RESUMEN
Interferon-gamma-inducible human large GTPases, hGBP1 and hGBP2, have a distinctive feature of hydrolyzing GTP to GDP and GMP through successive phosphate cleavages. In hGBP1, GMP is the major product, which is essential for its anti-pathogenic activities. However, its close homologue hGBP2 produces significantly less GMP, despite having a similar active site architecture. The molecular basis for less GMP formation and catalytic residue(s) in hGBP2 are not fully explored. To address these issues, we performed systematic biochemical, biophysical, and microsecond simulation studies. Our data suggest that the less GMP formation in hGBP2 is due to the lack of H-bond formation between the W79 side-chain (located near the active site) and main-chain carbonyl of K76 (present in the catalytic loop) in the substrate-bound hGBP2. The absence of this H-bond could not redirect the catalytic loop toward the beta phosphate after the cleavage of gamma-phosphate, a step essential for enhanced GMP formation. Furthermore, based on the mutational and structural analyses, this study for the first time indicates that the same residue, T75, mediates both phosphate cleavages in hGBP2 and hGBP1. This suggests the conservation of the catalytic residue in hGBP homologues. These findings emphasize the indispensable role of correct catalytic loop repositioning for efficient beta phosphate cleavage. This led us to propose a new substrate hydrolysis mechanism by hGBP1 and hGBP2, which may also be helpful to understand the GTP hydrolysis in other hGBP homologues. Overall, the study could provide insight into how these two close homologues play crucial roles in host-mediated immunity through different mechanisms.
Asunto(s)
GTP Fosfohidrolasas , Proteínas de Unión al GTP , Humanos , Proteínas de Unión al GTP/metabolismo , Guanosina Trifosfato/química , GTP Fosfohidrolasas/metabolismo , Hidrólisis , FosfatosRESUMEN
Inflammatory bowel disease (IBD) is a relapsing chronic idiopathic inflammatory condition. The increased risks of fractures in the spine and decreased BMD at all weight-bearing skeletal sites have been reported in IBD patients. The understanding of the mechanisms of IBD-induced bone loss is far from complete. Appropriate animal models are a prerequisite for studying IBD-induced bone loss, which prompted us to undertake quantitative meta-analyses by pooling data from the available IBD models that assessed various bone parameters. Sufficient data for meta-analysis are obtained from chemically- but not genetically induced models. Among the chemically induced models, only the effects of dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) on bone parameters have been reported. Meta-analysis showed that both DSS (Hedge's g = 2.124, p = 0.001) and TNBS (Hedge's g = 6.292, p = 0.000) increased inflammatory disease severity. In pooled analysis, bone volumes in femur (Hedge's g = - 3.42, p = 0.000) and tibia (Hedge's g = - 2.49, p = 0.000) showed significant losses upon DSS administration. Similarly, bone formation rate was significantly reduced upon IBD induction (Hedge's g = - 3.495, p = 0.006). Besides, cortical thickness was reduced and trabecular microstructure deteriorated by IBD induction. Insufficient data precluded us from determining the effect of IBD on bone strength and calciotropic hormones, as well as the impact of proinflammatory cytokines on bone turnover. This meta-analysis showed that IBD induction in rodents causes significant bone loss. Impaired osteoblast function appears to be the cause of this impact.
Asunto(s)
Enfermedades Óseas Metabólicas , Colitis , Enfermedades Inflamatorias del Intestino , Animales , Sulfato de Dextran , Modelos Animales de Enfermedad , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Ácido TrinitrobencenosulfónicoRESUMEN
Modafinil is primarily prescribed for treatment of narcolepsy and other sleep-associated disorders. However, its off-prescription use as a cognition enhancer increased considerably, specially among youths. Given its increasing use in young adults the effect of modafinil on peak bone accrual is an important issue but has never been investigated. Modafinil treatment to young male rats caused trabecular and cortical bone loss in tibia and femur, and reduction in biomechanical strength. Co-treatment of modafinil with alendronate (a drug that suppresses bone resorption) reversed the trabecular bone loss but failed to prevent cortical loss. Modafinil increased serum type 1 pro-collagen N-terminal protein (P1NP) and collagen type 1 cross-linked C-telopeptide (CTX-1) indicating a high turnover bone loss. The drug also increased receptor activator of nuclear factor κB ligand (RANKL) to osteoprotegerin (OPG) ratio in serum which likely resulted in increased osteoclast number per bone surface. Furthermore, conditioned medium from modafinil treated osteoblasts increased the expression of osteoclastogenic genes in bone marrow-derived macrophages and the effect was blocked by RANKL neutralizing antibody. In primary osteoblasts, modafinil stimulated cAMP production and using pharmacological approach, we showed that modafinil signalled via adenosine receptors (A2AR and A2BR) which resulted in increased RANKL expression. ZM-241,385 (an A2AR inhibitor) and MRS 1754 (an A2BR inhibitor) suppressed modafinil-induced upregulation of RANKL/OPG ratio in the calvarium of new born rat pups. Our data suggests that by activating osteoblast adenosine receptors modafinil increases the production of osteoclastogenic cytokine, RANKL that in turn results in high turnover bone loss in young rats.
Asunto(s)
Agonistas del Receptor de Adenosina A2/toxicidad , Compuestos de Bencidrilo/toxicidad , Remodelación Ósea/efectos de los fármacos , Hueso Esponjoso/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteoporosis/inducido químicamente , Ligando RANK/metabolismo , Receptor de Adenosina A2A/efectos de los fármacos , Receptor de Adenosina A2B/efectos de los fármacos , Promotores de la Vigilia/toxicidad , Animales , Fenómenos Biomecánicos , Hueso Esponjoso/metabolismo , Hueso Esponjoso/patología , Hueso Esponjoso/fisiopatología , Células Cultivadas , Hueso Cortical/efectos de los fármacos , Hueso Cortical/metabolismo , Hueso Cortical/patología , Hueso Cortical/fisiopatología , AMP Cíclico/metabolismo , Masculino , Modafinilo , Osteoblastos/metabolismo , Osteoblastos/patología , Osteogénesis/efectos de los fármacos , Osteoporosis/metabolismo , Osteoporosis/patología , Osteoporosis/fisiopatología , Osteoprotegerina/metabolismo , Ligando RANK/genética , Ratas Sprague-Dawley , Receptor de Adenosina A2A/metabolismo , Receptor de Adenosina A2B/metabolismo , Transducción de Señal , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Osteoarthritis (OA) is a chronic disease of articular joints that leads to degeneration of both cartilage and subchondral bone. These degenerative changes are further aggravated by proinflammatory cytokines including IL-1ß and TNF-α. Previously, we have reported that IL-3, a cytokine secreted by activated T cells, protects cartilage and bone damage in murine models of inflammatory and rheumatoid arthritis. However, how IL-3 protects cartilage degeneration is not yet known. In this study, we investigated the role of IL-3 on cartilage degeneration under both in vitro and in vivo conditions. We found that both mouse and human chondrocytes show strong expression of IL-3R at gene and protein levels. IL-3 increases the expression of mouse chondrocyte-specific genes, Sox9 and collagen type IIa, which were downregulated by IL-1ß. Moreover, IL-3 downregulated IL-1ß- and TNF-α-induced expression of matrix metalloproteinases in both mouse and human chondrocytes. Interestingly, IL-3 reduces the degeneration of articular cartilage and subchondral bone microarchitecture in a mouse model of human OA. Moreover, IL-3 showed the preventive and therapeutic effects on cartilage degeneration induced by IL-1ß in micromass pellet cultures of human mesenchymal stem cells. Thus, to our knowledge, we provide the first evidence that IL-3 has therapeutic potential in amelioration of degeneration of articular cartilage and subchondral bone microarchitecture associated with OA.
Asunto(s)
Cartílago Articular/patología , Regulación hacia Abajo , Interleucina-3/uso terapéutico , Metaloproteinasas de la Matriz/genética , Osteoartritis/tratamiento farmacológico , Animales , Cartílago Articular/efectos de los fármacos , Cartílago Articular/inmunología , Células Cultivadas , Condrocitos/efectos de los fármacos , Condrocitos/inmunología , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Modelos Animales de Enfermedad , Humanos , Interleucina-1beta/farmacología , Interleucina-3/administración & dosificación , Interleucina-3/farmacología , Subunidad alfa del Receptor de Interleucina-3/genética , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/inmunología , Ratones , Osteoartritis/inmunología , Osteoartritis/fisiopatología , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Aldehyde dehydrogenases (ALDHs) are a family of enzymes involved in detoxifying aldehydes. Previously, we reported that an ALDH inhibitor, disulfiram caused bone loss in rats and among ALDHs, osteoblast expressed only ALDH2. Loss-of-function mutation in ALDH2 gene is reported to cause bone loss in humans which suggested its importance in skeletal homeostasis. We thus studied whether activating ALDH2 by N-(1, 3-benzodioxol-5-ylmethyl)-2, 6-dichlorobenzamide (alda-1) had osteogenic effect. We found that alda-1 increased and acetaldehyde decreased the differentiation of rat primary osteoblasts and expressions of ALDH2 and bone morphogenetic protein-2 (BMP-2). Silencing ALDH2 in osteoblasts abolished the alda-1 effects. Further, alda-1 attenuated the acetaldehyde-induced lipid-peroxidation and oxidative stress. BMP-2 is essential for bone regeneration and alda-1 increased its expression in osteoblasts. We then showed that alda-1 (40mg/kg dose) augmented bone regeneration at the fracture site with concomitant increase in BMP-2 protein compared with control. The osteogenic dose (40mg/kg) of alda-1 attained a bone marrow concentration that was stimulatory for osteoblast differentiation, suggesting that the tissue concentration of alda-1 matched its pharmacologic effect. In addition, alda-1 promoted modeling-directed bone growth and peak bone mass achievement, and increased bone mass in adult rats which reiterated its osteogenic effect. In osteopenic ovariectomized (OVX) rats, alda-1 reversed trabecular osteopenia with attendant increase in serum osteogenic marker (procollagen type I N-terminal peptide) and decrease in oxidative stress. Alda-1 has no effect on liver and kidney function. We conclude that activating ALDH2 by alda-1 had an osteoanabolic effect involving increased osteoblastic BMP-2 production and decreased OVX-induced oxidative stress.
Asunto(s)
Aldehído Deshidrogenasa Mitocondrial/metabolismo , Benzamidas/farmacología , Benzodioxoles/farmacología , Proteína Morfogenética Ósea 2/biosíntesis , Regeneración Ósea/fisiología , Diferenciación Celular/fisiología , Osteoblastos/metabolismo , Animales , Proteína Morfogenética Ósea 2/agonistas , Regeneración Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Activadores de Enzimas/farmacología , Femenino , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Osteogénesis/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory synovitis leading to joint destruction and systemic bone loss. The inflammation-induced bone loss is mediated by increased osteoclast formation and function. Current antirheumatic therapies primarily target suppression of inflammatory cascade with limited or no success in controlling progression of bone destruction. Mesenchymal stem cells (MSCs) by virtue of their tissue repair and immunomodulatory properties have shown promising results in various autoimmune and degenerative diseases. However, the role of MSCs in prevention of bone destruction in RA is not yet understood. In this study, we investigated the effect of adipose-derived MSCs (ASCs) on in vitro formation of bone-resorbing osteoclasts and pathological bone loss in the mouse collagen-induced arthritis (CIA) model of RA. We observed that ASCs significantly inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis in both a contact-dependent and -independent manner. Additionally, ASCs inhibited RANKL-induced osteoclastogenesis in the presence of proinflammatory cytokines such as TNF-α, IL-17, and IL-1ß. Furthermore, treatment with ASCs at the onset of CIA significantly reduced clinical symptoms and joint pathology. Interestingly, ASCs protected periarticular and systemic bone loss in CIA mice by maintaining trabecular bone structure. We further observed that treatment with ASCs reduced osteoclast precursors in bone marrow, resulting in decreased osteoclastogenesis. Moreover, ASCs suppressed autoimmune T cell responses and increased the percentages of peripheral regulatory T and B cells. Thus, we provide strong evidence that ASCs ameliorate inflammation-induced systemic bone loss in CIA mice by reducing osteoclast precursors and promoting immune tolerance.
Asunto(s)
Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Resorción Ósea/inmunología , Células Madre Mesenquimatosas/inmunología , Osteoclastos/inmunología , Ligando RANK/antagonistas & inhibidores , Tejido Adiposo/citología , Animales , Artritis Experimental/patología , Artritis Reumatoide/patología , Autoinmunidad/inmunología , Linfocitos B/inmunología , Huesos/inmunología , Huesos/patología , Diferenciación Celular/inmunología , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Tolerancia Inmunológica/inmunología , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Recuento de Linfocitos , Masculino , Ratones , Ratones Endogámicos DBA , Linfocitos T Reguladores/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The drug, theophylline is frequently used as an additive to medications for people suffering from chronic obstructive pulmonary diseases (COPD). We studied the effect of theophylline in bone cells, skeleton and parameters related to systemic calcium homeostasis. Theophylline induced osteoblast apoptosis by increasing reactive oxygen species production that was caused by increased cAMP production. Bone marrow levels of theophylline were higher than its serum levels, indicating skeletal accumulation of this drug. When adult Sprague-Dawley rats were treated with theophylline, bone regeneration at fracture site was diminished compared with control. Theophylline treatment resulted in a time-dependent (at 4- and 8 weeks) bone loss. At 8 weeks, a significant loss of bone mass and deterioration of microarchitecture occurred and the severity was comparable to methylprednisone. Theophylline caused formation of hypomineralized osteoid and increased osteoclast number and surface. Serum bone resorption and formation marker were respectively higher and lower in the theophylline group compared with control. Bone strength was reduced by theophylline treatment. After 8 weeks, serum 25-D3 and liver 25-hydroxylases were decreased in theophylline group than control. Further, theophylline treatment reduced serum 1, 25-(OH)2 vitamin D3 (1,25-D3), and increased parathyroid hormone and fibroblast growth factor-23. Theophylline treated rats had normal serum calcium and phosphate but displayed calciuria and phosphaturia. Co-administration of 25-D3 with theophylline completely abrogated theophylline-induced osteopenia and alterations in calcium homeostasis. In addition, 1,25-D3 protected osteoblasts from theophylline-induced apoptosis and the attendant oxidative stress. We conclude that theophylline has detrimental effects in bone and prophylactic vitamin D supplementation to subjects taking theophylline could be osteoprotective.
Asunto(s)
Enfermedades Óseas Metabólicas/inducido químicamente , Osteoblastos/metabolismo , Teofilina/farmacología , Vitamina D/farmacología , Animales , Apoptosis/efectos de los fármacos , Biomarcadores , Médula Ósea/metabolismo , Regeneración Ósea/efectos de los fármacos , Calcifediol/metabolismo , Técnicas de Cultivo de Célula , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Fracturas Óseas/fisiopatología , Masculino , Metilprednisolona/farmacología , Hormona Paratiroidea/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Teofilina/farmacocinética , Factores de TiempoRESUMEN
The relationship between obesity and bone is complex. Epidemiological studies demonstrate positive as well as negative correlation between obesity and bone health. In the present study, we investigated the impact of high fat diet-induced obesity on peak bone mass. After 9 months of feeding young rats with high fat diet, we observed obesity phenotype in rats with increased body weight, fat mass, serum triglycerides and cholesterol. There were significant increases in serum total alkaline phosphatase, bone mineral density and bone mineral content. By micro-computed tomography (µ-CT), we observed a trend of better trabecular bones with respect to their microarchitecture and geometry. This indicated that high fat diet helps in achieving peak bone mass and microstructure at younger age. We subsequently shifted rats from high fat diet to normal diet for 6 months and evaluated bone/obesity parameters. It was observed that after shifting rats from high fat diet to normal diet, fat mass, serum triglycerides and cholesterol were significantly decreased. Interestingly, the gain in bone mineral density, bone mineral content and trabecular bone parameters by HFD was retained even after body weight and obesity were normalized. These results suggest that fat rich diet during growth could accelerate achievement of peak bone mass that is sustainable even after withdrawal of high fat diet.
Asunto(s)
Densidad Ósea , Dieta Alta en Grasa , Obesidad/etiología , Animales , Huesos/diagnóstico por imagen , Dieta Alta en Grasa/efectos adversos , Masculino , Radiografía , Ratas , Ratas WistarRESUMEN
OBJECTIVE: We report the incidence of spontaneous infarction of a falcine meningioma without preceding hemorrhage and shed light on the relation between intratumoral necrosis and hemorrhage. CLINICAL PRESENTATION: A 50 year-old woman presented with recurrent headaches and was found to harbor a falcine meningioma. The patient elected to observe the mass and 13 months later she developed new neurological deficits. Prior to scheduled resection, she presented with abdominal pain and underwent emergent laparoscopic cholecystectomy. Two days after the procedure, she developed sudden right hemiparesis associated with severe headache. MRI of the brain showed an intratumoral wedge-shaped hypointense area with significant peritumoral edema. The patient was started on high-dose corticosteroids with considerable improvement in strength. INTERVENTION: The patient underwent a complete resection of the tumor with no new neurological deficits post-operatively. Histopathological analysis confirmed a WHO grade II atypical meningioma with extensive necrosis without hemorrhage. CONCLUSION: This case highlights that tumor infarction, although rare, should be in the differential diagnosis of patients with meningiomas presenting with new neurological deficits. When this condition is recognized and treated in timely manner with high-dose corticosteroids and surgical resection, patients can have favorable long-term outcomes.
Asunto(s)
Neoplasias Encefálicas/patología , Infarto/patología , Neoplasias Meníngeas/patología , Meningioma/patología , Neoplasias Encefálicas/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Infarto/diagnóstico , Imagen por Resonancia Magnética/métodos , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Persona de Mediana Edad , Necrosis/patología , Neoplasias Supratentoriales/diagnóstico , Neoplasias Supratentoriales/patologíaRESUMEN
The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, the physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal DCAF15 as an acute myeloid leukemia (AML)-biased dependency. Loss of DCAF15 results in suppression of AML through compromised replication fork integrity and consequent accumulation of DNA damage. Accordingly, DCAF15 loss sensitizes AML to replication stress-inducing therapeutics. Mechanistically, we discover that DCAF15 directly interacts with the SMC1A protein of the cohesin complex and destabilizes the cohesin regulatory factors PDS5A and CDCA5. Loss of PDS5A and CDCA5 removal precludes cohesin acetylation on chromatin, resulting in uncontrolled chromatin loop extrusion, defective DNA replication, and apoptosis. Collectively, our findings uncover an endogenous, cell autonomous function of DCAF15 in sustaining AML proliferation through post-translational control of cohesin dynamics.
Asunto(s)
Proteínas de Ciclo Celular , Proteínas Cromosómicas no Histona , Cohesinas , Daño del ADN , Replicación del ADN , Leucemia Mieloide Aguda , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Humanos , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Línea Celular Tumoral , Acetilación , Animales , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Ratones , Cromatina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Apoptosis , Proliferación Celular , Células HEK293RESUMEN
A novel series of triazole integrated phenyl heteroterpenoids have been synthesized and screened for their in vitro activity against intracellular amastigote form of Leishmania donovani. Among all tested compounds, compound 3a was found to be the most active with IC50 6.4µM and better selectivity index (SI) 18 as compared to reference drugs, miltefosine and miconazole. When evaluated in vivo in L. donovani/hamster model, 3a has exhibited 79±11% inhibition of parasite multiplication at 50mgkg(-1)×5days on day 7 post treatment.
Asunto(s)
Antiparasitarios/farmacología , Diseño de Fármacos , Leishmania donovani/efectos de los fármacos , Leishmaniasis Visceral/tratamiento farmacológico , Terpenos/farmacología , Triazoles/farmacología , Animales , Antiparasitarios/síntesis química , Antiparasitarios/química , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Terpenos/síntesis química , Terpenos/química , Triazoles/síntesis química , Triazoles/química , Células VeroRESUMEN
Some novel α and ß ionone based chalcones and their dihydropyrazolidines/pyrazolidines have been synthesized and evaluated for their in vitro and in vivo antileishmanial activities against Leishmania donovani. Amongest all, one compound (4d) exhibited significant in vitro activity against intracellular amastigotes of Leishmania donovani with IC(50) values of 7.49 µM and was found promising as compared to reference drug, miltefosine. On the basis of good Selectivity Index (S.I.), the compound was further tested for its in vivo response against Leishmania donovani/hamster model and has shown significant inhibition of parasite multiplication (81%). The present study has helped us in identifying a new lead that could be exploited as a potential antileishmanial agent.
Asunto(s)
Antiprotozoarios/síntesis química , Compuestos Heterocíclicos/química , Pirazoles/síntesis química , Animales , Antiprotozoarios/uso terapéutico , Antiprotozoarios/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Chalconas/química , Chalconas/uso terapéutico , Chalconas/toxicidad , Cricetinae , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Compuestos Heterocíclicos/uso terapéutico , Compuestos Heterocíclicos/toxicidad , Humanos , Leishmaniasis/tratamiento farmacológico , Leishmaniasis Visceral/tratamiento farmacológico , Pirazoles/química , Pirazoles/uso terapéutico , Pirazoles/toxicidad , Relación Estructura-ActividadRESUMEN
Hypothalamic hamartomas are uncommon but well-recognized developmental malformations that are classically associated with gelastic seizures and other refractory seizure types. The clinical course is often progressive and, in addition to the catastrophic epileptic syndrome, patients commonly exhibit debilitating cognitive, behavioral, and psychiatric disturbances. Over the past decade, investigators have gained considerable knowledge into the pathobiological and neurophysiological properties of these rare lesions. In this review, the authors examine the causes and molecular biology of hypothalamic hamartomas as well as the principal clinical features, neuroimaging findings, and electrophysiological characteristics. The diverse surgical modalities and strategies used to manage these difficult lesions are outlined in the second article of this 2-part review.
Asunto(s)
Ondas Encefálicas/fisiología , Epilepsia/etiología , Hamartoma , Enfermedades Hipotalámicas , Electroencefalografía , Hamartoma/complicaciones , Hamartoma/diagnóstico , Hamartoma/terapia , Humanos , Enfermedades Hipotalámicas/complicaciones , Enfermedades Hipotalámicas/diagnóstico , Enfermedades Hipotalámicas/terapia , Magnetoencefalografía , Proteínas del Tejido Nervioso/metabolismo , NeuroimagenRESUMEN
Hypothalamic hamartomas are uncommon developmental heterotopic masses composed of an intermixed array of neurons, glia, and myelinated fibers closely associated with the mammillary bodies. Gelastic seizures, the hallmark feature of hypothalamic hamartomas, commonly present in early childhood. However, patients usually also display a disabling clinical syndrome, which may include various other types of refractory seizures with secondary generalization together with progressive cognitive, behavioral, and psychiatric dysfunction. The hamartoma itself has been unequivocally shown to be intrinsically epileptogenic. Over the past 2 decades there has been considerable effort to develop neurosurgical techniques to treat the epileptic syndrome effectively as well as to improve the neurocognitive and behavioral outcome.
Asunto(s)
Hamartoma/complicaciones , Hamartoma/terapia , Enfermedades Hipotalámicas/complicaciones , Enfermedades Hipotalámicas/terapia , Procedimientos Neuroquirúrgicos/métodos , Convulsiones/etiología , Resultado del Tratamiento , Preescolar , Estimulación Encefálica Profunda , Endoscopios , Humanos , Imagen por Resonancia Magnética , Masculino , Radiocirugia , Estimulación del Nervio VagoRESUMEN
A new series of aryl substituted ketene dithioacetals 6a-h was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. Two compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC(50) values 3.56 and 5.12 µM and were found promising as compared with reference drug, miltefosine. On the basis of good Selectivity Indices (S.I.), they were further tested for their in vivo response against L. donovani/hamster model and showed significant inhibition of parasite multiplication 78% and 83%, respectively. These compounds were better than the existing antileishmanials in respect to IC(50) and SI values, but were less active than miltefosine in vivo.
Asunto(s)
Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Leishmania donovani/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Acetales/síntesis química , Acetales/química , Acetales/farmacología , Animales , Antiprotozoarios/química , Cricetinae , Etilenos/síntesis química , Etilenos/química , Etilenos/farmacología , Cetonas/síntesis química , Cetonas/química , Cetonas/farmacología , Modelos Animales , Estructura Molecular , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacología , Compuestos de Sulfhidrilo/síntesis química , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/farmacologíaRESUMEN
A novel series of trans-2-aryloxy-1,2,3,4,-tetrahydronaphthyl azoles and related cyclohexyl azoles were synthesized and evaluated in vitro against Leishmania donovani. Compound 9 identified as most active analog with IC(50) value of 0.64 µg/mL and SI value of 34.78 against amastigotes, and is several folds more potent than the reference drugs sodium stilbogluconate and paromomycin. It also exhibited significant in vivo inhibition of 83.33%, and provided a new structural scaffold for antileishmanials.
Asunto(s)
Antiprotozoarios/síntesis química , Azoles/síntesis química , Diseño de Fármacos , Antiprotozoarios/química , Antiprotozoarios/farmacología , Azoles/química , Azoles/farmacología , Concentración 50 Inhibidora , Leishmania donovani/efectos de los fármacos , Estructura MolecularRESUMEN
Resveratrol/RES (3,5,4'-trihydroxy-trans-stilbene) is a natural compound found in many food items and red wine, which exhibits pleiotropic biological effects. Several preclinical studies evaluating the efficacy of RES in animal models of rheumatoid arthritis (RA) have been conducted, but the diversity of the experimental conditions and of their outcomes preclude definitive conclusions about RES's efficacy. We, therefore, performed a meta-analysis to assess its efficacy in mitigating experimental RA. We searched three databases until January 2021 and used the random-effects model for drawing inferences. Eighteen studies involving 544 animals were used in this study. Pooled analysis showed that experimental RA causes paw swelling (Hedge's g = 9.823, p = 0.000), increases polyarthritis score and arthritis index, and RES administration reduces paw volume (Hedge's g = -2.550, p = 0.000), polyarthritis score, and arthritis index besides amelioration in the histopathological score and cartilage loss. RA is accompanied by increased oxidative stress due to high malondialdehyde (MDA) level (p < 0.001) and low superoxide dismutase (SOD) activity (p = 0.002), and RES reduced MDA level (p < 0.001) and increased SOD activity (p < 0.001). Experimental RA exhibited an increase in pro-inflammatory cytokines viz. tumor necrosis factor (TNF)-α (p < 0.001), interleukin (IL)-6 (p = 0.002), and IL-1 (p < 0.001); however, insufficient quantitative data precluded us from assessing changes in the anti-inflammatory cytokine, IL-10. In experimental RA, RES decreased TNF-α (p < 0.001), IL-6 (p < 0.001) and IL-1 (p = 0.001) and increased IL-10. This meta-analysis suggests that RES can be a clinically effective therapy for RA, pending clinical trials.
Asunto(s)
Antioxidantes/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Resveratrol/farmacología , Animales , Antioxidantes/uso terapéutico , Artritis Experimental/diagnóstico , Artritis Experimental/inmunología , Artritis Experimental/patología , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Evaluación Preclínica de Medicamentos , Humanos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/inmunología , Resveratrol/uso terapéutico , Índice de Severidad de la EnfermedadRESUMEN
The ECM of cartilage is composed of proteoglycans (PG) that contain glycosaminoglycan (GAG), aggrecan, hyaluronic acid (HA) and other molecular components which play an important role in regulating chondrocyte functions via cell-matrix interactions, integrin-mediated signalling etc. Implantation of chondrocytes encapsulated in scaffolds that mimic the micro-architecture of proteoglycan, is expected to enhance cartilage repair. With an aim to create a hydrogel having macromolecular structure that resembles the cartilage-specific ECM, we constructed a hierarchal structure that mimic the PG. The bottle brush structure of the aggrecan was obtained using chondroitin sulphate and carboxymethyl cellulose which served as GAG and core protein mimic respectively. A proteoglycan-like structure was obtained by cross-linking it with modified chitosan that served as a HA substitute. The physico-chemical characteristics of the above cross-linked injectable hydrogel supported long term human articular chondrocyte subsistence and excellent post-injection viability. The chondrocytes encapsulated in the PMH expressed significant levels of articular cartilage specific markers like collagen II, aggrecan, GAGs etc., indicating the ability of the hydrogel to support chondrocyte differentiation. The biocompatibility and biodegradability of the hydrogels was confirmed using suitable in vivo studies. The results revealed that the PG-mimetic hydrogel could serve as a promising scaffold for chondrocyte implantation.
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Condrocitos/citología , Condrogénesis , Hidrogeles/química , Hidrogeles/farmacología , Inyecciones , Proteoglicanos/química , Animales , Carboximetilcelulosa de Sodio/química , Bovinos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Inmovilizadas/citología , Células Inmovilizadas/efectos de los fármacos , Quitosano/análogos & derivados , Quitosano/química , Condrocitos/efectos de los fármacos , Condrocitos/ultraestructura , Condrogénesis/efectos de los fármacos , Citoprotección/efectos de los fármacos , Módulo de Elasticidad , Humanos , Ratas Sprague-Dawley , Reología , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Conductive hydrogels are attracting considerable interest in view of their potential in a wide range of applications that include healthcare and electronics. Such hydrogels are generally incorporated with conductive materials/polymers. Herein, we present a series of conductive hydrogels (Ch-CMC-PDA), prepared with no additional conductive material. The hydrogels were synthesized using a combination of chitosan, cellulose (CMC) and dopamine (DA). The conductivity (0.01-3.4 × 10-3 S cm-1) in these gels is attributed to ionic conductivity. Very few conductive hydrogels are endowed with additional properties like injectability, adhesiveness and self-healing, which would help to widen their scope for applications. While the dynamic Schiff base coupling in our hydrogels facilitated self-healing and injectable properties, polydopamine imparted tissue adhesiveness. The porosity, rheological, mechanical and conductive properties of the hydrogels are regulated by the CMC-dialdehyde-polydopamine (CMC-D-PDA) content. The hydrogel was evaluated in various bioelectronics applications like ECG monitoring and triboelectric nanogenerators (TENG). The ability of the hydrogel to support cell growth and serve as a template for tissue regeneration was confirmed using in vitro and in vivo studies. In summary, the integration of such remarkable features in the ionic-conductive hydrogel would enable its usage in bioelectronics and biomedical applications.
Asunto(s)
Fuentes de Energía Bioeléctrica , Hidrogeles/química , Ingeniería de Tejidos , Celulosa/química , Quitosano/química , Dopamina/química , Conductividad Eléctrica , Humanos , Hidrogeles/síntesis química , Ensayo de Materiales , Estructura Molecular , Adhesivos TisularesRESUMEN
Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)-dependent manner. BAT-derived FGF21 mediates an adaptive response by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, which is activated independently of BAT thermogenic function.