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MYC inhibitors in multiple myeloma

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Cancer Drug Resistance 2021年第4期4卷 842-865页

作者： Sandra Martínez-Martín Laura Soucek Preclinical&Translational Research Program Vall d’Hebron Institute of Oncology(VHIO)Vall d’Hebron Barcelona Hospital CampusBarcelona 08035Spain Peptomyc S.L. Vall d’Hebron Barcelona Hospital CampusBarcelona 08035Spain Department of Biochemistry and Molecular Biology Universitat Autònoma de BarcelonaBellaterra 08193Spain InstitucióCatalana de Recerca i Estudis Avançats(ICREA) Barcelona 08010Spain

The importance of MYC function in cancer was discovered in the late 1970s when the sequence of the avian retrovirus that causes myelocytic leukemia was identified.Since then,over 40 years of unceasing research have highlighted the significance of this protein in malignant transformation,especially in hematologic diseases.Indeed,some of the earliest connections among the higher expression of proto-oncogenes(such as MYC),genetic rearrangements and their relation to cancer development were made in Burkitt lymphoma,chronic myeloid leukemia and mouse plasmacytomas.Multiple myeloma(MM),in particular,is a plasma cell malignancy strictly associated with MYC deregulation,suggesting that therapeutic strategies against it would be beneficial in treating this disease.However,targeting MYC was-and,somehow,still is-challenging due to its unique properties:lack of defined three-dimensional structure,nuclear localization and absence of a targetable enzymatic pocket.Despite these difficulties,however,many studies have shown the potential therapeutic impact of direct or indirect MYC inhibition.Different molecules have been tested,in fact,in the context of MM.In this review,we summarize the current status of the different compounds,including the results of their clinical testing,and propose to continue with the efforts to identify,repurpose,redesign or improve drug candidates to combine them with standard of care therapies to overcome resistance and enable better management of myeloma treatment.

关键词： MYC inhibition multiple myeloma undruggable target targeted therapies transcription factor epigenetics MYC downregulation

Thiopurine use associated with reduced B and natural killer cells in inflammatory bowel disease

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World Journal of Gastroenterology 2017年第18期23卷 3240-3251页

作者： James D Lord Donna M Shows translational research program Benaroya Research Institute Gastroenterology Division Virginia Mason Medical Center

AIM To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo.METHODS The thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease(IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy recipients.RESULTS Complete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the timeof sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer(NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T(MAIT) cells, invariant natural killer T(i NKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells(Tregs) or na?ve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iN KT and MAIT cells than healthy controls. CONCLUSION Thiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients.

关键词： Thiopurine Azathioprine Mercaptopurine 淋巴细胞自然漂亮房间过渡 B 房间煽动性的肠疾病

Neuroinflammation as a target for glaucoma therapy

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Neural Regeneration research 2019年第3期14卷 391-394页

作者： Adornetto Annagrazia Rossella Russo Parisi Vincenzo Department of Pharmacy Health and Nutritional Sciences Section of Preclinical and Translational Pharmacology University of Calabria Visual Neurophysiology and Neurophthalmology research Unit IRCCS G.B.Bietti Foundation

The pathogenesis of glaucoma is still not fully clarified but a growing body of evidence suggests that neuroinflammation and immune response are part of the sequence of pathological events leading to the optic neuropathy. Indeed, inflammation-involving the activation and proliferation of resident glial cells(astrocytes, Muller cells and microglia) and the release of a plethora of anti-and pro-inflammatory cytokines, chemokines and reactive oxygen species-has been reported as common features in clinical and experimental glaucoma. In the insulted retina, as for other neuronal tissues, pathogenic and reparative aspects coexist in the inflammatory process, with extent and persistency affecting the final outcome. In view of this, therapies aimed at modulating the immune and inflammatory responses may represent a promising approach for limiting the optic nerve damage and the loss of retinal ganglion cells associated with glaucoma.

关键词： glaucoma retinal ganglion cells neuroinflammation neurodegeneration microglia oxidative stress inflammasome immune response

The promise of neuroprotection by dietary restriction in glaucoma

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Neural Regeneration research 2022年第1期17卷 45-47页

作者： Rossella Russo Carlo Nucci Annagrazia Adornetto preclinical and translational Pharmacology Department of PharmacyHealth and Nutritional SciencesUniversity of CalabriaRendeItaly Ophthalmology Unit Department of Experimental MedicineUniversity of Rome Tor VergataRomeItaly

Glaucoma,a progressive age-related optic neuropathy characterized by the death of retinal ganglion cells,is the most common neurodegenerative cause of irreversible blindness worldwide.The therapeutic management of glaucoma,which is limited to lowering intraocular pressure,is still a challenge since visual loss progresses in a significant percentage of treated patients.Restricted dietary regimens have received considerable attention as adjuvant strategy for attenuating or delaying the progression of neurodegenerative diseases.Here we discuss the literature exploring the effects of modified eating patterns on retinal aging and resistance to stressor stimuli.

关键词： aging caloric restriction fasting glaucoma neurodegeneration retina retinal ganglion cells

Functional characterization of triterpene synthases in Cibotium barometz

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Synthetic and Systems Biotechnology 2023年第3期8卷 437-444页

作者： Zhongju Ji Baolian Fan Yidu Chen Jingyang Yue Jiabo Chen Rongrong Zhang Yi Tong Zhongqiu Liu Jincai Liang Lixin Duan Guangdong Provincial Key Laboratory of translational Cancer research of Chinese Medicines Joint International Research Laboratory of Translational Cancer Research of Chinese MedicinesInternational Institute for Translational Chinese MedicineSchool of Pharmaceutical SciencesGuangzhou University of Chinese MedicineGuangzhouChina

Cibotium barometz(Linn.)J.Sm.,a tree fern in the Dicksoniaceae family,is an economically important industrial exported plant in China and widely used in Traditional Chinese Medicine.C.barometz produces a range of bioactive triterpenes and their metabolites.However,the biosynthetic pathway of triterpenes in C.barometz remains unknown.To clarify the origin of diverse triterpenes in C.barometz,we conducted de novo transcriptome sequencing and analysis of C.barometz rhizomes and leaves to identify the candidate genes involved in C.barometz triterpene biosynthesis.Three C.barometz triterpene synthases(CbTSs)candidate genes were obtained.All of them were highly expressed in C.barometz rhizomes,consisting of the accumulation pattern of triterpenes in C.barometz.To characterize the function of these CbTSs,we constructed a squalene-and oxidosqualene-overproducing yeast chassis by overexpressing all the enzymes in the MVA pathway under the control of GAL-regulated promoter and disrupted the GAL80 gene in Saccharomyces cerevisiae simultaneously.Heterologous expressing CbTS1,CbTS2,and CbTS3 in engineering yeast strain produced cycloartenol,dammaradiene,and diploptene,respectively.Phylogenetic analysis revealed that CbTS1 belongs to oxidosqualene cyclase,while CbTS2 and CbTS3 belong to squalene cyclase.These results decipher enzymatic mechanisms underlying the origin of diverse triterpene in C.barometz.

关键词： 2,3-oxidosqualene cyclase Squalene cyclase Cibotium barometz Triterpene biosynthesis

The Wnt/β-catenin signaling:a multifunctional target for neuroprotective and regenerative strategies in Parkinson's disease

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Neural Regeneration research 2023年第2期18卷 306-308页

作者： Annalucia Serafino Mauro Cozzolino Institute of translational Pharmacology-National research Council of Italy RomeItaly

Parkinson's disease(PD)is the most frequent movement disorder and the second most prevalent age-related neurodegenerative disease(ND)worldwide.From the clinical point of view,it is characterized by severe motor compli... 详细信息

关键词： protective clinical rigidity

Relationship between polymorphisms of genes encoding microsomal epoxide hydrolase and glutathione S-transferase P1 and chronic obstructive pulmonary disease

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Chinese Medical Journal 2004年第5期117卷 661-667页

作者：肖丹王辰杜敏捷庞宝森张洪玉肖白刘敬忠翁心植苏丽 David C.Christiani Beijing Institute of Respiratory Medicine research Center of preclinical Medicine Occupational Health program

Background Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD) However, only 10%-20% of chronic heavy cigarette smokers develop symptomatic disease COPD is most likely the result of complex interactions between environmental and genetic factors Genetic susceptibility to COPD might depend on the variations in enzyme activities that detoxify cigarette smoke products, such as microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) In this study, we investigated the relationship between polymorphisms in the genes encoding mEH and glutathione S-transferase P1 (GSTP1) and COPD in a Chinese population Methods Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to find mEH polymorphism in exon 3 (Tyr113→His), exon 4 (His139→Arg) and GSTP1 polymorphism in exon 5 (Ile105→Val) in 100 COPD patients and 100 age- and sex-matched healthy controls Results The proportion of mEH exon 3 heterozygotes was significantly higher in patients with COPD than that in the control subjects (42% vs 32%) The odds ratio ( OR ) adjusted by age, sex, body mass index (BMI) and cigarette years was 2 96 (95% CI 1 24-7 09) There was no marked difference in very slow activity genotype versus other genotypes between COPD patients and the controls When COPD patients were non-smokers, the OR of very slow activity genotype versus other genotypes was more than 1 00; and when COPD patients were smokers (current smokers and ex-smokers), the OR was less than 1 00 There was no significant difference in GSTP1 polymorphism adjusted by age, sex, BMI and smoking between COPD patients and the controls Conclusions mEH exon 3 heterozygotes might be associated with susceptibility to COPD in China The interaction might exist between mEH genotype and smoke The gene polymorphism for GSTP1 might not be associated with susceptibility to COPD in the Chinese population

关键词： pulmonary disease chronic obstructive · microsomes · epoxide hydrolases · glutathione S-transferase P· polymorphism genetics

Promises and paradoxes of regulatory T cells in inflammatory bowel disease

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World Journal of Gastroenterology 2015年第40期21卷 11236-11245页

作者： James D LordJ translational program Benaroya research Institute at Virginia Mason Mailstop

Since their discovery two decades ago,CD4+CD25+Foxp3+ regulatory T cells(Tregs) have become the subject of intense investigation by immunologists. Unlike other T cells,which promote an immune response,Tregs actively inhibit inflammation when activated by their cognate antigen,thus raising hope that these cells could be engineered into a highly targeted,antigenspecific,immunosuppressant therapy. Although Tregs represent less than 10% of circulating CD4+T cells,they have been shown to play an essential role in preventing or limiting inflammation in a variety of animal models and human diseases. In particular,spontaneous intestinal inflammation has been shown to occur in the absence of Tregs,suggesting that there may be a Treg defect central to the pathogenesis of human inflammatory bowel disease(IBD). However,over the past decade,multiple groups have reported no qualitative or quantitative deficits in Tregs from the intestines and blood of IBD patients to explain why these cells fail to regulate inflammation in Crohn's disease and ulcerative colitis. In this review,we will discuss the history of Tregs,what is known about them in IBD,and what progress and obstacles have been seen with efforts to employ them for therapeutic benefit.

关键词： Foxp3 Regulatory T cells Crohn’s disease Th17 Ulce

Pharmacokinetics,distribution,and excretion of sodium oligomannate,a recently approved anti-Alzheimer's disease drug in China

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Journal of Pharmaceutical Analysis 2022年第1期12卷 145-155页

作者： Jiaojiao Lu Qiongqun Pan Jieqiang Zhou Yan Weng Kaili Chen Lv Shi Guanxiu Zhu Chunlin Chen Liang Li Meiyu Geng Zhenqing Zhang Jiangsu Key Laboratory of translational research and Therapy for Neuro-Psycho-Diseases College of Pharmaceutical SciencesSoochow UniversitySuzhouJiangsu215021China Shanghai Green Valley Pharma.Corp. Shanghai201203China Medicilon preclinical research(Shanghai)LLC Shanghai201299China State Key Laboratory of Drug research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China

The National Medical Products Administration has authorized sodium oligomannate for treating mild-to-moderate Alzheimer’s disease.In this study,an LC-MS/MS method was developed and validated to quantitate sodium oligomannate in different biomatrices.The plasma pharmacokinetics,tissue distribution,and excretion of sodium oligomannate in Sprague-Dawley rats and beagle dogs were systematically investigated.Despite its complicated structural composition,the absorption,distribution,metabolism,and excretion profiles of the oligosaccharides in sodium oligomannate of different sizes and terminal derivatives were indiscriminate.Sodium oligomannate mainly crossed the gastrointestinal epithelium through paracellular transport following oral administration,with very low oral bioavailability in rats(0.6%-1.6%)and dogs(4.5%-9.3%).Absorbed sodium oligomannate mainly resided in circulating body fluids in free form with minimal distribution into erythrocytes and major tissues.Sodium oligomannate could penetrate the blood-cerebrospinal fluid(CSF)barrier of rats,showing a constant area under the concentration-time curve ratio(CSF/plasma)of approximately 5%.The cumulative urinary excretion of sodium oligomannate was commensurate with its oral bioavailability,supporting that excretion was predominantly renal,whereas no obvious biliary secretion was observed following a single oral dose to bile duct-cannulated rats.Moreover,only 33.7%(male)and 26.3%(female)of the oral dose were recovered in the rat excreta within 96 h following a single oral administration,suggesting that the intestinal flora may have ingested a portion of unabsorbed sodium oligomannate as a nutrient.

关键词： Sodium oligomannate Alzheimer’s disease Pharmacokinetics LC-MS/MS Oligosaccharide