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Stem-c.ll Derived Exosomal mic.oRNAs as Biomarkers and Therapeutic. for Pediatric.c.rdiovasc.lar Disease

c.RRENT TREATMENT OPTIONS IN c.RDIOVASc.LAR MEDIc.NE 2025年第1期27卷 1-10页

作者： Wasserman, Aaron H. Abolibdeh, Bana Hamdan, Reema hong, charles c. Michigan State Univ Coll Human Med Dept Med E Lansing MI 48823 USA Michigan State Hlth Sci Henry Ford Hlth Detroit MI 48808 USA

Purpose of ReviewIn rec.nt years, several pre-c.inic.l studies have demonstrated the therapeutic.potential of stem c.ll-derived exosomes in the treatment of c.rdiovasc.lar disease (c.D). Here, we evaluate their potential as biomarkers for the detec.ion and monitoring of c.D, with a partic.lar foc.s on pediatric.heart *** FindingsExosomes isolated from stem c.ll sourc.s, inc.uding mesenc.ymal stem c.lls (MSc.) and pluripotent stem c.lls (PSc.), benefit c.rdiovasc.lar func.ion, inflammatory responses, and angiogenesis in injured and diseased hearts. These exosomes c.rry a variety of c.rgo, suc. as proteins, lipids, and nuc.eic.ac.ds. However, the majority c.ntain non-c.ding RNA *** of the existing literature for several non-c.ding RNAs and their relationship to c.D suggests that exosomes c.ntaining mic.oRNAs (miRNAs) c.n serve as promising biomarkers for c.D due to their presenc. in c.rc.lation, ease of isolation, and therapeutic.potential. These biomarkers are espec.ally promising as sc.eening and diagnostic.tools for the early detec.ion of pediatric.and c.ngenital heart disease.

关键词： c.rdiovasc.lar Disease c.ngenital Heart Disease Mesenc.ymal Stem c.lls Mic.oRNAs Non-c.ding RNAs Stem c.ll-Derived Exosomes

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Inhibition of GPR68 induc.s ferroptosis and radiosensitivity in diverse c.nc.r c.ll types

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Sc.ENTIFIc.REPORTS 2025年第1期15卷 1-14页

作者： Neitzel, Leif R. Fuller, Daniela T. c.rnell, Jessic. Rea, Samantha de Aguiar Ferreira, c.rolina Williams, charles H. hong, charles c. Michigan State Univ Coll Human Med Dept Med E Lansing MI 48824 USA Henry Ford Hlth Michigan State Univ Hlth Sci Detroit MI 48202 USA Univ Maryland Sch Med Dept Med Baltimore MD USA Michigan State Univ Inst Quantitat Hlth Sci & Engn E Lansing MI 48824 USA Michigan State Univ Dept Radiol E Lansing MI 48824 USA Michigan State Univ Dept Pharmacol & Toxicol E Lansing MI 48824 USA Michigan State Univ Dept Biomed Engn E Lansing MI 48824 USA

Radioresistanc. is thought to be a major c.nsequenc. of tumor milieu ac.dific.tion resulting from the Warburg effec.. Previously, using ogremorphin (OGM), a small molec.le inhibitor of GPR68, an extrac.llular proton sensing rec.ptor, we demonstrated that GPR68 is a key pro-survival pathway in glioblastoma c.lls. Here, we demonstrate that GPR68 inhibition also induc.s ferroptosis in lung c.ll c.rc.noma (A549) and panc.eatic.duc.al adenoc.rc.noma (Panc.2) c.lls. Moreover, OGM synergized with ionizing radiation to induc. lipid peroxidation, a hallmark of ferroptosis, as well as reduc. c.lony size in 2D and 3D c.ll c.lture. GPR68 inhibition is not ac.tely detrimental but inc.eases intrac.llular free ferrous iron, whic. is known to trigger reac.ive oxygen spec.es (ROS) generation. In summary, GPR68 inhibition induc.s lipid peroxidation in c.nc.r c.lls and sensitizes them to ionizing radiation in part through the mobilization of intrac.llular free ferrous iron. Our results suggest that GPR68 is a key mediator of c.nc.r c.ll radioresistanc. ac.ivated by ac.dic.tumor mic.oenvironment.

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A novel transgenic.reporter of extrac.llular ac.dific.tion in zebrafish eluc.dates skeletal musc.e T-tubule pH regulation

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DEVELOPMENTAL DYNAMIc. 2025年第0期 2025 Jan 22页

作者： Neitzel, Leif R. Silver, Maya Wasserman, Aaron H. Rea, Samantha hong, charles c. Williams, charles H. Michigan State Univ Coll Human Med Dept Med E Lansing MI 48824 USA Henry Ford Hlth Michigan State Hlth Sci Detroit MI USA Univ Maryland Sch Med Dept Med Baltimore MD USA

Disruption of extrac.llular pH and proton-sensing c.n profoundly impac. c.llular and protein func.ions, leading to developmental defec.s. To visualize c.anges in extrac.llular pH in the developing embryo, we generated a zebrafish transgenic.line that ubiquitously expresses the ratiometric.pH-sensitive fluoresc.nt protein pHluorin2, tethered to the extrac.llular fac. of the plasma membrane using a glyc.sylphosphatidylinositol (GPI) anc.or. Monitoring of pHluorin2 with ratiometric.fluoresc.nc. revealed dynamic.and disc.ete domains of extrac.llular ac.dific.tion over the first 72 h of embryonic.development. These inc.uded ac.dific.tion of the notoc.ord interc.lations, transient ac.dific.tion of the otic.plac.de, and persistent ac.dific.tion of the extrac.llular spac. of the myotome at distinc.ly different pH from that within the T-tubules. Knoc.down of c.ntronuc.ear myopathy genes Bin1b (OMIM: 255200) and MTM1 (OMIM: 310400), whic. disrupt T-tubule formation, also disrupted myotome ac.dific.tion. In this study we visualize extrac.llular ac.dic.mic.odomains in the tissues of whole live animals. This real-time reporter line for direc.ly measuring c.anges in extrac.llular pH c.n be used to illuminate the role of extrac.llular pH in normal physiologic.l development and disease states.

关键词： ac.d homeostasis development myotome transverse tubules T-tubules

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Inhibition of proton sensor GPR68 suppresses endothelial dysfunc.ion and ac.te lung injury c.used by Staphyloc.c.us aureus bac.erial partic.es

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FASEB JOURNAL 2025年第3期39卷 e70333页

作者： Karki, Pratap Ke, Yunbo Zhang, c.en-Ou Promnares, Kamoltip Li, Yue Williams, charles H. hong, charles c. Birukov, Konstantin G. Birukova, Anna A. Univ Maryland Sch Med Dept Med Div Pulm & Crit Care Baltimore MD USA Univ Maryland Sch Med Dept Anesthesiol Baltimore MD USA Univ Maryland Sch Med Div Cardiovasc Med Dept Med Baltimore MD USA Michigan State Univ Coll Human Med Dept Med E Lansing MI USA

Lung bac.erial infec.ions, inc.uding hospital-ac.uired pneumonia, remain a serious problem for public.health. Endothelial c.ll (Ec. exposure to heat-killed Staphyloc.c.us aureus (HKSA) represents a c.inic.l sc.nario of high titers of killed bac.erial partic.es present in the host after antibiotic.therapy, whic. triggers inflammatory c.sc.des, c.tokine storms, and Ec.dysfunc.ion leading to ac.te lung injury (ALI). GPR68 is a member of the proton-sensing G protein-c.upled rec.ptor family. Ac.ing as a pH sensor, GPR68 bec.mes ac.ivated upon pH reduc.ion and c.ntributes to pathologic.c.ll responses by ac.ivating ER stress and unfolded protein response. This study investigated the role of GPR68 in HKSA-induc.d Ec.dysfunc.ion and HKSA-induc.d ALI. HKSA robustly inc.eased GPR68 mRNA levels in human pulmonary Ec.and direc.ly stimulated GPR68 ac.ivity. A selec.ive GPR68 small molec.le inhibitor, OGM-8345, attenuated HKSA-induc.d Ec.permeability and protec.ed c.ll junc.ion integrity. OGM-8345 inhibited HKSA-induc.d ac.ivation of inflammatory genes TNF-alpha, IL-6, IL-8, IL-1 beta, and c.c.5 and dec.eased c.tokine sec.etion by HKSA-c.allenged Ec. c.-treatment with the GPR68 ac.ivator Ogerin or medium ac.dific.tion to pH 6.5 augmented HKSA-induc.d Ec.dysfunc.ion, whic. was resc.ed by OGM-8345. Intratrac.eal HKSA injec.ion inc.eased vasc.lar leak and lung inflammation in mic. whic. were monitored by lung Evans blue extravasation, inc.eased c.ll and protein c.unt in bronc.oalveolar lavage, and mRNA expression of inflammatory genes. ALI and barrier dysfunc.ion was attenuated by OGM-8345. We show for the first time the role of GPR68 in mediating HKSA-induc.d lung injury and the strong potential for OGM-8345 as a therapeutic.treatment of bac.erial pathogen-induc.d ALI assoc.ated with tissue ac.dific.tion.

关键词： ac.dosis endothelial permeability GPR68 HKSA inflammation lung injury OGM-8345

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Zebrafish small molec.le sc.eens: Taking the phenotypic.plunge

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c.MPUTATIONAL AND STRUc.URAL BIOTEc.NOLOGY JOURNAL 2016年 14卷 350-356页

作者： Williams, charles H. hong, charles c. Vanderbilt Univ Sch Med Dept Cell & Dev Biol Nashville TN 37232 USA Vanderbilt Univ Sch Med Dept Med Nashville TN 37232 USA Vanderbilt Univ Sch Med Dept Pharmacol Nashville TN 37232 USA Vanderbilt Univ Sch Med Vanderbilt Inst Chem Biol Nashville TN 37232 USA Vet Affairs Tennessee Valley Healthcare Syst Res Med Nashville TN 37212 USA

Target based c.emic.l sc.eens are a mainstay of modern drug disc.very, but the effec.iveness of this reduc.ionist approac. is being questioned in light of dec.ines in pharmac.utic.l R&D effic.enc.. In rec.nt years, phenotypic.sc.eens have gained inc.easing ac.eptanc. as a c.mplementary/alternative approac. to early drug disc.very. We disc.ss the various model organisms used in phenotypic.sc.eens, with partic.lar foc.s on zebrafish, whic. has emerged as a leading model of in vivo phenotypic.sc.eens. Additionally, we antic.pate therapeutic.opportunities, partic.larly in orphan disease spac., in the c.ntext of rapid advanc.s in human Mendelian genetic., elec.ronic.health rec.rd (EHR)-enabled genome-phenome assoc.ations, and genome editing. Published by Elsevier B.V. on behalf of the Researc. Network of c.mputational and Struc.ural Biotec.nology.

关键词： High-throughput sc.eening Whole-organism sc.eening Phenotypic.sc.eening Phenome-wide assoc.ation study

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Regenerative c.emic.l Biology: c.rrent c.allenges and Future Potential

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c.EMISTRY & BIOLOGY 2011年第4期18卷 413-424页

作者： Ao, Ada Hao, Jijun hong, charles c. Vanderbilt Univ Sch Med Dept Med Div Cardiovasc Med Nashville TN 37232 USA Vanderbilt Univ Sch Med Dept Pharmacol Nashville TN 37232 USA Vanderbilt Univ Sch Med Dept Cell & Dev Biol Nashville TN 37232 USA Vanderbilt Univ Sch Med Vanderbilt Inst Chem Biol Nashville TN 37232 USA Vet Affairs TVHS Nashville TN 37212 USA

The enthusiasm surrounding the c.inic.l potential of embryonic.stem c.lls (ESc.) and induc.d pluripotent stem c.lls (iPSc.) is tempered by the fac. that key issues regarding their safety, effic.c., and long-term benefits have thus far been suboptimal. Small molec.les c.n potentially relieve these problems at major junc.ions of stem c.ll biology and regenerative therapy. In this review we will introduc. rec.nt advanc.s in these important areas and the first generation of small molec.les used in the regenerative c.ntext. c.rrent c.emic.l biology studies will provide the arc.etype for future interdisc.plinary c.llaborations and improve c.inic.l benefits of c.ll-based therapies.

关键词： interdisc.plinary c.llaboration PROTOTYPE small molec.le Enthusiasm c.emic.l c.mpounds Embryonic.Stem c.lls biology Induc.d Pluripotent Stem c.lls Biologic.l Sc.enc. Disc.plines Regenerative

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Emerging roles of the bone morphogenetic.protein pathway in c.nc.r: potential therapeutic.target for kinase inhibition

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BIOc.EMIc.L SOc.ETY TRANSAc.IONS 2016年第4期44卷 1117-1134页

作者： Jiramongkolc.ai, Pawina Owens, Philip hong, charles c. Vanderbilt Univ Sch Med Dept Med Pharmacol & Cell & Dev Biol Nashville TN 37232 USA Vanderbilt Univ Vanderbilt Ingram Canc Ctr Sch Med Dept Canc Biol Nashville TN 37232 USA Vet Affairs Tennessee Valley Healthcare Syst Res Med Nashville TN 37212 USA

Bone morphogenetic.proteins (BMPs) belong to the transforming growth fac.or-beta (TGF-beta) family signalling pathway. Similar to TGF-beta, the c.mplex roles of BMPs in development and disease are demonstrated by their dic.otomous roles in various c.nc.rs and c.nc.r stages. Although early studies implic.ted BMP signalling in tumour suppressive phenotypes, the results of more rec.nt experiments rec.gnize BMPs as potent tumour promoters. Many of these c.mplexities are bec.ming illuminated by understanding the role of BMPs in their c.ntextual role in unique c.ll types of c.nc.r and the impac. of their surrounding tumour mic.oenvironment. Here we review the emerging roles of BMP signalling in c.nc.r, with a foc.s on the molec.lar underpinnings of BMP signalling in individual c.nc.rs as a valid therapeutic.target for c.nc.r prevention and treatment.

关键词： bone morphogenetic.protein (BMP) signalling c.nc.r small molec.le BMP inhibitors

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Applic.tions of small molec.le BMP inhibitors in physiology and disease

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c.TOKINE & GROWTH FAc.OR REVIEWS 2009年第5-6期20卷 409-418页

作者： hong, charles c. Yu, Paul B. Massachusetts Gen Hosp Div Cardiol Boston MA 02114 USA Massachusetts Gen Hosp Cardiovasc Res Ctr Boston MA 02114 USA Harvard Univ Sch Med Boston MA 02114 USA Vanderbilt Univ Div Cardiovasc Med Sch Med Nashville TN 37232 USA Vanderbilt Univ Ctr Inherited Heart Dis Sch Med Dept Med Nashville TN 37232 USA Vanderbilt Univ Ctr Inherited Heart Dis Sch Med Dept Pharmacol Nashville TN 37232 USA

Bone morphogenetic.proteins (BMPs) provide c.itic.l signals for determining c.ll fate, spec.fying gastrulation, embryonic.patterning, organogenesis, and the remodeling of diverse tissues. Rec.nt work has suggested that in addition to c.ordinating pivotal events in development, BMPs may also regulate c.rtain homeostatic.physiologic.l proc.sses independently of effec.s on c.ll growth or differentiation. We rec.ntly desc.ibed the identific.tion of dorsomorphin, a small molec.le inhibitor of BMP type I rec.ptors whic. inhibits BMP signaling in preferenc. to TGF-beta, Ac.ivin, and other ligands of the TGF-beta family. We desc.ibe a number of strategies using dorsomorphin and its derivatives as probes to assess the physiologic.roles of BMP signaling. We also disc.ss several potential applic.tions for small molec.le BMP inhibitors, inc.uding stem c.ll manipulation, and the therapeutic.modific.tion of bone remodeling, heterotopic.ossific.tion, and iron homeostasis. (c. 2009 Elsevier Ltd. All rights reserved.

关键词： High throughput sc.een Bone morphogenetic.protein TGF-beta Anemia Hepc.din c.rdiomyoc.te Embryonic.stem c.ll Fibrodysplasia ossific.ns progressiva Bone mineral density

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c.rdiac.Induc.ion of Embryonic.Stem c.lls by a Small Molec.le Inhibitor of Wnt/β-c.tenin Signaling

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Ac. c.EMIc.L BIOLOGY 2011年第2期6卷 192-197页

作者： Wang, Hanmin Hao, Jijun hong, charles c. Vet Affairs TVHS Res Med Nashville TN 37212 USA Fourth Mil Med Univ Xijing Hosp Dept Nephrol Xian 710032 Shaanxi Peoples R China Vet Affairs TVHS Dept Med Div Nephrol Med Nashville TN 37212 USA Vanderbilt Univ Sch Med Dept Med Div Cardiovasc Med Nashville TN 37232 USA Vanderbilt Univ Sch Med Dept Pharmacol Nashville TN 37232 USA Vanderbilt Univ Sch Med Vanderbilt Inst Chem Biol Nashville TN 37232 USA

In vitro differentiation of embryonic.stem c.lls is tightly regulated by the same key signaling pathways that c.ntrol pattern formation during embryogenesis. Small molec.les that selec.ively target these developmental pathways, inc.uding Wnt, and BMP signaling may be valuable for direc.ing differentiation of pluripotent stem c.lls toward many desired tissue types, but to date only few suc. c.mpounds have been shown to promote c.rdiac.differentiation. Here, we show that XAV939, a rec.ntly disc.vered small molec.le inhibitor of Wnt/beta-c.tenin signaling, c.n robustly induc. c.rdiomyogenesis in mouse ES c.lls. Our results suggest that a timely administration of XAV939 immediately following the formation of mesoderm progenitor c.lls promotes c.rdiomyogenic.development at the expense of other Embryonic.Stem c.lls mesoderm derived lineages, inc.uding the endothelial, smooth musc.e, and hematopoietic.lineages. Given the c.itic.l role that Wnt/beta-c.tenin signaling plays in many aspec.s of embryogenesis and tissue regeneration, XAV939 is a valuable c.emic.l probe to dissec. in vitro differentiation of stem c.lls and to explore their regenerative potential in a variety of c.ntexts.

关键词： Small molec.les c.lls c.ll signaling Genetic. Differentiation

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BMPing Up Healing c.pac.ty with FKBP12 Ligand

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c.LL c.EMIc.L BIOLOGY 2019年第5期26卷 619-620页

作者： Williams, charles H. hong, charles c. Univ Maryland Sch Med Dept Med Baltimore MD 21201 USA

While the wound healing property of the mac.olide FK506 is well known, the underlying mec.anismhas been elusive. In this issue of c.ll c.emic.l Biology, Peiffer et al. (2019) utilize FKBP12 ligand to demonstrate that wound healing effec.s of FK506 oc.ur via ac.ivation of the BMP (bone morphogenic.protein) signaling pathway.

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