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RRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor

Cellular & Molecular Immunology 2021年第6期18卷 1425-1436页

作者： Yun Chen Hongbin He Bolong Lin Yun Chen Xianming Deng Wei Jiang Rongbin Zhou Hefei National Laboratory for Physical Sciences at Microscale the CAS Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina Department of Geriatrics Gerontology Institute of Anhui Provincethe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina CAS Centre for Excellence in Cell and Molecular Biology University of Science and Technology of ChinaHefeiChina State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling NetworkSchool of Life SciencesXiamen UniversityXiamenFujianChina

The NLRP3 inflammasome plays a crucial role in innate immune-mediated inflammation and contributes to the pathogenesis of multiple autoinflammatory,metabolic and neurodegenerative diseases,but medications targeting the NLRP3 inflammasome are not available for clinical ***-001 is a well-tolerated anticancer agent currently being investigated in phase III clinical trials,but its effects on inflammatory diseases are not ***,we show that RRx-001 is a highly selective and potent NLRP3 inhibitor that has strong beneficial effects on NLRP3-driven inflammatory ***-001 inhibits the activation of the canonical,noncanonical,and alternative NLRP3 inflammasomes but not the AIM2,NLRC4 or Pyrin ***,RRx-001 covalently binds to cysteine 409 of NLRP3 via its bromoacetyl group and therefore blocks the NLRP3-NEK7 interaction,which is critical for the assembly and activation of the NLRP3 *** importantly,RRx-001 treatment attenuates the symptoms of lipopolysaccharide(LPS)-induced systemic inflammation,dextran sulfate sodium(DSS)-induced colitis and experimental autoimmune encephalomyelitis(EAE)in ***,our study identifies RRx-001 as a new potential therapeutic agent for NLRP3-driven diseases.

关键词： RRx-001 NLRP3 inflammasome inflammatory diseases

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Targeting STING oligomerization with licochalcone D ameliorates STING-driven inflammatory diseases

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Science China Life Sciences 2024年第12期67卷 2664-2677页

作者： Yinghui Zhang Yadan Liu Bing Jiang Lifan Chen Jie Hu Buying Niu Jie Chang Zisheng Fan Jingyi Zhou Yajie Wang Dan Teng Ning Ma Xiaofeng Wang Ruirui Yang Mingyue Zheng Sulin Zhang Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences University of Chinese Academy of Sciences School of Chinese Materia Medica Nanjing University of Chinese Medicine Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology Shanghai Tech University School of Physical Science and Technology Shanghai Tech University School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences State Key Laboratory of Pharmaceutical Biotechnology Nanjing University

The development of STING inhibitors for the treatment of STING-related inflammatory diseases continues to encounter significant challenges. The activation of STING is a multi-step process that includes binding with c GAMP, self-oligomerization, and translocation from the endoplasmic reticulum to the Golgi apparatus, ultimately inducing the expression of IRF3 and NF-κB-mediated interferons and inflammatory cytokines. It has been demonstrated that disruption of any of these steps can effectively inhibit STING activation. Traditional structure-based drug screening methodologies generally focus on specific binding sites. In this study, a Transformer CPI model based on protein primary sequences and independent of binding sites is employed to identify compounds capable of binding to the STING protein. The natural product Licochalcone D(Lico D) is identified as a potent and selective STING inhibitor. Lico D does not bind to the classical ligandbinding pocket; instead, it covalently modifies the Cys148 residue of STING. This modification inhibits STING oligomerization, consequently suppressing the recruitment of TBK1 and the nuclear translocation of IRF3 and NF-κB. Lico D treatment ameliorates the inflammatory phenotype in Trex1-/-mice and inhibits the progression of DSS-induced colitis and AOM/DSS-induced colitis-associated colon cancer(CAC).In summary, this study reveals the potential of Lico D in treating STING-driven inflammatory diseases. It also demonstrates the utility of the Transformer CPI model in discovering allosteric compounds beyond the conventional binding pockets.

关键词： cGAS-STING signaling STING inhibitor TransformerCPI model Licochalcone D inflammatory diseases

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Dual Role of Wnt5a in the Progression of inflammatory diseases

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Chinese Medical Sciences Journal 2022年第3期37卷 265-274,I0013页

作者： Xu Chen Hongling Liu Dehong Li Jinsui Wang Fenghui Zhao Department of Pathology Gansu Provincial HospitalLazhou 730000China Department of Occupational Medicine the Third Gansu Provincial HospitalLanzhou 730000China Department of Clinical Laboratory Gansu Provincial HospitalLanzhou 730000China

Wnt5a is a secreted Wnt ligand that plays a critical role in cellular pathways and inflammatory *** WNT5A gene encodes two protein isoforms,Wnt5a-long and Wnt5a-short,which differ based on different promoter methylation and have distinct ***,the mechanisms of the promoter methylation are *** on the extent of promoter methylation,Wnt5a exerts both anti-inflammatory and proinflammatory effects in inflammatory diseases,which may be involved in different Wnt5a ***,the Wnt5a isoforms may be potential diagnostic markers for inflammatory diseases and the mechanisms of the WNT5A gene promoter methylation need to be further investigated.

关键词： Wnt5a inflammatory diseases promoter methylation

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Molecular events in the jaw vascular unit:A traditional review of the mechanisms involved in inflammatory jaw bone diseases

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The Journal of Biomedical Research 2023年第5期37卷 313-325页

作者： Ruyu Wang Haoran Wang Junyu Mu Hua Yuan Yongchu Pang Yuli Wang Yifei Du Feng Han Department of Oral and Maxillofacial Surgery the Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China Jiangsu Province Key Laboratory of Oral diseases Nanjing Medical UniversityNanjingJiangsu 210029China Jiangsu Province Engineering Research Center of Stomatological Translational Medicine NanjingJiangsu 210029China International Joint Laboratory for Drug Target of Critical Illnesses Key Laboratory of Cardiovascular and Cerebrovascular MedicineSchool of PharmacyNanjing Medical UniversityNanjingJiangsu 211166China Department of Orthodontics the Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China.

inflammatory jaw bone diseases are common in stomatology,including periodontitis,peri-implantitis,medication-related osteonecrosis of the jaw,radiation osteomyelitis of the jaw,age-related osteoporosis,and other specific *** diseases may lead to tooth loss and maxillofacial deformities,severely affecting patients'quality of *** the years,the reconstruction of jaw bone deficiency caused by inflammatory diseases has emerged as a medical and socioeconomic ***,exploring the pathogenesis of inflammatory diseases associated with jaw bones is crucial for improving prognosis and developing new targeted *** evidence indicates that the integrated bone formation and dysfunction arise from complex interactions among a network of multiple cell types,including osteoblast-associated cells,immune cells,blood vessels,and lymphatic ***,the role of these different cells in the inflammatory process and the'rules'with which they interact are still not fully *** many investigations have focused on specific pathological processes and molecular events in inflammatory jaw diseases,few articles offer a perspective of ***,we review the changes and mechanisms of various cell types in inflammatory jaw diseases,with the hope of providing insights to drive future research in this field.

关键词： inflammatory diseases osteogenesis-related cells immune cells blood vessels lymphatic vessels jaw vascular unit

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Lanostane Tetracyclic Triterpenoids as Important Sources for Anti-inflammatory Drug Discovery

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World Journal of Traditional Chinese Medicine 2020年第3期6卷 229-238页

作者： Yu-Pei Yang Shumaila Tasneem Muhammad Daniyal Liu Zhang Yan-Zhe Jia Yu-Qing Jian Bin Li Wei Wang School of Pharmacy TCM and Ethnomedicine Innovation and Development International LaboratoryInnovative Drug Research InstituteHunan University of Chinese MedicineChangshaChina Department of Pharmacology Faculty of Pharmaceutical SciencesDow College of PharmacyDow University of Health Sciences.Gulzar‑e‑HijriKarachiPakistan

Inflammation is a defensive reaction of the human body to numerous detrimental stimuli,including physical trauma,noxious chemicals,as well as microbial *** inflammation is the pathological basis of multiple diseases,such as rheumatoid arthritis(RA),neurodegenerative diseases,liver disease,and lung *** triterpenoids are natural tetracyclic triterpenoids with significant anti-inflammatory *** extensive review of the published literature regarding the phytochemistry and anti-inflammatory pharmacology of lanostane triterpenoids has been performed and analyzed using several search engines,such as SciFinder,Web of Science,Scopus,PubMed,Google Scholar,and *** review is devoted to naturally occurring lanostane-type triterpenes with anti-inflammatory activity,including their sources,biosynthesis,and mechanism of *** review also discusses the inflammation-related diseases and the clinical significance of traditional Chinese medicine as multi-target therapeutic agents for the prevention and treatment of inflammatory *** the past 30 years,more than 100 new lanostane-type triterpenes have been reported from the families Schisandraceae,Ganodermataceae,and *** compounds,fomitopinic acid A,fomitosides E and F,obtusifoliol,4α,l4α-dimethyl-5α-ergosta-7,9(11),24(28)-trien-3β-ol,and gramisterol exhibited the most potent anti-inflammatory activity against cyclooxygenase-1(COX-1)and COX-2,with IC50 values ranging from 0.087 to 1.15μ*** of these compounds exhibited significant activity by mediating the inhibition of the pro-inflammatory cytokines,inducible nitric oxide synthase,and COX-2 *** review provides a basis for identifying anti-inflammatory drugs with high selectivity,high potency,and few adverse effects from lanostane-type triterpenes.

关键词： Inflammation inflammatory diseases lanostane triterpenoids rheumatoid arthritis

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Intrinsically bioactive multifunctional Poly(citrate-curcumin) for rapid lung injury and MRSA infection therapy

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Bioactive Materials 2024年第11期41卷 158-173页

作者： Tongtong Leng Long Zhang Junping Ma Xiaoyan Qu Bo Lei Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research College of StomatologyFrontier Institute of Science and TechnologyXi'an Jiaotong UniversityXi'an710054China Department of Respiratory and Critical Care Medicine The Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'an710004China

Dysregulated inflammation after trauma or infection could result in the further disease and delayed tissue *** conventional anti-inflammatory drug treatment suffers to the poor bioavailability and side ***,we developed an amphiphilic multifunctional poly(citrate-polyglycol-curcumin)(PCGC)nano oligomer with the robust anti-inflammatory activity for treating acute lung injury(ALI)and Methicillin-resistant staphylococcus aureus(MRSA)infected *** demonstrated the sustained curcumin release,inherent photoluminescence,good cellular compatibility,hemocompatibility,robust antioxidant activity and enhanced cellular *** could efficiently scavenge nitrogen-based free radicals,oxygen-based free radicals,and intracellular oxygen species,enhance the endothelial cell migration and reduce the expression of pro-inflammatory factors through the NF-κB signal *** the anti-inflammation and antioxidant properties,PCGC can shortened the inflammatory *** animal model of ALI,PCGC was able to reduce the pulmonary edema,bronchial cell infiltration,and lung inflammation,while exhibiting rapid metabolic behavior in *** MRSA-infection wound model showed that PCGC significantly reduced the expression of pro-inflammatory factors,promoted the angiogenesis and accelerated the wound *** transcriptome sequencing and molecular mechanism studies further demonstrated that PCGC could inhibit multiple inflammatory related pathways including TNFAIP3,IL-15RA,NF-κ*** work demonstrates that PCGC is efficient in resolving inflammation and promotes the prospect of application in inflammatory diseases as the drug-loaded therapeutic system.

关键词： Bioactive materials Bioactive polymers Citrate polymer Anti-inflammatory inflammatory diseases

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The function and regulation of TET2 in innate immunity and inflammation

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Protein & Cell 2021年第3期12卷 165-173页

作者： Boyi Cong Qian Zhang Xuetao Cao Laboratory of Immunity and Inflammation College of Life SciencesNankai UniversityTianjin 300071China National Key Laboratory of Medical Immunology Institute of ImmunologyNavy Military Medical UniversityShanghai 200433China Department of Immunology Center for ImmunotherapyInstitute of Basic Medical SciencesChinese Academy of Medical SciencesBeijing 100005China

TET2,a member of ten-eleven translocation(TET)family as a-ketoglutarate-and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine(5mC),has been widely recognized to be an important regulator for normal hematopoiesis especially *** and dysregulation of TET2 contribute to the development of multiple hematological *** studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic ***,we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling *** addition,we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases,which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.

关键词： TET2 innate immune response DNA demethylation inflammatory resolution inflammatory diseases

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hCINAP negatively regulates NF-κB signaling by recruiting the phosphatase PP1 to deactivate IKK complex

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Journal of Molecular Cell Biology 2015年第6期7卷 529-542页

作者： Linglong Qu Yapeng Ji Xi Zhu Xiaofeng Zheng State Key Lab of Protein and Plant Gene Research Beijing 100871China Department of Biochemistry and Molecular Biology School of Life SciencesPeking UniversityBeijing 100871China Department of Critical Care Medicine Peking University Third HospitalBeijing 100191China

Tight regulation of nuclear factor-kB(NF-kB)signaling is essential to maintain homeostasis in immune system in response to various stimuli,which hasbeen studied extensivelyand ***,the molecularmechanisms responsible for its negative regulation are not completely *** we demonstrate that human coilin-interacting nuclear ATPase protein(hCINAP)is a novel negative regulator in NF-kB signaling by deactivating IkB kinase(IKK)*** response to TNF stimulation,hCINAP dynamically associates with IKKa and IKKb and inhibits IKK ***,hCINAP directly interacts with the catalytic subunits of protein phosphatase 1(PP1)and mediates the formation of IKK–hCINAP–PP1 complex,serving as an adaptor protein that recruits PP1 to dephosphorylate ***,decreased levels of hCINAP are observed in several inflammatory diseases with NF-kB *** study suggests a novel mechanism underlying deactivation of IKK and provides new insight into the negative regulation of NF-kB signaling.

关键词： hCINAP NF-κB IKK complex phosphatase PP1 inflammatory diseases

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Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

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Acta Pharmaceutica Sinica B 2022年第2期12卷 600-620页

作者： Makhloufi Zoulikha Qingqing Xiao George Frimpong Boafo Marwa A.Sallam Zhongjian Chen Wei He Department of Pharmaceutics School of PharmacyChina Pharmaceutical UniversityNanjing 211198China Department of Industrial Pharmacy Faculty of PharmacyAlexandria UniversityAlexandria 21521Egypt Shanghai Skin Disease Hospital Tongji University School of MedicineShanghai 200443China

The use of small interfering RNAs(si RNAs)has been under investigation for the treatment of several unmet medical needs,including acute lung injury/acute respiratory distress syndrome(ALI/ARDS)wherein si RNA may be implemented to modify the expression of pro-inflammatory cytokines and chemokines at the m RNA *** properties such as clear anatomy,accessibility,and relatively low enzyme activity make the lung a good target for local si RNA ***,the translation of si RNA is restricted by the inefficient delivery of si RNA therapeutics to the target cells due to the properties of naked si ***,this review will focus on the various delivery systems that can be used and the different barriers that need to be surmounted for the development of stable inhalable si RNA formulations for human use before si RNA therapeutics for ALI/ARDS become available in the clinic.

关键词： Pulmonary administration Drug delivery Nanoparticles siRNA Cellular uptake Endosomal escape inflammatory diseases ALI/ARDS

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Neutrophil programming dynamics and its disease relevance

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Science China(Life Sciences) 2017年第11期60卷 1168-1177页

作者： Taojing Ran Shuo Geng Liwu Li Department of Biological Sciences Virginia Polytechnic Institute and State UniversityBlacksburg VA24061USA Guangdong Provincial Key Laboratory of Gastroenterotogy Department of GastroenterologyNanfang HospitalSouthern Medicat UniversityGuangzhou 510515China

Neutrophils are traditionally considered as first responders to infection and provide antimicrobial host defense. However, recent advances indicate that neutrophils are also critically involved in the modulation of host immune environments by dynamically adopting distinct functional states. Functionally diverse neutrophil subsets are increasingly recognized as critical components mediating host pathophysiology. Despite its emerging significance, molecular mechanisms as well as functional relevance of dynamically programmed neutrophils remain to be better defined. The increasing complexity of neutrophil functions may require integrative studies that address programming dynamics of neutrophils and their pathophysiological relevance. This review aims to provide an update on the emerging topics of neutrophil programming dynamics as well as their functional relevance in diseases.

关键词： programming dynamics immune priming inflammatory diseases

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