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As the most abundant internal mRNA modification, N6-methyladenosine (m6A) RNA methylation has been found to influence many biological events including bone mesenchymal stem cells (BMSCs) osteogenic differentiation. YTH N6-methyladenosine RNA binding protein C2 （YTHDC2） is an m6A reading protein with the ability to mediate the decay of combined methylated mRNA, however its role in BMSCs osteogenic differentiation remains unknown. In this study, we first found an increase of RUNX family transcription factor 2 （RUNX2） expression and a decrease of YTHDC2 expression during the process of BMSCs osteogenic differentiation. Furthermore, we transfected BMSCs with YTHDC2 interference fragment, resulting in an increased content of RUNX2 mRNA and protein inside BMSCs. Finally, through RNA Immunoprecipitation experiments, we confirmed that YTHDC2 protein can bind to RUNX2 mRNA and accelerate its decomposition. Moreover, the immunofluorescence staining also showed a negative correlation between YTHDC2 and RUNX2. In conclusion, during BMSCs osteogenic differentiation, YTHDC2 protein showed decreased expression, resulting in a higher level of RUNX2 (mRNA and protein) expression inside cells, indicating YTHDC2 as a promising molecular target for the regulation of BMSCs osteogenic differentiation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Introduction: Data from acute ischemic stroke patients throughout 2021 from one district of an archipelago city of China were collected and analyzed retrospectively to determine the management difference due to time lags from onset of symptoms to the arrival at the stroke center (FMCT) of two regions: main island (MI) and outer islets (OIs)., Methods: All patients information from 1 January to 31 December 2021 was retrieved through the electronic medical records system of the only stroke center in MI. After screening and exclusion, each patient's medical record was reviewed by two neurologists separately. Before OI patients were allocated to a group, their residential addresses at onset of the stroke were confirmed by telephone. Comparisons were analyzed between the two regions for gender, age, pre-stroke risk factors and peri-admission management parameters., Results: A total of 326 patients met the inclusion criteria: 300 from the MI group and 26 for the OI group. Intergroup comparisons for gender, age and most of the risk factors showed no significant difference. FMCT were shown to be significantly distinct (p<0.001). Hospitalization expenses also showed significant difference. The odds ratio of the definite treatment IV thrombolysis was 0.131 (OI group to MI group range: 0.017-0.987, p=0.021)., Conclusion: The diagnosis and treatment of acute ischemic stroke patients from OIs was significantly postponed compared to those from MI. Therefore, new effective and efficient solutions are urgently needed.

Background: Evidence indicates that chronic stress promotes progression of colorectal liver metastases (CLM). Mangiferin is the active chemical constituent of the rhizomes of Anemarrhena asphodeloides Bunge . Mangiferin (MGF) exerts anti-inflammatory, anti-proliferative, anti-angiogenic, anti-fibrotic and antioxidant effects in a variety of cancers. Its mechanism in chronic stress and tumor growth is still poorly understood., Methods: To investigate the effects of MGF on the CLM and tumor-associated depression, activated hepatic stellate cells (a-HSCs), HT-29 CRC cells, were used in chronic unpredictable mild stress (CUMS) of tumor-bearing models. Potential antidepressant activity was determined by FST, TST, SIT and serum cytokine (IL-6, IL-18 and TNF-α) examination. Downstream signaling molecules were detected by Western blot, immunohistochemistry and fluorescence microscopy., Results: CUMS induced depression behavior and depression-related cytokines and promoted tumor growth in CLM. MGF-treated mice significantly improved chronic stress behaviors by reducing depression-related cytokines. In addition, MGF treatment inhibits WAVE2 signaling pathway, leading to TGF-β1 induced HSC inhibition, thereby reducing depressive behavior and tumor growth in CLM., Conclusion: MGF can alleviate CUMS induced tumor growth and the treatment of CLM patients with MGF may be beneficial., Competing Interests: The authors declare no competing interests., (© 2023 The Authors. Published by Elsevier Ltd.)

Reprogramming lipid metabolism is considered a fundamental step in tumourigenesis that influences ferroptosis. However, molecular mechanisms between lipid metabolism and ferroptosis remain largely unknown. Results from the drug screening of 464 inhibitors (for 164 targets) applied to ferroptosis cells indicated that 4 inhibitors targeted bromodomain-containing protein 4 (BRD4) significantly inhibiting erastin-induced ferroptosis. Functional studies proved that the loss of BRD4 weakened oxidative catabolism in mitochondria, protecting cells from the excessive accumulation of lipid peroxides. Mechanism research revealed that the transcriptional levels of fatty acid metabolism-related genes (HADH, ACSL1 and ACAA2) participating in the β-oxidation of fatty acids (FAO) and polyunsaturated fatty acids (PUFAs) synthesis depended on the activity of super-enhancers (SEs) formed by BRD4 and HMGB2 in their promoter regions. Conclusively, this study demonstrated that BRD4 was indispensable for fatty acid metabolism based on its epigenetic regulatory mechanisms and affecting erastin-induced ferroptosis, providing a new theoretical reference for understanding the relationship between lipid metabolism and ferroptosis deeply., (© 2022. The Author(s).)

Background: Extended curettage has increasingly become the preferred treatment for giant cell tumour of bone (GCTB), but the high recurrence rate after curettage poses a major challenge for orthopaedic surgeons. Computed tomography (CT) is valuable in the evaluation of GCTB. Our aim was to identify specific features of GCTB around the knee in pre-operative CT images that might have prognostic value for local recurrence., Methods: We retrospectively analyzed data from 124 patients with primary GCTB around the knee who underwent extended curettage from 2010 through 2019. We collected demographic, clinical, and therapeutic data along with several CT-derived tumour characteristics. CT-derived tumor characteristics included tumour size, the distance between the tumour edge and articular surface (DTA), and destruction of posterior cortical bone (DPC). Akaike information criterion (AIC) was used to select which variables to enter into multivariate logistic regression models and to determine significant factors affecting recurrence., Results: The total recurrence rate was 21.0% (26/124), and the average follow-up time was 69.5 ± 31.2 months (24-127 months). Age, DTA (< 2 mm), and DPC were significantly related to recurrence, as determined by multivariate logistic regression. The C-index of the final model was 0.79 (95% CI: 0.71 to 0.88), representing a good model for predicting recurrence., Conclusion: Identifying certain features of GCTB around the knee on CT has prognostic value for patients treated with extended curettage. A three-factor model predicts tumour recurrence well after extended curettage., (© 2021. The Author(s).)

Background: The Coronavirus Disease 2019 (COVID-19) pandemic has rapidly spread across the whole world and brought strong psychological impact. This study aimed to evaluate the prevalence of post-traumatic stress disorders (PTSD) in the general people of southwestern China and associated factors 1 month after the outbreak of the COVID-19., Methods: This study was started on 4-10 Feb 2020 based on online survey. The present work was carried out in the provinces of southeastern China, including Sichuan Province, Guizhou Province, Yunnan Province, and Chongqing City.1593 respondents aged 18 years and above administered to this study. Data on whether they have experienced confirmed or suspected COVID-19 of themselves/family members/acquaintances were also collected, and based on 'yes' answers, the number of affected individuals (via COVID-19) were categorized into four exposure levels i.e., non-affected, less, moderately, or significantly affected. The civilian version of the PTSD checklist and the self-reported information about COVID-19 were used., Results: The prevalence of PTSD was approximately 25.2%(n = 401/1593). The chances of developing PTSD were 6.053(OR = 6.053, 95% CI 1.394 to 26.280) or 3.673(OR = 3.673, 95% CI 1.738 to 7.765) times higher among respondents who had been significantly and moderately affected than those who had not been affected, accordingly. Male (OR = 1.484, 95% CI 1.147 to 1.920),younger age individuals (40 ~ 49 age group/<30 age group, OR = 0.395, 95% CI 0.258 to 0.606) and health care workers (OR = 1.788, 95% CI 1.155 to 2.277) were at higher risk of developing PTSD., Conclusion: Our findings highlight that a positive correlation between the pandemic and PTSD. It is urgent to establish a screening and prevention systems for the population who are significantly exposed to COVID-19,and provide different psychological intervention strategies for different groups., (© 2021. The Author(s).)

Glucocorticoid-induced endothelial injury has been reported in several diseases. Although there are several theories, the exact mechanism underlying the role of glucocorticoids in this process remains unclear. Autophagy has been reported to occur as a response to different stimuli and can affect cell survival and function. In this study, we found that glucocorticoids induced apoptosis and endoplasmic reticulum (ER) stress in endotheliocytes. Furthermore, we discovered that glucocorticoids induced autophagy in these cells and the inositol requiring protein 1 (IRE1α)/X-box binding protein 1s (XBP-1s) axis, one of the downstream signaling pathways of ER stress, was associated with the glucocorticoid-induced autophagy. The autophagy partly protected endotheliocytes from glucocorticoid-induced apoptosis and inhibition of proliferation. In conclusion, glucocorticoid-induced endoplasmic reticulum stress activated the IRE1α/XBP-1s signaling and induced autophagy, which, in turn, played a protective role in endotheliocyte survival and proliferation, avoiding further cellular damage caused by glucocorticoids.

Peoral endoscopic myotomy (POEM) has been proved to be safe and effective for treating achalasia, however the presence of esophageal diverticulum would increase the technical difficulty. In this letter, we firstly report a case regarding POEM for achalasia with concomitant multiple esophageal diverticulums.

Background and Aim: Both peroral endoscopic myotomy (POEM) and pneumatic dilation (PD) has proved to be effective for treating achalasia in patients aged ≥ 65 years. However little is known about the comparison between POEM and PD. The aim of the study was to compare the safety and efficacy of POEM and PD for the treatment of achalasia in these patients., Methods: We retrospectively reviewed the medical records of patients aged 65 years-old or more who received POEM or PD for the treatment of achalasia at our hospital from January 2010 to December 2015, they were divided into the POEM group and the PD group. Demographics and data about safety and efficacy were collected retrospectively and compared between the two groups., Results: A total of 31 patients were enrolled, and 21 of them received POEM, while the other 10 received PD. The treatment success (Eckardt score ≤ 3) rate of POEM and PD at 3, 6, 12, 24 and 36 months after the treatment were comparable (p > 0.05). Treatment failure was noticed in 3 cases, 1 of them was in the POEM group and the other 2 in the PD group, there was no significant difference (p > 0.05). Multivariate analysis showed that sigmoid-type achalasia was a predictive factor of treatment failure. No severe complications were observed during operation and periodical follow-up., Conclusion: Short-term and intermediate efficacy of POEM and PD for treating achalasia in patients aged ≥ 65 years was comparable. A large scale, randomized study with long-term follow-up is necessary in order to make a definitive conclusion.

The use of mesenchymal stem cell (MSC) transplantation for ischemic heart disease has been reported for several years. The main mechanisms responsible for the efficacy of this technique include the differentiation of MSCs into cardiomyocytes and endothelial cells, as well as paracrine effects. However, the differentiation rates of MSCs are very low, and the differentiated cells are not mature. In addition, MSCs undergo massive cell death within a few days after transplantation to the ischemic myocardium. Paracrine effects may thus play a major role in MSCs transplantation. Angiotensin II (Ang II) is known to be produced locally in the ischemic myocardium, but the effects of hypoxia on the local renin-angiotensin system (RAS) in MSCs, and the role of the RAS in hypoxia-induced vascular endothelial growth factor (VEGF) secretion remain unknown. In this study, we demonstrated that hypoxia stimulated the local RAS in MSCs, while pretreatment with the Ang II type 1 (AT1) receptor antagonist losartan reduced hypoxia-induced hypoxia-inducible factor 1α (HIF-1α) and VEGF production. The ERK1/2 inhibitor U0126 and the Akt inhibitor LY294002 also inhibited hypoxia-induced HIF-1α and VEGF production. Overall, these results indicate that the local RAS in MSCs regulates hypoxia-induced VEGF production through ERK1/2, Akt and HIF-1α pathways via the AT1 receptor.