Leptin role in advanced lung cancer. A mediator of the acute phase response or a marker of the statu

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Leptin与SIRT1在骨肉瘤及骨转移瘤中的作用机制研究第一完成人

科学技术进步奖公示内容一、项目名称：Leptin与SIRT1在骨肉瘤及骨转移瘤中的作用机制研究二、提名单位：河北省卫生和计划生育委员会三、项目简介：本研究应用Leptin与SIRT1对骨肉瘤细胞进行实验，采用蛋白质印迹法检测细胞中相关蛋白的表达；流式细胞技术检测各组细胞凋亡；采用MTT 比色法测定细胞增殖率；免疫组化检测Leptin与SIRT1在骨肉瘤标本中的表达；进行临床资料随访，完善相关临床病例的回顾，得出数据进行统计学分析。

应用Leptin对肺癌细胞侵袭转移的机制进行研究，发现Leptin 可通过促进肺癌细胞发生上皮间质转化（Epithelial-mesenchymal transition，EMT）促进肺癌细胞侵袭、骨转移。

应用免疫组化方法检测Leptin及其受体在肺癌及骨转移瘤中的表达，完善相关临床资料及随访结果进行数据统计分析。

本研究证实了Leptin与SIRT1对骨肉瘤细胞有促进增值、侵袭、转移的作用；Leptin与SIRT1免疫组化结果可以作为骨肉瘤的预后指标；Leptin与SIRT1均可以促进EMT的发生发展；Leptin 可以促进肺癌发生骨转移，可以作为肺癌及骨转移瘤的预后指标。

Leptin与SIRT1有可能成为骨肉瘤及骨转移瘤的药物设计靶点。

四、全部完成人及技术贡献（公示内容包括姓名、排名、技术职称、工作单位、对本项目技术创造性贡献、曾获科学技术奖励情况）：1、冯和林第一副主任医师河北医科大学第四医院指导临床及基础试验的设计，审核数据及统计分析结果，论文撰写与修改2、张宁第二副主任医师河北医科大学第四医院基础实验，统计分析，论文撰写与修改3、吴宏增第三主治医师河北医科大学第四医院观察病例，收集数据，论文撰写4、许建发第四主治医师河北医科大学第四医院基础实验，收集数据，统计分析，论文撰写5、张进明第五副主任医师河北医科大学第四医院观察病例，收集数据，论文撰写五、主要完成单位及创新推广贡献、推广应用及经济社会效益情况：Leptin与SIRT1免疫组化结果可以作为骨肉瘤及骨转移瘤的预后指标，在临床工作中能够以操作简单、价格便宜的方式创造出最大的社会效益。

攀登鱼藤异黄酮脂质体有较好的物理性能及抗乳腺癌细胞的增殖活性

三阴性乳腺癌是指雌激素受体（ER ）、孕激素受体（PR ）和人表皮生长因子受体（HER-2）均为阴性的一类乳腺癌，具有肿瘤体积大、分化低、转移率和复发率高等特点，发病率占乳腺癌总数的15%~25%［1-3］，并且呈现出较高的致死率［4-5］。

乳腺癌的治疗方式主要包括乳房切除、化疗、放疗以及联合疗法等［6］。

与其他乳腺癌相比，三阴性乳腺癌易发生远处转移且无靶向治疗药物，主要依赖化疗方法［7-9］，但总体预后较差，5年存活率低于30%［3］，且存在较高的复发风险［10］。

目前，临床上应用的Preparation of warangalone-loaded liposomes and its inhibitory effect on breast cancer cellsMAO Lianzhi 1,LIU Huiping 2,LIU Huahuan 1,BIAN Zhongbo 1,ZHANG Qiuyu 1,LIAO Wenzhen2,SUN Suxia 11Department of Nutrition and Food Hygiene,School of Public Health,Southern Medical University,Guangzhou 510515,China;2ERA (Shenzhen)Biotechonology,Shenzhen 518000,China摘要：目的制备和鉴定攀登鱼藤异黄酮温敏脂质体并研究其抗乳腺癌作用。

方法MTT 法检测攀登鱼藤异黄酮、大豆异黄酮和金雀异黄酮对人乳腺癌细胞（MDA-MB-231、MCF7、SKBR3）增殖活性影响；克隆形成实验探讨攀登鱼藤异黄酮对三阴性乳腺癌细胞（MDA-MB-231）克隆形成的影响；细胞划痕实验检测MDA-MB-231细胞迁移；蛋白印迹法检测MDA-MB-231细胞迁移和侵袭蛋白MMP2，MMP9表达量；薄膜水化法制备温敏脂质体及攀登鱼藤异黄酮温敏脂质体；透射电子显微镜、动态光散射扫描仪以及紫外分光光度计分别鉴定攀登鱼藤异黄酮温敏脂质体形貌、粒径、包封率及稳定性，并用MTT 法检测攀登鱼藤异黄酮温敏脂质体抗小鼠乳腺癌细胞（4T1）增殖活性。

褪黑素对脂多糖诱导的脓毒症大鼠肺损伤的保护作用

褪黑素对脂多糖诱导的脓毒症大鼠肺损伤的保护作用宋洁琼;吴威;陈嵩;诸杜明;钟鸣【摘要】Objective:To investigate the protective effects of melatonin (MT)on lung injury induced by lipopolysaccharide (LPS)in rats with sepsis.Methods:Seventy-two rats were randomly divided into four groups with 18 rats in each group:control group (0.9%NS,i.v.),LPS group (LPS 1 mg/kg,i.v.),LPS+MT1 group (MT 0.1 mg/kg+LPS 1 mg/kg,i.v.)and LPS+MT2 group (MT 1 mg/kg+LPS 1 mg/kg,i.v.).Carotid arterial blood of all rats was collected at 6 h after administration and serum levels of tumor necrosis factor-α(TNF-α),interleukin-6 (IL-6)and interleukin-10 (IL-10) were detected by enzyme linked immunosorbent assay (ELISA ).The lung homogenate contents of superoxide dismutase (SOD),malondialdehyde(MDA)and myeloperoxidase (MPO)were also examined.Results:Compared with control group, the levels of serum TNF-α,IL-6 and IL-10 were significant higher in LPS group (P<0.01).With the MT intervention,the levels of TNF-αand IL-6 were significantly decreased but the IL-10 level was remarkably increased (P<0.05).This effect was more remarkable with the increase of the dose of MT.The level of SOD in LPS group was remarkably lower than in control group,but the levels of MDA and MPO were significantly higher(P<0.01).Compared with LPS group,the level of SOD in LPS+MT1 group was significantly increased,however,the contents of MDA and MPO were decreased (P<0.05).The same trend was more prominent in LPS+MT2 group.Conclusions:MT can decrease the lung injury by reducing theinflammatory response and lipid peroxidation induced by LPS in rats with sepsis.The protective effect was positively associated with the dose of MT.%目的：探讨褪黑素（MT）对脂多糖（LPS）诱导的脓毒症大鼠肺损伤组织的保护作用。

慢性肾衰竭血清瘦素、胰岛素样生长因子—1水平及意义

慢性肾衰竭血清瘦素、胰岛素样生长因子—1水平及意义瘦素(Leptin)是近几年来发现的一种由脂肪细胞产生的蛋白，它对调节机体食欲、体重和器官的能量消耗有重要作用。

肾脏是瘦素清除的主要器官，同时瘦素又可对肾脏直接发挥作用。

瘦素是慢性肾功能不全(CRF)时体内聚积的毒素之一，它与胰岛素样生长因子-1(IGF-1)共同作用于慢性肾功能衰竭患者的营养状况。

本文主要探讨慢性肾功能衰竭(CRF)血清瘦素和IGF-1的水平及意义。

一瘦素研究概况1994年hzang等首次鉴定并克隆出了人的肥胖基因，其与小鼠具有高度同源性，同时发现该基因编码的一种含167个酸的蛋白，分子量为16KD，为ob基因的表达产物，被命名为瘦(Leptin)[1]。

瘦素的生理功能包括:感受机营养状态[2]，进而抑制食物摄入:刺激或维持能量消耗;影响生殖泌系统;作为一种代谢激素促进一系列代谢过程，如胰岛素释放、糖的解作用、转运等。

瘦素缺乏或瘦素受体缺陷可导胖和垂体功能异常。

二 RCF患者血浆瘦素的变化及影响因素近期的研究认为肾功能衰竭患者同肥胖患者一样，血浆瘦素水平常明显高于正常。

由于瘦素分子量是16KD，可能通过肾小球滤过，假设人的瘦素清肾脏，那么有人做了这方面的研究，KumarS等测定了不同程度能损伤患者的主动脉和肾静脉血浆瘦素水平，发现瘦素的清除在与肾功能有关，同时连续测量通过肾脏的不同浓度和肾血流比率，计算出肾脏瘦素的净排出率为480ng/min，同时也发现在中度肾损伤患者肾脏没有瘦素清除[3]，另外监测到尿的瘦素水平低也表明在肾脏降解。

人体处于炎症状态时常常会表现食欲下降，有人用CRP(反应蛋白)增高代表机体存在炎症，研究发现尿毒症患者CRP瘦素确有相关关系，CRP高的患者往往血浆瘦素水平也高。

同时调查蛋白质摄入情况发现，CRP高的患者蛋白质摄入明显低于CRP正常患者。

提示炎症所致的食欲下降与它引起的瘦素增高有关[4]。

三瘦素水平相对增高对CRF病人的影响瘦素对慢性肾衰患者的不利影响可能不止是对机体营养状态的，瘦素增高交感神经兴奋性可能参与了慢性肾衰患者的血压异常，并且因为瘦素无法有效清除而致血压难以控制;慢性肾衰患者高瘦素血症与高胰岛素血症可能互为因果，互相促进;可能导致高脂血症。

基于网络药理学探讨白藜芦醇治疗肺癌的生物分子机制

基于网络药理学探讨白藜芦醇治疗肺癌的生物分子机制张丽慧，耿其顺，朱子家，王文斌，沈志博，李砺锋，薛文华，赵杰郑州大学第一附属医院，河南郑州 450052摘要：目的基于网络药理学，运用在线数据库研究白藜芦醇治疗肺癌的潜在作用机制。

方法通过中药系统药理学数据库与分析平台（TCMSP）、PubChem、SwissTargetPrediction、GeneCards数据库分别获取白藜芦醇和肺癌的相关基因，取二者交集基因，使用String数据库获得交集基因的蛋白相互作用（PPI）网络图，使用DA VID6.8对交集基因进行GO和KEGG富集分析。

采用Cytoscape3.7.2软件构建化合物-靶点-通路-疾病网络模型。

使用AutoDock4.2.6软件对白藜芦醇和重要靶点进行分子对接。

Western blot检测白藜芦醇对人肺癌H1975细胞p-Akt蛋白表达的影响。

结果获得白藜芦醇和肺癌交集基因78个，PPI网络图表明交集基因关系密切。

富集分析得到生物过程55项、分子功能26项、细胞组分18项，以及86条相关通路，其中以PI3K-Akt 通路富集靶点较多。

分子对接结果显示，白藜芦醇与PIK3CB、PIK3CA这2个重要靶点均能稳定结合。

Western blot检测结果显示，白藜芦醇能够显著降低人肺癌H1975细胞p-Akt蛋白表达。

结论白藜芦醇可能主要通过作用于PIK3CB、PIK3CA靶点，介导PI3K-Akt信号通路发挥治疗肺癌作用。

关键词：白藜芦醇；肺癌；网络药理学；作用机制；分子对接中图分类号：R273.42；R285 文献标识码：A 文章编号：1005-5304(2021)06-0046-06DOI：10.19879/ki.1005-5304.202004113 开放科学（资源服务）标识码（OSID）：Biomolecular Mechanism of Resveratrol Against Lung Cancer Based on Network Pharmacology ZHANG Lihui, GENG Qishun, ZHU Zijia, WANG Wenbin, SHEN Zhibo, LI Lifeng, XUE Wenhua, ZHAO Jie First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China Abstract:Objective To use the online databases to study the potential mechanism of resveratrol in treating lung cancer based on network pharmacology. Methods The genes related to resveratrol and lung cancer were obtained from TCMSP, PubChem, SwissTargetPrediction and GeneCards database, and the related intersection genes of resveratrol and lung cancer were screened out. The String database was used to draw the PPI network diagram of the intersection genes, and the DA VID 6.8 was used to perform GO and KEGG enrichment analysis. The compound-target-signal pathway-disease network model was constructed by using Cytoscape 3.7.2 software. AutoDock 4.2.6 software was used to perform molecular docking of resveratrol and important targets. Western blot was used to detect the effect of resveratrol on the expression of p-Akt protein in human lung cancer H1975 cell line. Results Totally 78 intersection genes of resveratrol and lung cancer were obtained, and the PPI network diagram showed that there was a close relationship between them. The enrichment analysis mainly obtained 55 biological processes, 26 molecular functions, 18 cellular components, and 86 related pathways, among which the PI3K-Akt pathway enriched the most targets. Molecular docking results showed that resveratrol could stably bind to two important targets, PIK3CB and PIK3CA. Western blot test results showed that resveratrol could significantly reduce the expression of p-Akt protein in human lung cancer H1975 cells. Conclusion Resveratrol may mainly act on the targets of PIK3CB and PIK3CA, and mediates the PI3K-Akt signaling pathway to exert anti-lung cancer action.Keywords: resveratrol; lung cancer; network pharmacology; action mechanism; molecular docking研究表明，肿瘤的发生发展与基因突变及多条信号通路改变有关[1-2]。

优质护理在脑梗死患者护理中的应用效果评价

review[J].Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub,2012,156:186-199.[12] Lubiński J,Lener MR,Marciniak W,et al.Serum essential elements andsurvival after cancer diagnosis[J].Nutrients,2023,15(11):2611.[13] Schenk JM,Till C,Neuhouser M,et al.Differential biopsy patternsinfluence associations between multivitamin use and prostate cancer risk in the selenium and vitamin e cancer prevention trial[J].Cancer Epidemiol Biomarkers Prev,2022,31:2063-2069.[14] Crowe FL,Appleby PN,Travis RC,et al.Endogenous hormones,nutritionalbiomarkers and prostate cancer collaborative group. Circulating fatty acids and prostate cancer risk: Individual participant meta-analysis of prospective studies[J].J Natl Cancer Inst,2014,106(9):dju240.[15] Parra-SS,Ahumada D,Petermann-Rocha F,et al.Association ofmeat,vegetarian,pescatarian and fish-poultry diets with risk of 19 cancer sites and all cancer:findings from the UK Biobank prospective cohort study and meta-analysis[J].BMC Med,2022,20:79.[16] Birney E.Mendelian randomization[J].Cold Spring Harb PerspectMed,2022,12(4):a041302.[17] Davey SG,Hemani G.Mendelian randomization:genetic anchors for causalinference in epidemiological studies[J].Hum Mol Genet,2014,23:89-98.[18] Dong H,Kong X,Wang X,et al.The causal effect of dietary compositionon the risk of breast cancer: A mendelian randomization study[J].Nutrients,2023,15(11):2586.[19] Yan H,Jin X,Zhang C,et al.Associations between diet and incidencerisk of lung cancer: A Mendelian randomization study[J].Front Nutr,2023,10:1149317.[20] Yin L,Yan H,Chen K,et al.Diet-derived circulating antioxidants andrisk of digestive system tumors: A mendelian randomization study[J].Nutrients,2022,14(16):3274.[21] Brasky TM,Darke AK,Song X,et al.Plasma phospholipid fatty acidsand prostate cancer risk in the SELECT trial[J].J Natl Cancer Inst,2013,105:1132-1141.[22] Outzen M,Tj ønneland A,Christensen J,et al.Fish consumption andprostate cancer risk and mortality in a Danish cohort study[J].Eur J Cancer Prev,2018,27:355-360.[23] Fu YQ,Zheng JS,Yang B,et al.Effect of individual omega-3 fatty acids onthe risk of prostate cancer: A systematic review and dose-response meta-analysis of prospective cohort studies[J].J Epidemiol,2015,25:261-274.[24] Burgess S,Swanson SA,Labrecque JA.are mendelian randomizationinvestigations immune from bias due to reverse causation[J].Eur J Epidemiol,2021,36:253-257.[25] Guo JZ,Xiao Q,Gao S,et al.Review of Mendelian Randomization Studieson Ovarian Cancer[J].Front Oncol,2021,11:681396.[2024-01-07收稿]脑血管疾病是指脑血管病变所引起的脑功能障碍。

mTORC1

mTORC1/2双重抑制剂OSI -027抑制高氧诱导的肺成纤维细胞增殖和分化*吴黎虹，唐坤，党红星△，符跃强，刘成军，李静，许峰（重庆医科大学附属儿童医院重症医学科，国家儿童健康与疾病临床医学研究中心，儿童发育疾病研究教育部重点实验室，儿科学重庆市重点实验室，重庆 400014）［摘要］目的：分析哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin ， mTOR ）复合物1/2（mTORcomplex 1/2， mTORC1/2）双重抑制剂OSI -027对高体积分数氧（高氧）所致人胚肺成纤维细胞增殖和分化的抑制作用。

方法：高氧（95% O 2）处理人胚肺成纤维细胞MRC -5建立增殖分化模型，分为对照组、高氧组、高氧+OSI -027组和高氧+雷帕霉素组。

Western blot 检测α-平滑肌肌动蛋白（α-smooth muscle actin ， α-SMA ）、I 型胶原蛋白（collagen type I ， Col I ）、增殖细胞核抗原（proliferating cell nuclear antigen ， PCNA ）、细胞周期蛋白D1（cyclin D1）、RhoA 、Rho 相关含卷曲螺旋蛋白激酶1（Rho -associated coiled -coil -containing protein kinase 1， ROCK1）、蛋白激酶B （protein kinase B ， PKB/AKT ）、p -AKT 和mTOR 的表达； CCK -8实验检测细胞活力；流式细胞术检测细胞周期。

结果：与对照组相比，PCNA 、cyclin D1、Col I 和α-SMA 表达随高氧处理时间增加而增加（P <0.05）。

与高氧组相比，OSI -027及雷帕霉素干预后，细胞活力下降，细胞周期被抑制在G 1期（P <0.05）。

抗肿瘤肽的研究及应用

抗肿瘤肽的研究及应用Anticancer Peptides: Research and ApplicationAbstract: Anticancer peptides are a promising class of therapeutic molecules that have gained increasing attention in the field of cancer treatment due to their selectivity and potency against cancer cells. In this article, we discuss the latest research and applications of anticancer peptides, including their sources, mechanisms of action, and promising preclinical and clinical data. We also examine the challenges and opportunities facing the field of anticancer peptides.Keywords: anticancer peptides, cancer therapy, peptide drugs, mechanism of action, preclinical research, clinical trials. IntroductionCancer is a major global health challenge, and traditional treatments such as chemotherapy, radiation therapy, and surgery have limitations due to their nonspecific nature and adverse side effects. Anticancer peptides, on the other hand, are a promising class of therapeutic molecules that have shown to be selective and effective against cancer cells with less toxicity. In this review, we discuss the latest research on anticancer peptides, including their sources, mechanisms of action, and promising preclinical and clinical data.Sources of Anticancer PeptidesAnticancer peptides can be found in a variety of sources, includingthe natural defense systems of animals, plants, and microbes, as well as designed peptides based on natural sequences. For example, the amphibian-derived peptide dermaseptin has been shown to exhibit potent anticancer activity through disruption of cancer cell membranes. Similarly, plant-derived peptides such as thionins and cyclotides have shown cytotoxic activity against cancer cells dueto their ability to penetrate the cell membrane. Microbial peptides such as lacticin 3147, designed based on bacterial lantibiotic peptides, have also demonstrated anticancer activity through multiple mechanisms of action.Mechanisms of ActionAnticancer peptides exert their cytotoxic effects through multiple mechanisms of action, including apoptosis, autophagy, necrosis, and senescence. Apoptosis is a programmed cell death mechanism that is activated when a cell is damaged, stressed, or infected. Anticancer peptides can induce apoptosis in cancer cells through various molecular pathways, such as mitochondrial pathway, death receptor pathway, and caspase-independent pathway. Autophagy is a process by which cells recycle damaged or unwanted cellular components through lysosomal degradation. Anticancer peptides such as tachyplesin can induce autophagy in cancer cells, leadingto their death. Necrosis is an uncontrolled form of cell death that occurs after severe cellular trauma or stress. Anticancer peptides can also induce necrosis in cancer cells through their ability to disrupt cell membranes. Senescence is a cellular state of irreversible growth arrest that can prevent the proliferation of cancer cells. Anticancer peptides such as p28 can induce senescence in cancer cells, leading to their growth arrest.Preclinical and Clinical DataPreclinical research on anticancer peptides has shown promising results in vitro and in animal models. For example, the amphibian-derived peptide caerin has shown potent anticancer activity against various cancer cell lines in vitro and reduced tumor growth in mouse xenograft models. Similarly, the microbial peptide lacticin 3147 has shown selective cytotoxicity against cancer cells in vitro and improved survival in mouse models of breast cancer. In addition, several natural and designed peptides have been found to have synergistic effects when combined with conventional chemotherapy drugs.Several anticancer peptides have also advanced to clinical trials, with some showing promising results. For example, the octapeptide d(KLAKLAK)2, which induces apoptosis in cancer cells, has been tested in phase I and phase II clinical trials for treatment of various types of cancer, including glioblastoma and multiple myeloma. Similarly, the cyclic peptide tasidotin has been tested in phase III clinical trials for the treatment of ovarian cancer, with promising results.Challenges and OpportunitiesDespite the promise of anticancer peptides, several challenges remain in their development and application. One challenge is the optimization of peptide pharmacokinetics and pharmacodynamics, including their stability, bioavailability, and selective targeting of cancer cells over normal cells. Another challenge is the high costof peptide production and purification, which can limit their accessibility and affordability. Furthermore, a better understanding of the mechanisms of action and resistance to anticancer peptidesis needed to select patients who are most likely to benefit from these therapies.In conclusion, anticancer peptides represent a promising class of therapeutic molecules for the treatment of cancer, with multiple mechanisms of action and potential for combination therapy. While several peptides have shown promising preclinical and clinical results, further research is needed to optimize their efficacy and safety for widespread clinical application.参考文献：1. Ghosh S et al. Anticancer Peptides: A Perspective. Frontiers in Biology. 2016; 11(1): 49-57.2. Jenssen H et al. Antimicrobial peptides for therapeutic use: obstacles and realistic outlook. Current Opinion in Pharmacology. 2006; 6(5): 468-472.3. Liu C et al. Anticancer Peptides. Biomedical Reports. 2016; 4(3): 319-324.4. Mann S et al. Anticancer peptides: Principles, diversity, and applications. Organic & Biomolecular Chemistry. 2021; 19(4): 668-684.5. Wang Y et al. Anticancer peptides: from design to clinic.Chemotherapy. 2017; 62(1): 1-13.Optimization of Peptide Pharmacokinetics and PharmacodynamicsOne of the major obstacles in the development of anticancer peptides is the optimization of their pharmacokinetics and pharmacodynamics. Peptides are generally less stable and have shorter half-lives than small molecule drugs, which can result in lower bioavailability and poorer pharmacokinetic properties. Peptide stability can be improved through modifications such as cyclization, amino acid substitutions, and the addition of chemical groups such as acetylation or amidation. Peptide bioavailability can be improved through formulations such as liposomes, nanoparticles, or conjugation to other molecules. In addition, selective targeting of cancer cells over normal cells can be achieved through conjugation to tumor-targeting peptides or antibodies.Cost of Peptide Production and PurificationAnother challenge in the development of anticancer peptides is the high cost of peptide production and purification. Peptide synthesis is often complex and time-consuming, requiring multiple steps and specialized equipment. In addition, peptide purification can also be challenging, as peptides can be difficult to separate from impurities. Strategies to reduce the cost of peptide production and purification include developing simplified synthesis methods or producing peptides using recombinant technologies, such as expression in bacteria or yeast.Mechanisms of Action and ResistanceA better understanding of the mechanisms of action and resistance to anticancer peptides is needed to optimize their efficacy and select patients who are most likely to benefit from these therapies. While the mechanisms of action of many anticancer peptides have been studied extensively, the mechanisms of resistance are less well understood. Mechanisms of resistance can include alterations in cellular uptake or efflux of peptides, changes in peptide binding or recognition by cancer cells, and activation of cellular defense mechanisms such as the unfolded protein response or autophagy.Clinical Testing of Anticancer PeptidesDespite these challenges, several anticancer peptides have advanced to clinical testing, with some showing promising results. The octapeptide d(KLAKLAK)2 has been tested in phase I and phase II clinical trials for treatment of various types of cancer, including glioblastoma and multiple myeloma, and has shown encouraging results. The cyclic peptide tasidotin has been tested in phase III clinical trials for the treatment of ovarian cancer, with promising results. In addition, several other peptides are currently in clinical trials, including AMP-514, a designed antimicrobial peptide with anticancer activity.ConclusionAnticancer peptides are a promising class of therapeutic molecules for the treatment of cancer, with multiple mechanisms of action and potential for combination therapy. While several peptides have shown promising preclinical and clinical results, further research isneeded to optimize their efficacy and safety for widespread clinical application. Optimization of peptide pharmacokinetics and pharmacodynamics, reduction of the cost of peptide production and purification, and a better understanding of the mechanisms of action and resistance will be crucial for the successful development of anticancer peptides as a new class of cancertherapies.Optimization of Peptide Pharmacokinetics and Pharmacodynamics:Peptide drugs, including anticancer peptides, face several challenges in terms of their pharmacokinetics and pharmacodynamics. Peptides are rapidly cleared from the bloodstream and can be rapidly degraded by enzymes, leading to a shorter half-life and lower bioavailability. This makes it difficult to achieve effective concentrations of the drug at the site of action within the body. To overcome these challenges, researchers have developed a range of strategies to enhance the pharmacological properties of peptides. For instance, cyclization or other chemical modifications can promote peptide stability, and conjugation to other molecules such as nanoparticles or polymers or coupling with tumor targeting peptides or antibodies can improve peptide distribution and drug efficacy. However, the optimization process still requires extensive preclinical testing and careful balancing of efficacy, toxicity and pharmacokinetics.Cost of Peptide Production and Purification:The cost of producing and purifying peptides can be prohibitive, particularly for rare or complex sequences of amino acids. Traditional synthetic approaches to peptide synthesis are slow andrequire expensive reagents, while biological methods rely on recombinant protein technology, which has its own limitations. To reduce costs, researchers are exploring alternative routes to peptide synthesis, such as incorporating modifications at the genetic level or using innovative methods such as microfluidics or solid-phase peptide synthesis. Purification of peptides from crude mixtures also presents challenges in terms of optimizing the purity and yield of the final product, with some purification techniques being expensive and time-consuming.Mechanisms of Action and Resistance:The mechanisms of action of anticancer peptides can be complex and varied, and some peptides may exert multiple functions, such as inhibiting tumor cell growth or inducing apoptosis. Understanding the specific mechanisms of action for a given peptide is essential for its clinical development, as well as the identification of potential resistance pathways. Some cancer cells are known to be resistant to some peptide drugs due to changes in cellular uptake or efflux, altered peptide binding or recognition, or activation of cellular defense mechanisms. Researchers are currently investigating the molecular mechanisms of resistance to gain deeper insights into how to circumvent these issues.Clinical Testing of Anticancer Peptides:Clinical trials play a critical role in the development of anticancer peptides. Phase I trials are typically used to evaluate the safety and toxicity of a peptide, while Phase II and III trials assess efficacy and drug performance under more realistic treatment scenarios.The clinical testing process for peptides is especially important, given that peptides are a relatively new therapeutic modality and require unique strategies for optimization of pharmacokinetics and pharmacodynamics. Strategies such as combination therapy are also under investigation to enhance the efficacy and reduce the risk of resistance. In addition, researchers are also exploring different cancer indications, including rare or orphan diseases, to identify new opportunities for the development of anticancer peptides. Overall, anticancer peptides hold huge promise as a new class of cancer therapies with multiple mechanisms of action and potential for combination therapy. While challenges still exist in terms of optimizing peptide pharmacokinetics, reducing costs, and developing a better understanding of the mechanisms of action and resistance, clinical trials are underway, suggesting that these peptides may offer a new and promising approach to fighting cancer in the future.。

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doi:10.1006/cyto.2002.1051,available online at onLEPTIN ROLE IN ADVANCED LUNG CANCER.A MEDIATOR OF THE ACUTE PHASE RESPONSE OR A MARKER OF THE STATUS OF NUTRITION?Marı´a Remedios Alema´n,1Francisco Santolaria,1Norberto Batista,2Marı´a J.de la Vega,3Emilio Gonza´lez-Reimers,1Antonio Milena3Marta Llanos,2Juan Luis Go´mez-Sirvent1Leptin is an anorexia inductor peptide produced by adipocytes and related to fat mass.Leptin is also produced by fat under proinﬂammatory cytokine action.Our objective is to study serum leptin levels in relation to nutritional status and acute phase response in advanced-stage non-small cell lung cancer.Seventy-six patients newly diagnosed of non surgical non-small cell lung cancer before chemotherapy treatment and30healthy controls were included.BMI,serum leptin and cholesterol levels and lymphocyte count were decreased in lung cancer patients.Cytokine IL-6, TNF- ,sTNF-RII,sIL-2R,IL-12,IL-10and IFN- ,and other acute phase reactants as 1 antitrypsin,ferritin,CRP and platelets were all raised in patients,whereas the IL-2was decreased.We found a direct relationship between leptin and other indicators of the status of nutrition,especially total fat mass.We also found a close relationship between the status of nutrition and the performance status(Karnofsky index).However,serum leptin and nutritional status were inversely correlated with acute phase proteins and proinﬂammatory cytokines, suggesting a stress-type malnutrition.Although serum leptin levels,nutritional status and Karnofsky index are related to survival,at multivariate analysis they all were displaced by the acute phase reaction markers.These results suggest that cancer anorexia and cachexia are not due to a dysregulation of leptin production.Circulating leptin concentrations are not elevated in weight-losing cancer patients and are inversely related to the intensity of the inﬂammatory response.In advanced lung cancer patients serum leptin concentrations only depend on the total amount of fat.2002Elsevier Science Ltd.All rights reserved.Leptin is a peptide member of the cytokine receptor family,which is produced primarily by fat cells.It regulates fat mass by decreasing food intake (it decreases the content of neuropeptide Y at the hypothalamus)and increasing resting energy expendi-ture.1Serum leptin concentrations are highly corre-lated with body fat content,2and its production by adipocytes rapidly declines during starvation. Besides this,leptin is also produced by fat under proinﬂammatory cytokine action,its increase having been reported in the acute phase reaction of sepsis. Leptin increases by the action of endotoxin or cytokines,and has been involved in the anorexia of infection.3–6Weight loss is frequently observed in advanced cancer.7,8Decreased food intake,hypermetabolism, and acute phase response with metabolic disturbances, partly due to host-derived and tumour substances, including various cytokines,are considered important wasting factors.9–12Since anorexia and hypermetab-olism frequently play a role in the development of cancer cachexia,it has been hypothesized that increased leptin secretion could be involved in its pathogenesis.There is evidence that ob gene expression may be up-regulated by pro-inﬂammatory cytokines such as TNF 13and IL-1,14which are also involved in the pathophysiology of cancer cachexia.However, Simons et al.15reported low or undetectable circulating leptin concentrations in patients with lung cancer andFrom the1Servicio de Medicina Interna,2Seccio´n de Oncologı´aMe´dica,3Servicio de Laboratorio,Hospital Universitario deCanarias,Tenerife,SpainCorrespondence to:Marı´a Remedios Alema´n,Servicio de MedicinaInterna,Hospital Universitario de Canarias,C/Ofra s/n,Univer-sidad de La Laguna,38320Tenerife,Spain.Tel:(922)678684;Fax:(922)653808;E-mail mraleman@comtf.esReceived3August2001;received in revised form17May2002;accepted for publication10June20021043–4666/02/$-see front matter 2002Elsevier Science Ltd.All rights reserved.KEY WORDS:lung cancer/malnutrition/acute phase reaction/cytokine/leptinCYTOKINE,Vol.19,No.1(7July),2002:pp21–2621weight loss,although these investigators did not examine the relationship with the inﬂammatory response.Wallace et al.16found that circulating leptin concentrations in gastrointestinal cancer patients were not related to inﬂammatory response,suggesting that cancer cachexia is not due to a dysregulation of leptin production.Moreover,Lopez Soriano et al.17found that anorexia was not related to leptin changes in experimental cancer.Our objective is to analyse the relation of serum leptin levels with the nutritional status and the inﬂam-matory response(acute phase reaction)in patients with advanced non-small cell lung cancer.RESULTSThe distribution by stage was:6III A non surgical, 30III B and40IV.The histological distribution was37 (48.7%)adenocarcinoma,22(28.9%)epidermoid and 17(22.4%)large cell carcinoma.Regarding status performance assessment,19(25%)had a Karnofsky of 90%,36(47%)a Karnofsky of80%,and21(27,6%)a Karnofsky of70%.Serum LDH levels were also raised in patients compared with controls(P<0.001).Thirty three patients(43.4%)reported anorexia, 30(23%)had lost at least5%of the body weight(27% of them had lost10%or more)and in12(15.8%) patients the BMI was under20kg/m2.Serum leptin, cholesterol and total lymphocyte count were all lower in patients regarding controls(P<0,001).However,we did notﬁnd signiﬁcant diﬀerences regarding serum albumin levels(Table1).Proinﬂammatory cytokines IL-6,TNF- ,sTNF-RII,sIL-2R and IL-12,antiinﬂammatory cytokine IL-10,other acute phase reactants as 1antitrypsin, ferritin,CRP and platelets and immune IFN- were all signiﬁcantly raised in lung cancer patients compared with controls whereas IL-2was decreased(Table1). Leptin,nutritional status and acute phase reaction High serum leptin levels were related with a better status of nutrition,assessed by serum albumin levels, body fat mass,BMI,serum leptin levels and subjective nutritional score.Moreover,we observed a very close, and highly signiﬁcant,correlation between serum leptin levels and fat mass assessed by bioimpedance (Spearman,rho=0.800,P<0.001)(Table2).We also observed a close relationship,between the nutritional status with the performance status(Karnofsky index): the worse the nutritional status the worse the perform-ance status(serum albumin:P=0.017,fat mass:P=0.015,serum leptin:P=0.015,BMI:P=0.019and SNS:P=0.021).We found a negative relation between serum leptin levels and PCR, 1antitrypsin,platelet count,serum ferritin and the proinﬂammatory cytokines IL-6, sTNF-RII and sIL-2R.So,the status of nutrition was worse and the leptin levels were lower in parallel with a more intense acute phase response(Table2).On the TABLE 1.Nutritional status,leptin,LDH,acute phase response and cytokines levels in patients and controlsPatientsX EE(x)ControlsX EE(x)P(UMW)General characteristicsLDH(U/L)417.66 22.83305.93 8.140.000 Nutritional statusLeptin(ng/ml)7.11 0.9118.50 4.170.000 Cholesterol(mg/dl)193.57 5.92211.40 5.830.000 Albumin(g/dl) 3.94 0.07 4.08 0.040.435 Acute phase responsePlatelets(cell/mm3)281.84 10.77217.97 8.100.001 CRP*(mg/dl) 5.08 0.530.87 0.060.001 1antitrypsin(mg/dl)219.56 8.26168.79 3.860.001 ferritin( g/dl)352.56 32.14155.23 19.880.001 CytokinesIL-6(pg/ml)34.06 21.44 5.25 0.080.002 TNF- (pg/ml)15.02 8.17 5.89 0.320.006 s-TNFRII(ng/ml) 3.44 0.20 1.99 0.070.001 s-IL-2R(UI/ml)906.27 64.64507.34 26.130.001 IL-12(pg/ml)37.77 12.3113.61 4.050.000 IL-10(pg/ml)18.61 1.687.68 1.140.000 IFN- (UI/ml) 1.61 0.220.25 0.030.001 IL-2(UI/ml)159.19 20.26267.61 26.530.001*CRP:C reactive protein.TABLE2.Relation between leptin and Karnofsky index and nutritional status and acute phase responseLeptinSpearman rho P Karnofsky index0.3640.001Nutritional statusBMI*(kg/m2)0.6430.001 SNS** 0.5720.001 Cholesterol(mg/dl)0.4390.001 Albumin(g/dl)0.3570.002fat mass(kg)0.8000.001 Acute phase response1antitrypsin(mg/dl) 0.2900.012 ferritin( g/dl) 0.3800.001 Platelets(cell/mm3) 0.2890.012 CRP***(mg/dl) 0.4620.001CytokinesIL-6(pg/ml) 0.4140.001 TNF- (pg/ml) 0.1510.197s-TNFRII(ng/ml) 0.3350.003s-IL-2R(UI/ml) 0.5030.001IL-12(pg/ml) 0.1990.088IL-10(pg/ml)0.0910.436IL-2(UI/ml)0.3330.003 IFN- (UI/ml)0.1290.270*BMI:body mass index;**SNS:subjective nutritional score;***CRP:C reactive protein.22/Alema´n et al.CYTOKINE,Vol.19,No.1(7July,2002:21–26)contrary,we found a direct relation between serum leptin levels and the proimmune lymphocyte cytokines IFN- and IL-2.Survival analysisThe median survival of the whole group was 198days.Patients with higher serum LDH levels,lower Karnofsky index and a more impaired nutritionalstatus (lower BMI,serum albumin and leptin levels (Fig.1),and worse subjective nutritional score)had a shorter survival,analysed by Kaplan and Meyer curves (Table 3).Patients with an enhanced acute phase response also showed an impaired prognosis.Excluding TNF ,all proinﬂammatory cytokines IL-6,sTNF-RII,sIL-2R and IL-12,were related to a worse prognosis.On the contrary,proimmune cytokines IFN- ,IL-2,were related to a better prognosis.Multivariate analysis (Cox regression analysis with covariates)showed that raised serum levels of sTNF-RII, 1antitrypsin,LDH and platelets were all survival factors with independent prognostic value,whereas all the nutritional variables,including serum leptin levels,and Karnofsky index were displaced by the acute phase reactants.DISCUSSIONPatients with advanced non-small cell lung cancer frequently su ﬀer anorexia,weight loss and malnutri-tion leading to a low BMI,low fat mass and serum leptin levels,all of them factors associated with a worse prognosis.The Karnofsky index is another well known prognostic factor in patients with cancer.Moreover,we observed a close relationship between the performance status and the nutritionalstatus,Figure 1.Decreased serum leptin levels are related to shortersurvival.However at multivariate analysis acute phase reaction (proinﬂam-matory cytokines)provide a better information about prognosis.TABLE 3.Survival in advanced non-small lung cancer patients.Univariate and multivariate analysisUnivariate analysisMultivariate analysis (Cox regression)Log rank testPMedian survivalCI 95%R.R.C.I.95%PGeneral characteristics LDH>400(UI/L)16.010.000113797–177 2.18 3.67–1.300.0033Karnofsky <90%11.910.0006184152–216Nutritional status Leptin <2.4( g/L)11.430.0007157126–223SNS*>211.740.0006162135–189BMI**<22(kg/m 2)4.290.0384162129–195Cholesterol <200(mg/dl)9.520.0020184160–208Acute phase responsePlatelets >320 103/mm 314.140.0002156149–163 2.20 4.45–1.080.0292CRP***>613.440.0002157123–191 1antitrypsin >170(mg/dl)18.800.0000176144–208 3.547.32–1.710.0007Ferritin >440( g/dl)7.870.0050157153–161CytokinesIL-6>5(pg/ml)16.010.0001176151–201rs-TNF- >3.6(ng/ml)20.760.0000156125–187 2.47 4.95–1.230.0114rs-IL-2>750(UI/ml)12.510.0004176147–205IL-12>4(pg/ml) 5.280.021*******–176IFN- <1.5(UI/ml) 5.810.0159192170–214IL-2<130(UI/ml) 3.980.0459184161–206TNF- >5(pg/ml)0.560.4554193176–210IL-10>9.5(pg/ml)1.650.1996193176–210*SNS subjective nutritional score;**BMI:body mass index;***CRP:C reactive protein.R.R.:relative risk;C.I.95%:conﬁdence interval.Cut-o ﬀpoints were selected according to those which provided a better signiﬁcance regarding survival with the Kaplan and Meier analysis.Leptin role in advanced lung cancer /23probably reﬂecting the eﬀect of muscle and other protein loss on performance.It is unclear whether leptin acts as an acute phase reactant,leading to anorexia and malnutrition,or if it is only a simple marker of fat mass in cancer associated malnutrition.Diﬀerent studies have shown that leptin concentrations are increased during cytokine-induced inﬂammatory response in sepsis patients,3–6suggesting that raised leptin levels may be related to anorexia. However in many common diseases leading to cachexia,in which there is also an inﬂammatory status caused by raised proinﬂammatory cytokines,serum leptin levels are decreased.This is the case of wasting associated to chronic obstructive pulmonary disease (COPD)in which,despite an increase of TNF ,there are low leptin levels which keep a relation with decreased fat mass,18,19or chronic heart failure cachexia,in which serum TNF and IL-1levels are increased but leptin ones are decreased.20,21Also,in chronic inﬂammatory bowel disease and in wasting AIDS low or normal serum leptin levels have been reported despite an increase of sTNF-RII.22,23 Our results are in accordance with last studios. Serum leptin levels were lower in patients than in controls and,more decreased in the malnourished patients(as expected the relation was especially close with fat mass),despite an increase of proinﬂammatory cytokines and acute phase reactants.In advanced lung cancer patients we found that acute phase reactants as CRP,ferritin and 1antitrypsin,the proinﬂammatory cytokines IL-6,TNF- ,sTNF-RII,sIL-2R,IL-12,the antiinﬂammatory IL-10and the proimmune IFN- were all raised,together with,an impaired nutritional status and low serum leptin levels.On the contrary, IL-2,a proimmune cytokine,was decreased,perhaps pointing to a depressed T cell immune response.More-over,the increased acute phase response and cytokine levels were related to an impaired status of nutrition including decreased serum leptin levels.So,the increase of acute phase reactants related to lower serum leptin levels and worse nutritional and performance status, suggest a stress-type malnutrition.Our results do not support the hypothesis that high serum leptin levels,produced by a intense acute phase reaction,could be involved in anorexia and cachexia associated to cancer.Moreover,serum leptin levels were not higher in patients with anorexia,and weight loss was associated with low serum leptin concentrations.These results are similar to the reports of Simons et al.(1997)15and Brown et al.(2001)24in lung cancer,and Wallace et al.(1998)16in gastro-intestinal cancer and Mantovani et al.(2000)25in pancreas cancer,in which leptin concentrations were not elevated in weight-loosing cancer patients.Although the median survival of the whole group is only198days,by survival analysis we found that the status of nutrition,including leptin,the performance status and the acute phase reaction,were related to prognosis.However,in the multivariate analysis the performance status was displaced by the status of nutrition and this one by the acute phase reaction, indicating that all of them are related,providing similar information about survival,and reinforcing the importance of acute phase reaction and stress malnutrition in the evolution of advanced lung cancer.As conclusion,serum leptin levels are not raised in patients with advanced non-small cell lung cancer,and its production is not induced by the inﬂammatory response.Moreover,concentrations of leptin seem appropriate for the amount of body fat.Therefore,it would appear that cancer anorexia and cachexia are due to stress malnutrition and they are not caused by a dysregulation of leptin production.Perhaps in advanced malnutrition serum leptin levels are more dependent on to fat mass than on cytokine eﬀect. MATERIALS AND METHODSPatientsBetween January1997and November1999we studied 76patients(67males and9females),with a median age of 62.5years(range36–75)recently diagnosed of non-small cell lung cancer,in advanced(non-surgical)stage,and before chemotherapy treatment.Patients were not included if brain metastasis were present,or if a poor performance status (Karnofsky index less than70%),or if any other chronic disease producing malnutrition was present.The control group was composed of30healthy subjects(26males and4 females)with a median age of58.5years(range38–75).All patients had been diagnosed by histological or cytological means.Status performance was assessed by the Karfnosky scale26.The TNM classiﬁcation27was assessed by chest and upper abdominal CT scan,and a bone radionuclide scan,and was used for sstaging.Serum lactic dehydrogenase(LDH) levels were also used as an index of tumour bulk. Nutritional assessmentWeight and height were recorded at admittance,with further calculation of body mass index(BMI)as weight/ height2.Anorexia and weight loss were also recorded with further calculation of weight lost percentage as:weight lost/(current weight+lost weight) 100.Subjective nutritional assessment included examination of the muscle masses of the upper and lower limbs and of the temporal muscle,deﬁning two degrees of atrophy(severe, moderate),and absence of atrophy.We assigned2.1and 0points to each category,respectively.Bichat’s fat and subcutaneous fat atrophy,recorded by physical examination were classiﬁed in the same way.Thus,we have deﬁned a subjective nutritional score(SNS)based on the sum of the assigned points,the poorest value being10,and0the best one,as previously reported.28The fat mass and fat-free mass24/Alema´n et al.CYTOKINE,Vol.19,No.1(7July,2002:21–26)were assessed by bioelectric impedance.We also determined serum of cholesterol,lymphocytes and serum albumin levels. Acute phase proteins,cytokines and leptin assessmentBlood samples were obtained at0800h in fasting con-ditions and serum was frozen at 40 C for further deter-mination.Assays performed were:serum leptin levels by Inmunoradiometric Assay(IRMA),CRP by Fluorescence Polarization Immunoassay(FPIA)(Diagnostic Division Abbott),IL-6,TNF- and sIL-2R by chemiluminescent immunometric assay(Diagnostic Products Corporation), IFN- ,IL-2and IL-12by immunoenzymatic assay (Immunotech),IL-10by enzyme immunometric assay in a microplate format(Diagnostic Products Corporation), sTNF-R by Enzyme Ampliﬁed Sensitivity Immunoassay (EASIA)performed on microtiter plate(Biosource).All the assays were of high standard quality with very low cross reactivity,i.e.very high speciﬁcity.We also determined cholesterol,albumin,ferritin and 1antitrypsin.The same analysis were performed to30healthy controls. 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