LY294002 potentiates the anti-cancer effect of oxaliplatin for gastric cancer via death receptor pathway

AIM:To examine the effects of combined treatment of oxaliplatin and phosphatidylinositol 3'-kinase inhibitor,2-(4-morpholinyl) -8-phenyl-4H-1-benzopyran-4-one(LY294002) for gastric cancer. METHODS:Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide assay.Apoptotic cells were detected by flow cytometric analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay.Western blotting and immuno-precipitation were used to examine protein expression and recruitment,respectively.Nuclear factorκB(NFκB) binding activities were investigated using electrophoretic mobility shift assay.Nude mice were used to investigate tumor growth. RESULTS:Treatment with combined oxaliplatin and LY294002 resulted in increased cell growth inhibi-tion and cell apoptosis in vitro,and increased tumor growth inhibition and cell death in the tumor mass in vivo.In MKN45 and AGS cells,oxaliplatin treatment promoted both protein kinase B(Akt) and NFκB activation,while pretreatment with LY294002 significantly attenuated oxaliplatin-induced Akt activity and NFκB binding.LY294002 promoted oxaliplatin-induced Fas ligand(FasL) expression,Fas-associated death domain protein recruitment,caspase-8,Bid,and caspase-3 activation,and the short form of cellular caspase-8/FLICEinhibitory protein(c-FLIPS) inhibition.In vivo,LY294002 inhibited oxaliplatin-induced activation of Akt and NFκB,and increased oxaliplatin-induced expression of FasL,inhibition of c-FLIPS,and activation of caspase-8,Bid,and caspase-3. CONCLUSION:Combination of oxaliplatin and LY294002 was therapeutically promising for gastric cancer treatment.The enhanced sensitivity of the combined treatment was associated with the activation of the death receptor pathway.

Comparison of Entanglement Sudden Death and Revival Between Independent and Coherent Double Pathways

Starting from famous Schrodinger equation within the framework of semi-c/assicai theory of light-matter interaction, we firstly obtain the anaiytical non-resonant solutions of the driven bipartite system＇s entanglement dynamics in independent and coherent double pathways. Numerical simulations show that under non-resonant condition, entanglement sudden death and revival between these transition patterns behave quite differently, indicating the utmost importance of transition pathways＇ interference. Furthermore, the laser pulse＇s area and detuning exert significant but quite distinct influences on the entanglement dynamics. Our analyses are helpful in manipulating entanglement in current experimental technology.

Molecular and metabolic landscape of adenosine triphosphateinduced cell death in cardiovascular disease

The maintenance of intracellular and extracellular adenosine triphosphate(ATP)levels plays a pivotal role in cardiac function.In recent years,burgeoning at-tention has been directed towards ATP-induced cell death(AICD),revealing it as a distinct cellular demise pathway triggered by heightened extracellular ATP concentrations,distinguishing it from other forms of cell death such as apoptosis and necrosis.AICD is increasingly acknowledged as a critical mechanism me-diating the pathogenesis and progression of various cardiovascular maladies,encompassing myocardial ischemia-reperfusion injury,sepsis-induced cardiomy-opathy,hypertrophic cardiomyopathy,arrhythmia,and diabetic cardiomyopathy.Consequently,a comprehensive understanding of the molecular and metabolic underpinnings of AICD in cardiac tissue holds promise for the prevention and amelioration of cardiovascular diseases.This review first elucidates the vital physiological roles of ATP in the cardiovascular system,subsequently delving into the intricate molecular mechanisms and metabolic signatures governing AICD.Furthermore,it addresses the potential therapeutic targets implicated in mitigating AICD for treating cardiovascular diseases,while also delineating the current constraints and future avenues for these innovative therapeutic targets,thereby furnishing novel insights and strategies for the prevention and management of cardiovascular disorders.

Pyroptosis,ferroptosis,and autophagy in spinal cord injury:regulatory mechanisms and therapeutic targets

Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.

Diabetes mellitus and glymphatic dysfunction:Roles for oxidative stress,mitochondria,circadian rhythm,artificial intelligence,and imaging

Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals and prevent the onset of chronic disability and ultimately death.Underlying cellular mechanisms for the onset and development of DM are multi-factorial in origin and involve pathways associated with the production of reactive oxygen species and the generation of oxidative stress as well as the dysfunction of mitochondrial cellular organelles,programmed cell death,and circadian rhythm impairments.These pathways can ultimately involve failure in the glymphatic pathway of the brain that is linked to circadian rhythms disorders during the loss of metabolic homeostasis.New studies incorporate a number of promising techniques to examine patients with metabolic disorders that can include machine learning and artificial intelligence pathways to potentially predict the onset of metabolic dysfunction.

Gambogic acid induces apoptosis and inhibits colorectal tumor growth via mitochondrial pathways

AIM: To investigate the effect of gambogic acid(GA) on apoptosis in the HT-29 human colon cancer cell line. METHODS: H-29 cells were used for in vitro experiments in this study. Relative cell viability was assessed using MTT assays. Cell apoptosis was detected by terminal deoxynucleotidyl transferase d UTP nick end labeling and Hoechst 33342 staining, and quantified by flow cytometry. Cellular ultrastructure was observed by transmission electron microscopy. Real-time PCR and Western blot analyses were used to evaluate gene and protein expression levels. For in vivo experiments, BALB/c nude mice received subcutaneous injections of HT-29 cells in the right armpit. When well-established xenografts were palpable with a tumor size of 75 mm3, mice were randomly assigned to a vehicle(negative) control, positive control or GA treatment group(n = 6 each). The animals in the treatment group received one of three dosages of GA(in saline; 5, 10 or 20 mg/kg) via the caudal vein twice weekly, whereas animals in the negative and positive control groups were given equal volumes of 0.9% saline or 10 mg/kg docetaxel, respectively, via the caudal vein once weekly. RESULTS: The cell viability assay showed that GA inhibited proliferation of HT-29 cells in a dose- and time-dependent manner after treatment with GA(0.00, 0.31, 0.62, 1.25, 2.50, 5.00 or 10.00 μmol/L) for 24, 48 or 72 h. After 48 h, the percentage of apoptotic cells in cells treated with 0.00, 1.25, 2.50 and 5.00 μmol/L GA was 1.4% ± 0.3%, 9.8% ± 1.2%, 25.7% ± 3.3% and 49.3% ± 5.8%, respectively. Ultrastructural analysis of HT-29 cells treated for 48 h with 2.5μmol/L GA revealed apoptotic bodies and condensed and fragmented nuclei. Levels of caspase-8,-9 and-3 m RNAs were significantly increased after treatment with GA(1.25, 2.50 or 5.00 μmol/L) for 48 h(P < 0.05 for all). Protein levels of apoptosis-related factors Fas, Fas L, FADD, cytochrome c, and Apaf-1 were increased in GA-treated cells, whereas levels of pro-caspase-8,-9 and-3 were significantly decreased(P < 0.05 for all). Furthermore, GA significantly and dose-dependently inhibited the growth of HT-29 tumors in a mouse xenograft model(P < 0.05).CONCLUSION: GA inhibits HT-29 proliferation via induction of apoptosis. The anti-cancer effects are likely mediated by death receptor(extrinsic) and mitochondrial(intrinsic) pathways.

Role of T cell death in maintaining immune tolerance during persistent viral hepatitis

Virus-specific T cells play an important role in the resolution of hepatic infection. However, during chronic hepatitis infection these cells lack their effector functions and fail to control the virus. Hepatitis B virus and hepatitis C virus have developed several mechanisms to generate immune tolerance. One of these strategies is the depletion of virus-specific T cells by apoptosis. The immunotolerogenic liver has unique property to retain and activate na ve T cell to avoid the over reactivation of immune response against antigens which is exploited by hepatotropic viruses to persist. The deletion of the virus-specific T cells occurs by intrinsic (passive) apoptotic mechanism. The pro-apoptotic molecule Bcl-2 interacting mediator (Bim) has attracted increasing attention as a pivotal involvement in apoptosis, as a regulator of tissue homeostasis and an enhancer for the viral persistence. Here, we reviewed our current knowledge on the evidence showing critical role of Bim in viral-specific T cell death by apoptotic pathways and helps in the immune tolerance.

Regulation of cell survival and death during Flavivirus infections

Flaviviruses, ss(+) RNA viruses, include many of mankind's most important pathogens. Their pathogenicity derives from their ability to infect many types of cells including neurons, to replicate, and eventually to kill the cells. Flaviviruses can activate tumor necrosis factor α and both intrinsic(Bax-mediated) and extrinsic pathways to apoptosis. Thus they can use many approaches for activating these pathways. Infection can lead to necrosis if viral load is extremely high or to other types of cell death if routes to apoptosis are blocked. Dengue and Japanese Encephalitis Virus can also activate autophagy. In this case the autophagy temporarily spares the infected cell, allowing a longer period of reproduction for the virus, and the autophagy further protects the cell against other stresses such as those caused by reactive oxygen species. Several of the viral proteins have been shown to induce apoptosis or autophagy on their own, independent of the presence of other viral proteins. Given the versatility of these viruses to adapt to and manipulate the metabolism, and thus to control the survival of, the infected cells, we need to understand much better how the specific viral proteins affect the pathways to apoptosis and autophagy. Only in this manner will we be able to minimize the pathology that they cause.

Adenosine triphosphate induced cell death: Mechanisms and implications in cancer biology and therapy

Adenosine triphosphate(ATP)induced cell death(AICD)is a critical cellular process that has garnered substantial scientific interest for its profound relevance to cancer biology and to therapeutic interventions.This comprehensive review unveils the intricate web of AICD mechanisms and their intricate connections with cancer biology.This review offers a comprehensive framework for comprehending the multifaceted role of AICD in the context of cancer.This is achieved by elucidating the dynamic interplay between systemic and cellular ATP homeostasis,deciphering the intricate mechanisms governing AICD,elucidating its intricate involvement in cancer signaling pathways,and scrutinizing validated key genes.Moreover,the exploration of AICD as a potential avenue for cancer treatment underscores its essential role in shaping the future landscape of cancer therapeutics.

Environmental hypoxia induces apoptosis in large yellow croaker Larimichthys crocea via both intrinsic and extrinsic pathways

Hypoxia has become an unfavorable factor affecting the sustainable development of the large yellow croaker Larimichthys crocea,an economically important mariculture fish in China.Apoptosis is a consequence of hypoxia on fish.However,the effects of hypoxia stress on apoptosis in L.crocea remain largely unknown.We investigated the effect of environmental hypoxia on apoptosis in L.crocea.Results show that hypoxia induced apoptosis in L.crocea both in vivo and in vitro.The mitochondrial membrane potential was significantly reduced in large yellow croaker fry(LYCF)cells.The expression levels of Bcell lymphoma/leukemia-2(Bcl-2)m RNA and protein were also significantly decreased in the liver and LYCF cells during 96 h and 48 h of hypoxia stress,respectively,whereas the expression level of Bcl-2 associated X(Bax)mRNA,Casp3 mRNA,and activity of caspase-3/7/9 were significantly increased,indicating that hypoxia induced caspase-dependent intrinsic apoptosis in L.crocea.The expression level of the apoptosis-inducing factor(AIF)protein was significantly increased in the liver and LYCF cells.The level of AIF protein was significantly decreased in the cytoplasm but increased in the nuclei of L.crocea,demonstrating that hypoxia induced the AIF-mediated caspase-independent intrinsic apoptosis.In addition,the activity of caspase-8 was significantly increased,indicating that hypoxia stress induced extrinsic apoptosis in L.crocea.Therefore,hypoxia induced apoptosis in L.crocea through both the intrinsic and extrinsic pathways.The present study accumulated basic biological information to help elucidate the mechanism of hypoxia response in marine fish.

Mechanism of delayed encephalopathy after acute carbon monoxide poisoning

Many hypotheses exist regarding the mechanism underlying delayed encephalopathy after acute carbon monoxide poisoning(DEACMP),including the inflammation and immune-mediated damage hypothesis and the cellular apoptosis and direct neuronal toxicity hypothesis;however,no existing hypothesis provides a satisfactory explanation for the complex clinical processes observed in DEACMP.Leucine-rich repeat and immunoglobulin-like domain-containing protein-1(LINGO-1)activates the Ras homolog gene family member A(Rho A)/Rho-associated coiled-coil containing protein kinase 2(ROCK2)signaling pathway,which negatively regulates oligodendrocyte myelination,axonal growth,and neuronal survival,causing myelin damage and participating in the pathophysiological processes associated with many central nervous system diseases.However,whether LINGO-1 is involved in DEACMP remains unclear.A DEACMP model was established in rats by allowing them to inhale 1000 ppm carbon monoxide gas for 40 minutes,followed by 3000 ppm carbon monoxide gas for an additional 20 minutes.The results showed that compared with control rats,DEACMP rats showed significantly increased water maze latency and increased protein and m RNA expression levels of LINGO-1,Rho A,and ROCK2 in the brain.Compared with normal rats,significant increases in injured neurons in the hippocampus and myelin sheath damage in the lateral geniculate body were observed in DEACMP rats.From days 1 to 21 after DEACMP,the intraperitoneal injection of retinoic acid(10 mg/kg),which can inhibit LINGO-1 expression,was able to improve the above changes observed in the DEACMP model.Therefore,the overexpression of LINGO-1 appeared to increase following carbon monoxide poisoning,activating the Rho A/ROCK2 signaling pathway,which may be an important pathophysiological mechanism underlying DEACMP.This study was reviewed and approved by the Medical Ethics Committee of Xiangya Hospital of Central South Hospital(approval No.201612684)on December 26,2016.

Dissecting the molecular pathophysiology of drug-induced liver injury

Drug-induced liver injury(DILI) has become a major topic in the field of Hepatology and Gastroenterology. DILI can be clinically divided into three phenotypes: hepatocytic, cholestatic and mixed. Although the clinical manifestations of DILI are variable and the pathogenesis complicated, recent insights using improved preclinical models, have allowed a better understanding of the mechanisms that trigger liver damage. In this review, we will discuss the pathophysiological mechanisms underlying DILI. The toxicity of the drug eventually induces hepatocellular damage through multiple molecular pathways, including direct hepatic toxicity and innate and adaptive immune responses. Drugs or their metabolites, such as the common analgesic, acetaminophen, can cause direct hepatic toxicity through accumulation of reactive oxygen species and mitochondrial dysfunction. The innate and adaptive immune responses play also a very important role in the occurrence of idiosyncratic DILI. Furthermore, we examine common forms of hepatocyte death and their association with the activation of specific signaling pathways.

Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4

Our previous studies showed that ferroptosis plays an important role in the acute and subacute stages of spinal cord injury.High intracellular iron levels and low glutathione levels make oligodendrocytes vulnerable to cell death after central nervous system trauma.In this study,we established an oligodendrocyte(OLN-93 cell line)model of ferroptosis induced by RSL-3,an inhibitor of glutathione peroxidase 4(GPX4).RSL-3 significantly increased intracellular concentrations of reactive oxygen species and malondialdehyde.RSL-3 also inhibited the main antiferroptosis pathway,i.e.,SLC7A11/glutathione/glutathione peroxidase 4(xCT/GSH/GPX4),and downregulated acyl-coenzyme A synthetase long chain family member 4.Furthermore,we evaluated the ability of several compounds to rescue oligodendrocytes from ferroptosis.Liproxstatin-1 was more potent than edaravone or deferoxamine.Liproxstatin-1 not only inhibited mitochondrial lipid peroxidation,but also restored the expression of GSH,GPX4 and ferroptosis suppressor protein 1.These findings suggest that GPX4 inhibition induces ferroptosis in oligodendrocytes,and that liproxstatin-1 is a potent inhibitor of ferroptosis.Therefore,liproxstatin-1 may be a promising drug for the treatment of central nervous system diseases.

Mechanisms involved in the cytotoxic effects of berberine on human colon cancer HCT-8 cells

Berberine,a constituent of some traditional Chinese medicinal plants,has been reported to have cytotoxicity effects on different human cancer cell lines.There is no available information about the effects and mechanism of action of berberine on human colon cancer cell line HCT-8.In this paper,the cytotoxicity of berberine on HCT-8 cancer cells was investigated by MTT assay,fluorescence microscopy and flow cytometry analysis.Our data revealed that berberine could significantly inhibit the growth of HCT-8 cells in a dose-and time-dependent manner.Morphology of apoptotic cells was studied with acridine orange/ethidium bromide staining.The concentrations of lactate dehydrogenase and both acid and alkaline phos-phatases were significantly increased in cell supernatants after berberine treatment,suggesting cell death.Furthermore,flow cytometry analysis showed that berberine could arrest HCT-8 cells at S phase in a time-dependent manner.To further investigate the apoptotic molecular mechanism,reverse transcription-poly-merase chain reaction(RT-PCR)and western blotting methods were used.The up-regulated mRNA and/or protein expressions of Fas,FasL,TNF-α,caspase-3 and down-regulation of pro-caspase-3 suggest that the death receptor pathway may be involved in the apoptotic pathway induced by berberine.Decrease of Bcl-2 and increase of Bax in mRNA and/or protein expressions showed that the Bcl-2 family proteins were involved in berberine-induced apoptosis.We also found that berberine-induced apoptosis was associated with an up-regulated expressions of p53 and prohibitin(PHB),and decreased vimentin expression.These results suggest that berberine can suppress cell growth and reduce cell survival by arresting the cell-cycle and by inducing apoptosis of HCT-8 cells.

Hippo signaling:bridging the gap between cancer and neurodegenerative disorders

During development,regulation of organ size requires a balance between cell proliferation,growth and cell death.Dysregulation of these fundamental processes can cause a variety of diseases.Excessive cell proliferation results in cancer whereas excessive cell death results in neurodegenerative disorders.Many signaling pathways known-to-date have a role in growth regulation.Among them,evolutionarily conserved Hippo signaling pathway is unique as it controls both cell proliferation and cell death by a variety of mechanisms during organ sculpture and development.Neurodegeneration,a complex process of progressive death of neuronal population,results in fatal disorders with no available cure to date.During normal development,cell death is required for sculpting of an organ.However,aberrant cell death in neuronal cell population can result in neurodegenerative disorders.Hippo pathway has gathered major attention for its role in growth regulation and cancer,however,other functions like its role in neurodegeneration are also emerging rapidly.This review highlights the role of Hippo signaling in cell death and neurodegenerative diseases and provide the information on the chemical inhibitors employed to block Hippo pathway.Understanding Hippo mediated cell death mechanisms will aid in development of reliable and effective therapeutic strategies in future.

Xanthotoxin induces apoptosis in SGC-7901 cells through death receptor pathway

Objective： To investigate the effects of xanthotoxin from Apiaceae medicinal plants on cell proliferation and apoptosis, and explore its mechanism of action against human gastric carcinoma SGC-7901 cells in vitro.Methods： SGC-7901, HepG-2, MCF-7, and A549 cells were treated with different concentrations of xanthotoxin（10, 20, 60, 80, 100, 120, 140, and 160 μg/mL） for 48 h, and the cell viability（IC50） was determined by MTT assay; Xanthotoxin-induced apoptosis in cells was observed by using Hoechst 33258 Staining Kit and Annexin V-FITC Apoptosis Detection Kit; Flow cytometry was used to detect apoptosis related proteins of Fas/FasL, Bid, and DR5/TRAIL proteins in human gastric carcinoma SGC-7901 cells after being treated by xanthotoxin; The influence of xanthotoxin on Caspase-8 protein expression in the cells was determined by Flouormetric Assay Kit.Results： Xanthotoxin obviously inhibited SGC-7901, HepG-2, MCF-7, and A549 cells proliferation, and its inhibition was in a concentration-dependent manner; flow cytometry results showed that in a certain concentration range, xanthotoxin can increase the expression levels of Fas/FasL and DR5/TRAIL proteins in a concentration-dependence manner. The content of Bid protein in cells was increased, and it showed concentration-dependence.Conclusion： Xanthotoxin may induce SGC-7901 cells apoptosis in a certain concentration range through the Fas/FasL protein mediated death receptor pathway, or by DR5/TRAIL mediated death receptor pathway, and increase the expression level of death receptor protein, activation Caspase-8, activating downstream effect factor, inducing cell apoptosis, or activate Caspase-8 cutting activate protein Bid, and then enter the mitochondrial pathway, induction of apoptosis.

The shikimate pathway regulates programmed cell death

Programmed cell death(PCD)is essential for both plant development and stress responses including immunity.However,how plants control PCD is not well-understood.The shikimate pathway is one of the most important metabolic pathways in plants,but its relationship to PCD is unknown.Here,we show that the shikimate pathway promotes PCD in Arabidopsis.We identify a photoperiod-dependent lesion-mimic mutant named Lesion in short-day(lis),which forms spontaneous lesions in short-day conditions.Mapbased cloning and whole-genome resequencing reveal that LIS encodes MEE32,a bifunctional enzyme in the shikimate pathway.Metabolic analysis shows that the level of shikimate is dramatically increased in lis.Through genetic screenings,three suppressors of lis(slis)are identified and the causal genes are cloned.SLISes encode proteins upstream of MEE32 in the shikimate pathway.Furthermore,exogenous shikimate treatment causes PCD.Our study uncovers a link between the shikimate pathway and PCD,and suggests that the accumulation of shikimate is an alternative explanation for the action of glyphosate,the most successful herbicide.

OSW-1 Induced Apoptosis in Hepatocellular Carcinoma through Generation of ROS, Cytochrome C and Noxa Activation Independent of p53 with Non-Activation of Caspase-3

Aim: To study the antitumor mechanism of OSW-1 in hepatocellular carcinoma. Materials and Methods: The expression profiling microarray was carried out to extract RNA from SK-Hep-1 which suffered from OSW-1. ρ0-SK-Hep-1 was maintained SK-Hep-1 in MEM containing 100 μg/L ethidium bromide (EB), 1 mM sodium pyruvate and 50 μg/ml uridine for 40 days. Then confirmed COX-I and COX-II of mitochondrial DNA were knocked out. Cells suffered from OSW-1 or doxorubicin. Then cells were washed twice with cold PBS and incubated with DCFH-DA. Fluorescent signal was recorded by using Infinite 200 Pro multimode Plate readers. Results: OSW-1 elevates generation of ROS and Cytochrome C which are associated with the induction of apoptosis in SK-Hep-1 cells. We also demonstrate that OSW-1 does not depend on p53 to up-regulate the BH3-only protein Noxa. What is more noteworthy that the Caspase-9 and FADD are down-regulated in above process. Conclusion: OSW-1 induced special apoptosis is different from the mitochondrial death pathway and the death receptor pathway and final result is not Caspase family’s activating. This provides a novel theory that nonmalignant cells are significantly less sensitive to OSW-1 than cancer cell lines.

Mechanism of hyperproteinemia-induced blood cell homeostasis imbalance in an animal model

Hyperproteinemia is a metabolic disorder associated with increased plasma protein concentration(PPC)and is often clinically complicated by malignant diseases or severe infections.At present,however,research on the molecular mechanism underlying high PPC(HPPC)is scant.Here,an animal model of primary hyperproteinemia was constructed in an invertebrate(Bombyx mori)to investigate the effects of HPPC on circulating blood cells.Results showed that HPPC affected blood cell homeostasis,leading to increased reactive oxygen species levels,and induced programmed cell death dependent on the endoplasmic reticulum-calcium ion signaling pathway.HPPC induced the proliferation of blood cells,mainly granulocytes,by activating the Janus kinase/signal transducer and activator of transcription(JAK/STAT)signaling pathway.Supplementation with the endocrine hormone active substance 20 E significantly reduced the impact of HPPC on blood cell homeostasis.Thus,we identified a novel signaling pathway by which HPPC affects blood cell homeostasis,which differs from hyperglycemia,hyperlipidemia,and hypercholesterolemia.In addition,we showed that down-regulation of gene expression of the hematopoietic factor Gcm could be used as a potential early detection indicator for hyperproteinemia.

c-Abl-MST1 Signaling Pathway Mediates Oxidative Stress Induced Neuronal Cell Death

Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. We have defined that the