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In Huntington disease (HD), the mutant huntingtin (mtHTT) protein is the principal cause of pathological changes that initiate primarily along the cortico-striatal axis. mtHTT is ubiquitously expressed and there is, accordingly, growing recognition that HD is a systemic disorder with functional interplay between the brain and the periphery. We have developed a monoclonal antibody, C6-17, targeting an exposed region of HTT near the aa586 Caspase 6 cleavage site. As recently published, mAB C6-17 can block cell-to-cell propagation of mtHTT in vitro. In order to reduce the burden of the mutant protein in vivo, we queried whether extracellular mtHTT could be therapeutically targeted in YAC128 HD mice. In a series of proof of concept experiments, we found that systemic mAB C6-17 treatment resulted in the distribution of the mAB C6-17 to peripheral and CNS tissues and led to the reduction of HTT protein levels. Compared to CTRL mAB or vehicle treated mice, the mAB C6-17 treated YAC128 animals showed improved body weight and motor behaviors, a delayed progression in motor deficits and reduced striatal EM48 immunoreactivity. These results provide the first proof of concept for the feasibility and therapeutic efficacy of an antibody-based anti-HTT passive immunization approach and suggest this modality as a potential new HD treatment strategy.
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Doença de Huntington , Camundongos , Animais , Doença de Huntington/metabolismo , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Proteína Huntingtina/genética , Imunoterapia , Modelos Animais de Doenças , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Progressão da DoençaRESUMO
Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder and an important cause of end stage renal disease (ESRD). Tolvaptan (a V2R antagonist) is the first disease modifier drug for treatment of ADPKD, but also causes severe polyuria. AMPK activators have been shown to attenuate cystic kidney disease. Methods: In this study, we tested the efficacy of the combined administration of salsalate (a direct AMPK activator) and tolvaptan using clinically relevant doses in an adult-onset conditional Pkd1 knock-out (KO) mouse model. Results: Compared to untreated Pkd1 mutant mice, the therapeutic effects of salsalate were similar to that of tolvaptan. The combined treatment tended to be more effective than individual drugs used alone, and was associated with improved kidney survival (p < 0.0001) and reduced kidney weight to body weight ratio (p < 0.0001), cystic index (p < 0.001) and blood urea levels (p < 0.001) compared to untreated animals, although the difference between combination and single treatments was not statistically significant. Gene expression profiling and protein expression and phosphorylation analyses support the mild beneficial effects of co-treatment, and showed that tolvaptan and salsalate cooperatively attenuated kidney injury, cell proliferation, cell cycle progression, inflammation and fibrosis, and improving mitochondrial health, and cellular antioxidant response. Conclusion: These data suggest that salsalate-tolvaptan combination, if confirmed in clinical testing, might represent a promising therapeutic strategy in the treatment of ADPKD.
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INTRODUCTION: It is established that the exon-skipping approach can restore dystrophin in Duchenne muscular dystrophy (DMD) patients. However, dystrophin restoration levels are low, and the field is evolving to provide solutions for improved exon skipping. DMD is a neuromuscular disorder associated with chronic muscle tissue loss attributed to the lack of dystrophin, which causes muscle inflammation, fibrosis formation, and impaired regeneration. Currently, four antisense oligonucleotides (AONs) based on phosphorodiamidate morpholino oligomer (PMO) chemistry are approved by US Food and Drug Administration for exon skipping therapy of eligible DMD patients. AREAS COVERED: This review describes a preclinical and clinical experience with approved and newly developed AONs for DMD, outlines efforts that have been done to enhance AON efficiency, reviews challenges of clinical trials, and summarizes the current state of the exon skipping approach in the DMD field. EXPERT OPINION: The exon skipping approach for DMD is under development, and several chemical modifications with improved properties are under (pre)-clinical investigation. Despite existing advantages of these modifications, their safety and effectiveness have to be examined in clinical trials, which are planned or ongoing. Furthermore, we propose clinical settings using natural history controls to facilitate studying the functional effect of the therapy.
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Distrofia Muscular de Duchenne , Estados Unidos , Humanos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Distrofina/genética , Terapia Genética , Oligonucleotídeos Antissenso/uso terapêutico , ÉxonsRESUMO
The stomach is a complex and physiologically necessary organ, yet large differences in physiology between mouse and human stomachs have impeded translation of physiological discoveries and drug screens performed using murine gastric tissues. Gastric cancer (GC) is a global health threat, with a high mortality rate and limited treatment options. The heterogeneous nature of GC makes it poorly suited for current "one size fits all" standard treatments. In this review, we discuss the rapidly evolving field of gastric organoids, with a focus on studies expanding cultures from primary human tissues and describing the benefits of mouse organoid models. We introduce the differing methods for culturing healthy gastric tissue from adult tissues or pluripotent stem cells, discuss the promise these systems have for preclinical drug screens, and highlight applications of organoids for precision medicine. Finally, we discuss the limitations of these models and look to the future to present potential ways gastric organoids will advance treatment options for patients with GC.
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Organoides , Neoplasias Gástricas , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Medicina de PrecisãoRESUMO
The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies for neurodegenerative diseases, including spinocerebellar ataxias. Spinocerebellar ataxia type 3 (SCA3)-or Machado-Joseph disease (MJD)-is the most common dominant ataxia, being mainly characterized by motor deficits; however, SCA3/MJD has a complex and heterogeneous pathophysiology, involving many CNS brain regions, contributing to the lack of effective therapies. Mesenchymal stem cells (MSCs) have been proposed as a potential therapeutic tool for CNS disorders. Beyond their differentiation potential, MSCs secrete a broad range of neuroregulatory factors that can promote relevant neuroprotective and immunomodulatory actions in different pathophysiological contexts. The objective of this work was to study the effects of (1) human MSC transplantation and (2) human MSC secretome (CM) administration on disease progression in vivo, using the CMVMJD135 mouse model of SCA3/MJD. Our results showed that a single CM administration was more beneficial than MSC transplantation-particularly in the cerebellum and basal ganglia-while no motor improvement was observed when these cell-based therapeutic approaches were applied in the spinal cord. However, the effects observed were mild and transient, suggesting that continuous or repeated administration would be needed, which should be further tested.
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Down syndrome is the main cause of intellectual disabilities with a large set of comorbidities from developmental origins but also that appeared across life span. Investigation of the genetic overdosage found in Down syndrome, due to the trisomy of human chromosome 21, has pointed to one main driver gene, the Dual-specificity tyrosine-regulated kinase 1A (Dyrk1a). Dyrk1a is a murine homolog of the drosophila minibrain gene. It has been found to be involved in many biological processes during development and in adulthood. Further analysis showed its haploinsufficiency in mental retardation disease 7 and its involvement in Alzheimer's disease. DYRK1A plays a role in major developmental steps of brain development, controlling the proliferation of neural progenitors, the migration of neurons, their dendritogenesis and the function of the synapse. Several strategies targeting the overdosage of DYRK1A in DS with specific kinase inhibitors have showed promising evidence that DS cognitive conditions can be alleviated. Nevertheless, providing conditions for proper temporal treatment and to tackle the neurodevelopmental and the neurodegenerative aspects of DS across life span is still an open question.
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Síndrome de Down/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Síndrome de Down/tratamento farmacológico , Síndrome de Down/metabolismo , Humanos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Quinases DyrkRESUMO
Resistance of cancer cells to current chemotherapeutic drugs has obliged the scientific community to seek innovative compounds. Ferrocifens, lipophilic organometallic compounds composed of a tamoxifen scaffold covalently bound to a ferrocene moiety, have shown very interesting antiproliferative, cytotoxic and immunologic effects. The formation of ferrocenyl quinone methide plays a crucial role in the multifaceted activity of ferrocifens. Lipid nanocapsules (LNCs), meanwhile, are nanoparticles obtained by a free organic solvent process. LNCs consist of an oily core surrounded by amphiphilic surfactants and are perfectly adapted to encapsulate these hydrophobic compounds. The different in vitro and in vivo experiments performed with this ferrocifen-loaded nanocarrier have revealed promising results in several multidrug-resistant cancer cell lines such as glioblastoma, breast cancer and metastatic melanoma, alone or in combination with other therapies. This review provides an exhaustive summary of the use of ferrocifen-loaded LNCs as a promising nanomedicine, outlining the ferrocifen mechanisms of action on cancer cells, the nanocarrier formulation process and the in vivo results obtained over the last two decades.
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BACKGROUND: Appropriately designed preclinical patient-derived xenograft (PDX) experiments are important to accurately inform human clinical trials. There is little experimental design guidance regarding choosing the number of PDX lines to study, and the number of mice within each PDX line. METHODS: Retrospective data from IDH-wildtype glioblastoma preclinical experiments evaluating a uniform regimen of fractionated radiation (RT), temozolomide (TMZ) chemotherapy, and concurrent RT/TMZ across 27 PDX lines were used to evaluate experimental designs and empirically estimate statistical power for ANOVA and Cox regression. RESULTS: Increasing the number of PDX lines resulted in more precise and reproducible estimates of effect size. To achieve 80% statistical power using ANOVA, experiments using a single PDX line required subsampling of 6 mice per PDX for each treatment group to detect a difference in survival of 135 days, and 9 mice per PDX to detect a difference of 100 days. Alternatively, a design that used 10 PDX lines had greater than 80% power to detect a difference of 135 days with a single mouse per PDX per treatment group, a difference of 100 days with 2 mice per PDX per treatment, and 35 days with more than 10 mice per PDX per treatment. Power for Cox regression was slightly smaller than ANOVA for very small experiments regardless of effect size and slightly higher than ANOVA for detecting a smaller effect size of 35 days difference in survival for moderate-to-large experiments. CONCLUSIONS: Experimental designs using few mice across many PDX lines can provide robust results and account for inter-tumor variability.
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Neoplasias Encefálicas , Glioblastoma , Animais , Linhagem Celular Tumoral , Camundongos , Projetos de Pesquisa , Estudos Retrospectivos , Temozolomida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tuberculosis (TB) is one of the deadliest infectious diseases of human civilization. Approximately one-third of global population is latently infected with the TB pathogen Mycobacterium tuberculosis (M.tb). The discovery of anti-TB antibiotics leads to decline in death rate of TB. However, the evolution of antibiotic-resistant M.tb-strain and the resurgence of different immune-compromised diseases re-escalated the death rate of TB. WHO has already cautioned about the chances of pandemic situation in TB endemic countries until the discovery of new anti-tubercular drugs, that is, the need of the hour. Analysing the pathogenesis of TB, it was found that M.tb evades the host by altering the balance of immune response and affects either by killing the cells or by creating inflammation. In the pre-antibiotic era, traditional medicines were only therapeutic measures for different infectious diseases including tuberculosis. The ancient literatures of India or ample Indian traditional knowledge and ethnomedicinal practices are evidence for the treatment of TB using different indigenous plants. However, in the light of modern scientific approach, anti-TB effects of those plants and their bioactive molecules were not established thoroughly. In this review, focus has been given on five bioactive molecules of different traditionally used Indian ethnomedicinal plants for treatment of TB or TB-like symptom. These compounds are also validated with proper identification and their mode of action with modern scientific approaches. The effectiveness of these molecules for sensitive or drug-resistant TB pathogen in clinical or preclinical studies was also evaluated. Thus, our specific aim is to highlight such scientifically validated bioactive compounds having anti-mycobacterial and immunomodulatory activity for future use as medicine or adjunct-therapeutic molecule for TB management.
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Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Humanos , Imunidade , Tuberculose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
Myeloproliferative neoplasms, such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are bone marrow disorders that result in the overproduction of mature clonal myeloid elements. Identification of recurrent genetic mutations has been described and aid in diagnosis and prognostic determination. Mouse models of these mutations have confirmed the biologic significance of these mutations in myeloproliferative neoplasm disease biology and provided greater insights on the pathways that are dysregulated with each mutation. The models are useful tools that have led to preclinical testing and provided data as validation for future myeloproliferative neoplasm clinical trials.
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Modelos Animais de Doenças , Transtornos Mieloproliferativos , Neoplasias , Animais , Camundongos , Mutação , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Neoplasias/diagnóstico , Neoplasias/genéticaRESUMO
We present the results of application of the combined correlation matrix method in some clinical studies. A practical algorithm is proposed for constructing a correlation matrix that compactly reflects a large number of interconnections for the situations when several diagnostic methods are used in an experimental clinical or preclinical trial. Several approaches to assessing and displaying the relationships are demonstrated for comparison.
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Moléculas de Adesão Celular/sangue , Receptores de Superfície Celular/sangue , Algoritmos , Pressão Sanguínea , Proteínas Morfogenéticas Ósseas/sangue , Quimiocina CCL11/sangue , Ensaios Clínicos como Assunto , Simulação por Computador , Interpretação Estatística de Dados , Fator 15 de Diferenciação de Crescimento/sangue , Fatores de Diferenciação de Crescimento/sangue , Humanos , Modelos Lineares , Desenvolvimento de Programas , Software , SístoleRESUMO
BACKGROUND/AIM: There is no established standard chemotherapy after administration of the combination endocrine plus CDK4/6 inhibitor therapy for luminal-type breast cancer. We used patient-derived xenograft (PDX) models to determine the antitumor activity of eribulin and capecitabine after endocrine therapy plus CDK4/6 inhibitor. MATERIALS AND METHODS: We examined the antitumor activity of fulvestrant, palbociclib, eribulin, and capecitabine in 4 luminal-type breast cancer PDX models (OD-BRE-0188, -0438, -0450, -0745). In OD-BRE-0438, we determined the antitumor activity of chemotherapy after fulvestrant-palbociclib treatment. We also performed immunohistochemical analysis to explore the effects of treatment on E-cadherin in tumor tissues. RESULTS: Fulvestrant, fulvestrant-palbociclib and chemotherapy had antitumor activity in the 4 PDX models. In OD-BRE-0438 (the most resistant to fulvestrant-palbociclib), eribulin had superior antitumor activity to capecitabine after fulvestrant plus palbociclib. Only eribulin tended to increase E-cadherin expression. CONCLUSION: Eribulin had superior antitumor activity to capecitabine after fulvestrant-palbociclib in the OD-BRE-0438 model.
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Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Fulvestranto/uso terapêutico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Fulvestranto/farmacologia , Furanos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Cetonas/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologiaRESUMO
The liver is one of the body's tissues that has regenerative abilities. But if the damage is too much, it needs to medical interventions for the regeneration. Liver donor shortage causes researchers to turn to other treatments. Tissue engineering is a new approach to liver regeneration. Hydrogels are polymeric networks of hydrophilic, flexible, and similar to natural tissue. Therefore, they are used to encapsulate cells These constructs are potent substrates to induce differentiation of stem cells to the hepatocytes. According to inadequate availability of the hepatocytes, an alternative cell is required to produce hepatocyte-like cells. Due to the self-renewal and differentiation properties of stem cells, they are suitable cell sources to replace the lostcells. This review has focused on liver regeneration, advantages and disadvantages of hydrogels for liver regeneration, injectable materials, hydrogel fabrication methods, including 3D printing, and stem cells for liver regeneration. Furthermore, this paper shows in vitro, preclinical, and clinical trial studies of hydrogel and stem cells for liver regeneration. Graphical abstract.
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Hidrogéis/farmacologia , Regeneração Hepática/fisiologia , Fígado/fisiologia , Células-Tronco/citologia , Engenharia Tecidual/métodos , Animais , Ensaios Clínicos como Assunto , Humanos , Células-Tronco/efeitos dos fármacosRESUMO
INTRODUCTION: The sexually transmitted infections (STIs) caused by viruses including human T cell leukemia virus type-1 (HTLV-1), human immunodeficiency virus-1 (HIV-1), human simplex virus-2 (HSV-2), hepatitis C virus (HCV), hepatitis B virus (HBV), and human papillomavirus (HPV) are major public health issues. These infections can cause cancer or result in long-term health problems. Due to high prevalence of STIs, a safe and effective vaccine is required to overcome these fatal viruses. AREAS COVERED: This review includes a comprehensive overview of the literatures relevant to vaccine development against the sexually transmitted viruses (STVs) using PubMed and Sciencedirect electronic search engines. Herein, we discuss the efforts directed toward development of effective vaccines using different laboratory animal models including mice, guinea pig or non-human primates in preclinical trials, and human in clinical trials with different phases. EXPERT OPINION: There is no effective FDA approved vaccine against the sexually transmitted viruses (STVs) except for HBV and HPV as prophylactic vaccines. Many attempts are underway to develop vaccines against these viruses. There are several approaches for improving prophylactic or therapeutic vaccines such as heterologous prime/boost immunization, delivery system, administration route, adjuvants, etc. In this line, further studies can be helpful for understanding the immunobiology of STVs in human. Moreover, development of more relevant animal models is a worthy goal to induce effective immune responses in humans.
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Antivirais/administração & dosagem , Doenças Virais Sexualmente Transmissíveis/tratamento farmacológico , Vacinas Virais/administração & dosagem , Animais , Modelos Animais de Doenças , Desenvolvimento de Medicamentos , Cobaias , Humanos , Camundongos , Primatas , Doenças Virais Sexualmente Transmissíveis/prevenção & controle , Doenças Virais Sexualmente Transmissíveis/virologiaRESUMO
A tremendous loss of financial and human resources from seven large-scale HIV vaccine efficacy trials suggest a need for a systematic approach to vaccine selection. We conducted a systematic analysis of three important envelope glycoprotein (Env) vaccine candidates: BG505 SOSIP.664, 1086.C gp140, and 1086.C gp120 to determine the most promising by comparing their structure and antigenicity. We found that the BG505 SOSIP trimer and 1086.C gp140 clearly outperformed the 1086.C gp120 monomer. BG505 SOSIP.664 bound the strongest to the most potent and broadest broadly neutralizing antibodies (bnAbs) PG9, PGT145, VRC01, and PGT121. Of interest, although BG505 SOSIP.664 did not bind to the CH58 mAb, 1086.C gp140 bound strongly to this mAb, which belongs to a class of non-neutralizing antibodies that may be protective based on correlates of protection studies of the RV144 HIV vaccine trial. The 1086.C gp120 monomer was the least antigenic of the three vaccine immunogens, binding the weakest to bnAbs and CH58 mAb. Taken together, the evidence provided here combined with previous preclinical immunogenicity and efficacy data strongly argue that the BG505 SOSIP.664 trimer and 1086.C gp140 are likely to be better vaccine immunogens than the monomeric 1086.C gp120, which was just recently tested and shown to be nonefficacious in a phase IIb/III trial. Thus, to best utilize our financial and valuable human resources, we propose a systematic approach by not only comparing structure and antigenicity, but also immunogenicity and efficacy of Env vaccine candidates in the preclinical phase to the selection of only the most promising vaccine candidates for clinical testing.
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Vacinas contra a AIDS , Infecções por HIV , HIV-1 , Anticorpos Neutralizantes , Anticorpos Anti-HIV , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/prevenção & controle , HIV-1/genética , Humanos , Multimerização Proteica , Produtos do Gene env do Vírus da Imunodeficiência Humana/genéticaRESUMO
Cancer is a multifaceted pathology, where cellular and acellular players interact to drive cancer progression and, in the worst-case, metastasis. The current methods to investigate the heterogeneous nature of cancer are inadequate, since they rely on 2D cell cultures and animal models. The cell line-based drug efficacy and toxicity assays are not able to predict the tumor response to anti-cancer agents and it is already widely discussed how molecular pathway are not recapitulated in vitro so called flat biology. On the other side, animal models often fail to detect the side-effects of drugs, mimic the metastatic progression or the interaction between cancer and immune system, due to biologic difference in human and animals. Moreover, ethical and regulatory issues limit animal experimentation. Every year pharma/biotech companies lose resources in drug discovery and testing processes that are successful only in 5% of the cases. There is an urgent need to validate accurate and predictive platforms in order to enhance drug-testing process taking into account the physiopathology of the tumor microenvironment. Three dimensional in vitro tumor models could enhance drug manufactures in developing effective drugs for cancer diseases. The 3D in vitro cancer models can improve the predictability of toxicity and drug sensitivity in cancer. Despite the demonstrated advantages of 3D in vitro disease systems when compared to 2D culture and animal models, they still do not reach the standardization required for preclinical trials. This review highlights in vitro models that may be used as preclinical models, accelerating the drug development process towards more precise and personalized standard of care for cancer patients. We describe the state-of-the art of 3D in vitro culture systems, with a focus on how these different approaches could be coupled in order to achieve a compromise between standardization and reliability in recapitulating tumor microenvironment and drug response.
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Detecção Precoce de Câncer , Neoplasias , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , Reprodutibilidade dos Testes , Microambiente TumoralRESUMO
As a part of the central nervous system (CNS), the adult mammalian spinal cord displays only very poor ability for self-repair in response to traumatic lesions, which mostly lead to more or less severe, life-long disability. While even adult CNS neurons have a certain plastic potential, their intrinsic regenerative capacity highly varies among different neuronal populations and in the end, regeneration is almost completely inhibited due to extrinsic factors such as glial scar and cystic cavity formation, excessive and persistent inflammation, presence of various inhibitory molecules, and absence of trophic support and of a growth-supportive extracellular matrix structure. In recent years, a number of experimental animal models have been developed to overcome these obstacles. Since all those studies based on a single approach have yielded only relatively modest functional recovery, it is now consensus that different therapeutic approaches will have to be combined to synergistically overcome the multiple barriers to CNS regeneration, especially in humans. In this review, we particularly emphasize the hope raised by the development of novel, implantable biomaterials that should favor the reconstruction of the damaged nervous tissue, and ultimately allow for functional recovery of sensorimotor functions. Since human spinal cord injury pathology depends on the vertebral level and the severity of the traumatic impact, and since the timing of application of the different therapeutic approaches appears very important, we argue that every case will necessitate individual evaluation, and specific adaptation of therapeutic strategies.
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Materiais Biocompatíveis/uso terapêutico , Procedimentos de Cirurgia Plástica , Traumatismos da Medula Espinal/terapia , Animais , Materiais Biocompatíveis/química , Modelos Animais de Doenças , Estudos de Avaliação como Assunto , Regeneração Tecidual Guiada/instrumentação , Regeneração Tecidual Guiada/métodos , Regeneração Tecidual Guiada/tendências , Humanos , Regeneração Nervosa/fisiologia , Próteses e Implantes , Procedimentos de Cirurgia Plástica/instrumentação , Procedimentos de Cirurgia Plástica/métodos , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Engenharia Tecidual/métodos , Engenharia Tecidual/tendênciasRESUMO
Post-traumatic epilepsy (PTE) is diagnosed in 20% of individuals with acquired epilepsy, and can impact significantly the quality of life due to the seizures and other functional or cognitive and behavioral outcomes of the traumatic brain injury (TBI) and PTE. There is no available antiepileptogenic or disease modifying treatment for PTE. Animal models of TBI and PTE have been developed, offering useful insights on the value of inflammatory, neurodegenerative pathways, hemorrhages and iron accumulation, calcium channels and other target pathways that could be used for treatment development. Most of the existing preclinical studies test efficacy towards pathologies of functional recovery after TBI, while a few studies are emerging testing the effects towards induced or spontaneous seizures. Here we review the existing preclinical trials testing new candidate treatments for TBI sequelae and PTE, and discuss future directions for efforts aiming at developing antiepileptogenic and disease-modifying treatments.
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Lesões Encefálicas Traumáticas/terapia , Epilepsia Pós-Traumática/terapia , Animais , Anticonvulsivantes/uso terapêutico , Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/metabolismo , Modelos Animais de Doenças , Encefalite/etiologia , Epilepsia Pós-Traumática/etiologia , Epilepsia Pós-Traumática/metabolismo , Humanos , Transdução de SinaisRESUMO
BACKGROUND: With the development of nanotechnology, nanocarrier has widely been applied in such fields as drug delivery, diagnostic and medical imaging and engineering in recent years. Among all of the available nanocarriers, mesoporous silica nanoparticles (MSNs) have become a hot issue because of their unique properties, such as large surface area and voidage, tunable drug loading capacity and release kinetics, good biosafety and easily modified surface. OBJECTIVE: We described the most recent progress in silica-assisted drug delivery and biomedical applications according to different types of Cargo in order to allow researchers to quickly learn about the advance in this field. METHODS: Information has been collected from the recently published literature available mainly through Title or Abstract search in SpringerLink and PubMed database. Special emphasis is on the literature available during 2008-2017. RESULTS: In this review, the major research advances of MSNs on the drug delivery and biomedical applications were summarized. The significant advantages of MSNs have also been listed. It was found that the several significant challenges need to be addressed and investigated to further advance the applications of these structurally defined nanomaterials. CONCLUSION: Through approaching this review, the researchers can be aware of many new synthetic methods, smart designs proposed in the recent year and remaining questions of MSNs at present.