Roles and mechanisms of the CD38/cyclic adenosine diphosphate ribose/Ca^(2+) signaling pathway

Mobilization of intracellular Ca2+ stores is involved inmany diverse cell functions, including: cell proliferation;differentiation; fertilization; muscle contraction; secre-tion of neurotransmitters, hormones and enzymes;and lymphocyte activation and proliferation. Cyclic ad-enosine diphosphate ribose(cADPR) is an endogenousCa2+ mobilizing nucleotide present in many cell typesand species, from plants to animals. cADPR is formedby ADP-ribosyl cyclases from nicotinamide adenine di-nucleotide. The main ADP-ribosyl cyclase in mammalsis CD38, a multi-functional enzyme and a type Ⅱ mem-brane protein. It has been shown that many extracel-lular stimuli can induce cADPR production that leadsto calcium release or influx, establishing cADPR as asecond messenger. cADPR has been linked to a widevariety of cellular processes, but the molecular mecha-nisms regarding cADPR signaling remain elusive. Theaim of this review is to summarize the CD38/cADPR/Ca2+ signaling pathway, focusing on the recent advanc-es involving the mechanism and physiological functionsof cADPR-mediated Ca2+ mobilization.

Effect of Ribose on Mature/Immature Raw Peanut Proteins and Their Allergenic Properties

Mature and immature roasted peanuts are reportedly different in the level of Maillard reaction adducts (MRA) and IgE binding (i.e., allergenic capacity). Heating and sugar-protein interaction are the cause for the difference. The objective of this study was to determine if mature and immature raw peanuts (not roasted) are also different through treatment with a reducing sugar such as ribose, glucose or fructose at a mild temperature. Extracts from mature and immature raw peanuts were treated with individual sugars at 37?C and 50?C, respectively, for 0 - 10 days, and then assayed for MRA with nitroblue tetrazolium (NBT) in a time-course manner for 60 min. IgE binding was determined in an enzyme- linked immunosorbent assay (ELISA), using a pooled plasma from peanut-allergic individuals. Of the sugars tested, only ribose produced a big difference or a unique curve pattern in MRA between treated mature and immature peanuts. The unique curve pattern was more pronounced at 50?C (day 5 - 10) than at 37?C. IgE binding under this condition increased, but only with the ribose-treated mature raw peanut. It was concluded that mature and immature raw peanuts were different in MRA and IgE binding when treated with ribose only, and that under such a condition, mature and immature raw peanuts could be identified.

Effects of 3-aminobenzamide on poly(ADP-ribose)polymerase expression,apoptosis and cell cycle progression of HeLa cells after X-ray irradiation

The aim of this paper is to study the changes of apoptosis and cell cycle progression in HeLa cells after the poly(ADP-ribose)polymerase(PARP)was inhibited by its inhibitor 3-aminobenzamide(3-AB)and the mechan-isms of PARP action on HeLa cells damaged by irra-diation.Flow cytometry(FCM)was used to examine the PARP expression and the percentage of apoptotic cells and cell cycle progression.The percentage of HeLa cells with positive expression of PARP protein 2,4,8 and 12 h after administrated with 3-AB was significantly lower than that of the control(P<0.01).The percentages of apoptotic cells in the 3-AB plus irradiation group at the time points of 2,8,12 and 24 h after 2 Gy irradiation were higher than that in the irradiation group(P<0.01 or P<0.05)and the percentage of G2 cells decreased signifi-cantly(P<0.01 or P<0.05).It indicates that 3-AB can rapidly inhibit PARP expression of HeLa cells,promote cell apoptosis and block G2 arrest induced by irradiation.

Determination of ribose and phosphorus contents in Haemophilus influenzae type b capsular polysaccharide by a quantitative NMR method using a single internal standard

The ribose and phosphorus contents in Haemophilus influenzae type b(Hib)capsular polysaccharide(CPS)are two important chemical indexes for the development and quality control of Hib conjugate vaccine.A quantitative ^(1)H-and ^(31)P-NMR method using a single internal standard was developed for simultaneous determination of ribose and phosphorus contents in Hib CPS.Hexamethylphosphoramide(HMPA)was successfully utilized as an internal standard in quantitative ^(1)H-NMR method for ribose content determination.The ribose and phosphorus contents were found to be affected by the concentration of polysaccharide solution.Thus,15–20 mg·L^(−1) was the optimal concentration range of Hib CPS in D_(2)O solution for determination of ribose and phosphorus contents by this method.The ribose and phosphorus contents obtained by the quantitative NMR were consistent with those obtained by traditional chemical methods.In conclusion,this quantitative ^(1)H-and ^(31)P-NMR method using a single internal standard shows good specificity,accuracy and precision,providing a valuable approach for the quality control of Hib glycoconjugate vaccines.

Blocking Cyclic Adenosine Diphosphate Ribose-mediated Calcium Overload Attenuates Sepsis-induced Acute Lung Injury in Rats

Background： Acute lung injury （ALI） is a common complication of sepsis that is associated with high mortality, lntracellular Ca^2＋ overload plays an important role in the pathophysiology of sepsis-induced ALl, and cyclic adenosine diphosphate ribose （cADPR） is an important regulator of intracellular Ca^2＋ mobilization. The cluster of differentiation 38 （CD38）/cADPR pathway has been found to play roles in multiple inflammatory processes but its role in sepsis-induced ALl is still unknown. This study aimed to investigate whether the CD38/cADPR signaling pathway is activated in sepsis-induced ALl and whether blocking cADPR-mediated calcium overload attenuates ALl. Methods： Septic rat models were established by cecal ligation and puncture （CLP）. Rats were divided into the sham group, the CLP group, and the CLP＋ 8-bromo-cyclic adenosine diphosphate ribose （8-Br-cADPR） group. Nicotinamide adenine dinucleotide （NAD＋）, cADPR, CD38, and intracellular Ca^2＋ levels in the lung tissues were measured at 6, 12, 24, and 48 h after CLP surgery. Lung histologic injury, tumor necrosis factor （TNF）-a, malondialdehyde （MDA） levels, and superoxide dismutase （SOD） activities were measured. Results： NAD＋, cADPR, CD38, and intracellular Ca-＋ levels in the lungs of septic rats increased significantly at 24 h after CLP surgery. Treatment with 8-Br-cADPR, a specific inhibitor of cADPR, significantly reduced intracellular Ca^2＋ levels （P = 0.007）, attenuated lung histological injury （P = 0.023）, reduced TNF-a and MDA levels （P 〈 0.001 and P = 0.002, respectively） and recovered SOD activity （P = 0.031） in the lungs of septic rats. Conclusions： The CD38/cADPR pathway is activated in the lungs of septic rats, and blocking cADPR-mediated calcium overload with 8-Br-cADPR protects against sepsis-induced ALl.

Kinetics of Reduction of Thionine with Ribose and the Structural Properties of the Dye at Different pH Using DFT Method

The reaction between the thionine （Th） and the ribose was observed spectrophotometrically and changes in absorbance of Th were recorded at variable concentration of dye, reductant and pH. A pseudo first order rate of reaction was found to establish the reduction kinetics of the dye, studied at a pH range of 0.34 to 12.8. Absorption spectrum of Th at different pH, with ribose showed a pH （12.8） dependent introversion. The reduction most probably took place with enediol intermediate of the sugar at high pH. A full geometry optimization of predominant species of Th namely, mono-deprotonated, di-deprotonated Th, and LTh （leuco thionine） respectively, at low and high pH, was performed at B3LYP level of theory. The data obtained from the energy minimization were in excellent agreement with other experimental and theoretical observations. The calculated enthalpies of formation for both reduction reactions （mono-deprotonated Th＋H＋→leucothionine and di-deprotonated Th＋2H＋→leucothionine） provided evidences for maximum reduction of the dye at high pH.

Role of poly(ADP-ribose) polymerase 1 in DNA methylation changes induced by hydroquinone in human bronchial epithelial cell

Objective To investigate the DNA methylation changes induced by hydroquinone(HQ)in human bronchial epithelial cells and to explore the role of poly(ADP-ribose)polymerase-1(PARP-1)in this process.Methods Human bronchial epithelial 16HBE cells and PARP-1-deficient 16HBE cells(16HBE-shPARP-1 cells)were exposed to HQ(10,20,40,60,and 80μmol/L)for

Poly(ADP-ribose) polymerase inhibition attenuates ischemia/reperfusion induced myocardial injury in rat via reducing myocardial nuclear factor κB activity

Objective To investigate the effect of Poly(ADP-ribose) polymerase(PARP) inhibition on ischemia/reperfusion(L/R) induced myocardial injury in rat and related mechanisms. Method Adult Wistar rats were randomly divided

Progress in immunotherapy for small cell lung cancer

Small-cell lung cancer(SCLC)is a special type of lung cancer that belongs to highly aggressive neuroendocrine tumors.At present,radiotherapy and chemotherapy remain the mainstay of treatment for SCLC.Progress in targeted therapies for SCLC with driver mutations has been slow,and these therapies are still under investigation in preclinical or early-phase clinical trials,and research on antiangiogenic tyrosine kinase inhibitors(e.g.,anlotinib)has achieved some success.Immunotherapy is becoming an important treatment strategy for SCLC after radiotherapy and chemotherapy.In this article we review the recent advances in immunotherapy for SCLC.

Effect of 5-Aminoisoquinolinone on the Adhesion of Colon Carcinoma

Objective： 5-Aminoisoquinolinone, a water-soluble, potent inhibitor of the activity of poly （adenosine 5＇-diphosphate ribose） polymerase, plays an important role in the tissue injury associated with ischaemia-reperfusion injury and inflammation by inhibiting the activity of poly （adenosine 5＇-diphosphate ribose） polymerase and the expression of cell adhesion molecules such as ICAM-1, P-selectin et al. But how about it in the tumor is not clear. The aim of the present study was to study the effects of 5-Aminoisoquinolinon on the adhesion of colon carcinoma line HT-29 cells to human umbilical vein endothelial cells; and the effects of 5-Aminoisoquinolinon on the expression of ICAM-1, P-selectin and the activity of poly （adenosine 5＇-diphosphate ribose） polymerase in colon carcinoma HT-29 cells. Methods： The adhesion of HT-29 cells to human umbilical vein endothelial cells was detected by adhesive experiment. Immunocytochemically Streptavidin-Peroxidase method was used to investigate the expression of ICAM-1, P-selectin and Poly （adenosine 5＇-diphosphate ribose）（ the product of poly （adenosine 5＇-diphosphate ribose） polymerase activation）. Results： the results of the adhesion assay of HT-29 cells to HUVEC showed that the OD570 value in each 5-AIQ-treated group was significant lower than that in the control group （5-AIQ-untreated） in a dose-dependent manner. The expression of ICAM-1, P-selectin and Poly （adenosine 5＇-diphosphate ribose） was significant lower in 5-Aminoisoquinolinone-treated HT-29 cell group than that in 5-Aminoisoquinolinoneuntreated groups. Conclusion： The data suggest that 5-Aminoisoquinolinone can inhibit the adhesion of HT-29 cells to human umbilical vein endothelial cells. 5-Aminoisoquinolinone also can inhibit poly （adenosine 5＇-diphosphate ribose） polymerase activation and the expressions of ICAM-1 and P-selectin in HT-29 cells. 5-Aminoisoquinolinone probably contributes to the prevention of tumor cell metastasis. Further study is needed.

POTENTIATION OF CADMIUM-INDUCED CHROMOSOME ABERRATION BY DNA REPAIR INHIBITORS IN CHO CELLS

Effect of four DNA repair inhibitors on the frequencyof chromosome aberration induced by cadmium chloridewas investigated.3-Aminobenzamide (3 AB), inhibitor of poly(ADP-ribose) polymerase,increased the frequency ofinduced chromosome aberrations when it

美国FDA批准Zejula(niraparib)用于成人复发性上皮性卵巢-输卵管癌或原发性腹膜癌的维持治疗

美国FDA于2017年3月27日批准Tesaro公司（Tesaro,Inc.）研制生产的Zejula（niraparib）用于成人复发性上皮性卵巢-输卵管癌或原发性腹膜癌的维持治疗,适用于经铂类药物化疗（platinum-based chemotherapy）后肿瘤得到有效抑制的患者。

美国FDA批准Lynparza(olaparib)用于治疗晚期卵巢癌

美国FDA于2014年12月19日批准Lynparza（olaparib）用于治疗因BRCA基因（gB RCAm）突变引起的晚期卵巢癌。FDA同时批准了一种对BRCA基因突变进行检测的仪器,名为BRACAnalysis CDx。 BRCA基因可以修复受损的DNA,抑制肿瘤细胞的生长。发生BRCA基因突变的女性更容易患卵巢癌。据估计，约10％～15％的卵巢癌患者与这种遗传性的BRCA基因突变有关。经BRACAnalysis CDx检测确认有BRCA基因突变的卵巢癌患者可接受Lynparza治疗。

分子动力学模拟极端嗜热核糖结合蛋白的热力学稳定性

采用分子动力学模拟方法研究极端嗜热性核糖结合蛋白(tteRBP)的嗜热机理.在常温(300 K)和最佳活性温度(375 K)时,分别对tteRBP分子进行动力学模拟,结果表明,整体分子均保持结构稳定,但分子内部的协调运动不同.在375 K时蛋白整体柔性显著提高,使分子能够局部调整构象以适应极端高温.蛋白结构变化的分析也确认了高温时构象局部微调对蛋白极端高温稳定性的关键作用.

ADP-RIBOSYL TRANSFERASE INHIBITORS POTENTIATING THE ANTITUMOR ACTIVITY OF PEPLOMYCIN

ADP-ribosyl transferase (ADPRT)transfers the ADP-ribose portion of NAD to either chromatin protein or another ADP-ribose molecule, to form polymer of (ADP-R)_n. This process is involved in many cellular biofunctions. In the last ten years, the evidence that ADPRT inhibitors inhibit DNA repair as well as potentiate the

STUDY OF RAMAN SPECTROSCOPY OF FIBRINOKINASE e-TPA

The e-TPA made in our institute, a fibrinokinase obtained from separation and purification of an animal tissue, is an effective pharmaceutical solvent of thrombus. The e-TPA is a bioactive proteolytic enzyme and is also an activator of profibrinolysin, therefore has the ability to make fibrin net structured thrombus degraded. The blood vessel embolisms of the heart and the brain are diseases harming

ENHANCED GROWTH-INHIBITING EFFECT OF BLEOMYCIN A5 BY INHIBITORS OF POLY(ADP-R) SYNTHETASE ON EAC in Vitro AND in Vivo

Poly(adenosine diphosphate-ribose) synthetase, called also adenosine diphosphateribose transferase (ADPRT), is mainly distributed in the nuclei of eucaryotic cells and can catalyze the formation of poly (ADP-R), using coenzyme Ⅰ (NAD) as a substrate.

Stomach and duodenum

2010342 Significance of PSD95 and synapsin-I expression in the gastric antrum of rats with diabetic gastroparesis. TIAN Aixia(田爱霞),et al. Dept Gastroenterol Union Hosp,Tongji Med Coll,Huazhong Sci Technol,Univ,Wuhan 430022.World Chin J Digestol 2010;18(4):1417-21. Objective To investigate the expression of postsynaptic density-95 (PSD95) and synapsin I

Mechanisms of resistance to PARP inhibitors - an evolving challenge in oncology

Poly-adenosine diphosphate ribose polymerase inhibitors(PARPi)lead to synthetic lethality when used in cancers harbouring a BRCA mutation or homologous recombination deficiency.There are now four PARPi approved by the Food and Drug Administration for therapeutic use is ovarian and breast cancer.In addition to this,there is data supporting its use in pancreatic adenocarcinoma and prostate cancer.However,development of resistance to PARPi limits the duration of response.Key mechanisms found to date include:(1)restoration of homologous recombination;(2)changes in PARP1;(3)suppression of non-homologous end joining;(4)replication fork protection;and(5)drug concentration.Gaining a better understanding of resistance mechanisms may guide combination therapies to overcome the resistance and improve the efficacy of PARPi.The purpose of this review is to describe the resistance mechanisms to PARPi and discuss their early detection.