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TuBG1 promotes hepatocellular carcinoma via ATR/P53-apoptosis and cycling pathways

Hepatobiliary & Pancreatic Diseases International 2024年第2期23卷 195-209页

作者： Yan Zhang Zhen-Zhen Wang An-Qi Han Ming-Ya Yang Li-Xin Zhu Fa-Ming Pan Yong Wang Department of General Surgery The Second Hospital of Anhui Medical UniversityHefei 230601China Department of General Surgery The First Affiliated Hospital of Anhui Medical UniversityHefei 230022China Department of Epidemiology and Biostatistics School of Public HealthAnhui Medical UniversityHefei 230032China The Key Laboratory of Major Autoimmune Diseases Anhui Medical UniversityHefei 230032China

Background:As reported,γ-tubulin(TuBG1)is related to the occurrence and development of various types of malignant tumors.However,its role in hepatocellular cancer(HCC)is not clear.The present study was to investigate the relationship between TuBG1 and clinical parameters and survival in HCC patients.Methods:The correlation between TuBG1 and clinical parameters and survival in HCC patients was ex-plored by bioinformatics analysis.Immunohistochemistry was used for the verification.The molecular function of TuBG1 was measured using colony formation,scratch assay,trans-well assay and flow cytometry.Gene set enrichment analysis(GSEA)was used to pick up the enriched pathways,followed by investigating the target pathways using Western blotting.The tumor-immune system interactions and drug bank database(TISIDB)was used to evaluate TuBG1 and immunity.Based on the TuBG1-related immune genes,a prognostic model was constructed and was further validated internally and externally.Results:The bioinformatic analysis found high expressed TuBG1 in HCC tissue,which was confirmed us-ing immunohistochemistry and Western blotting.After silencing the TuBG1 in HCC cell lines,more G1 arrested cells were found,cell proliferation and invasion were inhibited,and apoptosis was promoted.Furthermore,the silence of TuBG1 increased the expressions of Ataxia-Telangiectasia and Rad-3(ATR),phospho-P38 mitogen-activated protein kinase(P-P38MAPK),phospho-P53(P-P53),B-cell lymphoma-2 associated X protein(Bax),cleaved caspase 3 and P21;decreased the expressions of B-cell lymphoma-2(Bcl-2),cyclin D1,cyclin E2,cyclin-dependent kinase 2(CDK2)and CDK4.The correlation analysis of immunohistochemistry and clinical parameters and survival data revealed that TuBG1 was negatively corre-lated with the overall survival.The constructed immune prognosis model could effectively evaluate the prognosis.Conclusions:The increased expression of TuBG1 in HCC is associated with poor prognosis,which might be involved in the occurrence and development of HCC.

关键词： TuBG1 Hepatocellular carcinoma Apoptosis Cell cycling immunomodulators

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Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B:A comprehensive review of phases II and III therapeutic agents

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World Journal of Hepatology 2024年第3期16卷 331-343页

作者： Robert Lam Joseph K Lim Section of Digestive Diseases Yale University School of MedicineNew HavenCT 06520United States

Chronic hepatitis B virus(HBV)infection affects over 295 million people globally and an estimated 1.6 million people in the United States.It is associated with significant morbidity and mortality due to cirrhosis,liver failure,and liver cancer.Antiviral therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression,which in turn has been associated with a decreased risk of liver complications.However,current antiviral regimens are limited by concerns with adverse effects,adherence,resistance,long-term treatment,and ongoing risk for liver events.Novel investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen(HBsAg)loss and suppression of HBV DNA.Herein we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B,including core/capsid inhibitors,entry inhibitors,RNA interference(siRNA/ASO),HBsAg inhibitors,Toll-like receptor agonists,checkpoint inhibitors,and therapeutic vaccines.

关键词： Hepatitis B virus Treatment Clinical trials RNA interference Entry inhibitors Core inhibitors immunomodulators

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immunomodulators:still having a role?

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Gastroenterology Report 2022年第1期10卷 178-187页

作者： Jeffery M.Venner Charles N.Bernstein University of Manitoba IBD Clinical and Research Centre WinnipegManitobaCanada Department of Internal Medicine Max Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada

immunomodulators,particularly the thiopurines and to a lesser extent methotrexate,were standard of care for inflammatory bowel diseases,including Crohn’s disease and ulcerative colitis,for>40 years.While there has been a renaissance in available therapies with the advent of biologics and small molecules,an impetus remains for the ongoing use of thiopurines and methotrexate.This is particularly true for the maintenance of remission and when used in combination therapy with infliximab to suppress anti-biologic antibodies.This article summarizes the data behind immunomodulator use in Crohn’s disease,focusing on the beneficial role these drugs still have while acknowledging their clinical limitations.

关键词： immunomodulators 6-mercaptopurine(6-MP) azathioprine Crohn’s disease methotrexate

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Small molecule-based immunomodulators for cancer therapy

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Acta Pharmaceutica Sinica B 2022年第12期12卷 4287-4308页

作者： Yinrong Wu Zichao Yang Kui Cheng Huichang Bi Jianjun Chen Guangdong Provincial Key Laboratory of New Drug Screening NMPA Key Laboratory for Research and Evaluation of Drug MetabolismSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China

Immunotherapy has led to a paradigm shift in the treatment of cancer.Current cancer immunotherapies are mostly antibody-based,thus possessing advantages in regard to pharmacodynamics(e.g.,specificity and efficacy).However,they have limitations in terms of pharmacokinetics including long half-lives,poor tissue/tumor penetration,and little/no oral bioavailability.In addition,therapeutic antibodies are immunogenic,thus may cause unwanted adverse effects.Therefore,researchers have shifted their efforts towards the development of small molecule-based cancer immunotherapy,as small molecules may overcome the above disadvantages associated with antibodies.Further,small molecule-based immunomodulators and therapeutic antibodies are complementary modalities for cancer treatment,and may be combined to elicit synergistic effects.Recent years have witnessed the rapid development of small molecule-based cancer immunotherapy.In this review,we describe the current progress in small molecule-based immunomodulators(inhibitors/agonists/degraders)for cancer therapy,including those targeting PD-1/PD-L1,chemokine receptors,stimulator of interferon genes(STING),Toll-like receptor(TLR),etc.The tumorigenesis mechanism of various targets and their respective modulators that have entered clinical trials are also summarized.

关键词： Cancer immunotherapy Small molecules immunomodulators Inhibitors Agonists

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Symphony of nanomaterials and immunotherapy based on the cancer-immunity cycle

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Acta Pharmaceutica Sinica B 2022年第1期12卷 107-134页

作者： Qianqian Li Zhaoqing Shi Fan Zhang Weiwei Zeng Dunwan Zhu Lin Mei School of Pharmaceutical Sciences(Shenzhen) Sun Yat-sen UniversityShenzhen 518107China Tianjin Key Laboratory of Biomedical Materials Key Laboratory of Biomaterials and Nanotechnology for Cancer ImmunotherapyInstitute of Biomedical EngineeringChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300192China

The immune system is involved in the initiation and progression of cancer. Research on cancer and immunity has contributed to the development of several clinically successful immunotherapies. These immunotherapies often act on a single step of the cancer-immunity cycle. In recent years, the discovery of new nanomaterials has dramatically expanded the functions and potential applications of nanomaterials. In addition to acting as drug-delivery platforms, some nanomaterials can induce the immunogenic cell death(ICD) of cancer cells or regulate the profile and strength of the immune response as immunomodulators.Based on their versatility, nanomaterials may serve as an integrated platform for multiple drugs or therapeutic strategies, simultaneously targeting several steps of the cancer-immunity cycle to enhance the outcome of anticancer immune response. To illustrate the critical roles of nanomaterials in cancer immunotherapies based on cancer-immunity cycle, this review will comprehensively describe the crosstalk between the immune system and cancer, and the current applications of nanomaterials, including drug carriers, ICD inducers, and immunomodulators. Moreover, this review will provide a detailed discussion of the knowledge regarding developing combinational cancer immunotherapies based on the cancer-immunity cycle, hoping to maximize the efficacy of these treatments assisted by nanomaterials.

关键词： Cancer immunotherapy Nanomaterials Cancer-immunity cycle Drug delivery ICD inducers immunomodulators Photothermal therapy Photodynamic therapy Radio sensitizer

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Therapeutics to harness the immune microenvironment in multiple myeloma

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Cancer Drug Resistance 2022年第3期5卷 647-661页

作者： James J.Ignatz-Hoover James J.Driscoll University Hospitals Seidman Cancer CenterClevelandOH 44106USA Department of Biochemistry Case Western Reserve UniversityClevelandOH 44106USA Hematopoietic and Immune Cancer Biology Program Case Comprehensive Cancer CenterCase Western Reserve UniversityClevelandOH 44106USA

Multiple myeloma(MM)remains an incurable,genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow(BM)microenvironment.Current therapies leverage the unique biology of MM cells and target the immune microenvironment that drives tumor growth and facilitates immune evasion.Proteasome inhibitors and immunomodulatory drugs were initially introduced to complement and have now supplanted cytotoxic chemotherapy as frontline anti-myeloma agents.Recently,monoclonal antibodies,bispecific antibodies,and chimeric antigen receptor T cells were developed to revamp the immune system to overcome immune suppression and improve patient responses.While current MM therapies have markedly extended patient survival,acquired drug resistance inevitably emerges and drives disease progression.The logical progression for the next generation of MM therapies would be to design and validate agents that prevent and/or overcome acquired resistance to immunotherapies.The complex BM microenvironment promotes resistance to both current anti-myeloma agents and emerging immunotherapies.Myeloma cells are intertwined with a complex BM immune microenvironment that contributes to the development of adaptive drug resistance.Here,we describe recently FDA-approved and investigational anti-myeloma agents that directly or indirectly target the BM microenvironment to prevent or overcome drug resistance.Synergistic effects of anti-myeloma agents may foster the development of rationally-designed drug cocktails that prevent BM-mediated resistance to immunotherapies.

关键词： Multiple myeloma drug resistance proteasome inhibitors immunomodulators immunotherapeutics adaptive resistance bone marrow microenvironment

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Novel agents and new therapeutic approaches for treatment of multiple myeloma

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World Journal of Methodology 2014年第2期4卷 73-90页

作者： Roberto Ria Antonia Reale Angelo Vacca Section of Internal Medicine Department of Biomedical Sciences and Human On-cologyUniversity of Bari Medical SchoolI-70124 BariItaly

This review summarizes the therapeutic strategies and the drugs actually in development for the management of myeloma patients. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein(immunoglobulins, Bence Jones protein and free light chains). Multiple myeloma still remains an incurable disease with a high incidence rate in the elderly, despite the introduction of several new therapeutic agents(bortezomib, lenalidomide and thalidomide) which have changed its natural history. The high heterogeneity of this disease leads to large differences in clinical responses to treatments. Thus, the choice of the best treatment is a difficult issue. However, the introduction of new drugs has made it possible to achieve high response rates and good quality respons-es with long-term disease control. Interactions between tumor cells and their bone marrow microenvironment play a pivotal role in the development, maintenance, and progression of myeloma, inducing also drug resistance. These knowledges have improved treatment options, leading to the approval of new drugs which not only target the malignant cell itself, but also its microenvironment. These agents are in preclinical/early clinical evaluation and they appear to further improve disease control, but their use is still not approved outside of clinical trials.

关键词： immunomodulators Multiple myeloma New drugs Proteasome inhibitors Target therapy

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Treatment of pregnant women with a diagnosis of inflammatory bowel disease

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World Journal of Gastrointestinal Pharmacology and Therapeutics 2016年第4期7卷 490-502页

作者： Sule Poturoglu Asli Ciftcibasi Ormeci Ali Erkan Duman Department of Gastroenterology Haseki Training and Research Hospital

The frequency of diagnosis of inflammatory bowel disease(IBD) has increased in younger populations.For this reason,pregnancy in patients with IBD is a topic of interest,warranting additional focus on disease management during this period.The main objective of this article is to summarize the latest findings and guidelines on the management of potential problems from pregnancy to the breastfeeding stage.Fertility is decreased in patients with active IBD.Disease remission prior to conception will likely decrease the rate of pregnancy-related complications.Most of the drugs used for IBD treatment are safe during both pregnancy and breastfeeding.Two exceptions are methotrexate and thalidomide,which are contraindicated in pregnancy.Antitumor necrosis factor agents are not advised during the third trimester as they exhibit increased transplacental transmission and potentially cause immunosuppression in the fetus.Radiological and endoscopic examinations and surgical interventions should be performed only when absolutely necessary.Surgery increases the fetal mortality rate.The delivery method should be determined with consideration of the disease site and presence of progression or flare up.Treatment planning should be a collaborative effort among the gastroenterologist,obstetrician,colorectal surgeon and patient.

关键词：怀孕煽动性的肠疾病 immunomodulators Biologics 母乳喂养治疗

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Current therapy of pediatric Crohn's disease

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World Journal of Gastrointestinal Pathophysiology 2015年第2期6卷 33-42页

作者： Avishay Lahad Batia Weiss Pediatric Gastroenterology Hepatology and Nutrition Unit Edmond and Lily Safra Children’s Hospital Sheba Medical Center Tel-Aviv University

Inflammatory bowel diseases(IBD), including Crohn's disease(CD) and ulcerative colitis, are chronic relapsing and remitting diseases of the bowel, with an unknown etiology and appear to involve interaction between genetic susceptibility, environmental factors and the immune system. Although our knowledge and understanding of the pathogenesis and causes of IBD have improved significantly, the incidence in the pediatric population is still rising. In the last decade more drugs and treatment option have become available including 5-aminosalicylate,antibiotics, corticosteroids, immunomodulators and biological agents. Before the use of anti-tumor necrosis factor(TNF)-α became available to patients with IBD, the risk for surgery within five years of diagnosis was very high, however, with anti-TNF-α treatment the risk of surgery has decreased significantly. In the pediatric population a remission in disease can be achieved by exclusive enteral nutrition. Exclusive enteral nutrition also has an important role in the improvement of nutritional status and maintained growth. In this review we summarize the current therapeutic treatments in CD. The progress in the treatment options and the development of new drugs has led to optimized tactics for achieving the primary clinical goals of therapy- induction and maintenance of remission while improving the patient's growth and overall well-being.

关键词： Pediatric Crohn’s disease immunomodulators Antibiotics Nutrition Anti-tumor necrosis factor Steroids 5-aminosalicylic acid

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The Current and Future Role of Drugs and Probiotics in the Management of Inflammatory Bowel Disease

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Journal of Biosciences and Medicines 2015年第8期3卷 76-85页

作者： Maricelma da Silva Soares de Souza Sandra Maria Barbalho Ricardo de Alvares Goulart Antonely de Cássio Alves de Carvalho Department of Biochemistry and Pharmacology School of Medicine University of Marília Marília S&atilde o Paulo Brazil Department of Biochemistry and Pharmacology School of Medicine University of Marília and Food Technology School (FATEC) Marília S&atilde o Paulo Brazil Department of Gastroenteology University Hospital-UNIMAR Marília S&atilde o Paulo Brazil Diagnostic Center in Gastroenterology Ibaiti Paraná Brazil

Inflammatory Bowel Disease (IBD) and other auto-inflammatory disorders are conditions caused by chronic and persistent intestinal inflammation, which is mainly represented by Ulcerative Colitis (UC) or Crohn’s Disease (CD), both of which typically arise as chronic inflammation of the gastrointestinal mucosa. Doctor’s main focus for treating IBD is the decrease on inflammation processes when the disease is active and promotes the maintenance of inflammation at normal levels. However, to deal with these two parameters is not easy, because the drugs usually used are related to several side effects and they are not totally effective to reduce inflammation and to keep the remission. Authors agree that the therapy approach should include drugs, dietary intervention and use of alternative substances as probiotics. The standard treatment approach for patients with CD and UC is traditionally done with the use of anti-inflammatory agents, like corticosteroids, mesalamine, immunomodulators such as azathioprine and methotrexate, and biologic agents such as infliximab and others. Probiotics are known as viable micro-organisms (or live microorganisms or live microbial dietary supplements) that may promote beneficial physiologic or therapeutic properties when used correctly. The interest in the role of these substances in improving human health is the reason of several researches. They may be used to help the immune system, to control gastro-intestinal infections and to prevent several diseases. Prebiotics, symbiotics, and probiotics may be helpful as adjuvants in the treatment of IBD. Probiotics are normally well-tolerated and are associated with few side effects which are undoubtedly important in the treatment of any disease.

关键词： Inflammatory Bowel Diseases immunomodulators Biological Agents Probiotics

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