Pharmacology of hydrogen sulfide and its donors in cardiometabolic diseases.

Cardiometabolic diseases (CMDs) are major contributors to global mortality, emphasizing the critical need for novel therapeutic interventions. Hydrogen sulfide (H2S) has garnered enormous attention as a significant gasotransmitter with various physiological, pathophysiological, and pharmacological impacts within mammalian cardiometabolic systems. In addition to its roles in attenuating oxidative stress and inflammatory response, burgeoning research emphasizes the significance of H2S in regulating proteins via persulfidation, a well-known modification intricately associated with the pathogenesis of CMDs This review seeks to investigate recent updates on the physiological actions of endogenous H2S and the pharmacological roles of various H2S donors in addressing diverse aspects of CMDs across cellular, animal, and clinical studies. Of note, advanced methodologies including multi-omics, intestinal microflora analysis, organoid and single-cell sequencing techniques are gaining traction due to their ability to offer comprehensive insights into biomedical research. These emerging approaches hold promise in characterizing the pharmacological roles of H2S in health and diseases. We will critically assesse the current literatures to clarify the roles of H2S in diseases while also delineating the opportunities and challenges they present in H2S-based pharmacotherapy for CMDs. Significance Statement The comprehensive review covers recent developments in H2S biology and pharmacology in CMDs. Endogenous H2S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H2S.

Deficiency of neutral cholesterol ester hydrolase 1 (NCEH1) impairs endothelial function in diet-induced diabetic mice.

BACKGROUND: Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. METHODS: The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. RESULTS: Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. CONCLUSIONS: NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.

Impact of obesity-related indicators on first-pass effect in patients with ischemic stroke receiving mechanical thrombectomy.

PURPOSE: The first-pass effect (FPE), defined as complete revascularization after a single thrombectomy pass in large vessel occlusion, is a predictor of good prognosis in patients with acute ischemic stroke (AIS) receiving mechanical thrombectomy (MT). We aimed to evaluate obesity-related indicators if possible be predictors of FPE. METHODS: We consecutively enrolled patients with AIS who were treated with MT between January 2019 and December 2021 at our institution. Baseline characteristics, procedure-related data, and laboratory test results were retrospectively analyzed. A multivariable logistic regression analysis was performed to evaluate the independent predictors of FPE. RESULTS: A total of 151 patients were included in this study, of whom 47 (31.1%) had FPE. After adjusting for confounding factors, the independent predictors of achieving FPE were low levels of body mass index (BMI) (OR 0.85, 95% CI 0.748 to 0.971), non-intracranial atherosclerotic stenosis (OR 4.038, 95% CI 1.46 to 11.14), and non-internal carotid artery occlusion (OR 13.14, 95% CI 2.394 to 72.11). Patients with lower total cholesterol (TC) (< 3.11 mmol/L) were more likely to develop FPE than those with higher TC (≥ 4.63 mmol/L) (OR 4.280; 95% CI 1.24 to 14.74) CONCLUSION: Lower BMI, non-intracranial atherosclerotic stenosis, non-internal carotid artery occlusion, and lower TC levels were independently associated with increased rates of FPE in patients with AIS who received MT therapy. FPE was correlated with better clinical outcomes after MT.

Hydrogen sulfide in health and diseases: cross talk with noncoding RNAs.

Hydrogen sulfide (H2S) is previously described as a potentially lethal toxic gas. However, this gasotransmitter is also endogenously generated by the actions of cystathionine-ß-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) in mammalian systems, thus belonging to the family of gasotransmitters after nitric oxide (NO) and carbon monoxide (CO). The physiological or pathological significance of H2S has been extensively expanded for decades. Growing evidence has revealed that H2S exerts cytoprotective functions in the cardiovascular, nervous, and gastrointestinal systems by modulating numerous signaling pathways. With the continuous advancement of microarray and next-generation sequencing technologies, noncoding RNAs (ncRNAs) have gained recognition as key players in human health and diseases due to their considerable potential as predictive biomarkers and therapeutic targets. Coincidentally, H2S and ncRNAs are not independent regulators but interact with each other during the development and progression of human diseases. Specifically, ncRNAs might serve as downstream mediators of H2S or act on H2S-generating enzymes to govern endogenous H2S production. The purpose of this review is to summarize the interactive regulatory roles of H2S and ncRNAs in the initiation and development of various diseases and explore their potential health and therapeutic benefits. This review will also highlight the importance of cross talk between H2S and ncRNAs in disease therapy.

Near-Infrared-Induced Photothermal Enhanced Photocatalytic H2 Production for 3D/2D Heterojunctions of Snowflake-like CuS/g-C3N4 Nanosheets.

The conversion of solar power to hydrogen (H2) energy efficiently encounters some obstacles due to the lack of superior catalysts and efficient catalytic approaches. Herein, three-dimensional/two-dimensional (3D/2D) CuS/g-C3N4 photothermal catalysts were obtained via an easy, one-step hydrothermal method after pyrolysis. The favorable heterojunction interface for H2 production was constructed by snowflake-like CuS embedded in the graphite carbon nitride (g-C3N4) nanosheets, leading to the acceleration of charge transfer and separation, decrease of charge transfer distance, and perfect realization of photothermal effects (PTEs) induced by near-infrared (NIR) light. The 3D/2D CuS/g-C3N4 catalyst presents a topmost H2-production rate (1422 µmol h-1 g-1) under dual wavelength (420 + 850 nm) and a moderate H2-production rate under 420 nm, which are 12-fold and 9-fold higher than pure g-C3N4, respectively, owing to a strong action from PTEs induced by NIR. The feasible NIR-enhanced photothermal catalysis is expected to apply in multifarious heat-assisted photocatalysis processes by designing multifunctional composites with super PTE and photocatalytic capacity.

Disrupted cardiac fibroblast BCAA catabolism contributes to diabetic cardiomyopathy via a periostin/NAP1L2/SIRT3 axis.

BACKGROUND: Periostin is an extracellular matrix protein that plays a critical role in cell fate determination and tissue remodeling, but the underlying role and mechanism of periostin in diabetic cardiomyopathy (DCM) are far from clear. Thus, we aimed to clarify the mechanistic participation of periostin in DCM. METHODS: The expression of periostin was examined in DCM patients, diabetic mice and high glucose (HG)-exposed cardiac fibroblasts (CF). Gain- and loss-of-function experiments assessed the potential role of periostin in DCM pathogenesis. RNA sequencing was used to investigate the underlying mechanisms of periostin in DCM. RESULTS: A mouse cytokine antibody array showed that the protein expression of periostin was most significantly upregulated in diabetic mouse heart, and this increase was also observed in patients with DCM or HG-incubated CF. Periostin-deficient mice were protected from diabetes-induced cardiac dysfunction and myocardial damage, while overexpression of periostin held the opposite effects. Hyperglycemia stimulated the expression of periostin in a TGF-ß/Smad-dependent manner. RNA sequencing results showed that periostin upregulated the expression of nucleosome assembly protein 1-like 2 (NAP1L2) which recruited SIRT3 to deacetylate H3K27ac on the promoters of the branched-chain amino acid (BCAA) catabolism-related enzymes BCAT2 and PP2Cm, resulting in BCAA catabolism impairment. Additionally, CF-derived periostin induced hypertrophy, oxidative injury and inflammation in primary cardiomyocytes. Finally, we identified that glucosyringic acid (GA) specifically targeted and inhibited periostin to ameliorate DCM. CONCLUSION: Overall, manipulating periostin expression may function as a promising strategy in the treatment of DCM.

Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation.

Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1-/- SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression.

Nesfatin-1 functions as a switch for phenotype transformation and proliferation of VSMCs in hypertensive vascular remodeling.

The phenotypic transformation from differentiated to dedifferentiated vascular smooth muscle cells (VSMCs) plays a crucial role in VSMC proliferation and vascular remodeling in many cardiovascular diseases including hypertension. Nesfatin-1, a multifunctional adipocytokine, is critically involved in the regulation of blood pressure. However, it is still largely unexplored whether nesfatin-1 is a potential candidate in VSMC phenotypic switch and proliferation in hypertension. Experiments were carried out in Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), human VSMCs and primary rat aortic VSMCs. We showed that the expression of nesfatin-1 was upregulated in media layer of the aorta in SHR and SHR-derived VSMCs. Nesfatin-1 promoted VSMC phenotypic transformation, accelerated cell cycle progression and proliferation. Knockdown of nesfatin-1 inhibited the VSMC phenotype switch from a contractile to a synthetic state, attenuated cell cycle progression and retarded VSMC proliferation in SHR-derived VSMCs. Moreover, nesfatin-1-activated PI3K/Akt/mTOR signaling was abolished by JAK/STAT inhibitor WP1066, and the increased phosphorylation levels of JAK2/STAT3 in response to nesfatin-1 were suppressed by inhibition of PI3K/Akt/mTOR in VSMCs. Pharmacological blockade of the forming feedback loop between PI3K/Akt/mTOR and JAK2/STAT3 prevented the proliferation of nesfatin-1-incubated VSMCs and primary VSMCs from SHR. Chronic intraperitoneal injection of nesfatin-1 caused severe hypertension and cardiovascular remodeling in normal rats. In contrast, silencing of nesfatin-1 gene ameliorated hypertension, phenotype switching, and vascular remodeling in the aorta of SHR. Therefore, our data identified nesfatin-1 as a key modulator in hypertension and vascular remodeling by facilitating VSMC phenotypic switching and proliferation.

Superoxide Anions and NO in the Paraventricular Nucleus Modulate the Cardiac Sympathetic Afferent Reflex in Obese Rats.

This study was conducted to explore the hypothesis that the endogenous superoxide anions (O2-) and nitric oxide (NO) system of the paraventricular nucleus (PVN) regulates the cardiac sympathetic afferent reflex (CSAR) contributing to sympathoexcitation in obese rats induced by a high-fat diet (42% kcal as fat) for 12 weeks. CSAR was evaluated by monitoring the changes of renal sympathetic nerve activity (RSNA) and the mean arterial pressure (MAP) responses to the epicardial application of capsaicin (CAP) in anaesthetized rats. In obese rats with hypertension (OH group) or without hypertension (OB group), the levels of PVN O2-, angiotensinII (Ang II), Ang II type 1 receptor (AT1R), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were elevated, whereas neural NO synthase (nNOS) and NO were significantly reduced. Moreover, CSAR was markedly enhanced, which promoted the elevation of plasma norepinephrine levels. The enhanced CSAR was attenuated by PVN application of the superoxide scavenger polyethylene glycol-superoxide dismutase (PEG-SOD) and the NO donor sodium nitroprusside (SNP), and was strengthened by the superoxide dismutase inhibitor diethyldithiocarbamic acid (DETC) and the nNOS inhibitor N(ω)-propyl-l-arginine hydrochloride (PLA); conversely, there was a smaller CSAR response to PLA or SNP in rats that received a low-fat (12% kcal) diet. Furthermore, PVN pretreatment with the AT1R antagonist losartan or with PEG-SOD, but not SNP, abolished Ang II-induced CSAR enhancement. These findings suggest that obesity alters the PVN O2- and NO system that modulates CSAR and promotes sympathoexcitation.

Cytosolic phospholipase A2 protein as a novel therapeutic target for spinal cord injury.

OBJECTIVE: The objective of this study was to investigate whether cytosolic phospholipase A2 (cPLA2 ), an important isoform of PLA2 that mediates the release of arachidonic acid, plays a role in the pathogenesis of spinal cord injury (SCI). METHODS: A combination of molecular, histological, immunohistochemical, and behavioral assessments were used to test whether blocking cPLA2 activation pharmacologically or genetically reduced cell death, protected spinal cord tissue, and improved behavioral recovery after a contusive SCI performed at the 10th thoracic level in adult mice. RESULTS: SCI significantly increased cPLA2 expression and activation. Activated cPLA2 was localized mainly in neurons and oligodendrocytes. Notably, the SCI-induced cPLA2 activation was mediated by the extracellular signal-regulated kinase signaling pathway. In vitro, activation of cPLA2 by ceramide-1-phosphate or A23187 induced spinal neuronal death, which was substantially reversed by arachidonyl trifluoromethyl ketone, a cPLA2 inhibitor. Remarkably, blocking cPLA2 pharmacologically at 30 minutes postinjury or genetically deleting cPLA2 in mice ameliorated motor deficits, and reduced cell loss and tissue damage after SCI. INTERPRETATION: cPLA2 may play a key role in the pathogenesis of SCI, at least in the C57BL/6 mouse, and as such could be an attractive therapeutic target for ameliorating secondary tissue damage and promoting recovery of function after SCI.

Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming.

BACKGROUND: Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury. PURPOSE: This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved. METHODS/RESULTS: From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD+/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury. CONCLUSION: These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.

Potential clinical value of fibrinogen-like protein 1 as a serum biomarker for the identification of diabetic cardiomyopathy.

Diabetic individuals with diabetic cardiomyopathy (DbCM) present with abnormal myocardial structure and function. DbCM cannot be accurately diagnosed due to the lack of suitable diagnostic biomarkers. In this study, 171 eligible participants were divided into a healthy control (HC), type 2 diabetes mellitus (T2DM) patients without DbCM (T2DM), or DbCM group. Serum fibrinogen-like protein 1 (FGL-1) and other biochemical parameters were determined for all participants. Serum FGL-1 levels were significantly higher in patients with DbCM compared with those in the T2DM group and HCs. Serum FGL-1 levels were negatively correlated with left ventricular fractional shortening and left ventricular ejection fraction (LVEF) and positively correlated with left ventricular mass index in patients with DbCM after adjusting for age, sex and body mass index. Interaction of serum FGL-1 and triglyceride levels on LVEF was noted in patients with DbCM. A composite marker including serum FGL-1 and triglycerides could differentiate patients with DbCM from those with T2DM and HCs with an area under the curve of 0.773 and 0.789, respectively. Composite marker levels were negatively correlated with N-terminal B-type natriuretic peptide levels in patients with DbCM. Circulating FGL-1 may therefore be a valuable index reflecting cardiac functions in DbCM and to diagnose DbCM.

Cichoric acid ameliorates sepsis-induced acute kidney injury by inhibiting M1 macrophage polarization.

Cichoric acid (CA), a widely utilized polyphenolic compound in medicine, has garnered significant attention due to its potential health benefits. Sepsis-induced acute kidney disease (AKI) is related with an elevated risk of end-stage kidney disease (ESKD). However, it remains unclear whether CA provides protection against septic AKI. The aim of this study is to investigated the protective effect and possible mechanisms of CA against LPS-induced septic AKI. Sepsis-induced AKI was induced in mice through intraperitoneal injection of lipopolysaccharide (LPS), and RAW264.7 macrophages were incubated with LPS. LPS exposure significantly increased the levels of M1 macrophage biomarkers while reducing the levels of M2 macrophage indicators. This was accompanied by the release of inflammatory factors, superoxide anion production, mitochondrial dysfunction, activation of succinate dehydrogenase (SDH), and subsequent succinate formation. Conversely, pretreatment with CA mitigated these abnormalities. CA attenuated hypoxia-inducible factor-1α (HIF-1α)-induced glycolysis by lifting the NAD+/NADH ratio in macrophages. Additionally, CA disrupted the K (lysine) acetyltransferase 2A (KAT2A)/α-tubulin complex, thereby reducing α-tubulin acetylation and subsequently inactivating the NLRP3 inflammasome. Importantly, administration of CA ameliorated LPS-induced renal pathological damage, apoptosis, inflammation, oxidative stress, and disturbances in mitochondrial function in mice. Overall, CA restrained HIF-1α-mediated glycolysis via inactivation of SDH, leading to NLRP3 inflammasome inactivation and the amelioration of sepsis-induced AKI.

Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor Progression.

PURPOSE: Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) associated with neurofibromatosis type 1 (NF1). Despite similar histologic appearance, these neoplasms exhibit diverse evolutionary trajectories, with a subset progressing to malignant peripheral nerve sheath tumor (MPNST), the leading cause of premature death in individuals with NF1. Malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF) precursor lesions characterized by distinct histopathologic features and CDKN2A copy-number loss. Although genomic studies have uncovered key driver events promoting tumor progression, the transcriptional changes preceding malignant transformation remain poorly defined. EXPERIMENTAL DESIGN: Here we resolve gene-expression profiles in PNST across the neurofibroma-to-MPNST continuum in NF1 patients and mouse models, revealing early molecular features associated with neurofibroma evolution and transformation. RESULTS: Our findings demonstrate that ANF exhibit enhanced signatures of antigen presentation and immune response, which are suppressed as malignant transformation ensues. MPNST further displayed deregulated survival and mitotic fidelity pathways, and targeting key mediators of these pathways, CENPF and BIRC5, disrupted the growth and viability of human MPNST cell lines and primary murine Nf1-Cdkn2a-mutant Schwann cell precursors. Finally, neurofibromas contiguous with MPNST manifested distinct alterations in core oncogenic and immune surveillance programs, suggesting that early molecular events driving disease progression may precede histopathologic evidence of malignancy. CONCLUSIONS: If validated prospectively in future studies, these signatures may serve as molecular diagnostic tools to augment conventional histopathologic diagnosis by identifying neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care.

Vaccarin alleviates septic cardiomyopathy by potentiating NLRP3 palmitoylation and inactivation.

BACKGROUND: Sepsis often leads to significant morbidity and mortality due to severe myocardial injury. As is known, the activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome crucially contributes to septic cardiomyopathy (SCM) by facilitating the secretion of interleukin (IL)-1ß and IL-18. The removal of palmitoyl groups from NLRP3 is a crucial step in the activation of the NLRP3 inflammasome. Thus, the potential inhibitors that regulate the palmitoylation and inactivation of NLRP3 may significantly diminish sepsis-induced cardiac dysfunction. PURPOSE: The present study sought to explore the effects of the prospective flavonoid compounds targeting NLRP3 on SCM and to elucidate the associated underlying mechanisms. STUDY DESIGN: The palmitoylation and activation of NLRP3 were detected in H9c2 cells and C57BL/6 J mice. METHODS/RESULTS: Echocardiography, histological staining, western blotting, co-immunoprecipitation, qPCR, ELISA and network pharmacology were used to assess the impact of vaccarin (VAC) on SCM in mice subjected to lipopolysaccharide (LPS) injection. From the collection of 74 compounds, we identified that VAC had the strongest capability to suppress NLRP3 luciferase report gene activity in cardiomyocytes, and the anti-inflammatory characteristics of VAC were further ascertained by the network pharmacology. Exposure of LPS triggered apoptosis, inflammation, oxidative stress, mitochondrial disorder in cardiomyocytes. The detrimental alterations were significantly reversed upon VAC treatment in both septic mice and H9c2 cells exposed to LPS. In vivo experiments demonstrated that VAC treatment alleviated septic myocardial injury, indicated by enhanced cardiac function parameters, preserved cardiac structure, and reduced inflammation/oxidative response. Mechanistically, VAC induced NLRP3 palmitoylation to inactivate NLRP3 inflammasome by acting on zDHHC12. In support, the NLRP3 agonist ATP and the acylation inhibitor 2-bromopalmitate (2-BP) prevented the effects of VAC. CONCLUSION: Our findings suggest that VAC holds promise in protecting against SCM by mitigating cardiac oxidative stress and inflammation via priming NLRP3 palmitoylation and inactivation. These results lay the solid basis for further assessment of the therapeutic potential of VAC against SCM.

A Comprehensive Overview of the Role of Visual Cortex Malfunction in Depressive Disorders: Opportunities and Challenges.

Major depressive disorder (MDD) is a highly heterogeneous mental disorder, and its complex etiology and unclear mechanism are great obstacles to the diagnosis and treatment of the disease. Studies have shown that abnormal functions of the visual cortex have been reported in MDD patients, and the actions of several antidepressants coincide with improvements in the structure and synaptic functions of the visual cortex. In this review, we critically evaluate current evidence showing the involvement of the malfunctioning visual cortex in the pathophysiology and therapeutic process of depression. In addition, we discuss the molecular mechanisms of visual cortex dysfunction that may underlie the pathogenesis of MDD. Although the precise roles of visual cortex abnormalities in MDD remain uncertain, this undervalued brain region may become a novel area for the treatment of depressed patients.

Transcription factor cellular promoter 2 is required for upstream binding protein 1 -mediated angiogenesis.

OBJECTIVE: Angiogenesis is a key process of repairing tissue damage, and it is regulated by the delicate balance between anti-angiogenesis factors. In the present study, we investigate whether transcription factor cellular promoter 2 (TFCP2) is required for upstream binding protein 1 (UBP1)-mediated angiogenesis. METHODS: Levels of UBP1 and TFCP2 in human umbilical vein endothelial cells (HUVECs) are detected by quantitative polymerase chain reaction (q-PCR) and Western blotting (WB). Effects of UBP1 on angiogenesis and migration are detected by tube-like network formation on matrigel assay and scratch assay. The interaction between UBP1 and TFCP2 is predicted and verified by STRING and Co-immunoprecipitation (Co-IP). RESULTS: Firstly, the UBP1 expression level was up-regulated in the stimuli of vascular endothelial growth factor (VEGF) in HUVECs, and the knockdown of UBP1 inhibited angiogenesis and migration of HUVECs. Then, UBP1 interacted with TFCP2. Besides, the TFCP2 expression level was up-regulated in VEGF-stimulated HUVECs. Furthermore, knockdown of TFCP2 inhibited angiogenesis and migration in VEGF-stimulated HUVECs, and down-regulation of UBP1 enhanced the inhibition. CONCLUSION: TFCP2 also plays a key role in UBP1 mediated angiogenesis of HUVECs stimulated by VEGF. These findings will provide a new theoretical basis for the treatment of angiogenic diseases.

Impact of lipid profiles on parenchymal hemorrhage and early outcome after mechanical thrombectomy.

OBJECTIVE: We aimed to investigate the association of lipid parameters with parenchymal hemorrhage (PH) and early neurological improvement (ENI) after mechanical thrombectomy (MT) in stroke patients. METHODS: We retrospectively analyzed consecutive patients who underwent MT between January 2019 and February 2022 at a tertiary stroke center. PH was diagnosed and classified as PH-1 and PH-2 according to the European Cooperative Acute Stroke Study definition. ENI was defined as a decrease in the National Institutes of Health Stroke Scale (NIHSS) score by ≥8 or an NIHSS score of ≤1 at 24 h after MT. RESULTS: Among 155 patients, PH occurred in 41 (26.5%) patients, and 34 (21.9%) patients achieved ENI. In multivariate analysis, lower triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) value (OR = 0.51; 95% CI 0.30-0.89; p = 0.017) and higher HDL-C level (OR = 5.83; 95% CI 1.26-26.99; p = 0.024) were independently associated with PH. The combination of TG <0.77 mmol/L and HDL-C ≥ 0.85 mmol/L was the strongest predictor of PH (OR = 10.73; 95% CI 2.89-39.87; p < 0.001). A low HDL-C level was an independent predictor of ENI (OR 0.13; 95% CI 0.02-0.95; p = 0.045), and PH partially accounts for the failure of ENI in patients with higher HDL-C levels (estimate: -0.05; 95% CI: -0.11 to -0.01; p = 0.016). INTERPRETATION: The combination of lower TG level and higher HDL-C level can predict PH after MT. Postprocedural PH partially accounts for the failure of ENI in patients with higher HDL-C levels. Further studies into the pathophysiological mechanisms underlying this observation are of interest.

Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy.

INTRODUCTION: Meteorin-like hormone (Metrnl) is ubiquitously expressed in skeletal muscle, heart, and adipose with beneficial roles in obesity, insulin resistance, and inflammation. Metrnl is found to protect against cardiac hypertrophy and doxorubicin-induced cardiotoxicity. However, its role in diabetic cardiomyopathy (DCM) is undefined. OBJECTIVES: We aimed to elucidate the potential roles of Metrnl in DCM. METHODS: Gain- andloss-of-function experimentswere utilized to determine the roles of Metrnl in the pathological processes of DCM. RESULTS: We found that plasma Metrnl levels, myocardial Metrnl protein and mRNA expressions were significantly downregulated in both streptozotocin (STZ)-induced (T1D) mice and leptin receptor deficiency (db/db) (T2D) mice. Cardiac-specific overexpression (OE) of Metrnl markedly ameliorated cardiac injury and dysfunction in both T1D and T2D mice. In sharp contrast, specific deletion of Metrnl in the heart had the opposite phenotypes. In parallel, Metrnl OE ameliorated, whereas Metrnl downregulation exacerbated high glucose (HG)-elicited hypertrophy, apoptosis and oxidative damage in primary neonatal rat cardiomyocytes. Antibody-induced blockade of Metrnl eliminated the effects of benefits of Metrnl in vitro and in vivo. Mechanistically, Metrnl activated the autophagy pathway and inhibited the cGAS/STING signaling in a LKB1/AMPK/ULK1-dependent mechanism in cardiomyocytes. Besides, Metrnl-induced ULK1 phosphorylation facilitated the dephosphorylation and mitochondrial translocation of STING where it interacted with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase that was responsible for ubiquitination and degradation of STING, rendering cardiomyocytes sensitive to autophagy activation. CONCLUSION: Thus, Metrnl may be an attractive therapeutic target or regimen for treating DCM.

Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma.

PURPOSE: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. EXPERIMENTAL DESIGN: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. RESULTS: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo. CONCLUSIONS: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.