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MiR-653-5p drives osteoarthritis pathogenesis by modulating chondrocyte senescence
Background
Due to the unclear pathogenesis of osteoarthritis (OA), effective treatment for this ailment is presently unavailable. Accumulating evidence points to chondrocyte senescence as a key driver in OA development. This study aims to identify OA-specific microRNAs (miRNAs) targeting chondrocyte senescence to alleviate OA progression.
Methods
We screened and identified miRNAs differentially expressed in OA and normal cartilage, then confirmed the impact of miR-653-5p on chondrocyte functions and senescence phenotypes through in vitro experiments with overexpression/silencing. We identified interleukin 6 (IL-6) as the target gene of miR-653-5p and confirmed the regulatory influence of miR-653-5p on the IL-6/JAK/STAT3 signaling pathway through gain/loss-of-function studies. Finally, we assessed the therapeutic efficacy of miR-653-5p on OA using a mouse model with destabilization of the medial meniscus.
Results
MiR-653-5p was significantly downregulated in cartilage tissues and chondrocytes from OA patients. Overexpression of miR-653-5p promoted chondrocyte matrix synthesis and proliferation while inhibiting chondrocyte senescence. Furthermore, bioinformatics target prediction and the luciferase reporter assays identified IL-6 as a target of miR-653-5p. Western blot assays demonstrated that miR-653-5p overexpression inhibited the protein expression of IL-6, the phosphorylation of JAK1 and STAT3, and the expression of chondrocyte senescence phenotypes by regulating the IL-6/JAK/STAT3 signaling pathway. More importantly, the cartilage destruction was significantly alleviated and chondrocyte senescence phenotypes were remarkably decreased in the OA mouse model treated by agomiR-653-5p compared to the control mice.
Conclusions
MiR-653-5p showed a significant decrease in cartilage tissues of individuals with OA, leading to an upregulation of chondrocyte senescence phenotypes in the articular cartilage. AgomiR-653-5p emerges as a potential treatment approach for OA. These findings provide further insight into the role of miR-653-5p in chondrocyte senescence and the pathogenesis of OA.
Journal Article
Historical dictionary of the Chinese environment
\"Historical Dictionary of the Chinese Environment contains a chronology, an introduction, appendixes, and an extensive bibliography. The dictionary section has over 200 cross-referenced entries on environmental degradation including air and water pollution, deforestation, desertification, and resource depletion\"-- Provided by publisher.
Book
Stigma in People With Type 1 or Type 2 Diabetes
This study quantitatively measures diabetes stigma and its associated psychosocial impact in a large population of U.S. patients with type 1 or type 2 diabetes using an online survey sent to 12,000 people with diabetes. A majority of respondents with type 1 (76%) or type 2 (52%) diabetes reported that diabetes comes with stigma. Perceptions of stigma were significantly higher among respondents with type 1 diabetes than among those with type 2 diabetes, with the highest rate in parents of children with type 1 diabetes (83%) and the lowest rate in people with type 2 diabetes who did not use insulin (49%). Our results suggest that a disturbingly high percentage of people with diabetes experience stigma, particularly those with type 1 or type 2 diabetes who are on intensive insulin therapy. The experience of stigma disproportionately affects those with a higher BMI, higher A1C, and poorer self-reported blood glucose control, suggesting that those who need the most help are also the most affected by stigma.
Journal Article
Historical dictionary of Chinese culture
\"Covering wide-ranging topics including the arts and entertainment along with customs and traditions from the ancient imperial and modern eras, the Historical Dictionary of Chinese Culture provides more than 300 separate entries along with a comprehensive Chronology, Glossary of Chinese cultural terms, and extensive Bibliography of Western and Chinese language sources\"-- Provided by publisher.
Book
STAT3 promotes a youthful epigenetic state in articular chondrocytes
Epigenetic mechanisms guiding articular cartilage regeneration and age‐related disease such as osteoarthritis (OA) are poorly understood. STAT3 is a critical age‐patterned transcription factor highly active in fetal and OA chondrocytes, but the context‐specific role of STAT3 in regulating the epigenome of cartilage cells remain elusive. In this study, DNA methylation profiling was performed across human chondrocyte ontogeny to build an epigenetic clock and establish an association between CpG methylation and human chondrocyte age. Exposure of adult chondrocytes to a small molecule STAT3 agonist decreased DNA methylation, while genetic ablation of STAT3 in fetal chondrocytes induced global hypermethylation. CUT&RUN assay and subsequent transcriptional validation revealed DNA methyltransferase 3 beta (DNMT3B) as one of the putative STAT3 targets in chondrocyte development and OA. Functional assessment of human OA chondrocytes showed the acquisition of progenitor‐like immature phenotype by a significant subset of cells. Finally, conditional deletion of Stat3 in cartilage cells increased DNMT3B expression in articular chondrocytes in the knee joint in vivo and resulted in a more prominent OA progression in a post‐traumatic OA (PTOA) mouse model induced by destabilization of the medial meniscus (DMM). Taken together these data reveal a novel role for STAT3 in regulating DNA methylation in cartilage development and disease. Our findings also suggest that elevated levels of active STAT3 in OA chondrocytes may indicate an intrinsic attempt of the tissue to regenerate by promoting a progenitor‐like phenotype. However, it is likely that chronic activation of this pathway, induced by IL‐6 cytokines, is detrimental and leads to tissue degeneration. This study uncovers a context‐specific role of STAT3 in regulating chondrocyte development and disease suggesting that activation of STAT3 signaling may reduce epigenetic age by decreasing DNA methylation in adult cells and may be part of the regenerative mechanism induced by inflammatory processes. The novel DNA methylation‐based epigenetic clock developed will help researchers to capture pivotal aspects of biological age in adult chondrocytes. Finally, conditional deletion of Stat3 in cartilage cells resulted in a more prominent OA progression in a post‐traumatic osteoarthritic mouse model.
Journal Article
Historical dictionary of science and technology in modern China (Historical dictionaries of Asia, Oceania, and the Middle East)
The Historical Dictionary of Science and Technology in Modern China provides the most up-to-date information on science and technology in China from the late nineteenth century to the present. Special attention is given to the historical factors, scientists, and historical figures behind each scientific development. In particular, this book pays attention to the scientists who were persecuted to death or tortured during the Cultural Revolution (1966-1976), and whose scientific research was therefore tragically cut short. The historical dictionary provides information on science and technology in China from the late nineteenth century to the present including: a chronology;introduction; extensive bibliography;over 700 cross-referenced dictionary entries on major scientific and technological fields and sub-fields; entries on western scholars and educators who also impacted scientific achievements in China. This book is an excellent access point for students, researchers, and anyone wanting to know more about the science and technology in China.
eBook
In vitro behavior of tendon stem/progenitor cells on bioactive electrospun nanofiber membranes for tendon-bone tissue engineering applications
In order to accelerate the tendon-bone healing processes and achieve the efficient osteointegration between the tendon graft and bone tunnel, we aim to design bioactive electrospun nanofiber membranes combined with tendon stem/progenitor cells (TSPCs) to promote osteogenic regeneration of the tendon and bone interface.
In this study, nanofiber membranes of polycaprolactone (PCL), PCL/collagen I (COL-1) hybrid nanofiber membranes, poly(dopamine) (PDA)-coated PCL nanofiber membranes and PDA-coated PCL/COL-1 hybrid nanofiber membranes were successfully fabricated by electrospinning. The biochemical characteristics and nanofibrous morphology of the membranes, as well as the characterization of rat TSPCs, were defined in vitro. After co-culture with different types of electrospun nanofiber membranes in vitro, cell proliferation, viability, adhesion and osteogenic differentiation of TSPCs were evaluated at different time points.
Among all the membranes, the performance of the PCL/COL-1 (volume ratio: 2:1 v/v) group was superior in terms of its ability to support the adhesion, proliferation, and osteogenic differentiation of TSPCs. No benefit was found in this study to include PDA coating on cell adhesion, proliferation and osteogenic differentiation of TSPCs.
The PCL/COL-1 hybrid electrospun nanofiber membranes are biocompatible, biomimetic, easily fabricated, and are capable of supporting cell adhesion, proliferation, and osteogenic differentiation of TSPCs. These bioactive electrospun nanofiber membranes may act as a suitable functional biomimetic scaffold in tendon-bone tissue engineering applications to enhance tendon-bone healing abilities.
Journal Article
Pharmacological inactivation of a non-canonical gp130 signaling arm attenuates chronic systemic inflammation and multimorbidity induced by a high-fat diet
Interleukin-6 (IL-6) is a major pro-inflammatory cytokine that demonstrates a robust correlation with age and body mass index (BMI) as part of the senescence-associated secretory phenotype. IL-6 cytokines also play a crucial role in metabolic homeostasis and regenerative processes primarily via the canonical STAT3 pathway. Thus, selective modulation of IL-6 signaling may offer a unique opportunity for therapeutic interventions. Our recent studies identified a novel non-canonical signaling pathway that involves prolonged activation of SRC family of kinases (SFKs) by IL-6/gp130, where genetic or pharmacological inhibition of this pathway was protective in several acute injury models. This study was designed to assess the effect of a small molecule (R159) that inhibits the non-canonical signaling in a mouse model of multimorbidity induced by chronic inflammation. Aged mice were fed a high-fat diet (HFD) to exacerbate chronic inflammation and inflammaging-related conditions, and R159 significantly decreased systemic inflammatory responses in adipose tissue and liver. R159 was protective against trabecular bone and articular cartilage loss and markedly prevented neurogenesis decline. Moreover, R159 reduced weight gain induced by HFD and increased physical activity levels. These findings suggest that selective pharmacological inhibition of SFK signaling downstream of IL6/gp130 offers a promising strategy to alleviate systemic chronic inflammation and relevant multimorbidity.
Journal Article
Mental health problems among hotline callers during the early stage of COVID-19 pandemic
The study aims to explore the mental health of the hotline callers during the COVID-19 pandemic in China.
Callers (
= 10,490) from the Beijing Psychological Support Hotline from January 21st to June 30th in 2019 and 2020 were enrolled and divided into two groups (during (2020) and before (2019) COVID-19 pandemic). The severity of depressive symptoms, psychological distress, hopefulness, and suicidal ideation (SI) was assessed. Demographic characteristics and major concerns were also collected. Mann-Whitney U and chi-square test were used to compare the differences in mental health conditions and major concerns between two years and between different age groups. The multivariable logistic regression was used to explore whether mental health conditions were associated with pandemic and demographic factors.
Results from multivariable logistic regression analysis indicated that the change in suicidal ideation (OR = 1.52, 95% CI: 1.21-1.92) was significantly different across age groups. Callers during the pandemic reported a higher level of hopefulness (OR = 1.13, 95% CI [1.03-1.24]), a lower level of depressive symptoms (OR = 0.81, 95% CI [0.74-0.89]) and psychological distress (OR = 0.89, 95% CI [0.81-0.98]), and were less likely to report SI (OR = 0.69, 95% CI [0.61-0.77]) compared with callers before the pandemic.
Compared with callers before the pandemic, hotline callers during the early stage of COVID-19 pandemic did not present significant mental health problems. Younger callers during the pandemic were more vulnerable for the presence of suicidal ideation. Hotline-based crisis interventions might provide specific psychological support to cope with troubles during the pandemic.
Journal Article