A nomogram for predicting adverse pathologic features in low-risk papillary thyroid microcarcinoma.

BACKGROUND: Identifying risk factors for adverse pathologic features in low-risk papillary thyroid microcarcinoma (PTMC) can provide valuable insights into the necessity of surgical or non-surgical treatment. This study aims to develop a nomogram for predicting the probability of adverse pathologic features in low-risk PTMC patients. METHODS: A total of 662 patients with low-risk PTMC who underwent thyroid surgery were retrospectively analyzed in Qilu Hospital of Shandong University from May 2019 to December 2021. Logistic regression analysis was used to determine the risk factors for adverse pathologic features, and a nomogram was constructed based on these factors. RESULTS: Most PTMC patients with these adverse pathologic features had tumor diameters greater than 0.6 cm (p < 0.05). Other factors (age, gender, family history of thyroid cancer, history of autoimmune thyroiditis, and BRAFV600E mutation) had no significant correlation with adverse pathologic features (p > 0.05 each). The nomogram was drawn to provide a quantitative and convenient tool for predicting the risk of adverse pathologic features based on age, gender, family history of thyroid cancer, autoimmune thyroiditis, tumor size, and BRAFV600E mutation in low-risk PTMC patients. The areas under curves (AUC) were 0.645 (95% CI 0.580-0.702). Additionally, decision curve analysis (DCA) and calibration curves were used to evaluate the clinical benefits of this nomogram, presenting a high net benefit. CONCLUSION: Tumor size > 0.60 cm was identified as an independent risk factor for adverse pathologic features in low-risk PTMC patients. The nomogram had a high predictive value and consistency based on these factors.

Lifestyle behaviors and risk of cardiovascular disease and prognosis among individuals with cardiovascular disease: a systematic review and meta-analysis of 71 prospective cohort studies.

BACKGROUND: Healthy lifestyle behaviors (LBs) have been widely recommended for the prevention and management of cardiovascular disease (CVD). Despite a large number of studies exploring the association between combined LBs and CVD, a notable gap exists in integration of relevant literatures. We conducted a systematic review and meta-analysis of prospective cohort studies to analyze the correlation between combined LBs and the occurrence of CVD, as well as to estimate the risk of various health complications in individuals already diagnosed with CVD. METHODS: Articles published up to February 10, 2023 were sourced through PubMed, EMBASE and Web of Science. Eligible prospective cohort studies that reported the relations of combined LBs with pre-determined outcomes were included. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated using either a fixed or random-effects model. Subgroup analysis, meta-regression, publication bias, and sensitivity analysis were as well performed. RESULTS: In the general population, individuals with the healthiest combination of LBs exhibited a significant risk reduction of 58% for CVD and 55% for CVD mortality. For individuals diagnosed with CVD, adherence to the healthiest combination of LBs corresponded to a significant risk reduction of 62% for CVD recurrence and 67% for all-cause mortality, when compared to those with the least-healthy combination of LBs. In the analysis of dose-response relationship, for each increment of 1 healthy LB, there was a corresponding decrease in risk of 17% for CVD and 19% for CVD mortality within the general population. Similarly, among individuals diagnosed with CVD, each additional healthy LB was associated with a risk reduction of 27% for CVD recurrence and 27% for all-cause mortality. CONCLUSIONS: Adopting healthy LBs is associated with substantial risk reduction in CVD, CVD mortality, and adverse outcomes among individuals diagnosed with CVD. Rather than focusing solely on individual healthy LB, it is advisable to advocate for the adoption of multiple LBs for the prevention and management of CVD. TRIAL REGISTRATION: PROSPERO: CRD42023431731.

Exosomes derived from mesenchymal stem cells attenuate diabetic kidney disease by inhibiting cell apoptosis and epithelial-to-mesenchymal transition via miR-424-5p.

Diabetic kidney disease (DKD) is well-acknowledged as one of the most common complications in diabetes mellitus. Recent studies have demonstrated the promising role of mesenchymal stem cell-derived exosomes (MSC-exos) as a cell-free treatment strategy for DKD. The present study sought to investigate the therapeutic potential and the underlying mechanisms of MSC-exos in DKD. The authentication of MSC-exos was validated by western blot, transmission electron microscope (TEM), and nanosight tracking analysis (NTA). Apoptosis was detected by western blot, TUNEL staining, and flow cytometry. Epithelial-to-mesenchymal transition (EMT) was evaluated by western blot and immunofluorescence. The relationship between miR-424-5p and Yes-associated protein 1 (YAP1) was revealed by dual luciferase reporter assay. We observed that MSC-exos could attenuate DKD by decreasing cell apoptosis and inhibiting epithelial-to-mesenchymal transition (EMT) in diabetic kidneys in db/db mice. Besides, we documented that MSC-exos could reverse high glucose-induced apoptosis and EMT in HK2 cells. Interestingly, miR-424-5p derived from MSC-exos could inhibit YAP1 activation in HK2 cells, resulting in alleviation of high glucose-induced cell apoptosis and EMT. Our study provides novel insights into MSC-exos-mediated protective effect in DKD. MSC-exos could inhibit high glucose-induced apoptosis and EMT through miR-424-5p targeting of YAP1.

cGAS-STING mediates cytoplasmic mitochondrial-DNA-induced inflammatory signal transduction during accelerated senescence of pancreatic ß-cells induced by metabolic stress.

Type 2 diabetes mellitus (T2DM) is an age-related disease characterized by impaired pancreatic ß cell function and insulin resistance. Recent studies have shown that the accumulation of senescent ß cells under metabolic stress conditions leads to the progression of T2DM, while senolysis can improve the prognosis. However, the specific mechanism of ß cell senescence is still unclear. In this study, we found that the increased load of senescence pancreatic ß cells in both older mice and obese mice induced by high-fat diet (HFD) (DIO mice) was accompanied by activation of the Cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) pathway and using cGAS or STING small interfering RNA or STING inhibitor C176 to downregulate this pathway reduced the senescence-associated secretion profile (SASP) and senescence of Min6 cells treated with palmitic acid or hydrogen peroxide. C176 intervention in DIO mice also significantly reduced the inflammation and senescence of the islets, thereby protecting the function of pancreatic ß cell and glucose metabolism. Our study further revealed that mitochondrial DNA (mtDNA) leakage under metabolic stress conditions was critical for the activation of the cGAS-STING pathway, which can be reversed by the mtDNA depleting agent ethidium bromide. Consistently, mtDNA leakage was more severe in older mice and was accelerated by a chronic HFD. In conclusion, we demonstrate that cytoplasmic mtDNA activates the cGAS-STING pathway to mediate SASP during the accelerated senescence of pancreatic ß-cells induced by metabolic stress, and this process can be downregulated by the STING inhibitor C176.

Mesenchymal stem cell-conditioned medium improved mitochondrial function and alleviated inflammation and apoptosis in non-alcoholic fatty liver disease by regulating SIRT1.

Non-alcoholic fatty liver disease (NAFLD), an emerging risk factor for diabetes, is now recognized as the most common liver disease worldwide. Mesenchymal stem cells (MSCs), a promising tool in regenerative medicine, release abundant molecules into the conditioned medium (CM). Increasing evidence showed that MSC-CM is beneficial for diabetes-associated NAFLD. However, the mechanism of how MSC-CM improves NAFLD remains uncertain. In this study, to determine the effects of MSC-CM on NAFLD, streptozotocin (STZ) and high-fat diet (HFD) induced T2DM mice model and palmitic acid (PA)-stimulated L-O2 cells were used and treated with MSC-CM. Our results demonstrated that MSC-CM improved insulin resistance in diabetic mice, amended the pathological structure of the liver, enhanced the liver's total antioxidant capacity and mitochondrial function, reduced inflammation and cell apoptosis. We further verified that SIRT1 played a key role in mediating the protective effect of MSC-CM. These findings provide novel evidence that MSC-CM has the potential to treat T2DM patients with NAFLD clinically.

Aldosterone induced up-expression of ICAM-1 and ET-1 in pancreatic islet endothelium may associate with progression of T2D.

Previous studies have demonstrated that excess aldosterone impairs glucose metabolism. However, the underlying mechanism is still misty. Aldosterone has been proved a risk factor of fibrosis and inflammation. And the histology of islets from patients with type 2 diabetes (T2D) also displays inflammation and fibrosis. But it is unclear whether aldosterone has direct impact on islet inflammation and fibrosis in T2D. Islet endothelium plays a significant role in the maintenance of islet beta cell function and has a close relationship with islet fibrosis and inflammation. Therefore, we focused on the effect of aldosterone on the islet endothelium. In this study, we utilized a diabetic db/db mouse model and examined serum aldosterone levels, islet macrophages infiltration, and islet fibrosis. After we confirmed that there was an increased expression of intercellular cell adhesion molecule-1 (ICAM-1) and endothelin-1 (ET-1) in islet of diabetic mice compared with wild type mice. We next determined that aldosterone increased expression of ICAM-1 and ET-1 in both mRNA and protein levels in islet endothelium in vitro. And then we tested the expression of mineralocorticoid receptor (MR) in islet endothelium in vitro and in vivo. Our results showed that aldosterone can up-regulate the expression levels of ICAM-1 and ET-1 through MR. These findings suggest excess aldosterone might participate in islet inflammation and fibrosis in T2D.

Mesenchymal stromal cells ameliorate mitochondrial dysfunction in α cells and hyperglucagonemia in type 2 diabetes via SIRT1/FoxO3a signaling.

Dysregulation of α cells results in hyperglycemia and hyperglucagonemia in type 2 diabetes mellitus (T2DM). Mesenchymal stromal cell (MSC)-based therapy increases oxygen consumption of islets and enhances insulin secretion. However, the underlying mechanism for the protective role of MSCs in α-cell mitochondrial dysfunction remains unclear. Here, human umbilical cord MSCs (hucMSCs) were used to treat 2 kinds of T2DM mice and αTC1-6 cells to explore the role of hucMSCs in improving α-cell mitochondrial dysfunction and hyperglucagonemia. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay (ELISA). Mitochondrial function of α cells was assessed by the Seahorse Analyzer. To investigate the underlying mechanisms, Sirtuin 1 (SIRT1), Forkhead box O3a (FoxO3a), glucose transporter type1 (GLUT1), and glucokinase (GCK) were assessed by Western blotting analysis. In vivo, hucMSC infusion improved glucose and insulin tolerance, as well as hyperglycemia and hyperglucagonemia in T2DM mice. Meanwhile, hucMSC intervention rescued the islet structure and decreased α- to ß-cell ratio. Glucagon secretion from αTC1-6 cells was consistently inhibited by hucMSCs in vitro. Meanwhile, hucMSC treatment activated intracellular SIRT1/FoxO3a signaling, promoted glucose uptake and activation, alleviated mitochondrial dysfunction, and enhanced ATP production. However, transfection of SIRT1 small interfering RNA (siRNA) or the application of SIRT1 inhibitor EX-527 weakened the therapeutic effects of hucMSCs on mitochondrial function and glucagon secretion. Our observations indicate that hucMSCs mitigate mitochondrial dysfunction and glucagon hypersecretion of α cells in T2DM via SIRT1/FoxO3a signaling, which provides novel evidence demonstrating the potential for hucMSCs in treating T2DM.

Temporal changes in factors associated with COVID-19 vaccine hesitancy among Chinese adults: Repeated nationally representative survey.

Background: COVID-19 vaccine hesitancy has been cited as one of the main obstacles impacting vaccine coverage. However, factors that affect hesitancy may change over time. Understanding these evolving concerns and adapting strategies accordingly are crucial for effectively addressing vaccine hesitancy effectively and promoting public health. We aimed to explore the temporal changes in factors associated with COVID-19 VH during the COVID-19 pandemic and assess the dynamic evolution of VH. Methods: In August 2022 and February 2023, repeated online surveys were undertaken to collect information from 5378 adults across four regions of China. Multiple linear regression models assessed the influencing factors of COVID-19 VH. The association between protective motive theory (PMT) (perceived severity, susceptibility, benefits, barriers, and self-efficacy) and VH was evaluated by structural equation modeling (SEM). Results: Repeated measures showed that 573 (10.7%) and 1598 (29.7%) of the 5378 participants reported COVID-19 VH in the baseline and follow-up surveys, respectively. Educational levels, chronic disease, history of allergy, COVID-19 infection, and trust in medical staff and vaccine developers were positively associated with COVID-19 VH (P＜0.05). The application of SEM revealed that perceived severity, susceptibility, vaccination barriers, and self-efficacy in the PMT directly impacted on VH (P＜0.05). In addition, severity, susceptibility, benefits, and barriers had a significant direct effect on self-efficacy as ß = 0.113, ß = 0.070, ß = 0.722, ß = -0.516 respectively with P < 0.001. Conclusion: The prevalence of COVID-19 VH was relatively low in the baseline survey and much higher in the follow-up survey, with a significant increase in hesitancy rates among mainland Chinese residents. Acknowledging the substantial impact on the shaping of COVID-19 VH, one must consider factors including perceived severity, susceptibility, vaccination barriers, and self-efficacy.

Pesticide residues in common fruits and vegetables in Henan Province, China.

In this study 3307 samples of 24 vegetables and fruits from 18 regions of Henan Province, China, were collected in 2021 with the aim of assessing the levels of pesticide residues and analysing the differences between different sources in Henan Province. Thirteen kinds of pesticides were analysed by gas chromatography-mass spectrometry (GC-MS) and detection rates were compared by the chi-square test. In all samples, except ginger, pimento, edible fungi and yam, pesticide residues were detected. The detection rates of difenoconazole, acetamiprid, carbendazim, procymidone, emamectin benzoate, lambda-cyhalothrin, cypermethrin and dimethomorph in supermarkets and traditional farmers' markets were different. The difenoconazole group and the dimethomorph group were both statistically different (P < 0.05). This study showed common vegetables and fruits to contain pesticide residues in Henan Province and provided a scientific basis for their evaluation. Different sources take different regulatory measures to control pesticide residues to ensure food safety.

Comprehensive effects of lifestyle reform, adherence, and related factors on hypertension control: A review.

Despite the effectiveness of currently available antihypertensive medications, there is still a need for new treatment strategies that are more effective in certain groups of hypertensive and for additional resources to combat hypertension. However, medication non-adherence was previously recognized as a major problem in the treatment of hypertension. The mechanisms behind the positive impacts of lifestyle changes might occur in different ways. In comparison with other studies, the efficacy and effectiveness of lifestyle modifications and antihypertensive pharmaceutical treatment for the prevention and control of hypertension and concomitant cardiovascular disease have been demonstrated in randomized controlled trials. However, in this review, the attitudinal lifestyle modifications and barriers to blood pressure control were elaborated on. An effective method for reducing blood pressure (BP) and preventing cardiovascular events with antihypertensive medications has been outlined. Maintaining healthy lifestyle factors (body mass index, diet, smoking, alcohol consumption, sodium excretion, and sedentary behavior) could lower systolic blood pressure BP by 3.5 mm Hg and reduce the risk of cardiovascular disease (CVD) by about 30%, regardless of genetic susceptibility to hypertension. Conducting a lifestyle intervention using health education could improve lifestyle factors, such as reducing salt, sodium, and fat intake, changing eating habits to include more fruits and vegetables, not smoking, consuming less alcohol, exercising regularly, maintaining healthy body weight, and minimizing stressful conditions. Each behavior could affect BP by modulating visceral fat accumulation, insulin resistance, the renin-angiotensin-aldosterone system, vascular endothelial function, oxidative stress, inflammation, and autonomic function. Evidence of the joint effect of antihypertensive medications and lifestyle reforms suggests a pathway to reduce hypertension.

BRAF p.V600E genetic testing based on ultrasound-guided fine-needle biopsy improves the malignancy rate in thyroid surgery: our single-center experience in the past 10 years.

PURPOSE: Ultrasound-guided fine-needle aspiration biopsy (UG-FNAB) was implemented in Qilu Hospital of Shandong University in 2015 as a preoperative diagnostic method for thyroid surgery. BRAF p.V600E genetic testing was implemented in 2019. This study evaluated the impact of these two tests on the malignancy rate in patients undergoing thyroidectomy. METHODS: A total of 19,496 patients were included in the study. We retrospectively collected data from patients undergoing thyroid surgery in the Hospital Information System (HIS) of Qilu Hospital of Shandong University from January 2012 to December 2021. Meanwhile, data of FNAB, UG-FNAB, and BRAF p.V600E genetic testing were collected. Differences in means among groups were analyzed via one-way ANOVA, and differences in frequencies were analyzed via Pearson's chi-squared test. RESULTS: In this study, the 10-year period was divided into three stages, with the implementation of UG-FNAB in 2015 and that of BRAF p.V600E genetic testing in 2019 as dividing lines. The malignancy rate in thyroid surgery increased significantly during these three stages (48.06% vs. 73.47% vs. 88.17%; P < 0.001). In the same period (May 2019 to December 2021), the malignancy rate in thyroid surgery was significantly different between the Non-FNAB, UG-FNAB, and UG-FNAB-BRAF groups (78.87% vs. 95.63% vs. 98.32%; P < 0.001). CONCLUSIONS: The successful implementation of UG-FNAB and BRAF p.V600E genetic testing improved the malignancy rate in thyroid surgery and reduced unnecessary diagnostic surgery for benign and marginal lesions. It can, therefore, provide a clinical reference for other hospitals.

Dynamic Trends and Underlying Factors of COVID-19 Vaccine Booster Hesitancy in Adults: Cross-Sectional Observational Study.

BACKGROUND: COVID-19 vaccine hesitancy reduces vaccination rates, which is detrimental to building herd immunity and halting the spread of COVID-19 and its variations. Most researches have simply identified the reasons affecting COVID-19 vaccination reluctance without delving into its dynamics, which makes forecasting future trends difficult. OBJECTIVE: This study aimed to examine the current COVID-19 vaccine booster hesitancy rate in Chinese adults as well as the dynamics of vaccine hesitancy and its influencing factors. The results of this study will have practical implications for policy responses in mainland China, and effective COVID-19 booster vaccination in specific populations. METHODS: The web-based survey was completed by creating questionnaires and using a stratified random sampling method to collect information from adults (≥18 years old) among 2556 households in 4 geographical regions of China. We collected sociodemographic information, health status, awareness of COVID-19 and its vaccine, self-perceptions, trust in medical staff and vaccine developers, and so on. The odds ratios and 95% CI for the statistical associations were estimated using logistic regression models. RESULTS: Overall, 6659 participants (females: n=3540, 53.2%; males: n=3119, 46.8%) responded. In total, 533 (8%; 95% CI 7.4%-8.7%) participants presented a clear hesitancy in receiving the COVID-19 booster vaccination, while 736 (11.1%; 95% CI 10.3%-11.8%) expressed hesitancy in regular booster vaccination. A higher prevalence of vaccine hesitancy in both booster vaccination and regular booster vaccination was observed among participants with a history of allergies, experiencing chronic disease, lower levels of public health prevention measures or susceptibility or benefits or self-efficiency, higher levels of severity or barriers, and lower trust in both medical staff and vaccine developers (P<.05). The females and participants with higher education levels, higher levels of barriers, lower levels of susceptibility, and lower trust in vaccine developers preferred to have attitudinal changes from acceptance to hesitancy, while people with higher education levels, lower self-report health conditions, experiencing chronic disease, history of allergies, and lower trust in medical staff and developers were all positively associated with constant COVID-19 booster hesitancy. CONCLUSIONS: The prevalence of COVID-19 vaccine booster hesitancy is not high in mainland China. However, there is a slight increment in hesitancy on regular booster vaccination. Conducting targeted information guidance for people with higher education levels and chronic diseases, as well as improving accessibility to booster vaccination and increasing trust in medical staff and vaccine producers may be highly effective in reducing vaccine hesitancy.

Work-family conflict and anxiety among nurses of the maternal and child health institutions: the mediating role of job satisfaction.

Introduction: Over the past decades, anxiety has garnered significant attention from nursing population. Investigations have centered on the correlation between work-family conflict (WFC) and anxiety as well as the link between job satisfaction and anxiety among nurses. However, the role of job satisfaction plays in the relationship between work-family conflict and anxiety remains relatively unexplored. Methods: In April 2021, a cross-sectional survey was conducted among nurses (N = 3,770) working at the maternal and child health institutions in Henan province, China. Multiple linear regression model was used to explore the factors associated with anxiety. Model 4 in Hayes's PROCESS macro and Bootstrap method was performed to examine the mediating role of job satisfaction in the relationship between work-family conflict and anxiety. Results: The median (interquartile range) anxiety score was 5.00 (6.00). Work-family conflict was shown to be significantly correlated to job satisfaction (r = -0.517, p < 0.001) and anxiety (r = 0.457, p < 0.01). There was a strong negative correlation between job satisfaction and anxiety (r = -0.379, p < 0.01). The study also found that nurses aged 31-40 years, those with a junior college education (p = 0.001), those with an undergraduate or above education (p < 0.001), those who reported experiencing work-family conflict (p < 0.001), and those with lower job satisfaction (p < 0.001) were more likely to experience anxiety. Additionally, job satisfaction partially (a*b = 20.90%) mediated the relationship between work-family conflict and anxiety. Conclusion: The association between work-family conflict and anxiety among nurses in maternity and child health institutions was moderated by job satisfaction. Therefore, it is critical to enhance working conditions, minimize work-family conflict, and promoting job satisfaction among nurses may help to mitigate the negative effects of work-family conflict on anxiety.

The pattern from the first three rounds of vaccination: declining vaccination rates.

Introduction: Vaccination rates for the COVID-19 vaccine have recently been stagnant worldwide. We aim to analyze the potential patterns of vaccination development from the first three doses to reveal the possible trends of the next round of vaccination and further explore the factors influencing vaccination in the selected populations. Methods: On July 2022, a stratified multistage random sampling method in the survey was conducted to select 6,781 people from 4 provinces China, who were above the age of 18 years. Participants were divided into two groups based on whether they had a chronic disease. The data were run through Cochran-Armitage trend test and multivariable regression analyses. Results: A total of 957 participants with chronic disease and 5,454 participants without chronic disease were included in this survey. Vaccination rates for the first, second and booster doses in chronic disease population were93.70% (95% CI: 92.19-95.27%), 91.12% (95%CI: 94.43-95.59%), and 83.18% (95%CI: 80.80-85.55%) respectively. By contrast, the first, second and booster vaccination rates for the general population were 98.02% (95% CI: 97.65-98.39%), 95.01% (95% CI: 94.43-95.59%) and 85.06% (95% CI: 84.11-86.00%) respectively. The widening gap in vaccination rates was observed as the number of vaccinations increases. Higher self-efficacy was a significant factor in promoting vaccination, which has been observed in all doses of vaccines. Higher education level, middle level physical activity and higher public prevention measures play a positive role in vaccination among the general population, while alcohol consumption acts as a significant positive factor in the chronic disease population (p < 0.05). Conclusion: As the number of vaccinations increases, the trend of decreasing vaccination rate is becoming more pronounced. In future regular vaccinations, we may face low vaccination rates as the increasing number of infections and the fatigue associated with the prolonged outbreak hamper vaccination. Measures need to be found to counter this downward trend such as improving the self-efficacy of the population.

BRAFV600E genetic testing should be recommended for Bethesda III or V thyroid nodules based on fine-needle aspiration.

The preoperative diagnosis of thyroid nodules now routinely includes BRAFV600E genetic testing in most provincial and municipal hospitals in China. This study identified the most suitable patients of thyroid nodule for BRAFV600E genetic testing. We retrospectively collected data of patients from the Hospital Information System that had undergone fine needle aspiration biopsy (FNAB) from May 2019 to December 2021. Data of FNAB, BRAFV600E genetic testing, and post-surgical pathological diagnosis were collected. A total of 12,392 patients were included in this study. Among them, 7,010 patients underwent solely FNAB, while 5,382 patients had both FNAB and BRAFV600E genetic testing. In the FNAB group, 2,065 thyroid nodules were surgically removed, with a 93.12% malignancy rate. In the FNAB + BRAF group, 2,005 nodules were dissected, and the malignancy rate was 98.20%. However, it was evident that in the subgroups, the combination of FNAB and BRAFV600E genetic testing only benefited Bethesda III (p < 0.001) and V (p = 0.001) nodules. Overall, the combination of FNAB with BRAFV600E genetic testing significantly improved the malignancy rate of surgical thyroid nodes at our hospital when compared to FNAB alone. The subgroup analysis showed that BRAFV600E genetic testing only benefited Bethesda III and V nodules. These findings provide a clinical reference for rationally selecting the most suitable population for BRAFV600E genetic testing.

Mof plays distinct roles in hepatic lipid metabolism under healthy or non-alcoholic fatty liver conditions.

The disturbance of hepatic lipid metabolism has a strong association with non-alcoholic fatty liver disease (NAFLD) and diabetes. Mof, an acetyltransferase involved in obesity and carbon metabolism, has not been thoroughly examined in its connection to hepatic metabolism. We aimed to explore the impact of Mof on hepatic lipid metabolism. The alteration of Mof expression was found in both obese mice and NAFLD human liver. The genes regulated by Mof were closely associated with lipid metabolism. In normal mice or hepatic cells, the down-regulation or inhibition of Mof resulted in increased lipid accumulation due to decreased PPARα expression. Conversely, in diet-induced obesity (DIO) mice or hepatic cells treated with palmitic acid, the inhibition of Mof led to improved lipid metabolism, attributed to the reduction in p-mTOR/mTOR levels. In summary, Mof exhibited distinct roles in lipid metabolism under different conditions. The inhibition of Mof may hold potential as a therapeutic target for hepatic lipid metabolism disturbances.

Mesenchymal stromal cells ameliorate diabetes-induced muscle atrophy through exosomes by enhancing AMPK/ULK1-mediated autophagy.

BACKGROUND: Diabetes and obesity are associated with muscle atrophy that reduces life quality and lacks effective treatment. Mesenchymal stromal cell (MSC)-based therapy can ameliorate high fat-diet (HFD) and immobilization (IM)-induced muscle atrophy in mice. However, the effect of MSCs on muscle atrophy in type 2 diabetes mellitus (T2DM) and the potential mechanism is unclear. Here, we evaluated the efficacy and explored molecular mechanisms of human umbilical cord MSCs (hucMSCs) and hucMSC-derived exosomes (MSC-EXO) on diabetes- and obesity-induced muscle atrophy. METHODS: Diabetic db/db mice, mice fed with high-fat diet (HFD), mice with hindlimb immobilization (IM), and C2C12 myotubes were used to explore the effect of hucMSCs or MSC-EXO in alleviating muscle atrophy. Grip strength test and treadmill running were used to measure skeletal muscle strength and performance. Body composition, muscle weight, and muscle fibre cross-sectional area (CSA) was used to evaluate muscle mass. RNA-seq analysis of tibialis anterior (TA) muscle and Western blot analysis of muscle atrophy signalling, including MuRF1 and Atrogin 1, were performed to investigate the underlying mechanisms. RESULTS: hucMSCs increased grip strength (P = 0.0256 in db/db mice, P = 0.012 in HFD mice, P = 0.0097 in IM mice), running endurance (P = 0.0154 in HFD mice, P = 0.0006 in IM mice), and muscle mass (P = 0.0004 in db/db mice, P = 0.0076 in HFD mice, P = 0.0144 in IM mice) in all models tested, with elevated CSA of muscle fibres (P < 0.0001 in db/db mice and HFD mice, P = 0.0088 in IM mice) and reduced Atrogin1 (P = 0.0459 in db/db mice, P = 0.0088 in HFD mice, P = 0.0016 in IM mice) and MuRF1 expression (P = 0.0004 in db/db mice, P = 0.0077 in HFD mice, P = 0.0451 in IM mice). MSC-EXO replicated all these hucMSC-mediated changes (P = 0.0103 for grip strength, P = 0.013 for muscle mass, P < 0.0001 for CSA of muscle fibres, P = 0.0171 for Atrogin1 expression, and P = 0.006 for MuRF1 expression). RNA-seq revealed that hucMSCs activated the AMPK/ULK1 signalling and enhanced autophagy. Knockdown of AMPK or inhibition of autophagy with 3-methyladenine (3-MA) diminished the beneficial anti-atrophy effects of hucMSCs or MSC-EXO. CONCLUSIONS: Our results suggest that human umbilical cord mesenchymal stromal cells mitigate diabetes- and obesity-induced muscle atrophy via enhancing AMPK/ULK1-mediated autophagy through exosomes, with implications of applying hucMSCs or hucMSC-derived exosomes to treat muscle atrophy.

Relationship Between Muscle Cramps and Diabetic Retinopathy in Patients with Type 2 Diabetes.

Aim: Patients with type 2 diabetes (T2DM) often suffer from muscle cramps of varying severity. Studies have shown that muscle cramp is closely related to local microcirculation perfusion disorders. Diabetic retinopathy can not only reflect the microcirculation perfusion in the eye but also the systemic microcirculation in patients with diabetes. The aims of this study were to investigate the relationship between muscle cramps and diabetic retinopathy in patients with type 2 diabetes. Methods: A total of 150 adult patients with type 2 diabetes were enrolled and administered a questionnaire on muscle cramping, along with a visual analogue scale for pain. Diabetic retinopathy (DR) was determined by using fundus photography and graded as non-proliferative DR (NPDR) and proliferative DR (PDR). To assess whether there was an association between the muscle cramps and diabetic retinopathy, we conducted binomial logistic regression analysis. Results: Our study revealed that 48% of patients with T2DM experienced muscle cramps in the past three months. Patients self-reported suffering from muscle cramps exhibited a higher prevalence of DR (61% vs 38%, P < 0.05) and PDR (22% vs 4%, P < 0.05) compared with patients without muscle cramps. Serum 25-(OH) vitamin D, calcium, and magnesium levels were not significantly different between patients with and without muscle cramps. After adjusting for age, duration of diabetes, HbA1c, vitamin D, potassium, calcium, and magnesium, we demonstrated that diabetic retinopathy (OR, 2.18; 95% CI, 1.01-4.69; P< 0.05) and albumin (OR, 0.90; 95% CI, 0.82-1.00; P< 0.05) were highly associated with muscle cramps. Binomial logistic regression analysis also indicated that severity of DR is associated with muscle cramps. In addition, DR and PDR were found to be associated with muscle cramp frequency (P for trend < 0.05), duration (P for trend < 0.05), and pain severity (P for trend < 0.05). Conclusion: Muscle cramps occur frequently in diabetes and are correlated with diabetic retinopathy and albumin. Patients with PDR exhibited a higher frequency, severity, and longer duration relative to those with NPDR or without DR. Our findings suggested that muscle cramps in individuals with T2DM might be a result of microvascular dysfunction. Modulation of microvascular perfusion might thus provide a therapeutic target for alleviating muscle cramps.

Retinal Microvascular Signs in Pre- and Early-Stage Diabetic Retinopathy Detected Using Wide-Field Swept-Source Optical Coherence Tomographic Angiography.

Purpose Using a wide-field, high-resolution swept-source optical coherence tomographic angiography (OCTA), this study investigated microvascular abnormalities in patients with pre- and early-stage diabetic retinopathy. Methods 38 eyes of 20 people with diabetes mellitus (DM) type 2 without diabetic retinopathy (DR) and 39 eyes of 21 people with DR were enrolled in this observational and cross-sectional cohort study, and a refractive error-matched group consisting of 42 eyes of 21 non-diabetic subjects of similar age were set as the control. Each participant underwent a wide-field swept-source OCTA. On OCTA scans (1.2 × 1.2 cm), the mean central macular thickness (CMT), the vessel density of the inner retina, superficial capillary plexus (SCP), and deep capillary plexus (DCP) were independently measured in the whole area (1.2 cm diameter) via concentric rings with varying radii (0-0.3, 0.3-0.6, 0.6-0.9, and 0.9-1.2 cm). Results Patients whose eyes had pre-and early-stage DR showed significantly decreased vessel density in the inner retina, SCP, DCP and CMT (early-stage DR) compared with the control. In addition, compared with the average values upon wide-field OCTA, the decreases were even more pronounced for concentric rings with a radius of 0.9-1.2 cm in terms of the inner retina, SCP, DCP and CMT. Conclusions Widefield OCTA allows for a more thorough assessment of retinal changes in patients with pre- and early-stage DR.; retinal microvascular abnormalities were observed in both groups. In addition, the decreases in retinal vessel density were more significant in the peripheral concentric ring with a radius of 0.9-1.2 cm. The application of novel and wide-field OCTA could potentially help to detect earlier diabetic microvascular abnormalities.

cGAS-STING activation contributes to podocyte injury in diabetic kidney disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal diseases. DKD does not have efficacious treatment. The cGAS-STING pathway is activated in podocytes at the early stage of kidney dysfunction, which is associated with the activation of STING downstream effectors TBK1 and NF-κB but not IRF3. Lipotoxicity induces mitochondrial damage and mtDNA leakage to the cytosol through Bcl-2 associated X protein (BAX) in podocytes. BAX-mediated mtDNA cytosolic leakage can activate the cGAS-STING pathway in the absence of lipotoxicity and is sufficient to cause podocyte injury. Depletion of cytosolic mtDNA, genetic STING knockdown, or pharmacological inhibition of STING or TBK1 alleviates podocyte injury and improves renal functions in cultured podocytes or mouse models of diabetes and obesity. These results suggest that the mtDNA-cGAS-STING pathway promotes podocyte injury and is a potential therapeutic target for DKD or other obesity-related kidney diseases.