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Sulfation of chondroitin and bile acids converges to antagonize Wnt/β-catenin signaling and inhibit APC deficiency-induced gut tumorigenesis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1241-1256页

作者： Pengfei Xu Yue Xi Jong-Won Kim Junjie Zhu Min Zhang Meishu Xu Songrong Ren Da Yang Xiaochao Ma Wen Xie Center for Pharmacogenetics and Department of Pharmaceutical Sciences University of PittsburghPittsburghPA 15261USA Department of Hepatobiliary and Pancreatic Surgery Zhongnan Hospital of Wuhan UniversitySchool of Pharmaceutical SciencesWuhan UniversityWuhan 430071China Department of Pharmacology&Chemical Biology University of PittsburghPittsburghPA 15261USA

Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology.3’-Phosphoadenosine 5’-phosphosulfate(PAPS)synthase 2(PAPSS2)is the primary enzyme to generate the universal sulfonate donor *** involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli(APC)mutation-promoted colonic carcinogenesis has not been ***,we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages,and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon *** epithelial-specific heterozygous Apc deficient and Papss2-knockout(Apc^(Δgut-Het)Papss2^(Δgut))mice were created,and the phenotypes were compared to the spontaneous intestinal tumorigenesis of Apc^(Δgut-Het)***^(Δgut-Het)Papss2^(Δgutmice) were more sensitive to gut tumorigenesis,which was mechanistically accounted for by the activation of Wnt/β-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor(FXR)-transducin-like enhancer of split 3(TLE3)gene regulatory *** sulfate supplementation in Apc^(Δgut-Het)Papss2^(Δgutmice) alleviated intestinal *** summary,we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids-FXR-TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/β-catenin *** sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.

关键词： Colon cancer APC Wnt/b-catenin PAPSS2 Chondroitin sulfate Sulfation Bile acids FXR

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Transcranial photobiomodulation for the brain: a wide range of clinical applications

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Neural Regeneration Research 2024年第3期19卷 483-484页

作者： Michael R.Hamblin Laser Research Centre Faculty of Health ScienceUniversity of Johannesburg-Doornfontein CampusDoornfonteinSouth Africa

Photobiomodulation therapy(PBMT)is a rapidly growing approach to the healing,stimulation,protection,and regeneration of many human organs and tissue *** started in the 1960s as low-level laser therapy for wound healing,but since then the introduction of light-emitting diodes(LEDs)has dramatically increased the number of applications and reports of positive *** generally uses red(620-700 nm)and/or near-infrared(780-1270 nm)wavelengths of light at an intensity that causes no tissue heating,and its activity is based on well-established biological and cellular mechanisms(de Freitas and Hamblin,2016).While laser therapists continue to use various types of laser in their office practice,LEDs are ideally suited for home use devices because they are completely safe and without any known significant adverse *** the various body parts on which PBMT has been shown to exert beneficial effects,the brain stands out as perhaps the most promising *** has been shown to reduce neuroinflammation,while increasing mitochondrial function,oxygen consumption,and blood flow within the brain(Hamblin,2016).Moreover,PBMT can stimulate the processes of synaptogenesis,neurogenesis,and neuroplasticity thus helping the brain to heal itself.

关键词： healing stimulation wound

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Aryl hydrocarbon receptor:Linking environment to aging process in elderly patients with asthma

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Chinese Medical Journal 2024年第4期137卷 382-393页

作者： Tianrui Yang Rongjun Wan Wei Tu Sai Nithin Avvaru Peisong Gao Division of Allergy and Clinical Immunology Department of MedicineJohns Hopkins University School of MedicineBaltimoreMD 21224USA Department of Geriatric Medicine The First People’s Hospital of Yunnan ProvinceKunmingYunnan 650032China Department of Respiratory Medicine Xiangya HospitalCentral South UniversityChangshaHunan 410008China The State Key Laboratory of Respiratory Disease for Allergy Shenzhen Key Laboratory of Allergy and ImmunologyShenzhen University School of MedicineShenzhenGuangdong 518055China

Aging is a significant risk factor for various diseases,including asthma,and it often leads to poorer clinical outcomes,particularly in elderly *** is recognized that age-related diseases are due to a time-dependent accumulation of cellular damage,resulting in a progressive decline in cellular and physiological functions and an increased susceptibility to chronic *** effects of aging affect not only the elderly but also those of younger ages,posing significant challenges to global ***,understanding the molecular mechanisms associated with aging in different diseases is *** intriguing factor is the aryl hydrocarbon receptor(AhR),which serves as a cytoplasmic receptor and ligand-activated transcription factor and has been linked to the aging ***,we review the literature on several major hallmarks of aging,including mitochondrial dysfunction,cellular senescence,autophagy,mitophagy,epigenetic alterations,and microbiome ***,we provide an overview of the impact of AhR on these hallmarks by mediating responses to environmental exposures,particularly in relation to the immune ***,we explore how aging hallmarks affect clinical characteristics,inflammatory features,exacerbations,and the treatment of *** is suggested that AhR signaling may potentially play a role in regulating asthma phenotypes in elderly populations as part of the aging process.

关键词： Aging Environment Reactive oxygen species Senescence Aryl hydrocarbon receptor Asthma

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High-throughput screening of novel TFEB agonists in protecting against acetaminopheninduced liver injury in mice

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Acta Pharmaceutica Sinica B 2024年第1期14卷 190-206页

作者： Xiaojuan Chao Mengwei Niu Shaogui Wang Xiaowen Ma Xiao Yang Hua Sun Xujia Hu Hua Wang Li Zhang Ruili Huang Menghang Xia Andrea Ballabio Hartmut Jaeschke Hong-Min Ni Wen-Xing Ding Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKS 66160USA NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Department of Oncology the First Affiliated Hospital of Anhui Medical UniversityAnhui Medical UniversityHefei 230032China National Center for Advancing Translational Sciences National Institutes of HealthBethesdaMD 20892USA Telethon Institute of Genetics and Medicine TIGEMPozzuoliNaples 80131Italy Medical Genetics Department of Translational MedicineFederico II UniversityNaples 80131Italy Department of Molecular and Human Genetics Baylor College of MedicineHoustonTX 77030USA Department of Internal Medicine Division of GastroenterologyHepatology&MotilityUniversity of Kansas Medical CenterKansas CityKS 66160USA

Macroautophagy(referred to as autophagy hereafter)is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and *** studies showed that autophagy protects against acetaminophen(APAP)-induced injury(AILI)via selective removal of damaged mitochondria and APAP protein *** lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with *** the present study,we showed that transcription factor EB(TFEB),a master transcription factor for lysosomal biogenesis,was impaired by APAP resulting in decreased lysosomal biogenesis in mouse *** loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI,***,overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2(NRF2)activation to protect against *** also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB *** these agonists,salinomycin,an anticoccidial and antibacterial agent,activated TFEB and protected against AILI in *** conclusion,genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.

关键词： Autophagy DILI Drug screening Hepatotoxicity Lysosome Mitochondria Mitophagy NRF2

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Nanomaterials for Fighting Multidrug-Resistant Biofilm Infections

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Biomedical Engineering Frontiers 2023年第1期4卷 133-143页

作者： Vincent M.Rotello Department of Chemistry University of Massachusetts Amherst710 North Pleasant StreetAmherstMA 01003USA

Multidrug-resistant bacterial infections represent a dire threat to global *** development of antibiotic resistance in bacteria coupled with the lack of development of new antibiotics is creating infections requiring antibiotics of last resort,and even some infections for which we have no available ***-based infections present some of the most challenging targets for *** biofilm matrix provides a physical barrier that can impede access of antibiotics and antimicrobials to resident *** phenotypic diversity found in biofilms further exacerbates the difficulty of eliminating infections,with quiescent“persister”cells evading therapeutics and re-initiating infections after *** provide a tool for combatting these refractory biofilm *** distinctive size regime and physical properties of nanomaterials provide them with the capability to penetrate and disrupt *** can also access antimicrobial pathways inaccessible to conventional antimicrobials,providing a synergistic strategy for treating biofilm *** review will summarize key challenges presented by antibiotic resistance and biofilms when treating infection and provide selected examples of how nanomaterials are being used to address these challenges.

关键词： resort initiating eliminating

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Latitudinal and longitudinal regulation of tissue macrophages in inflammatory diseases

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Genes & Diseases 2022年第5期9卷 1194-1207页

作者： XiaoYi He Stephanie Tan Zhong Shao Xiao Wang Department of Neurology Affiliated Zhongshan Hospital of Dalian UniversityDalianLiaoning 116001PR China The Third Hospital of Fushun FushunLiaoning 113004PR China Stanley Manne Children’s Research Institute Ann&Robert H.Lurie Children’s Hospital of ChicagoChicagoIL 60611USA Department of Pediatrics Feinberg School of MedicineNorthwestern UniversityChicagoIL 60611USA

Macrophages are dominant innate immune *** demonstrate remarkable het-erogeneity and plasticity that are essential for homeostasis and host *** heterogeneity of tissue macrophages is shaped by the ontogeny,tissue factors,and environmental signals,a pattern in a tissue-associated latitudinal *** the same time,macrophages have long been considered as mainly plastic *** cells respond to stimulation quickly and in a stimulus-specific way by utilizing a longitudinal cascaded activation,including coordination of signal trans-ducer,epigenetic elements,and transcription factors,conclusively determine the macrophage phenotypes and *** the development of cutting-edge technologies,such as fate-mapping,single-cell transcriptomics,ipsc platform,nanotherapeutic materials,etc.,our under-standing of macrophage biology and the roles in the pathogenesis of diseases is much *** review summarizes recent progress on the latitudinal and longitudinal regulation of tissue macrophages in inflammatory *** latitudinal regulation covers the tissue macrophage or-igins,tissue factors,and environmental signals,reflecting the macrophage *** lon-gitudinal regulation focuses on how multiple factors shape the phenotypes and functions of macrophage subsets to gain plasticity in inflammatory diseases(i.e.,inflammatory bowel disease).In addition,how to target macrophages as a potential therapeutic approach and cutting edge-technologies for tissue macrophage study are also discussed in this review.

关键词： Epigenetic regulation Inflammatory disease microRNA Macrophage origin Macrophage polarization Single-cell RNA-sequencing Tissue macrophage

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Phase‘separating'53BP1 from DSB repair

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Genes & Diseases 2023年第1期10卷 1-3页

作者： Youwei Zhang Department of Pharmacology Case Comprehensive Cancer CenterSchool of MedicineCase Western ReserveUniversityClevelandOH44106USA

Eukaryotic chromosomes occupy specific territories in the nucleus,which is key for genome stability and *** on the spatiotemporal organization and compaction pattern,eukaryotic chromatins can be recognized as transcriptionally active and loosely packed euchromatin in the nuclear interior and transcriptionally repressive and highly compacted heterochromatin at the nuclear periphery or around nucleoli(Fig.1).

关键词： function. separating interior

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Does burning fat make tumor immune hot? Discovery of cD47 overexpression by radiation induced fatty acid oxidation

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Genes & Diseases 2023年第1期10卷 7-9页

作者： Nian Jiang Bowen Xie Ming Fan Jian Jian Li Department of Radiation Oncology University of California Davis School of MedicineSacramentoCA 95817USA Department of Neurosurgery National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaHunan 410008China Institute for Immunology and School of Medicine Tsinghua UniversityBeijing 100084China NCl-Designated Comprehensive Cancer Center University of California DavisSacramentoCA 95817USA

Although extensively studied,it is unknown what is the major cellular energy driving tumor metastasis after anti-cancer *** reprogramming is one of the fundamental hallmarks in carcinogenesis and tumor progression featured with the increased glycolysis in solid ***,accumulating evidence indicates that in addition to the rudimentary glycolytic pathway,tumor cells are capable of reactivating mitochondrial OxPHOS under genotoxic stress condition to meet the increasing cellular fuel demand for repairing and surviving anti-cancer *** dynamic metabolic rewiring may play a key role in cancer therapy resistance and ***,data from our group and others have demonstrated that cancer cells can re-activate mitochondrial oxidative respiration to boost an annexing energy to meet the increasing cellular fuel demand for tumor cells surviving genotoxic anti-cancer therapy with metastatic potential.

关键词： CD47 Immunecheckpoint Immunotherapy Metabolic rewiring Radiation therapy Tumor acquired resistance

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Extracellular CIRP dysregulates macrophage bacterial phagocytosis in sepsis

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Cellular & Molecular Immunology 2023年第1期20卷 80-93页

作者： Mian Zhou Monowar Aziz Hao-Ting Yen Gaifeng Ma Atsushi Murao Ping Wang Center for Immunology and Inflammation The Feinstein Institutes for Medical ResearchManhassetNYUSA Departments of Surgery and Molecular Medicine Zucker School of Medicine at Hofstra/NorthwellManhassetNYUSA

In sepsis, macrophage bacterial phagocytosis is impaired, but the mechanism is not well elucidated. Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern that causes inflammation. However, whether eCIRP regulates macrophage bacterial phagocytosis is unknown. Here, we reported that the bacterial loads in the blood and peritoneal fluid were decreased in CIRP^(−/−) mice and anti-eCIRP Ab-treated mice after sepsis. Increased eCIRP levels were correlated with decreased bacterial clearance in septic mice. CIRP−/− mice showed a marked increase in survival after sepsis. Recombinant murine CIRP (rmCIRP) significantly decreased the phagocytosis of bacteria by macrophages in vivo and in vitro. rmCIRP decreased the protein expression of actin-binding proteins, ARP2, and p-cofilin in macrophages. rmCIRP significantly downregulated the protein expression of βPIX, a Rac1 activator. We further demonstrated that STAT3 and βPIX formed a complex following rmCIRP treatment, preventing βPIX from activating Rac1. We also found that eCIRP-induced STAT3 phosphorylation was required for eCIRP’s action in actin remodeling. Inhibition of STAT3 phosphorylation prevented the formation of the STAT3-βPIX complex, restoring ARP2 and p-cofilin expression and membrane protrusion in rmCIRP-treated macrophages. The STAT3 inhibitor stattic rescued the macrophage phagocytic dysfunction induced by rmCIRP. Thus, we identified a novel mechanism of macrophage phagocytic dysfunction caused by eCIRP, which provides a new therapeutic target to ameliorate sepsis.

关键词： βPIX eCIRP Macrophage Phagocytosis Rac1 STAT3

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Noncovalent reversible binding-enabled facile fabrication of leak-free PDMS microfluidic devices without plasma treatment for convenient cell loading and retrieval

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Bioactive Materials 2022年第10期7卷 346-358页

作者： Bin Jiang Alisa White Wenquan Ou Sarah Van Belleghem Samantha Stewart James G.Shamul Shaik O.Rahaman John P.Fisher Xiaoming He Fischell Department of Bioengineering University of MarylandCollege ParkMD20742USA Department of Nutrition and Food Science University of MarylandCollege ParkMD20742USA Marlene and Stewart Greenebaum Comprehensive Cancer Center University of MarylandBaltimoreMD21201USA

The conventional approach for fabricating polydimethylsiloxane(PDMS)microfluidic devices is a lengthy and inconvenient procedure and may require a clean-room microfabrication facility often not readily ***,living cells can’t survive the oxygen-plasma and high-temperature-baking treatments required for covalent bonding to assemble multiple PDMS parts into a leak-free device,and it is difficult to disassemble the devices because of the irreversible covalent *** a result,seeding/loading cells into and retrieving cells from the devices are ***,we discovered that decreasing the curing agent for crosslinking the PDMS prepolymer increases the noncovalent binding energy of the resultant PDMS surfaces without plasma or any other *** enables convenient fabrication of leak-free microfluidic devices by noncovalent binding for various biomedical applications that require high pressure/flow rates and/or long-term cell culture,by simply hand-pressing the PDMS parts without plasma or any other treatment to bind/*** this method,multiple types of cells can be conveniently loaded into specific areas of the PDMS parts before assembly and due to the reversible nature of the noncovalent bonding,the assembled device can be easily disassembled by hand peeling for retrieving *** with 3D printers that are widely available for making masters to eliminate the need of photolithography,this facile yet rigorous fabrication approach is much faster and more convenient for making PDMS microfluidic devices than the conventional oxygen plasma-baking-based irreversible covalent bonding method.

关键词： Binding energy 3D printing Soft lithography Microfluidics Polydimethylsiloxane

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