believed to be mediated at least in part by lipopolysaccharide (LPS). Recent studies have shown that LPS induces apoptosis in different types of endothelium, including HUVEC. Previously we used EOLA1 (endothelial-overexpressed LPS-associated factor 1) cDNA as a bait and performed a yeast two-hybrid screening of a human liver cDNA library and identified metallothionein 2a (MT2a) as the associated protein. EOLA1 protein plays a role as a signal transduction factor. But the mechanism of EOLA1 mediated the protection of cell production of IL-6 and apopotosis in HUVEC is not known. MT2a is expressed in many kinds of cells and plays a role in inflammation. In this study, we demonstrated that LPS could induce EOLA1 expression in time-dependent and apparently contributed to the inhibition of IL-6 production and apoptosis induced by LPS treatment. We also found that deletion of EOLA1 promoted IL-6 production and apoptosis in the treatment of LPS in HUVEC. Furthermore, we demonstrated that MT2a was activated by LPS, and played a key role in LPS-induced IL-6 expression in HUVEC. We further provided the evidence that EOLA1 functioned as a negative regulator for LPS response by regulation of MT2a. These findings suggest that EOLA1 may have an important regulatory role during EC inflammatory responses.

Effect of yessotoxin on cytosolic calcium levels in human hepatocellular carcinoma cells in vitro

Yessotoxin (YTX) and its analogs are a type of marine toxins found in marine environments in numerous coastal countries. These toxins tend to accumulate in filter-feeding molluscs and may threaten the shellfish industry and public health. Several previous studies indicated that YTX may induce apoptosis in different types of cell lines, although the exact underlying mechanisms have not yet been elucidated. The aim of this study was to mainly focus on the effect of YTX on cytosolic Ca2+ levels in human hepatocellular carcinoma cells. In order to investigate the exact mechanism of YTX-evoked Ca2+ increase, laser scanning confocal microscopy was used, with the addition of the chelator ethylene glycol tetraacetic acid (EGTA) and nifedipine, an L-type Ca2+ channel blocker, to the reaction system. The results demonstrated that YTX caused cytosolic Ca2+ level increase in Bel7402 cells and the YTX-evoked Ca2+ increase was successfully blocked by EGTA and nifedipine. Therefore, our results indicated that YTX may cause apoptosis via inducing Ca2+ entry in Bel7402 cells.

Prosapogenin A induces apoptosis in human cancer cells in vitro via inhibition of the STAT3 signaling pathway and glycolysis

Signal transducer and activator of transcription 3 (STAT3) is considered to be an oncogene. Blocking STAT3 signaling may induce growth arrest and apoptosis in different types of tumors. Cancer cells utilize the glycolytic pathway to maintain cell growth even when adequate oxygen is present. Glycolysis inhibition is a potential therapeutic modality. In the present study, the effects of Prosapogenin A (PSA) from the traditional Chinese medicine, Veratrum, on apoptosis, the STAT3 signaling pathway and glycometabolism in cancer cells were investigated. The results indicated that PSA induced growth inhibition and apoptosis in HeLa, HepG2 and MCF-7 cells. PSA inhibited the STAT3 signaling pathway and modulated the expression of glycometabolism-related genes. The results indicate that the inhibition of the STAT3 signaling and glycometabolism pathways contributes to the PSA-mediated apoptosis of HeLa, HepG2 and MCF-7 cells.