RESUMEN

BACKGROUND: The pathogenesis of osteoarthritis (OA) involves the progressive degradation of articular cartilage. Exosomes derived from mesenchymal stem cells (MSC-EXOs) have been shown to mitigate joint pathological injury by attenuating cartilage destruction. Optimization the yield and therapeutic efficacy of exosomes derived from MSCs is crucial for promoting their clinical translation. The preconditioning of MSCs enhances the therapeutic potential of engineered exosomes, offering promising prospects for application by enabling controlled and quantifiable external stimulation. This study aims to address these issues by employing pro-inflammatory preconditioning of MSCs to enhance exosome production and augment their therapeutic efficacy for OA. METHODS: The exosomes were isolated from the supernatant of infrapatellar fat pad (IPFP)-MSCs preconditioned with a pro-inflammatory factor, TNF-α, and their production was subsequently quantified. The exosome secretion-related pathways in IPFP-MSCs were evaluated through high-throughput transcriptome sequencing analysis, q-PCR and western blot analysis before and after TNF-α preconditioning. Furthermore, exosomes derived from TNF-α preconditioned IPFP-MSCs (IPFP-MSC-EXOsTNF-α) were administered intra-articularly in an OA mouse model, and subsequent evaluations were conducted to assess joint pathology and gait alterations. The expression of proteins involved in the maintenance of cartilage homeostasis within the exosomes was determined through proteomic analysis. RESULTS: The preconditioning with TNF-α significantly enhanced the exosome secretion of IPFP-MSCs compared to unpreconditioned MSCs. The potential mechanism involved the activation of the PI3K/AKT signaling pathway in IPFP-MSCs by TNF-α precondition, leading to an up-regulation of autophagy-related protein 16 like 1(ATG16L1) levels, which subsequently facilitated exosome secretion. The intra-articular administration of IPFP-MSC-EXOsTNF-α demonstrated superior efficacy in ameliorating pathological changes in the joints of OA mice. The preconditioning of TNF-α enhanced the up-regulation of low-density lipoprotein receptor-related protein 1 (LRP1) levels in IPFP-MSC-EXOsTNF-α, thereby exerting chondroprotective effects. CONCLUSION: TNF-α preconditioning constitutes an effective and promising method for optimizing the therapeutic effects of IPFP-MSCs derived exosomes in the treatment of OA.

Asunto(s)

Exosomas , Células Madre Mesenquimatosas , Osteoartritis , Factor de Necrosis Tumoral alfa , Exosomas/metabolismo , Animales , Células Madre Mesenquimatosas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ratones , Osteoartritis/terapia , Osteoartritis/metabolismo , Tejido Adiposo/citología , Ratones Endogámicos C57BL , Masculino , Modelos Animales de Enfermedad , Cartílago Articular/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos , Células Cultivadas , Humanos

RESUMEN

High altitude environment is mainly characterized by low oxygen. Due to persistent hypoxia, nonhealing wounds are common in high-altitude areas. Moreover, Basic fibroblast growth factor (bFGF) is a versatile biologically active substance that has crucial impact on wound healing. Given the limited availability of atmospheric oxygen and reduced blood oxygen saturation in high-altitude area, and the challenge that arises from direct oxygen and bFGF delivery to wounds through the traumatized vascular structure, it necessitates an innovative solution for local and permeable delivery of oxygen and bFGF. In this study, we present a strategy that involves revamping traditional gel-based wound dressings through the incorporation of nanoparticles encapsulating oxygen and bFGF, engineered to facilitate the localized delivery of dissolved oxygen and bFGF to wound surfaces. The prospective evaluation of this delivery technique's therapeutic impacts on epithelial, endothelial and fibroblasts cells can be materialized. Further experiment corroborated these effects on a high-altitude wounds' murine model. Given its biocompatibility, efficacy, and utility, we posit that NOB-Gel exhibits remarkable translational potential for managing and hastening the healing process of an array of clinical wounds, more so for wounds inflicted at high altitudes.

RESUMEN

BACKGROUND: Recent studies have suggested a possible link between sarcopenia, immune dysregulation, and chronic inflammation, although the specific immune components implicated remain unclear. This investigation employs Mendelian Randomization (MR) to explore the reciprocal relationship between immune cells, inflammatory markers, and sarcopenia. METHOD: We performed two-sample and multivariate MR analyses using publicly accessible genome-wide association studies (GWAS) summary statistics. Our analyses included 731 immune cells, 41 inflammatory cytokines, and sarcopenia related traits (appendicular lean mass [ALM], low hand-grip strength [LHS], and walking pace [WP]), with additional sensitivity analyses conducted to confirm the findings. RESULTS: After false discovery rate (FDR) correction, significant associations were found between ten immune traits and ALM, with the CD127 marker in the Treg panel showing consistent positive correlation across four sites. In contrast, NKT%lymphocyte negatively correlated with WP (OR = 0.99, P = 0.023). In terms of inflammatory cytokines, macrophage colony-stimulating factor (MCSF) (OR = 1.03, P = 0.024) and hepatocyte growth factor (HGF) (OR = 1.03, P = 0.002) demonstrated positive associations with ALM, while interleukin-16 (IL-16) (OR = 0.99, P = 0.006) was inversely related. The reverse Mendelian randomization analysis found no direct causal links between sarcopenia traits and immune or inflammatory markers. Sensitivity analyses underscored the findings' resilience to pleiotropy, and adjusting for inter-trait dynamics weakened these relationships in the multivariable MR analysis. CONCLUSION: Our study reveals causal associations between specific immune phenotypes, inflammatory cytokines, and sarcopenia, providing insight into the development of sarcopenia and potential treatment strategies.

RESUMEN

Several exogenous probiotics are applicable in fish culture; however, challenges in isolation and verification have hindered the full utilization of numerous host probiotics. Therefore, this study aimed to apply the host probiotic Exiguobacterium acetylicum G1-33 to hybrid grouper (Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂) cultures and explore its mechanism of action. In total, 360 hybrid grouper were divided into four groups, which were fed the following for 60 days: three received commercial feed with varying concentrations of E. acetylicum G1-33 (106, 108, and 1010 CFU/g), while a control group received commercial feed. The results showed that supplementation with 106 and 108 CFU/g of E. acetylicum G1-33 enhanced gut morphology, upregulated growth-related genes (ghr1, igf-2, s6k1, tor), and promoted growth, with supplementation with 108 CFU/g resulting in the most notable enhancement. However, supplementation with 1010 CFU/g inhibited growth, possibly because of changes in intestinal morphology. Additionally, supplementation with E. acetylicum G1-33 upregulated the expression of immune-related genes (c3, myd88, Cu/Zn-sod, tlr3, and tnf2) in the liver and head kidney but led to an increase in malondialdehyde content, as well as a decrease in alkaline phosphatase and acid phosphatase activities, in the liver and serum, indicating increased oxidative stress. Moreover, supplementation with 106 and 108 CFU/g E. acetylicum G1-33 enhanced the widespread expression of immune-related genes in the head kidney and liver, respectively, and improved resistance to Vibrio harveyi, whereas supplementation with 1010 CFU/g weakened this resistance. In conclusion, E. acetylicum G1-33, particularly at 108 CFU/g, emerged as an effective probiotic, optimizing growth performance and immunity in hybrid grouper. This research is pioneering in its application of E. acetylicum in mariculture, potentially broadening the range of probiotic strategies in aquaculture.

RESUMEN

Joint diseases greatly impact the daily lives and occupational functioning of patients globally. However, conventional treatments for joint diseases have several limitations, such as unsatisfatory efficacy and side effects, necessitating the exploration of more efficacious therapeutic strategies. Mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) have demonstrated high therapeutic efficacyin tissue repair and regeneration, with low immunogenicity and tumorigenicity. Recent studies have reported that EVs-based therapy has considerable therapeutic effects against joint diseases, including osteoarthritis, tendon and ligament injuries, femoral head osteonecrosis, and rheumatoid arthritis. Herein, we review the therapeutic potential of various types of MSC-EVs in the aforementioned joint diseases, summarise the mechanisms underlying specific biological effects of MSC-EVs, and discuss future prospects for basic research on MSC-EV-based therapeutic modalities and their clinical translation. In general, this review provides an in-depth understanding of the therapeutic effects of MSC-EVs in joint diseases, as well as the underlying mechanisms, which may be beneficial to the clinical translation of MSC-EV-based treatment. The translational potential of this article: MSC-EV-based cell-free therapy can effectively promote regeneration and tissue repair. When used to treat joint diseases, MSC-EVs have demonstrated desirable therapeutic effects in preclinical research. This review may supplement further research on MSC-EV-based treatment of joint diseases and its clinical translation.

RESUMEN

This study aimed to develop a deep learning model to predict the risk stratification of all-cause death for older people with disability, providing guidance for long-term care plans. Based on the government-led long-term care insurance program in a pilot city of China from 2017 and followed up to 2021, the study included 42,353 disabled adults aged over 65, with 25,071 assigned to the training set and 17,282 to the validation set. The administrative data (including baseline characteristics, underlying medical conditions, and all-cause mortality) were collected to develop a deep learning model by least absolute shrinkage and selection operator. After a median follow-up time of 14 months, 17,565 (41.5%) deaths were recorded. Thirty predictors were identified and included in the final models for disability-related deaths. Physical disability (mobility, incontinence, feeding), adverse events (pressure ulcers and falls from bed), and cancer were related to poor prognosis. A total of 10,127, 25,140 and 7086 individuals were classified into low-, medium-, and high-risk groups, with actual risk probabilities of death of 9.5%, 45.8%, and 85.5%, respectively. This deep learning model could facilitate the prevention of risk factors and provide guidance for long-term care model planning based on risk stratification.

Asunto(s)

Aprendizaje Profundo , Cuidados a Largo Plazo , Humanos , Femenino , Masculino , Anciano , China/epidemiología , Estudios Prospectivos , Anciano de 80 o más Años , Causas de Muerte , Personas con Discapacidad/estadística & datos numéricos , Medición de Riesgo , Mortalidad/tendencias , Factores de Riesgo , Pronóstico

RESUMEN

Preventing the recurrence of melanoma after surgery and accelerating wound healing are among the most challenging aspects of melanoma management. Photothermal therapy has been widely used to treat tumors and bacterial infections and promote wound healing. Owing to its efficacy and specificity, it may be used for postoperative management of tumors. However, its use is limited by the uncontrollable distribution of photosensitizers and the likelihood of damage to the surrounding normal tissue. Hydrogels provide a moist environment with strong biocompatibility and adhesion for wound healing owing to their highly hydrophilic three-dimensional network structure. In addition, these materials serve as excellent drug carriers for tumor treatment and wound healing. It is possible to combine the advantages of both of these agents through different loading modalities to provide a powerful platform for the prevention of tumor recurrence and wound healing. This review summarizes the design strategies, research progress and mechanism of action of hydrogels used in photothermal therapy and discusses their role in preventing tumor recurrence and accelerating wound healing. These findings provide valuable insights into the postoperative management of melanoma and may guide the development of promising multifunctional hydrogels for photothermal therapy.

Asunto(s)

Hidrogeles , Melanoma , Terapia Fototérmica , Cicatrización de Heridas , Hidrogeles/química , Hidrogeles/administración & dosificación , Humanos , Melanoma/terapia , Terapia Fototérmica/métodos , Animales , Cicatrización de Heridas/efectos de los fármacos , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/uso terapéutico , Portadores de Fármacos/química , Recurrencia Local de Neoplasia/prevención & control

RESUMEN

Radiosensitizers play a pivotal role in enhancing radiotherapy (RT). One of the challenges in RT is the limited accumulation of nanoradiosensitizers and the difficulty in activating antitumor immunity. Herein, a smart strategy was used to achieve in situ aggregation of nanomanganese adjuvants (MnAuNP-C&B) to enhance RT-induced antitumor immunity. The aggregated MnAuNP-C&B system overcomes the shortcomings of small-sized nanoparticles that easily flow back into blood vessels and diffuse into surrounding tissues, and it also prolongs the retention time of nanomanganese within cancer cells and tumors. The MnAuNP-C&B system significantly enhances the radiosensitization effect in RT. Additionally, the pH-responsive disassembly of MnAuNP-C&B triggers the release of Mn2+, further promoting RT-induced activation of the STING pathway and eliciting robust antitumor immunity. Overall, our study presents a smart strategy wherein in situ aggregation of nanomanganese effectively inhibits tumor growth through radiosensitization and the activation of antitumor immunity.

Asunto(s)

Fármacos Sensibilizantes a Radiaciones , Animales , Ratones , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Humanos , Manganeso/química , Línea Celular Tumoral , Nanopartículas/química , Nanopartículas/uso terapéutico , Femenino , Ratones Endogámicos BALB C , Neoplasias/radioterapia , Neoplasias/inmunología , Antineoplásicos/química , Antineoplásicos/farmacología

RESUMEN

Nutrient avidity is one of the most distinctive features of tumours. However, nutrient deprivation has yielded limited clinical benefits. In Gaucher disease, an inherited metabolic disorder, cells produce cholesteryl-glucoside which accumulates in lysosomes and causes cell damage. Here we develop a nanoparticle (AbCholB) to emulate natural-lipoprotein-carried cholesterol and initiate Gaucher disease-like damage in cancer cells. AbCholB is composed of a phenylboronic-acid-modified cholesterol (CholB) and albumin. Cancer cells uptake the nanoparticles into lysosomes, where CholB reacts with glucose and generates a cholesteryl-glucoside-like structure that resists degradation and aggregates into microscale crystals, causing Gaucher disease-like damage in a glucose-dependent manner. In addition, the nutrient-sensing function of mTOR is suppressed. It is observed that normal cells escape severe damage due to their inferior ability to compete for nutrients compared with cancer cells. This work provides a bioinspired strategy to selectively impede the metabolic action of cancer cells by taking advantage of their nutrient avidity.

Asunto(s)

Enfermedad de Gaucher , Lisosomas , Nanopartículas , Humanos , Enfermedad de Gaucher/metabolismo , Enfermedad de Gaucher/patología , Nanopartículas/química , Lisosomas/metabolismo , Colesterol/metabolismo , Colesterol/química , Línea Celular Tumoral , Neoplasias/metabolismo , Neoplasias/patología , Ácidos Borónicos/química , Glucosa/metabolismo , Animales , Serina-Treonina Quinasas TOR/metabolismo

RESUMEN

BACKGROUND: Evidence of the optimal blood pressure (BP) target for older adults with disability in long-term care is limited. We aim to analyze the associations of BP with mortality in older adults in long-term care setting with different levels of disability. METHODS: This prospective cohort study was based on the government-led long-term care programme in Chengdu, China, including 41,004 consecutive disabled adults aged ≥ 60 years. BP was measured during the baseline survey by trained medical personnel using electronic sphygmomanometers. Disability profile was assessed using the Barthel index. The association between blood pressure and mortality was analyzed with doubly robust estimation, which combined exposure model by inverse probability weighting and outcome model fitted with Cox regression. The non-linearity was examined by restricted cubic spline. The primary endpoint was all-cause mortality, and the secondary endpoints were cardiovascular and non-cardiovascular mortality. RESULTS: The associations between systolic blood pressure (SBP) and all-cause mortality were close to a U-shaped curve in mild-moderate disability group (Barthel index ≥ 40), and a reversed J-shaped in severe disability group (Barthel index < 40). In mild-moderate disability group, SBP < 135 mmHg was associated with elevated all-cause mortality risks (HR 1.21, 95% CI, 1.10-1.33), compared to SBP between 135 and 150 mmHg. In severe disability group, SBP < 150 mmHg increased all-cause mortality risks (HR 1.21, 95% CI, 1.16-1.27), compared to SBP between 150 and 170 mmHg. The associations were robust in subgroup analyses in terms of age, gender, cardiovascular comorbidity and antihypertensive treatment. Diastolic blood pressure (DBP) < 67 mmHg (HR 1.29, 95% CI, 1.18-1.42) in mild-moderate disability group and < 79 mmHg (HR 1.15, 95% CI, 1.11-1.20) in severe disability group both demonstrated an increased all-cause mortality risk. CONCLUSION: The optimal SBP range was found to be higher in older individuals in long-term care with severe disability (150-170mmHg) compared to those with mild to moderate disability (135-150mmHg). This study provides new evidence that antihypertensive treatment should be administered cautiously in severe disability group in long-term care setting. Additionally, assessment of disability using the Barthel index can serve as a valuable tool in customizing the optimal BP management strategy. TRIAL REGISTRATION: Chinese Clinical Trial Registry (Registration Number: ChiCTR2100049973).

Asunto(s)

Presión Sanguínea , Personas con Discapacidad , Cuidados a Largo Plazo , Humanos , Masculino , Femenino , Anciano , China/epidemiología , Estudios Prospectivos , Cuidados a Largo Plazo/métodos , Cuidados a Largo Plazo/tendencias , Presión Sanguínea/fisiología , Persona de Mediana Edad , Anciano de 80 o más Años , Estudios de Cohortes , Hipertensión/mortalidad , Hipertensión/fisiopatología , Hipertensión/epidemiología , Mortalidad/tendencias , Pueblos del Este de Asia

RESUMEN

Neuromuscular blocking agents (NMBAs) are routinely used during anesthesia to relax skeletal muscle. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels; NMBAs can induce muscle paralysis by preventing the neurotransmitter acetylcholine (ACh) from binding to nAChRs situated on the postsynaptic membranes. Despite widespread efforts, it is still a great challenge to find new NMBAs since the introduction of cisatracurium in 1995. In this work, an effective ensemble-based virtual screening method, including molecular property filters, 3D pharmacophore model, and molecular docking, was applied to discover potential NMBAs from the ZINC15 database. The results showed that screened hit compounds had better docking scores than the reference compound d-tubocurarine. In order to further investigate the binding modes between the hit compounds and nAChRs at simulated physiological conditions, the molecular dynamics simulation was performed. Deep analysis of the simulation results revealed that ZINC257459695 can stably bind to nAChRs' active sites and interact with the key residue Asp165. The binding free energies were also calculated for the obtained hits using the MM/GBSA method. In silico ADMET calculations were performed to assess the pharmacokinetic properties of hit compounds in the human body. Overall, the identified ZINC257459695 may be a promising lead compound for developing new NMBAs as an adjunct to general anesthesia, necessitating further investigations.

Asunto(s)

Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Bloqueantes Neuromusculares , Receptores Nicotínicos , Bloqueantes Neuromusculares/química , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/química , Humanos , Descubrimiento de Drogas/métodos , Unión Proteica , Sitios de Unión , Ligandos

RESUMEN

Radiation-induced in situ tumor vaccination alone is very weak and insufficient to elicit robust antitumor immune responses. In this work, we address this issue by developing chiral vidarabine monophosphate-gadolinium nanowires (aAGd-NWs) through coordination-driven self-assembly. We elucidate the mechanism of aAGd-NW assembly and characterize their distinct features, which include a negative surface charge, ultrafine topography, and right-handed chirality. Additionally, aAGd-NWs not only enhance X-ray deposition but also inhibit DNA repair, thereby enhancing radiation-induced in situ vaccination. Consequently, the in situ vaccination induced by aAGd-NWs sensitizes radiation enhances CD8+ T-cell-dependent antitumor immunity and synergistically potentiates the efficacy immune checkpoint blockade therapies against both primary and metastatic tumors. The well-established aAGd-NWs exhibit exceptional therapeutic capacity and biocompatibility, offering a promising avenue for the development of radioimmunotherapy approaches.

Asunto(s)

Nanocables , Polímeros , Nanocables/química , Animales , Ratones , Polímeros/química , Línea Celular Tumoral , Gadolinio/química , Gadolinio/farmacología , Ratones Endogámicos C57BL , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Vacunas contra el Cáncer/inmunología , Femenino , Humanos , Vacunación/métodos , Neoplasias/inmunología

RESUMEN

BACKGROUND: Ulcerative colitis (UC) is one chronic and relapsing inflammatory bowel disease. Macrophage has been reputed as one trigger for UC. Recently, phosphodiesterase 4 (PDE4) inhibitors, for instance roflumilast, have been regarded as one latent approach to modulating macrophage in UC treatment. Roflumilast can decelerate cyclic adenosine monophosphate (cAMP) degradation, which impedes TNF-α synthesis in macrophage. However, roflumilast is devoid of macrophage-target and consequently causes some unavoidable adverse reactions, which restrict the utilization in UC. RESULTS: Membrane vesicles (MVs) from probiotic Escherichia coli Nissle 1917 (EcN 1917) served as a drug delivery platform for targeting macrophage. As model drugs, roflumilast and MnO2 were encapsulated in MVs (Rof&MnO2@MVs). Roflumilast inhibited cAMP degradation via PDE4 deactivation and MnO2 boosted cAMP generation by activating adenylate cyclase (AC). Compared with roflumilast, co-delivery of roflumilast and MnO2 apparently produced more cAMP and less TNF-α in macrophage. Besides, Rof&MnO2@MVs could ameliorate colitis in mouse model and regulate gut microbe such as mitigating pathogenic Escherichia-Shigella and elevating probiotic Akkermansia. CONCLUSIONS: A probiotic-based nanoparticle was prepared for precise codelivery of roflumilast and MnO2 into macrophage. This biomimetic nanoparticle could synergistically modulate cAMP in macrophage and ameliorate experimental colitis.

Asunto(s)

Aminopiridinas , Benzamidas , AMP Cíclico , Ciclopropanos , Macrófagos , Compuestos de Manganeso , Óxidos , Probióticos , Animales , Aminopiridinas/farmacología , Ratones , AMP Cíclico/metabolismo , Probióticos/farmacología , Ciclopropanos/farmacología , Ciclopropanos/química , Compuestos de Manganeso/química , Compuestos de Manganeso/farmacología , Benzamidas/farmacología , Benzamidas/química , Óxidos/farmacología , Óxidos/química , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/química , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Células RAW 264.7 , Escherichia coli/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Ratones Endogámicos C57BL , Masculino , Modelos Animales de Enfermedad

RESUMEN

The proportion of the elderly population is gradually increasing as a result of medical care advances, leading to a subsequent surge in geriatric diseases that significantly impact quality of life and pose a substantial healthcare burden. Sarcopenia, characterized by age-related decline in skeletal muscle mass and quality, affects a considerable portion of older adults, particularly the elderly, and can result in adverse outcomes such as frailty, fractures, bedridden, hospitalization, and even mortality. Skeletal muscle aging is accompanied by underlying metabolic changes. Therefore, elucidating these metabolic profiles and specific mechanisms holds promise for informing prevention and treatment strategies for sarcopenia. This review provides a comprehensive overview of the key metabolites identified in current clinical studies on sarcopenia and their potential pathophysiological alterations in metabolic activity. Besides, we examine potential therapeutic strategies for sarcopenia from a perspective focused on metabolic regulation.

RESUMEN

Rhenium (Re) shows the richest valence states from +2 to +7 in compounds, but its mixed-valence states are still missing thus far. In this work, we have explored the Re-O phase diagram with a wide range of stoichiometric compositions under high pressure through first-principles structural search calculations. Besides identifying two novel high-pressure phases of ReO2 and ReO3, we reveal two hitherto unknown Re-rich Re3O2 and O-rich ReO4 compounds. Re atoms in Re3O2 show mixed-valence states due to their inequivalent coordination environments, the first example in Re-based compounds. Electronic structure calculations demonstrate that the four discovered Re-O phases exhibit metallicity contributed by Re 5d electrons. Among them, ReO3 has a predicted critical temperature of up to 12 K at 50 GPa, derived from the interaction between Re 5d electrons and Re-derived low-frequency phonons. Our study points to new opportunities to disclose novel transition metal compounds with mixed-valence states.

RESUMEN

The prevalence of isolated systolic hypertension (ISH) has doubled between 2002-2005 and 2014 among the oldest-old population in China. However, the prevalence and characteristics of ISH among the oldest-old population in southwestern China remain less known. This study aimed to investigate the prevalence of ISH among the oldest-old population in Chengdu and identify associated factors to provide valuable information for disease etiology and prevention. We recruited 1,312 participants aged over 80 years by using a stratified cluster sampling method between September 2015 and June 2016, from three districts (Jinjiang, Qingyang, and Longquanyi) of Chengdu, the largest city of southwest China. A structured questionnaire, anthropometric data, and blood pressure were collected according to the standard method. Blood pressure was measured three times by using a standardized mercury sphygmomanometer after a 10-minute seated rest. Of 1312 participants, 53.0% (n = 695) had ISH. The prevalence of ISH in men and women was 54.7% and 51.3%, respectively, with no significant sex difference (P = .222). The prevalence of ISH increased with advanced age in men (P for trend = 0.029), 52.5% for the 80-84 years group, 55.2% for the 85-89 years group, and 70.4% for the 90-98 years group, respectively. Multivariable logistic regression analyses found that drinking (OR = 1.85, 95%CI = 1.26-2.71), being overweight (OR = 1.88, 95%CI = 1.19-2.96), and having a higher heart rate (OR = 0.66, 95%CI = 0.51-0.86) were associated with ISH. Stratified by sex, these three factors remained significant in men. Our work highlights that the burden of ISH is substantial among the oldest-old population in southwestern China.

Asunto(s)

Presión Sanguínea , Hipertensión , Humanos , Masculino , Femenino , China/epidemiología , Prevalencia , Hipertensión/epidemiología , Estudios Transversales , Factores de Riesgo , Anciano de 80 o más Años , Presión Sanguínea/fisiología , Determinación de la Presión Sanguínea/métodos , Determinación de la Presión Sanguínea/estadística & datos numéricos , Encuestas y Cuestionarios , Hipertensión Sistólica Aislada

RESUMEN

The effect of immunoinflammation on bone repair during the recovery process of bone defects needs to be further explored. It is reported that Mg2+ can promote bone repair with immunoregulatory effect, but the underlying mechanism on adaptive immunity is still unclear. Here, by using chitosan and hyaluronic acid-coated Mg2+ (CSHA-Mg) in bone-deficient mice, it is shown that Mg2+ can inhibit the activation of CD4+ T cells and increase regulatory T cell formation by inducing immunosuppressive dendritic cells (imDCs). Mechanistically, Mg2+ initiates the activation of the MAPK signaling pathway through TRPM7 channels on DCs. This process subsequently induces the downstream HIF-1α expression, a transcription factor that amplifies TGF-ß production and inhibits the effective T cell function. In vivo, knock-out of HIF-1α in DCs or using a HIF-1α inhibitor PX-478 reverses inhibition of bone inflammation and repair promotion upon Mg2+-treatment. Moreover, roxadustat, which stabilizes HIF-1α protein expression, can significantly promote immunosuppression and bone repair in synergism with CSHA-Mg. Thus, the findings identify a key mechanism for DCs and its HIF-1α-TGF-ß axis in the induction of immunosuppressive bone microenvironment, providing potential targets for bone regeneration.

Asunto(s)

Células Dendríticas , Subunidad alfa del Factor 1 Inducible por Hipoxia , Magnesio , Factor de Crecimiento Transformador beta , Animales , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Magnesio/farmacología , Ratones , Ratones Endogámicos C57BL , Microambiente Celular/efectos de los fármacos , Huesos/efectos de los fármacos , Huesos/metabolismo , Regeneración Ósea/efectos de los fármacos , Isoquinolinas/farmacología , Glicina/análogos & derivados , Glicina/farmacología , Canales Catiónicos TRPM/metabolismo , Transducción de Señal/efectos de los fármacos , Quitosano/farmacología , Quitosano/química , Compuestos de Mostaza , Fenilpropionatos

RESUMEN

In order to achieve the tunable unidirectional reflection amplification in a uniform atomic medium that is of vital importance to design high-quality nonreciprocal photonic devices, we propose a coherent closed three-level Δ-type atomic system by applying a microwave field, and a strong coupling field of linear variation along the x direction to control a probe field. In our scheme, the linearly increased coupling field destroys the spatial symmetry of probe susceptibility and effectively suppresses the reflection of one side; the microwave field constructs closed loop transitions to amplify the probe field and causes phase changes. The numerical simulation indicates that the unidirectional reflection amplification is sensitive to the relative phase ϕ and the coupling detuning Δc. Our results will open a new route toward harnessing optical non-reciprocity, which can provide more convenience and possibilities in the experimental realization.

RESUMEN

Photodynamic therapy (PDT) is often applied in a clinical setting to treat bladder cancer. However, current photosensitizers report drawbacks such as low efficacy, low selectivity, and numerous side effects, which have limited the clinical values of PDT for bladder cancer. Previously, we developed the first bladder cancer-specific aptamer that can selectively bind to and be internalized by bladder tumor cells versus normal uroepithelium cells. Here, we use an aptamer-based drug delivery system to deliver photosensitizer chlorine e6 (Ce6) into bladder tumor cells. In addition to Ce6, we also incorporate catalase into the drug complex to increase local oxygen levels in the tumor tissue. Compared with free Ce6, an aptamer-guided DNA nanotrain (NT) loaded with Ce6 and catalase (NT-Catalase-Ce6) can specifically recognize bladder cancer cells, produce oxygen locally, induce ROS in tumor cells, and cause mitochondrial apoptosis. In an orthotopic mouse model of bladder cancer, the intravesical instillation of NT-Catalase-Ce6 exhibits faster drug internalization and a longer drug retention time in tumor tissue compared with that in normal urothelium. Moreover, our modified PDT significantly inhibits tumor growth with fewer side effects such as cystitis than free Ce6. This aptamer-based photosensitizer delivery system can therefore improve the selectivity and efficacy and reduce the side effects of PDT treatment in mouse models of bladder cancer, bearing a great translational value for bladder cancer intravesical therapy.

Asunto(s)

Clorofilidas , Fotoquimioterapia , Porfirinas , Neoplasias de la Vejiga Urinaria , Animales , Ratones , Catalasa/uso terapéutico , Línea Celular Tumoral , Oxígeno , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Humanos