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1.
J Vet Med Sci ; 86(7): 824-827, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38839347

RESUMO

The expression of nicotinic acetylcholine receptor (nAChR) subunits on various immune cells suggests their involvement in allergic rhinitis. However, how exactly they contribute to this pathogenesis is not yet confirmed. Our present study examined the therapeutic potential of GTS-21, an α7 nAChR agonist, for treating allergic rhinitis by employing its mouse models. GTS-21 treatment reduced allergen-induced immediate nasal response in ovalbumin (OVA)-sensitized model. However, nasal hyperresponsiveness or eosinophil infiltration elicited in either the OVA-sensitized or T helper 2 cell-transplanted model was not affected by GTS-21. GTS-21 did not alter allergen-induced passive cutaneous anaphylaxis response in anti-dinitrophenyl IgE-sensitized mice. This evidence implies GTS-21's potential to alleviate allergic rhinitis without perturbing T cells or mast cells.


Assuntos
Alérgenos , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Ovalbumina , Rinite Alérgica , Receptor Nicotínico de Acetilcolina alfa7 , Animais , Rinite Alérgica/tratamento farmacológico , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Feminino , Camundongos , Piridinas/farmacologia , Piridinas/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Agonistas Nicotínicos/farmacologia , Compostos de Benzilideno/farmacologia , Compostos de Benzilideno/uso terapêutico
2.
Spectrochim Acta A Mol Biomol Spectrosc ; 319: 124577, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-38850612

RESUMO

Isophorone is a cyclic ketone that has gained significant attention in the field of organic chemistry due to its versatile reactivity and structural attributes. Derivatives of isophorone offer a broad spectrum of applications ranging from pharmaceuticals to polymer chemistry. With the aim of developing novel hybrid structures based on benzylidene by combining with isophorone scaffold, we report 3 derivatives of the benzylidene-isophorone hybrids and its potent anticancer activity. In order to optimize the anticancer activity of hybrids di-substitution of -Cl group in C2 and C6 position of phenyl ring (compound1), -OCH3 group in C2 and C5 position of phenyl ring (compound2), and -OCH3 group in C2 and C3 position of phenyl ring (compound3) of benzylidene (PhCH=) moiety were made. The structure of Compounds1,2 and 3 were elucidated using spectral and XRD methods. Compounds1,2 and 3 exhibit space group P c a 21, P-1, and P 1 21/n 1 respectively. Compounds1,2 and 3 were tested for the potent anticancer activity on MDA MB-231 cell line. All the three compounds exhibit good anticancer activity on the breast cancer cells. The parent hybrid with ortho, ortho directing -Cl (1) exhibits strong antiproliferation effect (IC50 = 0.028 µM) on MDA-MB 231 cell line. However, hybrid structures with ortho, meta directing -OCH3 (2) group showed moderate effect (IC50 = 0.061 µM) and hybrid with ortho, meta directing -OCH3 (3) substitution showed the least potent anticancer activity (IC50 = 0.074 µM). The benzylidene-isophorone hybrids exhibit anticancer effects in the following order: 1 > 2 > 3.


Assuntos
Antineoplásicos , Compostos de Benzilideno , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Compostos de Benzilideno/farmacologia , Compostos de Benzilideno/química , Proliferação de Células/efeitos dos fármacos , Modelos Moleculares , Cristalografia por Raios X , Cicloexanonas
3.
Molecules ; 29(12)2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38930952

RESUMO

Based on the fact that substances with a ß-phenyl-α,ß-unsaturated carbonyl (PUSC) motif confer strong tyrosinase inhibitory activity, benzylidene-3-methyl-2-thioxothiazolidin-4-one (BMTTZD) analogs 1-8 were prepared as potential tyrosinase inhibitors. Four analogs (1-3 and 5) inhibited mushroom tyrosinase strongly. Especially, analog 3 showed an inhibitory effect that was 220 and 22 times more powerful than kojic acid in the presence of l-tyrosine and l-dopa, respectively. A kinetic study utilizing mushroom tyrosinase showed that analogs 1 and 3 competitively inhibited tyrosinase, whereas analogs 2 and 5 inhibited tyrosinase in a mixed manner. A docking simulation study indicated that analogs 2 and 5 could bind to both the tyrosinase active and allosteric sites with high binding affinities. In cell-based experiments using B16F10 cells, analogs 1, 3, and 5 effectively inhibited melanin production; their anti-melanogenic effects were attributed to their ability to inhibit intracellular tyrosinase activity. Moreover, analogs 1, 3, and 5 inhibited in situ B16F10 cellular tyrosinase activity. In three antioxidant experiments, analogs 2 and 3 exhibited strong antioxidant efficacy, similar to that of the positive controls. These results suggest that the BMTTZD analogs are promising tyrosinase inhibitors for the treatment of hyperpigmentation-related disorders.


Assuntos
Agaricales , Antioxidantes , Inibidores Enzimáticos , Melaninas , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Agaricales/enzimologia , Animais , Antioxidantes/farmacologia , Antioxidantes/química , Camundongos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Melaninas/antagonistas & inibidores , Melaninas/biossíntese , Tiazolidinas/química , Tiazolidinas/farmacologia , Linhagem Celular Tumoral , Cinética , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Compostos de Benzilideno/farmacologia , Compostos de Benzilideno/química , Pironas
4.
Biochem Biophys Res Commun ; 721: 150129, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-38762933

RESUMO

Melanoma, the deadliest skin cancer, originates from epidermal melanocytes. The influence of preadipocytes on melanoma is less understood. We co-cultured mouse melanoma B16 cells with 3T3L1 preadipocytes to form mixed spheroids and observed increased melanoma proliferation and growth compared to B16-only spheroids. Metastasis-related proteins YAP, TAZ, and PD-L1 levels were also higher in mixed spheroids. Treatment with exosome inhibitor GW4869 halted melanoma growth and reduced expression of these proteins, suggesting exosomal crosstalk between B16 and 3T3L1 cells. MiR-155 expression was significantly higher in mixed spheroids, and GW4869 reduced its levels. Additionally, co-culturing with Raw264.7 macrophage cells increased M2 markers IL-4 and CD206 in Raw264.7 cells, effects that were diminished by GW4869. These results indicate that preadipocytes may enhance melanoma progression and metastasis via exosomal interactions.


Assuntos
Adipócitos , Exossomos , Macrófagos , Melanoma Experimental , Microambiente Tumoral , Animais , Camundongos , Macrófagos/metabolismo , Macrófagos/patologia , Macrófagos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/patologia , Adipócitos/efeitos dos fármacos , Melanoma Experimental/patologia , Melanoma Experimental/metabolismo , Células RAW 264.7 , Exossomos/metabolismo , Técnicas de Cocultura , Progressão da Doença , Células 3T3-L1 , Compostos de Benzilideno/farmacologia , Compostos de Anilina/farmacologia , Proliferação de Células/efeitos dos fármacos , Melanoma/patologia , Melanoma/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Linhagem Celular Tumoral , MicroRNAs/metabolismo , MicroRNAs/genética
5.
An Acad Bras Cienc ; 96(2): e20231247, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38808881

RESUMO

Thiosemicarbazones are promising classes of compounds with antitumor activity. For this study, six 2,4-dihydroxy-benzylidene-thiosemicarbazones compounds were synthesized. These compounds were submitted to different assays in silico, in vitro and in vivo to evaluate the toxicological, antioxidant and antitumor effects. The in silico results were evaluated by the SwissADME and pkCSM platforms and showed that all compounds had good oral bioavailability profiles. The in vitro and in vivo toxicity assays showed that the compounds showed low cytotoxicity against different normal cells and did not promote hemolytic effects. The single dose acute toxicity test (2000 mg/kg) showed that none of the compounds were toxic to mice. In in vitro antioxidant activity assays, the compounds showed moderate to low activity, with PB17 standing out for the ABTS radical capture assay. The in vivo antioxidant activity highlighted the compounds 1, 6 and 8 that promoted a significant increase in the concentration of liver antioxidant enzymes. Finally, all compounds showed promising antitumor activity against different cell lines, especially MCF-7 and DU145 lines, in addition, they inhibited the growth of sarcoma 180 at concentrations lower than 50 mg/kg. These results showed that the evaluated compounds can be considered as potential antitumor agents.


Assuntos
Antineoplásicos , Antioxidantes , Tiossemicarbazonas , Animais , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Camundongos , Humanos , Masculino , Linhagem Celular Tumoral , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Compostos de Benzilideno/farmacologia , Compostos de Benzilideno/química
6.
J Nanobiotechnology ; 22(1): 283, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38789980

RESUMO

BACKGROUND: Endothelial cell (EC)-driven intraneural revascularization (INRV) and Schwann cells-derived exosomes (SCs-Exos) both play crucial roles in peripheral nerve injury (PNI). However, the interplay between them remains unclear. We aimed to elucidate the effects and underlying mechanisms of SCs-Exos on INRV following PNI. RESULTS: We found that GW4869 inhibited INRV, as well as that normoxic SCs-Exos (N-SCs-Exos) exhibited significant pro-INRV effects in vivo and in vitro that were potentiated by hypoxic SCs-Exos (H-SCs-Exos). Upregulation of glycolysis emerged as a pivotal factor for INRV after PNI, as evidenced by the observation that 3PO administration, a glycolytic inhibitor, inhibited the INRV process in vivo and in vitro. H-SCs-Exos more significantly enhanced extracellular acidification rate/oxygen consumption rate ratio, lactate production, and glycolytic gene expression while simultaneously suppressing acetyl-CoA production and pyruvate dehydrogenase E1 subunit alpha (PDH-E1α) expression than N-SCs-Exos both in vivo and in vitro. Furthermore, we determined that H-SCs-Exos were more enriched with miR-21-5p than N-SCs-Exos. Knockdown of miR-21-5p significantly attenuated the pro-glycolysis and pro-INRV effects of H-SCs-Exos. Mechanistically, miR-21-5p orchestrated EC metabolism in favor of glycolysis by targeting von Hippel-Lindau/hypoxia-inducible factor-1α and PDH-E1α, thereby enhancing hypoxia-inducible factor-1α-mediated glycolysis and inhibiting PDH-E1α-mediated oxidative phosphorylation. CONCLUSION: This study unveiled a novel intrinsic mechanism of pro-INRV after PNI, providing a promising therapeutic target for post-injury peripheral nerve regeneration and repair.


Assuntos
Células Endoteliais , Exossomos , Glicólise , Traumatismos dos Nervos Periféricos , Células de Schwann , Células de Schwann/metabolismo , Exossomos/metabolismo , Animais , Células Endoteliais/metabolismo , Camundongos , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/terapia , Masculino , Ratos , MicroRNAs/metabolismo , MicroRNAs/genética , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica , Ratos Sprague-Dawley , Compostos de Anilina , Compostos de Benzilideno
7.
Int J Biol Macromol ; 267(Pt 1): 131453, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38588842

RESUMO

Enterovirus 71 (EV71) causes hand-foot-and-mouth disease (HFMD), neurological complications, and even fatalities in infants. Clinically, the increase of extracellular vesicles (EVs) in EV71 patients' serum was highly associated with the severity of HFMD. EV71 boosts EVs biogenesis in an endosomal sorting complex required for transport (ESCRT)-dependent manner to facilitate viral replication. Yet, the impact of EVs-derived from ESCRT-independent pathway on EV71 replication and pathogenesis is highly concerned. Here, we assessed the effects of EV71-induced EVs from ESCRT-independent pathway on viral replication and pathogenesis by GW4869, a neutral sphingomyelinase inhibitor. Detailly, in EV71-infected mice, blockade of the biogenesis of tissue-derived EVs in the presence of GW4869 restored body weight loss, attenuated clinical scores, and improved survival rates. Furthermore, GW4869 dampens EVs biogenesis to reduce viral load and pathogenesis in multiple tissues of EV71-infected mice. Consistently, GW4869 treatment in a human intestinal epithelial HT29 cells decreased the biogenesis of EVs, in which the progeny EV71 particle was cloaked, leading to the reduction of viral infection and replication. Collectively, GW4869 inhibits EV71-induced EVs in an ESCRT-independent pathway and ultimately suppresses EV71 replication and pathogenesis. Our study provides a novel strategy for the development of therapeutic agents in the treatment for EV71-associated HFMD.


Assuntos
Compostos de Anilina , Complexos Endossomais de Distribuição Requeridos para Transporte , Enterovirus Humano A , Vesículas Extracelulares , Replicação Viral , Animais , Replicação Viral/efeitos dos fármacos , Enterovirus Humano A/efeitos dos fármacos , Enterovirus Humano A/fisiologia , Camundongos , Vesículas Extracelulares/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Humanos , Compostos de Benzilideno/farmacologia , Infecções por Enterovirus/virologia , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/metabolismo , Carga Viral/efeitos dos fármacos , Feminino
8.
Int J Mol Sci ; 25(8)2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38674000

RESUMO

Stimulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) has shown beneficial effects in several acute inflammatory disease models. This study aims to examine whether treatment with the selective α7nAChR agonist PHA 568487 can dampen inflammation and thereby improve cardiac function after myocardial infarction in mice. The possible anti-inflammatory properties of α7nAChR agonist PHA 568487 were tested in vivo using the air pouch model and in a permanent occlusion model of acute myocardial infarction in mice. Hematologic parameters and cytokine levels were determined. Infarct size and cardiac function were assessed via echocardiography 24 h and one week after the infarction. Treatment with α7nAChR agonist PHA 568487 decreased 12 (CCL27, CXCL5, IL6, CXCL10, CXCL11, CXCL1, CCL2, MIP1a, MIP2, CXCL16, CXCL12 and CCL25) out of 33 cytokines in the air pouch model of acute inflammation. However, α7nAChR agonist PHA 568487 did not alter infarct size, ejection fraction, cardiac output or stroke volume at 24 h or at 7 days after the myocardial infarction compared with control mice. In conclusion, despite promising immunomodulatory effects in the acute inflammatory air pouch model, α7nAChR agonist PHA 568487 did not affect infarct size or cardiac function after a permanent occlusion model of acute myocardial infarction in mice. Consequently, this study does not strengthen the hypothesis that stimulation of the α7nAChR is a future treatment strategy for acute myocardial infarction when reperfusion is lacking. However, whether other agonists of the α7nAChR can have different effects remains to be investigated.


Assuntos
Modelos Animais de Doenças , Inflamação , Infarto do Miocárdio , Receptor Nicotínico de Acetilcolina alfa7 , Animais , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Camundongos , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/metabolismo , Masculino , Citocinas/metabolismo , Agonistas Nicotínicos/farmacologia , Agonistas Nicotínicos/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Camundongos Endogâmicos C57BL , Quinuclidinas/farmacologia , Quinuclidinas/uso terapêutico , Benzilaminas/farmacologia , Benzilaminas/uso terapêutico , Compostos de Benzilideno/farmacologia
9.
Bioelectromagnetics ; 45(5): 218-225, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38533693

RESUMO

Mounting literature indicates that electromagnetic pulses (EMP) is the promising modality to treat cancers with advantages such as noninvasiveness and few side-effects, but its appropriate parameters and underlying mechanisms such as its influence on tumor-derived exosomes (TDEs) are largely unknown. This study aimed to elucidate effects of EMP, exosome inhibition and their coaction on A549 lung adenocarcinoma cells. A549 cells were randomly divided into control group, GW4869 group treated by 20 µM GW4869, vehicle group treated by dimethyl sulfoxide, EMP group treated by EMP exposure, and EMPG group treated by EMP exposure combined with 20 µM GW4869. After EMP exposure, cell proliferation was determined by CCK8 assay, cell cycle and apoptosis was detected by flow cytometry, and cell migration was determined by transwell assay. The results showed that EMP or exosomes inhibition did not affect cell proliferation, cell cycle, apoptosis and cell migration (p > 0.05), but cell migration in EMPG group was significantly decreased compared with vehicle group (p < 0.05). We concluded that under the experimental condition, EMP or GW4869 alone had no effects on behaviors of A549 cells, but their coaction could effectively inhibit the migration of A549 cells.


Assuntos
Apoptose , Movimento Celular , Proliferação de Células , Exossomos , Humanos , Exossomos/metabolismo , Células A549 , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Compostos de Benzilideno/farmacologia , Compostos de Anilina/farmacologia , Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/radioterapia
10.
Angew Chem Int Ed Engl ; 63(19): e202403396, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38490953

RESUMO

Although solid-phase peptide synthesis combining with chemical ligation provides a way to build up customized polypeptides in general, many targets are still presenting challenges for the conventional synthetic process, such as hydrophobic proteins. New methods and strategies are still required to overcome these obstacles. In this study, kinetic studies of Cys/Pen ligation and its acidolysis were performed, from which the fast acidolysis of substituted N,S-benzylidene thioacetals (NBTs) was discovered. The study demonstrates the potential of NBTs as a promising Cys switchable protection, facilitating the chemical synthesis of peptides and proteins by efficiently disrupting peptide aggregation. The compatibility of NBTs with other commonly adopted Cys protecting groups and their applications in sequential disulfide bond formation were also investigated. The first chemical synthesis of the native human programmed death ligand 1 immunoglobulin V-like (PD-L1 IgV) domain was achieved using the NBT strategy, showcasing its potential in difficult protein synthesis.


Assuntos
Cisteína , Peptídeos , Cisteína/química , Peptídeos/química , Peptídeos/síntese química , Humanos , Acetais/química , Compostos de Benzilideno/química , Compostos de Benzilideno/síntese química , Proteínas/química , Proteínas/síntese química
11.
J Cell Mol Med ; 28(4): e18138, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38353469

RESUMO

Exosomes are recognized as important mediators of cell-to-cell communication, facilitating carcinogenesis. Although there have been significant advancements in exosome research in recent decades, no drugs that target the inhibition of sEV secretion have been approved for human use. For this study, we employed GW4869 and Nexinhib20 as inhibitors of exosome synthesis and trafficking combined. First, we found that Nexinhib20 and GW4869 effectively inhibited RAB27A and neutral sphingomyelinase 2 (nSMase2) nsMase2. Interestingly, the inhibition of nsMase2 and RAB27A decreased expression of CD9, CD63 and Tsg101, both at RNA and protein levels. We used a combination treatment strategy of cisplatin/etoposide plus GW4869 or Nexinhib20 on small cell lung cancer (SCLC) cell lines. The combination treatment of GW4869 or Nexinhib20 effectively enhanced the inhibitory effects of first-line chemotherapy on the SCLC cells. Furthermore, we demonstrated that reducing exosome release through GW4869 and Nexinhib20 treatment effectively reduced cellular proliferation and significantly induced apoptosis in SCLC cells. Also, we showed that combining exosome inhibition with chemotherapy has a significant synergistic effect on cellular proliferation. We also found increased p53 and p21 expressions with western blot and significantly changing Bax, BCL2, caspase-3 and caspase-9 expressions. Inhibiting the exosome pathway offers opportunities for developing novel, effective treatment strategies for SCLC.


Assuntos
Compostos de Benzilideno , Exossomos , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Exossomos/metabolismo , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Compostos de Anilina
12.
Int Immunopharmacol ; 129: 111603, 2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38310766

RESUMO

Acute lung injury (ALI) has received considerable attention in intensive care owing to its high mortality rate. It has been demonstrated that the selective alpha7 nicotinic acetylcholine receptor agonist Gainesville Tokushima scientists (GTS)-21 is promising for treating ALI caused by lipopolysaccharides (LPS). However, the precise underlying mechanism remains unknown. This study aimed to investigate the potential efficacy of GTS-21 in the treatment of ALI. We developed mouse models of ALI and alveolar epithelial type II cells (AT2s) injury following treatment with LPS and different polarized macrophage supernatants, respectively. Pathological changes, pulmonary edema, and lung compliance were assessed. Inflammatory cells count, protein content, and pro-inflammatory cytokine levels were analysed in the bronchoalveolar lavage fluid. The expression of angiotensin-converting enzyme (ACE), ACE2, syndecan-1 (SDC-1), heparan sulphate (HS), heparanase (HPA), exostosin (EXT)-1, and NF-κB were tested in lung tissues and cells. GTS-21-induced changes in macrophage polarization were verified in vivo and in vitro. Polarized macrophage supernatants with or without recombination a disintegrin and metalloproteinase-17 (ADAM-17) and small interfering (si)RNA ADAM-17 were used to verify the role of ADAM-17 in AT2 injury. By reducing pathological alterations, lung permeability, inflammatory response, ACE/ACE2 ratio, and glycocalyx shedding, as well as by downregulating the HPA and NF-κB pathways and upregulating EXT1 expression in vivo, GTS-21 significantly diminished LPS-induced ALI compared to that of the LPS group. GTS-21 significantly attenuated macrophage M1 polarization and augmented M2 polarization in vitro and in vivo. The destructive effects of M1 polarization supernatant can be inhibited by GTS-21 and siRNA ADAM-17. GTS-21 exerted a protective effect against LPS-induced ALI, which was reversed by recombinant ADAM-17. Collectively, GTS-21 alleviates LPS-induced ALI by attenuating AT2s ACE/ACE2 ratio and glycocalyx shedding through the inhibition of macrophage M1 polarization derived ADAM-17.


Assuntos
Lesão Pulmonar Aguda , Compostos de Benzilideno , Glicocálix , Piridinas , Animais , Camundongos , Lipopolissacarídeos , Proteína ADAM17 , Enzima de Conversão de Angiotensina 2 , NF-kappa B , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Pulmão
13.
Food Funct ; 15(6): 3050-3059, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38414407

RESUMO

The aim of this work was to evaluate the ameliorative effects of exosome biogenesis in cow's milk allergy (CMA) response. In this context, BALB/c mice were systemically sensitized with cow's milk proteins plus an aluminum adjuvant to induce CMA. The inhibitor GW4869 of exosome biogenesis was added before sensitization and then the anaphylactic reactions were evaluated both in vivo (clinical score and body temperature) and in vitro (serum histamine, allergen-specific antibodies, cytokines by ELISA and cell analysis by flow cytometry) to explore the role of exosomes in the development of CMA. Nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) showed that the size distribution and morphology of CMA-derived exosomes were not changed after GW4869 preconditioning, and the concentration of exosomes was much lower than that of the CMA group. In the GW4869 group, inhibition of release of exosomes modulated the induction of T helper 2 cell (Th2)-related substances, with a decrease in histamine and allergen-specific immunoglobulin (Ig) E, and the expression of Th1, Th2, and Th17 cells all decreased as well. Moreover, the experimental data were integrated by means of principal component analysis (PCA) to give an overview that the percentage of Th cells and concentrations of cytokines were more influenced by GW4869 treatment. These data for the first time demonstrated that exosomes are involved in the development of CMA and the blockade of exosome release with GW4869 suppressed the IgE-mediated immune response in CMA.


Assuntos
Compostos de Anilina , Compostos de Benzilideno , Exossomos , Hipersensibilidade a Leite , Bovinos , Feminino , Animais , Camundongos , Leite , Histamina , Linfócitos T Auxiliares-Indutores , Citocinas , Alérgenos , Hipersensibilidade a Leite/tratamento farmacológico , Imunoglobulina E
14.
Head Neck ; 46(3): 636-650, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38164660

RESUMO

BACKGROUND: Cisplatin (CDDP) plays a central role in chemotherapy for head and neck squamous cell carcinoma (HNSCC), but drug resistance in HNSCC chemotherapy remains a problem, and the mechanism of CDDP resistance is unclear. We investigated CDDP-resistance mechanisms mediated by extracellular vesicles (EVs) and ATPase copper transporting beta (ATP7B) in HNSCC. METHODS: We established CDDP-resistant sublines of HNSCC cells and verified their ATP7B expression. We used an EV secretion inhibitor (GW4869) and ATP7B short hairpin (sh)RNA transfection to examine the correlation between EV secretion and ATP7B expression. RESULTS: The CDDP-resistant HNSCC sublines showed decreased CDDP sensitivity and increased ATP7B expression. GW4869 suppressed ATP7B expression, and ATP7B shRNA transfection suppressed EV secretion. The suppressions of EV secretion and ATP7B expression both enhanced CDDP's cell-killing effect. CONCLUSIONS: EVs were involved in the ATP7B-mediated mechanism underlying CDDP resistance. Further clarification of the EV-induced CDDP-resistance mechanism may lead to novel therapeutic strategies for HNSCC.


Assuntos
Compostos de Anilina , Antineoplásicos , Compostos de Benzilideno , Vesículas Extracelulares , Neoplasias de Cabeça e Pescoço , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas de Transporte de Cobre , Resistencia a Medicamentos Antineoplásicos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Vesículas Extracelulares/metabolismo , Linhagem Celular Tumoral , Cobre/metabolismo , Cobre/farmacologia
15.
Sleep Breath ; 28(1): 319-329, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37726500

RESUMO

BACKGROUND: Exosomes are involved in cell-to-cell communication in numerous diseases including cardiovascular diseases, neurological diseases. Little attention has been dedicated to exosomal circular RNAs in obstructive sleep apnea (OSA)-related cardiovascular diseases. The aim of this study was to explore the role of exosomal circular RNA ZNF292 (circZNF292) on AC16 cells exposure to intermittent hypoxia (IH). METHODS: Exosome release inhibitor GW4869 was used to examine the effect of exosomes on IH-induced AC16 cells apoptosis. The expression of exosomal circZNF292 was detected by qRT-PCR in AC16 cells exposure to IH, and a luciferase reporter assay was conducted to confirm the connection between circZNF292 and miR-146a-5p. Exosomal circZNF292 was stably transfected with short hairpin RNAs (shRNAs) against circZNF292 and co-cultured with AC16 cells. The expression of miR-146a-5p and apoptosis-related protein was then measured to evaluate the effect of exosomal circZNF292. RESULTS: We found that IH contributed to the AC16 cells apoptosis, and the administration of GW4869 increased the apoptosis of cardiomyocytes when exposed to IH. The expression of exosomal circZNF292 decreased and miR-146a-5p increased significantly in AC16 cells exposed to IH compared to normoxic conditions. Bioinformatics analysis predicted a circZNF292/miR-146a-5p axis in IH-induced cardiomyocytes apoptosis. The dual-luciferase reporter system validated the direct interaction of circZNF292 and miR-146a-5p. Knockdown of circZNF292 increased the expressions of miR-146a-5p and accelerated the AC16 cardiomyocytes apoptosis. CONCLUSIONS: The findings of this study suggested a novel mechanism by which exosomes transmit intrinsic regulatory signals to the myocardium through the exosomal circZNF292/miR-146a-5p axis. This finding highlights the potential of targeting this pathway as a therapeutic approach for treating cardiovascular diseases associated with OSA.


Assuntos
Compostos de Anilina , Compostos de Benzilideno , Doenças Cardiovasculares , MicroRNAs , Apneia Obstrutiva do Sono , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , MicroRNAs/farmacologia , RNA Circular/genética , RNA Circular/metabolismo , RNA Circular/farmacologia , Miócitos Cardíacos/metabolismo , Doenças Cardiovasculares/metabolismo , Apoptose/genética , Hipóxia/genética , Hipóxia/metabolismo , Luciferases/metabolismo , Luciferases/farmacologia , Apneia Obstrutiva do Sono/metabolismo , Proteínas de Transporte , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/farmacologia
16.
Reprod Biomed Online ; 48(1): 103246, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37903673

RESUMO

RESEARCH QUESTION: Does human chorionic gonadotrophin (HCG) influence endometrial receptivity and epithelial-mesenchymal transition (EMT) via the FoxO1/miR223-5p/Wnt5α pathway? DESIGN: This study aimed to establish the co-culture system of human embryonic trophoblast cell line (HTR-8-Svneo) cells and human endometrial epithelial cell line (HEEC) cells. The expression of Wnt5α protein and EMT-related proteins in HTR-8-Svneo and HEEC cells treated in a gradient-dependent manner using HCG and exosome inhibitor GW4869 were detected in the co-culture system. RESULTS: In the HTR-8-Svneo/HEEC co-culture system, miR223-5p in HEEC cells increased significantly with induction of HTR-8-Svneo cells by 100 IU/ml HCG for 48 h (P = 0.046), and Wnt5α protein decreased significantly in HEEC cells (P = 0.021). Pretreatment of HTR-8-Svneo cells with GW4869, and knockdown of FoxO1 in HTR-8-Svneo cells, significantly inhibited the above effects of HCG on miR223-5p and Wnt5α expression in HEEC cells in the HTR-8-Svneo/HEEC co-culture system. HTR-8-Svneo cells induced with 100 IU/ml HCG for 48 h significantly enhanced the logarithmic phase proliferation activity of HEEC cells in the co-culture system (P < 0.001), while knockdown of FoxO1 in HTR-8-Svneo cells and inhibition of miR223-5p in HEEC cells suppressed proliferation of HEEC cells in the HTR-8-Svneo/HEEC co-culture system (P < 0.001). CONCLUSIONS: HCG exposure induces HTR-8-Svneo cells to up-regulate miR223-5p expression, which enters HEEC cells in the co-culture system through the exosomal pathway, and inhibits Wnt5α expression and the progress of EMT.


Assuntos
Compostos de Anilina , Compostos de Benzilideno , MicroRNAs , Trofoblastos , Humanos , Movimento Celular , Linhagem Celular , Transição Epitelial-Mesenquimal , Proliferação de Células , MicroRNAs/metabolismo
17.
Microbes Infect ; 26(1-2): 105236, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37813158

RESUMO

Gastric fibroblasts (GFs) are direct targets of Helicobacter pylori (H. pylori). GFs infected with H. pylori exhibit marked changes in their morphology and biological behavior. However, the molecular mechanisms by which H. pylori regulates GFs remain unknown. In this study, we cocultured GFs with H. pylori for 48 h. As a result, GFs exhibited an elongated and spindle-shaped morphology. Further, cancer-associated fibroblast (CAF) biomarkers were increased, and related behaviors were significantly enhanced in H. pylori-activated GFs. The number of extracellular vesicles (EVs) secreted by H. pylori-activated GFs remarkably increased. The miR-124-3p level was increased in secreted EVs but decreased in the cytoplasm of H. pylori-activated GFs. Overexpression of miRNA-124-3p in the original GFs significantly suppressed their proliferation and migration. In addition, the migration-promoting effects of H. pylori-activated GFs were suppressed by miR-124-3p and GW4869, which blocked EV generation. Finally, pull-down and luciferase assays revealed that SNAI2 is a target of miR-124-3p. The migration-inhibitory effects of GFs treated with miR-124-3p were eliminated by the overexpression of SNAI2, and the upregulation of SNAI2 in H. pylori-activated GFs was partially alleviated by miR-124-3p or GW4869. Overall, H. pylori infection promotes the proliferation and migration of GFs by accelerating the expulsion of EVs carrying miRNA-124-3p, a SNAI2 inhibitor.


Assuntos
Compostos de Anilina , Compostos de Benzilideno , Helicobacter pylori , MicroRNAs , Neoplasias Gástricas , Humanos , Linhagem Celular Tumoral , MicroRNAs/genética , Proliferação de Células
18.
Anal Chim Acta ; 1279: 341786, 2023 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-37827682

RESUMO

Although there are many drugs used for the treatment of mercury poisoning, it is remains confused that pathological symptoms associated with Hg2+-induced oxidative stress. It is reported that SO2 can be generated as the anti-oxidant, and plays an important role in maintaining redox balance in cells. There has not yet been a study to precisely track the changes in SO2 during mercury ion poisoning. We developed a novel dual-response fluorescence probe (CY-SPH) for respective or successive determination of Hg2+ and SO2 in neutral aqueous media. The nucleophilic addition of HSO3- toward CY-SPH caused a significant fluorescence enhancement at 455 nm while the Hg2+ -triggered desulfurization of CY-SPH to the final phenolic product (CY-OH) elicited a markedly enhanced emission at 760 nm, allowing for two-color visualization of Hg2+ and SO2 with good selectivity (detection limit: 67.2 nM for Hg2+ and 34.7 nM for SO2). Moreover, CY-OH could undergo further nucleophilic addition reaction with HSO3- and resulted in a decrease in emission at 760 nm and an increase in emission at 438 nm, enabling the ratiometric determination of SO2 with better sensitivity (detection limit, 3.50 nM). Significantly, CY-SPH can monitor the endogenous SO2 fluctuations upon mercury exposure by means of confocal fluorescence imaging, which may prove valuable for deciphering the relationship between SO2 levels and the mercury induced oxidative stress. We anticipated that this research will promote to understand the functions of SO2 under the oxidative stress by Hg2+.


Assuntos
Corantes Fluorescentes , Mercúrio , Humanos , Células HeLa , Compostos de Benzilideno
19.
Chemosphere ; 340: 139862, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37604346

RESUMO

The Arctic region is threatened by climate change and pollution caused by human activities which potentially influence the elemental concentrations available to and from the biota. To better understand this delicate balance, it is crucial to investigate the role of several factors. Therefore, we quantified the level of 43 chemical elements in soils from Elsa and Ebba Valleys, Petunia Bay, Spitsbergen, a region that has experienced lasting environmental impacts from historical mining activities. We evaluated the a) vertical sampling influence by examining the variation in element distribution between the soil upper and deeper layers, b) animal influence by verifying the role of native animals, particularly vertebrates, in introducing thought faeces elements to the soil and c) anthropogenic influence by studying the spatial geographical differences in element distribution based on the degree of human pressure between the valleys. Our analysis also includes data on soil organic matter (SOM) and mineral composition. Both valleys exhibited similar mineralogical composition, but Elsa Valley had higher concentrations of most analyzed elements compared to Ebba Valley. Despite the contribution of vertebrate feaces, no increase in element concentrations was observed in the animal-influenced soils. The sampled soil layers had similar chemical element profiles for most elements. SOM content tended to be higher in superficial soils and showed a strong positive correlation with most quantified elements. The higher concentrations in Elsa Valley reflect its past mining and mineral exploration, making this area more significantly impacted than Ebba Valley. Surprisingly, vertebrate animals do not appear to influence the concentrations of chemical elements or organic matter in soils. Our findings provide valuable insights into the legacy of past mining activities and mechanisms driving environmental change in the Arctic.


Assuntos
Meio Ambiente , Solo , Animais , Humanos , Svalbard , Compostos de Benzilideno
20.
Biophys Chem ; 296: 106982, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36868163

RESUMO

The formation of amyloid fibrils due to its association with fatal diseases, including Alzheimer's, has been investigated by many researchers. These common diseases, mostly become verified when it is too late to be treated. Currently, no cure is available for neurodegenerative diseases, and the process of diagnosing amyloid fibrils in the early stages, while there are fewer amyloid fibrils, has become an issue of interest. To do so, determining new probes with the highest binding affinity to the lowest number of amyloid fibrils is necessary. In this study, we proposed to employ new synthesized benzylidene-indandione derivatives as amyloid fibrils fluorescent detection probes. Native soluble proteins of insulin, bovine serum albumin (BSA), BSA amorphous aggregation, and insulin amyloid fibrils were used to evaluate our compounds' specificity to the amyloid structure. While ten synthesized compounds were examined individually, four of them including 3d, 3g, 3i, and 3j showed a high binding affinity with selectivity and specificity to amyloid fibrils, and their binding properties were also confirmed with in silico analysis. The drug-likeness prediction results for selected compounds by Swiss ADME server shows a satisfactory percentage of blood-brain barrier (BBB) permeability and gastrointestinal (GI) absorption for the compounds 3g, 3i, and 3j. More evaluation is needed to determine all properties of compounds in vitro and in vivo.


Assuntos
Doença de Alzheimer , Insulinas , Humanos , Peptídeos beta-Amiloides/química , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Compostos de Benzilideno , Soroalbumina Bovina/química
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