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1.
Folia Morphol (Warsz) ; 81(1): 101-106, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33511627

RESUMO

BACKGROUND: The pancreas is an exo-endocrine organ that undergoes rapid autolysis soon after death, which limits its utility in academics and research. The timeline of autolytic changes of pancreatic islets and its immunoreactivity is limited in the literature. Decay score has been used to grade the autolytic changes in organs like the brain, lung and liver. However, reports are not available in the pancreas/pancreatic islets. Knowledge regarding the decay score may be used as a torchbearer for the immunoreactivity of human pancreatic islets in autopsy cases. The present study is aimed to provide an optimal cut-off time based on the decay score before which pancreatic specimens should be collected for the purpose of immunohistochemical studies (IHC) of pancreatic islets. MATERIALS AND METHODS: Serial sections of 20 adult human pancreases obtained from the autopsy were subjected to haematoxylin and eosin (H&E) and immunohistochemical staining. Autolytic changes of pancreatic islets were graded by using decay score in H&E sections, which was compared with the results of the immunohistochemical reactivity of pancreatic islets in IHC sections. RESULTS AND CONCLUSIONS: Pancreatic islets immunoreactivity was found to be well preserved in the samples collected early within 9 hours with a decay score of less than 1.4. There was an inverse relation of decay score and immunoreactivity of pancreatic islets. The decay score of less than 1.4 has better-preserved immunoreactivity than having more than 1.4. This knowledge will help researchers working in the field of the endocrine pancreas.


Assuntos
Ilhotas Pancreáticas , Adulto , Autopsia , Humanos , Fígado , Pâncreas , Coloração e Rotulagem
2.
Pediatr Surg Int ; 36(8): 869-874, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32436063

RESUMO

Recent reports have recommended laparoscopic diverticulectomy for symptomatic Meckel diverticulum (MD) rather than laparoscopic-assisted extracorporeal resection. This technique may risk leaving residual ectopic mucosa leading to complications. This systematic review attempts to quantify the relative risks of both approaches. A systematic review was conducted according to PRISMA guidelines. Articles were eligible for inclusion if they reported data on the laparoscopic management of symptomatic MD in children. Eleven reports were identified, all of which were institutional retrospective studies. Pooled outcome data on 248 children showed no statistically significant difference in complications between laparoscopic diverticulectomy (n = 133) and laparoscopic-assisted segmental resection (n = 115) (3% vs. 6.1%, p = 0.39). One patient from the diverticulectomy group re-presented with recurrent bleeding necessitating segmental small bowel resection. Conclusions are limited by the number of patients and variable follow up. Short, wide MD with a height:base ratio of < 2; diverticula with thickening or ischemia at the base and those complicated by volvulus or small bowel obstruction are probably best treated by laparoscopic-assisted extracorporeal resection. For other symptomatic diverticula laparoscopic diverticulectomy is a reasonable approach with a less than 1% risk of leaving residual ectopic gastric mucosa.


Assuntos
Diverticulite/cirurgia , Laparoscopia/métodos , Divertículo Ileal/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Íleo/cirurgia , Lactente , Masculino , Estudos Retrospectivos
3.
PLoS One ; 13(5): e0196067, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29791449

RESUMO

BACKGROUND: Migrant labourers living in the slums of urban and industrial patches across India make up a key sub-population so far controlling Tuberculosis (TB) in the country is concerned. This is because many TB patients from these communities- remain under reached by the Revised National Tuberculosis Control Programme (RNTCP) of India. This marginalized community usually seeks early-stage healthcare from "friendly neighbourhood" non-formal health providers (NFHPs). Because, RNTCP has limited capacity to involve the NFHPs, an implementation research project was conceived, whereby an external partner would engage with the NFHPs to enable them to identify early TB symptomatics from this key sub-population who would be then tested using Xpert MTB/RIF technology. Diagnosed TB cases among them would be referred promptly to RNTCP for treatment. This paper aimed to describe the project and its impact. METHODS: Adopting a quasi-experimental before-after design, four RNTCP units from two major urban-industrial areas of Odisha were selected for intervention, which spanned five quarters and covered 151,400 people, of which 30% were slum-dwelling migrants. Two similar units comprised the control population. The hypothesis was, reaching the under reached in the intervention area through NFHPs would increase TB notification from these traditionally under-notifying units. RNTCP notification data during intervention was compared with pre-intervention era, adjusted for contemporaneous changes in control population. RESULTS: The project detected 488 Xpert+ TB cases, of whom 466 were administered RNTCP treatment. This translated into notification of additional 198 new bacteriologically positive cases to RNTCP, a 30% notification surge, after adjustment for 2% decline in control. This meant an average quarterly increase in notification of 41.20(20.08, 62.31; p<0.001) cases. The increase was immediate, evident from the rise in level in the time series analysis by 50.42(10.28, 90.55; p = 0.02) cases. CONCLUSION: Engagement with NFHPs contributed to an increase in TB notification to RNTCP from key under reached, slum-dwelling migrant populations.


Assuntos
Notificação de Doenças/estatística & dados numéricos , Pessoal de Saúde/estatística & dados numéricos , Características de Residência/estatística & dados numéricos , Migrantes/estatística & dados numéricos , Tuberculose/epidemiologia , Humanos , Índia
4.
Colloids Surf B Biointerfaces ; 155: 276-286, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28437753

RESUMO

In spite of being a very potent and promising drug against many types of cancer, docetaxel suffers the disadvantage of low solubility and poor bioavailability rendering it unsuitable for oral administration. Also, the available marketed formulation for intravenous administration has its inherent drawbacks owing to the presence of polysorbate 80. Here, we exploited the anticancer and P-gp inhibitory potential of naturally occurring frankincense oil to fabricate a stable docetaxel loaded nanoemulsified carrier system for oral delivery. The nanoemulsion possessing desirable particle size (122±12nm), polydispersity (0.086±0.007) and zeta potential (-29.8±2.1mV) was stable against all type of physical stresses and simulated physiological conditions tested. The formulation showed higher uptake in Caco-2 cells and inhibited P-gp transporter significantly (P<0.05). In MDA-MB-231 cells, it showed less IC50, arrested cells in G2-M phase and exhibited higher degree of apoptosis than marketed formulation Taxotere®. The 182.58±4.16% increment in relative oral bioavailability led to higher in vivo anti-proliferative activity manifesting 19% more inhibition than Taxotere®. Conclusively, it is revealed that the developed nanoemulsion will be a propitious approach towards alternative docetaxel therapy.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacocinética , Portadores de Fármacos , Franquincenso/química , Taxoides/farmacocinética , Triterpenos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Células CACO-2 , Linhagem Celular Tumoral , Docetaxel , Composição de Medicamentos , Emulsões , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Óleos de Plantas/química , Taxoides/sangue , Taxoides/farmacologia
6.
Eur J Pharm Sci ; 91: 105-13, 2016 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-27287423

RESUMO

In the present research,we simultaneously addressed the condition of osteomyelitis and osteoporosis by developing a gelatin based chemically cross linked cryogel system embedded with CaCO3 microspheres and ciprofloxacin hydrochloride was incorporated in both the microspheres and the 3D matrix of cryogel. The fabricated cryogel was characterized for the swelling ratio, swelling kinetics, porosity, pore volume, compression strength and in vitro rate of degradation which were found to be dependent on the concentration of gelatin, duration of freezing and number of freeze-thaw cycles. The sustained release of drug was obtained up to 21days after the initial burst, and the concentration was maintained above the MIC for the entire duration of the study. The in vitro antibacterial study in Staphylococcus aureus and Escherichia coli exhibited 33mm, 30mm, 28mm, 27mm and 43mm, 37mm, 37mm, and 36mm zone of inhibition respectively at day 1, 3, 5 and 7. The cell viability, number of cells in the growth phase and alkaline phosphatase levels were found to be significantly higher in rat osteoblasts cultured in cryogel as compared to 2D surface. All these results demonstrate the propitious potential of this microsphere incorporated, ciprofloxacin-loaded, industrially scalable cryogel system for therapeutic intervention in osteoporosis and associated osteomyelitis.


Assuntos
Antibacterianos/administração & dosagem , Carbonato de Cálcio/administração & dosagem , Ciprofloxacina/administração & dosagem , Sistemas de Liberação de Medicamentos , Osteomielite/tratamento farmacológico , Osteoporose/tratamento farmacológico , Fosfatase Alcalina/metabolismo , Animais , Antibacterianos/química , Antibacterianos/uso terapêutico , Carbonato de Cálcio/química , Carbonato de Cálcio/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ciprofloxacina/química , Ciprofloxacina/uso terapêutico , Criogéis , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/uso terapêutico , Liberação Controlada de Fármacos , Escherichia coli/efeitos dos fármacos , Gelatina/química , Microesferas , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Porosidade , Ratos , Staphylococcus aureus/efeitos dos fármacos
7.
Colloids Surf B Biointerfaces ; 133: 120-39, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26094145

RESUMO

Over the recent years the use of biocompatible and biodegradable nanoparticles in biomedicine has become a significant priority. Calcium based ceramic nanoparticles like calcium phosphate (CaP) and calcium carbonate (CaCO3) are therefore considered as attractive carriers as they are naturally present in human body with nanosize range. Their application in tissue engineering and localized controlled delivery of bioactives for bones and teeth is well established now, but recently their use has increased significantly as carrier of bioactives through other routes also. These delivery systems have become most potential alternatives to other commonly used delivery system because of their cost effectiveness, biodegradability, chemical stability, controlled and stimuli responsive behaviour. This review comprehensively covers their characteristic features, method of preparation and applications but the thrust is to focus their recent development, functionalization and use in systemic delivery. On the same platform mineralization of other nanoparticulate delivery system which has widened their application drug delivery will be discussed. The emphasis has been given on their pH dependent properties which make them excellent carriers for tumour targeting and intracellular delivery. Finally this review also attempts to discuss their drawback which limits their clinical utility.


Assuntos
Cálcio/metabolismo , Nanoestruturas
8.
JNMA J Nepal Med Assoc ; 53(200): 301-303, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27746477

RESUMO

A 57 year old male presented to our outpatient clinic with history of on and off melena, weight loss and decreasing appetite for 10 months duration and a noticeable mass on the right upper quadrant. Abdominal examination revealed an intra-abdominal lump in right upper quadrant which was subsequently evaluated by colonoscopy, which revealed an ulcero-proliferative growth in the hepatic flexure and the biopsy from it confirmed well-differentiated adenocarcinoma. Contrast enhanced computed tomography demonstrated hepatic flexure mass with possible invasion into adjacent duodenum without features of advanced disease. After completion of necessary preoperative assessment and investigations, patient was explored with curative intent and underwent extended right hemicolectomy with en bloc pancreaticodudenectomy. Patient was discharged on 10th postoperative day and at 14 months follows up; he was doing well without any evidence of recurrence.

9.
Cell Death Dis ; 5: e1422, 2014 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-25232676

RESUMO

Recently, we reported that extract of Dalbergia sissoo made from leaves and pods have antiresorptive and bone-forming effects. The positive skeletal effect attributed because of active molecules present in the extract of Dalbergia sissoo. Caviunin 7-O-[ß-D-apiofuranosyl-(1-6)-ß-D-glucopyranoside] (CAFG), a novel isoflavonoid show higher percentage present in the extract. Here, we show the osteogenic potential of CAFG as an alternative for anabolic therapy for the treatment of osteoporosis by stimulating bone morphogenetic protein 2 (BMP2) and Wnt/ß-catenin mechanism. CAFG supplementation improved trabecular micro-architecture of the long bones, increased biomechanical strength parameters of the vertebra and femur and decreased bone turnover markers better than genistein. Oral administration of CAFG to osteopenic ovariectomized mice increased osteoprogenitor cells in the bone marrow and increased the expression of osteogenic genes in femur and show new bone formation without uterine hyperplasia. CAFG increased mRNA expression of osteoprotegerin in bone and inhibited osteoclast activation by inhibiting the expression of skeletal osteoclastogenic genes. CAFG is also an effective accelerant for chondrogenesis and has stimulatory effect on the repair of cortical bone after drill-hole injury at the tissue, cell and gene level in mouse femur. At cellular levels, CAFG stimulated osteoblast proliferation, survival and differentiation. Signal transduction inhibitors in osteoblast demonstrated involvement of p-38 mitogen-activated protein kinase pathway stimulated by BMP2 to initiate Wnt/ß-catenin signaling to reduce phosphorylation of GSK3-ß and subsequent nuclear accumulation of ß-catenin. Osteogenic effects were abrogated by Dkk1, Wnt-receptor blocker and FH535, inhibitor of TCF-complex by reduction in ß-catenin levels. CAFG modulated MSC responsiveness to BMP2, which promoted osteoblast differentiation via Wnt/ß-catenin mechanism. CAFG at 1 mg/kg(/)day dose in ovariectomy mice (human dose ∼0.081 mg/kg) led to enhanced bone formation, reduced bone resorption and bone turnover better than well-known phytoestrogen genistein. Owing to CAFG's inherent properties for bone, it could be positioned as a potential drug, food supplement, for postmenopausal osteoporosis and fracture repair.


Assuntos
Doenças Ósseas Metabólicas/tratamento farmacológico , Células da Medula Óssea/efeitos dos fármacos , Proteína Morfogenética Óssea 2/metabolismo , Osso e Ossos/efeitos dos fármacos , Glicosídeos/farmacologia , Isoflavonas/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Animais Recém-Nascidos , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/patologia , Doenças Ósseas Metabólicas/fisiopatologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Proteína Morfogenética Óssea 2/genética , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Condrogênese/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica , Genisteína/farmacologia , Células HEK293 , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos Endogâmicos BALB C , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Ovariectomia , Fatores de Tempo , Transfecção , Via de Sinalização Wnt/genética , beta Catenina/genética
10.
Br J Pharmacol ; 171(17): 4038-50, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24837879

RESUMO

BACKGROUND AND PURPOSE: The aim of the present study was to evaluate the immunomodulatory and chemotherapeutic potential of alginate-(SA) coated nanocapsule (NCs) loaded with doxorubicin (SA-NCs-DOX) against visceral leishmaniasis in comparison with nano-emulsions containing doxorubicin (NE-DOX). EXPERIMENTAL APPROACH: NE-DOX was prepared using low-energy emulsification methods. Stepwise addition of protamine sulphate and SA in a layer-by-layer manner was used to form SA-NCs-DOX. SA-NCs-DOX, NE-DOX and Free DOX were compared for their cytotoxicity against Leishmania donovani-infected macrophages in vitro and generation of T-cell responses in infected hamsters in vivo. KEY RESULTS: Size and ζ potential of the NE-DOX and SA-NCs-DOX formulations were 310 ± 2.1 nm and (-)32.6 ± 2.1 mV, 342 ± 4.1 nm and (-)29.3 ± 1.2 mV respectively. SA-NCs-DOX was better (1.5 times) taken up by J774A.1 macrophages compared with NE-DOX. SA-NCs -DOX showed greater efficacy than NE-DOX against intramacrophagic amastigotes. SA-NCs-DOX treatment exhibited enhanced apoptotic efficiency than NE-DOX and free DOX as evident by cell cycle analysis, decrease in mitochondrial membrane potential, ROS and NO production. T-cell responses, when assessed through lymphoproliferative responses, NO production along with enhanced levels of iNOS, TNF-α, IFN-γ and IL-12 were found to be up-regulated after SA-NCs-DOX, compared with responses to NE-DOX in vivo. Parasitic burden was decreased in Leishmania-infected hamsters treated with SA-NCs-DOX, compared with NE-DOX. CONCLUSIONS AND IMPLICATIONS: Our results provide insights into the development of an alternative approach to improved management of leishmaniasis through a combination of chemotherapy with stimulation of the innate immune system.


Assuntos
Alginatos/farmacologia , Antiprotozoários/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Daunorrubicina/farmacologia , Leishmania donovani/efeitos dos fármacos , Nanocápsulas/química , Células Th1/efeitos dos fármacos , Alginatos/administração & dosagem , Alginatos/química , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/química , Linhagem Celular , Materiais Revestidos Biocompatíveis/administração & dosagem , Materiais Revestidos Biocompatíveis/química , Cricetinae , Daunorrubicina/administração & dosagem , Daunorrubicina/química , Ácido Glucurônico/administração & dosagem , Ácido Glucurônico/química , Ácido Glucurônico/farmacologia , Ácidos Hexurônicos/administração & dosagem , Ácidos Hexurônicos/química , Ácidos Hexurônicos/farmacologia , Leishmania donovani/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/parasitologia , Masculino , Camundongos , Células Th1/imunologia
11.
Pharmazie ; 69(3): 173-82, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24716405

RESUMO

Nanosuspensions are a smart formulation principle for dermal applications, as they increase the penetration of poorly soluble substances into the skin. Because microbial stability is a pre-requisite for dermal formulations, water containing formulations need to be preserved. Preservatives are known to possibly impair the physical stability of disperse systems, i.e. by causing agglomeration. These aggregation phenomena might occur during storage of the final product, but can already occur during the production process itself. Therefore, in this study the influence of six different preservatives on the diminution efficiency during the production of hesperetin nanocrystals was investigated. Particles with and without the addition of preservatives were produced by high pressure homogenization (HPH) and the final particle size was analysed and compared to the non-preserved suspension. All preservatives influenced the diminution progress during production and the final particle sizes obtained. The non-preserved suspension yielded a particle size of about 300 nm. Preservation with Hydrolite, Euxyl PE9010, Rokonsal and Phenonip led to sizes of about 400 nm. Preservation with Caprylyl glycol and MultiEx did not lead to nanoparticles (size > 1 microm) and caused a slight agglomeration of the nanosuspensions. Based on zeta potential measurements it was found that the impairment is related to the lipophilicity of the presverative, i.e. the lower the lipophilicity, the less is the impairment. In conclusion, preservatives impair the diminution efficacy during the production of nanosuspensions. Therefore, if possible, preservatives should be added to nanosuspensions after the production process. If preservatives are required during production, highly hydrophilic preservatives, e.g. Hydrolite E, should be used.


Assuntos
Hesperidina/química , Hesperidina/síntese química , Química Farmacêutica , Estabilidade de Medicamentos , Eletroquímica , Luz , Nanopartículas , Nanoestruturas , Tamanho da Partícula , Conservantes Farmacêuticos , Espalhamento de Radiação , Tensoativos , Suspensões
12.
Biomaterials ; 35(15): 4573-88, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24612818

RESUMO

Our main aim in the present investigation was to explore the in vitro and in vivo cancer targeting potential of the doxorubicin (DOX) laden d-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) tethered surface engineered MWCNTs nanoformulation (DOX/TPGS-MWCNTs) and compare it with pristine MWCNTs and free doxorubicin solution. The developed MWCNTs nanoformulations were extensively characterized by Fourier-transform infrared, Raman spectroscopy, x-ray diffraction, electron microscopy, and in vitro and in vivo studies using MCF-7 cancer cell line. The entrapment efficiency was determined to be 97.2 ± 2.50% (DOX/TPGS-MWCNTs) and 92.5 ± 2.62% (DOX/MWCNTs) ascribed to π-π stacking interactions. The developed formulations depicted the sustained release pattern at the lysosomal pH (pH 5.3). The DOX/TPGS-MWCNTs showed enhanced cytotoxicity, cellular uptake and were most preferentially taken up by the cancerous cells via endocytosis mechanism. The DOX/TPGS-MWCNTs nanoconjugate depicted the significantly longer survival span (44 days, p < 0.001) than DOX/MWCNTs (23 days), free DOX (18 days) and control group (12 days). The obtained results also support the extended residence time and sustained release profile of the drug loaded surface engineered nanotubes formulations in body as compared to DOX solution. Overall we can conclude that the developed MWCNTs nanoconjugate have higher cancer targeting potential on tumor bearing Balb/c mice.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Nanotubos de Carbono/química , Neoplasias/tratamento farmacológico , Vitamina E/análogos & derivados , Animais , Antibióticos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nanotubos de Carbono/ultraestrutura , Polietilenoglicóis/química , Vitamina E/química
13.
Cell Death Dis ; 4: e778, 2013 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-23969857

RESUMO

Withania somnifera or Ashwagandha is a medicinal herb of Ayurveda. Though the extract and purified molecules, withanolides, from this plant have been shown to have different pharmacological activities, their effect on bone formation has not been studied. Here, we show that one of the withanolide, withaferin A (WFA) acts as a proteasomal inhibitor (PI) and binds to specific catalytic ß subunit of the 20S proteasome. It exerts positive effect on osteoblast by increasing osteoblast proliferation and differentiation. WFA increased expression of osteoblast-specific transcription factor and mineralizing genes, promoted osteoblast survival and suppressed inflammatory cytokines. In osteoclast, WFA treatment decreased osteoclast number directly by decreasing expression of tartarate-resistant acid phosphatase and receptor activator of nuclear factor kappa-B (RANK) and indirectly by decreasing osteoprotegrin/RANK ligand ratio. Our data show that in vitro treatment of WFA to calvarial osteoblast cells decreased expression of E3 ubiquitin ligase, Smad ubiquitin regulatory factor 2 (Smurf2), preventing degradation of Runt-related transcription factor 2 (RunX2) and relevant Smad proteins, which are phosphorylated by bone morphogenetic protein 2. Increased Smurf2 expression due to exogenous treatment of tumor necrosis factor α (TNFα) to primary osteoblast cells was decreased by WFA treatment. This was corroborated by using small interfering RNA against Smurf2. Further, WFA also blocked nuclear factor kappa-B (NF-kB) signaling as assessed by tumor necrosis factor stimulated nuclear translocation of p65-subunit of NF-kB. Overall data show that in vitro proteasome inhibition by WFA simultaneously promoted osteoblastogenesis by stabilizing RunX2 and suppressed osteoclast differentiation, by inhibiting osteoclastogenesis. Oral administration of WFA to osteopenic ovariectomized mice increased osteoprogenitor cells in the bone marrow and increased expression of osteogenic genes. WFA supplementation improved trabecular micro-architecture of the long bones, increased biomechanical strength parameters of the vertebra and femur, decreased bone turnover markers (osteocalcin and TNFα) and expression of skeletal osteoclastogenic genes. It also increased new bone formation and expression of osteogenic genes in the femur bone as compared with vehicle groups (Sham) and ovariectomy (OVx), Bortezomib (known PI), injectible parathyroid hormone and alendronate (FDA approved drugs). WFA promoted the process of cortical bone regeneration at drill-holes site in the femur mid-diaphysis region and cortical gap was bridged with woven bone within 11 days of both estrogen sufficient and deficient (ovariectomized, Ovx) mice. Together our data suggest that WFA stimulates bone formation by abrogating proteasomal machinery and provides knowledge base for its clinical evaluation as a bone anabolic agent.


Assuntos
Anabolizantes/farmacologia , Osso e Ossos/patologia , Osteoporose/tratamento farmacológico , Inibidores de Proteassoma/química , Vitanolídeos/farmacologia , Cicatrização , Anabolizantes/química , Anabolizantes/farmacocinética , Anabolizantes/uso terapêutico , Animais , Biomarcadores/metabolismo , Fenômenos Biomecânicos/efeitos dos fármacos , Regeneração Óssea/efeitos dos fármacos , Regeneração Óssea/genética , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiopatologia , Calcificação Fisiológica/efeitos dos fármacos , Calcificação Fisiológica/genética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Feminino , Fêmur/efeitos dos fármacos , Fêmur/patologia , Fêmur/fisiopatologia , Camundongos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Osteoporose/genética , Osteoporose/patologia , Osteoporose/fisiopatologia , Ovariectomia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Proteólise/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Vitanolídeos/química , Vitanolídeos/farmacocinética , Vitanolídeos/uso terapêutico , Cicatrização/efeitos dos fármacos , Cicatrização/genética
14.
Pharmazie ; 66(5): 313-8, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21699063

RESUMO

Gene silencing by RNA interference is a rapidly growing therapeutic area for managing diseases. Despite research advances in this direction, the poor cellular uptake of synthetic small interfering RNAs is a major impediment to their clinical applications. Polymer and lipid-based systems are attractive carrier systems for delivery of siRNA and provide options for desirable engineering of carrier particles. In this review, there is a detailed discussion of RNAi delivery systems and recent advances in the field.


Assuntos
Portadores de Fármacos , Sistemas de Liberação de Medicamentos , RNA Interferente Pequeno/administração & dosagem , Animais , Emulsões , Marcação de Genes/métodos , Terapia Genética/métodos , Humanos , Lipídeos/química , Lipossomos , Nanopartículas , Polímeros/química , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico
15.
J Biomed Nanotechnol ; 7(1): 47-9, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21485797

RESUMO

A ciprofloxacin (CFn)-loaded lipid emulsion was developed for treatment of intra-abdominal infections, especially sepsis. Loading efficiency depended on the proportion of chitosan (CH) and sodium deoxycholate (SDC). The average globule size was 225 to 325 nm. Animal survival improved when the prototype formulation was administered to LPS-induced septic mice. At 4 microg/ml, reduction in TNF-alpha and NO production were observed (P < 0.05) but at lower concentration these changes were not significant (P > 0.05) as compared to positive control (LPS-1 microg/ml). This indicates that chitosan can modify LPS interaction with macrophages, and that formulations have potential to control inflammation associated with sepsis.


Assuntos
Quitosana/química , Ciprofloxacina/administração & dosagem , Ácido Desoxicólico/química , Lipopolissacarídeos , Nanocápsulas/química , Sepse/induzido quimicamente , Sepse/prevenção & controle , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/química , Ciprofloxacina/química , Composição de Medicamentos/métodos , Camundongos , Camundongos Endogâmicos BALB C , Sepse/patologia , Resultado do Tratamento
16.
J Biomed Nanotechnol ; 7(1): 123-4, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21485834

RESUMO

The present study was aimed to assess the improvement of existing treatment regimens of Amphotericin B nanoconstrcuts which synergises with alginate for immunostimulation against visceral leishmaniasis. The particle size of Lip-nano (Plain AmB nanoconstructs) and Alg-Lip-nano (alginate capped Lip-nano) was 108.3 +/- 4.3 and 134.2 +/- 5.1 while zeta potential was (+) 28.4 +/- 3.3 and (-) 19.8 +/- 2.1 respectively. Percentage of parasite inhibition (intramacrophagic amastigotes) at 0.1 microg/ml conc. of AmB in case of Alg-Lip-nano (58%) was significantly higher (P = 0.05) compared to Lip-nano (48%). This supports that alginate coating over particles can activate macrophages to synergistically act with AmB in effective killing of parasite. This observation generates interest that immunotherapy with chemotherapeutic activity of AmB can effectively increase cure rate in visceral leishmaniasis.


Assuntos
Alginatos/química , Anfotericina B/administração & dosagem , Leishmania/efeitos dos fármacos , Leishmania/fisiologia , Lipídeos/química , Nanocápsulas/química , Anfotericina B/química , Antiprotozoários/administração & dosagem , Antiprotozoários/química , Sobrevivência Celular/efeitos dos fármacos , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Nanocápsulas/administração & dosagem , Resultado do Tratamento
17.
J Biomed Nanotechnol ; 7(1): 125-6, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21485835

RESUMO

This study was aimed to develop chitosan coupled lipid nanoparticle (Ch-Ptx-Lip), where immunomodulatory activity of chitosan and chemotherapeutic effect of paclitaxel can synergistically enhance efficacy of this novel drug delivery system. Particle size, zeta potential and % Entrapment Efficiency (%EE) of Ch-Ptx-Lip was found to be 113.3 +/- 4.5 nm (PDI: 0.38), (+)35.7 +/- 2.9 mV and 96.4 +/- 1.8% respectively. Morphological evaluation of these particles by TEM shows circular bilayer structure along with outer polymer layers. Ch-Ptx-Lip showed significantly enhanced cytotoxicity (p < 0.05) compared with marketed formulation (Ptx Solution) and Ptx-Lip when evaluated in-vitro by MTT assay on MCF-7 cell lines. Improved efficacy with lower dose of drug can be a new strategy against cancer with minimum side effects and shorter treatment duration.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quitosana/química , Lipídeos/química , Nanocápsulas/química , Paclitaxel/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Nanocápsulas/administração & dosagem , Paclitaxel/química , Resultado do Tratamento
18.
J Biomed Nanotechnol ; 6(3): 293-302, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21179947

RESUMO

The present study was aimed to assess the efficacy of developed transfersome (TF-3) formulation bearing amphotericin B (AmB) against sensitive and resistant clinical isolates of L donovani and compared with conventional liposomal formulation (F-2) and free AmB (F-1). The skin permeation of AmB from TF-3 was performed using Franz diffusion cell using rat skin which showed fickian diffusion across the skin. When tested against L. donovani (intramacrophagic amastigotes), it has been observed that TF was more effective than F-1 and F-2 formulation in sensitive and resistant clinical isolates. The data provides evidences that the TF formulation owing to its fluidized behaviour imparted by sodium deoxycholate, enables to penetrate well in the infected cells and thus provide enhanced activity. The permeation study also supports this data as the flux value of AmB through TF formulation was 1.5 fold higher compared to conventional liposomes suggesting improved penetration and better partitioning in skin layers. Implicit to this preliminary data it is evident that the AmB loaded TF formulation has potential as alternate chemotherapeutic approach to control of VL. Potential utilities of novel formulation as a transdermal delivery of AmB for leishmaniasis necessitates further elaborated investigations which is underway in our laboratory.


Assuntos
Anfotericina B/administração & dosagem , Anfotericina B/química , Leishmaniose Visceral/tratamento farmacológico , Lipossomos/síntese química , Absorção Cutânea , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/química , Composição de Medicamentos , Resistência a Medicamentos , Camundongos , Ratos , Resultado do Tratamento
19.
Eur J Med Chem ; 45(12): 5965-78, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20970222

RESUMO

A series of [4-(aryloxy)phenyl]cyclopropyl methanones were synthesized by reaction of different benzyl alcohols with 4-chloro-4'-fluorobutyrophenone in DMF in the presence of NaH/TBAB. The methanones were further reduced to respective methanols. The antitubercular activity of these compounds was evaluated in vitro against Mycobacterium tuberculosis H37Rv. Compounds 19, 21, 35, 36 and 37 have shown minimum inhibitory concentration (MIC) of 3.12 µg/mL, while compounds 14, 25 and 18 have shown MIC of 1.56 µg/mL and 0.78 µg/mL respectively. One of the compounds, cyclopropyl-4-[4-(2-piperidin-1-yl-ethoxy)benzyloxy]phenyl}methanol (36) showed 98% killing of intracellular bacilli in mouse bone marrow derived macrophages and was active against MDR, XDR and rifampicin clinical isolates resistant strains with MIC 12.5 µg/mL. Compound 36 was orally active in vivo in mice against M. tuberculosis H37Rv with an increase in MST by 6 days with 1 log reduction in the bacillary density in lungs as compared to control on 30th day after infection.


Assuntos
Antituberculosos/farmacologia , Ciclopropanos/farmacologia , Metanol/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Antituberculosos/síntese química , Antituberculosos/química , Chlorocebus aethiops , Ciclopropanos/síntese química , Ciclopropanos/química , Feminino , Macrófagos/efeitos dos fármacos , Metanol/análogos & derivados , Metanol/síntese química , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Células Vero
20.
JNMA J Nepal Med Assoc ; 49(178): 96-9, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21485591

RESUMO

INTRODUCTION: Acute appendicitis is a common surgical emergency. Accurate diagnosis and timely intervention reduces mortality and morbidity. This study compared the efficacy of Tzanakis and Alvarado score in diagnosis of acute appendicitis. METHODS: A prospective, non randomized study was conducted in 100 consecutive patients who had undergone emergency appendectomy from May 2008 to October 2008. Tzanakis and Alvarado scores were obtained at the time of admission. Final diagnosis of acute appendicitis was based on histological findings. RESULTS: The sensitivity, specificity and overall diagnostic accuracy of Tzanakis score was 91.48% and 66.66% and 90% respectively. The sensitivity, specificity and overall diagnostic accuracy of Alvarado score was 81.91% and 66.66% and 81% respectively. Negative appendectomy rate was 6%. CONCLUSIONS: Tzanakis score is an effective modality to establish the accurate diagnosis of acute appendicitis.


Assuntos
Apendicite/diagnóstico , Técnicas de Diagnóstico do Sistema Digestório , Adolescente , Adulto , Idoso , Apendicite/patologia , Apendicite/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Procedimentos Desnecessários , Adulto Jovem
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