TRAIL与肿瘤治疗

TRAIL是肿瘤坏死因子(TNF)超家族的成员之一,通过与受体结合而诱导细胞程序性死亡.TRAIL能够选择性地诱导肿瘤细胞凋亡,而对正常组织细胞几乎没有毒性,因此目前受到人们广泛的关注.本文介绍了TRAIL及其受体的表达调控,TRAIL的凋亡途径,以及TRAIL在肿瘤治疗中的研究进展,以期为TRAIL应用于临床肿瘤治疗提供一定的参考.     

Defensin γ-thionin from Capsicum chinense improves butyrate cytotoxicity on human colon adenocarcinoma cell line Caco-2

BackgroundButyrate is a histone deacetylase inhibitor that induces apoptosis and inhibits cell proliferation of colorectal cancer cells. To improve its anticancer activity, butyrate has been evaluated mixed with drugs and different molecules. Plant antimicrobial peptides are attractive anticancer alternative molecules because they show selective cytotoxic activity against different cancer cell lines. In this work, we explore if the plant defensin γ-thionin (Capsicum chinense) can improve butyrate activity on Caco-2 cell line and we also determined the mechanism of death activated.ResultsThe combined treatment of γ-thionin (3.5 µM) and butyrate (50 mM) showed higher cytotoxicity on Caco-2 cells with respect to single treatments. Also, the combined treatment reduced cell proliferation and exhibited a higher rate of apoptosis than single treatments. Combined treatment induced caspases 8 and 9 activation to an extent comparable with that of butyrate while γ-thionin did not activate caspases. Additionally, reactive oxygen species generation preceded the onset of apoptosis, and superoxide anion production was higher in cells treated with the combined treatment.ConclusionsThe γ-thionin from Habanero chili pepper improved the butyrate cytotoxicity on Caco-2 cells. This effect occurred through apoptosis induction associated with reactive oxygen species production. Therefore, the combination of butyrate with cytotoxic antimicrobial peptides could be an attractive strategy for cancer therapy.How to cite: Velázquez-Hernández ME, Ochoa-Zarzosa A, López-Meza JE, Defensin γ-thionin from Capsicum chinense improves butyrate cytotoxicity on human colon adenocarcinoma cell line Caco-2. Electron J Biotechnol 2021;52. https://doi.org/10.1016/j.ejbt.2021.04.009     

Apoptosome and inflammasome: conserved machineries for caspase activation

Apoptosome and inlammasome are multimeric protein complexes that mediate the activation of speciic caspases at the onset of apoptosis and inlammation.he central component of apoptosome or inlammasome is a tripartite scafold protein,exempliied by Apaf-1 and NLRC4,which contains an amino-terminal homotypic interaction motif,a central nucleotide-binding oligomerization domain and a carboxyl-terminal ligand-sensing domain.In the absence of death cue or an inlammatory signal,Apaf-1 or NLRC4 exists in an auto-inhibited,monomeric state,which is stabilized by adenosine diphosphate(ADP).Binding to an apoptosis-or inlammation-inducing ligand,together with replacement of ADP by adenosine triphosphate(ATP),results in the formation of a multimeric apoptosome or inlammasome.he assembled apoptosome and inlammasome serve as dedicated machineries to facilitate the activation of speciic caspases.In this review,we describe the structure and functional mechanisms of mammalian inlammasome and apoptosomes from three representative organisms.Emphasis is placed on the molecular mechanism of caspase activation and the shared features of apoptosomes and inlammasomes.     

Effects of Long Term Ethanol Consumption on Cell Death in Liver

Apoptosis plays an important role in cellular homeostasis. In this study we have investigated whether apoptosis is a contributory factor to alcohol induced liver damage. Long term ethanol (1.6 g/kg body weight/day) exposure augmented liver apoptosis as reflected by high frequency of positive TUNEL staining nuclei and by an increased activity of caspase-3 and -8. Our study provides evidence that long-term ethanol consumption triggers apoptotic process in the liver.     

Secondary immunization inhibits drug induced apoptosis<Emphasis Type="Italic">in vivo</Emphasis>

Immunization with a proper dose of an antigenic stimulus leads to cell proliferation and antibody response of circulating lymphocytes. We have previously observed that Secondary immunized spleenocytes resist ceramide-mediated apoptosisin vitro. Our present study is aimed at investigating thein vivo effect of immunization on apoptosis. Mice were subjected to either Primary or Secondary dose with Tetanus Toxoid. Unimmunized spleenocytes served as controls. Unimmunized, Primary and Secondary immunized mice were later exposed to chemotherapeutic drugs such as Etoposide/Methotrexate/Vincristine to induce apoptosis. Apoptosis was studied by using the Feulgen reaction on 5μ thin parafin sections of spleen. It was observed that Secondary immunized mice showed a lower percentage of apoptosis as compared to Primary or Unimmunized mice that was subjected to either of the chemotherapeutic drugs. It was thus concluded that Secondary immunization inhibits the process of chemotherapeutic drug induced apoptosis in vivo.     

Effect of Lecithin on <Emphasis Type="SmallCaps">d</Emphasis>-Galactosamine Induced Hepatotoxicity Through Mitochondrial Pathway Involving Bcl-2 and Bax

Twenty four Wistar strain albino rats were used for the investigations. Lecithin 50 and 100 mg/kg b wt was administered for 1 week by oral route. Liver damage was induced by intra peritoneal administration of 400 mg/kg b wt d-galactosamine on the last day. At the end of the study animals were sacrificed and liver enzyme levels, histopathology, mitochondrial integrity, expression of p53, Bax and Bcl-2 mRNA levels were studied. Increases in the liver enzyme levels by d-GalN were significantly inhibited by pretreatment with lecithin. Histopathological observation further confirmed the hepatoprotective effect of lecithin. In addition, the disruption of mitochondrial membrane, up regulation of Bax and down regulation of Bcl-2 mRNA levels in the liver of d-GalN intoxicated rats were effectively prevented by pretreatment with lecithin. The results of the present study validate our conviction that d-GalN causes hepatic damage via mitochondrial pathway involving Bax and Bcl-2.     

Lysyl Oxidase: Its Diversity in Health and Diseases

The mechanical properties of extracellular matrix (ECM) and connective tissues is largely dependent on the collagen and elastin structure. Lysyl oxidase (LOX) plays a critical role in the formation and repair of the ECM by oxidizing lysine residues in elastin and collagen, thereby initiating the formation of covalent cross linkages which stabilize these fibrous proteins. Due to its multiple functions both extracellularly and intracellularly, lysyl oxidase is involved in several processes in the tumorigenic pathway, in many different cancer types and stages. Alteration in LOX activity is implicated in many diseases and disorders including inflammation and inflammatory diseases, fibrosis of distinct organs and fibrotic disorders, cancer promotion and progression. There are only sparse reports of mutations or epigenetic alterations in the LOX gene. This review provides the recent clinical developments in the molecular mechanisms and pathologic process, pointing out LOX as a potential therapeutic target in translational medicine.     

一氧化氮合酶抑制剂对大鼠缺氧缺血性脑损伤神经元凋亡的影响

目的研究神经元凋亡在大鼠缺氧缺血性脑损伤（HIBD）中的地位及作用。并探讨选择性一氧化氮合酶抑制剂-7-硝基-吲唑（7-NI）对大鼠HIBD时神经元凋亡的影响。方法24h时用HE染色、TUNEL法、透射电镜观察和检测神经元凋亡并评估7-NI对神经元凋亡的影响。结果HIBD后24h在海马、皮质等处检测到神经元凋亡。7-NI使海马及皮质部位的神经元凋亡数显著降低。结论神经元凋亡参与了HIBD后神经元迟发性死亡。7NI有显著的抗HIBD后神经元凋亡的作用。     

Ameliorating reactive oxygen species-induced <Emphasis Type="Italic">in vitro</Emphasis> lipid peroxidation in brain,liver, mitochondria and DNA damage by <Emphasis Type="Italic">Zingiber officinale</Emphasis> Roscoe

Iron is an essential nutrient for a number of cellular activities. However, excess cellular iron can be toxic by producing reactive oxygen species (ROS) such as superoxide anion (O₂⁻) and hydroxyl radical (HO^·) that damage proteins, lipids and DNA. Mutagenic and genotoxic end products of lipid peroxidation can induce the decline of mitochondrial respiration and are associated with various human ailments including aging, neurodegenerative disorders, cancer etc. Zingiber officinale Roscoe (ginger) is a widely used spice around the world. The protective effect of aqueous ethanol extract of Z. officinale against ROS-induced in vitro lipid peroxidation and DNA damage was evaluated in this study. The lipid peroxidation was induced by hydroxyl radical generated from Fenton’s reaction in rat liver and brain homogenates and mitochondrial fraction (isolated from rat liver). The DNA protection was evaluated using H₂O₂-induced changes in pBR-322 plasmid and Fenton reaction-induced DNA fragmentation in rat liver. The results indicated that Z. officinale significantly (P<0.001) protected the lipid peroxidation in all the tissue homogenate/mitochondria. The extract at 2 and 0.5 mg/ml could protect 92 % of the lipid peroxidation in brain homogenate and liver mitochondria respectively. The percent inhibition of lipid peroxidation at 1mg/ml of Z. officinale in the liver homogenate was 94 %. However, the extract could partially alleviate the DNA damage. The protective mechanism can be correlated to the radical scavenging property of Z. officinale. The results of the study suggest the possible nutraceutical role of Z. officinale against the oxidative stress induced human ailments.     

Defect in mitochondrial functions in damaged human mitral valve

Mitochondrial diseases are a heterogeneous group of disorders in which a primary mitochondrial dysfunction is proven by morphological, biochemical, and genetic examinations. The mitral valve has important function in the regulation of blood flow from one chamber to another. Often, the mitral valve becomes abnormal with age, in Rheumatic fever or it is abnormal from birth (Congenital) or it can be destroyed by infection i.e. bacterial endocarditis and needs replacement. Myocardial function depends on energy produced by mitochondria and in any of these disease conditions, mitochondrial functions and enzyme activities may be impaired. With this in view, we analyzed the relationship between preoperative clinical conditions (as per New York heart Association) and extent of mitochondrial enzyme activities in damaged Human mitral valve in two types of heart disease such as Rheumatic Heart Disease (RHD) and Bacterial Endocarditis (BE). Thirty nine Patients undergoing cardiopulmonary bypass (CPB) for routine valvular heart surgery were included in the study. Controls included 11 normal porcine mitral valve samples without any evidence of heart disease. Mitochondrial enzymes like cytochrome oxidase (COX), succinate dehydrogenase (SDH), malate dehydrogenase (MDH), citrate synthase (CS) and ATPase were determined. Mitochondrial COX, SDH, CS and Total ATPase activities were significantly decreased in disease condition like BE and RHD when compared with control (P<0.001). On the other hand as per New York Heart Association (NYHA) preoperative clinical classification, all the mitochondrial enzymes were significantly (p<0.05) impaired in class IV as compared with NYHA class I, II and III. Present study shows that impairment in the mitochondrial enzymes activities are more pronounced in bacterial endocarditis (BE). It also indicates that damage to mitochondrial enzymes are most pronounced in NYHA class IV.     

Recent insights on biochemical and molecular basis for developing antihaemostatic agents: A review

The normal coagulation process is initiated by disruption and exposure of the subendothelial components of blood vessels. Platelets adhere to subendothelium-bound von Willebrand factor via glycoprotein (GP) Ib complex. This initial interaction per se and the release of platelet agonists transduce signals that leads to the rise in intracellular Ca2+ which induces shape change, prostaglandin synthesis, release of granular contents and conformational changes in platelet Gp IIb-IIIa. Gp IIb-IIIa in activated platelets binds fibrinogen and other adhesive proteins and mediates platelet cohesion the primary haemostatic plug. Furthermore, the activated platelets due to aggregation, result in the formation of fibrin (secondary hemostasis). Normally the haemostatic process plays a delicate balance between keeping the blood in the fluid state to maintain flow and rapidly forming an occluding plug following vessel injury. Thrombosis occurs because of alteration in this delicate balance. Arterial thrombosis occurs in the setting of previous vessel wall injury mostly because of atherosclerosis, while venous thrombosis occurs in areas of stasis. The recent advances in understanding of the haemostatic process have led to a better understanding of the mechanism of action of many antithrombotic drugs and identification of new targets for drug development. The molecular target of the ticlopidine has been identified. Large numbers of IIb-IIIa inhibitors have been developed. The mechanism of action of heparin has been defined at the molecular level. As a result, a synthetic pentasaccharide, based on antithrombin-binding domain of heparin, has been developed and tested successfully in clinical trials. New generation direct thrombin inhibitors are being developed. Factor Xa has a critical position at the convergence of intrinsic and extrinsic pathway. The clinical tolerability and the efficacy of low molecular weight heparins has established that inhibition of further thrombin generation, by blocking factor Xa alone can be an effective way of preventing thrombus growth without inactivating thrombin. A large number of specific factor Xa inhibitors are under development. Some of these are in preliminary clinical trials and appear to be promising. Future clinical trials will determine whether these new drugs will provide better risk-benefit ratio in treatment of thrombotic disorders. Similarly role of thrombolytics has been clearly established in many diseases including coronary artery disease.     

Vitamin C in Disease Prevention and Cure: An Overview

The recognition of vitamin C is associated with a history of an unrelenting search for the cause of the ancient haemorrhagic disease scurvy. Isolated in 1928, vitamin C is essential for the development and maintenance of connective tissues. It plays an important role in bone formation, wound healing and the maintenance of healthy gums. Vitamin C plays an important role in a number of metabolic functions including the activation of the B vitamin, folic acid, the conversion of cholesterol to bile acids and the conversion of the amino acid, tryptophan, to the neurotransmitter, serotonin. It is an antioxidant that protects body from free radical damage. It is used as therapeutic agent in many diseases and disorders. Vitamin C protects the immune system, reduces the severity of allergic reactions and helps to fight off infections. However the significance and beneficial effect of vitamin C in respect to human disease such as cancer, atherosclerosis, diabetes, neurodegenerative disease and metal toxicity however remains equivocal. Thus further continuous uninterrupted efforts may open new vistas to understand its significance in disease management.     

Comparative analysis of RBC membrane lipids in thalassemia, and iron deficiency anemia in relation to hypochromia and oxidant injury

The effect of an intrinsic defect in the red cell and pronounced hypochromia on oxidative damage to RBC membrane lipids was compared in beta-thalassemia and iron deficiency anemia (IDA), which have a varied etiology but equivalent low hemogiobin content. The study was planned to correlate the etiology of the disorders to the severity of lipid imbalance and RBC hemolysis in membranes of both the conditions. Results indicated a fall of lysophosphatidylcholine(LPC), phosphatidylethanolamine(PE) and the unsaturated to saturated fatty acid ratio in both conditions, while phosphatidylcholine(PC) increased only in thalassemia. However, irrespective of the disease, sphingomyelin(SM), total cholesterol and phospholipid levels elevated and the hydrogen peroxide stress test indicated increased susceptibility of both pathologic RBCs to peroxidation. Present findings indicate that IDA and thalassemla, allow for considerable amounts of oxidative damage to membrane lipids, irrespective of their etiologles, and thus point hypochromia as an important contributor for inducing lipid imbalance and RBC hemolysis.     

Reconvene and Reconnect the Antioxidant Hypothesis in Human Health and Disease

The antioxidants are essential molecules in human system but are not miracle molecules. They are neither performance enhancers nor can prevent or cure diseases when taken in excess. Their supplemental value is debateable. In fact, many high quality clinical trials on antioxidant supplement have shown no effect or adverse outcomes ranging from morbidity to all cause mortality. Several Chochrane Meta-analysis and Markov Model techniques, which are presently best available statistical models to derive conclusive answers for comparing large number of trials, support these claims. Nevertheless none of these statistical techniques are flawless. Hence, more efforts are needed to develop perfect statistical model to analyze the pooled data and further double blind, placebo controlled interventional clinical trials, which are gold standard, should be implicitly conducted to get explicit answers. Superoxide dismutase (SOD), glutathione peroxidase and catalase are termed as primary antioxidants as these scavenge superoxide anion and hydrogen peroxide. All these three enzymes are inducible enzymes, thereby inherently meaning that body increases or decreases their activity as per requirement. Hence there is no need to attempt to manipulate their activity nor have such efforts been clinically useful. SOD administration has been tried in some conditions especially in cancer and myocardial infarction but has largely failed, probably because SOD is a large molecule and can not cross cell membrane. The dietary antioxidants, including nutrient antioxidants are chain breaking antioxidants and in tandem with enzyme antioxidants temper the reactive oxygen species (ROS) and reactive nitrogen species (RNS) within physiological limits. Since body is able to regulate its own requirements of enzyme antioxidants, the diet must provide adequate quantity of non-enzymic antioxidants to meet the normal requirements and provide protection in exigent condition. So far, there is no evidence that human tissues ever experience the torrent of reactive species and that in chronic conditions with mildly enhanced generation of reactive species, the body can meet them squarely if antioxidants defense system in tissues is biochemically optimized. We are not yet certain about optimal levels of antioxidants in tissues. Two ways have been used to assess them: first by dietary intake and second by measuring plasma levels. Lately determination of plasma/serum level of antioxidants is considered better index for diagnostic and prognostic purposes. The recommended levels for vitamin A, E and C and beta carotene are 2.2–2.8 μmol/l; 27.5–30 μmol/l; 40–50 μmol/l and 0.4–0.5 μmol/l, respectively. The requirement and recommended blood levels of other dietary antioxidants are not established. The resolved issues are (1) essential to scavenge excess of radical species (2) participants in redox homeostasis (3) selective antioxidants activity against radical species (4) there is no universal antioxidant and 5) therapeutic value in case of deficiency. The overarching issues are (1) therapeutic value as adjuvant therapy in management of diseases (2) supplemental value in developing population (3) selective interactivity of antioxidant in different tissues and on different substrates (4) quantitative contribution in redox balance (5) mechanisms of adverse action on excess supplementation (6) advantages and disadvantages of prooxidant behavior of antioxidants (7) behavior in cohorts with polymorphic differences (8) interaction and intervention in radiotherapy, diabetes and diabetic complications and cardiovascular diseases (9) preventive behavior in neurological disorders (10) benefits of non-nutrient dietary antioxidants (11) markers to assess optimized antioxidants status (12) assessment of benefits of supplementation in alcoholics and heavy smokers. The unresolved and intriguing issues are (1) many compounds such as vitamin A and many others possessing both antioxidant and non-antioxidant properties contribute to both the activities in vivo or exclusively only to non-antioxidant activity and (2) since human tissues do not experience the surge of FR, whether there is any need to develop stronger synthetic antioxidants. Theoretically such antioxidants may do more harm than good.     

Energy conversion in biological systems—part II. heat production in brown adipose tissue

This study involves the application of bond graphs to the generation of heat by cells in brown adipose tissue. In the first portion of this paper, data are presented to show the types of signals that can be measured at several sites in the system controlling thermogenesis—signals travelling from the brain to the tissue as well as signals over a feedback pathway from spinal cord temperature receptors back to the brain. Bond graphs are developed for several components of the system with an emphasis being placed on graphs describing the alternative mechanisms proposed for cellular energy conversion. The power flow is calculated using ENPORT for one mechanism for different values of plasma membrane resistance.     

Oxidative Stress and Skin Cancer: An Overview

Skin is the largest body organ that serves as an important environmental interface providing a protective envelope that is crucial for homeostasis. On the other hand, it is a major target for toxic insult by a broad spectrum of physical and chemical agents that are capable of altering its structure and function. There are a large number of dietary contaminants and drugs can manifest their toxicity in skin. These environmental toxicants or their metabolites are inherent oxidants and/or directly or indirectly drive the production of a variety of reactive oxidants also known as reactive oxygen species. These are short-lived entities that are continuously generated at low levels during the course of normal aerobic metabolism. These are believed to activate proliferative and cell survival signaling that can alter apoptotic pathways that may be involved in the pathogenesis of a number of skin disorders. The skin possesses an array of antioxidant defense mechanisms that interact with toxicants to obviate their deleterious effect. The “antioxidant power” of a food is an expression of its capability both to defend the human organism from the action of the free radicals and to prevent degenerative disorders. Plants like olive trees have their own built-in protection against the oxidative damage of the sun, and these built-in protectors function as cell protectors in our own body. Although many antioxidants have shown substantive efficacy in cell culture systems and in animal models of oxidant injury, unequivocal confirmation of their beneficial effects in human populations has proven elusive.     

Alpha-hederin induces the apoptosis of oral cancer SCC-25 cells by regulating PI3K/Akt/mTOR signaling pathway

BackgroundOral cancer is one of the common malignant tumors of the head and neck. However, current treatments have numerous side effects, and drugs from natural sources may have better therapeutic potential. This research investigated the induction of apoptosis by α-hederin (α-HN), a constituent of Pulsatilla chinensis (Bunge) Regel, in the oral cancer cell line SCC-25 and its underlying mechanism.ResultsSCC-25 cells were treated with 50, 100, and 200 μmol/L α-HN. Cell proliferation; extent of apoptosis; activities of caspases-3, 8, and 9; and the expression of Bcl-2, Bax, phosphorylated (p)-phosphoinositide 3-kinase (PI3K), p-Akt, and p-mammalian target of rapamycin (mTOR) proteins were determined using the 3-(4,5)-2-thiazole-(2,5)-diphenyl tetrazolium bromide, flow cytometry, caspase activity detection kits, and western blot assays, respectively. The results showed that the proliferation of SCC-25 cells in the α-HN-treated groups decreased significantly, and the inhibitory effect was time and concentration dependent. Compared with cells in the control group, the extent of apoptosis increased significantly, caspase-3 and -9 activities were significantly enhanced, and the Bcl-2 level was lowered and the Bax level was elevated significantly in SCC-25 cells treated with α-HN for 48 h (P < 0.05). The expression of p-PI3K, p-Akt, and p-mTOR was also significantly lower in SCC-25 cells treated with α-HN than that in the control group (P < 0.05).ConclusionThese results indicate that α-HN can inhibit proliferation and induce apoptosis of SCC-25 cells and may exert these effects by inhibiting the PI3K/Akt/mTOR signaling pathway.How to cite: Wang H, Wu B, Wang H. Alpha-hederin induces the apoptosis of oral cancer SCC-25 cells by regulating PI3K/Akt/mTOR signaling pathway. Electron J Biotechnol 2019;38. https://doi.org/10.1016/j.ejbt.2018.12.005     

交互过程视角下知识分享报酬的影响机制研究

基于440份配对调查数据,揭示交互过程视角下知识分享报酬对知识型团队成员知识分享行为的影响机制。研究表明：(1) 当知识型团队成员作为知识需求者时,知识寻求顾虑对知识寻求行为有阻碍影响,但对知识创造行为有促进影响,而作为知识拥有者时,知识给予顾虑对知识给予行为和知识创造行为均有阻碍影响;(2) 内在和外在报酬不仅对知识寻求和给予行为均有显著的直接影响,而且对知识寻求顾虑与知识寻求行为、知识给予顾虑与知识给予行为之间负向关系起到减弱型调节作用;(3) 除直接作用外,内在和外在报酬分别对两种主观顾虑与知识创造行为之间关系起到方向不同的调节作用,即内在报酬起到增强型调节作用,外在报酬起到减弱型调节作用。