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Ischaemic stroke causes neuron loss and long-term functional deficits. Unfortunately, effective approaches to preserving neurons and promoting functional recovery remain unavailable. Oligodendrocytes, the myelinating cells in the CNS, are susceptible to oxygen and nutrition deprivation and undergo degeneration after ischaemic stroke. Technically, new oligodendrocytes and myelin can be generated by the differentiation of oligodendrocyte precursor cells (OPCs). However, myelin dynamics and their functional significance after ischaemic stroke remain poorly understood. Here, we report numerous denuded axons accompanied by decreased neuron density in sections from ischaemic stroke lesions in human brain, suggesting that neuron loss correlates with myelin deficits in these lesions. To investigate the longitudinal changes in myelin dynamics after stroke, we labelled and traced pre-existing and newly-formed myelin, respectively, using cell-specific genetic approaches. Our results indicated massive oligodendrocyte death and myelin loss 2â weeks after stroke in the transient middle cerebral artery occlusion (tMCAO) mouse model. In contrast, myelin regeneration remained insufficient 4 and 8â weeks post-stroke. Notably, neuronal loss and functional impairments worsened in aged brains, and new myelin generation was diminished. To analyse the causal relationship between remyelination and neuron survival, we manipulated myelinogenesis by conditional deletion of Olig2 (a positive regulator) or muscarinic receptor 1 (M1R, a negative regulator) in OPCs. Deleting Olig2 inhibited remyelination, reducing neuron survival and functional recovery after tMCAO. Conversely, enhancing remyelination by M1R conditional knockout or treatment with the pro-myelination drug clemastine after tMCAO preserved white matter integrity and neuronal survival, accelerating functional recovery. Together, our findings demonstrate that enhancing myelinogenesis is a promising strategy to preserve neurons and promote functional recovery after ischaemic stroke.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Camundongos , Animais , Humanos , Idoso , Bainha de Mielina/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia , Oligodendroglia/patologia , Neurônios , Diferenciação Celular/fisiologiaRESUMO
Local density of states (LDOS) is emerging as powerful means of exploring classical-wave topological phases. However, the current LDOS detection method remains rare and merely works for static situations. Here, we introduce a generic dynamical method to detect both the static and Floquet LDOS, based on an elegant connection between dynamics of chiral density and local spectral densities. Moreover, we find that the Floquet LDOS allows to measure out Floquet quasienergy spectra and identify topological π modes. As an example, we demonstrate that both the static and Floquet higher-order topological phase can be universally identified via LDOS detection, regardless of whether the topological corner modes are in energy gaps, bands, or continuous energy spectra without band gaps. Our study opens a new avenue utilizing dynamics to detect topological spectral densities and provides a universal approach of identifying static and Floquet topological phases.
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We report a step-economic strategy for the direct synthesis of spiro polycyclic N-heterocycles and indolecarbazole-fused naphthoquinones by merging oxidative coupling and cascade palladium-catalyzed intramolecular oxidative cyclization. In the protocol, bi-indolylnaphthoquinones were first synthesized by oxidative coupling of indoles and naphthoquinones. Subsequent cascade palladium-catalyzed intramolecular oxidative cyclization of bi-indolylnaphthoquinones gave spiro polycyclic N-heterocycles and indolecarbazoles. The intramolecular oxidative cyclization approach could also be realized by the presence or absence of iron catalysts under standard conditions. This protocol is featured with moderate to excellent yields, a wide substrate scope, and divergent structures of products.
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OBJECTIVES: Cognitive impairment and change are a focus of research into late-life depression. The aims of this 5-year prospective study were (1) to observe cognitive status change; (2) to investigate the rate and risk ratio of dementia or cognitive decline; and (3) to examine the cognitive domain predictors for conversion to dementia within 5 years among a clinical cohort with remitted major depressive disorder (MDD). METHODS: The study cohort included 130 elderly persons with late-life remitted MDD and 100 normal controls. Comprehensive neuropsychological tests were conducted to determine cognitive domain status. Diagnoses of mild cognitive impairment (MCI) and dementia were made at baseline and at a follow-up visit at the 5-year point. In total, 98 cases and 55 normal controls completed the 5-year follow-up assessment. RESULTS: Of the study cohort with late-life remitted MDD, 28.6% had MCI and 25.5% developed dementia within 5 years. Patients with late-life remitted MDD had an approximate 3 times higher risk of subsequent cognitive decline as compared with the normal controls. Information-processing speed (p = 0.009) and memory (p = 0.041) could predict subsequent progression to dementia within 5 years among patients with MDD. CONCLUSIONS: This study demonstrated that compared with the general elderly population, elderly patients with depression have more significant impairment in cognitive function after 5 years. Further, we found that in depressed patients, deficits in information-processing speed and memory domains were highly suggestive of progression to dementia within 5 years.
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Disfunção Cognitiva , Demência , Transtorno Depressivo Maior , Humanos , Idoso , Transtorno Depressivo Maior/epidemiologia , Estudos Prospectivos , CogniçãoRESUMO
AIM: To obtain an in-depth understanding of the lived experiences, values, and beliefs of Taiwanese women with breast cancer who withdrew from cancer treatment. BACKGROUND: Fear of side effects, negative experiences and personal beliefs were identified as reasons for withdrawing from cancer treatments. Body-mind consciousness and body autonomy play a crucial role in cancer treatment decisions. DESIGN: Descriptive phenomenological approach. METHODS: We conducted semi-structured, face-to-face and in-depth interviews with 16 women diagnosed with breast cancer. Participants were purposefully selected from the Cancer Registry database. Employing a phenomenological approach, our aim was to explore the lived experiences of these individuals. Data analysis followed Giorgi's five-step process. To ensure a comprehensive report the COREQ checklist was applied. FINDINGS: 'The Determination to Preserve Me' is the essence of treatment withdrawal, identified by three themes and seven sub-themes. 'Raising Body-Mind Consciousness' was generated using body autonomy and preventing repeated psychological trauma from the participant's view. Their lifestyles, maintaining the family role, and returning to a normal trajectory help develop 'Maintaining Stability for Being a Patient and a Family Carer'. 'Self-Defending Against the Body Harm' was generated by concerns about maintaining health and preventing harm. CONCLUSION: Women's behaviours became transformed by suffering. Actions were influenced by physical and psychological distress, misconceptions about treatments, and appearance changes by self-determination through self-protection. RELEVANCE TO CLINICAL PRACTICE: Healthcare professionals should respect women's autonomy and work collaboratively to ensure their decision-making with accurate information and awareness of the potential risks and benefits of treatment withdrawal need to concern.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/psicologia , Pessoa de Meia-Idade , Adulto , Taiwan , Suspensão de Tratamento , Pesquisa Qualitativa , IdosoRESUMO
Perilla frutescens is a widely used medicinal and edible plant with a rich chemical composition throughout its whole plant. The Chinese Pharmacopoeia categorizes P. frutescens leaves(Perillae Folium), seeds(Perillae Fructus), and stems(Perillae Caulis) as three distinct medicinal parts due to the differences in types and content of active components. Over 350 different bioactive compounds have been reported so far, including volatile oils, flavonoids, phenolic acids, triterpenes, sterols, and fatty acids. Due to the complexity of its chemical composition, P. frutescens exhibits diverse pharmacological effects, including antibacterial, anti-inflammatory, anti-allergic, antidepressant, and antitumor activities. While scholars have conducted a substantial amount of research on different parts of P. frutescens, including analysis of their chemical components and pharmacological mechanisms of action, there has yet to be a systematic comparison and summary of chemical components, pharmacological effects, and mechanisms of action. Therefore, this study overviewed the chemical composition and structures of Perillae Folium, Perillae Fructus, and Perillae Caulis, and summarized the pharmacological effects and mechanisms of P. frutescens to provide a reference for better development and utilization of this valuable plant.
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Óleos Voláteis , Perilla frutescens , Perilla frutescens/química , Extratos Vegetais/farmacologia , Sementes/química , Frutas/química , Óleos Voláteis/farmacologia , Óleos Voláteis/análise , Folhas de Planta/químicaRESUMO
Purpose: To explore stable and sensitive indicators for clinical diagnosis of acute angle closure (AAC) secondary to lens subluxation (LS) through quantitative analysis of CASIA 2 imaging.Design: A prospective cross-sectional study. Methods: Setting: Clinical practice.Participants: 23 patients with unilateral acute angle closure secondary to lens subluxation and 23 cataract patients without lens subluxation were recruited. Lens subluxation was confirmed by ultrasound biomicroscope diagnosis. The contralateral eyes without LS served as fellow control group. The cataract eyes without LS were enrolled in blank control group.Intervention: Participants underwent ophthalmologic examinations including slit-lamp biomicroscope, best corrected visual acuity, intraocular pressure, central corneal thickness measurement, axial length, gonioscopy, ultrasound biomicroscope and 360-degree anterior chamber and crystalline lens scan protocols of CASIA 2 system.Main outcome measures: Automated circumferential anterior segment and lens morphological parameters under anterior segment optical coherence tomography were analyzed via three-dimensional analysis. Results: Significant differences were found in the front and back radius of the lens, the front and back radius of steep curvature of the lens, lens thickness, lens decentration, lens diameter, iris-trabecular contact (ITC) index, ITC area, anterior chamber depth (ACD), lens vault (LV), and iris volume between LS and controls. Among these parameters, LV, the anterior radius of steep curvature of the lens and ACD demonstrated the highest prediction power (AUC = 0.87, 0.89, and 0.86, respectively). The prediction power of tilt/axis was much higher in the Gaussian Naive Bayes model (AUCs = 0.90) than in the logistic model (AUCs = 0.74). Combination of LV_mean, LV_std, tilt and tilt axis in Gaussian Naive Bayes model presented as most stable and excellent diagnostic markers for AAC secondary to LS (AUCs = 0.98). Conclusions: The combination of markers including lens tilt and lens vault in the mathematic model facilitate clinical work as it not only provides novel diagnostic indications and possible prompt treatment for AAC secondary to lens subluxations, but also enhances our understanding of the pathogenic role of zonulopathy in angle closure glaucoma.
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Angiogenesis is crucial for successful bone defect repair. Co-transplanting Bone Marrow Stromal Cells (BMSCs) and Endothelial Cells (ECs) has shown promise for vascular augmentation, but it face challenges in hostile tissue microenvironments, including poor cell survival and limited efficacy. In this study, the mitochondria of human BMSCs are isolated and transplanted to BMSCs from the same batch and passage number (BMSCsmito). The transplanted mitochondria significantly boosted the ability of BMSCsmito-ECs to promote angiogenesis, as assessed by in vitro tube formation and spheroid sprouting assays, as well as in vivo transplantation experiments in balb/c mouse and SD rat models. The Dll4-Notch1 signaling pathway is found to play a key role in BMSCsmito-induced endothelial tube formation. Co-transplanting BMSCsmito with ECs in a rat cranial bone defect significantly improves functional vascular network formation, and improve bone repair outcomes. These findings thus highlight that mitochondrial transplantation, by acting through the DLL4-Notch1 signaling pathway, represents a promising therapeutic strategy for enhancing angiogenesis and improving bone repair. Hence, mitochondrial transplantation to BMSCS as a therapeutic approach for promoting angiogenesis offers valuable insights and holds much promise for innovative regenerative medicine therapies.
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An mpox outbreak occurred suddenly and rapidly spread worldwide in 2022. Research has demonstrated a link between the sexual behavior of men who have sex with men (MSM) and the contraction of mpox. This study assessed the factors related to mpox-vaccine uptake among MSM in Taiwan, focusing on the roles of information sources and emotional problems. In total, 389 MSM participated in an online survey. Data on the participants' vaccination statuses; anxiety symptoms, which were assessed using the State-Trait Anxiety Inventory; depressive symptoms, which were assessed using the Center for Epidemiologic Studies Depression Scale; and risk perceptions of contracting mpox were collected. Factors related to mpox-vaccine uptake were examined using a multivariable logistic regression model. The results revealed that MSM who were older (p < 0.001), perceived a higher risk of contracting mpox (p = 0.040), and received mpox information from health-care providers (p < 0.001) were more likely to receive mpox vaccination, whereas MSM who reported a greater severity of depression (p = 0.017) were less likely to receive mpox vaccination. However, age did not moderate the associations of perceiving a higher risk of contracting mpox, receiving mpox information from health-care providers, and depression with having an mpox vaccination. Health-care providers should consider these factors when developing intervention programs for enhancing mpox-vaccine uptake among MSM.
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Abstract: Subclinical hypothyroidism (SCH) is closely related to insulin resistance, and thyroid-stimulating hormone (TSH) level is an independent factor for insulin resistance associated with subclinical hypothyroidism. This study aims to explore the effects of TSH levels on insulin signal transduction in adipocytes and to establish the role of endoplasmic reticulum (ER) stress in this process. In this study, the SCH mouse model was established, and 3T3-L1 adipocytes were treated with TSH or tunicamycin (TM), with or without 4-phenylbutyric acid (4-PBA), an inhibitor of ER stress. Subclinical hypothyroidism mice exhibited impaired glucose tolerance, inactivation of the IRS-1/AKT pathway, and activation of the IRE1/JNK pathway in adipose tissue, which can all be alleviated by 4-PBA. Supplementation with levothyroxine restored the TSH to normal, alongside alleviated ER stress and insulin resistance in SCH mice, which is characterized by improved glucose tolerance, decreased mRNA expression of IRE1, and decreased phosphorylation of JNK in adipose tissue. In 3T3-L1 adipocytes, TSH induces insulin resistance, leading to a decrease in glucose uptake. This effect is mediated by the downregulation of IRS-1 tyrosine phosphorylation, reduced AKT phosphorylation, and inhibited GLUT4 protein expression. Notably, all these effects can be effectively reversed by 4-PBA. Moreover, TSH induced TNF-α and IL-6 production and upregulated the expression of ER stress markers. Similarly, these changes can be recovered by 4-PBA. These findings indicate that TSH has the capability to induce insulin resistance in adipocytes. The mechanism through which TSH disrupts insulin signal transduction appears to involve the ER stress-JNK pathway.
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Mesenchymal stem cell (MSC) migration determines the healing capacity of bone and is crucial in promoting bone regeneration. Migration of MSCs is highly dependent on degradation of extracellular matrix by proteolytic enzymes. However, the underlying mechanisms of how enzymolysis paves the way for MSCs to migrate from their niche to the defect area is still not fully understood. Here, this study shows that high-temperature requirement A3 (HtrA3) overcomes the physical barrier and provides anchor points through collagen IV degradation, paving the way for MSC migration. HtrA3 is upregulated in MSCs at the leading edge of bone defect during the early stage of healing. HtrA3 degrades the surrounding collagen IV, which increases the collagen network porosity and increases integrin ß1 expression. Subsequently, integrin ß1 enhances the mechanotransduction of MSCs, thus remodeling the cytoskeleton, increasing cellular stiffness and nuclear translocation of YAP, eventually promoting the migration and subsequent osteogenic differentiation of MSCs. Local administration of recombinant HtrA3 in rat cranial bone defects significantly increases new bone formation and further validates the enhancement of MSC migration. This study helps to reveal the novel roles of HtrA3, explore potential targets for regenerative medicine, and offer new insights for the development of bioactive materials.
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Macrophages play a pivotal role in the immunological cascade activated in response to biomedical implants, which predetermine acceptance or rejection of implants by the host via pro- and anti-inflammatory polarisation states. The role of chemical signals in macrophage polarisation is well-established, but how physical cues regulate macrophage function that may play a fundamental role in implant-bone interface, remains poorly understood. Here we find that bone marrow-derived macrophages (BMDM) cultured on polyacrylamide gels of varying stiffness exhibit different polarisation states. BMDM are 'primed' to a pro-inflammatory M1 phenotype on stiff substrates, while to an anti-inflammatory M2 phenotype on soft and medium stiffness substrates. It is further observed that matrix stiffening increases Piezo1 expression, as well as leads to subsequent activation of the mechanotransduction signalling effector YAP, thus favouring M1 polarisation whilst suppressing M2 polarisation. Moreover, upon treatment with YAP inhibitor, we successfully induce macrophage re-polarisation to the M2 state within the implant site microenvironment, which in turn promotes implant osseointegration. Collectively, our present study thus characterises the critical role of the Piezo1-YAP signalling axis in macrophage mechanosensing and stiffness-mediated macrophage polarisation and provides cues for the design of immuno-modulatory biomaterials that can regulate the macrophage phenotype.
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Canais Iônicos , Macrófagos , Mecanotransdução Celular , Transdução de Sinais , Proteínas de Sinalização YAP , Macrófagos/metabolismo , Animais , Camundongos , Canais Iônicos/metabolismo , Proteínas de Sinalização YAP/metabolismo , Camundongos Endogâmicos C57BL , Polaridade Celular/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células Cultivadas , Matriz Extracelular/metabolismo , Resinas Acrílicas/química , Resinas Acrílicas/farmacologia , Proteínas de Ciclo Celular/metabolismo , Osseointegração/efeitos dos fármacosRESUMO
Nonunion resulting from early bone resorption is common after bone transplantation surgery. In these patients, instability or osteoporosis causes hyperactive catabolism relative to anabolism, leading to graft resorption instead of fusion. Systemic zoledronate administration inhibits osteoclastogenesis and is widely used to prevent osteoporosis; however, evidence on local zoledronate application is controversial due to osteoblast cytotoxicity, uncontrolled dosing regimens, and local release methods. We investigated the effects of zolendronate on osteoclastogenesis and osteogenesis and explored the corresponding signaling pathways. In vitro cytotoxicity and differentiation of MC3T3E1 cells, rat bone marrow stromal cells (BMSCs) and preosteoclasts (RAW264.7 cells) were evaluated with different zolendronate concentrations. In vivo bone regeneration ability was tested by transplanting different concentrations of zolendronate with ß-tricalcium phosphate (TCP) bone substitute into rat femoral critical-sized bone defects. In vitro, zolendronate concentrations below 2.5 × 10-7 M did not compromise viability in the three cell lines and did not promote osteogenic differentiation in MC3T3E1 cells and BMSCs. In RAW264.7 cells, zoledronate inhibited extracellular regulated protein kinases and c-Jun n-terminal kinase signaling, downregulating c-Fos and NFATc1 expression, with reduced expression of fusion-related dendritic cellspecific transmembrane protein and osteoclast-specific Ctsk and tartrate-resistant acid phosphatase (. In vivo, histological staining revealed increased osteoid formation and neovascularization and reduced fibrotic tissue with 500 µM and 2000 µM zolendronate. More osteoclasts were found in the normal saline group after 6 weeks, and sequential osteoclast formation occurred after zoledronate treatment, indicating inhibition of bone resorption during early callus formation without inhibition of late-stage bone remodeling. In vivo, soaking ß-TCP artificial bone with 500 µM or 2000 µM zoledronate is a promising approach for bone regeneration, with potential applications in bone transplantation.
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Vaccination helps reduce the risk of coronavirus disease 2019 (COVID-19) infection in elderly individuals with major neurocognitive disorders (MNDs). However, some caregivers are hesitant to have their elderly family members with MNDs vaccinated against COVID-19. This study explored the factors influencing caregivers' intentions to vaccinate elderly family members with MNDs against COVID-19. A total of 232 caregivers of elderly family members with MNDs participated in this study. In this survey, data regarding COVID-19 vaccination acceptance, fear, side effects, family members' attitudes toward vaccination, mental health status, neuropsychiatric symptoms, and cognitive impairments were collected from the elderly participants with MNDs. The associations between these variables and the caregivers' intention to vaccinate their elderly family members with MNDs against COVID-19 were examined using a multivariable linear regression analysis model. The results revealed that caregivers' perceived familial support for vaccination, the perceived value of vaccination, and autonomy to vaccinate elder family members were positively correlated with caregivers' intention to vaccinate elderly family members with MNDs, whereas elderly family members' age was negatively correlated with caregiver intentions. This study demonstrated that caregiver factors (perceived familial support, value of vaccination, and autonomy) and elderly family members' age were correlated with caregiver intention. These factors should be considered in developing interventions to enhance caregivers' intentions to vaccinate their elderly family members with MNDs against COVID-19.
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OBJECTIVE: Previous studies have reported that the inappropriate use of allopurinol may increase the risk of cerebrovascular accidents, but some studies have also confirmed that allopurinol is a protective factor against stroke. To clarify whether there is a relevant causal relationship between allopurinol and cerebral infarction, we conducted a two-sample Mendelian randomization (MR) study. METHODS: Data on single nucleotide polymorphisms (SNPs) associated with allopurinol and genome-wide association studies of cerebral infarction were obtained from the genome-wide association study (GWAS) web site. Five basic MR analyses were performed using MR-Egger regression, weighted median (WM1), inverse variance weighting (IVW), weighted mode (WM2), and simple mode. Sensitivity analysis was subsequently performed to detect horizontal pleiotropy, heterogeneity, and potential outliers. The final analysis results were mainly based on the IVW estimates. RESULTS: A total of 10 SNPs were used as instrumental variables (IVs). MR analysis [(IVW: odds ratio (OR) = 1.053, 95% confidence interval (CI): 1.019-1.088, P = 0.002), (WM1: OR = 1.053, 95% CI: 1.009-1.098, P = 0.017), (WM2: OR = 1.050, 95% CI: 1.008-1.095, P = 0.044), (MR Egger: Q = 4.285, P = 0.830)] showed a positive causal association between allopurinol and the risk of cerebral infarction. Sensitivity analysis such as horizontal pleiotropy and heterogeneity increased the reliability of this result. CONCLUSION: The results of this study provide direct evidence that there is a causal relationship between allopurinol and cerebral infarction and that allopurinol may increase the risk of cerebral infarction.
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BACKGROUND: Stroke is a leading cause of disability and death worldwide. Currently, there is a lack of clinically effective treatments for the brain damage following ischemic stroke. Catalpol is a bioactive compound derived from the traditional Chinese medicine Rehmannia glutinosa and shown to be protective in various neurological diseases. However, the potential roles of catalpol against ischemic stroke are still not completely clear. PURPOSE: This study aimed to further elucidate the protective effects of catalpol against ischemic stroke. METHODS: A rat permanent middle cerebral artery occlusion (pMCAO) and oxygen-glucose deprivation (OGD) model was established to assess the effect of catalpol in vivo and in vitro, respectively. Behavioral tests were used to examine the effects of catalpol on neurological function of ischemic rats. Immunostaining was performed to evaluate the proliferation, migration and differentiation of neural stem cells (NSCs) as well as the angiogenesis in each group. The protein level of related molecules was detected by western-blot. The effects of catalpol on cultured NSCs as well as brain microvascular endothelial cells (BMECs) subjected to OGD in vitro were also examined by similar methods. RESULTS: Catalpol attenuated the neurological deficits and improved neurological function of ischemic rats. It stimulated the proliferation of NSCs in the subventricular zone (SVZ), promoted their migration to the ischemic cortex and differentiation into neurons or glial cells. At the same time, catalpol increased the cerebral vessels density and the number of proliferating cerebrovascular endothelial cells in the infracted cortex of ischemic rats. The level of SDF-1α and CXCR4 in the ischemic cortex was found to be enhanced by catalpol treatment. Catalpol was also shown to promote the proliferation and migration of cultured NSCs as well as the proliferation of BMECs subjected to OGD insult in vitro. Interestingly, the impact of catalpol on cultured cells was inhibited by CXCR4 inhibitor AMD3100. Moreover, the culture medium of BMECs containing catalpol promoted the proliferation of NSCs, which was also suppressed by AMD3100. CONCLUSION: Our data demonstrate that catalpol exerts neuroprotective effects by promoting neurogenesis and angiogenesis via the SDF-1α/CXCR4 pathway, suggesting the therapeutic potential of catalpol in treating cerebral ischemia.
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Quimiocina CXCL12 , Glucosídeos Iridoides , AVC Isquêmico , Neurogênese , Receptores CXCR4 , Animais , Masculino , Ratos , Angiogênese , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quimiocina CXCL12/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Glucosídeos Iridoides/farmacologia , AVC Isquêmico/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-Dawley , Receptores CXCR4/metabolismo , Rehmannia/química , Transdução de Sinais/efeitos dos fármacosRESUMO
White matter injury (WMI) causes oligodendrocyte precursor cell (OPC) differentiation arrest and functional deficits, with no effective therapies to date. Here, we report increased expression of growth hormone (GH) in the hypoxic neonatal mouse brain, a model of WMI. GH treatment during or post hypoxic exposure rescues hypoxia-induced hypomyelination and promotes functional recovery in adolescent mice. Single-cell sequencing reveals that Ghr mRNA expression is highly enriched in vascular cells. Cell-lineage labeling and tracing identify the GHR-expressing vascular cells as a subpopulation of pericytes. These cells display tip-cell-like morphology with kinetic polarized filopodia revealed by two-photon live imaging and seemingly direct blood vessel branching and bridging. Gain-of-function and loss-of-function experiments indicate that GHR signaling in pericytes is sufficient to modulate angiogenesis in neonatal brains, which enhances OPC differentiation and myelination indirectly. These findings demonstrate that targeting GHR and/or downstream effectors may represent a promising therapeutic strategy for WMI.
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Bainha de Mielina , Neovascularização Fisiológica , Pericitos , Animais , Pericitos/metabolismo , Pericitos/efeitos dos fármacos , Camundongos , Bainha de Mielina/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Hormônio do Crescimento/metabolismo , Hormônio do Crescimento/farmacologia , Animais Recém-Nascidos , Hipóxia/metabolismo , Diferenciação Celular/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Receptores da Somatotropina/metabolismo , Receptores da Somatotropina/genética , AngiogêneseRESUMO
Objective: To compare the effects of tofacitinib and adalimumab on the risk of adverse lipidaemia outcomes in patients with newly diagnosed rheumatoid arthritis (RA). Methods: Data of adult patients newly diagnosed with RA who were treated with tofacitinib or adalimumab at least twice during a 3-year period from 1 January 2018 to 31 December 2020, were enrolled in the TriNetX US Collaborative Network. Patient demographics, comorbidities, medications, and laboratory data were matched by propensity score at baseline. Outcome measurements include incidental risk of dyslipidemia, major adverse cardiac events (MACE) and all-cause mortality. Results: A total of 7,580 newly diagnosed patients with RA (1998 receiving tofacitinib, 5,582 receiving adalimumab) were screened. After propensity score matching, the risk of dyslipidaemia outcomes were higher in the tofacitinib cohort, compared with adalimumab cohort (hazard ratio [HR] with 95% confidence interval [CI], 1.250 [1.076-1.453]). However, there is no statistically significant differences between two cohorts on MACE (HR, 0.995 [0.760-1.303]) and all-cause mortality (HR, 1.402 [0.887-2.215]). Conclusion: Tofacitinib use in patients with RA may increase the risk of dyslipidaemia to some extent compared to adalimumab. However, there is no differences on MACE and all-cause mortality.
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Digital light processing (DLP) bioprinting, known for its high resolution and speed, enables the precise spatial arrangement of biomaterials and has become integral to advancing tissue engineering and regenerative medicine. Nevertheless, inherent light scattering presents significant challenges to the fidelity of the manufactured structures. Herein, we introduce a photoinhibition strategy based on Rutin nanoparticles (Rnps), attenuating the scattering effect through concurrent photoabsorption and free radical reaction. Compared to the widely utilized biocompatible photoabsorber tartrazine (Tar), Rnps-infused bioink enhanced printing speed (1.9×), interlayer homogeneity (58% less overexposure), resolution (38.3% improvement), and print tolerance (3× high-precision range) to minimize trial-and-error. The biocompatible and antioxidative Rnps significantly improved cytocompatibility and exhibited resistance to oxidative stress-induced damage in printed constructs, as demonstrated with human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs). The related properties of Rnps facilitate the facile fabrication of multimaterial, heterogeneous, and cell-laden biomimetic constructs with intricate structures. The developed photoinhibitor, with its profound adaptability, promises wide biomedical applications tailored to specific biological requirements.
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Bioimpressão , Luz , Nanopartículas , Rutina , Humanos , Rutina/química , Rutina/farmacologia , Nanopartículas/química , Engenharia Tecidual , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
This practice guideline focuses on the cognitive assessment for mild cognitive impairment in the Guangdong-Hong Kong-Macao Greater Bay Area. To achieve the standardization and normalization of its clinical practice and generate individualized intervention, the National Core Cognitive Center of the Second Affiliated Hospital of Guangzhou Medical University, the Cognitive Disorders Branch of Chinese Geriatic Society, the Dementia Group of Neurology Branch of Guangdong Medical Association and specialists from Hong Kong and Macao developed guidelines based on China's actual conditions and efficiency, economic cost and accuracy. The article addresses the significance, background, and the process of the assessment and follow-up to realize the promotion and dissemination of cognitive assessment.