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1.
Acta Gastroenterol Belg ; 84(2): 317-320, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34217182

RESUMO

Background and study aims: Hypoxic hepatitis (HH) is an acute liver injury that develops in patients with underlying diseases, such as heart failure, respiratory failure, septic/toxic shock. However, some patients do not have underlying diseases or episodes which are known to result in HH. Here, we analyzed the clinical characteristics of this particular patient group (called 'unknown HH' hereafter) to understand its pathogenesis. Patients and methods: Between October 2010 and January 2016, 157 consecutive patients with acute liver injury were admitted to our hospital. Among these patients, 15 patients were categorized as unknown HH. Medical histories and blood test results of unknown HH were analyzed. Results: Among 15 patients of unknown HH, 11 were habitual drinkers and all experienced one of digestive symptoms which might result in mild hypovolemia such as vomiting, diarrhea, appetite loss, and epigastralgia. All patients of unknown HH presented marked elevation of serum ferritin concentration paralleled with aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH) concentrations. The serum levels of ferritin, ALT, LDH, and prothrombin time-international normalized ratio (PT-INR) were rapidly decreased during hospitalization and all 15 patients of unknown HH recovered without any complication. Conclusions: We found the particular group of HH with marked elevation of serum ferritin probably due to intrahepatic macrophage activation. Anti-inflammatory treatments might be effective for this group of hypoxic hepatitis.


Assuntos
Hepatite , Alanina Transaminase , Aspartato Aminotransferases , Ferritinas , Humanos , Macrófagos
2.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198548

RESUMO

Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1ß inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.


Assuntos
Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Citoproteção , Glicólise , Macrófagos/metabolismo , Neoplasias Pancreáticas/patologia , Adenocarcinoma/imunologia , Animais , Carcinoma Ductal Pancreático/imunologia , Proliferação de Células/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transportador de Glucose Tipo 1/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Hidroxibenzoatos/farmacologia , Inflamação/patologia , Interleucina-1beta/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias Pancreáticas/imunologia , Análise de Sobrevida , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Carga Tumoral/efeitos dos fármacos
3.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199293

RESUMO

Metabolic syndrome (MetS) represents a cluster of disorders that increase the risk of a plethora of conditions, in particular type two diabetes, cardiovascular diseases, and certain types of cancers. MetS is a complex entity characterized by a chronic inflammatory state that implies dysregulations of adipokins and proinflammatory cytokins together with hormonal and growth factors imbalances. Of great interest is the implication of microRNA (miRNA, miR), non-coding RNA, in cancer genesis, progression, and metastasis. The adipose tissue serves as an important source of miRs, which represent a novel class of adipokines, that play a crucial role in carcinogenesis. Altered miRs secretion in the adipose tissue, in the context of MetS, might explain their implication in the oncogenesis. The interplay between miRs expressed in adipose tissue, their dysregulation and cancer pathogenesis are still intriguing, taking into consideration the fact that miRNAs show both carcinogenic and tumor suppressor effects. The aim of our review was to discuss the latest publications concerning the implication of miRs dysregulation in MetS and their significance in tumoral signaling pathways. Furthermore, we emphasized the role of miRNAs as potential target therapies and their implication in cancer progression and metastasis.


Assuntos
Carcinogênese/genética , Síndrome Metabólica/genética , MicroRNAs/metabolismo , Animais , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , MicroRNAs/genética , Transdução de Sinais/genética
4.
Molecules ; 26(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203711

RESUMO

Inflammation and stiffness in the arteries is referred to as vascular calcification. This process is a prevalent yet poorly understood consequence of cardiovascular disease and diabetes mellitus, comorbidities with few treatments clinically available. Because this is an active process similar to bone formation, it is hypothesized that osteoclasts (OCs), bone-resorbing cells in the body, could potentially work to reverse existing calcification by resorbing bone material. The receptor activator of nuclear kappa B-ligand (RANKL) is a molecule responsible for triggering a response in monocytes and macrophages that allows them to differentiate into functional OCs. In this study, OC and RANKL delivery were employed to determine whether calcification could be attenuated. OCs were either delivered via direct injection, collagen/alginate microbeads, or collagen gel application, while RANKL was delivered via injection, through either a porcine subdermal model or aortic injury model. While in vitro results yielded a decrease in calcification using OC therapy, in vivo delivery mechanisms did not provide control or regulation to keep cells localized long enough to induce calcification reduction. However, these results do provide context and direction for the future of OC therapy, revealing necessary steps for this treatment to effectively reduce calcification in vivo. The discrepancy between in vivo and in vitro success for OC therapy points to the need for a more stable and time-controlled delivery mechanism that will allow OCs not only to remain at the site of calcification, but also to be regulated so that they are healthy and functioning normally when introduced to diseased tissue.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Osteoclastos/fisiologia , Calcificação Vascular/terapia , Animais , Reabsorção Óssea/metabolismo , Proteínas de Transporte/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Elastina/metabolismo , Elastina/fisiologia , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana , Monócitos/metabolismo , Miócitos de Músculo Liso/metabolismo , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Ligante RANK/metabolismo , Ligante RANK/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Suínos , Calcificação Vascular/metabolismo
5.
Molecules ; 26(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203815

RESUMO

In continuation of our search for leads from medicinal plants against protozoal pathogens, we detected antileishmanial activity in polar fractions of a dichloromethane extract from Boswellia serrata resin. 11-keto-ß-boswellic acid (KBA) could be isolated from these fractions and was tested in vitro against Leishmania donovani axenic amastigotes along with five further boswellic acid derivatives. 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) showed the strongest activity with an IC50 value of 0.88 µM against axenic amastigotes but was inactive against intracellular amastigotes in murine macrophages.


Assuntos
Leishmania donovani/efeitos dos fármacos , Triterpenos/química , Triterpenos/farmacologia , Animais , Linhagem Celular , Humanos , Concentração Inibidora 50 , Leishmania donovani/metabolismo , Macrófagos , Camundongos , Extratos Vegetais/química , Ratos , Resinas Vegetais/química , Triterpenos/análise , Triterpenos/metabolismo
6.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204949

RESUMO

Idiopathic pulmonary fibrosis (IPF) is one of the most symptomatic progressive fibrotic lung diseases, in which patients have an extremely poor prognosis. Therefore, understanding the precise molecular mechanisms underlying pulmonary fibrosis is necessary for the development of new therapeutic options. Stress-activated protein kinases (SAPKs), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38) are ubiquitously expressed in various types of cells and activated in response to cellular environmental stresses, including inflammatory and apoptotic stimuli. Type II alveolar epithelial cells, fibroblasts, and macrophages are known to participate in the progression of pulmonary fibrosis. SAPKs can control fibrogenesis by regulating the cellular processes and molecular functions in various types of lung cells (including cells of the epithelium, interstitial connective tissue, blood vessels, and hematopoietic and lymphoid tissue), all aspects of which remain to be elucidated. We recently reported that the stepwise elevation of intrinsic p38 signaling in the lungs is correlated with a worsening severity of bleomycin-induced fibrosis, indicating an importance of this pathway in the progression of pulmonary fibrosis. In addition, a transcriptome analysis of RNA-sequencing data from this unique model demonstrated that several lines of mechanisms are involved in the pathogenesis of pulmonary fibrosis, which provides a basis for further studies. Here, we review the accumulating evidence for the spatial and temporal roles of SAPKs in pulmonary fibrosis.


Assuntos
Fibrose Pulmonar Idiopática/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , MAP Quinase Quinase 4/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Vasos Sanguíneos/enzimologia , Vasos Sanguíneos/crescimento & desenvolvimento , Fibroblastos/enzimologia , Humanos , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/patologia , Pulmão/embriologia , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/genética , Macrófagos/enzimologia
7.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34206998

RESUMO

BACKGROUND: N-octadecanoyl-5-hydroxytryptamide (C18-5HT) is an amide that can be obtained by the coupling of serotonin and octadecanoic acid. This study aims to characterize the in vivo and in vitro anti-inflammatory activity of C18-5HT. METHODS: A subcutaneous air pouch model (SAP) was used. The exudates were collected from SAP after carrageenan injection to assess cell migration and inflammatory mediators production. RAW 264.7 cells were used for in vitro assays. RESULTS: C18-5HT significantly inhibited leukocyte migration into the SAP as well as nitric oxide (NO) and cytokines production and protein extravasation. We also observed an reduction in some cytokines and an increase in IL-10 production. Assays conducted with RAW 264.7 cells indicated that C18-5HT inhibited NO and cytokine produced. CONCLUSIONS: Taken together, our data suggest that C18-5HT presents a significant effect in different cell types (leukocytes collected from exudate, mainly polumorphonuclear leukocytes and cell culture macrophages) and is a promising compound for further studies for the development of a new anti-inflammatory drug.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Serotonina/farmacologia , Animais , Carragenina/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-10/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Óxido Nítrico/metabolismo , Células RAW 264.7
8.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207168

RESUMO

Xanthone derivatives have shown promising antitumor properties, and 1-carbaldehyde-3,4-dimethoxyxanthone (1) has recently emerged as a potent tumor cell growth inhibitor. In this study, its effect was evaluated (MTT viability assay) against a new panel of cancer cells, namely cervical cancer (HeLa), androgen-sensitive (LNCaP) and androgen-independent (PC-3) prostate cancer, and nonsolid tumor derived cancer (Jurkat) cell lines. The effect of xanthone 1 on macrophage functions was also evaluated. The effect of xanthone 1-conditioned THP-1 human macrophage supernatants on the metabolic viability of cervical and prostate cancer cell lines was determined along with its interference with cytokine expression characteristic of M1 profile (IL-1 ≤ ß; TNF-α) or M2 profile (IL-10; TGF-ß) (PCR and ELISA). Nitric oxide (NO) production by murine RAW264.7 macrophages was quantified by Griess reaction. Xanthone 1 (20 µM) strongly inhibited the metabolic activity of the cell lines and was significantly more active against prostate cell lines compared to HeLa (p < 0.05). Jurkat was the cell most sensitive to the effect of xanthone 1. Compound 1-conditioned IL-4-stimulated THP-1 macrophage supernatants significantly (p < 0.05) inhibited the metabolic activity of HeLa, LNCaP, and PC-3. Xanthone 1 did not significantly affect the expression of cytokines by THP-1 macrophages. The inhibiting effect of compound 1 observed on the production of NO by RAW 264.7 macrophages was moderate. In conclusion, 1-carbaldehyde-3,4-dimethoxyxanthone (1) decreases the metabolic activity of cancer cells and seems to be able to modulate macrophage functions.


Assuntos
Antineoplásicos/farmacologia , Macrófagos/efeitos dos fármacos , Próstata/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Xantonas/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Células HeLa , Papillomavirus Humano 18/patogenicidade , Humanos , Células Jurkat , Macrófagos/metabolismo , Masculino , Camundongos , Óxido Nítrico/metabolismo , Células PC-3 , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Células RAW 264.7 , Células THP-1 , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia
9.
Science ; 373(6550)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34210853

RESUMO

The mechanisms by which macrophages regulate energy storage remain poorly understood. We identify in a genetic screen a platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF)-family ortholog, Pvf3, that is produced by macrophages and is required for lipid storage in fat-body cells of Drosophila larvae. Genetic and pharmacological experiments indicate that the mouse Pvf3 ortholog PDGFcc, produced by adipose tissue-resident macrophages, controls lipid storage in adipocytes in a leptin receptor- and C-C chemokine receptor type 2-independent manner. PDGFcc production is regulated by diet and acts in a paracrine manner to control lipid storage in adipose tissues of newborn and adult mice. At the organismal level upon PDGFcc blockade, excess lipids are redirected toward thermogenesis in brown fat. These data identify a macrophage-dependent mechanism, conducive to the design of pharmacological interventions, that controls energy storage in metazoans.


Assuntos
Adipócitos/imunologia , Dieta Hiperlipídica , Proteínas de Drosophila/metabolismo , Metabolismo Energético , Linfocinas/metabolismo , Macrófagos/imunologia , Obesidade/imunologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Termogênese , Tecido Adiposo Marrom/imunologia , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster , Feminino , Hemócitos/imunologia , Fígado/imunologia , Linfocinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Crescimento Derivado de Plaquetas/genética , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
J Transl Med ; 19(1): 290, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34225749

RESUMO

BACKGROUND: The worldwide pandemic caused by the SARS-CoV-2 virus is characterized by significant and unpredictable heterogeneity in symptoms that remains poorly understood. METHODS: Transcriptome and single cell transcriptome of COVID19 lung were integrated with deeplearning analysis of MHC class I immunopeptidome against SARS-COV2 proteome. RESULTS: An analysis of the transcriptomes of lung samples from COVID-19 patients revealed that activation of MHC class I antigen presentation in these tissues was correlated with the amount of SARS-CoV-2 RNA present. Similarly, a positive relationship was detected in these samples between the level of SARS-CoV-2 and the expression of a genomic cluster located in the 6p21.32 region (40 kb long, inside the MHC-II cluster) that encodes constituents of the immunoproteasome. An analysis of single-cell transcriptomes of bronchoalveolar cells highlighted the activation of the immunoproteasome in CD68 + M1 macrophages of COVID-19 patients in addition to a PSMB8-based trajectory in these cells that featured an activation of defense response during mild cases of the disease, and an impairment of alveolar clearance mechanisms during severe COVID-19. By examining the binding affinity of the SARS-CoV-2 immunopeptidome with the most common HLA-A, -B, and -C alleles worldwide, we found higher numbers of stronger presenters in type A alleles and in Asian populations, which could shed light on why this disease is now less widespread in this part of the world. CONCLUSIONS: HLA-dependent heterogeneity in macrophage immunoproteasome activation during lung COVID-19 disease could have implications for efforts to predict the response to HLA-dependent SARS-CoV-2 vaccines in the global population.


Assuntos
COVID-19 , Vacinas contra COVID-19 , Humanos , Pulmão , Macrófagos , RNA Viral , SARS-CoV-2
11.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199409

RESUMO

Diabetic nephropathy (DN) is characterized by albuminuria, loss of renal function, renal fibrosis and infiltration of macrophages originating from peripheral monocytes inside kidneys. DN is also associated with intrarenal overactivation of the renin-angiotensin system (RAS), an enzymatic cascade which is expressed and controlled at the cell and/or tissue levels. All members of the RAS are present in the kidneys and most of them are also expressed in monocytes/macrophages. This review focuses on the control of monocyte recruitment and the modulation of macrophage polarization by the RAS in the context of DN. The local RAS favors the adhesion of monocytes on renal endothelial cells and increases the production of monocyte chemotactic protein-1 and of osteopontin in tubular cells, driving monocytes into the kidneys. There, proinflammatory cytokines and the RAS promote the differentiation of macrophages into the M1 proinflammatory phenotype, largely contributing to renal lesions of DN. Finally, resolution of the inflammatory process is associated with a phenotype switch of macrophages into the M2 anti-inflammatory subset, which protects against DN. The pharmacologic interruption of the RAS reduces albuminuria, improves the trajectory of the renal function, decreases macrophage infiltration in the kidneys and promotes the switch of the macrophage phenotype from M1 to M2.


Assuntos
Quimiocina CCL2/genética , Nefropatias Diabéticas/genética , Osteopontina/genética , Sistema Renina-Angiotensina/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Ativação de Macrófagos/genética , Macrófagos/metabolismo , Macrófagos/patologia , Monócitos/metabolismo , Monócitos/patologia
12.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206763

RESUMO

Acute pancreatitis (AP) is an inflammatory disorder, involving acinar cell death and the release of inflammatory cytokines. Currently, there are limited effective therapeutic agents for AP. Betulinic acid (BA) is a pentacyclic triterpenoid extracted from Betula platyphylla that has been shown to have anti-inflammatory effects. In this study, we aimed to investigate the effects of BA on AP and elucidate the potential underlying mechanisms. AP was induced in mice through six intraperitoneal injections of cerulein. After the last cerulein injection, the mice were sacrificed. Our results revealed that pre- and post-treatment with BA significantly reduced the severity of pancreatitis, as evidenced by a decrease in histological damage in the pancreas and lung, serum amylase and lipase activity and pancreatic myeloperoxidase activity. Furthermore, BA pretreatment reduced proinflammatory cytokine production, augmentation of chemokines, and infiltration of macrophages and neutrophils in the pancreas of AP mice. In addition, mice that were pretreated with BA showed a reduction in Iκ-Bα degradation and nuclear factor-kappa B (NF-κB) binding activity in the pancreas. Moreover, BA reduced the production of proinflammatory cytokines and NF-κB activation in pancreatic acinar cells (PACs). These findings suggest that BA may have prophylactic and therapeutic effects on AP via inhibition of the NF-κB signaling pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , NF-kappa B/metabolismo , Pancreatite/tratamento farmacológico , Triterpenos Pentacíclicos/uso terapêutico , Amilases/sangue , Animais , Anti-Inflamatórios/farmacologia , Células Cultivadas , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Lipase/sangue , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Triterpenos Pentacíclicos/farmacologia , Peroxidase/metabolismo , Transdução de Sinais
13.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206766

RESUMO

Interactions between the peripheral nervous system and resident macrophages (MMs) modulate intestinal homeostatic functions. Activation of ß2-adrenergic receptors on MMs has been shown to reduce bacterial challenges. These MMs are also crucial for the development of bowel inflammation in postoperative ileus (POI), an iatrogenic, noninfectious inflammation-based motility disorder. However, the role of the sympathetic nervous system (SNS) in the immune modulation of these MMs during POI or other noninfectious diseases is largely unknown. By employing 6-OHDA-induced denervation, we investigated the changes in the muscularis externa by RNA-seq, quantitative PCR, and flow cytometry. Further, we performed transcriptional phenotyping of sorted CX3CR1+ MMs and ex vivo LPS/M-CSF stimulation on these MMs. By combining denervation with a mouse POI model, we explored distinct changes on CX3CR1+ MMs as well as in the muscularis externa and their functional outcome during POI. Our results identify SNS as an important mediator in noninfectious postoperative inflammation. Upon denervation, MMs anti-inflammatory genes were reduced, and the muscularis externa profile is shaped toward a proinflammatory status. Further, denervation reduced MMs anti-inflammatory genes also in the early phase of POI. Finally, reduced leukocyte infiltration into the muscularis led to a quicker recovery of bowel motility in the late phase of POI.


Assuntos
Pseudo-Obstrução Intestinal/imunologia , Macrófagos/imunologia , Sistema Nervoso Simpático/fisiopatologia , Animais , Receptor 1 de Quimiocina CX3C/metabolismo , Denervação/efeitos adversos , Pseudo-Obstrução Intestinal/etiologia , Leucócitos/imunologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso/citologia
14.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206847

RESUMO

Recently, we clarified the function of mediastinal fat-associated lymphoid clusters (MFALCs) in the progression of several respiratory diseases. However, their role has not yet been identified in the lung asthmatic condition. Hence, we compared the immune cells in lung and MFALCs of C57BL/6N mice on days 3 and 7 following intranasal instillation of either papain (papain group "PG") or phosphate buffer saline (PBS) (vehicle group "VG"). The PG showed significantly prominent MFALCs, numerous goblet cells (GCs), and higher index ratios of different immune cells (macrophages, natural helper cells (NHC), B- and T-lymphocytes) within the MFALCs and lung than in the VG on both days 3 and 7. Interestingly, a tendency of decreased size of MFALCs and a significant reduction in the number of GCs and immune cells were observed within the MFALCs and lung in the PG on day 7 than on day 3. Furthermore, the quantitative parameters of these immune cells in MFALCs were significantly and positively correlated with the size of MFALCs and immune cells in the lung. This suggested that the possible crosstalk between immune cells within MFALCs and the lung could play a critical role in the progression and recovery of the acute inflammatory lung asthma.


Assuntos
Asma/imunologia , Pulmão/imunologia , Tecido Linfoide/imunologia , Macrófagos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Tecido Adiposo/imunologia , Animais , Células Cultivadas , Células Caliciformes/imunologia , Imunidade Inata , Masculino , Mediastino , Camundongos , Camundongos Endogâmicos C57BL
15.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206906

RESUMO

Leishmania survival inside macrophages depends on factors that lead to the immune response evasion during the infection. In this context, the metabolic scenario of the host cell-parasite relationship can be crucial to understanding how this parasite can survive inside host cells due to the host's metabolic pathways reprogramming. In this work, we aimed to analyze metabolic networks of bone marrow-derived macrophages from C57BL/6 mice infected with Leishmania amazonensis wild type (La-WT) or arginase knocked out (La-arg-), using the untargeted Capillary Electrophoresis-Mass Spectrometry (CE-MS) approach to assess metabolomic profile. Macrophages showed specific changes in metabolite abundance upon Leishmania infection, as well as in the absence of parasite-arginase. The absence of L. amazonensis-arginase promoted the regulation of both host and parasite urea cycle, glycine and serine metabolism, ammonia recycling, metabolism of arginine, proline, aspartate, glutamate, spermidine, spermine, methylhistidine, and glutathione metabolism. The increased L-arginine, L-citrulline, L-glutamine, oxidized glutathione, S-adenosylmethionine, N-acetylspermidine, trypanothione disulfide, and trypanothione levels were observed in La-WT-infected C57BL/6-macrophage compared to uninfected. The absence of parasite arginase increased L-arginine, argininic acid, and citrulline levels and reduced ornithine, putrescine, S-adenosylmethionine, glutamic acid, proline, N-glutamyl-alanine, glutamyl-arginine, trypanothione disulfide, and trypanothione when compared to La-WT infected macrophage. Moreover, the absence of parasite arginase leads to an increase in NO production levels and a higher infectivity rate at 4 h of infection. The data presented here show a host-dependent regulation of metabolomic profiles of C57BL/6 macrophages compared to the previously observed BALB/c macrophages infected with L. amazonensis, an important fact due to the dual and contrasting macrophage phenotypes of those mice. In addition, the Leishmania-arginase showed interference with the urea cycle, glycine, and glutathione metabolism during host-pathogen interactions.


Assuntos
Aminoácidos/metabolismo , Interações Hospedeiro-Parasita , Leishmaniose/metabolismo , Macrófagos/metabolismo , Metaboloma , Poliaminas/metabolismo , Animais , Arginase/metabolismo , Células Cultivadas , Leishmania/enzimologia , Leishmania/patogenicidade , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas de Protozoários/metabolismo
16.
BMC Infect Dis ; 21(1): 655, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233649

RESUMO

BACKGROUND: Macrophages, besides resting latently infected CD4+ T cells, constitute the predominant stable, major non-T cell HIV reservoirs. Therefore, it is essential to eliminate both latently infected CD4+ T cells and tissue macrophages to completely eradicate HIV in patients. Until now, most of the research focus is directed towards eliminating latently infected CD4+ T cells. However, few approaches have been directed at killing of HIV-infected macrophages either in vitro or in vivo. HIV infection dysregulates the expression of many host genes essential for the survival of infected cells. We postulated that exploiting this alteration may yield novel targets for the selective killing of infected macrophages. METHODS: We applied a pooled shRNA-based genome-wide approach by employing a lentivirus-based library of shRNAs to screen novel gene targets whose inhibition should selectively induce apoptosis in HIV-infected macrophages. Primary human MDMs were infected with HIV-eGFP and HIV-HSA viruses. Infected MDMs were transfected with siRNAs specific for the promising genes followed by analysis of apoptosis by flow cytometry using labelled Annexin-V in HIV-infected, HIV-exposed but uninfected bystander MDMs and uninfected MDMs. The results were analyzed using student's t-test from at least four independent experiments. RESULTS: We validated 28 top hits in two independent HIV infection models. This culminated in the identification of four target genes, Cox7a2, Znf484, Cstf2t, and Cdk2, whose loss-of-function induced apoptosis preferentially in HIV-infected macrophages. Silencing these single genes killed significantly higher number of HIV-HSA-infected MDMs compared to the HIV-HSA-exposed, uninfected bystander macrophages, indicating the specificity in the killing of HIV-infected macrophages. The mechanism governing Cox7a2-mediated apoptosis of HIV-infected macrophages revealed that targeting respiratory chain complex II and IV genes also selectively induced apoptosis of HIV-infected macrophages possibly through enhanced ROS production. CONCLUSIONS: We have identified above-mentioned novel genes and specifically the respiratory chain complex II and IV genes whose silencing may cause selective elimination of HIV-infected macrophages and eventually the HIV-macrophage reservoirs. The results highlight the potential of the identified genes as targets for eliminating HIV-infected macrophages in physiological environment as part of an HIV cure strategy.


Assuntos
Apoptose/genética , Proteínas de Fluorescência Verde , Infecções por HIV , Macrófagos , RNA Interferente Pequeno , Linfócitos T CD4-Positivos/virologia , Estudo de Associação Genômica Ampla , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Linfócitos T
17.
Ann Palliat Med ; 10(6): 6410-6418, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34237962

RESUMO

BACKGROUND: Sepsis is common in intensive care units and has a high mortality rate; yet, its pathogenesis and treatment remain unclear. Recent studies have shown that long non-coding RNA plasmacytoma variant translocation 1 (lncRNA-PVT1) plays a pro-inflammatory role in immune-related inflammatory diseases. Therefore, we investigated whether lncRNA-PVT1 plays an important pro-inflammatory effect in the inflammatory response of sepsis. METHODS: Quantitative real-time PCR (RT-qPCR) was employed for the detection of lncRNA-PVT1, interleukin 1ß (IL-1ß), and tumor necrosis factor α (TNF-α) mRNA, and the correlations between their expressions were analyzed. After lncRNA-PVT1 knockdown by lncRNA Smart Silencer, abnormal expressions of lncRNA-PVT1, and IL-1ß and TNF-α mRNA were detected. The expressions of total and phosphorylated protein of p38 were detected by western blotting. The effect of silencing lncRNA-PVT1 on p38 mitogen-activated protein kinase (MAPK) signaling pathway during lipopolysaccharide (LPS)-induced inflammation was subsequently analyzed. The MAPK selective inhibitor, SB202190, was used to block this signaling pathway, and the expressions of lncRNA-PVT1 and TNF-α were detected by RT-qPCR. Furthermore, the effect of partial blockade of the p38 MAPK signaling pathway by SB202190 on the levels of lncRNA-PVT1 was explored. RESULTS: Following treatment of THP-1-derived macrophages with different concentrations of LPS, the levels of lncRNA-PVT1 and IL-1ß, TNF-α mRNA were increased in a dose-dependent manner. Silencing of lncRNA-PVT1 reduced the expressions of IL-1ß and TNF-α mRNA via inhibition of the p38 MAPK signaling pathway. Specifically, inhibiting the p38 MAPK pathway significantly decreased the LPS-induced lncRNA-PVT1 elevation. CONCLUSIONS: Our observations suggest that lncRNA-PVT1 can be silenced to ameliorate LPS-induced inflammation in macrophages via inhibition of the p38 MAPK pathway. Further, the p38 MAPK pathway can regulate the expression of lncRNA-PVT1 via a positive feedback loop.


Assuntos
Lipopolissacarídeos , RNA Longo não Codificante , Humanos , Inflamação/genética , Macrófagos/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
J Transl Med ; 19(1): 290, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: covidwho-1298054

RESUMO

BACKGROUND: The worldwide pandemic caused by the SARS-CoV-2 virus is characterized by significant and unpredictable heterogeneity in symptoms that remains poorly understood. METHODS: Transcriptome and single cell transcriptome of COVID19 lung were integrated with deeplearning analysis of MHC class I immunopeptidome against SARS-COV2 proteome. RESULTS: An analysis of the transcriptomes of lung samples from COVID-19 patients revealed that activation of MHC class I antigen presentation in these tissues was correlated with the amount of SARS-CoV-2 RNA present. Similarly, a positive relationship was detected in these samples between the level of SARS-CoV-2 and the expression of a genomic cluster located in the 6p21.32 region (40 kb long, inside the MHC-II cluster) that encodes constituents of the immunoproteasome. An analysis of single-cell transcriptomes of bronchoalveolar cells highlighted the activation of the immunoproteasome in CD68 + M1 macrophages of COVID-19 patients in addition to a PSMB8-based trajectory in these cells that featured an activation of defense response during mild cases of the disease, and an impairment of alveolar clearance mechanisms during severe COVID-19. By examining the binding affinity of the SARS-CoV-2 immunopeptidome with the most common HLA-A, -B, and -C alleles worldwide, we found higher numbers of stronger presenters in type A alleles and in Asian populations, which could shed light on why this disease is now less widespread in this part of the world. CONCLUSIONS: HLA-dependent heterogeneity in macrophage immunoproteasome activation during lung COVID-19 disease could have implications for efforts to predict the response to HLA-dependent SARS-CoV-2 vaccines in the global population.


Assuntos
COVID-19 , Vacinas contra COVID-19 , Humanos , Pulmão , Macrófagos , RNA Viral , SARS-CoV-2
19.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204506

RESUMO

Ergosta-7, 9 (11), 22-trien-3ß-ol (EK100) was isolated from Cordyceps militaris, which has been used as a traditional anti-inflammatory medicine. EK100 has been reported to attenuate inflammatory diseases, but its anti-inflammatory mechanism is still unclear. We were the first to investigate the effect of EK100 on the Toll-like receptor 4 (TLR4)/nuclear factor of the κ light chain enhancer of B cells (NF-κB) signaling in the lipopolysaccharide (LPS)-stimulated RAW264.7 cells and the green fluorescent protein (GFP)-labeled NF-κB reporter gene of Drosophila. EK100 suppressed the release of the cytokine and attenuated the mRNA and protein expression of pro-inflammatory mediators. EK100 inhibited the inhibitor kappa B (IκB)/NF-κB signaling pathway. EK100 also inhibited phosphatidylinositol-3-kinase (PI3K)/Protein kinase B (Akt) signal transduction. Moreover, EK100 interfered with LPS docking to the LPS-binding protein (LBP), transferred to the cluster of differentiation 14 (CD14), and bonded to TLR4/myeloid differentiation-2 (MD-2) co-receptors. Compared with the TLR4 antagonist, resatorvid (CLI-095), and dexamethasone (Dexa), EK100 suppressed the TLR4/AKT signaling pathway. In addition, we also confirmed that EK100 attenuated the GFP-labeled NF-κB reporter gene expression in Drosophila. In summary, EK100 might alter LPS docking to LBP, CD14, and TLR4/MD-2 co-receptors, and then it suppresses the TLR4/NF-κB inflammatory pathway in LPS-stimulated RAW264.7 cells and Drosophila.


Assuntos
Anti-Inflamatórios/farmacologia , Drosophila/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Antígeno 96 de Linfócito/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Anti-Inflamatórios/química , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Receptores de Lipopolissacarídeos/química , Lipopolissacarídeos/química , Lipopolissacarídeos/imunologia , Antígeno 96 de Linfócito/química , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Modelos Moleculares , Conformação Molecular , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Ligação Proteica , Relação Estrutura-Atividade , Receptor 4 Toll-Like/química
20.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208396

RESUMO

Non-small cell lung cancer (NSCLC) continues to be the leading cause of cancer death worldwide. Recently, targeting molecules whose functions are associated with tumorigenesis has become a game changing adjunct to standard anti-cancer therapy. As evidenced by the results of preclinical and clinical investigations, whole-body irradiations (WBI) with X-rays at less than 0.1-0.2 Gy per fraction can induce remissions of various neoplasms without inciting adverse side effects of conventional chemo- and radiotherapy. In the present study, a murine model of human NSCLC was employed to evaluate for the first time the anti-neoplastic efficacy of WBI combined with inactivation of CTLA-4, PD-1, and/or HSP90. The results indicate that WBI alone and in conjunction with the inhibition of the function of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed death-1 (PD-1) receptor immune checkpoints (ICs) and/or heat shock protein 90 (HSP90) markedly reduced tumorigenesis in mice implanted by three different routes with the syngeneic Lewis lung cancer cells and suppressed clonogenic potential of Lewis lung carcinoma (LLC1) cells in vitro. These results were associated with the relevant changes in the profile of pro- and anti-neoplastic immune cells recruited to the growing tumors and the circulating anti- and pro-inflammatory cytokines. In contrast, inhibition of the tested molecular targets used either separately or in combination with each other did not exert notable anti-neoplastic effects. Moreover, no significant synergistic effects were detected when the inhibitors were applied concurrently with WBI. The obtained results supplemented with further mechanistic explanations provided by future investigations will help design the effective strategies of treatment of lung and other cancers based on inactivation of the immune checkpoint and/or heat shock molecules combined with low-dose radiotherapy.


Assuntos
Proteínas de Choque Térmico/metabolismo , Proteínas de Checkpoint Imunológico/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/radioterapia , Transplante de Neoplasias , Dosagem Radioterapêutica , Irradiação Corporal Total , Animais , Células Clonais , Pulmão/patologia , Contagem de Linfócitos , Linfócitos do Interstício Tumoral , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Ensaio Tumoral de Célula-Tronco
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