Pretreatment with interleukin-15 attenuates inflammation and apoptosis by inhibiting NF-κB signaling in sepsis-induced myocardial dysfunction.

Sepsis-induced myocardial dysfunction (SIMD) is associated with poor prognosis and increased mortality in patients with sepsis. Cytokines are important regulators of both the initiation and progression of sepsis. Interleukin-15 (IL-15), a pro-inflammatory cytokine, has been linked to protective effects against myocardial infarction and myocarditis. However, the role of IL-15 in SIMD remains unclear. We established a mouse model of SIMD via cecal ligation puncture (CLP) surgery and a cell model of myocardial injury via lipopolysaccharide (LPS) stimulation. IL-15 expression was prominently upregulated in septic hearts as well as cardiomyocytes challenged with LPS. IL-15 pretreatment attenuated cardiac inflammation and cell apoptosis and improved cardiac function in the CLP model. Similar cardioprotective effects of IL-15 pretreatment were observed in vitro. As expected, IL-15 knockdown had the opposite effect on LPS-stimulated cardiomyocytes. Mechanistically, we found that IL-15 pretreatment reduced the expression of the pro-apoptotic proteins cleaved caspase-3 and Bax and upregulated the anti-apoptotic protein Bcl-2. RNA sequencing and Western blotting further confirmed that IL-15 pretreatment suppressed the activation of nuclear factor kappa B (NF-κB) signaling in mice with sepsis. Besides, the addition of NF-κB inhibitor can significantly attenuate cardiomyocyte apoptosis compared to the control findings. Our results suggest that IL-15 pretreatment attenuated the cardiac inflammatory responses and reduced cardiomyocyte apoptosis by partially inhibiting NF-κB signaling in vivo and in vitro, thereby improving cardiac function in mice with sepsis. These findings highlight a promising therapeutic strategy for SIMD.

Cardiac Piezo1 Exacerbates Lethal Ventricular Arrhythmogenesis by Linking Mechanical Stress with Ca2+ Handling After Myocardial Infarction.

Ventricular arrhythmogenesis is a key cause of sudden cardiac death following myocardial infarction (MI). Accumulating data show that ischemia, sympathetic activation, and inflammation contribute to arrhythmogenesis. However, the role and mechanisms of abnormal mechanical stress in ventricular arrhythmia following MI remain undefined. We aimed to examine the impact of increased mechanical stress and identify the role of the key sensor Piezo1 in ventricular arrhythmogenesis in MI. Concomitant with increased ventricular pressure, Piezo1, as a newly recognized mechano-sensitive cation channel, was the most up-regulated mechanosensor in the myocardium of patients with advanced heart failure. Piezo1 was mainly located at the intercalated discs and T-tubules of cardiomyocytes, which are responsible for intracellular calcium homeostasis and intercellular communication. Cardiomyocyte-conditional Piezo1 knockout mice (Piezo1Cko) exhibited preserved cardiac function after MI. Piezo1Cko mice also displayed a dramatically decreased mortality in response to the programmed electrical stimulation after MI with a markedly reduced incidence of ventricular tachycardia. In contrast, activation of Piezo1 in mouse myocardium increased the electrical instability as indicated by prolonged QT interval and sagging ST segment. Mechanistically, Piezo1 impaired intracellular calcium cycling dynamics by mediating the intracellular Ca2+ overload and increasing the activation of Ca2+-modulated signaling, CaMKII, and calpain, which led to the enhancement of phosphorylation of RyR2 and further increment of Ca2+ leaking, finally provoking cardiac arrhythmias. Furthermore, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), Piezo1 activation remarkably triggered cellular arrhythmogenic remodeling by significantly shortening the duration of the action potential, inducing early afterdepolarization, and enhancing triggered activity.This study uncovered a proarrhythmic role of Piezo1 during cardiac remodeling, which is achieved by regulating Ca2+ handling, implying a promising therapeutic target in sudden cardiac death and heart failure.

EphrinB2 drives osteogenic fate of adult cardiac fibroblasts in a calcium influx dependent manner.

Cardiac calcification is a crucial but underrecognized pathological process, greatly increasing the risk of cardiovascular diseases. Little is known about how cardiac fibroblasts, as a central mediator, facilitate abnormal mineralization. Erythropoietin-producing hepatoma interactor B2 (EphrinB2), previously identified as an angiogenic regulator, is involved in fibroblast activation, while its role in the osteogenic differentiation of cardiac fibroblasts is unknown. Bioinformatics analysis was conducted to characterize the expression of the Ephrin family in human calcified aortic valves and calcific mouse hearts. The effects of EphrinB2 on cardiac fibroblasts to adopt osteogenic fate was determined by gain- and loss-of-function. EphrinB2 mRNA level was downregulated in calcified aortic valves and mouse hearts. Knockdown of EphrinB2 attenuated mineral deposits in adult cardiac fibroblasts, whereas overexpression of EphrinB2 promoted their osteogenic differentiation. RNA sequencing data implied that Ca2+-related S100/receptor for advanced glycation end products (RAGE) signaling may mediate EphrinB2-induced mineralization in cardiac fibroblasts. Moreover, L-type calcium channel blockers inhibited osteogenic differentiation of cardiac fibroblasts, implying a critical role in Ca2+ influx. In conclusion, our data illustrated an unrecognized role of EphrinB2, which functions as a novel osteogenic regulator in the heart through Ca2+ signaling and could be a potential therapeutic target in cardiovascular calcification.NEW & NOTEWORTHY In this study, we observed that adult cardiac fibroblasts but not neonatal cardiac fibroblasts exhibit the ability of osteogenic differentiation. EphrinB2 promoted osteogenic differentiation of cardiac fibroblasts through activating Ca2+-related S100/RAGE signaling. Inhibition of Ca2+ influx using L-type calcium channel blockers inhibited EphrinB2-mediated calcification of cardiac fibroblasts. Our data implied an unrecognized role of EphrinB2 in regulating cardiac calcification though Ca2+-related signaling, suggesting a potential therapeutic target of cardiovascular calcification.

Sulfur-Doped rGO Aerogel Enables the Anchoring of 1T/2H MoS2 for Durable Oxygen Reduction Reaction Catalyst Support.

Durability is crucial for the long-term application of cathode oxygen reduction reaction (ORR) catalysts in fuel cells. In this work, sulfur was successfully doped into reduced graphene oxide (rGO) aerogels to achieve the formation of 1T/2H hybrid phase MoS2 , obtaining MoS2 @S-rGO-300 composite ORR catalyst support. After loading ultrafine Pt nanoparticles, Pt/MoS2 @S-rGO-300 showed not only an enhanced ORR activity, but also a significantly improved stability after 10000 cycles. The mass activity retention for Pt/MoS2 @S-rGO-300 after cycles reached 89.94 %, while that of Pt/rGO was only 37.44 %. Density functional theory calculations revealed that the enlarged binding energy between Pt atoms and MoS2 @S-rGO-300 led to the prevention of Pt agglomeration as well as Ostwald ripening.

Increased serum methylmalonic acid levels were associated with the presence of cardiovascular diseases.

Background: Functional vitamin B12 deficiency is common in cardiovascular diseases (CVDs), such as heart failure and myocardial infarction. Methylmalonic acid (MMA) is a specific and sensitive marker of vitamin B12 deficiency. However, there are scarce data in regard to the relationship between MMA and CVDs. Materials and methods: In this cross-sectional study, we analyzed data of 5,313 adult participants of the National Health and Nutrition Examination Survey (NHANES) 2013-2014. Associations between MMA and other variables were assessed with linear regression models. Univariable and multivariable logistic regression models were employed to explore the association between MMA and CVDs. Results: The weighted prevalence of CVDs was 8.8% in the general population of the USA. Higher MMA levels were found in participants with CVDs (p < 0.001). Linear regression models revealed positive associations between serum MMA level and age (p < 0.001), glycohemoglobin (p = 0.023), fasting glucose (p = 0.044), mean cell volume (p = 0.038), and hypertension (p = 0.003). In the multivariable logistic model adjusting for age, gender, ethnicity, smoking, hypertension, glycohemoglobin, body mass index (BMI), low-density lipoprotein-cholesterol (LDL-C), renal dysfunction and vitamin B12, serum MMA (adjusted odds ratio, 3.08; 95% confidence interval: 1.63-5.81, p = 0.002, per ln nmol/L increment) was associated with CVDs. Conclusion: Our study demonstrated that elevated serum MMA levels were independently associated with the presence of CVDs and may be used to predict the occurrence of CVDs.

Recent Advances in Multiresponsive Flexible Sensors towards E-skin: A Delicate Design for Versatile Sensing.

Multiresponsive flexile sensors with strain, temperature, humidity, and other sensing abilities serving as real electronic skin (e-skin) have manifested great application potential in flexible electronics, artificial intelligence (AI), and Internet of Things (IoT). Although numerous flexible sensors with sole sensing function have already been reported since the concept of e-skin, that mimics the sensing features of human skin, was proposed about a decade ago, the ones with more sensing capacities as new emergences are urgently demanded. However, highly integrated and highly sensitive flexible sensors with multiresponsive functions are becoming a big thrust for the detection of human body motions, physiological signals (e.g., skin temperature, blood pressure, electrocardiograms (ECG), electromyograms (EMG), sweat, etc.) and environmental stimuli (e.g., light, magnetic field, volatile organic compounds (VOCs)), which are vital to real-time and all-round human health monitoring and management. Herein, this review summarizes the design, manufacturing, and application of multiresponsive flexible sensors and presents the future challenges of fabricating these sensors for the next-generation e-skin and wearable electronics.

Mechanistically Scoping Cell-Free and Cell-Dependent Artificial Scaffolds in Rebuilding Skeletal and Dental Hard Tissues.

Rebuilding mineralized tissues in skeletal and dental systems remains costly and challenging. Despite numerous demands and heavy clinical burden over the world, sources of autografts, allografts, and xenografts are far limited, along with massive risks including viral infections, ethic crisis, and so on. Per such dilemma, artificial scaffolds have emerged to provide efficient alternatives. To date, cell-free biomimetic mineralization (BM) and cell-dependent scaffolds have both demonstrated promising capabilities of regenerating mineralized tissues. However, BM and cell-dependent scaffolds have distinctive mechanisms for mineral genesis, which makes them methodically, synthetically, and functionally disparate. Herein, these two strategies in regenerative dentistry and orthopedics are systematically summarized at the level of mechanisms. For BM, methodological and theoretical advances are focused upon; and meanwhile, for cell-dependent scaffolds, it is demonstrated how scaffolds orchestrate osteogenic cell fate. The summary of the experimental advances and clinical progress will endow researchers with mechanistic understandings of artificial scaffolds in rebuilding hard tissues, by which better clinical choices and research directions may be approached.

Phase change mediated mechanically transformative dynamic gel for intelligent control of versatile devices.

Traditional devices, including conventional rigid electronics and machines, as well as emerging wearable electronics and soft robotics, almost all have a single mechanical state for particular service purposes. Nonetheless, dynamic materials with interchangeable mechanical states, which enable more diverse and versatile applications, are urgently necessary for intelligent and adaptive application cases in the future electronic and robot fields. Here, we report a gel-like material composed of a crosslinking polymer network impregnated with a phase changing molten liquid, which undergoes an exceptional stiffness transition in response to a thermal stimulus. Vice versa, the material switches from a soft gel state to a rigid solid state with a dramatic stiffness change of 105 times (601 MPa versus 4.5 kPa) benefiting from the liquid-solid phase change of the crystalline polymer once cooled. Such reversibility of the phase and mechanical transition upon thermal stimuli enables the dynamic gel mechanical transformation, demonstrating potential applications in an adhesive thermal interface gasket (TIG) to facilitate thermal transport, a high-temperature warning sensor and an intelligent gripper. Overall, this dynamic gel with a tunable stiffness change paves a new way to design and fabricate adaptive smart materials toward intelligent control of versatile devices.

Piezo1-Mediated Mechanotransduction Promotes Cardiac Hypertrophy by Impairing Calcium Homeostasis to Activate Calpain/Calcineurin Signaling.

[Figure: see text].

Glutamine metabolism: from proliferating cells to cardiomyocytes.

Glutamine is a major energy source for rapidly dividing cells, such as hematopoietic stem cells and cancer cells. Reliance on glutamine is therefore regarded as a metabolic hallmark of proliferating cells. Moreover, reprogramming glutamine metabolism by various factors, including tissue type, microenvironment, pro-oncogenes, and tumor suppressor genes, can facilitate stem cell fate decisions, tumor recurrence, and drug resistance. However, the significance of glutamine metabolism in cardiomyocytes, an end-differentiated cell type, is not fully understood. Existing evidence suggests important roles of glutamine metabolism in the development of cardiovascular diseases. In this review, we have focused on glutaminolysis and its regulatory network in proliferating cells. We have summarized current findings about the role of glutamine utilization in cardiomyocytes and have discussed possibilities of targeting glutamine metabolism for the treatment of cardiovascular diseases.

Heme Oxygenase-1 in Macrophages Impairs the Perfusion Recovery After Hindlimb Ischemia by Suppressing Autolysosome-Dependent Degradation of NLRP3.

[Figure: see text].

Emerging roles of fibroblasts in cardiovascular calcification.

Cardiovascular calcification, a kind of ectopic mineralization in cardiovascular system, including atherosclerotic calcification, arterial medial calcification, valve calcification and the gradually recognized heart muscle calcification, is a complex pathophysiological process correlated with poor prognosis. Although several cell types such as smooth muscle cells have been proven critical in vascular calcification, the aetiology of cardiovascular calcification remains to be clarified due to the diversity of cellular origin. Fibroblasts, which possess remarkable phenotypic plasticity that allows rapid adaption to fluctuating environment cues, have been demonstrated to play important roles in calcification of vasculature, valve and heart though our knowledge of the mechanisms controlling fibroblast phenotypic switching in the calcified process is far from complete. Indeed, the lack of definitive fibroblast lineage-tracing studies and typical expression markers of fibroblasts raise major concerns regarding the contributions of fibroblasts during all the stages of cardiovascular calcification. The goal of this review was to rigorously summarize the current knowledge regarding possible phenotypes exhibited by fibroblasts within calcified cardiovascular system and evaluate the potential therapeutic targets that may control the phenotypic transition of fibroblasts in cardiovascular calcification.

Burden of valvular heart disease, 1990-2017: Results from the Global Burden of Disease Study 2017.

BACKGROUND: Valvular heart disease (VHD) is expected to cause an increase in public-health problems in the coming years, especially in elderly populations. We aim to estimate the incidence, mortality, and burden of VHD, by age, from 1990 to 2017 in 195 countries and territories. METHODS: We estimated the incidence, mortality, and burden of VHD based on the Global Burden of Disease Study 2017. All metrics are presented with their 95% uncertainty intervals (UIs). The Socio-demographic Index was used to identify whether developmental status correlates with health outcomes. RESULTS: The global incidence of rheumatic heart disease (RHD) decreased by 8.67% between 1990 and 2017, while that of non-rheumatic VHD (NRVHD) increased by 45.10%. There was a 54.00% decrease in age-standardized death rate (ASDR) for RHD, but a small and non-significant decrease (-3.00%) in the ASDR for NRVHD. The global age-standardized disability-adjusted life years (DALY) rate of RHD decreased by 53.52%, while there was a 12.62% reduction in the age-standardized DALY rate of NRVHD. CONCLUSIONS: The burden from different VHDs demonstrated a diverse change at a global level between 1990 and 2017. Although RHD burden has an obvious means of mitigation, a substantially high incidence of NRVHD was observed over this time period, especially in the elderly, which may lead to high health care costs and signify the potential for even higher costs in the future.

Dop1 enhances conspecific olfactory attraction by inhibiting miR-9a maturation in locusts.

Dopamine receptor 1 (Dop1) mediates locust attraction behaviors, however, the mechanism by which Dop1 modulates this process remains unknown to date. Here, we identify differentially expressed small RNAs associated with locust olfactory attraction after activating and inhibiting Dop1. Small RNA transcriptome analysis and qPCR validation reveal that Dop1 activation and inhibition downregulates and upregulates microRNA-9a (miR-9a) expression, respectively. miR-9a knockdown in solitarious locusts increases their attraction to gregarious volatiles, whereas miR-9a overexpression in gregarious locusts reduces olfactory attraction. Moreover, miR-9a directly targets adenylyl cyclase 2 (ac2), causing its downregulation at the mRNA and protein levels. ac2 responds to Dop1 and mediates locust olfactory attraction. Mechanistically, Dop1 inhibits miR-9a expression through inducing the dissociation of La protein from pre-miR-9a and resulting in miR-9a maturation inhibition. Our results reveal a Dop1-miR-9a-AC2 circuit that modulates locust olfactory attraction underlying aggregation. This study suggests that miRNAs act as key messengers in the GPCR signaling.