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Obesity and colorectal cancer:Role of adipokines in tumor initiation and progression

World Journal of Gastroenterology 2014年第18期20卷 5177-5190页

作者： Silvia Riondino Mario Roselli Raffaele Palmirotta David Della-Morte Patrizia Ferroni Fiorella Guadagni department of Systems Medicine Medical OncologyTor Vergata Clinical CenterUniversity of Rome "Tor Vergata"00133 RomeItaly biomarker discovery and Advanced Technologies (BioDAT) Laboratory IRCCS San Raffaele Pisana-Research Center00166 RomeItaly

Obesity-associated diseases account for a large portion of public health challenges. Among obesity-related disorders, a direct and independent relationship has been ascertained for colorectal cancer (CRC). The evidence that adipocyte hypertrophy and excessive adipose tissue accumulation (mainly visceral) can promote pathogenic adipocyte and adipose tissue-related diseases, has led to formulate the concept of “adiposopathy”, defined as adipocyte and adipose tissue dysfunction that contributes to metabolic syndrome. Adipose tissue can, indeed, be regarded as an important and highly active player of the innate immune response, in which cytokine/adipokine secretion is responsible for a paracrine loop between adipocytes and macrophages, thus contributing to the systemic chronic low-grade inflammation associated with visceral obesity, which represents a favorable niche for tumor development. The adipocyte itself participates as a central mediator of this inflammatory response in obese individuals by secreting hormones, growth factors and proinflammatory cytokines, which are of particular relevance for the pathogenesis of CRC. Among adipocyte-secreted hormones, the most relevant to colorectal tumorigenesis are adiponectin, leptin, resistin and ghrelin. All these molecules have been involved in cell growth and proliferation, as well as tumor angiogenesis and it has been demonstrated that their expression changes from normal colonic mucosa to adenoma and adenocarcinoma, suggesting their involvement in multistep colorectal carcinogenesis. These findings have led to the hypothesis that an unfavorable adipokine profile, with a reduction of those with an anti-inflammatory and anti-cancerous activity, might serve as a prognostic factor in CRC patients and that adipokines or their analogues/antagonists might become useful agents in the management or chemoprevention of CRC.

关键词： Obesity Colorectal cancer Inflammation Adiponectin Leptin Resistin Ghrelin Cytokines

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Pancreatic cancer serum biomarker PC-594:Diagnostic performance and comparison to CA19-9

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World Journal of Gastroenterology 2015年第21期21卷 6604-6612页

作者： Shawn A Ritchie Bassirou Chitou Qingan Zheng Dushmanthi Jayasinghe Wei Jin Asuka Mochizuki Dayan B Goodenowe department of biomarker discovery and validation Phenome- nome DiscoveriesSaskatoonSK S7N 4L8Canada department of Manufacturing Phenomenome DiscoveriesSaskatoonSK S7N 4L8Canada Phenomenome Laboratory Services Phenomenome Discoveries

AIM:To investigate serum PC-594 fatty acid levels as a potential biomarker in North American pancreatic cancer(PaC) patients,and to compare its performance to ***:Using tandem mass spectrometry,we evaluated serum PC-594 levels from 84 North American patients with confirmed PaC and 99 cancer-free control *** determined CA19-9 levels by *** between Pa C patients and controls,and association with clinical variables was determined by analysis of variance and *** performance was evaluated by receiver-operator characteristic(ROC)curve analysis,and PC-594 correlation with age and CA19-9 determined by regression ***:Mean PC-594 levels were 3.7 times lower in Pa C patients compared to controls(P 0.05).Using 1.25 μmol/L as a PC-594 threshold produced a relative risk(RR) of 9.4(P biomarker levels are significantly reduced in North American Pa C patients,and showed superior diagnostic performance compared to CA19-9.

关键词： Pancreatic cancer Risk Screening Blood Fatty acid biomarker Metabolite PC-594

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Structure and function of epididymal protein cysteine-rich secretory protein-1

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Asian Journal of Andrology 2007年第4期9卷 508-514页

作者： Kenneth P. Roberts Daniel S. Johnston Michael A. Nolan Joseph L. Wooters Nicole C. Waxmonsky Laura B. Piehl Kathy M. Ensrud-Bowlin David W. Hamilton department of Urologic Surgery Cell Biology and Development University of Minnesota Minneapolis MN 55455 Contraception Women＇s Health ＆ Musculoskeletal Biology Woman＇s Health Research Institute Wyeth Research Collegeville PA 19426 USA Inflammation department Molecular Profiling and Biomarker Discovery Wyeth Research Cambridge MA 02140 USA Biological Technologies Molecular Profiling and Biomarker Discovery Wyeth Research Cambridge MA 02140 USA department of Genetics Cell Biology and Development University of Minnesota Minneapolis MN 55455 USA

Cysteine-rich secretory protein-1 （CRISP-1） is a glycoprotein secreted by the epididymal epithelium. It is a member of a large family of proteins characterized by two conserved domains and a set of 16 conserved cysteine residues. In mammals, CRISP-1 inhibits sperm-egg fusion and can suppress sperm capacitation. The molecular mechanism of action of the mammalian CRISP proteins remains unknown, but certain non-mammalian CRISP proteins can block ion channels. In the rat, CRISP-1 comprises two forms referred to as Proteins D and E. Recent work in our laboratory demonstrates that the D form of CRISP-1 associates transiently with the sperm surface, whereas the E form binds tightly. When the spermatozoa are washed, the E form of CRISP-1 persists on the sperm surface after all D form has dissociated. Cross-linking studies demonstrate different protein-protein interaction patterns for D and E, although no binding partners for either protein have yet been identified. Mass spectrometric analyses revealed a potential post-translational modification on the E form that is not present on the D form. This is the only discernable difference between Proteins D and E, and presumably is responsible for the difference in behavior of these two forms of rat CRISP- 1. These studies demonstrate that the more abundant D form interacts with spermatozoa transiently, possibly with a specific receptor on the sperm surface, consistent with a capacitation-suppressing function during sperm transit and storage in the epididymis, and also confirm a tightly bound population of the E form that could act in the female reproductive tract. （Asian J Androl 2007 July; 9： 508-514）

关键词： cysteine-rich secretory protein-1 epididymis sperm capacitation

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Future of the current anticoronaviral agents: A viewpoint on thevalidation for the next COVIDs and pandemics

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BIOCELL 2023年第10期47卷 2133-2139页

作者： AMGAD M.RABIE Drug discovery&Clinical Research department Dikernis General Hospital(DGH)Dikernis35744Egypt

Despite the global decline in the severity of the coronavirus disease 2019 (COVID-19) cases, the disease stillrepresents a major concern to the relevant scientific and medical communities. The primary concern of drug scientists,virologists, and other concerned specialists in this respect is to find ready-to-use suitable and potent anticoronaviraltherapies that are broadly effective against the different species/strains of the coronaviruses in general, not only againstthe current and previous coronaviruses (e.g., the recently-appeared severe acute respiratory syndrome coronavirus 2“SARS-CoV-2”), i.e., effective antiviral agents for treatment and/or prophylaxis of any coronaviral infections, includingthose of the coming ones from the next species and strains (if any). As an expert in this field, I tried, in this up-to-dateperspective “viewpoint” article, to evaluate the suitability and applicability of using the currently-availableanticoronaviral agents for the next coronavirus diseases (COVIDs) and coronaviral pandemics, highlighting the mostimportant general guidelines that should be considered in the next pandemics from the therapeutic points of view.

关键词： SARS-CoV-2/COVID-19 Spike(S)protein/Main protease(Mpro)/RNA-dependent RNA polymerase(RdRp) General anticoronaviral drug Specific anti-COVID-19 medication Molnupiravir/Nirmatrelvir/Riboprine/Ensitrelvir Drug design and development

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HNRNPC as a pan-cancer biomarker and therapeutic target involved in tumor progression and immune regulation

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Oncology research 2025年第1期33卷 83-102页

作者： Yuezhou Zhang Zhao Zhang Jinxin Dong Changan Liu department of Hepatobiliary Surgery The Second Affiliated Hospital of Chongqing Medical University Chongqing 400016 China. department of Hepatobiliary Surgery The First Affiliated Hospital of Chongqing Medical University Chongqing 400016 China.

Background:Aberrant expression of RNA-binding proteins (RBPs) has been linked to a variety of diseases, including hematological disorders, cardiovascular diseases, and multiple types of cancer. Heterogeneous nuclear ribonucleoprotein C (HNRNPC), a member belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family, plays a pivotal role in nucleic acid metabolism. Previous studies have underscored the significance of HNRNPC in tumorigenesis; however, its specific role in malignant tumor progression remains inadequately characterized.Methods:We leveraged publicly available databases, including The Cancer Genome Atlas (TCGA), to explore the potential involvement of HNRNPC across various cancers. Additionally, we performed experimental validation studies focused on liver cancer.Results:Our analysis revealed that HNRNPC is overexpressed in a wide range of common malignancies, including liver and lung cancers, and is strongly linked to unfavorable outcomes. Furthermore, HNRNPC was observed to be closely linked to tumor immunity. Through immune checkpoint analysis and immune cell infiltration assessment, HNRNPC emerged as a potential target for modulating tumor immunotherapy. Notably, silencing of HNRNPC markedly inhibited the proliferation, metastasis, and infiltration of liver cancer cells.Conclusion:In summary, our findings highlight HNRNPC as a prognostic marker in various cancers, including liver cancer, and suggest its involvement in shaping the tumor immune microenvironment. These insights offer potential avenues for improving clinical outcomes in tumors with elevated HNRNPC expression, particularly through immunotherapeutic strategies.

关键词： Hepatocellular carcinoma Heterogeneous nuclear ribonucleoprotein C (HNRNPC) Immunotherapeutic target Pan-cancer analysis Prognostic biomarker Tumor immunity

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HCS strategy targeting dysregulation of the VHL/HIF pathway for drug discovery

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Advances in Bioscience and Biotechnology 2013年第3期4卷 398-405页

作者： Bastien Cautain Nuria de Pedro Maria Munoz de Escalona Jose R.Tormo Olga Genilloud Francisca Vicente Screening and Target validation department Fundacion MedinaGranadaSpain

One-third of top-selling drugs are derived from natural products. When only a fraction of the bioactive natural products diversity has been explored, huge opportunities still remain for discovering novel leads for the development of new drugs. Clear cell renal cell carcinoma (ccRCC) is a highly vascular tumour arising from epithelial elements. Mutations in the Von Hippel-Lindau (VHL) gene are responsible for VHL disease and arise in the majority of Renal Cell Carcinoma (RCC) as well as in other types of cancer. Renal carcinoma cell lines with naturally occurring VHL mutations (RCC4 VA) and their genetically matched wild-type VHL (RCC4 VHL) counterparts were seeded onto 96-well plates and allowed to attach overnight. Fungal extracts were tested on both cell lines. Clinically useful antitumor agents were used as positive controls and as reference points to establish the efficacy and selectivity of the new compounds. Renal cell carcinoma cell lines expressing VHL or not were treated with Carboxyfluorescein succinimidyl ester (CFSE). The day after cell inoculation, extracts were added and during the following days of incubation, fluorescence intensity was measured as a surrogate marker for cell viability. The most promising extracts selectively inhibited growth of pVHL-defi- cient cells but not of wild-type VHL cells. We used High Content Bio-imaging, a complete cellular imaging workflow that integrates instruments and software to acquire and analyze images, to evaluate their effect. Cell imaging can reveal effects that would be overlooked by other cell assay approaches. This target-based whole cell screen is a new strategy, which ensures cell permeability and target selectivity especially in natural product screening where natural product purification is a labour of extensive work. This approach permitted a dynamic study where fluorescence was measured without affecting cell viability and enabling a better detection of cytotoxic effects such as autophagy, senescence or

关键词： High Content Screening Natural Products HIF Drug discovery

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NPS31807, a Standardized Extract from <i>Sphaeranthus indicus</i>, Inhibits Inflammatory, Migratory and Proliferative Activity in Keratinocytes and Immune Cells

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Pharmacology & Pharmacy 2012年第2期3卷 178-194页

作者： Debarshi Chakrabarti Ashish Suthar Gurunathan Jayaraman Bhaskaran Muthuvelan Somesh Sharma Muralidhara Padigaru department of biomarker discovery Piramal Life Sciences India Limited Mumbai India department of Herbal Development Piramal Life Sciences India Limited Mumbai India School of Biosciences and Technology VIT University Vellore India

Chronic inflammation induced hyper-proliferation, and migration of keratinocytes are pathological hallmarks of psoriasis. Extracts from Sphaeranthus spp. demonstrate pharmacological activity in-vitro and in-vivo. However, the activity in modulating disease relevant pathways in psoriasis has not been reported. In the current study, a standardized herbal extract from Sphaeranthus indicus (NPS31807) was used to study the mechanistic activity under conditions of inflammation, keratinocyte proliferation and migration using cell based and gene expression assays. NPS31807 treatment reduced levels of pro-inflammatory cytokines from human macrophages and activated epidermal keratinocytes in a dose dependent manner. Treatment with NPS31807 diminished NFκB and AP-1 transcription activity in human macrophages. Lowered nuclear translocation of p65 sub-unit in macrophages by treatment confirmed reduced activity of NFκB. Gene expression profiling showed attenuated expression of genes involved with inflammation such as TNF signaling, and angiogenesis by NPS31807. Inhibition of angiogenesis and matrix metalloproteinase production in keratinocytes was confirmed using RTq-PCR assays. Pretreatment with NPS31807 led to significant reduction of STAT3 phosphorylation and mitogen induced cellular migration. NPS31807 induced inhibition of proliferative genes and BrdU uptake in epidermal keratinocytes. In summary, our study provides novel molecular insights into the anti-inflammatory, anti-migratory and anti-proliferative properties of NPS31807. In summary, NPS31807, an extract from Sphaeranthus indicus can be used as therapeutic option in inflammatory and auto-immune conditions such as psoriasis.

关键词： Herbal Extract Cytokine Psoriasis NPS31807 Keratinocyte Sphaeranthus Phytopharmaceutical

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Integrated analysis of public datasets for the discovery and validation of survival-associated genes in solid tumors

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The Innovation 2024年第3期5卷 129-137页

作者： Balázs Gyorffy department of Biophysics Medical SchoolUniversity of Pecs7624 PecsHungary department of Bioinformatics Semmelweis University1094 BudapestHungary Cancer biomarker Research Group Institute of Molecular Life SciencesHUN-REN Research Centre for Natural Sciences1117 BudapestHungary

Identifying genes with prognostic significance that can act as biomarkers in solid tumors can help stratify patients and uncover novel therapy ***,our goal was to expand our previous ranking analysis of survival-associated genes in various solid tumors to include colon cancer specimens with available transcriptomic and clinical data.A Gene Expression Omnibus search was performed to identify available datasets with clinical data and raw gene expression measurements.A combined database was set up and integrated into our Kaplan-Meier plotter,making it possible to identify genes with expression changes linked to altered *** a demonstration of the utility of the platform,the most powerful genes linked to overall survival in colon cancer were identified using uni-and multivariate Cox regression *** combined colon cancer database includes 2,137 tumor samples from 17 independent *** most significant genes associated with relapse-free survival with a false discovery rate below 1%in colon cancer carcinoma were RBPMS(hazard rate[HR]=2.52),TIMP1(HR=2.44),and COL4A2(HR=2.36).The three strongest genes associated with shorter survival in stage II colon cancer include CSF1R(HR=2.86),FLNA(HR=2.88),and TPBG(HR=2.65).In summary,a new integrated database for colon cancer is presented.A colon cancer analysis subsystem was integrated into our Kaplan-Meier plotter that can be used to mine the entire database(https://***).The portal has the potential to be employed for the identification and prioritization of promising biomarkers and therapeutic target candidates in multiple solid tumors including,among others,breast,lung,ovarian,gastric,pancreatic,and colon cancers.

关键词： colon tumors analysis

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Molecular mechanism of peritoneal dissemination in gastric cancer

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Journal of Cancer Metastasis and Treatment 2018年第1期4卷 451-458页

作者： Qing-Jiang Hu Shuhei Ito Kazuyoshi Yanagihara Koshi Mimori department of Surgery Kyushu University Beppu HospitalBeppu 874-0838Japan department of Surgery and Science Kyushu University HospitalFukuoka 812-8582Japan Division of biomarker discovery Exploratory Oncology Research&Clinical Trial CenterNational Cancer CenterKashiwa 277-8577Japan

Peritoneal dissemination(PD)is the most common cause of metastasis in gastric cancer(GC).Because there are no standard treatments for PD,it is associated with a poor *** clinicians have performed intraperitoneal chemotherapy for GC with PD,the outcome remains ***,the development of novel treatments and diagnostic tools for PD is expected to improve the prognosis of GC patients with ***,it is essential to elucidate the molecular mechanisms involved in the development of PD in *** this review,the molecular mechanisms of PD(three steps:detachment from the primary tumor,adaptation to the microenvironment of the peritoneal cavity,and attachment to peritoneal mesothelial cells)and new topics in GC are highlighted.

关键词： Gastric cancer peritoneal dissemination molecular mechanism

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Identification of epididymis-specific transcripts in the mouse and rat by transcriptional profiling

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Asian Journal of Andrology 2007年第4期9卷 522-527页

作者： Daniel S. Johnston Terry T. Turner Joshua N. Finger Tracy L. Owtscharuk Gregory S. Kopf Scott A. Jelinsky Contraception Women＇s Health and Musculoskeletal Biology Wyeth Research Collegeville PA 19426 USA department of Urology University of Virginia Health Science System Charlottesville VA 22908 Cell Biology University of Virginia Health Science System Charlottesville VA 22908 USA Biological Technologies Molecular Profiling and Biomarker Discovery Wyeth Research Cambridge MA 02140 USA

As part of our efforts to identify novel contraceptive targets in the epididymis we performed transcriptional profiling on each of the 10 and 19 segments of the mouse and rat epididymidis, respectively, using Affymetrix whole genome microarrays. A total of 17 096 and 16 360 probe sets representing transcripts were identified as being expressed in the segmented mouse and rat epididymal transcriptomes, respectively. Comparison of the expressed murine transcripts against a mouse transcriptional profiling database derived from 22 other mouse tissues identified 77 transcripts that were expressed uniquely in the epididymis. The expression of these genes was further evaluated by reverse transcription polymerase chain reaction （RT-PCR） analysis of RNA from 21 mouse tissues. RT-PCR analysis confirmed epididymis-specific expression of Defensin Beta 13 and identified two additional genes with expression restricted only to the epididymis and testis. Comparison of the 16 360 expressed transcripts in the rat epididymis with data of 21 other tissues from a rat transcriptional profiling database identified 110 transcripts specific for the epididymis. Sixty-two of these transcripts were further investigated by qPCR analysis. Only Defensin 22 （E3 epididymal protein） was shown to be completely specific for the epididymis. In addition, 14 transcripts showed more than 100-fold selective expression in the epididymis. The products of these genes might play important roles in epididymal and/or sperm function and further investigation and validation as contraceptive targets are warranted. The results of the studies described in this report are available at the Mammalian Reproductive Genetics （MRG） Database （http：//mrg. ***/）. （Asian J Androl 2007July; 9： 522-527）

关键词： mouse rat epididymis transcriptional profiling contraception microarray epididymis-specific epididymis-selective

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