RESUMO
The coexistence of leishmaniasis, Chagas disease, and neoplasia in endemic areas has been extensively documented. The use of common drugs in the treatment of these pathologies invites us to search for new molecules with these characteristics. In this research, we report 16 synthetic chalcone derivatives that were investigated for leishmanicidal and trypanocidal activities as well as for antiproliferative potential on eight human cancers and two nontumor cell lines. The final compounds 8−23 were obtained using the classical base-catalyzed Claisen−Schmidt condensation. The most potent compounds as parasiticidal were found to be 22 and 23, while compounds 18 and 22 showed the best antiproliferative activity and therapeutic index against CCRF-CEM, K562, A549, and U2OS cancer cell lines and non-toxic VERO, BMDM, MRC-5, and BJ cells. In the case of K562 and the corresponding drug-resistant K562-TAX cell lines, the antiproliferative activity has shown a more significant difference for compound 19 having 10.3 times higher activity against the K562-TAX than K562 cell line. Flow cytometry analysis using K562 and A549 cell lines cultured with compounds 18 and 22 confirmed the induction of apoptosis in treated cells after 24 h. Based on the structural analysis, these chalcones represent new compounds potentially useful for Leishmania, Trypanosoma cruzi, and some cancer treatments.
Assuntos
Doença de Chagas , Chalcona , Leishmania , Leishmaniose , Tripanossomicidas , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Chalcona/farmacologia , Humanos , Leishmaniose/tratamento farmacológico , Naftalenos/uso terapêutico , Relação Estrutura-Atividade , Tripanossomicidas/químicaRESUMO
Chronic pain (CP) is a severe clinical entity with devastating physical and emotional consequences for patients, which can occur in a myriad of diseases. Often, conventional treatment approaches appear to be insufficient for its management. Moreover, considering the adverse effects of traditional analgesic treatments, specialized pro-resolving lipid mediators (SPMs) have emerged as a promising alternative for CP. These include various bioactive molecules such as resolvins, maresins, and protectins, derived from ω-3 polyunsaturated fatty acids (PUFAs); and lipoxins, produced from ω-6 PUFAs. Indeed, SPMs have been demonstrated to play a central role in the regulation and resolution of the inflammation associated with CP. Furthermore, these molecules can modulate neuroinflammation and thus inhibit central and peripheral sensitizations, as well as long-term potentiation, via immunomodulation and regulation of nociceptor activity and neuronal pathways. In this context, preclinical and clinical studies have evidenced that the use of SPMs is beneficial in CP-related disorders, including rheumatic diseases, migraine, neuropathies, and others. This review integrates current preclinical and clinical knowledge on the role of SPMs as a potential therapeutic tool for the management of patients with CP.
Assuntos
Dor Crônica/metabolismo , Dor Crônica/terapia , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Mediadores da Inflamação/metabolismo , Manejo da Dor , Animais , HumanosRESUMO
Twelve 7-chloroquinoline derivatives were designed and synthesized using the principle of molecular hybridization through the coupling of 2-[2-(7-chloroquinolin-4-ylthio)-4-methylthiazol-5-yl]acetic acid 1 with various benzoyl hydrazines 2a-l. The synthetic compounds were tested as antimalarials. Some of them showed an efficient in vitro activity as inhibitors of ß-hematin formation and an in vivo activity in a murine model, resulting in compounds 8 and 9 as the most active ones with IC50 values of 0.65 ± 0.09 and 0.64 ± 0.16 µM, respectively. The effects of the compounds on the cell viability, cell cycle, and apoptosis induction of A549 and MCF-7 cancer cell lines were also examined. Our data showed that compounds 6 and 12 were the most active agents, decreasing the cell viability of MCF-7 cells with IC50 values of 15.41 and 12.99 µM, respectively. None of the compounds analyzed significantly affected the viability of peripheral blood mononuclear cells. Also, significant induction of apoptosis was observed when both cancer cell lines were incubated with compounds 6 and 12. In MCF-7 cells, treatment with these compounds led to cell cycle arrest in the G0/G1 phase. The results obtained suggest that these structures may be useful in developing new therapies for malaria and cancer treatment.
Assuntos
Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Hidrazinas/farmacologia , Quinolinas/farmacologia , Células A549 , Ácido Acético/síntese química , Ácido Acético/química , Ácido Acético/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Concentração Inibidora 50 , Células MCF-7 , Malária/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologiaRESUMO
The yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, members of the Hippo signaling pathway, which play a critical role in cell growth regulation, embryonic development, regeneration, proliferation, and cancer origin and progression. The mechanism involves the nuclear binding of the un-phosphorylated YAP/TAZ complex to release the transcriptional enhanced associate domain (TEAD) from its repressors. The active ternary complex is responsible for the aforementioned biological effects. Overexpression of YAP/TAZ has been reported in cancer stem cells and tumor resistance. The resistance involves chemotherapy, targeted therapy, and immunotherapy. This review provides an overview of YAP/TAZ pathways' role in carcinogenesis and tumor microenvironment. Potential therapeutic alternatives are also discussed.
Assuntos
Carcinogênese/metabolismo , Carcinogênese/patologia , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismo , Microambiente Tumoral , Proteínas de Sinalização YAP , Animais , Resistencia a Medicamentos Antineoplásicos , Humanos , Mecanotransdução CelularRESUMO
BACKGROUND: Various pieces of evidence have shown that people who consume foods rich in polyphenolic and flavonoids compounds have a lower incidence of inflammatory, autoimmune diseases and cancer. OBJECTIVE: The study aimed to review the most potent compounds that affect the immune response and diseases associated with it. METHODS: Publications in PubMed and EmBase, from 1974-2018, and patents form Free patents online, Scifinder, Espacenet and Mendeley in which flavonoids, their semi-synthetic and synthetic derivatives are involved in immunosuppressive or immunostimulatory responses in vitro and in vivo. RESULTS: In vitro, flavonoids and their derivatives inhibit various transcriptional factors, which modulate differentiation, proliferation, activation of immune cells and enhance regulatory T cell generation. Some flavonoids exert anti-inflammatory effects through: Blockade of NF-κB, and NLRP3 inflammasome, inhibition of pro-inflammatory cytokine production, IL-1ß, IL-2, IL-6, TNF-α, IL-17A, down regulation of chemokines, and reduction of reactive oxygen and nitrogen species. Nevertheless, several reports have shown that some flavonoids enhance immune response by enhancing: oxygen and nitrogen radicals, antibody production, cytotoxic activity against tumours by increasing activating receptors and down regulating inhibitory receptors. In consequence, flavonoids may be potentially useful for treatment of infectious diseases and cancer. CONCLUSION: The most potent flavonoids in inflammation that modify immune responses are apigenin, quercetin and Epigallocatechin-3-Gallate (EGCG) although, other compounds are still under study and cannot be excluded. The most relevant patents concerning the use of flavones and other polyphenols were revised. A promising future of these compounds in different therapies is discussed.
Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças Autoimunes/terapia , Flavonoides/uso terapêutico , Neoplasias/terapia , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes/imunologia , Citocinas/metabolismo , Humanos , Imunidade Celular , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Neoplasias/imunologia , Patentes como Assunto , Transdução de SinaisRESUMO
Chemically modified versions of bioactive substances, are particularly useful in overcoming barriers associated with drug formulation, drug delivery and poor pharmacokinetic properties. In this study, a series of fourteen (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate (2-15) were prepared by using a one step synthesis from 1 previously described by us as potential antimalarial and antitumor agent. Molecules were evaluated as inhibitors of ß-hematin formation, where most of them showed a significant inhibition value (%â¯>â¯70). The best inhibitors were tested in vivo as potential antimalarials in mice infected with P. berghei ANKA, chloroquine susceptible strain. Three of them (5, 6, and 15) displayed antimalarial activity comparable to that of chloroquine. Also, molecules were evaluated for their cytotoxic activity against two human cancer cell lines (Jurkat E6.1 and HL60) and primary culture of human lymphocytes. Most of the synthesized compounds, except for analogs 2-6, 8, and 10-12, displayed cytotoxicity against cancer cell lines without affecting normal cells. The potency of the compounds was 15â¯â«â¯1, and 14â¯>â¯7, 9, and 13. Flow cytometry analysis demonstrated an increase in apoptotic cell death after 24â¯h. The compounds may affect tumor cell autophagy and consequently increase cell apoptosis.
Assuntos
Acrilatos/química , Antimaláricos/química , Antineoplásicos/química , Cloroquina/química , Acrilatos/farmacologia , Acrilatos/uso terapêutico , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Cloroquina/farmacologia , Células HL-60 , Hemina/antagonistas & inibidores , Hemina/metabolismo , Humanos , Células Jurkat , Malária/tratamento farmacológico , Malária/patologia , Malária/veterinária , Camundongos , Plasmodium berghei/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
There have been few changes over the last 50 years in the treatment of Systemic lupus erythematosus (SLE), using non-specific anti-inflammatory agents such as: nonsteroidal anti-inflammatory drugs along with the immune cell modulating agent hydroxychloroquine for mild disease, and broad spectrum immunosuppressants plus antiinflammatories such as corticosteroids, azathioprine, cyclophosphamide, or mycophenolate during flares or severe disease with organ involvement. In some patients, the response is inadequate and side effects appear from mild unpleasant up to severe toxicity. Drug metabolism and clearance may be severely compromised. Therefore, it is a priority to develop better treatments with fewer adverse events that can be used at different stages of disease activity. In recent years, a member of the tumor necrosis factor (TNF) family, soluble human B Lymphocyte Stimulator protein (BLyS), also referred to as B-cell activating factor (BAFF) and TNFSF13B has been studied extensively. This protein is synthesized by myeloid cell lines, specifically interacts with B lymphocytes and increases their life-span. BlyS plays a key role in the selection, maturation and survival of B cells and it has a significant role in the pathogenesis of SLE. In this review, we analyzed the role of BLyS as a diagnostic/prognostic marker and/or therapeutic target for lupus patients, and the different clinical studies published using belimumab.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Fator Ativador de Células B/análise , Fator Ativador de Células B/imunologia , Ensaios Clínicos como Assunto , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/imunologiaRESUMO
The use of vaccines in pregnant, immunocompromised or chronic diseases patients has been widely discussed in the literature recently. Vaccines continue to be a safe and effective method to induce or recall immune response to several infective agents or even induce an effective response in chronically infected patients. The general presumption of adverse events, lack of response and unwanted tolerance seem to be responsible for the decreased vaccination rate in these patients. In the present review, the use of rational vaccination schemes, new patents of use, along as new approaches and patents have been discussed with the scope to diminish the high morbidity and mortality often encountered in these patients.
Assuntos
Hospedeiro Imunocomprometido/imunologia , Gravidez/imunologia , Vacinas/imunologia , Doença Crônica , Feminino , Humanos , VacinaçãoRESUMO
Adjuvants may promote immune responses: by recruiting professional antigen-presenting cells (APCs) to the vaccination site, increasing the delivery of antigens to APCs, or by activating APCs to produce cytokines and by triggering T cell responses. Aluminium salts have been effective at promoting protective humoral immunity; however, they are not effective in generating cell-mediated immunity. A number of different approaches have been developed to potentiate immune response and they have been partially successful. Research has been conducted into vaccine delivery systems (VDS); enhancing cross-presentation by targeting antigens to (APCs). Antigen discovery has increased over the past decade, and consequently, it has accelerated vaccine development demanding a new generation of VDS that combines different types of adjuvants into specific formulations with greater activity. The new approaches offer a wide spectrum of opportunities in vaccine research with direct applications in the near future.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Vacinas/administração & dosagem , Compostos de Alumínio/administração & dosagem , Animais , Apresentação de Antígeno , Células Apresentadoras de Antígenos/imunologia , Citocinas/administração & dosagem , Emulsões/administração & dosagem , Humanos , ISCOMs/administração & dosagem , Ligantes , Lipossomos/administração & dosagem , Nanopartículas/administração & dosagem , Saponinas/administração & dosagem , Receptores Toll-Like/metabolismoRESUMO
Autophagy is a complex process in which cell homeostasis of proteins, organelles, exocytic and endocytic vacuoles is controlled. There is a direct link between autophagy and cell death with antigen processing, generation of inflammatory response and immune response. In different diseases, deficiencies in autophagy have been reported. In cancer, it has been proposed that autophagy, at its beginning, is capable of inducing cell death; however, in aggressive tumours and metastasis, the process is responsible for pharmacologic resistance and tumour survival. More research has to be done in order to allow us to understand the process and generate therapeutic options in different pathologies important for the human being. Some patents focused on methodology of autophagosome formation and analysis which seem to be important for pathological description and eventually in future therapeutic approaches have also been reviewed in this article.
Assuntos
Autofagia , Morte Celular , Fagossomos/metabolismo , Animais , Autofagia/imunologia , Carcinogênese , Resistencia a Medicamentos Antineoplásicos , Homeostase/imunologia , Humanos , Imunidade , Patentes como AssuntoRESUMO
Endometriosis is an inflammatory disease characterized by the presence of endometrial glandular epithelial and stromal cells growing in the extra-uterine environment. The disease affects: ovarian function, oocyte quality, embryo development and implantation, and uterine function resulting in infertility or spontaneous pregnancy loss. Even though the world's prevalence is above 10 %, an effective treatment has not yet been found. New pharmacological approaches have been designed and patented that could serve as future therapies for this disease.
Assuntos
Descoberta de Drogas/métodos , Endometriose/tratamento farmacológico , Saúde da Mulher/tendências , Desenho de Fármacos , Feminino , Humanos , Patentes como AssuntoRESUMO
PURPOSE: In search for new drugs derived from natural products for the possible treatment of cancer, we studied the action of agelasine B, a compound purified from a marine sponge Agelas clathrodes. METHODS: Agelasine B was purified from a marine sponge Agelas clathrodes and assayed for cytotoxicity by MTT on two human breast cancer cells (MCF-7 and SKBr3), on a prostate cancer cells (PC-3) and on human fibroblasts. Changes in the intracellular Ca(2+) concentrations were assessed with FURA 2 and by confocal microscopy. Determination of Ca(2+)-ATPase activity was followed by Pi measurements. Changes in the mitochondria electrochemical potential was followed with Rhodamine 123. Apoptosis and DNA fragmentation were determined by TUNEL experiments. RESULTS: Upon agelasine B treatment, cell viability of both human breast cancer cell lines was one order of magnitude lower as compared with fibroblasts (IC(50) for MCF-7 = 2.99 µM; SKBr3: IC(50) = 3.22 µM vs. fibroblasts: IC(50) = 32.91 µM), while the IC(50) for PC-3 IC(50) = 6.86 µM. Agelasine B induced a large increase in the intracellular Ca(2+) concentration in MCF-7, SKBr3, and PC-3 cells. By the use of confocal microscopy coupled to a perfusion system, we could observe that this toxin releases Ca(2+) from the endoplasmic reticulum (ER). We also demonstrated that agelasine B produces a potent inhibition of the ER Ca(2+)-ATPase (SERCA), and that this compound induced the fragmentation of DNA. Accordingly, agelasine B reduced the expression of the anti-apoptotic protein Bcl-2 and was able to activate caspase 8, without affecting the activity of caspase 7. CONCLUSIONS: Agelasine B in MCF-7 cells induce the activation of apoptosis in response to a sustained increase in the [Ca(2+)]( i ) after blocking the SERCA activity. The reproduction of the effects of agelasine B on cell viability and on the [Ca(2+)]( I ) obtained on SKBr3 and PC-3 cancer cells strongly suggests the generality of the mechanism of action of this toxin.
Assuntos
Agelas/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Naftalenos/farmacologia , Purinas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/isolamento & purificação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Cálcio/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Marcação In Situ das Extremidades Cortadas , Concentração Inibidora 50 , Masculino , Microscopia Confocal , Naftalenos/administração & dosagem , Naftalenos/isolamento & purificação , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Purinas/administração & dosagem , Purinas/isolamento & purificaçãoRESUMO
Systemic diseases affect skeletal muscle, and inflammation and oxidative stress are some of the involved mechanisms. There is scarce information about the effects of essential hypertension on skeletal muscle. The soleus and extensor digitorum longus (EDL) muscles of spontaneously hypertensive rats (SHR) were studied compared to control Wistar Kyoto (WKY) rats. The levels of nitrite and nitrate in micromol/mg-protein; endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) nitric oxide synthases, nitrotyrosine and tumour necrosis factor alpha (TNF-alpha) in ng/mg-protein were determined. Compared with controls, the SHR showed increased levels of nitrotyrosine (soleus 24.4 +/- 5.0 vs. 3.3 +/- 0.3, p<0.001; EDL 20.2 +/- 4.3 vs. 4.5 +/- 0.4, p<0.0037), iNOS (soleus 26.6 +/- 3.7 vs. 8.3 +/- 0.9; EDL 21.3 +/- 3.7 vs. 11.0 +/- 0.8, both p<0.0001) and TNF-alpha (soleus 2.2 +/- 0.5 vs. 0.6 +/- 0.1, p<0.05; EDL 1.9 +/- 0.2 vs. 0.6 +/- 0.1, p<0.02). A decrease of eNOS was found in soleus muscle (20.6 +/- 1.4 vs. 30.3 +/- 1.2, p<0.00001); of nNOS (soleus 16.8 +/- 1.4 vs. 20.7 +/- 1.8, p< 0.05; EDL 13.6 +/- 1.3 vs. 21.9 +/- 1.8, p<.005) and nitrite in EDL (5.8 +/- 0.3 vs. 7.1 +/- 0.5, p<0.026).There was a positive correlation between TNF-alpha vs. nitrotyrosine in soleus (r=0.798; p<0.031) and a tendency in EDL (r=0.739; p=0.059); iNOS vs. nitrotyrosine (soleus: r=0.908; p<0.0001; EDL: r=0.707; p<0.01), a tendency between TNF-alpha and iNOS (EDL: r=0.736; p<0.059); and a negative correlation between eNOS vs. nitrotyrosine in soleus muscle (r=-0.816; p<0.0012). In conclusion, in skeletal muscles of SHR an inflammatory process was found evidenced by the increase in TNF-alpha, nitrotyrosine and iNOS. The decreased levels of constitutive synthases, together with the higher level of iNOS, are indicative of endothelial dysfunction.
Assuntos
Hipertensão/metabolismo , Músculo Esquelético/metabolismo , Estresse Oxidativo , Animais , Endotélio Vascular/fisiopatologia , Masculino , Músculo Esquelético/química , Miosite/metabolismo , Óxido Nítrico Sintase Tipo I/análise , Óxido Nítrico Sintase Tipo II/análise , Óxido Nítrico Sintase Tipo III/análise , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Fator de Necrose Tumoral alfa/análise , Tirosina/análogos & derivados , Tirosina/análiseRESUMO
Las enfermedades sistémicas crónicas afectan el músculo esquelético, siendo la inflamación y el estrés oxidativo algunos de los mecanismos involucrados. El efecto de la hipertensión arterial esencial sobre el músculo esquelético no es bien conocido. Se estudiaron los músculos soleo y extensor digitorum longus (EDL) de ratas espontáneamente hipertensas (SHR), comparadas con las controles normotensas Wistar Kyoto (WKY). Se determinaron los niveles de nitritos y nitratos en µmoles/mg-proteína; las sintasas del óxido nítrico: endotelial (eNOS); neuronal (nNOS); e inducible (iNOS), nitrotirosina y el factor de necrosis tumoral-alfa (TNF-α) en ng/mg-proteína. En las SHR, en el soleo y el EDL respectivamente, se incrementó la nitrotirosina (24,4 ± 5,0 vs. 3,3 ± 0,3, p<0,001; 20,2 ± 4,3 vs. 4,5 ± 0,4, p<0,0037), iNOS (26,6 ± 3,7 vs. 8,3 ± 0,9; 21,3 ± 3,7 vs. 11,0 ± 0,8 ambos p<0,0001), y TNF-α (2,2 ± 0,5 vs. 0,6 ± 0,1, p<0,05; 1,9 ± 0,2 vs. 0,6 ± 0,1, p<0,02); hubo disminución de eNOS en el soleo (20,6 ± 1,4 vs. 30,3 ± 1,2, p<0,00001); de nNOS (soleo 16,8 ± 1,4 vs. 20,7 ± 1,8, p< 0,05; EDL 13,6 ± 1,3 vs. 21,9 ± 1,8, p<0,005) y de nitrito en el EDL (5,8 ± 0,3 vs. 7,1 ± 0,5, p<0,026). En las SHR se observó correlación positiva entre TNF-α vs. nitrotirosina: soleo (r=0,798; p<0,031) y tendencia en EDL (r=0,739; p<0,057); iNOS vs. nitrotirosina (soleo: r=0,908 p<0,0001; EDL: r=0,707; p=0,01), tendencia entre TNF-α vs. iNOS en EDL (r=0,736; p=0,059); y correlación negativa entre eNOS vs. nitrotirosina en soleo (r=-0,816; p=0,0012). En conclusión, las SHR presentan un proceso inflamatorio muscular, evidenciado por el incremento de TNF-α, nitrotirosina, e iNOS. La disminución de las sintasas constitutivas, con incremento de la iNOS es evidencia de la disfunción endotelial.
Systemic diseases affect skeletal muscle, and inflammation and oxidative stress are some of the involved mechanisms. There is scarce information about the effects of essential hypertension on skeletal muscle. The soleus and extensor digitorum longus (EDL) muscles of spontaneously hypertensive rats (SHR) were studied compared to control Wistar Kyoto (WKY) rats. The levels of nitrite and nitrate in µmol/mg-protein; endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) nitric oxide synthases, nitrotyrosine and tumour necrosis factor alpha (TNF-α) in ng/mg-protein were determined. Compared with controls, the SHR showed increased levels of nitrotyrosine (soleus 24.4 ± 5.0 vs. 3.3±0.3, p<0.001; EDL 20.2 ± 4.3 vs. 4.5 ± 0.4, p<0.0037), iNOS (soleus 26.6 ± 3.7 vs. 8.3 ± 0.9; EDL 21.3 ± 3.7 vs. 11.0 ± 0.8, both p<0.0001) and TNF-α (soleus 2.2 ± 0.5 vs. 0.6 ± 0.1, p<0.05; EDL 1.9 ± 0.2 vs. 0.6 ± 0.1, p<0.02). A decrease of eNOS was found in soleus muscle (20.6 ± 1.4 vs. 30.3 ± 1.2, p<0.00001); of nNOS (soleus 16.8 ± 1.4 vs. 20.7 ± 1.8, p< 0.05; EDL 13.6 ± 1.3 vs. 21.9 ± 1.8, p<0.005) and nitrite in EDL (5.8 ± 0.3 vs. 7.1 ± 0.5, p<0.026).There was a positive correlation between TNF-α vs. nitrotyrosine in soleus (r=0.798; p<0.031) and a tendency in EDL (r=0.739; p=0.059); iNOS vs. nitrotyrosine (soleus: r=0.908; p<0.0001; EDL: r=0.707; p<0.01), a tendency between TNF-α and iNOS (EDL: r=0.736; p<0.059); and a negative correlation between eNOS vs. nitrotyrosine in soleus muscle (r=-0.816; p<0.0012). In conclusion, in skeletal muscles of SHR an inflammatory process was found evidenced by the increase in TNF-α, nitrotyrosine and iNOS. The decreased levels of constitutive synthases, together with the higher level of iNOS, are indicative of endothelial dysfunction.
Assuntos
Animais , Masculino , Ratos , Hipertensão/metabolismo , Músculo Esquelético/metabolismo , Estresse Oxidativo , Endotélio Vascular/fisiopatologia , Músculo Esquelético/química , Miosite/metabolismo , Óxido Nítrico Sintase Tipo I/análise , Óxido Nítrico Sintase Tipo II/análise , Óxido Nítrico Sintase Tipo III/análise , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Fator de Necrose Tumoral alfa/análise , Tirosina/análise , Tirosina/análogos & derivadosRESUMO
Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease characterized mainly by pulmonary airflow limitation that is not fully reversible. New different pharmacological approaches to decrease inflammation of the airways and consequently disease progression and increase airway obstruction reversibility have been developed. In the present article, we review the new patents on phosphoinositide 3 kinase and NFκb inhibitors for future therapies.
Assuntos
Anti-Inflamatórios/uso terapêutico , Imidazolinas/uso terapêutico , NF-kappa B/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Esteroides/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Humanos , Imidazolinas/farmacologia , Patentes como Assunto , Esteroides/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
Patients with systemic lupus erythematosus (SLE) have a high risk of developing cardiovascular disease; however, the mechanisms involved in the early onset of atherosclerosis in these patients are not clear. Scavenger receptors, CD36 and CD163 are expressed by mononuclear phagocytes and participate in the binding and uptake of oxidized low-density lipoproteins (Ox-LDL), contributing to foam-cells formation and atherosclerosis development. The aim of the present study was to evaluate CD36(+) and CD163(+) expression and Ox-LDL removal by monocytes from SLE and atherosclerotic patients, compared to similar age-range healthy controls. Healthy controls, SLE, and atherosclerotic patients were evaluated for carotid intima media thickness (CIMT), lipid profile, and native LDL (N-LDL) and Ox-LDL binding/endocytosis. SLE patients presented decreased high-density lipoproteins (HDL) and increased Triglyceride levels, and half of the SLE patients had increased CIMT, compared to their healthy controls (HC(SLE)). The number of CD14(+)CD163(+) cells was increased in atherosclerosis healthy controls (HC(Atheros)) compared to HC(SLE), but there were no differences between SLE or atherosclerotic patients and their respective healthy controls. Clearance assays revealed a similar capacity to bind/endocytose Ox-LDL by monocytes from SLE patients and HC(SLE), and an increased binding and endocytosis of Ox-LDL by monocytes from atherosclerotic patients, compared to HC(Atheros). The decreased CD36 and CD163 expression observed in atherosclerotic and SLE patients, respectively, suggest that these inflammatory conditions modulate these receptors differentially. The increased CIMT observed in SLE patients cannot be explained by Ox-LDL binding/endocytosis, which was comparable to their controls.
Assuntos
Aterosclerose/complicações , Aterosclerose/imunologia , Endocitose/imunologia , Lipoproteínas LDL/metabolismo , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Monócitos/imunologia , Adulto , Idoso , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Antígenos CD36/imunologia , Humanos , Receptores de Lipopolissacarídeos/imunologia , Pessoa de Meia-Idade , Oxirredução , Ligação Proteica/imunologia , Receptores de Superfície Celular/imunologia , Adulto JovemRESUMO
Acute lung injury following envenomation by Tityus scorpion species is due in part to activation of the inflammatory response leading to release of cytotoxic leukocyte-derived products, including cytokines and possibly reactive oxygen species (ROS). Tityus zulianus envenomation in Venezuela produces cardiorespiratory complications and death by lung injury whereas stings by Tityus discrepans produce mainly gastrointestinal and pancreatic alterations. To ascertain the role played by granulocytes in the envenomation by T. zulianus (TzV) and T. discrepans (TdV), human peripheral blood neutrophils, eosinophils, and monocytes were exposed to scorpion venoms (0.001-5 µg/mL) and the kinetics (5-15 min) of peroxide production determined by flow cytometry, using 2',7'-dichlorodihydrofluorescein diacetate (succinimidyl ester) as a fluorescent substrate. TzV induced a significantly (p<0.01) more potent increase in peroxide production in neutrophils (for 5 and 10 min of incubation), and to a lesser extent in monocytes (5-15 min), compared to TdV. TzV induced necrosis in neutrophils at doses higher than 5 µg/mL. No effect was observed on eosinophils, suggesting that TzV specifically targets neutrophil intracellular ROS production. The TzV-stimulated pathway is protein kinase C-dependent because it was almost completely (>90%) abolished by staurosporine. The stimulatory effect is associated with the lowest molecular mass venom peptides as gel filtration fractions TzII and TzIII significantly enhanced peroxide production. The combined used of the intracellular ROS agonist, phorbol myristate acetate (PMA), and TzV produced a modest but significant increase in peroxide production suggesting the possibility of overlapping signaling cascades amongst PMA and TzV. Up-regulation of intracellular neutrophil ROS production may be an important in vivo target for TzV which could have a role to play in the cardiorespiratory complications elicited after envenomation by this species.
Assuntos
Ativação de Neutrófilo/efeitos dos fármacos , Venenos de Escorpião/toxicidade , Adulto , Eosinófilos/efeitos dos fármacos , Feminino , Citometria de Fluxo , Humanos , Cinética , Masculino , Peso Molecular , Monócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Concentração Osmolar , Oxirredução/efeitos dos fármacos , Peptídeos/química , Peptídeos/isolamento & purificação , Peptídeos/toxicidade , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Venenos de Escorpião/química , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Thalidomide and its immunomodulatory imide drugs (IMiDs) analogues CC-5013 (Revlimid, Lenalidomide) and CC-4047 (Actimid, Pomalidomide) have been used as anti-inflammatory and anticancerous drugs in the recent years. Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor-alpha (TNF-alpha), interleukins (IL) 1-beta, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T, NKT and NK lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity. On the other hand, the compounds are anti-angiogenic, anti-proliferative, and pro-apoptotic. Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment. In this review, we explore the current trend of the different structures, the new patents, and the possible new applications in different pathologies.