Association of metabolic syndrome severity with frailty progression among Chinese middle and old-aged adults: a longitudinal study.

BACKGROUND: The binary diagnosis of Metabolic Syndrome(MetS) fails to accurately evaluate its severity, and the association between MetS severity and frailty progression remains inadequately elucidated. This study aims to clarify the relationship between the severity of MetS and the progression of frailty among the middle-aged and elderly population in China. METHOD: Participants from the 2011-2018 China Health and Retirement Longitudinal Study(CHARLS) were included for a longitudinal analysis. The study employs a frailty index(FI) based on 32 health deficits to diagnose frailty and to assess FI trajectories. An age-sex-ethnicity-specific MetS scoring model (MetS score) was used to assess metabolic syndrome severity in Chinese adults. The Cumulative MetS score from 2012 to 2015 was calculated using the formula: (MetS score in wave 1 + MetS score in wave 3) / 2 × time(2015 - 2012). The association between MetS score, Cumulative MetS score, and the risk and trajectory of frailty were evaluated using Cox regression/logistic regression, and linear mixed models. Restricted Cubic Splines(RCS) models were utilized to detect potential non-linear associations. RESULTS: A higher MetS score was significantly associated with an increased risk of frailty(HR per 1 SD increase = 1.205; 95%CI: 1.14 to 1.273) and an accelerated FI trajectory(ß per 1 SD increase = 0.113 per year; 95%CI: 0.075 to 0.15 per year). Evaluating changes in MetS score using a Cumulative MetS score indicated that each 1 SD increase in the Cumulative MetS score increased the risk of frailty by 22.2%(OR = 1.222; 95%CI: 1.133 to 1.319) and accelerated the rate of increase in FI(ß = 0.098 per year; 95%CI: 0.058 to 0.138 per year). RCS model results demonstrated a dose-response curve relationship between MetS score and Cumulative MetS score with frailty risk. Stratified analysis showed consistency across subgroups. The interaction results indicate that in males and individuals under aged 60, MetS score may accelerate the increase in FI, a finding consistent across both models. CONCLUSIONS: Our findings underscore the positive correlation between the severity of MetS and frailty progression in the middle-aged and elderly, highlighting the urgent need for early identification of MetS and targeted interventions to reduce the risk of frailty.

Longitudinal relationship between weight-adjusted waist index and depressive symptoms in middle-aged and older Chinese adults: A prospective cohort study.

BACKGROUND: The association between obesity and depressive symptoms remains controversial. The Weight-adjusted waist index (WWI) shows advantages in assessing central obesity. This study aimed to investigate the longitudinal relationship between WWI and depressive symptoms. METHOD: This prospective cohort study utilized data from the China Health and Retirement Longitudinal Study (CHARLS) spanning 2011-2020. Depressive symptoms were assessed using the 10-item Center for Epidemiological Studies Depressive Symptoms Scale (CESD-10) scores. Linear mixed models were used to examine longitudinal associations. RESULTS: A total of 6835 participants over the age of 45 were included. WWI was positively associated with CESD-10 scores (ß per 1 SD increase = 0.052SD; 95%CI: 0.021 to 0.083SD) and was linked to a faster increase in CESD-10 scores over time (ß = 0.095SD/year; 95%CI: 0.090 to 0.100 SD/year). Conversely, BMI was negatively associated with CESD-10 scores (ß per 1 SD increase = -0.067SD; 95%CI: -0.097 to -0.038SD). However, the negative association between BMI and CESD-10 scores weakened over time (ß per 1 SD increase = 0.008SD/y; 95%CI: 0.003 to 0.013 SD/y). Nonlinear associations were detected between both WWI and BMI with CESD-10 scores. LIMITATIONS: Self-reported depressive symptoms assessments may have introduced information bias. The observational design limits ruling out unobserved confounding factors. CONCLUSIONS: Our findings highlight the association between WWI and the long-term progression of depressive symptoms in middle-aged and older adults. WWI may enhance our understanding of the link between obesity and depressive symptoms and could be superior to BMI in predicting depressive symptom progression.

Retinal organoids and microfluidic chip-based approaches to explore the retinitis pigmentosa with USH2A mutations.

Retinitis pigmentosa (RP) is a leading cause of vision impairment and blindness worldwide, with limited medical treatment options. USH2A mutations are one of the most common causes of non-syndromic RP. In this study, we developed retinal organoids (ROs) and retinal pigment epithelium (RPE) cells from induced pluripotent stem cells (iPSCs) of RP patient to establish a sustainable in vitro RP disease model. RT-qPCR, western blot, and immunofluorescent staining assessments showed that USH2A mutations induced apoptosis of iPSCs and ROs, and deficiency of the extracellular matrix (ECM) components. Transcriptomics and proteomics findings suggested that abnormal ECM-receptor interactions could result in apoptosis of ROs with USH2A mutations via the PI3K-Akt pathway. To optimize the culture conditions of ROs, we fabricated a microfluidic chip to co-culture the ROs with RPE cells. Our results showed that this perfusion system could efficiently improve the survival rate of ROs. Further, ECM components such as laminin and collagen IV of ROs in the RP group were upregulated compared with those maintained in static culture. These findings illustrate the potential of microfluidic chip combined with ROs technology in disease modelling for RP.

Muse cell spheroids have therapeutic effect on corneal scarring wound in mice and tree shrews.

Stem cell therapy holds promises for treating corneal scarring. Here, we use multilineage-differentiating stress-enduring (Muse) cells to study their differentiation and therapeutic potential for treating corneal injury. Muse cells were isolated from lipoaspirate, which presented biphenotype properties of both pluripotent stem cells and some mesenchymal stem cells. Muse cells expanded by about 100-fold from the initial seeding cell number to Muse spheroids with the maintenance of the Muse cell phenotype and high cell viability at 33 days by static spheroid culture. We revealed that Muse spheroids were activated by the dynamic rotary cell culture system (RCCS), as characterized by increased stemness, improved activity, and enhanced adherence. Gene and protein expression of the pluripotent markers OCT3/4, SOX2, and NANOG and of the proliferation marker KI67 in Muse spheroids cultured under RCCS were higher than those in the static group. These activated Muse spheroids enabled ready differentiation into corneal stromal cells (CSCs) expressing characteristic marker genes and proteins. Furthermore, implantation of Muse cells-differentiated CSCs (Muse-CSCs) laden assembled with two orthogonally stacked stretched compressed collagen (cell-SCC) in mouse and tree shrew wounded corneas prevented the formation of corneal scarring, increased corneal re-epithelialization and nerve regrowth, and reduced the severity of corneal inflammation and neovascularization. cell-SCC retained the capacity to suppress corneal scarring after long-distance cryopreserved transport. Thus, Muse cell therapy is a promising avenue for developing therapeutics for treating corneal scarring.

Protective effects of human iPS-derived retinal pigmented epithelial cells on retinal degenerative disease.

BACKGROUND: Retinitis pigmentosa (RP) is an inherited retinal disease characterized by progressive loss of photoreceptor cells. This study aim at exploring the effect of retinal pigment epithelium (RPE) derived from human-induced pluripotent stem cell (hiPSC-RPE) on the retina of retinal degeneration 10 (rd10) mice, which are characterized with progressive photoreceptor death. METHODS: We generated RPE from hiPSCs by sequential supplementation with retinal-inducing factors and RPE specification signaling factors. The three-dimensional (3D) spheroid culture method was used to obtain optimal injectable hiPSC-RPE cells. Subretinal space transplantation was conducted to deliver hiPSC-RPE cells into the retina of rd10 mice. Neurotrophic factor secretion from transplanted hiPSC-RPE cells was detected by enzyme-linked immunosorbent assay (ELISA). Immunostaining, Western blotting, electroretinography (ERG), and visual behavior testing were performed to determine the effects of hiPSC-RPE on the retinal visual function in rd10 mice. RESULTS: Our data demonstrated that hiPSC-RPE cells exhibited classic RPE properties and phenotype after the sequential RPE induction from hiPSCs. hiPSC-RPE cells co-cultured with mouse retinal explants or retinal ganglion cells 5 (RGC5) exhibited decreased apoptosis. The viability and functional properties of hiPSC-RPE cells were enhanced by 3D spheroid culture. Transplanted hiPSC-derived RPE cells were identified by immunostaining with human nuclear antigen staining in the retina of rd10 14 days after subretinal space injection. The pigment epithelium-derived factor level was increased significantly. The expression of CD68, microglial activation marker, reduced after transplantation. The light avoidance behavior and ERG visual function in rd10 mice improved by the transplantation of hiPSC-RPE cells. CONCLUSION: Our findings suggest that injectable hiPSC-RPE cells after 3D spheroid culture can rescue the structure and function of photoreceptors by sub-retinal transplantation, which lay the foundation for future clinical cell therapy to treat RP and other retinal degeneration diseases.

Modeling Retinitis Pigmentosa: Retinal Organoids Generated From the iPSCs of a Patient With the USH2A Mutation Show Early Developmental Abnormalities.

Retinitis pigmentosa (RP) represents a group of inherited retinopathies with early-onset nyctalopia followed by progressive photoreceptor degeneration causing irreversible vision loss. Mutations in USH2A are the most common cause of non-syndromic RP. Here, we reprogrammed induced pluripotent stem cells (iPSCs) from a RP patient with a mutation in USH2A (c.8559-2A > G/c.9127_9129delTCC). Then, multilayer retinal organoids including neural retina (NR) and retinal pigment epithelium (RPE) were generated by three-step "induction-reversal culture." The early retinal organoids derived from the RP patient with the USH2A mutation exhibited significant defects in terms of morphology, immunofluorescence staining and transcriptional profiling. To the best of our knowledge, the pathogenic mutation (c.9127_9129delTCC) in USH2A has not been reported previously among RP patients. Notably, the expression of laminin in the USH2A mutation organoids was significantly lower than in the iPSCs derived from healthy, age- and sex-matched controls during the retinal organogenesis. We also observed that abnormal retinal neuroepithelium differentiation and polarization caused defective retinal progenitor cell development and retinal layer formation, disordered organization of NRs in the presence of the USH2A mutation. Furthermore, the USH2A mutation bearing RPE cells presented abnormal morphology, lacking pigmented foci and showing an apoptotic trend and reduced expression of specific makers, such as MITF, PEDF, and RPE65. In addition, the USH2A mutation organoids had lower expression of cilium-associated (especially CFAP43, PIFO) and dopaminergic synapse-related genes (including DLGAP1, GRIK1, SLC17A7, and SLC17A8), while there was higher expression of neuron apoptotic process-related genes (especially HIF1A, ADARB1, and CASP3). This study may provide essential assistance in the molecular diagnosis and screening of RP. This work recapitulates the pathogenesis of USH2A using patient-specific organoids and demonstrated that alterations in USH2A function due to mutations may lead to cellular and molecular abnormalities.