Apoptotic Signal Transduction Pathways Research Articles

Potential Biochemical Pesticide-Synthesis of Neofuranocoumarin and Inhibition the Proliferation of Spodoptera frugiperda Cells through Activating the Mitochondrial Pathway.

Furanocoumarins, the secondary metabolites of plants, are considered to be natural insecticides and fungicides because they prevent the invasion of plant pathogenic microorganisms and the predation of herbivorous insects. In this study, novel 2-arylfuranocoumarin derivatives were designed to synthesize by condensation, esterification, bromination, and Wittig reaction. The results showed an excellent photosensitive activity of 2-thiophenylfuranocoumarin (I34). Cell Counting Kit-8 detected that I34 could inhibit the proliferation of Spodoptera frugiperda (Sf9) cells in a time- and concentration-dependent manner under ultraviolet A (UV-A) light for 3 min. The inverted microscope revealed that cells treated with I34 swelled, the membrane was ruptured, and apoptotic bodies appeared. The flow cytometry detected that I34 could induce apoptosis of Sf9 cells, increase the level of intracellular reactive oxygen species (ROS), decrease the mitochondrial membrane potential, and block cell cycle arrest in the G2/M phase. Transmission electron microscopy detected cell mitochondrial cristae damage, matrix degradation, and mitochondrial vacuolation. Further enzyme activity detection revealed that the enzyme activities of apoptosis-related proteins caspase-3 and caspase-9 increased significantly (p < 0.05). Finally, Western blotting analysis detected that the phosphorylation level of Akt and Bad and the expression of the apoptosis inhibitor protein Bcl-XL were inhibited, cleaved-PARP and P53 were increased, and cytochrome C was released from the mitochondria into the cytoplasm. Moreover, under UV-A irradiation, I34 promoted the increase in ROS in Sf9 cells, activated the mitochondrial apoptotic signal transduction pathway, and finally, inhibited cell proliferation. Thus, novel furanocoumarins exhibit a potential application prospect as a biochemical pesticide.

Close link between breast cancer &amp; apoptosis

The mammary gland represents an unique model system to allow investigation of factors that underpin biological initiation of apoptotic processes and related signal transduction pathways. One advantage is that the mammary gland, unlike most other organs, has the capacity to go through many cycles of growth, differentiation and anatomical structural development. Indeed, the mammary gland has evolved highly efficient processes (that straddle both lactation and post-lactational phases) which regulate the balance between cell death and proliferation. This paper will discuss the molecular and cellular aspects of apoptosis in the mammary gland with a particular emphasis on the role of apoptosis in breast cancer development.

Marine biome-derived secondary metabolites, a class of promising antineoplastic agents: A systematic review on their classification, mechanism of action and future perspectives

Cancer is one of the most deadly diseases on the planet. Over the past decades, numerous antineoplastic compounds have been discovered from natural resources such as medicinal plants and marine species as part of multiple drug discovery initiatives. Notably, several marine flora (e.g. Ascophyllum nodosum, Sargassum thunbergii) have been identified as a rich source for novel cytotoxic compounds of different chemical forms. Despite the availability of enormous chemically enhanced new resources, the anticancer potential of marine flora and fauna has received little attention. Interestingly, numerous marine-derived secondary metabolites (e.g., Cytarabine, Trabectedin) have exhibited anticancer effects in preclinical cancer models. Most of the anticancer drugs obtained from marine sources stimulated apoptotic signal transduction pathways in cancer cells, such as the intrinsic and extrinsic pathways. This review highlights the sources of different cytotoxic secondary metabolites obtained from marine bacteria, algae, fungi, invertebrates, and vertebrates. Furthermore, this review provides a comprehensive overview of the utilisation of numerous marine-derived cytotoxic compounds as anticancer drugs, as well as their modes of action (e.g., molecular target). Finally, it also discusses the future prospects of marine-derived drug developments and their constraints.

Ultrahigh Pressure Facilitates the Acylation of Malvidin and Chlorogenic Acid to Increase the Stability and Protective Effect of Malvidin Derivatives on H2O2-Induced ARPE-19 Cells.

We explored the effects of ultrahigh-pressure technology and chlorogenic acid on the color stability and structure-activity relationship of malvidin (MV). Experimental conditions were optimized through single-factor experiments and response surface analysis at a pressure of 300 MPa, mass ratio of MV to chlorogenic acid of 1:3.64 (w/w), and time of 5 min. Compared with MV, MV derivatives showed higher stability and in vitro antioxidant activity. X-ray diffraction analysis, UV-vis spectroscopy, Fourier transform infrared spectroscopy, high-performance liquid chromatography, and mass spectrometry were conducted to determine the structures of MV derivatives for the first time. Ultrahigh pressure facilitated acylation of chlorogenic acid and MV and produced four new MV derivatives. Analysis of the effect of malvidin-3-O-6-(acrylic acid-(2-hydroxy, 4-carboxy-cyclohexanol) ester)-guaiacol (Mv3ACEC) on ARPE-19 cells exposed to H2O2 by RNA transcriptome sequencing showed that Mv3ACEC simultaneously inhibited various inflammatory and apoptotic signal transduction pathways, exerted a synergistic effect, and partly inhibited cell apoptosis through the MAPK signaling pathway. Therefore, the results show that ultrahigh pressure will cause acylation of chlorogenic acid and MV to produce four new MV derivatives, and MV derivatives protect ARPE-19 cells from H2O2-induced oxidative stress.

Study of the Active Components and Molecular Mechanism of Tripterygium wilfordii in the Treatment of Diabetic Nephropathy.

We aimed to explore the active ingredients and molecular mechanism of Tripterygium wilfordii (TW) in the treatment of diabetic nephropathy (DN) through network pharmacology and molecular biology. First, the active ingredients and potential targets of TW were obtained through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and related literature materials, and Cytoscape 3.7.2 software was used to construct the active ingredient-target network diagram of TW. Second, the target set of DN was obtained through the disease database, and the potential targets of TW in the treatment of DN were screened through a Venn diagram. A protein interaction network diagram (PPI) was constructed with the help of the String platform and Cytoscape 3.7.2. Third, the ClueGO plug-in tool was used to enrich the GO biological process and the KEGG metabolic pathway. Finally, molecular docking experiments and cell pathway analyses were performed. As a result, a total of 52 active ingredients of TW were screened, and 141 predicted targets and 49 target genes related to DN were identified. The biological process of GO is mediated mainly through the regulation of oxygen metabolism, endothelial cell proliferation, acute inflammation, apoptotic signal transduction pathway, fibroblast proliferation, positive regulation of cyclase activity, adipocyte differentiation and other biological processes. KEGG enrichment analysis showed that the main pathways involved were AGE-RAGE, vascular endothelial growth factor, HIF-1, IL-17, relaxin signalling pathway, TNF, Fc epsilon RI, insulin resistance and other signaling pathways. It can be concluded that TW may treat DN by reducing inflammation, reducing antioxidative stress, regulating immunity, improving vascular disease, reducing insulin resistance, delaying renal fibrosis, repairing podocytes, and reducing cell apoptosis, among others, with multicomponent, multitarget and multisystem characteristics.

Research progress on cell signal transduction pathway mediating age-related cataract

Age-related cataract is a blinding eye disease that affects vision due to opacity of intraocular lens, ranking first in the world. Under oxidative stress, the activation of apoptosis related signal transduction pathways in lens epithelial cells is the main mechanism mediating age-related cataract. There are many related signaling pathways for apoptosis, and it is a complex network system. The purpose of this literature review is to summarize different apoptotic cell signal transduction pathways that mediate age-related cataract, laying the foundation for further researching.

Neuroprotective effects of exogenous erythropoietin in Wistar rats by downregulating apoptotic factors to attenuate N-methyl-D-aspartate-mediated retinal ganglion cells death.

The aim of this study was to investigate whether exogenous erythropoietin (EPO) administration attenuates N-methyl-D-aspartate (NMDA)-mediated excitotoxic retinal damage in Wistar rats. The survival rate of retinal ganglion cells (RGCs) were investigated by flat mount analysis and flow cytometry. A total of 125 male Wistar rats were randomly assigned to five groups: negative control, NMDA80 (i.e., 80 nmoles NMDA intravitreally injected), NMDA80 + 10ng EPO, NMDA80 + 50ng EPO, and NMDA80 + 250ng EPO. The NMDA80 + 50ng EPO treatment group was used to evaluate various administrated points (pre-/co-/post- administration of NMDA80). Meanwhile, the transferase dUTP Nick-End Labeling (TUNEL) assay of RGCs, the inner plexiform layer (IPL) thickness and the apoptotic signal transduction pathways of μ-calpain, Bax, and caspase 9 were assessed simultaneously using an immunohistochemical method (IHC). When EPO was co-administered with NMDA80, attenuated cell death occurred through the downregulation of the apoptotic indicators: μ-calpain was activated first (peak at ~18hrs), followed by Bax and caspase 9 (peak at ~40hrs). Furthermore, the images of retinal cross sections have clearly demonstrated that thickness of the inner plexiform layer (IPL) was significantly recovered at 40 hours after receiving intravitreal injection with NMDA80 and 50ng EPO. Exogenous EPO may protect RGCs and bipolar cell axon terminals in IPL by downregulating apoptotic factors to attenuate NMDA-mediated excitotoxic retinal damage.

Mechanistic approach of the inhibitory effect of chrysin on inflammatory and apoptotic events implicated in radiation-induced premature ovarian failure: Emphasis on TGF-β/MAPKs signaling pathway

Radiotherapy is one of the most relevant treatment modalities for various types of malignancies. However, it causes premature ovarian failure (POF) and subsequent infertility in women of reproductive age; hence urging the development of effective radioprotective agents. Chrysin, a natural flavone, possesses several pharmacological activities owing to its antioxidant, anti-inflammatory and anti-apoptotic properties. Therefore, the aim of this study was to investigate the efficacy of chrysin in limiting γ-radiation-mediated POF and to elucidate the underlying molecular mechanisms. Immature female Sprague-Dawley rats were subjected to a single dose of γ-radiation (3.2 Gy) and/or treated with chrysin (50 mg/kg) once daily for two weeks before and three days post-irradiation. Chrysin prevented the radiation-induced ovarian dysfunction by restoring estradiol levels, preserving the normal ovarian histoarchitecture and combating the follicular loss. Eelectron microscopic analysis showed that the disruption of ultrastructure components due to radiation exposure was hampered by chrysin administration. Mechanistically, chrsyin was able to reduce the levels of the inflammatory markers NF-κB, TNF-α, iNOS and COX-2 in radiation-induced ovarian damage. Chrysin also exhibited potent anti-apoptotic effects against radiation-induced cell death by downregulating the expression of cytochrome c and caspase 3. Radiation obviously induced upregulation of TGF-β protein with subsequent phospholyration and hence activation of downstream mitogen-activated protein kinases (MAPKs); p38 and JNK. Notably, administration of chrysin successfully counteracted these effects. These findings revealed that chrysin may be beneficial in ameliorating radiation-induced POF, predominantly via downregulating TGF-β/MAPK signaling pathways leading subsequently to hindering inflammatory and apoptotic signal transduction pathways implicated in POF.

The role of Pim-2 in apoptotic signal transduction pathway of hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors. The objective was to investigate the role of serine/threonine kinase Pim-2 in apoptosis signal transduction pathway, because there is little study about its contribution to apoptosis in hepatocellular carcinoma.Methods: The Pim-2 gene and protein expression were examined by qRT-PCR, Western blot and immunohistochemical stain in HCC tissues and normal liver tissues. The plasmid pCI-neo-Pim2 was transfected into human hepatoma cell line SMMC7721 by lipofectamine. Total RNAs were extracted from SMMC7721 cell in logarithm growth phase. The mRNA expression of Pim-2, Akt-1 (protein kinase B), 4E-BP1 (translation repressor of mammalian target of rapamycln), SOCS-1 (repressor of cytokine), Bad（Bcl-xL/Bcl-2 associated death promoter, Bim（Bc1-2 interacting mediator of cell death）and Puma (p53 upregulated modulator of apoptosis) were identified by qRT-PCR. The cell cycle of post-transfected SMMC7721 cells was assessed by flow cytometry.Results: Pim-2 expression was enhanced in HCC. In post-transfected SMMC7721 cells, Pim-2 mRNA expression was up-regulated, level of Bad mRNA was attenuated, furthermore, the transcription level of Akt-1, SOCS-1, 4E-BP1, Bim and Puma gene wasn’t variety. Up-graulated Pim-2 can’t cause distinct change of cell cycle or apoptosis in hepatoma cell.Conclusions: The serine/threonine kinase Pim-2 plays an import role in the development of HCC, Pim-2 dependent maintenance of cell size and survival correlated with its ability to maintain down-regulated expression of the BH3 protein Bad. Pim-2 is not a trigger in cell-autonomous survival or inhibiting apoptosis in hepatocellular carcinoma. Pim-2 is a redundancy pathway of survival signaling.

Abstract 3504: Arginylated BiP/oxidized DJ-1 complex mediates crosstalk between the endoplasmic reticulum and mitochondria

Abstract In cell death induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), although much is known about signal pathways involving external signals through cell surface receptors or internal signals through mitochondrial dysfunction, little is known about signal pathways activated by endoplasmic reticulum (ER) stress during TRAIL treatment. Here, we report that TRAIL-induced caspase activation is a prerequisite for TRAIL-induced ER stress response. During TRAIL treatment, ER chaperon BiP dissociates from ER stress sensors such as PERK and IRE1α and the activation of the PERK-eIF2α-ATF4-CHOP apoptotic signal transduction pathway occurs. Meanwhile ER-stress induces BiP release to the cytosol and ATE1-encoded Arg-tRNA transferase arginylates BiP. TRAIL also induces loss of ΔΨm and redox sensor DJ-1 detects mitochondria-derived ROS. Oxidized DJ-1 binds to arginylated BiP (R-BiP) in the cytosol. DJ-1 binding activity was abrogated in C106A and C53A but not C46A mutant. R-BiP/oxidized DJ-1 complex may mediate crosstalk between the ER and mitochondria. Key words: TRAIL; endoplasmic reticulum; apoptosis; colorectal cancer Citation Format: Dae-Hee Lee. Arginylated BiP/oxidized DJ-1 complex mediates crosstalk between the endoplasmic reticulum and mitochondria. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3504.

Turkish propolis supresses MCF-7 cell death induced by homocysteine.

Elevated plasma homocysteine (Hcy) level is a most important risk factor for various vascular diseases including coronary, cerebral and peripheral arterial and venous thrombosis. Propolis is produced by honeybee from various oils, pollens and wax materials. Therefore, it has various biological properties including antioxidant, antitumor and antimicrobial activities. This study investigated the effects of propolis and Hcy on apoptosis in cancer cells. According to our findings, Hcy induced apoptosis in human breast adenocarcinoma (MCF-7) cells by regulating numerous genes and proteins involved in the apoptotic signal transduction pathway. In contrast, treatment with propolis inhibited caspase- 3 and -9 induced by Hcy in MCF-7 cells. It can be concluded that Hcy may augment the activity of anticancer agents that induce excessive reactive oxygen species (ROS) generation and apoptosis in their target cells. In contrast to the previous studies herein we found that propolis in low doses protected cancer cells inhibiting cellular apoptosis mediated by intracellular ROS-dependent mitochondrial pathway.

3-MCPD 1-Palmitate Induced Tubular Cell Apoptosis In Vivo via JNK/p53 Pathways.

Fatty acid esters of 3-chloro-1, 2-propanediol (3-MCPD esters) are a group of processing induced food contaminants with nephrotoxicity but the molecular mechanism(s) remains unclear. This study investigated whether and how the JNK/p53 pathway may play a role in the nephrotoxic effect of 3-MCPD esters using 3-MCPD 1-palmitate (MPE) as a probe compound in Sprague Dawley rats. Microarray analysis of the kidney from the Sprague Dawley rats treated with MPE, using Gene Ontology categories and KEGG pathways, revealed that MPE altered mRNA expressions of the genes involved in the mitogen-activated protein kinase (JNK and ERK), p53, and apoptotic signal transduction pathways. The changes in the mRNA expressions were confirmed by qRT-PCR and Western blot analyses and were consistent with the induction of tubular cell apoptosis as determined by histopathological, TUNEL, and immunohistochemistry analyses in the kidneys of the Sprague Dawley rats. Additionally, p53 knockout attenuated the apoptosis, and the apoptosis-related protein bax expression and cleaved caspase-3 activation induced by MPE in the p53 knockout C57BL/6 mice, whereas JNK inhibitor SP600125 but not ERK inhibitor U0126 inhibited MPE-induced apoptosis, supporting the conclusion that JNK/p53 might play a critical role in the tubular cell apoptosis induced by MPE and other 3-MCPD fatty acid esters.

Anticancer Effects of Sinulariolide-Conjugated Hyaluronan Nanoparticles on Lung Adenocarcinoma Cells.

Lung cancer is one of the most clinically challenging malignant diseases worldwide. Sinulariolide (SNL), extracted from the farmed coral species Sinularia flexibilis, has been used for suppressing malignant cells. For developing anticancer therapeutic agents, we aimed to find an alternative for non-small cell lung cancer treatment by using SNL as the target drug. We investigated the SNL bioactivity on A549 lung cancer cells by conjugating SNL with hyaluronan nanoparticles to form HA/SNL aggregates by using a high-voltage electrostatic field system. SNL was toxic on A549 cells with an IC50 of 75 µg/mL. The anticancer effects of HA/SNL aggregates were assessed through cell viability assay, apoptosis assays, cell cycle analyses, and western blotting. The size of HA/SNL aggregates was approximately 33–77 nm in diameter with a thin continuous layer after aggregating numerous HA nanoparticles. Flow cytometric analysis revealed that the HA/SNL aggregate-induced apoptosis was more effective at a lower SNL dose of 25 µg/mL than pure SNL. Western blotting indicated that caspases-3, -8, and -9 and Bcl-xL and Bax played crucial roles in the apoptotic signal transduction pathway. In summary, HA/SNL aggregates exerted stronger anticancer effects on A549 cells than did pure SNL via mitochondria-related pathways.

TRAIL-Induced Caspase Activation Is a Prerequisite for Activation of the Endoplasmic Reticulum Stress-Induced Signal Transduction Pathways.

It is well known that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis can be initially triggered by surface death receptors (the extrinsic pathway) and subsequently amplified through mitochondrial dysfunction (the intrinsic pathway). However, little is known about signaling pathways activated by the TRAIL-induced endoplasmic reticulum (ER) stress response. In this study, we report that TRAIL-induced apoptosis is associated with the endoplasmic reticulum (ER) stress response. Human colorectal carcinoma HCT116 cells were treated with TRAIL and the ER stress-induced signal transduction pathway was investigated. During TRAIL treatment, expression of ER stress marker genes, in particular the BiP (binding immunoglobulin protein) gene, was increased and activation of the PERK (PKR-like ER kinase)-eIF2α (eukaryotic initiation factor 2α)-ATF4 (activating transcription factor 4)-CHOP (CCAAT-enhancer-binding protein homologous protein) apoptotic signal transduction pathway occurred. Experimental data from use of a siRNA (small interfering RNA) technique, caspase inhibitor, and caspase-3-deficient cell line revealed that TRAIL-induced caspase activation is a prerequisite for the TRAIL-induced ER stress response. TRAIL-induced ER stress was triggered by caspase-8-mediated cleavage of BAP31 (B cell receptor-associated protein 31). The involvement of the proapoptotic PERK-CHOP pathway in TRAIL-induced apoptosis was verified by using a PERK knockout (PERK(-/-)) mouse embryo fibroblast (MEF) cell line and a CHOP(-/-) MEF cell line. These results suggest that TRAIL-induced the activation of ER stress response plays a role in TRAIL-induced apoptotic death.

Soluble Receptor for Advanced Glycation End Product Ameliorates Chronic Intermittent Hypoxia Induced Renal Injury, Inflammation, and Apoptosis via P38/JNK Signaling Pathways.

Obstructive sleep apnea (OSA) associated chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH) triggered tissue damage. Receptor for advanced glycation end product (RAGE) and its ligand high mobility group box 1 (HMGB1) are expressed on renal cells and mediate inflammatory responses in OSA-related diseases. To determine their roles in CIH-induced renal injury, soluble RAGE (sRAGE), the RAGE neutralizing antibody, was intravenously administered in a CIH model. We also evaluated the effect of sRAGE on inflammation and apoptosis. Rats were divided into four groups: (1) normal air (NA), (2) CIH, (3) CIH+sRAGE, and (4) NA+sRAGE. Our results showed that CIH accelerated renal histological injury and upregulated RAGE-HMGB1 levels involving inflammatory (NF-κB, TNF-α, and IL-6), apoptotic (Bcl-2/Bax), and mitogen-activated protein kinases (phosphorylation of P38, ERK, and JNK) signal transduction pathways, which were abolished by sRAGE but p-ERK. Furthermore, sRAGE ameliorated renal dysfunction by attenuating tubular endothelial apoptosis determined by immunofluorescence staining of CD31 and TUNEL. These findings suggested that RAGE-HMGB1 activated chronic inflammatory transduction cascades that contributed to the pathogenesis of the CIH-induced renal injury. Inhibition of RAGE ligand interaction by sRAGE provided a therapeutic potential for CIH-induced renal injury, inflammation, and apoptosis through P38 and JNK pathways.

Induction of Apoptosis in MCF-7 Cells via Oxidative Stress Generation, Mitochondria-Dependent and Caspase-Independent Pathway by Ethyl Acetate Extract of Dillenia suffruticosa and Its Chemical Profile.

Dillenia suffruticosa, which is locally known as Simpoh air, has been traditionally used to treat cancerous growth. The ethyl acetate extract of D. suffruticosa (EADs) has been shown to induce apoptosis in MCF-7 breast cancer cells in our previous study. The present study aimed to elucidate the molecular mechanisms involved in EADs-induced apoptosis and to identify the major compounds in the extract. EADs was found to promote oxidative stress in MCF-7 cells that led to cell death because the pre-treatment with antioxidants α-tocopherol and ascorbic acid significantly reduced the cytotoxicity of the extract (P<0.05). DCFH-DA assay revealed that treatment with EADs attenuated the generation of intracellular ROS. Apoptosis induced by EADs was not inhibited by the use of caspase-inhibitor Z-VAD-FMK, suggesting that the cell death is caspase-independent. The use of JC-1 dye reflected that EADs caused disruption in the mitochondrial membrane potential. The related molecular pathways involved in EADs-induced apoptosis were determined by GeXP multiplex system and Western blot analysis. EADs is postulated to induce cell cycle arrest that is p53- and p21-dependent based on the upregulated expression of p53 and p21 (P<0.05). The expression of Bax was upregulated with downregulation of Bcl-2 following treatment with EADs. The elevated Bax/Bcl-2 ratio and the depolarization of mitochondrial membrane potential suggest that EADs-induced apoptosis is mitochondria-dependent. The expression of oxidative stress-related AKT, p-AKT, ERK, and p-ERK was downregulated with upregulation of JNK and p-JNK. The data indicate that induction of oxidative-stress related apoptosis by EADs was mediated by inhibition of AKT and ERK, and activation of JNK. The isolation of compounds in EADs was carried out using column chromatography and elucidated using the nuclear resonance magnetic analysis producing a total of six compounds including 3-epimaslinic acid, kaempferol, kaempferide, protocatechuic acid, gallic acid and β-sitosterol-3-O-β-D-glucopyranoside. The cytotoxicity of the isolated compounds was determined using MTT assay. Gallic acid was found to be most cytotoxic against MCF-7 cell line compared to others, with IC50 of 36 ± 1.7 μg/mL (P<0.05). In summary, EADs generated oxidative stress, induced cell cycle arrest and apoptosis in MCF-7 cells by regulating numerous genes and proteins that are involved in the apoptotic signal transduction pathway. Therefore, EADs has the potential to be developed as an anti-cancer agent against breast cancer.

The role of nitric oxide synthase signaling pathway in the Zn-induced cellular responses in MCF-7 cells

Trace amount zinc plays key roles in biological systems, while in excessive amount it causes toxic effects. Evidence shows that there exists a crosstalk between NO and Zn apoptotic signal transduction pathway. However, the potential mechanism of Zn-induced cellular responses through the NOS signaling pathway has not been determined yet. In this research, trace amount ZnCl2 (1nM) could induce the NO production, however it appears that this influence does not extend to genetic level in MCF-7 cells. Whereas, excess ZnCl2 (100μM, 1mM) could lead to a decreased NO production first with the release of Ca2+, and then induce the NO production with the transcriptional and translational activation of NOSs. The ROS generation was also induced by excess ZnCl2, causing the elF2α phosphorylation. The alleviation effect of N-acetyl-l-cysteine or l-arginine on the Zn-induced ROS generation and apoptosis suggested that Zn-induced apoptosis was associated with the NOS-mediated oxidative stress.

Inflammatory mediators in necrotizing enterocolitis

Necrotizing enterocolitis （ NEC） is a common neonatal emergency and severe case. It is a se-rious threat to the neonates. Apoptotic signal transduction pathway can be classified into extrinsic apoptotic path-way,the intrinsic apoptosis pathway and endoplasmic reticulum pathways. Inflammatory mediators can induce apoptosis in intestinal epithelial cells through the three ways mentioned above. It plays an important role in the development of NEC,which might be important for the pathogenesis of NEC. Key words: Necrotizing enterocolitis; Apoptosis; Inflammatory mediator

Protective Effects of Korean Red Ginseng on Radiation-Induced Oral Mucositis in a Preclinical Rat Model

Numerous studies' attempts to improve radiation-induced oral mucositis have not produced a qualified treatment yet. Our aim was to investigate the effectiveness of Korean red ginseng (KRG) on radiation-induced damage in an in vivo rat model. After 20 Gy of irradiation, rats were divided randomly into the following 4 groups: control, KRG only, radiotherapy (RT) only, and RT + KRG group. The rats were monitored in terms of survival rate, activity, mucositis grade, oral intake, and body weight. The tongue, buccal mucosa, and submandibular gland (SMG) were harvested, and the weight of the SMG was analyzed. The samples then underwent hematoxylin and eosin, TUNEL, and immunohistochemical staining. Radiation-induced severe oral mucositis and SMG injury led to poor oral intake and delayed healing, resulting in the death of some rats. We found that survival rate, oral intake, and body weight increased. Moreover, rats treated with KRG showed less severe mucositis and decreased histologic changes of the oral mucosa and SMG. Furthermore, we showed that the protective effects of KRG were caused by inhibition of the apoptotic signal transduction pathway linked to caspase-3. In conclusion, KRG protects the oral mucosa and SMG from radiation-induced damage by inhibiting caspase-mediated apoptosis in rats.

Cell death in intervertebral disc degeneration

Degeneration of intervertebral disc (IVD) is mainly a chronic process of excessive destruction of the extracellular matrix (ECM), and also is thought to be the primary cause of low back pain. Presently, however, the underlying mechanism of IVD degeneration is still not elucidated. Cellular loss from cell death has been believed to contribute to the degradation of ECM and plays an important role in the process of IVD degeneration, but the mechanisms of cell death in degenerated IVD remain unclear. Apoptosis, a very important type of IVD cell death, has been considered to play a crucial role in the process of degeneration. Autophagy, a non-apoptosis death type of programmed cell death, has been considered extensively involved in many pathological and physiological processes, including the degenerative diseases. Thus, the research on cell death in IVD degeneration has become a new focus recently. In this review, by analyzing the available literature pertaining to cell death in IVD and discussing the inducing factors of IVD degeneration, NP cells and ECM in IVD degeneration, apoptotic signal transduction pathways involved in IVD cell death, the relationship of cell death with IVD degeneration and potential therapeutic strategy for IVD degeneration by regulating cell death, we conclude that different stimuli induce cell death in IVD via various signal transduction pathways, and that cell death may play a key role in the degenerative process of IVD. Regulation of cell death could be a potential and attractive therapeutic strategy for IVD degeneration.