Astragalus membranaceus Polysaccharide Regulates Small Intestinal Microbes and Activates IL-22 Signal Pathway to Promote Intestinal Stem Cell Regeneration in Aging Mice.

Aging can cause degenerative changes in multiple tissues and organs. Gastrointestinal diseases and dysfunctions are common in the elderly population. In this study, we investigated the effects of Astragalus membranaceus polysaccharide (APS) and Astragalus membranaceus ethanol extract (AEE) on age-related intestinal dysfunction and gut microbiota dysbiosis in naturally aging mice. The energy expenditure and physical activity of 23-month-old C57BL6/J mice were recorded using a metabolic cage system. Pathological changes in the intestine were evaluated using Alcian blue staining. The protein levels of leucine-rich repeats containing G protein-coupled receptor 5 (Lgr5) and Stat3 in the small intestine were determined using immunohistochemistry. The intestinal cell migration distance was assessed using bromodeoxyuridine (BrdU) immunofluorescence staining. The gene transcription levels of intestinal stem cell (ISC) markers and ISC-related signaling pathways were detected using quantitative real-time PCR (qRT-PCR). Microbiota analysis based on 16S rDNA was performed to evaluate the composition of the gut microbiota. APS and AEE improved a series of aging phenotypes in female but not in male aging mice. APS and AEE ameliorate intestinal dysfunction and histopathological changes in aging mice. APS had a more significant anti-aging effect than AEE, particularly on intestinal dysfunction. APS promotes ISC regeneration by activating the IL-22 signaling pathway. Cohousing (CH) experiments further confirmed that APS induced the IL-22 signaling pathway by increasing the abundance of Lactobacillus, thereby promoting the regeneration of ISCs. Our results show that APS may serve as a promising agent for improving age-related intestinal dysfunction.

COP-22 Alleviates D-Galactose-Induced Brain Aging by Attenuating Oxidative Stress, Inflammation, and Apoptosis in Mice.

Aging is a natural and inevitable process of organisms. With the intensification of population aging, research on aging has become a hot topic of global attention. The most obvious manifestation of human aging is the aging of brain function, which has been linked to the development of neurodegenerative diseases. In this study, COP-22, a mono-carbonyl curcumin derivative, was evaluated for its anti-aging ability, especially its ability to resist brain aging induced by D-galactose (D-gal) in mice. For brain protection, COP-22 could resist D-gal-induced oxidative stress by increasing the activity of antioxidative defense enzymes and enhancing antioxidant capacity in the brain tissue; COP-22 could improve the dysfunction of the cholinergic system by decreasing the increased activity of acetylcholinesterase and increasing the reduced content of acetylcholine induced by D-gal; and COP-22 could protect nerve cells of the brain. Further, western blot was used to determine related proteins of the brain. We found that COP-22 could effectively protect against brain injury (SIRT1, p53, p21, and p16) by inhibiting oxidative stress (Nrf2 and HO-1), inflammation (IL-6 and TNF-α), and apoptosis (Bax and caspase-3) in D-gal-induced aging mice. Additionally, COP-22 demonstrated the ability to reduce oxidative stress in serum and liver caused by D-gal, as well as relieve the damages in the liver and kidney induced by D-gal. These results indicated that COP-22 had potential anti-aging activity and could be used in the therapy of aging and aging-associated diseases like Alzheimer disease.

Butyrate promotes post-stroke outcomes in aged mice via interleukin-22.

Aging increases the risk of stroke, may exacerbate neuroinflammatory responses, reduce angiogenesis, and promote white matter damage post-stroke, all of which contribute to long-term functional recovery. Butyric acid, an important gut microbial metabolite, showed the highest correlation with the outcomes of ischemic stroke, and butyrate was selected as an effective treatment for aged stroke mice. Here, we tested the neurorestorative effect and potential therapeutic mechanisms of butyrate in aged mice with stroke. Aged male C57BL/6 J mice (17-19 months) were subjected to photothrombotic stroke. We performed butyrate supplementation in the drinking water for 3 weeks before surgery until 14 days after the stroke. At 14 days after ischemic stroke, white matter damage, leukocyte infiltration, and blood-brain barrier permeability were all decreased in the aged stroke mice that received the butyrate treatment, which also improved neurological outcomes by stimulating angiogenesis. Stroke reduces the level of interleukin-22 (IL-22) and butyrate treatment significantly enhanced IL-22 expression in the brain. To further validate the mechanisms of butyrate promoting neurological function after stroke, monoclonal antibodies were used to block IL-22 in aged stroke mice when butyrate treatment was provided. Blocking IL-22 in butyrate-treated aged stroke fails to improve functional outcomes and attenuated butyrate-induced angiogenesis, increased axon/white matter density and blood-brain barrier (BBB) integrity, but has no effect on inflammatory cells infiltration. In conclusion, butyrate improves outcomes in aged mice after stroke by promoting angiogenesis and BBB integrity and reducing leukocyte infiltration. To some extent, IL-22 may contribute to butyrate treatment induced vascular remodeling and increased BBB integrity responses in aged stroke mice.

Scoliosis Research Society-22r score is affected by standing whole body sagittal alignment, age, and sex, but not by standing balance or skeletal muscle mass in healthy volunteers.

PURPOSE: Aging and spinal disease impair standing whole body sagittal alignment (WBS alignment), which leads to stooping. When WBS alignment deteriorates, compensatory mechanisms are activated to maintain standing posture. Increase of the compensation impairs health-related quality of life (HRQOL). The purpose of this research was to determine whether postural factors, age, and sex affect HRQOL. METHODS: This cross-sectional study evaluated the influence of WBS alignment, standing body sway (balance), skeletal muscle mass (SMM), aging, and sex on HRQOL in healthy volunteers (n = 150; mean age 40.9 years [20-76], 96 women). Age, sex, weight, height, and body mass index (BMI) were obtained. HRQOL was assessed with Scoliosis Research Society-22 (SRS-22r). WBS alignment and balance were measured by EOS imaging with simultaneous force plate measurement. SMM was measured using a medical body composition analyzer. Based on the bivariate analysis between the SRS-22r subtotal and all parameters, selected ten parameters were used for multivariate logistic regression analysis to identify affecting factors to SRS-22r. RESULTS: Men had significantly higher weight, height, BMI, and SRS-22r score in all domains. The L4-S1 lumbar lordosis angle was greater in men, and pelvic tilt and knee hyperextension were greater in women. Women had a more stable standing posture, whereas men had significantly higher SMM values. Multivariate logistic regression analysis revealed that age, sex, and TPA were identified as significant factors affecting SRS-22r. CONCLUSIONS: In healthy volunteers, SRS-22r is affected by aging, sex (woman had a lower score), and sagittal malalignment. Neither Standing balance nor SMM, however, affect SRS-22r.4.

Who Works Less When a Parent Needs Long-Term Care? Gender Disparities in Labor Market Effects in Mexico.

We use longitudinal data from the Mexican Health and Aging Study to analyze the effect of having a parent in need of long-term care on labor supply of men and women aged 50-64 in Mexico. After accounting for both individual and time fixed effects, we find that parents' need of long-term care is associated with both a significant drop in the likelihood of working (by 2.42 percentage points), and a reduction in the number of hours worked (by 7.3%) among women who remain employed. In contrast, we find no effect on the labor supply of men. In a context of rapid population aging, the increase in the need of long-term care risks to hinder the efforts to reduce gender imbalances in the labor market.

Syringaresinol derived from Panax ginseng berry attenuates oxidative stress-induced skin aging via autophagy.

Background: In aged skin, reactive oxygen species (ROS) induces degradation of the extracellular matrix (ECM), leading to visible aging signs. Collagens in the ECM are cleaved by matrix metalloproteinases (MMPs). Syringaresinol (SYR), isolated from Panax ginseng berry, has various physiological activities, including anti-inflammatory action. However, the anti-aging effects of SYR via antioxidant and autophagy regulation have not been elucidated. Methods: The preventive effect of SYR on skin aging was investigated in human HaCaT keratinocytes in the presence of H2O2, and the keratinocyte cells were treated with SYR (0-200 µg/mL). mRNA and protein levels of MMP-2 and -9 were determined by real-time PCR and Western blotting, respectively. Radical scavenging activity was researched by 2,2 diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assays. LC3B level was assessed by Western blotting and confocal microscopy. Results: SYR significantly reduced gene expression and protein levels of MMP-9 and -2 in both H2O2-treated and untreated HaCaT cells. SYR did not show cytotoxicity to HaCaT cells. SYR exhibited DPPH and ABTS radical scavenging activities with an EC50 value of 10.77 and 10.35 µg/mL, respectively. SYR elevated total levels of endogenous and exogenous LC3B in H2O2-stimulated HaCaT cells. 3-Methyladenine (3-MA), an autophagy inhibitor, counteracted the inhibitory effect of SYR on MMP-2 expression. Conclusion: SYR showed antioxidant activity and up-regulated autophagy activity in H2O2-stimulated HaCaT cells, lowering the expression of MMP-2 and MMP-9 associated with skin aging. Our results suggest that SYR has potential value as a cosmetic additive for prevention of skin aging.

Neural Networks for Classification and Image Generation of Aging in Genetic Syndromes.

Background: In medical genetics, one application of neural networks is the diagnosis of genetic diseases based on images of patient faces. While these applications have been validated in the literature with primarily pediatric subjects, it is not known whether these applications can accurately diagnose patients across a lifespan. We aimed to extend previous works to determine whether age plays a factor in facial diagnosis as well as to explore other factors that may contribute to the overall diagnostic accuracy. Methods: To investigate this, we chose two relatively common conditions, Williams syndrome and 22q11.2 deletion syndrome. We built a neural network classifier trained on images of affected and unaffected individuals of different ages and compared classifier accuracy to clinical geneticists. We analyzed the results of saliency maps and the use of generative adversarial networks to boost accuracy. Results: Our classifier outperformed clinical geneticists at recognizing face images of these two conditions within each of the age groups (the performance varied between the age groups): 1) under 2 years old, 2) 2-9 years old, 3) 10-19 years old, 4) 20-34 years old, and 5) ≥35 years old. The overall accuracy improvement by our classifier over the clinical geneticists was 15.5 and 22.7% for Williams syndrome and 22q11.2 deletion syndrome, respectively. Additionally, comparison of saliency maps revealed that key facial features learned by the neural network differed with respect to age. Finally, joint training real images with multiple different types of fake images created by a generative adversarial network showed up to 3.25% accuracy gain in classification accuracy. Conclusion: The ability of clinical geneticists to diagnose these conditions is influenced by the age of the patient. Deep learning technologies such as our classifier can more accurately identify patients across the lifespan based on facial features. Saliency maps of computer vision reveal that the syndromic facial feature attributes change with the age of the patient. Modest improvements in the classifier accuracy were observed when joint training was carried out with both real and fake images. Our findings highlight the need for a greater focus on age as a confounder in facial diagnosis.

CD22 Blockage Restores Age-Related Impairments of Microglia Surveillance Capacity.

Microglia, the innate immune cells of the brain, are essential for maintaining homeostasis by their ramified, highly motile processes and for orchestrating the immune response to pathological stimuli. They are implicated in several neurodegenerative diseases like Alzheimer's and Parkinson's disease. One commonality of these diseases is their strong correlation with aging as the highest risk factor and studying age-related alterations in microglia physiology and associated signaling mechanism is indispensable for a better understanding of age-related pathomechanisms. CD22 has been identified as a modifier of microglia phagocytosis in a recent study, but not much is known about the function of CD22 in microglia. Here we show that CD22 surface levels are upregulated in aged versus adult microglia. Furthermore, in the amyloid mouse model PS2APP, Aß-containing microglia also exhibit increased CD22 signal. To assess the impact of CD22 blockage on microglia morphology and dynamics, we have established a protocol to image microglia process motility in acutely prepared brain slices from CX3CR1-GFP reporter mice. We observed a significant reduction of microglial ramification and surveillance capacity in brain slices from aged versus adult mice. The age-related decrease in surveillance can be restored by antibody-mediated CD22 blockage in aged mice, whereas surveillance in adult mice is not affected by CD22 inhibition. Moreover to complement the results obtained in mice, we show that human iPSC-derived macrophages exhibit an increased phagocytic capacity upon CD22 blockage. Downstream analysis of antibody-mediated CD22 inhibition revealed an influence on BMP and TGFß associated gene networks. Our results demonstrate CD22 as a broad age-associated modulator of microglia functionality with potential implications for neurodegenerative disorders.

Vitis Vinifera Leaf Extract Protects Against Glutamate-Induced Oxidative Toxicity in HT22 Hippocampal Neuronal Cells and Increases Stress Resistance Properties in Caenorhabditis Elegans.

Vitis vinifea has been used for traditional medicines, food, beverages, and dietary antioxidant supplements. The chemical compositions and biological activities of the fruits and seeds have been extensively investigated. However, the biological effects of the leaves are limited, and its anti-neurodegeneration or antiaging activities are little known. The current work aims to study the beneficial effects of V. vinifera leaf extract on neuroprotective effects in HT22 cells, antiaging, and oxidative stress resistance properties in the Caenorhabditis elegans model. The ethanol extract was characterized by phytochemical composition using gas/liquid chromatography-mass spectrometry and reversed-phase high-performance liquid chromatography. The beneficial effects of V. vinifera ethanol (VVE) extract on antioxidant properties, neuroprotective effects, and the underlying mechanisms were studied by in vitro and in vivo studies. In HT22 cells, we found that VVE has a protective effect against glutamate-mediated oxidative stress-induced cell death. The gene expression of cellular antioxidant enzymes such as CAT, SODs, GSTs, and GPx was upregulated by VVE treatment. Moreover, VVE was also shown to alleviate oxidative stress and attenuate reactive oxygen species accumulation in C. elegans. We demonstrated that VVE could upregulate the expression of stress-response genes gst-4 and sod-3 and downregulate the expression of hsp-16.2. Our results suggest that the oxidative stress resistance properties of VVE are possibly involved in DAF-16/FoxO transcription factors. VVE reduced age-related markers (lipofuscin) while did not extend the life span of C. elegans under normal conditions. This study reports the neuroprotective effect and antioxidant activity of V. vinifera leaf extract and suggests its potential as a dietary or alternative supplement to defend against oxidative stress and age-related diseases.

A Non-stop identity complex (NIC) supervises enterocyte identity and protects from premature aging.

A hallmark of aging is loss of differentiated cell identity. Aged Drosophila midgut differentiated enterocytes (ECs) lose their identity, impairing tissue homeostasis. To discover identity regulators, we performed an RNAi screen targeting ubiquitin-related genes in ECs. Seventeen genes were identified, including the deubiquitinase Non-stop (CG4166). Lineage tracing established that acute loss of Non-stop in young ECs phenocopies aged ECs at cellular and tissue levels. Proteomic analysis unveiled that Non-stop maintains identity as part of a Non-stop identity complex (NIC) containing E(y)2, Sgf11, Cp190, (Mod) mdg4, and Nup98. Non-stop ensured chromatin accessibility, maintaining the EC-gene signature, and protected NIC subunit stability. Upon aging, the levels of Non-stop and NIC subunits declined, distorting the unique organization of the EC nucleus. Maintaining youthful levels of Non-stop in wildtype aged ECs safeguards NIC subunits, nuclear organization, and suppressed aging phenotypes. Thus, Non-stop and NIC, supervise EC identity and protects from premature aging.

Heat Shock Protein 22 in Physiological and Pathological Hearts: Small Molecule, Large Potentials.

Small heat shock protein 22 (HSP22) belongs to the superfamily of heat shock proteins and is predominantly expressed in the heart, brain, skeletal muscle, and different types of cancers. It has been found that HSP22 is involved in variant cellular functions in cardiomyocytes and plays a vital role in cardiac protection against cardiomyocyte injury under diverse stress. This review summarizes the multiple functions of HSP22 in the heart and the underlying molecular mechanisms through modulating gene transcription, post-translational modification, subcellular translocation of its interacting proteins, and protein degradation, facilitating mitochondrial function, cardiac metabolism, autophagy, and ROS production and antiapoptotic effect. We also discuss the association of HSP22 in cardiac pathologies, including human dilated cardiomyopathy, pressure overload-induced heart failure, ischemic heart diseases, and aging-related cardiac metabolism disorder. The collected information would provide insights into the understanding of the HSP22 in heart diseases and lead to discovering the therapeutic targets.

Catalytic Performances of Cu/MCM-22 Zeolites with Different Cu Loadings in NH3-SCR.

The NH3-SCR activities and hydrothermal stabilities of five xCu/MCM-22 zeolites with different Cu loadings (x = 2-10 wt%) prepared by incipient wetness impregnation method were systematically investigated. The physicochemical properties of xCu/MCM-22 zeolites were analyzed by XRD, nitrogen physisorption, ICP-AES, SEM, NH3-TPD, UV-vis, H2-TPR and XPS experiments. The Cu species existing in xCu/MCM-22 are mainly isolated Cu2+, CuOx and unreducible copper species. The concentrations of both isolated Cu2+ and CuOx species in xCu/MCM-22 increase with Cu contents, but the increment of CuOx species is more distinct, especially in high Cu loadings (>4 wt%). NH3-SCR experimental results demonstrated that the activity of xCu/MCM-22 is sensitive to Cu content at low Cu loadings (≤4 wt%). When the Cu loading exceeds 4 wt%, the NH3-SCR activity of xCu/MCM-22 is irrelevant to Cu content due to the severe pore blockage effects caused by aggregated CuOx species. Among the five xCu/MCM-22 zeolites, 4Cu/MCM-22 with moderate Cu content has the best NH3-SCR performance, which displays higher than 80% NOx conversions in a wide temperature window (160-430 °C). Furthermore, the hydrothermal aging experiments (xCu/MCM-22 was treated at 750 °C for 10 h under 10% water vapor atmosphere) illustrated that all the xCu/MCM-22 zeolites exhibit high hydrothermal stability in NH3-SCR reactions.

Age-Related Parkinsonian Signs in Microdeletion 22q11.2.

BACKGROUND: The recurrent hemizygous 22q11.2 deletion associated with 22q11.2 deletion syndrome has been identified as a genetic risk factor for early-onset PD. However, little is known about early motor signs in this condition. OBJECTIVES: We examined the presence, severity and possible factors associated with parkinsonism in adults with 22q11.2 deletion syndrome and without PD. METHODS: We compared motor signs between 82 adults with 22q11.2 deletion syndrome and 25 healthy controls, using the MDS-UPDRS part III, and three-dimensional motion-tracker technology to quantify components of bradykinesia. RESULTS: Median MDS-UPDRS part III total and bradykinesia subscores were significantly higher in 22q11.2 deletion syndrome (median age: 26 years; range, 17-65) than in controls (P = 0.000; P = 0.000, respectively). Age was a significant contributor to bradykinesia subscore (B = 0.06; P = 0.01) and to the electronic bradykinesia component, velocity (B = -0.02; P = 0.000); psychotic illness did not significantly impact these analyses. In 22q11.2 deletion syndrome, MDS-UPDRS-defined bradykinesia was present in 18.3%, rigidity in 14.6%, and rest tremor in 12.2%. CONCLUSIONS: Parkinsonian motor signs appear to be common and age related in 22q11.2 deletion syndrome. Longitudinal studies are needed to investigate possible symptom progression to PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Altered glucocorticoid metabolism represents a feature of macroph-aging.

The aging process is characterized by a chronic, low-grade inflammatory state, termed "inflammaging." It has been suggested that macrophage activation plays a key role in the induction and maintenance of this state. In the present study, we aimed to elucidate the mechanisms responsible for aging-associated changes in the myeloid compartment of mice. The aging phenotype, characterized by elevated cytokine production, was associated with a dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and diminished serum corticosteroid levels. In particular, the concentration of corticosterone, the major active glucocorticoid in rodents, was decreased. This could be explained by an impaired expression and activity of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an enzyme that determines the extent of cellular glucocorticoid responses by reducing the corticosteroids cortisone/11-dehydrocorticosterone to their active forms cortisol/corticosterone, in aged macrophages and peripheral leukocytes. These changes were accompanied by a downregulation of the glucocorticoid receptor target gene glucocorticoid-induced leucine zipper (GILZ) in vitro and in vivo. Since GILZ plays a central role in macrophage activation, we hypothesized that the loss of GILZ contributed to the process of macroph-aging. The phenotype of macrophages from aged mice was indeed mimicked in young GILZ knockout mice. In summary, the current study provides insight into the role of glucocorticoid metabolism and GILZ regulation during aging.

Effect of Hydrothermal Aging Treatment on Decomposition of NO by Cu-ZSM-5 and Modified Mechanism of Doping Ce against This Influence.

Cu-ZSM-5 and Ce-doped Cu-Ce-ZSM-5 samples were prepared by liquid-phase ion exchange method. The two catalysts were subjected to hydrothermal aging treatment in the simulated flue gas of a coal-fired power station at an ageing temperature of 650-850 °C. The denitration experiment found that the activity of the aged Cu-ZSM-5 was 19.6% to 41% lower than that of the fresh Cu-ZSM-5 at the optimal decomposition temperature of NO at 550 °C, while the aged Cu-Ce-ZSM-5 had only a 14.8% to 31.5% reduction in activity than the fresh Cu-Ce-ZSM-5. The samples were characterized by XRD, BET, H2-TPR, XPS, NO-TPD, etc. The results showed that hydrothermal aging treatment leads to the dealumination of the ZSM-5 framework and reduces the specific surface area and pore volume of the micropore in the sample. It also exacerbates the isolated Cu2+, and the active center {Cu2+-O2--Cu2+}2+ dimers migrate towards the sample surface and form inactive CuO. Doping with Ce can promote the dispersion of Cu(OH)+, which was the precursor of {Cu2+-O2--Cu2+}2+. Ce3+ can preferentially occupy the less active bridged hydroxyl exchange sites, so that copper ions occupy the more active aluminum hydroxyl sites, thereby inhibiting the migration of active centers.

Contribuições técnicas e socioculturais da prevenção quaternária para a atenção primária à saúde: caminhos e desafios / Technical and socio-cultural contributions of quaternary prevention for primary health care: paths and challenges / Contribuciones técnicas y socioculturales de prevención cuaternaria para la atención primaria de salud: caminos y desafíos

Introdução: No contexto do Sistema Único de Saúde, o conceito da prevenção quaternária adentra timidamente os níveis de atenção à saúde, no entanto, sofre expansão significativa no âmbito da atenção primária à saúde. Objetivo: Identificar por meio da sistematização de evidências científicas, as contribuições técnicas e socioculturais da prevenção quaternária no âmbito da atenção primária à saúde no Brasil. Métodos: Trata-se de uma revisão integrativa de estudos presentes nas bases de dados científicas da Scientific Electronic Library Online, Biblioteca Virtual em Saúde, biblioteca virtual da Comissão de Aperfeiçoamento de Pessoal do Nível Superior e MEDLINE via PubMed com a utilização dos descritores "prevenção quaternária" e "atenção primária à saúde", em inglês e português. Resultados: O corpus de análise foi composto por 22 artigos, sendo que a produção científica sobre o tema se deu de forma mais intensa a partir do ano de 2015 e, em sua maioria, possuíam como abordagem metodológica ensaios teóricos. Dentre as contribuições técnicas destacaram-se a introdução do ensino da prevenção quaternária de modo continuado aos graduandos e profissionais; a construção de protocolos e documentos de amparo profissional; a utilização de modelos explicativos dinâmicos na socialização do quadro clínico; a conduta profissional com os usuários e as contribuições socioculturais envolvendo mudanças na percepção profissional e comunitária sobre o fenômeno saúde-doença, assim como o incentivo a práticas de desmedicalização sociocultural em relação à dor, incapacidade, desconforto, envelhecimento, nascimento e morte. Conclusão: Apesar do reconhecimento das potencialidades da prevenção quaternária, faz-se necessário fortalecer estratégias que possibilitem o desenvolvimento de políticas públicas para fomentar e gerenciar alianças estratégicas com tomadores de decisão, profissionais de saúde e cidadãos, para fomentar a redução de diagnósticos e tratamentos excessivos, contribuindo com a qualidade do cuidado.

Introduction: In the context of the Unified Health System, the concept of quaternary prevention shyly enters the levels of health care, however, undergoes significant expansion in the scope of primary health care. Objective: To identify, through the systematization of scientific evidence, the technical and socio-cultural contributions of quaternary prevention within the scope of primary health care in Brazil. Methods: This is an integrative review of studies present in the scientific databases of the Scientific Electronic Library Online, Regional Portal of the Virtual Health Library of the Latin American and Caribbean Center on Health Sciences Information of the Pan American Health Organization, virtual library of the Higher Education Personnel Improvement Commission, and MEDLINE through PubMed using the descriptors "quaternary prevention" and "primary health care", in English and Portuguese. Results: The corpus of analysis consisted of 22 articles, and the scientific production on the topic took place more intensively from the year 2015 and, for the most part, had theoretical essays as methodological approach. Among the technical contributions, we highlight the introduction of teaching on quaternary prevention in a continuous way to undergraduates and professionals; the construction of protocols and documents of professional support; the use of dynamic explanatory models in the socialization of the clinical picture and professional conduct with users and socio-cultural contributions involve changes in the professional and community perception about the phenomenon of illness and health conception, as well as the incentive to practices of socio-cultural demedicalization in relation to pain, disability, discomfort, aging, birth, and death. Conclusion: Despite the recognition of the potential of quaternary prevention, it is necessary to strengthen strategies that enable the development of public policies to foster and manage strategic alliances with decision makers, health professionals and citizens, to promote the reduction of excessive diagnoses and treatments, contributing to the quality of care.

Introducción: En el contexto del Sistema Único de Salud, el concepto de prevención cuaternaria entra tímidamente en los niveles de atención de salud, sin embargo, experimenta una expansión significativa en el alcance de la Atención Primaria de Salud. Objetivo: Identificar, a través de la sistematización de evidencia científica, las contribuciones técnicas y socioculturales de la prevención cuaternaria en el ámbito de la Atención Primaria de Salud en Brasil. Métodos: Esta es una revisión integradora de estudios presentes en las bases de datos científicas de la Biblioteca Electrónica Científica en línea, Portal Regional de la Biblioteca Virtual en Salud del Centro Latinoamericano y del Caribe de Información en Ciencias de la Salud de la Organización Panamericana de la Salud, biblioteca virtual de la Comisión de Mejoramiento del Personal de Educación Superior y MEDLINE a través de PubMed utilizando los descriptores de prevención cuaternaria y atención primaria de salud, en inglés y portugués. Resultados: El corpus de análisis estuvo conformado por 22 artículos, siendo la producción científica sobre el tema más intensiva desde 2015 y, en su mayor parte, tuvo ensayos teóricos como abordaje metodológico. Entre los aportes técnicos, destacamos la implantación de la docencia en prevención cuaternaria de forma continua a estudiantes de pregrado y profesionales; construcción de protocolos y documentos de apoyo profesional, uso de modelos explicativos dinámicos en la socialización del cuadro clínico y conducta profesional con los usuarios y los aportes socioculturales implican cambios en la percepción profesional y comunitaria sobre el fenómeno de la enfermedad y la concepción de la salud, así como el incentivo a prácticas de desmedicalización sociocultural en relación al dolor, discapacidad, malestar, envejecimiento, nacimiento y muerte. Conclusión: A pesar del reconocimiento del potencial de la prevención cuaternaria, es necesario fortalecer estrategias que permitan el desarrollo de políticas públicas para fomentar y gestionar alianzas estratégicas con los tomadores de decisiones, profesionales de la salud y ciudadanos, para promover la reducción de diagnósticos y tratamientos excesivos, contribuyendo a la calidad de la atención.

Mechanism of Ginseng Radix et Rhizoma, Notoginseng Radix et Rhizoma and Chuanxiong Rhizoma Extracts in Delaying High Glucose-induced Vascular Calcification in Mice / 中国实验方剂学杂志

Objective::To investigate the protective effect of Ginseng Radix et Rhizoma, Notoginseng Radix et Rhizoma and Chuanxiong Rhizoma extracts on vascular calcification induced by high glucose in mice by observing the expression of osteopontin (OPN) and smooth muscle 22α (SM22α) as well as vascular calcium deposition in the common carotid artery and thoracic aorta of mice. Method::Totally 130 male C57BL/6 mice were randomly divided into normal control group and high glucose group. The mice in high glucose group were intraperitoneally injected with streptozotocin(STZ), and fed on a high-fat diet for 7 months. Then, the mice were randomly divided into model group, low-dose and high-dose Ginseng Radix et Rhizoma, Notoginseng Radix et Rhizoma and Chuanxiong Rhizoma extracts groups (0.819, 1.638 g·kg-1), and metformin group (150 mg·kg-1). Each group was intragastrically administered once a day for 9 weeks. The changes in blood glucose were measured. Seven days before the end of the administration, a group of 4-week old male C57BL/6 mice were purchased and fed normally for one week as a youth group. At the end of the administration, the common carotid artery and thoracic aorta tissues of the mice were collected. Von Kossa staining was used to determine the degree of calcium deposition in the common carotid artery and thoracic aorta. The expression levels of OPN and SM22α protein in the common carotid artery and thoracic aorta were detected by immunohistochemistry. The expression of OPN and SM22α protein in the common carotid artery of mice was determined by Western blot. Result::As compared with the young group, the blood glucose of the normal control group was slightly increased without statistical difference, the common carotid artery and thoracic aorta were uniformly stained, and no black granular precipitate was observed. As compared with the normal control group, the blood glucose of the model group was increased (P<0.01), with a large amount of brown-black particles deposited in the intimal elastic fibers, showing obvious calcium salt deposition. As compared with the model group, blood glucose was significantly decreased in each administration group (P<0.05, P<0.01), and the degree of vascular calcium salt deposition was significantly reduced. There were no significant changes in expression levels of OPN protein and SM22α protein in the common carotid artery and thoracic aorta between the youth group and normal control group. As compared with the normal control group, the expression of intimal OPN protein in the common carotid artery and thoracic aorta of the model group was positive, SM22α protein expression was weakly positive, and the gray value of OPN protein expression in the common carotid artery was significantly increased (P<0.01), while the gray value of SM22α protein was decreased significantly (P<0.01). As compared with the model group, the expression levels of intimal OPN protein and SM22α protein in the common carotid artery and thoracic aorta of each administration group were significantly improved, and the gray value of OPN protein expression in the common carotid artery was reduced (P<0.05, P<0.01), while SM22α protein expression was significantly increased (P<0.01). Conclusion::High glucose can induce calcification of common carotid artery and thoracic aorta in mice and accelerate vascular aging. This formation process may be related to the expression of OPN and SM22α. Ginseng Radix et Rhizoma, Notoginseng Radix et Rhizoma and Chuanxiong Rhizoma extracts can reduce vascular calcification and delay vascular aging by regulating the expression of OPN and SM22α.

Involvement of N-type Ca2+ channel in microglial activation and its implications to aging-induced exaggerated cytokine response.

Voltage-dependent calcium channel (VDCC) is generally believed to be active only in excitable cells. However, we have reported recently that N-type VDCC (Cav2.2) could become functional in non-excitable cells under pathological conditions. In the present study, we show that Cav2.2 channels are also functional in physiological microglial activation process. By using a mouse microglial cell line (MG6), we examined the effects of a Cav2.2 blocker on the activation of MG6 cells, when treated with lipopolysaccharide (LPS) / interferon γ (IFNγ) or with interleukin-4 (IL-4). As a result, blocking the activation of Cav2.2 enhanced so-called alternative activation process of microglia (transition to neuroprotective M2 microglia) without changing the efficacy of the transition to neuroinflammatory M1 microglia. This enhanced M2 transition involved the activation of a transcription factor hypoxia inducible factor 2 (HIF-2), since a specific blocker of HIF-2 completely abolished this enhancement. We then examined whether Cav2.2 activation was involved in aging-related neuroinflammation. Using primary culture of microglia, we found that the efficacy of microglial M1 transition was enhanced but that M2 transition was reduced by aging, in agreement with a general notion that aging induces enhanced neuroinflammation. Finally, we show here that the moderate blockade of Cav2.2 expression in microglia restores this age-dependent reduction of microglial M2 transition and reduces the aging-induced exaggerated cytokine response, as revealed by a fast recovery from depressive-like behaviors in microglia-specific Cav2.2 deficient mice. These results suggest a critical role for microglial Cav2.2 channel in the aging-related neuroinflammation.

Age-specific changes in the molecular phenotype of patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) shows differential clinical presentation in older compared with younger patients. Nevertheless, changes in the AD molecular profile with age are unknown. OBJECTIVE: We sought to characterize age-related changes in the AD profile. METHODS: We evaluated age-specific changes in lesional and nonlesional tissues and blood from patients with moderate-to-severe AD (n = 246) and age-matched control subjects (n = 71) using immunohistochemistry, quantitative real-time PCR, and Singulex in a cross-sectional study. Patients were analyzed by age group (18-40, 41-60, and ≥61 years). RESULTS: Although disease severity/SCORAD scores were similar across AD age groups (mean, approximately 60 years; P = .873), dendritic cell infiltrates (CD1b+ and FcεRI+, P < .05) decreased with age. TH2 measures (IL5, IL13, CCL13, CCL18, and CCL26) significantly decreased with age in patients with AD, despite increasing with age in control subjects. Consistent with TH2 axis decreases, serum IgE levels and eosinophil counts negatively correlated with age in patients with AD (r = -0.24 and r = -0.23, respectively; P < .05). TH22-secreted IL22 expression levels also decreased with age uniquely in patients with AD (P < .05). Expression of TH1-related (IFNG, IL12/23p40, STAT1, and CXCL9; P < .05 for CXCL9) and TH17-related (IL17A and IL20; P < .05 for IL20) markers increased with age in both patients with AD and control subjects. Expression of terminal differentiation measures significantly increased in older patients with AD (loricrin [LOR] and filaggrin [FLG], P < .05), whereas expression of S100As (S100A8, P < .01) and hyperplasia markers (epidermal thickness, keratin 16, and Ki67; P < .05 for keratin 16) decreased. Serum trends in AD mimicked skin findings, with TH2 downregulation (CCL26; r = -0.32, P < .1) and TH1 upregulation (IFN-γ; r = 0.48, P < .01) with age. CONCLUSION: The adult AD profile varies with age. Although TH1/TH17 skewing increases in both patients with AD and control subjects, patients with AD show unique decreases in TH2/TH22 polarization and normalization of epithelial abnormalities. Thus age-specific treatment approaches might be beneficial for AD.

Aging impairs protective host defenses against Clostridioides (Clostridium) difficile infection in mice by suppressing neutrophil and IL-22 mediated immunity.

BACKGROUND: Morbidity and mortality associated with Clostridioides (formerly Clostridium) difficile infection (CDI) rises progressively with advanced age (≥65 years) due in part to perturbations of the gut microbiota and immune dysfunction. Epidemiological data of community-acquired CDI suggests increased susceptibility may begin earlier during middle-age (45-64 years) but the causation remains unknown. METHODS: Middle-aged (12-14 months) and young (2-4 months) adult mice were infected with C. difficile, and disease severity, gut microbiome and innate immune response were compared. Cytokine reconstitution studies were performed in infected middle-aged mice. RESULTS: Infection of middle-aged mice with C. difficile led to greater disease compared to young controls, which was associated with increases in C. difficile burden and toxin titers, and elevated bacterial translocation. With the exception of an expansion of C. difficile in middle-aged mice, microbiome analysis revealed no age-related differences. In contrast, middle-aged mice displayed a significant defect in neutrophil recruitment to the colon, with diminished levels of innate immune cytokines IL-6, IL-23 and IL-22. Importantly, recombinant IL-22 administration during CDI reduced morbidity and prevented death in middle-aged mice. CONCLUSION: Increased susceptibility to C. difficile occurs in middle-aged mice modeling the community-acquired CDI demographics and is driven by an impaired innate immune response.