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1.
Stem Cell Res Ther ; 12(1): 496, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503553

RESUMO

BACKGROUND: Fulminant hepatitis is a severe life-threatening clinical condition with rapid progressive loss of liver function. It is characterized by massive activation and infiltration of immune cells into the liver and disturbance of inflammatory cytokine production. Mesenchymal stem cells (MSCs) showed potent immunomodulatory properties. Transplantation of MSCs is suggested as a promising therapeutic approach for a host of inflammatory conditions. METHODS: In the current study, a well-established concanavalin A (Con A)-induced fulminant hepatitis mouse model was used to investigate the effects of transplanting human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on fulminant hepatitis. RESULTS: We showed that hWJ-MSCs effectively alleviate fulminant hepatitis in mouse models, primarily through inhibiting T cell immunity. RNA sequencing of liver tissues and human T cells co-cultured with hWJ-MSCs showed that NF-κB signaling and glycolysis are two main pathways mediating the protective role of hWJ-MSCs on both Con A-induced hepatitis in vivo and T cell activation in vitro. CONCLUSION: In summary, our data confirmed the potent therapeutic role of MSCs-derived from Wharton's jelly of human umbilical cord on Con A-induced fulminant hepatitis, and uncovered new mechanisms that glycolysis metabolic shift mediates suppression of T cell immunity by hWJ-MSCs.

2.
Medicine (Baltimore) ; 100(36): e27178, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516515

RESUMO

ABSTRACT: Small nucleolar RNA host gene 16 (SNHG16) has recently been reported as a potential biomarker in various cancers. However, the prognostic value of SNHG16 in hepatocellular carcinoma (HCC) has not been investigated yet. Therefore, the purpose of this study was to reveal the association between SNHG16 expression and clinicopathological characteristics of HCC.Standards-compliant literature was retrieved from multiple public databases, and data on overall survival, disease-free survival, and clinicopathological characteristics related to SNGH16 were extracted and meta-analysis was performed. Additionally, the Cancer Genome Atlas data were analyzed through the gene expression profiling interactive analysis database to verify previous results.A total of 5 reports involving 410 patients with HCC were enrolled. The high expression of SNHG16 indicated worse overall survival (hazard ratio, 2.10; 95% CI, 1.22-3.60; P = .007) and disease-free survival (hazard ratio, 3.38; 95% CI, 1.10-10.40; P = .03). Additionally, the high expression of SNHG16 predicted a larger tumor size, metastasis, and advanced TNM stage.SNHG16 could serve as a potential biomarker of poor prognosis in HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , RNA Longo não Codificante/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/patologia , Prognóstico
3.
Front Cell Dev Biol ; 9: 681171, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249933

RESUMO

Macrophages are involved in almost every aspect of biological systems and include development, homeostasis and repair. Mesenchymal stem cells (MSCs) have good clinical application prospects due to their ability to regulate adaptive and innate immune cells, particularly macrophages, and they have been used successfully for many immune disorders, including inflammatory bowel disease (IBD), acute lung injury, and wound healing, which have been reported as macrophage-mediated disorders. In the present review, we focus on the interaction between MSCs and macrophages and summarize their methods of interaction and communication, such as cell-to-cell contact, soluble factor secretion, and organelle transfer. In addition, we discuss the roles of MSC-macrophage crosstalk in the development of disease and maintenance of homeostasis of inflammatory microenvironments. Finally, we provide optimal strategies for applications in immune-related disease treatments.

4.
Mol Med Rep ; 24(1)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33955510

RESUMO

Metabolic dysfunction­associated fatty liver disease (MAFLD) is a serious threat to human health. Parthenolide (PAR) displays several important pharmacological activities, including the promotion of liver function recovery during hepatitis. The aim of the present study was to assess the effect of PAR on MAFLD in a mouse model. Body weight, liver to body weight ratios, histological score, alanine transaminase, aspartate transaminase, total cholesterol and triglyceride levels were determined to evaluate liver injury. Liver hydroxyproline concentrations were also assessed. The expression levels of lipid metabolism­related genes (sterol regulatory element binding protein­1c, fatty acid synthase, acetyl CoA carboxylase 1, stearoyl CoA desaturase 1 and carbohydrate response element­binding protein, peroxisome proliferator­activated receptor α, carnitine palmitoyl transferase 1α and acyl­CoA dehydrogenase short chain), liver fibrosis­associated genes (α­smooth muscle actin, tissue inhibitor of metalloproteinase 1 and TGF­ß1), pro­inflammatory cytokines (TNF­α, IL­1ß and IL­6) and oxidative stress­associated enzymes (malondialdehyde, superoxide dismutase and glutathione peroxidase) were measured in mice with MAFLD. The expression levels of genes associated with the HIPPO pathway were also measured. In vivo experiments using a specific inhibitor of HIPPO signalling were performed to verify the role of this pathway in the effects of PAR. PAR exerted beneficial effects on liver injury, lipid metabolism, fibrosis, inflammation and oxidative stress in mice with MAFLD, which was mediated by activation of the HIPPO pathway.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Fibrose/genética , Fibrose/metabolismo , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Masculino , Doenças Metabólicas/complicações , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos
5.
Mol Cell ; 81(13): 2736-2751.e8, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33932349

RESUMO

Cholesterol metabolism is tightly associated with colorectal cancer (CRC). Nevertheless, the clinical benefit of statins, the inhibitor of cholesterol biogenesis mevalonate (MVA) pathway, is inconclusive, possibly because of a lack of patient stratification criteria. Here, we describe that YAP-mediated zinc finger MYND-type containing 8 (ZMYND8) expression sensitizes intestinal tumors to the inhibition of the MVA pathway. We show that the oncogenic activity of YAP relies largely on ZMYND8 to enhance intracellular de novo cholesterol biogenesis. Disruption of the ZMYND8-dependent MVA pathway greatly restricts the self-renewal capacity of Lgr5+ intestinal stem cells (ISCs) and intestinal tumorigenesis. Mechanistically, ZMYND8 and SREBP2 drive the enhancer-promoter interaction to facilitate the recruitment of Mediator complex, thus upregulating MVA pathway genes. Together, our results establish that the epigenetic reader ZMYND8 endows YAP-high intestinal cancer with metabolic vulnerability.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Colorretais/metabolismo , Ácido Mevalônico/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Camundongos , Camundongos Transgênicos , Proteínas Supressoras de Tumor/genética
6.
Front Oncol ; 11: 635233, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33869021

RESUMO

Survivin as a member of the inhibitor of apoptosis proteins (IAPs) family is undetectable in normal cells, but highly expressed in cancer cells and cancer stem cells (CSCs) which makes it an attractive target in cancer therapy. Survivin dominant negative mutants have been reported as competitive inhibitors of endogenous survivin protein in cancer cells. However, there is a lack of systematic comparative studies on which mutants have stronger effect on promoting apoptosis in cancer cells, which will hinder the development of novel anti-cancer drugs. Here, based on the previous study of survivin and its analysis of the relationship between structure and function, we designed and constructed a series of different amino acid mutants from survivin (TmSm34, TmSm48, TmSm84, TmSm34/48, TmSm34/84, and TmSm34/48/84) fused cell-permeable peptide TATm at the N-terminus, and a dominant negative mutant TmSm34/84 with stronger pro-apoptotic activity was selected and evaluated systematically in vitro. The double-site mutant of survivin (TmSm34/84) showed more robust pro-apoptotic activity against A549 cells than others, and could reverse the resistance of A549 CSCs to adriamycin (ADM) (reversal index up to 7.01) by decreasing the expression levels of survivin, P-gp, and Bcl-2 while increasing cleaved caspase-3 in CSCs. This study indicated the selected survivin dominant negative mutant TmSm34/84 is promising to be an excellent candidate for recombinant anti-cancer protein by promoting apoptosis of cancer cells and their stem cells and sensitizing chemotherapeutic drugs.

7.
Cell Death Dis ; 12(3): 240, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664231

RESUMO

Liver diseases with different pathogenesis share common pathways of immune-mediated injury. Chitinase-3-like protein 1 (CHI3L1) was induced in both acute and chronic liver injuries, and recent studies reported that it possesses an immunosuppressive ability. CHI3L1 was also expressed in mesenchymal stem cells (MSCs), thus we investigates the role of CHI3L1 in MSC-based therapy for immune-mediated liver injury here. We found that CHI3L1 was highly expressed in human umbilical cord MSCs (hUC-MSCs). Downregulating CHI3L1 mitigated the ability of hUC-MSCs to inhibit T cell activation, proliferation and inflammatory cytokine secretion in vitro. Using Concanavalin A (Con A)-induced liver injury mouse model, we found that silencing CHI3L1 significantly abrogated the hUC-MSCs-mediated alleviation of liver injury, accompanying by weakened suppressive effects on infiltration and activation of hepatic T cells, and secretion of pro-inflammatory cytokines. In addition, recombinant CHI3L1 (rCHI3L1) administration inhibited the proliferation and function of activated T cells, and alleviated the Con A-induced liver injury in mice. Mechanistically, gene set enrichment analysis showed that JAK/STAT signalling pathway was one of the most significantly enriched gene pathways in T cells co-cultured with hUC-MSCs with CHI3L1 knockdown, and further study revealed that CHI3L1 secreted by hUC-MSCs inhibited the STAT1/3 signalling in T cells by upregulating peroxisome proliferator-activated receptor δ (PPARδ). Collectively, our data showed that CHI3L1 was a novel MSC-secreted immunosuppressive factor and provided new insights into therapeutic treatment of immune-mediated liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Proteína 1 Semelhante à Quitinase-3/metabolismo , Fígado/enzimologia , Ativação Linfocitária , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/enzimologia , Comunicação Parácrina , Linfócitos T/enzimologia , Animais , Proliferação de Células , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Técnicas de Cocultura , Concanavalina A , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Fígado/imunologia , Fígado/patologia , Camundongos Endogâmicos C57BL , Fosforilação , Receptores Citoplasmáticos e Nucleares/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T/imunologia , Cordão Umbilical/citologia
8.
Front Immunol ; 12: 609544, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33692786

RESUMO

Cell-cell contact participates in the process of mesenchymal stromal cell (MSC)-mediated T cell modulation and thus contributes to MSC-based therapies for various inflammatory diseases, especially T cell-mediated diseases. However, the mechanisms underlying the adhesion interactions between MSCs and T cells are still poorly understood. In this study, we explored the interaction between MSCs and T cells and found that activated T cells could rapidly adhere to MSCs, leading to significant reduction of TNF-α and IFN-γ mRNA expression. Furthermore, TCR-proximal signaling in activated T cells was also dramatically suppressed in the MSC co-culture, resulting in weakened Ca2+ signaling. MSCs rapidly suppressed TCR signaling and its downstream signaling in a cell-cell contact-dependent manner, partially through the ICAM-1/CD43 adhesion interaction. Blockade of either ICAM-1 on MSCs or CD43 on T cells significantly reversed this rapid suppression of proinflammatory cytokine expression in T cells. Mechanistically, MSC-derived ICAM-1 likely disrupts CD43-mediated TCR microcluster formation to limit T cell activation. Taken together, our results reveal a fast mechanism of activated T cell inhibition by MSCs, which provides new clues to unravel the MSC-mediated immunoregulatory mechanism for aGVHD and other severe acute T cell-related diseases.


Assuntos
Citocinas/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Leucossialina/metabolismo , Ativação Linfocitária/imunologia , Células-Tronco Mesenquimais/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Biomarcadores , Cálcio , Comunicação Celular/imunologia , Humanos , Ativação Linfocitária/genética , Células-Tronco Mesenquimais/imunologia , Ligação Proteica , Transdução de Sinais , Linfócitos T/imunologia
9.
J Pathol ; 253(1): 106-118, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33009820

RESUMO

Neuroendocrine prostate cancer (NEPC) is a more aggressive subtype of castration-resistant prostate cancer (CRPC). Although it is well established that PHF8 can enhance prostate cancer cell proliferation, whether PHF8 is involved in prostate cancer initiation and progression is relatively unclear. By comparing the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with or without Phf8 knockout, we systemically examined the role of PHF8 in prostate cancer development. We found that PHF8 plays a minimum role in initiation and progression of adenocarcinoma. However, PHF8 is essential for NEPC because not only is PHF8 highly expressed in NEPC but also animals without Phf8 failed to develop NEPC. Mechanistically, PHF8 transcriptionally upregulates FOXA2 by demethylating and removing the repressive histone markers on the promoter region of the FOXA2 gene, and the upregulated FOXA2 subsequently regulates the expression of genes involved in NEPC development. Since both PHF8 and FOXA2 are highly expressed in NEPC tissues from patients or patient-derived xenografts, the levels of PHF8 and FOXA2 can either individually or in combination serve as NEPC biomarkers and targeting either PHF8 or FOXA2 could be potential therapeutic strategies for NEPC treatment. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Adenocarcinoma/enzimologia , Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/enzimologia , Epigênese Genética , Fator 3-beta Nuclear de Hepatócito/metabolismo , Histona Desmetilases/metabolismo , Neoplasias da Próstata/enzimologia , Fatores de Transcrição/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/secundário , Animais , Biomarcadores Tumorais/genética , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/secundário , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Fator 3-beta Nuclear de Hepatócito/genética , Histona Desmetilases/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Fatores de Transcrição/genética , Transcrição Genética , Regulação para Cima
10.
J Hepatol ; 74(5): 1176-1187, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33217494

RESUMO

BACKGROUND & AIMS: Liver fibrosis is a wound healing response that arises from various aetiologies. The intermediate filament protein Nestin has been reported to participate in maintaining tissue homeostasis during wound healing responses. However, little is known about the role Nestin plays in liver fibrosis. This study investigated the function and precise regulatory network of Nestin during liver fibrosis. METHODS: Nestin expression was assessed via immunostaining and quantitative real-time PCR (qPCR) in fibrotic/cirrhotic samples. The induction of Nestin expression by transforming growth factor beta (TGFß)-Smad2/3 signalling was investigated through luciferase reporter assays. The functional role of Nestin in hepatic stellate cells (HSCs) was investigated by examining the pathway activity of profibrogenic TGFß-Smad2/3 signalling and degradation of TGFß receptor I (TßRI) after interfering with Nestin. The in vivo effects of knocking down Nestin were examined with an adeno-associated virus vector (serotype 6, AAV6) carrying short-hairpin RNA targeting Nestin in fibrotic mouse models. RESULTS: Nestin was mainly expressed in activated HSCs and increased with the progression of liver fibrosis. The profibrogenic pathway TGFß-Smad2/3 induced Nestin expression directly. Knocking down Nestin promoted caveolin 1-mediated TßRI degradation, resulting in TGFß-Smad2/3 pathway impairment and reduced fibrosis marker expression in HSCs. In AAV6-treated murine fibrotic models, knocking down Nestin resulted in decreased levels of inflammatory infiltration, hepatocellular damage, and a reduced degree of fibrosis. CONCLUSION: The expression of Nestin in HSCs was induced by TGFß and positively correlated with the degree of liver fibrosis. Knockdown of Nestin decreased activation of the TGFß pathway and alleviated liver fibrosis both in vitro and in vivo. Our data demonstrate a novel role of Nestin in controlling HSC activation in liver fibrosis. LAY SUMMARY: Liver fibrosis has various aetiologies but represents a common process in chronic liver diseases that is associated with high morbidity and mortality. Herein, we demonstrate that the intermediate filament protein Nestin plays an essential profibrogenic role in liver fibrosis by forming a positive feedback loop with the TGFß-Smad2/3 pathway, providing a potential therapeutic target for the treatment of liver fibrosis.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33361311

RESUMO

Schistosomiasis poses a serious threat to human health and remains a major tropical and parasitic disease in more than 70 countries. Praziquantel (PZQ) has been the primary treatment for schistosomiasis for nearly 4 decades. However, its efficacy against migratory-stage schistosomula is limited. Radicicol (RAD), a ß-resorcylic acid lactone derived from Paecilomyces sp. strain SC0924, was investigated as an alternative treatment for Schistosoma japonicum In vitro tests showed that within 72 h, RAD (10 µmol/liter) completely killed schistosomula of both skin and liver stages with an efficacy significantly higher than that of PZQ, although it was less potent against adult worms than PZQ. In vivo, RAD reduced worm burdens and liver eggs by 91.18% and 86.01%, respectively, by killing migratory-stage schistosomula. Optical microscopy and scanning electron microscopy revealed that RAD damaged the epiderm and tegument morphology of S. japonicum worms at various stages and altered their motility to different degrees. RAD exhibited schistosomicidal effects at different stages in vitro and in vivo, especially at the migratory stage, implying that its mechanism could be different from that of PZQ. Collectively, these results showed that RAD is promising as a lead for the development of drugs to control the migratory-stage schistosomula of S. japonicum.


Assuntos
Schistosoma japonicum , Esquistossomicidas , Animais , Humanos , Chumbo , Macrolídeos , Praziquantel/farmacologia , Schistosoma mansoni , Esquistossomicidas/farmacologia
12.
Front Endocrinol (Lausanne) ; 11: 586857, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329393

RESUMO

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic or parasympathetic paraganglia (PGLs). About 40% of PPGLs result from germline mutations and therefore they are highly inheritable. Although dysfunction of any one of a panel of more than 20 genes can lead to PPGLs, mutations in genes involved in the VHL/HIF axis including PHD, VHL, HIF-2A (EPAS1), and SDHx are more frequently found in PPGLs. Multiple lines of evidence indicate that pseudohypoxia plays a crucial role in the tumorigenesis of PPGLs, and therefore PPGLs are also known as metabolic diseases. However, the interplay between VHL/HIF-mediated pseudohypoxia and metabolic disorder in PPGLs cells is not well-defined. In this review, we will first discuss the VHL/HIF axis and genetic alterations in this axis. Then, we will dissect the underlying mechanisms in VHL/HIF axis-driven PPGL pathogenesis, with special attention paid to the interplay between the VHL/HIF axis and cancer cell metabolism. Finally, we will summarize the currently available compounds/drugs targeting this axis which could be potentially used as PPGLs treatment, as well as their underlying pharmacological mechanisms. The overall goal of this review is to better understand the role of VHL/HIF axis in PPGLs development, to establish more accurate tools in PPGLs diagnosis, and to pave the road toward efficacious therapeutics against metastatic PPGLs.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Proteínas Reguladoras de Apoptose/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Mutação em Linhagem Germinativa , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Feocromocitoma/genética , Proteínas Repressoras/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/metabolismo , Animais , Antineoplásicos/uso terapêutico , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Cromafins/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Feocromocitoma/tratamento farmacológico , Feocromocitoma/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Repressoras/antagonistas & inibidores , Proteína Supressora de Tumor Von Hippel-Lindau/antagonistas & inibidores , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
13.
Front Oncol ; 10: 564694, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194641

RESUMO

Background: Mutation-caused loss-of-function of factors involved in DNA damage response (DDR) is responsible for the development and progression of ~20% of prostate cancer (PCa). Some mutations can be used in cancer risk assessment and informed treatment decisions. Methods: Target capture-based deep sequencing of 11 genes was conducted with total DNA purified from the proband's peripheral blood. Sanger sequencing was conducted to screen potential germline mutations in the proband's family members. Targeted sequencing of a panel of 1,021 genes was done with DNA purified from the tumor tissue. Results: Two previously unreported germline mutations in the DDR pathway, BRCA2 (c.8474_8487delCATACCCTATACAG, p.A2825Vfs*15) and PALB2 (c.472delC, p.Q158Rfs*19) were identified in a patient with metastatic PCa. A specific therapeutic regimen including androgen deprivation therapy, locally radical radiotherapy, and systemic platinum chemotherapy worked well against his cancer. In addition, the metastatic ovarian cancer in the proband's half-sister harboring the same BRCA2 germline mutation also responded well to platinum chemotherapy. Conclusions: The newly identified germline mutations in DDR plays important role in PCa development. Since specific regimen worked well against this cancer, screening of DDR mutation could provide better management for patients with these mutation-mediated PCa.

14.
Front Immunol ; 11: 1843, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922398

RESUMO

The therapeutic potential of mesenchymal stem cells (MSCs) has been investigated in many preclinical and clinical studies. This potential is dominantly based on the immunosuppressive properties of MSCs. Although the therapeutic profiles of MSC transplantation are still not fully characterized, accumulating evidence has revealed that B cells change after MSC infusion, in particular inducing regulatory B cells (Bregs). The immunosuppressive effects of Bregs have been demonstrated, and these cells are being evaluated as new targets for the treatment of inflammatory diseases. MSCs are capable of educating B cells and inducing regulatory B cell production via cell-to-cell contact, soluble factors, and extracellular vesicles (EVs). These cells thus have the potential to complement each other's immunomodulatory functions, and a combined approach may enable synergistic effects for the treatment of immunological diseases. However, compared with investigations regarding other immune cells, investigations into how MSCs specifically regulate Bregs have been superficial and insufficient. In this review, we discuss the current findings related to the immunomodulatory effects of MSCs on regulatory B cells and provide optimal strategies for applications in immune-related disease treatments.


Assuntos
Linfócitos B Reguladores/imunologia , Imunomodulação/imunologia , Células-Tronco Mesenquimais/imunologia , Animais , Humanos , Transplante de Células-Tronco Mesenquimais
15.
Cell Death Dis ; 11(9): 762, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938907

RESUMO

PKC-δ is an important molecule for B-cell proliferation and tolerance. B cells have long been recognized to play a part in osteoimmunology and pathological bone loss. However, the role of B cells with PKC-δ deficiency in bone homeostasis and the underlying mechanisms are unknown. We generated mice with PKC-δ deletion selectively in B cells by crossing PKC-δ-loxP mice with CD19-Cre mice. We studied their bone phenotype using micro-CT and histology. Next, immune organs were obtained and analyzed. Western blotting was used to determine the RANKL/OPG ratio in vitro in B-cell cultures, ELISA assay and immunohistochemistry were used to analyze in vivo RANKL/OPG balance in serum and bone sections respectively. Finally, we utilized osteoclastogenesis to study osteoclast function via hydroxyapatite resorption assay, and isolated primary calvaria osteoblasts to investigate osteoblast proliferation and differentiation. We also investigated osteoclast and osteoblast biology in co-culture with B-cell supernatants. We found that mice with PKC-δ deficiency in B cells displayed an osteopenia phenotype in the trabecular and cortical compartment of long bones. In addition, PKC-δ deletion resulted in changes of trabecular bone structure in association with activation of osteoclast bone resorption and decrease in osteoblast parameters. As expected, inactivation of PKC-δ in B cells resulted in changes in spleen B-cell number, function, and distribution. Consistently, the RANKL/OPG ratio was elevated remarkably in B-cell culture, in the serum and in bone specimens after loss of PKC-δ in B cells. Finally, in vitro analysis revealed that PKC-δ ablation suppressed osteoclast differentiation and function but co-culture with B-cell supernatant reversed the suppression effect, as well as impaired osteoblast proliferation and function, indicative of osteoclast-osteoblast uncoupling. In conclusion, PKC-δ plays an important role in the interplay between B cells in the immune system and bone cells in the pathogenesis of bone lytic diseases.


Assuntos
Linfócitos B/metabolismo , Doenças Ósseas Metabólicas/metabolismo , Reabsorção Óssea/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Proteína Quinase C-delta/deficiência , Ligante RANK/metabolismo , Animais , Linfócitos B/enzimologia , Linfócitos B/patologia , Doenças Ósseas Metabólicas/patologia , Reabsorção Óssea/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoblastos/patologia , Osteoclastos/patologia , Ligante RANK/biossíntese , Regulação para Cima
16.
Front Oncol ; 10: 1234, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32850370

RESUMO

Epithelial-to-mesenchymal transition (EMT) is one of the important underlying molecular mechanisms for most types of cancers including bladder cancer. The precise underlying molecular mechanism in EMT-mediated bladder cancer progression is far from completed. LSD1, a histone lysine-specific demethylase, is known to promote cancer cell proliferation, metastasis, and chemoresistance. We found in this study that LSD1 is highly upregulated in bladder cancer specimens, especially those underwent chemotherapy, and the elevated levels of LSD1 are highly associated with bladder cancer grades, metastasis status, and prognosis. Inhibiting or knockdown LSD1 repressed not only EMT process but also cancer progression. Mechanistically, LSD1 complexes with ß-catenin to transcriptionally upregulate LEF1 and subsequently enhances EMT-mediated cancer progression. More importantly, LSD1 specific inhibitor GSK2879552 is capable of repressing tumor progression in patient-derived tumor xenograft. These findings altogether suggest that LSD1 can serve as not only a prognostic biomarker but also a promising therapeutic target in bladder cancer treatment.

17.
Cancer Cell ; 38(3): 350-365.e7, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32619406

RESUMO

The level of SETD2-mediated H3K36me3 is inversely correlated with that of EZH2-catalyzed H3K27me3. Nevertheless, it remains unclear whether these two enzymatic activities are molecularly intertwined. Here, we report that SETD2 delays prostate cancer (PCa) metastasis via its substrate EZH2. We show that SETD2 methylates EZH2 which promotes EZH2 degradation. SETD2 deficiency induces a Polycomb-repressive chromatin state that enables cells to acquire metastatic traits. Conversely, mice harboring nonmethylated EZH2 mutant or SETD2 mutant defective in binding to EZH2 develop metastatic PCa. Furthermore, we identify that metformin-stimulated AMPK signaling converges at FOXO3 to stimulate SETD2 expression. Together, our results demonstrate that the SETD2-EZH2 axis integrates metabolic and epigenetic signaling to restrict PCa metastasis.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Neoplasias da Próstata/genética , Transdução de Sinais/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos Nus , Camundongos SCID , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Transplante Heterólogo
18.
Stem Cells Dev ; 29(16): 1073-1083, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32552417

RESUMO

Mesenchymal stromal cells (MSCs) have become a promising treatment for inflammation-related diseases, and their therapeutic efficacy mainly depends on crosstalk between MSCs and inflammation. However, methods to improve the immunosuppressive efficiency of MSCs in different diseases still need to be developed. In this study, we investigated whether preconditioning MSCs with a disease-related inflammatory cytokine could increase their immunosuppressive properties and improve therapeutic efficacy. In a contact hypersensitivity (CHS) mouse model, inflammatory profile screening revealed that among all tested cytokines, monocyte chemotactic protein-1 (MCP-1) exhibited the most significantly increased level in the local microenvironment. As expected, MSCs preconditioned with MCP-1 (P-MSCs) exhibited an enhanced ability to downregulate proinflammatory cytokine secretion, induce regulatory T cells, inhibit T cell proliferation, and polarize M2-type macrophages. In vivo experiments showed that P-MSCs alleviated ear swelling and local proinflammatory cytokine production more effectively than control MSCs. Mechanistically, MCP-1 could significantly activate the signal transducer and activator of transcription 3 (STAT3) signaling pathway and induce the expression of cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) in MSCs. STAT3 inhibitor reversed the MCP-1-mediated enhancing of their immunosuppressive ability. Collectively, our findings demonstrate that CHS-related MCP-1 preconditioning enhanced the immunomodulatory effects of MSCs and improved their therapeutic efficacy in CHS. Enhancing the immunosuppressive efficacy of MSCs by preconditioning with certain disease-related inflammatory cytokines may provide a new strategy for MSC-based therapies for inflammatory diseases.

19.
Ann Transl Med ; 8(6): 334, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32355778

RESUMO

Background: Acute lung injury (ALI) is a devastating syndrome with no effective pharmacological therapies in the clinic. Mesenchymal stromal cells (MSCs) have been demonstrated to promote inflammation resolution and tissue repair in ALI. However, the specific mechanisms of this have not been clearly elucidated. Stanniocalcin-2 (STC2) is a stress-responsive protein that has anti-oxidative properties. Our previous study found that STC2 is a highly expressed stanniocalcin in MSCs, which may be involved in immunomodulatory activities. However, the role of STC2 in MSCs to resolve ALI has never been elucidated. Methods: Specific shRNA was used to downregulate STC2 in MSCs. We detected ROS, cell apoptosis, and paracrine factors changes in MSCs. STC2-associated antioxidant genes were also investigated by Co-immunoprecipitation (Co-IP) and immunofluorescence. Macrophage (THP1 cells) phenotype transitions were measured by flow cytometry after coculturing with MSCs in vitro. Then, we used MSCs to treat LPS-induced ALI in mice, and assessed injury scores inflammation, and antioxidant activities in the lungs of the mice. Alveolar macrophage (AM) phenotypes and CFSE-labeled MSC apoptosis in collected bronchoalveolar fluids (BALF) were also analyzed by flow cytometry. Results: After the STC2 knockdown, MSCs increased ROS generation and cell apoptosis after PX12 pretreatment. The antioxidant protein Nrf2 was colocalized with STC2 in the nucleus. A lack of STC2 expression in MSCs produced less interleukin 10 (IL10) and blunted macrophage polarization in THP1 cells. Furthermore, in the murine LPS-induced ALI model, the STC2 knockdown counteracted the inflammatory resolution and antioxidative effect of MSCs in the lungs. MSCshSTC2-treated mice had a higher lung injury score than the controls, which may be attributed to diminished AM polarization and increased apoptosis of MSCs in vivo. Conclusions: Collectively, these results suggested that STC2 is essential to the anti-oxidative and anti-inflammation properties of MSCs and could prove to be crucial for stem cell therapies for ALI.

20.
Nanoscale ; 12(19): 10623-10638, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32373859

RESUMO

Therapeutic recombinant proteins have numerous advantages and benefits over chemical drugs, particularly high specificity and good biocompatibility. However, the therapeutic potential and clinical application of current anticancer protein drugs are limited as most biomarkers are located within cells, and multiple physiological barriers exist between the point of administration and the intracellular biomarker. Herein, we report a novel strategy to accurately deliver a cell-permeable dominant-negative TATm-Survivin (TmSm) protein (T34A) to intracellular survivin in cancer cells by overcoming multiple barriers in vivo. A poly(d,l-lactide-co-glycolide) (PLGA) inner core, a polyethylene glycol (PEG) modification, and a TATm peptide were simultaneously introduced to mediate tumor tissue targeting and response to pH-triggered TmSm release. Compared to free TmSm, the PEGylated-PLGA nanoparticle platform achieved a significantly higher cellular uptake efficiency (1.79-fold for A549 and 1.77-fold for Capan-2), effectively decreased IC50 (1.22-fold for A549 and 1.17-fold for Capan-2), and largely elevated apoptosis in different cancer cells (1.17-fold for A549 and 1.15-fold for Capan-2). Besides, this newly developed nanoplatform showed increased protein drug accumulation in the tumor site in A549-bearing nude mice and reached a tumor inhibition rate of 55.81% (1.35-fold versus free TmSm) by reducing the expression of intracellular survivin. All these results confirmed that our newly developed delivery strategy is a very promising tool, which helps protein drugs to cross multiple barriers in vivo and achieves precise targeting to intracellular biomarkers. This strategy could also be applied to other types of protein drugs to further improve their clinical anticancer therapeutic efficacy.


Assuntos
Neoplasias Pulmonares , Nanopartículas , Preparações Farmacêuticas , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , Polietilenoglicóis , Survivina
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