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Ischemic stroke can lead to systemic inflammation, which can activate peripheral immune cells, causing neuroinflammation and brain injury. Meningeal lymphatics play a crucial role in transporting solutes and immune cells out of the brain and draining them into cervical lymph nodes (CLNs). However, the role of meningeal lymphatics in regulating systemic inflammation during the reperfusion stage after ischemia is not well understood. In this study, we demonstrated that brain infarct size, neuronal loss, and the effector function of inflammatory macrophage subsets were reduced after ischemia-reperfusion and disruption of meningeal lymphatics. Spatial memory function was improved in the late stage of ischemic stroke following meningeal lymphatic disruption. Brain-infiltrating immune cells, including neutrophils, monocytes, and T and natural killer cells, were reduced after cerebral ischemia-reperfusion and meningeal lymphatic disruption. Single-cell RNA sequencing analysis revealed that meningeal lymphatic disruption reprogrammed the transcriptome profile related to chemotaxis and leukocyte migration in CLN lymphatic endothelial cells (LECs), and it also decreased chemotactic CCN1 expression in floor LECs. Replenishment of CCN1 through intraventricular injection increased brain infarct size and neuronal loss, while restoring numbers of macrophages/microglia in the brains of meningeal lymphatic-disrupted mice after ischemic stroke. Blocking CCN1 in cerebrospinal fluid reduced brain infarcts and improves spatial memory function after ischemia-reperfusion injury. In summary, this study indicates that CCN1-mediated detrimental inflammation was alleviated after cerebral ischemia-reperfusion injury and meningeal lymphatic disruption. CCN1 represents a novel therapeutic target for inhibiting systemic inflammation in the brain-CLN axis after ischemia-reperfusion injury.
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Neuronal damage resulting from traumatic brain injury (TBI) causes disruption of neuronal projections and neurotransmission that contribute to behavioral deficits. Cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following TBI. ROS often damage DNA, lipids, proteins, and carbohydrates while RNS attack proteins. The products of lipid peroxidation 4-hydroxynonenal (4-HNE) and protein nitration 3-nitrotyrosine (3-NT) are often used as indicators of oxidative and nitrosative damages, respectively. Increasing evidence has shown that striatum is vulnerable to damage from TBI with a disturbed dopamine neurotransmission. TBI results in neurodegeneration, oxidative stress, neuroinflammation, neuronal apoptosis, and autophagy in the striatum and contribute to motor or behavioral deficits. Pomalidomide (Pom) is a Food and Drug Administration (FDA)-approved immunomodulatory drug clinically used in treating multiple myeloma. We previously showed that Pom reduces neuroinflammation and neuronal death induced by TBI in rat cerebral cortex. Here, we further compared the effects of Pom in cortex and striatum focusing on neurodegeneration, oxidative and nitrosative damages, as well as neuroinflammation following TBI. Sprague-Dawley rats subjected to a controlled cortical impact were used as the animal model of TBI. Systemic administration of Pom (0.5 mg/kg, intravenous [i.v.]) at 5 h post-injury alleviated motor behavioral deficits, contusion volume at 24 h after TBI. Pom alleviated TBI-induced neurodegeneration stained by Fluoro-Jade C in both cortex and striatum. Notably, Pom treatment reduces oxidative and nitrosative damages in cortex and striatum and is more efficacious in striatum (93% reduction in 4-HNE-positive and 84% reduction in 3-NT-positive neurons) than in cerebral cortex (42% reduction in 4-HNE-positive and 55% reduction in 3-NT-positive neurons). In addition, Pom attenuated microgliosis, astrogliosis, and elevations of proinflammatory cytokines in cortical and striatal tissue. We conclude that Pom may contribute to improved motor behavioral outcomes after TBI through targeting oxidative/nitrosative damages and neuroinflammation.
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Lesiones Traumáticas del Encéfalo , Enfermedades Neuroinflamatorias , Talidomida/análogos & derivados , Ratas , Animales , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Estrés Oxidativo , Citocinas/metabolismo , Corteza Cerebral/metabolismo , Modelos Animales de EnfermedadRESUMEN
Platelets assume a pivotal role in the pathogenesis of cardiovascular diseases (CVDs), emphasizing their significance in disease progression. Consequently, addressing CVDs necessitates a targeted approach focused on mitigating platelet activation. Eugenol, predominantly derived from clove oil, is recognized for its antibacterial, anticancer, and anti-inflammatory properties, rendering it a valuable medicinal agent. This investigation delves into the intricate mechanisms through which eugenol influences human platelets. At a low concentration of 2 µM, eugenol demonstrates inhibition of collagen and arachidonic acid (AA)-induced platelet aggregation. Notably, thrombin and U46619 remain unaffected by eugenol. Its modulatory effects extend to ATP release, P-selectin expression, and intracellular calcium levels ([Ca2+]i). Eugenol significantly inhibits various signaling cascades, including phospholipase Cγ2 (PLCγ2)/protein kinase C (PKC), phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3ß, mitogen-activated protein kinases, and cytosolic phospholipase A2 (cPLA2)/thromboxane A2 (TxA2) formation induced by collagen. Eugenol selectively inhibited cPLA2/TxA2 phosphorylation induced by AA, not affecting p38 MAPK. In ADP-treated mice, eugenol reduced occluded lung vessels by platelet thrombi without extending bleeding time. In conclusion, eugenol exerts a potent inhibitory effect on platelet activation, achieved through the inhibition of the PLCγ2-PKC and cPLA2-TxA2 cascade, consequently suppressing platelet aggregation. These findings underscore the potential therapeutic applications of eugenol in CVDs.
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Eugenol , Embolia Pulmonar , Humanos , Ratones , Animales , Eugenol/farmacología , Eugenol/uso terapéutico , Eugenol/metabolismo , Fosfolipasa C gamma/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Modelos Animales de Enfermedad , Activación Plaquetaria , Agregación Plaquetaria , Plaquetas/metabolismo , Fosforilación , Proteína Quinasa C/metabolismo , Tromboxano A2/metabolismo , Colágeno/metabolismo , Embolia Pulmonar/tratamiento farmacológico , Embolia Pulmonar/metabolismo , Fosfolipasas A2 Citosólicas/metabolismoRESUMEN
Platelets assume a pivotal role in the cardiovascular diseases (CVDs). Thus, targeting platelet activation is imperative for mitigating CVDs. Ginkgetin (GK), from Ginkgo biloba L, renowned for its anticancer and neuroprotective properties, remains unexplored concerning its impact on platelet activation, particularly in humans. In this investigation, we delved into the intricate mechanisms through which GK influences human platelets. At low concentrations (0.5-1 µM), GK exhibited robust inhibition of collagen and arachidonic acid (AA)-induced platelet aggregation. Intriguingly, thrombin and U46619 remained impervious to GK's influence. GK's modulatory effect extended to ATP release, P-selectin expression, intracellular calcium ([Ca2+ ]i) levels and thromboxane A2 formation. It significantly curtailed the activation of various signaling cascades, encompassing phospholipase Cγ2 (PLCγ2)/protein kinase C (PKC), phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3ß and mitogen-activated protein kinases. GK's antiplatelet effect was not reversed by SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor), and GK had no effect on the phosphorylation of vasodilator-stimulated phosphoproteinSer157 or Ser239 . Moreover, neither cyclic AMP nor cyclic GMP levels were significantly increased after GK treatment. In mouse studies, GK notably extended occlusion time in mesenteric vessels, while sparing bleeding time. In conclusion, GK's profound impact on platelet activation, achieved through inhibiting PLCγ2-PKC cascade, culminates in the suppression of downstream signaling and, ultimately, the inhibition of platelet aggregation. These findings underscore the promising therapeutic potential of GK in the CVDs.
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Biflavonoides , Nucleótidos Cíclicos , Fosfolipasas , Humanos , Animales , Ratones , Nucleótidos Cíclicos/metabolismo , Nucleótidos Cíclicos/farmacología , Fosfolipasa C gamma/metabolismo , Ácido Araquidónico/farmacología , Ácido Araquidónico/metabolismo , Fosfolipasas/metabolismo , Fosfolipasas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Agregación Plaquetaria/farmacología , Activación Plaquetaria , Plaquetas/metabolismo , Agregación Plaquetaria , Proteína Quinasa C/metabolismo , Fosforilación , Colágeno/metabolismoRESUMEN
Our systematic review and meta-analysis estimated the prevalence of post-COVID sleep disturbances in adult population. We systematically searched relevant studies from four databases that reported post-COVID sleep disturbances prevalence with a mean or median follow-up duration of ≥28 days. We identified 153 eligible papers, with a total COVID-19 population of 252437. Employing multilevel mixed-effects meta-analyses, we estimated the overall pooled prevalence of post-COVID sleep disturbances being 28.98% (25.73-32.34), with the highest prevalence reported in Europe and the lowest in Southeast Asia. Poor sleep quality was the most prevalent definition of sleep disturbances, followed by excessive daytime sleepiness, insomnia, sleep apnea. Prevalence estimates were notably higher when measured with Epworth sleepiness scale, or Pittsburgh sleep quality index compared to symptom questionnaires, self-reports, or personal interviews. Female sex (Odds ratio, OR = 1.59, 1.38-1.83) and severe/critical acute COVID-19 (OR = 1.36, 1.09-1.69) emerged as substantial risk factors. Our review underscore the persistent prevalence of sleep disturbances among COVID-19 survivors, and the importance of factors such as geography, definition, measures of sleep disorders, sex, and severity of acute COVID-19 infection. These findings highlight the urgent need for further investigation into the underlying molecular mechanisms driving these sleep disturbances to develop effective therapeutic strategies.
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COVID-19 , Trastornos del Inicio y del Mantenimiento del Sueño , Trastornos del Sueño-Vigilia , Humanos , Adulto , Femenino , Estudios de Seguimiento , Prevalencia , COVID-19/complicaciones , COVID-19/epidemiología , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , Trastornos del Sueño-Vigilia/epidemiología , Trastornos del Sueño-Vigilia/diagnóstico , Calidad del SueñoRESUMEN
Stress-induced hyperglycemia (SIH) is associated with poor functional recovery and high mortality in patients with acute ischemic stroke (AIS). However, intensive controlling of blood glucose by using insulin was not beneficial in patients with AIS and acute hyperglycemia. This study investigated the therapeutic effects of the overexpression of glyoxalase I (GLO1), a detoxifying enzyme of glycotoxins, on acute hyperglycemia-aggravated ischemic brain injury. In the present study, adeno-associated viral (AAV)-mediated GLO1 overexpression reduced infarct volume and edema level but did not improve neurofunctional recovery in the mice with middle cerebral artery occlusion (MCAO). AAV-GLO1 infection significantly enhanced neurofunctional recovery in the MCAO mice with acute hyperglycemia but not in the mice with normoglycemia. Methylglyoxal (MG)-modified proteins expression significantly increased in the ipsilateral cortex of the MCAO mice with acute hyperglycemia. AAV-GLO1 infection attenuated the induction of MG-modified proteins, ER stress formation, and caspase 3/7 activation in MG-treated Neuro-2A cells, and reductions in synaptic plasticity and microglial activation were mitigated in the injured cortex of the MCAO mice with acute hyperglycemia. Treatment with ketotifen, a potent GLO1 stimulator, after surgery, alleviated neurofunctional deficits and ischemic brain damage in the MCAO mice with acute hyperglycemia. Altogether, our data substantiate that, in ischemic brain injury, GLO1 overexpression can alleviate pathologic alterations caused by acute hyperglycemia. Upregulation of GLO1 may be a therapeutic strategy for alleviating SIH-aggravated poor functional outcomes in patients with AIS.
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Lesiones Encefálicas , Isquemia Encefálica , Hiperglucemia , Accidente Cerebrovascular Isquémico , Lactoilglutatión Liasa , Accidente Cerebrovascular , Humanos , Ratones , Animales , Accidente Cerebrovascular Isquémico/complicaciones , Lactoilglutatión Liasa/genética , Lactoilglutatión Liasa/metabolismo , Hiperglucemia/complicaciones , Hiperglucemia/metabolismo , Glucemia , Infarto de la Arteria Cerebral Media/complicaciones , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/patología , Isquemia Encefálica/complicaciones , Isquemia Encefálica/patologíaRESUMEN
A globally aging population results in the long-term care of people with chronic illnesses, affecting the living quality of the elderly. Integrating smart technology and long-term care services will enhance and maximize healthcare quality, while planning a smart long-term care information strategy could satisfy the variety of care demands regarding hospitals, home-care institutions, and communities. The evaluation of a smart long-term care information strategy is necessary to develop smart long-term care technology. This study applies a hybrid Multi-Criteria Decision-Making (MCDM) method, which uses the Decision-Making Trial and Evaluation Laboratory (DEMATEL) integrated with the Analytic Network Process (ANP) for ranking and priority of a smart long-term care information strategy. In addition, this study considers the various resource constraints (budget, network platform cost, training time, labor cost-saving ratio, and information transmission efficiency) into the Zero-one Goal Programming (ZOGP) model to capture the optimal smart long-term care information strategy portfolios. The results of this study indicate that a hybrid MCDM decision model can provide decision-makers with the optimal service platform selection for a smart long-term care information strategy that can maximize information service benefits and allocate constrained resources most efficiently.
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In metabolic syndrome, dysregulated signalling activity of the insulin receptor pathway in the brain due to persistent insulin resistance (IR) condition in the periphery may lead to brain IR (BIR) development. BIR causes an upsurge in the activity of glycogen synthase kinase-3 beta, increased amyloid beta (Aß) accumulation, hyperphosphorylation of tau, aggravated formation of Aß oligomers and simultaneously neurofibrillary tangle formation, all of which are believed to be direct contributors in Alzheimer's Disease (AD) pathology. Likewise, for Parkinson's Disease (PD), BIR is associated with alpha-synuclein alterations, dopamine loss in brain areas which ultimately succumbs towards the appearance of classical motor symptoms corresponding to the typical PD phenotype. Modulation of the autophagy process for clearing misfolded proteins and alteration in histone proteins to alleviate disease progression in BIR-linked AD and PD have recently evolved as a research hotspot, as the majority of the autophagy-related proteins are believed to be regulated by histone posttranslational modifications. Hence, this review will provide a timely update on the possible mechanism(s) converging towards BIR induce AD and PD. Further, emphasis on the potential epigenetic regulation of autophagy that can be effectively targeted for devising a complete therapeutic cure for BIR-induced AD and PD will also be reviewed.
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Enfermedad de Alzheimer , Resistencia a la Insulina , Enfermedad de Parkinson , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Resistencia a la Insulina/fisiología , Epigénesis Genética , Histonas/genética , Histonas/metabolismo , Histonas/uso terapéutico , Encéfalo/metabolismo , AutofagiaRESUMEN
The incidence of traumatic brain injury (TBI) increases dramatically with advanced age and accumulating evidence indicates that age is one of the important predictors of an unfavorable prognosis after brain trauma. Unfortunately, thus far, evidence-based effective therapeutics for geriatric TBI is limited. By using middle-aged animals, we first confirm that there is an age-related change in TBI susceptibility manifested by increased inflammatory events, neuronal death and impaired functional outcomes in motor and cognitive behaviors. Since thyroid hormones function as endogenous regulators of oxidative stress, we postulate that age-related thyroid dysfunction could be a crucial pathology in the increased TBI severity. By surgically removing the thyroid glands, which recapitulates the age-related increase in TBI-susceptible phenotypes, we provide direct evidence showing that endogenous thyroid hormone-dependent compensatory regulation of antioxidant events modulates individual TBI susceptibility, which is abolished in aged or thyroidectomized individuals. The antioxidant capacity of melatonin is well-known, and we found acute melatonin treatment but not liothyronine (T3) supplementation improved the TBI-susceptible phenotypes of oxidative stress, excitotoxic neuronal loss and promotes functional recovery in the aged individuals with thyroid dysfunction. Our study suggests that monitoring thyroid function and acute administration of melatonin could be feasible therapeutics in the management of geriatric-TBI in clinic.
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Renocardiac syndromes are a critical concern among patients with chronic kidney disease (CKD). High level of indoxyl sulfate (IS), a protein-bound uremic toxin, in plasma is known to promote the pathogenesis of cardiovascular diseases by impairing endothelial function. However, the therapeutic effects of the adsorbent of indole, a precursor of IS, on renocardiac syndromes is still debated. Therefore, novel therapeutic approaches should be developed to treat IS-associated endothelial dysfunction. In the present study, we have found that cinchonidine, a major Cinchona alkaloid, exhibited superior cell-protective effects among the 131 test compounds in IS-stimulated human umbilical vein endothelial cells (HUVECs). IS-induced cell death, cellular senescence, and impairment of tube formation in HUVECs were substantially reversed after treatment with cinchonidine. Despite the cinchonidine did not alter reactive oxygen species formation, cellular uptake of IS and OAT3 activity, RNA-Seq analysis showed that the cinchonidine treatment downregulated p53-modulated gene expression and substantially reversed IS-caused G0/G1 cell cycle arrest. Although the mRNA levels of p53 were not considerably downregulated by cinchonidine in IS-treated HUVECs, the treatment of cinchonidine promoted the degradation of p53 and the cytoplasmic-nuclear shuttling of MDM2. Cinchonidine exhibited cell-protective effects against the IS-induced cell death, cellular senescence, and impairment of vasculogenic activity in HUVECs through the downregulation of p53 signaling pathway. Collectively, cinchonidine may be a potential cell-protective agent to rescue IS-induced endothelial cell damage.
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Síndrome Cardiorrenal , Alcaloides de Cinchona , Humanos , Síndrome Cardiorrenal/metabolismo , Alcaloides de Cinchona/metabolismo , Alcaloides de Cinchona/farmacología , Regulación hacia Abajo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Indicán/farmacología , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Imbalance in brain glucose metabolism and epigenetic modulation during the disease course of insulin resistance (IR) associated with Parkinson's disease (PD) risk remains a prime concern. Fibroblast growth factor 21 (FGF21), the metabolic hormone, improves insulin sensitivity and elicits anti-diabetic properties. Chronic stress during brain IR may modulate the FGF21 expression and its dynamic release via epigenetic modifications. Metformin regulates and increases the expression of FGF21 which can be modulating in obesity, diabetes, and IR. Hence, this study was designed to investigate the FGF21 expression modulation via an epigenetic mechanism in PD and whether metformin (MF), an autophagy activator, and sodium butyrate (NaB), a pan histone deacetylase inhibitor, alone and in combination, exert any therapeutic benefit in PD pathology exacerbated by high-fat diet (HFD). Our results portray that the combination treatment with MF and NaB potentially attenuated the abnormal lipid profile and increased motor performance for the rats fed with HFD for 8 weeks followed by intrastriatal 6-hydroxy dopamine administration. The enzyme-linked immunosorbent assay (ELISA) estimations of C-reactive protein, tumor necrosis factor-α, interleukin-1 beta and 6, and FGF21 exhibited extensive downregulation after treatment with the combination. Lastly, mRNA, western blot, histological, and cresyl violet staining depicted that the combination treatment can restore degenerated neuronal density and increase the protein level compared to the disease group. The findings from the study effectively conclude that the epigenetic mechanism involved in FGF21 mediated functional abnormalities in IR-linked PD pathology. Hence, combined treatment with MF and NaB may prove to be a novel combination in ameliorating IR-associated PD in rats, probably via the upregulation of FGF21 expression.
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Resistencia a la Insulina , Metformina , Enfermedad de Parkinson , Animales , Ratas , Dieta Alta en Grasa , Epigénesis Genética , Metformina/farmacología , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
The Internet of Medical Things (IoMT) is an emerging technology in the healthcare revolution which provides real-time healthcare information communication and reasonable medical resource allocation. The COVID-19 pandemic has had a significant effect on people's lives and has affected healthcare capacities. It is important for integrated IoMT platform development to overcome the global pandemic challenges. This study proposed the national IoMT platform strategy portfolio decision-making model from the non-financial (technology, organization, environment) and financial perspectives. As a solution to the decision problem, initially, the decision-making trial and evaluation laboratory (DEMATEL) technology were employed to capture the cause-effect relationship based on the perspectives and criteria obtained from the insight of an expert team. The analytic network process (ANP) and pairwise comparisons were then used to determine the weights for the strategy. Simultaneously, this study incorporated IoMT platform resource limitations into the zero-one goal programming (ZOGP) method to obtain an optimal portfolio selection for IoMT platform strategy planning. The results showed that the integrated MCDM method produced reasonable results for selecting the most appropriate IoMT platform strategy portfolio when considering resource constraints such as system installation costs, consultant fees, infrastructure costs, reduction of medical staff demand, and improvement rates for diagnosis efficiency. The decision-making model of the IoMT platform in this study was conclusive and significantly compelling to aid government decision makers in concentrating their efforts on planning IoMT strategies in response to various pandemic and medical resource allocations.
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Yohimbine (YOH) has antiproliferative effects against breast cancer and pancreatic cancer; however, its effects on vascular proliferative diseases such as atherosclerosis remain unknown. Accordingly, we investigated the inhibitory mechanisms of YOH in vascular smooth muscle cells (VSMCs) stimulated by platelet-derived growth factor (PDGF)-BB, a major mitogenic factor in vascular diseases. YOH (5-20 µM) suppressed PDGF-BB-stimulated a mouse VSMC line (MOVAS-1 cell) proliferation without inducing cytotoxicity. YOH also exhibited antimigratory effects and downregulated matrix metalloproteinase-2 and -9 expression in PDGF-BB-stimulated MOVAS-1 cells. It also promoted cell cycle arrest in the initial gap/first gap phase by upregulating p27Kip1 and p53 expression and reducing cyclin-dependent kinase 2 and proliferating cell nuclear antigen expression. We noted phospholipase C-γ1 (PLCγ1) but not ERK1/2, AKT, or p38 kinase phosphorylation attenuation in YOH-modulated PDGF-BB-propagated signaling pathways in the MOVAS-1 cells. Furthermore, YOH still inhibited PDGF-BB-induced cell proliferation and PLCγ1 phosphorylation in MOVAS-1 cells with α2B-adrenergic receptor knockdown. YOH (5 and 10 mg/kg) substantially suppressed neointimal hyperplasia in mice subjected to CCA ligation for 21 days. Overall, our results reveal that YOH attenuates PDGF-BB-stimulated VSMC proliferation and migration by downregulating a α2B-adrenergic receptor-independent PLCγ1 pathway and reduces neointimal formation in vivo. Therefore, YOH has potential for repurposing for treating atherosclerosis and other vascular proliferative diseases.
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Aterosclerosis , Músculo Liso Vascular , Animales , Aterosclerosis/metabolismo , Becaplermina/metabolismo , Becaplermina/farmacología , Movimiento Celular , Proliferación Celular , Células Cultivadas , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Neointima/metabolismo , Proteínas Proto-Oncogénicas c-sis/metabolismo , Receptores Adrenérgicos/metabolismo , Transducción de Señal , Yohimbina/farmacologíaRESUMEN
Alzheimer type of dementia is accompanied with progressive loss of cognitive function that directly correlates with accumulation of amyloid beta plaques. It is known that Fibroblast growth factor 21 (FGF21), a metabolic hormone, with strong neuroprotective potential, is induced during oxidative stress in Alzheimer's disease. Interestingly, FGF21 cross-talks with autophagy, a mechanism involved in the clearance of abnormal protein aggregate. Moreover, autophagy activation by Rapamycin delivers neuroprotective role in Alzheimer's disease. However, the synergistic neuroprotective efficacy of overexpressed FGF21 along with Rapamycin is not yet investigated. Therefore, the present study examined whether overexpressed FGF21 along with autophagy activation ameliorated neurodegenerative pathology in Alzheimer's disease. We found that cognitive deficits in rats with intracerebroventricular injection of Amyloid beta1-42 oligomers were restored when injected with FGF21-expressing lentiviral vector combined with Rapamycin. Furthermore, overexpression of FGF21 along with Rapamycin downregulated protein levels of Amyloid beta1-42 and phosphorylated tau and expression of major autophagy proteins along with stabilization of oxidative stress. Moreover, FGF21 overexpressed rats treated with Rapamycin revamped the neuronal density as confirmed by histochemical, cresyl violet and immunofluorescence analysis. These results generate compelling evidence that Alzheimer's disease pathology exacerbated by oligomeric amyloid beta may be restored by FGF21 supplementation combined with Rapamycin and thus present an appropriate treatment paradigm for people affected with Alzheimer's disease.
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Enfermedad de Alzheimer , Fármacos Neuroprotectores , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Animales , Factores de Crecimiento de Fibroblastos , Humanos , Lentivirus/genética , Lentivirus/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Placa Amiloide , Ratas , Sirolimus/farmacología , Sirolimus/uso terapéuticoRESUMEN
Insulin resistance (IR) and accumulation of amyloid beta (Aß) oligomers are potential causative factor for Alzheimer's Disease (AD). Simultaneously, enhanced clearance level of these oligomers through autophagy activation bring novel insights into their therapeutic paradigm. Autophagy activation is negatively correlated with mammalian target of rapamycin (mTOR) and dysregulated mTOR level due to epigenetic alterations can further culminate towards AD pathogenesis. Therefore, in the current study we explored the neuroprotective efficacy of rapamycin (rapa) and vorinostat (vori) in-vitro and in-vivo. Aß1-42 treated SH-SY5Y cells were exposed to rapa (20 µM) and vori (4 µM) to analyse mRNA expression of amyloid precursor protein (APP), brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), neuronal growth factor (NGF), beclin-1, microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate (LC3), lysosome-associated membrane protein 2 (LAMP2) and microtubule associated protein 2 (MAP2). In order to develop IR condition, rats were fed a high fat diet (HFD) for 8 weeks and then subjected to intracerebroventricular Aß1-42 administration. Subsequently, their treatment was initiated with rapa (1 mg/kg, i.p.) and vori (50 mg/kg, i.p.) once daily for 28 days. Morris water maze was performed to govern cognitive impairment followed by sacrification for subsequent mRNA, biochemical, western blot and histological estimations. For all the measured parameters, a significant improvement was observed amongst the combination treatment group in contrast to that of the HFD + Aß1-42 group and that of the groups treated with the drugs alone. Outcomes of the present study thus suggest that combination therapy with rapa and vori provide a prospective therapeutic approach to ameliorate AD symptoms exacerbated by IR.
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Enfermedad de Alzheimer , Resistencia a la Insulina , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Autofagia , Epigénesis Genética , Resistencia a la Insulina/fisiología , Mamíferos/metabolismo , ARN Mensajero , Ratas , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Cerebral ischemia is an acute disorder characterized by an abrupt reduction in blood flow that results in immediate deprivation of both glucose and oxygen. The main types of cerebral ischemia are ischemic and hemorrhagic stroke. When a stroke occurs, several signaling pathways are activated, comprising necrosis, apoptosis, and autophagy as well as glial activation and white matter injury, which leads to neuronal cell death. Current treatments for strokes include challenging mechanical thrombectomy or tissue plasminogen activator, which increase the danger of cerebral bleeding, brain edema, and cerebral damage, limiting their usage in clinical settings. Monoclonal antibody therapy has proven to be effective and safe in the treatment of a variety of neurological disorders. In contrast, the evidence for stroke therapy is minimal. Recently, Clone MTS510 antibody targeting toll-like receptor-4 (TLR4) protein, ASC06-IgG1 antibody targeting acid sensing ion channel-1a (ASIC1a) protein, Anti-GluN1 antibodies targeting N-methyl-D-aspartate (NMDA) receptor associated calcium influx, GSK249320 antibody targeting myelin-associated glycoprotein (MAG), anti-High Mobility Group Box-1 antibody targeting high mobility group box-1 (HMGB1) are currently under clinical trials for cerebral ischemia treatment. In this article, we review the current antibody-based pharmaceuticals for neurological diseases, the use of antibody drugs in stroke, strategies to improve the efficacy of antibody therapeutics in cerebral ischemia, and the recent advancement of antibody drugs in clinical practice. Overall, we highlight the need of enhancing blood-brain barrier (BBB) penetration for the improvement of antibody-based therapeutics in the brain, which could greatly enhance the antibody medications for cerebral ischemia in clinical practice.
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STUDY OBJECTIVE: The purpose of this feasibility study is to develop and validate a new assessment tool and scoring system for multitasking competency for physicians in-training in a timed simulated setting. The multitasking competency includes ability to appropriately prioritize and implement tasks for different patients who present simultaneously. METHODS: We designed three single task stations with different levels of difficulty and priority. These skill stations were then combined to create a multitasking simulation scenario. Skill checklists and the global rating scale were utilized to assess the participants' performance. A multitasking score, multitasking index, and priority score were developed to measure the multitasking ability of participants. RESULTS: Thirty-three first-year postgraduate physicians were recruited for this prospective study. The total performance scores were significantly higher for the single-tasking stations than for the multitasking scenario. In terms of the time needed to complete the tasks, the participants spent more time on the multitasking scenario than on the single-tasking scenario. There were significant correlations between the global rating scale and the multitasking score (rho = 0.693, p < 0.001) and between the global rating scale and the multitasking index (rho = 0.515, p < 0.001). The multitasking score, multitasking index, and priority score did not have any significant correlations with the total single-tasking score. CONCLUSION: We demonstrated that the use of a simulated multitasking scenario could be an effective method of assessing multitasking ability and allow assessors to offer better quality feedback.
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Competencia Clínica , Medicina de Emergencia/educación , Adulto , Simulación por Computador , Estudios de Factibilidad , Femenino , Humanos , Masculino , Comportamiento Multifuncional , Estudios ProspectivosRESUMEN
The blood-brain barrier (BBB) plays a vital role in the protection and maintenance of homeostasis in the brain. In this way, it is an interesting target as an interface for various types of drug delivery, specifically in the context of the treatment of several neuropathological conditions where the therapeutic agents cannot cross the BBB. Drug toxicity and on-target specificity are among some of the limitations associated with current neurotherapeutics. In recent years, advances in nanodrug delivery have enabled the carrier system containing the active therapeutic drug to target the signaling pathways and pathophysiology that are closely linked to central nervous system (CNS) disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), brain tumor, epilepsy, ischemic stroke, and neurodegeneration. At present, among the nano formulations, solid lipid nanoparticles (SLNs) have emerged as a putative drug carrier system that can deliver the active therapeutics (drug-loaded SLNs) across the BBB at the target site of the brain, offering a novel approach with controlled drug delivery, longer circulation time, target specificity, and higher efficacy, and more importantly, reducing toxicity in a biomimetic way. This paper highlights the synthesis and application of SLNs as a novel nontoxic formulation strategy to carry CNS drugs across the BBB to improve the use of therapeutics agents in treating major neurological disorders in future clinics.
RESUMEN
Therapeutic options for Parkinson's disease (PD) are limited to a symptomatic approach, making it a global threat. Targeting aggregated alpha-synuclein (α-syn) clearance is a gold standard for ameliorating PD pathology, bringing autophagy into the limelight. Expression of autophagy related genes are under the regulation by histone modifications, however, its relevance in PD is yet to be established. Here, preformed fibrillar form (PFF) of α-syn was used to induce PD in wistar rats, which were thereafter subjected to treatment with trehalose (tre, 4g/kg, orally), a potent autophagy inducer and sodium butyrate (SB, 300 mg/kg, orally), a pan histone deacetylase inhibitor alone as well as in combination. The combination treatment significantly reduced motor deficits as evidenced after rotarod, narrow beam walk, and open field tests. Novel object location and recognition tests were performed to govern cognitive abnormality associated with advanced stage PD, which was overcome by the combination treatment. Additionally, with the combination, the level of pro-inflammatory cytokines were significantly reduced, along with elevated levels of dopamine and histone H3 acetylation. Further, mRNA analysis revealed that levels of certain autophagy related genes and proteins implicated in PD pathogenesis significantly improved after administration of both tre and SB. Immunofluorescence and H&E staining in the substantia nigra region mirrored a potential improvement after treatment with both tre and SB. Therefore, outcomes of the present study were adequate to prove that combinatorial efficacy with tre and SB may prove to be a formidable insight into ameliorating PD exacerbated by PFF α-syn as compared to its individual efficacy.
Asunto(s)
Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Ácido Butírico/farmacología , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Ratas , Ratas Wistar , Trehalosa/farmacología , alfa-SinucleínaRESUMEN
Patients might be willing to pay more to obtain better quality medical services when they recognize that high-level hospitals have better quality. However, published papers have not found solid empirical evidence to support this possibility. Therefore, the purpose of this study is to empirically investigate patients' willingness to pay (WTP) for an outpatient copayment. The study aims to analyze the difference between the two WTP values: to implement a hierarchy of medical care and to improve the quality of medical services. This study administered a questionnaire using the contingent valuation method with a quasi-bidding game for patients' WTP and the SERVQUAL scale for medical service quality. The Wilcoxon signed-rank test was employed to test the difference between the two WTP values, notably to implement a hierarchy of medical care and to improve the quality of medical services. Both of the WTP values are higher than the academic medical centre's current copayment NT$420 (approximately US$14); the percentage of respondents willing to pay a higher copayment declined when the outpatient copayment was increased, and the patients' WTP to have better medical service quality was significantly higher than that to implement a hierarchy of medical care. Patients' desire to receive better medical services from higher-level hospitals might be stronger than their desire to implement hierarchical medical care. This study reported the relationship between the respondents' perceived medical service quality and WTP for having better service quality by using regression models. The respondents' perceptions of medical service quality, especially for "reliability" and "assurance," would positively affect their WTP. Policy makers should focus on improving the quality of medical services.