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.

Antiangiogenic medications for cancer treatment have generally failed in showing substantial benefits in terms of prolonging life on their own; their effects are noticeable only when combined with chemotherapy. Moreover, treatments based on prolonged antiangiogenics administration have demonstrated to be ineffective in stopping tumor progression. In this scenario, nanotherapeutics can address certain issues linked to existing antiangiogenic treatments. More specifically, they can provide the ability to target the tumor's blood vessels to enhance drug accumulation and manage release, ultimately decreasing undesired side effects. Additionally, they enable the administration of multiple angiogenesis inhibitors at the same time as chemotherapy. Key reports in this field include the design of polymeric nanoparticles, inorganic nanoparticles, vesicles, and hydrogels for loading antiangiogenic substances like endostatin and interleukin-12. Furthermore, nanoformulations have been proposed to efficiently control relevant pro-angiogenic pathways such as VEGF, Tie2/Angiopoietin-1, HIF-1α/HIF-2α, and TGF-β, providing powerful approaches to block tumor growth and metastasis. In this article, we outline a selection of nanoformulations for antiangiogenic treatments for cancer that have been developed in the past ten years.

Based on the available evidence, the cold-inducible RNA-binding protein (CIRBP) appears to play a role in increasing the stability of hypoxia-inducible factor 1-alpha (HIF1α) mRNA. This research aimed to examine the levels of CIRBP and HIF1α mRNA within breast tumor tissues and explore the relationship between their gene expression and tumor Microvascular density (MVD).

The results revealed a significant upregulation of CIRBP (5.07-fold) and HIF1α (4.5-fold) gene expression in BC samples compared to the surrounding normal tissues (p < 0.001). This upregulation was also associated with various clinicopathologic features. Furthermore, there was a correlation between CIRBP mRNA expression, HIF1α mRNA expression, and MVD. Consequently, this study suggests that CIRBP may have a role in promoting angiogenesis in BC.

Hypoxia, characterized by reduced oxygen levels, plays a pivotal role in cancer progression, profoundly influencing tumor behavior and therapeutic responses. A hallmark of solid tumors, hypoxia drives significant metabolic adaptations in cancer cells, primarily mediated by hypoxia-inducible factor-1α (HIF-1α), a key transcription factor activated in low-oxygen conditions. This hypoxic environment promotes epithelial-mesenchymal transition (EMT), enhancing cancer cell migration, metastasis, and the development of cancer stem cell-like properties, which contribute to therapy resistance. Moreover, hypoxia modulates the expression of circular RNAs (circRNAs), leading to their accumulation in the tumor microenvironment. These hypoxia-responsive circRNAs regulate gene expression and cellular processes critical for cancer progression, making them promising candidates for diagnostic and prognostic biomarkers in various cancers. This review delves into the intricate interplay between hypoxic circRNAs, microRNAs, and RNA-binding proteins, emphasizing their role as molecular sponges that modulate gene expression and signaling pathways involved in cell proliferation, apoptosis, and metastasis. It also explores the relationship between circRNAs and the tumor microenvironment, particularly how hypoxia influences their expression and functional dynamics. Additionally, the review highlights the potential of circRNAs as diagnostic and prognostic tools, as well as their therapeutic applications in innovative cancer treatments. By consolidating current knowledge, this review underscores the critical role of circRNAs in cancer biology and paves the way for future research aimed at harnessing their unique properties for clinical advancements. Specifically, this review examines the biogenesis, expression patterns, and mechanistic actions of hypoxic circRNAs, focusing on their ability to act as molecular sponges for microRNAs and their interactions with RNA-binding proteins. These interactions impact key signaling pathways related to tumor growth, metastasis, and drug resistance, offering new insights into the complex regulatory networks governed by circRNAs under hypoxic stress.

Abnormal tumor blood vessels can significantly promote the malignant progression of tumors, prompting researchers to focus on drugs that normalize these vessels for clinical treatment. The combination of the Qi-tonifying drug Astragali Radix and the blood-activating drug Curcumae Rhizoma, referred to as AC, exhibited significant anti-tumor metastasis effects. However, the association between the anti-tumor metastasis effect of AC and its potential role in regulating tumor vascular remodeling warrants further exploration.

This study aimed to elucidate the mechanism through which AC induces tumor blood vessel normalization in colon cancer (CC).

The potential active components of AC were identified through UPLC-MS/MS. An orthotopic transplantation model of CC was established in BALB/c mice using the CT26-Lucifer cell line, and the effects of AC were evaluated using IVIS imaging, hematoxylin and eosin (H&E) staining, and immunohistochemistry. Network pharmacology and molecular biology analyses were employed to identify the potential direct targets of AC. Subsequently, RT-PCR and Western blotting techniques were utilized to validate the findings obtained from network pharmacology. Furthermore, ELISA and other methodologies were used to investigate glycolysis-related indicators, along with immunofluorescence technology to demonstrate changes in vascular leakage and perfusion characteristics associated with blood vessel normalization.

We identified HIF-1α as a potential direct target of AC. This interaction influences the glycolytic processes in both tumor cells and tumor-associated endothelial cells (TECs) by directly binding to HIF-1α and modulating its nuclear translocation, thereby determining the integrity of TEC junctions. Mechanistically, AC directly regulates the key enzyme PFKFB3 in glycolysis by modulating HIF-1α expression and inhibiting its nuclear translocation. This action reduces tumor glycolytic flux, decreases the internalization of VE-cad, and influences the expression of downstream matrix metalloproteinases (MMPs), thereby strengthening the adherens and tight junctions between TECs and restoring vascular integrity.

This study presents novel findings that AC can regulate glycolysis through the inhibition of HIF-1α nuclear translocation, thereby promoting the normalization of tumor blood vessels and effectively inhibiting tumor metastasis. These results suggested that AC may serve as an effective therapeutic agent for normalizing tumor blood vessels.

The focus on breast cancer treatment has shifted from the cytotoxic effects of single drugs on tumor cells to multidimensional multi‑pathway synergistic intervention strategies targeting the tumor microenvironment (TME). The activation of the Wnt signaling pathway in the TME of breast cancer cells serves a key regulatory role in tissue homeostasis and is a key driver of the carcinogenic process. Modulating the crosstalk between the Wnt pathway and TME of breast cancer is key for understanding the biological behavior of breast cancer and advancing the development of novel antitumor drugs. The present review aimed to summarize the complex mechanisms of the Wnt signaling pathway in the breast cancer TME, interactions between the Wnt signaling pathway and components of the breast cancer TME and breast cancer‑associated genes, as well as the interactions between the Wnt signaling pathway and other signaling cascades at the molecular level. Furthermore, the present review aimed to highlight the unique advantages of the Wnt signaling pathway in the macro‑regulation of the TME and the current therapeutic strategies targeting the Wnt signaling pathway, their potential clinical value and future research directions in breast cancer treatment.

The emergence of resistance to antitumor drugs in cancer cells presents a notable obstacle in cancer therapy. Metabolic reprogramming is characterized by enhanced glycolysis, disrupted lipid metabolism, glutamine dependence and mitochondrial dysfunction. In addition to promoting tumor growth and metastasis, metabolic reprogramming mediates drug resistance through diverse molecular mechanisms, offering novel opportunities for therapeutic intervention. Non‑coding RNAs (ncRNAs), a diverse class of RNA molecules that lack protein‑coding function, represent a notable fraction of the human genome. Due to their distinct expression profiles and multifaceted roles in various cancers, ncRNAs have relevance in cancer pathophysiology. ncRNAs orchestrate metabolic abnormalities associated with drug resistance in cancer cells. The present review provides a comprehensive analysis of the mechanisms by which metabolic reprogramming drives drug resistance, with an emphasis on the regulatory roles of ncRNAs in glycolysis, lipid metabolism, mitochondrial dysfunction and glutamine metabolism. Furthermore, the present review aimed to discuss the potential of ncRNAs as biomarkers for predicting chemotherapy responses, as well as emerging strategies to target ncRNAs that modulate metabolism, particularly in the context of combination therapy with anti‑cancer drugs.

This study investigated the regulatory potential of salidroside (SAL), a primary active compound in Rhodiola rosea L., on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha (HIF-1a) pathway in osteoblasts. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were employed to validate whether the receptor activator of nuclear factor-?B ligand (RANKL) is the downstream target gene of HIF-1a in osteoblasts. The study also utilized lipopolysaccharide (LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo. Furthermore, conditioned medium (CM) from SAL-pretreated osteoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1a pathway. Hypoxic condition-induced overexpression of HIF-1a upregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells. In vivo, SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1a by downregulating the expression of RANKL, vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), and angiopoietin-like 4 (ANGPTL4). In the paracrine experiment, conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1a/RANKL, VEGF, IL-6, and ANGPTL4 pathways. RANKL emerges as the downstream target gene regulated by HIF-1a in osteoblasts. SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1a/RANKL, VEGF, IL-6, and ANGPTL4 pathways. SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion.

Dendritic cell (DC) vaccine is a promising immunotherapy for hepatocellular carcinoma (HCC) via triggering antigen-specific anti-tumor immunity. Hypoxia contributes to higher level and broader spectrum of antigen expression in tumor cells.

This study aims to compare immunological activity and therapeutic efficacy between hypoxic and normoxic HCC cell line lysate-pulsed DC vaccines.

The results showed that hypoxic HCC cell line lysate-pulsed DC vaccines exhibited a stronger activity in producing interleukin-12 and promoting T cell proliferation and cytotoxicity in vitro. In HCC mice, hypoxic HCC cell line lysate-pulsed DC vaccines displayed a better efficacy in improving survival time and tumor volume and inducing intratumoral cytotoxic T cell infiltration and activation as well as tumor cell apoptosis. Adenylate kinase 4-derived antigens were important for hypoxic HCC cell line lysate-pulsed DC vaccine-elicited T cell killing.

In conclusion, this study demonstrated hypoxic HCC cell line lysate-pulsed DC vaccine as a potential therapeutic strategy for HCC.

Tumours reprogram pathways that regulate nutrient uptake and metabolism to meet the biosynthetic, bioenergetic, and redox requirements of cancer cells. This phenomenon is known as metabolic reprogramming and is edited by the deletion of oncogenes and the activation of proto-oncogenes. This article highlights the pathological mechanisms associated with metabolic reprogramming in laryngeal cancer (LC), including enhanced glycolysis, tricarboxylic acid cycle, nucleotide synthesis, lipid synthesis and metabolism, and amino acid metabolism, with a special emphasis on glutamine, tryptophan, and arginine metabolism. All these changes are regulated by HPV infection, hypoxia, and metabolic mediators in the tumour microenvironment. We analyzed the function of metabolic reprogramming in the development of drug resistance during standard LC treatment, which is challenging. In addition, we revealed recent advances in targeting metabolic strategies, assessing the strengths and weaknesses of clinical trials and treatment programs to attack resistance. This review summarises some currently important biomarkers and lays the foundation for therapeutic pathways in LC.

Lung cancer is the leading cause of cancer-related mortality worldwide, with the prevalence of the disease continually rising. Therefore, identifying disease-modifying risk factors is critical, with increasing recognition of the impact of sleep quality/sleep disorders. This narrative review summarizes the evidence on the role of five domains of sleep on lung cancer incidence and progression: (i) sleep quality/duration, (ii) sleep disordered breathing, (iii) circadian rhythm disturbances, (iv) sleep-related movement disorders, and (v) personal, environmental, and social factors that modulate each of these associations. Epidemiological evidence supports reduced sleep duration, increased sleep duration, poor sleep quality, insomnia, obstructive sleep apnea, evening chronotype, peripheral limb movements in sleep, and less robustly for night shift work and restless leg syndrome to be associated with increased risk of lung cancer development, with potential impacts on cancer survival outcomes. Proposed mechanisms underlying the biological plausibility of these epidemiological associations are also explored, with common theories relating to immune dysregulation, metabolic alterations, reductions in melatonin, sympathetic overactivation, increased reactive oxygen species, production of protumorigenic exosomes, and inflammation. We also summarized potential treatments addressing impaired sleep quality/sleep disorders and their ability to attenuate the risk of lung cancer and improve cancer survival. Although evidence on reversibility is inconsistent, there are trends toward positive outcomes. Future research should focus on clinical trials to confirm cause and effect relationships, large epidemiologic studies for incidence/prognosis, clarification on the relative efficacy of treatment modalities, and more in vivo animal models to establish the molecular mechanisms underlying these relationships.

MicroRNAs (miRNAs) are a class of short non-coding RNAs that play a crucial role in the post-transcriptional regulation of gene expression. They are associated with various biological processes related to tumors. Among the numerous miRNAs, miR-29 has garnered attention for its role in regulating tumor angiogenesis. In numerous human tumors, miR-29 has been demonstrated to negatively correlate with the capacity for angiogenesis and the degree of malignancy, as well as with the expression levels of pro-angiogenic factors such as vascular endothelial growth factor vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and matrix metalloproteinase (MMP)-2. Multiple studies, utilizing techniques like dual-luciferase reporter assays, have confirmed that miR-29 directly targets the 3'-untranslated region (UTR) of mRNAs for VEGF, PDGF, and MMP-2. Extensive investigations involving tumor cell lines and animal models have shown that the overexpression of miR-29, achieved through miRNA transfection or the introduction of miRNA mimics, effectively inhibits angiogenesis by upregulating these pro-angiogenic factors. Conversely, downregulation of miR-29 using specific inhibitors promotes angiogenesis. While small molecule inhibitors and antibodies targeting VEGF constitute a primary strategy in anti-angiogenesis therapies, miR-29's ability to target multiple pro-angiogenic molecules positions it as a promising candidate for future therapeutic interventions, especially with ongoing advancements in nucleic acid drug design and delivery systems.

This paper examined the role of solute carrier family 2 member 1 (SLC2A1) in colorectal cancer (CRC) progression, focusing on its expression levels, functional implications, and regulatory mechanisms involving Yes-associated protein 1 (YAP1) and the Wnt signaling pathway.

GEO datasets (GSE14297, GSE18462, GSE40367) were analyzed to identify genes linked to metastasis in CRC, and TCGA-COAD system was used to analyze the expression pattern and prognostic values of SLC2A1 in CRC. Functional studies were conducted using CRC cell lines (Caco-2 and SW480). Cell viability, migration and invasion, and apoptosis were examined using EdU assays, Transwell assays, and flow cytometry. YAP1's regulatory role on SLC2A1 was investigated using ChIP-qPCR and luciferase reporter assays. The Wnt/β-catenin agonist SKL2001 was used for functional rescue experiments.

SLC2A1 was upregulated in CRC cells, and its upregulation was associated with tumor metastasis and unfavorable outcomes according to bioinformatics. Knockdown of SLC2A1 resulted in reduced cell viability, decreased migration, and increased apoptosis in Caco-2 and SW480 cells. Additionally, YAP1 was identified as a transcriptional activator of SLC2A1. Knockdown of YAP1 decreased SLC2A1 expression and reduced expression of Wnt target genes, thus suppressing malignant behavior of tumor cells. However, further overexpression of SLC2A1 restored cell viability and migration in YAP1-deficient cells. The YAP1- SLC2A1 axis activated the Wnt/β-catenin by reducing GSK3β activity.

SLC2A1 is critical in CRC progression, with YAP1 serving as a key regulator of its expression and function. The YAP1-SLC2A1-Wnt axis represents a potential therapeutic target for CRC, providing insights into metabolic adaptations that support tumor growth and metastasis.

Chronic degenerative changes in cartilage and subchondral bone that lead to instability of the cartilage microenvironment are essential for the development of osteoarthritis (OA) in the old. Synchronous repair of cartilage and subchondral bone may be a key strategy for OA treatment. PDGF-BB effectively promoted chondrocyte regeneration and angiogenesis. However, the mechanisms by which PDGF-BB affects subchondral bone and the delivery of PDGF-BB to the joint cavity need to be further explored. In this study, we used sodium hyaluronate to deliver PDGF-BB (SH-PDGF) to the joint space and aimed to determine the mechanisms of SH-PDGF in repairing cartilage and subchondral bone and stabilising the cartilage microenvironment. In this research, we determined the pharmacokinetics of PDGF-BB and SH-PDGF in cartilage. Moreover, we investigated the effects of PDGF-BB and SH-PDGF on cartilage and the subchondral bone microenvironment by identifying changes in the HIF-VEGF-Notch axis and SDF-1-CXCR4 axis in an OA rat model. The results showed that PDGF-BB increased cell viability, decreased HIF-1α levels, inhibited inflammation and improved matrix metabolism in osteoarthritic chondrocytes under hyperoxic or hypoxic conditions. We also found that PDGF-BB and SH-PDGF showed similar effects on repairing cartilage and subchondral bone simultaneously. However, SH-PDGF had some advantages over PDGF-BB in prolonging the injection interval and decreasing the injection time. These protective effects were mediated by the inhibition of both the HIF-1α-VEGF-Notch axis and the SDF-1-CXCR4 axis. The underlying mechanisms include the inhibition of HIF-1α-VEGF-Notch-mediated vessel invasion and SDF-1-CXCR4 axis-mediated crosstalk between cartilage and subchondral tissue.

The extracellular matrix (ECM) and its primary chemical components, including collagen, play a pivotal role in carcinogenesis and tumor progression. The ECM actively regulates cell proliferation, migration, and, importantly, resistance to various adverse factors. It is widely recognized as a key factor in modifying the resistance of tumor cells to various treatment modalities and cytotoxic compounds. However, the role of the ECM in tumor cell adaptation to nutritional deficiencies and hypoxic conditions remains significantly less studied. Since it is generally accepted that tumor cells resistance increases when cultured in a three-dimensional matrix, we sought to experimentally test the universality of this statement. In this work, we analyzed the responses of tumor cells with varying origins and proliferative activities, including human bladder carcinoma, epidermoid carcinoma, and ovarian carcinoma, to deprivation of serum, glucose and oxygen. We compared cell resistance to suboptimal conditions when cultured in a monolayer on tissue culture (TC)-treated polystyrene, on collagen-coated surfaces, or within a three-dimensional hydrogel composed of collagen type I. All three cell lines were stably transfected with fluorescent protein genes. To register the cell growth dynamics, we used a fluorescence-based technique that allows long-term quantitative observations without disrupting the hydrogel. The analyzed cell lines demonstrated different patterns of relative sensitivity to suboptimal conditions. We revealed that the direction and intensity of the collagen matrix effect depend on the cell type. Slowly proliferating ovarian carcinoma cells showed no noticeable changes in their behavior when cultured in a gel compared to a monolayer. In the case of bladder carcinoma, we registered predominantly resistance-stimulating effect of the collagen matrix, but it was significant only under serum deprivation. The most pronounced effect of collagen was registered for epidermoid carcinoma. Importantly, this effect was ambivalent: gel-embedded cells demonstrated significantly enhanced resistance to serum deprivation, but, at the same time, they were more responsive to glucose starvation and hypoxic conditions. We attribute the registered phenomenon to the individual characteristics of tumor cells with different origins and metabolic activities.

Endothelial cell glycolysis plays a novel and significant role in Schwann cells and peripheral nerve injury repair, which represents an emerging and important area of research. Glycolysis in endothelial cells is a conserved and tightly regulated biological process that provides essential energy (ATP) and intermediates by ultimately converting glucose into lactate. This metabolic pathway is crucial for maintaining the normal function of endothelial cells. During peripheral nerve injury repair, endothelial cell glycolysis influences the function of Schwann cells and the efficiency of nerve regeneration. Beyond glycolysis, endothelial cells also secrete various factors, including growth factors and extracellular vesicles, which further modulate Schwann cell activity and contribute to the repair process. This review will summarize the role of endothelial cell glycolysis in Schwann cell function and peripheral nerve injury repair, aiming to provide new insights for the development of novel strategies for peripheral nerve injury treatment.

Hypoxia-Inducible Factor-1α (HIF-1α) is crucial in the progression of ovarian cancer, especially in influencing its tumor microenvironment and promoting pathogenic pathways that worsen female infertility. In hypoxic settings, HIF-1α is stabilized and activates the transcription of genes associated with angiogenesis, metabolic reprogramming, epithelial-to-mesenchymal transition, and therapeutic resistance. Angiogenesis and glycolytic reprogramming mediated by HIF-1 tumor proliferation, survival, and metastasis. Its dysfunction concurrently impairs ovarian homeostasis, undermining follicular growth, hormone synthesis, and the ovarian vascular network, consequently contributing to infertility. Moreover, HIF-1α induces persistent inflammation and oxidative stress, promoting an environment damaging to reproductive health. Due to its dual function in ovarian cancer growth and infertility, HIF-1α is a potential therapeutic target. Strategies including small molecule inhibitors and nanoparticle-mediated delivery of drugs possess the potential to reduce HIF-1α activity, hence reducing cancer progression while protecting fertility. This review seeks to clarify the molecular basis of HIF-1α in ovarian cancer and its effects on female infertility, providing insights into novel treatment approaches that target both controlling the disease and preserving fertility.

Despite being heavily infiltrated by immune cells, tuberculosis (TB) granulomas often subvert the host response to Mycobacterium tuberculosis (Mtb) infection and support bacterial persistence. We previously discovered that human TB granulomas are enriched for immunosuppressive factors typically associated with tumor-immune evasion, raising the intriguing possibility that they promote tolerance to infection. In this study, our goal was to identify the prime drivers for establishing this tolerogenic niche and to determine if the magnitude of this response correlates with bacterial persistence. To do this, we conducted a multimodal spatial analysis of 52 granulomas from 16 non-human primates (NHP) who were infected with low dose Mtb for 9-12 weeks. Notably, each granuloma's bacterial burden was individually quantified allowing us to directly ask how granuloma spatial structure and function relate to infection control. We found that a universal feature of TB granulomas was partitioning of the myeloid core into two distinct metabolic environments, one of which is hypoxic. This hypoxic environment associated with pathologic immune cell states, dysfunctional cellular organization of the granuloma, and a near-complete blockade of lymphocyte infiltration that would be required for a successful host response. The extent of these hypoxia-associated features correlated with worsened bacterial burden. We conclude that hypoxia governs immune cell state and organization within granulomas and is a potent driver of subverted immunity during TB.

In tumor treatment, the sequence and timing of drug action have a large influence on therapeutic efficacy. Multi-drug sequential release systems (MDSRS) enable the sequential and/or on-demand release of multiple drugs following the single administration of a therapeutic agent. Several researchers have explored MDSRS, providing fresh strategies for synergistic cancer therapy. This review article first introduces the main characteristics of MDSRS. It then elaborates on the design principles of MDSRS. Subsequently, it summarizes the various structures of carriers used for constructing MDSRS, including core-shell structure, Layer-by-layer structure, Janus structure and hydrogel. Next, through specific examples, the article emphasizes the application of MDSRS in cancer treatment, focusing on their role in remodeling the tumor microenvironment (TME) and enhancing therapeutic effects through multiple mechanisms. Finally, the article discusses the current limitations and challenges of these systems and proposes potential future solutions. Overall, this review underscores the importance of the sequence and timing of drug therapy in cancer treatment, providing valuable theoretical and technical guidance for pharmaceutical research.

Persistent bleeding and limited repair capacity greatly threaten patients with bone destruction. Designing inorganic-organic biomimetic scaffolds with quick hemostasis and osteogenesis functions will solve this problem. A novel degradable and naringin (NG) loaded porous scaffold (SCB-N) based on APTES-modified bioactive glass (ABG), carboxymethyl chitosan and silk fibroin is developed. ABG and NG enhance the strength of the scaffolds. The scaffolds can release NG and bioactive ions (Ca2+ and Si4+), promoting the expression of osteogenesis (OCN, BMP-2), angiogenesis (VEGF), and neurogenesis (TB3, GFAP) genes in bone mesenchymal stem cells (BMSCs) and the related proteins (OCN, BMP-2, VEGF, GFAP). When implanting the scaffolds in rat cranial critical size defects, all scaffolds exhibit good compatibility, and SCB-N2 (with ABG and 1 mg/mL NG) group significantly promotes new bone regeneration and the formation of M2-type macrophages. Transcriptome sequencing results confirmed the osteogenic differentiation of BMSCs stimulated by SCB-N2 scaffolds is mainly regulated through MAPK and Wnt signaling pathways. Moreover, SCB-N2 group demonstrates quick hemostasis in vitro and in vivo due to the high adsorption ability and Ca ions release. The novel bionic scaffolds loaded with ion/traditional Chinese medicine monomer, possess the capabilities of hemostasis, neurovascularization, osteogenesis and immunomodulation, therefore exhibiting potential in bone repair.

Non‑small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite significant advances in targeted therapy and immunotherapy, the overall prognosis of patients with NSCLC remains poor. Hypoxia is a critical driving factor in tumor progression, influencing the biological behavior of tumor cells through complex molecular mechanisms. The present review systematically examined the role of the hypoxic microenvironment in NSCLC, demonstrating its crucial role in promoting tumor cell growth, invasion and metastasis. Additionally, it has been previously reported that the hypoxic microenvironment enhances tumor cell resistance by activating hypoxia‑inducible factor and regulating exosome secretion. The hypoxic microenvironment also enables tumor cells to adapt to low oxygen and nutrient‑deficient conditions by enhancing metabolic reprogramming, such as through upregulating glycolysis. Further studies have shown that the hypoxic microenvironment facilitates immune escape by modulating tumor‑associated immune cells and suppressing the antitumor response of the immune system. Moreover, the hypoxic microenvironment increases tumor resistance to radiotherapy, chemotherapy and other types of targeted therapy through various pathways, significantly reducing the therapeutic efficacy of these treatments. Therefore, it could be suggested that early detection of cellular hypoxia and targeted therapy based on hypoxia may offer new therapeutic approaches for patients with NSCLC. The present review not only deepened the current understanding of the mechanisms of action and role of the hypoxic microenvironment in NSCLC but also provided a solid theoretical basis for the future development of precision treatments for patients with NSCLC.

The ubiquitin-proteasome system (UPS) is an important type of protein post-translational modification that affects the quantity and quality of various proteins and influences cellular processes such as the cell cycle, transcription, oxidative stress, and autophagy. Nanomaterials (NMs), which exhibit excellent physicochemical properties, can directly interact with the UPS and act as molecular-targeted drugs to induce changes in biological processes. This review provides an overview of the influence of NMs on the UPS of misfolded proteins and key proteins, which are related to cancer, neurodegenerative diseases and oxidative stress. This review also summarizes the role of modification processes involved in ubiquitination the biological effects of NMs and the mechanism of such effects of NMs through regulation of the UPS. This review deepens our understanding of the influence of NMs on the protein degradation process and provides new potential therapeutic targets for disease.

4',5,6,7-tetrahydoxyisoflavone (6-hydroxygenistein, 6-OHG) is a hydroxylated derivative of genistein with excellent antioxidant activity, but whether 6-OHG can protect hypoxia-induced damage is unclear. The objective of current study was to evaluate the protective effect and underling mechanism of 6-OHG against hypoxia-induced injury via network pharmacology and cellular experiments. 6-OHG-related and hypoxia injury-related targets were screened by public databases. The intersected targets were used for constructing PPI network and performing GO and KEGG functional analysis. We induced injury in PC12 cells under hypoxia conditions and observed the effects and molecular mechanisms of 6-OHG on cellular damage. Network pharmacological analysis predicted that 6-OHG delayed hypoxia injury by mitigating oxidative stress, inflammatory response and apoptosis. Cellular experiments suggested that 6-OHG treatment mitigated cell damage, enhanced cell viability, reduced ROS production and MDA level, increased SOD and CAT activities and elevated GSH level in PC12 cell exposed to hypoxia. Additionally, 6-OHG treatment reduced the TNF-α and IL-6 levels and elevated the IL-10 content, while downregulated the NF-κB and TNF-α expressions. 6-OHG also inhibited the caspase-3 and - 9 activation and the Bax and cleaved caspase-3 expressions, and elevated the Bcl-2 expression. Moreover, 6-OHG remarkably enhanced Nrf2 nuclear translocation and increased HO-1 expression. Molecular docking also proved the strong binding affinities of 6-OHG with Nrf2 and HO-1. Furthermore, ML385, a specific Nrf2 inhibitor, eliminated the beneficial effects of 6-OHG. In summary, 6-OHG can alleviate hypoxia-induced injury in PC12 cells through activating Nrf2/HO-1 signaling pathway and may be developed as candidate for preventing neuro-damage induced by hypoxia.

Venous thromboembolism, characterized by deep vein thrombosis and pulmonary embolism, is the third cardiovascular disease in the world. Deep vein thrombosis occurs when a blood clot forms in areas of impaired blood flow, and it is significantly affected by environmental factors. Local hypoxia, caused by venous stasis, plays a critical role in deep vein thrombosis under normal conditions, and this effect is intensified when the Po2 decreases, such as during air travel or high-altitude exposure. The lower oxygen levels and reduced pressure at high altitudes further contribute to deep vein thrombosis development. These conditions increase the pro-coagulant activity of neutrophils, platelets, and red blood cells, which interact on the surface of activated endothelial cells, promoting clot formation. Understanding the mechanisms involved in thrombus formation when Po2 is reduced, with or without pressure reduction, is crucial for preventing the development of venous thromboembolisms in such conditions and identifying innovative therapeutic targets. This literature review explores the mechanisms involved in thrombus formation related to high-altitude conditions and discusses the pro-coagulant consequences induced by environmental disturbances.

As adult stem cells with various advantages, Bone marrow-derived mesenchymal stem cells (BMSCs) are valuable resources for veterinary treatment and animal reproduction. Previous studies have shown that hypoxia can induce epithelial-mesenchymal transition (EMT) and improve mesenchymal characteristics of BMSCs in vitro culture. However, the mechanism by which hypoxia improves the interstitial characteristics of buffalo BMSCs (bBMSCs) remains unclear. In this study, the effects of hypoxia on the mesenchymal characteristics of bBMSCs and the expression level of lncRNA H19 were examined, and then the effects of lncRNA H19 on maintaining the mesenchymal characteristics of bBMSCs under hypoxic culture conditions (5 % oxygen) as well as its mechanism also were explored, so as to further understand the molecular mechanism of mesenchymal characteristics maintenance of bBMSCs. The results showed that hypoxic culture conditions promoted EMT of bBMSCs, with lncRNA H19 expression up-regulated. When lncRNA H19 was knocked down in hypoxia, the expression level of Vimentin was down-regulated, the expression level of E-Cadherin was up-regulated, and EMT was inhibited. Meanwhile, the genes (p-PI3K and p-AKT1) involved in PI3K/AKT signaling pathway were inhibited by lncRNA H19 Knockdown. IGF-1 (10 ng/mL), an activator of PI3K/AKT signaling pathway, was added to rescued the inhibition of PI3K/AKT signaling pathway caused by lncRNA H19 Knockdown, with the effects of lncRNA H19 on EMT related genes also partially reversed. These findings not only provide theoretical guidance to elucidate the detailed regulation mechanism of hypoxia on mesenchymal nature maintenance of bBMSCs, but also provide positive support to further establish the stable in vitro culture system of bBMSCs.

Lung cancer remains an influential global health concern, necessitating the development of innovative therapeutic strategies. The tumour stroma, which is known as tumour microenvironment (TME) has a central impact on tumour expansion and treatment resistance. The stroma of lung tumours consists of numerous cells and molecules that shape an environment for tumour expansion. This environment not only protects tumoral cells against immune system attacks but also enables tumour stroma to attenuate the action of antitumor drugs. This stroma consists of stromal cells like cancer-associated fibroblasts (CAFs), suppressive immune cells, and cytotoxic immune cells. Additionally, the presence of stem cells, endothelial cells and pericytes can facilitate tumour volume expansion. Nanoparticles are hopeful tools for targeted drug delivery because of their extraordinary properties and their capacity to devastate biological obstacles. This review article provides a comprehensive overview of contemporary advancements in targeting the lung tumour stroma using nanoparticles. Various nanoparticle-based approaches, including passive and active targeting, and stimuli-responsive systems, highlighting their potential to improve drug delivery efficiency. Additionally, the role of nanotechnology in modulating the tumour stroma by targeting key components such as immune cells, extracellular matrix (ECM), hypoxia, and suppressive elements in the lung tumour stroma.

Lung cancer continues to be the leading cause of cancer-related mortality worldwide. Early detection and a comprehensive understanding of tumor-immune interactions are crucial for improving patient outcomes. This study aimed to develop a novel biomarker panel utilizing peripheral blood transcriptomics and machine learning algorithms for early lung cancer diagnosis, while simultaneously providing insights into tumor-immune crosstalk mechanisms. Leveraging a training cohort (GSE135304), we employed multiple machine learning algorithms to formulate a Lung Cancer Diagnostic Score (LCDS) based on peripheral blood transcriptomic features. The LCDS model's performance was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC) in multiple validation cohorts (GSE42834, GSE157086, and an in-house dataset). Peripheral blood samples were obtained from 20 lung cancer patients and 10 healthy control subjects, representing an in-house cohort recruited at the Sixth People's Hospital of Chengdu. We employed advanced bioinformatics techniques to explore tumor-immune interactions through comprehensive immune infiltration and pathway enrichment analyses. Initial screening identified 844 differentially expressed genes, which were subsequently refined to 87 genes using the Boruta feature selection algorithm. The random forest (RF) algorithm demonstrated the highest accuracy in constructing the LCDS model, yielding a mean AUC of 0.938. Lower LCDS values were significantly associated with elevated immune scores and increased CD4+ and CD8+ T-cell infiltration, indicative of enhanced antitumor-immune responses. Higher LCDS scores correlated with activation of hypoxia, peroxisome proliferator-activated receptor (PPAR), and Toll-like receptor (TLR) signaling pathways, as well as reduced DNA damage repair pathway scores. Our study presents a novel, machine learning-derived peripheral blood transcriptomic biomarker panel with potential applications in early lung cancer diagnosis. The LCDS model not only demonstrates high accuracy in distinguishing lung cancer patients from healthy individuals but also offers valuable insights into tumor-immune interactions and underlying cancer biology. This approach may facilitate early lung cancer detection and contribute to a deeper understanding of the molecular and cellular mechanisms underlying tumor-immune crosstalk. Furthermore, our findings on the relationship between LCDS and immune infiltration patterns may have implications for future research on therapeutic strategies targeting the immune system in lung cancer.

Substantial advancements have been made in recent years in comprehending immune memory, which enhances the secondary response through prior infections. The ability of vertebrate T and B lymphocytes to exhibit classic recall responses has long been regarded as a distinguishing characteristic. However, natural killer (NK) cells have been found to acquire immunological memory in a manner akin to T and B cells. The fundamental principles derived from the investigation of NK cell memory offer novel insights into innate immunity and have the potential to pave the way for innovative strategies to enhance therapeutic interventions against multiple diseases including cancer. Here, we reviewed the fundamental characteristics, memory development and regulatory mechanism of NK cell memory. Moreover, we will conduct a comprehensive evaluation of the accomplishments, obstacles, and future direction pertaining to the utilization of NK cell memory in the field of cancer immunotherapy.

Metastatic cancer accounts for most cancer-related deaths, and identifying specific molecular targets that contribute to metastatic progression is crucial for the development of effective treatments. Hypoxia, a feature of solid tumors, plays a role in cancer progression by inducing resistance to therapy and accelerating metastasis. Here, we report that CCAAT/enhancer-binding protein beta (C/EBPβ) transcriptionally regulates hypoxia-inducible factor 1 subunit alpha (HIF1A) and thus promotes migration and invasion of non-small-cell lung cancer (NSCLC) cells under hypoxic conditions. Our results show that knockdown or forced expression of C/EBPβ was correlated with HIF-1α expression and that C/EBPβ directly bound to the promoter region of HIF1A. Silencing HIF1A inhibited the enhanced migration and invasion induced by C/EBPβ overexpression in NSCLC cells under hypoxia. Expression of the HIF-1α target gene, SLC2A1, was also altered in a C/EBPβ-dependent manner, and knockdown of SLC2A1 reduced migration and invasion enhanced by C/EBPβ overexpression. These results indicate that C/EBPβ is a critical regulator for the invasion of NSCLC cells in the hypoxic tumor microenvironment. Collectively, the C/EBPβ-HIF-1α-GLUT1 axis represents a potential therapeutic target for preventing metastatic progression of NSCLC and improving patient outcomes.

Breast cancer is a complicated malignancy and is known as the most common cancer in women. Considerable experiments have been devoted to explore the basic impacts of the tumor stroma, particularly the extracellular matrix (ECM) and stromal components, on tumor growth and resistance to treatment. ECM is made up of an intricate system of proteins, glycosaminoglycans, and proteoglycans, and maintains structural support and controls key signaling pathways involved in breast tumors. ECM can block different drugs such as chemotherapy and immunotherapy drugs from entering the tumor stroma. Furthermore, the stromal elements, such as cancer-associated fibroblasts (CAFs), immune cells, and blood vessels, have crucial impacts on tumor development and therapeutic resistance. Recently, promising outcomes have been achieved in using nanotechnology for delivering drugs to tumor stroma and crossing ECM in breast malignancies. Nanoparticles have various benefits for targeting the breast tumor stroma, such as improved permeability and retention, extended circulation time, and the ability to actively target the area. This review covers the latest developments in nanoparticle therapies that focus on breast tumor ECM and stroma. We will explore different approaches using nanoparticles to target the delivery of anticancer drugs like chemotherapy, small molecule drugs, various antitumor products, and other specific synthetic therapeutic agents to the breast tumor stroma. Furthermore, we will investigate the utilization of nanoparticles in altering the stromal elements, such as reprogramming CAFs and immune cells, and also remodeling ECM.

Lung cancer remains the primary cause of cancer-related mortality, with factors such as postoperative tumor recurrence, metastasis, and therapeutic drug resistance exacerbating patient outcomes. Immunotherapy has emerged as a transformative approach, challenging conventional treatment paradigms for lung cancer. Consequently, advancing research in lung cancer immunotherapy is imperative. Recent studies indicate that numerous regulators within the tumor microenvironment (TME) drive tumor angiogenesis and epithelial-mesenchymal transition (EMT); these processes are interdependent, reciprocal, and collectively contribute to tumor progression. Tumor angiogenesis not only supplies adequate oxygen and nutrients for cellular proliferation but also establishes pathways facilitating tumor metastasis and creating hypoxic regions that foster drug resistance. Concurrently, EMT enhances metastatic potential and reinforces drug-resistance genes within tumor cells, creating a reciprocal relationship with angiogenesis. This interplay ultimately results in tumor invasion, metastasis, and therapeutic resistance. This paper reviews key regulators of angiogenesis and EMT, examining their impact on lung cancer immunotherapy and progression, and investigates whether newly identified regulators could influence lung cancer treatment, thus offering valuable insights for developing future therapeutic strategies.

To develop in vitro respiratory models, it is crucial to identify the factors involved in epithelial cell differentiation. In this study, we comprehensively analyzed the effects of air-liquid interface (ALI) culture on epithelial cell differentiation using single-cell RNA sequencing (scRNA-seq). ALI culture induced a pronounced shift in cell composition, marked by a fivefold increase in ciliated cells and a reduction of more than half in basal cells. Transcriptional signatures associated with epithelial cell differentiation, analyzed using iPathwayGuide software, revealed the downregulation of VEGFA and upregulation of CDKN1A as key signals for epithelial differentiation. Our findings highlight the efficacy of the ALI culture for replicating the human lung airway epithelium and provide valuable insights into the crucial factors that influence human ciliated cell differentiation.

Lung cancer is the leading factor of cancer-related death in the worldwide. Hexavalent chromium [Cr(VI)] is a potential carcinogen for inducing lung cancers. To understand new mechanism of Cr(VI)-induced tumorigenesis and cancer development, we identified that PDK1 expression levels were greatly increased in chromium-transformed cells (Cr-T) compared to the parental BEAS-2B (B2B) cells by proteomic profiling and Western blotting; PDK1 levels were also induced in lung cancer cell lines and in lung samples of mice exposed to Cr(VI). Cr(VI) increased Warburg effect, cell migration, proliferation and colony formation through PDK1 upregulation. To identify the mechanism of PDK1 induction, we performed miRNA-seq analysis of Cr-T and B2B cells, and found miR-493 levels was significantly suppressed by Cr(VI). PDK1 was induced by miR-493 suppression, and was a direct target of miR-493. Interestingly, we also found HIF-1α was directly targeting by miR-493 and was induced by miR-493 downregulation. HIF-1α expression levels were upregulated in lung samples of mice with Cr(VI)-exposure. PDK1 was induced by HIF-1α, showing miR-493 suppression can directly induce PDK1 as well as through HIF-1α induction. MiR-493 overexpression was sufficient to suppress tumor growth, PDK1 and HIF-1α expression in vivo. We also showed that levels of miR-493 suppression, HIF-1α and PDK1 elevations were strongly correlated with poor prognosis of lung cancer subjects. These results demonstrate both HIF-1α and PDK1 expression are induced by Cr(VI)-mediated miR-493 suppression, and MiR-493/HIF-1α/PDK1 axis is a new pathway in Cr(VI)-inducing carcinogenesis and tumor growth.

COPD is an inflammatory lung disease that limits airflow and remodels the pulmonary vascular system. This study delves into the therapeutic potential and mechanistic underpinnings of Panax notoginseng Saponins (PNS) in alleviating inflammation and pulmonary vascular remodeling in a COPD rat model. Symmap and ETCM databases provided Panax notoginseng-related target genes, and the CTD and DisGeNET databases provided COPD-related genes. Intersection genes were subjected to protein-protein interaction analysis and pathway enrichment to identify downstream pathways. A COPD rat model was established, with groups receiving varying doses of PNS and a Roxithromycin control. The pathological changes in lung tissue and vasculature were examined using histological staining, while molecular alterations were explored through ELISA, RT-PCR, and Western blot. Network pharmacology research suggested PNS may affect the TLR4/NF-κB pathway linked to COPD development. The study revealed that, in contrast to the control group, the COPD model exhibited a significant increase in inflammatory markers and pathway components such as TLR4, NF-κB, HIF-1α, VEGF, ICAM-1, SELE mRNA, and serum TNF-α, IL-8, and IL-1β. Treatment with PNS notably decreased these markers and mitigated inflammation around the bronchi and vessels. Taken together, the study underscores the potential of PNS in reducing lung inflammation and vascular remodeling in COPD rats, primarily via modulation of the TLR4/NF-κB/HIF-1α/VEGF pathway. This research offers valuable insights for developing new therapeutic strategies for managing and preventing COPD.

Despite various therapeutic attempts, an approved treatment for Methanol-induced optic neuropathy (MION), a sight-threatening disorder, is still lacking. Erythropoietin known as an erythropoietic cytokine, possesses various non-hematopoietic properties that make it a candidate for MION treatment. This systematic review aims to assess the potential therapeutic role of erythropoietin in MION.

We systematically searched English and Persian databases including PubMed, Scopus, Embase, Web of Science, and Scientific Information Database (SID) as of July 2024. Two independent authors screened the articles based on their titles, abstracts, and full texts to finalize the included articles in this study. The selected articles underwent quality assessments via the Joanna Briggs Institute (JBI) checklists.

Out of 139 studies identified in the databases, 11 were finally included in the analysis. These studies encompassed 212 participants, with 192 receiving erythropoietin treatment. Visual acuity (VA) improved in 184 patients, with improvements ranging from no light perception to full vision recovery, or minor enhancements such as an improvement from 1.75 ± 0.72 to 1.32 ± 0.79 LogMAR. Only 8 patients showed no change or experienced deterioration. Additionally, 21 cases exhibited a reduction in retinal nerve fiber layer thickness, with one showing a reduction towards the normal range.

This review highlights erythropoietin's positive impact on VA in patients with MION. However, simultaneous use of erythropoietin and corticosteroids in studies without control groups complicates evaluating erythropoietin's independent efficacy. Future research should involve large, controlled trials to clarify erythropoietin's role and establish it as a standard treatment.

CRD42023485772.

Glioblastoma multiforme (GBM) is the most common adult primary brain tumor. The standard of care involves maximal surgery followed by radiotherapy and concomitant chemotherapy with temozolomide (TMZ), in addition to adjuvant TMZ. However, the recurrence rate of GBM within 1-2 years post-diagnosis is still elevated and has been attributed to the accumulation of multiple factors including the heterogeneity of GBM, genomic instability, angiogenesis, and chronic tumor hypoxia. Tumor hypoxia activates downstream signaling pathways involved in the adaptation of GBM to the newly oxygen-deprived environment, thereby contributing to the resistance and recurrence phenomena, despite the multimodal therapeutic approach used to eradicate the tumor. Therefore, in this review, we will focus on the development and implication of chronic or limited-diffusion hypoxia in tumor persistence through genetic and epigenetic modifications. Then, we will detail the hypoxia-induced activation of vital biological pathways and mechanisms that contribute to GBM resistance. Finally, we will discuss a proteomics-based approach to encourage the implication of personalized GBM treatments based on a hypoxia signature.

This study aims to explore the inhibitory effect of selenium on cervical cancer through suppression of glucose metabolic reprogramming and its underlying mechanisms.

Sodium selenite (SS) treated HeLa and SiHa cells were assessed for proliferation using the CCK-8 assay and immunofluorescence. DNA synthesis was measured with the EdU assay. A nude mouse xenograft model evaluated SS's anti-cervical cancer effects. Reactive oxygen species (ROS) and mitochondrial membrane potential were measured using flow cytometry, DCFH-DA, and JC-1 probes, respectively. Apoptosis was detected via Annexin V/PI staining and Western blot. Glucose uptake, lactate production, and ATP generation were determined using 2-NBDG probes and assay kits. The mRNA and protein levels of glycolysis-related genes HK2, GLUT1, and PDK1 were measured using RT-qPCR and Western blot.

SS inhibited HeLa and SiHa cells viability in a dose- and time-dependent manner. Intraperitoneal injection of SS in nude mice significantly inhibited HeLa cell xenograft growth without evident hepatotoxicity or nephrotoxicity. SS inhibited glucose metabolic reprogramming in cancer cells primarily via ROS-mediated AKT/mTOR/HIF-1α pathway inhibition. Pretreatment with N-acetylcysteine (NAC) or MHY1485 (an mTOR activator) partially reversed the inhibitory effects of SS on glucose metabolic reprogramming, cell proliferation, and migration, as well as its pro-apoptotic effects.

SS exhibited anti-cervical cancer effects, likely through the induction of ROS generation and inhibition of glucose metabolic reprogramming in cervical cancer cells, thereby inhibiting cell proliferation and promoting apoptosis. These findings provide new insights into understanding the molecular mechanisms underlying SS for potential new drug development for cervical cancer.