BACKGROUND:Retinopathy of prematurity (ROP), an oxygen-induced retinopathy (OIR), triggers a series of vascular lesions and inflammatory responses and results in visual impairment or even blindness. Triptolide (TP) possesses many pharmacological properties, including immunosuppressive and anti-tumour effects. However, the effects of TP on ROP and its underlying mechanisms remain unclear. PURPOSE:To investigate whether TP could inhibit the progression of OIR and to elucidate its underlying mechanisms. METHODS:The 7-day-old mice (P7) were kept in a 75% hyperoxia incubator for 5 days to induce an OIR model, followed by TP treatment for 5 days. Biomedical analysis and histopathological examinations of harvested retinas were conducted to explore the effect of TP. Furthermore, the impact of TP on retinal neovascularisation and microglial activation was validated using human umbilical vein endothelial cells (HUVECs) and human microglial clone 3 cells (HMC3s). RESULTS:TP treatment could significantly alleviate retinal pathological neovascularisation by inhibiting microglial activation. It downregulated the elevated levels of inflammatory cytokines (inducible nitric oxide synthase, tumour necrosis factor-α, Cox2 and interleukin (IL)-1β) and angiogenesis-related factors (hypoxia-inducible factor-1α, matrix metalloproteinase-2 and vascular endothelial growth factor-A) in OIR retinas and hypoxic HMC3s. HUVECs' migration, proliferation and tube-forming capacities were also markedly suppressed under TP treatment. Further analysis suggested that TP exerted its anti-angiogenic effect in a way similar to NF-κB inhibitor (BAY117082). CONCLUSION:TP alleviates pathological neovascularisation in OIR, potentially through the inhibition of inflammation mediated by NF-κB pathway.

Microvascular obstruction (MVO) is a fundamental mechanism underlying the occurrence of no-reflow, which contributes to myocardial ischemia–reperfusion injury (MI/RI). Despite its significance, the precise pathophysiology of MVO remains incompletely understood. In this study, we aim to investigate the role of CD80/86, co-stimulatory molecules crucial for T cell activation, in exacerbating MVO during MI/RI, and elucidate their potential mechanism of action. The results revealed a significant increase in cardiac CD80/86 in mice after I/R treatment. Strikingly, the deletion of CD80/86 greatly improved cardiac function, reduced infarct size, and mitigated apoptosis 24 h after MI/R. Mechanistically, CD80/86 deletion or inhibition led to a reduction in E-selectin expression, subsequently decreasing the infiltration of macrophages and T cells, thereby counteracting MVO and ameliorating the development of no-reflow during MI/RI. In conclusion, our data highlight the crucial involvement of CD80/86 in regulating macrophage and T cells infiltration, leading to the alleviation of MVO and myocardial MI/RI. The insights gained from this study suggest that targeted inhibition of CD80/86 holds promise as a potential therapeutic strategy to protect cardiac function in patients with acute myocardial infarction undergoing reperfusion therapy. Further research in this direction could pave the way for improved treatment options in the management of ischemic heart conditions.

Ocular neovascularization is a leading cause of blindness. Hypoxia is associated with retinal angiogenesis. Hypoxia results in lactate accumulation, which typically precedes protein lactylation, and this plays a crucial role in ocular neovascularization. However, the underlying mechanism remains unclear. Here, we investigate the role of the DNA methyltransferase, DNMT3A, in regulating lactylation following hypoxia in ocular neovascularization. DNMT3A controls endothelial cell angiogenesis via regulating lactate-derived HIF-1α lactylation. During oxygen-induced retinopathy progression, we detected increased levels of DNMT3A, HIF-1α lactylation, and vascular endothelial growth factor (VEGF) in endothelial cells. Exogenous lactate administration significantly enhances vascularization, while inhibiting lactate uptake in the presence or absence of DNMT3A prevents endothelial cell angiogenesis and attenuates HIF-1α lactylation. We demonstrate that modulating DNMT3A expression alters HIF-1α lactylation levels, influencing angiogenesis in vitro and in vivo. DNMT3A facilitates lactate transport into the nucleus, where it promotes VEGFA upregulation through HIF-1α lactylation, thereby stimulating endothelial cell angiogenesis. Targeting the lactate-DNMT3A/HIF-1α lactylation/VEGFA pathway could provide new therapeutic strategies for treating ocular neovascularization disorders.

12/15-Lipoxygenase (LOX) is a member of the LOX family that catalyzes the step from arachidonic acid to hydroxy-eicosatetraenoic acids (HETEs). Previous studies demonstrated that 12/15-LOX plays a critical role in the development of atherosclerosis, hypertension, heart failure, and other diseases; however, its role in myocardial ischemic injury was contraversal. Here, we investigated the inhibition of 12/15-LOX by baicalein on acute cardiac injury and dissected its molecular mechanism. In a mouse model of acute ischemia/reperfusion (I/R) injury, 12/15-LOX was significantly upregulated in the peri-infarct area surrounding the primary infarction. In cultured cardiac myocytes, baicalein suppressed apoptosis and caspase 3 activity in response to simulated ischemia/reperfusion (I/R). Moreover, administration of 12/15-LOX inhibitor, baicalein, significantly attenuated myocardial infarct size induced by I/R injury. Moreover, baicalein treatment significantly inhibited cardiomyocyte apoptosis, inflammatory responses and oxidative stress in the heart after I/R injury. The mechanisms underlying these effects were associated with the activation of ERK1/2 and AKT pathways and inhibition of activation of p38 MAPK, JNK1/2, and NF-kB/p65 pathways in the I/R-treated hearts and neonatal cardiomyoctes. Our data indicated that 12/15-LOX inhibitor baicalein can prevent myocardial I/R injury by modulation of multiple mechanisms, and suggest that baicalein could represent a novel therapeutic drug for acute myocardial infarction.

Ischemic cardiomyopathy (ICM) is a significant global public health issue, with its pathophysiology encompassing atherosclerotic plaque formation, thrombosis, hypoperfusion, ischemic cell death, and left ventricular remodeling. Lactate is not only regarded as an energy metabolite but also acts as a signaling molecule that influences various physiological processes, regulating metabolism and muscle contraction. Lactylation, an emerging epigenetic modification, affects protein functionality and gene expression through the P300 enzyme. In ICM, lactate accumulation leads to pH imbalance and myocardial cell dysfunction, impacting cellular signaling. This paper will analyze the role of lactylation in ICM, focusing on coronary artery disease (ASCVD) and myocardial infarction (MI). It will also explore the differential expression and immunological characteristics of lactylation-related genes in normal and ICM tissues, providing potential targets for future research.

Excessive alcohol consumption is a major cause of alcoholic cardiomyopathy (ACM) and myocardial injury. This study aims to investigate the role of transcription factor EB (TFEB) in ethanol-induced cardiac anomalies using a murine model, AC16 human cardiomyocytes, and human plasma. Wild-type mice treated with a TFEB activator (Compound 1) or vehicle (25 mg/kg/d) were challenged with or without ethanol (3 g/kg/d, i.p.) for three consecutive days. Cardiac geometry and function were evaluated by echocardiography. The expressions of TFEB, molecules related to mitochondria, markers of apoptosis, mitophagy and lysosomes were examined in heart tissues and AC16 cardiomyocytes. Mitochondrial function, lysosome activity, and their localizations were measured in AC16 cardiomyocytes. Levels of TFEB and autophagic markers were also detected in human serum from healthy individuals and patients with ACM. Ethanol administration in mice induced severe cardiac dysfunction accompanied by upregulated P62 and LC3B, downregulated TFEB, lysosomal markers and mitophagy-associated receptors in heart tissues. Ethanol toxicity also led to reduced mitochondrial and lysosomal activity. Interestingly, TFEB activation mitigated the detrimental effects caused by ethanol. Inhibition of autophagy abolished the anti-apoptotic effect of TFEB in AC16 cells. In conclusion, TFEB is beneficial in ethanolinduced cardiac anomalies by reducing apoptosis, recovering lysosomal activity, and restoring proper mitophagy and autophagic flux.

Diabetic cataract (DC), a well-recognized complication in diabetic patients, can progress to blindness if not adequately managed, with currently limited therapeutic strategies. Icariin (ICA), a natural compound derived from Epimedium, has been demonstrated exhibiting anti-inflammatory and anti-oxidant, but its impact on diabetic cataracts remains elusive. In this study, we used both in vitro SRA01/04 cells and in vivo SD rats' model to explored the protective effects of ICA in cataract formation. Following network pharmacology, proteomic and surface plasmon resonance (SPR) analyses further demonstrated that ICA interacts with insulin-like growth factor-binding protein-3 (IGFBP3) and modulates oxidative stress as well as apoptosis via the PI3K/AKT signaling pathway. These findings collectively demonstrated that ICA could alleviate high glucose-induced oxidative stress and cell apoptosis in vitro and in vivo, suggesting that ICA is a potent natural compound with protective effects in DC, offering an effective therapeutic approach for the disease management.

Myocardial edema mediated by endothelial dysfunction plays an important role in sepsis-induced cardiomyopathy (SIC); however, its mechanism is unclear. The current study aimed to provide evidence on the cardioprotection of CD1d-dependent natural killer T (NKT) cells and clarify the possible mechanism in a mouse model of sepsis. Wild-type (WT) and CD1d-dependent NKT-cells inactivation (CD1dko) mice were subjected to sepsis induced by intraperitoneal injection of lipopolysaccharide (LPS). The NKT-cells number and CD1d expression were both increased in the hearts and blood of WT mice after LPS treatment. Compared with WT mice, CD1dko mice exhibited remarkably accelerated LPS-induced mortality, cardiac dysfunction, myocardial injury, endothelial apoptosis, microvascular damage, microvascular permeability and cardiac edema. Mechanistically, CD1d deficiency further increased LPS-induced accumulation of T lymphocytes in the myocardium and upregulation of IL-6 protein levels. Administration of an IL-6 neutralizing antibody to CD1dko mice improved cardiac dysfunction, myocardial injury and edema induced by LPS. Our study identified that CD1d-dependent NKT-cells inactivation exacerbated SIC via T lymphocytes infiltration and IL-6 production. Hence, activation of CD1d-dependent NKT cells may be a potential candidate strategy for SIC treatment.

Over the last decade, immuno-oncologic drugs especially CD3-engaging bispecific antibodies (biAbs) are experiencing fast-paced evolution, but big challenges still exist in the clinical development of biAbs in solid tumors, especially non-small cell lung cancer (NSCLC). In this study, we choose a ROR1 × CD3 biAb in scFv-Fc format, named R11 × v9 biAb, to investigate its tumor-inhibiting role in NSCLC. Notably, the ROR1-engaging arm binds both human and mouse ROR1. We found that R11 × v9 biAb specifically binds T cells and tumor cells simultaneously, and dose-dependent cytotoxicity was detected for various ROR1+ NSCLC cell lines. Further, R11 × v9 biAb mediated T-cell derived proinflammatory cytokine secretion, boosted granzyme B and perforin production from CD8+ T cells, and recruited more CD4+ T cells and CD8+ T cells into the tumor tissues. The antitumor activity of R11 × v9 biAb was confirmed in two xenograft mouse models of ROR1+ NSCLC. Importantly, no harmful side effects were observed in these in vivo studies, warranting further preclinical and clinical studies of R11 × v9 biAb in NSCLC.

Supplementary Data from The Combination of a Histone Deacetylase Inhibitor with the Bcl-2 Homology Domain-3 Mimetic GX15-070 Has Synergistic Antileukemia Activity by Activating Both Apoptosis and Autophagy

Background Different T‐lymphocyte subsets, including CD1d‐dependent natural killer T (NKT) cells, play distinct roles in hypertension, highlighting the importance of identifying key immune cells for its treatment. This study aimed to determine the unknown effects of CD1d‐dependent NKT cells on hypertension and vascular injury. Methods and Results Hypertension models were induced in male CD1d knockout (CD1dko), wild‐type, and adoptive bone marrow transfer mice by angiotensin II (Ang II) or deoxycorticosterone acetate salt. Blood pressure was measured by the tail‐cuff system and radiotelemetry. Vascular injury was assessed by histologic studies or aortic ring assay. Inflammation was detected by flow cytometry, quantitative real‐time polymerase chain reaction, or ELISA. Results showed that Ang II infusion significantly reduced CD1d expression and NKT cell numbers in the aorta of mice. CD1dko mice exhibited worsened blood pressure elevation, vascular injury, and inflammatory response induced by Ang II or deoxycorticosterone acetate salt. However, these effects were markedly reversed in wild‐type mice treated with NKT cell–specific activator. Adoptive transfer of CD1dko bone marrow cells to wild‐type mice also significantly worsened Ang II–induced responses. Mechanistically, CD1dko increased Ang II–induced interleukin‐6 production and activated signal transducer and activator of transcription 3 and orphan nuclear receptor γ, subsequently inducing interleukin‐17A production. Neutralizing interleukin‐17A partially reversed Ang II–induced hypertension and vascular injury in CD1dko mice. In addition, levels of NKT cells were lower in the blood of patients with hypertension (n=57) compared with normotensive individuals (n=87). Conclusions These findings reveal a previously unknown role for CD1d‐dependent NKT cells in hypertension and vascular injury, indicating that NKT cell activation could be a promising therapeutic target for hypertension.

热化学储热材料是通过化学反应过程中化学键的破坏与重组来实现热能的储存与释放.与其他储热材料相比,热化学储热材料具有储热密度高、长周期稳定储热等优势.水合盐热化学储热材料可以高效储存太阳能和工业余热等中低温热源,在热化学储热领域具有很高的关注度.纯水合盐材料(如LiCl、LiBr、CaCl2)液解相对湿度较低,水合(脱水)反应包含固-气水合(脱水)反应、气-液-固三相液解(结晶)、液-气吸收三个过程,这种循环过程可显著提高水合盐的储热密度.若吸水量控制不佳则易引起严重的传质和腐蚀问题.对于液解相对湿度较高、储热密度较高的水合盐,如SrBr2和MgSO4,其传热性能差、孔隙率和渗透率低.将水合盐嵌入多孔基质中形成多孔基质水合盐复合储热材料可进一步强化其传热,并同时解决水合盐的潮解结块问题.近年来,人们对多孔基质水合盐复合储热材料进行了深入研究,获得了多种储热密度高、具有良好循环稳定性的复合储热材料.多孔基质水合盐复合储热材料设计过程中,多孔基质的选择尤为重要.目前研究的热点主要集中于膨胀石墨、沸石、蛭石、硅胶、活性氧化硅等.将LiCl和膨胀石墨(EG)制成的复合材料用于10 kWh的低温热化学吸附储热装置中,系统的储热密度高达3142 kJ/kg;以活性氧化铝(AA)为多孔基质、LiCl为嵌入盐制得了一种新型复合材料(AL),其中AL25(盐含量为14.68％,质量分数)复合材料的结构稳定,储热性能最优,具有最高的储热密度为1041.5 kJ/kg,充热温度为120℃;在不使用多孔基质的条件下,MgCl2·MgSO4二元水合盐在超过50次循环实验后,仍保持良好的性能,说明其具有非常高的循环稳定性.本文基于反应动力学、平衡吸附量和化学反应平衡等理论,从传热和传质性能、循环稳定性和储热密度等方面综述了水合盐热化学储热材料的研究成果,探讨了水合盐热化学储热材料存在的问题,以期为开发高效水合盐热化学储热材料提供参考.

Angiogenic factor with G patch and FHA domains 1 (AGGF1) is a newly identified proangiogenic protein, which plays an important role in vascular disease and angiogenesis. However, its role in myocardial ischemia/reperfusion (I/R) injury remains unknown. This study investigated whether AGGF1 is involved in the pathogenesis of mouse myocardial I/R injury and the underlying mechanisms. Wild-type (WT) C57BL/6 J mice were treated at 30 min prior to I/R injury with anti-AGGF1 neutralizing antibody (3 mg/kg) or recombinant human AGGF1 (rhAGGF1, 0.25 mg/kg). After I/R injury, the infarct size, the number of TUNEL-positive cardiomyocytes, Bax/Bcl2 ratio, inflammatory cytokine expression and angiogenesis were markedly increased as compared with sham control. Treatment of WT mice with anti-AGGF1 neutralizing antibody resulted in exaggeration of myocardial I/R injury but reducing angiogenesis. In contrast, administration of rhAGGF1 markedly reversed these effects. Furthermore, anti-AGGF1- or rhAGGF1-mediated effects on I/R-induced cardiac apoptosis, inflammation and angiogenesis were dose dependent. In addition, the protective effects of AGGF1 on cardiomyocyte apoptosis and inflammation were confirmed in cultured cardiomyocytes after I/R. Finally, these effects were associated with activation of ERK1/2, Stat3 and HIF-1α/VEGF pathways and inhibition of activation of NF-κB, p53 and JNK1/2 pathways. In conclusion, we report the first in vivo and in vitro evidence that AGGF1 reduces myocardial apoptosis and inflammation and enhances angiogenesis, leading to decreased infarct size after I/R injury. These results may provide a novel therapeutic approach for ischemic heart diseases.

The pathogenesis of cardiac hypertrophy is tightly associated with activation of intracellular hypertrophic signalling pathways, which leads to the synthesis of various proteins. Tripartite motif 10 (TRIM10) is an E3 ligase with important functions in protein quality control. However, its role in cardiac hypertrophy was unclear. In this study, neonatal rat cardiomyocytes (NRCMs) and TRIM10-knockout mice were subjected to phenylephrine (PE) stimulation or transverse aortic constriction (TAC) to induce cardiac hypertrophy in vitro and in vivo, respectively. Trim10 expression was significantly increased in hypertrophied murine hearts and PE-stimulated NRCMs. Knockdown of TRIM10 in NRCMs alleviated PE-induced changes in the size of cardiomyocytes and hypertrophy gene expression, whereas TRIM10 overexpression aggravated these changes. These results were further verified in TRIM10-knockout mice. Mechanistically, we found that TRIM10 knockout or knockdown decreased AKT phosphorylation. Furthermore, we found that TRIM10 knockout or knockdown increased ubiquitination of phosphatase and tensin homolog (PTEN), which negatively regulated AKT activation. The results of this study reveal the involvement of TRIM10 in pathological cardiac hypertrophy, which may occur by prompting of PTEN ubiquitination and subsequent activation of AKT signalling. Therefore, TRIM10 may be a promising target for treatment of cardiac hypertrophy.

Aims:CD1d is a member of the cluster of differentiation 1 (CD1) family of glycoproteins expressed on the surface of various antigen-presenting cells, which is recognized by natural killer T (NKT) cells. CD1d-dependent NKT cells play an important role in immune-mediated diseases; but the role of these cells in regulating cardiac remodelling remains unknown.Methods and results:Cardiac remodelling was induced by angiotensin (Ang) II infusion for 2 weeks. Ang II-induced increase in hypertension, cardiac performance, hypertrophy and fibrosis, inflammatory response, and activation of the NF-kB and TGF-β1/Smad2/3 pathways was significantly aggravated in CD1d knockout (CD1dko) mice compared with wild-type (WT) mice, but these effects were markedly abrogated in WT mice treated with α-galactosylceramide (αGC), a specific activator of NKT cells. Adoptive transfer of CD1dko bone marrow cells to WT mice further confirmed the deleterious effect of CD1dko. Moreover, IL-10 expression was significantly decreased in CD1dko hearts but increased in αGC-treated mice. Co-culture experiments revealed that CD1dko dendritic cells significantly reduced IL-10 mRNA expression from NKT cells. Administration of recombinant murine IL-10 to CD1dko mice improved hypertension, cardiac performance, and adverse cardiac remodelling induced by Ang II, and its cardioprotective effect was possibly associated with activation of STAT3, and inhibition of the TGF-β1 and NF-kB pathways.Conclusion:These findings revealed a previously undefined role for CD1d-dependent NKT cells in Ang II-induced cardiac remodelling, hence activation of NKT cells may be a novel therapeutic target for hypertensive cardiac disease.