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Cell Death Discovery Jun 2024Head and neck squamous cell carcinomas (HNSCCs) are amongst the most aggressive, complex, and heterogeneous malignancies. The standard of care treatments for HNC... (Review)
Review
Head and neck squamous cell carcinomas (HNSCCs) are amongst the most aggressive, complex, and heterogeneous malignancies. The standard of care treatments for HNC patients include surgery, radiotherapy, chemotherapy, or their combination. However, around 50% do not benefit while suffering severe toxic side effects, costing the individuals and society. Decades have been spent to improve HNSCC treatment outcomes with only limited success. Much of the research in HNSCC treatment has focused on understanding the genetics of the HNSCC malignant cells, but it has become clear that tumour microenvironment (TME) plays an important role in the progression as well as treatment response in HNSCC. Understanding the crosstalk between cancer cells and TME is crucial for inhibiting progression and treatment resistance. Cancer-associated fibroblasts (CAFs), the predominant component of stroma in HNSCC, serve as the primary source of extra-cellular matrix (ECM) and various pro-tumoral composites in TME. The activation of CAFs in HNSCC is primarily driven by cancer cell-secreted molecules, which in turn induce phenotypic changes, elevated secretive status, and altered ECM production profile. Concurrently, CAFs play a pivotal role in modulating the cell cycle, stemness, epithelial-mesenchymal transition (EMT), and resistance to targeted and chemoradiotherapy in HNSCC cells. This modulation occurs through interactions with secreted molecules or direct contact with the ECM or CAF. Co-culture and 3D models of tumour cells and other TME cell types allows to mimic the HNSCC tumour milieu and enable modulating tumour hypoxia and reprograming cancer stem cells (CSC). This review aims to provide an update on the development of HNSCC tumour models comprising CAFs to obtain better understanding of the interaction between CAFs and tumour cells, and for providing preclinical testing platforms of current and combination with emerging therapeutics.
PubMed: 38926351
DOI: 10.1038/s41420-024-02053-9 -
Redox Biology Jun 2024Pulmonary vascular remodeling and inflammation play an important role in the hypoxic-induced lung diseases. Our previous investigations showed that peptide from yak milk...
Pulmonary vascular remodeling and inflammation play an important role in the hypoxic-induced lung diseases. Our previous investigations showed that peptide from yak milk residues could alleviate inflammation. In this study, our results suggest that peptide (LV) from yak milk residues peptide had protective effect of lung in the animal models of hypoxic-induced lung injury. LV Gavage could improve pulmonary vascular remodeling in the lung tissues of hypoxic mice. A comprehensive analysis of metabolomics and transcriptomics revealed that 5-KETE, 8,9-EET, and 6-keto-prostaglandin F1a might be potential targets to prevent lung injury in the hypoxic mice. These metabolites can be regulated by MAPK/VEGF and inflammatory pathways. Our data indicated that LV treatment could inhibit apoptosis and inflammation via Nrf2/NF-κB/MAPK/PHD-2 pathway and protected hypoxic-induced lung epithelial cells injury. Taken together, our results suggest that LV provides a novel therapeutic clue for the prevention of hypoxia-induced lung injury and inflammation-related lung diseases.
PubMed: 38925040
DOI: 10.1016/j.redox.2024.103252 -
ELife Jun 2024During tuberculosis (TB), migration of dendritic cells (DCs) from the site of infection to the draining lymph nodes is known to be impaired, hindering the rapid...
During tuberculosis (TB), migration of dendritic cells (DCs) from the site of infection to the draining lymph nodes is known to be impaired, hindering the rapid development of protective T-cell-mediated immunity. However, the mechanisms involved in the delayed migration of DCs during TB are still poorly defined. Here, we found that infection of DCs with (Mtb) triggers HIF1A-mediated aerobic glycolysis in a TLR2-dependent manner, and that this metabolic profile is essential for DC migration. In particular, the lactate dehydrogenase inhibitor oxamate and the HIF1A inhibitor PX-478 abrogated Mtb-induced DC migration in vitro to the lymphoid tissue-specific chemokine CCL21, and in vivo to lymph nodes in mice. Strikingly, we found that although monocytes from TB patients are inherently biased toward glycolysis metabolism, they differentiate into poorly glycolytic and poorly migratory DCs compared with healthy subjects. Taken together, these data suggest that because of their preexisting glycolytic state, circulating monocytes from TB patients are refractory to differentiation into migratory DCs, which may explain the delayed migration of these cells during the disease and opens avenues for host-directed therapies for TB.
Topics: Dendritic Cells; Glycolysis; Monocytes; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mycobacterium tuberculosis; Cell Movement; Animals; Tuberculosis; Mice; Toll-Like Receptor 2; Mice, Inbred C57BL; Female
PubMed: 38922679
DOI: 10.7554/eLife.89319 -
Toxins May 2024A major pathogenic factor is the cholesterol-dependent cytolysin pneumolysin, binding membrane cholesterol and producing permanent lytic or transient pores. During...
A major pathogenic factor is the cholesterol-dependent cytolysin pneumolysin, binding membrane cholesterol and producing permanent lytic or transient pores. During brain infections, vascular damage with variable ischemia occurs. The role of ischemia on pneumolysin's pore-forming capacity remains unknown. In acute brain slice cultures and primary cultured glia, we studied acute toxin lysis (via propidium iodide staining and LDH release) and transient pore formation (by analyzing increases in the intracellular calcium). We analyzed normal peripheral tissue glucose conditions (80 mg%), normal brain glucose levels (20 mg%), and brain hypoglycemic conditions (3 mg%), in combinations either with normoxia (8% oxygen) or hypoxia (2% oxygen). At 80 mg% glucose, hypoxia enhanced cytolysis via pneumolysin. At 20 mg% glucose, hypoxia did not affect cell lysis, but impaired calcium restoration after non-lytic pore formation. Only at 3 mg% glucose, during normoxia, did pneumolysin produce stronger lysis. In hypoglycemic (3 mg% glucose) conditions, pneumolysin caused a milder calcium increase, but restoration was missing. Microglia bound more pneumolysin than astrocytes and demonstrated generally stronger calcium elevation. Thus, our work demonstrated that the toxin pore-forming capacity in cells continuously diminishes when oxygen is reduced, overlapping with a continuously reduced ability of cells to maintain homeostasis of the calcium influx once oxygen and glucose are reduced.
Topics: Streptolysins; Glucose; Animals; Bacterial Proteins; Oxygen; Cholesterol; Streptococcus pneumoniae; Brain; Calcium; Cells, Cultured; Neuroglia
PubMed: 38922127
DOI: 10.3390/toxins16060232 -
Journal of Functional Morphology and... May 2024Hypoxia increases inspiratory muscle work and consequently contributes to a reduction in exercise performance. We evaluate the effects of inspiratory muscle warm-up...
Hypoxia increases inspiratory muscle work and consequently contributes to a reduction in exercise performance. We evaluate the effects of inspiratory muscle warm-up (IMW) on a 10 km cycling time trial in normoxia (NOR) and hypoxia (HYP). Eight cyclists performed four time trial sessions, two in HYP (FiO: 0.145) and two in NOR (FiO: 0.209), of which one was with IMW (set at 40% of maximal inspiratory pressure-MIP) and the other was with the placebo effect (PLA: set at 15% MIP). Time trials were unchanged by IMW (NOR: 893.8 ± 31.5 vs. NOR: 925.5 ± 51.0 s; HYP: 976.8 ± 34.2 vs. HYP: 1008.3 ± 56.0 s; > 0.05), while ventilation was higher in HYP (107.7 ± 18.3) than HYP (100.1 ± 18.9 L.min; ≤ 0.05), and SpO was lower (HYP: 73 ± 6 vs. HYP: 76 ± 6%; ≤ 0.05). A post-exercise-induced reduction in inspiratory strength was correlated with exercise elapsed time during IMW sessions (HYP: r = -0.79; ≤ 0.05; NOR: r = -0.70; ≤ 0.05). IMW did not improve the 10 km time trial performance under normoxia and hypoxia.
PubMed: 38921633
DOI: 10.3390/jfmk9020097 -
Insects Jun 2024The skin beetle is regularly found beyond North America where it originated. The larvae cause considerable concern in museums, as they damage hides or furs in addition...
The skin beetle is regularly found beyond North America where it originated. The larvae cause considerable concern in museums, as they damage hides or furs in addition to being a special source of damage to collections of dried plants in herbaria or collections of insects and other zoological specimens. arrived in Europe in the mid-20th century and was associated mostly with stored food products, but over time, it has become recognised as a museum pest. Although it is still uncommon and may only be observed in a small fraction of museums, when the insect is found in large numbers, it can cause problems. Catches from blunder traps in Austrian museums and from an online database in the UK were used to track changing concern over the insect. As a single female beetle can continue to reproduce because the species is parthenogenetic, its presence can persist over long periods of time. Although small populations in museums are typically found in the adult form, the larval forms are more common where a site is infested by high numbers, perhaps because the larvae and adults must range more widely for food. Although can be controlled using pesticides, it is also possible to kill the larvae within infested materials through freezing or anoxia.
PubMed: 38921120
DOI: 10.3390/insects15060405 -
Current Issues in Molecular Biology Jun 2024Human papillomavirus 16 (HPV 16) infection is associated with several types of cancer, such as head and neck, cervical, anal, and penile cancer. Its oncogenic potential...
Bioinformatics Analysis Reveals E6 and E7 of HPV 16 Regulate Metabolic Reprogramming in Cervical Cancer, Head and Neck Cancer, and Colorectal Cancer through the PHD2-VHL-CUL2-ELOC-HIF-1α Axis.
Human papillomavirus 16 (HPV 16) infection is associated with several types of cancer, such as head and neck, cervical, anal, and penile cancer. Its oncogenic potential is due to the ability of the E6 and E7 oncoproteins to promote alterations associated with cell transformation. HPV 16 E6 and E7 oncoproteins increase metabolic reprogramming, one of the hallmarks of cancer, by increasing the stability of hypoxia-induced factor 1 α (HIF-1α) and consequently increasing the expression levels of their target genes. In this report, by bioinformatic analysis, we show the possible effect of HPV 16 oncoproteins E6 and E7 on metabolic reprogramming in cancer through the E6-E7-PHD2-VHL-CUL2-ELOC-HIF-1α axis. We proposed that E6 and E7 interact with VHL, CUL2, and ELOC in forming the E3 ubiquitin ligase complex that ubiquitinates HIF-1α for degradation via the proteasome. Based on the information found in the databases, it is proposed that E6 interacts with VHL by blocking its interaction with HIF-1α. On the other hand, E7 interacts with CUL2 and ELOC, preventing their binding to VHL and RBX1, respectively. Consequently, HIF-1α is stabilized and binds with HIF-1β to form the active HIF1 complex that binds to hypoxia response elements (HREs), allowing the expression of genes related to energy metabolism. In addition, we suggest an effect of E6 and E7 at the level of PHD2, VHL, CUL2, and ELOC gene expression. Here, we propose some miRNAs targeting PHD2, VHL, CUL2, and ELOC mRNAs. The effect of E6 and E7 may be the non-hydroxylation and non-ubiquitination of HIF-1α, which may regulate metabolic processes involved in metabolic reprogramming in cancer upon stabilization, non-degradation, and translocation to the nucleus.
PubMed: 38921041
DOI: 10.3390/cimb46060370 -
Cells Jun 2024Tumour hypoxia is a known microenvironmental culprit for treatment resistance, tumour recurrence and promotion of metastatic spread. Despite the long-known existence of... (Review)
Review
Tumour hypoxia is a known microenvironmental culprit for treatment resistance, tumour recurrence and promotion of metastatic spread. Despite the long-known existence of this factor within the tumour milieu, hypoxia is still one of the greatest challenges in cancer management. The transition from invasive and less reliable detection methods to more accurate and non-invasive ways to identify and quantify hypoxia was a long process that eventually led to the promising results showed by functional imaging techniques. Hybrid imaging, such as PET-CT, has the great advantage of combining the structural or anatomical image (offered by CT) with the functional or metabolic one (offered by PET). However, in the context of hypoxia, it is only the PET image taken after appropriate radiotracer administration that would supply hypoxia-specific information. To overcome this limitation, the development of the latest hybrid imaging systems, such as PET-MRI, enables a synergistic approach towards hypoxia imaging, with both methods having the potential to provide functional information on the tumour microenvironment. This study is designed as a systematic review of the literature on the newest developments of PET-MRI for the imaging of hypoxic cells in breast cancer. The analysis includes the affinity of various PET-MRI tracers for hypoxia in this patient group as well as the correlations between PET-specific and MRI-specific parameters, to offer a broader view on the potential for the widespread clinical implementation of this hybrid imaging technique.
Topics: Humans; Breast Neoplasms; Magnetic Resonance Imaging; Positron-Emission Tomography; Female; Cell Hypoxia; Tumor Microenvironment; Tumor Hypoxia
PubMed: 38920676
DOI: 10.3390/cells13121048 -
Frontiers in Physiology 2024Maternal obstructive sleep apnea (OSA) during pregnancy is the risk factor for impaired fetal growth with low birth weight in the offspring. However, it is unclear...
INTRODUCTION
Maternal obstructive sleep apnea (OSA) during pregnancy is the risk factor for impaired fetal growth with low birth weight in the offspring. However, it is unclear whether gestational intermittent hypoxia (IH, a hallmark of maternal OSA) has long-term detrimental consequences on the skeletal development of offspring. This study aimed to investigate postnatal maxillofacial bone growth and cartilage metabolism in male and female offspring that were exposed to gestational IH.
METHODS
Mother rats underwent IH at 20 cycles/h (nadir, 4% O; peak, 21% O; 0% CO) for 8 h per day during gestational days (GD) 7-20, and their male and female offspring were analyzed postnatally at 5 and 10 weeks of age. All male and female offspring were born and raised under normoxic conditions.
RESULTS
There was no significant difference in whole-body weight and tibial length between the IH male/female offspring and their control counterparts. In contrast, the mandibular condylar length was significantly shorter in the IH male offspring than in the control male offspring at 5 and 10 weeks of age, while there was no significant difference in the female offspring. Real-time polymerase chain reaction (PCR) showed that gestational IH significantly downregulated the mRNA level of SOX9 (a chondrogenesis marker) and upregulated the mRNA level of HIF-1α (a hypoxia-inducible factor marker) in the mandibular condylar cartilage of male offspring, but not in female offspring.
CONCLUSION
Gestational IH induced underdeveloped mandibular ramus/condyles and reduced mRNA expression of SOX9, while enhancing mRNA expression of HIF-1α in a sex-dependent manner.
PubMed: 38919850
DOI: 10.3389/fphys.2024.1397262 -
Biodesign Research 2024Recently, there has been increasing interest in the use of bacteria for cancer therapy due to their ability to selectively target tumor sites and inhibit tumor growth....
Recently, there has been increasing interest in the use of bacteria for cancer therapy due to their ability to selectively target tumor sites and inhibit tumor growth. However, the complexity of the interaction between bacteria and tumor cells evokes unpredictable therapeutic risk, which induces inflammation, stimulates the up-regulation of cyclooxygenase II (COX-2) protein, and stimulates downstream antiapoptotic gene expression in the tumor microenvironment to reduce the antitumor efficacy of chemotherapy and immunotherapy. In this study, we encapsulated celecoxib (CXB), a specific COX-2 inhibitor, in liposomes anchored to the surface of Nissle 1917 (ECN) through electrostatic absorption (C@ECN) to suppress ECN-induced COX-2 up-regulation and enhance the synergistic antitumor effect of doxorubicin (DOX). C@ECN improved the antitumor effect of DOX by restraining COX-2 expression. In addition, local T lymphocyte infiltration was induced by the ECN to enhance immunotherapy efficacy in the tumor microenvironment. Considering the biosafety of C@ECN, a hypoxia-induced lysis circuit, pGEX-Pvhb-Lysis, was introduced into the ECN to limit the number of ECNs in vivo. Our results indicate that this system has the potential to enhance the synergistic effect of ECN with chemical drugs to inhibit tumor progression in medical oncology.
PubMed: 38919710
DOI: 10.34133/bdr.0038