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1.
J Vasc Surg ; 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34597786

RESUMO

OBJECTIVE: Upper extremity (UE) access is frequently used for F-BEVAR, particularly for complex repairs. Traditionally, left-side UE access has been used to avoid crossing the arch and the origin of the supra-aortic vessels, which could potentially result in cerebral embolization and an increased risk of perioperative cerebrovascular events. More recently, right UE has been more frequently used as it is more convenient and ergonomic. The purpose of this study was to assess the outcomes and cerebrovascular events after F-BEVAR with the use of right vs. left-side upper extremity access. METHODS: During an 8-year period, 453 patients (71% male) underwent F-BEVAR at a single institution. UE access was used in more complex repairs. Left UE access was favored in the past, whereas right UE access is currently the preferred UE access side. Brachial artery cutdown was used in all patients for the placement of a 12F sheath. Outcomes were compared between patients undergoing right vs. left UE access. Endpoints included cerebrovascular events, perioperative mortality, technical success and local access related complications. RESULTS: UE access was used in 361 (80%) patients. The right-side was used in 232 (64%) and the left-side in 129 (36%) patients for the treatment of 88 (25%) juxtarenal, 135 (38%) suprarenal and 137 (38%) thoracoabdominal aortic aneurysms. Most procedures were elective (94%). Technical success was achieved in 354 patients (98%). In-patient or 30-day mortality was 3.3%. Five (1%) perioperative strokes occurred in patients undergoing right UE access, of which 3 were ischemic and 2 were hemorrhagic. No transient ischemic attacks (TIAs) occurred perioperatively. Two hemorrhagic strokes were associated to permissive hypertension to prevent spinal cord ischemia. No perioperative strokes occurred in patients undergoing left UE access (P=.16). Overall, perioperative strokes occurred with similar frequency in patients undergoing UE (5, 1%) and femoral access only (1, 1%) (P=.99). Arm access related complications occurred in 15 (5%) patients, 11 (4.8%) on the right-side and 4 (6%) on the left-side (P=.74). CONCLUSIONS: Right upper extremity access can be used for F-BEVAR with low morbidity and minimal risk of perioperative ischemic stroke or TIAs. In general, upper extremity access is not associated with an increased risk of perioperative stroke compared to femoral access only. Tight blood pressure control is, however, critical to avoid intracranial bleeding related to uncontrolled hypertension.

2.
Virology ; 564: 33-38, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34619630

RESUMO

Endemic seasonal coronaviruses cause morbidity and mortality in a subset of patients, but no specific treatment is available. Molnupiravir is a promising pipeline antiviral drug for treating SARS-CoV-2 infection potentially by targeting RNA-dependent RNA polymerase (RdRp). This study aims to evaluate the potential of repurposing molnupiravir for treating seasonal human coronavirus (HCoV) infections. Molecular docking revealed that the active form of molnupiravir, ß-D-N4-hydroxycytidine (NHC), has similar binding affinity to RdRp of SARS-CoV-2 and seasonal HCoV-NL63, HCoV-OC43 and HCoV-229E. In cell culture models, treatment of molnupiravir effectively inhibited viral replication and production of infectious viruses of the three seasonal coronaviruses. A time-of-drug-addition experiment indicates the specificity of molnupiravir in inhibiting viral components. Furthermore, combining molnupiravir with the protease inhibitor GC376 resulted in enhanced antiviral activity. Our findings highlight that the great potential of repurposing molnupiravir for treating seasonal coronavirus infected patients.

3.
Sci Rep ; 11(1): 14172, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238948

RESUMO

Cotton leaf curl disease (CLCuD), caused by begomoviruses in combination with betasatellite molecule, has adversely affected cotton industry of Indian subcontinent. To devise a CLCuD-control strategy, RNAi-mediated approach was followed in this study. Gossypium hirsutum cv. HS6 plants were transformed with intron-hairpin RNAi (ihpRNAi-C4) construct carrying silencing suppressor C4 gene of Cotton leaf curl Multan virus (CLCuMuV). Efficacy of the construct in imparting CLCuD resistance was evaluated in transgenic (T0, T1) cotton lines. Accumulation of CLCuMuV/betasatellite and attenuation of CLCuD symptoms in the transgenic lines were monitored at different times interval after virus inoculation. Northern hybridization revealed the expression of C4-gene derived siRNA. Expression of the ihpRNAi transcript was recorded higher in transgenic lines expressing siRNA which supposedly targeted the C4 gene. A significant delay in detection of virus as well as betasatellite was observed in the transgenic lines. At 30 days post inoculation (dpi), none of the lines tested positive. At 45 dpi, however, it could be detected in few lines having much lower titre as compared to non-transformed control plants. Notably, till 60 dpi, no significant progression of the virus/betasatellite DNA was observed and the plants did not exhibit any characteristic CLCuD symptoms. A tolerance phenomenon leading to escape of CLCuD symptoms in the transformed cotton was described.

4.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203309

RESUMO

The prevalence of NAFLD (non-alcoholic fatty liver disease) is a rapidly increasing problem, affecting a huge population around the globe. However, CVDs (cardiovascular diseases) are the most common cause of mortality in NAFLD patients. Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense LDL (low-density lipoprotein) particles, and decreased HDL-C (high-density lipoprotein cholesterol) levels, is often observed in NAFLD patients. In this review, we summarize recent genetic evidence, proving the diverse nature of metabolic pathways involved in NAFLD pathogenesis. Analysis of available genetic data suggests that the altered operation of fatty-acid ß-oxidation in liver mitochondria is the key process, connecting NAFLD-mediated dyslipidemia and elevated CVD risk. In addition, we discuss several NAFLD-associated genes with documented anti-atherosclerotic or cardioprotective effects, and current pharmaceutical strategies focused on both NAFLD treatment and reduction of CVD risk.


Assuntos
Aterosclerose/metabolismo , Doenças Cardiovasculares/metabolismo , Dislipidemias/metabolismo , Fígado/metabolismo , Animais , Humanos , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia
5.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201756

RESUMO

Diabetes mellitus and related disorders significantly contribute to morbidity and mortality worldwide. Despite the advances in the current therapeutic methods, further development of anti-diabetic therapies is necessary. Mitochondrial dysfunction is known to be implicated in diabetes development. Moreover, specific types of mitochondrial diabetes have been discovered, such as MIDD (maternally inherited diabetes and deafness) and DAD (diabetes and Deafness). Hereditary mitochondrial disorders are caused by certain mutations in the mitochondrial DNA (mtDNA), which encodes for a substantial part of mitochondrial proteins and mitochondrial tRNA necessary for mitochondrial protein synthesis. Study of mtDNA mutations is challenging because the pathogenic phenotype associated with such mutations depends on the level of its heteroplasmy (proportion of mtDNA copies carrying the mutation) and can be tissue-specific. Nevertheless, modern sequencing methods have allowed describing and characterizing a number of mtDNA mutations associated with human disorders, and the list is constantly growing. In this review, we provide a list of mtDNA mutations associated with diabetes and related disorders and discuss the mechanisms of their involvement in the pathology development.


Assuntos
Diabetes Mellitus/genética , Genoma Mitocondrial/genética , Inflamação/genética , Mutação , Animais , Doença Crônica , DNA Mitocondrial/genética , Surdez/genética , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Camundongos , Doenças Mitocondriais/genética
6.
Front Immunol ; 12: 697588, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305934

RESUMO

The Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP) represents a key intracellular signalling molecule regulating diverse immune responses. Its capacity to function as an adaptor molecule has been widely investigated in relation to Toll-like Receptor (TLR)-mediated innate immune signalling. Since the discovery of TIRAP in 2001, initial studies were mainly focused on its role as an adaptor protein that couples Myeloid differentiation factor 88 (MyD88) with TLRs, to activate MyD88-dependent TLRs signalling. Subsequent studies delineated TIRAP's role as a transducer of signalling events through its interaction with non-TLR signalling mediators. Indeed, the ability of TIRAP to interact with an array of intracellular signalling mediators suggests its central role in various immune responses. Therefore, continued studies that elucidate the molecular basis of various TIRAP-protein interactions and how they affect the signalling magnitude, should provide key information on the inflammatory disease mechanisms. This review summarizes the TIRAP recruitment to activated receptors and discusses the mechanism of interactions in relation to the signalling that precede acute and chronic inflammatory diseases. Furthermore, we highlighted the significance of TIRAP-TIR domain containing binding sites for several intracellular inflammatory signalling molecules. Collectively, we discuss the importance of the TIR domain in TIRAP as a key interface involved in protein interactions which could hence serve as a therapeutic target to dampen the extent of acute and chronic inflammatory conditions.

7.
Drugs R D ; 21(3): 273-283, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34324175

RESUMO

BACKGROUND AND OBJECTIVE: Coronavirus disease 2019 is a novel disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus. It was first detected in December 2019 and has since been declared a pandemic causing millions of deaths worldwide. Therefore, there is an urgent need to develop effective therapeutics against coronavirus disease 2019. A critical step in the crosstalk between the virus and the host cell is the binding of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to the peptidase domain of the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of host cells. METHODS: An in silico approach was employed to design a 13-amino acid peptide inhibitor (13AApi) against the RBD of the SARS-CoV-2 spike protein. Its binding specificity for RBD was confirmed by molecular docking using pyDockWEB, ClusPro 2.0, and HDOCK web servers. The stability of 13AApi and the SARS-CoV-2 spike protein complex was determined by molecular dynamics simulation using the GROMACS program while the physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of 13AApi were determined using the ExPASy tool and pkCSM server. Finally, in vitro validation of the inhibitory activity of 13AApi against the spike protein was performed by an enzyme-linked immunosorbent assay. RESULTS: In silico analyses indicated that the 13AApi could bind to the RBD of the SARS-CoV-2 spike protein at the ACE2 binding site with high affinity. In vitro experiments validated the in silico findings, showing that 13AApi could significantly block the RBD of the SARS-CoV-2 spike protein. CONCLUSIONS: Blockage of binding of the SARS-CoV-2 spike protein with ACE2 in the presence of the 13AApi may prevent virus entry into host cells. Therefore, the 13AApi can be utilized as a promising therapeutic agent to combat coronavirus disease 2019.


Assuntos
Enzima de Conversão de Angiotensina 2/efeitos dos fármacos , Antivirais/farmacologia , Peptídeos/farmacologia , Glicoproteína da Espícula de Coronavírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/farmacocinética , Antivirais/toxicidade , Sítios de Ligação , Simulação por Computador , Desenho de Fármacos , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Peptídeos/farmacocinética , Peptídeos/toxicidade , Ligação Proteica/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Especificidade por Substrato
8.
Ann Vasc Surg ; 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34147637

RESUMO

BACKGROUND: Spinal drains are used to ameliorate spinal cord ischemia (SCI), but their use may result in inherent morbidity and mortality. Although prophylactic spinal drain has proven of benefit in open repairs, that is not the case for endovascular repairs. The aim of this study was to assess the outcomes of spinal cord protection with and without the routine use of spinal drains during fenestrated-branched endovascular repair (F-BEVAR). METHODS: A retrospective single center study was performed using a prospectively maintained dataset of all patients undergoing F-BEVAR over a 4-year period. The primary endpoint of the study was the frequency of SCI. Prophylactic spinal drain was placed pre-operatively in 33 patients (23%) with a median time for removal of 3 days (IQR, 2-3 days). Routine intraoperative neuromonitoring was used. Spinal cord protection relied primarily on maintaining a perioperative systolic blood pressure between 140 and 160 mm Hg or a mean arterial pressure >90 mm Hg, avoiding hypotension, preservation of as many collateral beds as possible, staged repairs and early lower extremity reperfusion based on neuromonitoring. RESULTS: A total of 145 patients, 104 men (71%) and 41 women (28%) with a median age of 70 years (interquartile range [IQR], 53-62) underwent F-BEVAR. Branched custom-made devices (CMDs) (11%), fenestrated CMDs (70%) and off-the-shelf T-Branch device (17%) were used with a median number of branches/fenestrations of 4 (IQR, 3-4). SVS classification of implantation zones were determined as follows: 9 (6%) zone 2, 21 (20%) zone 3, 26 (18%) zone 4 and 89 (61%) zone 5. SCI was present in 8 patients (5.5%) and classified according to the SVS SCI grading system as follows: 1 grade 1, 5 grade 2 and 2 grade 3a. When evaluating implantation zone independently of coverage length and patency of collateral beds, a high implantation zone (1-4) was not associated with SCI (P = 0.9). Similarly, prophylactic spinal drain did not demonstrate association with the occurrence of SCI (3[9%] vs. 5[4%], with and without spinal drain, respectively) (P = 0.3). For patients with high implantation zones, staged repair was performed in 38 patients (26%) at a median time of 2 months (IQR, 2-6 months). Among these patients, the frequency of SCI was 13%. Staged repair was associated with an 80% reduction in the frequency of SCI (OR, 0.19 [95% CI, 0.04-0.084]) (P = 0.02). CONCLUSION: F-BEVAR can be performed with a minimal risk of SCI without the need for routine prophylactic spinal drains. High implantation zones did not predict SCI after F-BEVAR; however, staged repair significantly decreased the risk of SCI after F-BEVAR.

9.
Int J Mol Sci ; 22(9)2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33923295

RESUMO

NAFLD (non-alcoholic fatty liver disease) is a widespread liver disease that is often linked with other life-threatening ailments (metabolic syndrome, insulin resistance, diabetes, cardiovascular disease, atherosclerosis, obesity, and others) and canprogress to more severe forms, such as NASH (non-alcoholic steatohepatitis), cirrhosis, and HCC (hepatocellular carcinoma). In this review, we summarized and analyzed data about single nucleotide polymorphism sites, identified in genes related to NAFLD development and progression. Additionally, the causative role of mitochondrial mutations and mitophagy malfunctions in NAFLD is discussed. The role of mitochondria-related metabolites of the urea cycle as a new non-invasive NAFLD biomarker is discussed. While mitochondria DNA mutations and SNPs (single nucleotide polymorphisms) canbe used as effective diagnostic markers and target for treatments, age and ethnic specificity should be taken into account.


Assuntos
DNA Mitocondrial/genética , Mitocôndrias/genética , Mutação , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo Único , Animais , Progressão da Doença , Humanos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fatores de Risco
10.
Cell Biol Int ; 45(6): 1191-1201, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33501735

RESUMO

Atherosclerosis is a chronic inflammatory disease arising due to an imbalance in lipid metabolism and maladaptive immune response driven by the accumulation of cholesterol-laden macrophages in the artery wall. Interactions between monocytes/macrophages and endothelial cells play an essential role in the pathogenesis of atherosclerosis. In our current study, nitric oxide synthase 1 (NOS1)-derived nitric oxide (NO) has been identified as a regulator of macrophage and endothelial cell interaction. Oxidized LDL (OxLDL) activates NOS1, which results in the expression of CD40 ligand in macrophages. OxLDL-stimulated macrophages produce some soluble factors which increase the CD40 receptor expression in endothelial cells. This increases the interaction between the macrophages and endothelial cells, which leads to an increase in the inflammatory response. Inhibition of NOS1-derived NO might serve as an effective strategy to reduce foam cell formation and limit the extent of atherosclerotic plaque expansion.

11.
Eur Radiol ; 31(4): 2377-2383, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33037910

RESUMO

OBJECTIVE: To determine the prevalence of pulmonary metastases on re-staging chest CT at the time of first local recurrence (LR) of trunk or extremity soft tissue sarcoma (STS). MATERIALS AND METHODS: Retrospective review of all patients diagnosed with recurrent STS between May 2007 and April 2018. Data collected included patient age and sex, site of primary STS, time to LR, recurrence site, initial tumour grade, recurrent tumour grade, findings of initial staging chest CT, and prevalence of pulmonary metastases on re-staging chest CT. RESULTS: The study included 109 patients (males = 68, females = 41; mean age 56 years, range 9-92 years). The commonest tumour sub-types were myxofibrosarcoma (27.5%), undifferentiated pleomorphic/spindle cell sarcoma (20.2%), synovial sarcoma (10.1%), and malignant peripheral nerve sheath tumour (10.1%). Initial staging chest CT demonstrated pulmonary metastases in 1 of 77 (1.3%) patients for whom CT was available for review. The mean time to LR was 30.8 months (range 3-224 months). Pulmonary metastases were diagnosed on re-staging chest CT in 26 of 109 cases (23.9%), being commonest with grade 3 STS (36.1%). Pleomorphic sarcoma (85.7%) and undifferentiated spindle cell sarcoma (33.3%) were the 2 commonest tumour sub-types associated with pulmonary metastases at first LR. CONCLUSION: Re-staging chest CT at the time of first LR of STS identified a prevalence of 23.9% pulmonary metastases, which supports the need for chest CT at the time of LR in line with the UK guidelines for the management of bone and soft tissue sarcoma. KEY POINTS: • Pulmonary metastases were diagnosed in 1.3% of soft tissue sarcomas at presentation. • Pulmonary metastases were identified in ~ 24% of patients at first local recurrence of soft tissue sarcoma, most commonly with pleomorphic sarcoma and Trojani grade tumours. • No patient with a low-grade recurrence had pulmonary metastases.


Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Extremidades/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Estudos Retrospectivos , Sarcoma/diagnóstico por imagem , Neoplasias de Tecidos Moles/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto Jovem
12.
Curr Res Struct Biol ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33319212

RESUMO

With the rapid growth of the COVID-19 (coronavirus disease 2019) pandemic across the globe, therapeutic attention must be directed to fight the novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). However, developing new antiviral drugs and vaccine development is time-consuming, so one of the best solutions to tackle this virus at present is to repurpose ready-to-use drugs. This paper proposes the repurposing of the Food and Drug Administration (FDA)-approved, purchasable, and naturally occurring drugs as a dual-inhibitor for the SARS-CoV-2 cysteine proteases-3Chemotrypsin-like protease or main protease (3CLpro or Mpro) and Papain-like protease (PLpro)-that are responsible for processing the translated polyprotein chain from the viral RNA-yielding functional viral proteins. For virtual screening, an unbiased, blind docking was performed, which produced the top six dual-inhibition candidates for 3CLpro and PLpro. The six repurposed drugs that have been proposed block the catalytic dyad His41 and Cys145 of 3CLpro as well as the catalytic triad Cys111, His272, and Asp286 along with oxyanion hole-stabilizing residue Trp106 of PLpro in the crystal structure. Repurposing such naturally occurring drugs will not only pave the way for rapid in vitro and in vivo studies to battle the SARS-CoV-2 but will also expedite the quest for a potent anti-coronaviral drug.

13.
Cell Mol Bioeng ; : 1-9, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33072222

RESUMO

Purpose: SARS-CoV-2 is a SARS-like novel coronavirus strain first identified in December 2019 in Wuhan, China. The virus has since spread globally, resulting in the current ongoing coronavirus disease 19 (COVID-19) pandemic. SARS-CoV-2 spike protein is a critical factor in the COVID-19 pathogenesis via interactions with the host cell angiotensin-converting enzyme 2 (ACE2) PD domain. Worldwide, numerous efforts are being made to combat COVID19. In the current study, we identified potential peptidomimetics against the SARS-CoV-2 spike protein. Methods: We utilized the information from ACE2-SARS-CoV-2 binary interactions, and based on crucial interacting interface residues, novel peptidomimetics were designed. Results: Top scoring peptidomimetics were found to bind at the ACE2 binding site of the receptor-binding domain (RBD) of SARS-CoV-2 spike protein. Conclusions: The current studies could pave the way for further investigations of these novel and potent compounds against the SARS-CoV-2.

14.
Drugs R D ; 20(3): 161-169, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32592145

RESUMO

BACKGROUND AND OBJECTIVE: Coronavirus disease (COVID-19) is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to the incessant spread of the disease with substantial morbidity and mortality rates, there is an urgent demand for effective therapeutics and vaccines to control and diminish this pandemic. A critical step in the crosstalk between the virus and the host cell is the binding of SARS-CoV-2 spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of the host cells. Hence, inhibition of this interaction could be a promising strategy to combat the SARS-CoV-2 infection. METHODS: Docking and Molecular Dynamics (MD) simulation studies revealed that designed peptide maintains their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. RESULTS: We have designed a novel peptide that could inhibit SARS-CoV-2 spike protein interaction with ACE2, thereby blocking the cellular entry of the virus. CONCLUSION: Our findings suggest that computationally developed inhibitory peptide may be developed as an anti-SARS-CoV-2 agent for the treatment of SARS-CoV-2 infection. We further plan to pursue the peptide in cell-based assays and eventually for clinical trials.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Peptídeos/farmacologia , Pneumonia Viral/prevenção & controle , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2 , Antivirais/farmacologia , Betacoronavirus/isolamento & purificação , COVID-19 , Infecções por Coronavirus/virologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , SARS-CoV-2 , Vacinas Virais/farmacologia
15.
Int Immunopharmacol ; 83: 106382, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32193098

RESUMO

Vascular inflammation plays a decisive role in the formation of foam cells and in the pathophysiology of atherosclerosis. However, the underlying mechanisms of these processes are not clearly understood. Macrophages engulf oxidized low-density lipoproteins (OxLDLs) via a scavenger receptor (SR), an event that mediates the elaboration of proinflammatory cytokines to initiate necrotic core formation in atherogenic plaques. In this study, we demonstrate that Nitric oxide synthase 1 (NOS1)-derived nitric oxide (NO) promotes OxLDL uptake and enhances the release of proinflammatory cytokines by macrophages. Conversely, we show that NOS1 inhibition by N(G)-nitro-L-arginine methyl ester (L-NAME) suppresses OxLDL uptake and proinflammatory cytokine expression. Current studies indicate that NOS1 plays a crucial role in vascular inflammation and in the progression of atherosclerosis. Therefore, interference with NOS1 enzymatic activity should serve as an effective strategy to reduce foam cell formation and limit the extent of atherosclerotic plaque expansion.


Assuntos
Aterosclerose/imunologia , Células Espumosas/imunologia , Inflamação/imunologia , Óxido Nítrico Sintase Tipo I/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Humanos , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores
16.
Int J Cancer ; 146(12): 3474-3484, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32144767

RESUMO

Modulation of prostate stromal cells (PrSCs) within tumor tissues is gaining attention for the treatment of solid tumors. Using our original in vitro coculture system, we previously reported that leucinostatin (LCS)-A, a peptide mycotoxin, inhibited prostate cancer DU-145 cell growth through reduction of insulin-like growth factor 1 (IGF-I) expression in PrSCs. To further obtain additional bioactive compounds from LCS-A, we designed and synthesized a series of LCS-A derivatives as compounds that target PrSCs. Among the synthesized LCS-A derivatives, LCS-7 reduced IGF-I expression in PrSCs with lower toxicity to PrSCs and mice than LCS-A. As LCS-A has been suggested to interact with mitochondrial adenosine triphosphate (ATP) synthase, a docking study was performed to elucidate the mechanism of reduced IGF-I expression in the PrSCs. As expected, LCS-A and LCS-7 directly interacted with mitochondrial ATP synthase, and like LCS-A and LCS-7, other mitochondrial ATP synthase inhibitors also reduced the expression of IGF-I by PrSCs. Furthermore, LCS-A and LCS-7 significantly decreased the growth of mouse xenograft tumors. Based on these data, we propose that the mitochondrial ATP synthases-IGF-I axis of PrSCs plays a critical role on cancer cell growth and inhibition could be a potential anticancer target for prostate cancer.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Células Estromais/efeitos dos fármacos , Animais , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Humanos , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Simulação de Acoplamento Molecular , Próstata/citologia , Próstata/efeitos dos fármacos , Próstata/patologia , Neoplasias da Próstata/patologia , Células Estromais/metabolismo , Células Estromais/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Inflamm Res ; 69(5): 435-451, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32162012

RESUMO

BACKGROUND: This review focuses on exosomes derived from various cancer cells. The review discusses the possibility of differentiating macrophages in alternatively activated anti-inflammatory pro-tumorigenic M2 macrophage phenotypes and classically activated pro-inflammatory, anti-tumorigenic M1 macrophage phenotypes in the tumor microenvironment (TME). The review is divided into two main parts, as follows: (1) role of exosomes in alternatively activating M2-like macrophages-breast cancer-derived exosomes, hepatocellular carcinoma (HCC) cell-derived exosomes, lung cancer-derived exosomes, prostate cancer-derived exosomes, Oral squamous cell carcinoma (OSCC)-derived exosomes, epithelial ovarian cancer (EOC)-derived exosomes, Glioblastoma (GBM) cell-derived exosomes, and colorectal cancer-derived exosomes, (2) role of exosomes in classically activating M1-like macrophages, oral squamous cell carcinoma-derived exosomes, breast cancer-derived exosomes, Pancreatic-cancer derived modified exosomes, and colorectal cancer-derived exosomes, and (3) exosomes and antibody-dependent cellular cytotoxicity (ADCC). This review addresses the following subjects: (1) crosstalk between cancer-derived exosomes and recipient macrophages, (2) the role of cancer-derived exosome payload(s) in modulating macrophage fate of differentiation, and (3) intracellular signaling mechanisms in macrophages regarding the exosome's payload(s) upon its uptake and regulation of the TME. EVIDENCE: Under the electron microscope, nanoscale exosomes appear as specialized membranous vesicles that emerge from the endocytic cellular compartments. Exosomes harbor proteins, growth factors, cytokines, lipids, miRNA, mRNA, and DNAs. Exosomes are released by many cell types, including reticulocytes, dendritic cells, B-lymphocytes, platelets, mast cells, and tumor cells. It is becoming clear that exosomes can impinge upon signal transduction pathways, serve as a mediator of signaling crosstalk, thereby regulating cell-to-cell wireless communications. CONCLUSION: Based on the vesicular cargo, the molecular constituents, the exosomes have the potential to change the fate of macrophage phenotypes, either M1, classically activated macrophages, or M2, alternatively activated macrophages. In this review, we discuss and describe the ability of tumor-derived exosomes in the mechanism of macrophage activation and polarization.


Assuntos
Exossomos/imunologia , Macrófagos/imunologia , Neoplasias/imunologia , Animais , Humanos , Fenótipo
18.
Mol Cell Biochem ; 467(1-2): 107-116, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32108279

RESUMO

Hepatic stellate cells (HSCs) are known to play a key role in the progression of liver fibrosis by producing excessive extracellular matrix (ECM). Matrix metalloproteinases (MMPs) belong to a family of endopeptidases, which have a well-established role in the degradation of ECM. Our study suggests that, besides the degradation of the extracellular matrix, matrix metalloproteinase-8 (MMP-8) has a non-canonical role in activating the quiescent HSCs to myofibroblasts by regulating the expression of Col1A1 and αSMA. We have identified that MMP-8 secreted from macrophages as a response to LPS stimulation activates HSCs via ERK1/2-dependent pathway. In addition to this, we determined that MMP-8 may regulate the homodimerization of c-Jun in LX-2 cells, during the trans-differentiation process from quiescent HSC to activate myofibroblasts. Macrophage-released MMP-8 plays a master role in activating the dormant HSCs to activate myofibroblasts through the Erk-mediated pathway and Jun cellular translocation leading to liver fibrosis. Significance MMP-8 can be used as a therapeutic target against liver fibrosis.


Assuntos
Células Estreladas do Fígado/citologia , Lipopolissacarídeos/efeitos adversos , Sistema de Sinalização das MAP Quinases , Metaloproteinase 8 da Matriz/metabolismo , Técnicas de Cultura de Células , Transdiferenciação Celular , Colágeno Tipo I/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Humanos , Miofibroblastos/citologia , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Multimerização Proteica , Proteínas Proto-Oncogênicas c-jun/química , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Células THP-1
19.
Int Immunopharmacol ; 71: 188-197, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30909134

RESUMO

Bacterial endotoxin-induced sepsis causes 30-40% of the deaths in the intensive care unit (ICU) globally, for which there is no pharmacotherapy. Lipopolysaccharide (LPS), a bacterial endotoxin, stimulates the Toll-like receptor (TLR)-4 signalling pathways to upregulate the expression of various inflammatory mediators. Here, we show that the TIRAP and c-Jun protein signalling complex forms in macrophages in response to LPS stimulation, which increases the AP1 transcriptional activity, thereby amplifying the expression of inflammatory mediators. Using a computer-aided molecular docking platform, we identified gefitinib as a putative inhibitor of the TIRAP-c-Jun signalling complex. Further, we demonstrated the ability of gefitinib to inhibit the interaction of TIRAP-c-Jun with in vitro experiments and with a mouse model of sepsis. Importantly, pre-treatment with gefitinib increased the survival of the mice that received a lethal dose of LPS compared to that of the controls. These findings verify the ability of gefitinib to directly disrupt the interaction of TIRAP and c-Jun, thereby inhibiting a major inflammatory response that is often observed in patients experiencing sepsis.


Assuntos
Gefitinibe/farmacologia , Macrófagos/fisiologia , Glicoproteínas de Membrana/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-jun/antagonistas & inibidores , Receptores de Interleucina-1/antagonistas & inibidores , Sepse/tratamento farmacológico , Animais , Células Cultivadas , Modelos Animais de Doenças , Gefitinibe/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Lipopolissacarídeos/imunologia , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-jun/metabolismo , Receptores de Interleucina-1/metabolismo , Sepse/imunologia , Sepse/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo
20.
J Cell Biochem ; 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30805961

RESUMO

Foam cell formation is a hallmark event during atherosclerosis. The current paradigm is that lipid uptake by a scavenger receptor in macrophages initiates necrosis core formation that characterizes atherosclerosis. We report that NOS1-derived nitric oxide (NO) facilitates low-density lipoprotein (LDL) uptake by macrophages independent of the inflammatory response. LDL uptake could be dramatically suppressed by NOS1 specific inhibitor 1-(2-trifluoromethylphenyl) imidazole (TRIM). Importantly, the notion that NOS1 can mediate uptake of lipoproteins suggests that the foam cell formation is regulated by NOS1-derived NO-mediated mechanism. This is a novel study involving NOS1 as a critical player of foam cell formation and reveals much about the key molecular proteins involved in atherosclerosis. Targeting NOS1 would be a useful strategy in reducing LDL uptake by macrophages and hence dampening the atherosclerosis progression.

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