Search Results (978)

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy characterized by complex interactions within the tumor microenvironment (TME) that facilitate immune evasion and tumor progression. The TME consists of diverse cellular components, including cancer-associated fibroblasts, immune and endothelial cells, and extracellular matrix elements, that collectively modulate tumor growth, metastasis, and resistance to therapy. Immune evasion in HNSCC is orchestrated through multiple mechanisms, including the suppression of cytotoxic T lymphocytes, recruitment of immunosuppressive cells, such as regulatory T and myeloid-derived suppressor cells, and upregulation of immune checkpoint molecules (e.g., PD-1/PD-L1 and CTLA-4). Natural killer (NK) cells, which play a crucial role in anti-tumor immunity, are often dysfunctional within the HNSCC TME due to inhibitory signaling and metabolic constraints. Additionally, endothelial cells contribute to tumor angiogenesis and immune suppression, further exacerbating disease progression. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors and NK cell-based strategies, have shown promise in restoring anti-tumor immunity. Moreover, TP53 mutations, frequently observed in HNSCC, influence tumor behavior and therapeutic responses, highlighting the need for personalized treatment approaches. This review provides a comprehensive analysis of the molecular and cellular mechanisms governing immune evasion in HNSCC with a focus on novel therapeutic strategies aimed at improving patient outcomes. Full article

A dietary supplement, trans-resveratrol and hesperetin (tRES+HESP)—also known as GlucoRegulate—induces increased expression of glyoxalase 1 (Glo1) by activation of transcription factor Nrf2, countering accumulation of the reactive dicarbonyl glycating agent, methylglyoxal. tRES+HESP corrected insulin resistance and decreased fasting and postprandial plasma glucose and low-grade inflammation in overweight and obese subjects in a clinical trial. The aim of this study was to explore, for the first time, health-beneficial gene expression other than Glo1 induced by tRES+HESP in human endothelial cells and fibroblasts in primary culture and HepG2 hepatoma cell line and activity of cis-resveratrol (cRES) as a Glo1 inducer. We measured antioxidant response element-linked gene expression in these cells in response to 5 µM tRES+HESP by the NanoString method. tRES+HESP increases gene expression linked to the prevention of dicarbonyl stress, lipid peroxidation, oxidative stress, proteotoxicity and hyperglycemia-linked glycolytic overload. Downstream benefits were improved regulation of glucose and lipid metabolism and decreased inflammation, extracellular matrix remodeling and senescence markers. The median effective concentration of tRES was ninefold lower than cRES in the Glo1 inducer luciferase reporter assay. The GlucoRegulate supplement provides a new treatment option for the prevention of type 2 diabetes and metabolic dysfunction–associated steatotic liver disease and supports healthy aging. Full article

Background: Against the backdrop of the large-scale and intensive development of the livestock industry, enhancing the reproductive efficiency of cattle has become a crucial factor in industrial development. Holstein cows, as the most predominant dairy cattle breed globally, are characterized by high milk yield and excellent milk quality. However, their reproductive efficiency is comprehensively influenced by a variety of complex factors, and improving their reproductive performance faces numerous challenges. The ovary, as the core organ of the female reproductive system, plays a decisive role in embryonic development and pregnancy maintenance. It is not only the site where eggs are produced and developed but it also regulates the cow’s estrous cycle, ovulation process, and the establishment and maintenance of pregnancy by secreting various hormones. The normal functioning of the ovary is crucial for the smooth development of the embryo and the successful maintenance of pregnancy. Methods: Currently, traditional sequencing technologies have obvious limitations in deciphering ovarian function and reproductive regulatory mechanisms. To overcome the bottlenecks of traditional sequencing technologies, this study selected Holstein cows as the research subjects. Ovarian samples were collected from one pregnant and one non-pregnant Holstein cow, and single-nucleus transcriptome sequencing technology was used to conduct an in-depth study on the ovarian cells of Holstein cows. Results: By constructing a cell type-specific molecular atlas of the ovaries, nine different cell types were successfully identified. This study compared the proportions of ovarian cell types under different physiological states and found that the proportion of endothelial cells decreased during pregnancy, while the proportions of granulosa cells and luteal cells increased significantly. In terms of functional enrichment analysis, oocytes during both pregnancy and non-pregnancy play roles in the “cell cycle” and “homologous recombination” pathways. However, non-pregnant oocytes are also involved in the “progesterone-mediated oocyte maturation” pathway. Luteal cells during pregnancy mainly function in the “cortisol synthesis and secretion” and “ovarian steroidogenesis” pathways; non-pregnant luteal cells are mainly enriched in pathway processes such as the “AMPK signaling pathway”, “pyrimidine metabolism”, and “nucleotide metabolism”. Cell communication analysis reveals that there are 51 signaling pathways involved in the pregnant ovary, with endothelial cells, granulosa cells, and luteal cells serving as the core communication hubs. In the non-pregnant ovary, there are 48 pathways, and the interaction between endothelial cells and stromal cells is the dominant mode. Conclusions: This study provides new insights into the regulatory mechanisms of reproductive efficiency in Holstein cows. The differences in the proportions of ovarian cell types, functional pathways, and cell communication patterns under different physiological states, especially the increase in the proportions of granulosa cells and luteal cells during pregnancy and the specificity of related functional pathways, indicate that these cells play a crucial role in the reproductive process of cows. These findings also highlight the importance of ovarian cells in pathways such as “cell cycle”, “homologous recombination”, and “progesterone-mediated oocyte maturation”, as well as the cell communication mechanisms in regulating ovarian function and reproductive performance. Full article

Background: Metabolic syndrome (MetS) is a complex clinical condition characterized by the coexistence of interrelated metabolic abnormalities that significantly increase the risk of cardiovascular diseases and type 2 diabetes mellitus. Endocan—an endothelial cell-specific molecule—is considered a biomarker of endothelial dysfunction and inflammation. This study aimed to evaluate the relationship between serum endocan levels and the severity of MetS, assessed using the MetS-Z score. Methods: This study included 120 patients with MetS and 50 healthy controls. MetS was diagnosed according to the NCEP-ATP III criteria. MetS-Z scores were calculated using the MetS Severity Calculator. Serum levels of endocan, sICAM-1, and sVCAM-1 were measured using the ELISA method. Results: Serum levels of endocan, sICAM-1, and sVCAM-1 were significantly higher in the MetS group compared to the control group (all p < 0.001). When the MetS group was divided into tertiles based on MetS-Z scores, stepwise and statistically significant increases were observed in the levels of endocan and other endothelial markers from the lowest to highest tertile (p < 0.0001). Correlation analysis revealed a strong positive association between the MetS-Z score and serum endocan levels (r = 0.584, p < 0.0001). ROC curve analysis showed that endocan has high diagnostic accuracy for identifying MetS (AUC = 0.967, p = 0.0001), with a cutoff value of >88.0 ng/L. Conclusions: Circulating levels of endocan were significantly increased in MetS and were associated with the severity of MetS, suggesting that endocan may play a role in the cellular response to endothelial dysfunction-related injury in patients with MetS. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis are cardiometabolic twin disorders with shared underlying pathophysiological mechanisms such as insulin resistance and chronic inflammation. This review explores the salient role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in linking hepatic dysfunction to cardiovascular disease. Findings in mice with genetic modulation of Ceacam1 gene established a critical role for CEACAM1 protein in regulating insulin and lipid metabolism and endothelial integrity and modulating immune response. Loss of CEACAM1 in hepatocytes impairs insulin clearance, causing chronic hyperinsulinemia, a process that ultimately leads to insulin resistance and hepatic and extra-hepatic fat accumulation, which in turn causes inflammatory infiltration. This prompts a paradigm shift that positions impaired hepatic CEACAM1 function as a mechanistic underpinning of the link between insulin resistance, MASH, and atherosclerosis. Full article

Preeclampsia (PE) is a multifactorial hypertensive disorder unique to pregnancy and a leading cause of maternal and fetal morbidity and mortality worldwide. Its pathogenesis involves placental dysfunction and an exaggerated maternal inflammatory response. Uric acid (UA), traditionally regarded as a marker of renal impairment, is increasingly recognized as an active contributor to the development of PE. Elevated UA levels are associated with oxidative stress, endothelial dysfunction, immune activation, and reduced renal clearance. Clinically, UA is measured in the second and third trimesters to assess disease severity and guide obstetric management, with higher levels correlating with early-onset PE and adverse perinatal outcomes. Its predictive accuracy improves when combined with other clinical and biochemical markers, particularly in low-resource settings. Mechanistically, UA and its monosodium urate crystals can activate the NLRP3 inflammasome, a cytosolic multiprotein complex of the innate immune system. This activation promotes the release of IL-1β and IL-18, exacerbating placental, vascular, and renal inflammation. NLRP3 inflammasome activation has been documented in placental tissues, immune cells, and kidneys of women with PE and is associated with hypertension, proteinuria, and endothelial injury. Experimental studies indicate that targeting UA metabolism or inhibiting NLRP3 activation, using agents such as allopurinol, metformin, or MCC950, can mitigate the clinical and histopathological features of PE. These findings support the dual role of UA as both a biomarker and a potential therapeutic target in the management of the disease. Full article

Quercetin (QE) is a naturally occurring flavonoid found in many fruits, vegetables, and other plant-based foods. It is recognized for its diverse pharmacological activities. Among its many therapeutic potentials, its antidiabetic properties are of particular interest due to the growing worldwide prevalence of diabetes mellitus. QE improves glycemic control by enhancing insulin sensitivity, stimulating glucose uptake, and preserving pancreatic beta cell function. These effects are mediated by the modulation of key molecular pathways, including AMPK, PI3K/Akt, and Nrf2/ARE, as well as by the suppression of oxidative stress and pro-inflammatory cytokines, such as TNF-α and IL-6. Furthermore, QE mitigates the progression of diabetic complications such as nephropathy, retinopathy, and vascular dysfunction, reducing lipid peroxidation and protecting endothelial function. However, the clinical application of quercetin is limited by its low water solubility, poor bioavailability, and extensive phase II metabolism. Advances in formulation strategies, including the use of nanocarriers, co-crystals, and phospholipid complexes, have shown promise in improving its pharmacokinetics. This review elucidates the mechanistic basis of QE quercetin antidiabetic action and discusses strategies to enhance its therapeutic potential in clinical settings. Full article

Chronic kidney disease (CKD)-associated anemia is a global health concern and is linked to vascular and ocular complications. Hypoxia-inducible factor (HIF) stabilizers, or HIF prolyl hydroxylase inhibitors (PHIs), are promising candidates for the treatment of CKD-associated anemia. Since hypoxia and angiogenesis are involved in eye diseases, this study examined the effects of HIF-PHIs on metabolism and gene expression in retinal pigment epithelium (RPE) cells. Results revealed that PHIs differentially induced angiogenic (VEGFA, ANG) and glycolytic (PDK1, GLUT1) gene expression, with Roxadustat causing the strongest transcriptional changes. However, Roxadustat-induced angiogenic signals did not promote endothelial tube formation. Moreover, it did not induce oxidative stress, inflammation, or significant antioxidant gene responses in ARPE-19 cells. Roxadustat also reduced the inflammatory cytokine response to tumor necrosis factor-α, including IL-6, IL-8, and MCP-1, and did not exacerbate VEGF expression under high-glucose conditions. Overall, Roxadustat triggered complex gene expression changes without promoting inflammation or oxidative stress in RPE cells. Despite these findings, ophthalmologic monitoring is advised during PHI treatment in CKD patients receiving HIF-PHIs. Full article

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by systemic inflammation, endothelial dysfunction, and placental insufficiency. While inadequate trophoblast invasion and impaired spiral artery remodeling have long been recognized as central to its pathogenesis, emerging evidence underscores the critical roles of dysregulated iron metabolism and its crosstalk with immune responses, particularly macrophage-mediated inflammation, in driving PE development. This review systematically explores the dynamic changes in iron metabolism during pregnancy, including increased maternal iron demand, placental iron transport mechanisms, and the molecular regulation of placental iron homeostasis. We further explore the contribution of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, to trophoblast dysfunction and pregnancy-related diseases, including PE. Macrophages, pivotal immune regulators at the maternal–fetal interface, exhibit distinct polarization states that shape tissue remodeling and immune tolerance. We outline their origin, distribution, and polarization in pregnancy, and emphasize their aberrant phenotype and function in PE. The bidirectional crosstalk between iron and macrophages is also dissected: iron shapes macrophage polarization and function, while macrophages reciprocally modulate iron homeostasis. Notably, excessive reactive oxygen species (ROS) and pro-inflammatory cytokines secreted by M1-polarized macrophages may exacerbate trophoblast ferroptosis, amplifying placental injury. Within the context of PE, we delineate how iron overload and macrophage dysfunction synergize to potentiate placental inflammation and oxidative stress. Key iron-responsive immune pathways, such as the HO-1/hepcidin axis and IL-6/TNF-α signaling, are discussed in relation to disease severity. Finally, we highlight promising therapeutic strategies targeting the iron–immune axis, encompassing three key modalities—iron chelation therapy, precision immunomodulation, and metabolic reprogramming interventions—which may offer novel avenues for PE prevention and treatment. Full article

Diabetic foot ulcers (DFUs), which affect approximately 15% of individuals with diabetes mellitus (DM), result from complex molecular disturbances involving chronic hyperglycemia, immune dysfunction, and infection. At the molecular level, chronic hyperglycemia promotes the formation of advanced glycation end products (AGEs), activates the AGE-RAGE-NF-κB axis, increases oxidative stress, and impairs macrophage polarization from the pro-inflammatory M1 to the reparative M2 phenotype, collectively disrupting normal wound healing processes. The local wound environment is further worsened by antibiotic-resistant polymicrobial infections, which sustain inflammatory signaling and promote extracellular matrix degradation. The rising threat of antimicrobial resistance complicates infection management even further. Recent studies emphasize that optimal glycemic control using antihyperglycemic agents such as metformin, Glucagon-like Peptide 1 receptor agonists (GLP-1 receptor agonists), and Dipeptidyl Peptidase 4 enzyme inhibitors (DPP-4 inhibitors) improves overall metabolic balance. These agents also influence angiogenesis, inflammation, and tissue regeneration through pathways including AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and vascular endothelial growth factor (VEGF) signaling. Evidence indicates that maintaining glycemic stability through continuous glucose monitoring (CGM) and adherence to antihyperglycemic treatment enhances antibiotic effectiveness by improving immune cell function and reducing bacterial virulence. This review consolidates current molecular evidence on the combined effects of glycemic and antibiotic therapies in DFUs. It advocates for an integrated approach that addresses both metabolic and microbial factors to restore wound homeostasis and minimize the risk of severe outcomes such as amputation. Full article

Deposition of intramuscular fat (IM), also known as marbling, is the deciding factor of beef quality grade in the U.S. Defining molecular mechanisms underlying the differential deposition of adipose tissue in distinct anatomical areas in beef cattle is key to the development of strategies for marbling enhancement while limiting the accumulation of excessive subcutaneous adipose tissue (SAT). The objective of this exploratory study was to define the IM and SAT transcriptional heterogeneity at the whole tissue and single-nuclei levels in beef steers. Longissimus dorsi muscle samples (9–11th rib) were collected from two finished beef steers at harvest to dissect matched IM and adjacent SAT (backfat). Total RNA from IM and SAT was isolated and sequenced in an Illumina NovaSeq 6000. Nuclei from the same samples were isolated by dounce homogenization, libraries generated with 10× Genomics, and sequenced in an Illumina NovaSeq 6000, followed by analysis via Cell Ranger pipeline and Seurat in RStudio (v4.3.2) By the expression of signature marker genes, single-nuclei RNA sequencing (snRNAseq) analysis identified mature adipocytes (AD; ADIPOQ, LEP), adipose stromal and progenitor cells (ASPC; PDGFRA), endothelial cells (EC; VWF, PECAM1), smooth muscle cells (SMC; NOTCH3, MYL9) and immune cells (IMC; CD163, MRC1). We detected six cell clusters in SAT and nine in IM. Across IM and SAT, AD was the most abundant cell type, followed by ASPC, SMC, and IMC. In SAT, AD made up 50% of the cellular population, followed by ASPC (31%), EC (14%), IMC (1%), and SMC (4%). In IM depot, AD made up 23% of the cellular population, followed by ASPC at 19% of the population, EC at 28%, IMC at 7% and SMC at 12%. The abundance of ASPC and AD was lower in IM vs. SAT, while IMC was increased, suggesting a potential involvement of immune cells on IM deposition. Accordingly, both bulk RNAseq and snRNAseq analyses identified activated pathways of inflammation and metabolic function in IM. These results demonstrate distinct transcriptional cellular heterogeneity between SAT and IM depots in beef steers, which may underly the mechanisms by which fat deposits in each depot. The identification of depot-specific cell populations in IM and SAT via snRNAseq analysis has the potential to reveal target genes for the modulation of fat deposition in beef cattle. Full article

Tissue hypoxia is commonly observed in head cancers and contributes to both molecular and functional changes in tumour cells. It is known to stimulate erythropoiesis, angiogenesis, and metabolic alterations within tumour cells. Glioblastoma, a type of brain tumour, is characterized by rapid proliferation and aggressive growth. Recent studies have indicated that natural products may hold potential as components of cancer therapy. Among these, Polish propolis and its active compound, quercetin, have demonstrated promising anti-cancer properties. The aim of this study was to evaluate the concentrations of selected cytokines—specifically IL-6, IL-9, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF-BB), interferon gamma-induced protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1)—produced by astrocytes of the CCF-STTG1 cell line. The cytotoxic effects of ethanolic extract of propolis (EEP) and quercetin were assessed using the MTT assay. Astrocytes were stimulated with lipopolysaccharide (LPS, 200 ng/mL) and/or IFN-α (100 U/mL), followed by treatment with EEP or quercetin (25–50 µg/mL) under hypoxic conditions for two hours. Cytokine concentrations were measured using the xMAP Luminex Multiplex Immunoassay and the Multiplex Bead-Based Cytokine Kit. Our study demonstrated that Polish propolis and its component quercetin modulate the tumour microenvironment in vitro, primarily by altering the levels of specific cytokines. The HCA analysis revealed that IL-6 and MCP-1 formed a distinct cluster at the highest linkage distance (approximately 100% of Dmax), suggesting that their expression patterns are significantly different from those of the other cytokines and that they are more similar to each other than to the rest. PCA analysis showed that EEP-PL (50 μg/mL) with IFN-α and EEP-PL (50 μg/mL) with LPS exert similar activities on cytokine secretion by astrocytes. Similar effects were demonstrated for EEP-PL 50 μg/mL + LPS + IFN-α, EEP-PL 25 μg/mL + IFN-α and EEP-PL 25 μg/mL + LPS + IFN-α. Our findings suggest that Polish propolis and quercetin may serve as promising natural agents to support the treatment of stage IV malignant astrocytoma. Nonetheless, further research is needed to confirm these results. Full article

Heart failure (HF) has become an epidemic, with a prevalence of ~7 million cases in the USA. Despite accounting for nearly 50% of all HF cases, heart failure with a preserved ejection fraction (HFpEF) remains challenging to treat. Common pathophysiological mechanisms in HFpEF include oxidative stress, microvascular dysfunction, and chronic unresolved inflammation. Our lab focuses on oxidative stress-mediated cellular dysfunction, particularly the toxic effects of lipid peroxidation products like 4-hydroxy-2-nonenal (4HNE). Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, plays a vital role in detoxifying 4HNE and thereby protecting the heart against pathological stress. ALDH2 activity is reduced in various metabolic stress-mediated cardiac pathologies. The dysfunction of coronary vascular endothelial cells (CVECs) is critical in initiating HFpEF development. Thus, we hypothesized that ectopic overexpression of ALDH2 in CVECs could mitigate metabolic stress-induced HFpEF pathogenesis. In this study, we tested the efficacy of intracardiac injections of the ALDH2 gene into CVECs in db/db mice—a model of obesity-induced type 2 diabetes mellitus (T2DM)—and their controls, db/m mice, by injection with ALDH2 constructs (AAV9-VE-cadherin-hALDH2-HA tag-P2A) or control constructs (AAV9-VE-cadherin-HA tag-P2A-eGFP). We found that intracardiac ALDH2 gene transfer increased ALDH2 levels specifically in CVECs compared to other myocardial cells. Additionally, we observed increased ALDH2 levels and activity, along with decreased 4HNE adducts, in the hearts of mice receiving ALDH2 gene transfer compared to control GFP transfer. Furthermore, ALDH2 gene transfer to CVECs improved diastolic function compared to GFP control alone. In conclusion, ectopic ALDH2 expression in CVECs can contribute, at least partially, to the amelioration of HFpEF. Full article

Cataract surgery, while commonly considered a routine, highly effective, and generally low-risk ophthalmic procedure, has been associated with corneal endothelial cell loss (ECL), a phenomenon particularly pronounced in patients with type 2 diabetes mellitus (DM2). This increased susceptibility in diabetic patients is often attributed to pre-existing corneal abnormalities, including compromised structural integrity and reduced endothelial cell density. Additionally, metabolic stress factors inherent to diabetes, such as chronic hyperglycemia and associated oxidative stress, further exacerbate endothelial vulnerability. Consequently, diabetic patients may experience significantly greater endothelial cell loss during and after cataract surgery, necessitating targeted surgical strategies and careful perioperative management to preserve corneal health and visual outcomes. This paper aims to conduct an extensive and detailed review of the existing scientific literature to thoroughly investigate the relationship between ECL and cataract surgery in patients diagnosed with DM2. This study conducts a critical evaluation to elucidate the mechanisms contributing to high endothelial vulnerability in individuals with diabetes. It systematically compares the rates of ECL observed in diabetic and non-diabetic populations undergoing cataract surgery, examines molecular alterations following the procedure in patients with and without DM2, identifies key risk factors influencing surgical outcomes, evaluates the impact of various surgical techniques, discusses preventative measures, and examines the long-term consequences of ECL in this specific population. Furthermore, this review analyzes the existing research to identify gaps in knowledge and suggest potential directions for future investigations. Full article

Atherosclerosis (AS), a progressive inflammatory disease of coronary arteries, the aorta, and the internal carotid artery, is considered one of the main contributors to cardiovascular disorders. Blood flow is restricted by accumulating lipid-rich macrophages (foam cells), calcium, fibrin, and cellular debris into plaques on the intima of arterial walls. Butyrate maintains gut barrier integrity and modulates immune responses. Butyrate regulates G-protein-coupled receptor (GPCR) signaling and activates nuclear factor kappa-B (NF-κB), activator protein-1 (AP-1), and interferon regulatory factors (IFRs) involved in the production of proinflammatory cytokines. Depending on the inflammatory stimuli, butyrate may also inactivate NF-κB, resulting in the suppression of proinflammatory cytokines and the stimulation of anti-inflammatory cytokines. Butyrate modulates mitogen-activated protein kinase (MAPK) to promote or suppress macrophage inflammation, muscle cell growth, apoptosis, and the uptake of oxidized low-density lipoprotein (ox-LDL) in macrophages. Activation of the peroxisome proliferator-activated receptor γ (PPARγ) pathway plays a role in lipid metabolism, inflammation, and cell differentiation. Butyrate inhibits interferon γ (IFN-γ) signaling and suppresses NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) involved in inflammation and scar tissue formation. The dual role of butyrate in AS is discussed by addressing the interactions between butyrate, intestinal epithelial cells (IECs), endothelial cells (ECs) of the main arteries, and immune cells. Signals generated from these interactions may be applied in the diagnosis and intervention of AS. Reporters to detect early AS is suggested. This narrative review covers the most recent findings published in PubMed and Crossref databases. Full article