Nonlinear Closed-Loop Predictive Control of Heart Rate and Blood Pressure Using Vagus Nerve Stimulation: An In Silico Study.

We propose a nonlinear model-based control technique for regulating the heart rate and blood pressure using vagus nerve neuromodulation. The closed-loop framework is based on an in silico model of the rat cardiovascular system for the simulation of the hemodynamic response to multi-location vagal nerve stimulation. The in silico model is derived by compartmentalizing the various physiological components involved in the closed-loop cardiovascular system with intrinsic baroreflex regulation to virtually generate nominal and hypertension-related heart dynamics of rats in rest and exercise states. The controller, using a reduced cycle-averaged model, monitors the outputs from the in silico model, estimates the current state of the reduced model, and computes the optimum stimulation locations and the corresponding parameters using a nonlinear model predictive control algorithm. The results demonstrate that the proposed control strategy is robust with respect to its ability to handle setpoint tracking and disturbance rejection in different simulation scenarios.

Orietation-controlled synthesis and Raman study of 2D SnTe.

Tin telluride (SnTe), as a narrow bandgap semiconductor material, has great potential for developing photodetectors with wide spectra and ultra-fast response. At the same time, it is also an important topological crystal insulator material, with different topological surface states on several common surfaces. Here, we introduce different Sn sources and control the growth of regular SnTe nanosheets along the (100) and (111) planes through the atmospheric pressure chemical vapor deposition method. It has been proven through various characterizations that the synthesized SnTe is a high-quality single crystal. In addition, the angular resolved Raman spectra of SnTe nanosheets grown on different crystal planes are first demonstrated. The experimental results showed that square SnTe nanosheets grown along the (100) plane exhibit in-plane anisotropy. At the same time, we use micro-nanofabrication technology to manufacture SnTe-based field effect transistors and photodetectors to explore their electrical and optoelectronic properties. It has been confirmed that transistors based on grown SnTe nanosheets exhibit p-type semiconductor characteristics and have a high response to infrared light. This work provides a new approach for the controllable synthesis of SnTe and adds new content to the research of SnTe-based infrared detectors.

Kallistatin Improves High-Fat-Induced Insulin Resistance via Epididymal Adipose Tissue-Derived Exosomes.

Objective: Studies have found that high expression of human Kallistatin (HKS) in adipose tissue can improve obesity and its associated comorbidities, but the underlying mechanism of specific regulation is unclear. Methods: An obesity model was built by injecting 8-week-old C57BL/6 mice (n = 6 mice per group) with Ad.Null and Ad.HKS adenovirus into epididymal adipose tissue and fed with a high-fat diet (HFD). Insulin resistance-related proteins, AKT and IRS1, were detected in the liver, subcutaneous fat, and skeletal muscle by western blotting after one month of HFD. Epididymal adipose tissue was isolated after 24 h for culture, and exosomes were extracted by differential centrifugation. Enzyme-linked immunosorbent assay detected the expression of HKS protein in serum and exosomes. To examine the role of exosomes in AML12 insulin resistance, we used epididymal adipose tissue-derived exosomes or transfected Ad.HKS into mature 3T3L1-derived exosomes to interfere with palmitic acid (PA)-induced mouse AML12 insulin resistance model. GW4869 was used to inhibit exosome biogenesis and release. Results: Our results showed that HFD-induced mice with high expression of HKS in epididymal adipose tissue had slower weight gain, lower serum triglycerides, reduced free fatty acids, and improved liver insulin resistance compared with the Ad.Null group. We also demonstrated that HKS was enriched in epididymal adipose tissue-derived exosomes and released through the exosome pathway. In PA-induced AML12 cells, insulin resistance was alleviated after incubation of the HKS-related exosome; this effect was reversed with GW4869. Conclusion: High expression of HKS in epididymal adipose tissue could lead to its exocrine secretion in the form of exosomes and improve liver insulin resistance by promoting the phosphorylation of AKT. Production of high HKS vesicles might be a possible way to alleviate insulin resistance associated with obesity.

Tunable heterostructural prism for planar polaritonic switch.

The study of phonon polaritons in van der Waals materials at the nanoscale has gained significant attention in recent years due to its potential applications in nanophotonics. The unique properties of these materials, such as their ability to support sub-diffraction imaging, sensing, and hyperlenses, have made them a promising avenue for the development of new techniques in the field. Despite these advancements, there still exists a challenge in achieving dynamically reversible manipulation of phonon polaritons in these materials due to their insulating properties. In this study, we present experimental results on the reversible manipulation of anisotropic phonon polaritons in α-MoO3 on top of a VO2 film, a phase-change material known for its dramatic changes in dielectric properties between its insulating and metallic states. Our findings demonstrate that the engineered VO2 film enables a switch in the propagation of polaritons in the mid-infrared region by modifying the dielectric properties of the film through temperature changes. Our results represent a promising approach to effectively control the flow of light energy at the nanoscale and offer the potential for the design and fabrication of integrated, flat sub-diffraction polaritonic devices. This study adds to the growing body of work in the field of nanophotonics and highlights the importance of considering phase-change materials for the development of new techniques in this field.

Inhibition of miR-195-3p protects against cardiac dysfunction and fibrosis after myocardial infarction.

Cardiac fibrosis following myocardial infarction is a major risk factor for heart failure. Recent evidence suggests that miR-195-3p is up-regulated in fibrotic diseases, including kidney and liver fibrosis. However, its function and underlying mechanisms in cardiac fibrosis after MI remain unknown. To investigate the role of miR-195-3p in MI-induced cardiac fibrosis, we established acute MI models by ligating adult C57B/L6 mice LAD coronary artery while sham-operated mice were used as controls. In vivo inhibition of miR-195-3p was conducted by intramyocardial injection of AAV9-anti-miR-195-3p. In vitro overexpression and inhibition of miR-195-3p were performed by transfecting cultured Cardiac Fibroblasts (CFs) with synthetic miRNA mimic and inhibitor. Our results showed that MI induced the expression of miR-195-3p and that inhibition of miR-195-3p reduced myofibroblast differentiation and collagen deposition and protected cardiac function. In vitro stimulation of CFs with TGF-ß1 resulted in a significant increase in miR-195-3p expression. Inhibition of miR-195-3p attenuated the TGF-ß1-induced expression of ECM proteins, migration, and proliferation. PTEN expression was significantly reduced in the hearts of MI mice, in activated CFs, and in CFs transfected with miR-195-3p mimic. Inhibition of miR-195-3p markedly restored PTEN expression in MI mice and TGF-ß1-treated CFs. In conclusion, this study highlights the crucial role of miR-195-3p in promoting cardiac fibrosis and dysfunction after MI. Inhibiting miR-195-3p could be a promising therapeutic strategy for preventing cardiac fibrosis and preserving cardiac function after MI. Additionally, the study sheds light on the mechanisms underlying the effects of miR-195-3p on fibrosis, including its regulation of PTEN/AKT pathway.

TRIM44 aggravates cardiac fibrosis after myocardial infarction via TAK1 stabilization.

Myocardial infarction (MI) is one of the most dangerous cardiovascular events. Cardiac fibrosis is a common pathological feature of remodeling after injury that is related to adverse clinical results with no effective treatment. Previous studies have confirmed that TRIM44, an E3 ligase, can promote the proliferation and migration of various tumor cells. However, the role of TRIM44 in cardiac fibrosis remains unknown. Models of TGF-ß1 stimulation and MI-induced fibrosis were established to investigate the role and potential underlying mechanism of TRIM44 in cardiac fibrosis. The results showed that cardiac fibrosis was significantly inhibited after TRIM44 knockdown in a mouse model of MI, while it was enhanced when TRIM44 was overexpressed. Furthermore, in vitro studies showed that fibrosis markers were significantly reduced in cardiac fibroblasts (CFs) with TRIM44 knockdown, whereas TRIM44 overexpression promoted the expression of fibrosis markers. Mechanistically, TRIM44 maintains TAK1 stability by inhibiting the degradation of k48-linked polyubiquitination-mediated ubiquitination, thereby increasing phosphorylated TAK1 expression in the fibrotic environment and activating MAPKs to promote fibrosis. Pharmacological inhibition of TAK1 phosphorylation reversed the fibrogenic effects of TRIM44 overexpression. Combined, these results suggest that TRIM44 is a potential therapeutic target for cardiac fibrosis.

Visceral adipose tissue-directed human kallistatin gene therapy improves adipose tissue remodeling and metabolic health in obese mice.

OBJECTIVE: Adipose tissue remodeling is a dynamic process that is pathologically expedited in the obese state and is closely related to obesity-associated disease progression. This study aimed to explore the effects of human kallistatin (HKS) on adipose tissue remodeling and obesity-related metabolic disorders in mice fed with a high-fat diet (HFD). METHODS: Adenovirus-mediated HKS cDNA (Ad.HKS) and a blank adenovirus (Ad.Null) were constructed and injected into the epididymal white adipose tissue (eWAT) of 8-weeks-old male C57B/L mice. The mice were fed normal or HFD for 28 days. The body weight and circulating lipids levels were assessed. Intraperitoneal glucose tolerance test (IGTT) and insulin tolerance test (ITT) were also performed. Oil-red O staining was used to assess the extent of lipid deposition in the liver. Immunohistochemistry and HE staining were used to measure HKS expression, adipose tissue morphology, and macrophage infiltration. Western blot and qRT-PCR were used to evaluate the expression of adipose function-related factors. RESULTS: At the end of the experiment, the expression of HKS in the serum and eWAT of the Ad.HKS group was higher than in the Ad.Null group. Furthermore, Ad.HKS mice had lower body weight and decreased serum and liver lipid levels after four weeks of HFD feeding. IGTT and ITT showed that HKS treatment maintained balanced glucose homeostasis. Additionally, inguinal white adipose tissue (iWAT) and eWAT in Ad.HKS mice had a higher number of smaller-size adipocytes and had less macrophage infiltration than Ad.Null group. HKS significantly increased the mRNA levels of adiponectin, vaspin, and eNOS. In contrast, HKS decreased RBP4 and TNFα levels in the adipose tissues. Western blot results showed that local injection of HKS significantly upregulated the protein expressions of SIRT1, p-AMPK, IRS1, p-AKT, and GLUT4 in eWAT. CONCLUSIONS: HKS injection in eWAT improves HFD-induced adipose tissue remodeling and function, thus significantly improving weight gain and dysregulation of glucose and lipid homeostasis in mice.

Identification of major hub genes involved in high-fat diet-induced obese visceral adipose tissue based on bioinformatics approach.

High-fat diet (HFD) can cause obesity, inducing dysregulation of the visceral adipose tissue (VAT). This study aimed to explore potential biological pathways and hub genes involved in obese VAT, and for that, bioinformatic analysis of multiple datasets was performed. The expression profiles (GSE30247, GSE167311 and GSE79434) were downloaded from Gene Expression Omnibus. Overlapping differentially expressed genes (ODEGs) between normal diet and HFD groups in GSE30247 and GSE167311 were selected to run protein-protein interaction network, GO and KEGG analysis. The hub genes in ODEGs were screened by Cytoscape software and further verified in GSE79434 and obese mouse model. A total of 747 ODEGs (599 up-regulated and 148 down-regulated) were screened, and the GO and KEGG analysis showed that the up-regulated ODEGs were significantly enriched in inflammatory response and extracellular matrix receptor interaction pathways. On the other hand, the down-regulated ODEGs were involved in metabolic pathways; however, there were no significant KEGG pathways. Furthermore, six hub genes, Mki67, Rac2, Itgb2, Emr1, Tyrobp and Csf1r were acquired. These pathways and genes were verified in GSE79434 and VAT of obese mice. This study revealed that HFD induced VAT expansion, inflammation and fibrosis, and the hub genes could be used as therapeutic biomarkers in obesity.

Delivery of Mir-196c-3p with NIR-II light-triggered gel attenuates cardiomyocyte ferroptosis in cardiac ischemia-reperfusion injury.

Ferroptosis plays an important role in ischemia-reperfusion (I/R)-induced cardiac injury and there are many defects in current targeted delivery of miRNAs for the treatment of ferroptosis. We herein report a unique hydrogel (Gel) that can be triggered by a near-infrared-II (NIR-II) light with deep tissue penetration and biocompatible maximum permissible exposure (MPE) value for in situ treatment after I/R. The mir-196c-3p mimic (mimics) and photothermal nanoparticles (BTN) were co-encapsulated in an injectable Gel (mimics + Gel/BTN) with NIR-II light-triggered release. Using 1064 nm light irradiation, local microenvironment photothermal-triggered on-demand noninvasive controllable delivery of miRNA was achieved, aiming to inhibit I/R-induced ferroptosis. Consequently, declined ferroptosis in cardiomyocytes and improved cardiac function, survival rate in rats was achieved through the controlled release of Gel/BTN mimics in I/R model to simultaneously inhibit ferroptosis hub genes NOX4, P53, and LOX expression.

High serum fibroblast growth factor 21 levels were related to the prognosis and ventricular remodeling of heart failure patients with mildly reduced and reduced ejection fraction.

INTRODUCTION: Previous studies have shown that fibroblast growth factor 21 (FGF21) is involved in the ventricular remodeling process in heart failure with preserved ejection fraction (HFpEF). We hypothesized that high levels of FGF21 correlated with the ventricular remodeling of heart failure patients with mildly reduced (HFmrEF) and reduced ejection fraction (HFrEF). METHODS: A total of 203 participants with HFmrEF or HFrEF were enrolled and followed up from June 2018 to June 2021. 68 subjects without heart failure (HF) underwent physical examinations during the same time were selected as the control group. The primary endpoint was the occurrence of major adverse cardiovascular events (MACEs), which were defined as all-cause or cardiac mortality and rehospitalization for decompensation. Serum FGF21 levels were measured early the next morning after admission using enzyme-linked immunosorbent assay (ELISA). RESULTS: The FGF21 levels were significantly higher in patients with HFmrEF or HFrEF than that in the control group (213.57 ± 42.65 pg/mL, 222.93 ± 34.36 pg/mL vs 171.00 ± 12.86 pg/mL, p < .001). The serum levels of FGF21 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were both higher in the endpoint event group than those of non-endpoint event group regardless of the HFmrEF or HFrEF group (p < .001). Spearman's correlation revealed that FGF21 was positively correlated with left ventricular end-systolic diameter left ventricular end-diastolic diameter left ventricular mass index (p < .01). Moreover, there was a negative correlation between FGF21 and left ventricular ejection fraction in addition to relative wall thickness (p < .001). The area under the receiver operating characteristic (ROC) curve (AUC) of FGF21 was 0.874. The optimal cut-off value of FGF21 determined by ROC curve was 210.11 pg/mL. The Kaplan-Meier analysis demonstrated that the low FGF21 levels group had an increased MACE-free survival rate compared with the high FGF21 levels group. On univariate and multivariate Cox analysis, it was seen that both serum FGF21 and NT-proBNP were independent predictors of a poor prognosis in HF patients. CONCLUSION: Baseline levels of FGF21 and NT-proBNP were related to the ventricular remodeling of patients with a mildly reduced or reduced ejection fraction. FGF21 and NT-proBNP both had good prognostic value for MACEs in heart failure patients with a mildly reduced and reduced ejection fraction.

The triglycerides-glucose index and the triglycerides to high-density lipoprotein cholesterol ratio are both effective predictors of in-hospital death in non-diabetic patients with AMI.

Background: The triglycerides-glucose index (TyG) and the triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) are simple indicators for assessing insulin resistance in epidemiological studies. We aimed to clarify the relationship between indicators of insulin resistance and prognosis in non-diabetic acute myocardial infarction (AMI) patients. Methods: A total of 1,648 AMI patients without diabetes were enrolled from the Department of Cardiology, Zhongda Hospital, between 2012.03 and 2018.12. The medical history, laboratory and imaging data of patients were collected through the medical record system, and all-cause death events were recorded. Pearson analysis was used to study the correlation among different variables. Logistic regression analysis was used to analyze the predictive effect of TyG and TG/HDL-C in in-hospital death of AMI patients. Results: 1. In AMI group, the TyG index was significantly increased in death groups compared to no-death groups (P = 0.025). TG/HDL-C was not significantly increased in the death group of AMI patients (P = 0.588). The patients were respectively divided into Q1-Q4 groups and T1-T4 groups according to the quartiles of TyG and TG/HDL-C. The trends of in-hospital mortality in the Q4 group of TyG and T4 group of TG/HDL-C were higher than in other groups, although these differences were not significant. 2. Pearson correlation analysis showed that TyG was positively correlated with lipid-related markers, including ApoB (r = 0.248, P < 0.001), total cholesterol (TC) (r = 0.270, P < 0.001), low-density lipoprotein cholesterol (LDL-C) (r = 0.238, P < 0.001). Spearman analysis showed that TG/HDL-C was also positively associated with TC (r = 0.107, P < 0.001), ApoB (r = 0.180, P < 0.001) and LDL-C (r = 0.164, P < 0.001). 3. Logistic regression analysis showed that TyG (OR = 3.106, 95% CI [2.122-4.547], P < 0.001) and TG/HDL-C (OR = 1.167, 95% CI [1.062-1.282], P = 0.001) were both important factors to predict the in-hospital death of AMI patients without diabetes. Conclusions: TyG index and TG/HDL-C, as emerged simple markers of insulin resistance, were both important predictors of in-hospital death in AMI patients without diabetes.

CONTROL-CORE: A Framework for Simulation and Design of Closed-Loop Peripheral Neuromodulation Control Systems.

Closed-loop Vagus Nerve Stimulation (VNS) based on physiological feedback signals is a promising approach to regulate organ functions and develop therapeutic devices. Designing closed-loop neurostimulation systems requires simulation environments and computing infrastructures that support i) modeling the physiological responses of organs under neuromodulation, also known as physiological models, and ii) the interaction between the physiological models and the neuromodulation control algorithms. However, existing simulation platforms do not support closed-loop VNS control systems modeling without extensive rewriting of computer code and manual deployment and configuration of programs. The CONTROL-CORE project aims to develop a flexible software platform for designing and implementing closed-loop VNS systems. This paper proposes the software architecture and the elements of the CONTROL-CORE platform that allow the interaction between a controller and a physiological model in feedback. CONTROL-CORE facilitates modular simulation and deployment of closed-loop peripheral neuromodulation control systems, spanning multiple organizations securely and concurrently. CONTROL-CORE allows simulations to run on different operating systems, be developed in various programming languages (such as Matlab, Python, C++, and Verilog), and be run locally, in containers, and in a distributed fashion. The CONTROL-CORE platform allows users to create tools and testbenches to facilitate sophisticated simulation experiments. We tested the CONTROL-CORE platform in the context of closed-loop control of cardiac physiological models, including pulsatile and nonpulsatile rat models. These were tested using various controllers such as Model Predictive Control and Long-Short-Term Memory based controllers. Our wide range of use cases and evaluations show the performance, flexibility, and usability of the CONTROL-CORE platform.

Tripartite motif 38 attenuates cardiac fibrosis after myocardial infarction by suppressing TAK1 activation via TAB2/3 degradation.

The role of tripartite motif (TRIM) 38, a ubiquitin E3 ligase regulating various pathophysiological processes, in cardiac fibrosis remains unclear. Here, a model of angiotensin II and myocardial infarction (MI)-induced fibrosis was established to explore its role in cardiac fibrosis and its underlying mechanisms. Cardiac fibrosis in the mouse MI model was mitigated by TRIM38 overexpression, but aggravated by its depletion. Consistently, in vitro overexpression or knockdown of TRIM38 ameliorated or aggravated the proliferation and secretion of cardiac fibroblasts (CFs) exposed to fibrotic stimulation, respectively. Mechanistically, TRIM38 suppressed cardiac fibrosis progression by attenuating TAK1/MAPK signaling. Inhibiting TAK1/MAPK signaling with a pharmacological inhibitor greatly reversed the effects of TRIM38 knockdown on CF secretion. Specifically, TRIM38 interacted with and "targeted" TAB2 and TAB3 for degradation, subsequently inhibiting TAK1 phosphorylation and negatively regulating MAPK signaling. These findings can help develop therapeutic strategies to treat and prevent cardiac fibrosis.

METTL3 mediates Ang-II-induced cardiac hypertrophy through accelerating pri-miR-221/222 maturation in an m6A-dependent manner.

BACKGROUND: METTL3 is the core catalytic enzyme in m6A and is involved in a variety of cardiovascular diseases. However, whether and how METTL3 plays a role during angiotensin II (Ang-II)-induced myocardial hypertrophy is still unknown. METHODS: Neonatal rat cardiomyocytes (NRCMs) and C57BL/6J mice were treated with Ang-II to induce myocardial hypertrophy. qRT-PCR and western blots were used to detect the expression of RNAs and proteins. Gene function was verified by knockdown and/or overexpression, respectively. Luciferase and RNA immunoprecipitation (RIP) assays were used to verify interactions among multiple genes. Wheat germ agglutinin (WGA), hematoxylin and eosin (H&E), and immunofluorescence were used to examine myocardial size. m6A methylation was detected by a colorimetric kit. RESULTS: METTL3 and miR-221/222 expression and m6A levels were significantly increased in response to Ang-II stimulation. Knockdown of METTL3 or miR-221/222 could completely abolish the ability of NRCMs to undergo hypertrophy. The expression of miR-221/222 was positively regulated by METTL3, and the levels of pri-miR-221/222 that bind to DGCR8 or form m6A methylation were promoted by METTL3 in NRCMs. The effect of METTL3 knockdown on hypertrophy was antagonized by miR-221/222 overexpression. Mechanically, Wnt/ß-catenin signaling was activated during hypertrophy and restrained by METTL3 or miR-221/222 inhibition. The Wnt/ß-catenin antagonist DKK2 was directly targeted by miR-221/222, and the effect of miR-221/222 inhibitor on Wnt/ß-catenin was abolished after inhibition of DKK2. Finally, AAV9-mediated cardiac METTL3 knockdown was able to attenuate Ang-II-induced cardiac hypertrophy in mouse model. CONCLUSIONS: Our findings suggest that METTL3 positively modulates the pri-miR221/222 maturation process in an m6A-dependent manner and subsequently activates Wnt/ß-catenin signaling by inhibiting DKK2, thus promoting Ang-II-induced cardiac hypertrophy. AAV9-mediated cardiac METTL3 knockdown could be a therapeutic for pathological myocardial hypertrophy.

High-density lipoprotein cholesterol to apolipoprotein A-1 ratio is an important indicator predicting in-hospital death in patients with acute coronary syndrome.

BACKGROUND: Dyslipidemia plays a pivotal role in the pathogenesis of acute coronary syndrome (ACS). This study aims to investigate the value of two indices associated with lipid metabolism, low-density lipoprotein cholesterol to apolipoprotein B ratio (LBR) and high-density lipoprotein cholesterol to apolipoprotein A-1 ratio (HAR), to predict in-hospital death in patients with ACS. METHODS: This single-center, retrospective, observational study included 3,366 consecutive ACS patients in Zhongda Hospital, Southeast University from July 2013 to January 2018. The clinical and laboratory data were extracted, and the in-hospital death and hospitalization days were also recorded. RESULTS: All patients were equally divided into four groups according to quartiles of HAR: Q1 (HAR < 1.0283), Q2 (1.0283 ≤ HAR < 1.0860), Q3 (1.0860 ≤ HAR < 1.1798), and Q4 (HAR ≥ 1.1798). Overall, HAR was positively associated with the counts of neutrophils and monocytes, whereas negatively correlated to lymphocyte counts. HAR was negatively correlated to left ventricular ejection fraction (LVEF). Compared to other three groups, in-hospital mortality (vs. Q1, Q2, and Q3, p < 0.001) and hospitalization length (vs. Q1, Q2, and Q3, p < 0.001) were significantly higher in the Q4 group. When grouped by LBR, however, there was no significant difference in LVEF, in-hospital mortality, and hospitalization length among groups. After adjusting potential impact from age, systolic blood pressure, creatine, lactate dehydrogenase, albumin, glucose, and uric acid, multivariate analysis indicated that HAR was an independent factor predicting in-hospital death among ACS patients. CONCLUSIONS: HAR had good predictive value for patients' in-hospital death after the occurrence of acute coronary events, but LBR was not related to in-hospital adverse events.

Data Driven Control of Vagus Nerve Stimulation for the Cardiovascular System: An in Silico Computational Study.

Vagus nerve stimulation is an emerging therapy that seeks to offset pathological conditions by electrically stimulating the vagus nerve through cuff electrodes, where an electrical pulse is defined by several parameters such as pulse amplitude, pulse width, and pulse frequency. Currently, vagus nerve stimulation is under investigation for the treatment of heart failure, cardiac arrhythmia and hypertension. Through several clinical trials that sought to assess vagus nerve stimulation for the treatment of heart failure, stimulation parameters were determined heuristically and the results were inconclusive, which has led to the suggestion of using a closed-loop approach to optimize the stimulation parameters. A recent investigation has demonstrated highly specific control of cardiovascular physiology by selectively activating different fibers in the vagus nerve. When multiple locations and multiple stimulation parameters are considered for optimization, the design of closed-loop control becomes considerably more challenging. To address this challenge, we investigated a data-driven control scheme for both modeling and controlling the rat cardiovascular system. Using an existing in silico physiological model of a rat heart to generate synthetic input-output data, we trained a long short-term memory network (LSTM) to map the effect of stimulation on the heart rate and blood pressure. The trained LSTM was utilized in a model predictive control framework to optimize the vagus nerve stimulation parameters for set point tracking of the heart rate and the blood pressure in closed-loop simulations. Additionally, we altered the underlying in silico physiological model to consider intra-patient variability, and diseased dynamics from increased sympathetic tone in designing closed-loop VNS strategies. Throughout the different simulation scenarios, we leveraged the design of the controller to demonstrate alternative clinical objectives. Our results show that the controller can optimize stimulation parameters to achieve set-point tracking with nominal offset while remaining computationally efficient. Furthermore, we show a controller formulation that compensates for mismatch due to intra-patient variabilty, and diseased dynamics. This study demonstrates the first application and a proof-of-concept for using a purely data-driven approach for the optimization of vagus nerve stimulation parameters in closed-loop control of the cardiovascular system.

Kallistatin/Serpina3c inhibits cardiac fibrosis after myocardial infarction by regulating glycolysis via Nr4a1 activation.

BACKGROUND: Fibrotic remodeling is an essential aspect of heart failure. Human kallistatin (KS, mouse Serpina3c homologs) inhibits fibrosis after myocardial infarction (MI) but the specific underlying mechanism is unknown. METHODS: A total of 40 heart failure patients (HFPs) were enrolled and their plasma KS was measured using ELISA. Serpina3c-/- and C57BL/6 mice were used to construct the MI model. TGF-ß1 or a hypoxic condition was established to interfere with the functioning of cardiac fibroblasts (CFs). RNA-seq was performed to assess the effect of Serpina3c on the transcriptome. FINDINGS: The levels of KS were used as a predictor of readmission among the HFPs. Serpina3c expression decreased in MI hearts and CFs. Serpina3c-/- led to the aggravation of MI fibrosis, and increased the proliferation of CFs. The overexpression of Serpina3c in CFs had the opposite effect. Glycolysis-related genes were significantly increased in Serpina3c-/- group by RNA-seq. Enolase (ENO1), which is a key enzyme in glycolysis, increased most significantly. Inhibition of ENO1 could antagonize the promotion of Serpina3c-/- on the proliferation of CFs. Co-IP was performed to verify the interaction between Serpina3c and Nr4a1. Serpina3c-/- inhibited the acetylation of Nr4a1 and increased the degradation of Nr4a1. Activation of Nr4a1 could negatively regulate the expression of ENO1 and inhibited the proliferation of Serpina3c-/- CFs in Serpina3c-/- MI mice. INTERPRETATION: Serpina3c inhibits the transcriptional activation of ENO1 by regulating the acetylation of Nr4a1, thereby reducing the fibrosis after MI by inhibiting glycolysis. Serpina3c is a potential target for prevention and treatment of heart failure after MI.

Dapagliflozin Attenuates Contrast-induced Acute Kidney Injury by Regulating the HIF-1α/HE4/NF-κB Pathway.

ABSTRACT: Contrast-induced acute kidney injury (CI-AKI) causes clinically acquired nephropathy in patients who undergo coronary interventions. Hypoxic injury to proximal tubular epithelial cells is a pathological mechanism of CI-AKI. Previous studies have shown that hypoxia activates HIF-1α/HE4/NF-κB to enhance renal fibrosis, and the SGLT-2 inhibitor luseogliflozin inhibits hypoxia-inducible factor (HIF)-1α expression to reduce the progression of diabetic nephropathy. However, the therapeutic effects and mechanisms of SGLT-2 inhibitors on CI-AKI are unclear. We explored the role of the HIF-1α/HE4/NF-κB pathway in CI-AKI and how dapagliflozin effectively treats CI-AKI by inhibiting this pathway. In vitro, cells were divided into the control, hypoxia, hypoxia + dapagliflozin, and hypoxia + pSilencer-HIF-1α groups. Cellular hypoxia, apoptosis, and related protein expression were evaluated by immunofluorescence, western blotting, and flow cytometry, respectively. Dapagliflozin significantly decreased oxygen consumption, HIF-1α, human epididymis protein 4 (HE4), NF-κB expression, and apoptotic cells compared with the control (P < 0.01). In vivo, rats were divided into the control (C), diabetes (D), diabetes + contrast media, and diabetes + contrast media + dapagliflozin groups. Rats in the latter 2 groups were treated with dapagliflozin for 2 days. CI-AKI was induced by intravenously injecting indomethacin, N-nitro-l-arginine methyl ester, and iohexol. The effects of dapagliflozin on CI-AKI rats were elucidated by assessing renal function, H&E staining, and immunohistochemistry. Serum creatinine, urea nitrogen, TUNEL-positive tubular cells, HIF-1α, HE4, NF-κB expression, and histopathological scores were increased in diabetes + contrast media rats compared with C, D, and diabetes + dapagliflozin + contrast media rats (P < 0.01). Thus, dapagliflozin may ameliorate CI-AKI through suppression of HIF-1α/HE4/NF-κB signaling in vitro and in vivo.

Serpina3c regulates adipose differentiation via the Wnt/ß-catenin-PPARγ pathway.

OBJECTIVE: The Serpin protein family plays an important role in regulating the functioning of the adipose tissue. This study aimed to study the underlying mechanisms of Serpina3c in regulating adipogenesis. METHODS: We developed a Serpina3c knockout (Serpina3c-/-) mouse model and Serpina3c knockdown and overexpression 3T3-L1 preadipocyte models to evaluate the role of Serpina3c in adipose differentiation. Mice were fed on ND for 12-month or HFD for one month. The body weight, glucose tolerance, and insulin tolerance of the mice were subsequently measured. Lipid depositions and adipose tissue morphology were then detected using Oil red O staining and HE staining. qRT-PCR and Western blot were used to detect the expression of adipose differentiation transcription factors. RESULTS: Serpina3c-/- mice exhibited lower body weight and white adipose tissue (WAT) weight than WT mice after 12 months of being fed on ND. Additionally, there was an increase in serum and hepatic triglyceride (TG) levels in Serpina3c-/- mice, without changes in glucose metabolism. Wnt/ß-catenin was upregulated while PPARγ expression was decreased in knockout mice WAT. Impaired adipocyte differentiation caused by Serpina3c knockdown was reversed by IWR-1 and kallistatin through an increase in PPARγ expression. Serpina3c-/- mice fed on HFD for one month had a lower body weight and WAT than WT, accompanied by increased lipid depositions in the liver and muscles and severe insulin resistance. CONCLUSION: Serpina3c promotes adipogenesis and maintains normal fat function by inhibiting the Wnt/ß-catenin pathway.