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1.
NPJ Syst Biol Appl ; 10(1): 53, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760412

RESUMO

Breast cancer is one of the prevailing cancers globally, with a high mortality rate. Metastatic breast cancer (MBC) is an advanced stage of cancer, characterised by a highly nonlinear, heterogeneous process involving numerous singling pathways and regulatory interactions. Epithelial-mesenchymal transition (EMT) emerges as a key mechanism exploited by cancer cells. Transforming Growth Factor-ß (TGFß)-dependent signalling is attributed to promote EMT in advanced stages of breast cancer. A comprehensive regulatory map of TGFß induced EMT was developed through an extensive literature survey. The network assembled comprises of 312 distinct species (proteins, genes, RNAs, complexes), and 426 reactions (state transitions, nuclear translocations, complex associations, and dissociations). The map was developed by following Systems Biology Graphical Notation (SBGN) using Cell Designer and made publicly available using MINERVA ( http://35.174.227.105:8080/minerva/?id=Metastatic_Breast_Cancer_1 ). While the complete molecular mechanism of MBC is still not known, the map captures the elaborate signalling interplay of TGFß induced EMT-promoting MBC. Subsequently, the disease map assembled was translated into a Boolean model utilising CaSQ and analysed using Cell Collective. Simulations of these have captured the known experimental outcomes of TGFß induced EMT in MBC. Hub regulators of the assembled map were identified, and their transcriptome-based analysis confirmed their role in cancer metastasis. Elaborate analysis of this map may help in gaining additional insights into the development and progression of metastatic breast cancer.


Assuntos
Neoplasias da Mama , Transição Epitelial-Mesenquimal , Transdução de Sinais , Fator de Crescimento Transformador beta , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Feminino , Transdução de Sinais/genética , Biologia de Sistemas/métodos , Redes Reguladoras de Genes/genética , Regulação Neoplásica da Expressão Gênica/genética
2.
Sci Rep ; 14(1): 10910, 2024 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-38740884

RESUMO

Transforming growth factor-ß (TGF-ß) signaling plays a significant role in multiple biological processes, including inflammation, immunity, and cell death. However, its specific impact on the cochlea remains unclear. In this study, we aimed to investigate the effects of TGF-ß signaling suppression on auditory function and cochlear pathology in mice with kanamycin-induced ototoxicity. Kanamycin and furosemide (KM-FS) were systemically administered to 8-week-old C57/BL6 mice, followed by immediate topical application of a TGF-ß receptor inhibitor (TGF-ßRI) onto the round window membrane. Results showed significant TGF-ß receptor upregulation in spiral ganglion neurons (SGNs) after KM-FA ototoxicity, whereas expression levels in the TGF-ßRI treated group remained unchanged. Interestingly, despite no significant change in cochlear TGF-ß expression after KM-FS ototoxicity, TGF-ßRI treatment resulted in a significant decrease in TGF-ß signaling. Regarding auditory function, TGF-ßRI treatment offered no therapeutic effects on hearing thresholds and hair cell survival following KM-FS ototoxicity. However, SGN loss and macrophage infiltration were significantly increased with TGF-ßRI treatment. These results imply that inhibition of TGF-ß signaling after KM-FS ototoxicity promotes cochlear inflammation and SGN degeneration.


Assuntos
Canamicina , Camundongos Endogâmicos C57BL , Ototoxicidade , Transdução de Sinais , Gânglio Espiral da Cóclea , Fator de Crescimento Transformador beta , Animais , Canamicina/toxicidade , Transdução de Sinais/efeitos dos fármacos , Ototoxicidade/etiologia , Ototoxicidade/metabolismo , Ototoxicidade/patologia , Fator de Crescimento Transformador beta/metabolismo , Camundongos , Gânglio Espiral da Cóclea/efeitos dos fármacos , Gânglio Espiral da Cóclea/metabolismo , Gânglio Espiral da Cóclea/patologia , Cóclea/metabolismo , Cóclea/efeitos dos fármacos , Cóclea/patologia , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Furosemida/farmacologia , Masculino
3.
Support Care Cancer ; 32(6): 365, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38758235

RESUMO

BACKGROUND: Cancer-related depression is a well-documented condition that significantly impacts long-term quality of life. Brain-derived neurotrophic factor (BDNF), a neurotrophin essential for neurogenesis and neuronal plasticity, has been implicated in various neuropsychological disorders including depression associated with cancer. Cytokines, on the other hand, play a crucial role in regulating depression, potentially by influencing BDNF expression. Transforming growth factor-ß (TGF-ß), a key immune regulator within the tumor microenvironment, has been found to elevate BDNF levels, establishing a link between peripheral immune responses and depression. The study aims to investigate the correlation of TGF-ß and BDNF in cancer-related depression. METHODS: This study involved a cohort of 153 gynecological patients, including 61 patients with gynecological cancer and 92 patients without cancer. Depression levels were assessed using the subscale of Hospital Anxiety and Depression Scale (HADS-D), and TGF-ß and BDNF plasma levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: The study revealed elevated plasma TGF-ß levels in patients with cancer (32.24 ± 22.93 ng/ml) compared to those without cancer (25.24 ± 19.72 ng/ml) (P = 0.046). Additionally, reduced levels of BDNF were observed in patients presenting depression symptoms (44.96 ± 41.06 pg/ml) compared to those without depression (133.5 ± 176.7 pg/ml) (P = 0.036). Importantly, a significant correlation between TGF-ß and BDNF was found in patients without cancer but with depression (correlation coefficient = 0.893, **P < 0.01). Interestingly, cancer appeared to influence the association between TGF-ß and BDNF in patients with depression, as evidenced by a significant difference in the correlation of TGF-ß and BDNF between cancer and non-cancer groups (P = 0.041). CONCLUSIONS: These findings underscore the active involvement of TGF-ß and BDNF crosstalk in the context of cancer-related depression.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Depressão , Fator de Crescimento Transformador beta , Humanos , Fator Neurotrófico Derivado do Encéfalo/sangue , Feminino , Estudos Transversais , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta/metabolismo , Depressão/etiologia , Pessoa de Meia-Idade , Adulto , Neoplasias dos Genitais Femininos/complicações , Neoplasias dos Genitais Femininos/psicologia , Qualidade de Vida , Ensaio de Imunoadsorção Enzimática , Idoso , Escalas de Graduação Psiquiátrica , Estudos de Casos e Controles
4.
Bull Exp Biol Med ; 176(5): 603-606, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38730107

RESUMO

Polymorphism of genes of transforming growth factor TGFB and its receptors (TGFBRI, TGFBRII, and TGFBRIIII) in patients with primary open-angle glaucoma was analyzed. The frequency of the TGFBRII CC genotype in patients is increased relative to the control group (OR=6.10, p=0.0028). Heterozygosity in this polymorphic position is reduced (OR=0.18, p=0.0052). As the effects of TGF-ß is mediated through its receptors, we analyzed complex of polymorphic variants of the studied loci in the genome of patients. Two protective complexes consisting only of receptor genes were identified: TGFBRI TT:TGFBRII CG (OR=0.10, p=0.02) and TGFBRII CG:TGFBRIII CG (OR=0.09, p=0.01). The study showed an association of TGFBRII polymorphism with primary open-angle glaucoma and the need to study functionally related genes in the development of the disease, which should contribute to its early diagnosis and prevention.


Assuntos
Glaucoma de Ângulo Aberto , Humanos , Glaucoma de Ângulo Aberto/genética , Feminino , Masculino , Pessoa de Meia-Idade , Sibéria , Idoso , Polimorfismo de Nucleotídeo Único/genética , Predisposição Genética para Doença/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Frequência do Gene/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Estudos de Casos e Controles , Genótipo , Fator de Crescimento Transformador beta/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Polimorfismo Genético/genética
5.
Cell Rep Med ; 5(5): 101550, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38723624

RESUMO

Tumor recurrence after chemoradiotherapy is challenging to overcome, and approaches to predict the recurrence remain elusive. Here, human cervical cancer tissues before and after concurrent chemoradiotherapy (CCRT) analyzed by single-cell RNA sequencing reveal that CCRT specifically promotes CD8+ T cell senescence, driven by atypical chemokine receptor 2 (ACKR2)+ CCRT-resistant tumor cells. Mechanistically, ACKR2 expression is increased in response to CCRT and is also upregulated through the ligation of CC chemokines that are produced by activated myeloid and T cells. Subsequently, ACKR2+ tumor cells are induced to produce transforming growth factor ß to drive CD8+ T cell senescence, thereby compromising antitumor immunity. Moreover, retrospective analysis reveals that ACKR2 expression and CD8+ T cell senescence are enhanced in patients with cervical cancer who experienced recurrence after CCRT, indicating poor prognosis. Overall, we identify a subpopulation of CCRT-resistant ACKR2+ tumor cells driving CD8+ T cell senescence and tumor recurrence and highlight the prognostic value of ACKR2 and CD8+ T cell senescence for chemoradiotherapy recurrence.


Assuntos
Linfócitos T CD8-Positivos , Senescência Celular , Quimiorradioterapia , Recidiva Local de Neoplasia , Neoplasias do Colo do Útero , Humanos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/tratamento farmacológico , Quimiorradioterapia/métodos , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/genética , Animais , Camundongos , Linhagem Celular Tumoral , Prognóstico , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento Transformador beta/metabolismo , Senescência de Células T
6.
Mol Biol Rep ; 51(1): 677, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38796641

RESUMO

BACKGROUND: One of the main causes of diabetic nephropathy is oxidative stress induced by hyperglycemia. Apelin inhibits insulin secretion. Besides, renal expression of TGF-ß is increased in diabetes mellitus (DM). The preventive effect of quercetin (Q) against renal functional disorders and tissue damage developed by DM in rats was assessed. METHODS: Forty male Wistar rats were grouped into normal control (NC), normal + quercetin (NQ: quercetin, 50 mg/kg/day by gavage), diabetic control (DC: streptozotocin, 65 mg/kg, i.p.), diabetic + quercetin pretreatment (D + Qpre), and diabetic + quercetin post-treatment (D + Qpost). All samples (24-hour urine, plasma, pancreatic, and renal tissues) were obtained at the terminal of the experiment. RESULTS: Compared to NC and NQ groups, DM ended in elevated plasma and glucose levels, decreased plasma insulin level, kidney dysfunction, augmented levels of malondialdehyde, decreased level of reduced glutathione, reduced enzymatic activities of superoxide dismutase and catalase, elevated gene expression levels of apelin and TGF-ß, also renal and pancreatic histological damages. Quercetin administration diminished entire the changes. However, the measure of improvement in the D + Qpre group was higher than that of the D + Qpost group. CONCLUSION: Quercetin prevents renal dysfunction induced by DM, which might be related to the diminution of lipid peroxidation, strengthening of antioxidant systems, and prevention of the apelin/ TGF-ß signaling pathway.


Assuntos
Apelina , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Rim , Estresse Oxidativo , Quercetina , Ratos Wistar , Fator de Crescimento Transformador beta , Animais , Quercetina/farmacologia , Ratos , Masculino , Fator de Crescimento Transformador beta/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/tratamento farmacológico , Apelina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Insulina/metabolismo , Insulina/sangue , Diabetes Mellitus Tipo 1/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos
7.
Cancer Lett ; 592: 216953, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38729557

RESUMO

TGFBR2, a key regulator of the TGFß signaling pathway, plays a crucial role in gastric cancer (GC) metastasis through its endosomal recycling process. Despite its importance, the mechanisms governing this process remain unclear. Here, we identify integrin ß5 (ITGB5) as a critical mediator that promotes TGFBR2 endosomal recycling. Our study reveals elevated expression of ITGB5 in GC, particularly in metastatic cases, correlating with poor patient outcomes. Knockdown of ITGB5 impairs GC cell metastasis both in vitro and in vivo. Mechanistically, ITGB5 facilitates epithelial-mesenchymal transition mediated by TGFß signaling, thereby enhancing GC metastasis. Acting as a scaffold, ITGB5 interacts with TGFBR2 and SNX17, facilitating SNX17-mediated endosomal recycling of TGFBR2 and preventing lysosomal degradation, thereby maintaining its surface distribution on tumor cells. Notably, TGFß signaling directly upregulates ITGB5 expression, establishing a positive feedback loop that exacerbates GC metastasis. Our findings shed light on the role of ITGB5 in promoting GC metastasis through SNX17-mediated endosomal recycling of TGFBR2, providing insights for the development of targeted cancer therapies.


Assuntos
Endossomos , Transição Epitelial-Mesenquimal , Receptor do Fator de Crescimento Transformador beta Tipo II , Transdução de Sinais , Neoplasias Gástricas , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Humanos , Endossomos/metabolismo , Animais , Linhagem Celular Tumoral , Cadeias beta de Integrinas/metabolismo , Cadeias beta de Integrinas/genética , Nexinas de Classificação/genética , Nexinas de Classificação/metabolismo , Camundongos , Metástase Neoplásica , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento Transformador beta/metabolismo
8.
J Oral Pathol Med ; 53(5): 321-330, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38693618

RESUMO

BACKGROUND: To evaluate the presence of myofibroblasts (MFs) in the development of lip carcinogenesis, through the correlation of clinical, histomorphometric and immunohistochemical parameters, in actinic cheilitis (ACs) and lower lip squamous cell carcinomas (LLSCCs). METHODS: Samples of ACs, LLSCCs, and control group (CG) were prepared by tissue microarray (TMA) for immunohistochemical TGF-ß, α-SMA, and Ki-67 and histochemical hematoxylin and eosin, picrosirius red, and verhoeff van gieson reactions. Clinical and microscopic data were associated using the Mann-Whitney, Kruskal-Wallis/Dunn, and Spearman correlation tests (SPSS, p < 0.05). RESULTS: ACs showed higher number of α-SMA+ MFs when compared to CG (p = 0.034), and these cells were associated with the vertical expansion of solar elastosis (SE) itself (p = 0.027). Areas of SE had lower deposits of collagen (p < 0.001), immunostaining for TGF-ß (p < 0.001), and higher density of elastic fibers (p < 0.05) when compared to areas without SE. A positive correlation was observed between high-risk epithelial dysplasia (ED) and the proximity of SE to the dysplastic epithelium (p = 0.027). LLSCCs showed a higher number of α-SMA+ MFs about CG (p = 0.034), as well as a reduction in the deposition of total collagen (p = 0.009) in relation to ACs and CG. There was also a negative correlation between the amount of α-SMA+ cells and the accumulation of total collagen (p = 0.041). Collagen and elastic density loss was higher in larger tumors (p = 0.045) with nodal invasion (p = 0.047). CONCLUSIONS: Our findings show the possible role of MFs, collagen fibers, and elastosis areas in the lip carcinogenesis process.


Assuntos
Carcinoma de Células Escamosas , Queilite , Matriz Extracelular , Neoplasias Labiais , Miofibroblastos , Humanos , Queilite/patologia , Queilite/metabolismo , Neoplasias Labiais/patologia , Neoplasias Labiais/metabolismo , Miofibroblastos/patologia , Carcinoma de Células Escamosas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Matriz Extracelular/patologia , Idoso , Fator de Crescimento Transformador beta , Adulto , Actinas , Imuno-Histoquímica , Antígeno Ki-67 , Colágeno , Tecido Elástico/patologia
9.
Invest Ophthalmol Vis Sci ; 65(5): 15, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38717426

RESUMO

Purpose: Mutations in the genes encoding type IV collagen alpha 1 (COL4A1) and alpha 2 (COL4A2) cause a multisystem disorder that includes ocular anterior segment dysgenesis (ASD) and glaucoma. We previously showed that transforming growth factor beta (TGFß) signaling was elevated in developing anterior segments from Col4a1 mutant mice and that reducing TGFß signaling ameliorated ASD, supporting a role for the TGFß pathway in disease pathogenesis. Here, we tested whether altered TGFß signaling also contributes to glaucoma-related phenotypes in Col4a1 mutant mice. Methods: To test the role of TGFß signaling in glaucoma-relevant phenotypes, we genetically reduced TGFß signaling using mice with mutated Tgfbr2, which encodes the common receptor for all TGFß ligands in Col4a1+/G1344D mice. We performed slit-lamp biomicroscopy and optical coherence tomography for qualitative and quantitative analyses of anterior and posterior ocular segments, histological analyses of ocular tissues and optic nerves, and intraocular pressure assessments using rebound tonometry. Results: Col4a1+/G1344D mice showed defects of the ocular drainage structures, including iridocorneal adhesions, and phenotypes consistent with glaucomatous neurodegeneration, including thinning of the nerve fiber layer, retinal ganglion cell loss, optic nerve head excavation, and optic nerve degeneration. We found that reducing TGFß receptor 2 (TGFBR2) was protective for ASD, ameliorated ocular drainage structure defects, and protected against glaucomatous neurodegeneration in Col4a1+/G1344D mice. Conclusions: Our results suggest that elevated TGFß signaling contributes to glaucomatous neurodegeneration in Col4a1 mutant mice.


Assuntos
Colágeno Tipo IV , Glaucoma , Pressão Intraocular , Receptor do Fator de Crescimento Transformador beta Tipo II , Transdução de Sinais , Tomografia de Coerência Óptica , Fator de Crescimento Transformador beta , Animais , Camundongos , Colágeno Tipo IV/metabolismo , Colágeno Tipo IV/genética , Transdução de Sinais/fisiologia , Pressão Intraocular/fisiologia , Glaucoma/metabolismo , Glaucoma/genética , Glaucoma/patologia , Fator de Crescimento Transformador beta/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Modelos Animais de Doenças , Doenças do Nervo Óptico/metabolismo , Doenças do Nervo Óptico/genética , Camundongos Endogâmicos C57BL , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/metabolismo , Segmento Anterior do Olho/metabolismo , Segmento Anterior do Olho/patologia , Nervo Óptico/patologia , Nervo Óptico/metabolismo , Microscopia com Lâmpada de Fenda , Fenótipo , Tonometria Ocular , Mutação
10.
Int J Mol Sci ; 25(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38731846

RESUMO

Activated TGFß signaling in the tumor microenvironment, which occurs independently of epithelial cancer cells, has emerged as a key driver of tumor progression in late-stage colorectal cancer (CRC). This study aimed to elucidate the contribution of TGFß-activated stroma to serrated carcinogenesis, representing approximately 25% of CRCs and often characterized by oncogenic BRAF mutations. We used a transcriptional signature developed based on TGFß-responsive, stroma-specific genes to infer TGFß-dependent stromal activation and conducted in silico analyses in 3 single-cell RNA-seq datasets from a total of 39 CRC samples and 12 bulk transcriptomic datasets consisting of 2014 CRC and 416 precursor samples, of which 33 were serrated lesions. Single-cell analyses validated that the signature was expressed specifically by stromal cells, effectively excluding transcriptional signals derived from epithelial cells. We found that the signature was upregulated during malignant transformation and cancer progression, and it was particularly enriched in CRCs with mutant BRAF compared to wild-type counterparts. Furthermore, across four independent precursor datasets, serrated lesions exhibited significantly higher levels of TGFß-responsive stromal activation compared to conventional adenomas. This large-scale analysis suggests that TGFß-dependent stromal activation occurs early in serrated carcinogenesis. Our study provides novel insights into the molecular mechanisms underlying CRC development via the serrated pathway.


Assuntos
Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas B-raf , Células Estromais , Fator de Crescimento Transformador beta , Microambiente Tumoral , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/genética , Células Estromais/metabolismo , Células Estromais/patologia , Microambiente Tumoral/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Mutação , Transcriptoma , Transdução de Sinais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Análise de Célula Única , Perfilação da Expressão Gênica , Adenoma/genética , Adenoma/patologia , Adenoma/metabolismo
11.
Int J Mol Sci ; 25(9)2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38732058

RESUMO

Monitoring inflammatory cytokines is crucial for assessing healing process and photobiomodulation (PBM) enhances wound healing. Meanwhile, cAMP response element-binding protein (CREB) is a regulator of cellular metabolism and proliferation. This study explored potential links between inflammatory cytokines and the activity of CREB in PBM-treated wounds. A total of 48 seven-week-old male SD rats were divided into four groups (wound location, skin or oral; treatment method, natural healing or PBM treatment). Wounds with a 6 mm diameter round shape were treated five times with an 808 nm laser every other day (total 60 J). The wound area was measured with a caliper and calculated using the elliptical formula. Histological analysis assessed the epidermal regeneration and collagen expression of skin and oral tissue with H&E and Masson's trichrome staining. Pro-inflammatory (TNF-α) and anti-inflammatory (TGF-ß) cytokines were quantified by RT-PCR. The ratio of phosphorylated CREB (p-CREB) to unphosphorylated CREB was identified through Western blot. PBM treatment significantly reduced the size of the wounds on day 3 and day 7, particularly in the skin wound group (p < 0.05 on day 3, p < 0.001 on day 7). The density of collagen expression was significantly higher in the PBM treatment group (in skin wound, p < 0.05 on day 3, p < 0.001 on day 7, and p < 0.05 on day 14; in oral wound, p < 0.01 on day 7). The TGF-ß/TNF-α ratio and the p-CREB/CREB ratio showed a parallel trend during wound healing. Our findings suggested that the CREB has potential as a meaningful marker to track the wound healing process.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Terapia com Luz de Baixa Intensidade , Ratos Sprague-Dawley , Cicatrização , Animais , Cicatrização/efeitos da radiação , Terapia com Luz de Baixa Intensidade/métodos , Masculino , Ratos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Pele/metabolismo , Pele/efeitos da radiação , Pele/patologia , Pele/lesões , Citocinas/metabolismo , Fosforilação/efeitos da radiação , Fator de Necrose Tumoral alfa/metabolismo , Colágeno/metabolismo , Fator de Crescimento Transformador beta/metabolismo
12.
Int J Mol Sci ; 25(9)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38732119

RESUMO

High-risk human papillomavirus (HR-HPV; HPV-16) and cigarette smoking are associated with cervical cancer (CC); however, the underlying mechanism(s) remain unclear. Additionally, the carcinogenic components of tobacco have been found in the cervical mucus of women smokers. Here, we determined the effects of cigarette smoke condensate (CSC; 3R4F) on human ectocervical cells (HPV-16 Ect/E6E7) exposed to CSC at various concentrations (10-6-100 µg/mL). We found CSC (10-3 or 10 µg/mL)-induced proliferation, enhanced migration, and histologic and electron microscopic changes consistent with EMT in ectocervical cells with a significant reduction in E-cadherin and an increase in the vimentin expression compared to controls at 72 h. There was increased phosphorylation of receptor tyrosine kinases (RTKs), including Eph receptors, FGFR, PDGFRA/B, and DDR2, with downstream Ras/MAPK/ERK1/2 activation and upregulation of common EMT-related genes, TGFB SNAI2, PDGFRB, and SMAD2. Our study demonstrated that CSC induces EMT in ectocervical cells with the upregulation of EMT-related genes, expression of protein biomarkers, and activation of RTKs that regulate TGFB expression, and other EMT-related genes. Understanding the molecular pathways and environmental factors that initiate EMT in ectocervical cells will help delineate molecular targets for intervention and define the role of EMT in the initiation and progression of cervical intraepithelial neoplasia and CC.


Assuntos
Células Epiteliais , Transição Epitelial-Mesenquimal , Fator de Crescimento Transformador beta , Humanos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Fator de Crescimento Transformador beta/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Células Epiteliais/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases/genética , Colo do Útero/patologia , Colo do Útero/metabolismo , Colo do Útero/virologia , Fumaça/efeitos adversos , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/patologia , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/etiologia , Papillomavirus Humano 16/patogenicidade , Nicotiana/efeitos adversos , Papillomavirus Humano
13.
J Cell Mol Med ; 28(10): e18400, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38780513

RESUMO

Osteosarcoma is the most common primary bone malignancy in children and adolescents. Overexpression of polo-like kinase 1 (PLK1) is frequent in osteosarcoma and drives disease progression and metastasis, making it a promising therapeutic target. In this study, we explored PLK1 knockdown in osteosarcoma cells using RNA interference mediated by high-fidelity Cas13d (hfCas13d). PLK1 was found to be significantly upregulated in osteosarcoma tumour tissues compared to normal bone. sgRNA-mediated PLK1 suppression via hfCas13d transfection inhibited osteosarcoma cell proliferation, induced G2/M cell cycle arrest, promoted apoptosis, reduced cell invasion and increased expression of the epithelial marker E-cadherin. Proximity labelling by TurboID coupled with co-immunoprecipitation identified novel PLK1 interactions with Smad3, a key intracellular transducer of TGF-ß signalling. PLK1 knockdown impaired Smad2/3 phosphorylation and modulated TGF-ß/Smad3 pathway inactivation. Finally, in vivo delivery of hfCas13d vectors targeting PLK1 substantially attenuated osteosarcoma xenograft growth in nude mice. Taken together, this study highlights PLK1 as a potential therapeutic target and driver of disease progression in osteosarcoma. It also demonstrates the utility of hfCas13d-mediated gene knockdown as a strategy for targeted therapy. Further optimization of PLK1 suppression approaches may ultimately improve clinical outcomes for osteosarcoma patients.


Assuntos
Apoptose , Proteínas de Ciclo Celular , Proliferação de Células , Camundongos Nus , Osteossarcoma , Quinase 1 Polo-Like , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas , Interferência de RNA , Transdução de Sinais , Proteína Smad3 , Fator de Crescimento Transformador beta , Osteossarcoma/patologia , Osteossarcoma/genética , Osteossarcoma/metabolismo , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Animais , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteína Smad3/metabolismo , Proteína Smad3/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Fator de Crescimento Transformador beta/metabolismo , Camundongos , Apoptose/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino
14.
Sci Immunol ; 9(95): eade3814, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38787963

RESUMO

Patients with heart failure (HF) often experience repeated acute decompensation and develop comorbidities such as chronic kidney disease and frailty syndrome. Although this suggests pathological interaction among comorbidities, the mechanisms linking them are poorly understood. Here, we identified alterations in hematopoietic stem cells (HSCs) as a critical driver of recurrent HF and associated comorbidities. Bone marrow transplantation from HF-experienced mice resulted in spontaneous cardiac dysfunction and fibrosis in recipient mice, as well as increased vulnerability to kidney and skeletal muscle insults. HF enhanced the capacity of HSCs to generate proinflammatory macrophages. In HF mice, global chromatin accessibility analysis and single-cell RNA-seq showed that transforming growth factor-ß (TGF-ß) signaling was suppressed in HSCs, which corresponded with repressed sympathetic nervous activity in bone marrow. Transplantation of bone marrow from mice in which TGF-ß signaling was inhibited similarly exacerbated cardiac dysfunction. Collectively, these results suggest that cardiac stress modulates the epigenome of HSCs, which in turn alters their capacity to generate cardiac macrophage subpopulations. This change in HSCs may be a common driver of repeated HF events and comorbidity by serving as a key carrier of "stress memory."


Assuntos
Insuficiência Cardíaca , Imunidade Inata , Memória Imunológica , Camundongos Endogâmicos C57BL , Animais , Insuficiência Cardíaca/imunologia , Camundongos , Masculino , Multimorbidade , Fator de Crescimento Transformador beta/metabolismo , Células-Tronco Hematopoéticas/imunologia , Transdução de Sinais/imunologia , Macrófagos/imunologia , Imunidade Treinada
15.
J Biomech ; 169: 112152, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38763809

RESUMO

The healthy adult aorta is a remarkably resilient structure, able to resist relentless cardiac-induced and hemodynamic loads under normal conditions. Fundamental to such mechanical homeostasis is the mechano-sensitive cell signaling that controls gene products and thus the structural integrity of the wall. Mouse models have shown that smooth muscle cell-specific disruption of transforming growth factor-beta (TGFß) signaling during postnatal development compromises this resiliency, rendering the aortic wall susceptible to aneurysm and dissection under normal mechanical loading. By contrast, disruption of such signaling in the adult aorta appears to introduce a vulnerability that remains hidden under normal loading, but manifests under increased loading as experienced during hypertension. We present a multiscale (transcript to tissue) computational model to examine possible reasons for compromised mechanical homeostasis in the adult aorta following reduced TGFß signaling in smooth muscle cells.


Assuntos
Aorta , Modelos Cardiovasculares , Transdução de Sinais , Fator de Crescimento Transformador beta , Remodelação Vascular , Fator de Crescimento Transformador beta/metabolismo , Animais , Camundongos , Aorta/patologia , Aorta/metabolismo , Remodelação Vascular/fisiologia , Simulação por Computador , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/fisiologia , Humanos
16.
BMC Gastroenterol ; 24(1): 163, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38745150

RESUMO

BACKGROUND: The liver regeneration is a highly complicated process depending on the close cooperations between the hepatocytes and non-parenchymal cells involving various inflammatory cells. Here, we explored the role of myeloid-derived suppressor cells (MDSCs) in the processes of liver regeneration and liver fibrosis after liver injury. METHODS: We established four liver injury models of mice including CCl4-induced liver injury model, bile duct ligation (BDL) model, concanavalin A (Con A)-induced hepatitis model, and lipopolysaccharide (LPS)-induced hepatitis model. The intrahepatic levels of MDSCs (CD11b+Gr-1+) after the liver injury were detected by flow cytometry. The effects of MDSCs on liver tissues were analyzed in the transwell co-culture system, in which the MDSCs cytokines including IL-10, VEGF, and TGF-ß were measured by ELISA assay and followed by being blocked with specific antibodies. RESULTS: The intrahepatic infiltrations of MDSCs with surface marker of CD11b+Gr-1+ remarkably increased after the establishment of four liver injury models. The blood served as the primary reservoir for hepatic recruitment of MDSCs during the liver injury, while the bone marrow appeared play a compensated role in increasing the number of MDSCs at the late stage of the inflammation. The recruited MDSCs in injured liver were mainly the M-MDSCs (CD11b+Ly6G-Ly6Chigh) featured by high expression levels of cytokines including IL-10, VEGF, and TGF-ß. Co-culture of the liver tissues with MDSCs significantly promoted the proliferation of both hepatocytes and hepatic stellate cells (HSCs). CONCLUSIONS: The dramatically and quickly infiltrated CD11b+Gr-1+ MDSCs in injured liver not only exerted pro-proliferative effects on hepatocytes, but also accounted for the activation of profibrotic HSCs.


Assuntos
Antígeno CD11b , Cirrose Hepática , Regeneração Hepática , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides , Animais , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/imunologia , Camundongos , Cirrose Hepática/patologia , Cirrose Hepática/metabolismo , Regeneração Hepática/fisiologia , Antígeno CD11b/metabolismo , Masculino , Modelos Animais de Doenças , Fígado/patologia , Fígado/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Concanavalina A , Ligadura , Lipopolissacarídeos , Interleucina-10/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Células Estreladas do Fígado/metabolismo , Técnicas de Cocultura , Hepatócitos/metabolismo , Hepatócitos/patologia , Ductos Biliares
17.
J Clin Invest ; 134(10)2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38747285

RESUMO

Transforming growth factor ß (TGF-ß) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGF-ß remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGF-ß in fibrotic diseases. WNT5A was identified as a predominant noncanonical WNT ligand in fibrotic diseases such as systemic sclerosis, sclerodermatous chronic graft-versus-host disease, and idiopathic pulmonary fibrosis, stimulating fibroblast-to-myofibroblast transition and tissue fibrosis by activation of latent TGF-ß. The activation of latent TGF-ß requires rapid JNK- and ROCK-dependent cytoskeletal rearrangements and integrin αV (ITGAV). Conditional ablation of WNT5A or its downstream targets prevented activation of latent TGF-ß, rebalanced TGF-ß signaling, and ameliorated experimental fibrosis. We thus uncovered what we believe to be a novel mechanism for the aberrant activation of latent TGF-ß in fibrotic diseases and provided evidence for targeting WNT5A/JNK/ROCK signaling in fibrotic diseases as a new therapeutic approach.


Assuntos
Fibroblastos , Fibrose , Fator de Crescimento Transformador beta , Proteína Wnt-5a , Quinases Associadas a rho , Proteína Wnt-5a/metabolismo , Proteína Wnt-5a/genética , Animais , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/genética , Camundongos , Humanos , Fibroblastos/metabolismo , Fibroblastos/patologia , Quinases Associadas a rho/metabolismo , Quinases Associadas a rho/genética , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/genética , Camundongos Knockout , Proteínas Wnt/metabolismo , Proteínas Wnt/genética , Sistema de Sinalização das MAP Quinases , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Transdução de Sinais , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/genética
18.
PLoS One ; 19(5): e0302662, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38748716

RESUMO

Kaab Dum, a prominent indigenous rice variety cultivated in the Pak Phanang Basin of Nakhon Si Thammarat, Thailand, is the focus of our study. We investigate the therapeutic potential of indigenous Kaab Dum rice extract in the context of chronic wounds. Our research encompasses an examination of the nutritional compositions and chemical profiles of Kaab Dum rice extract. Additionally, we assess how the extract affects chronic wounds in TGF-ß-induced HaCaT cells. Our evaluation methods include the detection of cellular oxidative stress, the examination of endoplasmic reticulum (ER) stress, wound healing assays, analysis of cell cycle arrest and the study of cellular senescence through senescence-associated ß-galactosidase (SA-ß-gal) staining. Our research findings demonstrate that TGF-ß induces oxidative stress in HaCaT cells, which subsequently triggers ER stress, confirmed by the expression of the PERK protein. This ER stress results in cell cycle arrest in HaCaT cells, characterized by an increase in p21 protein, a cyclin-dependent kinase inhibitor (CDKI). Ultimately, this leads to cellular senescence, as confirmed by SA-ß-gal staining. Importantly, our study reveals the effectiveness of Kaab Dum rice extract in promoting wound healing in the chronic wound model. The extract reduces ER stress and senescent cells. These beneficial effects are potentially linked to the antioxidant and anti-inflammatory properties of the rice extract. The findings of our study have the potential to make significant contributions to the development of enhanced products for both the prevention and treatment of chronic wounds.


Assuntos
Senescência Celular , Estresse do Retículo Endoplasmático , Queratinócitos , Oryza , Extratos Vegetais , Cicatrização , Humanos , Oryza/química , Senescência Celular/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Extratos Vegetais/farmacologia , Tailândia , Linhagem Celular , Células HaCaT , Estresse Oxidativo/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , População do Sudeste Asiático
19.
Stem Cell Res Ther ; 15(1): 144, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38764077

RESUMO

BACKGROUND: The aim of this study was to evaluate potential synergistic effects of a single, local application of human umbilical cord MSC-derived sEVs in combination with a low dose of recombinant human rhBMP-2 to promote the regeneration of a metaphyseal femoral defect in an osteoporotic rat model. METHODS: 6 weeks after induction of osteoporosis by bilateral ventral ovariectomy and administration of a special diet, a total of 64 rats underwent a distal femoral metaphyseal osteotomy using a manual Gigli wire saw. Defects were stabilized with an adapted Y-shaped mini-locking plate and were subsequently treated with alginate only, or alginate loaded with hUC-MSC-sEVs (2 × 109), rhBMP-2 (1.5 µg), or a combination of sEVs and rhBMP-2 (n = 16 for each group). 6 weeks post-surgery, femora were evaluated by µCT, descriptive histology, and biomechanical testing. RESULTS: Native radiographs and µCT analysis confirmed superior bony union with callus formation after treatment with hUC-MSC-sEVs in combination with a low dose of rhBMP-2. This finding was further substantiated by histology, showing robust defect consolidation 6 weeks after treatment. Torsion testing of the explanted femora revealed increased stiffness after application of both, rhBMP-2 alone, or in combination with sEVs, whereas torque was only significantly increased after treatment with rhBMP-2 together with sEVs. CONCLUSION: The present study demonstrates that the co-application of hUC-MSC-sEVs can improve the efficacy of rhBMP-2 to promote the regeneration of osteoporotic bone defects.


Assuntos
Proteína Morfogenética Óssea 2 , Vesículas Extracelulares , Fêmur , Osteoporose , Proteínas Recombinantes , Cordão Umbilical , Animais , Proteína Morfogenética Óssea 2/farmacologia , Proteína Morfogenética Óssea 2/genética , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/genética , Osteoporose/patologia , Ratos , Feminino , Humanos , Fêmur/patologia , Fêmur/efeitos dos fármacos , Fêmur/diagnóstico por imagem , Cordão Umbilical/citologia , Vesículas Extracelulares/metabolismo , Regeneração Óssea/efeitos dos fármacos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta/farmacologia , Modelos Animais de Doenças , Microtomografia por Raio-X , Células-Tronco Mesenquimais/metabolismo
20.
Int J Mol Sci ; 25(10)2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38791217

RESUMO

The dermal-epidermal junction (DEJ) is essential for maintaining skin structural integrity and regulating cell survival and proliferation. Thus, DEJ rejuvenation is key for skin revitalization, particularly in age-related DEJ deterioration. Radiofrequency (RF) treatment, known for its ability to enhance collagen fiber production through thermal mechanisms and increase heat shock protein (HSP) expression, has emerged as a promising method for skin rejuvenation. Additionally, RF activates Piezo1, an ion channel implicated in macrophage polarization toward an M2 phenotype and enhanced TGF-ß production. This study investigated the impact of RF treatment on HSP47 and HSP90 expression, known stimulators of DEJ protein expression. Furthermore, using in vitro and aged animal skin models, we assessed whether RF-induced Piezo1 activation and the subsequent M2 polarization could counter age-related DEJ changes. The RF treatment of H2O2-induced senescent keratinocytes upregulated the expression of HSP47, HSP90, TGF-ß, and DEJ proteins, including collagen XVII. Similarly, the RF treatment of senescent macrophages increased Piezo1 and CD206 (M2 marker) expression. Conditioned media from RF-treated senescent macrophages enhanced the expression of TGF-ß and DEJ proteins, such as nidogen and collagen IV, in senescent fibroblasts. In aged animal skin, RF treatment increased the expression of HSP47, HSP90, Piezo1, markers associated with M2 polarization, IL-10, and TGF-ß. Additionally, RF treatment enhanced DEJ protein expression. Moreover, RF reduced lamina densa replication, disrupted lesions, promoted hemidesmosome formation, and increased epidermal thickness. Overall, RF treatment effectively enhanced DEJ protein expression and mitigated age-related DEJ structural changes by increasing HSP levels and activating Piezo1.


Assuntos
Epiderme , Animais , Epiderme/metabolismo , Epiderme/efeitos da radiação , Camundongos , Derme/metabolismo , Queratinócitos/metabolismo , Macrófagos/metabolismo , Envelhecimento da Pele/efeitos da radiação , Pele/metabolismo , Pele/efeitos da radiação , Pele/patologia , Humanos , Envelhecimento/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico HSP47/metabolismo , Proteínas de Choque Térmico HSP47/genética
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