Dynamics of Endothelial Cell Generation and Turnover in Arteries During Homeostasis and Diseases.

BACKGROUND: Endothelial cell (EC) generation and turnover by self-proliferation contributes to vascular repair and regeneration. The ability to accurately measure the dynamics of EC generation would advance our understanding of cellular mechanisms of vascular homeostasis and diseases. However, it is currently challenging to evaluate the dynamics of EC generation in large vessels such as arteries because of their infrequent proliferation. METHODS: By using dual recombination systems based on Cre-loxP and Dre-rox, we developed a genetic system for temporally seamless recording of EC proliferation in vivo. We combined genetic recording of EC proliferation with single-cell RNA sequencing and gene knockout to uncover cellular and molecular mechanisms underlying EC generation in arteries during homeostasis and disease. RESULTS: Genetic proliferation tracing reveals that ≈3% of aortic ECs undergo proliferation per month in adult mice during homeostasis. The orientation of aortic EC division is generally parallel to blood flow in the aorta, which is regulated by the mechanosensing protein Piezo1. Single-cell RNA sequencing analysis reveals 4 heterogeneous aortic EC subpopulations with distinct proliferative activity. EC cluster 1 exhibits transit-amplifying cell features with preferential proliferative capacity and enriched expression of stem cell markers such as Sca1 and Sox18. EC proliferation increases in hypertension but decreases in type 2 diabetes, coinciding with changes in the extent of EC cluster 1 proliferation. Combined gene knockout and proliferation tracing reveals that Hippo/vascular endothelial growth factor receptor 2 signaling pathways regulate EC proliferation in large vessels. CONCLUSIONS: Genetic proliferation tracing quantitatively delineates the dynamics of EC generation and turnover, as well as EC division orientation, in large vessels during homeostasis and disease. An EC subpopulation in the aorta exhibits more robust cell proliferation during homeostasis and type 2 diabetes, identifying it as a potential therapeutic target for vascular repair and regeneration.

Cellular and molecular characteristics of stromal Lkb1 deficiency-induced gastrointestinal polyposis based on single-cell RNA sequencing.

Liver kinase B1 (Lkb1), encoded by serine/threonine kinase (Stk11), is a serine/threonine kinase and tumor suppressor that is strongly implicated in Peutz-Jeghers syndrome (PJS). Numerous studies have shown that mesenchymal-specific Lkb1 is sufficient for the development of PJS-like polyps in mice. However, the cellular origin and components of these Lkb1-associated polyps and underlying mechanisms remain elusive. In this study, we generated tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 and Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, performed single-cell RNA sequencing (scRNA-seq) and imaging-based lineage tracing, and aimed to investigate the cellular complexity of gastrointestinal polyps associated with PJS. We found that Lkb1flox/+;Myh11-Cre/ERT2 mice developed gastrointestinal polyps starting at 9 months after tamoxifen treatment. scRNA-seq revealed aberrant stem cell-like characteristics of epithelial cells from polyp tissues of Lkb1flox/+;Myh11-Cre/ERT2 mice. The Lkb1-associated polyps were further characterized by a branching smooth muscle core, abundant extracellular matrix deposition, and high immune cell infiltration. In addition, the Spp1-Cd44 or Spp1-Itga8/Itgb1 axes were identified as important interactions among epithelial, mesenchymal, and immune compartments in Lkb1-associated polyps. These characteristics of gastrointestinal polyps were also demonstrated in another mouse model, tamoxifen-inducible Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, which developed obvious gastrointestinal polyps as early as 2-3 months after tamoxifen treatment. Our findings further confirm the critical role of mesenchymal Lkb1/Stk11 in gastrointestinal polyposis and provide novel insight into the cellular complexity of Lkb1-associated polyp biology. © 2024 The Pathological Society of Great Britain and Ireland.

Assessment of six surrogate insulin resistance indexes for predicting cardiometabolic multimorbidity incidence in Chinese middle-aged and older populations: Insights from the China health and retirement longitudinal study.

AIMS: Insulin resistance (IR) is associated with cardiometabolic multimorbidity (CMM). We aimed to explore the predictive value of six surrogate IR indexes-Chinese visceral adiposity index (CVAI), lipid accumulation product (LAP), triglyceride-glucose (TyG), atherogenic index of plasma (AIP), TyG-body mass index (TyGBMI), and TyG-waist circumference (TyGwaist)-to establish the CMM incidence in Chinese middle-aged and older populations. MATERIAL AND METHODS: To estimate the odds ratio (OR) with a 95% confidence interval (95% CI) for incident CMM using six surrogates, we analysed data from the China Health and Retirement Longitudinal Study using multivariate logistic regression models. The nonlinear dose-response correlation was evaluated using restricted cubic spline analysis; predictive performance was assessed using receiver operator characteristic curves. RESULTS: Among 6451 eligible participants, 268 (4.2%) developed CMM during the 4-year follow-up period. The ORs (95% CI) for incident CMM increased with increasing CVAI quartiles (Q) [Q2: 1.71, 1.03-2.90; Q3: 2.72, 1.70-4.52; Q4: 5.16, 3.29-8.45; all p < 0.05] after full adjustment, with Q1 as the reference. Other indexes yielded similar results. These associations remained significant in individuals with a normal body mass index. Notably, CVAI, AIP, and TyG exhibited a linear dose-response relationship with CMM (Pnonlinear ≥0.05), whereas LAP, TyGBMI, and TyGwaist displayed significant nonlinear correlations (Pnonlinear <0.05). The area under the curve for the CVAI (0.691) was significantly superior to that of other indexes (all p < 0.05). CONCLUSIONS: The six IR surrogates were independently associated with CMM incidence. CVAI may be the most appropriate indicator for predicting CMM in middle-aged and older Chinese populations.

Genetic Lineage Tracing of Pericardial Cavity Macrophages in the Injured Heart.

BACKGROUND: Macrophages play an important role in cardiac repair after myocardial infarction (MI). In addition to the resident macrophages and blood-derived monocytes, Gata6+ cavity macrophages located in the pericardial space were recently reported to relocate to the injured myocardium and prevent cardiac fibrosis. However, there is no direct genetic evidence to support it. METHODS: We used dual recombinases (Cre and Dre) to specifically label Gata6+ pericardial macrophages (GPCMs) in vivo. For functional study, we generated genetic systems to specifically ablate GPCMs by induced expression of DTR (diphtheria toxin receptor) or knockout of Gata6 (GATA binding protein 6) gene in GPCMs. We used these genetic systems to study GPCMs in pericardium intact MI model. RESULTS: Dual recombinases-mediated genetic system targeted GPCMs specifically and efficiently. Lineage tracing study revealed accumulation of GPCMs on the surface of MI heart without deep penetration into the myocardium. We did not detect significant change of cardiac fibrosis or function of MI hearts after cell ablation or Gata6 knockout in GPCMs. CONCLUSIONS: GPCMs minimally invade the injured heart after MI. Nor do they prevent cardiac fibrosis and exhibit reparative function on injured heart. This study also underlines the importance of using specific genetic tool for studying in vivo cell fates and functions.

Myeloid SENP3 deficiency protects mice from diet and age-induced obesity via regulation of YAP1 SUMOylation.

Obesity is characterized by chronic low-grade inflammation, which is driven by macrophage infiltration in adipose tissue and leads to elevated cytokines such as interleukin-1ß (IL-1ß) in the circulation and tissues. Previous studies demonstrate that SENP3, a redox-sensitive SUMO2/3-specific protease, is strongly implicated in the development and progression of cancer and cardiovascular diseases. However, the role of SENP3 in obesity-associated inflammation remains largely unknown. To better understand the effects of SENP3 on adipose tissue macrophage (ATM) activation and function within the context of obesity, we generated mice with myeloid-specific deletion of SENP3 (Senp3flox/flox;Lyz2-Cre mice). We found that the expression of SENP3 is dramatically increased in ATMs during high-fat diet (HFD)-induced obesity in mice. Senp3flox/flox;Lyz2-Cre mice show lower body weight gain and reduced adiposity and adipocyte size after challenged with HFD and during aging. Myeloid-specific SENP3 deletion attenuates macrophage infiltration in adipose tissue and reduces serum levels of inflammatory factors during diet and age-induced obesity. Furthermore, we found that SENP3 knockout markedly inhibits cytokine release from macrophage after lipopolysaccharide and palmitic acid treatment in vitro. Mechanistically, in cultured peritoneal macrophages, SENP3 protein level is enhanced by IL-1ß, in parallel with the upregulation of Yes-associated protein 1 (YAP1). Moreover, we demonstrated that SENP3 modulates de-SUMO modification of YAP1 and SENP3 deletion abolishes the upregulation of YAP1 induced by IL-1ß. Most importantly, SENP3 deficiency reduces YAP1 protein level in adipose tissue during obesity. Our results highlight the important role of SENP3 in ATM inflammation and diet and age-induced obesity.

Transient Receptor Vanilloid Subtype 4-Mediated Ca2+ Influx Promotes Glomerular Endothelial Inflammation in Sepsis-Associated Acute Kidney Injury.

Sepsis-associated acute kidney injury (S-AKI) is a frequent complication in patients who are critically ill, which is often initiated by glomerular endothelial cell dysfunction. Although transient receptor vanilloid subtype 4 (TRPV4) ion channels are known to be permeable to Ca2+ and are widely expressed in the kidneys, the role of TRPV4 on glomerular endothelial inflammation in sepsis remains elusive. In the present study, we found that TRPV4 expression in mouse glomerular endothelial cells (MGECs) increased after lipopolysaccharide (LPS) stimulation or cecal ligation and puncture challenge, which increased intracellular Ca2+ in MGECs. Furthermore, the inhibition or knockdown of TRPV4 suppressed LPS-induced phosphorylation and translocation of inflammatory transcription factors NF-κB and IRF-3 in MGECs. Clamping intracellular Ca2+ mimicked LPS-induced responses observed in the absence of TRPV4. In vivo experiments showed that the pharmacologic blockade or knockdown of TRPV4 reduced glomerular endothelial inflammatory responses, increased survival rate, and improved renal function in cecal ligation and puncture-induced sepsis without altering renal cortical blood perfusion. Taken together, our results suggest that TRPV4 promotes glomerular endothelial inflammation in S-AKI and that its inhibition or knockdown alleviates glomerular endothelial inflammation by reducing Ca2+ overload and NF-κB/IRF-3 activation. These findings provide insights that may aid in the development of novel pharmacologic strategies for the treatment of S-AKI.

Ginsenoside Rb1 Improves Post-Cardiac Arrest Myocardial Stunning and Cerebral Outcomes by Regulating the Keap1/Nrf2 Pathway.

The prognosis of cardiac arrest (CA) is dismal despite the ongoing progress in cardiopulmonary resuscitation (CPR). ginsenoside Rb1 (Gn-Rb1) has been verified to be cardioprotective in cardiac remodeling and cardiac ischemia/reperfusion (I/R) injury, but its role is less known in CA. After 15 min of potassium chloride-induced CA, male C57BL/6 mice were resuscitated. Gn-Rb1 was blindly randomized to mice after 20 s of CPR. We assessed the cardiac systolic function before CA and 3 h after CPR. Mortality rates, neurological outcome, mitochondrial homeostasis, and the levels of oxidative stress were evaluated. We found that Gn-Rb1 improved the long-term survival during the post-resuscitation period but did not affect the ROSC rate. Further mechanistic investigations revealed that Gn-Rb1 ameliorated CA/CPR-induced mitochondrial destabilization and oxidative stress, partially via the activation of Keap1/Nrf2 axis. Gn-Rb1 improved the neurological outcome after resuscitation partially by balancing the oxidative stress and suppressing apoptosis. In sum, Gn-Rb1 protects against post-CA myocardial stunning and cerebral outcomes via the induction of the Nrf2 signaling pathway, which may offer a new insight into therapeutic strategies for CA.

L-shaped association of serum 25-hydroxyvitamin D concentrations with cardiovascular and all-cause mortality in individuals with osteoarthritis: results from the NHANES database prospective cohort study.

BACKGROUND: The relationship between vitamin D status and mortality in patients with osteoarthritis (OA) is unknown. This study investigated the associations of serum 25-hydroxyvitamin D [25(OH)D] concentrations with all-cause and cause-specific mortality among American adults with OA. METHODS: This study included 2556 adults with OA from the National Health and Nutrition Examination Survey (2001-2014). Death outcomes were ascertained by linkage to National Death Index (NDI) records through 31 December 2015. Cox proportional hazards model and two-piecewise Cox proportional hazards model were used to elucidate the nonlinear relationship between serum 25(OH)D concentrations and mortality in OA patients, and stratified analyses were performed to identify patients with higher mortality risk. RESULTS: During 16,606 person-years of follow-up, 438 all-cause deaths occurred, including 74 cardiovascular disease (CVD)-related and 78 cancer deaths. After multivariable adjustment, lower serum 25(OH)D levels were significantly and nonlinearly associated with higher risks of all-cause and CVD mortality among participants with OA. Furthermore, we discovered L-shaped associations between serum 25(OH)D levels and all-cause and CVD mortality, with mortality plateauing at 54.40 nmol/L for all-cause mortality and 27.70 nmol/L for CVD mortality. Compared to participants with 25(OH)D levels below the inflection points, those with higher levels had a 2% lower risk for all-cause mortality (hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.96-0.99) and 17% lower risk for CVD mortality (HR 0.83, 95% CI 0.72-0.95). CONCLUSIONS: Nonlinear associations of serum 25(OH)D levels with all-cause and CVD mortality were observed in American patients with OA. The thresholds of 27.70 and 54.40 nmol/L for CVD and all-cause mortality, respectively, may represent intervention targets for lowering the risk of premature death and cardiovascular disease, but this needs to be confirmed in large clinical trials.

SENP2 Promotes VSMC Phenotypic Switching via Myocardin De-SUMOylation.

Myocardin is a master regulator of smooth muscle cell (SMC) differentiation, which induces the expression of smooth-muscle-specific genes through its direct association with serum response factor (SRF). During the past two decades, significant insights have been obtained regarding the regulatory control of myocardin expression and transcriptional activity at the transcriptional, post-transcriptional, and post-translational levels. However, whether and how SUMOylation plays important roles in modulating myocardin function remain elusive. In this study, we found that myocardin is modified by SUMO-1 at lysine 573, which can be reversibly de-conjugated by SENP2. SUMO-1 modification promotes myocardin protein stability, whereas SENP2 facilitates its proteasome-dependent degradation. Moreover, we found that PIAS4 is the SUMO E3 ligase that enhances the SUMOylation and protein stability of myocardin. Most importantly, we found that SENP2 promotes phenotypic switching of VSMC. We therefore concluded that SENP2 promotes VSMC phenotypic switching via de-SUMOylation of myocardin and regulation of its protein stability.

Prenatal diagnosis of pulmonary artery sling associated with tracheal agenesis: A case report.

Pulmonary artery sling (PAS) and tracheal agenesis (TA) are rare diseases, and most cases of PAS are associated with tracheal bronchial malformations. However, PAS associated with TA is yet to be reported. We report a case of PAS with TA diagnosed prenatally. Due to the extremely low incidence, physicians do not have sufficient understanding of these diseases and it is challenging to diagnose these diseases by prenatal ultrasound, with high rates of misdiagnosis. Prenatal examination of the pulmonary artery branches, trachea, and esophagus is useful; therefore, improving the accuracy of prenatal diagnosis will help in perinatal management and counseling.

Ubiquitin C-Terminal Hydrolase L1 regulates autophagy by inhibiting autophagosome formation through its deubiquitinating enzyme activity.

Ubiquitination modification has been shown to play a key role in autophagy. Increasing studies reported the involvement of de-ubiquitinating enzymes (DUBs) in autophagy pathway. To systematically search how DUBs manipulate autophagy, we utilized a double fluorescence tagged LC3 stable HeLa cell line, and did a genome wide screen of 55 human DUBs which is about 60% coverage of the DUB family. We found a bunch of DUBs have impact on autophagy by either changing the LC3 puncta formation or the autophagy flux. One of them, Ubiquitin C-Terminal Hydrolase L1 (UCHL1) correlated to Parkinson's disease, strongly affects autophagy by inhibiting autophagosome formation. We found UCHL1 overexpression inhibits LC3 puncta formation and is dependent on its DUB activity. Knockdown of UCHL1 significantly promotes LC3 puncta formation. Further study revealed that UCHL1 may affect autophagy by interacting with LC3 but not other autophagy related proteins. Interestingly, a Parkinson's disease related mutant UCHL1 I93 M defects its DUB activity and can no longer inhibit autophagosome formation. We further screened 22 commercially available DUB inhibitors and found two potent UCHL1 inhibitors LDN-57444 (LDN) and NSC632839 (NSC), when treating cells, both strongly induce LC3 puncta formation. Taken together, our results indicated a new insight into the manner in which DUB regulates autophagy and provided potential drugs for the Parkinson's disease.

Lunapark Is a Component of a Ubiquitin Ligase Complex Localized to the Endoplasmic Reticulum Three-way Junctions.

The endoplasmic reticulum (ER) network comprises sheets and tubules that are connected by dynamic three-way junctions. Lunapark (Lnp) localizes to and stabilizes ER three-way junctions by antagonizing the small GTPase Atlastin, but how Lnp shapes the ER network is unclear. Here, we used an affinity purification approach and mass spectrometry to identify Lnp as an interacting partner of the ER protein quality control ubiquitin ligase gp78. Accordingly, Lnp purified from mammalian cells has a ubiquitin ligase activity in vitro Intriguingly, biochemical analyses show that this activity can be attributed not only to associated ubiquitin ligase, but also to an intrinsic ubiquitin ligase activity borne by Lnp itself. This activity is contained in the N-terminal 45 amino acids of Lnp although this segment does not share homology to any known ubiquitin ligase motifs. Despite its interaction with gp78, Lnp does not seem to have a broad function in degradation of misfolded ER proteins. On the other hand, the N-terminal ubiquitin ligase-bearing motif is required for the ER three-way junction localization of Lnp. Our study identifies a new type of ubiquitin ligase and reveals a potential link between ubiquitin and ER morphology regulation.

Effect of crowding stress on the immune response in turbot (Scophthalmus maximus) vaccinated with attenuated Edwardsiella tarda.

The aim of this study was to evaluate the immune responses in turbot, Scophthalmus maximus, treated with 1 × 107 cfu/ml attenuated Edwardsiella tarda (0.1 ml/fish) under low density (LD; ∼5.25-5.13 kg/m2, initial to final density), medium density (MD; ∼10.41-13.95 kg/m2), and high density (HD; ∼20.53-30.77 kg/m2) conditions for 8 weeks. The results showed that there was a peak value in the percentage of sIg+ (surface immunoglobulin-positive) cells in blood leucocytes (BL), spleen leucocytes (SL), and pronephros leucocytes (PL) during the sixth week in the HD, which was delayed by week compared with the other groups. The specific immunoglobulin M (IgM) antibody levels increased from the first week in all groups and reached a peak in the fifth week in the LD and MD groups, but in the sixth week in the HD group. The serum cortisol levels were greater in the HD group compared with the other groups in the last 3 or 4 weeks. These results show that stocking turbot at a LD obtained the most effective immunization, and thus we conclude that crowding stress may reduce the ability to deal with immune challenge.

Ni/CdS bifunctional Ti@TiO2 core-shell nanowire electrode for high-performance nonenzymatic glucose sensing.

In this work, a Ni/CdS bifunctional Ti@TiO2 core-shell nanowire electrode with excellent electrochemical sensing property was successfully constructed through a hydrothermal and electrodeposition method. Field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) were employed to confirm the synthesis and characterize the morphology of the as-prepared samples. The results revealed that the CdS layer between Ni and TiO2 plays an important role in the uniform nucleation and the following growth of highly dispersive Ni nanoparticle on the Ti@TiO2 core-shell nanowire surface. The bifunctional nanostructured electrode was applied to construct an electrochemical nonenzymatic sensor for the reliable detection of glucose. Under optimized conditions, this nonenzymatic glucose sensor displayed a high sensitivity up to 1136.67 µA mM(-1) cm(-2), a wider liner range of 0.005-12 mM, and a lower detection limit of 0.35 µM for glucose oxidation. The high dispersity of Ni nanoparticles, combined with the anti-poisoning faculty against the intermediate derived from the self-cleaning ability of CdS under the photoexcitation, was considered to be responsible for these enhanced electrochemical performances. Importantly, favorable reproducibility and long-term performance were also obtained thanks to the robust frameworks. All these results indicate this novel electrode is a promising candidate for nonenzymatic glucose sensing.

SUMOylation of TEAD1 Modulates the Mechanism of Pathological Cardiac Hypertrophy.

Pathological cardiac hypertrophy is the leading cause of heart failure and has an extremely complicated pathogenesis. TEA domain transcription factor 1 (TEAD1) is recognized as an important transcription factor that plays a key regulatory role in cardiovascular disease. This study aimed to explore the role of TEAD1 in cardiac hypertrophy and to clarify the regulatory role of small ubiquitin-like modifier (SUMO)-mediated modifications. First, the expression level of TEAD1 in patients with heart failure, mice, and cardiomyocytes is investigated. It is discovered that TEAD1 is modified by SUMO1 during cardiac hypertrophy and that the process of deSUMOylation is regulated by SUMO-specific protease 1 (SENP1). Lysine 173 is an essential site for TEAD1 SUMOylation, which affects the protein stability, nuclear localization, and DNA-binding ability of TEAD1 and enhances the interaction between TEAD1 and its transcriptional co-activator yes-associated protein 1 in the Hippo pathway. Finally, adeno-associated virus serotype 9 is used to construct TEAD1 wild-type and KR mutant mice and demonstrated that the deSUMOylation of TEAD1 markedly exacerbated cardiomyocyte enlargement in vitro and in a mouse model of cardiac hypertrophy. The results provide novel evidence that the SUMOylation of TEAD1 is a promising therapeutic strategy for hypertrophy-related heart failure.

Co(3)O(4) microspheres with free-standing nanofibers for high performance non-enzymatic glucose sensor.

Co3O4 microspheres with free-standing or bundled nanofibers (NFs) were fabricated for use as a platform for non-enzymatic glucose sensing. The sensor based on free-standing Co3O4 NFs displays enhanced sensitivity (1440 µA mM(-1) cm(-2)), a wider linear range (0.005-12 mM) and superior selectivity. The application of this glucose sensor in human blood serum has also been demonstrated successfully.

Integrated transcriptome and metabolome analysis reveals a possible mechanism for the regulation of lipid metabolism via vitamin A in rice field eel (Monopterus albus).

To understand the effects of vitamin A on lipid deposition in rice field eels, integrated liver transcriptome and metabolome were conducted and the changes in the genes and metabolites were assessed. Three groups of rice field eel were fed with 0, 200, and 16,000 IU/kg vitamin A supplementations in their diets for 70 days. The total lipid content in the whole body of the rice field eels was significantly increased with the vitamin A supplementations (p < 0.05). Comparative transcriptome analysis revealed 14 pathways and 46 differentially expressed genes involved in lipid metabolism. Sphingolipid metabolism, glycerolipid metabolism, primary bile acid biosynthesis and steroid hormone biosynthesis were significantly enriched pathways. In these pathways, three differential genes phospholipid phosphatase 1a (PLPP1a), phospholipid phosphatase 2b (PLPP2b), cytochrome P450 21a2 (CYP21a2) were consistent with the change trend of lipid content, and the other three differential genes aldo-keto reductase family 1 member D1 (AKR1D1), uridine diphosphate glucuronic acid transferase 1a1 (UGT1a1), cytochrome P450 1a (CYP1a) were opposite. Metabolomic analysis revealed that primary bile acid biosynthesis, sphingolipid metabolism, steroid hormone biosynthesis and biosynthesis of unsaturated fatty acids were all critical for rice field eel metabolic changes in response to vitamin A. Six important differential metabolites (eicosapentaenoic acid, sphinganine, 11-beta-hydroxyprogesterone, hydroxyeicosatetraenoic acid, cholic acid, and glycochenodeoxycholate) were identified and have provided new insights into how vitamin A regulates lipid deposition. Integrated transcriptome and metabolome analyses revealed that primary bile acid biosynthesis was the only remarkably enriched pathway in both the transcriptome and metabolome while that sphingosine was the main metabolite. Based on the above results, we have concluded that vitamin A promotes lipid deposition in the rice field eel through the primary bile acid synthesis pathway, and lipid deposits are widely stored in cell membranes, mainly in the form of sphingosine. These results will provide reference data to help improve our understanding of how vitamin A regulates lipid metabolism.

Role of Pericytes in Cardiomyopathy-Associated Myocardial Infarction Revealed by Multiple Single-Cell Sequencing Analysis.

Acute myocardial infarction (AMI) is one of the leading causes of cardiovascular death worldwide. AMI with cardiomyopathy is accompanied by a poor long-term prognosis. However, limited studies have focused on the mechanism of cardiomyopathy associated with AMI. Pericytes are important to the microvascular function in the heart, yet little attention has been paid to their function in myocardial infarction until now. In this study, we integrated single-cell data from individuals with cardiomyopathy and myocardial infarction (MI) GWAS data to reveal the potential function of pericytes in cardiomyopathy-associated MI. We found that pericytes were concentrated in the left atrium and left ventricle tissues. DLC1/GUCY1A2/EGFLAM were the top three uniquely expressed genes in pericytes (p < 0.05). The marker genes of pericytes were enriched in renin secretion, vascular smooth muscle contraction, gap junction, purine metabolism, and diabetic cardiomyopathy pathways (p < 0.05). Among these pathways, the renin secretion and purine metabolism pathways were also found in the process of MI. In cardiomyopathy patients, the biosynthesis of collagen, modulating enzymes, and collagen formation were uniquely negatively regulated in pericytes compared to other cell types (p < 0.05). COL4A2/COL4A1/SMAD3 were the hub genes in pericyte function involved in cardiomyopathy and AMI. In conclusion, this study provides new evidence about the importance of pericytes in the pathogenesis of cardiomyopathy-associated MI. DLC1/GUCY1A2/EGFLAM were highly expressed in pericytes. The hub genes COL4A2/COL4A1/SMAD3 may be potential research targets for cardiomyopathy-associated MI.

Allicin promotes functional recovery in ischemic stroke via glutathione peroxidase-1 activation of Src-Akt-Erk.

Allicin exhibits various pharmacological activities and has been suggested to be beneficial in the treatment of stroke. However, the underlying mechanisms are largely unknown. Here, we confirmed that allicin protected the brain from cerebral injury, which could be ascribed to its anti­apoptotic and anti­inflammatory effects, as well as the regulation of lipid metabolism, using proteomics and metabolomics analysis. Our results suggested that allicin could significantly ameliorate behavioral characteristics, cerebral infarct area, cell apoptosis, inflammatory factors, and lipid metabolic-related factors (arachidonic acid, 15-hydroperoxy-eicosatetraenoic acid (15S-HPETE), palmitoylcarnitine, and acylcarnitine) by recalibrating astrocyte homeostasis in mice with photothrombotic stroke (PT). In astrocytes, allicin significantly increased glutathione peroxidase 1 (GPX1) levels and inhibited the arachidonic acid-related pathway, which was also observed in the brains of mice with PT. Allicin was proven to inhibit hypoxia-induced astrocyte apoptosis by increasing GPX1 expression, activating proto-oncogene tyrosine-protein kinase Src (Src)- protein kinase B (AKT)-extracellular signal-regulated kinase (ERK) phosphorylation, and decreasing lipid peroxidation. Thus, we concluded that allicin significantly prevented and ameliorated ischemic stroke by increasing GPX1 levels to complete the complex physiological process.