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1.
Int J Biol Macromol ; : 133906, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39019364

RESUMO

This novel research addresses the critical need for sustainable and efficient materials, aiming to enhance the optical and thermoelectric properties of Aluminum doped Zinc Oxide (Al doped ZnO) on cellulose fabric for diverse applications. At first stage, Cellulosic fabric of Al doped ZnO were experimentally studied in detail with respect to varying levels of annealing temperature. Structural analysis unveiled structural evolution in hexagonal crystal formations with a reduction in particle size up to 27.5 % on average, with increased temperature. Further, Raman spectroscopy revealed the doping effects on the vibrational modes of ZnO, potentially due to alterations in lattice structure. The ZnO optical modes are found as E2 (low) = 110 cm-1 with observed phonon frequency in the Raman spectra of ZnO at A1 (TO) = 364 cm-1. Fourier transform infrared spectroscopy (FTIR) revealed the presence of characteristic stretching of developed material. Furthermore, the optical characters revealed a decrement of 43.22 % in bandgap values with increasing annealing temperature. The analysis of thermoelectric attributes documented that the prominent sample annealed at 300°C exhibited the maximum Seebeck coefficient and power factor of 2.1 × 10-3 µV/oC and 5.8 × 10-21 Wm-1 K-2, respectively. At second stage the optical characteristics of experimentally optimized sample were rigorously studied through the application of soft of Material Studio while varying the doping ratio.

3.
Bioorg Med Chem Lett ; 89: 129311, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37149230

RESUMO

Braylin (10b) is a 8,8-dimethyl chromenocoumarin present in the plants of the family Rutaceae and Meliaceae and possesses vasorelaxing and anti-inflammatory activities. In this study, six 6-alkoxy (10b, 15-19), and twelve 6-hydroxy-alkyl amine (20a-20l) derivatives of braylin (11 and 12) were synthesized to delineate its structural requirement for vasorelaxing activity. The synthesized compounds were evaluated for vasorelaxation response in preconstricted intact rat Main Mesenteric Artery (MMA). The compounds showed l-type VDCC channel blockade depended and endothelium-independent vasorelaxation within the range of Emax < 50.00-96.70 % at 30 µM. Amongst all, 6-alkoxy derivatives were more active than 6-hydroxy-alkyl amine derivatives. The structural refinements about braylin showed that deletion of its methoxy group or homologation beyond ethoxy group presented deleterious effect on vasorelaxation response of braylin. Interestingly, substituting the ethoxy group in 10b presented the best activity and selectivity towards l-type VDCC channel blockade, a specific target cardiovascular function.


Assuntos
Canais de Cálcio Tipo L , Vasodilatação , Animais , Ratos , Álcoois , Aminas/farmacologia , Canais de Cálcio Tipo L/farmacologia
4.
Eur J Pharmacol ; 943: 175558, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36731722

RESUMO

PURPOSE: Protective effect of 17ß-estradiol is well-known in pulmonary hypertension. However, estrogen-based therapy may potentially increase the risk of breast cancer, necessitating a search for novel drugs. This study, therefore, investigated the ameliorative effects of a selective estrogen receptor modulator, ormeloxifene, in pulmonary hypertension. METHODS: Cardiomyocytes (H9C2) and human pulmonary arterial smooth muscle cells (HPASMCs) were exposed to hypoxia (1% O2) for 42 and 96 h, respectively, with or without ormeloxifene pre-treatment (1 µM). Also, female (ovary-intact or ovariectomized) and male Sprague-Dawley rats received monocrotaline (60 mg/kg, once, subcutaneously), with or without ormeloxifene treatment (2.5 mg/kg, orally) for four weeks. RESULTS: Hypoxia dysregulated 17ß-hydroxysteroid dehydrogenase (17ßHSD) 1 & 2 expressions, reducing 17ß-estradiol production and estrogen receptors α and ß in HPASMC but increasing estrone, proliferation, inflammation, oxidative stress, and mitochondrial dysfunction. Similarly, monocrotaline decreased plasma 17ß-estradiol and uterine weight in ovary-intact rats. Further, monocrotaline altered 17ßHSD1 & 2 expressions and reduced estrogen receptors α and ß, increasing right ventricular pressure, proliferation, inflammation, oxidative stress, endothelial dysfunction, mitochondrial dysfunction, and vascular remodeling in female and male rats, with worsened conditions in ovariectomized rats. Ormeloxifene was less uterotrophic; however, it attenuated both hypoxia and monocrotaline effects by improving pulmonary 17ß-estradiol synthesis. Furthermore, ormeloxifene decreased cardiac hypertrophy and right ventricular remodeling induced by hypoxia and monocrotaline. CONCLUSION: This study demonstrates that ormeloxifene promoted pulmonary 17ß-estradiol synthesis, alleviated inflammation, improved the NOX4/HO1/Nrf/PPARγ/PGC-1α axis, and attenuated pulmonary hypertension. It is evidently safe at tested concentrations and may be effectively repurposed for pulmonary hypertension treatment.


Assuntos
Hipertensão Pulmonar , Moduladores Seletivos de Receptor Estrogênico , Ratos , Masculino , Feminino , Humanos , Animais , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/prevenção & controle , Hipertensão Pulmonar/induzido quimicamente , Ratos Sprague-Dawley , Receptor alfa de Estrogênio , Monocrotalina/efeitos adversos , Estradiol/farmacologia , Estradiol/uso terapêutico , Artéria Pulmonar , Inflamação , Hipóxia
5.
J Biol Chem ; 299(2): 102799, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36528062

RESUMO

Collagen triple helices are critical in the function of mannan-binding lectin (MBL), an oligomeric recognition molecule in complement activation. The MBL collagen regions form complexes with the serine proteases MASP-1 and MASP-2 in order to activate complement, and mutations lead to common immunodeficiencies. To evaluate their structure-function properties, we studied the solution structures of four MBL-like collagen peptides. The thermal stability of the MBL collagen region was much reduced by the presence of a GQG interruption in the typical (X-Y-Gly)n repeat compared to controls. Experimental solution structural data were collected using analytical ultracentrifugation and small angle X-ray and neutron scattering. As controls, we included two standard Pro-Hyp-Gly collagen peptides (POG)10-13, as well as three more peptides with diverse (X-Y-Gly)n sequences that represented other collagen features. These data were quantitatively compared with atomistic linear collagen models derived from crystal structures and 12,000 conformations obtained from molecular dynamics simulations. All four MBL peptides were bent to varying degrees up to 85o in the best-fit molecular dynamics models. The best-fit benchmark peptides (POG)n were more linear but exhibited a degree of conformational flexibility. The remaining three peptides showed mostly linear solution structures. In conclusion, the collagen helix is not strictly linear, the degree of flexibility in the triple helix depends on its sequence, and the triple helix with the GQG interruption showed a pronounced bend. The bend in MBL GQG peptides resembles the bend in the collagen of complement C1q and may be key for lectin pathway activation.


Assuntos
Colágeno , Ativação do Complemento , Lectina de Ligação a Manose , Colágeno/química , Lectina de Ligação a Manose/química , Lectina de Ligação a Manose/metabolismo , Soluções/química , Conformação Proteica , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Relação Estrutura-Atividade , Estabilidade Proteica , Espalhamento a Baixo Ângulo , Difração de Nêutrons , Ultracentrifugação , Simulação de Dinâmica Molecular , Cristalografia por Raios X , Maleabilidade
6.
J Heart Lung Transplant ; 42(1): 1-6, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36283952

RESUMO

Pulmonary hypertension (PH) is a rare condition associated with significant morbidity and mortality. The priorities for future research in PH according to patients, caregivers, and clinicians have not been established. We performed a James Lind Alliance priority setting partnership in Canada. An initial survey of 249 respondents (76% patients and/or caregivers, 12.5% clinicians) generated 1588 questions, which were combined into 187 summary questions. An evidence check identified 352 systematic reviews and guidelines which were mapped to the summary questions, which determined that 157 summary questions were unanswered by existing research. An interim prioritisation survey (240 respondents, 66% patients and/or caregivers, 18% clinicians) asked respondents to choose which of the 157 summary questions were among the 30-40 most important. In a final workshop patients, caregivers, and clinicians discussed and ranked the top 25 questions from the interim survey to identify the Top 10 PH research priorities. These results will inform researchers and funding bodies about patient, caregiver, and clinician priorities for future research on PH.


Assuntos
Pesquisa Biomédica , Hipertensão Pulmonar , Humanos , Hipertensão Pulmonar/terapia , Prioridades em Saúde , Cuidadores , Inquéritos e Questionários
7.
Eur J Pharmacol ; 929: 175132, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35792173

RESUMO

BACKGROUND: Chronic inflammation and oxidative stress play important role in development of hypertension. Recently, we have reported novel fluorophenyl benzimidazole (FPD) for vasorelaxation and antihypertensive activity in SHRs. The present study envisaged the anti-inflammatory, anti-oxidant and cardio-protective properties of FPD in L-NAME model of hypertension with special emphasis on reversal of vascular remodeling, gene expression and restoration of hemodynamic. METHODS: Antihypertensive activity of FPD was evaluated in L-NAME treated Wistar rats, and the parameters studied were anti-inflammatory activity, histomorphological changes, gene expression profile and anti-oxidant properties. RESULTS: FPD at 50 and 100 mg kg-1 once daily for 15 days significantly reduced SBP, DBP and MAP in L-NAME treated rats and the values were well comparable to vehicle control group. Further, FPD treatment showed a significant increase in hepatic GSH content, SOD, catalase activity, decreased MDA level and restoration of pro and anti-inflammatory cytokine levels. The mRNA expression profile of genes associated with regulation of vascular tone, remodeling and inflammation showed a significant level of alteration by chronic L-NAME treatment and was dose-dependently restored upon treatment with FPD. Further, FPD treatment restored serum lipid profile, CK, CK-MB and LDH level and also reversed the histomorphological changes like intimal wall thickening, hyperplasia of cardiomyocytes and ventricular wall thickening. CONCLUSIONS: Taken together, FPD produced potent antihypertensive activity in L-NAME model through vasorelaxation, anti-oxidative and anti-inflammatory properties leading to restoration of serum lipid profile, cardiac biomarker, expression profile of target genes and reversal of histomorphological changes.


Assuntos
Anti-Hipertensivos , Hipertensão , Animais , Anti-Hipertensivos/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Pressão Sanguínea , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lipídeos , NG-Nitroarginina Metil Éster/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Estresse Oxidativo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar
8.
Eur J Pharmacol ; 917: 174757, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35032484

RESUMO

BACKGROUND: Novel naphthoquinone, 2-benzyllawsone (LT-9) was evaluated against vascular hyporeactivity and sepsis in cecal ligation and puncture (CLP) model in mice in view of its preliminary antibacterial and anti-inflammatory properties and to explore whether pretreatment with the molecule could restore vascular tone and contractile response to norepinephrine. METHODS: Evaluation of LT-9 against vascular hyporeactivity, hypotension, and sepsis-related inflammation and infection was carried out in the CLP model in Swiss albino mice and aortic smooth muscle cells in vitro. RESULTS: LT-9 showed potent reversal of the vascular hyporeactivity in CLP mice aorta. The increased contraction response to norepinephrine in CLP mouse aorta by LT-9 was mediated by opening of L-type voltage-dependent calcium channels (VDCC) verified by ex vivo experiment where LT-9 enhanced contraction response to CaCl2 in the aorta while abolishing the contraction response of known VDCC opener Bay K8644. LT-9 in aortic smooth muscle cells showed Fluo-4 mediated increase in calcium fluorescence. Oral administration of LT-9 at 50 and 100 mg kg-1 day-1 for 15 days significantly enhanced the mean survival time, improved hemodynamic and Electrocardiogram (ECG) profile, and aortic tissue reactivity in CLP mice. Further, LT-9 significantly reversed the perturbation of the expression profile of inflammatory cytokines, reduced the splenic microbial load, and was well tolerated in oral toxicity. CONCLUSIONS: LT-9 showed potent biological activity against sepsis and was found to be well tolerated in the toxicity study in Swiss albino mice and showed promise for the benzyllawsone class of molecules against sepsis for the development of novel pharmacophore.


Assuntos
Sepse
9.
Bioorg Med Chem ; 42: 116252, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34153643

RESUMO

Breast cancer is the second leading cause of cancer deaths in women with significant morbidity and mortality. Present study describes design, synthesis and detailed pharmacology of indole derivatives exhibiting remarkable broad spectrum antiproliferative activity against breast cancer cells. Detailed mechanistic evaluations confirmed induction of G0/G1 arrest, apoptosis induction, loss of mitochondrial integrity, enhanced ROS generation, autophagy, estrogen receptor ß-transactivation and increased tubulin polymerization. In in-vivo efficacy studies in rodent model, these indole derivatives induced significant regression in mice mammary tumour on 21 days daily oral dose. Moreover, compounds 19 and 23 were safe in Swiss albino mice in safety studies. These diarylindoles may further be optimized for better efficacy.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Desenho de Fármacos , Indóis/farmacologia , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indóis/síntese química , Indóis/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
10.
Front Pharmacol ; 12: 611109, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33859561

RESUMO

Background: The current study presents the novel angiotensin II receptor blocker fluorophenyl benzimidazole (FPD) as an antihypertensive agent in the SHR model of hypertension. We investigated the role of cGMP, voltage-dependent L-type calcium channels, and BKCa channels in the vasorelaxant mechanisms of FPD in the rat superior mesenteric artery. Methods: The antihypertensive effect of FPD was examined using an invasive technique measuring blood pressure in SHR animals. Using a myograph, tension measurement was completed in the superior mesenteric artery to elucidate the mechanisms of vasorelaxation involving AT1 receptors, the NO/cGMP pathway, L-type calcium channels, and BKCa channels. Ion flux (Ca2+, K+) studies were conducted in aortic smooth muscle cells. Putative targets proteins were determined by in silico docking studies. A safety evaluation of FPD was carried out using Swiss albino mice. Results: FPD significantly decreased blood pressure in SHR. It relaxed superior mesenteric arteries in a concentration-dependent manner and significantly inhibited angiotensin II-induced contraction. The relaxation response was also mediated by an increase in tissue cGMP levels, inhibition of L-type calcium channels, and the opening of BKCa channels. FPD further enhanced efflux of K+ and inhibited Bay K8644-stimulated Ca2+ influx in aortic smooth muscle cells and docked well in an in silico study with the targets. It was well tolerated in the toxicity study. Conclusion: The present study reports the antihypertensive activity of novel AT-1 receptor blocker FPD at 50 and 100 mg kg-1 with cGMP, L-type calcium channels, and BKCa channels as putative targets of vasorelaxation, and was found safe in oral toxicity.

12.
J Ethnopharmacol ; 271: 113911, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33571614

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Kaempferia galanga L. rhizome (KGR) is part of more than sixty-one Ayurvedic formulations and commonly known as 'Chandramula'. KGR is widely used in traditional Indian medicines to treat fever (jwar), rheumatism (Amavata), respiratory (Shwasa), hypertension (Vyanabala vaishamya) and cardiovascular disorders (Vyanavayu Dushtijanya Hrudrog). Although ethnomedicinal properties have extensively been demonstrated in traditional medicines of south-east countries i.e. China, India, Indonesia, and Malaysia, the chemico-biological validation are still lacking. AIM OF THE STUDY: Chemico-biological standardization with respect to its vasorelaxation potential is the main objective of the present study. To investigate the vasorelaxation potential of key phytochemical of KGR, i.e., ethyl-p-methoxycinnamate (EPMC) and to study it's the mechanism of action. MATERIALS AND METHODS: A HPLC method was developed and validated for the quality assessment of KGR using its two major phytochemicals i.e. ethyl-p-methoxycinnamate (EPMC) and ethyl cinnamate (EC) in KGR. The vasorelaxation effect of major phytochemicals of KGR was evaluated on the main mesenteric arteries isolated from male Wistar rats. Specific BKca channel blocker tetraethylammonium (TEA), receptor antagonist, nitric oxide scavenging capacity, and antioxidant potential were also evaluated for its plausible mechanism. RESULTS: Present validated HPLC method facilitates simultaneous quantitation of EPMC and EC faster than classical GC techniques. EPMC has shown a dose-dependent relaxation in rat main mesenteric arteries (MMA) contracted by U46619 with an Emax of 58.68 ± 3.31%. Similarly, in endothelium-denuded MMA rings, relaxation was also observed (Emax of 61.83 ± 3.38%). Moreover, relaxation response to EPMC has strongly inhibited (Emax 14.76 ± 2.29%) when the tissue exposed to depolarizing high K+ containing buffer for the contraction. The point correlation dimension (pD2) values were also significantly decreased in high K+ treated arterial rings compared to control. Interestingly, when MMA rings incubated with a specific BKca channel blocker (TEA, 1 mM), the relaxation response to EPMC was also significantly blocked. CONCLUSIONS: The first time this study demonstrated the chemical standardization of K. galanga rhizome and EPMC is responsible for its vasorelaxation potential as demonstrated by the endothelium-independent response mediated by Ca2+ dependent potassium channels.


Assuntos
Alpinia/química , Cinamatos/farmacologia , Rizoma/química , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Acetaminofen/toxicidade , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Biomarcadores/metabolismo , Cinamatos/metabolismo , Cinamatos/uso terapêutico , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/uso terapêutico , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Camundongos , Óxido Nítrico/antagonistas & inibidores , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Padrões de Referência , Vasodilatadores/uso terapêutico
13.
Int J Mol Sci ; 23(1)2021 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-35008785

RESUMO

Microglia/astrocyte and B cell neuroimmune responses are major contributors to the neurological deficits after traumatic spinal cord injury (SCI). Bruton tyrosine kinase (BTK) activation mechanistically links these neuroimmune mechanisms. Our objective is to use Ibrutinib, an FDA-approved BTK inhibitor, to inhibit the neuroimmune cascade thereby improving locomotor recovery after SCI. Rat models of contusive SCI, Western blot, immunofluorescence staining imaging, flow cytometry analysis, histological staining, and behavioral assessment were used to evaluate BTK activity, neuroimmune cascades, and functional outcomes. Both BTK expression and phosphorylation were increased at the lesion site at 2, 7, 14, and 28 days after SCI. Ibrutinib treatment (6 mg/kg/day, IP, starting 3 h post-injury for 7 or 14 days) reduced BTK activation and total BTK levels, attenuated the injury-induced elevations in Iba1, GFAP, CD138, and IgG at 7 or 14 days post-injury without reduction in CD45RA B cells, improved locomotor function (BBB scores), and resulted in a significant reduction in lesion volume and significant improvement in tissue-sparing 11 weeks post-injury. These results indicate that Ibrutinib exhibits neuroprotective effects by blocking excessive neuroimmune responses through BTK-mediated microglia/astroglial activation and B cell/antibody response in rat models of SCI. These data identify BTK as a potential therapeutic target for SCI.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Neuroimunomodulação , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/imunologia , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Formação de Anticorpos/efeitos dos fármacos , Astrócitos/patologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Peso Corporal/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Imunoglobulina G/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Atividade Motora/efeitos dos fármacos , Neuroimunomodulação/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Plasmócitos/efeitos dos fármacos , Plasmócitos/metabolismo , Ratos , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Baço/patologia , Sindecana-1/metabolismo , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos
14.
J Coll Physicians Surg Pak ; 30(11): 1213-1216, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33222743

RESUMO

OBJECTIVE: To determine the variability of breast density assessment and the need for additional imaging using computed radiography (CR) mammography versus digital radiography (DR) mammography. STUDY DESIGN: Cohort study. PLACE AND DURATION OF STUDY: Department of Radiology, The Aga Khan University Hospital, Karachi from March to June 2018. METHODOLOGY: Patients who underwent screening CR mammography, followed by DR mammography a year later, were selected. Only disease-free individuals were included in the study. Evaluation of breast density was done subjectively, using the breast imaging reporting and data system (BI-RADS) by two independent experienced radiologists. Statistical analysis was performed using the Wilcox Signed Rank-sum test to compare both modalities. Fisher Exact method was used to compare the need for ultrasound imaging.   Results: A total of 295 patients were included in the study. The mean age of the patients was 52.76 ± 0.64 years. There was a significant difference in the change of breast density when comparing both modalities (Z= -11.839, p <0.001). A statistically significant reduction in the need for further breast ultrasound was observed after DR mammography than with CR mammography (p <0.001).  Conclusion: Use of DR mammography, especially in patients with dense breast parenchyma, is a better screening tool overall. It translates to better feasibility for the radiologist and is more economical for the patient. DR mammography decreases unnecessary imaging and leads to better visualisation, thus providing a more accurate categorisation of breast density. Key Word: Computed radiography mammography, Breast density, Screening, Breast cancer, Digital mammography, Ultrasound.


Assuntos
Neoplasias da Mama , Mamografia , Densidade da Mama , Neoplasias da Mama/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Ultrassonografia Mamária
15.
Eur J Med Chem ; 188: 111986, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31884407

RESUMO

Breast cancer is the second leading cause of deaths in women globally. Present communication deals with design and synthesis of a few diarylnaphthyls as possible anti-breast cancer agents. Among the thirty three representatives with significant antiproliferative activity compounds 23 and 50 were quite efficacious against human breast cancer cells. Compound 50 induced apoptosis in both MCF-7 and MDA-MB-231 cells and exerted S phase and G2/M phase arrest respectively via distinct mechanistic pathways. It showed moderate microtubule destabilization. Further, it exhibited DNA topoisomerase-II inhibition effect in MCF-7 cells. It was well tolerable and found safe up to 300 mg/kg dose in Swiss albino mice. The dual action antiproliferative effect of compound 50 is quite interesting and warrants for future development.


Assuntos
Antineoplásicos/farmacologia , Naftalenos/farmacologia , Pirrolidinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Naftalenos/síntese química , Naftalenos/toxicidade , Pirrolidinas/síntese química , Pirrolidinas/toxicidade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/toxicidade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/toxicidade
16.
Bioorg Med Chem Lett ; 30(1): 126759, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711783

RESUMO

A series of substituted 8,8-dimethyl-8H-pyrano[2,3-f]chromen-2-ones (chromeno-coumarin hybrids) was synthesized from scopoletin (11) as vasorelaxing agents. The synthesized compounds 21a-f, 22, 23a-e and scopoletin (11) were evaluated for vasorelaxation in endothelium intact rat main mesenteric artery (MMA). Compounds 11, 21a, 21c-f and 22 showed significant vasorelaxation in precontracted MMA within the range of EC50 value 1.58-5.02 µM. These derivatives presented 29.40-70.89 fold increased sensitivity for experimental tissue compared to scopoletin (11), the parent molecule. Among others, 22 was found to be the most active compound which had EC50 1.58 µM with 70.89 fold increased sensitivity. The mechanistic evaluation of 22 showed that it exerted vasorelaxation through Ca2+-activated K+ (BKca) channel and the effect was endothelium-independent.


Assuntos
Descoberta de Drogas/métodos , Vasodilatação/efeitos dos fármacos , Humanos , Relação Estrutura-Atividade
17.
Eur J Pharmacol ; 858: 172482, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31233749

RESUMO

In the present study, we report that neolignan1 (Diethyl-4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate) relaxes the superior mesenteric artery in a concentration dependent manner (pD2 value 5.392 ±â€¯0.04; n = 8 for endothelium intact and 5.204 ±â€¯0.03; n = 8 for endothelium denuded mesenteric rings, respectively). The relaxation response of neolignan1 was found to be endothelium independent and sensitive to 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-on (ODQ; 1 µM) and tetraethyl ammonium (TEA; 1 mM). In-silico studies showed good LibDock score (92.66) of neolignan1 with BKCa channel and are in well corroboration with ex-vivo study. Further, neolignan1 significantly decreased the systolic blood pressure, diastolic blood pressure and mean arterial pressure in the Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 50 mg/kg) treated Wistar rats at the dose of 30 and 100 mg/kg given once orally for 15 days. In addition, neolignan1 is well tolerated up to 100 mg/kg when given as a repeated dose, once orally for 28 days in Swiss albino mice. Neolignan1 was well absorbed from oral route, reached peak at 4 h and eliminated below detection level by 12 h after administration. Our present study concludes that neolignan1 produced relaxation in superior mesenteric artery by opening of BKCa channel and produced significant antihypertensive activity in L-NAME treated Wistar rats and was well tolerated by the experimental animal.


Assuntos
Anti-Hipertensivos/farmacologia , Ácidos Cumáricos/farmacologia , Lignanas/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Animais , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/farmacocinética , Ácidos Cumáricos/metabolismo , Ácidos Cumáricos/farmacocinética , Feminino , Humanos , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/química , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Lignanas/metabolismo , Lignanas/farmacocinética , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Camundongos , Simulação de Acoplamento Molecular , Conformação Proteica , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos
18.
Chem Biol Drug Des ; 94(3): 1694-1705, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31152581

RESUMO

Diverse benzylidene indanones and their derivatives were synthesized as anticancer agents. Two of the analogues, that is 7 and 22, exhibited significant antiproliferative activity against several human cancer cell lines. Both the compounds possessed antimitotic activity and induced apoptosis in DLD1 colorectal adenocarcinoma cells through activation of caspase pathways. In cell cycle analysis, both the compounds induced predominantly G2/M phase arrest in DLD1 cells. Molecular docking studies revealed that compound 7 occupies colchicine binding pocket of ß-tubulin. Both the compounds were safe in acute oral toxicity in rodents. Both the compounds are further being optimized for better efficacy.


Assuntos
Antineoplásicos/síntese química , Neoplasias Colorretais/tratamento farmacológico , Hidrocarbonetos Aromáticos/química , Indanos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indanos/química , Indanos/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Transdução de Sinais , Relação Estrutura-Atividade , Tubulina (Proteína)/química
19.
Cureus ; 11(2): e4044, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31016072

RESUMO

Polypoid adenomyoma is a rare uterine endometrial polypoid tumor of mixed epithelial and mesenchymal origin. Although the clinical and pathologic features of polypoid adenomyomas have been described extensively, imaging findings for these tumors have not been frequently reported in the literature. On imaging, their features may be confused with prolapsed leiomyomas or malignancy. Hemorrhagic cystic spaces in a prolapsed uterine tumor within the vagina should raise consideration of a diagnosis of polypoid adenomyoma. Such blood-containing cystic spaces would be unusual findings in leiomyomas and malignancy. Diagnosing polypoid adenomyoma is vital because it can potentially be managed by hysteroscopic resection, unlike an ordinary form of adenomyosis.

20.
J Neurotrauma ; 36(18): 2618-2630, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30747048

RESUMO

We previously reported the serendipitous observation that fenbendazole, a benzimidazole anthelmintic, improved functional and pathological outcomes following thoracic spinal cord contusion injury in mice when administered pre-injury. Fenbendazole is widely used in veterinary medicine. However, it is not approved for human use and it was uncertain if only post-injury administration would offer similar benefits. In the present study we evaluated post-injury administration of a closely related, human anthelmintic drug, flubendazole, using a rat spinal cord contusion injury model. Flubendazole, administered i.p. 5 or 10 mg/kg day, beginning 3 h post-injury and daily thereafter for 2 or 4 weeks, resulted in improved locomotor function after contusion spinal cord injury (SCI) compared with vehicle-treated controls. Histological analysis of spinal cord sections showed that such treatment with flubendazole also reduced lesion volume and improved total tissue sparing, white matter sparing, and gray matter sparing. Flubendazole inhibited the activation of glial fibrillary acidic protein (GFAP); suppressed cyclin B1 expression and Bruton tyrosine kinase activation, markers of B cell activation/proliferation and inflammation; and reduced B cell autoimmune response. Together, these results suggest the use of the benzimidazole anthelmintic flubendazole as a potential therapeutic for SCI.


Assuntos
Mebendazol/análogos & derivados , Fármacos Neuroprotetores/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/patologia , Medula Espinal/efeitos dos fármacos , Animais , Antinematódeos/farmacologia , Reposicionamento de Medicamentos , Feminino , Mebendazol/farmacologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia
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