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Intestinal dysfunction plays a pivotal role in the development of acute pancreatitis (AP), however, the underlying mechanisms of intestinal dysfunction on severity of hyperlipidemic acute pancreatitis (HLAP) are still unclear. Herein, we explored the role of intestinal function on the severity of HLAP. We found that HLAP patients exhibit higher lipid and inflammatory response than AP patients. Hyperlipidemia significantly elevates serum lipids and worsen pancreatic damage in AP mice. In addition, significant exacerbated intestinal barrier damage and inflammation were observed in experimental HLAP mice, as evidenced by increased serum amylase and lipase levels, and pancreatic edema. Further, RNA-Seq showed that a markedly decrease of glutathione S-transferase pi (GSTpi) in colonic tissue of HLAP mice compared with AP mice, accompanied with increased serum lipopolysaccharides level. However, colonic GSTpi overexpression by adeno-associated virus significantly attenuated intestinal damage and subsequent pancreatic inflammation in HLAP mice. Mechanistically, GSTpi mitigated HLAP-mediated colonic NLRP3 inflammasome activation and barrier dysfunction. These results suggest that intestinal GSTpi deficiency exacerbates the severity of experimental HLAP, providing new insights for the clinical treatment of HLAP.
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Hiperlipidemias , Ratones Endogámicos C57BL , Pancreatitis , Animales , Pancreatitis/patología , Humanos , Ratones , Masculino , Modelos Animales de Enfermedad , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Índice de Severidad de la Enfermedad , Inflamasomas/metabolismo , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Intestinos/patología , Ratones Noqueados , Femenino , Colon/patología , Páncreas/patologíaRESUMEN
The interactions of insect vector-virus-plant have important ecological and evolutionary implications. The constant struggle of plants against viruses and insect vectors has driven the evolution of multiple defense strategies in the host as well as counter-defense strategies in the viruses and insect vectors. Cotton leaf curl Multan virus (CLCuMuV) is a major causal agent of cotton leaf curl disease in Asia and is exclusively transmitted by the whitefly Bemisia tabaci. Here, we report that plants infected with CLCuMuV and its betasatellite, cotton leaf curl Multan betasatellite (CLCuMuB) enhance the performance of B. tabaci vector, and ßC1 encoded by CLCuMuB plays an important role in begomovirus-whitefly-tobacco tripartite interactions. We showed that CLCuMuB ßC1 suppresses the jasmonic acid signaling pathway by interacting with the subtilisin-like protease 1.7 (NtSBT1.7) protein, thereby enhancing whitefly performance on tobacco plants. Further studies revealed that in the wild type plants, NtSBT1.7 could process tobacco preprohydroxyproline-rich systemin B (NtpreproHypSysB). After CLCuMuB infection, CLCuMuB ßC1 could interfere with the processing of NtpreproHypSysB by NtSBT1.7, thereby impairing plant defenses against whitefly. These results contribute to our understanding of the tripartite interactions among virus, plant, and whitefly, thus offering ecological insights into the spread of vector insect populations and the prevalence of viral diseases.
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BACKGROUND: Cardiovascular disease is one of the main causes of global mortality, and there is an urgent need for effective treatment strategies. Gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) promotes the development of cardiovascular diseases, and shizukaol C, a natural sesquiterpene isolated from Chloranthus multistachys with various biological activities, might exhibit beneficial role in preventing TMAO-induced vascular inflammation. PURPOSE: The purpose of this study was to investigate the anti-inflammatory effects and the underlying mechanisms of shizukaol C on TMAO-induced vascular inflammation. METHODS: The effect and underlying mechanism of shizukaol C on TMAO-induced adhesion molecules expression, bone marrow-derived macrophages (BMDM) adhesion to VSMC were evaluated by western blot, cell adhesion assay, co-immunoprecipitation, immunofluorescence assay, and quantitative Real-Time PCR, respectively. To verify the role of shizukaol C in vivo, TMAO-induced vascular inflammation model were established using guidewire-induced injury on mice carotid artery. Changes in the intima area and the expression of GSTpi, VCAM-1, CD68 were examined using haematoxylin-eosin staining, and immunofluorescence assay. RESULTS: Our data demonstrated that shizukaol C significantly suppressed TMAO-induced adhesion molecule expression and the bone marrow-derived macrophages (BMDM) adhesion in vascular smooth muscle cells (VSMC). Mechanically, shizukaol C inhibited TMAO-induced c-Jun N-terminal kinase (JNK)-nuclear factor-kappa B (NF-κB)/p65 activation, and the JNK inhibition was dependent on the shizukaol C-mediated glutathione-S-transferase pi (GSTpi) expression. By further molecular docking and protein-binding analysis, we demonstrated that shizukaol C directly binds to Keap1 to induce Nrf2 nuclear translocation and upregulated GSTpi expression. Consistently, our in vivo experiment showed that shizukaol C elevated the expression level of GSTpi in carotid arteries and alleviates TMAO-induced vascular inflammation. CONCLUSION: Shizukaol C exerts anti-inflammatory effects in TMAO-treated VSMC by targeting Keap1 and activating Nrf2-GSTpi signaling and resultantly inhibits the downstream JNK-NF-κB/p65 activation and VSMC adhesion, and alleviates TMAO-induced vascular inflammation in vivo, suggesting that shizukaol C may be a potential drug for treating TMAO-induced vascular diseases.
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Inflamación , Músculo Liso Vascular , Sesquiterpenos , Animales , Masculino , Ratones , Antiinflamatorios/farmacología , Adhesión Celular/efectos de los fármacos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Proteína 1 Asociada A ECH Tipo Kelch/efectos de los fármacos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Metilaminas/farmacología , Ratones Endogámicos C57BL , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Sesquiterpenos/farmacología , Transducción de Señal/efectos de los fármacos , Gutatión-S-Transferasa pi/efectos de los fármacos , Gutatión-S-Transferasa pi/metabolismoRESUMEN
Disturbances in intestinal immune homeostasis predispose susceptible individuals to type 1 diabetes (T1D). G-protein-coupled receptor 41 (GPR41) is a receptor for short-chain fatty acids (SCFAs) mainly produced by gut microbiota, which plays key roles in maintaining intestinal homeostasis. In this study, we investigated the role of GPR41 in the progression of T1D. In non-obese diabetic (NOD) mice, we found that aberrant reduction of GPR41 expression in the pancreas and colons was associated with the development of T1D. GPR41-deficient (Gpr41-/-) mice displayed significantly exacerbated streptozotocin (STZ)-induced T1D compared to wild-type mice. Furthermore, Gpr41-/- mice showed enhanced gut immune dysregulation and increased migration of gut-primed IFN-γ+ T cells to the pancreas. In bone marrow-derived dendritic cells from Gpr41-/- mice, the expression of suppressor of cytokine signaling 3 (SOCS) was significantly inhibited, while the phosphorylation of STAT3 was significantly increased, thus promoting dendritic cell (DC) maturation. Furthermore, adoptive transfer of bone marrow-derived dendritic cells (BMDC) from Gpr41-/- mice accelerated T1D in irradiated NOD mice. We conclude that GPR41 is essential for maintaining intestinal and pancreatic immune homeostasis and acts as a negative regulator of DC maturation in T1D. GPR41 may be a potential therapeutic target for T1D.
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Células Dendríticas , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Ratones Endogámicos NOD , Ratones Noqueados , Receptores Acoplados a Proteínas G , Estreptozocina , Animales , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/metabolismo , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Ratones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/inmunología , Ratones Endogámicos C57BL , Factor de Transcripción STAT3/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/genética , Interferón gamma/metabolismo , Páncreas/metabolismo , Páncreas/patología , Páncreas/inmunología , Masculino , Femenino , Microbioma GastrointestinalRESUMEN
Chronic pancreatitis (CP) is a progressive and irreversible fibroinflammatory disorder, accompanied by pancreatic exocrine insufficiency and dysregulated gut microbiota. Recently, accumulating evidence has supported a correlation between gut dysbiosis and CP development. However, whether gut microbiota dysbiosis contributes to CP pathogenesis remains unclear. Herein, an experimental CP was induced by repeated high-dose caerulein injections. The broad-spectrum antibiotics (ABX) and ABX targeting Gram-positive (G+) or Gram-negative bacteria (G-) were applied to explore the specific roles of these bacteria. Gut dysbiosis was observed in both mice and in CP patients, which was accompanied by a sharply reduced abundance for short-chain fatty acids (SCFAs)-producers, especially G+ bacteria. Broad-spectrum ABX exacerbated the severity of CP, as evidenced by aggravated pancreatic fibrosis and gut dysbiosis, especially the depletion of SCFAs-producing G+ bacteria. Additionally, depletion of SCFAs-producing G+ bacteria rather than G- bacteria intensified CP progression independent of TLR4, which was attenuated by supplementation with exogenous SCFAs. Finally, SCFAs modulated pancreatic fibrosis through inhibition of macrophage infiltration and M2 phenotype switching. The study supports a critical role for SCFAs-producing G+ bacteria in CP. Therefore, modulation of dietary-derived SCFAs or G+ SCFAs-producing bacteria may be considered a novel interventive approach for the management of CP.
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IMPORTANCE: Many plant viruses are transmitted by insect vectors in a circulative manner. For efficient transmission, the entry of the virus from vector hemolymph into the primary salivary gland (PSG) is a step of paramount importance. Yet, vector components mediating virus entry into PSG remain barely characterized. Here, we demonstrate the role of clathrin-mediated endocytosis and early endosomes in begomovirus entry into whitefly PSG. Our findings unravel the key components involved in begomovirus transport within the whitefly body and transmission by their whitefly vectors and provide novel clues for blocking begomovirus transmission.
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Begomovirus , Endocitosis , Hemípteros , Animales , Begomovirus/fisiología , Clatrina/metabolismo , Endosomas , Hemípteros/metabolismo , Hemípteros/virología , Enfermedades de las Plantas , Glándulas Salivales/metabolismo , Glándulas Salivales/virologíaRESUMEN
Plants face constant threats from insect herbivores, which limit plant distribution and abundance in nature and crop productivity in agricultural ecosystems. In recent decades, the whitefly Bemisia tabaci, a group of phloem-feeding insects, has emerged as pests of global significance. In this article, we summarize current knowledge on plant defenses against whitefly and approaches to engineer plant resistance to whitefly. Physically, plants deploy trichome and acylsugar-based strategies to restrain nutrient extraction by whitefly. Chemically, toxic secondary metabolites such as terpenoids confer resistance against whitefly in plants. Moreover, the jasmonate (JA) signaling pathway seems to be the major regulator of whitefly resistance in many plants. We next review advances in interfering with whitefly-plant interface by engineering of plant resistance using conventional and biotechnology-based breeding. These breeding programs have yielded many plant lines with high resistance against whitefly, which hold promises for whitefly control in the field. Finally, we conclude with an outlook on several issues of particular relevance to the nature and engineering of plant resistance against whitefly.
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The genomic components of multipartite viruses are encapsidated in separate virus particles, and the frequencies of genomic components represent one of the key genetic features. Many begomoviruses of economic significance are bipartite, and the details of the association between their genomic components remain largely unexplored. We first analyzed the temporal dynamics of the quantities of DNA-A and DNA-B and the B/A ratio of the squash leaf curl China virus (SLCCNV) in plants and found that while the quantities of DNA-A and DNA-B varied significantly during infection, the B/A ratio remained constant. We then found that changes in the B/A ratio in agrobacteria inoculum may significantly alter the B/A ratio in plants at 6 days post inoculation, but the differences disappeared shortly thereafter. We next showed that while the quantities of DNA-A and DNA-B among plants infected by agrobacteria, sap transmission and whitefly-mediated transmission differed significantly, the B/A ratios were similar. Further analysis of gene expression revealed that the ratio of the expression of genes encoded by DNA-A and DNA-B varied significantly during infection. Finally, we monitored the temporal dynamics of the quantities of DNA-A and DNA-B and the B/A ratio of another bipartite begomovirus, and a constant B/A ratio was similarly observed. Our findings highlight the maintenance of a constant ratio between the two genomic components of bipartite begomoviruses during infection and transmission, and provide new insights into the biology of begomoviruses.
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Begomovirus , Begomovirus/genética , Vacunación , Virión , GenómicaRESUMEN
BACKGROUND: Acute pancreatitis (AP) is a recurrent inflammatory disease. Studies have shown that intestinal homeostasis is essential for the treatment of AP. Formononetin is a plant-derived isoflavone with antioxidant properties that can effectively treat a variety of inflammatory diseases. This study aims to investigate the role of formononetin in protecting against AP and underlying mechanism. METHODS: Caerulein was used to induce AP. The inflammatory cytokines were detected using Quantitative real-time PCR and commercial kits. Histological examination was applied with hematoxylin and eosin staining. Western blot was conducted to detect expression of intestinal barrier protein and signaling molecular. Molecular docking was performed to assess protein-ligand interaction. RESULTS: In this study, we found formononetin administration significantly reduced pancreatic edema, the activities of serum amylase, lipase, myeloperoxidase, and serum endotoxin. The mRNA levels of inflammatory cytokines such as tumor necrosis factor α, monocyte chemoattractant protein-1, interleukin-6, and interleukin-1 beta (IL-1ß) in pancreas were also significantly decreased by formononetin. The following data showed formononetin pretreatment up-regulated the expressions of tight junction proteins in the colon, and decreased Escherichia coli translocation in the pancreas. In addition, formononetin inhibited the activation of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3 in pancreatic and colonic tissues of AP mice. Moreover, formononetin activated Kelch Like ECH Associated Protein 1 (Keap1) / Nuclear factor erythroid2-related factor 2 (Nrf2) signaling pathway to reduce reactive oxygen species (ROS) levels. Docking results showed that formononetin interact with Keap1 through hydrogen bond. CONCLUSIONS: These findings demonstrate that formononetin administration significantly mitigate AP through reducing oxidative stress and restoring intestinal homeostasis, and provide insights into the new treatment for AP.
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Recombination is common in plant viruses such as geminiviruses, but the ecological and pathogenic consequences have been explored only in a few cases. Here, we found that a new begomovirus, tomato yellow leaf curl Shuangbai virus (TYLCSbV), probably originated from the recombination of Ageratum yellow vein China virus (AYVCNV) and tobacco curl shoot virus (TbCSV). Agrobacterium-mediated inoculation showed that TYLCSbV and AYVCNV have similar levels of infectivity on tomato and tobacco plants. However, the two viruses exhibit contrasting specificities for vector transmission, that is, TYLCSbV was efficiently transmitted by the whitefly Bemisia tabaci Mediterranean (MED) rather than by the whitefly B. tabaci Middle East-Asia Minor 1 (MEAM1), whereas AYVCNV was more efficiently transmitted by MEAM1. We also showed that the transmission efficiencies of TYLCSbV and AYVCNV are positively correlated with the accumulation of the viruses in whitefly whole bodies and organs/tissues. The key coat protein amino acids that determine their accumulation are between positions 147 and 256. Moreover, field surveys suggest that MED has displaced MEAM1 in some regions where TYLCSbV was collected. Viral competition assays indicated that TYLCSbV outcompeted AYVCNV when transmitted by MED, while the outcome was the opposite when transmitted by MEAM1. Our findings suggest that recombination has resulted in a shift of vector specificity that could provide TYLCSbV with a potential selective transmission advantage, and the population shift of whitefly cryptic species could have influenced virus evolution towards an extended trajectory of transmission.
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Begomovirus , Hemípteros , Virus de Plantas , Animales , Begomovirus/genética , Enfermedades de las PlantasRESUMEN
AIMS: Accumulating evidence supports the indispensable role of protein arginine methyltransferase 5 (PRMT5) in the pathological progression of several human cancers. As an important enzyme-regulating protein methylation, how PRMT5 participates in vascular remodelling remains unknown. The aim of this study was to investigate the role and underlying mechanism of PRMT5 in neointimal formation and to evaluate its potential as an effective therapeutic target for the condition. METHODS AND RESULTS: Aberrant PRMT5 overexpression was positively correlated with clinical carotid arterial stenosis. Vascular smooth muscle cell (SMC)-specific PRMT5 knockout inhibited intimal hyperplasia with an enhanced expression of contractile markers in mice. Conversely, PRMT5 overexpression inhibited SMC contractile markers and promoted intimal hyperplasia. Furthermore, we showed that PRMT5 promoted SMC phenotypic switching by stabilizing Kruppel-like factor 4 (KLF4). Mechanistically, PRMT5-mediated KLF4 methylation inhibited ubiquitin-dependent proteolysis of KLF4, leading to a disruption of myocardin (MYOCD)-serum response factor (SRF) interaction and MYOCD-SRF-mediated the transcription of SMC contractile markers. CONCLUSION: Our data demonstrated that PRMT5 critically mediated vascular remodelling by promoting KLF4-mediated SMC phenotypic conversion and consequently the progression of intimal hyperplasia. Therefore, PRMT5 may represent a potential therapeutic target for intimal hyperplasia-associated vascular diseases.
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Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel , Animales , Humanos , Ratones , Arginina , Hiperplasia/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Metilación , Miocitos del Músculo Liso/metabolismo , Neointima/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/farmacología , Remodelación VascularRESUMEN
The begomovirus-betasatellite complex constantly threatens crops in Asia. However, the quantitative relationship between begomoviruses and betasatellites remains largely unknown. The quantities of tobacco curly shoot virus (TbCSV) and its betasatellite (TbCSB) and their ratio varied significantly in initial infection, and thereafter, the ratio tended to become constant. The TbCSB/TbCSV ratio in agrobacteria inoculum significantly affected that in plants in the initial infection but not thereafter. Null-mutation of ßC1 that encodes a multifunctional protein important for pathogenesis in TbCSB significantly reduced the TbCSB/TbCSV ratio in plants. Viral inoculum plants with higher TbCSB/TbCSV ratios promoted whitefly transmission of the virus. The expression of AV1 encoded by TbCSV, ßC1 encoded by TbCSB and the ßC1/AV1 ratio varied significantly in the initial infection and thereafter the ratio tended to become constant. Additionally, the temporal dynamics of the ratio between another begomovirus and its betasatellite was similar to that of TbCSV and was positively regulated by ßC1. These results indicate that the ratio between monopartite begomoviruses and betasatellites tend to become constant as infection progresses, and is modulated by ßC1, but a higher betasatellite/begomovirus ratio in virally inoculated plants promotes virus transmission by whiteflies. Our findings provide novel insights into the association between begomoviruses and betasatellites.
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Begomovirus , Begomovirus/genética , Nicotiana , Genes Virales , Asia , Enfermedades de las Plantas , ADN Viral/genéticaRESUMEN
Pulmonary fibrosis is a progressive and fatal fibrotic lung disease with mysterious pathogenesis and limited effective therapies. G protein-coupled receptors (GPRs) participate in a variety of physiologic functions, and several GPRs have critical fibrosis-promoting or -inhibiting roles in pulmonary fibrosis. Here, we explored the role of GPR41 in the pathobiology of pulmonary fibrosis. We found that GPR41 expression was elevated in lung tissues of mice with bleomycin-induced pulmonary fibrosis and lung fibroblasts treated with transforming growth factor-ß1 (TGF-ß1). Knockout of GPR41 attenuated pulmonary fibrosis in mice, as evidenced by improved lung morphology, decreased lung weight and collagen secretion, and down-regulated α-SMA, collagen type I alpha and fibronectin expression in lungs. Additionally, GPR41 knockout inhibited the differentiation of fibroblasts to myofibroblasts, and decreased myofibroblast migration. By further mechanistic analysis, we demonstrated that GPR41 regulated TGF-ß1-induced fibroblast-to-myofibroblast differentiation and Smad2/3 and ERK1/2 phosphorylation via its Gαi/o subunit but not Gßγ subunit. Together, our data indicate that GPR41 is involved in pulmonary fibroblast activation and fibrosis, and GPR41 represents a potential therapeutic target for pulmonary fibrosis.
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Fibrosis Pulmonar , Animales , Ratones , Bleomicina , Diferenciación Celular , Fibroblastos/metabolismo , Proteínas de Unión al GTP/metabolismo , Pulmón , Sistema de Señalización de MAP Quinasas , Ratones Endogámicos C57BL , Ratones Noqueados , Miofibroblastos/metabolismo , Fosforilación , Fibrosis Pulmonar/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Antimicrobial peptides (AMPs) play essential roles in maintaining intestinal health and have been suggested as possible therapeutic strategies against inflammatory bowel disease (IBD). However, the instability of AMPs in the process of transmission in vivo limits their application in the treatment of IBD. In this study, we constructed the mBD14-producing Lactococcus lactis NZ9000 (L. lactis/mBD14) to achieve enteric delivery of mBD14 and evaluated its protective effect on dextran sodium sulfate (DSS)-induced colitis. Mice treated with L. lactis/mBD14 exhibited milder symptoms of colitis (P < 0.01). Additionally, L. lactis/mBD14 treatment reversed DSS-induced epithelial dysfunction and reduced the production of pro-inflammatory cytokines in colon (P < 0.01). Mechanistically, L. lactis/mBD14 significantly inhibited NOD-like receptor pyrin domain containing three inflammasome-mediated pro-inflammatory response (P < 0.05) and regulated microbiota homeostasis by promoting the abundance of probiotic bacteria Akkermansia muciniphila and Faecalibacterium prausnitzii and decreasing the pathogenic Escherichia coli (P < 0.01). Taken together, this study demonstrates the protective effect of L. lactis/mBD14 in DSS-induced colitis, and suggests that oral administration of L. lactis/mBD14 may represent a potential therapeutic strategy for IBD.
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Colitis , Enfermedades Inflamatorias del Intestino , Lactococcus lactis , beta-Defensinas , Animales , Ratones , beta-Defensinas/genética , Enfermedades Inflamatorias del Intestino/terapia , Lactococcus lactis/genética , Colitis/inducido químicamente , Colitis/genética , Colitis/patología , Sulfato de Dextran/efectos adversos , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
Long-term treatment with adriamycin (ADR) is associated with higher incidences of cumulative cardiotoxicity manifest as heart failure. ADR-induced cardiomyopathy is characterized by extensive fibrosis that is caused by cardiac fibroblast activation. To date, however, no specific treatment is available to alleviate ADR-induced cardiotoxicity. Protein arginine methyltransferase 5 (PRMT5), a major enzyme responsible for methylation of arginine, regulates numerous cellular processes such as cell differentiation. In the present study we investigated the role of PRMT5 in cardiac fibrosis. Mice were administered ADR (3 mg/kg, i.p., every 2 days) for 2 weeks. We showed that aberrant PRMT5 expression was largely co-localized with α-SMA-positive activated cardiac fibroblasts in ADR-injected mice and in ADR-treated cardiac fibroblasts in vitro. PRMT5-overexpression exacerbated, whereas PRMT5 knockdown alleviated ADR-induced cardiac fibrosis in vivo and TGF-ß1-induced cardiac fibroblast activation in vitro. We demonstrated that PRMT5-overexpression enhanced methylated-Smad3 levels in vivo and in vitro. Pretreatment with a specific PRMT5 inhibitor EPZ015666 (5 nM) or overexpression of a catalytically inactive mutant of PRMT5, PRMT5(E444Q), reduced PRMT5-induced methylation of Smad3, thus suppressing PRMT5-mediated cardiac fibroblast activation in vitro. Furthermore, ADR activated cardiac fibroblasts was depending on autocrine TGF-ß1. Taken together, our results demonstrate that PRMT5 promotes ADR-induced cardiac fibrosis via activating cardiac fibroblasts, suggesting that it may be a potential therapeutic target of ADR-caused cardiotoxicity.
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Cardiomiopatías , Factor de Crecimiento Transformador beta1 , Ratones , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Doxorrubicina , Cardiotoxicidad/metabolismo , Fibrosis , Fibroblastos/metabolismo , Cardiomiopatías/patología , Proteína smad3/metabolismoRESUMEN
Hupelactones A (1) and B (2), two new eudesmanolide-type enantiomers of the corresponding compounds, along with four mono- (3-6) and nine dimeric- (7-15) known sesquiterpenoids were isolated from the whole plant of Chloranthus henryi var. hupehensis (syn. C. henryi). The new structures including the absolute configurations were determined by comparison with previously reported enantiomers, extensive spectroscopic methods in combination with electronic circular dichroism (ECD) calculations. All the isolates were evaluated for their inhibitory activities against the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in murine BV-2 microglial cells. Among them, the dimeric lindenane sesquiterpenoids shizukaols F (8) and G (11) exhibited the most potent activities, with IC50 values of 2.65 and 4.60 µM, respectively.
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Magnoliopsida , Sesquiterpenos , Animales , Ratones , Estructura Molecular , Magnoliopsida/química , Microglía , Sesquiterpenos/farmacología , Sesquiterpenos/química , Óxido NítricoRESUMEN
Acute pancreatitis (AP) is an acute inflammatory abdominal disease frequently associated with intestinal barrier dysfunction. Biochanin A (BCA), a dietary isoflavone, has gained increasing interest with its pronounced biological activities. However, its potential beneficial effects on AP have not been demonstrated. Herein, we explored the protective effect of BCA on caerulein-induced AP in BALB/c mice and underlying mechanisms. BCA alleviated AP as evidenced by reduced serum amylase and lipase levels, pancreatic edema, pancreatic myeloperoxidase activity, and improved pancreatic morphology. Amelioration of pancreatic damage by BCA was associated with reduced levels of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and monocyte chemotactic protein-1 in both pancreas and colon. Moreover, BCA attenuated AP-associated barrier damage by upregulating the expression of tight junction proteins zonulin occluding (ZO)-1, ZO-2, occludin, and claudin-1. Concomitantly, the translocation of pathogenic bacteria Escherichia coli (E. coli) to pancreas was reduced by BCA. More importantly, reduction of E. coli dissemination by BCA inhibited the TLR4-MAPK/NF-κB signaling and NLRP3 inflammasome activation, thereby protecting against AP and related intestinal injury. Consistently, TLR4 inhibition by TAK-242 pre-treatment counteracted the anti-inflammatory effects of BCA in acinar cells. Taken together, our study extends beneficial effects of BCA to AP prevention, and dietary BCA supplement may be a potential strategy to safeguard AP.
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Pancreatitis , Ratones , Animales , Pancreatitis/inducido químicamente , Pancreatitis/tratamiento farmacológico , Pancreatitis/metabolismo , Ceruletida/toxicidad , Receptor Toll-Like 4 , Enfermedad Aguda , Escherichia coli , FN-kappa B/metabolismoRESUMEN
Whiteflies of the Bemisia tabaci complex transmit hundreds of plant viruses belonging to the genera Begomovirus and Crinivirus, among others. Tripartite interactions of whitefly-virus-plant frequently occur during virus infection and transmission. Specifically, virus transmission-related behavior of whitefly, such as preference and feeding, may be altered by viruses and thus exert significant impacts on the outcome of virus spread and epidemics. Here, we provide an overview on the current understanding of the manipulation of whitefly behavior by plant viruses. Plant viruses can significantly modulate whitefly preference and feeding behavior, either directly or in a plant-mediated manner. In general, non-viruliferous whiteflies tend to prefer virus-infected plants, and viruliferous whiteflies are more likely to prefer uninfected plants. In most cases, virus infection of plants and/or whitefly seems to exhibit positive or no effects on whitefly feeding on plants. The significance and evolution of these patterns are then discussed. Finally, we suggest several future directions of research, such as the exploration of temporal dynamics and the dissection of underlying mechanisms of virus-induced changes in whitefly behavior.
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SCOPE: Dietary fibers can alter gut microbiota and microbial metabolite profiles. SCFAs are produced by bacterial fermentation of fiber, mediating immune homeostasis through G-protein-coupled receptors (GPCRs). GPR109a, a receptor for niacin and butyrate, expressed by immune cells and non-immune cells, is a key factor regulating immune responses. However, the role and underlying mechanisms of GPR109a in type 1 diabetes (T1D) remain unclear. METHODS AND RESULTS: Experimental T1D was induced by streptozotocin in GPR109a-deficient (Gpr109a-/- ) and wild type mice. The study found that Gpr109a-/- mice were more susceptible to T1D with dysregulated immune responses, along with increased M1 macrophage polarization (from 10.55% to 21.48%). Further, an adoptive transfer experiment demonstrated that GPR109a-deficient macrophages promoted the homing of intestine-derived type 1 cytotoxic T cells to pancreas (from 18.91% to 24.24%), thus disturbing the pancreatic immune homeostasis in non-obese diabetic mice. Mechanistically, GPR109a deficiency promoted M1 macrophage polarization associated with the activation of suppressor of cytokine signaling 3-signal transducer and activator of transcription 1 signaling pathway. CONCLUSION: The findings reveal that macrophage GPR109a deficiency accelerates the development of T1D. Activation of GPR109a on macrophage by dietary components may provide a new strategy for preventing or treating T1D.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Receptores Nicotínicos , Ratones , Animales , Receptores Nicotínicos/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Macrófagos/metabolismoRESUMEN
Viruses pose a great threat to animal and plant health worldwide, with many being dependent on insect vectors for transmission between hosts. While the virus-host arms race has been well established, how viruses and insect vectors adapt to each other remains poorly understood. Begomoviruses comprise the largest genus of plant-infecting DNA viruses and are exclusively transmitted by the whitefly Bemisia tabaci. Here, we show that the vector Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway plays an important role in mediating the adaptation between the begomovirus tomato yellow leaf curl virus (TYLCV) and whiteflies. We found that the JAK/STAT pathway in B. tabaci functions as an antiviral mechanism against TYLCV infection in whiteflies as evidenced by the increase in viral DNA and coat protein (CP) levels after inhibiting JAK/STAT signaling. Two STAT-activated effector genes, BtCD109-2 and BtCD109-3, mediate this anti-TYLCV activity. To counteract this vector immunity, TYLCV has evolved strategies that impair the whitefly JAK/STAT pathway. Infection of TYLCV is associated with a reduction of JAK/STAT pathway activity in whiteflies. Moreover, TYLCV CP binds to STAT and blocks its nuclear translocation, thus, abrogating the STAT-dependent transactivation of target genes. We further show that inhibition of the whitefly JAK/STAT pathway facilitates TYLCV transmission but reduces whitefly survival and fecundity, indicating that this JAK/STAT-dependent TYLCV-whitefly interaction plays an important role in keeping a balance between whitefly fitness and TYLCV transmission. This study reveals a mechanism of plant virus-insect vector coadaptation in relation to vector survival and virus transmission.