Vascular dementia is a highly heterogeneous neurodegenerative disorder induced by a variety of factors. Currently, there are no definitive treatments for the cognitive dysfunction associated with vascular dementia. However, early detection and preventive measures have proven effective in reducing the risk of onset and improving patient prognosis. Nitric oxide plays an integral role in various physiological and pathological processes within the central nervous system. In recent years, nitric oxide has been implicated in the regulation of synaptic plasticity and has emerged as a crucial factor in the pathophysiology of vascular dementia. At different stages of vascular dementia, nitric oxide levels and bioavailability undergo dynamic alterations, with a marked reduction in the later stages, which significantly contributes to the cognitive deficits associated with the disease. This review provides a comprehensive review of the emerging role of nitric oxide in the physiological and pathological processes underlying vascular dementia, focusing on its effects on synaptic dysfunction, neuroinflammation, oxidative stress, and blood‒brain barrier integrity. Furthermore, we suggest that targeting the nitric oxide soluble guanylate cyclase-cyclic guanosine monophosphate pathway through specific therapeutic strategies may offer a novel approach for treating vascular dementia, potentially improving both cognitive function and patient prognosis. The review contributes to a better understanding of the multifaceted role of nitric oxide in vascular dementia and to offering insights into future therapeutic interventions.

With the gradual legalisation of recreational cannabis, associated health effects have received widespread attention, but their association with female infertility remains unclear. The aim of this study was to explore the association between cannabis use and infertility among females of childbearing age in the United States.

Data were obtained from the National Health and Nutrition Examination Survey 2013-2018; 1694 female participants aged 18-45 years were included. The association between cannabis use and female infertility was analysed by logistic regression analysis. All data were weighted before analysis.

After adjusting for all covariates, former cannabis users demonstrated significantly elevated odds of infertility compared with never-users (odds ratio: 2.04, 95% confidence interval: 1.21-3.43, P = 0.012), whereas current cannabis users exhibited no significant difference in infertility odds relative to never-users. In subgroup analysis, former users aged 18-35 years exhibited higher odds of infertility than never-users (odds ratio: 2.37, 95% confidence interval: 1.11-5.04, P = 0.027); but former cannabis users aged 36-45 years demonstrated no significant difference in infertility odds compared with never-users. Among former cannabis users aged 18-35 years, those with sustained abstinence exceeding 3 years demonstrated significantly elevated odds of infertility compared with never-users (odds ratio: 2.94, 95% confidence interval: 1.29-6.71, P = 0.005). In contrast, individuals with shorter abstinence durations (<3 years) showed no significant difference in infertility odds relative to never-users.

Among females of childbearing age, the odds of infertility was not elevated among current cannabis users compared with never-users, while the odds of infertility was elevated among former users. This relationship between cannabis use and female fertility is more often reflected in the distant term (>3 years of cessation), and this adverse association is more pronounced among females in the most active reproductive years (18-35).

Cardiovascular diseases (CVDs), including conditions like ischemic heart disease, heart failure (HF), and atherosclerosis (AS), have complex pathogenesis that involves both behavioral and metabolic factors. Nicotinamide N-methyltransferase (NNMT) is an enzyme involved in the methylation of nicotinamide (NAM), and its increased activity is associated with disruptions in the NAD+ and methionine cycles. These disruptions are considered significant risk factors for cardiovascular diseases, though the specific mechanisms of NNMT remain unclear. This review discusses the role of NNMT in cardiovascular diseases by modulating NAD+ and methionine metabolism, including mechanisms such as NAD+ depletion, mitochondrial energy crisis, SIRTs deactivation, PARP hyperactivation, as well as hyperhomocysteinemia and epigenetic dysregulation. NNMT is linked to diseases such as atherosclerosis, pulmonary arterial hypertension, heart failure, and coronary heart disease, playing a critical role in their progression. Moreover, the potential of NNMT as a therapeutic target for cardiovascular diseases is explored. RNAi therapies, NNMT small-molecule inhibitors, and exercise therapies are promising treatment approaches, but there are limitations in current research, including discrepancies between animal models and human tissue expression, the dual role of NNMT, and the dose-dependent effects of NNMT inhibitors. Future studies should further clarify NNMT's mechanisms and assess its feasibility as a therapeutic target, aiming to develop more effective treatments and enhance prevention and treatment strategies for cardiovascular diseases.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disorder with a complex pathogenesis that requires combination therapies rather than monotherapies. Extracellular vesicles (EVs) exhibit inherently efficient delivery to the liver and can be engineered to carry various therapeutic substances, making them promising agents. In this study, EVs were engineered to display fibroblast growth factor 21 (FGF21) on their surface and encapsulate miR-223 (223/F-EVs), aiming to improve steatosis and alleviate inflammation and fibrosis, respectively. Introducing the 223/F-EVs into human liver cell lines significantly reduced both basal and induced levels of lipid storage, inflammation, and fibrosis markers. Furthermore, using an FGF21-blocking antibody or miR-223 inhibitor effectively diminished the efficacy of the 223/F-EVs, confirming the essential roles of FGF21 and miR-223 in these processes. In a Choline-Deficient, l-Amino acid-defined, High-Fat Diet (CDAHFD)-fed mouse model, intravenously administered 223/F-EVs demonstrated liver-preferential delivery and a marked reduction in the MASH phenotype without compromising bone density, unlike conventional FGF21 treatment. Collectively, 223/F-EVs convey FGF21 and miR-223 exclusively to the liver, offering strategic advantages by mitigating MASH progression via multiple pathways. This study lays a solid foundation for further investigation of engineered EVs as a transformative therapeutic approach for treating MASH.

Identifying molecular targets of physiologically active organic compounds remains a major challenge in contemporary biomedical research and drug discovery. In recent years, the development of activity-based protein profiling (ABPP) techniques has proven to be superior to classical molecular target identification methods. ABPP can be classified into activity-based probes (AcBPs) and affinity-based probes (AfBPs). AfBPs bind to target proteins through reversible non-covalent interactions, thus minimizing the impact on the natural biological functions of the protein. The development of AfBPs has great potential for studying drug targets, optimizing drugs, and improving therapeutic efficacy. As a result, there has been a dramatic increase in research and development focused on affinity probes with the use of a wide range of AfBPs such as biotin probes, FITC probes, BRET probes, and radiolabeled probes. This tutorial describes the process of designing and synthesizing different types of AfBPs from biologically active compounds, and then utilizing the probes to identify the target proteins. It also provides insights for subsequent drug discovery and development.

The changes in viscosity and the concentration of ONOO- in mitochondria can effectively reflect the physiological and pathological status of cells. Therefore, the development of effective fluorescent probes for the sensing of viscosity and the concentration of ONOO- in mitochondria has great significance. In this article, a mitochondrial targeted fluorescent probe named Mito-RP was synthesized for the dual responsive sensing of viscosity and ONOO- by introducing pyridine ring and phenylboronic acid ester structure into 4-dimethylamino-cinnamaldehyde with long conjugated chain structure as the parent material. Mito-RP exhibits 600 folds fluorescence enhancement of viscosity in the red-light channel at 700 nm, with pyridine cation as the mitochondrial anchoring group. Simultaneously, Mito-RP appears excellent selectivity towards ONOO- using boronic acid esters as response sites. A new ratio fluorescence analysis method was constructed based on the linear correlation between the emission intensity ratio of Mito-RP at 616 nm/700 nm and the concentration of ONOO-. The linear range is 0.05-33 μM and the detection limit is 9.2 nM. Meanwhile, Mito-RP successfully monitored the changes in viscosity during lipopolysaccharide induced inflammation and rapamycin induced mitochondrial autophagy in HeLa cells. In addition, Mito-RP has also achieved visual imaging of intracellular exogenous/endogenous ONOO-. These studies provide a novel method for in-depth investigation of mitochondrial function and its role in diseases.

Peroxynitrite (ONOO-) is a reactive nitrogen species whose abnormal accumulation in the body can lead to various diseases, including those related to oxidative stress. Accurate detection of ONOO- levels is essential for the diagnosis and treatment of these diseases. To address this need, we developed a lysosome-targeted fluorescent probe Lyso-PE for detecting ONOO- in tumors. In the presence of ONOO-, probe Lyso-PE showed a large Stokes shift of 100 nm. The probe exhibited high sensitivity, selectivity, and rapid response toward ONOO-. Additionally, Lyso-PE displayed excellent lysosomal targeting and was successfully employed in imaging the exogenous peroxynitrite in tumor cells. In the 4T1 subcutaneous graft tumor model, the probe could effectively distinguish tumors and normal tissues with the help of fluorescence imaging in vivo. Moreover, Lyso-PE could be used for tumor resection guided by fluorescent signals in vivo. These results suggested that Lyso-PE could enhance our understanding of lysosomal function in disease, identify new therapeutic targets, and aid in developing new diagnostic and therapeutic strategies with significant clinical implications.

The 29th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held on November 22nd, 2024, at Loyola University Chicago, Health Science Campus, Maywood, Illinois. The meeting was divided into three plenary sessions and a poster session. The overall focus of this year's meeting was on alcohol and host immunity, alcohol and organ dysfunction, and alcohol, inflammation, and tissue injury. The presentations in each session shared the latest developments on the impact of alcohol in a wide variety of fields including trauma, emergency care and hospitalization, cardiovascular health, neurodegenerative disease, gut microbiome, and hepatology.

Decidualization is essential for establishing pregnancy in both mice and humans. Cellular stresses, including nucleolar stress and DNA damage, are involved in this process. Inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme for de novo guanosine triphosphate (GTP) synthesis, forms membrane-free macromolecular structures called "cytoophidia" under specific conditions. However, whether IMPDH cytoophidia are present during decidualization remains unknown. In this study, we found that IMPDH2 cytoophidia are primarily detected in mouse decidual cells during early pregnancy. On day 5 of pregnancy, more IMPDH2 cytoophidia are observed at implantation sites than at inter-implantation sites. Physiologically, uteri activated by estrogen exhibit more IMPDH2 cytoophidia than those maintained in a delayed state by progesterone. Although GTP is required for in vitro decidualization in mice, elevated GTP level impairs this process. Furthermore, IMPDH2 cytoophidia can induce nucleolar stress and DNA damage in mice. In the human endometrium, IMPDH2 cytoophidia are observed during the menstrual cycle, particularly enriched in the secretory phase. They promote human decidualization and naturally enhance cellular senescence. Our findings highlight the physiological relevance of IMPDH2 cytoophidia during early pregnancy in mice and humans.

An Adverse Outcome Pathway (AOP) is a conceptual framework in toxicology and risk assessment that outlines the series of events from a chemical's molecular interaction to the resulting adverse health effect. This framework offers a structured approach to organizing biological knowledge, making it especially useful for understanding the mechanisms through which chemicals cause harm. Following a comprehensive analysis of the literature, an AOP was elucidated for key events linking DNA adduct formation, caused by compounds such as platinum anticancer drugs, to tubular necrosis, resulting in kidney failure. Currently, cisplatin, carboplatin and oxaliplatin are the three most utilised Pt-based drugs used globally for the treatment of cancer. The hydrolysis of platinum anticancer agents post-cellular uptake yields electrophilic intermediates that covalently bind to nucleophilic sites on DNA to form adducts that represent the molecular initiating event. When DNA repair mechanisms become unbalanced, the nephrotoxic response following the formation of DNA adducts leads to DNA damage and mitochondrial dysfunction. These events promote the generation and release of reaction oxygen species (ROS) to induce oxidative stress, causing cell death and inflammation. Upon detachment from the basement membrane, these compromised cells are subsequently deposited in the tubular lumen. Tubular obstruction and inflammatory responses to proximal tubule insult can lead to secondary toxicity and tubular necrosis, further exacerbating kidney injury and precipitating a progressive decline of renal function, finally resulting in kidney failure.

Xiao Jianzhong Granules (XJZG), a well-known traditional prescription with protective effects on the gastric mucosa, as documented in the Treatise on Typhoid and Miscellaneous Diseases. Clinical studies have proven that XJZG exhibits significant anti-colitis properties and effectively alleviates duodenal ulcers. However, despite its clinical popularity, comprehensive studies on its chemical composition and in vivo metabolism remain limited. In the present study, gas chromatography coupled with mass spectrometry (GC-MS) and ultra-high-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry (UHPLC Q-Exactive Orbitrap MS) were used to analyze the chemical composition of XJZG, while it is in vivo metabolic profile was further assessed with UHPLC Q-Exactive Orbitrap MS. Additionally, ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-MS/MS) was utilized to quantify its primary components. As a result, a total of 51 volatiles were characterized by GC-MS, and 139 compounds were characterized by UHPLC Q-Exactive Orbitrap MS in vitro. In addition, 51 prototype components and 133 metabolites were characterized in vivo. Notably, 5 new compounds were discovered in this process. The main metabolic reactions included oxidation, reduction, hydrolysis, glucuronidation, and sulfate esterification. In quantitative analysis, 17 components were determined and successfully applied for detection by UPLC-MS/MS in multiple reaction monitoring mode. The quantitative methods were validated and met the requirements. Through multivariate statistical analysis, 6 components were selected as potential quality markers for XJZG based on PCA and OPLS-DA. Additionally, our study provides supplementary chemical evidence to further elucidate the material basis of XJZG.

The stimulator of interferon genes (STING) pathway plays a critical role in innate immunity, acting as a central mediator that links cytosolic DNA sensing to inflammatory signaling. STING not only responds to cellular metabolic states but also actively regulates key metabolic processes, including glycolysis, lipid metabolism, and redox balance. This bidirectional interaction underscores the existence of a dynamic feedback mechanism between STING signaling and metabolic pathways, which is essential for maintaining cellular homeostasis. This review provides a comprehensive analysis, beginning with an in-depth overview of the classical STING signaling pathway, followed by a detailed examination of its reciprocal regulation of various metabolic pathways. Additionally, it explores the role and mechanisms of STING signaling in metabolic disorders, including obesity, diabetes, and atherosclerosis. By integrating these insights into the mutual regulation between STING and its metabolism, novel therapeutic strategies targeting this pathway in metabolic diseases have been proposed.

Cannabis use by people who are pregnant is increasing. Understanding how prenatal cannabinoid exposure (PCE) affects infants and children is of high public health significance. Epidemiological studies have associated PCE with cognitive symptoms, including impaired learning, memory, attention, and executive control, and affective symptoms, including anxiety, emotional dysregulation, and social impairments, in children, adolescents, and young adults. PCE is also associated with neurobiological changes including decreased corticolimbic white matter and functional connectivity; however, the underlying mechanisms for these persisting effects remain unknown. Rodent models are essential for uncovering the effects of PCE on the developing brain. This review summarizes rodent studies focused on the cognitive and affective behavioral and neurobiological outcomes of PCE. Rodent studies have reported cognitive deficits, including impaired learning, memory, attention, and executive control, and affect-related impairments, including anxiety-like behavior, altered stress coping, social impairments, and anhedonia-like behavior, in adolescent and adult offspring. Studies have also demonstrated that PCE affects several underlying neurotransmitter systems, producing dopamine hyperactivity, glutamate and serotonin hypoactivity, and dysregulating GABA and opioid signaling. Evidence further suggests a marked difference in outcomes between males and females, with males being more susceptible to the enduring effects of PCE. However, studies that investigate female-specific outcomes or sex as a biological variable are scarce. Altogether, rodent studies provide corroborating evidence that PCE produces lasting cognitive and affective impairments underpinned by altered neurobiological mechanisms. Research is critically needed to improve our understanding of the risks associated with cannabis use during pregnancy and effects across the lifespan.

Current evidence underscores that oxidative stress (OS) is a pivotal factor in the formation of vulnerable plaques in individuals with coronary heart disease (CHD). The Oxidative Balance Score (OBS), a comprehensive measure of systemic OS, consists of 15 antioxidants and 5 pro-oxidants, with higher scores indicating greater antioxidant activity. We hypothesized that a high OBS would be associated with improved coronary plaque stability in CHD patients.

A total of 635 patients diagnosed with CHD were included in this study. After accounting for confounding variables, we found a significant inverse association between higher OBS and the formation of thin-capped fibroatheroma (TCFA) (OR = 0.933, 95 % CI: 0.913, 0.953). This relationship exhibited a nonlinear pattern, plateauing at an OBS score of 18.1. Mediation analysis revealed that OBS significantly mediates the relationship between food intake (soy, grains, vegetables, fruits) and plaque stability (p < 0.05).

Our findings indicate that a higher OBS is inversely associated with the presence of vulnerable plaques. Adopting a diet rich in antioxidants, characterized by increased consumption of soy, grains, vegetables, and fruits, along with an antioxidant-focused lifestyle, may serve as an effective preventive strategy to enhance plaque stability in CHD patients.

Atherosclerosis is induced by lipid accumulation, inflammation, and endothelial dysfunction, and is the leading cause of death from cardiovascular disease worldwide. The P2Y6 receptor can be activated by the extracellular release of UDP. The evidence from the last decade has highlighted its critical therapeutic effect in atherosclerosis, yet with unclear mechanisms. This review introduced the P2Y6 receptor in atherosclerosis, and its mechanisms of atherosclerosis-promoting in macrophages, endothelial cells, and vascular smooth muscle cells. Finally, we discussed the development and potential of P2Y6 receptor antagonists in treating atherosclerosis.

Periodontitis is notable for its high prevalence in the oral cavity and its association with systemic diseases. Functional alterations in vasomotor activity occur in the arteries of rats with mild periodontitis, primarily due to decreased soluble guanylate cyclase (sGC) enzyme activity. This study aims to investigate the functional response of mesenteric resistance arteries (MRA) obtained from rats with mild periodontitis. Vascular reactivity of MRAs from rats in the ligature (L) or sham (S) groups was assessed using a wire myograph. Additionally, antioxidant enzyme activity, the presence of nitrated proteins, cyclic guanosine monophosphate (cGMP) levels, and electron paramagnetic resonance (EPR) spectroscopy were analyzed. The MRAs from the L group showed lower pD2 values in response to sodium nitroprusside or sildenafil and decreased Emax to the sGC stimulator Bay 41-2271 compared to the S group. However, no differences were observed between the groups with respect to the sGC activator Bay 60-2770. The L group exhibited increased nitrotyrosine protein expression, enhanced catalase activity, and reduced superoxide dismutase activity, along with decreased cGMP content after SNP stimulation. The EPR spectrum of the L group showed a weak peak at g 6.00, compared to the S group, confirming the oxidation of sGC heme-iron (Fe+2) to heme-Fe+3. In the early phase of bilateral ligature-induced periodontitis in rats, functional changes in the nitric oxide (NO)-cGMP pathway occur in the MRA due to reduced sGC activity and excessive production of iNOS-derived NO, superoxide anion, or a combination of both.

Hair analysis is increasingly used to index long-term cumulative hormone levels. However, it remains unclear from which scalp region hair should be sampled to yield best results. Here, we conduct an in-depth, systematic investigation into this question, comparing quality characteristics between the two most promising sampling areas, the posterior vertex and the occipital region. To advance standardization in future research, we specify anatomical landmarks to clearly define sampling regions.

Participants (N = 53) provided a total of twelve hair samples across two time points, three months apart. At each time point, six hair samples (three from each region) were analyzed for concentrations of cortisol, cortisone, progesterone, dehydroepiandrosterone and endocannabinoids (AEA, 1/2-AG, OEA, SEA, PEA) via liquid chromatography-tandem mass spectrometry. Patterns of intra-region variability, mean differences, test-retest correlations and associations with external criteria (anthropometrics and perceived stress) were compared between regions.

Overall, no consistent differences were found between the posterior vertex and occipital region with regard to intra-region variability, test-retest correlations and external associations. However, significant mean differences in analyte concentrations were observed: hair cortisol and cortisone were higher in the occipital region, while OEA, SEA and PEA were higher at the posterior vertex.

Our findings highlight the importance of sampling from a defined scalp region for endocrine hair analyses. While neither scalp region was unequivocally superior, differences in mean concentrations call for increased standardization of methodological practice in future research. We propose anatomical landmarks for precise region localization and offer practical recommendations concerning the choice of sampling region.

Frontotemporal dementia (FTD) comprises a group of disorders characterized by a progressive decline in behavior or language linked to the degeneration of the frontal and anterior temporal lobes followed by hippocampal atrophy. There are no effective treatments for FTD and for this reason, novel pharmacological targets, such as the endocannabinoid system (ECS), are being explored. Previous results from our laboratory showed a TAUP301L-dependent increase in CB2 receptor expression in hippocampal neurons of a FTD mouse model, alongside the neuroprotective impact of CB2 ablation. In this study, we evaluated the therapeutic potential of a new CB2 antagonist (PGN36) in our TAU-dependent FTD mouse model. Six-month-old mice received stereotaxic injections of an adeno-associated virus expressing human TAUP301L protein (AAV-TAUP301L) into the right hippocampus and were treated daily with PGN36 (5 mg/kg, i.p.) or vehicle for three weeks. By integrating behavioral tests, RNA-seq, qPCR expression analysis, and immunofluorescence in the AAV expressing TAU mouse model, we found that PGN36 treatment reverses key features of the neurodegenerative process triggered by TAUP301L overexpression. PGN36 treatment effectively countered TAUP301L-induced cognitive decline by reducing TAU protein expression levels and restoring markers of synaptic plasticity. Notably, we observed neuroprotection in the dentate gyrus granular layer, which we attribute to the modulation of pyroptosis. This programmed cell death pathway, is triggered by TAUP301L overexpression. PGN36 appears to modulate the pyroptotic cascade, thereby preventing the pyroptosis-induced neuronal loss. These findings collectively underscore the neuroprotective potential of this novel CB2 antagonist treatment against TAU-associated FTD.

Hepatic ischemia/reperfusion (I/R) injury occurs after liver resection surgery, trauma, shock, and transplantation. This study aimed to identify and characterize the role of the YTH domain-containing protein 1 (YTHDC1)/MAFF/vacuole membrane protein 1 (VMP1) axis in hepatic I/R injury. YTHDC1, MAFF, and VMP1 were significantly overexpressed in the hepatic tissues of mice with I/R and hepatocytes exposed to hypoxia-reoxygenation (H/R). Knockdown of MAFF exacerbated oxidative stress and inflammatory injury in mice induced with hepatic I/R, which were reversed by overexpression of VMP1. Similarly, I/R-associated injury mitigated by YTHDC1 overexpression was reversed by MAFF knockdown. Mechanistically, YTHDC1 mediated the nuclear export and stability of MAFF mRNA and promoted MAFF translation. Collectively, the findings establish that YTHDC1-mediated m6A-dependent MAFF expression determines hepatocyte oxidative stress via VMP1, providing valuable insights into the potential mechanisms underlying hepatic I/R injury and offering potential therapeutic strategies for its treatment.

Extracellular ATP has been reported to potentiate signalling by several Class B G protein-coupled receptors (GPCRs). The adenosine A2a receptor (A2aR) is a Class A GPCR that regulates many physiological processes, and a potential therapeutic target for many diseases. In vivo, A2aR is exposed transiently to extracellular ATP within the cellular microenvironment under both physiological and pathological conditions. The modulating effects of extracellular ATP seen with Class B GPCRs have not previously been investigated in other classes of GPCRs. In the present study, we investigated the effects of extracellular ATP on A2aR signalling. We also studied the actions of similar molecules to explore the structure-activity relationship. Cyclic 3',5'-adenosine monophosphate (cAMP) levels were monitored following agonist-induced receptor activation in cells co-transfected with plasmids encoding A2aR and a luminescent cAMP biosensor. Extracellular ATP increased the potency of both adenosine and selective A2aR agonists by approximately an order of magnitude. In the absence of agonist, ATP did not activate A2aR, arguing against an effect due to ATP metabolism to adenosine. The potentiating effect of ATP was mimicked by other nucleotides and similarly by phosphorylated sugars. Non-phosphorylated sugars produced comparable effects, but higher concentrations were required to do so. This difference in potency implies that the phosphate group is important for modulating A2aR activity. Here, we present the first evidence that A2aR can be positively modulated by extracellular ATP, thus the effect of ATP is not limited to Class B GPCRs.

Fine particulate matter (PM2.5) is an independent risk factor for vascular diseases. In this context, activated macrophages release inflammatory molecules that can contribute to endothelial dysfunction. While the effects of PM2.5's solid fraction on vascular endothelial cells are well-documented, the effect of its polar compounds circulating in the bloodstream remains unclear. In this study, we examined the effects of direct and indirect (macrophage-mediated) exposure to aqueous PM2.5 on the endothelium. CF-1 mice received intranasal instillations of PM2.5 (30 μg in 10 μL) or saline, 5 days per week for two weeks. These animals exhibited considerable endothelial dysfunction linked to oxidative stress. Similarly, macrophages (RAW264.7 lineage) exposed to aqueous PM2.5 (10-fold dilution) exhibited oxidative stress and inflammation, indicating that their reactive phenotype may contribute to the outcomes observed in vivo. Interestingly, their conditioned medium (10 % v/v) enhanced endothelial cell function (EOMA lineage) by reducing reactive oxygen species (ROS) production and promoting an endothelial nitric oxide synthase (eNOS)-dependent increase in nitrite levels, with the exact opposite effect observed in cells directly exposed to aqueous PM2.5. These findings suggest that the macrophage secretome, rather than residual metals, may be responsible for these effects. Consistent with these findings, incubation with the animals' plasma (1 % v/v) also stimulated nitrite production. Additionally, caveolin-1, a key mediator of vesicle uptake, was overexpressed in endothelial cells exposed to conditioned medium, suggesting its involvement in monocyte-endothelium crosstalk. Finally, our results indicated that the macrophage secretome might serve as a mild stimulus, activating protective mechanisms in endothelial cells, whereas direct exposure to aqueous PM2.5 induces dysfunction.

Atherosclerosis and its associated cardiovascular complications remain significant global public health challenges, underscoring the urgent need for effective therapeutic strategies. Endothelial cells are critical for maintaining vascular health and homeostasis, and their dysfunction is a key contributor to the initiation and progression of atherosclerosis. Targeting endothelial dysfunction has, therefore, emerged as a promising approach for the prevention and management of atherosclerosis. Among natural products, flavonoids, a diverse class of plant-derived phenolic compounds, have garnered significant attention for their anti-atherosclerotic properties. A growing body of evidence demonstrates that flavonoids can mitigate endothelial dysfunction, highlighting their potential as endothelial dysfunction-targeted therapeutics for atherosclerosis. In this review, we summarize current knowledge on the roles of natural flavonoids in modulating various aspects of endothelial dysfunction and their therapeutic effects on atherosclerosis, focusing on the underlying molecular mechanisms. We also discuss the challenges and future prospects of translating natural flavonoids into clinical applications for cardiovascular medicine. This review aims to provide critical insights to advance the development of novel endothelium-protective pharmacotherapies for atherosclerosis.

Targeting ferroptosis vulnerabilities in tumors has become an increasingly promising therapeutic strategy. While the regulatory effects of natural products on ferroptosis are progressively being elucidated, the role of cardiac glycosides in modulating ferroptosis remains poorly understood.

This study aims to investigate the ferroptosis-sensitizing effects of periplocymarin (PPM), a cardiac glycoside derived from the traditional plant Periploca sepium, and to elucidate the underlying molecular mechanisms.

The effects of PPM on ferroptosis regulation were comprehensively assessed through functional assays, followed by sequencing analysis to identify associated signaling pathways. Subsequent mechanistic validation experiments were conducted to confirm the upstream and downstream regulatory components involved in this ferroptosis-modulating axis.

PPM induced slow and mild apoptosis in gastric cancer cells through the inhibition of glycolysis. However, when combined with ferroptosis inducers, it promoted rapid and robust ferroptosis. In vivo, PPM sensitized gastric cancer xenografts to cisplatin-induced ferroptosis with no observable cardiotoxicity or renal impairment. Mechanistically, PPM targeted the α1 subunit of the Na+/K+-ATPase (ATP1A1), leading to the activation of Src, which subsequently induced tyrosine phosphorylation of YAP/TAZ in a Hippo-independent manner, promoting their nuclear translocation. The YAP/TAZ-TEAD transcriptional complex directly bound to the TFRC promoter region between nucleotides 401-409 upstream of the transcription start site, thereby activating TFRC transcription. This resulted in increased iron influx, elevated lipid peroxidation, and heightened sensitivity to ferroptosis. Notably, ATP1A1 was essential for ferroptosis resistance, as its knockdown mimicked the sensitizing effect of PPM on ferroptosis. Moreover, the oncogenic Src-YAP/TAZ-TFRC axis may have represented a ferroptosis vulnerability and a potential biomarker in ferroptosis therapy for cancer. Importantly, other cardiac glycosides targeting Na+/K+-ATPase, such as digitoxin and bufalin, also enhanced ferroptosis sensitivity in gastric cancer cells through activation of YAP/TAZ signaling.

Our findings establish the cardiac glycoside PPM as a novel ferroptosis sensitizer that targets ATP1A1 to activate the Src-YAP/TAZ-TFRC axis, providing mechanistic insights for repurposing cardiac glycosides as ferroptosis modulators in precision combinatorial cancer therapy.

Adenosine signaling is emerging as a key regulator of hematopoietic lineage commitment, influencing both erythropoiesis and myelopoiesis. This review explores the distinct roles of adenosine receptors in balancing these processes, particularly under stress conditions. Since adenosine extracellular levels are increased in multiple hematological disorders, including sickle cell disease, deciphering the mechanisms downstream of adenosine receptor activation is crucial to understand the pathophysiology of these conditions.

Extracellular adenosine levels in the bone marrow microenvironment are tightly regulated by CD39/CD73 activity and ENT1 uptake. Recent studies have shown that ENT1-mediated adenosine transport is crucial for adenosine intracellular metabolism and normal erythropoiesis, while increased extracellular adenosine levels impact hematopoietic differentiation through adenosine receptor activation. . High dose of exogenous adenosine inhibits erythroid proliferation by inducing G1 arrest and p53-mediated apoptosis. Furthermore, A 2B and A 3 receptor signaling inhibits erythroid differentiation, while adenosine signaling through A 3 also favors granulopoiesis.

Collectively, these findings highlight adenosine signaling as a critical and multifaceted regulator of hematopoietic balance, offering novel insights into its therapeutic potential for managing disorders characterized by ineffective erythropoiesis and aberrant myelopoiesis.

The critical role of nitric oxide (NO), a potent signalling molecule, in various physiological processes has driven the development of NO delivery strategies for numerous therapeutic applications. However, NO's short half-life poses a significant challenge for its effective delivery. Glutathione peroxidase, a selenium-containing antioxidant enzyme, can catalyse the decomposition of S-nitrosothiols (endogenous NO prodrugs) to produce NO in situ. Inspired by this, we explored selenium nanoparticles (SeNPs) for their enzyme-mimicking NO-generating activity. Stabilised with polyvinyl alcohol (PVA) or chitosan (CTS), SeNPs demonstrated tuneable NO generation when exposed to varying concentrations of NO prodrug, nanoparticles, and glutathione (GSH). In the presence of GSH, a naturally occurring antioxidant in the human body, 0.1 µg mL-1 of SeNPs could catalytically generate 7.5 µM of NO under physiological conditions within 30 min. We investigated the effects of nanoparticle crystallinity and NO prodrug type on NO generation, as well as the stability and sustained NO generation of the catalytic nanoparticles. PVA-stabilised SeNPs were non-toxic to NIH 3T3 cells and effectively dispersed Pseudomonas aeruginosa biofilms upon NO generation. This study broadens the repertoire of nanomaterials for NO generation and highlights SeNPs as a non-toxic alternative for therapeutic NO delivery.

Cardiac diastolic dysfunction is a hallmark of diabetic cardiomyopathy (DCM), particularly in postmenopausal women where estrogen deficiency exacerbates cardiac remodeling. This study investigated the roles of NLRP3 inflammasome activation and cardiac mast cell (CMC) behavior in diabetic ovariectomized (OVX) rat models. Female Wistar rats were divided into five groups: sham-operated, OVX, diabetic (Sham-DM), OVX-diabetic (OVX-DM), and OVX-DM treated with the NLRP3 inhibitor MCC950. Diabetes was induced using a high-calorie quick fat diet (13.8% crude fat, 24.35% crude protein, 25% sucrose; 406.80 kcal/100 g) followed by a single intraperitoneal injection of streptozotocin (30 mg/kg). MCC950 (10 mg/kg BW, intraperitoneally) was administered daily for 4 weeks. Echocardiography revealed significant diastolic dysfunction in OVX-DM rats, with increased left ventricular internal diameter (LVIDd) and reduced mitral valve E/A ratio, while MCC950 treatment partially restored diastolic function (p < 0.05). Masson's trichrome staining showed increased myocardial fibrosis in OVX-DM rats (2.59 ± 0.20%) compared to Sham-DM (1.94 ± 0.16%, p < 0.05), which was reduced with MCC950 treatment (0.88 ± 0.13%, p < 0.05). Western blot analysis demonstrated elevated expression of NLRP3, cleaved caspase-1, IL-1β, and GSDMD-N in OVX-DM hearts. MCC950 significantly reduced cleaved caspase-1, IL-1β, and GSDMD-N expression without altering NLRP3 protein levels. Additionally, mast cell degranulation was markedly increased in OVX-DM rats (62.14%) compared to controls (P < 0.05) and was attenuated by MCC950 (31.06%, P < 0.05). These findings suggest that NLRP3 inflammasome activation under conditions of estrogen deficiency and diabetes contributes to myocardial pyroptosis and mast cell degranulation, driving cardiac remodeling in postmenopausal DCM. Targeting NLRP3 pathways may provide an effective therapeutic strategy to mitigate diastolic dysfunction, fibrosis, and inflammation in diabetic hearts.

Blue light (BL) is a known risk factor for age-related macular degeneration (AMD), a retinal pathology where damage to the retinal pigment epithelium (RPE) is one of the earliest events. While the endocannabinoid system (ECS) is implicated in various physio-pathological conditions of the retina, its role in BL-injured RPE has not yet been addressed. To fill this gap, we developed an in vitro model of BL-induced human RPE damage showing key features of AMD: cytotoxicity, cell cycle arrest, oxidative stress, inflammation, and cellular senescence. Notably, our model demonstrates modulation of gene and protein expression of specific ECS elements, particularly cannabinoid receptors 1 and 2 (CB1 and CB2), thus providing unprecedented evidence of ECS dysregulation in RPE cells upon BL exposure.

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that form the interface between the hepatic vasculature and parenchymal cells, playing a crucial role in maintaining hepatic homeostasis. Under pathological conditions, LSECs undergo capillarization, marked by the loss of fenestrae and formation of a basement membrane, thereby impairing microcirculation and promoting fibrosis. Beyond capillarization, LSECs experience a spectrum of pathological changes-including angiogenesis, endothelial-to-mesenchymal transition (EndMT), autophagy, and senescence-all of which contribute to fibrogenesis through distinct molecular pathways. Moreover, LSECs orchestrate liver fibrotic remodeling through dynamic crosstalk with hepatic stellate cells (HSCs), hepatocytes, Kupffer cells, and immune cells, exerting both pro- and anti-fibrotic effects. This review comprehensively summarizes LSECs dysfunction in hepatic fibrosis, with a particular focus on intercellular communication and emerging therapeutic strategies. Elucidating the regulatory networks that govern LSECs behavior may uncover new opportunities for the diagnosis and treatment of chronic liver disease.

Inflammation plays a crucial role in progression of cardiovascular diseases (CVDs); thus, the discovery of rapid and precise analytical tools to assess inflammation related to CVDs is highly desirable for their diagnosis and therapeutic discovery. However, a straightforward and systematic method for quantitative assessment of inflammation levels in heart organoids has yet to be developed. Herein, we describe the construction of human heart inflammatory organoids with intricate structures and diverse cell lineages and the development of an artificial intelligence (AI)-enabled method for quantitative assessment of inflammation levels in this model. Furthermore, we devised a novel therapeutic strategy to boost endogenous energy molecule production in heart inflammatory organoids to address energy metabolic disorders. This research provides a convenient method for quantitative inflammation evaluation and offers a promising tool for drug discovery.

Aortic dissection (AD) is a life-threatening disease. Tankyrase1 (TNKS1), a PARylating ADP-ribosyl transferase, plays a major role in myogenesis, a vital process known to drive muscle fiber formation and regeneration.This study explores the impact of TNKS1 on the transformation of human aortic smooth muscle cells (HASMCs) in AD.

Single-cell RNA sequencing was performed and clusters were used for between-disease differential gene expression analyses. In the AD aorta, WB, immunofluorescence and RT-q-PCR revealed that TNKS1 expression was elevated, accompanied by a disorganized cell phenotype. Further examination like WB，immunofluorescence,Scratch-Wound Assay confirmed the upregulation of TNKS1 triggers phenotypic switching.Subsequent studies revealed that ferroptosis played a key role in TNKS1-induced phenotypic switching. Increased ferroptosis markers, such as elevated iron content,ROS and lipid peroxidation, were observed in HASMCs overexpressing TNKS1, while inhibition of ferroptosis restored the contractile phenotype.Co-IP assay demonstrated a direct protein-protein interaction between TNKS1 and SLC7A11 at the molecular level. In vivo, the upregulation of TNKS1 not only activated ferroptosis but also triggered phenotypic transformation.

This study demonstrates that TNKS1 is a key regulator of AD pathogenesis, driving HASMC phenotypic switching through ferroptosis activation, ultimately leading to aortic wall destabilization and dissection. Targeting TNKS1 or the ferroptosis pathway may offer novel therapeutic strategies for AD prevention and treatment.

This study investigates the association between recurrent spontaneous abortion (RSA) and macrophage polarization, exploring adenosine (Ado) as a potential biomarker and therapeutic target. By analyzing decidual tissues from RSA patients and normal pregnancies, we found reduced CD39 expression and lower adenosine levels in RSA, accompanied by increased M1 macrophage polarization and decreased M2 macrophage expression. In vitro experiments demonstrated that adenosine inhibited M1 polarization while promoting M2 polarization, an effect reversed by adenosine deaminase (ADA). Single-cell RNA sequencing revealed decreased adenosine receptor A2aR expression in M1 macrophages of RSA patients, while glycolysis-related enzyme hexokinase 2 (HK2) was overexpressed. These findings suggest that adenosine plays a key role in macrophage polarization and immune homeostasis at the maternal-fetal interface, with glycolysis potentially contributing to this process, highlighting its potential as a target for RSA diagnosis and treatment.

Exposure to dioxin-like polychlorinated biphenyls (DL-PCBs) has been linked to blood pressure changes in adult populations. However, limited research has explored the impact of DL-PCB exposure on BP in children, a vulnerable population undergoing critical developmental stages. This study aimed to investigate the association between exposure to DL-PCBs and blood pressure in primary school children. A cross-sectional study was conducted between 2023 and 2024 involving 5240 children aged 7-10 years. Serum levels of 12 DL-PCB congeners were assessed using Gas Chromatography-Mass Spectrometry (GC-MS). Statistical analysis included multivariable linear regression, stratified by sex, and mixture analysis using Bayesian Kernel Machine Regression (BKMR), generalized quantile g-computation (g-comp), and generalized weighted quantile sum regression (gWQS). In the linear regression analysis, several congeners (PCB77, PCB81, PCB118, PCB126, PCB167, PCB169) were significantly associated with increased systolic blood pressure (SBP), pulse pressure (PP), and mean arterial pressure (MAP) in the adjusted models. Specifically, PCB81, PCB126, PCB167, and PCB169 were associated with higher PP, and PCB77, PCB81, PCB118, PCB126, PCB167, and PCB169 were linked to higher MAP. The associations were generally stronger in boys. The mixture analyses confirmed the non-linear and interactive effects of DL-PCB exposure on BP indicators, with cumulative exposure showing a significant impact on both SBP and MAP ( for MAP: g-comp (β = 1.707, 95 % CI: 1.129, 2.285; p < 0.001) and gWQS (β = 1.195, 95 % CI: 0.555, 1.836; p < 0.001)). Overall, exposure to DL-PCBs was linked to elevated blood pressure in primary school children, especially for specific congeners, emphasizing potential cardiovascular risks and the need for further research on long-term effects.

Immunotherapy faces significant challenges due to low clinical response rates and immune escape mechanisms, which ultimately lead to drug resistance. Previous studies suggest that adenosine-2A receptor (A2AR) signaling plays a critical role in immunosuppression and immune escape. However, no potent and selective A2AR inhibitors are currently available for clinical use to address immunotherapy resistance in tumors. In this study, we identified a novel small molecule compound, HZ-086, as a potent and selective inhibitor of A2AR. HZ-086 restored the activation of T-cell signaling which is suppressed by adenosine analogs in vitro. Additionally, HZ-086 enhanced T-cell-mediated cytotoxicity, increased the secretion of cytokines for antitumor and subsequently inhibited growth of tumor cells in vitro and in vivo. Furthermore, HZ-086 inhibited tumor growth, enhances anti-tumor capacity, and reversed PD-L1 resistance in vivo. When combined with FD-L1, a PD-L1 small molecule inhibitor discovered by our lab, HZ-086 achieved over 80 % tumor growth inhibition (TGI) and restored immune response in anti-PD-L1 monoclonal antibody-resistant tumors. This combination treatment also promoted the infiltration and activation of CD8+ T lymphocytes within the tumor microenvironment. Our findings demonstrate that adenosine-A2AR signaling mediates resistance to immunotherapy and discover a novel potent and selective A2AR inhibitor with high efficacy in enhancing antitumor immune responses and reversing PD-L1 resistance. The combination of A2AR inhibitor and PD-L1 inhibitor represents a promising therapeutic strategy for antitumor therapy.

Incretin analogues, used for the treatment of type 2 diabetes mellitus and obesity, such as GLP1-receptor agonist liraglutide (Lira) have been shown to reduce major adverse cardiac events in recent clinical trials of heart failure. Tirzepatide (TZP), a dual GIP/GLP1-receptor agonist has shown promising results in the SUMMIT trial as improved cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF). However, data regarding their use in heart failure with reduced ejection fraction (HFrEF) is lacking. We performed a head-to-head comparative study in a mouse model of non-ischaemic cardiac injury induced by continuous angiotensin II (AngII) infusion, as AngII is a key driver of both heart failure forms.

Osmotic minipumps were inserted for subcutaneous (s.c.) administration of AngII (1.5 mg/kg/day) in 5-month-old male Balb/c mice or sham surgery was performed. Animals were treated with vehicle (Veh), Lira (300 µg/day i.p.) or TZP (48 µg/day s.c.) for 14 days in the following groups: Sham/Veh (n = 7), AngII/Veh (n = 15), Sham/Lira (n = 7), AngII/Lira (n = 15), Sham/TZP (n = 8), AngII/TZP (n = 15). Cardiac structural, functional and molecular characteristics were assessed by echocardiography, ECG, immunohistochemistry, flow cytometry and qRT-PCR.

Mortality was significantly higher in AngII/Veh animals compared to controls, while AngII/TZP mice showed significantly reduced mortality after 14 days of treatment. Both Lira and TZP caused significant weight reduction compared to controls. AngII given alone also reduced body mass, and this reduction was further enhanced by TZP. Treatment with both compounds preserved cardiac systolic and diastolic function compared with AngII/Veh animals, as shown by normal ejection fraction and E/e', respectively. Both Lira and TZP decreased the AngII-induced elevation of cardiac fibrosis and hypertrophy markers, including Ctgf, Col1a1, Col3a1, and Nppa, while TZP also reduced the elevated Nppb level. TZP also reduced systemic inflammation, as shown by the reduction in serum CRP levels.

Lira and TZP preserved cardiac function and decreased markers of hypertrophy and fibrosis in mice with AngII-induced heart failure, whereas TZP also significantly decreased mortality. In addition to HFpEF, the use of incretin analogues may also be of clinical relevance in the treatment of HFrEF. However, as patients with heart failure, AngII level is elevated and can cause weight loss/cachexia, the usage of incretin analogues to treat non-obese heart failure patients should be considered.

The persistent threat of SARS-CoV-2 and the emergence of new variants has prompted the development of a novel, easily administered modality that can overcome viral mutations. The engineered ACE2 decoy shows neutralizing activity comparable to monoclonal antibodies and is broadly effective against SARS-CoV-2 variants and ACE2-utilizing sarbecoviruses. In addition to intravenous administration, this decoy has shown antiviral efficacy through nebulized aerosol inhalation in murine and primate models, offering a dose-sparing advantage. Clinically, dry powder formulation is ideal for convenience and storage but poses challenges for protein biologics. This study developed a freeze-dried spray formulation of the ACE2 decoy for inhalation. The trehalose and leucine-based excipient maintained neutralizing activity and prevented aggregate formation. The dry powder showed aerodynamic distribution from bronchi to alveoli, aiding protection against SARS-CoV-2 infections. Neutralizing activity, structural stability, and powder dispersibility were preserved after 6 months of storage. In a mouse model of SARS-CoV-2 infection, significant reductions in viral replication and lung pathology were observed with intratracheal administration 24 h post-infection. The ACE2 decoy retained activity against recent JN.1 and current KP.3 strains, confirming its robust efficacy against viral mutations. This ACE2 decoy powder inhalant is a self-administered, next-generation treatment addressing the ongoing immune-evading evolution of SARS-CoV-2.

Alcohol consumption contributes to systemic organ dysfunction, but its direct effect on kidney health is unclear. Epidemiological studies show inconsistent findings due to reliance on conventional markers like serum creatinine (sCr) and blood urea nitrogen (BUN), which are insensitive to early chronic kidney disease (CKD) and influenced by factors such as muscle mass, diet, and hydration status. Experimental studies indicate that alcohol may directly exacerbate renal damage through mitochondrial dysfunction, oxidative stress, and inflammation. Furthermore, indirect effects from alcohol-induced altered intestinal permeability and microbiome, liver injury, microcirculatory/cardiac dysfunction and muscle damage may also facilitate kidney damage. Notably, alcohol-related liver disease can lead to hepatorenal syndrome, a severe form of kidney dysfunction driven by circulatory disturbances and systemic inflammation. This overview explores the adverse effects of alcohol misuse on kidney health and disease, emphasizing the need for comprehensive epidemiological studies with more sensitive kidney injury biomarkers. It also highlights the importance of using clinically relevant preclinical models to clarify the underlying mechanisms of alcohol-related kidney injury and to enhance our understanding of its long-term clinical consequences.

Oxidative stress and poly(ADP-ribosyl)ation (PARylation) leads to tissue damage and inflammation in multiple lung diseases, likely in COVID-19. In a previous study we evidenced PARylation in multiple pulmonary cell types in patients who died of COVID-19, but not in patients who died of non-COVID-19 causes. We extended these observations in this retrospective immunohistochemical study by enlarging and stratifying the study population to identify subpopulations with high expression of the markers assessed in the study. We showed that pulmonary PARylation and oxidative stress peaked in the exudative and then decreased in the proliferative phase. PARylation correlated with viral load and with the oxidative stress in the tissues, however, correlation between viral load and oxidative stress was marginal suggesting that oxidative stress and the presence of SARS-CoV-2 can independently induce PARylation. Pulmonary oxidative stress, PARylation and TNFα expression correlated with the serum markers of liver and kidney damage, oxygen transport, tissue hypoxia, lymphocytopenia, blood clotting and disseminated intravascular coagulation. In males the time of hospitalization (time to death) was inversely correlated with pulmonary PARylation. Furthermore, males, died of COVID-19, were ∼15 years younger than females, however, there was no difference in pulmonary oxidative stress and PARylation between genders at death. Taken together, pulmonary PARylation and oxidative stress manifests early, in the exudative phase of COVID-19 and PARylation contributes to worse clinical outcome for males. These results suggest repurposing pharmacological PARP inhibitors for acute COVID-19 to counteract tissue damage.