Lung cancer's mortality is among the highest compared to other cancers globally. However, a recent study has shown that ivermectin, an antiparasitic drug, may have a promising anticancer effect on lung cancer. The present study aimed to investigate the impact of ivermectin on EGFR.3/PI3K4/AKT5/mTOR6 signaling pathway in NSCLC.7 Mice were divided into four groups; (1) normal; (2) oral ivermectin alone (5 mg/kg) daily; (3) NSCLC was induced by urethane (1.5 g/kg, i.p.) at days one and sixty; (4) NSCLC group treated with ivermectin. The effect of ivermectin on macroscopic, microscopic, and lung index was assessed. The antitumor and antiproliferative effects of ivermectin were investigated by CYFRA 21-1 level and Ki-67, respectively. IHC determined the molecular expression of EGFR8, while phosphorylated PI3K, AKT, and mTOR were quantified by Western blotting assay. ELISA assay of active caspase 3, Bcl-29, and BAX10 was used to assess the apoptotic effect of ivermectin. Finally, VEGF11 lung content was measured. Findings showed that ivermectin improved macro and microscopic pathological changes. Ivermectin induced cytotoxic effect as indicated by CYFRA 21-1 suppression besides enhancing BAX/Bcl-2 ratio and active caspase 3. The immunoexpression of Ki-67 and EGFR declined. Ivermectin remarkably reduced p-PI3K, p-AKT, p-mTOR, and VEGF expressions. Overall, the study proposes ivermectin as a promising drug for lung cancer through its orchestral regulation of EGFR/PI3K/AKT/mTOR/VEGF signaling.

Despite continuous therapeutic interventions, the prognosis of hepatocellular carcinoma (HCC) remains very poor. Thus, quest for novel treatment strategies to improve therapeutic window of HCC therapy is paramount. Arsenic trioxide (ATO) is commonly used as the first-line treatment for acute promyelocytic leukemia (APL). Isoliquiritigenin (ISL) is a potential plant-based bioactive molecule with versatile biological and pharmacological effects including anticancer effect. The present study aimed to investigate the potential synergistic effects of combination of ISL and ATO in HCC cells. The data revealed that the combination of ISL and ATO synergistically inhibited HCC cell proliferation. The collective data demonstrate that synergistic anticancer effect of combined treatment of ISL + ATO was achieved via cooperative induction of mitochondrial apoptosis through ROS generation and inhibition of PI3K/Akt/mTOR pathway. In addition, ROS generation and suppression of PI3K/Akt/mTOR pathway were found to be two independent events in induction of apoptosis. Finally, we observed that combination treatment effectively suppressed tumor growth in nude mice xenograft model through induction of intrinsic apoptosis and inhibition of PI3K/Akt/mTOR pathway. In conclusion, the findings of this study suggest that both drugs work synergistically to exert anti-tumor effect in HCC, both in-vitro and in-vivo and could offer novel strategy for liver cancer treatment.

Ovarian cancer (OC) is a frequently occurring gynecological tumor, and its global incidence has recently increased. Coronin-like actin-binding protein 1C (CORO1C) is known to activate the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) pathway and promote tumor progression. However, its role in OC remains unclear. This study investigated the role of CORO1C in OC malignancy. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) was used to examine AKT and CORO1C mRNA expression in clinical OC tissues and cells. Immunohistochemical analysis and western blotting were used to examine protein expression in OC tissues and cells, respectively. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), scratch wound-healing, and Transwell assays were performed to examine cell proliferation and migration. RNA-Seq was used to validate the relationship between AKT and CORO1C expression. The results showed that CORO1C was highly expressed in clinical OC tissues and SKOV3 cells, correlating with the International Federation of Gynecology and Obstetrics (FIGO) stage. Furthermore, CORO1C knockout inhibited the proliferation, migration, and invasion of SKOV3 cells; altered the gene expression patterns in these cells; and was closely associated with the PI3K/AKT pathway. Western blotting confirmed that CORO1C knockout reduced the levels of phosphorylated PI3K and AKT. Additionally, CORO1C knockout increased phosphatase and tensin homologs deleted on chromosome 10 (PTEN) protein expression, whereas CORO1C overexpression decreased it. In conclusion, this study demonstrated that high CORO1C levels in OC are associated with greater metastasis and worse prognosis. CORO1C negatively regulates PTEN expression, activates the PI3K/AKT pathway, and promotes OC cell malignancy In patients with OC, CORO1C may function as an effective therapeutic and predictive biomarker.

Resistance to radiotherapy is a significant challenge in the clinical management of non-small cell lung cancer (NSCLC). This study investigates a novel multimodal therapeutic strategy that combines oncolytic Newcastle disease virus (NDV) with an anti-VEGFR2 single-chain variable fragment (NDV-anti-VEGFR2) to enhance radiosensitivity in NSCLC. We engineered NDV-anti-VEGFR2 and assessed its efficacy in sensitizing Calu-1 cells to radiation. In vitro results demonstrated that NDV-anti-VEGFR2 significantly inhibited tumor cell proliferation when combined with radiotherapy. In vivo experiments revealed that NDV-anti-VEGFR2, combined with radiation, achieved a tumor growth inhibition rate of 86.48%, surpassing the effects of NDV or radiation alone. Mechanistic investigations indicated that NDV-anti-VEGFR2 mitigated hypoxia by downregulating HIF-1α and impaired DNA repair pathways, as evidenced by reduced levels of RAD51 and γ-H2AX. These findings suggest that NDV-anti-VEGFR2 not only normalizes tumor vasculature but also enhances the cytotoxic effects of radiation by compromising DNA repair mechanisms. Collectively, our results support the clinical potential of NDV-anti-VEGFR2 combined with radiotherapy as a promising strategy to overcome radiotherapy resistance in NSCLC. Future studies in immunocompetent models are warranted to elucidate the immune-mediated effects of this innovative therapeutic approach.

Allosteric inhibitors of the tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) hold therapeutic promise in cancers with overactive RAS/ERK signaling, but adaptive resistance to SHP2 inhibitors may limit benefits. Here, we utilized tumor cells that proliferate similarly with or without endogenous SHP2 to explore means to overcome this growth independence from SHP2. We found that SHP2 depletion profoundly altered the output of vascular regulators, cytokines, chemokines, and other factors from SHP2 growth-resistant cancer cells. Tumors derived from inoculation of SHP2-depleted, but SHP2 growth-independent, mouse melanoma and colon carcinoma cell lines displayed a typically subverted architecture, in which proliferative tumor cells surrounding a remodeled vessel formed "vascular islands", each limited by surrounding hypoxic and dead tumor tissue, where inflammatory blood cells were limited. Although vascular islands generally reflect protected sanctuaries for tumor cells, we found that vascular island-resident, highly proliferative, SHP2-depleted tumor cells acquired an increased sensitivity to blockage of MEK/ERK signaling, resulting in reduced tumor growth. Our results show that the response to targeted therapies in resistant tumor cells was controlled by tumor cell-induced vascular changes and tumor architectural reorganization, providing a compelling approach to elicit tumor responses by exploiting tumor- and endothelium-dependent biochemical changes.

The angiogenic response is essential for the repair of ischemic brain tissue. Integrin α6 (Itga6) expression has been shown to increase under hypoxic conditions and is expressed exclusively in vascular structures; however, its role in post-ischemic angiogenesis remains poorly understood. In this study, we demonstrate that mice with endothelial cell-specific knockout of Itga6 exhibit reduced neovascularization, reduced pericyte coverage on microvessels, and accelerated breakdown of microvascular integrity in the peri-infarct area. In vitro, endothelial cells with ITGA6 knockdown display reduced proliferation, migration, and tube-formation. Mechanistically, we demonstrated that ITGA6 regulates post-stroke angiogenesis through the PI3K/Akt-eNOS-VEGFA axis. Importantly, the specific overexpression of Itga6 in endothelial cells significantly enhanced neovascularization and enhanced the integrity of microvessels, leading to improved functional recovery. Our results suggest that endothelial cell Itga6 plays a crucial role in key steps of post-stroke angiogenesis, and may represent a promising therapeutic target for promoting recovery after stroke.

Ovarian cancer usually metastasizes from the ovary to adjacent organs through direct invasion with blood vessels formed by endothelial cells. Targeting apoptosis of ovarian cancer and angiogenesis is promising for anticancer therapy. Leaves of Ipomoea sp. have reportedly shown promise in treating ovarian cancer. Here, we investigated the apoptosis-inducing and anti-angiogenic effects of compounds isolated from Ipomoea batatas vines (IBV). Phytochemical examination of IBV led to the isolation and verification of eight compounds (1-8): chlorogenic acid (1), 3,4-dicaffeoylquinic acid (2), 3,5-dicaffeoylquinic acid (3), 4,5-dicaffeoylquinic acid (4), 1,3,5-tricaffeoylquinic acid (5), N-trans-feruloyltyramine (6), scopoletin (7), and esculetin (8). Of these, 1,3,5-tricaffeoylquinic acid (5) showed the highest cytotoxicity in A2780 human ovarian cancer cells, inducing apoptotic death in more than 37% cells and decreasing viability to less than 25% at 100 μM. Compound 5 increased the levels of cleaved caspase-8, Bax, cleaved PARP, and caspase-3/9, and decreased the levels of cleaved Bcl-2. Further, 5 inhibited tubule formation in HUVECs. VEGFR2, ERK, PI3K, Akt, and mTOR protein expression was also suppressed by 5. Then, a simple, rapid, and reliable LC-MS/ MS method was developed to determine the contents of the isolated compounds from IBV. Overall, 5 has potential for treating ovarian cancer as it induces apoptosis in ovarian cancer cells and inhibits tube formation.

Contrasting almost all other mammalian wintering strategies, Eurasian common shrews, Sorex araneus, endure winter by shrinking their brain, skull, and most organs, only to then regrow to breeding size the following spring. How such tiny mammals achieve this unique brain size plasticity while maintaining activity through the winter remains unknown. To discover potential adaptations underlying this trait, we analyzed seasonal differential gene expression in the shrew hypothalamus, a brain region that both regulates metabolic homeostasis and drastically changes size, and compared hypothalamus gene expression across species. We discovered seasonal variation in suites of genes involved in energy homeostasis and apoptosis, shrew-specific upregulation of genes involved in the development of the hypothalamic blood-brain barrier and calcium signaling, as well as overlapping seasonal and comparative gene expression divergence in genes implicated in the development and progression of human neurological and metabolic disorders, including CCDC22. With high metabolic rates and facing harsh winter conditions, S. araneus have evolved both adaptive and plastic mechanisms to sense and regulate their energy budget. Many of these changes mirrored those identified in human neurological and metabolic disease, highlighting the interactions between metabolic homeostasis, brain size plasticity, and longevity.

Reactive oxygen species (ROS), a class of highly reactive molecules, are closely linked to the pathogenesis of various cancers. While ROS primarily originate from normal cellular processes, external stimuli can also contribute to their production. Cancer cells typically exhibit elevated ROS levels due to disrupted redox homeostasis, characterized by an imbalance between antioxidant and oxidant species. ROS play a dual role in cancer biology: at moderate levels, they facilitate tumor progression by regulating oncogenes and tumor suppressor genes, inducing mutations, promoting proliferation, extracellular matrix remodeling, invasion, immune modulation, and angiogenesis. However, excessive ROS levels can cause cellular damage and initiate apoptosis, necroptosis, or ferroptosis.

This review explores molecular targets involved in redox homeostasis dysregulation and examines the impact of ROS on the tumor microenvironment (TME). Literature from recent in vitro and in vivo studies was analyzed to assess how ROS modulation contributes to cancer development and therapy.

Findings indicate that ROS influence cancer progression through various pathways and cellular mechanisms. Targeting ROS synthesis or enhancing ROS accumulation in tumor cells has shown promising anticancer effects. These therapeutic strategies exhibit significant potential to impair tumor growth while also interacting with elements of the TME.

The ROS serve as both promoters and suppressors of cancer depending on their intracellular concentration. Their complex role offers valuable opportunities for targeted cancer therapies. While challenges remain in precisely modulating ROS for therapeutic benefit, they hold promise as synergistic agents alongside conventional treatments, opening new avenues in cancer management.

This study aims to evaluate and compare the effect of fibroblastic growth factor 2 (FGF-2) and photobiomodulation, solely or in combination, in angiogenic differentiation of human periodontal ligament stem cells (hPDLSCs). The study comprises the following groups: control group (hPDLSCs only), FGF-2 (50 ng/mL) group, two photobiomodulation groups with a 4 J/cm2 energy density of 808 nm diode laser (1-Session or 2-Session), and two groups with the combination of each 1-Session or 2-Session photobiomodulation with FGF-2 (50 ng/mL). The 4',6-diamidino-2-phenylindole (DAPI) staining, and Methyl Thiazolyl Tetrazolium (MTT) assay were undertaken on days 2, 4, and 6. Quantitative Real-time Polymerase Chain Reaction (RT-qPCR) analysis on days 2, 4, 6, 8, and 11 was conducted to investigate VEGF-A and ANG-I genes. Coherently, the results of the DAPI and MTT showed the Laser (2-Session) group had higher cell viability than others on day 6. All groups demonstrated a growth pattern in the expression of VEGF-A and ANG-I from day 2 to 8 and, afterward, a significant downgrowth to day 11 (p < 0.05). The most amounts of expression of VEGF-A and ANG-I on day 8 were seen in the Laser (2-Session) group. Two-time application of photobiomodulation using a diode laser with 808 nm wavelength after 2 and 4 days of cell seeding can be associated with higher cell viability and angiogenic differentiation of hPDLSCs compared to the one-time application of photobiomodulation and administration of FGF-2.

Quercetin is a natural product with multiple activities, which possesses a promising antitumor effect on malignancies. The involvement of proline 4-hydroxylase II (P4HA2) in collagen synthesis is crucial in the growth of tumor cells. Apoptosis is a programmed cell death requisite for the stability of the intracellular environment. However, the relationship between quercetin and cell apoptosis, as well as the impact of P4HA2 in this connection, has not yet been specified in hepatocellular carcinoma(HCC).

The present study used HCC cells to investigate how quercetin regulates P4HA2 and influences cell proliferation and apoptosis.

The outcomes reveal that quercetin can impede the viability and growth of HCC cells and generate cell apoptosis in a dose-dependent manner. Additionally, quercetin prompts downregulation of P4HA2, leading to cell apoptosis in HCC cells, and knocking down P4HA2 can enhance this effect. Furthermore, we pretreated HCC cells with inhibitors (Z-VAD-FMK, LY294002) or activators (740Y-P) and found that the PI3K/Akt/mTOR pathway was occupied with quercetin-induced cell apoptosis.

This investigation reveals that quercetin compels apoptosis in HCC cells by diminishing P4HA2 and restraining the PI3K/Akt/mTOR axis.

mTORopathies represent a group of neurodevelopmental disorders linked to dysregulated mTOR signaling, resulting in conditions such as tuberous sclerosis complex, focal cortical dysplasia, hemimegalencephaly, and Smith-Kingsmore Syndrome. These disorders often manifest with epilepsy, cognitive impairments, and, in some cases, structural brain anomalies. The mTOR pathway, a central regulator of cell growth and metabolism, plays a crucial role in brain development, where its hyperactivation leads to abnormal neuroplasticity, tumor formation, and heightened neuronal excitability. Current treatments primarily rely on mTOR inhibitors, such as rapamycin, which reduce seizure frequency and tumor size but fail to address underlying genetic causes. Advances in gene editing, particularly via CRISPR/Cas9, offer promising avenues for precision therapies targeting the genetic mutations driving mTORopathies. New delivery systems, including viral and non-viral vectors, aim to enhance the specificity and efficacy of these therapies, potentially transforming the management of these disorders. While gene editing holds curative potential, challenges remain concerning delivery, long-term safety, and ethical considerations. Continued research into mTOR mechanisms and innovative gene therapies may pave the way for transformative, personalized treatments for patients affected by these complex neurodevelopmental conditions.

To study the angiogenic capacity of antimicrobial peptide LL37 (cathelicidin antimicrobial peptide), explore its molecular mechanisms, and provide new ideas for treating lower limb ischemic diseases.

LL37 was applied exogenously to human umbilical vein endothelial cells (HUVECs), and its effects on cell proliferation, migration, and angiogenesis were assessed using Cell Counting Kit-8 (CCK-8), plate cloning, scratch, and angiogenesis assays. A mouse lower limb ischemia model was established, with LL37 injected intramuscularly on days 0, 4, and 8. Blood flow recovery was evaluated by laser Doppler flowmetry. Immunofluorescence staining detected cluster of differentiation 31 (CD31) and cluster of differentiation 34 (CD34) expression, while Hematoxylin and Eosin (H&E) staining assessed muscle cell morphology. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting analyzed gene and protein expression changes in HUVECs.

LL37 enhanced the proliferative, migratory, and pro-angiogenic abilities of HUVECs. It significantly improved blood flow recovery in ischemic limbs, with higher CD31/CD34 expression and more intact muscle morphology. qRT-PCR analysis demonstrated elevated expression of angiogenesis-related genes in LL37-treated HUVECs. Western blotting revealed increased vascular endothelial growth factor A (VEGFA) expression and enhanced phosphorylation levels of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in LL37-treated cells.

LL37 promotes angiogenesis via the VEGFA-PI3K/AKT/mTOR pathway, showing potential for treating lower limb ischemia by improving perfusion.

Idiopathic multicentric Castleman disease is a rare lymphoproliferative disorder that is clinically classified into idiopathic plasmacytic lymphadenopathy (IPL); thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO); and not otherwise specified (NOS). Although each subtype shows varying degrees of hypervascularity, no statistical data on the degree of vascularization have been reported. Additionally, the mechanisms underlying vascularization in each clinical subtype are poorly understood. Here, we aimed to clarify these mechanisms by evaluating the histopathological characteristics of each clinical subtype across 37 patients and performing a whole-transcriptome analysis focusing on angiogenesis-related gene expression. Histologically, TAFRO and NOS exhibited a significantly higher degree of vascularization than IPL (IPL vs TAFRO, P < .001; IPL vs NOS, P = .002). In addition, the germinal centers (GCs) were significantly more atrophic in TAFRO than in IPL. In TAFRO and NOS, "whirlpool vessels" in GCs were seen in most cases (TAFRO, 9/9, 100%; NOS, 6/8, 75%) but not in IPL (IPL vs TAFRO, P < .001; IPL vs NOS, P = .007). Likewise, immunostaining for Ets-related gene revealed higher levels in endothelial cells of GCs in TAFRO than in IPL (P = .014), and TAFRO and NOS were associated with a significantly higher number of endothelial cells in interfollicular areas compared with that in IPL (TAFRO vs IPL, P < .001; NOS vs IPL, P = .002). Gene expression analysis revealed that the PI3K-Akt signaling pathway was significantly enriched in the TAFRO and NOS (TAFRO/NOS) groups. This pathway, which may be activated by vascular endothelial growth factor A and some integrins, is known to affect angiogenesis by increasing vascular permeability, which may explain the clinical manifestations of anasarca and/or fluid retention in TAFRO/NOS. These results suggest that the PI3K-Akt pathway plays an important role in the pathogenesis of TAFRO/NOS.

The World Health Organization has recently underlined the increasing global burden of cancer, with a particularly alarming impact on underserved populations. In recent years, 1,3,4-thiadiazole has emerged as a versatile pharmacophore to obtain bioactive compounds. The pharmacological properties of this ring are primarily attributed to its role as a bioisostere of pyrimidine, the core structure of three nucleic bases. This structural feature endows 1,3,4-thiadiazole derivatives with the ability to interfere with DNA replication processes. Additionally, the mesoionic behavior of this heterocycle gives it important properties, such as the ability to cross biological membranes and interact with target proteins. Noteworthy, in analogy to the other sulfur heterocycles, the presence of C-S σ* orbitals, conferring small regions of low electron density on the sulfur atom, makes interaction with the target easier. This review focuses on the most promising anticancer agents with 1,3,4-thiadiazole structure reported in the past five years, providing information that may be useful to medicinal chemists who intend to develop new anticancer derivatives.

Ciliopathies are disorders that affect primary or secondary cellular cilia or structures associated with ciliary function. Primary cilia (PC) are essential for metabolic regulation and embryonic development, and pathogenic variants in cilia-related genes are linked to several pediatric conditions, including renal-hepatic diseases and congenital defects. Biliary atresia (BA) is a progressive infantile cholangiopathy and the leading cause of pediatric liver transplantation. Although the exact etiology of BA remains unclear, evidence suggests a multifactorial pathogenesis influenced by both genetic and environmental factors. Patients with BA and laterality defects exhibit genetic variants associated with ciliopathies. Interestingly, even isolated BA without extrahepatic anomalies presents morphological and functional ciliary abnormalities, suggesting that environmental triggers may disrupt the ciliary function. Among these factors, hypoxia has emerged as a potential modulator of this dysfunction. Hypoxia-inducible factor 1-alpha (HIF-1α) plays a central role in hepatic responses to oxygen deprivation, influencing bile duct remodeling and fibrosis, which are key processes in BA progression. This review explores the crosstalk between hypoxia and hepatic ciliopathies, with a focus on BA. It discusses the molecular mechanisms through which hypoxia may drive disease progression and examines the therapeutic potential of targeting hypoxia-related pathways. Understanding how oxygen deprivation influences ciliary function may open new avenues for treating biliary ciliopathies and improving patient outcomes.

This study aimed to comprehensively evaluate the diagnostic potential of urinary exosomal microRNA (miRNA) in IgA vasculitis (IgAV) kidney injury by meticulously comparing the miRNA expression profiles in urine exosomes between children diagnosed with IgAV and those with IgA vasculitis nephritis (IgAVN). Urine samples were obtained from children with IgAV who were treated at our hospital from October 2022 to October 2023. These samples were then categorized into the IgAV group and the IgAVN group. High-throughput sequencing and bioinformatics analysis techniques were employed to conduct a thorough analysis of the differentially expressed miRNAs between the two groups. Additionally, the correlation between urinary exosomal miRNA and clinical parameters was evaluated. A total of 57 urinary exosomal miRNAs exhibited differential expression between the IgAV and IgAVN groups. Specifically, in the IgAVN group, 42 miRNAs were upregulated, while 15 were downregulated. Lasso regression analysis and ROC analysis identified five candidate urinary exosomal miRNAs with high diagnostic accuracy. A prediction of 95 target genes related to the candidate miRNAs led to the construction of an exosomal miRNA-mRNA regulatory network consisting of four key miRNAs and ten hub genes. Gene function and metabolic pathway analyses indicated that these ten hub genes were predominantly enriched in pro-fibrotic and inflammatory pathways. The analysis incorporating clinical parameters demonstrated a significant correlation between hsa-miR-383-5p and urinary protein levels. This research identified exosomal miRNAs and mRNAs with differential expression patterns associated with IgAVN and constructed the corresponding exosomal miRNA-mRNA network. It was determined that hsa-miR-3065-5p, hsa-miR-383-5p, hsa-miR-25-3p, and hsa-miR-450b-5p might mediate the pathogenesis of IgAVN by targeting pro-fibrotic and inflammatory pathways. Among them, exosomal hsa-miR-383-5p is highly likely to serve as a novel non-invasive biomarker for assessing the disease status of IgAVN, thereby offering new perspectives on the non-invasive diagnosis and treatment of IgAVN.

The translation of biomedical devices and drug research is an expensive and long process with a low probability of receiving FDA approval. Developing physiologically relevant in vitro models with human cells offers a solution to not only improving the odds of FDA approval but also to expand our ability to study complex in vivo systems in a simpler fashion. Animal models remain the standard for pre-clinical testing; however, the data from animal models is an unreliable extrapolation when anticipating a human response in clinical trials, thus contributing to the low rates of translation. In this review, we focus on in vitro vascular or angiogenic models because of the incremental role that the vascular system plays in the translation of biomedical research. The first section of this review discusses the most common angiogenic cytokines that are used in vitro to initiate angiogenesis, followed by angiogenic inhibitors where both initiators and inhibitors work to maintain vascular homeostasis. Next, we evaluate previously published in vitro models, where we evaluate capturing the physical environment for biomimetic in vitro modeling. These topics provide a foundation of parameters that must be considered to improve and achieve vascular biomimicry. Finally, we summarize these topics to suggest a path forward with the goal of engineering human in vitro models that emulate the in vivo environment and provide a platform for biomedical device and drug screening that produces data to support clinical translation.

Nasopharyngeal carcinoma (NPC) is a major global health issue, especially in Southeast Asia. Solamargine (SM), an alkaloid from natural plants, inhibits various cancer cells. This study evaluates SM's effects on invasion, migration, EMT markers, angiogenesis, and related pathways in the NPC-specific C666-1 cell line.

In vitro assays, including wound healing, Transwell invasion, Western blot, and tube formation, were used to assess SM's impact on C666-1 NPC and HUVEC cells. SM concentrations were 2 µM and 5 µM, with axitinib (4 µM) as the control. Network pharmacology and GO-KEGG enrichment analyses were conducted to explore SM's targets and mechanisms in NPC.

SM significantly inhibited C666-1 NPC cell invasion and migration by reducing EMT markers Vimentin and Snail. In HUVEC cells, SM decreased viability, invasion, migration, and tube formation, likely through VEGF signaling inactivation, EZH2 inhibition, and miR-203a-3p upregulation. Network pharmacology and GO-KEGG analyses identified key targets and pathways, suggesting SM's anti-NPC effects through multiple mechanisms.

SM inhibits NPC cell invasion and migration by regulating EMT, suppressing angiogenesis, and modulating key pathways. These findings highlight SM's potential as an anti-cancer agent for NPC and provide new insights into its mechanisms. Network pharmacology and GO-KEGG analysis further identify its therapeutic targets, offering valuable directions for future drug development.

In the field of large-area trauma flap transplantation, preventing avascular necrosis remains a critical challenge. Key mechanisms for improving flap viability include angiogenesis promotion, oxidative stress inhibition, and cell death prevention. Recently, two-dimensional ultrathin Ti3C2TX (MXene) nanosheets have gained attention for their potential contributions to these processes, though MXene's physiological impact on flap survival had not been previously investigated. This study is the first to confirm MXene's biological effects on the ischaemic microenvironment post-skin flap transplantation. Findings indicated that MXene significantly decreased the necrotic area in ischaemic flaps (37.96% ± 2.00%), with reductions of 30.40% ± 1.86% at 1 mg/mL and 20.19% ± 2.11% at 2 mg/mL in a concentration-dependent manner. Mechanistically, MXene facilitated in situ angiogenesis, mitigated oxidative stress, suppressed pro-inflammatory pyroptosis, and activated the PI3K-Akt pathway, particularly influencing vascular endothelial cells. Comparative transcriptome analysis of skin tissues with and without MXene treatment provided additional evidence, highlighting mechanisms such as pro-inflammatory pyroptosis, ROS metabolic processes, endothelial cell proliferation regulation, and PI3K-Akt signaling pathway activation. Overall, MXene demonstrated biological activity, effectively promoting ischaemic flaps survival and presenting a novel strategy for addressing ischaemic necrosis in skin flaps.

Subarachnoid hemorrhage (SAH), characterized by the presence of hemoglobin (Hb) in the subarachnoid space, significantly impacts cerebral vessels, leading to various pathological outcomes. The toxicity of cell-free Hb released from erythrocytes and its metabolites after SAH causes vasoconstriction and neuronal damage, and correlates with delayed ischemic neurological deficits (DIND). While animal models have provided substantial and invaluable data in the research of aneurysmal SAH, the specific effects of subarachnoid blood on cerebral arteries remain greatly understudied. Here, we describe the changes in the genetic profile of human cerebral arteries exposed to free Hb for 48 h. We performed an ex vivo exposure, followed by mRNA sequencing of the vessels. Compared to controls 54 genes were downregulated, and 53 genes were upregulated in human cerebral arteries after Hb exposure. Enrichment analysis identified the ferroptosis pathway as the most significantly affected. Further lipid peroxidation (LPO) assays and elevated ACSL4 gene expression support a ferroptosis pathway. Additionally, Hb exposure altered key signaling pathways essential for vascular stability (PI3K-Akt, MAPK), modified G-protein signaling mediated by RGS1/2, and suppressed key transcription factors such as KLF5, NR4A1, and FOS. Our results underscore the critical role of Hb in driving pathological responses in brain vessels. Furthermore, our dataset could be valuable for developing interventions after SAH and may help identify the underlying causes of vascular injury.

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous metastatic lymphoma that can be treated by targeting angiogenesis. Apolipoprotein C1 (APOC1) plays a significant role in the proliferation and metastasis of various malignant tumors; however, its role in DLBCL-particularly its effects on angiogenesis-remains largely unexplored. This study investigates the correlation between APOC1 expression and patient prognosis in DLBCL. Using APOC1 gene knockdown, apoptosis, migration, and invasion were assessed through flow cytometry, the EDU assay, wound healing, and Transwell assays. Additionally, human umbilical vein endothelial cells (HUVEC) angiogenesis was evaluated. Advanced techniques, such as immunofluorescence, TUNEL assay, and immunohistochemical labeling were employed to analyze the effects of APOC1 knockdown on the PI3K/AKT/mTOR signaling pathway and tumor formation in nude mice. Results showed that APOC1 is overexpressed in DLBCL tissues and cells, with high APOC1 levels associated with poor patient prognosis. In vitro experiments revealed that APOC1 knockdown increased apoptosis and inhibited cell proliferation, migration, invasion, HUVEC angiogenesis, and PI3K/AKT/mTOR signaling pathway protein expression in DLBCL cells. Similarly, in vivo studies demonstrated that APOC1 knockdown significantly reduced tumor growth, angiogenesis-related proteins, and phosphorylated PI3K/AKT/mTOR pathway proteins in nude mice. APOC1 knockdown promotes apoptosis and suppresses angiogenesis in DLBCL cells by inhibiting the PI3K/AKT/mTOR pathway.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but debilitating disease characterized by a progressive necrosis of jaw bones in patients who have received anti-resorptive or anti-angiogenic therapies. Unfortunately, we still have no validated preventive or pharmaceutical interventions to help these patients, primarily due to our limited understanding of MRONJ pathogenesis. Here, we offer an extensive review of recent studies relevant to MRONJ pathogenesis. We present a hypothesis regarding the coupling of bone resorption and angiogenesis that relies on osteoblast-derived, matrix-bound vascular endothelial growth factors to explain why ONJ is associated with both anti-resorptive and anti-angiogenic agents.

A narrative review was conducted by searching databases, including PubMed, Scopus, Google Scholar, and Web of Science, to retrieve relevant reports.

Reduced bone resorption leads to reduced angiogenesis, and vice versa, creating a vicious cycle that ultimately results in ischemic necrosis of the jaw. Additionally, we suggest that reduced angiogenesis, induced by anti-resorptive or anti-angiogenic agents, aggravates bacterial infection-induced bone necrosis, explaining why the jaw bone is particularly susceptible to necrosis.

Our novel hypothesis will facilitate the advancement of future research and the development of more targeted approaches to managing MRONJ.

The oxidative stress-induced premature senescence of trabecular meshwork (TM) represents a pivotal risk factor for the development of glucocorticoid-induced glaucoma (GIG). This study aimed to elucidate the pathogenesis of TM senescence in GIG. MethodsIntraocular pressure (IOP), transmission electron microscopy and senescence-associated protein expression in TM were evaluated in GIG mice. Protein expression of phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) and monoamine oxidase A (MAOA), phosphorylation of AKT were quantified. ROS and mitochondrial superoxide levels were measured to evaluate cellular oxidative stress. Cell cycle analysis, β-galactosidase staining, senescence-associated protein expression were employed to assess the aging status of primary human trabecular meshwork cells (pHTMs). ResultsmRNA-seq and KEGG analysis indicating PI3K/AKT pathway as a key regulator in TM of GIG. PI3K inhibitor significantly prevented IOP elevation and abnormal mitochondrial morphology of TM in the GIG mouse model. PI3K inhibitor or selective silencing of PIK3R1 alleviated dexamethasone (DEX)-induced oxidative stress, also mitochondrial dysfunction, inhibiting MAOA expression in pHTMs. The same phenomenon was observed in the GIG models with inhibition of MAOA. Further KEGG analysis indicates that cellular senescence is the key factor in the pathogenesis of GIG. TM senescence was observed in both GIG mouse and cell models. Inhibition of the PI3K/AKT/MAOA pathway significantly alleviated DEX-induced premature cellular senescence of TM in GIG models. Glucocorticoids activated the PI3K/AKT/MAOA pathway, leading to mitochondrial dysfunction, oxidative stress, and premature aging in TM, elevating IOP. This mechanism could be associated with the onset and progression of GIG, providing a potential approach for its treatment.

Is to review the latest data on the role of key organic and inorganic compounds of the essential trace element selenium, selenium-containing nanocomposites and nanoparticles, and selenoproteins in lung cancer therapy.

Sodium selenite, methylselenic acid, selenomethionine, selenium nanoparticles, mammalian selenoproteins KEY OBJECTIVES:: To describe the molecular mechanisms of the cytotoxic effect of sodium selenite, methylselenic acid and selenomethionine on lung cancer cells, to discuss the latest advances in lung cancer nanomedicine using selenium-based nanoparticles and nanocomposites and to assess the prospects for creating antitumor drugs based on them, to assess the role of selenoproteins in the progression or inhibition of lung cancer and to study the molecular mechanisms of such regulation CONCLUSIONS:: This review provides a complete picture of the role of selenium and selenium-containing agents of various natures in the regulation of carcinogenesis and therapy of lung cancer, which significantly complements the fundamental data on the functions of these compounds, on the molecular mechanisms of regulation of processes associated with lung cancer. This knowledge provides insight into the latest developments and future prospects in the treatment and prevention of lung cancer with the active participation of the trace element selenium.

The aim of this study was to explore the role and potential mechanisms of Ephrin-B2 signaling in osteogenesis-angiogenesis coupling and to provide guidance for periodontal tissue engineering.

Considering the close relationship between periodontitis and periodontal bone defects, single-cell transcriptomic data from periodontal tissues in published databases (GEO number: GSE171213) were analyzed to characterize Ephrin-B2 signaling between osteoblastic lineages and endothelial cells. To observe the effects and mechanisms of Ephrin-B2 in angiogenesis and periodontal bone regeneration, osteoblasts were constructed that overexpress Ephrin-B2 and were then co-cultured with human umbilical vein cells (HUVECs).

Single-cell sequencing revealed a deficiency in Ephrin-B2 signaling from osteoblastic lineages in periodontitis, resulting in impaired transduction of Ephrin-B2 signaling between osteoblasts and endothelial cells. In an osteoblast-endothelial cell co-culture system, Ephrin-B2 signaling from osteoblasts promoted angiogenesis. The downstream pathway might be related to VEGFR2-PI3K. The cotransplantation of osteoblasts overexpressing Ephrin-B2 and HUVECs facilitated angiogenesis and new bone generation in vivo.

This study confirmed that Ephrin-B2 signaling is an indispensable positive regulatory factor in the osteogenesis-angiogenesis coupling of periodontal tissue remodeling. These findings may help to optimize transplantation strategies and provide a new solution for the targeted treatment of periodontal bone defects.

Sufficient vascularization is a prerequisite for periodontal bone regeneration. The cotransplantation of angiogenic endothelial cells and bone-forming cells is a promising tissue engineering strategy. To facilitate the effect of the transplantation, we found evidence of Ephrin-B2 signaling deficiency in osteoblastic lineages and vascular endothelial cells of periodontitis patients from single-cell sequencing data. Moreover, by constructing a cotransplantation system with overexpression of Ephrin-B2, we found its positive role in promoting periodontal vascularized bone regeneration. The present study elucidates the positive role and potential mechanisms of Ephrin-B2 signaling in osteogenesis-angiogenesis coupling, which will help to promote the effect of periodontal tissue engineering.

Many patients undergoing clinical regenerative treatments experience severe conditions arising from endothelial disruption. In chronic cardiac and perivascular diseases, deficiencies in vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), and heparin, which are essential for maintaining and activating endothelial cells, can lead to angiogenic dysregulation. Endothelial disruption caused by ischemic hypoxia and a deficiency in these factors is associated with many vascular diseases. However, their pathogenic processes remain unclear at the cellular level. Therefore, the present study aimed to develop a culture system that mimics the disease environment to test the effectiveness of drug candidates in restoring damaged blood vessels in chronic vascular diseases, including coronary artery disease and peripheral vascular disease. This study focused on VEGF, IGF, and heparin and developed a pseudo-disease culture system by pre-treating human umbilical vein endothelial cells (HUVECs) with a starvation medium (EGM-2™ medium lacking VEGF, IGF, and heparin) to examine the ability of HUVECs to form a traditional 2D vascular network. The results indicated that a deficiency in these proteins results in disruptions in tube morphogenesis. Moreover, the results suggested that dysregulation of the PI3K/AKT pathway plays a key role for in vascular disruption in HUVECs. The proposed pseudo-disease starvation system provides a simple way to visualize pathological disruptions to blood vessels and assess the efficacy of drugs for vascular regeneration.

The online version contains supplementary material available at 10.1007/s10616-025-00736-4.

The cadherin family, which includes T-cadherin, plays a significant role in angiogenesis, a critical process involved in tumor growth, metastasis, and recurrence. T-cadherin is extensively expressed in both normal and tumor vascular tissues and has been shown to facilitate the proliferation and migration of vascular cells in some studies. However, T-cadherin also exerts inhibitory effects on angiogenesis in various tumor tissues. The functional role of T-cadherin may vary depending on the tumor type and the interaction between tumor cells and vascular cells, suggesting that it acts as a modulator rather than a primary driver of angiogenesis. Additionally, T-cadherin exhibits distinct characteristics depending on the tumor microenvironment. This review provides an overview of recent research on the role of T-cadherin in tumor angiogenesis and discusses its potential as a diagnostic or therapeutic marker in the field of tumor biology.

Cigarette smoke (CS) creates a "cancer field" in the lung that promotes malignant transformation. The molecular changes within this field are not fully characterized. We examined the significance of microRNA-1 (miR-1) downregulation as one of these changes. We found that tumor miR-1 levels in three non-small cell lung cancer cohorts show inverse correlations with the smoking burden. Lung MiR-1 levels follow a spatial gradient, have prognostic significance, and correlate inversely with the molecular markers of injury. In CS-exposed lungs, miR-1 is specifically downregulated in the endothelium. Exposure to CS induces angiogenesis by selectively degrading mature miR-1 via a vascular endothelial growth factor-driven pathway. Applying a multi-step molecular screen, we identified angiogenic genes regulated by miR-1 in the lungs of smokers. Knockdown of one of these genes, Notch homolog protein 3, simulates the anti-angiogenic effects of miR-1. These findings suggest that miR-1 can be used as an indicator of malignant transformation.

The pathophysiological mechanism of intracranial aneurysm (IA) involves the dynamic interaction of ECM abnormalities, hemodynamic stress, and inflammatory response. The rupture of intracranial aneurysm will cause serious consequences. Multiple studies have confirmed the important role and potential application of endothelial progenitor cells (EPCs) in vascular repair. This review focuses on the specific mechanism of EPCs in the treatment of intracranial aneurysms, which promote re-endothelialization and angiogenesis through bone marrow mobilization, targeted migration to the site of injury, differentiation into mature endothelial cells, and secretion of angiogenic factors. In addition, EPCs maintain ECM homeostasis by regulating MMP/IMP balance, inhibiting aneurysm wall thinning and structural damage. Based on the vascular repair mechanism of EPCs, new treatment strategies such as "biologically active" spring coils (loaded with EPCs or SDF-1α) and flow diverters(FDs) combined with EPCs therapy have been developed to synergistically promote carotid endothelialization of aneurysms and reduce the risk of recurrence. Future research needs to further validate the long-term efficacy and precise regulatory mechanisms of EPCs in clinical translation, providing new directions for IA treatment.

This study explores the relationship between gout and metabolic dysfunction-associated steatotic liver disease (MASLD), two metabolic conditions linked to worsening health outcomes. While hyperuricemia's association with MASLD is established, the specific connection between gout and MASLD remains less explored. Using data from the UK Biobank, the study employs COX proportional hazard models, multi-state survival analysis, and Mendelian randomization to assess the independent and mutual risks of gout and MASLD. Findings indicate a mutual risk increase: male gout patients, those younger than 60, and those with high BMI are particularly susceptible to MASLD, while female MASLD patients are at heightened risk for gout. Shared risk factors for both conditions include high BMI, hypertension, diabetes, and hyperuricemia. The study further identifies a bidirectional causal link, with gout leading to MASLD, mediated by gut microbiota Ruminococcaceae and proteins like IL-2 and GDF11, implicating specific metabolic pathways. The findings highlight a clinical and mechanistic correlation, emphasizing the need for targeted interventions to address these overlapping metabolic pathways in future treatments.

Age-related macular degeneration (AMD) is a prevalent retinal disorder that leads to central vision loss, mainly due to chronic inflammation. Tumor necrosis factor-alpha (TNF-α) is a critical mediator of inflammatory responses within the retinal environment. This study has investigated TNF-α's influence on inflammatory cytokine production and endothelial barrier integrity in human microglial (HMC3) and endothelial (HUVEC) cells. We found that TNF-α significantly elevated the expression and secretion of interleukin-6 (IL-6) and interleukin-1β (IL-1β) in HMC3 cells and disrupted endothelial tight junctions in HUVECs, as evidenced by weakened ZO-1 staining and compromised barrier function. To mitigate these effects and further investigate the in vitro mechanism of actions in CRG-01's in vivo therapeutic efficacy of anti-inflammation, we employed AAV2-shmTOR, CRG-01, as the candidate for therapeutic vector targeting the mammalian target of the rapamycin (mTOR) pathway. TNF-α-induced IL-6, IL-1β, and NF-κB signaling in HMC3 cells were significantly reduced by AAV2-shmTOR treatment, which may present a promising avenue for the fight against AMD. It also effectively preserved endothelial tight junction integrity in TNF-α-treated HUVECs, providing reassurance about its effectiveness. Furthermore, the supernatant medium collected from AAV2-shmTOR-treated HMC3 cells decreased oxidative stress, protein oxidation, and cytotoxicity in ARPE retinal pigment epithelial cells. These results strongly suggested that CRG-01, the candidate therapeutic vector of AAV2-shmTOR, may have a therapeutic potential to treat AMD-related retinal inflammation.

Severe acute hypoxic stress is a major contributor to the pathology of human diseases, including ischemic disorders. Current treatments focus on managing consequences of hypoxia, with few addressing cellular adaptation to low-oxygen environments. Here, we investigate whether accelerating hypoxia adaptation could provide a strategy to alleviate acute hypoxic stress. We develop a high-content phenotypic screening platform to identify compounds that fast-track adaptation to hypoxic stress. Our platform captures a high-dimensional phenotypic hypoxia response trajectory consisting of normoxic, acutely stressed, and chronically adapted cell states. Leveraging this trajectory, we identify compounds that phenotypically shift cells from the acutely stressed state towards the adapted state, revealing mTOR/PI3K or BET inhibition as strategies to induce this phenotypic shift. Importantly, our compound hits promote the survival of liver cells exposed to ischemia-like stress, and rescue cardiomyocytes from hypoxic stress. Our "phenopushing" platform offers a general, target-agnostic approach to identify compounds and targets that accelerate cellular adaptation, applicable across various stress conditions.

Wound healing is a complex physiological process fundamentally dependent on angiogenesis for effective tissue repair. Endothelial progenitor cells (EPCs) have shown significant potential in promoting angiogenesis, primarily through their secretome, rich in proteins and extracellular vesicles (EVs) essential for cell signaling and tissue regeneration. This study investigates the effect of a collagen-bound proteoglycan mimetic (LXW7-DS-SILY or LDS), that binds to the αvβ3 integrin receptor, on the EPC secretome, with a dual focus on the proteomic content and the functional properties of EVs. Utilizing high-resolution two-dimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS) alongside bioinformatic analysis, we identified significant alterations in protein expression profiles, particularly in angiogenesis and wound healing pathways. The functional impact of these changes was validated through biological assays, where the whole secretome and the EV fraction from EPCs seeded on collagen-bound LDS markedly enhanced vascular network formation, driven by the increase of growth factors and angiogenic regulators such as FGFR1, NRP1, and ANGPT2 within the EV fraction. Gene Ontology (GO) enrichment analysis further highlighted the enrichment of proteins within the EVs driving biological processes, including 'response to wounding' and 'positive regulation of cell motility'. These results underscore that LDS modulates the EPC secretome and significantly enhances its angiogenic potential, offering a promising therapeutic strategy for non-healing and ischemic wounds and suggesting that biomaterials can be modified to control the EV secretome to enhance tissue repair. Functional assays validating the omics data highlight the robustness of LDS as a targeted therapeutic for enhancing angiogenesis and tissue repair in clinical settings. Moreover, the pivotal role of EVs in mediating pro-angiogenic effects offers insights into developing biomaterial therapies that exploit key regulators within the EPC secretome for wound healing. STATEMENT OF SIGNIFICANCE: This manuscript explores how a proteoglycan mimetic that binds to both collagen and the αvβ3 integrin receptor affects the proteome component of the secretome from endothelial progenitor cells (EPCs). It presents functional biological data, analytical data, and proteomic analysis of the soluble and extracellular vesical (EV) components of the secratome. The proteomic data maps to the observed enhanced angiogenic potential of the EVs. These results suggest that by controlling the cellular environment and judicially engineering how cells interact with a biomaterial can influence the proteomic composition of EVs to enhance tissue regeneration. This is the foundation of future work aimed at engineering biomaterial cell systems to influence the proteomic component of EVs for therapeutic use.