RESUMEN
Skin aging is an unavoidable natural phenomenon caused by intrinsic and extrinsic factors. In modern society, the pursuit of a wrinkle-free and aesthetically appealing face has gained considerable prominence. Numerous studies have aimed at mitigating the appearance of facial wrinkles. Antiaging research focused on regulating the function of mitochondria, the main reactive oxygen species-generating organelles, has been extensively conducted. In this study, we investigated the correlation between facial wrinkles and the expression of PPARGC1B, considering the association of this gene with mitochondrial function, to identify its potential as a target for exploring antiaging cosmetic materials. We elucidated the role of PPARGC1B in the skin and identified five bioactive materials that modulated its expression. The effectiveness of these materials was verified through in vitro experiments on human dermal fibroblasts. We prepared cosmetic formulations incorporating the five materials and confirmed their ability to enhance dermal collagen in three-dimensional skin models and reduce facial wrinkles under the eyes and nasolabial fold areas in human subjects. The study findings have significant implications for developing novel antiaging cosmetic formulations by reinforcing mitochondrial functions.
RESUMEN
Recombinant adeno-associated virus (rAAV)-based gene therapies offer an immense opportunity for rare diseases, such as amyotrophic lateral sclerosis (ALS), which is defined by the loss of the upper and the lower motor neurons. Here, we describe generation, characterization, and utilization of a novel vector system, which enables expression of the active form of hepatocyte growth factor (HGF) under EF-1α promoter with bovine growth hormone (bGH) poly(A) sequence and is effective with intrathecal injections. HGF's role in promoting motor neuron survival had been vastly reported. Therefore, we investigated whether intrathecal delivery of HGF would have an impact on one of the most common pathologies of ALS: the TDP-43 pathology. Increased astrogliosis, microgliosis and progressive upper motor neuron loss are important consequences of ALS in the motor cortex with TDP-43 pathology. We find that cortex can be modulated via intrathecal injection, and that expression of HGF reduces astrogliosis, microgliosis in the motor cortex, and help restore ongoing UMN degeneration. Our findings not only introduce a novel viral vector for the treatment of ALS, but also demonstrate modulation of motor cortex by intrathecal viral delivery, and that HGF treatment is effective in reducing astrogliosis and microgliosis in the motor cortex of ALS with TDP-43 pathology.
Asunto(s)
Esclerosis Amiotrófica Lateral , Corteza Motora , Animales , Bovinos , Humanos , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/terapia , Proteínas de Unión al ADN/genética , Gliosis , Factor de Crecimiento de Hepatocito/genética , Corteza Motora/patologíaRESUMEN
Protein kinase M ζ is well known for its role in maintaining memory and pain. Previously, we revealed that the activation of protein kinase M ζ in the anterior cingulate cortex plays a role in sustaining neuropathic pain. However, the mechanism by which protein kinase M ζ is expressed in the anterior cingulate cortex by peripheral nerve injury, and whether blocking of protein kinase M ζ using its inhibitor, zeta inhibitory peptide, produces analgesic effects in neuropathic pain maintained chronically after injury, have not previously been resolved. In this study, we show that protein kinase M ζ expression in the anterior cingulate cortex is enhanced by peripheral nerve injury in a transcription-independent manner. We also reveal that the inhibition of protein kinase M ζ through zeta inhibitory peptide treatment is enough to reduce mechanical allodynia responses in mice with one-month-old nerve injuries. However, the zeta inhibitory peptide treatment was only effective for a limited time.
Asunto(s)
Dolor Crónico/enzimología , Dolor Crónico/genética , Giro del Cíngulo/enzimología , Neuralgia/enzimología , Neuralgia/genética , Proteína Quinasa C/metabolismo , Transcripción Genética , Animales , Péptidos de Penetración Celular , Dolor Crónico/patología , Giro del Cíngulo/patología , Lipopéptidos/farmacología , Potenciación a Largo Plazo , Masculino , Ratones Endogámicos C57BL , Neuralgia/patología , Nervios Periféricos/patología , Receptores AMPA , Sinapsis/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
Skin aging is a multifaceted biological phenomenon influenced by a combination of intrinsic or extrinsic factors. There is an increasing interest in anti-aging materials including components that improve skin wrinkles. Despite the availability of several such wrinkle-improving materials, the demand for ingredients with outstanding efficacy is increasing. Therefore, this study aimed to explore the mechanisms of wrinkle-related genes reported in previous genome-wide association studies (GWASs), identify materials that regulate these genes, and develop an effective anti-wrinkle formula containing the active ingredients that regulate the expression of these genes. We selected two candidate genes, EDAR and BNC2, that are reportedly related to periorbital wrinkles. We investigated their functions in the skin through in vitro experiments using human skin cell lines (keratinocytes and fibroblasts). Moreover, we identified ingredients that regulate the expression of these two genes and confirmed their efficacy through in vitro experiments using the skin cell lines. Finally, we developed a formula containing these ingredients and confirmed that it enhanced dermal collagen in the 3D skin and improved fine wrinkles under the eyes more effectively than retinol in humans, when applied for 8 weeks. Our results are significant and relevant, as we have discovered a special formula for wrinkle improvement with reliable efficacy that surpasses the efficacy of retinol and does not cause side-effects such as skin irritation.
Asunto(s)
Envejecimiento de la Piel , Vitamina A , Humanos , Vitamina A/farmacología , Envejecimiento de la Piel/genética , Estudio de Asociación del Genoma Completo , Piel , Expresión Génica , Receptor Edar , Proteínas de Unión al ADNRESUMEN
Calcium/Calmodulin-dependent protein kinase II (CaMKII) plays a key role in the molecular mechanism of memory formation. CaMKII is known to be activated specifically in the activated spines during memory formation. However, it is unclear whether the specific activation of CaMKII is necessary for encoding information. Here, we overexpressed active form of CaMKII (CaMKII*) in the hippocampal CA1 region to activate CaMKII nonspecifically. Moreover, we examined context-discrimination performance of mice. We found that the mice with overexpression of CaMKII* showed impaired context-discrimination ability, while the contextual fear conditioning remained intact. These results indicate that spatial specificity of CaMKII activation is necessary for context discrimination.
Asunto(s)
Región CA1 Hipocampal/enzimología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Condicionamiento Clásico , Discriminación en Psicología , Animales , Región CA1 Hipocampal/metabolismo , Activación Enzimática , Células HEK293 , Humanos , RatonesRESUMEN
Memory resides in engram cells distributed across the brain. However, the site-specific substrate within these engram cells remains theoretical, even though it is generally accepted that synaptic plasticity encodes memories. We developed the dual-eGRASP (green fluorescent protein reconstitution across synaptic partners) technique to examine synapses between engram cells to identify the specific neuronal site for memory storage. We found an increased number and size of spines on CA1 engram cells receiving input from CA3 engram cells. In contextual fear conditioning, this enhanced connectivity between engram cells encoded memory strength. CA3 engram to CA1 engram projections strongly occluded long-term potentiation. These results indicate that enhanced structural and functional connectivity between engram cells across two directly connected brain regions forms the synaptic correlate for memory formation.
Asunto(s)
Región CA1 Hipocampal/fisiología , Región CA3 Hipocampal/fisiología , Memoria/fisiología , Neuronas/fisiología , Sinapsis/fisiología , Animales , Región CA1 Hipocampal/citología , Región CA3 Hipocampal/citología , Condicionamiento Clásico , Miedo , Proteínas Fluorescentes Verdes/análisis , Células HEK293 , Humanos , Potenciación a Largo Plazo , Masculino , Ratones Endogámicos C57BL , Neuroimagen/métodos , Plasticidad NeuronalRESUMEN
Peripheral nerve injury can induce pathological conditions that lead to persistent sensitized nociception. Although there is evidence that plastic changes in the cortex contribute to this process, the underlying molecular mechanisms are unclear. Here, we find that activation of the anterior cingulate cortex (ACC) induced by peripheral nerve injury increases the turnover of specific synaptic proteins in a persistent manner. We demonstrate that neural cell adhesion molecule 1 (NCAM1) is one of the molecules involved and show that it mediates spine reorganization and contributes to the behavioral sensitization. We show striking parallels in the underlying mechanism with the maintenance of NMDA-receptor- and protein-synthesis-dependent long-term potentiation (LTP) in the ACC. Our results, therefore, demonstrate a synaptic mechanism for cortical reorganization and suggest potential avenues for neuropathic pain treatment.