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1.
Biochem Pharmacol ; 171: 113710, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31726046

RESUMO

Enteric viruses that inhabit the intestine have profound effects on innate and adaptive immunity of the gut and thus distant organs. Acute pancreatitis (AP) is a common abdominal inflammatory disease, in which gut bacteria play an indispensable part, particularly in the severe form with local and systemic complications. So far, little is known about the role of enteric viruses in the pathophysiology of AP. In this study, we evaluated the effect of enteric virus depletion by oral anti-viral cocktail (AVC) on caerulein (Cae)-hyperstimulation induced experimental AP and underlying mechanisms. We found that AVC treatment alleviated experimental AP, accompanied by suppressed innate immune cell infiltration and TLR9 expression and signaling in pancreas and intestine. Furthermore, AVC administration reduced AP-induced interleukin-6 (IL-6) production, IL-6-activated signal transducers and activators of transcription 3 (STAT3) signaling. Concordantly, expression of AP-induced STAT3-responsive chemokines, especially monocyte chemotactic protein-1 (MCP-1) and chemokine (C-X-C motif) ligand 1 (CXCL1) was reduced, thereby contributing to modulated pancreatic immune milieu. Treatment of mice with a toll-like receptor 9 (TLR9) agonist abolished the protective effect of AVC by activation of IL6/STAT3 signaling and downstream chemokine production. Conversely, treatment of mice with TLR9 antagonists, mimicking AVC, exerted protective effects against AP. Collectively, these results suggest that depletion of enteric viruses protects mice from experimental AP through inhibiting TLR9 signaling. Our study therefore implies a previously unrecognized role of enteric viruses in AP.

2.
Pharmacol Res ; 152: 104592, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31830521

RESUMO

Pulmonary fibrosis is a progressive and fatal fibrotic lung disease with mysterious pathogenesis and limited effective therapies. The aberrantly activated lung myofibroblasts with resultant excessive accumulation of extracellular matrix is a central event in the progression of pulmonary fibrosis. Lysine-specific demethylase 1 (LSD1) has been suggested to epigenetically regulate cell differentiation, migration and invasion in tumor microenvironment. However, its function in pulmonary fibrosis remains unclear. The present study aimed to investigate the potential effect and underlying mechanisms of LSD1 in pulmonary fibrosis. Here, we found that LSD1 expression was elevated in lung tissues of mice with bleomycin-induced pulmonary fibrosis and lung fibroblasts treated with transforming growth factor-ß1 (TGF-ß1). In vivo knockdown of LSD1 by lentiviral shRNA transfection attenuated pulmonary fibrosis in mice, as evidenced by improved lung morphology, decreased lung coefficient and collagen secretion, and down-regulated α-SMA, collagen type I alpha and fibronectin expression in lungs. Additionally, in vitro knockdown of LSD1 inhibited the differentiation of fibroblasts to myofibroblasts, and decreased myofibroblast migration. By further mechanistic analysis, we demonstrated that knockdown of LSD1 prevented fibroblast--to-myofibroblast differentiation and subsequent pulmonary fibrosis by suppressing TGF-ß1/Smad3 signaling pathway through modulation of a balance between histone H3 lysine 9 methylation and histone H3 lysine 4 methylation. Together, our data indicate that LSD1 activation contributes to pulmonary myofibroblast differentiation and fibrosis by targeting TGF-ß1/Smad3 signaling, and suggest LSD1 as a therapeutic target for the treatment of pulmonary fibrosis.

3.
Front Immunol ; 10: 1733, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417546

RESUMO

Intestinal homeostasis underpins the development of type 1 diabetes (T1D), and dietary manipulations to enhance intestinal homeostasis have been proposed to prevent T1D. The current study aimed to investigate the efficacy of supplementing a novel specific low-methoxyl pectin (LMP) dietary fiber in preventing T1D development. Female NOD mice were weaned onto control or 5% (wt/wt) LMP supplemented diets for up to 40 weeks of age, overt diabetes incidence and blood glucose were monitored. Then broad-spectrum antibiotics (ABX) treatment per os for 7 days followed by gut microbiota transfer was performed to demonstrate gut microbiota-dependent effects. Next-generation sequencing was used for analyzing the composition of microbiota in caecum. Concentration of short chain fatty acids were determined by GC-MS. The barrier reinforcing tight junction proteins zonula occludens-2 (ZO-2), claudin-1 and NOD like receptor protein 3 (NLRP3) inflammasome activation were determined by Western blot. The proportion of CD25+Foxp3+CD4+ regulatory T cell (Foxp3+ Treg) in the pancreas, pancreatic and mesenteric lymph nodes was analyzed by flow cytometry. We found that LMP supplementation ameliorated T1D development in non-obese diabetic (NOD) mice, as evidenced by decreasing diabetes incidence and fasting glucose levels in LMP fed NOD mice. Further microbiota analysis revealed that LMP supplementation prevented T1D-associated caecal dysbiosis and selectively enriched caecal bacterial species to produce more SCFAs. The LMP-mediated microbial balance further enhanced caecal barrier function and shaped gut-pancreatic immune environment, as characterized by higher expression of tight junction proteins claudin-1, ZO-2 in caecum, increased Foxp3+ Treg population and decreased NLRP3 inflammasome activation in both caecum and pancreas. The microbiota-dependent beneficial effect of LMP on T1D was further proven by the fact that aberration of caecal microbiota by ABX treatment worsened T1D autoimmunity and could be restored with transfer of feces of LMP-fed NOD mice. These data demonstrate that this novel LMP limits T1D development by inducing caecal homeostasis to shape pancreatic immune environment. This finding opens a realistic option for gut microbiota manipulation and prevention of T1D in humans.

4.
Mol Nutr Food Res ; 63(21): e1900307, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31423661

RESUMO

SCOPE: This study aims to examine the protective effects of specific low-methoxyl pectin (LMP) on the development of type 1 diabetes (T1D). METHODS AND RESULTS: Female non-obese diabetic (NOD) mice are weaned onto either control or 5% LMP supplemented diets for up to 22 weeks of age. T1D incidence, gut barrier function, and pancreatic-gut immune responses are analyzed. LMP supplementation significantly dampened the onset of T1D in NOD mice. LMP supplementation induces caecal homeostasis, as indicated by the increasing SCFAs production, higher expression of tight junction proteins claudin 1, zonula occludens-2 in caecum. Furthermore, LMP-mediated caecal homeostasis impacts gut-pancreatic immunity, as evidenced by increased regulatory T cell population, modulated inflammatory cytokine expression, and suppressed NOD like receptor protein 3 (NLRP3) inflammasome activation in both caecum and pancreas. CONCLUSION: The data demonstrate that LMP limits T1D development by inducing caecal homeostasis to shape pancreatic immune environment, providing a scientific basis for using LMP as a novel functional supplementation to intervene T1D.

5.
Br J Pharmacol ; 176(23): 4446-4461, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31347703

RESUMO

BACKGROUND AND PURPOSE: Acute pancreatitis (AP) is a common acute abdominal condition, frequently associated with intestinal barrier dysfunction, which aggravates AP retroactively. Butyrate exhibits anti-inflammatory effects in a variety of inflammatory diseases. However, its potential beneficial effect on AP and the underlying mechanisms have not been investigated. EXPERIMENTAL APPROACH: Experimental AP was induced by caerulein hyperstimulation in wild-type and GPR109A-/- mice. Sodium butyrate was administered intragastrically for 7 days prior to caerulein hyperstimulation. Anti-inflammatory mechanisms of butyrate were further investigated in peritoneal macrophages. KEY RESULTS: Butyrate prophylaxis attenuated AP as shown by reduced serum amylase and lipase levels, pancreatic oedema, myeloperoxidase activity, and improved pancreatic morphology. Amelioration of pancreatic damage by butyrate was associated with reduced levels of TNF-α, IL-6, and CCL2 and suppressed activation of the NLRP3 inflammasome in both pancreas and colon. Further, butyrate ameliorated pancreatic inflammation by suppressing interactions between histone deacetylase 1 (HDAC1) and AP1 and STAT1 with increased histone acetylation at H3K9, H3K14, H3K18, and H3K27 loci, resulting in suppression of NLRP3 inflammasome activation and modulation of immune cell infiltration in pancreas. Additionally, butyrate mediated STAT1/AP1-NLRP3 inflammasome suppression via HDAC1 inhibition was demonstrated in peritoneal macrophage. In colon, butyrate inhibited NLRP3 inflammasome activation via GPR109A. Accordingly, the modulatory effects of butyrate on AP, AP-associated gut dysfunction, and NLRP3 inflammasome activation were diminished in GPR109A-/- mice. CONCLUSION AND IMPLICATIONS: Our study dissected tissue-specific anti-inflammatory mechanisms of butyrate during AP, suggesting that increased colonic levels of butyrate may be a strategy to protect against AP.

6.
BMC Med ; 17(1): 42, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30782145

RESUMO

BACKGROUND: Cathelicidins are a major group of natural antimicrobial peptides which play essential roles in regulating host defense and immunity. In addition to the antimicrobial and immunomodulatory activities, recent studies have reported the involvement of cathelicidins in cardiovascular diseases by regulating inflammatory response and microvascular dysfunction. However, the role of cathelicidins in myocardial apoptosis upon cardiac ischemia/reperfusion (I/R) injury remains largely unknown. METHODS: CRAMP (cathelicidin-related antimicrobial peptide) levels were measured in the heart and serum from I/R mice and in neonatal mouse cardiomyocytes treated with oxygen glucose deprivation/reperfusion (OGDR). Human serum cathelicidin antimicrobial peptide (LL-37) levels were measured in myocardial infarction (MI) patients. The role of CRAMP in myocardial apoptosis upon I/R injury was investigated in mice injected with the CRAMP peptide and in CRAMP knockout (KO) mice, as well as in OGDR-treated cardiomyocytes. RESULTS: We observed reduced CRAMP level in both heart and serum samples from I/R mice and in OGDR-treated cardiomyocytes, as well as reduced LL-37 level in MI patients. Knockdown of CRAMP enhanced cardiomyocyte apoptosis, and CRAMP KO mice displayed increased infarct size and myocardial apoptosis. In contrast, the CRAMP peptide reduced cardiomyocyte apoptosis and I/R injury. The CRAMP peptide inhibited cardiomyocyte apoptosis by activation of Akt and ERK1/2 and phosphorylation and nuclear export of FoxO3a. c-Jun was identified as a negative regulator of the CRAMP gene. Moreover, lower level of serum LL-37/neutrophil ratio was associated with readmission and/or death in MI patients during 1-year follow-up. CONCLUSIONS: CRAMP protects against cardiomyocyte apoptosis and cardiac I/R injury via activation of Akt and ERK and phosphorylation and nuclear export of FoxO3a. Increasing LL-37 might be a novel therapy for cardiac ischemic injury.


Assuntos
Anti-Infecciosos/uso terapêutico , Catelicidinas/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Anti-Infecciosos/farmacologia , Catelicidinas/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
7.
Front Immunol ; 9: 751, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29719535

RESUMO

Acute pancreatitis (AP) is one common clinical acute abdominal disease, for which specific pharmacological or nutritional therapies remain elusive. Lactose, a macronutrient and an inducer of host innate immune responses, possesses immune modulatory functions. The current study aimed to investigate potential modulatory effects of lactose and the interplay between the nutrient and pancreatic immunity during experimentally induced AP in mice. We found that either prophylactic or therapeutic treatment of lactose time-dependently reduced the severity of AP, as evidenced by reduced pancreatic edema, serum amylase levels, and pancreatic myeloperoxidase activities, as well as by histological examination of pancreatic damage. Overall, lactose promoted a regulatory cytokine milieu in the pancreas and reduced infiltration of inflammatory neutrophils and macrophages. On acinar cells, lactose was able to suppress caerulein-induced inflammatory signaling pathways and to suppress chemoattractant tumor necrosis factor (TNF)-α and monocyte chemotactic protein-1 production. Additionally, lactose acted on pancreas-infiltrated macrophages, increasing interleukin-10 and decreasing tumor necrosis factor alpha production. Notably, lactose treatment reversed AP-associated infiltration of activated neutrophils. Last, the effect of lactose on neutrophil infiltration was mimicked by a galectin-3 antagonist, suggesting a potential endogenous target of lactose. Together, the current study demonstrates an immune regulatory effect of lactose to alleviate AP and suggests its potential as a convenient, value-added therapeutic macronutrient to control AP, and lower the risk of its systemic complications.


Assuntos
Fatores Imunológicos/uso terapêutico , Lactose/uso terapêutico , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Doença Aguda , Animais , Ceruletídeo , Citocinas/imunologia , Feminino , Fatores Imunológicos/farmacologia , Lactose/farmacologia , Macrófagos/imunologia , Camundongos Endogâmicos BALB C , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/imunologia , Pancreatite/patologia , Fenótipo
9.
Front Immunol ; 8: 1345, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29097999

RESUMO

Recent evidence indicates that indigenous Clostridium species induce colonic regulatory T cells (Tregs), and gut lymphocytes are able to migrate to pancreatic islets in an inflammatory environment. Thus, we speculate that supplementation with the well-characterized probiotics Clostridium butyricum CGMCC0313.1 (CB0313.1) may induce pancreatic Tregs and consequently inhibit the diabetes incidence in non-obese diabetic (NOD) mice. CB0313.1 was administered daily to female NOD mice from 3 to 45 weeks of age. The control group received an equal volume of sterile water. Fasting glucose was measured twice a week. Pyrosequencing of the gut microbiota and flow cytometry of mesenteric lymph node (MLN), pancreatic lymph node (PLN), pancreatic and splenic immune cells were performed to investigate the effect of CB0313.1 treatment. Early oral administration of CB0313.1 mitigated insulitis, delayed the onset of diabetes, and improved energy metabolic dysfunction. Protection may involve increased Tregs, rebalanced Th1/Th2/Th17 cells and changes to a less proinflammatory immunological milieu in the gut, PLN, and pancreas. An increase of α4ß7+ (the gut homing receptor) Tregs in the PLN suggests that the mechanism may involve increased migration of gut-primed Tregs to the pancreas. Furthermore, 16S rRNA gene sequencing revealed that CB0313.1 enhanced the Firmicutes/Bacteroidetes ratio, enriched Clostridium-subgroups and butyrate-producing bacteria subgroups. Our results provide the basis for future clinical investigations in preventing type 1 diabetes by oral CB0313.1 administration.

10.
Front Immunol ; 8: 1209, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29018453

RESUMO

Acute pancreatitis (AP) is a common abdominal inflammatory disorder and one of the leading causes of hospital admission for gastrointestinal disorders. No specific pharmacological or nutritional therapy is available but highly needed. Inulin-type fructans (ITFs) are capable of modifying gut immune and barrier homeostasis in a chemistry-dependent manner and hence potentially applicable for managing AP, but their efficacy in AP has not been demonstrated yet. The current study aimed to examine and compare modulatory effects of ITFs with different degrees of fermentability on pancreatic-gut immunity and barrier function during experimentally induced AP in mice. BALB/c mice were fed short (I)- or long (IV)-chain ITFs supplemented diets for up to 3 days before AP induction by caerulein. Attenuating effects on AP development were stronger with ITF IV than with ITF I. We found that long-chain ITF IV attenuated the severity of AP, as evidenced by reduced serum amylase levels, lipase levels, pancreatic myeloperoxidase activity, pancreatic edema, and histological examination demonstrating reduced pancreatic damage. Short-chain ITF I demonstrated only partial protective effects. Both ITF IV and ITF I modulated AP-associated systemic cytokine levels. ITF IV but not ITF I restored AP-associated intestinal barrier dysfunction by upregulating colonic tight junction modulatory proteins, antimicrobial peptides, and improved general colonic histology. Additionally, differential modulatory effects of ITF IV and ITF I were observed on pancreatic and gut immunity: ITF IV supplementation prevented innate immune cell infiltration in the pancreas and colon and tissue cytokine production. Similar effects were only observed in the gut with ITF I and not in the pancreas. Lastly, ITF IV but not ITF I downregulated AP-triggered upregulation of IL-1 receptor-associated kinase 4 (IRAK-4) and phosphor-c-Jun N-terminal kinase (p-JNK), and a net decrease of phosphor-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 (p-NF-κB p65) nuclear translocation and activation in the pancreas. Our findings demonstrate a clear chain length-dependent effect of inulin on AP. The attenuating effects are caused by modulating effects of long-chain inulin on the pancreatic-gut immunity via the pancreatic IRAK-4/p-JNK/p-NF-κBp65 signaling pathway and on prevention of disruption of the gut barrier.

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