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BACKGROUND: Cushing's syndrome (CS) is associated with increased risk for heart failure, which often initially manifests as left ventricular diastolic dysfunction (LVDD). In this study, we aimed to explore the potential risk factors of LVDD in CS by incorporating body composition parameters. METHODS: A retrospective study was conducted on patients diagnosed with endogenous CS no less than 18 years old. The control group consisted of healthy individuals who were matched to CS patients in terms of gender, age, and BMI. LIFEx software (version 7.3) was applied to measure epicardial adipose tissue volume (EATV) on non-contrast chest CT, as well as abdominal adipose tissue and skeletal muscle mass at the first lumbar vertebral level. Echocardiography was used to evaluate left ventricular (LV) diastolic function. Body compositions and clinical data were examined in relation to early LVDD. RESULTS: A total of 86 CS patients and 86 healthy controls were enrolled. EATV was significantly higher in CS patients compared to control subjects (150.33 cm3 [125.67, 189.41] vs 90.55 cm3 [66.80, 119.84], p < 0.001). CS patients had noticeably increased visceral fat but decreased skeletal muscle in comparison to their healthy counterparts. Higher prevalence of LVDD was found in CS patients based on LV diastolic function evaluated by E/A ratio (p < 0.001). EATV was proved to be an independent risk factor for LVDD in CS patients (OR = 1.015, 95%CI 1.003-1.026, p = 0.011). If the cut-point of EATV was set as 139.252 cm3 in CS patients, the diagnostic sensitivity and specificity of LVDD were 84.00% and 55.60%, respectively. CONCLUSION: CS was associated with marked accumulation of EAT and visceral fat, reduced skeletal muscle mass, and increased prevalence of LVDD. EATV was an independent risk factor for LVDD, suggesting the potential role of EAT in the development of LVDD in CS.
This study explored the potential risk factors of LVDD in endogenous CS by incorporating body composition parameters. EATV was identified as an independent risk factor for LVDD. Targeted therapeutic interventions to reduce excessive cortisol-induced EAT accumulation may be promising to mitigate the risk of LVDD development in patients with CS.
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Tecido Adiposo , Síndrome de Cushing , Ecocardiografia , Pericárdio , Disfunção Ventricular Esquerda , Humanos , Masculino , Síndrome de Cushing/fisiopatologia , Síndrome de Cushing/complicações , Síndrome de Cushing/epidemiologia , Feminino , Estudos Retrospectivos , Adulto , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/etiologia , Pericárdio/diagnóstico por imagem , Tecido Adiposo/diagnóstico por imagem , Tecido Adiposo/fisiopatologia , Pessoa de Meia-Idade , Diástole , Fatores de Risco , Estudos de Casos e Controles , Tomografia Computadorizada por Raios X , Tecido Adiposo EpicárdicoRESUMO
Background: The primary aim of this study is to investigate the correlation between serum levels of fibrinogen-to-prealbumin ratio (FPR) and C-reactive protein-to-prealbumin ratio (CPR) and prognostic outcomes among patients with severe fever with thrombocytopenia syndrome (SFTS). SFTS, characterized by elevated mortality rates, represents a substantial public health challenge as an emerging infectious disease. Methods: The study included 159 patients with SFTS. Clinical and laboratory data were compared between the survival and death groups. Univariate and multivariate logistic regression analysis were utilized to identify independent risk factors for mortality. The predictive efficacy of FPR and CPR was evaluated using receiver operating characteristic (ROC) curve. Survival analysis was conducted using the Kaplan-Meier curve and the log-rank test was employed for comparison. Results: The death group exhibited significantly elevated levels of FPR and CPR compared to the survival group (P < 0.05). Multivariate logistic regression analysis confirmed that both FPR and CPR independently correlated with a poorer prognosis among patients with SFTS. The ROC curve analysis indicated that FPR and CPR had superior predictive capabilities compared to C-reactive protein and fibrinogen. Kaplan-Meier survival analysis demonstrated that patients with SFTS who have FPR > 0.045 (log-rank test; χ2 = 17.370, P < 0.001) or CPR > 0.05 (log-rank test; χ2 = 19.442, P < 0.001) experienced significantly lower survival rates within a 30-day follow-up period. Conclusion: Elevated levels of FPR and CPR serve as distinct risk factors for mortality among patients with SFTS, indicating their potential to predict an unfavorable prognosis in these patients.
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Proteína C-Reativa , Fibrinogênio , Pré-Albumina , Curva ROC , Febre Grave com Síndrome de Trombocitopenia , Humanos , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Masculino , Feminino , Fibrinogênio/análise , Fibrinogênio/metabolismo , Prognóstico , Pessoa de Meia-Idade , Idoso , Febre Grave com Síndrome de Trombocitopenia/sangue , Febre Grave com Síndrome de Trombocitopenia/mortalidade , Pré-Albumina/análise , Pré-Albumina/metabolismo , Biomarcadores/sangue , Fatores de Risco , Adulto , Phlebovirus , Estimativa de Kaplan-Meier , Estudos RetrospectivosRESUMO
BACKGROUND: The incidence of colorectal cancer (CRC) is increasing annually. Laparoscopic radical resection of CRC is a minimally invasive procedure preferred in clinical practice. AIM: To investigate the clinical effect of laparoscopic radical resection of CRC on the basis of propensity score matching (PSM). METHODS: The clinical data of 100 patients who received inpatient treatment for CRC at Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City) were analyzed retrospectively. The control group included patients who underwent open surgery (n = 43), and those who underwent laparoscopic surgery formed the observation group (n = 57). The baseline information of both groups was equipoised using 1 × 1 PSM. Differences in the perioperative parameters, inflammatory response, immune function, degree of pain, and physical status between the groups were analyzed. RESULTS: Thirty patients from both groups were successfully matched. After PSM, baseline data showed no statistically significant differences between the groups: (1) Perioperative parameters: The observation group had a longer surgery time, less intraoperative blood loss, earlier first ambulation and first anal exhaust times, and shorter gastric tube indwelling time than the control group; (2) Inflammatory response: 24 h after surgery, the levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) between groups were higher than preoperatively. IL-6, CRP, and TNF-α levels in the observation group were lower than in the control group; (3) Immune function: At 24 h after surgery, counts of CD4-positive T-lymphocytes (CD4+) and CD4+/CD8-positive T-lymphocytes (CD8+) in both groups were lower than those before surgery, whereas CD8+ was higher than that before surgery. At 24 h after surgery, both CD4+ counts and CD4+/CD8+ in the observation group were higher than those in the control group, whereas CD8+ counts were lower; (4) Degree of pain: The visual analog scale scores in the observation group were lower than those in the control group at 24 and 72 h after surgery; and (5) Physical status: One month after surgery, the Karnofsky performance score in the observation group was higher than that in the control group. CONCLUSION: Laparoscopic radical resection of CRC has significant benefits, such as reducing postoperative pain and postoperative inflammatory response, avoiding excessive immune inhibition, and contributing to postoperative recovery.
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Inhibition of immunocyte infiltration and activation has been suggested to effectively ameliorate nonalcoholic steatohepatitis (NASH). Paired immunoglobulin-like receptor B (PirB) and its human ortholog receptor, leukocyte immunoglobulin-like receptor B (LILRB2), are immune-inhibitory receptors. However, their role in NASH pathogenesis is still unclear. Here, we demonstrate that PirB/LILRB2 regulates the migration of macrophages during NASH by binding with its ligand angiopoietin-like protein 8 (ANGPTL8). Hepatocyte-specific ANGPTL8 knockout reduces MDM infiltration and resolves lipid accumulation and fibrosis progression in the livers of NASH mice. In addition, PirB-/- bone marrow (BM) chimeras abrogate ANGPTL8-induced MDM migration to the liver. And yet, PirB ectodomain protein could ameliorate NASH by sequestering ANGPTL8. Furthermore, LILRB2-ANGPTL8 binding-promoted MDM migration and inflammatory activation are also observed in human peripheral blood monocytes. Taken together, our findings reveal the role of PirB/LILRB2 in NASH pathogenesis and identify PirB/LILRB2-ANGPTL8 signaling as a potential target for the management or treatment of NASH.
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Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Camundongos , Proteína 8 Semelhante a Angiopoietina , Macrófagos , Glicoproteínas de Membrana , Monócitos , Receptores Imunológicos/genéticaRESUMO
Background: Stickler syndrome (SS) is a group of hereditary collagenopathies caused by a variety of collagen and non-collagen genes. Affected patients have characteristic manifestations involving ophthalmic, articular, craniofacial and auditory disorders. SS is classified into several subtypes according to clinical and molecular features. Type 3 SS is an ultra-rare disease, known as non-ocular SS or otospondylomegaepiphyseal dysplasia (OSMED) with only a few pathogenic COL11A2 variants reported to date. Case presentation: A 29-year-old Chinese male was referred to our hospital for hearing loss and multiple joint pain. He presented a phenotype highly suggestive of OSMED, including progressive sensorineural deafness, spondyloepiphyseal dysplasia with large epiphyses, platyspondyly, degenerative osteoarthritis, and sunken nasal bridge. We detected compound heterozygous mutations in COL11A2, both of which were predicted to be splicing mutations. One is synonymous mutation c.3774C>T (p.Gly1258Gly) supposed to be a splice site mutation, the other is a novel intron mutation c.4750 + 5 G>A, which is a highly conservative site across several species. We also present a review of the current known pathogenic mutation spectrum of COL11A2 in patients with type 3 SS. Conclusion: Both synonymous extonic and intronic variants are easily overlooked by whole-exome sequencing. For patients with clinical manifestations suspected of SS syndrome, next-generation whole-genome sequencing is necessary for precision diagnosis and genetic counseling.
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BACKGROUND: Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare form of adrenal Cushing's syndrome. The slowly progressing expansion of bilateral adrenal tissues usually persists for dozens of years, leading to delayed onset with severe conditions due to chronic mild hypercortisolism. About 20-50% cases were found to be caused by inactivating mutation of armadillo repeat-containing protein 5 (ARMC5) gene. CASE PRESENTATION: A 51-year-old man was admitted for severe diabetes mellitus, resistant hypertension, centripedal obesity and edema. PBMAH was diagnosed after determination of adrenocorticotropic hormone and cortisol levels, dexamethasone suppression tests and abdominal contrast-enhanced CT scanning. The metabolic disorders of the patient remarkably improved after sequentially bilateral laparoscopic adrenalectomy combined with hormone replacement. Sanger sequencing showed germline nonsense mutation of ARMC5 c.967C>T (p.Gln323Ter). The second somatic missense mutation of ARMC5 was detected in one out of two resected nodules, reflecting the second-hit model of tumorigenesis. Routine genetic testing in his apparently healthy offspring showed one of two daughters and one son harbored the germline mutation. CONCLUSIONS: In conclusion, our case report highlight the importance of genetic testing in the molecular diagnosis of PBMAH. Genetic screening in related family members will find out asymptomatic variant carriers to guide life-long follow-up.
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HiperplasiaRESUMO
BACKGROUND: Hyponatremia induced by syndrome of inappropriate antidiuretic hormone secretion (SIADH) was common electrolyte disturbance encountered in critically ill neurological diseases, which has normal or increased fluid volume. Brain natriuretic peptide (BNP), which is released in equal proportion to N-terminal pro-brain natriuretic peptide (NT-proBNP), plays vital roles in regulation of volume status. The relationship between SIADH and NT-proBNP levels in neurological diseases has rarely been reported. METHODS: A retrospective cross-sectional study was conducted to analyze plasma NT-proBNP levels in 33 patients with SIADH and 23 controlled eunatremic patients with neurological diseases. RESULTS: Baseline NT-proBNP levels were compared between two groups [SIADH group: median 311 pg/mL, interquartile range (IQR) 110-768 pg/mL] vs. eunatremic group: median 46 pg/mL, IQR, 12-96 pg/mL) (P<0.05). Plasma NT-proBNP levels were markedly increased in hyponatremic patients who had two or more complications than those who had less complication (P<0.05). In SIADH patients, NT-proBNP levels in remission phase were lower to levels at baseline. Furthermore, no death was seen in eunatremic patients, while five SIADH patients died from complications. CONCLUSIONS: SIADH had higher plasma NT-proBNP levels and poorer prognosis compared to eunatremic neurological patients. NT-proBNP serves as a biomarker of disease severity while not extracellular volume (ECV) status in critically ill neurological patients.
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Two different types of organic montmorillonite, namely quaternary ammonium salt intercalated MMT (CMMT) and quaternary phosphonium salt intercalated MMT (PMMT) were used as fillers in the flame-retardant polyamide (PA6) based on aluminium salts of diisobutylphosphinic acid (ABPA). The influence of different types of organic montmorillonite (OMMT) on the structure and properties of flame-retardant PA6 nanocomposites were systematically investigated. The X-ray diffraction and transmission electron microscopy results suggested that the introduction of OMMT improved the dispersion of the flame retardant particles independently of the type of OMMT. The derivative thermogravimetry (DTG) curve transformed to one peak from two peaks (representing the degradation of ABPA and PA6, respectively) after incorporation of the OMMT, which further confirmed better ABPA dispersion. Viscoelastic measurements demonstrated that a mechanically stable network structure was formed with the introduction of OMMT or ABPA and OMMT, while PA6/ABPA/PMMT presented the highest storage modulus and viscosity, suggesting a more efficient network structure. From UL-94 and limited oxygen index (LOI) tests, PA6/ABPA/PMMT presented the best flame performance, with a UL-94 of V-0 and a LOI of 33%. In addition, the PA6/ABPA/PMMT presented the lowest peak heat release rate (pHRR) among the investigated samples. Combined with the char layer analysis, it can be deduced that the introduction of PMMT improved the dispersion of ABPA, and promoted the formation of more efficient network structure, before promoting more compact char structures, which finally resulted in improved flame retardancy.
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BACKGROUND: Most strategies for antirejection and tolerance induction in clinical transplantation have focused on modifying adaptive immunity, it is unclear whether pharmacological suppressing the innate immune system can promote transplant tolerance. METHODS: We inhibited innate immunity by using our self-generated inhibitor of myeloid differentiation factor 88 (MyD88), TJ-M2010-5, and investigated its therapeutic effects and mechanisms in cardiac and skin transplant models. RESULTS: TJ-M2010-5 directly and indirectly interacted with the Toll/IL-1R domain of MyD88, inhibiting MyD88 homodimerization. In vitro, TJ-M2010-5 inhibited maturation of dendritic cells, which suppressed nuclear translocation of NF-κB and T cell activation. In vivo, short-term (10 days) monotherapy of TJ-M2010-5 resulted in long time survival of 50% of the cardiac allografts, and longer-term (14 days) combination treatment of TJ-M2010-5 with CD154 mAb resulted in survival of 29% of skin allografts, which outperformed far more than CsA did and stimulated the proliferation of CD4CD25FoxP3 Regulatory T cells in recipient mice. CONCLUSIONS: Pharmacological inhibition of MyD88 signaling by this novel inhibitor TJ-M2010-5 shows a powerful anti-rejection effect, which may have therapeutic potential in clinical transplantation. The inhibition of both innate and adaptive immunity may be necessary for tolerance induction in nonsolid organs.
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Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Coração , Imunossupressores/farmacologia , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Piperazinas/farmacologia , Transplante de Pele , Tiazóis/farmacologia , Tolerância ao Transplante/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Transplante de Coração/efeitos adversos , Imunidade Inata/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Animais , Fator 88 de Diferenciação Mieloide/metabolismo , Miocárdio/imunologia , Miocárdio/metabolismo , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Transplante de Pele/efeitos adversos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Fator de Transcrição RelA/imunologia , Fator de Transcrição RelA/metabolismo , TransfecçãoRESUMO
The activation of innate immunity via myeloid differentiation factor 88 (MyD88) contributes to ischemia reperfusion (I/R) induced acute kidney injury (AKI) and chronic kidney injury. However, since there have not yet been any effective therapy, the exact pharmacological role of MyD88 in the prevention and treatment of renal ischemia reperfusion injury (IRI) is not known. We designed a small molecular compound, TJ-M2010-2, which inhibited MyD88 homodimerization. We used an established unilateral I/R mouse model. All mice undergoing 80 min ischemia through uninephrectomy died within five days without intervention. However, treatment with TJ-M2010-2 alone significantly improved the survival rate to 58.3%. Co-treatment of TJ-M2010-2 with the CD154 antagonist increased survival rates up to 100%. Twenty-eight days post-I/R of 60 min ischemia without nephrectomy, TJ-M2010-2 markedly attenuated renal interstitial and inhibited TGF-ß1-induced epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. Furthermore, TJ-M2010-2 remarkably inhibited TLR/MyD88 signaling in vivo and in vitro. In conclusion, our findings highlight the promising clinical potential of MyD88 inhibitor in preventing and treating acute or chronic renal I/R injuries, and the therapeutic functionality of dual-system inhibition strategy in IRI-induced AKI. Moreover, MyD88 inhibition ameliorates renal I/R injury-induced tubular interstitial fibrosis by suppressing EMT.
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Anticorpos Monoclonais/farmacologia , Ligante de CD40/antagonistas & inibidores , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Piperazinas/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Tiazóis/farmacologia , Animais , Sítios de Ligação , Ligante de CD40/genética , Ligante de CD40/imunologia , Desenho de Fármacos , Quimioterapia Combinada , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Expressão Gênica , Imunidade Inata/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica/efeitos dos fármacos , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/mortalidade , Análise de SobrevidaRESUMO
Recognition of evolutionarily conserved ligands by Toll-like receptors (TLRs) triggers signaling cascades in innate immune cells to amplify adaptive immune responses. Nearly all TLRs require MyD88 to transduce downstream signaling. MyD88 deficiency has been shown to promote the allograft acceptance in mice. However, direct evidence for therapeutic potential of MyD88 inhibitors remains lacking. Herein, we used a MyD88 inhibitor, namely ST2825, to explore its therapeutic potential and mechanisms in fully allogeneic skin and heart transplant models. Phenotypic maturation of dendritic cells stimulated by TLR ligands was alleviated by ST2825 in parallel with reduced T-cell proliferation in vitro. A short-course treatment with ST2825 significantly prolonged cardiac graft survival (mean survival time = 18.5 ± 0.92 days vs. 7.25 ± 0.46 days). ST2825-treated group had significantly reduced proinflammatory cytokines in allografts compared with control group. ST2825 combined with anti-CD154 induced long-term skin allograft acceptance in about one-third of recipients (>100 days). 'Skin-tolerant' recipients showed attenuated donor-specific IFN-γ responses, intact IL-4 responses, and compromised alloantibody responses. We conclude that MyD88 inhibitor ST2825 attenuates acute cardiac rejection and promotes donor-specific hyporesponsiveness in stringent skin transplant models. The direct evidence suggests that pharmacological inhibition of MyD88 hold promising potential for transplant rejection.
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Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/imunologia , Transplante de Coração/métodos , Compostos Heterocíclicos com 2 Anéis/farmacologia , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Compostos de Espiro/farmacologia , Animais , Ligante de CD40/metabolismo , Ilhas de CpG , Células Dendríticas/citologia , Feminino , Rejeição de Enxerto/imunologia , Inflamação , Isoanticorpos/imunologia , Linfócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pele/patologia , Transplante de Pele , Doadores de Tecidos , Tolerância ao Transplante , Transplante HomólogoRESUMO
BACKGROUND: Emerging studies indicate that B-type natriuretic peptide (BNP), a well-known biomarker for heart failure, also plays pivotal roles in metabolic control. Circulating BNP levels progressively increase as ages grow older. However, the association between BNP levels and lipid metabolism in the elderly remains unknown. METHODS: A total of 680 eligible volunteers (male/female: 334/346) aged between 60 and 80 years old without overt heart failure (BNP <100 pg/ml) were enrolled. Random nonfasting venous samples were obtained for biochemical analysis. The subjects were stratified based on BNP quartiles: BNP Q1 (range: 2.2-9.0 pg/ml), Q2 (9.1-20.4 pg/ml), Q3 (20.5-44.4 pg/ml) and Q4 (44.6-99.7 pg/ml). Difference of metabolic parameters was compared among the subjects grouped by BNP quartiles. Univariate correlation and multiple linear regression were performed to analyze the association between BNP levels and metabolic parameters. The odds ratios (OR) and 95 % confidence intervals (CI) for dyslipidemia in subjects within BNP Q1-3 relative to subjects within BNP Q4 were calculated. RESULTS: Circulating BNP levels positively correlated with age, while negatively correlated with body mass index (BMI), eGFR and non-HDL. Subjects with lower BNP quartiles had significantly elevated prevalence of dyslipidemia, including hypertriglyceridemia, hyper-LDL-emia and hypercholesterolemia. The OR of hypertriglyceridemia and hypercholesterolemia for subjects within BNP Q1-2 significantly increased relative to BNP Q4. CONCLUSIONS: The elderly people with higher BNP levels have significantly reduced risks for nonfasting dyslipidemia. Verification of the cause-effect relationship between BNP and dyslipidemia may bring therapeutic implications.
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Jejum/sangue , Lipídeos/sangue , Peptídeo Natriurético Encefálico/sangue , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Dislipidemias/sangue , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Macrophages function as an essential component of innate immune system, contributing to both the initiation and appropriate resolution of inflammation. The exposure of macrophages to the microbial products, such as lipopolysaccharide (LPS), can strongly shift the balance between tissue homeostasis and inflammation in favor of causing systemic damage, in which macrophage M1 polarization play important roles. Strategies aiming at restoring the balance of macrophage polarization remain to be further explored. Herein, we have demonstrated that poliovirus receptor (PVR), the receptor of TIGIT, was dramatically upregulated on the surface of mouse peritoneal macrophages when exposed to LPS. TIGIT-Fc fusion protein not only inhibited the macrophage activation, but also skewed M1/M2 balance toward an anti-inflammatory profile, especially enhanced the secretion of IL-10. The activation of TIGIT/PVR pathway in macrophages correlated with increased nuclear translocation of c-Maf, which promotes IL-10 transcription. Treatment with fibroblasts stably secreting TIGIT-Fc fusion protein significantly reversed the lethal and sublethal endotoxic shock, which facilitated peritoneal macrophages to switch towards anti-inflammatory M2 cytokine profiles. These findings highlight a novel role of the TIGIT/PVR pathway in macrophage M2 polarization and suggest that TIGIT may have the potential to optimize the treatment of macrophage-involved inflammatory diseases.
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Macrófagos Peritoneais/efeitos dos fármacos , Receptores Imunológicos/imunologia , Receptores Virais/imunologia , Proteínas Recombinantes de Fusão/farmacologia , Animais , Regulação da Expressão Gênica , Células HEK293 , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/mortalidade , Inflamação/patologia , Interleucina-10/genética , Interleucina-10/imunologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Fenótipo , Proteínas Proto-Oncogênicas c-maf/genética , Proteínas Proto-Oncogênicas c-maf/imunologia , Receptores Imunológicos/genética , Receptores Virais/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Transdução de Sinais , Análise de SobrevidaRESUMO
Sclerosteosis, characterized by the hyperostosis of cranial and tubular bones, is a rare autosomal recessive hereditary disorder caused by mutation of SOST gene. Four nonsense mutations of SOST have been identified worldwide. Here, we report two affected siblings who carried a novel nonsense mutation of SOST in a consanguineous family from China. The proband manifested typical symptoms of sclerosteosis, whereas the symptoms were absent in another affected sibling. Two nucleotide substitutions in exon 2 of SOST were identified, c.444_445TC>AA, resulting in a premature stop codon, p.Cys148âStop. This truncated mutation loses 66 amino acid residues which contain 3 cysteine residues of the cysteine-knot motif, leading to loss of function of SOST. The symptoms of sclerosteosis may be clinically heterogeneous in some patients, even with the same mutation. Our results support the notion that founder effects from the ancestors contribute to the disease onset.
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Proteínas Morfogenéticas Ósseas/genética , Códon sem Sentido/genética , Consanguinidade , Marcadores Genéticos/genética , Hiperostose/genética , Mutação/genética , Sindactilia/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Sequência de Bases , Família , Feminino , Homozigoto , Humanos , Hiperostose/diagnóstico por imagem , Recém-Nascido , Masculino , Dados de Sequência Molecular , Linhagem , Radiografia , Sindactilia/diagnóstico por imagem , Adulto JovemRESUMO
BACKGROUND: The TLR/MyD88 signaling pathway is an important driver of inflammation and cancer and is a possible target for antitumor therapy. METHODS: We generated a MyD88 inhibitor (TJ-M2010-5), which was designed to bind to the TIR domain of MyD88 to interfere with its homodimerization, and the TLR/MyD88 signal pathway. We utilized a mouse model of azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated cancer (CAC) in combination with TJ-M2010-5 administration to investigate the anti-inflammation-related cancer effect of MyD88 inhibitor in vivo. Data were analyzed with one-way and repeated measures analysis of variance. Differences in survival between groups were compared using the log rank test. All statistical tests were two-sided. RESULTS: TJ-M2010-5 inhibited MyD88 homodimerization in transfected HEK293 cells in a concentration-dependent manner and suppressed MyD88 signaling in LPS-responsive RAW 264.7 cells in vitro. In a 10-week CAC mouse model (n = 30 per group), TJ-M2010-5 treatment statistically significantly reduced AOM/DSS-induced colitis and completely prevented CAC development with less related body mass loss, resulted in 0% mortality of treated mice (compared with 53% mortality of control mice), decreased cell proliferation, and increased apoptosis in colon tissue. TJ-M2010-5 treatment also inhibited production of inflammatory cytokines and chemokines (TNF-α, IL-6,G-CSF, MIP-1ß, TGF-ß1, IL-11, IL-17A, IL-22 and IL-23) and infiltration of immune cells (macrophages, dendritic cells, neutropihls and CD(+)4 T cells) in colon tissues of mice. CONCLUSIONS: Our findings suggest that TLR/MyD88 signaling may be a therapeutic target for CAC intervention and MyD88 inhibitors may be a promising therapeutic modality for treating patients with colitis or CAC.
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Antineoplásicos/farmacologia , Colite/complicações , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/prevenção & controle , Citocinas/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Multimerização Proteica/efeitos dos fármacos , Animais , Quimiocinas/antagonistas & inibidores , Neoplasias Colorretais/etiologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos BALB C , Fator 88 de Diferenciação Mieloide/metabolismo , Piperazinas/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Tiazóis/farmacologiaAssuntos
DNA/metabolismo , Nanopartículas , Polietilenoimina/síntese química , Soro/metabolismo , Dióxido de Silício/síntese química , Transfecção/métodos , Animais , Transporte Biológico , Células COS , Chlorocebus aethiops , DNA/química , Células HEK293 , Humanos , Metacrilatos/química , Nanotecnologia , Tamanho da Partícula , Polietilenoimina/análogos & derivados , Silanos/químicaAssuntos
DNA/metabolismo , Dendrímeros/química , Magnetismo , Nanopartículas de Magnetita/química , Polietilenoimina/química , Transfecção/métodos , Animais , Transporte Biológico , Células COS , Chlorocebus aethiops , DNA/química , Genes Reporter , Luciferases/genética , Luciferases/metabolismo , Microscopia Confocal , Nanotecnologia , Soro/metabolismo , Fatores de TempoRESUMO
AIM: To develop a hepatocyte cell line, we immortalized primary porcine hepatocytes with a retroviral vector SSR#69 containing the Simian Virus 40 T antigen (SV40Tag). METHODS: We first established a method of porcine hepatocyte isolation with a modified four-step retrograde perfusion technique. Then the porcine hepatocytes were immortalized with retroviral vector SSR#69 expressing SV40T and hygromycin-resistance genes flanked by paired loxP recombination targets. SV40T cDNA in the expanded cells was subsequently excised by Cre/LoxP site-specific recombination. RESULTS: The resultant hepatocytes with high viability (97%) were successfully immortalized with retroviral vector SSR#69. One of the immortalized clones showed the typical morphological appearance, TJPH-1, and was selected by clone rings and expanded in culture. After excision of the SV40T gene with Cre-recombinase, cells stopped growing. The population of reverted cells exhibited the characteristics of differentiated hepatocytes. CONCLUSION: In conclusion, we herein describe a modified method of hepatocyte isolation and subsequently established a porcine hepatocyte cell line mediated by retroviral transfer and site-specific recombination.