Use of tailored loading-dose clopidogrel in patients undergoing selected percutaneous coronary intervention based on adenosine diphosphate-mediated platelet aggregation

Background Adenosine phosphate-mediated platelet aggregation is a prognostic factor for major adverse cardiac events in patients who have undergone selective percutaneous coronary interventions. This study aimed to assess whether an adjusted loading dose of clopidogrel could more effectively inhibit platelet aggregation in patients undergoing selected percutaneous coronary intervention.Methods A total of 205 patients undergoing selected percutaneous coronary intervention were enrolled in this multicenter, prospective, randomized study. Patients receiving domestic clopidogrel （n=104） served as the Talcom （Taijia）group; others （n=101） received Plavix, the Plavix group, Patients received up to 3 additional 300-mg loading doses of clopidogrel to decrease the adenosine phosphate-mediated platelet aggregation index by more than 50% （the primary endpoint） compared with the baseline. The secondary endpoint was major adverse cardiovascular events at 12 months.Results Compared with the rational loading dosage, the tailored loading dosage better inhibited platelet aggregation based on a ＞50% decrease in adenosine phosphate-mediated platelet aggregation （rational loading dosage vs. tailored loading dosage, 48% vs. 73%, P=0.028）. There was no significant difference in the eligible index between the Talcom and Plavix groups （47% vs. 49% at 300 mg; 62% vs. 59% at 600 mg; 74% vs. 72% at 900 mg; P ＞0.05） based on a standard adenosine diphosphate-mediated platelet aggregation decrease of ＞50%. After 12 months of follow-up, there were no significant differences in major adverse cardiac events （2.5% vs. 2.9%, P=5.43）. No acute or subacute stent thrombosis events occurred.Conclusion An adjusted loading dose of clopidogrel could have significant effects on antiplatelet aggregation compared with a rational dose, decreasing 1-year major adverse cardiac events in patients undergoing percutaneous coronary interventions based on adenosine phosphate-mediated platelet aggregation with no increase in bleeding.

Adenosine Diphosphate Ribosylation Factor-GTPase-Activating Protein Stimulates the Transport of AUX1 Endosome,Which Relies on Actin Cytoskeletal Organization in Rice Root Development

Polar auxin transport,which depends on polarized subcellular distribution of AUXIN RESISTANT 1/LIKE AUX1（AUX1/LAX） influx carriers and PIN-FORMED（PIN） efflux carriers,mediates various processes of plant growth and development.Endosomal recycling of PIN1 is mediated by an adenosine diphosphate（ADP）ribosylation factor（ARF）-GTPase exchange factor protein,GNOM.However,the mediation of auxin influx carrier recycling is poorly understood.Here,we report that overexpression of OsAGAP,an ARF-GTPase-activating protein in rice,stimulates vesicle transport from the plasma membrane to the Golgi apparatus in protoplasts and transgenic plants and induces the accumulation of early endosomes and AUX1.AUX1 endosomes could partially colocalize with FM4-64 labeled early endosome after actin disruption.Furthermore,OsAGAP is involved in actin cytoskeletal organization,and its overexpression tends to reduce the thickness and bundling of actin filaments.Fluorescence recovery after photobleaching analysis revealed exocytosis of the AUX1 recycling endosome was not affected in the OsAGAP overexpression cells,and was only slightly promoted when the actin filaments were completely disrupted by Lat B.Thus,we propose that AUX1 accumulation in the OsAGAP overexpression and actin disrupted cells may be due to the fact that endocytosis of the auxin influx carrier AUX1 early endosome was greatly promoted by actin cytoskeleton disruption.

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.

Electrochemical Studies of Effect of Eu^(3+) on Adenosine-5′-Diphosphate at Mercury Electrode

Ｎｕｃｌｅｉｃａｃｉｄｓｐｌａｙｉｍｐｏｒｔａｎｔｒｏｌｅｓｉｎｔｈｅｍｏｌｅｃｕｌａｒｂｉｏｌｏｇｙ．Ｔｈｅｅｎｏｒｍｏｕｓｇｒｏｗｔｈｉｎｔｈｅｎｕｃｌｅｉｃａｃｉｄｒｅｓｅａｒｃｈｈａｓｒｅｓｕｌｔｅｄｉｎａｎｅｅｄｆｏｒｍｅｔｈｏｄｓｓｕｉｔ...

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.

Component Analysis of Shuanghuanglian Freeze-dried Powder and Its Effects on Human Hepatocyte Function when Combined with Cefradine

[Objectives]To detect the contents of components in Shuanghuanglian freeze-dried powder and to explore the effects of Shuanghuanglian freeze-dried powder and its components on human hepatocytes(HL-7702)alone or in combination with cefradine.[Methods]High performance liquid chromatography(HPLC)was used to detect the contents of baicalin,wogonin,chlorogenic acid and forsythin,the main components of Shuanghuanglian freeze-dried powder.HL-7702 cells were cultured with Shuanghuanglian freeze-dried powder and the main components of Shuanghuanglian freeze-dried powder alone or in combination with cefradine.Enzyme linked immunosorbent assay(ELISA)was used to detect the contents of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in the cell supernatant after culture,and HPLC was used to detect the expression level of adenosine diphosphate(ADP)and adenosine triphosphate(ATP);agarose gel electrophoresis was used to detect the expression of cyclooxygenase 2(COX-2)and heme oxygenase-1(HO-1)in HL-7702 cells.[Results]In Shuanghuanglian freeze-dried powder for injection,the content of baicalin was the highest,and the content of wogonin was the lowest.Compared with the control group,the expressions of AST and ALT in human hepatocytes(HL-7702)in high-dose baicalin group,forsythin group and wogonin group decreased(P<0.05,P<0.01),while the expression of ALT in chlorogenic acid+cefradine group(0.046 mg/mL)and forsythin+cefradine group(0.046 mg/mL)increased(P<0.05,P<0.01),and the expression of AST had no significant difference(P>0.05);the results in the low-dose group were similar to those in the high-dose group.Compared with the control group,ATP expression in chlorogenic acid group,chlorogenic acid+cefradine group(0.046 mg/mL)and forsythin+cefradine group(0.046 mg/mL)in the high-dose group decreased(P<0.05,P<0.01),and ADP expression was not significantly different(P>0.05);in the low-dose group,the expression of ATP and ADP increased in baicalin group(P<0.05),but decreased in wogonin group,baicalin+cefradine group(0.046 mg/mL)and wogonin group+cefradine group(0.046 mg/mL)(P<0.05,P<0.01).Compared with the control group,the expressions of COX-2 and HO-1 in HL-7702 cells in the cefradine group showed no significant difference(P>0.05).The expression of HO-1 and COX-2 in the different dose groups of Shuanghuanglian and the group combined with cefradine increased,and the difference was significant(P<0.05,P<0.01).[Conclusions]The components of Shuanghuanglian freeze-dried powder for injection had effects on hepatocytes,of which baicalin had a significant effect,and the effect of cefradine on hepatocytes was increased when used in combination with cefradine.

Effect on platelet aggregation activity: extracts from 31 Traditional Chinese Medicines with the property of activating blood and resolving stasis

OBJECTIVE: To evaluate the anti-platelet aggregation effects of extracts from 31 Traditional Chinese Medicines(TCM) with the property of activating blood and resolving stasis in terms of TCM theory.METHODS: The 31 TCMs extracts were prepared using water, 90% ethanol and ethyl acetate., and the effects on anti-platelet aggregation were tested on a platelet aggregation analyzer in vitro with adenosine 5'-diphosphate, bovine thrombin and arachi-donic acid(AA) as aggregation inducers, respectively. Aspirin was the positive control.RESULTS: Lots of the tested TCMs had inhibitory effects with concentration-dependent manner on platelet aggregations induced by various agonists.Especially, some of the TCMs such as Chuanxiong(Rhizoma Chuanxiong), Yanhusuo(Rhizoma Corydalis Yanhusuo) and Danshen(Radix Salviae Miltiorrhizae) showed good anti-platelet aggregation effect similar or higher than that in positive control group.CONCLUSION: The study provided scientific references that several TCMs such as Chuanxiong(Rhizoma Chuanxiong), Yanhusuo(Rhizoma Corydalis Yanhusuo) and Danshen(Radix Salviae Miltiorrhizae),possess the property of anti-platelet aggregation.

ADP-ribosylhydrolases:from DNA damage repair to COVID-19

Adenosine diphosphate(ADP)-ribosylation is a unique post-translational modification that regulates many biological processes,such as DNA damage repair.During DNA repair,ADP-ribosylation needs to be reversed by ADP-ribosylhydrolases.A group of ADP-ribosylhydrolases have a catalytic domain,namely the macrodomain,which is conserved in evolution from prokaryotes to humans.Not all macrodomains remove ADP-ribosylation.One set of macrodomains loses enzymatic activity and only binds to ADP-ribose(ADPR).Here,we summarize the biological functions of these macrodomains in DNA damage repair and compare the structure of enzymatically active and inactive macrodomains.Moreover,small molecular inhibitors have been developed that target macrodomains to suppress DNA damage repair and tumor growth.Macrodomain proteins are also expressed in pathogens,such as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).However,these domains may not be directly involved in DNA damage repair in the hosts or pathogens.Instead,they play key roles in pathogen replication.Thus,by targeting macrodomains it may be possible to treat pathogen-induced diseases,such as coronavirus disease 2019(COVID-19).