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Triple-negative breast cancer (TNBC) is a subtype of breast cancer with aggressive behavior and poor prognosis. Current therapeutic options available for TNBC patients are primarily chemotherapy. With our evolving understanding of this disease, novel targeted therapies, including poly ADP-ribose polymerase (PARP) inhibitors, antibody-drug conjugates, and immune-checkpoint inhibitors, have been developed for clinical use. Previous reports have demonstrated the essential role of estrogen receptor ß (ERß) in TNBC, but the detailed molecular mechanisms downstream ERß activation in TNBC are still far from elucidated. In this study, we demonstrated that a specific ERß agonist, LY500307, potently induces R-loop formation and DNA damage in TNBC cells. Subsequent interactome experiments indicated that the residues 151 to 165 of U2 small nuclear RNA auxiliary factor 1 (U2AF1) and the Trp439 and Lys443 of ERß were critical for the binding between U2AF1 and ERß. Combined RNA sequencing and ribosome sequencing analysis demonstrated that U2AF1-regulated downstream RNA splicing of 5-oxoprolinase (OPLAH) could affect its enzymatic activity and is essential for ERß-induced R-loop formation and DNA damage. In clinical samples including 115 patients from The Cancer Genome Atlas (TCGA) and 32 patients from an in-house cohort, we found a close correlation in the expression of ESR2 and U2AF1 in TNBC patients. Collectively, our study has unraveled the molecular mechanisms that explain the therapeutic effects of ERß activation in TNBC, which provides rationale for ERß activation-based single or combined therapy for patients with TNBC.
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Empalme Alternativo , Benzopiranos , Receptor beta de Estrógeno , Estructuras R-Loop , Factor de Empalme U2AF , Neoplasias de la Mama Triple Negativas , Humanos , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/metabolismo , Factor de Empalme U2AF/química , Factor de Empalme U2AF/genética , Factor de Empalme U2AF/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Terapia Combinada , Células MDA-MB-231 , Empalme Alternativo/efectos de los fármacos , Benzopiranos/farmacología , Benzopiranos/uso terapéutico , Unión Proteica , Sitios de UniónRESUMEN
[This corrects the article DOI: 10.1371/journal.pgen.1009233.].
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OBJECTIVE: The present study identified potentially pivotal miRNAs contributing to chondrogenic differentiation in temporomandibular joint suffering abnormal stress. MATERIALS AND METHODS: Sprague-Dawley rats were randomly divided into control and experimental unilateral mastication (EUM) group. Bone micro-structure parameters was detected by micro-CT, and FGF-1 and MMP-1 expression was examined by immunohistochemistry. Differentially expressed miRNAs of bilateral condyle cartilage were screened via miRNA microarray at 4- and 8-week EUM, then further verified using quantitative reverse-transcription PCR. Over-expression of five differentially expressed miRNAs in chondrocytes was triggered by transfecting miRNA mimics. The expression of MMP-13, Col-II, OPN, and Runx2 was verified by western blotting. RESULTS: Expressions of FGF-1 and MMP-1 in right condyles gradually increased from 2 to 6 weeks after EUM. A total of 20 differentially expressed miRNAs were regulated by EUM, which related to cell proliferation, invasion, and osteoblast differentiation pathways. The over-expression of miR-148a-3p and miR-1-3p led to down-regulation of Col-II, while MMP-13 and Runx2 were up-regulated by induction of hypotrophic differentiation or IL-1ß stimulation. These findings suggested that miR-148a-3p and miR-1-3p promote chondrogenic differentiation. CONCLUSIONS: Several pivotal miRNAs were found to be related to chondrogenic differentiation, which provides novel insight into pathogenic mechanisms of cartilage homeostasis.
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MicroARNs , Ratas , Animales , MicroARNs/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 1 de la Matriz , Factor 1 de Crecimiento de Fibroblastos , Masticación , Ratas Sprague-Dawley , Cartílago/metabolismo , HomeostasisRESUMEN
Runx1 is highly expressed in osteoblasts, however, its function in osteogenesis is unclear. We generated mesenchymal progenitor-specific (Runx1f/fTwist2-Cre) and osteoblast-specific (Runx1f/fCol1α1-Cre) conditional knockout (Runx1 CKO) mice. The mutant CKO mice with normal skeletal development displayed a severe osteoporosis phenotype at postnatal and adult stages. Runx1 CKO resulted in decreased osteogenesis and increased adipogenesis. RNA-sequencing analysis, Western blot, and qPCR validation of Runx1 CKO samples showed that Runx1 regulates BMP signaling pathway and Wnt/ß-catenin signaling pathway. ChIP assay revealed direct binding of Runx1 to the promoter regions of Bmp7, Alk3, and Atf4, and promoter mapping demonstrated that Runx1 upregulates their promoter activity through the binding regions. Bmp7 overexpression rescued Alk3, Runx2, and Atf4 expression in Runx1-deficient BMSCs. Runx2 expression was decreased while Runx1 was not changed in Alk3 deficient osteoblasts. Atf4 overexpression in Runx1-deficient BMSCs did not rescue expression of Runx1, Bmp7, and Alk3. Smad1/5/8 activity was vitally reduced in Runx1 CKO cells, indicating Runx1 positively regulates the Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 signaling pathway. Notably, Runx1 overexpression in Runx2-/- osteoblasts rescued expression of Atf4, OCN, and ALP to compensate Runx2 function. Runx1 CKO mice at various osteoblast differentiation stages reduced Wnt signaling and caused high expression of C/ebpα and Pparγ and largely increased adipogenesis. Co-culture of Runx1-deficient and wild-type cells demonstrated that Runx1 regulates osteoblast-adipocyte lineage commitment both cell-autonomously and non-autonomously. Notably, Runx1 overexpression rescued bone loss in OVX-induced osteoporosis. This study focused on the role of Runx1 in different cell populations with regards to BMP and Wnt signaling pathways and in the interacting network underlying bone homeostasis as well as adipogenesis, and has provided new insight and advancement of knowledge in skeletal development. Collectively, Runx1 maintains adult bone homeostasis from bone loss though up-regulating Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 and WNT/ß-Catenin signaling pathways, and targeting Runx1 potentially leads to novel therapeutics for osteoporosis.
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Proteína Morfogenética Ósea 7/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Osteogénesis/genética , Osteoporosis/genética , Factor de Transcripción Activador 4/genética , Adipocitos/metabolismo , Adipogénesis/genética , Animales , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Proteínas de Unión al ADN/genética , Regulación del Desarrollo de la Expresión Génica/genética , Homeostasis/genética , Humanos , Células Madre Mesenquimatosas , Ratones , Ratones Noqueados , Osteoblastos/metabolismo , Osteoporosis/patología , Regiones Promotoras Genéticas/genética , RNA-Seq , Proteínas Represoras/genética , Proteína Smad1/genética , Proteína 1 Relacionada con Twist/genética , Vía de Señalización Wnt/genéticaRESUMEN
The osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) is critical for bone formation and regeneration. A high non-/delayed-union rate of fracture healing still occurs in specific populations, implying an urgent need to discover novel targets for promoting osteogenesis and bone regeneration. Long non-coding (lnc)RNAs are emerging regulators of multiple physiological processes, including osteogenesis. Based on differential expression analysis of RNA sequencing data, we found that lncRNA AC132217.4, a 3'UTR-overlapping lncRNA of insulin growth factor 2 (IGF2), was highly induced during osteogenic differentiation of BMSCs. Afterward, both gain-of-function and loss-of-function experiments proved that AC132217.4 promotes osteoblast development from BMSCs. As for its molecular mechanism, we found that AC132217.4 binds with IGF2 mRNA to regulate its expression and downstream AKT activation to control osteoblast maturation and function. Furthermore, we identified two splicing factors, splicing component 35 KDa (SC35) and heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), which regulate the biogenesis of AC132217.4 at the post-transcriptional level. We also identified a transcription factor, ALX1, which regulates AC132217.7 expression at the transcriptional level to promote osteogenesis. Importantly, in-vivo over-expression of AC132217.4 essentially promotes the bone healing process in a murine tibial drill-hole model. Our study demonstrates that lncRNA AC132217.4 is a novel anabolic regulator of BMSC osteogenesis and could be a plausible therapeutic target for improving bone regeneration.
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Proteínas de Homeodominio , Células Madre Mesenquimatosas , Osteogénesis , ARN Largo no Codificante , Animales , Diferenciación Celular/genética , Proteínas de Homeodominio/genética , Factor II del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/metabolismo , Ratones , Osteogénesis/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Transducción de SeñalRESUMEN
Calvarial bone is one of the most complex sequences of developmental events in embryology, featuring a uniquely transient, pluripotent stem cell-like population known as the cranial neural crest (CNC). The skull is formed through intramembranous ossification with distinct tissue lineages (e.g. neural crest derived frontal bone and mesoderm derived parietal bone). Due to CNC's vast cell fate potential, in response to a series of inductive secreted cues including BMP/TGF-ß, Wnt, FGF, Notch, Hedgehog, Hippo and PDGF signaling, CNC enables generations of a diverse spectrum of differentiated cell types in vivo such as osteoblasts and chondrocytes at the craniofacial level. In recent years, since the studies from a genetic mouse model and single-cell sequencing, new discoveries are uncovered upon CNC patterning, differentiation, and the contribution to the development of cranial bones. In this review, we summarized the differences upon the potential gene regulatory network to regulate CNC derived osteogenic potential in mouse and human, and highlighted specific functions of genetic molecules from multiple signaling pathways and the crosstalk, transcription factors and epigenetic factors in orchestrating CNC commitment and differentiation into osteogenic mesenchyme and bone formation. Disorders in gene regulatory network in CNC patterning indicate highly close relevance to clinical birth defects and diseases, providing valuable transgenic mouse models for subsequent discoveries in delineating the underlying molecular mechanisms. We also emphasized the potential regenerative alternative through scientific discoveries from CNC patterning and genetic molecules in interfering with or alleviating clinical disorders or diseases, which will be beneficial for the molecular targets to be integrated for novel therapeutic strategies in the clinic.
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Diferenciación Celular , Redes Reguladoras de Genes/genética , Osteogénesis , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Mesodermo/citología , Mesodermo/metabolismo , Cresta Neural/citología , Cresta Neural/metabolismo , Osteoblastos/citología , Osteoblastos/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
OBJECTIVE: This meta-analytic study examined the effects of exercise training on depressive symptoms in mild stroke patients and the moderating effects of exercise type, therapeutic method, culture, sex, and gross domestic product (GDP) in the patient's country. METHODS: The Metafor package in R was chosen to conduct the meta-analysis, and the quality of each empirical study was evaluated according to the grading system in Cochrane. We included 36 empirical studies and 1477 patients. RESULTS: The results showed that the treatment effect of exercise training on depression in mild stroke patients was significant. The moderating effects of culture and therapeutic method were significant, but not for exercise type, sex, or GDP in the patient's country. The moderating effect of culture can be explained by the therapeutic method in different cultures. CONCLUSION: Fitness exercise is an effective method for improving depressive symptoms in mild stroke patients. Its effectiveness is moderated by the therapeutic method but is not affected by demographics, exercise type, gender, or GDP level.
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Depresión , Accidente Cerebrovascular , Anciano , Depresión/etiología , Depresión/terapia , Ejercicio Físico , Terapia por Ejercicio/métodos , Humanos , Persona de Mediana Edad , Accidente Cerebrovascular/complicacionesRESUMEN
In recent years, immunotherapy, as an emerging anti-tumor therapy, has shown great potential in the treatment of both solid and hematologic tumors. There is increasing preclinical and clinical evidence linking the composition of gut microbiome with the efficacy as well as adverse effects of immune checkpoint inhibitor anti-tumor therapy. We summarized in this review the modulatory role of the gut microbiome in antitumor therapy with different immune checkpoint inhibitors. We also discussed the limitations of existing research and prospective development of the further clinical strategies.
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Microbioma Gastrointestinal , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias/tratamiento farmacológico , Estudios ProspectivosRESUMEN
The mechanism underlying how transcription factors regulate mesenchymal stem cell lineage commitment remains unclear. To determine the role of core-binding factor subunit beta (Cbfß) in osteoblast lineage commitment, we generated three mouse models by deleting Cbfß at different osteoblast lineage stages. We demonstrated that the Cbfßf/fPrx1-Cre, Cbfßf/fCol2α1-Cre, and Cbfßf/fOsx-Cre mice exhibited severe osteoporosis with substantial accumulation of marrow adipocytes resembling aged bone from enhanced adipogenesis, indicating that mesenchymal stem cells and osteoblasts can be programed and reprogramed, respectively, into adipocytes. Consistently, Cbfß-deficient calvarial cells and bone marrow mesenchymal stem cells displayed strong adipogenic potential, with 5- to â¼70-fold increased adipocyte gene expression, which can be rescued by Cbfß overexpression. Canonical Wnt signaling was impeded in the Cbfß-deficient cells, with â¼80% decrease of Wnt10b expression. Accordingly, ChIP and luciferase assays demonstrated that Cbfß/RUNX2 binds to Wnt10b promoter driving Wnt10b expression. Furthermore, Wnt3a suppressed adipogenesis but did not rescue osteoblastogenesis in Cbfß-deficient cells. Notably, mixing culture of Cbfß-deficient with normal cells demonstrates that Cbfß functions not only through WNT paracrine pathway but also through endogenous signaling. Further analysis shows that Cbfß/RUNX2 inhibits c/ebpα expression at transcriptional level. Our results show that, besides its osteogenic role, Cbfß governs osteoblast-adipocyte lineage commitment both cell nonautonomously through enhancing ß-catenin signaling and cell autonomously through suppressing adipogenesis gene expression to maintain osteoblast lineage commitment, indicating Cbfß may be a therapeutic target for osteoporosis.
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Adipocitos/metabolismo , Adipogénesis , Subunidad beta del Factor de Unión al Sitio Principal/metabolismo , Regulación de la Expresión Génica , Osteoblastos/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismo , Adipocitos/citología , Animales , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Subunidad beta del Factor de Unión al Sitio Principal/genética , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Ratones , Ratones Transgénicos , Osteoblastos/citología , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Proteína Wnt3A/genética , Proteína Wnt3A/metabolismo , beta Catenina/genéticaRESUMEN
The pathogenesis of cleidocranial dysplasia (CCD) as well as the specific role of core binding factor ß (Cbfß) and the Runt-related transcription factor (RUNX)/Cbfß complex in postnatal skeletogenesis remain unclear. We demonstrate that Cbfß ablation in osteoblast precursors, differentiating chondrocytes, osteoblasts, and odontoblasts via Osterix-Cre, results in severe craniofacial dysplasia, skeletal dysplasia, abnormal teeth, and a phenotype recapitulating the clinical features of CCD. Cbfß(f/f)Osterix-Cre mice have fewer proliferative and hypertrophic chondrocytes, fewer osteoblasts, and almost absent trabecular bone, indicating that Cbfß may maintain trabecular bone formation through its function in hypertrophic chondrocytes and osteoblasts. Cbfß(f/f)Collagen, type 1, alpha 1 (Col1α1)-Cre mice show decreased bone mineralization and skeletal deformities, but no radical deformities in teeth, mandibles, or cartilage, indicating that osteoblast lineage-specific ablation of Cbfß results in milder bone defects and less resemblance to CCD. Activating transcription factor 4 (Atf4) and Osterix protein levels in both mutant mice are dramatically reduced. ChIP assays show that Cbfß directly associates with the promoter regions of Atf4 and Osterix. Our data further demonstrate that Cbfß highly up-regulates the expression of Atf4 at the transcriptional regulation level. Overall, our genetic dissection approach revealed that Cbfß plays an indispensable role in postnatal skeletal development and homeostasis in various skeletal cell types, at least partially by up-regulating the expression of Atf4 and Osterix. It also revealed that CCD may result from functional defects of the Runx2/Cbfß heterodimeric complex in various skeletal cells. These insights into the role of Cbfß in postnatal skeletogenesis and CCD pathogenesis may assist in the development of new therapies for CCD and osteoporosis.
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Condrocitos/fisiología , Displasia Cleidocraneal/fisiopatología , Subunidad beta del Factor de Unión al Sitio Principal/fisiología , Osteoblastos/fisiología , Osteogénesis/fisiología , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Animales , Animales Recién Nacidos , Western Blotting , Células Cultivadas , Condrocitos/metabolismo , Displasia Cleidocraneal/genética , Displasia Cleidocraneal/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Subunidad beta del Factor de Unión al Sitio Principal/genética , Subunidad beta del Factor de Unión al Sitio Principal/metabolismo , Regulación del Desarrollo de la Expresión Génica , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microscopía Confocal , Microscopía Fluorescente , Osteoblastos/metabolismo , Osteogénesis/genética , Regiones Promotoras Genéticas/genética , Unión Proteica , Multimerización de Proteína , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Cráneo/citología , Cráneo/metabolismo , Factor de Transcripción Sp7 , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Despite recent insights gained from the effects of targeted deletion of the Finkel-Biskis-Jinkins osteosarcoma oncogene (c-fos), Spleen focus-forming virus (SFFV) proviral integration 1 (PU.1), microphthalmia-associated transcription factor, NF-κB, and nuclear factor of activated cells cytoplasmic 1 (NFATc1) transcription factor genes, the mechanism underlying transcription factors specifying osteoclast (OC) lineage commitment from monocyte/macrophage remains unclear. To characterize the mechanism by which transcription factors regulate OC lineage commitment, we mapped the critical cis-regulatory element in the promoter of cathepsin K (Ctsk), which is expressed specifically in OCs, and found that CCAAT/enhancer binding protein α (C/EBPα) is the critical cis-regulatory element binding protein. Our results indicate that C/EBPα is highly expressed in pre- OCs and OCs. The combined presence of macrophage colony-stimulating factor and receptor activator of NF-κB ligand significantly induces high C/EBPα expression. Furthermore, C/EBPα(-/-) newborn mice exhibited impaired osteoclastogenesis, and a severe osteopetrotic phenotype, but unaffected monocyte/macrophage development. Impaired osteoclastogenesis of C/EBPα(-/-) mouse bone marrow cells can be rescued by c-fos overexpression. Ectopic expression of C/EBPα in mouse bone marrow cells and monocyte/macrophage cells, in the absence of receptor activator of NF-κB ligand, induces expression of receptor activator of NF-κB, c-fos, Nfatc1, and Ctsk, and it reprograms monocyte/macrophage cells to OC-like cells. Our results demonstrate that C/EBPα directly up-regulates c-fos expression. C/EBPα(+/-) mice exhibit an increase in bone density compared with C/EBPα(+/+) controls. These discoveries establish C/EBPα as the key transcriptional regulator of OC lineage commitment, providing a unique therapeutic target for diseases of excessive bone resorption, such as osteoporosis and arthritis.
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Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Linaje de la Célula , Osteoclastos/metabolismo , Osteoclastos/patología , Animales , Animales Recién Nacidos , Secuencia de Bases , Biomarcadores/metabolismo , Proteína alfa Potenciadora de Unión a CCAAT/deficiencia , Catepsina K/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Línea Celular , Linaje de la Célula/efectos de los fármacos , Linaje de la Célula/genética , ADN/metabolismo , Fémur/diagnóstico por imagen , Fémur/efectos de los fármacos , Fémur/patología , Fémur/fisiopatología , Regulación de la Expresión Génica/efectos de los fármacos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Monocitos/citología , Tamaño de los Órganos/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Osteoclastos/enzimología , Osteogénesis/efectos de los fármacos , Osteogénesis/genética , Osteopetrosis/diagnóstico por imagen , Osteopetrosis/patología , Osteopetrosis/fisiopatología , Fenotipo , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ligando RANK/farmacología , Radiografía , Secuencias Reguladoras de Ácidos Nucleicos/genética , Tibia/diagnóstico por imagen , Tibia/efectos de los fármacos , Tibia/patología , Tibia/fisiopatologíaRESUMEN
Transforming growth factor-ßs (TGF-ßs) and bone morphometric proteins (BMPs) belong to the TGF-ß superfamily and perform essential functions during osteoblast and chondrocyte lineage commitment and differentiation, skeletal development, and homeostasis. TGF-ßs and BMPs transduce signals through SMAD-dependent and -independent pathways; specifically, they recruit different receptor heterotetramers and R-Smad complexes, resulting in unique biological readouts. BMPs promote osteogenesis, osteoclastogenesis, and chondrogenesis at all differentiation stages, while TGF-ßs play different roles in a stage-dependent manner. BMPs and TGF-ß have opposite functions in articular cartilage homeostasis. Moreover, TGF-ß has a specific role in maintaining the osteocyte network. The precise activation of BMP and TGF-ß signaling requires regulatory machinery at multiple levels, including latency control in the matrix, extracellular antagonists, ubiquitination and phosphorylation in the cytoplasm, nucleus-cytoplasm transportation, and transcriptional co-regulation in the nuclei. This review weaves the background information with the latest advances in the signaling facilitated by TGF-ßs and BMPs, and the advanced understanding of their diverse physiological functions and regulations. This review also summarizes the human diseases and mouse models associated with disordered TGF-ß and BMP signaling. A more precise understanding of the BMP and TGF-ß signaling could facilitate the development of bona fide clinical applications in treating bone and cartilage disorders.
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Proteínas Morfogenéticas Óseas , Condrogénesis , Factor de Crecimiento Transformador beta , Animales , Humanos , Ratones , Huesos/metabolismo , Cartílago/metabolismo , Homeostasis , Factor de Crecimiento Transformador beta/metabolismo , Proteínas Morfogenéticas Óseas/metabolismoRESUMEN
Osteoarthritis and psoriasis arthritis are two degenerative forms of arthritis that share similar yet also different manifestations at the histological, cellular, and clinical levels. Rheumatologists have marked them as two entirely distinct arthropathies. Given recent discoveries in disease initiation and progression, potential mechanisms, cellular signaling pathways, and ongoing clinical therapeutics, there are now more opportunities for discovering osteoarthritis drugs. This review summarized the osteoarthritis and psoriasis arthritis signaling pathways, crosstalk between BMP, WNT, TGF-ß, VEGF, TLR, and FGF signaling pathways, biomarkers, and anatomical pathologies. Through bench research, we demonstrated that regenerative medicine is a promising alternative for treating osteoarthritis by highlighting significant scientific discoveries on entheses, multiple signaling blockers, and novel molecules such as immunoglobulin new antigen receptors targeted for potential drug evaluation. Furthermore, we offered valuable therapeutic approaches with a multidisciplinary strategy to treat patients with osteoarthritis or psoriasis arthritis in the coming future in the clinic.
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Ovarian cancer is a major cause of death among gynecological cancers due to its highly aggressive nature. Immunotherapy has emerged as a promising avenue for ovarian cancer treatment, offering targeted approaches with reduced off-target effects. With the advent of next-generation sequencing, it has become possible to identify genomic alterations that can serve as potential targets for immunotherapy. Furthermore, immunogenomics research has revealed the importance of genetic alterations in shaping the cancer immune responses. However, the heterogeneity of immunogenicity and the low tumor mutation burden pose challenges for neoantigen-based immunotherapies. Further research is needed to identify neoantigen-specific tumor-infiltrating lymphocytes (TIL) and establish guidelines for patient inclusion criteria in TIL-based therapy. The study of neoantigens and their implications in ovarian cancer immunotherapy holds great promise, and efforts focused on personalized treatment strategies, refined neoantigen selection, and optimized therapeutic combinations will contribute to improving patient outcomes in the future.
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Antígenos de Neoplasias , Neoplasias Ováricas , Humanos , Femenino , Antígenos de Neoplasias/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/terapia , Inmunoterapia Adoptiva , Mutación , InmunoterapiaRESUMEN
OBJECTIVE: Although several studies have found dietary intake is related to multiple myeloma (MM) and its precursor status risks, the role of one's nutritional status has been ignored and its role in plasma cell neoplasm development is still unclear. This study aimed to explore the relationship between various clinical indices of nutritional status and the risk of monoclonal gammopathy of undetermined significance (MGUS) in the population. METHODS: We selected 9520 participants from the NHANES III and NHANES 1999-2004 studies. Controlling nutritional status index (CONUT), prognostic nutritional index (PNI), geriatric nutritional risk index (GNRI) and body mass index (BMI) were calculated as indices of nutritional status of the participants. Associations between nutritional indices and MGUS were investigated using multiple logistic regression, subgroup analysis, and an RCS model. RESULTS: In our study, 266 participants had MGUS, with a prevalence of 2.79%. This study found that CONUT and PNI identified populations with poor nutritional status and had a significant positive correlation with the risk of MGUS. In multivariate logistic regression, compared with the lower CONUT score (<3) group, the OR for the group with higher scores (≥3) was 1.805 (95%CI: 1.271, 2.564). Compared with the lowest quartile group, the highest quartile PNI score group had an OR of 0.509 (95%CI: 0.290, 0.896). GNRI had no significant correlation with the risk of MGUS, with an OR of 0.737 (95%CI: 0.443, 1.227). CONCLUSION: This study found that older adults with CONUT and PNI scores indicating poorer nutrition had a higher risk of MGUS.
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Desnutrición , Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Humanos , Anciano , Evaluación Nutricional , Estado Nutricional , Encuestas Nutricionales , Gammopatía Monoclonal de Relevancia Indeterminada/epidemiología , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Pronóstico , Estudios RetrospectivosRESUMEN
Wnt signaling executes an indispensable performance in osteoblast differentiation, bone development, homeostasis, and remodeling. Wnt signals trigger the intracellular Wnt signaling cascade to initiate regulating the implication of ß-catenin in the bone environment. Going through the novel discoveries done via high-throughput sequencing technologies on genetic mouse models, we highlighted the significant contribution of Wnt ligands, co-receptors, inhibitors, their related skeletal phenotypes in mouse models and the similar bone disorders clinically observed in human beings. Moreover, the crosstalk between Wnt signaling pathway and BMP, TGF-ß, FGF, Hippo, Hedgehog, Notch and PDGF signaling pathways is thoroughly demonstrated to be the underlying gene regulatory network that orchestrates osteoblast differentiation and bone development. We also introspected the significance of Wnt signaling transduction in the reorganization of cellular metabolism by stimulating glycolysis, glutamine catabolism, and fatty acid oxidation in osteoblast-lineage cells that display an important regulatory arbor in the cellular bioenergetics of the bone. Throughout this evaluation, most to date therapeutical approaches towards osteoporosis and other bone maladies found in human beings, are formulated with an aspiration to holistically revamp the present clinical applications involving various monoclonal antibodies therapies that lack specificity, efficacy, and safety into more requisite advanced therapeutics that satisfy these three requirements for further clinical considerations. Conclusively, our review provides comprehensive scientific findings related to the fundamental significance of Wnt signaling cascades in skeletal system and the underlying gene regulatory network with other signaling pathways enlightening researchers with the possibility to further integrate the identified target molecules into therapeutic strategies for skeletal disorders treatment in the clinic.
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B cells play an essential role in adaptive immunity and are intimately correlated with pleiotropic immune-mediated diseases. Each B cell occupies a unique B cell receptor (BCR), and all BCRs throughout our body form "BCR repertoire." With the development of sequencing technology and coupled bioinformatics, accumulating evidence indicates that BCR repertoire largely varies under physiological and pathological conditions. Therefore, comprehensive grasp of BCR repertoire will provide new insights into the pathogenesis of immune-mediated diseases and help exploit efficient diagnostic and treatment strategies. In this review, we start with an overview of BCR repertoire and related sequencing technologies and summarize their current applications in immune-mediated diseases. We also underscore the challenges of this emerging field and propose promising future directions in advancing BCR repertoire exploration.
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Osteoporosis, characterized by reduced bone mass, aberrant bone architecture, and elevated bone fragility, is driven by a disruption of bone homeostasis between bone resorption and bone formation. However, up to now, no drugs are perfect for osteoporosis treatment due to different defects. In this study, we demonstrated that norcantharidin (NCTD) could inhibit osteoclast formation and bone resorption by attenuating the ERK, ROS and NLRP3 inflammasomes pathways in vitro. Moreover, our in vivo study further confirms its preventive effects on estrogen-deficiency bone loss by inhibiting osteoclast formation and functions. Therefore, we could conclude that NCTD might be a potential candidates for the prevention and treatment of osteoporosis.
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Temporomandibular joint disorders (TMD) are a common health condition caused by the structural or functional disorders of masticatory muscles and the temporomandibular joint (TMJ). Abnormal mandibular movement in TMD patients may cause pain, chronic inflammation, and other discomfort, which could be relieved by a variety of drugs through various delivery systems. In this study, we summarized commonly used therapeutic agents in the management of TMD as well as novel bioactive molecules in preclinical stage and clinical trials. The emerging therapy strategies such as novel intra-TMJ delivery systems and implants based on tissue engineering are also discussed. This comprehensive review will strengthen our understanding of pharmacological approaches for TMD therapy.
RESUMEN
Heredity is the major factor contributing to the susceptibility to ankylosing spondylitis(AS). Janus kinase 2 (JAK2) has been associated with AS. Urine-derived cells from an AS patient with JAK2 mutation were used to generate induced pluripotent stem cells (iPSCs) with five episomal iPSC reprogramming vectors (pCXLE-hOCT3/4-shp53-F, pCXLE-hSK, pCXLE-hUL, pCXLE-EGFP and pCXWB-EBNA1). The iPSCs were pluripotent and will be valuable for research on the role and mechanism of JAK2 in the pathogenesis of AS.