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1.
Essays Biochem ; 64(3): 443-462, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32885825

RESUMO

Today, persistent and uncontrolled inflammation is appreciated to play a pivotal role in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other diseases of public health concern (e.g. Coronavirus Disease 2019 (COVID-19) and periodontal disease). The ideal response to initial challenge in humans is a self-limited inflammatory response leading to complete resolution. The resolution phase is now widely recognized as a biosynthetically active process, governed by a superfamily of endogenous chemical mediators that stimulate resolution of inflammatory responses, namely specialized proresolving mediators (SPMs). Because resolution is the natural ideal response, the SPMs have gained attention. SPMs are mediators that include ω-6 arachidonic acid-derived lipoxins, ω-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-derived resolvins, protectins and maresins, cysteinyl-SPMs, as well as n-3 docosapentaenoic acid (DPA)-derived SPMs. These novel immunoresolvents, their biosynthetic pathways and receptors have proven to promote resolution of inflammation, clearance of microbes, reduce pain and promote tissue regeneration via specific cellular and molecular mechanisms. As of 17 August, 2020, PubMed.gov reported >1170 publications for resolvins, confirming their potent protective actions from many laboratories worldwide. Since this field is rapidly expanding, we provide a short update of advances within 2-3 years from human and preclinical animal studies, together with the structural-functional elucidation of SPMs and identification of novel SPM receptors. These new discoveries indicate that SPMs, their pathways and receptors could provide a basis for new approaches for treating inflammation-associated diseases and for stimulating tissue regeneration via resolution pharmacology and precision nutrition.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Inflamação/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Animais , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Ácidos Docosa-Hexaenoicos/imunologia , Ácidos Docosa-Hexaenoicos/metabolismo , Humanos , Inflamação/metabolismo , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo
2.
Am J Physiol Heart Circ Physiol ; 319(4): H793-H796, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32886002

RESUMO

The 60-kDa heat shock protein (HSP60) is a chaperone essential for mitochondrial proteostasis ensuring thus sufficient aerobic energy production. In pathological conditions, HSP60 can be translocated from the mitochondria and excreted from the cell. In turn, the extracellular HSP60 has a strong ability to trigger and enhance inflammatory response with marked proinflammatory cytokine induction, which is mainly mediated by Toll-like receptor binding. Previous studies have found increased circulating levels of HSP60 in hypertensive patients, as well as enhanced HSP60 expression and membrane translocation in the hypertrophic myocardium. These observations are of particular interest, since they could provide a possible pathophysiological explanation of the severe course and worse outcome of severe acute respiratory syndrome coronavirus 2 infection in hypertensive patients, repeatedly reported during the recent coronavirus disease 2019 (COVID-19) pandemic and related to hyperinflammatory response and cytokine storm development during the third phase of the disease. In this regard, pharmacological inhibition of HSP60 could attract attention to potentially ameliorate inappropriate inflammatory reaction in severe COVID-19 patients. Among HSP60 antagonizing drugs, mizoribine is the most intriguing, since it is clinically approved and exerts antiviral activity. However, this topic requires to be further scrutinized.


Assuntos
Betacoronavirus/patogenicidade , Chaperonina 60/metabolismo , Infecções por Coronavirus/metabolismo , Hipertensão/metabolismo , Mediadores da Inflamação/metabolismo , Pneumonia Viral/metabolismo , Animais , Chaperonina 60/antagonistas & inibidores , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Imunossupressores/uso terapêutico , Mediadores da Inflamação/antagonistas & inibidores , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Prognóstico , Ribonucleosídeos/uso terapêutico , Transdução de Sinais
3.
Medicine (Baltimore) ; 99(36): e22070, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899074

RESUMO

BACKGROUND: A number of recent studies have investigated the optimal dosage and timing of dexamethasone in total hip arthroplasty (THA) but have inconsistent findings. Therefore, we designed the randomized controlled research to look for the optimal intravenous dexamethasone dose for the treatment of early postoperative pain after the THA. METHODS: The Declaration of Helsinki principles was followed and the Consolidated Standards of Reporting Trials guidelines for randomized controlled trials was adhered in this study. The First Medical Center in People's Liberation Army General Hospital approved the study (2020-089). After written informed consent was obtained, patients aged between 18 and 80 years with Physical Status I to III of American Society of Anesthesiologists, scheduled for primary unilateral THA, were included in this present work. Randomization is the use of a computer-formed list via a secretary, at a ratio of 1:1:1. The major end points were pain scores at 24 hours, 48 hours, and 72 hours after surgery, with visual analog scale (VAS) utilized at rest, and at 45 degrees passive hip flexion. The secondary outcomes involved the total consumption of morphine, opioid-related side effects, hip range of motion, inflammation markers, and the length of hospital stay. RESULTS: We assumed that the patients who received 3 doses of dexamethasone intravenously possessed the best postoperative results compared to those who received 1 or 2 doses of the dexamethasone. TRIAL REGISTRATION: This study protocol was registered in Research Registry (researchregistry5864).


Assuntos
Anti-Inflamatórios/administração & dosagem , Artroplastia de Quadril/efeitos adversos , Dexametasona/administração & dosagem , Dor Pós-Operatória/tratamento farmacológico , Administração Intravenosa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/uso terapêutico , Estudos de Casos e Controles , Dexametasona/uso terapêutico , Humanos , Mediadores da Inflamação/metabolismo , Tempo de Internação , Pessoa de Meia-Idade , Morfina/efeitos adversos , Entorpecentes/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Amplitude de Movimento Articular , Escala Visual Analógica , Adulto Jovem
4.
Medicine (Baltimore) ; 99(39): e22172, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991410

RESUMO

Osteoporosis is a severe chronic skeletal disorder that increases the risks of disability and mortality; however, the mechanism of this disease and the protein markers for prognosis of osteoporosis have not been well characterized. This study aims to characterize the imbalanced serum proteostasis, the disturbed pathways, and potential serum markers in osteoporosis by using a set of bioinformatic analyses. In the present study, the large-scale proteomics datasets (PXD006464) were adopted from the Proteome Xchange database and processed with MaxQuant. The differentially expressed serum proteins were identified. The biological process and molecular function were analyzed. The protein-protein interactions and subnetwork modules were constructed. The signaling pathways were enriched. We identified 209 upregulated and 230 downregulated serum proteins. The bioinformatic analyses revealed a highly overlapped functional protein classification and the gene ontology terms between the upregulated and downregulated protein groups. Protein-protein interactions and pathway analyses showed a high enrichment in protein synthesis, inflammation, and immune response in the upregulated proteins, and cell adhesion and cytoskeleton regulation in the downregulated proteins. Our findings greatly expand the current view of the roles of serum proteins in osteoporosis and shed light on the understanding of its underlying mechanisms and the discovery of serum proteins as potential markers for the prognosis of osteoporosis.


Assuntos
Mineração de Dados/métodos , Osteoporose/sangue , Proteoma/fisiologia , Biomarcadores , Adesão Celular/fisiologia , Biologia Computacional , Citoesqueleto/metabolismo , Regulação para Baixo , Humanos , Mediadores da Inflamação/metabolismo , Mapas de Interação de Proteínas/fisiologia , Proteômica , Regulação para Cima
5.
Yonsei Med J ; 61(8): 679-688, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32734731

RESUMO

PURPOSE: Hyperoxia-induced bronchopulmonary dysplasia (BPD) is a lung disease in preterm infants. We aimed to explore the role of cell division cycle 2 (CDC2) on histopathologic changes of lung tissues, as well as the viability, apoptosis, and inflammation of lung cells in rats with hyperoxia-induced BPD. MATERIALS AND METHODS: Hyperoxia-induced BPD in neonatal rats and hyperoxia-induced A549 cells were constructed. The mRNA expression of CDC2 was detected by qRT-PCR. The fibrosis score of lung tissues was evaluated by hematoxylin-eosin staining. The viability and apoptosis of A549 cells were detected by cell counting kit-8 assay and flow cytometry. The protein expressions of bcl-2, bax, and caspase-3 were measured by western blot. The levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1ß in A549 cells were detected by enzyme-linked immunosorbent assay. The pcDNA3.1-CDC2 was injected into rats to determine the role of CDC2 in hyperoxia-induced BPD in vivo. RESULTS: The expression of CDC2 was decreased in lung tissues of neonatal rats with hyperoxia-induced BPD and hyperoxia-induced A549 cells. The fibrosis score was increased in the lung tissues of neonatal rats with hyperoxia-induced BPD. Overexpression of CDC2 increased the viability and protein expression of bcl-2; and inhibited the apoptosis, inflammation, and protein expression of bax and caspase-3 in hyperoxia-induced A549 cells. Up-regulation of CDC2 alleviated the histopathologic changes in lung tissues of neonatal rats with hyperoxia-induced BPD. CONCLUSION: Overexpression of CDC2 promoted the viability and inhibited the apoptosis and inflammation of hyperoxia-induced cells, and alleviated the histopathologic changes of lung tissues in neonatal rats with hyperoxia-induced BPD.


Assuntos
Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/prevenção & controle , Proteína Quinase CDC2/metabolismo , Hiperóxia/complicações , Células A549 , Animais , Animais Recém-Nascidos , Apoptose , Ciclo Celular , Sobrevivência Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Hiperóxia/patologia , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Ratos Wistar
6.
Nat Commun ; 11(1): 4167, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820177

RESUMO

Muscle regeneration depends on a robust albeit transient inflammatory response. Persistent inflammation is a feature of age-related regenerative deficits, yet the underlying mechanisms are poorly understood. Here, we find inflammatory-related CC-chemokine-receptor 2 (Ccr2) expression in non-hematopoietic myogenic progenitors (MPs) during regeneration. After injury, the expression of Ccr2 in MPs corresponds to the levels of its ligands, the chemokines Ccl2, 7, and 8. We find stimulation of Ccr2-activity inhibits MP fusion and contribution to myofibers. This occurs in association with increases in MAPKp38δ/γ signaling, MyoD phosphorylation, and repression of the terminal myogenic commitment factor Myogenin. High levels of Ccr2-chemokines are a feature of regenerating aged muscle. Correspondingly, deletion of Ccr2 in MPs is necessary for proper fusion into regenerating aged muscle. Finally, opportune Ccr2 inhibition after injury enhances aged regeneration and functional recovery. These results demonstrate that inflammatory-induced activation of Ccr2 signaling in myogenic cells contributes to aged muscle regenerative decline.


Assuntos
Mediadores da Inflamação/metabolismo , Músculo Esquelético/fisiopatologia , Receptores CCR2/metabolismo , Regeneração/fisiologia , Transdução de Sinais/fisiologia , Fatores Etários , Animais , Transplante de Células/métodos , Quimiocina CCL2/metabolismo , Quimiocina CCL7/metabolismo , Quimiocina CCL8/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Desenvolvimento Muscular/genética , Músculo Esquelético/lesões , Músculo Esquelético/metabolismo , Miogenina/genética , Miogenina/metabolismo , Receptores CCR2/genética , Regeneração/genética , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/metabolismo , Células Satélites de Músculo Esquelético/transplante , Transdução de Sinais/genética , Ferimentos e Lesões/genética , Ferimentos e Lesões/fisiopatologia , Ferimentos e Lesões/terapia
7.
PLoS One ; 15(8): e0237086, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764782

RESUMO

Paramylon is a novel ß-glucan that is stored by Euglena gracilis Z, which is a unicellular photosynthesizing green alga with characteristics of both animals and plants. Recent studies have indicated that paramylon functions as an immunomodulator or a dietary fiber. Currently, chronic kidney disease (CKD) is a global health problem, and there is no effective preventive treatment for CKD progression. However, paramylon may suppress the progression of CKD via the elimination of uremic toxins or modulation of gut microbiota, leading to the alleviation of inflammation. The aim of this study was to evaluate the effect of paramylon in CKD rat model. Eight-week-old male Wistar rats with a 5/6 nephrectomy were given either a normal diet or a diet containing 5% paramylon for 8 weeks. Proteinuria was measured intermittently. Serum and kidney tissues were harvested after sacrifice. We performed a renal molecular and histopathological investigation, serum metabolome analysis, and gut microbiome analysis. The results showed that paramylon attenuated renal function, glomerulosclerosis, tubulointerstitial injury, and podocyte injury in the CKD rat model. Renal fibrosis, tubulointerstitial inflammatory cell infiltration, and proinflammatory cytokine gene expression levels tended to be suppressed with paramylon treatment. Further, paramylon inhibited the accumulation of uremic toxins, including tricarboxylic acid (TCA) cycle-related metabolites and modulated a part of CKD-related gut microbiota in the CKD rat model. In conclusion, we suggest that paramylon mainly inhibited the absorption of non-microbiota-derived uremic solutes, leading to protect renal injury via anti-inflammatory and anti-fibrotic effects. Paramylon may be a novel compound that can act against CKD progression.


Assuntos
Glucanos/farmacologia , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Administração Oral , Animais , Ciclo do Ácido Cítrico/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Euglena gracilis/química , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Glucanos/isolamento & purificação , Glucanos/uso terapêutico , Humanos , Mediadores da Inflamação/metabolismo , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Rim/imunologia , Rim/patologia , Masculino , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/uso terapêutico , Proteinúria/sangue , Proteinúria/patologia , Ratos , Ratos Wistar , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/urina , Toxinas Biológicas/sangue , Toxinas Biológicas/metabolismo
8.
PLoS One ; 15(8): e0237015, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760098

RESUMO

Graves' orbitopathy (GO) is characterised in early stages by orbital fibroblast inflammation, which can be aggravated by oxidative stress and often leads to fibrosis. Protein tyrosine protein 1B (PTP1B) is a regulator of inflammation and a therapeutic target in diabetes. We investigated the role of PTP1B in the GO mechanism using orbital fibroblasts from GO and healthy non-GO subjects. After 24 hours of transfection with PTPN1 siRNA, the fibroblasts were exposed to interleukin (IL)-1ß, cigarette smoke extract (CSE), H2O2, and transforming growth factor (TGF)-ß stimulations. Inflammatory cytokines and fibrosis-related proteins were analysed using western blotting and/or enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) release was detected using an oxidant-sensitive fluorescent probe. IL-1ß, tumor necrosis factor (TNF)-α, bovine thyroid stimulating hormone (bTSH), high-affinity human stimulatory monoclonal antibody of TSH receptor (M22), and insulin-like growth factor-1 (IGF-1) significantly increased PTP1B protein production in GO and non-GO fibroblasts. PTPN1 silencing significantly blocked IL-1ß-induced inflammatory cytokine production, CSE- and H2O2-induced ROS synthesis, and TGF-ß-induced expression of collagen Iα, α-smooth muscle actin (SMA), and fibronectin in GO fibroblasts. Silencing PTPN1 also decreased phosphorylation levels of Akt, p38, and c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER)-stress response proteins in GO cells. PTP1B may be a potential therapeutic target of anti-inflammatory, anti-oxidant and anti-fibrotic treatment of GO.


Assuntos
Oftalmopatia de Graves/enzimologia , Oftalmopatia de Graves/terapia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Adulto , Animais , Apoptose , Bovinos , Sobrevivência Celular , Citocinas/biossíntese , Estresse do Retículo Endoplasmático , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Inativação Gênica , Oftalmopatia de Graves/patologia , Humanos , Técnicas In Vitro , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
9.
Cardiovasc Pathol ; 49: 107261, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32771878

RESUMO

Cardiac inflammation in Coxsackievirus B3 (CVB3)-induced myocarditis is a consequence of viral-related cardiac injury and immune response. Caspase-associated recruitment domain 9 (CARD9) is a critical adaptor protein involved in transduction of signals from various innate pattern recognition receptors. In this study, the role of CARD9 in acute viral myocarditis was evaluated. CARD9-/- and C57BL/6 mice were infected with CVB3. On day 7 postinfection, myocardial tissue and blood samples were collected and examined. After CARD9 knockout, mRNA and protein levels of transforming growth factor-ß(TGF-ß), interleukin-17A(IL-17A), and CARD domain of B-cell CLL/lymphoma 10(BCL-10) in the myocardium were markedly lower in CARD9-/- mice than in C57BL/6 mice with CVB3-induced viral myocarditis. This trend was similar for the pathological scores for inflammation and serum levels of cytokines interleukin-6(IL-6), interleukin-10(IL-10), interferon -γ(IFN-γ), TGF-ß, and IL-17A. These results suggest that the CARD9-mediated secretion of pro-inflammatory cytokines plays an important role in the immune response to acute viral myocarditis.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Infecções por Coxsackievirus/metabolismo , Enterovirus Humano B/imunologia , Miocardite/metabolismo , Miocárdio/metabolismo , Linfócitos T/metabolismo , Animais , Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/genética , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/virologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Mediadores da Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/genética , Miocardite/imunologia , Miocardite/virologia , Miocárdio/imunologia , Miocárdio/patologia , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/virologia
10.
Life Sci ; 258: 118206, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32758623

RESUMO

Scientists are looking for new therapies to cope with the rise in cancer worldwide. Since cancer cells overexpress peptide receptors and owing to small size, easy uptake by tumor cells, easy preparation, and with no toxicity, the use of radiolabeled peptides with high specificity and affinity for accurate imaging and therapy has attracted much attention. To develop an ideal imaging or treatment radiolabeled peptide, there are some aspects in the components of radiolabeled peptide including radionuclide, peptide, chelator, and spacer that should be considered. Some peptides, including somatostatin, RGD, neurotensin, bombesin, exendin, vasoactive intestinal peptide, and gastrin are currently under (pre)clinical investigations. Today, nanoparticles are suitable tools for targeting peptide for molecular imaging and therapy of tumors with low toxicity. This paper presents some essential aspects in developing a valuable radiolabeled peptide and some radiolabeled peptides with regard to their applications in tumor imaging and therapy in pre-clinical and clinical phases.


Assuntos
Diagnóstico por Imagem/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Fragmentos de Peptídeos/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Animais , Diagnóstico por Imagem/tendências , Humanos , Mediadores da Inflamação/metabolismo
11.
Vascul Pharmacol ; 133-134: 106779, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32814163

RESUMO

Atherosclerosis is a very common macrovascular complication in type 2 diabetes mellitus, and cardiovascular disease is the primary cause of death in diabetes patients. Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are a newly identified class of drugs targeting the renal proximal tubules to increase glucose excretion. Large-scale clinical trials have confirmed the cardiovascular protective effects of SGLT inhibitors in patients with diabetes diagnosed with or at a higher risk of atherosclerotic cardiovascular disease. In addition to its direct effect on glycemic control, the function of SGLT-2i in the alleviation of volume load, renal protection, and reduction of inflammation plays an essential role in its therapeutic effect on atherosclerosis. SGLT-2i are known to decrease the levels of inflammatory factors in circulation and in arteries in situ, inhibit foam cell formation and macrophage infiltration, and sustain plaque stability, ultimately blocking the development and progression of atherosclerosis.


Assuntos
Anti-Infecciosos/uso terapêutico , Artérias/efeitos dos fármacos , Aterosclerose/tratamento farmacológico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inflamação/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Anti-Infecciosos/efeitos adversos , Artérias/metabolismo , Artérias/patologia , Aterosclerose/diagnóstico , Aterosclerose/metabolismo , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Humanos , Inflamação/diagnóstico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Placa Aterosclerótica , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
12.
Hum Cell ; 33(4): 907-918, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32780299

RESUMO

Acute respiratory distress syndrome (ARDS) is the main cause for the COVID-19 infection-related morbidity and mortality. Recent clinical evidences suggest increased level of cytokines and chemokines targeting lung tissue as a prominent etiological factor. The immunomodulatory effect of mesenchymal stem cells (MSCs) as the alternative therapy for the treatment of inflammatory and autoimmune diseases is well known. Several studies have also revealed that similar therapeutic impacts of parent MSCs are also exhibited by MSCs-derived extracellular vesicles (EVs) including exosomes. In this review, we explored the therapeutic potential of both MSCs and exosomes in mitigating the COVID-19 induced cytokine storm as well as promoting the regeneration of alveolar tissue, attributed to the intrinsic cytokines and growth factor present in the secretome. The preliminary studies have demonstrated the safety and efficacy of MSCs and exosomes in mitigating symptoms associated with COVID-19. Thus, they can be used on compassionate basis, owing to their ability to endogenously repair and decrease the inflammatory reactions involved in the morbidity and mortality of COVID-19. However, more preclinical and clinical studies are warranted to understand their mechanism of action and further establish their safety and efficacy.


Assuntos
Infecções por Coronavirus/terapia , Exossomos , Transplante de Células-Tronco Mesenquimais , Pneumonia Viral/terapia , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Células-Tronco Mesenquimais/imunologia , Pandemias , Pneumonia Viral/etiologia , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Síndrome do Desconforto Respiratório do Adulto/terapia
13.
Arterioscler Thromb Vasc Biol ; 40(9): 2070-2083, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32762445

RESUMO

OBJECTIVE: Emerging evidence suggests that C3aR (C3a anaphylatoxin receptor) signaling has protective roles in various inflammatory-related diseases. However, its role in atherosclerosis has been unknown. The purpose of the study was to investigate the possible protective role of C3aR in aortic atherosclerosis and explore molecular and cellular mechanisms involved in the protection. Approach and Results: C3ar-/-/Apoe-/- mice were generated by cross-breeding of atherosclerosis-prone Apoe-/- mice and C3ar-/- mice. C3ar-/-/Apoe-/- mice and Apoe-/- mice (as a control) underwent high-fat diet for 16 weeks were assessed for (1) atherosclerotic plaque burden, (2) aortic tissue inflammation, (3) recruitment of CD11b+ leukocytes into atherosclerotic lesions, and (4) systemic inflammatory responses. Compared with Apoe-/- mice, C3ar-/-/Apoe-/- mice developed more severe atherosclerosis. In addition, C3ar-/-/Apoe-/- mice have increased local production of proinflammatory mediators (eg, CCL2 [chemokine (C-C motif) ligand 2], TNF [tumor necrosis factor]-α) and infiltration of monocyte/macrophage in aortic tissue, and their lesional macrophages displayed an M1-like phenotype. Local pathological changes were associated with enhanced systemic inflammatory responses (ie, elevated plasma levels of CCL2 and TNF-α, increased circulating inflammatory cells). In vitro analyses using peritoneal macrophages showed that C3a stimulation resulted in upregulation of M2-associated signaling and molecules, but suppression of M1-associated signaling and molecules, supporting the roles of C3a/C3aR axis in mediating anti-inflammatory response and promoting M2 macrophage polarization. CONCLUSIONS: Our findings demonstrate a protective role for C3aR in the development of atherosclerosis and suggest that C3aR confers the protection through C3a/C3aR axis-mediated negative regulation of proinflammatory responses and modulation of macrophage toward the anti-inflammatory phenotype.


Assuntos
Aorta/metabolismo , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Inflamação/prevenção & controle , Macrófagos Peritoneais/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Aorta/imunologia , Aorta/patologia , Doenças da Aorta/imunologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiotaxia , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , NF-kappa B/metabolismo , Fenótipo , Placa Aterosclerótica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Acoplados a Proteínas-G/deficiência , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
PLoS One ; 15(8): e0237040, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764823

RESUMO

As type-I-allergies show an increasing prevalence in the general populace, orthodontic patients may also be affected by histamine release during treatment. Human periodontal ligament fibroblasts (PDLF) are regulators of orthodontic tooth movement. However, the impact of histamine on PDLF in this regard is unknown. Therefore PDLF were incubated without or with an orthodontic compressive force of 2g/cm2 with and without additional histamine. To assess the role of histamine-1-receptor (H1R) H1R-antagonist cetirizine was used. Expression of histamine receptors and important mediators of orthodontic tooth movement were investigated. PDLF expressed histamine receptors H1R, H2R and H4R, but not H3R. Histamine increased the expression of H1R, H2R and H4R as well as of interleukin-6, cyclooxygenase-2, and prostaglandin-E2 secretion even without pressure application and induced receptor activator of NF-kB ligand (RANKL) protein expression with unchanged osteoprotegerin secretion. These effects were not observed in presence of H1R antagonist cetirizine. By expressing histamine receptors, PDLF seem to be able to respond to fluctuating histamine levels in the periodontal tissue. Increased histamine concentration was associated with enhanced expression of proinflammatory mediators and RANKL, suggesting an inductive effect of histamine on PDLF-mediated osteoclastogenesis and orthodontic tooth movement. Since cetirizine inhibited these effects, they seem to be mainly mediated via histamine receptor H1R.


Assuntos
Histamina/farmacologia , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/fisiologia , Técnicas de Movimentação Dentária , Células Cultivadas , Cetirizina/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Expressão Gênica/efeitos dos fármacos , Histamina/fisiologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Mediadores da Inflamação/metabolismo , Modelos Biológicos , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ligamento Periodontal/citologia , Ligante RANK/genética , Ligante RANK/metabolismo , Receptores Histamínicos H1/fisiologia , Estresse Mecânico
15.
ACS Chem Neurosci ; 11(13): 1868-1870, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32605374

RESUMO

Cytokine storm in COVID-19 is characterized by an excessive inflammatory response to SARS-CoV-2 that is caused by a dysregulated immune system of the host. We are proposing a new hypothesis that SARS-CoV-2 mediated inflammation of nucleus tractus solitarius (NTS) may be responsible for the cytokine storm in COVID 19. The inflamed NTS may result in a dysregulated cholinergic anti-inflammatory pathway and hypothalamic-pituitary-adrenal axis.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Citocinas/metabolismo , Pneumonia Viral/metabolismo , Núcleo Solitário/metabolismo , Axônios/imunologia , Axônios/metabolismo , Axônios/virologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Nervos Cranianos/imunologia , Nervos Cranianos/metabolismo , Nervos Cranianos/virologia , Citocinas/imunologia , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/virologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Pandemias , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/virologia , Pneumonia Viral/imunologia , Núcleo Solitário/imunologia , Núcleo Solitário/virologia
16.
Int J Nanomedicine ; 15: 4079-4090, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606665

RESUMO

Purpose: The aim of this study is to develop efficient localized therapy of sertaconazole nitrate for the treatment of vaginal candidiasis. Methods: Sertaconazole nitrate-loaded cationic liposomes were prepared by thin-film hydration method and coated with different concentrations of pectin (0.05%, 0.1% and 0.2%) to develop mucoadhesive liposomes. The formulated mucoadhesive vesicles were characterized in terms of morphology, entrapment efficiency, particle size, zeta value, mucoadhesive properties and drug release. The selected formula was incorporated into a gel base and further characterized by an ex vivo permeation study in comparison with conventional sertaconazole gel. Also, the in vivo study was performed to assess the efficacy of sertaconazole mucoadhesive liposomal gel in treating rats with vaginal candidiasis. Results: The mucoadhesive liposomes were spherical. Coating liposomes with pectin results in increased entrapment efficiency and particle size compared with uncoated vesicles. On the contrary, zeta values were reduced upon coating liposomes with pectin indicating efficient coating of liposomes with pectin. Mucoadhesive liposomes showed a more prolonged and sustained drug release compared with uncoated liposomes. Ex vivo study results showed that mucoadhesive liposomal gel increased sertaconazole tissue retention and reduced drug tissue penetration. In the invivo study, the mucoadhesive liposomal gel showed a significant reduction in the microbial count with a subsequent reduction in inflammatory responses with the lowest histopathological change compared with conventional gel. Conclusion: The study confirmed the potentiality of employing mucoadhesive liposomes as a successful carrier for the vaginal delivery of antifungal drugs.


Assuntos
Antifúngicos/uso terapêutico , Candidíase Vulvovaginal/tratamento farmacológico , Imidazóis/uso terapêutico , Muco/química , Tiofenos/uso terapêutico , Adesividade , Animais , Anti-Infecciosos/farmacologia , Biomarcadores/metabolismo , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Feminino , Géis , Humanos , Imidazóis/farmacologia , Imunoglobulina G/metabolismo , Imunoglobulina M/metabolismo , Mediadores da Inflamação/metabolismo , Lipossomos/ultraestrutura , Mucinas/metabolismo , Tamanho da Partícula , Ratos Sprague-Dawley , Ovinos , Eletricidade Estática , Tiofenos/farmacologia , Vagina/patologia , beta-Glucanas/metabolismo
17.
Ther Adv Cardiovasc Dis ; 14: 1753944720934937, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32611276

RESUMO

Ivabradine is a pure heart-rate lowering drug that is nowadays used, accordingly to the last ESC Guidelines, to reduce mortality and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction and in symptomatic patiens with inappropriate sinus tachycardia. Moreover, interesting effect of ivabradine on endothelial and myocardial function and on oxidative stress and inflamation pathways are progressively emerging. The aim of this paper is to highlight newer evidences about ivabradine effect (and consequently possible future application of the drug) in pathological settings different from guidelines-based clinical practice.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Ivabradina/uso terapêutico , Animais , Função Atrial/efeitos dos fármacos , Fármacos Cardiovasculares/efeitos adversos , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Ivabradina/efeitos adversos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Função Ventricular/efeitos dos fármacos
18.
J Stroke Cerebrovasc Dis ; 29(8): 104941, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689643

RESUMO

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health threat. Some COVID-19 patients have exhibited widespread neurological manifestations including stroke. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been reported in patients with COVID-19. COVID-19-associated coagulopathy is increasingly recognized as a result of acute infection and is likely caused by inflammation, including inflammatory cytokine storm. Recent studies suggest that axonal transport of SARS-CoV-2 to the brain can occur via the cribriform plate adjacent to the olfactory bulb that may lead to symptomatic anosmia. The internalization of SARS-CoV-2 is mediated by the binding of the spike glycoprotein of the virus to the angiotensin-converting enzyme 2 (ACE2) on cellular membranes. ACE2 is expressed in several tissues including lung alveolar cells, gastrointestinal tissue, and brain. The aim of this review is to provide insights into the clinical manifestations and pathophysiological mechanisms of stroke in COVID-19 patients. SARS-CoV-2 can down-regulate ACE2 and, in turn, overactivate the classical renin-angiotensin system (RAS) axis and decrease the activation of the alternative RAS pathway in the brain. The consequent imbalance in vasodilation, neuroinflammation, oxidative stress, and thrombotic response may contribute to the pathophysiology of stroke during SARS-CoV-2 infection.


Assuntos
Betacoronavirus/patogenicidade , Encéfalo/fisiopatologia , Infecções por Coronavirus/fisiopatologia , Encefalite Viral/fisiopatologia , Pneumonia Viral/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Betacoronavirus/metabolismo , Coagulação Sanguínea , Encéfalo/metabolismo , Encéfalo/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Encefalite Viral/epidemiologia , Encefalite Viral/metabolismo , Encefalite Viral/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Mediadores da Inflamação/metabolismo , Estresse Oxidativo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Sistema Renina-Angiotensina , Transdução de Sinais , Glicoproteína da Espícula de Coronavírus/metabolismo , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/virologia , Vasodilatação , Virulência
19.
Rev Cardiovasc Med ; 21(2): 225-240, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32706211

RESUMO

In spite of medical advances, cardiovascular disease remains a significant concern, imposing a great burden upon the economy and public health of nations by causing the highest morbidity and mortality cases globally. Moreover, it is well established that inflammation is closely linked to the pathogenesis of cardiovascular diseases. Hence, targeting inflammation seems to be a promising strategy in reducing cardiovascular risks. Currently, the importance of natural products in modern medicine is well recognised and continues to be of interest to the pharmaceutical industry. Phenolic acids are a class of phytochemical compounds that are well-known for their health benefits. They consists of various phytochemical constituents and have been widely studied in various disease models. Research involving both animals and humans has proven that phenolic acids possess cardioprotective properties such as anti-hypertensive, anti-hyperlipidemia, anti-fibrotic and anti-hypertrophy activity. Furthermore, numerous studies have proven that phenolic acids in phytochemical constituents such as gallic acid, caffeic acid and chlorogenic acid are promising anti-inflammatory agents. Hence, in this review, we outline and review recent evidence on the role of phenolic acids and their anti-inflammatory significance in studies published during the last 5 years. We also discuss their possible mechanisms of action in modulating inflammation related to cardiovascular disease.


Assuntos
Anti-Inflamatórios/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Sistema Cardiovascular/efeitos dos fármacos , Dieta , Hidroxibenzoatos/administração & dosagem , Mediadores da Inflamação/metabolismo , Inflamação/prevenção & controle , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Transdução de Sinais
20.
Rev Cardiovasc Med ; 21(2): 275-287, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32706215

RESUMO

Inflammation and oxidative stress are involved in the pathogenesis of cardiovascular diseases such as atherosclerosis, hypertension and ischemic heart disease. Natural products play an important role as nutritional supplements with potential health benefits in cardiovascular diseases. Polygonum minus (PM) is an aromatic plant that is widely used as a flavoring agent in cooking and has been recognized as a plant with various medicinal properties including antioxidative and anti-inflammatory actions. Phytoconstituents found in PM such as phenolic and flavonoid compounds contribute to the plant's antioxidative and anti-inflammatory effects. We conducted this review to systematically identify articles related to the antioxidative and anti-inflammatory activities of PM. A computerized database search was conducted on Ovid MEDLINE, PubMed, Scopus, and ACS publication, from 1946 until May 2020, and the following keywords were used: 'Kesum OR Polygonum minus OR Persicaria minor' AND 'inflammat* OR oxida* OR antioxida*'. A total of 125 articles were obtained. Another eight additional articles were identified through Google Scholar and review articles. Altogether, 17 articles were used for data extraction, comprising 16 articles on antioxidant and one article on anti-inflammatory activity of PM. These studies consist of 14 in vitro studies, one in vivo animal study, one combined in vitro and in vivo study and one combined in vitro and ex vivo study. All the studies reported that PM exhibits antioxidative and anti-inflammatory activities which are most likely attributed to its high phenolic and flavonoid content.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Flavonoides/uso terapêutico , Mediadores da Inflamação/antagonistas & inibidores , Inflamação/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Polygonum/química , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/efeitos adversos , Antioxidantes/isolamento & purificação , Flavonoides/efeitos adversos , Flavonoides/isolamento & purificação , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Extratos Vegetais/efeitos adversos , Extratos Vegetais/isolamento & purificação , Transdução de Sinais
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