This review was written to be included in the Special Collection 'Therapy Ultrasound: Medicine's Swiss Army Knife?' The purpose of this review is to provide basic presentation and interpretation of the fundamentals of hyperthermia biology, as it pertains to uses of therapeutic ultrasound. The fundamentals are presented but in the setting of a translational interpretation and a view toward the future. Subjects that require future research and development are highlighted. The effects of hyperthermia are time and temperature dependent. Because intra-tumoral temperatures are non-uniform in tumors, one has to account for differential biologic effects in different parts of a tumor that occur simultaneously during and after hyperthermia.

Cancer stem cells (CSCs) represent a distinct subpopulation of cancer cells that orchestrate cancer initiation, progression, metastasis, and therapeutic resistance. Despite advances in conventional therapies, the persistence of CSCs remains a major obstacle to achieving cancer eradication. Nanomedicine-based approaches have emerged for precise CSC targeting and elimination, offering unique advantages in overcoming the limitations of traditional treatments. This review systematically analyzes recent developments in nanomedicine for CSC-targeted therapy, emphasizing innovative nanomaterial designs addressing CSC-specific challenges. We first provide a detailed examination of CSC biology, focusing on their surface markers, signaling networks, microenvironmental interactions, and metabolic signatures. On this basis, we critically evaluate cutting-edge nanomaterial engineering designed to exploit these CSC traits, including stimuli-responsive nanodrugs, nanocarriers for drug delivery, and multifunctional nanoplatforms capable of generating localized hyperthermia or reactive oxygen species. These sophisticated nanotherapeutic approaches enhance selectivity and efficacy in CSC elimination, potentially circumventing drug resistance and cancer recurrence. Finally, we present an in-depth analysis of current challenges in translating nanomedicine-based CSC-targeted therapies from bench to bedside, offering critical insights into future research directions and clinical implementation. This review aims to provide a comprehensive framework for understanding the intersection of nanomedicine and CSC biology, contributing to more effective cancer treatment modalities.

Hypoxia is generally considered the major cause of renal tubular injury. The interaction between sirtuin 1 (SIRT1) and hypoxia inducible factor 1 subunit alpha (HIF-1α) is a key mediator of hypoxia-induced renal tubular damage. In this study, we identified morusin from a screen of SIRT1 inducers and reported its potential for the treatment of diabetic kidney disease (DKD).

Intraperitoneal injection of morusin in db/db and STZ-induced diabetic mice was assessed for its effect on tubulointerstitial damage. The expression and acetylation level of HIF-1α were analyzed by immunoblotting or immunostaining. The effects of morusin treatment on hypoxia-induced extracellular matrix (ECM) accumulation, apoptosis and IL-16 production in HK2 cells were evaluated by immunoblotting. Luciferase reporter gene and ChIP analysis was used to determine whether IL-16 was the target genes of HIF-1α.

In db/db and STZ-induced mice, morusin treatment alleviated kidney injury and inhibited renal inflammation and fibrosis. Mechanistic analysis using animal models and HK2 cells revealed that morusin treatment upregulated SIRT1 expression by enhancing its stability, and reduced the expression and acetylation levels of HIF-1α as well as expression of its regulated genes, thereby inhibiting ECM accumulation, apoptosis and IL-16 production. Furthermore, morusin decreased expression of the IL-16 through inhibited HIF-1α binding to the IL-16 promoter.

Our study is the first to demonstrate that morusin ameliorated tubulointerstitial damage in diabetic mice by regulating SIRT1/HIF-1α/IL-16 signaling pathway. Taken together, our findings suggest that morusin is a clinical candidate compound to prevent DKD.

Therapeutic resistance poses a significant challenge in treating most cancers and often leads to poor clinical outcomes and even treatment failure. One of the primary mechanisms that confer multidrug resistance phenotype to cancer cells is the hyperactivity of certain drug efflux transporters. P-GP, MRP1, and BCRP are the key ABC efflux pumps that collectively extrude a broad spectrum of chemotherapeutic drugs. Besides, HIF1A, a master transcription regulatory protein, is also associated with cancer development and therapeutic resistance. Thereby, this study aimed to delve into the mechanisms of drug resistance, specifically focusing on HIF1A-driven overexpression of ABC transporters. A total of 57 chemoresistant and 57 paired control tissue samples (breast, colorectal, and ovarian) from Bangladeshi cancer patients were analyzed to determine the co-expression level of ABC transporters and HIF1A. Molecular docking was also conducted to evaluate the interactions of HIF1A protein and hypoxia response element (HRE) sequences in the promoter regions transporter genes. This study revealed that HIF1A is significantly overexpressed in chemoresistant tissues, suggesting its pivotal role in chemoresistance mechanisms across malignancies and its potential as a target to overcome therapeutic resistance. The findings from this study also suggest a direct upregulation of ABCB1, ABCC1, and ABCG2 transcription by HIF1A in chemoresistant cancer cells by binding to the HRE sequence in the promoter regions. Thus, inhibition of these interactions of HIF1A appears to be a promising approach to reverse chemoresistance. The findings of this study can serve as a foundation for future research, resolving molecular intricacies to improve treatment outcomes in chemoresistant patients.

In 2020, sepsis has been defined a worldwide health major issue (World Health Organization). Lung, urinary tract and abdominal cavity are the preferred sites of sepsis-linked infection. Research has highlighted that the advancement of sepsis is not only related to the presence of inflammation or microbial or host pattern recognition. Clinicians and researchers now recognized that a severe immunosuppression is also a common feature found in patients with sepsis, increasing the susceptibility to secondary infections. Lipopolysaccharides (LPS) are expressed on the cell surface of Gram-negative, whereas Gram-positive bacteria express peptidoglycan (PGN) and lipoteichoic acid (LTA). The main mechanism by which LPS trigger host innate immune responses is binding to TLR4-MD2 (toll-like receptor4-myeloid differentiation factor 2), whereas, PGN and LTA are exogenous ligands of TLR2. Nucleotide-binding oligomerization domain (NOD)-like receptors are the most well-characterized cytosolic pattern recognition receptors, which bind microbial molecules, endogenous by-products and environmental triggers. It has been demonstrated that high-density lipoproteins (HDL), besides their major role in promoting cholesterol efflux, possess diverse pleiotropic properties, ranging from a modulation of the immune system to anti-inflammatory, anti-apoptotic, and anti-oxidant functions. In addition, HDL are able at i) binding LPS, preventing the activating of TLR4, and ii) inducing the expression of ATF3 (Activating transcription factor 3), a negative regulator of the TLR signalling pathways, contributing at justifying their capacity to hamper infection-based illnesses. Therefore, reconstituted HDL (rHDL), constituted by apolipoprotein A-I/apolipoprotein A-IMilano complexed with phospholipids, may be considered as a new therapeutic tool for the management of sepsis.

The combination of ascorbate (vitamin C) and menadione sodium bisulfite (MSB, vitamin K3), here called VC/VK3 (also named Apatone®, or M/A), has shown selective cytotoxicity in cancer cells and is under clinical investigation as a cancer therapy. However, the mechanisms of VC/VK3-induced cell death are not fully understood. In this in vitro study using human glioblastoma and non-transformed glial cell lines, we found that VC/VK3 caused higher toxicity in cancer cells in an H2O2- and iron-dependent manner, suggesting that ferroptosis may play a role in the cell death process. Furthermore, selenium supplementation significantly protected cancer cells from VC/VK3 treatment concomitantly with enhanced expression levels and enzymatic activity of antioxidant selenoproteins, including thioredoxin reductases (TXNRDs) and glutathione reductases (GPXs). We also found that VC/VK3 competes for electrons with thioredoxin (TXN), impairing peroxiredoxin 1 (PRDX1) in cells. Finally, chemically inhibiting TXNRDs or the glutathione-dependent antioxidant systems exaggerated the toxicity of VC/VK3. Overall, this study elucidated parts of the cell death mechanisms of VC/VK3 and identified combination strategies to overcome selenium-mediated resistance, advancing the translational potential of this prooxidant treatment.

Hypoxia contributes to tumor progression, promoting cancer cell motility, invasion and metastasis. Lysophosphatidic acid (LPA) receptors are implicated in the pathogenesis of cancer. In this study, we investigated the role of LPA receptor signaling in modulating malignant behavior under hypoxic conditions (1 % O2) in lung cancer cells. We generated highly migratory A549-R12 cells from the parental lung cancer A549 cells for this purpose. LPAR1 and LPAR2 expression levels were lower in both A549 and A549-R12 cells cultured at 1 % O2 compared to those cultured at 21 % O2, while LPAR3 expression remained unchanged between the two cell lines. Cell motility increased in both A549 and A549-R12 cells cultured at 1 % O2. Notably, A549-R12 cells exhibited greater motility under 1 % O2 conditions than A549 cells. Treatment with AM966 (an LPA1 antagonist) and (2S)-OMPT (an LPA3 agonist) further increased the motility of A549-R12 cells, while GRI-977143 (an LPA2 agonist) decreased their motility. Moreover, the invasion activity of A549-R12 cells was higher than that of A549 cells, with 1 % O2 conditions significantly enhancing A549-R12 cell invasion. AM966 and (2S)-OMPT stimulated, whereas GRI-977143 inhibited, the invasion of A549-R12 cells. In the presence of LPA, cell viability to cisplatin (CDDP) was higher in A549-R12 cells cultured at both 21 % and 1 % O2 compared to A549 cells. These results suggest that LPA receptor signaling plays a key role in regulating malignant progression in highly migratory lung cancer cells under hypoxic conditions.

Ferroptosis is a novel type of programmed cell death associated with lung injury induced by chronic intermittent hypoxia (CIH). 2-Methoxyestradiol (2-ME2), as an inhibitor of Hypoxia-inducible factor 1 alpha (HIF-1α), affects HIF-1α-related biological processes. This study aimed to explore the role and mechanism of 2-ME2 on CIH-induced lung injury. CIH-associated lung injury was verified in SD rats. 2-ME2 was administered intraperitoneally at a dosage of 20 mg/kg to verify its treatment efficacy. CIH treated Human bronchoalveolar epithelial cells (BEAS-2B) were used to explore the mechanism of 2-ME2. HIF-1α knockdown cell lines and SLC7A11-overexpressing cell lines were established to explore the role of HIF-1α/SLC7A11 pathway in CIH-induced ferroptosis. The ChIP-qPCR was employed to determine the presence of binding sites between HIF-1α and the SLC7A11 promoter region. In vivo experiments demonstrated that, in comparison with the control group, there was an increase in lung injury scores and collagen ratio in the lung tissue of rats belonging to the CIH group, along with an upregulation of HIF-1α expression and alterations in the expression of ferroptosis-related genes (all p < 0.05). 2-ME2 mitigated the lung injury and ferroptosis induced by CIH in vivo. In vitro experiments revealed that, compared to BEAS-2B cells under normoxic conditions, HIF-1α expression increased significantly in BEAS-2B cells exposed to CIH. This was accompanied by alterations in the expression of ferroptosis-related genes (all p < 0.05) and an increase in both reactive oxygen species (ROS) and Fe2+ levels (both p < 0.05). HIF-1α knockdown, or SLC7A11 overexpression, reversed CIH-induced BEAS-2B cell ferroptosis. ChIP-qPCR confirmed the direct interaction between HIF-1α and SLC7A11 promoter region. The HIF-1α inhibitor, 2-ME2, effectively reverses CIH-induced lung tissue ferroptosis. The potential mechanism of 2-ME2 in inhibiting ferroptosis may involve suppressing the HIF-1α/SLC7A11 pathway.

Mosquito bites are prevalent occurrences among various populations worldwide, mosquito repellent chemical components (MRCCs) have been extensively utilized. MRCCs have been frequently identified in environmental settings nowadays. However, the implications of these compounds on skin conditions, particularly Atopic Dermatitis (AD), are not well understood. In this investigation, we analyzed three commercially available MRCCs: DEET (N,N-diethyl-3-methylbenzamide), IR3535 (ethyl butylacetylaminopropionate), and picaridin (2-(2-hydroxyethyl)-piperidinecarboxylic acid 1-methyl ester). A comprehensive analysis was conducted utilizing various databases to identify potential targets associated with exposure to these MRCCs and their correlation with AD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed that exposure to these MRCCs influences inflammation-related pathways. Additionally, molecular docking studies indicated significant binding affinities of DEET, IR3535, and picaridin to critical core targets and receptor proteins. Furthermore, a series of cellular assays were conducted to empirically evaluate the actual effects of these three MRCCs on the induction of AD. The results suggest that MRCCs may facilitate the progression of AD by influencing inflammatory processes. This study provides a conceptual framework for understanding the association between MRCCs and the risk of AD, thereby contributing to the formulation of strategies aimed at mitigating their effects on dermatological disorders.

Tuning protein expression by targeting RNA structure using small molecules is an unexplored avenue for cancer treatment. To understand whether this vulnerability could be therapeutically targeted in the most lethal form of prostate cancer, castration-resistant prostate cancer (CRPC), we use a clinical small molecule, zotatifin, that targets the RNA helicase and translation factor eukaryotic initiation factor 4A (eIF4A). Zotatifin represses tumorigenesis in patient-derived and xenograft models and prolonged survival in vivo alongside hormone therapy. Genome-wide transcriptome, translatome, and proteomic analysis reveals two important translational targets: androgen receptor (AR), a key oncogene in CRPC, and hypoxia-inducible factor 1A (HIF1A), an essential cancer modulator in hypoxia. We solve the structure of the 5' UTRs of these oncogenic mRNAs and strikingly observe complex structural remodeling of these select mRNAs by this small molecule. Remarkably, tumors treated with zotatifin become more sensitive to anti-androgen therapy and radiotherapy. Therefore, "translatome therapy" provides additional strategies to treat the deadliest cancers.

Hypoxia-inducible factor-1α (HIF-1α) has become a significant therapeutic target for breast cancer and other cancers by regulating the expression of downstream genes such as erythropoietin, thereby improving cell survival in hypoxic conditions.

We jointly applied a multistage screening system encompassing machine learning, molecular docking, and molecular dynamics simulations to conduct virtual screening of the "Traditional Chinese Medicine Monomer Library" for potential HIF-1α inhibitors. The virtual screening was conducted in three sequential stages, applying the following selection criteria sequentially: an activity prediction score greater than or equal to 0.8, a stronger binding affinity, and an MM-PBSA binding free energy lower than the reference compound.

We retrieved 361 compounds with HIF-1α inhibitory activity data from the ChEMBL database for the construction and evaluation of machine learning models. Among the six constructed models, the random forest model based on RDKit molecular descriptor with the optimal comprehensive performance was employed for virtual screening. Ultimately, four compounds were selected for binding mode analyses and 100 ns molecular dynamics simulations. The results showed that the compounds Arnidiol and Epifriedelanol exhibit the most stable interactions with the HIF-1α protein, which can serve as potential HIF-1α inhibitors for future investigations.

Chaihu-Danggui Tang (CHDGT) has a long history in traditional Chinese medicine (TCM) as an adjuvant therapy for breast cancer (BC), but its precise anti-tumor mechanisms remain unknown. In this study, we used network pharmacology, molecular docking, and experimental validation methods to investigate the core components, key targets, and possible mechanisms through which CHDGT may exert therapeutic effects in BC treatment.

The Traditional Chinese Medicine Systems Pharmacology (TCMSP) was employed to obtain the active ingredient and targets of CHDGT. Meanwhile, the GeneCards databases were used to retrieve pertinent targets for BC. The Venn plot was used to obtain intersection targets. Cytoscape software was used to construct an "CHDGT-active ingredients-targets" network and identify core targets. The common targets after STRING processing were imported into the Metascape database for GO and KEGG pathway enrichment analysis. Molecular docking of key ingredients and core targets of drugs was accomplished using Autodock and PyMol software. The cell and animal experiments confirmed CHDGT efficacy and mechanism in treating BC.

We screened 5 key effector components, 8 core targets, and multiple signaling pathways of CHDGT in treating BC. In vitro, the results of CCK-8 assay showed that CHDGT can dose-dependently inhibits BC cell growth, and at 100 mg L-1 after 48 hours, the cell inhibition rate reached approximately 50%. Further analysis showed that CHDGT can promote apoptosis of BC cell, and regulate the expression levels of apoptosis-related genes, such as Caspase3, p53, and Bcl-2. The animal experiments verified that CHDGT can significantly inhibit the progression of BC, the tumor inhibition rate of CHDGT-H groups was as high as 60.06 ± 4.82%. In addition, H&E staining and blood biochemical analysis suggest that CHDGT exhibits favorable safety.

This study may provide perspectives for the development of anticancer Chinese herbs for the treatment of BC.

Pathologic implications of dysregulated pulmonary vascular metabolism to pulmonary arterial hypertension (PAH) are increasingly recognized, but their clinical applications have been limited. We hypothesized that metabolite quantification across the pulmonary vascular bed in connective tissue disease-associated (CTD-associated) PAH would identify transpulmonary gradients of pathobiologically relevant metabolites, in an exercise stage-specific manner. Sixty-three CTD patients with established or suspected PAH underwent exercise right heart catheterization. Using mass spectrometry-based metabolomics, metabolites were quantified in plasma samples simultaneously collected from the pulmonary and radial arteries at baseline and during resistance-free wheeling, peak exercise, and recovery. We identified uptake and excretion of metabolites across the pulmonary vascular bed, unique and distinct from single vascular site analysis. We demonstrated the physiological relevance of metabolites previously shown to promote disease in animal models and end-stage human lung tissues, including acylcarnitines, glycolytic intermediates, and tryptophan catabolites. Notably, pulmonary vascular metabolite handling was exercise stage specific. Transpulmonary metabolite gradients correlated with hemodynamic endpoints largely during free-wheeling. Glycolytic intermediates demonstrated physiologic significance at peak exercise, including net uptake of lactate in those with more advanced disease. Contribution of pulmonary vascular metabolism to CTD-PAH pathogenesis and therapeutic candidacy of metabolism modulation must be considered in the context of physiologic stress.

The traditional action of Rabdosia rubescens (Hemsl.) H. Hara is heat-clearing and detoxifying, relieve sore throat, dissipate binds and disperse swelling. DLC, as an extract prepared from Rabdosiae Rubescentis Herba, could regulate the polarization of tumor associated macrophages (TAMs). For TAMs play an important role in the tumor microenvironment. It is worthy to further explore the mechanism of DLC on the polarized function of macrophages.

The aim of this study is to investigate the activity and molecular mechanisms of DLC on dissipating binds and dispersing swelling by modulating the gastric cancer microenvironment and macrophage polarization.

We conducted comprehensive qualitative and quantitative chromatographic analyses to characterize the main components of DLC. To evaluate its anti-tumor effects, immunofluorescence, MTT assay, plate cloning, transcriptomics analysis, western blotting, and siRNA knockdown experiments were performed to assess DLC's action on gastric cancer cell proliferation. Additionally, we utilized Trypan blue staining, a THP-1 and MGC-803 co-culture model, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and a mouse xenograft model with five distinct dosage groups to systematically investigate DLC's effects on macrophage polarization.

Key compounds in DLC were identified. The vivo tests demonstrated the tumor inhibition rate of the 5 g/kg DLC group reached 66.99 %, surpassing that of the 5-fluorouracil group (59.94 %). Mechanistically, DLC upregulated SIRT1 expression and suppressed NF-κB pathway, thereby preventing p65 from translocating into nuclear and modulating downstream p53/MDM2/USP7 signaling. Moreover, DLC enhanced M1 macrophage factors such as TNF-α, IL-6 while inhibiting M2 marker TGF-β, effectively repolarizing M2 TAMs toward an M1 phenotype. This effect was associated with suppressed protein expression of HIF-1α, p-p65, and p-PI3K.

This study provides insights into DLC's mechanisms in regulating tumor microenvironment remodeling and promoting macrophage polarization toward an anti-tumor phenotype. These results provide a solid basis for DLC's potential clinical treament in gastric cancer, highlighting its promise as a natural therapeutic agent.

In the tumor microenvironment (TME), hypoxia is critical in promoting tumor invasiveness and progression. Cobalt chloride (CoCl2) mimics hypoxia by inducing comparable cellular responses. Lysophosphatidic acid (LPA) receptors (LPA1 to LPA6) play key roles in regulating cancer cell functions. In this study, we investigated the impact of LPA receptor signaling on malignant properties of colon cancer DLD-1 cells under hypoxic condition induced by CoCl2. LPAR1 and LPAR2 expression levels were elevated in DLD-1 cells treated with CoCl2. CoCl2 treatment also stimulated DLD-1 cell motility. This enhanced motility induced by CoCl2 was reduced with LW6 (HIF-1 inhibitor). Additionally, the motility of CoCl2-treated DLD-1 cells was suppressed by AM966 (LPA1 antagonist) and enhanced by GRI-977143 (LPA2 agonist). Conversely, CoCl2 treatment decreased DLD-1 cell invasion. While AM966 further inhibited cell invasion, GRI-977143 elevated it. The cell viability to fluorouracil (5-FU) was higher in CoCl2-treated DLD-1 cells. This increased viability to 5-FU was further enhanced by both AM966 and GRI-977143. When CoCl2-treated DLD-1 cells were cultured in low-glucose media, LPAR1 expression was upregulated compared to high-glucose media, while LPAR2 expression was downregulated. Additionally, motility and invasion in CoCl2-treated DLD-1 cells were further stimulated under low-glucose conditions. These results suggest that LPA receptor signaling contributes to the malignant potential of DLD-1 cells in a hypoxic environment induced by CoCl2 treatment.

Glioblastoma Multiforme (GBM) is a highly malignant and diffusely invasive WHO Grade IV brain tumor arising from glial and neural stem cells. GBM is characterized by rapid proliferation and migration, aggressive invasion of local brain parenchyma, a hypoxic microenvironment, resistance to apoptosis and high vascular remodeling and angiogenesis. These hallmarks contribute to a near universal tumor recurrence after treatment or resection and poor patient prognosis. Ion channels, a superfamily of proteins responsible for permitting ion flux across otherwise impermeant membranes, show extensive remodeling in GBM with aberrant function mechanistically linked to manipulation of each of these hallmarks. In this review, we will discuss the known links between ion channel expression and activity and cellular processes that are enhanced or perturbed during GBM formation or progression. We will also discuss the extent to which basic or translational findings on ion channels in GBM samples or cell lines have shown preclinical promise towards the development of improved therapeutics against GBMs.

Hexavalent chromium [Cr (VI)] is a known environmental pollutant, which promotes tumorigenesis. Hypoxia-inducible factor-1α (HIF-1α) is crucial for cancer development. Here, we found that Cr (VI) treatment promoted lactate utilization by increasing monocarboxylate transporter 1 (MCT1) and monocarboxylate transporter 4 (MCT4) expression, while increasing the expression of HIF-1α in A549 cells but reducing HIF-1α and MCT1 in HELF cells. CoCl2, an HIF-1α inducer, increased MCT1, while the HIF-1α inhibitor YC-1 and MCT1 inhibitor AZD3965 suppressed Cr (VI)-induced lactate utilization and cell growth. Chromatin immunoprecipitation (ChIP) assay revealed HIF-1α bound to the MCT1 promoter to enhance its transcription. Using Reactivating p53 and Inducing Tumor Apoptosis (RITA), which can increase the protein level of p53, we discovered that the low level of p53 protein in A549 cells determined the effect of Cr (VI)-induced HIF-1α. These findings highlighted the role of p53 protein level in the effects of Cr (VI) on HIF-1α/MCT1 to induce lactate utilization and cell growth. Targeting the p53/HIF-1α/MCT1 pathway could inhibit Cr (VI)-mediated tumorigenesis.

Androgen deprivation therapy remains a cornerstone in managing prostate cancer. However, its recurrence often leads to the more aggressive castration-resistant prostate cancer (CRPC). Although second-line androgen receptor signaling inhibition treatments such as enzalutamide and abiraterone are available, their effectiveness against CRPC is only transient. High-dose testosterone (Hi-T) has recently emerged as a promising treatment for CRPC, primarily through the suppression of E2F and MYC signaling. However, the roles of Rb family proteins in influencing this therapeutic response remain debated. In this study, we utilized a CRPC patient-derived xenograft model that includes both Rb pathway-proficient and -deficient cell populations based on the positive or negative expression of RB family genes. Single-cell RNA sequencing analysis revealed that Rb-proficient cells displayed a robust response to Hi-T, whereas Rb-deficient cells exhibited significant resistance. Notably, our analysis indicated increased enrichment of the hypoxia signature in the Rb-deficient cell population. Further studies in RB1-silenced CRPC cell lines showed that treatment with a hypoxia-inducible factor-1α inhibitor can restore the sensitivity of Rb-deficient cells to high-dose dihydrotestosterone treatment. In conclusion, our research provides new molecular insights into CRPC tumor cell responses to Hi-T and proposes a new strategy to resensitize Rb-deficient CRPC cells to Hi-T treatment.

Draconis Sanguis (DS), a precious traditional Chinese medicine for activating blood and dissolving stasis, has been used in treating ischemic cardiovascular diseases. However, the underlying mechanism of DS against heart failure after myocardial ischemia (MI) remains unclear, especially concerning angiogenesis and energy metabolism, which have never been elucidated.

This study aimed to explore the protective mechanism of DS in ischemic heart failure (IHF) from the perspectives of angiogenesis and energy metabolism.

We investigated the effects of DS on an in vivo model of IHF induced by ligation of the left anterior descending coronary artery (LADCA) and an in vitro model of HUVECs injury induced by hypoxia. High-performance liquid chromatography (HPLC) was performed to identify components of DS. Echocardiography, histopathology, and cardiac enzymes analysis were used to examine the anti-ischemic heart failure effect of DS. Transcriptome sequencing, positron emission tomography (PET), HPLC, and chocardiography were performed on heart tissues to explore the underlying mechanism. Furthermore, the relevant targets were investigated by real-time quantitative PCR (RT-qPCR), Western blotting, immunohistochemistry, and immunofluorescence. Finally, potential pharmacodynamic substances were identified with a cell model and molecular docking.

The results showed DS increased survival of rats with IHF for 28 days by 10 %, significantly ameliorated cardiac function in rats with IHF, increased left ventricular ejection fraction by 20 %, and it reduced pathological changes and cardiac enzymes levels. These results indicated that DS alleviated myocardial ischaemia injury. The effects described above were related to the regulation of the HIF-1α/VEGF signallings pathway to promote angiogenesis in the ischemic myocardium, increase the local oxygen supply and optimize myocardial energy metabolism "promoting lipid and inhibiting glucose" and increasing local ATP production. Moreover, DS compounds were identified; these compounds protected HUVECs from hypoxia and glucose deprivation, significantly upregulated HIF-1α gene expression, and were shown to be related to this mechanism in vitro experiments.

DS ameliorates cardiac function by optimizing myocardial energy metabolism after promoting angiogenesis via HIF-1α/VEGF signalling pathway regulation.

Hypoxia in the tumor environment leads to an activation of genotypes that favors the tumor, promoting angiogenesis, epithelial-mesenchymal transition, cell invasion, and metastasis. It is considered a prognostic factor related to the progression and aggressiveness of Head and Neck Cancer (HNC). Hypoxia-inducible factor (HIF) is the main gene activated by hypoxia and has been associated with tumor advancement. Thus, this work aims to evaluate the performance of the compounds Acriflavine, Resveratrol, Topotecan, and RNA interference (siRNA) as HIF inhibitors as well as a therapeutic approach. Molecular docking results have suggested that the evaluated compounds present potential interactions with HIF-1α and HIF-2α. In vitro analysis, they demonstrated that treatments with Acriflavine and Topotecan caused a decrease in the gene expression of HIFs in the HN13 cell line (carcinoma of the oral cavity). Furthermore, treatments performed with siRNAs effectively inhibited gene expression of HIFs in HN13 and FaDu (carcinoma of the pharynx) cell lines. Considering the role of hypoxia and HIFs in tumor aggressiveness; the present study shows the potential of the evaluated compounds as a therapeutic use for the prevention of tumor progression in head and neck cancer.

Beta cell replacement therapy via pancreatic islet transplantation offers a promising treatment for type 1 diabetes as an alternative to insulin injections. However, posttransplantation oxygenation remains a critical challenge; isolated islets from donors lose vascularity and rely on slow oxygen diffusion for survival until revascularization occurs in the host tissue. This often results in significant hypoxia-induced acute graft loss. Overcoming the oxygenation barrier is crucial for advancing islet transplantation. This review is structured in three sections: the first examines oxygen dynamics in islet transplantation, focusing on factors affecting oxygen supply, including vascularity. It highlights oxygen dynamics specific to both transplant sites and islet grafts, with particular attention to extrahepatic sites such as subcutaneous tissue. The second section explores current oxygen delivery strategies, categorized into two main approaches: augmenting oxygen supply and enhancing effective oxygen solubility. The final section addresses key challenges, such as the lack of a clearly defined oxygen threshold for islet survival and the limited precision in measuring oxygen levels within small islet constructs. Recent advancements addressing these challenges are introduced. By deepening the understanding of oxygen dynamics and identifying current obstacles, this review aims to guide the development of innovative strategies for future research and clinical applications. These advancements are anticipated to enhance transplantation outcomes and bring us closer to a cure for type 1 diabetes.

Rectal cancer surgery is challenging due to the complex anatomy, making it difficult to achieve clear surgical margins. Radiotherapy (RT) plays a crucial role, especially in treating locally recurrent rectal cancer and preserving anal function. However, its effectiveness is often limited by tumor hypoxia, particularly prevalent in hypoxic regions near the bowel wall in colorectal cancer. Hypoxia contributes to both radiation resistance and apoptosis resistance, compromising RT outcomes. To overcome hypoxia-driven radiotherapy resistance, this work designs and engineers a radiotherapy-sensitizing bioplatform for efficient cancer RT. It combines lanthanum oxide nanoparticles (La2O3 NPs) with cyanobacteria, which produces oxygen through photosynthesis. This bioplatform uniquely reduces tumor hypoxia, enhances radiation deposition, and improves RT efficacy. La2O3 NPs further enhance reactive oxygen species (ROS) production induced by radiation, triggering pyroptosis via the ROS-NLRP3-GSDMD pathway, while RT amplifies pyroptosis through GSDME, circumventing tumor apoptosis resistance. The further integrated thermosensitive hydrogels ensure precise localization of the bioplatform, reducing systemic toxicity and improving therapeutic specificity. Compared to conventional therapies, this dual-action system addresses hypoxia, RT resistance, and apoptosis resistance more effectively. In vivo and in vitro hypoxia models validate its potent anti-tumor efficacy, offering valuable insights for refining clinical treatment paradigms.

This study aimed to investigate the association between tumor hypoxia, assessed through anti-HIF (hypoxia-inducible factor) staining, and aggressiveness in prostate cancer using a pharmacokinetic model, particularly those derived from the Tofts model, in predicting tumor aggressiveness.

From January 2019 to April 2021, we conducted a retrospective search of patients with confirmed prostate cancer and a previous magnetic resonance imaging (MRI) examination. After exclusions, a total of 57 consecutive patients were enrolled. Patient data, including demographic, laboratory, and pathologic variables, were collected. MRI acquisition followed PI-RADS guidelines, encompassing T2-weighted, diffusion-weighted imaging, and dynamic contrast-enhanced imaging. An experienced abdominal radiologist conducted both morphologic and quantitative MRI analyses, evaluating parameters such as lesion size, apparent diffusion coefficient values, and the Tofts pharmacokinetics (TF) model. The histopathologic analysis included the International Society of Uropathology (ISUP) score and hypoxia marker immunohistochemistry.

There were no significant demographic and imaging differences between hypoxic and nonhypoxic tumors, except for elevated prostate-specific antigen levels in the latter and decreased normalized apparent diffusion coefficient in the former. Morphologic assessments revealed larger lesions in the hypoxia group. While Ktrans showed a positive association with hypoxia, it did not independently predict high-risk lesions.

Our results suggest that pharmacokinetic analysis by the Tofts model was associated with tumors with hypoxia. However, this parameter was not an independent predictor of more aggressive tumors. Further studies, with a larger number of patients, multi-institutional and prospective, are needed to verify this possible association.

Hypoxia-induced metabolic reprogramming is closely linked to breast cancer progression. Through transcriptomic analysis, we identified PRMT1 as a direct target of hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions in breast cancer cells. In turn, PRMT1 enhances the expression of HIF1α-driven glycolytic genes. Mechanistically, PRMT1 methylates HIF2β at arginine 42, facilitating the formation, chromatin binding, and the transcriptional activity of the HIF1α/HIF2β heterodimer. Genetic and pharmacological inhibition of PRMT1 suppresses HIF2β methylation, HIF1α/HIF2β heterodimer formation, chromatin binding, glycolytic gene expression, lactate production, and the malignant behaviors of breast cancer cells. Moreover, combination treatment with iPRMT1, a PRMT1 inhibitor, and menadione, an HIF1α/P300 interaction inhibitor, demonstrates synergistic effects in suppressing breast tumor growth. Clinically, PRMT1 and PRMT1-mediated HIF2β methylation were significantly elevated in breast tumors compared with adjacent normal tissues. In conclusion, our findings reveal the critical role of PRMT1-mediated arginine methylation in glycolytic gene expression, metabolic reprogramming, and breast tumor growth.

Aggressive solid tumors are associated with rapid growth, early hypoxia, a lack of targeted therapies, and a poor prognosis. The hypoxic niches within the rapidly growing solid tumors give rise to a stem-cell-like phenotype with higher metastasis and drug resistance. To overcome the drug resistance of these regions, we used hypoxia-responsive polymersomes with an encapsulated anticancer drug (doxorubicin, Dox) and a stemness modulator (all-trans retinoic acid, ATRA). Reductase enzymes overexpressed in hypoxia reduce the azobenzene linker of the polymers, disrupt the bilayer structure of the polymersomes, and release the encapsulated drugs. We used triple-negative breast cancer (TNBC) as a representative of aggressive and hypoxic solid tumors. We observed that ATRA synergistically enhanced the efficacy of Dox in killing cancer cells. A synergistic combination of the two drug-encapsulated polymersomes reduced the volumes of patient-derived TNBC spheroids by 90%. In contrast, Dox alone decreased the spheroid volumes by 70% and encapsulated ATRA by 19%. Mechanistic studies revealed that ATRA inhibited efflux pumps, leading to a higher concentration of doxorubicin within TNBC cells. In addition, the combination of encapsulated Dox and ATRA significantly decreased stemness expression of the TNBC cells in hypoxia compared to that of Dox alone.

Osteosarcoma (OS) remains a challenging malignancy with poor prognosis, especially in metastatic or recurrent cases. Despite progress, the molecular mechanisms driving OS, particularly the regulation of autophagy, are not fully understood. Here, through integrated analysis of single-cell and transcriptomic data, we identify a novel long non-coding RNA (lncRNA), OLMALINC, as a critical autophagy regulator in OS. OLMALINC is significantly upregulated in OS tissues, with its expression correlating to poor clinical outcomes. Functional studies show that altering OLMALINC expression impacts OS cell progression and autophagy. Mechanistically, transcriptome analysis and RNA immunoprecipitation reveal Ubiquitin-Specific Peptidase 1 (USP1) as a direct downstream target of OLMALINC. The OLMALINC-USP1 axis inhibits autophagy and activates the hypoxia-inducible factor 1 (HIF-1α) pathway, promoting OS progression. Therapeutically, combining the USP1 inhibitor ML-323 with doxorubicin demonstrated synergistic anti-tumor effects in vitro and in vivo, enhancing autophagy and apoptosis while inhibiting tumor growth. These findings uncover a novel OLMALINC-USP1-HIF-1α axis in OS progression and highlight the potential of combining autophagy modulation with chemotherapy for improved therapeutic outcomes.

Fumarate is a key metabolite produced primarily by the tricarboxylic acid (TCA) and urea cycles. In addition to having a metabolic role, its electrophilicity enables it to covalently modify cysteines; moreover, because of its α-ketoglutarate (α-KG)-like structure, it can also act as a competitive inhibitor of α-KG-dependent dioxygenases for epigenetic remodeling. Recent advances have broadened the role of fumarate as a bridge between metabolism and both innate and adaptive immunity, suggesting potentially important functions in anticancer immunity and autoimmune diseases. Here we review the connections between fumarate metabolism and immunity; we describe the mechanisms of fumarate regulation in cancer, autoimmunity, and other diseases; and we explore the clinical implications of fumarate and its esters for immunotherapy.

Potassium channel tetramerization domain-containing 1 (KCTD1) plays a critical role in transcriptional regulation and adipogenesis, but its significance in hepatocellular cancer (HCC) has not been reported.

Immunohistochemistry, Western blotting and quantitative real-time PCR analysis were performed to assess the expression of KCTD1 and related genes in HCC cells. MTT assays, colony formation, cell migration, invasion and the in-vivo mouse models were utilized to evaluate the function of KCTD1 in HCC progression. Co-immunoprecipitation, chromatin immunoprecipitation and luciferase reporter assays were conducted to elucidate the molecular mechanisms of KCTD1 in HCC.

KCTD1 expression was increased in human HCC tissues and closely associated with advanced tumor stages. KCTD1 overexpression enhanced growth, migration, and invasion of Huh7 and HepG2 cells both in vitro and in vivo, while KCTD1 knockdown reversed these effects in MHCC97H cells. Mechanistically, KCTD1 interacted with hypoxia-inducible factor 1 alpha (HIF-1α) and enhanced HIF-1α protein stability with the inhibited prolyl-hydroxylases (PHD)/Von Hippel-Lindau (VHL) pathway, consequently activating the Vascular Endothelial Growth Factor (VEGF)/VEGFR2 pathway in HCC cells. Sorafenib and KCTD1 knockdown synergistically inhibited intrahepatic tumor growth following in situ injection of MHCC97H cells. miR-129-5p downregulated KCTD1 by binding to KCTD1 3'UTR. Finally, 45 µg exosomes from miR-129-5p-overexpressing MHCC97H cells combined with 25 mg/kg sorafenib to decrease HCC tumor size.

These results suggested that KCTD1 protects HIF-1α from degradation and activates the VEGF signaling cascade to enhance HCC progression. Therefore, KCTD1 may serve as a novel target of HCC and pave the way for an efficient combined therapy in advanced HCC.

Hypoxia in solid tumors, including head and neck cancer (HNC), contributes to treatment resistance, aggressive tumor phenotypes, and poorer clinical outcomes. Perfluorocarbon nanodroplets have emerged as promising drugs to alleviate tumor hypoxia. These versatile nanocarriers can also encapsulate and deliver various therapeutic agents, offering a multifunctional approach to cancer treatment. However, a detailed characterization of hypoxia alleviation, particularly the duration of hypoxia treatment drug residence, has not been thoroughly investigated. In this study, we developed and characterized perfluoropentane nanodroplets (PFP NDs) for the codelivery of oxygen and the photoactivatable drug benzoporphyrin derivative (BPD) to hypoxic HNC spheroids. The PFP NDs exhibited excellent stability, efficient oxygen loading/release, and biocompatibility. Using 3D multicellular tumor spheroids of FaDu and SCC9 HNC cells, we investigated the spatiotemporal dynamics of hypoxia within these spheroids and the ability of oxygenated PFP NDs to alleviate hypoxia. Our results showed that oxygen-loaded PFP NDs effectively penetrated the core of tumor spheroids, significantly reducing hypoxia, as evidenced by the downregulation of hypoxia-inducible factors HIF-1α and HIF-2α. Importantly, we demonstrated sustained hypoxia alleviation for up to 3 h post-treatment with PFP NDs. BPD-loaded PFP NDs successfully delivered the photosensitizer into the spheroid core in a time-dependent manner. Furthermore, we evaluated the efficacy of oxygen-dependent treatment modality, namely, photodynamic therapy (PDT) with BPD and oxygen-loaded PFP NDs compared to free BPD. The NDs formulation exhibited superior PDT outcomes, which were attributed to improved oxygen availability during the treatment. This study provides comprehensive evidence for the potential of PFP NDs as a codelivery platform to overcome hypoxia-mediated treatment resistance and enhance PDT efficacy in HNC. Our findings pave the way for further investigation of this promising approach in more complex in vivo models, potentially leading to improved therapeutic strategies for hypoxic solid tumors.

The decidual endometrial stromal cells play a critical role in the establishment of uterine receptivity and pregnancy in human. Our previous studies demonstrate that protein tyrosine phosphatase 2 SHP2 is highly expressed in decidualized cells and governs the decidualization progress. However, the role and mechanism of SHP2 in the function of decidual cells remain unclear. Here, we screened proteins interacting with SHP2 in decidual hTERT-immortalized human endometrial stromal cells (T-HESCs) and identified Hypoxia-inducible factor-1 (HIF-1) signaling pathway as a potential SHP2-mediated signaling pathway through proximity-dependent biotinylation (BioID) analysis. Immunoprecipitation (Co-IP) revealed an interaction between SHP2 and HIF-1α, which colocalized to the nucleus in decidual cells. Furthermore, the SHP2 expression correlated with the transcriptional activation of HIF-1α and its downstream genes Beta-enolase (Eno3), Pyruvate kinase 2 (Pkm2), Aldolase C (Aldoc), and Facilitative glucose transporter 1 (Glut1). Knockdown or inhibition of SHP2 significantly reduced the mRNA and protein levels of HIF-1α and its downstream genes, as well as lactate production in decidual cells. We also established a hypoxia model of T-HESCs and 293 T cells and found that hypoxic treatment induced the expression of SHP2 and HIF-1α, which colocalized in the nucleus. SHP2 forced-expression rescued the inhibitory effects of SHP2 deficiency on HIF-1α expression and lactate production. Finally, SHP2 binds to the promoter regions of HIF-1α and its target genes (Eno3, Pkm2, Aldoc, and Glut1). Collectively, our results suggest that SHP2 influences the function of decidual cells by HIF-1α signaling and provide a novel function mechanism of decidual stromal cells.

HEK293 cells are a versatile cell line extensively used in the production of recombinant proteins and viral vectors, notably Adeno-associated virus (AAV) (Bulcha et al., 2021). Despite their high transfection efficiency and adaptability to various culture conditions, challenges remain in achieving sufficient yields of active viral particles. This study presents a comprehensive multi-omics analysis of two HEK293 strains under good manufacturing practice conditions, focusing on the metabolic and cellular responses during AAV production. The investigation included lipidomic, exometabolomic, and transcriptomic profiling across different conditions and time points. Genome-scale metabolic models (GSMMs) were reconstructed for these strains to elucidate metabolic shifts and identify potential bottlenecks in AAV production. Notably, the study revealed significant differences between a High-producing (HP) and a Low-producing (LP) HEK293 strains, highlighting pseudohypoxia in the LP strain. Key findings include the identification of hypoxia-inducible factor 1-alpha (HIF-1α) as a critical regulator in the LP strain, linking pseudohypoxia to poor AAV productivity. Inhibition of HIF-1α resulted in immediate cessation of cell growth and a 2.5-fold increase in viral capsid production, albeit with a decreased number of viral genomes, impacting the full-to-empty particle ratio. This trade-off is significant because it highlights a key challenge in AAV production: achieving a balance between capsid assembly and genome packaging to optimize the yield of functional viral vectors. Overall this suggests that while HIF-1α inhibition enhances capsid assembly, it simultaneously hampers nucleotide synthesis via the pentose phosphate pathway (PPP), necessary for nucleotide synthesis, and therefore for AAV genome replication.

Malignant melanoma (MM) is a highly aggressive skin tumor with a rising incidence and poor prognosis. Although current clinical treatments, including surgery, targeted therapy, immunotherapy, and radiotherapy, have shown some efficacy, therapeutic options remain limited for elderly patients and those with metastatic disease, highlighting the urgent need for novel therapeutic strategies. In recent years, the unique far-infrared radiation (FIR) properties of graphene have demonstrated potential applications in cancer treatment. However, the mechanisms underlying FIR's effects in MM therapy remain poorly understood.

This study systematically evaluated the inhibitory effects of FIR on MM through in vitro cell experiments, animal models, and molecular mechanism analysis. First, the B16F10 melanoma cell line was used as the experimental model. The effects of FIR on cell proliferation, apoptosis, and the cell cycle were assessed using CCK-8 assays and flow cytometry, while RNA sequencing was conducted to analyze the associated signaling pathways. Second, specific caspase inhibitors were employed to further validate the mechanisms of FIR-induced apoptosis. Finally, a syngeneic tumor transplantation model in C57BL/6J mice was established to comfirm the anti-tumor efficacy of FIR in vivo, thereby comprehensively elucidating its anti-cancer mechanisms.

The results demonstrated that FIR significantly inhibits MM. In vitro experiments revealed that FIR treatment markedly suppressed B16F10 cell proliferation, induced apoptosis, caused G0/G1 phase cell cycle arrest, and downregulated the expression of hypoxia-related proteins such as HIF-1α. In animal studies, FIR significantly inhibited tumor growth. RNA sequencing revealed that FIR exerts its anti-cancer effects through multiple signaling pathways. Notably, the use of caspase inhibitors Z-DEVD-FMK and Z-LEHD-FMK, which specifically inhibit caspase-3 and caspase-9, respectively, can rescue cells from apoptosis induced by FIR treatment.

This study systematically elucidated that FIR exerts anti-tumor effects through multiple mechanisms, including inducing MM cell apoptosis, exacerbating hypoxic stress, and causing cell cycle arrest. The findings provide new insights and approaches for MM treatment and establish a theoretical foundation for the clinical application of FIR in cancer therapy.

Cancer treatment has long been hindered by the complexity of the tumor microenvironment (TME) and the mechanisms that tumors employ to evade immune detection. Recently, the combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic therapies has emerged as a promising approach to improve cancer treatment outcomes. This review delves into the role of immunostimulatory molecules and ICIs in enhancing anti-tumor immunity, while also discussing the therapeutic potential of anti-angiogenic strategies in cancer. In particular, we highlight the critical role of endoplasmic reticulum (ER) stress in angiogenesis. Moreover, we explore the potential of macrophage reprogramming to bolster anti-tumor immunity, with a focus on restoring macrophage phagocytic function, modulating hypoxic tumor environments, and targeting cytokines and chemokines that shape immune responses. By examining the underlying mechanisms of combining ICIs with anti-angiogenic therapies, we also review recent clinical trials and discuss the potential of biomarkers to guide and predict treatment efficacy.

Hypoxic cells exhibit radioresistance, which is associated with poor prognosis in cancer patients. Understanding the molecular mechanisms underlying radioresistance in hypoxic tumor cells is crucial for improving radiotherapy efficacy. In this study, we examined the role of FDX1 in regulating cellular responses to severe hypoxia in glioblastoma cell lines T98G and A172. We found that FDX1 expression was upregulated under severe hypoxia, and its knockdown reduced the hypoxia-induced activation of key radioresistance factors and cellular survival mechanisms, including ATM, DNA-PKcs, Akt, and EGFR. FDX1 knockdown also sensitized T98G cells to radiation under severe hypoxia. Furthermore, FDX1 was found to regulate HIF-1α protein level, while HIF-1α did not regulate FDX1 expression. These results suggest that FDX1 may be a novel therapeutic target to overcome radioresistance in glioblastoma under severe hypoxia.

Phototherapy has emerged as a promising modality in cancer treatment, garnering considerable attention for its minimal side effects, exceptional spatial selectivity, and optimal preservation of normal tissue function. This innovative approach primarily encompasses three distinct paradigms: Photodynamic Therapy (PDT), Photothermal Therapy (PTT), and Photoimmunotherapy (PIT). Each of these modalities exerts its antitumor effects through unique mechanisms-specifically, the generation of reactive oxygen species (ROS), heat, and immune responses, respectively. However, significant challenges impede the advancement and clinical application of phototherapy. These include inadequate ROS production rates, subpar photothermal conversion efficiency, difficulties in tumor targeting, and unfavorable physicochemical properties inherent to traditional phototherapeutic agents (PTs). Additionally, the hypoxic microenvironment typical of tumors complicates therapeutic efficacy due to limited agent penetration in deep-seated lesions. To address these limitations, ongoing research is fervently exploring innovative solutions. The unique advantages offered by nano-PTs and nanocarrier systems aim to enhance traditional approaches' effectiveness. Strategies such as generating oxygen in situ within tumors or inhibiting mitochondrial respiration while targeting the HIF-1α pathway may alleviate tumor hypoxia. Moreover, utilizing self-luminescent materials, near-infrared excitation sources, non-photoactivated sensitizers, and wireless light delivery systems can improve light penetration. Furthermore, integrating immunoadjuvants and modulating immunosuppressive cell populations while deploying immune checkpoint inhibitors holds promise for enhancing immunogenic cell death through PIT. This review seeks to elucidate the fundamental principles and biological implications of phototherapy while discussing dominant mechanisms and advanced strategies designed to overcome existing challenges-ultimately illuminating pathways for future research aimed at amplifying this intervention's therapeutic efficacy.

The objective of this study was to assess the correlation between the expression of HSP70-2 and the development of oral potentially malignant disorders (OPMD) and oral squamous cell carcinoma (OSCC). Furthermore, the study evaluates the potential function of HSP70-2 in the pathogenesis of malignant diseases of the oral cavity.

Using immunohistochemistry, RT-qPCR, Western blot, indirect immunofluorescence, and flow cytometry, the expression of HSP70-2 mRNA and protein in OPMD and OSCC tissues and cells was investigated. Using liposomal vector transient transfection to specifically knock down HSP70-2 gene expression in pertinent cell lines in vitro, the role of HSP70-2 in the development of oral malignant disorders was further investigated.

Studies on OPMD and OSCC tissues and cell lines revealed that HSP70-2 mRNA and protein were substantially expressed. Furthermore, it was discovered that the expression levels corresponded with the degree of disease development. Downregulating the HSP70-2 gene specifically reduces the proliferation, viability, colony-forming ability, migration, and invasion of OPMD and OSCC cells. Furthermore, it will cause apoptosis and control cell cycle arrest.

HSP70-2 exhibited a significantly differential expression in both NM, OPMD, and OSCC tissues and cells. Furthermore, HSP70-2 plays a function in the development of oral malignant illnesses.

HSP70-2 is a promising biomarker for predicting the malignant transformation of Oral leukoplakia (OLK) and early diagnosis of OSCC. It is highly anticipated that HSP70-2 will be a potential target for the early intervention and blockage of OLK malignant transformation, given its established role in the development of oral malignant disorders. With regard to the treatment of OSCC, the same provides a referable target for siRNA-based therapeutic modalities.

Hypoxic microenvironment plays a critical role in solid tumor growth, metastasis and angiogenesis. Hypoxia-inducible factors (HIFs), which are canonical transcription factors in response to hypoxia, are stabilized under hypoxia and coordinate the process of hypoxia-induced gene expression, leading to cancer progression. Increasing evidence has uncovered that long noncoding RNAs (lncRNAs), which are closely associated with cancer, play crucial roles in hypoxia-mediated HCC progression, while the mechanisms are largely unknown. Here, we identified SZT2-AS1 as a novel lncRNA in HCC, which was induced by hypoxia in a HIF-1-dependent manner and promoted HCC growth, metastasis and angiogenesis both in vitro and in vivo. And SZT2-AS1 also mediated the hypoxia-induced HCC progression. Clinical data indicated that SZT2-AS1 level was substantially increased in HCC and closely associated with poor clinical outcomes, acting as an independent prognostic predictor. Mechanistically, SZT2-AS1 recruited HIF-1α and HIF-1β to form the HIF-1 heterodimer, and it was required for the occupancy of HIF-1 to hypoxia response elements (HREs) and HIF target gene transcription. In addition, SZT2-AS1 was required for hypoxia-induced histone trimethylation (H3K4me3 and H3K36me3) at HREs. Through recruiting methyltransferase SMYD2, SZT2-AS1 promoted trimethylation of H3K4 and H3K36 in HCC cells. Taken together, our results uncovered a lncRNA-involved positive feedback mechanism under hypoxia and established the clinical value of SZT2-AS1 in prognosis and as a potential therapeutic target in HCC.