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1.
Artigo em Inglês | MEDLINE | ID: mdl-38175411

RESUMO

RNA interference (RNAi) is a conserved molecular mechanism that plays a critical role in post-transcriptional gene silencing across diverse organisms. This review delves into the role of RNAi in plant functional genomics and its applications in crop improvement, highlighting its mechanistic insights and practical implications. The review begins with the foundational discovery of RNAi's mechanism, tracing its origins from petunias to its widespread presence in various organisms. Various classes of regulatory non-coding small RNAs, including siRNAs, miRNAs, and phasiRNAs, have been uncovered, expanding the scope of RNAi-mediated gene regulation beyond conventional understanding. These RNA classes participate in intricate post-transcriptional and epigenetic processes that influence gene expression. In the context of crop enhancement, RNAi has emerged as a powerful tool for understanding gene functions. It has proven effective in deciphering gene roles related to stress resistance, metabolic pathways, and more. Additionally, RNAi-based approaches hold promise for integrated pest management and sustainable agriculture, contributing to global efforts in food security. This review discusses RNAi's diverse applications, such as modifying plant architecture, extending shelf life, and enhancing nutritional content in crops. The challenges and future prospects of RNAi technology, including delivery methods and biosafety concerns, are also explored. The global landscape of RNAi research is highlighted, with significant contributions from regions such as China, Europe, and North America. In conclusion, RNAi remains a versatile and pivotal tool in modern plant research, offering novel avenues for understanding gene functions and improving crop traits. Its integration with other biotechnological approaches such as gene editing holds the potential to shape the future of agriculture and sustainable food production.

2.
J Obstet Gynaecol India ; 73(3): 214-222, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37324366

RESUMO

Introduction: ERAS is an evidence-based management protocol for perioperative care, to accelerate patient recovery. The field of obstetrics has been a late adapter of ERAS pathway for CS, and the literature is limited from Indian population. Material and Methods: This prospective non-randomized comparative clinical study was conducted on 190 pregnant patients, out of which 95 were subjected to ERAS protocol (Group 1) and remaining 95 cases were enrolled in existing traditional protocol (Group 2). The primary objective was to compare quality of recovery based on obstetric-specific QoR 11 questionnaire between patients undergoing ERAC and traditional protocol for elective LSCS. Secondary objective was to compare perioperative bleeding, breast feeding initiation and difficulties, first oral intake, ambulation attempts, decatheterization, surgical site infection and length of hospital stay. Results: At 24 h postoperatively, mean QoR score was significantly higher for patients in the ERAC group (85.5 ± 7.46 vs 57.1 ± 11.33, p value < 0.01). In the ERAC group, 50.5% of the mothers started breastfeeding within first hour. The mean duration to start oral intake postoperatively was significantly lower in ERAC group. In the ERAC group, ambulation and decatheterization were attempted within 6 h postoperatively in 86.3%. The mean length of hospital stay was significantly lower for patients in the ERAC group (68.8 ± 1.9 vs 105.4 ± 25.7 h, p value < 0.001). Conclusion: The use of ERAC protocol at cesarean delivery significantly improves quality of recovery and length of hospital stay.

3.
BMC Health Serv Res ; 22(1): 1137, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36076224

RESUMO

BACKGROUND: The economic burden of autism is substantial and includes a range of costs, including healthcare, education, productivity losses, informal care and respite care, among others. In India, approximately, 2 million children aged 2-9 years have autism. Given the likely substantial burden of illness and the need to identify effective and cost-effective interventions, this research aimed to produce a comprehensive cost of illness inventory (COII) suitable for children with autism in South Asia (India) to support future research. METHODS: A structured and iterative design process was followed to create the COII, including literature reviews, interviews with caregivers, pilot testing and translation. Across the development of the COII, thirty-two families were involved in the design and piloting of the tool. The COII was forward translated (from English to Hindi) and back translated. Each stage of the process of development of the COII resulted in the further refinement of the tool. RESULTS: Domains covered in the final COII include education, childcare, relocation, healthcare contacts (outpatient, inpatient, medical emergencies, investigations and medication), religious retreats and rituals, specialist equipment, workshops and training, special diet, support and care, certification, occupational adjustments and government rebates/schemes. Administration and completion of the COII determined it to be feasible to complete in 35 minutes by qualified and trained researchers. The final COII is hosted by REDCap Cloud and is a bilingual instrument (Hindi and English). CONCLUSIONS: The COII was developed using experiences gathered from an iterative process in a metropolitan area within the context of one low- and middle-income country (LMIC) setting, India. Compared to COII tools used for children with autism in high-income country settings, additional domains were required, such as complimentary medication (e.g. religious retreats and homeopathy). The COII will allow future research to quantify the cost of illness of autism in India from a broad perspective and will support relevant economic evaluations. Understanding the process of developing the questionnaire will help researchers working in LMICs needing to adapt the current COII or developing similar questionnaires.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/terapia , Criança , Efeitos Psicossociais da Doença , Humanos , Índia , Inquéritos e Questionários
4.
Arch Microbiol ; 203(9): 5509-5517, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34417854

RESUMO

Salmonella Typhimurium (ST) is a Gram-negative zoonotic pathogenic bacterium that causes infectious disease in humans as well as in animals. It causes foodborne diarrheal or gastrointestinal illness and fever called salmonellosis, which is a leading cause of millions of deaths worldwide. Salmonellaenterica serovar Typhimurium (S. Typhimurium) during its pathogenesis take away the actin cytoskeleton of their host cells and this is the crucial step of its infection cycle. Cyclophilin A, a type of peptidyl-prolyl isomerase that's encoded by the ppiA gene in ST, plays pleiotropic roles in maintaining bacterial physiology. In this investigation, the proteomic characterization of the peptidyl-prolyl cis-trans isomerase- A (Cyclophilin A) from Salmonella Typhimurium is reported. Cyclophilin A (CypA) protein from Salmonella Typhimurium proved to be highly conserved and homologous protein sequence compared to other organisms. This protein was expressed in Escherichia coli followed by its purification in a recombinant form protein exhibited a characteristic PPIases activity (Vmax = 0.8752 ± 0.13892 µmoles/min, Km = 0.9315 ± 0.5670 µM) in comparison to control. The mass spectrometry analysis of Cyp A protein-peptide showed a highest sequence similarity with the cyclophilin protein of Salmonella. PPIases proteins (enzyme) data suggest that Ppi-A has roles in the protein folding that may be contributing to the virulence of Salmonella by isomerization of protein outline. These results suggest an active and vital role of this protein in protein folding along with regulation in Salmonella Typhimurium.


Assuntos
Proteínas de Escherichia coli , Salmonella typhimurium , Animais , Proteínas da Membrana Bacteriana Externa , Ciclofilinas/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , Peptidilprolil Isomerase/genética , Peptidilprolil Isomerase/metabolismo , Dobramento de Proteína , Proteômica , Salmonella typhimurium/genética , Salmonella typhimurium/metabolismo
5.
Br J Haematol ; 184(6): 925-936, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30537114

RESUMO

The L265P somatic mutation in the Myeloid Differentiation Primary Response 88 (MYD88) gene is a recurrent mutation in chronic lymphocytic leukaemia (CLL). This mutation has functional effects in various haematological malignancies but its role in CLL remains to be fully elucidated. Here, we report that MYD88 L265P mutations are associated with mutated immunoglobulin heavy-chain gene (IGHV-M) status and that among IGHV-M patients, the presence of MYD88 L265P is associated with younger age at diagnosis. Using microarray and RNA-Seq gene expression analysis, we further observe that the MYD88 L265P mutation is associated with a distinctive gene expression signature that predicts both failure-free survival and overall survival. This association was validated in an independent cohort of patients. To determine whether MYD88 L265P mutations can be therapeutically exploited in CLL, we treated primary cells with an inhibitor of interleukin 1 receptor-associated kinase 4 (IRAK4), a critical effector of the MYD88 pathway. IRAK4 inhibition decreased downstream nuclear factor-κB signalling and cell viability in CLL cells, indicating the potential of the MYD88 pathway as a therapeutic target in CLL.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Fator 88 de Diferenciação Mieloide/genética , Adulto , Idoso , Estudos de Coortes , Citocinas/biossíntese , Feminino , Genes de Cadeia Pesada de Imunoglobulina , Humanos , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Fator 88 de Diferenciação Mieloide/metabolismo , Prognóstico , Transdução de Sinais , Transcriptoma
6.
Artigo em Inglês | MEDLINE | ID: mdl-29485014

RESUMO

BACKGROUND: Mesenchymal Stem Cells (MSCs) are self-renewing, multipotent progenitor cells with multilineage potential to differentiate into all cell types of mesodermal origin, such as adipocytes, osteocytes and chondrocytes. Mesenchymal Stem Cells (MSCs) are adult stem cells which can be isolated from human and animal sources. OBJECTIVE: Besides the differentiation potential of MSCs, these also regulate the immune response in numerous ailments. The present review expedites the immunomodulating prospective of MSCs. METHODS: Scrupulous search of the literature and patents available on MSCs and their role in the immunomodulation was carried out using Medline, PubMed, PubMed Central, Science Direct and other scientific databases. The retrieved information has been analyzed and compiled. RESULTS: MSCs have unique regulation of microenvironment in the host tissue by secreting cytokines and immune-receptors which results in immunomodulatory effects. MSCs can be used as an effective tool in the treatment of chronic diseases because of its property to secrete anti-inflammatory molecules, having multilineage potential and immunomodulation. CONCLUSION: The present review is focused on the use of MSCs due to their unique immunomodulatory characteristics. MSCs reach to the site of inflammation and interact with immune cells to bring immunosuppressive and anti-inflammatory effects. Along with these unique therapeutic properties, MSCs may be a useful therapeutic approach for various disorders.


Assuntos
Imunomodulação , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/fisiologia , Animais , Diferenciação Celular , Humanos , Hipersensibilidade/terapia , Hipertensão/terapia , Óxido Nítrico/fisiologia , Osteoartrite/terapia , Patentes como Assunto
7.
J Exp Med ; 212(13): 2189-201, 2015 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-26621451

RESUMO

Pathological activation of the Toll-like receptor signaling adaptor protein MYD88 underlies many autoimmune and inflammatory disease states. In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the oncogenic MYD88 L265P mutation occurs in 29% of cases, making it the most prevalent activating mutation in this malignancy. IRAK4 kinase accounts for almost all of the biological functions of MYD88, highlighting IRAK4 as a therapeutic target for diseases driven by aberrant MYD88 signaling. Using innovative structure-based drug design methodologies, we report the development of highly selective and bioavailable small molecule IRAK4 inhibitors, ND-2158 and ND-2110. These small molecules suppressed LPS-induced TNF production, alleviated collagen-induced arthritis, and blocked gout formation in mouse models. IRAK4 inhibition promoted killing of ABC DLBCL lines harboring MYD88 L265P, by down-modulating survival signals, including NF-κB and autocrine IL-6/IL-10 engagement of the JAK-STAT3 pathway. In ABC DLBCL xenograft models, IRAK4 inhibition suppressed tumor growth as a single agent, and in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib or the Bcl-2 inhibitor ABT-199. Our findings support pharmacological inhibition of IRAK4 as a therapeutic strategy in autoimmune disorders, in a genetically defined population of ABC DLBCL, and possibly other malignancies dependent on aberrant MYD88 signaling.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia , Animais , Artrite Experimental/tratamento farmacológico , Doenças Autoimunes/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Descoberta de Drogas , Gota/tratamento farmacológico , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Fator 88 de Diferenciação Mieloide/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Quinase Syk , Fator de Necrose Tumoral alfa/biossíntese
8.
J Med Chem ; 58(1): 96-110, 2015 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-25479567

RESUMO

IRAK4, a serine/threonine kinase, plays a key role in both inflammation and oncology diseases. Herein, we summarize the compelling biology surrounding the IRAK4 signaling node in disease, review key structural features of IRAK4 including selectivity challenges, and describe efforts to discover clinically viable IRAK4 inhibitors. Finally, a view of knowledge gained and remaining challenges is provided.


Assuntos
Quinases Associadas a Receptores de Interleucina-1/química , Inibidores de Proteínas Quinases/química , Estrutura Terciária de Proteína , Bibliotecas de Moléculas Pequenas/química , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Humanos , Inflamação/tratamento farmacológico , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Estrutura Molecular , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia
9.
Nat Prod Commun ; 8(7): 911-3, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23980422

RESUMO

Both 3-farnesyl salicylic acid and 3-geranyl salicylic acid were synthesized from 2,6-dibromophenol and showed low levels of antimicrobial activity against E. coli strains.


Assuntos
Anti-Infecciosos/síntese química , Piper/química , Salicilatos/síntese química , Salicilatos/farmacologia
10.
Bioorg Med Chem Lett ; 20(6): 1965-8, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20153643

RESUMO

Analog 8, a 3-pyridinecarbonitrile with an (E)-2-[6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl]vinyl group at C-5, had an IC(50) value of 1.1 nM for the inhibition of PKCtheta and potently blocked the production of IL-2 in both stimulated murine T cells (IC(50)=34 nM) and human whole blood (IC(50)=500 nM).


Assuntos
Isoenzimas/antagonistas & inibidores , Nitrilas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Humanos , Interleucina-2/biossíntese , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Nitrilas/química , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
11.
Inflamm Res ; 59(3): 207-18, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19763788

RESUMO

OBJECTIVE: Mast cell and basophil activation contributes to inflammation, bronchoconstriction, and airway hyperresponsiveness in asthma. Because IL-33 expression is inflammation inducible, we investigated IL-33-mediated effects in concert with both IgE-mediated and IgE-independent stimulation. METHODS: Because the HMC-1 mast cell line can be activated by GPCR and RTK signaling, we studied the effects of IL-33 on these pathways. The IL-33- and SCF-stimulated HMC-1 cells were co-cultured with human lung fibroblasts and airway smooth muscle cells in a collagen gel contraction assay. IL-33 effects on IgE-mediated activation were studied in primary mast cells and basophils. RESULT: IL-33 synergized with adenosine, C5a, SCF, and NGF receptor activation. IL-33-stimulated and SCF-stimulated HMC-1 cells demonstrated enhanced collagen gel contraction when cultured with fibroblasts or smooth muscle cells. IL-33 also synergized with IgE receptor activation of primary human mast cells and basophils. CONCLUSION: IL-33 amplifies inflammation in both IgE-independent and IgE-dependent responses.


Assuntos
Basófilos/efeitos dos fármacos , Basófilos/metabolismo , Imunoglobulina E/metabolismo , Interleucinas/farmacologia , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Basófilos/citologia , Linhagem Celular , Quimiocinas/metabolismo , Técnicas de Cocultura , Colágeno/metabolismo , Citocinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Histamina/metabolismo , Humanos , Interleucina-33 , MAP Quinase Quinase 4/metabolismo , Mastócitos/citologia , Músculo Liso/citologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Receptores Purinérgicos P1/metabolismo , Fator de Células-Tronco/farmacologia
14.
Bioorg Med Chem Lett ; 19(18): 5423-5, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19682896

RESUMO

We earlier reported that 3-pyridinecarbonitriiles with a 4-methylindolyl-5-amino group at C-4 and a phenyl group at C-5 were inhibitors of PKCtheta. Keeping the group at C-4 of the pyridine core constant, we varied the water solubilizing group on the phenyl ring at C-5 and then replaced the C-5 phenyl ring with several monocyclic heteroaryl rings, including furan, thiophene and pyridine. Analog 6e with a 4-methylindol-5-ylamino group at C-4 and a 5-[(4-methylpiperazin-1-yl)methyl]-2-furyl group C-5 had an IC50 value of 4.5 nM for the inhibition of PKCtheta.


Assuntos
Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Nitrilas/química , Nitrilas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Piridinas/farmacologia , Animais , Concentração Inibidora 50 , Isoenzimas/genética , Camundongos , Camundongos Knockout , Proteína Quinase C/genética , Proteína Quinase C-theta , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
15.
Bioorg Med Chem Lett ; 19(19): 5799-802, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19703774

RESUMO

We previously reported that a 3-pyridinecarbonitrile analog with a furan substituent at C-5 and a 4-methylindol-5-ylamino substituent at C-4, 1, was a potent inhibitor of PKCtheta (IC50=4.5 nM). Replacement of the C-5 furan ring of 1 with bicyclic heteroaryl rings, led to compounds with significantly improved potency against PKCtheta. Analog 6b with a 4-methylindol-5-ylamino group at C-4 and a 5-[(4-methylpiperazin-1-yl)methyl]-1-benzofuran-2-yl group at C-5 had an IC50 value of 0.28 nM for the inhibition of PKCtheta.


Assuntos
Aminopiridinas/química , Isoenzimas/antagonistas & inibidores , Nitrilas/química , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridinas/química , Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/farmacologia , Meia-Vida , Humanos , Interleucina-2/metabolismo , Isoenzimas/metabolismo , Camundongos , Microssomos Hepáticos/metabolismo , Nitrilas/síntese química , Nitrilas/farmacologia , Proteína Quinase C/metabolismo , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Linfócitos T/imunologia , Linfócitos T/metabolismo
16.
Bioorg Med Chem Lett ; 19(13): 3623-6, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19447612

RESUMO

The key intermediate, 4-chloro-5-iodo-3-pyridinecarbonitrile, allowed for ready optimization of the PKCtheta inhibitory activity of a series of 3-pyridinecarbonitriles. Analog 13b with a 4-methylindol-5-ylamino group at C-4 and a 4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl group at C-5 had an IC(50) value of 7.4nM for the inhibition of PKCtheta.


Assuntos
Indóis/química , Isoenzimas/antagonistas & inibidores , Nitrilas/química , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridinas/química , Animais , Indóis/síntese química , Indóis/farmacologia , Isoenzimas/metabolismo , Camundongos , Nitrilas/síntese química , Nitrilas/farmacologia , Proteína Quinase C/metabolismo , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 19(9): 2461-3, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19345579

RESUMO

A series of 4-indolylamino-5-phenyl-3-pyridinecarbonitrile inhibitors of PKCtheta were synthesized as potential anti-inflammatory agents. The effects of specific substitution on the 5-phenyl moiety and variations of the positional isomers of the 4-indolylamino substituent were explored. This study led to the discovery of compound 12d, which had an IC(50) value of 18nM for the inhibition of PKCtheta.


Assuntos
Isoenzimas/antagonistas & inibidores , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Piridinas/síntese química , Trifosfato de Adenosina/química , Animais , Anti-Inflamatórios/farmacologia , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Isoenzimas/química , Camundongos , Modelos Químicos , Estrutura Molecular , Isoformas de Proteínas , Proteína Quinase C/química , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Relação Estrutura-Atividade
18.
Cytokine ; 46(1): 111-8, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19237298

RESUMO

IL-13 is known to affect many processes that contribute to an asthmatic phenotype, including inflammation, fibrosis, and mucus production. Members of the aquaporin (AQP) family of transmembrane water channels are targets of regulation in models of lung injury and inflammation. Therefore, we examined AQP mRNA and protein expression in allergen and IL-13-induced mouse models of asthma. Lungs from ovalbumin sensitized and ovalbumin challenged (OVA/OVA) and IL-13 treated mice showed airway thickening, increased mucus production, and pulmonary eosinophilia. Pulmonary function tests showed a significant increase in methacholine-induced airway hyperreactivity in OVA/OVA and IL-13-treated mice as compared with controls. Quantitative PCR analysis revealed differential regulation of AQPs in these two models. AQP1 and AQP4 mRNA expression was downregulated in the OVA/OVA model, but not in the IL-13 model. AQP5 mRNA was reduced in both models, whereas AQP3 was upregulated only in the IL-13 model. Western analysis showed that diminished expression of an apically localized aquaporin, (AQP5), and concomitant upregulation of a basolateral aquaporin (AQP3 or AQP4) are characteristic features of both inducible asthma models. These results demonstrate that aquaporins are common targets of gene expression in both allergen and IL-13 induced mouse models of asthma.


Assuntos
Aquaporina 5/biossíntese , Aquaporina 5/metabolismo , Asma/metabolismo , Regulação da Expressão Gênica , Interleucina-13/biossíntese , Animais , Aquaporina 1/biossíntese , Aquaporina 4/biossíntese , Broncoconstritores/farmacologia , Modelos Animais de Doenças , Feminino , Inflamação , Pulmão/metabolismo , Cloreto de Metacolina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Biológicos
19.
Bioorg Med Chem Lett ; 19(3): 766-9, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19111463

RESUMO

Thieno[2,3-b]pyridine-5-carbonitrile 16 with a 4-methyl-5-indolylamine at C-4 and a 5-methoxy-2-(dimethylamino)-methylphenyl group at C-2 had an IC(50) value of 16 nM for the inhibition of PKCtheta. While moderate inhibition of PKCdelta was also observed (IC(50)=130 nM), 16 had IC(50) values of greater than 5 microM against Lyn and other members of the Src kinase family.


Assuntos
Química Farmacêutica/métodos , Indóis/síntese química , Isoenzimas/antagonistas & inibidores , Nitrilas/química , Proteína Quinase C/antagonistas & inibidores , Piridinas/química , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Indóis/farmacologia , Concentração Inibidora 50 , Modelos Químicos , Nitrilas/síntese química , Nitrilas/farmacologia , Proteína Quinase C-theta , Relação Estrutura-Atividade , Quinases da Família src/antagonistas & inibidores
20.
J Med Chem ; 51(19): 5958-63, 2008 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-18783200

RESUMO

The protein kinase C (PKC) family of serine/threonine kinases is implicated in a wide variety of cellular processes. The PKC theta (PKCtheta) isoform is involved in TCR signal transduction and T cell activation and regulates T cell mediated diseases, including lung inflammation and airway hyperresponsiveness. Thus inhibition of PKCtheta enzyme activity by a small molecule represents an attractive strategy for the treatment of asthma. A PKCtheta high-throughput screening (HTS) campaign led to the identification of 4-(3-bromophenylamino)-5-(3,4-dimethoxyphenyl)-3-pyridinecarbonitrile 4a, a low microM ATP competitive PKCtheta inhibitor. Structure based hit-to-lead optimization led to the identification of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-ylamino)-3-pyridinecarbonitrile 4p, a 70 nM PKCtheta inhibitor. Compound 4p was selective for inhibition of novel PKC isoforms over a panel of 21 serine/threonine, tyrosine, and phosphoinositol kinases, in addition to the conventional and atypical PKCs, PKCbeta, and PKCzeta, respectively. Compound 4p also inhibited IL-2 production in antiCD3/anti-CD28 activated T cells enriched from splenocytes.


Assuntos
Indóis/farmacologia , Isoenzimas/antagonistas & inibidores , Nitrilas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Indóis/síntese química , Indóis/química , Interleucina-2/antagonistas & inibidores , Interleucina-2/biossíntese , Isoenzimas/deficiência , Isoenzimas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/química , Proteína Quinase C/deficiência , Proteína Quinase C/efeitos dos fármacos , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Estereoisomerismo , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
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