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1.
Biochem Pharmacol ; 192: 114727, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34390739

RESUMO

Thalidomide is an antiinflammatory, antiangiogenic and immunomodulatory agent which has been used for the treatment of erythema nodosum leprosum and multiple myeloma. It has also been employed in treating complex regional pain syndromes. The current study aimed to reveal the molecular mechanisms underlying thalidomide-induced pain antihypersensitive effects in neuropathic pain. Thalidomide gavage, but not its more potent analogs lenalidomide and pomalidomide, inhibited mechanical allodynia and thermal hyperalgesia in neuropathic pain rats induced by tight ligation of spinal nerves, with ED50 values of 44.9 and 23.5 mg/kg, and Emax values of 74% and 84% MPE respectively. Intrathecal injection of thalidomide also inhibited mechanical allodynia and thermal hyperalgesia in neuropathic pain. Treatment with thalidomide, lenalidomide and pomalidomide reduced peripheral nerve injury-induced proinflammatory cytokines (TNFα, IL-1ß and IL-6) in the ipsilateral spinal cords of neuropathic rats and LPS-treated primary microglial cells. In contrast, treatment with thalidomide, but not lenalidomide or pomalidomide, stimulated spinal expressions of IL-10 and ß-endorphin in neuropathic rats. Particularly, thalidomide specifically stimulated IL-10 and ß-endorphin expressions in microglia but not astrocytes or neurons. Furthermore, pretreatment with the IL-10 antibody blocked upregulation of ß-endorphin in neuropathic rats and cultured microglial cells, whereas it did not restore thalidomide-induced downregulation of proinflammatory cytokine expression. Importantly, pretreatment with intrathecal injection of the microglial metabolic inhibitor minocycline, IL-10 antibody, ß-endorphin antiserum, and preferred or selective µ-opioid receptor antagonist naloxone or CTAP entirely blocked thalidomide gavage-induced mechanical antiallodynia. Our results demonstrate that thalidomide, but not lenalidomide or pomalidomide, alleviates neuropathic pain, which is mediated by upregulation of spinal microglial IL-10/ß-endorphin expression, rather than downregulation of TNFα expression.


Assuntos
Interleucina-10/biossíntese , Microglia/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Talidomida/uso terapêutico , beta-Endorfina/biossíntese , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Interleucina-10/agonistas , Masculino , Microglia/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Talidomida/farmacologia , beta-Endorfina/agonistas
2.
Pharmazie ; 75(8): 375-380, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32758336

RESUMO

Diabetes mellitus (DM) is one of the major risk factors for COVID-19 complications as it is one of the chronic immune-compromising conditions especially if patients have uncontrolled diabetes, poor HbA1c and/or irregular blood glucose levels. Diabetic patients' mortality rates with COVID-19 are higher than those of cardiovascular or cancer patients. Recently, Bacillus Calmette-Guérin (BCG) vaccine has shown successful results in reversing diabetes in both rats and clinical trials based on different mechanisms from aerobic glycolysis to beta cells regeneration. BCG is a multi-face vaccine that has been used extensively in protection from tuberculosis (TB) and leprosy and has been repositioned for treatment of bladder cancer, diabetes and multiple sclerosis. Recently, COVID-19 epidemiological studies confirmed that universal BCG vaccination reduced morbidity and mortality in certain geographical areas. Countries without universal policies of BCG vaccination (Italy, Nederland, USA) have been more severely affected compared to countries with universal and long-standing BCG policies that have shown low numbers of reported COVID-19 cases. Some countries have started clinical trials that included a single dose BCG vaccine as prophylaxis from COVID-19 or an attempt to minimize its side effects. This proposed research aims to use BCG vaccine as a double-edged weapon countering both COVID-19 and diabetes, not only as protection but also as therapeutic vaccination. The work includes a case study of regenerated pancreatic beta cells based on improved C-peptide and PCPRI laboratory findings after BCG vaccination for a 9 year old patient. The patient was re-vaccinated based on a negative tuberculin test and no scar at the site of injection of the 1st BCG vaccination at birth. The authors suggest and invite the scientific community to take into consideration the concept of direct BCG re-vaccination (after 4 weeks) because of the reported gene expressions and exaggerated innate immunity consequently. As the diabetic MODY-5 patient (mutation of HNF1B, Val2Leu) was on low dose Riomet® while eliminating insulin gradually, a simple analytical method for metformin assay was recommended to ensure its concentration before use as it is not approved yet by the Egyptian QC labs.


Assuntos
Vacina BCG/administração & dosagem , Infecções por Coronavirus/imunologia , Diabetes Mellitus/imunologia , Células Secretoras de Insulina/citologia , Pneumonia Viral/imunologia , Animais , Vacina BCG/imunologia , COVID-19 , Criança , Infecções por Coronavirus/complicações , Diabetes Mellitus/fisiopatologia , Humanos , Masculino , Pandemias , Pneumonia Viral/complicações , Ratos , Regeneração/imunologia , Fatores de Risco , Vacinação/métodos
3.
ACS Appl Mater Interfaces ; 12(33): 36823-36836, 2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32706234

RESUMO

Periosteum orchestrates bone repair. Previously developed artificial periosteum was mainly focusing on materials modification to simply enhance bone formation, but few were attempting to make the artificial periosteum fit different bone repair stages. Here, we constructed a functionalized periosteum, which was composed of an electrospun scaffold grafted with leptin receptor antibody (LepR-a) and BMP2-loaded hollow MnO2 (h-MnO2) nanoparticles through a polydopamine (PDA)-assisted technique. The bionic periosteum showed suitable mechanical properties and favorable biocompatibility. It effectively recruited skeletal stem cells (SSCs) through antigen-antibody interactions, as in in vitro cell adhesion tests, we observed that more SSCs attached to the LepR-a-grafted periosteum compared to the control group. In vivo, the LepR-a-grafted periosteum covered on the cranial defect in Prx1-Cre/ERT2, -EGFP mice recruited more Prx1-EGFP cells to the fracture site compared to control groups at post-surgery day 3, 7, and 14. Co-staining with Sp7 indicated that most of the recruited Prx1-EGFP cells underwent osteogenic lineage commitment. Sustained BMP2 release from h-MnO2 promoted osteogenesis by accelerating the osteogenic differentiation of recruited SSCs, as demonstrated by alkaline phosphatase (ALP) and alizarin red staining (ARS) in vitro and microcomputed tomography (micro-CT) in vivo. Interestingly, we also observed the growth of osteogenic coupled capillaries (CD31hiEmcnhi) in the bone repair site, which might be induced by increased platelet-derived growth factor-BB (PDGF-BB) in the regenerative microenvironment subsequent to SSCs' differentiation. Taken together, the findings from this study indicate that the multifunctionalized periosteum efficiently recruited and motivated the SSCs in vivo and orchestrated the osteogenic microenvironment for bone repair in a sequence manner. Thus, the construction of the bionic periosteum to couple with natural bone regeneration stages has been demonstrated to be effective in facilitating bone healing.


Assuntos
Materiais Biocompatíveis/química , Indóis/química , Compostos de Manganês/química , Nanoestruturas/química , Óxidos/química , Periósteo/metabolismo , Polímeros/química , Tecidos Suporte/química , Fosfatase Alcalina/metabolismo , Animais , Proteína Morfogenética Óssea 2/metabolismo , Regeneração Óssea , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos , Modelos Animais , Células-Tronco Embrionárias Murinas , Osteogênese , Ratos , Receptores para Leptina/metabolismo , Propriedades de Superfície , Tamoxifeno/metabolismo , Engenharia Tecidual
4.
Regul Toxicol Pharmacol ; 113: 104640, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32169672

RESUMO

Acacia catechu (A. catechu) or Khair (Hindi) is used in several herbal preparations in the Ayurvedic system of medicine in India. Traditionally, this drug is beneficial against several gastrointestinal and stomach related ailments, and leprosy. The present investigation was carried out to evaluate the sub-acute oral toxicity of the ethanolic extract of A. catechu seeds in Wistar albino rats. Results obtained from the quantitative chemical analysis of A. catechu seed extract were compared with commercially available standards. A. catechu seed extract was administered orally at the doses of 250, 500 and 1000 mg/kg b.w. daily for 28 days. General behavior, bodyweight and mortality were examined during the entire study period. At the end of 28 days, hematological and biochemical parameters along with the relative organ weights were determined. It was observed that the extract did not induce death or any significant changes in the body weight, relative weight of vital organs and in hematological parameters for up to a dose of 1000 mg/kg. The oral administration of the plant extract did not produce any significant changes in the levels of glucose. In addition, there were no significant changes in the activity of both hepatotoxic and nephrotoxic marker enzymes in the serum. Oral administration of A. catechu also did not produce any significant changes in the levels of oxidative markers. Furthermore, the findings from the biochemical studies were, well corroborated with the histological findings.


Assuntos
Acacia/química , Modelos Animais , Extratos Vegetais/administração & dosagem , Sementes/química , Administração Oral , Animais , Feminino , Ratos , Ratos Wistar , Testes de Toxicidade Subaguda
5.
J Biomed Mater Res A ; 108(6): 1380-1389, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32105397

RESUMO

Spinal cord injury (SCI) is a central nervous disorder that can result in permanent motor and sensory damage due to a severed communication pathway. Although there is currently no effective treatment, nerve guide tubes have been used to bridge the injured stumps and act as drug delivery systems. In this study, biosynthesized cellulose (BC) nerve guides were prepared, and nerve growth factor (NGF)-a model growth factor-was incorporated into the tubular nerve guide in order to obtain a nerve guide/drug delivery system to assist the regeneration. To achieve this, Gluconacetobacter hansenii was cultivated in a special bioreactor to produce biosynthesized cellulose tubes (BCTs) in situ, and the physical and mechanical properties of the BCTs obtained from different cultivation time points were evaluated. Our results showed that the properties of the BCTs were comparable to those of the native human neural tissues, and that the NGF released from the BCTs was bioactive for at least 7 days as evaluated by PC12 cell cultures in vitro. In summary, this study evaluated the use of BCT as a drug releasing nerve guide, and our results showed that the BCT is an attractive strategy to enhance nerve regeneration after the SCI.


Assuntos
Celulose/química , Regeneração Tecidual Guiada , Fator de Crescimento Neural/administração & dosagem , Traumatismos da Medula Espinal/terapia , Tecidos Suporte/química , Acetobacteraceae/química , Acetobacteraceae/citologia , Acetobacteraceae/metabolismo , Animais , Reatores Biológicos , Celulose/metabolismo , Sistemas de Liberação de Medicamentos , Fator de Crescimento Neural/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Células PC12 , Ratos
6.
Cancer Chemother Pharmacol ; 85(3): 563-571, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31915967

RESUMO

PURPOSE: It has been supposed that cardiac toxicity of doxorubicin is due to its production of free radicals and inflammatory cytokines. Dapsone, an antibiotic drug which is the principal in a multidrug regimen for the treatment of leprosy, is a sulfone with anti-inflammatory and antioxidant immunosuppressive properties. Therefore, we designed this study to investigate the possible effects of dapsone on doxorubicin-induced cardiotoxicity. METHODS: Male rats were administrated doxorubicin (2.5 mg/kg) and dapsone (1, 3, 10 mg/kg) intraperitoneally six times in 2 weeks. Then electrocardiographic (ECG) parameters (QRS complexes, RR and QT intervals) alternation, papillary muscle contraction and excitation, and histopathological changes were assessed. Also, the heart tissue levels of malondialdehyde (MDA) as oxidant factor and superoxide dismutase (SOD) as antioxidant enzyme, tumor necrosis factor-alpha (TNF-α) and serum level of CK-MB were analyzed. RESULTS: Administration of dapsone with doxorubicin significantly reversed alterations induced by doxorubicin in serum levels of CK-MB, ECG parameters, papillary muscle contractility and excitation. Furthermore, the measurement of MDA, SOD and TNF-α tissue level indicated that dapsone significantly reduced oxidative stress and inflammation. These findings were consistent with histopathological analysis. CONCLUSION: Dapsone exerts cardioprotective effects on doxorubicin-induced cardiotoxicity through its anti-inflammatory and antioxidant mechanism.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Dapsona/farmacologia , Doxorrubicina/efeitos adversos , Coração/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Cardiotoxicidade/metabolismo , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Malondialdeído/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
7.
Redox Biol ; 26: 101278, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31382215

RESUMO

Many epilepsies are acquired conditions following an insult to the brain such as a prolonged seizure, traumatic brain injury or stroke. The generation of reactive oxygen species (ROS) and induction of oxidative stress are common sequelae of such brain insults and have been shown to contribute to neuronal death and the development of epilepsy. Here, we show that combination therapy targeting the generation of ROS through NADPH oxidase inhibition and the endogenous antioxidant system through nuclear factor erythroid 2-related factor 2 (Nrf2) activation prevents excessive ROS accumulation, mitochondrial depolarisation and neuronal death during in vitro seizure-like activity. Moreover, this combination therapy prevented the development of spontaneous seizures in 40% of animals following status epilepticus (70% of animals were seizure free after 8 weeks) and modified the severity of epilepsy when given to chronic epileptic animals.


Assuntos
Antioxidantes/farmacologia , Epilepsia/etiologia , Hansenostáticos/farmacologia , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Biomarcadores , Doença Crônica , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Epilepsia/prevenção & controle , Ácido Caínico/metabolismo , Hansenostáticos/administração & dosagem , Hansenostáticos/química , Masculino , NADPH Oxidases/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo
8.
J Control Release ; 309: 125-144, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31344425

RESUMO

Nowadays the use of sustainable polymers as poly-lactic acid (PLA) and poly-δ-decalactone (PDL) in drug delivery is advantageous compared to polymers derived from fossil fuels. The present work aimed to produce microparticles (MPs) derived from novel sustainable polymers, loaded with triamcinolone acetonide (TA) for treatment of rheumatoid arthritis via intra-articular (IA) delivery. PDL was synthesized from green δ-decalactone monomers and co-polymerized with methoxy-polyethylene glycol (mPEG) forming PEG-PDL with different molecular weights. The Hansen's solubility parameters were applied to select the most compatible polymer with the drug. An o/w emulsion/solvent evaporation technique was used for MPs fabrication, using 3 [3] full factorial design. Selection of the optimized MPs was performed using Expert Design® software's desirability function. The optimized formulations were characterized using scanning electron microscope, powder X-ray diffraction, differential scanning calorimetry, infrared spectroscopy and in vitro release studies. The inhibition percents of inflammation and histopathological studies were assessed in complete Freund's adjuvant-induced rats' knee joints evaluating the effect of IA injections of selected MPs compared to the free drug suspension. Solubility studies revealed high compatibility and miscibility between TA and PEG-PDL1700, which was blended with PLA for convenient MPs formation. The in vitro characterization studies confirmed the formation of drug-copolymer co-crystals. The in vivo studies ensured the superiority of the newly designed composite MPs in inflammation suppression, compared to the free drug suspension and PLA MPs as well. The present study proved the advantage of using sustainable polymers in a novel combination for effective drug delivery and suggesting its usefulness in designing versatile platforms for therapeutic applications.


Assuntos
Anti-Inflamatórios/administração & dosagem , Artrite/tratamento farmacológico , Portadores de Fármacos/química , Poliésteres/química , Triancinolona Acetonida/administração & dosagem , Animais , Anti-Inflamatórios/uso terapêutico , Artrite/patologia , Sistemas de Liberação de Medicamentos , Injeções Intra-Articulares , Lactonas/química , Masculino , Polietilenoglicóis/química , Ratos , Triancinolona Acetonida/uso terapêutico
9.
Eur J Pharm Sci ; 136: 104937, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31128208

RESUMO

Thalidomide (TLD) is used to treat erythema nodosum leprosum (ENL), multiple myeloma, aphthous ulceration and wasting syndrome in HIV patients. The API can be found in two crystalline habits known as α-TLD and ß-TLD. The saturation solubility (Cs) and the dissolution profiles under non-sink and sink conditions of both polymorphs were assessed. In addition, mini-capsules containing α-TLD or ß-TLD without excipients were orally given (10 mg/kg) to Wistar rats. An intravenous (i.v.) dose was also administrated (5 mg/kg). The Cs values for α-TLD and ß-TLD were not significantly different (α = 56.2 ±â€¯0.5 µg·mL-1; ß = 55.2 ±â€¯0.2 µg·mL-1). However, the dissolution profile of α-TLD presented the fastest rate and the largest extension of drug dissolution than that from ß-TLD (80% in 4 h versus 55% in 4 h). The α-TLD provided a more favorable pharmacokinetic than the ß-TLD (maximum plasma concentration - Cmax: 5.4 ±â€¯0.90 µg·mL-1versus 2.6 ±â€¯0.2 µg·mL-1; area under the curve of the concentration-time profile from time zero to infinity - AUC0-∞: 44.3 ±â€¯8.8 µg·h·mL-1versus 33.9 ±â€¯4.7 µg·h·mL-1; absolute bioavailability - F: 92.2 ±â€¯18.5% versus 70.5 ±â€¯9.9%, respectively). Drug suppliers and pharmaceutical companies should strictly control the technological processes involved in the TLD API synthesis as well as in the production of the pharmaceutical dosage form in order to guarantee the inter-batch homogeneity and therefore, product compliance.


Assuntos
Talidomida/química , Talidomida/farmacocinética , Animais , Área Sob a Curva , Disponibilidade Biológica , Cápsulas/química , Cápsulas/farmacocinética , Liberação Controlada de Fármacos/efeitos dos fármacos , Excipientes/química , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Masculino , Ratos , Ratos Wistar , Solubilidade/efeitos dos fármacos
10.
Front Biosci (Landmark Ed) ; 24: 712-722, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844707

RESUMO

Although not without controversy, as a general trend, the human sperm count is declining world-wide. One major reason for such a decline is an increase in the human life-span.  According to the life history tradeoff theory, fecundity is inversely related to the lifespan; the longer the lifespan, the lower the fecundity. This is essential to the maintainance of diversity and balance of different species. Such a corrleation validated by experimental data that show that the extension of life in Caenorhabditis elegans, Drosophila and Rodents is  associated with reduction in fecundity. The demographic data from a public data source, shows that the total fertility rate is positively correlated with the infant death rate, it is inversely correlated with the life expectancy. We postulate that the fall in spermatogenesis might be regulated by the neuroendocrine system that underlie human longevity.


Assuntos
Expectativa de Vida , Oligospermia/epidemiologia , Contagem de Espermatozoides , Animais , Coeficiente de Natalidade , Caenorhabditis elegans , Dinamarca , Drosophila melanogaster , Poluentes Ambientais , Escherichia coli/fisiologia , Fertilidade , Saúde Global , Humanos , Estilo de Vida , Longevidade , Masculino , Modelos Teóricos , Mycobacterium leprae/fisiologia , Mycobacterium tuberculosis/fisiologia , Ratos , Leveduras/fisiologia
11.
Brain Res ; 1708: 181-187, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30571982

RESUMO

Status epilepticus (SE) is a serious medical condition, as it may trigger epileptogenesis. SE produces continuous generalized seizures resulting in irreversible brain damage. Therefore, the use of neuroprotective agents to prevent cell damage, may reduce the impact of SE. The use of diazepam (DZP), has shown limited neuroprotective effect in SE patients. According to previous reports, dapsone (DDS) is able to reduce both cell damage and seizures, when administered 30 min before the onset of seizures. This study is aimed to evaluate the ability of DDS, alone or in combination with DZP starting their administration once the SE is onset to evaluate the control of seizures in rats. Results showed a reduced convulsive electrical activity after 30 min, 1 and 2 h after SE induced by kainic acid (KA) administration, in the animals treated with DZP alone or in combination with DDS. At 24 h, we observed electrical activity similar to baseline in all groups receiving treatment. The animals treated with DDS and DZP alone or in combination showed an increase in the number of viable pyramidal cells but only the combination showed a lower number of damaged pyramidal neurons of hippocampal CA3. In conclusion, DDS plus DZP was able to control SE and to prevent SE-induced damage, when administered in combination with DZP. As DDS is already in use for patients with leprosy, that combination may be a safe, good option for human cases of SE.


Assuntos
Dapsona/farmacologia , Estado Epiléptico/tratamento farmacológico , Animais , Anticonvulsivantes/farmacologia , Diazepam/farmacologia , Eletroencefalografia , Hipocampo/efeitos dos fármacos , Ácido Caínico/efeitos adversos , Masculino , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Células Piramidais/efeitos dos fármacos , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Estado Epiléptico/induzido quimicamente
13.
Trop Med Int Health ; 23(2): 193-198, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29230912

RESUMO

OBJECTIVES: To determine the average time in months between the beginning of symptoms and the diagnostic confirmation of leprosy by the health system and to investigate factors associated with diagnostic delay. METHODS: A total of 249 patients older than 15 years diagnosed with leprosy between 2011 and 2015, in 20 endemic municipalities of north-eastern Colombia, provided informed consent and were interviewed face-to-face. Clinical histories from health centres or hospitals where study participants were treated for leprosy were also reviewed. RESULTS: The mean delay in diagnosis of leprosy was 33.5 months. About 14.9% of patients showed a visible deformity or damage (disability grade 2, DG2) at the time of diagnosis. In multivariable regression analysis, five or more consultancies required to confirm the diagnosis and not seeking care immediately after noticing first symptoms were associated with longer diagnostic delay. CONCLUSIONS: Our study found a significant delay in diagnosis of leprosy in north-eastern Colombia, which might explain the continuously high rate of DG2 among new cases being notified in the country. Both patient- and health system-related factors were associated with longer diagnostic delay. Interventions to increase awareness of disease among the general population and timely referral to a specialised health professional are urgently needed in our study setting.


Assuntos
Controle de Doenças Transmissíveis/organização & administração , Diagnóstico Tardio/estatística & dados numéricos , Nível de Saúde , Hanseníase/diagnóstico , Adolescente , Adulto , Animais , Análise por Conglomerados , Colômbia , Pessoas com Deficiência/estatística & dados numéricos , Feminino , Humanos , Hanseníase/prevenção & controle , Masculino , Ratos , Medição de Risco , Fatores de Tempo
14.
J Ethnopharmacol ; 197: 294-305, 2017 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-27484929

RESUMO

ETHNO-PHARMACOLOGICAL RELEVANCE: Pattanga is botanically equated as Caesalpinia sappan Linn. (Family: Caesalpiniaceae) and is used in Ayurveda system of medicine since ages. According to Ayurveda, useful part is Heartwood, which is bitter, astringent and acrid and is useful in vitiated conditions of vata and pitta, burning sensation, wounds, ulcers, leprosy, skin diseases, menorrhagia, leucorrhea, and diabetes. It is used as a major ingredient in Ayurvedic formulations and preparations like Patrangasava, Chandanadya Thalia, and Karpuradyarka. AIM OF THE STUDY: The present study is planned to evaluate the gastroprotective activity of the selected Ayurvedic drug using three different in vivo gastric ulcer models, so as to provide scientific evidence for the Ayurvedic claims. MATERIALS AND METHODS: For this study, Wistar albino rats fasted overnight were selected. The hydroalcoholic extract of Caesalpinia sappan heartwood at the dose level 250 and 500mg/kg body weight was selected and administered orally before necrotizing agents. Antioxidant and antiulcer parameters were evaluated and the stomach samples were subjected for histopathological studies. In addition, PGE2 estimation and protein expressions of COX-1, COX-2 and iNOS were analyzed by Western blot. The plant extract was subjected to LCMS/MS analysis. In addition, Cytoprotective effect in isolated gastric mucosal cells, TUNEL Assay, Acid neutralizing capacity assay, H+/K+ ATPase inhibitory assay were performed. RESULTS: The ulcer protection was found to be 92%, 86% and 64% against ethanol, NSAID and pylorus ligation induced ulcer respectively. The hydro-alcoholic extract of C. sappan heartwood exhibited cytoprotective effect with 76.82% reduction against indomethacin-induced cytotoxicity at the concentration of 25µg/ml. C. sappan showed 63.91% inhibition in H+/K+ ATPase inhibitory assay at the concentration 500µg/ml. CONCLUSIONS: Our results depict that Caesalpinia sappan heartwood possesses gastroprotective activity, possibly mediated through cytoprotection and antioxidant mechanisms. The data obtained in the present study provides scientific support for the traditional use of Caesalpinia sappan in the management of peptic ulcer.


Assuntos
Caesalpinia/química , Mucosa Gástrica/efeitos dos fármacos , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/química , Antiulcerosos/farmacologia , Antioxidantes/farmacologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Etanol/química , Feminino , Mucosa Gástrica/metabolismo , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Indometacina/farmacologia , Proteínas de Membrana/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fitoterapia/métodos , Extratos Vegetais/química , Substâncias Protetoras/química , Ratos , Ratos Wistar , Úlcera Gástrica/metabolismo
15.
Endocrinology ; 157(5): 1813-25, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27007072

RESUMO

Leptin availability in perinatal life critically affects metabolic programming. We tested the hypothesis that uteroplacental insufficiency and intrauterine stress affect perinatal leptin availability in rat offspring. Pregnant rats underwent bilateral uterine vessel ligation (LIG; n = 14), sham operation (SOP; n = 12), or no operation (controls, n = 14). Fetal livers (n = 180), placentas (n = 180), and maternal blood were obtained 4 hours (gestational day [E] 19), 24 hours (E20), and 72 hours (E22) after surgery. In the offspring, we took blood samples on E22 (n = 44), postnatal day (P) 1 (n = 29), P2 (n = 16), P7 (n = 30), and P12 (n = 30). Circulating leptin (ELISA) was significantly reduced in LIG (E22, P1, P2) and SOP offspring (E22). Postnatal leptin surge was delayed in LIG but was accelerated in SOP offspring. Placental leptin gene expression (quantitative RT-PCR) was reduced in LIG (E19, E20, E22) and SOP (E20, E22). Hepatic leptin receptor (Lepr-a, mediating leptin degradation) gene expression was increased in LIG fetuses (E20, E22) only. Surprisingly, hypoxia-inducible factors (Hif; Western blot) were unaltered in placentas and were reduced in the livers of LIG (Hif1a, E20; Hif2a, E19, E22) and SOP (Hif2a, E19) fetuses. Gene expression of prolyl hydroxylase 3, a factor expressed under hypoxic conditions contributing to Hif degradation, was increased in livers of LIG (E19, E20, E22) and SOP (E19) fetuses and in placentas of LIG and SOP (E19). In summary, reduced placental leptin production, increased fetal leptin degradation, and persistent perinatal hypoleptinemia are present in intrauterine growth restriction offspring, especially after uteroplacental insufficiency, and may contribute to perinatal programming of leptin resistance and adiposity in later life.


Assuntos
Leptina/metabolismo , Placenta/metabolismo , Insuficiência Placentária/metabolismo , Receptores para Leptina/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Leptina/sangue , Leptina/genética , Fígado/metabolismo , Insuficiência Placentária/sangue , Insuficiência Placentária/genética , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores para Leptina/genética
16.
Hum Mol Genet ; 24(14): 4078-93, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25904107

RESUMO

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known genetic cause of Parkinson's disease, and LRRK2 is also linked to Crohn's and Hansen's disease. LRRK2 is expressed in many organs in mammals but is particularly abundant in the kidney. We find that LRRK2 protein is predominantly localized to collecting duct cells in the rat kidney, with much lower expression in other kidney cells. While genetic knockout (KO) of LRRK2 expression is well-tolerated in mice and rats, a unique age-dependent pathology develops in the kidney. The cortex and medulla of LRRK2 KO rat kidneys become darkly pigmented in early adulthood, yet aged animals display no overt signs of kidney failure. Accompanying the dark pigment we find substantial macrophage infiltration in LRRK2 KO kidneys, suggesting the presence of chronic inflammation that may predispose to kidney disease. Unexpectedly, the dark kidneys of the LRRK2 KO rats are highly resistant to rhabdomyolysis-induced acute kidney injury compared with wild-type rats. Biochemical profiling of the LRRK2 KO kidneys using immunohistochemistry, proteomic and lipidomic analyses show a massive accumulation of hemoglobin and lipofuscin in renal tubules that account for the pigmentation. The proximal tubules demonstrate a corresponding up-regulation of the cytoprotective protein heme oxygenase-1 (HO-1) which is capable of mitigating acute kidney injury. The unusual kidney pathology of LRRK2 KO rats highlights several novel physiological roles for LRRK2 and provides indirect evidence for HO-1 expression as a protective mechanism in acute kidney injury in LRRK2 deficiency.


Assuntos
Nefropatias/genética , Proteínas Serina-Treonina Quinases/genética , Rabdomiólise/genética , Animais , Citoproteção , Células Epiteliais/metabolismo , Predisposição Genética para Doença , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Nefropatias/etiologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/metabolismo , Proteômica , Ratos , Rabdomiólise/complicações , Regulação para Cima
17.
Pharm Res ; 32(8): 2516-26, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25690341

RESUMO

PURPOSE: Recent controversial publications, citing studies purporting to show that P-gp mediates the transport of propranolol, proposed that passive biological membrane transport is negligible. Based on the BDDCS, the extensively metabolized-highly permeable-highly soluble BDDCS class 1 drug, propranolol, shows a high passive permeability at concentrations unrestricted by solubility that can overwhelm any potential transporter effects. Here we reinvestigate the effects of passive diffusion and carrier-mediated transport on S-propranolol. METHODS: Bidirectional permeability and inhibition of efflux transport studies were carried out in MDCK, MDCK-MDR1 and Caco-2 cell lines at different concentrations. Transcellular permeability studies were conducted at different apical pHs in the rat jejunum Ussing chamber model and PAMPA system. RESULTS: S-propranolol exhibited efflux ratios lower than 1 in MDCK, MDCK-MDR1 and Caco-2 cells. No significant differences of Papp, B->A in the presence and absence of the efflux inhibitor GG918 were observed. However, an efflux ratio of 3.63 was found at apical pH 6.5 with significant decrease in Papp, A->B and increase in Papp, B->A compared to apical pH 7.4 in Caco-2 cell lines. The pH dependent permeability was confirmed in the Ussing chamber model. S-propranolol flux was unchanged during inhibition by verapamil and rifampin. Furthermore, pH dependent permeability was also observed in the PAMPA system. CONCLUSIONS: S-propranolol does not exhibit active transport as proposed previously. The "false" positive efflux ratio can be explained by the pH partition theory. As expected, passive diffusion, but not active transport, plays the primary role in the permeability of the BDDCS class 1 drug propranolol.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antagonistas Adrenérgicos beta/metabolismo , Propranolol/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Bloqueadores dos Canais de Cálcio/farmacologia , Difusão , Cães , Interações Medicamentosas , Humanos , Concentração de Íons de Hidrogênio , Hansenostáticos/farmacologia , Células Madin Darby de Rim Canino , Masculino , Permeabilidade , Ratos , Ratos Sprague-Dawley , Rifampina/farmacologia , Estereoisomerismo , Verapamil/farmacologia
18.
Berlin; s.n; 2015. 9 p. ilus, tab, graf.
Não convencional em Inglês | SES-SP, SESSP-ILSLPROD, SES-SP, SESSP-ILSLACERVO, SES-SP | ID: biblio-1015053

RESUMO

There are no studies investigating the role of nutritional status and immunity associated with Jorge Lobo's disease. The objective of this study was to evaluate the effects of protein-calorie malnutrition on the immune response of BALB/c mice inoculated with Lacazia loboi. In this study,the animals were divided into four groups: G1: inoculated with restricted diet, G2: not inoculated with restricted diet, G3: inoculated with regular diet, G4: not inoculated with regular diet. The animals of groups G1 and G2 were submitted to malnutrition for 20 days and once installed the animals were inoculated intradermally into the footpad. After 4 months, they were euthanised for the isolation of peritoneal lavage cells and removal of the footpad. The production of IL-2, IL-4, IL-10, IL-12, IFN-γ, TNF-α, H2 O2 and nitric oxide (NO) was evaluated in the peritoneal lavage cells. The footpad was evaluated regarding the size of macroscopic lesions, number of fungi and viability index. The results showed that the infection did not exert great influence on the body weight of the mice and previous malnutrition was an unfavourable factor for viability index, number of fungi, macroscopic lesion size in the footpad and production of H2 O2 , NO, IL-12, IL-10 and IFN-γ, suggesting that malnutrition significantly altered fungal activity and peritoneal cells. The results suggest considerable interaction between nutrition and immunity in Jorge Lobo's disease


Assuntos
Animais , Ratos , Estado Nutricional , Lobomicose/imunologia , Lobomicose/microbiologia , Desnutrição/complicações , Lacazia/imunologia
19.
In. Virmond, Marcos da Cunha Lopes; Grzybowski, Andrzej. Clinics in Dermatology: Leprosy: 1. New York, Elsevier, 2015. p.46-54, ilus, tab, graf.
Não convencional em Inglês | SES-SP, HANSEN, SESSP-ILSLACERVO, SES-SP | ID: biblio-1048321

RESUMO

All patients with leprosy have some degree of nerve involvement. Perineural inflammation is the histopathologic hallmark of leprosy, and this localization may reflect a vascular route of entry of Mycobacterium leprae into nerves. Once inside nerves, M leprae are ingested by Schwann cells, with a wide array of consequences. Axonal atrophy may occur early in this process; ultimately, affected nerves undergo segmental demyelination. Knowledge of the mechanisms of nerve injury in leprosy has been greatly limited by the minimal opportunities to study affected nerves in man. The nine-banded armadillo provides the only animal model of the pathogenesis of M leprae infection. New tools available for this model enable the study and correlation of events occurring in epidermal nerve fibers, dermal nerves, and nerve trunks, including neurophysiologic parameters, bacterial load, and changes in gene transcription in both neural and inflammatory cells. The armadillo model is likely to enhance understanding of the mechanisms of nerve injury in leprosy and offers a means of testing proposed interventions.


Assuntos
Humanos , Animais , Masculino , Feminino , Ratos , Células de Schwann/microbiologia , Doenças do Sistema Nervoso Periférico/microbiologia , Hanseníase/complicações , Mycobacterium leprae/isolamento & purificação , Neurite (Inflamação)/microbiologia , Doenças do Sistema Nervoso Periférico/etiologia , Progressão da Doença
20.
Botucatu; s.n; 2015. 5 p. tab.
Não convencional em Inglês | SES-SP, SESSP-ILSLPROD, SES-SP, SESSP-ILSLACERVO, SES-SP | ID: biblio-1085422

RESUMO

Background: Jorge Lobo’s disease, also known as lacaziosis, is a cutaneous-subcutaneous mycosis with chronic evolution. It is caused by the fungus Lacazia loboi. Herein we report a study that relates the genotoxicity caused by L. loboi in isogenic mice with nutritional status, through a normal or restricted diet. Methods: DNA damage was assessed in the peripheral blood by the comet assay (tail intensity).Results: The results for leukocytes showed increases in the mean tail intensity in mice under dietary restriction, in infected mice under dietary restriction and in infected mice ingesting a normal diet. Conclusion: These results indicate that dietary restriction and L. loboi infection may increase DNA damage levels in mice, as detected by the comet assay


Assuntos
Animais , Ratos , Desnutrição , Ensaio Cometa , Genotoxicidade , Lacazia , Lobomicose , Dano ao DNA
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