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1.
Nat Commun ; 15(1): 4792, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38839760

RESUMO

Innate lymphoid cell precursors (ILCPs) develop into distinct subsets of innate lymphoid cells (ILCs) with specific functions. The epigenetic program underlying the differentiation of ILCPs into ILC subsets remains poorly understood. Here, we reveal the genome-wide distribution and dynamics of the DNA methylation and hydroxymethylation in ILC subsets and their respective precursors. Additionally, we find that the DNA hydroxymethyltransferase TET1 suppresses ILC1 but not ILC2 or ILC3 differentiation. TET1 deficiency promotes ILC1 differentiation by inhibiting TGF-ß signaling. Throughout ILCP differentiation at postnatal stage, gut microbiota contributes to the downregulation of TET1 level. Microbiota decreases the level of cholic acid in the gut, impairs TET1 expression and suppresses DNA hydroxymethylation, ultimately resulting in an expansion of ILC1s. In adult mice, TET1 suppresses the hyperactivation of ILC1s to maintain intestinal homeostasis. Our findings provide insights into the microbiota-mediated epigenetic programming of ILCs, which links microbiota-DNA methylation crosstalk to ILC differentiation.


Assuntos
Diferenciação Celular , Metilação de DNA , Proteínas de Ligação a DNA , Imunidade Inata , Linfócitos , Proteínas Proto-Oncogênicas , Animais , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Camundongos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Linfócitos/metabolismo , Linfócitos/imunologia , Camundongos Endogâmicos C57BL , Microbioma Gastrointestinal , Epigênese Genética , Camundongos Knockout , Fator de Crescimento Transformador beta/metabolismo , Transdução de Sinais
2.
Sci Rep ; 14(1): 12744, 2024 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-38830931

RESUMO

Transforming growth factor ß (TGF-ß) is implicated in both mesothelial-to-mesenchymal transition (MMT) and cellular senescence of human peritoneal mesothelial cells (HPMCs). We previously showed that senescent HPMCs could spontaneously acquire some phenotypic features of MMT, which in young HPMCs were induced by TGF-ß. Here, we used electron microscopy, as well as global gene and protein profiling to assess in detail how exposure to TGF-ß impacts on young and senescent HPMCs in vitro. We found that TGF-ß induced structural changes consistent with MMT in young, but not in senescent HPMCs. Of all genes and proteins identified reliably in HPMCs across all treatments and states, 4,656 targets represented overlapping genes and proteins. Following exposure to TGF-ß, 137 proteins and 46 transcripts were significantly changed in young cells, compared to 225 proteins and only 2 transcripts in senescent cells. Identified differences between young and senescent HPMCs were related predominantly to wound healing, integrin-mediated signalling, production of proteases and extracellular matrix components, and cytoskeleton structure. Thus, the response of senescent HPMCs to TGF-ß differs or is less pronounced compared to young cells. As a result, the character and magnitude of the postulated contribution of HPMCs to TGF-ß-induced peritoneal remodelling may change with cell senescence.


Assuntos
Senescência Celular , Células Epiteliais , Peritônio , Fator de Crescimento Transformador beta , Humanos , Senescência Celular/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Peritônio/citologia , Peritônio/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células Cultivadas , Epitélio/metabolismo , Epitélio/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Perfilação da Expressão Gênica
3.
Sci Rep ; 14(1): 12779, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834729

RESUMO

To evaluate the safety and efficacy of combining EW-7197 with irreversible electroporation (IRE) for improving wound healing, 16 male Sprague-Dawley rats were randomly divided into four groups of four rats each after dorsal excisional wound induction: sham control group; oral administration of EW-7197 for 7 days group; one-time application of IRE group; and one-time application of IRE followed by oral administration of EW-7197 for 7 days group. Measurement of wound closure rate, laser Doppler scanning, histological staining (hematoxylin and eosin and Masson's trichrome), and immunohistochemical analyses (Ki-67 and α-SMA) were performed to evaluate the efficacy. Fifteen of 16 rats survived throughout the study. Statistically significant differences in wound closure rates were observed between the combination therapy group and the other three groups (all P < 0.05). The degrees of inflammation, α-SMA, and Ki-67 were reduced in the EW-7197 and IRE monotherapy groups; however, not statistically significant. The fibrosis score exhibited significant reduction in all three treatment groups, with the most prominent being in the combination therapy group. This study concludes that oral administration of EW-7197 combined with IRE demonstrated effectiveness in improving skin wound in a rat excisional model and may serve as a potential alternative for promoting healing outcomes.


Assuntos
Eletroporação , Ratos Sprague-Dawley , Pele , Cicatrização , Animais , Cicatrização/efeitos dos fármacos , Masculino , Ratos , Eletroporação/métodos , Pele/metabolismo , Pele/patologia , Fator de Crescimento Transformador beta/metabolismo , Modelos Animais de Doenças , Terapia Combinada/métodos
4.
Arch Dermatol Res ; 316(7): 338, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38847916

RESUMO

Diabetic foot ulcer (DFU) is a predominant complication of diabetes mellitus with poor prognosis accompanied by high amputation and mortality rates. Dang-Gui-Si-Ni decoction (DSD), as a classic formula with a long history in China, has been found to improve DFU symptoms. However, mechanism of DSD for DFU therapy remains unclear with no systematic elaboration. In vivo, following establishment of DFU rat model, DSD intervention with low, medium and high doses was done, with Metformin (DM) as a positive control group. With wound healing detection, pathological changes by HE staining, inflammatory factor expression by ELISA and qRT-PCR, oxidative stress levels by ELISA, and AGEs/RAGE/TGF-ß/Smad2/3 expression by Western blot were performed. In vitro, intervention with LY2109761 (TGF-ß pathway inhibitor) based on DSD treatment in human dermal fibroblast-adult (HDF-a) cells was made. Cell viability by CCK8, migration ability by cell scratch, apoptosis by flow cytometry, and AGEs/RAGE/TGF-ß/Smad2/3 expression by Western blot were measured. DFU rats exhibited elevated AGEs/RAGE expression, whereas decreased TGF-ß1 and p-Smad3/Smad3 protein expression, accompanied by higher IL-1ß, IL-6, TNF-α levels, and oxidative stress. DSD intervention reversed above effects. Glucose induction caused lower cell viability, migration, TGF-ß1 and p-Smad3/Smad3 protein expression, with increased apoptosis and AGEs/RAGE expression in HDF-a cells. These effects were reversed after DSD intervention, and further LY2109761 intervention inhibited DSD effects in cells. DSD intervention may facilitate wound healing in DFU by regulating expression of AGEs/RAGE/TGF-ß/Smad2/3, providing scientific experimental evidence for DSD clinical application for DFU therapy.


Assuntos
Pé Diabético , Medicamentos de Ervas Chinesas , Produtos Finais de Glicação Avançada , Proteína Smad2 , Proteína Smad3 , Cicatrização , Pé Diabético/tratamento farmacológico , Pé Diabético/metabolismo , Pé Diabético/patologia , Animais , Cicatrização/efeitos dos fármacos , Ratos , Medicamentos de Ervas Chinesas/farmacologia , Proteína Smad2/metabolismo , Humanos , Proteína Smad3/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Masculino , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Ratos Sprague-Dawley , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos
5.
Exp Oncol ; 46(1): 22-29, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38852056

RESUMO

BACKGROUND: Molecules and cytokines can be targeted in cancer therapy. Transforming growth factor-beta (TGF-ß) is a cytokine that acts on protein kinase receptors in the plasma membrane. The signaling pathway of TGF-ß can trigger the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, a signal transduction pathway important in cancer growth and development. However, this PI3K/AKT cascade can be inhibited by phosphatase and tensin homolog (PTEN) tumor suppressor genes. AIM: To determine the inhibitory effect of Holothuria scabra methanol extract (HSE) on breast cancer growth through the TGF-ß/PI3K pathways and PTEN tumor suppressor gene on a breast cancer (BC) mice model. MATERIALS AND METHODS: Female C57BL6 mice were subcutaneously injected with carcinogen DMBA 1 mg/kg body weight (BW) and fed a high-fat diet (HFD). Mice were randomly divided into five groups (n = 6): negative control (NC) administered with a standard diet, positive control (PC) administered with DMBA and HFD, and three treatment groups (T1, T2, and T3) treated with HSE doses of 0.33, 0.66, and 0.99 g/kg BW for 12 weeks. TGF-ß concentration in the blood serum of mice was assessed by ELISA and the PIK3CA and PTEN gene expression by qRT-PCR. RESULTS: The treatment with HSE resulted in a significant decrease in TGF-ß concentrations in the blood sera of treatment groups T1 (35.31 ± 17.33), T2 (43.31 ± 17.42), and T3 (48.67 ± 20.94) pg/mL compared to the PC group (162.09 ± 11.60) pg/mL (p < 0.001). However, only HSE at a dose of 0.99 g/kg BW decreased the PIK3CA gene expression (p = 0.026), and at a dose of 0.66 g/kg BW increased the PTEN expression up to 4.93-fold. CONCLUSION: HSE is capable of inhibiting the TGF-ß/PIK3CA pathway and increasing the PTEN gene expression.


Assuntos
PTEN Fosfo-Hidrolase , Fosfatidilinositol 3-Quinases , Extratos Vegetais , Transdução de Sinais , Fator de Crescimento Transformador beta , Animais , PTEN Fosfo-Hidrolase/metabolismo , Feminino , Fator de Crescimento Transformador beta/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Extratos Vegetais/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Holothuria/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Metanol/química , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Humanos , Proliferação de Células/efeitos dos fármacos
6.
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
7.
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
8.
Med Oncol ; 41(6): 137, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38705933

RESUMO

Metastasis poses a significant challenge in combating tumors. Even in papillary thyroid cancer (PTC), which typically exhibits a favorable prognosis, high recurrence rates are attributed to metastasis. Cytoplasmic linker protein 170 (CLIP170) functions as a classical microtubule plus-end tracking protein (+TIP) and has shown close association with cell migration. Nevertheless, the specific impact of CLIP170 on PTC cells remains to be elucidated. Our analysis of the GEO and TCGA databases unveiled an association between CLIP170 and the progression of PTC. To explore the impact of CLIP170 on PTC cells, we conducted various assays. We evaluated its effects through CCK-8, wound healing assay, and transwell assay after knocking down CLIP170. Additionally, the influence of CLIP170 on the cellular actin structure was examined via immunofluorescence; we further investigated the molecular expressions of epithelial-mesenchymal transition (EMT) and the transforming growth factor-ß (TGF-ß) signaling pathways through Western blotting and RT-qPCR. These findings were substantiated through an in vivo nude mouse model of lung metastasis. We observed a decreased expression of CLIP170 in PTC in contrast to normal thyroid tissue. Functionally, the knockdown of CLIP170 (CLIP170KD) notably enhanced the metastatic potential and EMT of PTC cells, both in vitro and in vivo. Mechanistically, CLIP170KD triggered the activation of the TGF-ß pathway, subsequently promoting tumor cell migration, invasion, and EMT. Remarkably, the TGF-ß inhibitor LY2157299 effectively countered TGF-ß activity and significantly reversed tumor metastasis and EMT induced by CLIP170 knockdown. In summary, these findings collectively propose CLIP170 as a promising therapeutic target to mitigate metastatic tendencies in PTC.


Assuntos
Transição Epitelial-Mesenquimal , Proteínas Associadas aos Microtúbulos , Proteínas de Neoplasias , Transdução de Sinais , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Fator de Crescimento Transformador beta , Animais , Feminino , Humanos , Masculino , Camundongos , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/genética , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Metástase Neoplásica , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Fator de Crescimento Transformador beta/metabolismo
9.
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
10.
Mol Biol Rep ; 51(1): 658, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38748314

RESUMO

BACKGROUND: The formation of chronic wounds accounts for considerable costs in health care systems. Despite the several benefits of decellularized small intestinal submucosa (SIS) as an appropriate scaffold for different tissue regeneration, it has shortcomings such as lack of antibacterial features and inappropriate mechanical properties for skin tissue regeneration. We aimed to examine the efficacy and safety of decellularized SIS scaffold enhanced with cellulose acetate (CA) and silver (Ag) nanoparticles (NPs) for healing full-thickness wounds. METHODS AND RESULTS: The scaffolds were prepared by decellularizing bovine SIS and electrospinning CA/Ag nanoparticles and characterized using a transmission electron microscope (TEM), scanning electron microscope (SEM), tensile testing, and X-ray diffraction. In vivo evaluations were performed using full-thickness excisions covered with sterile gauze as the control group, SIS, SIS/CA, and SIS/CA/Ag scaffolds on the dorsum of twenty male Wistar rats divided into four groups randomly with 21-days follow-up. All in vivo specimens underwent Masson's trichrome (MT) staining for evaluation of collagen deposition, transforming growth factor-ß (TGF-ß) immunohistochemistry (IHC), and Haematoxylin Eosin (H&E) staining. The IHC and MT data were analyzed with the ImageJ tool by measuring the stained area. The TEM results revealed that Ag nanoparticles are successfully incorporated into CA nanofibers. Assessment of scaffolds hydrophilicity demonstrated that the contact angle of SIS/CA/Ag scaffold was the lowest. The in vivo results indicated that the SIS/CA/Ag scaffold had the most significant wound closure. H&E staining of the in vivo specimens showed the formation of epidermal layers in the SIS/CA/Ag group on day 21. The percentage of the stained area of MT and TGF-ß IHC staining's was highest in the SIS/CA/Ag group. CONCLUSION: The decellularized SIS/CA/Ag scaffolds provided the most significant wound closure compared to other groups and caused the formation of epidermal layers and skin appendages. Additionally, the collagen deposition and expression of TGF-ß increased significantly in SIS/CA/Ag group.


Assuntos
Celulose , Mucosa Intestinal , Intestino Delgado , Nanopartículas Metálicas , Nanofibras , Ratos Wistar , Prata , Alicerces Teciduais , Cicatrização , Animais , Prata/química , Celulose/análogos & derivados , Celulose/química , Cicatrização/efeitos dos fármacos , Nanopartículas Metálicas/química , Ratos , Nanofibras/química , Alicerces Teciduais/química , Mucosa Intestinal/metabolismo , Masculino , Intestino Delgado/metabolismo , Bovinos , Fator de Crescimento Transformador beta/metabolismo , Engenharia Tecidual/métodos , Colágeno
11.
Commun Biol ; 7(1): 544, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714800

RESUMO

Numerous myofibroblasts are arisen from endothelial cells (ECs) through endothelial to mesenchymal transition (EndMT) triggered by TGF-ß. However, the mechanism of ECs transforms to a different subtype, or whether there exists an intermediate state of ECs remains unclear. In present study, we demonstrate Midkine (MDK) mainly expressed by CD31 + ACTA2+ECs going through partial EndMT contribute greatly to myofibroblasts by spatial and single-cell transcriptomics. MDK is induced in TGF-ß treated ECs, which upregulates C/EBPß and increases EndMT genes, and these effects could be reversed by siMDK. Mechanistically, MDK promotes the binding ability of C/EBPß with ACTA2 promoter by stabilizing the C/EBPß protein. In vivo, knockout of Mdk or conditional knockout of Mdk in ECs reduces EndMT markers and significantly reverses fibrogenesis. In conclusion, our study provides a mechanistic link between the induction of EndMT by TGF-ß and MDK, which suggests that blocking MDK provides potential therapeutic strategies for renal fibrosis.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT , Fibrose , Midkina , Midkina/metabolismo , Midkina/genética , Animais , Camundongos , Humanos , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Transição Epitelial-Mesenquimal , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/genética , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fator de Crescimento Transformador beta/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Rim/metabolismo , Rim/patologia , Camundongos Knockout , Transição Endotélio-Mesênquima
12.
Genome Biol ; 25(1): 117, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715110

RESUMO

BACKGROUND: Preeclampsia, one of the most lethal pregnancy-related diseases, is associated with the disruption of uterine spiral artery remodeling during placentation. However, the early molecular events leading to preeclampsia remain unknown. RESULTS: By analyzing placentas from preeclampsia, non-preeclampsia, and twin pregnancies with selective intrauterine growth restriction, we show that the pathogenesis of preeclampsia is attributed to immature trophoblast and maldeveloped endothelial cells. Delayed epigenetic reprogramming during early extraembryonic tissue development leads to generation of excessive immature trophoblast cells. We find reduction of de novo DNA methylation in these trophoblast cells results in selective overexpression of maternally imprinted genes, including the endoretrovirus-derived gene PEG10 (paternally expressed gene 10). PEG10 forms virus-like particles, which are transferred from the trophoblast to the closely proximate endothelial cells. In normal pregnancy, only a low amount of PEG10 is transferred to maternal cells; however, in preeclampsia, excessive PEG10 disrupts maternal vascular development by inhibiting TGF-beta signaling. CONCLUSIONS: Our study reveals the intricate epigenetic mechanisms that regulate trans-generational genetic conflict and ultimately ensure proper maternal-fetal interface formation.


Assuntos
Pré-Eclâmpsia , Trofoblastos , Remodelação Vascular , Pré-Eclâmpsia/genética , Gravidez , Feminino , Humanos , Trofoblastos/metabolismo , Remodelação Vascular/genética , Placenta/metabolismo , Metilação de DNA , Epigênese Genética , Células Endoteliais/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Impressão Genômica , Fator de Crescimento Transformador beta/metabolismo , Retardo do Crescimento Fetal/genética , Placentação/genética , Proteínas de Ligação a RNA , Proteínas Reguladoras de Apoptose
13.
Pak J Pharm Sci ; 37(1): 33-41, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38741398

RESUMO

The objective of this research is to assess how salvianolate impacts inflammation and oxidative stress in a laboratory setting, as well as to investigate the underlying mechanisms. HK-2 cells were subjected to different treatments, including normal glucose, mannitol, high glucose and high glucose plus salvianolate. Cell proliferation, death, MDA levels, IL-1ß, IL-6, TNF-α, MCP-1 concentrations, ROS levels, MMP, MPTP and ATP levels were assessed using various kits. The protein expressions of NOX4, TGF-ß1, P-Smad2, P-Smad3, Smad4 and Smad7 were ascertained through western blot analysis. Our results indicated salvianolate could reduce the release of IL-1ß, IL-6, TNF-α, as well as MCP-1, alleviate the levels of oxidative stress markers NOX4 and MDA, and improve mitochondrial function by increasing MMP and ATP levels while reducing ROS and MPTP opening. Furthermore, salvianolate inhibited the TGF-ß1/Smad2, Smad3 signaling pathway, suppressed Smad4 expression and increased Smad7 expression. Salvianolate seems to mitigate inflammation and oxidative stress through a variety of mechanisms. These discoveries offer valuable understanding into the possible mechanisms by which salvianolate may be employed in the treatment of diabetic nephropathy.


Assuntos
Glucose , Inflamação , Estresse Oxidativo , Transdução de Sinais , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Glucose/metabolismo , Humanos , Linhagem Celular , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Proteínas Smad/metabolismo , Extratos Vegetais/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Anti-Inflamatórios/farmacologia , Proliferação de Células/efeitos dos fármacos
14.
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
15.
Exp Dermatol ; 33(5): e15098, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38770557

RESUMO

Healing of complex wounds requires dressings that must, at least, not hinder and should ideally promote the activity of key healing cells, in particular fibroblasts. This in vitro study assessed the effects of three wound-dressings (a pure Ca2+ alginate: Algostéril®, a Ca2+ alginate + carboxymethylcellulose: Biatain alginate® and a polyacrylate impregnated with lipido-colloid matrix: UrgoClean®) on dermal fibroblast activity. The results showed the pure calcium alginate to be non-cytotoxic, whereas the other wound-dressings showed moderate to strong cytotoxicity. The two alginates stimulated fibroblast migration and proliferation, whereas the polyacrylate altered migration and had no effect on proliferation. The pure Ca2+ alginate significantly increased the TGF-ß-induced fibroblast activation, which is essential to healing. This activation was confirmed by a significant increase in Vascular endothelial growth factor (VEGF) secretion and a higher collagen production. The other dressings reduced these fibroblast activities. The pure Ca2+ alginate was also able to counteract the inhibitory effect of NK cell supernatants on fibroblast migration. These in vitro results demonstrate that tested wound-dressings are not equivalent for fibroblast activation. Only Algostéril was found to promote all the fibroblast activities tested, which could contribute to its healing efficacy demonstrated in the clinic.


Assuntos
Alginatos , Movimento Celular , Proliferação de Células , Fibroblastos , Fator A de Crescimento do Endotélio Vascular , Cicatrização , Fibroblastos/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Humanos , Alginatos/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Colágeno/metabolismo , Bandagens , Fator de Crescimento Transformador beta/metabolismo , Carboximetilcelulose Sódica , Células Cultivadas , Células Matadoras Naturais/efeitos dos fármacos , Resinas Acrílicas , Ácidos Hexurônicos , Ácido Glucurônico , Pele
16.
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
17.
PLoS One ; 19(5): e0302786, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38722973

RESUMO

A role for exportin 4 (XPO4) in the pathogenesis of liver fibrosis was recently identified. We sought to determine changes in hepatic XPO4 promoter methylation levels during liver fibrosis. The quantitative real-time RT-PCR technique was used to quantify the mRNA level of XPO4. Additionally, pyrosequencing was utilized to assess the promoter methylation status of XPO4. The methylation rate of the XPO4 promoter was significantly increased with fibrosis in human and mouse models, while XPO4 mRNA expression negatively correlated with methylation of its promoter. DNA methyltransferases (DNMTs) levels (enzymes that drive DNA methylation) were upregulated in patients with liver fibrosis compared to healthy controls and in hepatic stellate cells upon transforming growth factor beta (TGFß) stimulation. The DNA methylation inhibitor 5-Aza or specific siRNAs for these DNMTs led to restoration of XPO4 expression. The process of DNA methylation plays a crucial role in the repression of XPO4 transcription in the context of liver fibrosis development.


Assuntos
Metilação de DNA , Carioferinas , Cirrose Hepática , Regiões Promotoras Genéticas , Cirrose Hepática/genética , Cirrose Hepática/patologia , Cirrose Hepática/metabolismo , Humanos , Carioferinas/genética , Carioferinas/metabolismo , Animais , Camundongos , Masculino , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Camundongos Endogâmicos C57BL
18.
Sci Adv ; 10(18): eadj8042, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38691608

RESUMO

Overactivation of the transforming growth factor-ß (TGFß) signaling in Duchenne muscular dystrophy (DMD) is a major hallmark of disease progression, leading to fibrosis and muscle dysfunction. Here, we investigated the role of SETDB1 (SET domain, bifurcated 1), a histone lysine methyltransferase involved in muscle differentiation. Our data show that, following TGFß induction, SETDB1 accumulates in the nuclei of healthy myotubes while being already present in the nuclei of DMD myotubes where TGFß signaling is constitutively activated. Transcriptomics revealed that depletion of SETDB1 in DMD myotubes leads to down-regulation of TGFß target genes coding for secreted factors involved in extracellular matrix remodeling and inflammation. Consequently, SETDB1 silencing in DMD myotubes abrogates the deleterious effect of their secretome on myoblast differentiation by impairing myoblast pro-fibrotic response. Our findings indicate that SETDB1 potentiates the TGFß-driven fibrotic response in DMD muscles, providing an additional axis for therapeutic intervention.


Assuntos
Histona-Lisina N-Metiltransferase , Fibras Musculares Esqueléticas , Distrofia Muscular de Duchenne , Transdução de Sinais , Fator de Crescimento Transformador beta , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Fator de Crescimento Transformador beta/metabolismo , Humanos , Animais , Diferenciação Celular , Camundongos , Mioblastos/metabolismo , Fibrose , Regulação da Expressão Gênica
19.
Front Biosci (Landmark Ed) ; 29(5): 184, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38812320

RESUMO

This review article explores the intricate correlation between growth factors and bone metastases, which play a crucial role in the development of several types of malignancies, namely breast, prostate, lung, and renal cancers. The focal point of our discussion is on crucial receptors for growth factors, including Epidermal Growth Factor Receptor (EGFR), Transforming Growth Factor-ß (TGFß), Vascular Endothelial Growth Factor Receptor (VEGFR), and Fibroblast Growth Factor Receptor (FGFR). These receptors, which are essential for cellular activities including growth, differentiation, and survival, have important involvement in the spread of cancer and the interactions between tumors and the bone environment. We discuss the underlying mechanisms of bone metastases, with a specific emphasis on the interaction between growth factor receptors and the bone microenvironment. EGFR signaling specifically enhances the process of osteoclast development and the formation of osteolytic lesions, especially in breast and lung malignancies. TGFß receptors have a role in both osteolytic and osteoblastic metastases by releasing TGFß, which attracts cancer cells and promotes bone remodeling. This is a crucial element in the spread of prostate cancer to the bones. The functions of FGFR and VEGFR in the processes of bone formation and tumor angiogenesis, respectively, highlight the complex and diverse nature of these interactions. The review emphasizes the possibility of targeted therapeutics targeting these receptors to interrupt the cycle of tumor development and bone degradation. Therapeutic approaches include focusing on the VEGF/VEGFR, EGF/EGFR, FGF/FGFR, and TGFß/TGFßR pathways. These include a variety of compounds, such as small molecule inhibitors and monoclonal antibodies, which have shown potential to interfere with tumor-induced alterations in bone. The text discusses clinical trials and preclinical models, offering insights into the effectiveness and constraints of various treatments. Ultimately, this study provides a succinct but thorough summary of the present knowledge and treatment strategies focused on growth factor receptors in bone metastases. This highlights the significance of comprehending the signaling of growth factor receptors in the microenvironment where tumors spread to the bones, as well as the possibility of using targeted therapies to enhance the results for cancer patients with bone metastases. The advancement of treating bone metastases hinges on the development of treatments that specifically target the intricate relationships between malignancies and bone.


Assuntos
Neoplasias Ósseas , Humanos , Neoplasias Ósseas/secundário , Neoplasias Ósseas/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
20.
Cell Mol Biol (Noisy-le-grand) ; 70(5): 243-247, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38814208

RESUMO

Burns are the most severe type of trauma, and the resulting ischemia and hypoxia damage can promote the dysfunction and even failure of tissues and organs throughout the body, endangering patients' life safety. Recombinant human growth hormone (rhGH) has the functions of promoting protein synthesis to reverse negative nitrogen balance, accelerating wound healing, and improving immune function, which is widely used in the treatment of burns. However, the exact mechanism and pathway of rhGH's action is not yet fully understood. In this study, we observed the wound repair effect of recombinant human growth hormone (rhGH) on burned mice and further analyzed the mechanism of action, which can provide more comprehensive reference opinions for clinical practice. First, by establishing a burn mouse model and and intervening with different doses of rhGH, we found that the wound healing capacity of mice was significantly enhanced and the inflammatory and oxidative stress responses were obviously alleviated, confirming the excellent promotion of wound repair and anti-inflammatory and antioxidant effects of rhGH. Subsequently, we found that the expression of p-ERK1/2/ERK1/2, EGF, TGF-ß, and VEGF proteins was elevated in the traumatic tissues of mice after rhGH intervention, suggesting that the pathway of action of rhGH might be related to the activation of ERK pathway to promote the regeneration of traumatic capillaries.


Assuntos
Queimaduras , Hormônio do Crescimento Humano , Sistema de Sinalização das MAP Quinases , Neovascularização Fisiológica , Proteínas Recombinantes , Cicatrização , Animais , Queimaduras/tratamento farmacológico , Queimaduras/patologia , Cicatrização/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Camundongos , Hormônio do Crescimento Humano/farmacologia , Humanos , Neovascularização Fisiológica/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais de Doenças , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Camundongos Endogâmicos C57BL , Fator de Crescimento Epidérmico/farmacologia , Angiogênese
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