Search Results (827)

Heterotopic ossification (HO) refers to the pathological formation of bone in soft tissues, typically following trauma, surgical procedures, or as a result of genetic disorders. Notably, injuries to the central nervous system significantly increase the risk of HO, a condition referred to as neurogenic HO (NHO). This review outlines the cellular and molecular mechanisms driving HO, focusing on the inflammatory response, progenitor cell reprogramming, and current treatment strategies. HO is primarily fuelled by a prolonged and dysregulated inflammatory response, characterized by sustained expression of osteoinductive cytokines secreted by M1 macrophages. These cytokines promote the aberrant differentiation of fibro-adipogenic progenitor cells (FAPs) into osteoblasts, leading to ectopic mineralization. Additional factors such as hypoxia, BMP signalling, and mechanotransduction pathways further contribute to extracellular matrix (ECM) remodelling and osteogenic reprogramming of FAPs. In the context of NHO, neuroendocrine mediators enhance ectopic bone formation by influencing both local inflammation and progenitor cell fate decisions. Current treatment options such as nonsteroidal anti-inflammatory drugs (NSAIDs), radiation therapy, and surgical excision offer limited efficacy and are associated with significant risks. Novel therapeutic strategies targeting inflammation, neuropeptide signalling, and calcium metabolism may offer more effective approaches to preventing or mitigating HO progression. Full article

Bone is the most frequent site of distant metastasis in advanced prostate cancer (PCa), contributing substantially to patient morbidity and mortality. Hypoxia, a defining feature of the solid tumour microenvironment, plays a pivotal role in driving bone-tropic progression by promoting epithelial-to-mesenchymal transition (EMT), cancer stemness, extracellular matrix (ECM) remodelling, and activation of key signalling pathways such as Wingless/Integrated (Wnt) Wnt/β-catenin and PI3K/Akt. Hypoxia also enhances the secretion of extracellular vesicles (EVs), enriched with pro-metastatic cargos, and upregulates bone-homing molecules including CXCR4, integrins, and PIM kinases, fostering pre-metastatic niche formation and skeletal colonisation. In this review, we analysed current evidence on how hypoxia orchestrates PCa dissemination to bone, focusing on the molecular crosstalk between HIF signalling, Wnt activation, EV-mediated communication, and cellular plasticity. We further explore therapeutic strategies targeting hypoxia-related pathways, such as HIF inhibitors, hypoxia-activated prodrugs, and Wnt antagonists, with an emphasis on overcoming therapy resistance in castration-resistant PCa (CRPC). By examining the mechanistic underpinnings of hypoxia-driven bone metastasis, we highlight promising translational avenues for improving patient outcomes in advanced PCa. Full article

Diabetic wounds are a devastating complication that cause chronic pain, recurrent infections, and limb amputations due to impaired healing. Despite advances in wound care, existing therapies often fail to address the underlying molecular dysregulation, highlighting the need for innovative and safe therapeutic approaches. Among these, D-amino acids such as D-tryptophan (D-Trp) have emerged as key regulators of cellular processes; however, their therapeutic potential in diabetic wounds remains largely unexplored. Here, we investigate the therapeutic potential of D-Trp in streptozotocin (STZ)-induced diabetic mice, comparing it with phosphate-buffered saline (PBS) controls and vascular endothelial growth factor (VEGF) as a positive control. Wound healing, inflammation, and histopathology were assessed. Protein and gene expression were analyzed via Western blot and RT-qPCR, respectively. Biolayer interferometry (BLI) measured the binding of D-Trp to hypoxia-inducible factor-1α (HIF-1α). D-Trp accelerated wound healing by modulating extracellular matrix (ECM) remodeling, signaling, and apoptosis. It upregulated matrix metalloproteinases (MMP1, MMP3, MMP-9), Janus kinase 2 (JAK2), and mitogen-activated protein kinase (MAPK) proteins while reducing pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], IL-6). D-Trp also suppressed caspase-3 and enhanced angiogenesis through HIF-1α activation. These findings suggest that D-Trp promotes healing by boosting ECM turnover, reducing inflammation, and activating MAPK/JAK pathways. Thus, D-Trp is a promising therapeutic for diabetic wounds. Full article

The tumor microenvironment contains distinctive biomarkers, including acidic pH, elevated levels of reactive oxygen species (ROS), and hypoxia, necessitating the development of efficient biosensors for simplified cancer detection. This study presents an O₂-responsive hydrogel biosensor composed of [1,1′-biphenyl]-2,2′,4,4′,5,5′-hexaol (HDP) and polyvinyl alcohol (PVA) that exploits polyphenol-mediated interactions under N₂ and O₂ microenvironments. The oxidative susceptibility of the polyphenolic HDP moiety influences its distinct mechanical, physical, and electrochemical properties, allowing the differentiation between cancerous and normal cells. The in vitro assessments with cancer cell lines (HeLa and B16F10) and normal cell lines (CHO-K1) enabled distinctive electrical and mechanophysical outputs, as evidenced by enhanced mechanical compressive modulus and high conductivity, regulated by normoxic cellular states. In addition, the inherent ROS-scavenging capability of the HDP–PVA hydrogel sensor supports its potential application in hypoxia-related diseases, including cancer. Full article

High mortality rates and poor quality of life result from the late-stage detection and frequent recurrence of gynecological neoplasms. Background/Objectives: The aim of this study was to conduct a systematic analysis of the energy parameters of photodynamic therapy (PDT) in the treatment of cervical and vulvar lesions, with a focus on stimulating immune responses leading to human papillomavirus (HPV) eradication and lesion regression without adverse effects, such as thermal damage. Methods: A total of 46 peer-reviewed studies published between January 2010 and April 2024 were analyzed. These studies focused on PDT applications for cervical and vulvar lesions, sourced from Google Scholar, Scopus, and Web of Science. Results: Although PDT shows promise, significant limitations exist, such as insufficient consideration of individual tumor characteristics, restricted treatment depths, and the heterogeneous distribution and low selectivity of photosensitizer (PS) accumulation in tumors. Tumor hypoxia further reduces PDT’s effectiveness, and most studies overlook immune system activation, which is crucial for targeting HPV infections and improving antitumor responses. Conclusions: Advancing the research into PDT’s molecular and cellular mechanisms, optimizing the immune response stimulation, and improving the PS and delivery methods could enhance the safety and effectiveness of cervical and vulvar neoplasm treatments. The use of personalized PDT parameters may reduce the side effects and enhance the outcomes for patients suffering from gynecological diseases. Full article

Cellular and molecular characteristics of the tumor microenvironment are fundamental for the formation of niches. These structures include both cellular and matrix components and have been shown to protect and promote cancer formation and progression. The peculiarities of tumor niches have been suggested by many authors as targets with high therapeutic potential. This narrative review analyzes the chemical characteristics of the tumor microenvironment and describes experimental and clinical approaches to influence its contribution to cancer promotion and the spread of metastases. In particular, the possible chemical differences, like pH, oxygen levels, and cell composition, to be used for the design of drugs or the delivery of antiproliferative moieties for a more precise oncology approach, will be discussed. The literature proposes a vast number of molecules, but this review focuses on hypoxia-activated molecules, pH-sensitive nanocarriers, metal-based drugs, and gasotransmitters targeting selectively the tumor microenvironment as possible negative modulators of the contribution of niches to tumor promotion. The chemical peculiarities of the tumor niche are discussed for possible pharmacological developments. Full article

Hypoxia, characterized by a reduction in tissue oxygen levels, is a hallmark of many solid tumors and affects a range of cellular processes, including DNA repair. In low-oxygen conditions, cancer cells often suppress key DNA repair pathways such as homologous recombination (HR), leading to the accumulation of DNA damage and increased genomic instability. These changes not only drive tumor progression but also contribute to resistance against conventional therapies. Hypoxia significantly reduces the effectiveness of oxygen-dependent treatments, including radiotherapy and many chemotherapeutic agents. To address this limitation, bioreductive drugs have been developed that become selectively activated in hypoxic environments, providing targeted cytotoxic effects within oxygen-deprived tumor regions. Additionally, the rapid growth of tumors often results in disorganized and inefficient vasculature, further impairing the delivery of oxygen and therapeutic agents. This review explores the molecular mechanisms by which hypoxia disrupts DNA repair and contributes to treatment resistance. It also presents emerging therapeutic strategies aimed at targeting the hypoxic tumor microenvironment to improve treatment efficacy and patient outcomes. Full article

The intervertebral disc, an anatomical compartment interposed between vertebral bodies, plays a key role in spine flexibility and compression loading. It comprises three tissues: the nucleus pulposus, the annulus fibrosus, and the end plates. Degeneration-related changes in the extracellular matrix of the nucleus pulposus upon ageing or pathological conditions prompted the present investigation into the impact of proteoglycan reduction, the main constituent of the healthy nucleus pulposus, on its physicochemical properties and cellular phenotypical changes. To mimic the native extracellular matrix, three-dimensional NP-mimicking constructs were developed using a biomimetic hydrogel composed of collagen type I, collagen type II, and proteoglycans. This system was fabricated using a bottom-up approach, employing highly pure monomeric collagen types I and II, which were induced to form a reconstituted fibrillar structure closely resembling the natural NP microenvironment. A comprehensive physicochemical characterization was conducted at varying proteoglycan percentages using scanning electron microscopy (SEM), FTIR, rheological tests, and water retention property analysis. The effect of microenvironment changes on the phenotype of nucleus pulposus cells was studied by their encapsulation within the various collagen–proteoglycan hydrogels. The morphological and immunochemistry analysis of the cells was performed to study the cell–matrix adhesion pathways and the expression of the cellular regulator hypoxia-inducible factor 1 alpha. These were linked to the analysis of the synthesis of healthy or pathological extracellular matrix components. The findings reveal that the reduction in proteoglycan content in the nucleus pulposus tissue triggers a pathological pathway, impairing the rheological and water retention properties. Consequently, the cell phenotypes are altered, inducing the synthesis of collagen type I rather than securing the natural physiological remodelling process by the synthesis of collagen type II and proteoglycans. Identifying the proteoglycan content threshold that triggers these pathological phenotypical changes could provide new diagnostic markers and early therapeutic strategies for intervertebral disc degeneration. Full article

High-altitude pulmonary edema (HAPE) is a severe condition associated with high-altitude environments, and its molecular mechanism has not been fully elucidated. This study systematically analyzed the DNA methylation status of HAPE patients and healthy controls using reduced-representation bisulfite sequencing (RRBS) and 850K DNA methylation chips, identifying key differentially methylated regions (DMRs). Targeted bisulfite sequencing (TBS) revealed significant abnormalities in DMRs of five genes, azurocidin 1 (AZU1), growth factor receptor bound protein 7 (GRB7), mannose receptor C-type 2 (MRC2), RUNX family transcription factor 3 (RUNX3), and septin 9 (SEPT9). The abnormal expression of AZU1 was validated using peripheral blood leukocytes from HAPE patients and normal controls, as well as rat lung tissue, indicating its potential importance in the pathogenesis of HAPE. To further validate the function of AZU1, we conducted experimental studies using a hypobaric hypoxia injury model in Human Umbilical Vein Endothelial Cells (HUVEC). The results showed that AZU1 was significantly upregulated under hypobaric hypoxia. Knocking down AZU1 mitigates the reduction in HUVEC proliferation, angiogenesis, and oxidative stress damage induced by acute hypobaric hypoxia. AZU1 induces cellular oxidative stress via the p38/mitogen-activated protein kinase (p38/MAPK) signaling pathway. This study is the first to elucidate the mechanism of AZU1 in HAPE via the p38/MAPK pathway, offering novel insights into the molecular pathology of HAPE and laying a foundation for future diagnostic and therapeutic strategies. Full article

Obesity is a global health crisis with profound implications for cancer risk, particularly within the gastrointestinal (GI) tract. Mounting evidence demonstrates that excess adiposity contributes to the initiation, progression, and poor outcomes of GI malignancies through a constellation of interrelated mechanisms. This review comprehensively examines the biologic pathways linking obesity to cancers of the esophagus, stomach, colon, liver, pancreas, and gallbladder. Chronic low-grade inflammation, driven by adipose tissue-derived cytokines and immune cell infiltration, plays a central role in tumorigenesis via the activation of NF-κB, STAT3, and other pro-oncogenic signaling cascades. Hyperinsulinemia and insulin resistance increase mitogenic IGF-1 signaling, while dysregulated adipokines, particularly elevated leptin and reduced adiponectin, promote cellular proliferation and impair tumor suppression. Dysbiosis of the gut microbiome and alterations in bile acid metabolism generate carcinogenic metabolites that contribute to DNA damage and immune evasion. Additionally, obesity-induced tissue hypoxia fosters tumor growth through HIF-1α-mediated pathways. We further highlight organ-specific associations, such as visceral adiposity’s role in Barrett’s esophagus and hepatocellular carcinoma emerging from metabolic dysfunction-associated steatotic liver disease (MASLD). Importantly, emerging data suggest that weight loss, achieved via lifestyle, pharmacologic, or surgical interventions, may mitigate these carcinogenic pathways and improve tumor biology. As obesity prevalence continues to rise globally, elucidating its mechanistic ties to GI malignancies is essential for risk stratification, prevention strategies, and personalized care. By integrating epidemiologic and molecular insights, this review underscores the need for multidisciplinary approaches to curb the oncogenic burden of obesity and improve outcomes in GI oncology. Full article

Age-related macular degeneration (AMD) is a common cause of blindness worldwide, and it is projected to affect several million individuals by 2040. The human retinal pigment epithelium (hRPE) degenerates in dry AMD, prompting the need to develop stem cell therapies to replace the lost tissue by autologous transplantation and restore the visual function. Nevertheless, the molecular factors behind the hRPE cell fate determination have not been elucidated. Here we identify all molecular determinants of the hRPE cell fate identity by comprehensive and unbiased screening of predicted pioneer factors in the human genome: such TFs mediate coordinated transitions in chromatin accessibility and transcriptional outcome along three major stages of the hRPE genesis. Furthermore, we compile a complete census of all transcription factor-specific binding sites by footprinting analysis of the human epigenome along the RPE developmental trajectory. Gene regulatory networks were found to be involved in cellular responses to glucose and hypoxia, RPE nitrosative stress, type II epithelial-to-mesenchymal transition (EMT), and type III tumorigenic EMT, providing routes for therapeutic intervention on pleiotropic targets dysregulated in AMD, diabetic retinopathy, and cancer progression. Genome editing technologies may leverage this repository to devise functional screenings of regulatory elements and pharmacogenomic therapies in complex diseases, paving the way for strategies in precision medicine. Full article

Prenatal hypoxia (PH) adversely affects the development of the fetal heart, contributing to persistent cardiovascular impairments in postnatal life. A key component in regulating cardiac physiology is the nitric oxide (NO) system, which influences vascular tone, myocardial contractility, and endothelial integrity during development. Exposure to PH disrupts NO-related signaling pathways, leading to endothelial dysfunction, mitochondrial damage, and an escalation of oxidative stress—all of which exacerbate cardiac injury and trigger cardiomyocyte apoptosis. The excessive generation of reactive nitrogen species drives nitrosative stress, thereby intensifying inflammatory processes and cellular injury. In addition, the interplay between NO and hypoxia-inducible factor (HIF) shapes adaptive responses to PH. NO also modulates the synthesis of heat shock protein 70 (HSP70), a critical factor in cellular defense against stress. This review emphasizes the involvement of NO in cardiovascular injury caused by PH and examines the cardioprotective potential of NO modulators—Angiolin, Thiotriazoline, Mildronate, and L-arginine—as prospective therapeutic agents. These agents reduce oxidative stress, enhance endothelial performance, and alleviate the detrimental effects of PH on the heart, offering potential new strategies to prevent cardiovascular disorders in offspring subjected to prenatal hypoxia. Full article

Gestational chronic hypoxia impacts prenatal development, leading to fetal growth restriction (FGR), defined as the fetus’s failure to reach its genetic growth potential. Postnatal hypoxia in the cerebral tissue can induce a redox imbalance and mitochondrial dysfunction, consequently increasing neuronal death. However, these data cannot necessarily be extrapolated to prenatal hypoxia. In this regard, this study aims to describe the effect of gestational hypoxia on redox balance and apoptosis cell death mechanisms in the prefrontal cortex of guinea pigs. Ten Guinea pig (Cavia porcellus) pregnant dams were utilized in this study; five gestated in normoxia (Nx; three newborn males, and two females) and five gestated under chronic hypobaric hypoxia (Hx; two newborn males, and three females). We monitored the pregnancies by ultrasound examinations from gestational days 20 to 65 (term ~ 70). At birth, pups were euthanized, and the fetal brain was collected for cellular redox measurement, mitochondrial enzyme expression, and apoptosis assay. Gestation under hypoxia induced an imbalance in the expression of anti- and pro-oxidant enzymes, resulting in increased oxidative stress. Additionally, a decrease in cytochrome I and III expression and neuronal density in the neonatal prefrontal cortex was observed. Finally, DNA fragmentation was increased by the TUNEL assay in the brain tissue of newborns gestated under chronic hypoxia. Our findings demonstrate the association of gestational hypoxia with oxidative stress and neuronal death in newborns, which may predispose to neuronal dysfunction in adulthood. Full article

Background/objectives: Hypoxia in the tumor microenvironment is linked to aggressiveness, epithelial–mesenchymal transition, metastasis, and therapy resistance. Targeting hypoxia to enhance antitumor immunity is crucial for overcoming therapeutic resistance. Here, we investigated the ability of Evofosfamide, a prodrug that gets activated under hypoxic conditions, to sensitize breast cancer cells to cell death. Evofosfamide is converted into bromo-isophosphoramide mustard, a potent DNA cross-linking agent that is expected to enhance the killing of cancer cells under hypoxic conditions, where these cells typically exhibit resistance. Methods: Representative breast cancer cell lines, MCF-7 and MDA-MB-231, were treated with Evofosfamide under normoxia and hypoxia. Changes in cell viability and the mechanism of cell death were measured using neutral red dye uptake, Annexin-FITC/propidium iodide staining, and Western blot analysis of markers—PARP1 and caspase 3/7. We tested Evofosfamide’s ability to counteract hypoxic suppression of type I Interferon signaling genes using quantitative PCR (qPCR), as well as its capacity to trigger natural killer (NK)-cell-mediated cytotoxicity. Results: Evofosfamide enhanced cell killing in both MCF-7 and MDA-MB-231 cells under hypoxic conditions compared to normoxic conditions. Cell killing was accompanied by increased cellular reactive oxygen species (ROS), diminished mitochondrial membrane potential, and induction of apoptosis, as demonstrated by the fragmentation or laddering of genomic DNA, the activation of caspase 3/7, and the cleavage of PARP. qPCR analysis revealed that Evofosfamide was capable of restoring type I interferon signaling in hypoxic breast cancer cells, leading to the subsequent cytolytic activity of NK cells against the tumor cells. Conclusions: Thus, conditioning the breast cancer cells with Evofosfamide resulted in enhanced cell killing under hypoxia, further underscoring its potential as a sensitizer to target hypoxia-driven tumors. Full article

Hypoxia leads to endothelial dysfunction and increased blood–brain barrier (BBB) permeability, promoting the incidence of diseases such as stroke and acute high-altitude illness. Brain microvascular endothelial cells (BMECs) are important structural and functional components of the BBB; however, the molecular changes that occur in BMECs during hypoxia remain unknown. We reported the molecular and functional changes in BMECs under hypoxia through whole-transcriptome sequencing, small RNA microarray, TMT quantitative proteomic, and untargeted metabolomic analyses. We found that hypoxia affected pathways such as ncRNA processing, the HIF-1 signaling pathway, the cell cycle, DNA replication, glucose metabolism, protein synthesis, and inflammation pathways. ncRNA processing was significantly downregulated. However, the levels of some miRNAs, tRNAs, tsRNAs, snoRNAs, lncRNAs, and circRNAs were significantly upregulated under hypoxia. These results suggest that ncRNAs may play an important role in oxidative stress and cellular adaptation to hypoxia, helping us understand the pathological process of BBB injury and providing potential targets for the treatment of BBB-related cerebrovascular diseases. Full article