Phosphatase and tensin homolog (PTEN) hamartoma tumour syndrome (PHTS) is a rare disorder caused by germline mutations in the tumour suppressor gene PTEN, a key negative regulator of phosphatidylinositol 3-kinase (PI3K)/AKT signalling. Children with PHTS often develop lipomas, for which only surgical resection is available as treatment. We investigated the effects of the selective PI3K-inhibitor alpelisib on Pten-deficient lipomas. After incubation with alpelisib or the non-selective PI3K inhibitor wortmannin, we analysed histology, gene expression, and Pi3k pathway in lipoma and control epididymal adipose tissue (epiWAT). Alpelisib increased adipocyte area in lipomas compared to epiWAT. Baseline gene expression showed higher levels of markers for proliferation (Pcna), fibrosis (Tgfb1), and adipogenesis (Pparg) in lipomas, while hormone-sensitive lipase expression was lower than in epiWAT. Following alpelisib incubation, target genes of Pi3k signalling and extracellular matrix factors were reduced. We confirmed Pi3k inhibition through detecting decreased Akt levels compared to control treatment. Human lipoma samples treated with alpelisib showed variable lipolysis responses, suggesting variability in therapeutic outcomes. We established an ex vivo model to study alpelisib effects on Pten-deficient lipomas. These results underscore the therapeutic potential of targeted PI3K inhibition in the treatment of PHTS-associated lipomas, particularly in cases that are inoperable.

Cerebral ischemia is a prevalent cerebrovascular disorder, with the restoration of blocked blood vessels serving as the current standard clinical treatment. However, reperfusion can exacerbate neuronal damage and neurological dysfunction, resulting in cerebral ischemia-reperfusion (I/R) injury. Presently, clinical treatment strategies for cerebral I/R injury are limited, creating an urgent need to identify new effective therapeutic targets. The PI3K/AKT signaling pathway, a pro-survival pathway associated with cerebral I/R injury, has garnered significant attention. We conducted a comprehensive review of the literature on the PI3K/AKT pathway in the context of cerebral I/R. Our findings indicate that activation of the PI3K/AKT signaling pathway following cerebral I/R can alleviate oxidative stress, reduce endoplasmic reticulum stress (ERS), inhibit inflammatory responses, decrease neuronal apoptosis, autophagy, and pyroptosis, mitigate blood-brain barrier (BBB) damage, and promote neurological function recovery. Consequently, this pathway ultimately reduces neuronal death, alleviates brain tissue damage, decreases the volume of cerebral infarction, and improves behavioral impairments. These results suggest that the PI3K/AKT signaling pathway is a promising therapeutic target for further research and drug development, holding significant potential for the treatment of cerebral I/R injury.

This study comprehensively investigated the effects of different ammonia nitrogen models during transportation on the energy metabolism, redox system, apoptosis, and changes in muscle quality of fish using molecular biology and metabolomics. Exposure to ammonia nitrogen caused intensive stress response as evidenced by alteration on the levels of biochemical indicators (cortisol, glucose, urea nitrogen, alanine transaminase, lactic dehydrogenase, superoxide dismutase, and glutathione peroxidase) and structural disruption of organs (including gill, cephalic kidney, kidney, and liver). As a result of the ammonia nitrogen stress, the redox system became imbalance, leading to disturbance in energy metabolism primarily through the pathways of D-amino acid metabolism, alanine/aspartate/glutamate metabolism, and purine metabolism. Additionally, apoptosis occurred following stress, regulated by FoxO, mTOR, NF-κB, and PI3K/AKT signaling pathways. Besides redox system, energy metabolism, and apoptosis, the change of muscle quality were also influenced by ammonia nitrogen concentration and exposure duration. Drip loss increased with higher ammonia nitrogen concentrations and longer exposure time, while shear force value showed an inverse trend. Although no significant changes were observed in a* and b* values following ammonia nitrogen exposure, the highest W and L* values were found in the low-concentration groups. The correlation of spearman indicates the changes in muscle quality, including drip loss, shear force, and color, induced by ammonia nitrogen during transportation was attributed to the interplay of redox system, energy metabolism, and apoptosis.

5-Fluorouracil (5-FU) chemotherapy resistance is a critical determinant of poor prognosis in patients with colorectal cancer (CRC). One critical mechanism underlying this resistance is the clearance of reactive oxygen species (ROS) generated by 5-FU, which diminishes its cytotoxic efficacy. Here, we identified the differential expression of UDP-glucose dehydrogenase (UGDH) in resistant cells through sequencing, and downstream targets EEF1A2 and PRDX1 were identified via immunoprecipitation-mass spectrometry (IP-MS). Stable knockdown and overexpression cell models were generated using a lentiviral system. The effects of gene manipulation on 5-FU resistance in CRC were evaluated both in vitro and in vivo through flow cytometry for reactive oxygen species (ROS) and apoptosis, as well as TUNEL immunofluorescence assays. Sequencing was utilized to enrich the relevant pathways. Our study firstly demonstrates that ROS-induced activation of the PI3K/AKT signaling pathway upregulates UGDH expression. UGDH promotes 5-FU resistance by collaborating with downstream effectors EEF1A2 and PRDX1 to clear ROS and inhibit tumor cell apoptosis. UGDH serves as a potential biomarker for 5-FU resistance in CRC, with its expression levels providing a crucial basis for therapeutic decision-making.

Oral cancer (OC) has become increasingly prevalent in recent years, making it one of the most often occurring types of cancer in patients. The clinical identification of OC is usually a time-consuming procedure, and the outlook for individuals with OC is generally unfavorable, as no particular biomarkers have been established to far. The main risk factors linked to OC are high levels of tobacco and alcohol intake, together with a reduced occurrence of viral infections, such as human papillomavirus. Furthermore, there is evidence suggesting that genetic characteristics that can be passed down from parents to offspring play a role in increasing the likelihood of getting ovarian cancer. MicroRNAs (miRNAs) are brief RNA molecules that do not code for proteins and have the ability to either repress or promote the growth of tumors during cancer development. They have been discovered to control multiple signaling pathways within cells, and their abnormal regulation has been demonstrated to be crucial in initiating and furthering the development of cancer. Additionally, they have the ability to either facilitate or impede the entire multi-stage process of cancer metastasis, including epithelial-mesenchymal transition (EMT), migration, and invasion, by selectively targeting essential genes involved in these pathways. Several microRNAs have the ability to regulate gene expression through various ways. In addition, like other types of cancer, OC has shown alterations in the expression of miRNAs, and certain miRNAs may have the ability to be used for diagnosis and treatment. The investigation of these miRNA could perhaps result in advancements in the specified instances of OC.

Intracerebral hemorrhage (ICH) remains a life-threatening condition due to its high mortality and limited treatment options. This study explores a novel therapeutic strategy using engineered exosomes derived from endothelial progenitor cells (EPC-EXOs) to improve ICH outcomes. EPC-EXOs were modified with a CD47-enriched red blood cell membrane via co-extrusion to enhance their anti-phagocytic properties, thereby reducing degradation by activated microglia after ICH. A minimally invasive endoscopic-guided delivery system was developed to facilitate the targeted intranasal administration of these engineered EPC-EXOs (m-Oe-EXOs), allowing direct entry into brain tissue. We confirmed m-Oe-EXOs' high retention and effective distribution in the brain. Functional analysis demonstrated that EPC-EXOs significantly promoted the proliferation, migration, and angiogenesis of brain microvascular endothelial cells (BMECs), with proteomic analysis identifying HSP90 as a key protein activating the Akt pathway in BMECs. In vivo, m-Oe-EXOs demonstrated therapeutic efficacy by improving blood-brain barrier integrity, reducing hematoma volume, and enhancing neurological recovery in ICH rats. Collectively, our findings highlight the potential of minimally invasive, endoscopic-guided delivery of m-Oe-EXOs as an innovative approach for ICH treatment, providing new insights into targeted, exosomes-based regenerative therapies.

This study aimed to explore the neuroprotective effects of Melatonin (Mel) administration on cerebral ischemia-reperfusion injury (CIRI) and elucidate its underlying mechanism in vivo to provide a theoretical foundation for the clinical application of Mel.

CIRI models were established in male adult Sprague Dawley rats by middle cerebral artery occlusion (MCAO) for 2 h. Water content of brain tissue was assessed using both dry/wet weight method and T2-weighted Imaging (T2WI). The infarct volume of the brain was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Cell morphology changes and brain damage were detected through hematoxylin & eosin (H&E) staining and NeuN immunofluorescence staining. The integrity of blood-brain barrier (BBB) was examined using transmission electron microscopy (TEM). The expression of aquaporin 4 (AQP4) protein was quantified through western blots analysis and immunofluorescence staining. The expression of p-PI3K, p-AKT and Nrf2 proteins were detected by immunohistochemistry staining and western blots analysis.

Compared with the CIRI group, Mel administration significantly reduced the infarct volume and ameliorated the morphology alterations, accompanied by an increase in the number of neurons. The water content of brain tissue decreased significantly, and the value of relative average diffusion coefficient (rADC) of injured brain increased in the CIRI + Mel group as compared with the CIRI group. Compared with the CIRI group, Mel administration improved the damage to the tight junctions of endothelial cells in the cerebral cortex. The expression of AQP4 protein decreased, and that of p-PI3K, p-AKT and Nrf2 proteins increased in the CIRI + Mel group compared with the CIRI group. After administration of p-PI3K inhibitor LY294002, the expression of AQP4 was upregulated, and that of the p-PI3K, p-AKT and Nrf2 proteins decreased compared with the CIRI + Mel group.

Mel administration exerts neuroprotective effects against CIRI by mitigating brain edema through upregulating the PI3K/AKT/Nrf2 signaling pathway, and then attenuating brain damage in CIRI rats.

Breast cancer (BC) is a prevalent malignancy that poses significant risks to the health of women worldwide. The incidence and mortality rates of BC continue to be high, despite improvements in diagnosis and treatment, indicating a need for novel prevention strategies. Kaempferol (KAM) is a common dietary flavonoid with known antitumour properties, but its role in the chemoprevention of BC and the underlying mechanisms largely unexplored.

This study aimed to evaluate the chemopreventive effects of KAM on carcinogen-induced BC in vivo and in vitro and to elucidate the underlying molecular mechanisms.

In this study, we used an N-methyl-N-nitrosourea (NMU)-induced rat model of BC and 17β-oestradiol (E2)-treated MCF-10A cells to evaluate the chemopreventive effects of KAM on mammary tumorigenesis. The antioxidant capacity of KAM was assessed by measuring oxidative damage marker levels and antioxidant enzyme expression. Flow cytometry and Hoechst 33258 staining were utilized to analyse cell cycle distribution and apoptosis. The core target of KAM was identified by network pharmacology and validated by molecular docking, MD simulation, CESTA, and BLI. KEGG enrichment analysis, molecular biology tests and the application of specific protein inhibitors were conducted to elucidate the molecular mechanisms modulated by KAM.

In vivo, KAM inhibited the progression of mammary tumours and delayed pathological changes in the morphological structure of mammary gland cells to varying degrees. In vitro, KAM reduced cell viability, migration, and anchorage-independent growth while triggering cell cycle arrest and apoptosis in E2-treated MCF-10A cells. Furthermore, KAM increased cellular antioxidant capacity and attenuated E2-induced oxidative stress. Mechanistically, KAM directly interacted with Src and inhibited its phosphorylation, thus leading to PI3K/AKT pathway inhibition. Notably, the inhibition of E2-induced cell migration and anchorage-independent growth in vitro by Src- or PI3K/AKT pathway-specific inhibitors was not further enhanced when the cells were cultured with KAM.

In summary, KAM targets the Src-mediated PI3K/AKT pathway to reduce oxidative stress and facilitate apoptosis and cell cycle arrest, thereby inhibiting mammary tumorigenesis. Our study is the first to identify Src kinase as a direct target of KAM in mammary tumorigenesis. These findings give significant perspectives on the potential application of KAM in BC chemoprevention.

Cancer is a health and treatment challenge that the world is facing, and many efforts are being made to develop treatment solutions for all forms of cancer. Radiotherapy (RT), one of the cancer treatment methods, can cause toxicity in healthy cells, even though it has positive effects on killing cancer cells. It is possible for cancer cells to develop resistance to radiotherapy. To address these issues, it can be beneficial to combine treatments. Combining plants with conventional cancer treatment is a viable option, and their potential can be utilized in this area. The therapeutic properties of silymarin and its active ingredient silibinin have been used in traditional medicine for a long time. The purpose of this review is to investigate the radioprotective and radio-sensitizing properties of silymarin/silibinin in cancer treatment.

This article focuses on the phosphatidylethanolamine-binding protein (PEBP) family proteins, detailing PEBP1 and PEBP4 due to limited information on PEBP2 and PEBP3, in cellular signaling pathways and research in a spectrum of pathologies, including diverse cancers, metabolic disorders, immunological diseases and a subset of organ-specific diseases. It outlines the mechanisms through which PEBP1 and PEBP4 regulate essential signaling pathways that are critical for cellular processes such as proliferation, apoptosis, and metastasis. Recent advancements have shown further understanding of these proteins' roles in pathophysiology and their potential as future therapeutic targets. The findings suggest that the impact of PEBP1 and PEBP4 on the course of different diseases has underscored their potential for more in-depth medical research and novel clinically targeted therapies.

Bladder cancer is a prevalent malignancy with high mortality rates worldwide. Hypoxia is a critical factor in the development and progression of cancers. However, whether and how hypoxia-related genes (HRGs) could affect the development and the chemotherapy response of bladder cancer is still largely unexplored. This study comprehensively explored the complex molecular landscape associated with hypoxia in bladder cancer by analyzing 260 hypoxia genes based on transcriptomic and genomic data in 411 samples. Employing the 109 dysregulated hypoxia genes for consensus clustering, we delineated two distinct bladder cancer clusters characterized by disparate survival outcomes and distinct oncogenic roles. We defined a HPscore that was correlated with a variety of clinical features, including TNM stages and pathologic grades. Tumor immune landscape analysis identified three immune clusters and close interactions between hypoxia genes and the various immune cells. Utilizing a network-based method, we defined 129 HRGs exerting influence on apoptotic processes and critical signaling pathways in cancer. Further analysis of chemotherapy drug sensitivity identified potential drug-target HRGs. We developed a Risk Score model that was related to the overall survival of bladder cancer patients based on doxorubicin-target HRGs: ACTG2, MYC, PDGFRB, DHRS2, and KLRD1. This study not only enhanced our understanding of bladder cancer at the molecular level but also provided promising avenues for the development of targeted therapies, representing a significant step toward the identification of effective treatments and addressing the urgent need for advancements in bladder cancer management.

In recent years, energy metabolism in cancer has received increasing attention as an important component of tumor biology, and the functions of transcription factors, mitochondria, reactive oxygen species (ROS) and the autophagy-lysosome system in which have been elucidated. G-quadruplex (G4) is a molecular switch that regulates gene transcription or translation. As an anticancer target, the effect of G4 on cancer cell proliferation, apoptosis, cycle and autophagy has been recognized. The energy metabolism system is a unified whole composed of transcription factors, metabolic regulators, metabolites and signaling pathways that run through the entire cancer process. However, the role of G4 in this complex metabolic network has not been systematically elucidated. In this review, we analyze the close correlation between G4 and transcription factors, mitochondria, ROS and the autophagy-lysosome system and suggest that G4 can exert a marked effect on cancer energy metabolism by regulating the above mentioned key regulatory elements. The anticancer effects of some G4 ligands through regulation of energy metabolism have also been summarized, confirming the clear involvement of G4 in energy metabolism. Although much more research is needed, we propose that G4 may play a critical role in the complex energy metabolism system of cancer, which is a promising target for anticancer strategies focusing on energy metabolism.

Meat is a staple in many cultural diets, and the consumption of processed meats has increased significantly worldwide. The widespread use of sodium nitrate (NaNO3) as a preservative and the unintentional leaching of bisphenol A (BPA) from packaging into meats have raised health concerns. This study evaluates the combined toxicity of BPA and NaNO3 despite their individual safety assessments. Our findings reveal that coexposure to BPA and NaNO3 at levels found in processed meats induces mortality and malformations in zebrafish larvae. The combined exposure triggers oxidative stress, lipid peroxidation, dyslipidemia, inflammation, and apoptosis. Network toxicology analysis elucidates the molecular mechanisms underlying metabolic dysfunction caused by these substances. Dysregulation of genes related to thyroid function (tsh-β, dio-1, thr-b) and inflammation (tnf-α, il-1β, il-6, nfκb) was observed in the co-exposure group. Additionally, this group exhibited increased lipid accumulation, elevated cholesterol and triglyceride levels, and dysregulation of essential lipid metabolism genes (srebp2, pcsk9). Co-exposure also impaired larval motility and behavior, evidenced by hypolocomotion and reduced acetylcholinesterase levels. Further gene expression analysis showed increased levels of pi3k and akt, two major signaling molecules. Ultimately, the simultaneous exposure to BPA and NaNO3 leads to disruptions in the endocrine system and abnormal lipid levels via activating the PI3K/AKT/SREBP pathway.

Breast cancer stem cells (BCSCs) are a unique subpopulation of tumor cells driving tumor resistance, progression, metastasis, and recurrence. Reprogrammed cellular metabolism and key signaling pathways, including Wnt/β-catenin, TGF-β, STAT3, and PI3K/AKT/mTOR pathway play a vital role in maintaining BCSCs. Importantly, PI3K/Akt/mTOR pathway regulates metabolism, survival, growth, and invasion, with PIK3CA, encoding the PI3K catalytic subunit p110α, the most frequently mutated gene in breast cancer. This study investigates the effects of alpha-lipoic acid (LA) on the metabolic profile of BCSCs, focusing on its interaction with PI3K signaling. LA was found to bind PI3K, disrupting cancer-associated metabolic pathways and significantly inhibiting BCSC metabolism. Metabolomic analysis of MCF-7 and MDA-MB-231-derived breast cancer spheroids showed LA-induced metabolic shifts. In MCF-7 spheroids, LA induced upaccumulation of 15 metabolites and downaccumulation of 5, while in MDA-MB-231 spheroids, it induced upaccumulation of 3 and downaccumulation of 16. LA also enhanced the sensitivity of breast cancer spheroids to doxorubicin (Dox), demonstrating a synergistic effect. Mechanistically, LA modulates the PI3K/Akt/mTOR pathway, impairing cell survival and proliferation. These findings highlight the potential of LA as a therapeutic agent for reprogramming cancer metabolism and enhancing chemotherapy efficacy. These results provide a strong rationale for incorporating LA into combination therapy strategies for breast cancer treatment.

Statins, recognized for their lipid-lowering capabilities, have demonstrated osteoanabolic and anti-resorptive effects on bone metabolism. The effects encompass the overexpression of bone morphogenetic proteins, heightened osteoblast activity, and the control of inflammation. Nevertheless, conventional systemic administration of statins has difficulties, including restricted bone bioavailability and possible adverse effects. Recent improvements in targeted and localized drug delivery are revolutionizing the therapeutic landscape for statins in bone applications. This review consolidates existing knowledge regarding the molecular processes by which statins influence bone metabolism and describes novel drug delivery methods such as nano-carriers, biomaterial scaffolds, and controlled-release systems. It seeks to address current knowledge deficiencies and offer insights into how enhanced bioavailability and specificity can optimize the efficiency of statins in bone regeneration. The review integrates molecular insights with novel pharmacological strategies to inform future research and clinical applications, pinpointing critical areas for exploration, such as optimal dose, delivery safety, and clinical efficacy.

Tenacissoside H(TDH), a natural compound extracted from the dried vine stems of Marsdenia tenacissima (Roxb.) Wight et Arn., is considered to have anti-tumor effects. However, the anti-tumor activity of TDH against ATC remains unknown.

Ferroptosis, a novel form of programmed cell death, presents a promising target for therapeutic intervention, particularly in overcoming drug resistance in anaplastic thyroid carcinoma (ATC). We investigated the inhibitory effects of TDH on ATC cells, elucidating its ferroptosis-inducing mechanism, which to our knowledge has not been explored before.

Our findings indicate that TDH exerts an effect on the survival, proliferation, and migration of ATC cells. The strength of effect is dependent on dosage. Notably, ferroptosis marker proteins (GPX4, xCT, HO-1, TFR) were significantly downregulated following TDH treatment, whereas GPX4 and xCT expressions were partially restored post treatment with ferrostatin-1. Furthermore, in vivo studies confirmed that TDH effectively inhibited tumor growth in xenografted 8505C cells.

TDH could be considered a potential agent against ATC via inducing ferroptosis, providing a novel pharmacological basis for treating ATC.

Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates key cellular processes including cell growth, autophagy and metabolism. Hyperactivation of the mTOR pathway causes a group of rare and ultrarare genetic diseases. mTOR pathway diseases have diverse clinical manifestations that are managed by distinct medical disciplines but share a common underlying molecular basis. There is a now a deep understanding of the molecular underpinning that regulates the mTOR pathway but effective treatments for most mTOR pathway diseases are lacking. Translating scientific knowledge into clinical applications to benefit the unmet clinical needs of patients is a major challenge common to many rare diseases. In this article we expound how mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients. We outline the germline and somatic mutations in the mTOR pathway that cause rare diseases and summarise the prevalence, genetic basis, clinical manifestations, pathophysiology and current treatments for each disease in this group. We describe the challenges and opportunities for progress in elucidating the underlying mechanisms, improving diagnosis and prognosis, as well as the development and approval of new therapies for mTOR pathway diseases. We illustrate the crucial role of patient public involvement and engagement in rare disease and mTOR pathway disease research. Finally, we explain how the mTOR Pathway Diseases node, part of the Research Disease Research UK Platform, will address these challenges to improve the understanding, diagnosis and treatment of mTOR pathway diseases.

Prostate cancer (PCa) is the most common cancer in men and the leading cause of cancer death worldwide. Overactivation of PI3K signaling has been reported to be associated with PCa. TGX221 is an effective specific inhibitor of PI3K, but its clinical application is greatly limited due to its poor solubility. Herein, by using folic acid-PEG-cholesterol semi-succinate (FA-PEG-CHEMS) as the targeting component, we developed a folate receptor-targeted pH-sensitive liposomal delivery system loaded with TGX221 (FA-Lip-TGX221) that could realize effective delivery and controlled release of drugs in the tumor. The prepared liposomes exhibited a uniform particle size and high stability. In addition, FA-Lip-TGX221 could be effectively internalized by PC-3 cells due to its ability to target folate receptors, thereby accumulating in tumor tissues. Meanwhile, in vitro and in vivo experiments suggested that FA-Lip-TGX221 could activate the PERK-ATF4-CHOP signaling pathway by inhibiting PI3K/110β signaling in PCa, thus significantly promoting endoplasmic reticulum (ER) stress-mediated cancer cell death. In conclusion, FA-Lip-TGX221 is a promising nano-delivery vehicle for the treatment of PCa, and also provide valuable references for all tumors overexpressing folate receptors.

Excessive and variable inflammation in bone defects is a key factor that impedes effective bone repair. Herein, an ultrasound-controlled composite hydrogel (LNT-SeNPs@Gel) integrating gelatin-methacryloyl and lentinan-decorated selenium nanoparticles (LNT-SeNPs) is developed, exhibiting strong antioxidant and anti-inflammatory properties to remodel the inflammatory microenvironment of bone defects. This hydrogel serves as a platform for integrating bifunctional ultrasound (ultrasound modulation, USc and ultrasound for repairing, USr), facilitating cascade treatment and reducing the overall treatment period. During the inflammatory phase of bone repair, USc remotely modulates the LNT-SeNPs@Gel hydrogel, regulating the release of LNT-SeNPs to inhibit the overproduction of reactive oxygen species (ROS) and inflammatory factors, ultimately remodeling the inflammatory microenvironment. Subsequently, USr could activate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway regulated by selenoproteins to enhance the osteogenesis of MC3T3-E1 cells, thereby accelerating the bone repair process. Consequently, the combination of bifunctional ultrasound and LNT-SeNPs@Gel significantly improves bone repair outcomes and reduces the treatment period in rats. In conclusion, this study implies that the coordinated integration of the dual effects of ultrasound is a promising strategy for handling the complex and lengthy bone defects repair.

Glycosylation is a fundamental post-translational modification that plays a pivotal role in cancer progression, influencing cell adhesion, immune evasion, metastasis, and drug resistance. Among glycosyltransferases, Core 2 β-1,6-N-acetylglucosaminyltransferase 3 (GCNT3) has emerged as a key regulator of tumor behavior, with its effects varying across different cancers. While elevated GCNT3 expression is associated with better prognosis and chemotherapy response in ovarian cancer, it correlates with poor survival, tumor invasiveness, and immune suppression in pancreatic and lung cancers. This dual nature underscores the complexity of GCNT3's role in cancer biology. As a biomarker, GCNT3 has shown potential for prognostic and therapeutic applications, particularly in colorectal and ovarian cancers. Targeting GCNT3 therapeutically presents challenges due to its role in normal physiological glycosylation, and the lack of selective inhibitors. Current research suggests that GCNT3-targeted therapies, in combination with immunotherapy or chemotherapy, could improve treatment outcomes by modulating mucin production, tumor metabolism, and immune responses. This review critically explores GCNT3's diverse functions, its impact on cancer progression, and its potential as a therapeutic target, highlighting the need for cancer-specific approaches and future innovations in drug development to harness its clinical potential effectively.

Longevity is defined by the ability to maintain both physical and mental health throughout a long life and may results from adaptive mechanisms that mitigate aging's detrimental effects.

The 20-year follow-up study of 3,312 unrelated individuals aged 18-114 years from the Volga-Ural region of Eurasia investigated variants in cellular homeostasis genes IGF1, PIK3R1, AKT1, MTOR, NFE2L2, KEAP1, HIF1A, TP53, and SIRT1, to identify associations with clinical aging phenotypes and healthy longevity.

In men, KEAP1 (rs1048290) CC genotype was a longevity and survival marker (OR = 2.39, P = 3E-05, HR = 0.54, P = 2.4E-03). NFE2L2 (rs6721961) TT genotype was linked to higher mortality (HR = 1.77, P = 0.031), particularly combined with KEAP1 (rs1048290) G and AKT1 (rs3803304) C alleles (HR = 2.8, P = 0.023). In women, AKT1 (rs3803304) C allele interacted with NFE2L2 (rs6721961) TT genotype (SF = 0.13, P = 3.6E-03), and was linked to longevity (OR = 2.22, P = 6.3E-03) and protection against cerebrovascular diseases (OR = 0.62, P = 5.1E-03). AKT1 (rs3803304) GG genotype, along with HIF1A (rs11549465) T and SIRT1 (rs3758391) T alleles (SF = 2.52, P = 1.5E-03), promoted survival (HR = 0.71, P = 0.014). In men, HIF1A (rs11549465) TT genotype predicted cardiovascular mortality (HR = 7.5, P = 5.5E-03). SIRT1 (rs3758391) TT genotype was associated with improved survival in individuals with diabetes (HR = 0.4, P = 5.8E-03) and multimorbidity (HR = 0.48, P = 0.025).

Variants in NFE2L2, KEAP1, SIRT1, AKT1, and HIF1A, along with their interactions, were significantly associated with survival in age-related diseases and healthy longevity.

Clinically aggressive lactotroph pituitary neuroendocrine tumors (PitNET) are invasive tumors with an unusually rapid growth rate despite maximally tolerated doses of dopamine agonist (DA). We aimed to unravel the molecular heterogeneity of lactotroph PitNET and to identify biomarkers of aggressiveness and resistance to pharmacological treatment. A total of 13 patients harboring DA-resistant lactotroph PitNET were included in this study. Visium Spatial Transcriptomics (ST), whole transcriptome sequencing (WTS), and whole exome sequencing (WES) were performed in tumors from 4 of these patients; WTS and WES was carried out in 5; tumors from two patients underwent ST and WES and tumors from two other patients underwent only ST. Tumors were classified as null or partial responders according to their response to DA treatment. The eight PitNET analyzed by ST exhibited significant intratumoral heterogeneity, with clones showing alterations in PI3K/AKT and lipid metabolism pathways, particularly inositol phosphate, glycerophospholipid, and sphingolipid metabolism. The cell-cell communication analysis showed FGF-FGFR ligand receptor interaction whilst the transcription factors RXRA and CREM showed participation in both groups. A trajectory exploration was performed by including all PitNET together in a single analysis to determine whether there was a tendency or molecular pathway showing a differentiation pattern that would guide the transition from a partially responsive PitNET to a completely unresponsive one. We did not observe any such pattern. All of these findings were corroborated in the cohort of DA-resistant PitNETs in which only bulk WTS and WES were performed. The bulk WTS corroborated lipid metabolism and PI3K-AKT pathway alteration in PitNET, whereas the WES showed only SF3β1 and TP53 variants in one tumor each. Our work suggests that the PI3K/AKT pathway may constitute a molecular target at which to aim therapeutic strategies designed to treat aggressive and DA-resistant lactotroph PitNET.

Changes in cell signaling pathways, which in normal conditions determine the maintenance of cell homeostasis and the correctness of its basic processes, may cause the transformation of a normal cell into a cancer cell. Alterations in cellular metabolism leading to oncogenesis are considered to be a hallmark of cancer cells. Therefore, a thorough understanding of cellular enzymes affecting metabolism and respiration, as well as intracellular pathways connected with them, seems crucial. These changes may be both prognostic and predictive factors, especially in terms of using molecularly targeted therapies. Aberrations in the pathways responsible for cell growth and angiogenesis are considered particularly important in the process of oncogenesis. Gliomas are the most common primary malignant tumors of the brain. The most important molecular disorders determining their particularly malignant nature are aberrations in the pathways responsible for cell growth and angiogenesis, such as the PI3K/Akt or RAS/MAPK/ERK signaling pathway, as well as excessive activity of enzymes, like hexokinases, which play a key role in glycolysis, autophagy, and apoptosis. The multitude of alterations detected in glioma cells, high heterogeneity, and the immunosuppressive environment within the tumor are the main features causing failures in the attempts to implement modern therapies.

Gliomas represent the most prevalent primary neoplasm in the adult central nervous system. Despite advancements in therapeutic modalities, such as surgical intervention, radiotherapy, chemotherapy, and tumor treatment, the 5-year survival rate of glioma patients remains low. Therefore, there is an urgent need to develop additional treatment methods. Recent studies have suggested that FAM111B is involved in DNA repair, cell cycle regulation, and apoptosis. FAM111B mutations and overexpression are related to cancer.

We found that FAM111B was significantly overexpressed in glioma tissues compared to the adjacent tissues by analyzing data from the TCGA_GBM&LGG and CGGA databases. Moreover, overexpression of FAM111B was associated with shorter overall survival, and disease-specific survival and tended to increase with disease stage progression. Cellular experiments confirmed these results. These results suggest that overexpression of FAM111B promotes the proliferation, migration, and invasion of glioma cells, whereas the knockdown of FAM111B inhibits these activities. We also found that FAM111B regulated glioma cell proliferation, migration, and invasion via the PI3K/AKT pathway.

FAM111B is capable of enhancing the proliferation, invasion, and migration capabilities of glioma cells and promotes the malignant progression of glioma via the PI3K/Akt signaling pathway.

This is the first study to demonstrate that FAM111B plays a crucial role in the proliferation, migration, and invasion of glioma cells. The malignant phenotype of FAM111B has also been shown to be closely associated with the PI3K/AKT pathway. FAM111B may be a predictive biomarker and a potential therapeutic target for gliomas.

Esophageal cancer, a leading global cancer, lacks effective therapies. Inhibition of histone deacetylase 6 (HDAC6) is a promising antitumor strategy, yet its role in esophageal cancer remains underexplored. Through structural optimization of our previously developed 1,3-diaryl-1,2,4-triazole-capped HDAC6 inhibitors, we identified compound 38k, exhibiting remarkably enhanced HDAC6 inhibition (IC50 = 3.12 nM) and 352-fold selectivity over HDAC1. Molecular docking analysis, CETSA, and BLI confirmed its strong HDAC6 binding. Moreover, 38k displayed robust in vitro and in vivo antiesophageal cancer efficacy, along with an advantageous pharmacokinetic and safety profile. Notably, combining 38k with a PI3K inhibitor synergistically enhanced the efficacy (75.02% tumor growth inhibition vs 50.94% monotherapy), likely by counteracting HDAC6 inhibition-induced PI3K/AKT activation. These findings validate HDAC6 as a therapeutic target and highlight 38k as a promising candidate for esophageal cancer treatment, particularly in combination regimens.

As the first-line treatment for hemangioma (IH), the mechanism of propranolol (PRN) remains unclear. In clinical practice, challenges such as PRN resistance and rebound after discontinuation of PRN are frequently encountered. Hence, this research seeks to investigate the mechanisms underlying PRN-induced regression of IH.

Hexokinase 2 (HK2) expression was assessed via immunohistochemistry and double-labeling staining. Glycolysis in hemangioma-derived stem cells (HemSCs) was evaluated by measuring glucose uptake, lactate, and ATP production. Peroxisome proliferator-activated receptor Gamma (PPARγ) and vascular endothelial cadherin (VE-cadherin) levels were analyzed using Western blot and qPCR. PRN-treated HemSCs were examined for adipogenic differentiation via Oil Red O and BODIPY staining.

Our results demonstrate that PRN inhibits HemSCs proliferation and endothelial differentiation while promoting adipogenesis by suppressing glycolysis. This effect occurs through HK2 downregulation, likely mediated by PI3K-Akt pathway inhibition. Notably, HK2 expression was significantly lower in CD133+ cells from involutive hemangiomas versus proliferative lesions.

This study presents the first evidence for the essential role of glycolysis in regulating the proliferation and differentiation of HemSCs, while the efficiency of PRN may be associated with the inhibition of HK2-mediated glycolysis in HemSCs by suppressing the activities of PI3K-Akt pathway.

Glycolysis level is high in HemSCs. Glycolysis is required in propranolol perturbated the HemSCs differentiation. PRN could inhibit glycolysis of HemSCs through down-regulation of HK2 expression. PRN suppressed endothelial differentiation and accelerated adipogenesis of HemSCs. PRN down-regulated HK2 expression through restrained the PI3k-Akt pathway. Schematic of treatment mechanism of PRN in IH. HK2 is highly expressed in HemSCs. PRN may be associated with the inhibition of HK2-mediated glycolysis in HemSCs by suppressing the activities of PI3K-Akt pathway which finally promotes regression of IH.

Sialyltransferases are enzymes involved in the addition of sialic acid to glycoproteins and glycolipids, influencing various physiological and pathological processes. The expression and function of sialyltransferases in tumors, particularly in kidney renal clear cell carcinoma (KIRC) remained underexplored. This study aimed to develop a prognostic model based on sialyltransferase-related genes (SRGs) to predict the prognosis and treatment response of patients with KIRC.

We utilized RNA-Seq data of KIRC from The Cancer Genome Atlas (TCGA) database, selecting samples with survival data and clinical outcomes. Somatic mutation and neoantigen data were analyzed using the "maftools" package, and genes involved in the sialylation process were identified through the Molecular Signatures Database. Validation cohorts of KIRC samples were obtained from the International Cancer Genome Consortium (ICGC) database. Single-cell RNA sequencing (scRNA-seq) data were downloaded from the Gene Expression Omnibus (GEO) platform, and preprocessing, normalization, and dimensionality reduction analyses were conducted using the "Seurat" package. Differentially expressed sialylation genes were identified using the "limma" package, and their functional enrichment was assessed via Gene Ontology GO and KEGG analyses. Consensus clustering analysis was performed to identify molecular subtypes of KIRC based on sialylation, and drug sensitivity of different subtypes was evaluated using the "pRRophetic" package. A risk signature model comprising 5 SRGs was constructed through univariate and multivariate Cox regression analyses and validated in both the TCGA and ICGC cohorts. The "estimate" package was utilized to calculate immune and stromal scores for each KIRC sample, assessing the tumor immune microenvironment characteristics of different subtypes.

Analysis of scRNA-seq data identified 25 cell subtypes, categorized into 9 cell types. CD4 + memory cells exhibited the highest potential interactions with other cell subtypes. We identified 14 differentially expressed sialylation genes and confirmed their enrichment in various biological pathways through GO and KEGG analyses. Consensus clustering analysis based on sialylation identified 2 molecular subtypes: C1 and C2. The C2 subtype demonstrated higher sialylation scores and poorer prognosis. Drug sensitivity analysis indicated that the C1 subtype had better responses to Dasatinib and Lapatinib, whereas the C2 subtype was more sensitive to Epothilone B and Vinorelbine. The risk signature model, constructed with five distinct SRGs, exhibited strong predictive accuracy, as indicated by Area Under the Curve (AUC) values of 0.68, 0.69, and 0.70 for 1-, 3-, and 5-year survival, respectively, across both the TCGA and ICGC validation cohorts. Immune microenvironment analysis revealed that the C1 subtype exhibited higher immune and stromal scores, while the C2 subtype showed significantly enhanced expression of immune checkpoint genes.

This study successfully developed a prognostic model based on SRGs, effectively predicting the prognosis and drug response of KIRC patients. The model demonstrated significant predictive performance and potential clinical application value. Furthermore, the study highlighted the critical role of sialylation in KIRC, offering new insights into its underlying mechanisms in tumor biology. These findings could guide personalized treatment strategies for KIRC patients, emphasizing the importance of sialylation in cancer prognosis and therapy.

Obesity-related osteoarthritis (OA) and the molecular mechanisms governing multiple joint structural changes that occur with obesity are not well understood. This study investigated the progression of obesity in mice and validated the results using human joint samples post-arthroplasty. The results show that obesity is associated with the degeneration of the cartilage layer and abnormal remodeling of the subchondral bone layer, and this occurs alongside aging and DNA damage in chondrocytes, osteoclasts, and stem cells. Regulation of p53-FOXO3 gene loop expression in response to DNA damage effectively inhibits chondrocyte apoptosis, catabolism, and excessive osteoclast differentiation, while the intra-articular delivery of a lentivirus expressing FOXO3 to mouse joints alleviates the progression of OA. The excessive differentiation of subchondral bone marrow osteoclasts is ferroptosis-dependent and driven by the senescence-associated secretory phenotype. The results have identified multiple potential targets for future research into the progression of obesity-related OA.

Smoking induces a decrease in breast milk volume, adverse changes in milk composition, and a shorter lactation period in breastfeeding women. In breastfeeding women, nicotine from tobacco is transferred from the blood to breast milk. Previously, we reported that nicotine adversely affects milk production and tight junctions (TJs) in mammary epithelial cells (MECs) in vitro. However, the mechanisms by which nicotine influences milk production and TJs in MECs remain unclear. During lactation, MECs are in contact with acetylcholine (ACh) in milk and express multiple nicotinic ACh receptors (nAChRs). In this study, we investigated whether nAChRs and ACh are involved in milk production TJs in MECs using a culture model of MECs that exhibit milk production ability and formation of less-permeable TJs. The results showed that nAChRα2 and nAChRα3 agonists, Br-PBTC and NS3861, respectively, suppressed casein secretion and increased claudin-4, a TJ protein. In addition, Br-PBTC and NS3861 inactivated STAT5 and Akt, which are signaling molecules that facilitate milk production in MECs. However, ACh did not influence casein secretion, claudin expression, or the activation of STAT5 and Akt in MECs. In contrast, the acetylcholinesterase inhibitor (donepezil) and nAChRα3 antagonist (α-conotoxin PIA) inhibited casein secretion concurrently inactivating STAT5 and Akt. Furthermore, short-term treatment with Br-PDTC and NS3861 on the apical side of MECs induced the inactivation of STAT5 and Akt. These findings indicate that MECs regulate milk production and TJ formation by regulating the acetylcholine levels in milk and that nicotine adversely affect milk production in MEC by disrupting the ACh/nAChR axis.

The dissemination of malignant cells to the brain is a late-stage complication of cancer, leading to significant morbidity and mortality. Brain metastases (BM) affect 20-30% of cancer patients, primarily originating from lung cancer, breast cancer, and melanoma. Despite advances in molecular-targeted therapies, brain metastatic disease remains incurable, with a poor median survival of ≤12 months if left untreated. The lack of therapeutic efficacy is mainly attributed to the presence of the blood-brain barrier (BBB) and genetic differences between BM and their primary tumors. Previously published data have identified potential driver mutations of BM. However, the mechanisms underlying brain cancer dissemination remain unknown. Recent studies emphasize the pivotal role of metabolic adaptations in supporting the metastatic process, particularly in the nutrient-poor microenvironment characteristic of the brain. Understanding the interplay between metabolism and genetic alterations associated with brain metastatic disease could unveil novel therapeutic targets that are more effective in treating patients. This review focuses on relevant metabolic pathways in cancer, particularly brain cancer dissemination, while also presenting information on current preclinical models of BM, relevant clinical trials, and preclinical studies targeting metabolic reprogramming, providing an overview for advancing therapeutic strategies in BM.

Metabolic reprogramming, a hallmark of malignancy, enables tumor cells to adapt to the harsh and dynamic tumor microenvironment (TME) by altering metabolic pathways. Hypoxia, prevalent in solid tumors, activates hypoxia inducible factor 1α (HIF-1α). HIF-1α drives metabolic reprogramming, enhancing glycolysis primarily through the Warburg effect to reduce oxygen dependence and facilitate tumor cell growth/proliferation. The above process is associated with accelerated tumor cell dedifferentiation and enhanced stemness, generating cancer stem cells (CSCs) which possesses the potential for self-renewal and differentiation that can differentiate into a wide range of subtypes of tumor cells and fuel tumor heterogeneity, metastasis, and recurrence, complicating therapy. This review examines the HIF-1α-glycolysis-dedifferentiation crosstalk mechanisms, expecting that indirect inhibition of HIF-1α by targeting metabolic enzymes, metabolites, or their signaling pathways will offer an effective therapeutic strategy to improve the cancer treatment outcomes.

This study aimed to investigate the molecular mechanism by which the Harmine derivative B-9-3 inhibits angiogenesis and promotes apoptosis in non-small cell lung cancer (NSCLC).

Three non-small cell lung cancer (NSCLC) models (human NSCLC cell line A549, human lung squamous cell carcinoma cell line H226, human large cell lung carcinoma cell line H460) were established. Cell proliferation was assessed using CCK-8 assays and colony formation assays. Cell motility was evaluated through scratch wound healing, invasion, and migration assays. Cell apoptosis was analyzed by Hoechst 33258 staining, AO/EB fluorescence staining, and flow cytometry. Real-time PCR was used to measure the mRNA expression of B-cell lymphoma/leukemia-2 (Bcl-2), Bcl-2-associated X protein (Bax), and Caspase-3, while Western blotting was performed to assess the protein levels of vascular endothelial growth factor A (VEGFA), phosphatidylinositol 3-kinases p110 Beta (PI3K), phospho-phosphatidylinositol 3-kinases (p-PI3K), protein kinase B (AKT), phosphorylated protein kinase B (p-AKT), Bax, Bcl-2, and Caspase-3.

Compared to the control group, B-9-3 (50, 100, 200 μg/mL) inhibited the growth and motility of the three types of lung cancer cells, suppressed cell invasion and migration, and promoted cell apoptosis and necrosis. The apoptosis rates in three types of non-small cell lung cancer (NSCLC) cells were significantly increased. The mRNA expressions of Bax and Caspase-3 were markedly upregulated, while that of Bcl-2 was significantly downregulated. Additionally, the protein levels of VEGFA, p-PI3K/PI3K, p-AKT/AKT, and Bcl-2 were notably reduced, whereas the protein levels of Bax and Caspase-3 were significantly elevated.

The harmine derivative B-9-3 may exert its anti-NSCLC effects by inhibiting angiogenesis and promoting lung cancer cell apoptosis via the VEGFA/PI3K/AKT signaling pathway.

Cancer therapy-related cardiovascular toxicity (CTR-CVT) poses a major challenge in managing cancer patients, contributing significantly to morbidity and mortality among survivors. CTR-CVT includes various cardiovascular issues, such as cardiomyopathy, myocardial ischemia, arrhythmias, and vascular dysfunction, which significantly impact patient prognosis and quality of life. Metabolic reprogramming, characterized by disruptions in glucose, lipid, and amino acid metabolism, represents a shared pathophysiological feature of cancer and cardiovascular diseases; however, the precise mechanisms underlying CTR-CVT remain inadequately understood. In recent years, strategies targeting metabolic pathways have shown promise in reducing cardiovascular risks while optimizing cancer treatment efficacy. This review systematically summarizes metabolic reprogramming characteristics in both cancer and cardiovascular diseases, analyzes how anticancer therapies induce cardiovascular toxicity through metabolic alterations, and explores emerging therapeutic strategies targeting metabolic dysregulation. By integrating current research advancements, this review aims to enhance the understanding of CTR-CVT and provide groundwork for the development of safer and more effective cancer approaches.

Phosphoinositide 3-kinases (PI3Ks) signaling represents an important pathway regulating cell proliferation, survival, invasion, migration, and metabolism. Notably, PI3K/AKT/mTOR signaling is frequently dysregulated in the majority of malignancies. Among the class IA PI3Ks (PI3Kα/β/δ), emerging evidence has implicated that PI3Kδ is not only overexpressed in leukocytes but also in solid tumors, including prostate cancer. The critical role of PI3Kδ in tumorigenesis and in the creation of a suppressive tumor microenvironment, along with the recent finding of PI3Kδ splice isoforms in promoting tumor aggressiveness and resistance, further demonstrates the potential of developing novel PI3Kδ-targeted cancer therapies. In this review, we comprehensively describe the functional mechanisms underlying the PI3Kδ-driven tumor progression and immune regulation in prostate cancer diseases. Furthermore, the recent preclinical and clinical studies on the development of PI3Kδ-/PI3K-targeted inhibitors as single agents and in combination therapies (with chemotherapy, radiation, hormone therapy, or immunotherapy) are summarized. Finally, we discuss the potential novel therapies for improving the treatment efficacies, as well as the current limitations and challenges of PI3Kδ-based therapies for prostate cancer.

Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors of head and neck with high incidence and poor prognosis. Curcumin, as a drug-food congener, has a broad spectrum of anticancer effects, and based on this property, we further focused on EF24, a small molecule compound using curcumin as a backbone, to study the effects of both in OSCC.

Cell experiments were performed to test the inhibitory effect of curcumin and EF24 on OSCC cells. The potential mechanism was further analyzed by transcriptome sequencing, and the DEGs after drug treatment were determined. PPI networks were created using Cytoscape software.

Both curcumin and EF24 inhibit the viability, migration, and invasion, and induce apoptosis of OSCC cells and the IC50 of EF24 was much lower than that of curcumin. Analysis of DEGs identified 893 DEGs following curcumin treatment, of which 794 were up-regulated and 99 were down-regulated; 797 DEGs following EF24 treatment were identified, of which 665 were up-regulated and 132 were down-regulated. Curcumin and EF24 were found to down-regulate lipid metabolism by key enzymes that regulate fatty acid and cholesterol synthesis. Furthermore, the number of T cell CD4 + memory is up-regulated and the immune response is enhanced.

It is suggested that curcumin and EF24 inhibit the metabolic reprogramming of tumor cells and at the same time regulate TME, and improve the immunotherapy of tumors, which opens the way for the future treatment of OSCC with this approach alone or in conjunction with immune-checkpoint blocking.

Hypertrophic scar (HTS) is a prevalent chronic inflammatory skin disorder characterized by abnormal proliferation and extracellular matrix deposition. N-Myc downstream regulated gene 2 (Ndrg2) is a cell stress response gene related to cell proliferation, differentiation and various fibrotic diseases. However, the role of Ndrg2 in HTS is unknown and warrants further investigation. In this study, we confirmed that the expression of Ndrg2 was increased in HTS of human and a bleomycin-induced fibrosis mouse model. We then used Ndrg2 knockout mice and found Ndrg2 deletion could significantly reduce the synthesis of collagen and alleviate skin fibrosis. In addition, the proliferation and migration of Ndrg2-interfered HTS-derived fibroblasts decreased and those of Ndrg2-overexpressed normal skin-derived fibroblasts increased. Further, by western blot analysis, we verified that the expression of phosphorylated-PI3K, PI3K, phosphorylated-AKT and AKT were all increased after Ndrg2 overexpressed in normal skin-derived fibroblasts. Moreover, PI3K inhibitor (LY294002) administration significantly rescued the effect of Ndrg2 overexpression on skin fibrosis. In summary, our results demonstrated that Ndrg2 could promote HTS fibrosis by mediating PI3K/AKT signaling pathway. Our data suggest that Ndrg2 may be a promising therapeutic target for HTS.

Sepsis-induced inflammatory lung injury includes acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). There are currently no effective treatments for ALI/ARDS, but clinical outcomes could be improved by inhibiting lung injury and/or promoting post-sepsis vascular repair. In this review, we describe studies of endothelial cell metabolic pathways in sepsis-induced ALI/ARDS and vascular repair and identify areas of research that deserve attention in future studies. We also describe studies of metabolic interventions that aim to inhibit ALI/ARDS and/or promote post-sepsis vascular repair, including those that target endothelial cell metabolites, endothelial cell metabolic signaling pathways, and endothelial cell metabolism.

Endothelial cells are integral to both the injury and repair phases of ALI/ARDS. During the injury phase of ALI/ARDS, lung endothelial cell survival decreases, and lung endothelial cell-to-endothelial cell (EC-EC) junctions are weakened. During the repair phase after sepsis-induced lung injury, lung endothelial cell proliferation and lung EC-EC junction reannealing occur. These crucial aspects of ALI/ARDS and post-sepsis vascular repair, that is, endothelial cell viability, growth, and junction integrity, are controlled by a myriad of metabolites and metabolic signaling pathways in endothelial cells.

Metabolic signaling pathways in endothelial cells represent a novel class of putative targets for the prevention and treatment of sepsis-induced inflammatory lung injury. Therapies that target metabolic signaling in endothelial cells are currently being explored as potential treatments for sepsis-induced inflammatory lung injury.