Hypoxic Conditions Research Articles

Influence of Hypoxic Condition on Cytotoxicity, Cellular Migration, and Osteogenic Differentiation Potential of Aged Periodontal Ligament Cells.

This study aimed to investigate and compare the influence of hypoxic conditions on cytotoxicity, cellular migration, and osteogenic differentiation of aged periodontal ligament (PDL) cells. Isolated human PDL cells from aged and young subjects were cultured under hypoxic conditions, which were treated with hydrogen peroxide (H2O2) (0, 25, 50, 100, 200, and 500 µM). To assess cytotoxicity, lactate dehydrogenase release was determined by the optical density at 490 nm, and the percentage of cell death was calculated. An in vitro wound healing assay was performed over 24 to 48 hours for cellular migration determination. Osteogenic differentiation was determined by alizarin red staining and osteogenic gene expression, including the expression of runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), and osteopontin (OPN). There was a significant difference in the percentage of cell death with high hypoxic condition (200 and 500 µM) compared to low hypoxic conditions on both day 1 and 2. The highest cellular migration was depicted at 50 µM in both young and aged groups of the in vitro wound healing assay. Osteogenic gene expression of RUNX2 in the aged group was increased at 25 and 50 µM hypoxic condition at day 7, but the expression was gradually decreased after 14 days. On the contrary, the expression of ALP and OPN in the aged group was increased at day 14. Only OPN had been found to be statistically significantly different when compared with gene expression at day 7 and 14 (p < 0.05). The results showed no statistically significant differences when compared with the young and aged groups in all genes and all concentrations. The concentration of low hypoxic condition (25-50 µM) was proposed to promote cell viability, cellular migration, and osteogenic differentiation in aged PDL cells. We suggested that the potential of aged PDL cells for use in cell therapy for periodontal regeneration might possibly be similar to that of young PDL cells.

Analysis on promotive effect of rocking culture on keratinocyte differentiation in three-dimensional reconstitution human epidermis.

A three-dimensional culture system of keratinocytes achieves cornification as a terminal differentiation that can mimic the formation of stratified epidermis. At the onset of keratinocyte differentiation, air-exposure treatment is essential for promotion. We have previously reported that the stimulation of differentiation is accompanied by down-regulation of the transcriptional activity of the hypoxia-inducible factor (HIF) and also found that rocking treatment of cultured keratinocytes in the submerged condition restored their differentiation. A comparative study between with and without rocking was then carried out to investigate the characteristics of the recovered differentiation by morphological and biochemical analysis. In addition, transcriptome analysis revealed the expected similar pattern between air-exposure and rocking culture, including HIF-regulating transcripts. Furthermore, the promotive effect of rocking treatment was impaired under hypoxic culture conditions (1% O2). We showed that the restored promotion of differentiation by rocking culture is mainly due to the abrogation of transcriptional events by hypoxia.

Regulation of copper uptake by the SWI/SNF chromatin remodeling complex in Candida albicans affects susceptibility to antifungal and oxidative stresses under hypoxia.

Candida albicans is a human colonizer and also an opportunistic yeast occupying different niches that are mostly hypoxic. While hypoxia is the prevalent condition within the host, the machinery that integrates oxygen status to tune the fitness of fungal pathogens remains poorly characterized. Here, we uncovered that, Snf5, a subunit of the chromatin remodeling complex SWI/SNF, is required to tolerate antifungal stress particularly under hypoxia. RNA-seq profiling of snf5 mutant exposed to amphotericin B and fluconazole under hypoxic conditions uncovered a signature that is reminiscent of copper (Cu) starvation. We found that under hypoxic and Cu-starved environments, Snf5 is critical for preserving Cu homeostasis and the transcriptional modulation of the Cu regulon. Furthermore, snf5 exhibits elevated levels of reactive oxygen species and an increased sensitivity to oxidative stress principally under hypoxia. Supplementing growth medium with Cu or increasing gene dosage of the copper transporter CTR1 alleviated snf5 growth defect and attenuated ROS levels in response to antifungal challenge. Genetic interaction analysis suggests that Snf5 and the bona fide Cu homeostasis regulator Mac1, function in separate pathways. Together, our data underlined a unique role of SWI/SNF complex as a potent regulator of copper metabolism and antifungal stress under hypoxia.

Seasonal hypoxia enhances sediment iron-bound phosphorus release in a subtropical river reservoir.

Dams worldwide commonly accelerate the eutrophication of reservoirs. While the seasonal hypoxia in deep reservoirs is widely acknowledged, there is limited research on its impact on benthic phosphorus (P) cycling and P fraction release from the reservoir sediments. Here we show that seasonal hypoxia enhances sediment P release and P fluxes at the sediment-water interface (SWI) which might alter P dynamics in deep reservoirs. We conducted a detailed measurement of sediment P fractions through the SEDEX approach, combined with a labile P gradient analysis using the diffusive gradients in thin films (DGT) technique to understand P cycling patterns in sediments during the transition period from spring (oxic) to late summer (hypoxic) conditions. The sediment P pool was predominantly composed of iron-bound phosphorus (FeP, 76-80 %), primarily due to the widespread occurrence of lateritic red soil (rich in Fe2O3/MnO2) in subtropical areas. More organic-P was observed in summer compared to spring. A significant increase in labile P occurred at the depth of 0-4 cm and 0-1 cm in spring and summer, respectively, where sediment P release was primarily governed by the reduction of FeP and the generation of S2-. A higher apparent fluxes of phosphate across the SWI were observed in summer characterized by higher temperature and lower oxygen levels. The current results suggest that seasonal hypoxia was a crucial factor affecting P cycling and diffusion in deep reservoirs. These findings present important implications for the ecology and management of the watershed-coast ecosystem.

HYPOXIA induces lncRNA HOTAIR for recruiting RELA in papillary thyroid cancer cells to upregulate miR-181a and promote angiogenesis.

Papillary thyroid carcinoma (PTC) is one of the most common subtypes of thyroid carcinoma. Exosomal miR-181a plays an important role in the development of PTC. This study examined the regulatory mechanism of miR-181a under conditions of hypoxia and its impact on angiogenesis. A ribonucleoprotein immunoprecipitation (RIP) experiment was conducted to verify the interaction between HOTAIR and RELA. The relationship between RELA and the miR-181a promoter was detected by ChIP-qPCR. Short hairpin (sh) RNA was designed to knock down HOTAIR in TPC cells. The underlying mechanism of miR-181a was verified by use of dual-luciferase assays and rescue experiments. The regulatory effect of GATA6 on angiogenesis was studied using CCK8, EdU, Transwell, and western blot assays. A RIP assay showed that HOTAIR could bind to RELA under hypoxic conditions. ChIP-qPCR and dual luciferase assays showed RELA could interact with the miR181a promoter and upregulate miR-181a. Knockdown of HOTAIR downregulated miR-181a in TPC-1 cells, and the downregulation could be rescued by RELA overexpression. MiR-181a downregulated GATA6 in HUVEC cells. Overexpression of GATA6 inhibited HUVEC proliferation, migration, tube formation, and EGFR expression. Exosomal miR-181a promoted angiogenesis by downregulating GATA6 expression. HOTAIR activated RELA to upregulate miR-181a during hypoxia. Exosomal miR-181a promotes tumor angiogenesis by downregulating GATA6.

Molecular engineering design of twisted-backbone pure Type-I organic photosensitizers for hypoxic photodynamic therapy.

Photodynamic therapy (PDT), an emerging tumor therapeutic strategy has received tremendous attention. Enslaved by the high dependence of oxygen, Type-II photosensitizers (PSs) mediated PDT is restricted by the hypoxic environment of tumors. By transferring electrons to water or other substrates instead of oxygen, Type-I PSs hold the promise of achieving an ideal therapeutic effect under hypoxic conditions. In this study, three twisted-backbone PSs (CBz-TQs-1, CBz-TQs-2 and CBz-TQs-3) are synthesized and studied. Owing to different substituent effects, the ROS generation mechanism transfers from pure Type-II of their prototype PSs (TQs-1, TQs-2 and TQs-3) to mixed Type-I/II of CBz-TQs-1 and CBz-TQs-2 to pure Type-I of CBz-TQs-3. Moreover, CBz-TQs-3 exhibits an ultra-high ROS quantum yield (∼1.0). The in vitro and in vivo PDT effects of water-dissolvable nanoparticles (NPs) of CBz-TQs-3 are investigated. The results show that the phototoxicity of CBz-TQs-3 is not affected by hypoxic environments. In addition, a remarkable tumor ablation can be found after CBz-TQs-3 NPs mediated PDT on Balb/c mice with xenograft tumors. It proves that a twisted backbone strategy is beneficial for designing pure Type-I PSs with high-efficient hypoxic PDT.

Sex and APOE Genotype Influence Respiratory Function Under Hypoxic and Hypoxic-Hypercapnic Conditions.

The apolipoprotein (APOE) gene has been studied due to its influence on Alzheimer's disease (AD) development and work in an APOE mouse model recently demonstrated impaired respiratory motor plasticity following spinal cord injury (SCI). Individuals with AD often co-present with obstructive sleep apnea (OSA) characterized by cessations in breathing during sleep. Despite the prominence of APOE genotype and sex as factors in AD progression, little is known about the impact of these variables on respiratory control. Ventilation is tightly regulated across many systems, with respiratory rhythm formation occurring in the brainstem but modulated in response to chemoreception. Alterations within these modulatory systems may result in disruptions of appropriate respiratory control and ultimately, disease. Using mice expressing two different humanized APOE alleles, we characterized how sex and the presence of APOE3 or APOE4 influences ventilation during baseline breathing (normoxia) and during respiratory challenge. We show that sex and APOE genotype influence breathing during hypoxic challenge, which may have clinical implications in the context of AD and OSA. Additionally, female mice, while responding robustly to hypoxia, were unable to recover to baseline respiratory levels, emphasizing sex differences in disordered breathing.

Novel Acetamide-Based HO-1 Inhibitor Counteracts Glioblastoma Progression by Interfering with the Hypoxic–Angiogenic Pathway

Glioblastoma multiforme (GBM) represents the deadliest tumor among brain cancers. It is a solid tumor characterized by uncontrolled cell proliferation generating the hypoxic niches in the cancer core. By inducing the transcription of hypoxic inducible factor (HIF), hypoxia triggers many signaling cascades responsible for cancer progression and aggressiveness, including enhanced expression of vascular endothelial growth factor (VEGF) or antioxidant enzymes, such as heme oxygenase-1 (HO-1). The present work aimed to investigate the link between HO-1 expression and the hypoxic microenvironment of GBM by culturing two human glioblastoma cell lines (U87MG and A172) in the presence of a hypoxic mimetic agent, deferoxamine (DFX). By targeting hypoxia-induced HO-1, we have tested the effect of a novel acetamide-based HO-1 inhibitor (VP18/58) on GBM progression. Results have demonstrated that hypoxic conditions induced upregulation and nuclear expression of HO-1 in a cell-dependent manner related to malignant phenotype. Moreover, our data demonstrated that the HO-1 inhibitor counteracted GBM progression by modulating the HIFα/HO-1/VEGF signaling cascade in cancer cells bearing more malignant phenotypes.

Examining the Influence of Cognitive Load and Environmental Conditions on Autonomic Nervous System Response in Military Aircrew: A Hypoxia–Normoxia Study

Executing flight operations demand that military personnel continuously perform tasks that utilize low- and high-order cognitive functions. The autonomic nervous system (ANS) is crucial for regulating the supply of oxygen (O2) to the brain, but it is unclear how sustained cognitive loads of different complexities may affect this regulation. Therefore, in the current study, ANS responses to low and high cognitive loads in hypoxic and normoxic conditions were evaluated. The present analysis used data from a previously conducted, two-factor experimental design. Healthy subjects (n = 24) aged 19 to 45 years and located near Fort Novosel, AL, participated in the parent study. Over two, 2-h trials, subjects were exposed to hypoxic (14.0% O2) and normoxic (21.0% O2) air while simultaneously performing one, 15-min and one, 10-min simulation incorporating low- and high-cognitive aviation-related tasks, respectively. The tests were alternated across five, 27-min epochs; however, only epochs 2 through 4 were used in the analyses. Heart rate (HR), HR variability (HRV), and arterial O2 saturation were continuously measured using the Warfighter MonitorTM (Tiger Tech Solutions, Inc., Miami, FL, USA), a previously validated armband device equipped with electrocardiographic and pulse oximetry capabilities. Analysis of variance (ANOVA) regression models were performed to compare ANS responses between the low- and high-cognitive-load assessments under hypoxic and normoxic conditions. Pairwise comparisons corrected for familywise error were performed using Tukey’s test within and between high and low cognitive loads under each environmental condition. Across epochs 2 through 4, in both the hypoxic condition and the normoxic condition, the high-cognitive-load assessment (MATB-II) elicited heightened ANS activity, reflected by increased HR (+2.4 ± 6.9 bpm) and decreased HRV (−rMSSD: −0.4 ± 2.7 ms and SDNN: −13.6 ± 14.6 ms). Conversely, low cognitive load (ADVT) induced an improvement in ANS activity, with reduced HR (−2.6 ± 6.3 bpm) and increased HRV (rMSSD: +1.8 ± 6.0 ms and SDNN: vs. +0.7 ± 6.3 ms). Similar observations were found for the normoxic condition, albeit to a lower degree. These within-group ANS responses were significantly different between high and low cognitive loads (HR: +5.0 bpm, 95% CI: 2.1, 7.9, p &lt; 0.0001; rMSSD: −2.2 ms, 95% CI: −4.2, −0.2, p = 0.03; SDNN: −14.3 ms, 95% CI: −18.4, −10.1, p &lt; 0.0001) under the hypoxic condition. For normoxia, significant differences in ANS response were only observed for HR (+4.3 bpm, 95% CI: 1.2, 7.4, p = 0.002). Lastly, only high cognitive loads elicited significant differences between hypoxic and normoxic conditions but just for SDNN (−13.3 ms, 95% CI, −17.5, −8.9, p &lt; 0.0001). Our study observations suggest that compared to low cognitive loads, performing high-cognitive-load tasks significantly alters ANS activity, especially under hypoxic conditions. Accounting for this response is critical, as military personnel during flight operations sustain exposure to high cognitive loads of unpredictable duration and frequency. Additionally, this is likely compounded by the increased ANS activity consequent to pre-flight activities and anticipation of combat-related outcomes.

Role of Hypoxia and Rac1 Inhibition in the Metastatic Cascade

The hypoxic condition has a pivotal role in solid tumors and was shown to correlate with the poor outcome of anticancer treatments. Hypoxia contributes to tumor progression and leads to therapy resistance. Two forms of a hypoxic environment might have relevance in tumor mass formation: chronic and cyclic hypoxia. The main regulators of hypoxia are hypoxia-inducible factors, which regulate the cell survival, proliferation, motility, metabolism, pH, extracellular matrix function, inflammatory cells recruitment and angiogenesis. The metastatic process consists of different steps in which hypoxia-inducible factors can play an important role. Rac1, belonging to small G-proteins, is involved in the metastasis process as one of the key molecules of migration, especially in a hypoxic environment. The effect of hypoxia on the tumor phenotype and the signaling pathways which may interfere with tumor progression are already quite well known. Although the role of Rac1, one of the small G-proteins, in hypoxia remains unclear, predominantly, in vitro studies performed so far confirm that Rac1 inhibition may represent a viable direction for tumor therapy

Interplay of hypoxia and host cells in the translocation, invasion and dissemination of Taenia solium in neurocysticercosis

Neurocysticercosis, caused by the invasion of the central nervous system (CNS) by Taenia solium larvae, poses a significant global health burden. Despite its prevalence and severe neurological consequences, understanding of the molecular and signalling pathways facilitating parasite dissemination and CNS invasion is limited. The lack of comprehensive knowledge of host-parasite interactions and associated proteins involved in T. solium infection hinders the development of targeted interventions to mitigate its ability to cross the epithelia barrier. This is complicated by reduced oxygen availability in the intestine, a phenomenon called hypoxia. Hypoxia can result in epithelial barrier disruption and cell damage, thereby promoting the translocation and dissemination of T. solium. This study aims to establish the role of hypoxia in T. solium invasion and disseminated infections. The effect of hypoxia on the migration, viability and morphological characteristics of T. solium would be determined using transwell invasion assays, flow cytometry and microscopy. T. solium oncosphere development and dissemination under hypoxic and normoxic conditions will be monitored using animal models. Also, host-parasite transcriptome and proteome profiling will be performed to determine pathways triggered under hypoxic conditions. It is expected that hypoxia would promote the invasion and dissemination of T. solium by enhancing epithelial and endothelial cell permeability. , hypoxia will induce the expression of binding and adhesion proteins and other virulence markers such as enolase, serpin, and glutathione transferases that are involved in host invasion. Understanding the role of hypoxia in the translocation mechanism of T. solium can be leveraged to provide insights into host tissues dissemination and the development of appropriate interventions.

Hypoxic adipose stem cell-derived exosomes carrying high-abundant USP22 facilitate cutaneous wound healing through stabilizing HIF-1α and upregulating lncRNA H19.

Hypoxic preconditioning has been recognized as a promotive factor for accelerating cutaneous wound healing. Our previous study uncovered that exosomal lncRNA H19, derived from adipose-derived stem cells (ADSCs), plays a crucial role in orchestrating cutaneous wound healing. Herein, we aimed to explore whether there is a connection between hypoxia and ADSC-derived exosomes (ADSCs-exos) in cutaneous wound healing. Exosomes extracted from ADSCs under normoxic and hypoxic conditions were identified using transmission electron microscope (TEM) and particle size analysis. The effects of ADSCs-exos on the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) were evaluated by CCK-8, EdU, wound healing, and tube formation assays. Expression patterns of H19, HIF-1α, and USP22 were measured. Co-immunoprecipitation, chromatin immunoprecipitation, ubiquitination, and luciferase reporter assays were conducted to confirm the USP22/HIF-1α/H19 axis, which was further validated in a mice model of skin wound. Exosomes extracted from hypoxia-treated ADSCs (termed as H-ADSCs-exos) significantly increased cell proliferation, migration, and angiogenesis in H2O2-exposed HUVECs, and promoted cutaneous wound healing invivo. Moreover, H-ADSCs and H-ADSCs-exos, which exhibited higher levels of H19, were found to be transcriptionally activated by HIF-1α. Mechanically, H-ADSCs carrying USP22 accounted for deubiquitinating and stabilizing HIF-1α. Additionally, H-ADSCs-exos improved cell proliferation, migration, and angiogenesis in H2O2-triggered HUVECs by activating USP22/HIF-1α axis and promoting H19 expression, which may provide a new clue for the clinical treatment of cutaneous wound healing.

Lactobacillus delbrueckii subsp. bulgaricus Alleviates Acute Injury in Hypoxic Mice

Acute mountain sickness (AMS) is a common ailment in high-altitude areas caused by the body’s inadequate adaptation to low-pressure, low-oxygen environments, leading to organ edema, oxidative stress, and impaired intestinal barrier function. The gastrointestinal tract, being the first to be affected by ischemia and hypoxia, is highly susceptible to injury. This study investigates the role of Lactobacillus delbrueckii subsp. bulgaricus in alleviating acute hypoxic-induced intestinal and tissue damage from the perspective of daily consumed lactic acid bacteria. An acute hypoxia mouse model was established to evaluate tissue injury, oxidative stress, inflammatory responses, and intestinal barrier function in various groups of mice. The results indicate that strain 4L3 significantly mitigated brain and lung edema caused by hypoxia, improved colonic tissue damage, and effectively increased the content of tight junction proteins in the ileum, reducing ileal permeability and alleviating mechanical barrier damage in the intestines due to acute hypoxia. Additionally, 4L3 helped to rebalance the intestinal microbiota. In summary, this study found that Lactobacillus delbrueckii subsp. bulgaricus strain 4L3 could alleviate acute intestinal damage caused by hypoxia, thereby reducing hypoxic stress. This suggests that probiotic lactic acid bacteria that exert beneficial effects in the intestines may alleviate acute injury under hypoxic conditions in mice, offering new insights for the prevention and treatment of AMS.

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Anaerobic productivity is characterized by the body’s ability to perform muscle work due to anaerobic processes of energy supply and is characterized by their power and capacity. Data on the age-related dynamics of the body’s anaerobic productivity are contradictory. Studying the anaerobic capabilities of girls in the mountainous regions of Zakarpattia Oblast, we understand that the somatotype and functional capabilities of the body are formed in this category of persons in conditions of relative hypoxia. Szymczak R.K. et al researching the effect on the physiology of the body of a long stay at a very high altitude (over 3500 m), male climbers note that in conditions of hypoxia, the anaerobic productivity of the body decreases, the maximum respiratory volume increases, and the relative content of the fat component of the body weight decreases. Therefore, the study of indicators of anaerobic productivity of the body’s energy supply in healthy girls may allow developing individual and population medical prognosis in the future. The level of physical health was assessed by indicators of anaerobic productivity of the body, assessing the ability of women living in mountainous regions to adapt to performing physical work in an anaerobic mode. For this purpose, we used the Wingat anaerobic test method described by Yu.M. Furman et al, the method of Shogy A., Cherebetin G. and somatotype was determined according to Heath-Carter. Having studied the anaerobic capabilities of 102 girls aged 16 to 20, residents of the mountainous regions of the Transcarpathian region. we noted that the performance of physical work in the anaerobic regime of the body’s energy supply depends on the somatotype. The power of anaerobic alactate and lactate processes turned out to be the highest in girls with an endomesomorphic somatotype. The power of anaerobic alactate and lactate processes turned out to be the lowest in girls with an ectomorphic somatotype. Studying the level of anaerobic productivity of females based on the relative indicator of the capacity of anaerobic lactate processes of energy supply showed that girls with a balanced somatotype have the lowest level of anaerobic capacity compared to girls of other somatotypes.

A Microphysiological Model to Mimic the Placental Remodeling during Early Stage of Pregnancy under Hypoxia-Induced Trophoblast Invasion

Placental trophoblast invasion is critical for establishing the maternal–fetal interface, yet the mechanisms driving trophoblast-induced maternal arterial remodeling remain elusive. To address this gap, we developed a three-dimensional microfluidic placenta-on-chip model that mimics early pregnancy placentation in a hypoxic environment. By studying human umbilical vein endothelial cells (HUVECs) under oxygen-deprived conditions upon trophoblast invasion, we observed significant HUVEC artery remodeling, suggesting the critical role of hypoxia in placentation. In particular, we found that trophoblasts secrete matrix metalloproteinase (MMP) proteins under hypoxic conditions, which contribute to arterial remodeling by the degradation of extracellular matrix components. This MMP-mediated remodeling is critical for facilitating trophoblast invasion and proper establishment of the maternal–fetal interface. In addition, our platform allows real-time monitoring of HUVEC vessel contraction during trophoblast interaction, providing valuable insights into the dynamic interplay between trophoblasts and maternal vasculature. Collectively, our findings highlight the importance of MMP-mediated arterial remodeling in placental development and underscore the potential of our platform to study pregnancy-related complications and evaluate therapeutic interventions.

Novel angiogenesis inhibitors with superoxide anion radical amplification effect: Surmounting the Achilles’ heels of angiogenesis inhibitors and photosensitizers

Angiogenesis inhibitors and photosensitizers are pivotal in tumor clinical treatment, yet their utilization is constrained. Herein, eleven novel angiogenesis inhibitors were developed through hybridization strategy to overcome their clinical limitations. These title compounds boast excitation wavelengths within the “therapeutic window”, enabling deep tissue penetration. Notably, they could generate superoxide anion radicals via the Type I mechanism, with compound 36 showed the strongest superoxide anion radical generating capacity. Biological evaluation demonstrated remarkable cellular activity of all the title compounds, even under hypoxic conditions. Among them, compound 36 stood out for its superior anti-proliferative activity in both normoxic and hypoxic environments, surpassing individual angiogenesis inhibitors and photosensitizers. Compound 36 induced cell apoptosis via superoxide anion radical generation, devoid of dark toxicity. Molecular docking revealed that the target-recognizing portion of compound 36 was able to insert into the ATP binding pocket of the target protein similar to sorafenib. Collectively, our results suggested that hybridization of angiogenesis inhibitors and photosensitizers was a potential strategy to address the limitations of their clinical use.

Targeting HIF-1α with Specific DNA Yokes for Effective Anticancer Therapy.

Hypoxia, a ubiquitous hallmark in cancer, underscores the significance of targeting HIF-1α, the principal transcriptional factor of hypoxic responses, for effective cancer therapy. Herein, DNA yokes, a novel class of DNA nanomaterials harboring specific HIF-1α binding sequences (hypoxia response elements, HREs), are introduced as nanopharmaceuticals for cancer treatment. Comprising a basal tetrahedral DNA nanostructure and four HRE-bearing overhanging chains, DNA yokes exhibit exceptional stability and prolonged intracellular retention. The investigation reveals their capacity to bind HIF-1α, thereby disrupting its interaction with the downstream genomic DNAs and impeding transcriptional activity. Moreover, DNA yokes facilitate HIF-1α degradation via the ubiquitination pathway, thereby sequestering it from downstream targets and ultimately promoting its degradation. In addition, DNA yokes attenuate cancer cell proliferation, migration, and invasion under hypoxic conditions, while also displaying preferential accumulation within tumors, thereby inhibiting tumor growth and metastasis in vivo. This study pioneers a novel approach to cancer therapy through the development of DNA-based drugs characterized by high stability and low toxicity to normal cells, positioning DNA yokes as promising candidates for cancer treatment.

Influence of acute dietary nitrate supplementation on oxygen delivery/consumption and critical impulse during maximal effort forearm exercise in males: a randomized crossover trial.

Beetroot juice supplementation (BRJ) increases nitric oxide bioavailability under conditions of hypoxia and acidosis, characteristics of maximal effort exercise, which is required to identify forearm critical impulse. We hypothesized BRJ would improve oxygen delivery:demand matching and forearm critical impulse performance. Healthy males (20.8±2.4 years) participated in a randomized crossover trial between October 2017-May 2018 (Queen's University, Kingston, ON). Participants completed 10-minutes of rhythmic maximal effort forearm handgrip exercise 2.5 hours post placebo (PL) vs. BRJ (9 completed PL/BRJ vs. 4 completed BRJ/PL) within a 2 week period. Data are presented as mean±SD. There was a main effect of drink (PL > BRJ) for oxygen extraction (P=0.033,ηp2=0.351) and oxygen consumption/force (P=0.017,ηp2=0.417). There was a drink x time interaction (PL > BRJ) for oxygen consumption/force (P=0.035,ηp2=0.216) between 75-360s (1.25-6 min) from exercise onset. BRJ did not influence oxygen delivery (P=0.953,ηp2=0.000), oxygen consumption (P=0.064,ηp2=0.278), metabolites [[lactate] (P=0.196,ηp2=0.135), pH (P=0.759,ηp2=0.008)] or power-duration performance parameters [critical impulse (P=0.379,d=0.253), W' (P=0.733,d=0.097)]. BRJ during all-out handgrip exercise does not influence oxygen delivery or exercise performance. Oxygen cost of contraction with BRJ is reduced as contraction impulse is declining during maximal effort exercise resulting in less oxygen extraction. https://osf.io/pga37/registrations.

Hypoxia-inducible factor in breast cancer: role and target for breast cancer treatment

Globally, breast cancer stands as the most prevalent form of cancer among women. The tumor microenvironment of breast cancer often exhibits hypoxia. Hypoxia-inducible factor 1-alpha, a transcription factor, is found to be overexpressed and activated in breast cancer, playing a pivotal role in the anoxic microenvironment by mediating a series of reactions. Hypoxia-inducible factor 1-alpha is involved in regulating downstream pathways and target genes, which are crucial in hypoxic conditions, including glycolysis, angiogenesis, and metastasis. These processes significantly contribute to breast cancer progression by managing cancer-related activities linked to tumor invasion, metastasis, immune evasion, and drug resistance, resulting in poor prognosis for patients. Consequently, there is a significant interest in Hypoxia-inducible factor 1-alpha as a potential target for cancer therapy. Presently, research on drugs targeting Hypoxia-inducible factor 1-alpha is predominantly in the preclinical phase, highlighting the need for an in-depth understanding of HIF-1α and its regulatory pathway. It is anticipated that the future will see the introduction of effective HIF-1α inhibitors into clinical trials, offering new hope for breast cancer patients. Therefore, this review focuses on the structure and function of HIF-1α, its role in advancing breast cancer, and strategies to combat HIF-1α-dependent drug resistance, underlining its therapeutic potential.

Regulation of Cancer-Associated miRNAs Expression under Hypoxic Conditions.

Solid tumors frequently experience hypoxia or low O2 levels. In these conditions, hypoxia-inducible factor 1 alpha (HIF-1α) is activated and acts as a transcription factor that regulates cancer cell adaptation to O2 and nutrient deprivation. HIF-1α controls gene expression associated with various signaling pathways that promote cancer cell proliferation and survival. MicroRNAs (miRNAs) are 22-nucleotide noncoding RNAs that play a role in various biological processes essential for cancer progression. This review presents an overview of how hypoxia regulates the expression of multiple miRNAs in the progression of cancer cells.