Ferrostatin-1 specifically targets mitochondrial iron-sulfur clusters and aconitase to improve cardiac function in Sirtuin 3 cardiomyocyte knockout mice.

AIMS: Ferroptosis is a form of iron-regulated cell death implicated in ischemic heart disease. Our previous study revealed that Sirtuin 3 (SIRT3) is associated with ferroptosis and cardiac fibrosis. In this study, we tested whether the knockout of SIRT3 in cardiomyocytes (SIRT3cKO) promotes mitochondrial ferroptosis and whether the blockade of ferroptosis would ameliorate mitochondrial dysfunction. METHODS AND RESULTS: Mitochondrial and cytosolic fractions were isolated from the ventricles of mice. Cytosolic and mitochondrial ferroptosis were analyzed by comparison to SIRT3loxp mice. An echocardiography study showed that SIRT3cKO mice developed heart failure as evidenced by a reduction of EF% and FS% compared to SIRT3loxp mice. Comparison of mitochondrial and cytosolic fractions of SIRT3cKO and SIRT3loxp mice revealed that, upon loss of SIRT3, mitochondrial, but not cytosolic, total lysine acetylation was significantly increased. Similarly, acetylated p53 was significantly upregulated only in the mitochondria. These data demonstrate that SIRT3 is the primary mitochondrial deacetylase. Most importantly, loss of SIRT3 resulted in significant reductions of frataxin, aconitase, and glutathione peroxidase 4 (GPX4) in the mitochondria. This was accompanied by a significant increase in levels of mitochondrial 4-hydroxynonenal. Treatment of SIRT3cKO mice with the ferroptosis inhibitor ferrostatin-1 (Fer-1) for 14 days significantly improved preexisting heart failure. Mechanistically, Fer-1 treatment significantly increased GPX4 and aconitase expression/activity, increased mitochondrial iron­sulfur clusters, and improved mitochondrial membrane potential and Complex IV activity. CONCLUSIONS: Inhibition of ferroptosis ameliorated cardiac dysfunction by specifically targeting mitochondrial aconitase and iron­sulfur clusters. Blockade of mitochondrial ferroptosis may be a novel therapeutic target for mitochondrial cardiomyopathies.

Relation of myocardial dysfunction to biomarkers, COVID-19 severity and all-cause mortality.

AIMS: The COVID-19 infection has been described as affecting myocardial injury. However, the relation between left ventricular global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS), disease severity and all-cause mortality in COVID-19 is unclear. METHODS AND RESULTS: The study consisted of 220 patients with COVID-19, including 127 (57.5%) with mild, 43 (19.5%) with moderate and 50 (22.7%) with severe/critical conditions. Myocardial dysfunction was analysed by GLS, GCS and GRS using two-dimensional speckle-tracking echocardiography. Hazard ratios and Kaplan-Meier curves were produced to assess the association between strains and cardiac biomarker indices with a composite outcome of all-cause mortality. With an average follow-up period of 11 days, 19 patients reached the endpoint (death). Significant associations were found for the three strain parameters and the levels of blood urea nitrogen (BUN) (r = 0.206, 0.221 and 0.355, respectively). Cardiac troponin I (cTnI) was closely related to the GLS and GCS (r = 0.240 and 0.324, respectively). In multivariable Cox regression, GCS > -21.6% was associated with all-cause death {hazard ratio, 4.007 [95% confidence interval (CI), 11.347-11.919]}. CONCLUSIONS: GLS, GCS and GRS are significantly related to myocardial dysfunction in patients with COVID-19. Worsening GCS poses an increased risk of death in COVID-19.

Endothelial specific prolyl hydroxylase domain-containing protein 2 deficiency attenuates aging-related obesity and exercise intolerance.

Obesity and exercise intolerance greatly reduce the life quality of older people. Prolyl hydroxylase domain-containing protein 2 (PHD2) is an important enzyme in modulating hypoxia-inducible factor-alpha (HIF) protein. Using vascular endothelial cell-specific PHD2 gene knockout (PHD2 ECKO) mice, we investigated the role of endothelial PHD2 in aging-related obesity and exercise capacity. Briefly, PHD2 ECKO mice were obtained by crossing PHD2-floxed mice with VE-Cadherin (Cdh5)-Cre transgenic mice. The effect of PHD2 ECKO on obesity and exercise capacity in PHD2 ECKO mice and control PHD2f/f mice were determined in young mice (6 to 7 months) and aged mice (16-18 months). We found that aged PHD2 ECKO mice, but not young mice, exhibited a lean phenotype, characterized by lower fat mass, and its ratio to lean weight, body weight, or tibial length, while their food uptake was not reduced compared with controls. Moreover, as compared with aged control mice, aged PHD2 ECKO mice exhibited increased oxygen consumption at rest and during exercise, and the maximum rate of oxygen consumption (VO2 max) during exercise. Furthermore, as compared with corresponding control mice, both young and aged PHD2 ECKO mice demonstrated improved glucose tolerance and lower insulin resistance. Together, these data demonstrate that inhibition of vascular endothelial PHD2 signaling significantly attenuates aging-related obesity, exercise intolerance, and glucose intolerance.

Effects of the COVID-19 Pandemic on Dairy Consumption Trends: An Empirical Investigation of Accounting Data in China.

The COVID-19 pandemic may have had a negative impact on dairy consumption trends. Many dairy products are perishable and have relatively high income elasticity, causing their susceptibility to market fluctuations in general, including those specifically caused by the pandemic. However, the pandemic has also brought some other prospective possibilities. For example, during the pandemic, people paid more attention to nutrition and health issues and increased the number of meals prepared and eaten at home. In consideration of the particular circumstances during the pandemic, the Chinese government issued several policies to promote the population's dairy consumption, and the Chinese dairy cattle sector actively implemented the policy of "guarantee price, quality, and supply". These factors may have caused the Chinese population to increase their consumption of dairy products during the pandemic. Before the pandemic, the consumption of dairy products in the Chinese population showed an overall upward trend. The question addressed in this study is how has COVID-19 affected dairy consumption trends during the pandemic? This study uses accounting data from the Chinese dairy cattle sector to empirically analyze the impact of the COVID-19 pandemic on dairy consumption trends through economic theories and translog revenue function. Our study found that COVID-19 increased consumers' consumption of dairy products in China, but those people experiencing poverty may still have experienced inadequate dairy intake. This study has contributed to the body of work in this area in the literature and provides response strategies for the dairy cattle sector and the authorities.

p53 Acetylation Exerts Critical Roles in Pressure Overload-Induced Coronary Microvascular Dysfunction and Heart Failure in Mice.

BACKGROUND: Coronary microvascular dysfunction (CMD) has been shown to contribute to cardiac hypertrophy and heart failure (HF) with preserved ejection fraction. At this point, there are no proven treatments for CMD. METHODS: We have shown that histone acetylation may play a critical role in the regulation of CMD. By using a mouse model that replaces lysine with arginine at residues K98, K117, K161, and K162R of p53 (p534KR), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p534KR could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF. Wild-type and p534KR mice were subjected to pressure overload by transverse aortic constriction to induce cardiac hypertrophy and HF. RESULTS: Echocardiography measurements revealed improved cardiac function together with a reduction of apoptosis and fibrosis in p534KR mice. Importantly, myocardial capillary density and coronary flow reserve were significantly improved in p534KR mice. Moreover, p534KR upregulated the expression of cardiac glycolytic enzymes and Gluts (glucose transporters), as well as the level of fructose-2,6-biphosphate; increased PFK-1 (phosphofructokinase 1) activity; and attenuated cardiac hypertrophy. These changes were accompanied by increased expression of HIF-1α (hypoxia-inducible factor-1α) and proangiogenic growth factors. Additionally, the levels of SERCA-2 were significantly upregulated in sham p534KR mice, as well as in p534KR mice after transverse aortic constriction. In vitro, p534KR significantly improved endothelial cell glycolytic function and mitochondrial respiration and enhanced endothelial cell proliferation and angiogenesis. Similarly, acetylation-deficient p534KR significantly improved coronary flow reserve and rescued cardiac dysfunction in SIRT3 (sirtuin 3) knockout mice. CONCLUSIONS: Our data reveal the importance of p53 acetylation in coronary microvascular function, cardiac function, and remodeling and may provide a promising approach to improve hypertension-induced CMD and to prevent the transition of cardiac hypertrophy to HF.

TIGAR Deficiency Blunts Angiotensin-II-Induced Cardiac Hypertrophy in Mice.

Hypertension is the key contributor to pathological cardiac hypertrophy. Growing evidence indicates that glucose metabolism plays an essential role in cardiac hypertrophy. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to regulate glucose metabolism in pressure overload-induced cardiac remodeling. In the present study, we investigated the role of TIGAR in cardiac remodeling during Angiotensin II (Ang-II)-induced hypertension. Wild-type (WT) and TIGAR knockout (KO) mice were infused with Angiotensin-II (Ang-II, 1 µg/kg/min) via mini-pump for four weeks. The blood pressure was similar between the WT and TIGAR KO mice. The Ang-II infusion resulted in a similar reduction of systolic function in both groups, as evidenced by the comparable decrease in LV ejection fraction and fractional shortening. The Ang-II infusion also increased the isovolumic relaxation time and myocardial performance index to the same extent in WT and TIGAR KO mice, suggesting the development of similar diastolic dysfunction. However, the knockout of TIGAR significantly attenuated hypertension-induced cardiac hypertrophy. This was associated with higher levels of fructose 2,6-bisphosphate, PFK-1, and Glut-4 in the TIGAR KO mice. Our present study suggests that TIGAR is involved in the control of glucose metabolism and glucose transporters by Ang-II and that knockout of TIGAR attenuates the development of maladaptive cardiac hypertrophy.

Charged Microdroplets as Microelectrochemical Cells for CO2 Reduction and C-C Coupling.

Charged microdroplets offer novel electrochemical environments, distinct from traditional solid-liquid or solid-liquid-gas interfaces, due to the intense electric fields at liquid-gas interfaces. In this study, we propose that charged microdroplets serve as microelectrochemical cells (MECs), enabling unique electrochemical reactions at the gas-liquid interface. Using electrospray-generated microdroplets, we achieved multielectron CO2 reduction and C-C coupling to synthesize ethanol using molecular catalysts. These catalysts effectively harness and relay electrons, enhancing the longevity of solvated electrons and enabling multielectron reactions. Importantly, we revealed the intrinsic relationship between the size and charge density of a MEC and its reaction selectivity. Employing in situ mass spectrometry, we identified reaction intermediates (molecular catalyst adducts with HCOO) and oxidation products, elucidating the CO2 reduction mechanism and the comprehensive reaction procedure. Our research underscores the promising role of charged microdroplets in pioneering new electrochemical systems.

The Therapeutic Potential of Targeting Ferroptosis in the Treatment of Mitochondrial Cardiomyopathies and Heart Failure.

ABSTRACT: Ferroptosis is a form of iron-regulated cell death implicated in a wide array of diseases, including heart failure, hypertension, and numerous cardiomyopathies. In addition, mitochondrial dysfunction has been associated with several of these same disease states. However, the role of the mitochondrion in ferroptotic cell death remains debated. As a major regulator of cellular iron levels, the mitochondria may very well play a crucial role in the mechanisms behind ferroptosis, but at this point, this has not been adequately defined. Emerging evidence from our laboratory and others indicates a critical role of mitochondrial Sirtuin 3, a deacetylase linked with longevity and protection against numerous conditions, in the prevention of cardiovascular diseases. Here, we provide a brief overview of the potential roles of Sirtuin 3 in mitochondrial iron homeostasis and its contribution to the mitochondrial cardiomyopathy of Friedreich's ataxia and diabetic cardiomyopathy. We also discuss the current knowledge of the involvement of ferroptosis and the mitochondria in these and other cardiovascular disease states, including doxorubicin-induced cardiomyopathy, and provide insight into areas requiring further investigation.

Sequence and directivity in cardiac muscle injury of COVID-19 patients: an observational study.

Objective: To compare cardiac function indicators between mild and moderate to severe COVID-19 patients and to try to identify the sequence and directivity in cardiac muscle injury of COVID-19 patients. Methods: From December 2022 to January 2023, all patients with laboratory-confirmed SARS-CoV-2 infection in Shanghai General Hospital Jiading Branch were enrolled. The clinical classification was stratified into mild, moderate, or severe groups. We collected the clinical and laboratory information, transthoracic echocardiographic and speckle-tracking echocardiographic parameters of patients and compared the differences among different groups. Results: The values of echocardiographic parameters in mild group were lower than that in moderate or severe group (P < 0.05) except LVEF. The values of LVEF of mild and moderate group were higher than severe group (P < 0.05). There were no significant differences between moderate and severe group. Positive correlations were observed between left ventricular global longitudinal strain (LVGLS) and myoglobin (r = 0.72), E/e' and age (r = 0.79), E/e' and BNP (r = 0.67). The multivariate analysis shows that SpO2 (OR = 0.360, P = 0.02), LVGLS (OR = 3.196, P = 0.003) and E/e' (OR = 1.307, P = 0.036) were the independent risk factors for mild cases progressing to moderate or severe. According to the receiver operating characteristic (ROC) curves, when all the COVID-19 patients was taken as the sample size, the area under the curve (AUC) of the LVGLS was the highest (AUC = 0.861). The AUC of the LVGLS was higher than LVGCS (AUC = 0.565, P < 0.001). Conclusion: When mild COVID-19 progresses to moderate or severe, both systolic and diastolic functions of the heart are impaired. LVGLS was the independent risk factor for mild cases progressing to moderate or severe cases. Longitudinal changes may manifest earlier than circumferential changes as myocardial disease progresses in COVID-19.

Gender and age disparities in small-to-medium arterial stiffness among the Chinese population.

BACKGROUND AND AIMS: Arterial pressure-volume index (API) is a non-invasive tool for assessing small-to-medium-sized arterial stiffness. This study aimed to investigate the potential age- and sex-related differences in the API and explore the practical implications of such differences. METHODS AND RESULTS: The study analysed 7620 subjects for whom API measurements were available. Linear regression and restrictive cubic spline models were used to investigate the associations between potential risk conditions and the API. Additionally, this study employed a backward stepwise regression method to identify the independent factors associated with a high API. Middle-aged to older women had higher API values and a higher prevalence of high API than men in the same age group. However, the opposite was observed among younger individuals, with women having lower API values than men. This study also identified a J-shaped relationship between API and age, where API values began to increase at a certain age and rapidly increased after that. In women, the API started to increase at 31 years of age and rapidly increased after 54 years of age. In men, the API started to increase at 38 years of age, followed by a rapid increase after 53 years of age. CONCLUSION: This study's observation of a significant age-sex interaction in small-to-medium-sized arterial stiffening offers a valuable explanation for cardiovascular disease risk and provides important parameters for using API measurements to evaluate such risk.

Uncoupling of the center-to-periphery arterial stiffness gradient and pulse pressure amplification in viral pneumonia infection.

OBJECTIVES: Arterial stiffness is a common manifestation of viral pneumonia infections, including COVID-19. Nevertheless, the relationship between the center-to-periphery arterial stiffness gradient and pulse pressure amplification (PPA) in infectious diseases remains unclear. This study aimed to investigate this relationship utilizing arterial pressure volume index (API) and arterial velocity pulse index (AVI) ratio. METHODS: API/AVI and PPA were measured in 219 participants with COVID-19 and 374 normal participants. Multiple linear regression was used to assess the association of API/AVI and PPA, and restricted cubic spline was used to investigate the non-linear relationship between API/AVI and PPA. Receiver operating characteristic curve (ROC) analysis was used to evaluate the effects of API/AVI in identifying COVID-19 infection and severe stage. RESULTS: There was a significant J-shaped relationship between API/AVI and PPA in COVID-19 group, while a M-shaped relationship was observed in normal group. API/AVI decreased rapidly as PPA decreased until API/AVI decreased slowly at PPA of 1.07, and then API/AVI decreased slowly again at PPA of 0.78. ROC results showed that API/AVI demonstrated excellent accuracy in identifying COVID-19 infection (AUC = 0.781) and a high specificity (84.88%) in identifying severe stage. CONCLUSIONS: There was a J-shaped association between the API/AVI and PPA in viral infected patients, while a M-shaped relationship in the normal participants. API/AVI is better for identifying infected and uninfected patients, with a high specificity in identifying those in severe stages of the disease. The attenuation or reversal of API/AVI may be associated with the loss of PPA coupling.

AutoBar: Automatic Barrier Coverage Formation for Danger Keep Out Applications in Smart City.

Barrier coverage is a fundamental application in wireless sensor networks, which are widely used for smart cities. In applications, the sensors form a barrier for the intruders and protect an area through intrusion detection. In this paper, we study a new branch of barrier coverage, namely warning barrier coverage (WBC). Different from the classic barrier coverage, WBC has the inverse protect direction, which moves the sensors surrounding a dangerous region and protects any unexpected visitors by warning them away from the dangers. WBC holds a promising prospect in many danger keep out applications for smart cities. For example, a WBC can enclose the debris area in the sea and alarm any approaching ships in order to avoid their damaging propellers. One special feature of WBC is that the target region is usually dangerous and its boundary is previously unknown. Hence, the scattered mobile nodes need to detect the boundary and form the barrier coverage themselves. It is challenging to form these distributed sensor nodes into a barrier because a node can sense only the local information and there is no global information of the unknown region or other nodes. To this end, in response to the newly proposed issue of the formation of barrier cover, we propose a novel solution AutoBar for mobile sensor nodes to automatically form a WBC for smart cities. Notably, this is the first work to trigger the coverage problem of the alarm barrier, wherein the regional information is not pre-known. To pursue the high coverage quality, we theoretically derive the optimal distribution pattern of sensor nodes using convex theory. Based on the analysis, we design a fully distributed algorithm that enables nodes to collaboratively move toward the optimal distribution pattern. In addition, AutoBar is able to reorganize the barrier even if any node is broken. To validate the feasibility of AutoBar, we develop the prototype of the specialized mobile node, which consists of two kinds of sensors: one for boundary detection and another for visitor detection. Based on the prototype, we conduct extensive real trace-driven simulations in various smart city scenarios. Performance results demonstrate that AutoBar outperforms the existing barrier coverage strategies in terms of coverage quality, formation duration, and communication overhead.

Direct Analysis of Micro-biopsy Samples by Polarity Gradient Focusing Dip-and-Go Mass Spectrometry.

Direct analysis of micro-biopsy samples by mass spectrometry at single-cell level still faces major challenges. In this work, we developed a polarity gradient focusing dip-and-go strategy (PGF-Dip&Go) during induced electrospray ionization mass spectrometry (iESI-MS) analysis for real-time enrichment and spatial separation of compounds such as lipids, alkaloids, fatty amines, and drugs. Compared with direct iESI-MS analysis, enrichment of analytes (enrichment factor of 5.0-100.0) and spatial separation between different analytes were achieved. Owing to the enrichment effect and salt cleanup effect, the sensitivity of PGF-Dip&Go has been improved by 25-10,000 times compared with direct iESI-MS. PGF-Dip&Go has been successfully applied for the analysis of lipids in a 200 pL micro-biopsy section from an individual fish egg. Lysophosphatidylcholine (LPC), phosphatidylcholine (PC), and triglyceride (TG) were significantly enriched and separated according to their polarity differences, proving the potential of PGF-Dip&Go to be a noninvasive and powerful analytical tool for in situ analysis of complex small volumes in the future.

Inhibition of NK1.1 signaling attenuates pressure overload-induced heart failure, and consequent pulmonary inflammation and remodeling.

Background: Inflammation contributes to heart failure (HF) development, the progression from left ventricular failure to pulmonary remodeling, and the consequent right ventricular hypertrophy and failure. NK1.1 plays a critical role in Natural killer (NK) and NK T (NKT) cells, but the role of NK1.1 in HF development and progression is unknown. Methods: We studied the effects of NK1.1 inhibition on transverse aortic constriction (TAC)-induced cardiopulmonary inflammation, HF development, and HF progression in immunocompetent male mice of C57BL/6J background. Results: We found that NK1.1+ cell-derived interferon gamma+ (IFN-γ+) was significantly increased in pulmonary tissues after HF. In addition, anti-NK1.1 antibodies simultaneously abolished both NK1.1+ cells, including the NK1.1+NK and NK1.1+NKT cells in peripheral blood, spleen, and lung tissues, but had no effect on cardiopulmonary structure and function under control conditions. However, systemic inhibition of NK1.1 signaling by anti-NK1.1 antibodies significantly rescued mice from TAC-induced left ventricular inflammation, fibrosis, and failure. Inhibition of NK1.1 signaling also significantly attenuated TAC-induced pulmonary leukocyte infiltration, fibrosis, vessel remodeling, and consequent right ventricular hypertrophy. Moreover, inhibition of NK1.1 signaling significantly reduced TAC-induced pulmonary macrophage and dendritic cell infiltration and activation. Conclusions: Our data suggest that inhibition of NK1.1 signaling is effective in attenuating systolic overload-induced cardiac fibrosis, dysfunction, and consequent pulmonary remodeling in immunocompetent mice through modulating the cardiopulmonary inflammatory response.

Multi-scale structural characteristics of black Tartary buckwheat resistant starch by autoclaving combined with debranching modification.

The impact of autoclaving or autoclave-debranching treatments on the multi-scale structure of resistant starch (RS) and the relationship with starch digestion remains unclear, despite their widespread use in its preparation. This work investigated the relationship between RS structure in black Tartary buckwheat and its digestibility by analyzing the effects of autoclaving and autoclave-debranching combined treatments on the multi-scale structure of RS. The results showed that black Tartary buckwheat RS exhibited a more extensive honeycomb-like network structure and enhanced thermal stability than either black Tartary buckwheat native starch (BTBNS) or common buckwheat native starch (CBNS). Autoclaving and autoclaving-debranching converted A-type native starch to V-type and possibly the formation of flavonoid-starch complexes. Autoclaving treatment significantly increased the proportion of short A chain (DP 6-12) and the amylose (AM) content, reduced the viscosity and the total crystallinity. Notably, the autoclave-debranching co-treatment significantly enhanced the resistance of starch to digestion, promoted the formation of perfect microcrystallines, and increased the AM content, short-range ordered degree, and the proportion of long B2 chain (DP 25-36). This study reveals the relationship between the multi-scale structure and digestibility of black Tartary buckwheat RS by autoclaving combined with debranching modification.

Relative contributions of arterial stiffness to cardiovascular disease risk score in Chinese women in framingham and China-PAR model.

Background: Arterial stiffness played an important role in the development of cardiovascular disease (CVD) events. The aim of this study was to verify the relative importance of arterial stiffness for different CVD risk scores in a large sample of Chinese women. Methods: We measured arterial velocity pulse index (AVI) and CVD risk scores in 2220 female participants (mean age 57 years). Framingham Risk Score (FRS), and the prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) were used to estimate CVD risk, respectively. The relationships between AVI and risk scores were investigated by linear regressions and restricted cubic spline (RCS) analysis. To determine the relative importance of AVI in predicting CVD risk scores, random forest analysis was used. Results: There was a significant positive correlation between AVI and FRS, China-PAR in all subgroup groups stratified by age, blood pressure and BMI. AVI showed higher importance in predicting CVD risk scores in FRS model, compared with these traditional risk factors. In China-PAR model, although AVI was not as predictive as SBP, it had better predictive power than many known risk factors such as lipids. Furthermore, AVI had significant J-shaped associations both with FRS and China-PAR scores. Conclusions: AVI was significantly associated with CVD risk score. In FRS and China-PAR model, AVI showed relatively high importance in predicting CVD risk scores. These findings may support the use of arterial stiffness measurements in CVD risk assessment.

SIRT3 Deficiency Enhances Ferroptosis and Promotes Cardiac Fibrosis via p53 Acetylation.

Cardiac fibrosis plays an essential role in the development of diastolic dysfunction and contributes to heart failure with preserved ejection fraction (HFpEF). Our previous studies suggested Sirtuin 3 (SIRT3) as a potential target for cardiac fibrosis and heart failure. In the present study, we explored the role of SIRT3 in cardiac ferroptosis and its contribution to cardiac fibrosis. Our data showed that knockout of SIRT3 resulted in a significant increase in ferroptosis, with increased levels of 4-hydroxynonenal (4-HNE) and downregulation of glutathione peroxidase 4 (GPX-4) in the mouse hearts. Overexpression of SIRT3 significantly blunted ferroptosis in response to erastin, a known ferroptosis inducer, in H9c2 myofibroblasts. Knockout of SIRT3 resulted in a significant increase in p53 acetylation. Inhibition of p53 acetylation by C646 significantly alleviated ferroptosis in H9c2 myofibroblasts. To further explore the involvement of p53 acetylation in SIRT3-mediated ferroptosis, we crossed acetylated p53 mutant (p534KR) mice, which cannot activate ferroptosis, with SIRT3KO mice. SIRT3KO/p534KR mice exhibited a significant reduction in ferroptosis and less cardiac fibrosis compared to SIRT3KO mice. Furthermore, cardiomyocyte-specific knockout of SIRT3 (SIRT3-cKO) in mice resulted in a significant increase in ferroptosis and cardiac fibrosis. Treatment of SIRT3-cKO mice with the ferroptosis inhibitor ferrostatin-1 (Fer-1) led to a significant reduction in ferroptosis and cardiac fibrosis. We concluded that SIRT3-mediated cardiac fibrosis was partly through a mechanism involving p53 acetylation-induced ferroptosis in myofibroblasts.

Effects of Six Processing Parameters on the Size of PCL Fibers Prepared by Melt Electrospinning Writing.

Melt electrospinning writing is a new and promising method for fabricating micro/nanofibers, which has shown great prospects in the biomedical fields such as 3D printing of porous scaffolds. The diameter of the melt electrospinning writing fiber can determine the resolution of the microstructure; thus, the controllability of the fiber diameter is of great significance to the whole fabrication process. In this paper, an orthogonal design experiment (six factors, three levels) was used to explore the impacts of six melt electrospinning parameters (melt temperature, collector speed, tip-to-collector distance, melt flow rate, voltage, and needle gauge) on the fiber diameter. In this experiment, the diameter of fibers obtained with the designed experimental parameters and conditions varied from 10.30 µm to 20.02 µm. The range analysis of orthogonal test results showed that the melt flow rate was the most important factor influencing the diameter of melt electrospinning writing fiber, while the voltage was the least influential factor. The variance analysis of orthogonal test results showed that melt temperature, collector velocity, tip-to-collector distance and melt flow rate had a significant influence on the diameter of melt electrospinning writing fiber. On the basis of the first-order regression equation, the fiber diameter of poly-ε-caprolactone can be accurately controlled, thus improving the engineering applications of poly-ε-caprolactone.

Novel KCNJ16 variants identified in a Chinese patient with hypokalemic metabolic acidosis.

BACKGROUND: Biallelic pathogenic variants in the KCNJ16 gene result in hypokalemic tubulopathy and deafness (HKTD) (MIM #619406), which is a rare autosomal recessive disease characterized by hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Currently, nine individuals with HKTD have been reported, and seven pathogenic variants in KCNJ16 have been revealed. METHODS: A 5-year-6-month-old Chinese female patient displayed hypokalemic metabolic acidosis, salt wasting, renin-angiotensin-aldosterone system (RAAS) activation, arrhythmia, myocardial damage, cardiogenic shock and secondary diffuse brain oedema. Trio-based whole-exome sequencing (WES) was applied to detect the genetic cause. RESULTS: Novel compound heterozygous variants, c.190A>C (p.Thr64Pro) and c.628C>G (p.His210Asp), in KCNJ16 were detected in the patient, and these variants were inherited from the patient's mother and father, respectively. Then, we systematically reviewed the available clinical manifestations of individuals with HKTD. We found that HKTD patients are at risk of cardiogenic shock and secondary diffuse brain oedema, which urges clinicians to make early diagnoses with prompt treatments. CONCLUSION: These findings expand the variant spectrum of KCNJ16, enrich the clinical characteristics of HKTD, and provide a solid base for the genetic counseling, diagnosis and treatment of this condition.

PLOD2 promotes colorectal cancer progression by stabilizing USP15 to activate the AKT/mTOR signaling pathway.

Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) has been reported as an oncogenic gene, affecting various malignant tumors, including endometrial carcinoma, osteosarcoma, and gastric cancer. These effects are mostly due to the enhanced deposition of collagen precursors. However, more studies need to be conducted on how its lysyl hydroxylase function affects cancers like colorectal carcinoma (CRC). Our present results showed that PLOD2 expression was elevated in CRC, and its higher expression was associated with poorer survival. Overexpression of PLOD2 also facilitated CRC proliferation, invasion, and metastasis in vitro and in vivo. In addition, PLOD2 interacted with USP15 by stabilizing it in the cytoplasm and then activated the phosphorylation of AKT/mTOR, thereby promoting CRC progression. Meanwhile, minoxidil was demonstrated to downregulate the expression of PLOD2 and suppress USP15, and the phosphorylation of AKT/mTOR. Our study reveals that PLOD2 plays an oncogenic role in colorectal carcinoma, upregulating USP15 and subsequently activating the AKT/mTOR pathway.