Associations of genetic polymorphisms of the transporters organic cation transporter 2(OCT2),multidrug and toxin extrusion 1(MATE1),and ATP-binding cassette subfamily C member 2(ABCC2) with platinum-based chemotherapy response and toxicity in non-small cel

Background:Platinum-based chemotherapy is the first-line treatment of non-small cell lung cancer(NSCLC);it is therefore important to discover biomarkers that can be used to predict the efficacy and toxicity of this treatment.Four important transporter genes are expressed in the kidney,including organic cation transporter 2(OCT2),multidrug and toxin extrusion 1(MATEl),ATP-binding cassette subfamily B member 1 {ABCB1),and ATP-binding cassette subfamily C member 2(ABCC2),and genetic polymorphisms in these genes may alter the efficacy and adverse effects of platinum drugs.This study aimed to evaluate the association of genetic polymorphisms of these transporters with platinumbased chemotherapy response and toxicity in NSCLC patients.Methods:A total of 403 Chinese NSCLC patients were recruited for this study.All patients were newly diagnosed with NSCLC and received at least two cycles of platinum-based chemotherapy.The tumor response and toxicity were evaluated after two cycles of treatment,and the patients' genomic DNA was extracted.Seven single-nucleotide polymorphisms in four transporter genes were selected to investigate their associations with platinum-based chemotherapy toxicity and response.Results:OCT2 rs316019 was associated with hepatotoxicity(P = 0.026) and hematological toxicity(P = 0.039),and MATEl rs2289669 was associated with hematological toxicity induced by platinum(P = 0.016).In addition,ABCC2rs717620 was significantly associated with the platinum-based chemotherapy response(P = 0.031).ABCB1 polymorphisms were associated with neither response nor toxicity.Conclusion:OCT2 rs316019,MATEl rs2289669,and ABCC2 rs717620 might be potential clinical markers for predicting chemotherapy toxicity and response induced by platinum-based treatment in NSCLC patients.Trial registration Chinese Clinical Trial Registry

A novel prognosis signature based on two cuprotosis-related genes for kidney renal clear cell carcinoma

Background:Cuprotosis is a newly discovered Copper-dependence form of cell death.Cuprotosis-related genes(CRGs)regulating mitochondrial metabolism and protein lipoylation suggest the critical roles cuprotosis for in cancer.However,the prognostic value of CRGs in the highly immunogenic cancer type,kidney renal clear cell carcinoma(KIRC)needs to be further studied.Herein,we aim to identify novel prognostic genes and construct a CRGs prognostic signature for KIRC.Methods:We downloaded the mRNA sequencing data from the Cancer Genome Atlas,differentially expressed CRGs were screened out and their bio-function was elucidated.Then we used Cox regression analysis to establish a prediction model of CRGs.Subsequently,a prognostic scoring model based on the regression coefficients of the screened out CRGs and their corresponding mRNA expressions were constructed and validated.Results:Seven differentially expressed CRGs were screened.A two-gene model was built to separate samples into high-risk and low-risk groups.Overall survival was lower in the high-risk group than in the low-risk group(p<0.05).The receiver operating characteristic curve showed a good diagnostic efficiency of the signature.We verified this prognostic model in the Cancer Genome Atlas test cohorts.The risk score was identified as an independent prognostic factor via multivariate Cox regression.Moreover,the nomogram was used to predict 1-/3-/5-year OS of KIRC patients.Furthermore,risk score has a very significant effect on the infiltration of immune cells and the expression of immune checkpoints.Conclusions:To conclude,we constructed a novel prognostic signature based on CRGs.Targeting cuprotosis may represent a promising approach for the treatment of KIRC.

Chronic stress as an emerging risk factor for the development and progression of glioma

Gliomas tend to have a poor prognosis and are the most common primary malignant tumors of the central nervous system.Compared with patients with other cancers,glioma patients often suffer from increased levels of psychological stress,such as anxiety and fear.Chronic stress(CS)is thought to impact glioma profoundly.However,because of the complex mechanisms underlying CS and variability in individual tolerance,the role of CS in glioma remains unclear.This review suggests a new proposal to redivide the stress system into two parts.Neuronal activity is dominant upstream.Stress-signaling molecules produced by the neuroendocrine system are dominant downstream.We discuss the underlying molecular mechanisms by which CS impacts glioma.Potential pharmacological treatments are also summarized from the therapeutic perspective of CS.

Association between DNA mismatch repair gene polymorphisms and platinum-based chemotherapy toxicity in non-small cell lung cancer patients

Background:Chemotherapy toxicity is a serious problem from which non-small cell lung cancer(NSCLC) patients suffer.The mismatch repair(MMR) system is associated with platinum-based chemotherapy toxicity in NSCLC patients.In this study,we aimed to investigate the relationship between genetic polymorphisms in the MMR pathway and platinum-based chemotherapy toxicity in NSCLC patients.Methods:A total of 220 Chinese lung cancer patients who received at least two cycles of platinum-based chemotherapy were recruited for this study.Toxicity was evaluated in each patient after two cycles of chemotherapy.A total of 44 single nucleotide polymorphisms were selected to investigate their associations with platinum-based chemotherapy toxicity.Results:MutS homolog 2[MSH2) rs6544991[odds ratio(OR) 2.98,95%confidence interval(CI) 1.20-7.40,P = 0.019]was associated with gastrointestinal toxicity in the dominant model;MSH3 rs6151627(OR 2.38,95%CI 1.23-4.60,P = 0.010),rs6151670(OR 2.05,95%CI 1.07-3.93,P = 0.031),and rs7709909(OR 2.38,95%CI 1.23-4.64,P = 0.010)were associated with hematologic toxicity in the dominant model.Additionally,MSH5 rs805304 was significantly associated with overall toxicity(OR 2.21,95%CI 1.19-4.09,P = 0.012),and M5H5 rs707939 was significantly associated with both overall toxicity(OR 0.42,95%CI 0.23-0.76,P = 0.004) and gastrointestinal toxicity(OR 0.44,95%CI 0.20-0.96,P = 0.038) in the dominant model.Conclusion:Genetic polymorphisms in the MMR pathway are potential clinical markers for predicting chemotherapy toxicity in NSCLC patients.

The TBK1-OPTN Axis Mediates Crosstalk Between Mitophagy and the Innate Immune Response: A Potential Therapeutic Target for Neurodegenerative Diseases

Recently,Richter et al.[1]revealed the potential functions of the interaction between the serine/threonine kinase Tank-binding kinase 1（TBK1）and the autophagy receptor optineurin（OPTN）.The TBK1-OPTN axis targets damaged mitochondria for degradation via PINK1/parkin-mediated mitophagy[2,3].Indeed,TBK1 can phosphorylate OPTN at Ser177,Ser473,or Ser513 to enhance the binding capacity of OPTN with poly-ubiquitin（poly-UB）chains.Conversely,

Structure and Anti-HIV Activity of Betulinic Acid Analogues

Firstly discovered in 1980s, human immunodeficiency virus （HIV） continues to affect more and more people. However, there is no effective drug available for the therapy of HIV infection. Betulinic acid existing in various medicinal herbs and fruits exhibits multiple biological effects, especially its outstanding anti-HIV activity, which has drawn the attentions of many pharmacists. Among the derivatives of betulinic acid, some compounds exhibited inhibitory activities at the nanomolar concentration, and have entered phase II clinical trials. This paper summarizes the current investigations on the anti-HIV activity of betulinic acid analogues, and provides valuable data for subsequent researches.

Synthesis and Anti-Cancer Activities of Resveratrol Derivatives

A novel series of resveratrol derivatives were synthesized according to Wittig-Horner reaction with 3,5-dihydroxybenzyl alcohol or 3,5-dimethoxybenzyl alcohol or 4-hydroxybenzyl alcohol as raw material and the inhibitory activities on breast carcinoma (MDA-MB-231) and gastric carcinoma cell lines (SGC-7901) in vitro were evaluated by the standard methyl thiazole tetrazolium (MTT) method. The result of biological test shows that some of resveratrol derivatives possess stronger anti-cancer activities than 5-FU. Compound 5c shows the strongest activity against breast carcinoma (MDA-MB-231) and gastric carcinoma cell lines (SGC-7901) with IC50 value of 50.19 ± 1.02 μM, 122.68.27 ± 2.04 μM, compared to that IC50 value of 5-FU is 98.59±3.61 μM,156.74±6.16 μM, respectively.

A polymorphism in GAS5 promoter impacts efficacy of cytarabine-based chemotherapy in Chinese AML patients

OBJECTIVE SNPs in lnc RNAs may alter the expression or secondary structure of lnc RNAs and then impact their functions.Whether lnc RNA SNPs affect the prognosis of acute myeloid leukemia(AML)remains unknown.To search the association between lnc RNA SNPs and AML outcomes,thirty tag SNPs in GAS5,H19,MALAT1,WT1-as and SRA were genotyped in313 AML patients.METHODS Survival analysis was performed in both AML patients recruited presently and GEO samples.The expression of GAS5 and TP63 was analyzed by real-time quantitative PCR.Dual-luciferase reporter gene assay was used to confirm the interactions between GAS5 rs55829688 and TP63.RESULTS Survival analysis indicated that rs55829688(T>C),located in GAS5 promoter,was significantly associated with the prognosis of AML.The average overall survival(OS)for patients with the rs55829688 CC genotype was significantly shorter than those carrying the rs55829688 T allele(P=0.018).Patients with rs55829688 CC genotype showed higher GAS5 expression in PBMCs than carriers of rs55829688T allele(P=0.025).Rs55829688 CC homozygotes also harbored a longer platelets recovery than those with rs55829688 T allele(P=0.040).In vitro study showed that GAS5 promoter harboring the rs55829688 C al ele showed marginal y increased reporter gene activity(P=0.054),and the promoter activity was increased by TP63 in a dose-dependent manner(P=0.001).Moreover,GAS5 expression was associated with AML OS in the GEO GSE12417 dataset,and GAS5 higher expression predict shorter OS(P=0.011).CONCLUSION Rs55829688 polymorphism could increase GAS5 expression by interacting with TP63 and was associated with worse OS in Chinese AML patients.

DNMT3A genetic polymorphisms predict disease prognosis in R882 mutation negative AML patients

OBJECTIVE To evaluate the association between DNA(cytosine-5)-methyltransferase 3 alpha(DNMT3A)genetic polymorphisms and the disease prognosis of R882 mutation negative acute myeloid leukemia(AML)patients.METHODS DNMT3A 11 SNPs(rs11695471,rs2289195,rs734693,rs2276598,rs1465825,rs7590760,rs13401241,rs7581217,rs749131,rs41284843 and rs7560488)were genotyped using a MassA RRAY platform or Sanger sequencing method in 317 diagnostic non-FABM3 AML patients without R882 mutation from southern China.AML patients underwent combined chemotherapy with cytarabine and anthracyclines.Overall survival(OS)and Disease-free survival(DFS)as major end points were defined.The prognostic(median OS and DFS)evaluations were performed by Kaplan-Meier curve and Cox′s proportional hazard model.RESULTS We found that the rs2289195 G>A SNP could act as a poor prognostic predictor independently(HR=0.442,P=0.035 for OS;HR=0.431,P=0.031 for DFS),while the rs1465825 T>C SNP and rs7590760 G>C SNP appeared to predict independently poor prognosis for both OS(HR=1.453,P=0.037 for rs1465825;HR=1.584,P=0.063 for rs7590760)and DFS(HR=1.459,P=0.057 for rs1465825;HR=1.965,P=0.017for rs7590760).However,no significant associations between other DNMT3A polymorphisms and prognosis(OS in conjunction with DFS)were observed.CONCLUSION DNMT3A polymorphisms may be potential predictive markers for AML prognosis in R882 mutation negative patients,which might improve prognostic stratification of AML.

AMPylation Signaling Participates in Diverse Processes with Pleiotropic Actions

Truttmann MC et al.[1] recently reported that AMPylation of heat shock protein 70 (HSP70) family of chaperones participates in altering the aggregation properties and maintaining protein homeostasis (proteostasis), thereby playing a vital role in the development of neurodegenerative diseases (NDs). NDs are commonly manifested by protein aggregates, which exert harmful effects on proteostasis. Interestingly, it has been observed that AMPylation of heat shock proteins (HSPs) can maintain proteostasis by inhibiting the formation of protein aggregates. As previous studies only indicate that HSPs could regulate proteostasis, such a novel discovery further demonstrates the involvement of HSP70 AMPylation in the regulation of protein aggregation and the maintenance of proteostasis. Therefore, AMPylation can be considered to possess a therapeutic potential to target certain physiological processes related to proteostasis, such as age-related diseases.

Apelin/APJ system and kidney disease

Apelin is an endogenous ligand of the apelin receptor(APJ),a seven-transmembrane G protein-coupled receptor.Apelin and APJ exist in a variety of tissues,with special status in the heart,lung and tumors.Furthermore,many research shows that the apelin/APJ system exerts a broad range of activities that affect kidney systems.This review we summarize the role of apelin/APJ system on renal fibrosis,renal ischemia/reperfusion injury and diabetic nephropathy,polycystic kidney disease,hemodialysis.It was found that the level expression of apelin m RNA in the inner stripe of kidney outer medulla was the highest,and the region is significantly correlated with water and sodium balance.In UUO mice model,intraperitoneal injection of Apelin can reduceα-SMA,the expression of TGF-1 and its receptor,and between renal stromal components also significantly decreased.These results show that Apelin can reduce the deposition of ECM and improve renal interstitial fibrosis.In renal ischemia/reperfusion injury studies show that apelin-13 can significantly reduce the damage induced by renal tubularlesions,renal cell death and the normal renal function is not completely lead to large damage.But in diabetic nephropathy,Apelin-APJ system can promote or slow DN disease progression is controversial,still needs further research.Analysis the receiver operating characteristic curve found that in the process of identifying ADPKD disease apelin and copeptin shows good receiver operating characteristic curve(ROC),cox proportional hazards regression model also showed apelin can predict on the progress of kidney disease.In hemodialysis patients the apelin levels and PTH levels were positively correlated,it could prompt apelin can protect bone dialysis patients.Apelin also can reduce Pit-1 inhibition of vascular smooth muscle cell osteoblast calcification and thus improve the aortic calcification,so Apelin may have a potential role in the treatment of vascular calcification in CKD.In kidney disease conditions,Apelin/APJ system plays a variety of biological functions,because of the Apelin protective on kidney,Apelin/APJ may be a potential material for the treatment of chronic kidney disease.

SENP2:A Novel Regulatory Mechanism of Brown Adipocyte Differentiation

Mammalian adipose tissues can be broadly divided into white adipose tissue(WAT),beige adipose tissue,and brown adipose tissue(BAT)[1].The function of WAT is to store superfluous energy and is characterized by unilamellar lipid droplets.WAT,as a prominent endocrine organ,regulates feeding and satiety by producing hormones.

Synthetic Resveratrol Derivatives and Their Biological Activities: A Review

Resveratrol, a naturally derived stilbene that exists in various foods and beverages, has attracted extensive exploration due to its multiple biological activities, such as anticancer, antioxidant, cardiovascular protection, anti-inflammatory, antiviral, chemopreventive effect, neuroprotective effect, immunomodulation and so on. However, owing to its poor oral bioavailability, the application of resveratrol is greatly restricted. Because of that, a large amount of efforts had been made by researchers on designing its derivatives to obtain compounds with improved efficiency and low toxicity for developing more active drugs for clinical application. In this report, we review the current development of studying on resveratrol derivatives including their properties and activities. Additionally, this article also presents the synthetic routes of correlative resveratrol derivatives.

Sterol carrier protein 2: A promising target in the pathogenesis of atherosclerosis

Atherosclerosis, the underlying pathophysiological basis of cardiovascular disease, has been recognized as a lipid-driven chronic inflammatory disease. Sterol carrier protein 2 (SCP-2) is a 13-kDa non-specific lipid-transfer protein expressed by various tissues and cells, such as liver, heart, vascular smooth muscle cells (VSMCs), and macrophages. SCP-2 has an extensive role in cardiovascular and metabolic diseases. Recently, SCP-2 was reported to promote the development of atherosclerosis by regulating lipid metabolism and peroxidation, endocannabinoid metabolism, vascular inflammation, and fatty acid metabolism. In this review, we summarized the recent advances regarding the role of SCP-2 in the pathogenesis of atherosclerosis and tried to provide a rationale for future investigation and a better understanding of the biological functions of SCP-2 in atherosclerotic cardiovascular disease.

Quinoline-based anti-MRSA agents: Current development, structure-activity relationships, and mechanisms

Methicillin-resistant Staphylococcus aureus (MRSA), the most common pathogen in hospital and community environments, can cause serious and even fatal infections. The antibiotics currently used for clinical treatment of MRSA have developed resistance, and there is an urgent need to develop new antimicrobials to treat infections caused by MRSA strains. Quinoline analogues play an important role in the development of antimicrobials. Herein, we discussed the current development of antibacterial activities of quinoline analogues, mainly for anti-MRSA activity, and their structure-activity relationships (SARs) from the perspective of using the quinoline nucleus to search for novel potential anti-MRSA candidates. Additionally, the mechanisms of some representative quinoline analogues against MRSA were clarified. Altogether, this review could provide further insights for the rational development of quinoline-based antibacterial drugs, especially against MRSA.

Preparation of Rutin-liposome Drug Delivery Systems and Evaluation on Their in vitro Antioxidant Activity

Objective To prepare, characterize and evaluate the antioxidant activity of rutin-liposome（RL）. Methods Liposomes of rutin were prepared by film dispersion method and the encapsulation efficiency（EE） was determined by RP-HPLC. Human umbilical vein endothelial cells（HUVECs） were injuried by H_2O_2 and treated with either free aqueous rutin or the RL delivery systems. The viability of HUVECs was determined by MTT and ELISA. Results The drug delivery system showed uniform rutin loaded nanoparticles with average particle size of（147.20 ± 1.42） nm, polydispersity index of（0.191 ± 0.003） nm, Zeta potential of（-20.0 ± 1.0） mV, and the drug EE was closed to 90.0%. The antioxidant effect of the drug delivery system to H_2O_2-damaged HUVECs showed that RL could increase injury cells viability compared to free aqueous rutin, which was accompanied with an obvious decrease in malondialdehyde（MDA）, lactate dehydrogenase（LDH） while increase the level of nitrogen oxide（NOS）. Conclusion The nanostructured RL is improved on the antioxidant effect and may be treating the different diseases caused by free radicals.

Ph_3P^+CF_2CO_2^- as an F^- and:CF_2 source for trifluoromethylthiolation of alkyl halides

As trifluoromethylthiolation has received increasing attention recently, many CF_3S-reagents and trifluoromethylthiolation methods have been developed. Herein we describe trifluoromethylthiolation of alkyl halides by using Ph_3 P^+CF_2CO_2 as a fluoride and difluorocarbene source. Difluorocarbene is a versatile intermediate, but its side reactions are usually ignored and the by-products would therefore be discarded. In this work, a side reaction of difluorocarbene, the generation of a fluoride anion from difluorocarbene, was developed into a synthetic tool. Although the trifluoromethylthiolation reaction involved multi-sequential steps, the cleavage of C-F bond, the formation of CF_2=S bond, F-C(S)F_2 bond,and C-SCF_3 bond, the conversion proceeded fast and was completed within 10 min.

A Turn-On Fluorescent Probe for Highly Selective and Sensitive Detection of Palladium

新奇刺激荧光灯为钯的察觉的探查被设计了。探查能有选择地并且易感知地在答案检测钯，并且察觉的限制是打算的是 11.4 nmol·L −1 。而且，探查成功地在生活房间为钯的荧光成像被使用。

A robust reporting system for measurement of SARS-CoV-2 spike fusion efficiency

Dear Editor,During the COVID-19 pandemic,several SARS-CoV-2 variants such as Alpha,Delta,and Omicron successively became dominant worldwide.The infection of SARS-CoV-2 is triggered by the binding of spike protein to the cell-surface receptor angiotensinconverting enzyme 2(ACE2),which then fuses with cell membrane or lysosomal membrane after endocytosis.1 Extensive cell fusion and syncytia formation are a signature feature of severe SARS-CoV-2 and may play an important role in COVID-19 pathogenesis.Research has shown that SARS-CoV-2 spikemediated cell fusion leads to the formation of abnormal and multinucleated cells in the lungs of patients.2 Accordingly,the fusion ability of SARS-CoV-2 spike protein may be a leading indicator of viral infectivity and disease severity in SARS-CoV-2 patients.

Nanoparticle(NP)-mediated APOC1 silencing to inhibit MAPK/ERK and NF-κB pathway and suppress breast cancer growth and metastasis

Breast cancer is one of the most common malignant tumors with high mortality and poor prognosis in women.There is an urgent need to discover new therapeutic targets for breast cancer metastasis.Herein,we identified that Apolipoprotein C1(APOC1)was up-regulated in primary tumor of breast cancer patient that recurrence and metastasis by immunohistochemistry(IHC).Kaplan-Meier Plotter database showed that high levels of APOC1 in breast cancer patients were strongly associated with worse overall survival(OS)and relapse-free survival(RFS).Mechanistically,APOC1 silencing significantly inhibits MAPK/ERK kinase pathway and restrains the NF-κB to decrease the transcription of target genes related to growth and metastasis in vitro.Based on this regulatory mechanism,we developed these findings into potential therapeutic drugs,glutathione(GSH)responsive nanoparticles(NPs)were used for systemic APOC1 siRNA delivery,NPs(siAPOC1)silenced APOC1 expression,and subsequently resulted in positive anti-tumor effects in orthotopic and liver metastasis models in vivo.Taken together,GSH responsive NPmediated siAPOC1 delivery was proved to be effective in regulating growth and metastasis in multiple tumor models.These findings show that APOC1 could be a potential biomarker to predict the prognosis of breast cancer patients and NP-mediated APOC1 silencing could be new strategies for exploration of new treatments for breast cancer metastasis.