Chronic Hypoxia Research Articles

Chronic Intermittent Hypoxia Aggravates Progression of Diabetic Nephropathy via Inducing Endoplasmic Reticulum Stress and Mitochondrial Dysfunction

Chronic Intermittent Hypoxia Aggravates Progression of Diabetic Nephropathy via Inducing Endoplasmic Reticulum Stress and Mitochondrial Dysfunction

A prospective study on the cardiorespiratory effects of air pollution among residents of the Tibetan Plateau

The Tibetan Plateau is characterized by high ozone concentration which poses a significant public health concern. However, the causal evidence linking ozone pollution to adverse cardiopulmonary health impacts, as well as the understanding of its underlying biological mechanisms, remains limited. Additionally, exposure levels to particulate and other gaseous air pollutants along with their associated health effects in this region are largely unknown. To address these gaps, we conducted a prospective follow-up study in Tibet from May 2021 to November 2021. In consideration of the potential synergistic effects of chronic hypobaric hypoxia, two Tibetan cities with different altitudes, Lhasa (3650 m) and Nyingchi (3000 m), were chosen to implement atmospheric monitoring and health measurement. We employed cutting-edge, high-precision instruments at stationary monitoring sites to measure ambient air pollution and collected particle samples. Portable devices were used to monitor personal exposure levels of ozone and black carbon. A total of 212 healthy Tibetan college students participated in up to four clinical visits, yielding 774 visits in total, during which functional endpoints were measured and biological samples were collected. The primary aim of this study is to evaluate the cardiorespiratory effects of ambient ozone under hypoxic conditions, where its impact may be amplified due to the region's unique environmental characteristics. The secondary aim is to provide a comprehensive assessment of other air pollutants, including their exposure levels, sources, and health effects. By addressing these aims, the study offers valuable insights into air quality and its health implications in this unique high-altitude setting. This paper outlines the research motivation, measurement framework, and preliminary findings.

Food web structure across basins in Lake Erie, a large freshwater ecosystem

Understanding spatial variation of aquatic food web structure and how ecosystem boundaries should be delineated is important. Here, we investigated the spatial variation in food web structure within Lake Erie across its three basins using δ13C and δ15N. Fish and lower trophic level composition were similar but differences in food web structure were observed between basins. The food web in the central basin had the smallest δ13C and δ15N range and total area based on stable isotope values by the aquatic community, likely due to chronic epibenthic hypoxia in the summer that affects fish habitat and resources. The largest δ15N range was in the east, driven by the high trophic position of lake trout present in this deepest basin. The western basin had the largest mean distance to the centroid (CD) of all three basins, indicating a large trophic diversity, probably due to high nutrient loadings and productivity. This research revealed spatial variability of food web structure in large lake ecosystems and the importance of considering smaller sub-units, such as basin, in large lakes.

PPARγ/ETV2 axis regulates endothelial-to-mesenchymal transition in pulmonary hypertension.

Endothelial-to-mesenchymal transition (EndoMT) plays an important role in pulmonary hypertension (PH) but the molecular mechanisms regulating EndoMT remain to be defined. We demonstrate that the axis of the transcription factors PPARγ (Peroxisome Proliferator-Activated Receptor gamma) and ETV2 (ETS variant 2) play important roles in the pathogenesis of PH. Decreased levels of the expression of PPARγ and ETV2 along with reduced endothelial and increased EndoMT markers are consistently observed in lungs and pulmonary artery endothelial cells (PAECs) of idiopathic pulmonary arterial hypertension patients, in hypoxia-exposed mouse lungs, human PAECs, and in induced-EndoMT cells. Etv2 +/- mice spontaneously developed PH and right ventricular hypertrophy (RVH), associated with increased EndoMT markers and decreased EC markers. Interestingly, chronic hypoxia exacerbated right ventricular systolic pressure and RVH in Etv2 +/- mice. PPARγ transcriptionally activates the ETV2 promoter. Consistently, while mice overexpressing endothelial PPARγ increases the expression of ETV2 and endothelial markers with reduced EndoMT markers, endothelial PPARγ KO mice show decreased ETV2 expression and enhanced EndoMT markers. Inducible overexpression of ETV2 under induced-EndoMT cell model reduces number of cells with mesenchymal morphology and decreases expression of mesenchymal markers with increased EC makers, compared to control. Therefore, our study suggests that PPARγ-ETV2 signaling regulates PH pathogenesis through EndoMT.

Study on the mechanism of echinacoside in preventing and treating hypoxic pulmonary hypertension based on proteomic analyses.

Hypoxic pulmonary hypertension (HPH), a chronic condition affecting the cardiopulmonary system, has high mortality. Echinacoside (ECH) is a phenylethanoid glycoside, which is used to ameliorate pulmonary vascular remodeling and pulmonary vasoconstriction in rats. Accordingly, we aimed to explore the mechanism of ECH in preventing and treating HPH. Sprague Dawley rats were housed in a hypobaric hypoxia chamber for 28 days to obtain the HPH model. The experimental rats were randomly allocated into the following several groups: normoxia group, chronic hypoxia group, and ECH group. The therapeutic results of ECH (10, 20, and 40 mg/kg) showed that ECH reduced mPAP, Hb, Hct, and RVHI in HPH rats. Then this work employed label-free quantitative proteomic analysis, western blotting, and RT-PCR to investigate the mechanism by which ECH prevents HPH. The results found that in the chronic hypoxia group, the levels of ACSL1, COL6A1, COL4A2, COL1A1, and PC increased compared to the normoxia group. However, the opposite effect was observed in the chronic hypoxia group treated with ECH. The study indicates that the administration of ECH may slow the pathological progression of HPH by suppressing the inflammatory response, inhibiting smooth muscle cell proliferation, and minimizing the deposition of extracellular matrix.

Identification biomarkers in disease progression of obstructive sleep apnea from children serum based on WGCNA and Mfuzz.

Obstructive sleep apnea (OSA) syndrome is a prevalent form of respiratory sleep disorder, with an increasing prevalence among children. The consequences of OSA include obesity, diabetes, cardiovascular disease, and neuropsychological diseases. Despite its pervasive impact, a significant proportion of individuals especially children remain unaware that they suffer from OSA. Consequently, there is an urgent need for an accessible diagnostic approach. In this study, we conducted a bioinformatic analysis to identify potential biomarkers from a proteomics dataset comprising serum samples from children with OSA in the progression stage. In the Gene Set Enrichment Analysis (GSEA), we observed that the complement and immune response pathways persisted throughout the development of OSA and could be detected in the early stages. Subsequent to soft clustering and WGCNA analysis, it was revealed that the Hippo pathway, including ITGAL and FERMT3, plays a role in mild OSA. The analysis revealed a significant alteration of the complement and coagulation pathways, including TFPI and MLB2, in moderate OSA. In severe OSA, there was an association between hypoxia and the extracellular matrix (ECM) receptor interaction and collagen binding. In summary, it can be posited that the systemic inflammation may persist throughout the progression of OSA. Furthermore, severe OSA is characterized by abnormal vascular endothelial function, which may be attributed to chronic hypoxia. Finally, four potential biomarkers (ITGAL, TFPI, TTR, ANTXR1) were identified based on LASSO regression, and a prediction model for OSA progression was constructed based on the biomarkers.

Cardiovascular Ultrasound Predictors for Brain Alterations in Fetuses With Heart Disease: An Exploratory Review of the Literature.

To identify cardiovascular ultrasound predictors for brain anomalies in fetuses with heart disease. A literature search was performed in the following databases: MEDLINE through OVID, EMBASE, Cochrane Registry Center for Controlled Trials (CENTRAL), and LILACS, from their inception until May 2023. Clinical studies, cross-sectional studies, case-control studies, cohorts, and systematic reviews were included. Data extraction was performed, and the risk of bias was assessed using the QUADAS-2 tool. Among 2705 studies evaluated, after filtering information, 10 articles were selected that met the inclusion criteria. These studies noted the following outcomes: a decrease in fetal head circumference, changes in brain maturation measured in days, decreased depth of brain fissures, and a decrease in total brain volume. The studies show a statistically significant correlation with the presence of the following cardiovascular predictors: low or mixed oxygen content in the ascending aorta (p < 0.001), retrograde flow in the aortic arch (p < 0.001), lower z values of the MCA-PI (p < 0.05), higher UA-PI z values (p < 0.01), and lower CPR (p < 0.05). In addition, lower values of left ventricular flow (p < 0.01), ductus arteriosus (p < 0.0001), and combined cardiac output index (p < 0.01) were reported. This review describes the most relevant evidence correlating the effects of hemodynamic changes that lead to states of chronic hypoxia related to the aforementioned changes in the central nervous system.

Chronic hypoxia drives the occurrence of ferroptosis in liver of fat greening (Hexagrammos otakii) by activating HIF-1α and promoting iron production

BackgroundHypoxia caused by global climate change and human activities has become a growing concern eliciting serious effect and damages to aquatic animals. Hexagrammos otakii is usually a victim of hypoxia which caused by high density aquaculture and high nutrient input. The mechanism underlying ferroptosis regulation after hypoxia-stress in liver of H. otakii, however, remains elusive. MethodsFor a duration of 15 days, expose the H. otakii to low concentrations of dissolved oxygen (3.4 ± 0.2 mg/L). Detecting alterations in the H. otakii liver tissue by chemical staining, immunohistochemistry, and electron microscopy. The expression variations of relevant genes in the liver of the H. otakii were simultaneously detected using Western blot and qPCR. A correlation analysis was performed between HIF-1α and iron ion expression in the liver of H. otakii following hypoxic stress. ResultsIn this study, we conducted the whole ferroptosis integrated analysis of H. otakii under chronic hypoxic condition. Reactive oxygen species (ROS) are highly accumulated under the hypoxia treatment (Superoxide Dismutase, SOD; Catalase, CAT), and which results in a significantly enhanced of lipid peroxidation (Lipid Peroxidation, LPO; Malondialdehyde, MDA; Aminotransferase, AST; Alanine aminotransferase, ALT) in liver tissue. The HIF-1α signaling is activated to cope with the hypoxia stress through strategies including changing iron ion concentration (Fe3+ and TFR1) to breaking the oxidation balance (GSH and GSH-Px), and enhancing ferroptosis gene expression (GPX4). The expression of genes related to ferroptosis pathway (DMT1, FTH1, STEAP3, ACSL4, γ-GCS, SLC7A11) is significantly upregulated and associated to the expression of iron and HIF-1α. ConclusionsIt is demonstrated that the HIF-1α/Fe3+/ROS/GPX4 axis is involved in promoting ferroptosis in fat greening hepatocytes following hypoxia-stress. Ultimately, our findings unveil a process by which hypoxic stress strongly encourages ferroptosis by triggering HIF-1α and boosting iron synthesis.

Long-term liver deportalisation in stable and time prolonged prehepatic portal hypertension model affects expression of hypoxia, angiogenesis, apoptosis, and autophagy markers in the young rats’ liver

prehepatic portal hypertension in children cause severe and life-threatening complications, that highlights the need in in-depth investigations of pathogenetic mechanisms, which contribute to prehepatic portal hypertension-associated liver pathology. In developed stable experimental prehepatic portal hypertension model in adolescent rat males we aimed to assess the expression levels of the key molecular markers of hypoxia, angiogenesis, autophagy, and apoptosis in the liver tissue after 6-month deportalization. Partial portal vein ligation was performed in 4-week old male rats. After 6-months tissue samples from PHP-model, sham operated and control animals were studied by western blot to identify protein levels of markers related to prehepatic portal hypertension -induced liver injury. Partial portal vein occlusion upregulated hypoxia inducible factor -1α (by 4.67 folds vs. control, p&lt;0.001) and vascular endothelial growth factor protein expression levels (by 2.33 folds vs. control, p&lt;0.001) suggesting chronic hypoxia development. Abnormally high levels of angiostatin isoforms were found (by 9.88 folds vs. control, p&lt;0.001) to signify angiogenesis dysregulation. Significant caspase-3 (23.4-fold increase vs. control, p&lt;0.001) overexpression is executive phase of apoptotic cell death evidence. Dramatic LC3 level expression indicates existence of crosstalk between autophagy and apoptosis that contribute to fibrotic changes. Hypoxia-induced events, impaired angiogenesis regulation, enhanced autophagy and apoptosis are contributing factors of prehepatic portal hypertension -induced liver injury. A better understanding of subtle molecular mechanisms of this pathology may pave the way for innovative treatment options.

Hypoxia induces ROS-resistant memory upon reoxygenation in vivo promoting metastasis in part via MUC1-C

Hypoxia occurs in 90% of solid tumors and is associated with metastasis and mortality. Breast cancer cells that experience intratumoral hypoxia are 5x more likely to develop lung metastasis in animal models. Using spatial transcriptomics, we determine that hypoxic cells localized in more oxygenated tumor regions (termed ‘post-hypoxic’) retain expression of hypoxia-inducible and NF-kB-regulated genes, even in the oxygen-rich bloodstream. This cellular response is reproduced in vitro under chronic hypoxic conditions followed by reoxygenation. A subset of genes remains increased in reoxygenated cells. MUC1/MUC1-C is upregulated by both HIF-1α and NF-kB-p65 during chronic hypoxia. Abrogating MUC1 decreases the expression of superoxide dismutase enzymes, causing reactive oxygen species (ROS) production and cell death. A hypoxia-dependent genetic deletion of MUC1, or MUC1-C inhibition by GO-203, increases ROS levels in circulating tumor cells (CTCs), reducing the extent of metastasis. High MUC1 expression in tumor biopsies is associated with recurrence, and MUC1+ CTCs have lower ROS levels than MUC1- CTCs in patient-derived xenograft models. This study demonstrates that therapeutically targeting MUC1-C reduces hypoxia-driven metastasis.

Association between frailty and activities of daily living disability in older adults residing in a high-altitude Peruvian Andean community: the Aunqui-Andes study

BackgroundThe prevalence of frailty and activities of daily living (ADL) disability may be higher in high-altitude Andean regions, due to chronic hypoxia, malnutrition, and physical challenges. and their association is relevant. This study aimed to evaluate the association between frailty and ADL disability among older adults residing in the Totos district in Peru during the year 2022.MethodsA cross-sectional study was conducted in Totos district (mean altitude: 3286 m above sea level), located in Ayacucho, Peru, during 2022. A complete census was employed including residents aged 60 and above. The exposure variable was frailty, defined by fulfilling 3 or more criteria of the Fried phenotype. The outcome variable was ADL disability, defined as a score below 95 on the Barthel index. Generalized linear models with a Poisson family, logarithmic link function, and robust variances were employed to estimate crude prevalence ratios and adjusted prevalence ratios (aPRs), along with their corresponding 95% confidence intervals (CIs).ResultsWe evaluated 272 older adults with a mean age of 74 years, of whom 59.9% were female, 62.1% were cohabiting or married and 83.1% had not completed primary education. We found that 19.5% were frail, while 51.1% had ADL disability. In the adjusted regression model, we found frailty increased the prevalence of ADL disability (aPR = 1.77; 95%CI: 1.44–2.16; p < 0.001).ConclusionFrailty was associated with an increased prevalence of ADL disability. These findings could contribute to establishing government intervention plans to manage disability and frailty within the high-risk group comprising older adults living at high altitudes.

Prevalence of Hypothyroidism in Children with Transfusion Dependent Thalassemia Patient Attending in A Tertiary Care Hospital of Bangladesh

Background: Blood transfusions and iron chelation are standard treatments for β-thalassemia major and Hb E-Beta-Thalassemia. However, repeated transfusions raise body iron levels, leading to secondary hemosiderosis and complications in the heart, endocrine system, and liver. Thyroid dysfunction results from gland infiltration, chronic hypoxia, free radical damage, and iron overload. This study aimed to find out the prevalence of hypothyroidism in transfusion-dependent thalassemic children attending Bangladesh Shishu Hospital &amp; Institute. Methods: A descriptive cross-sectional study was conducted at the Thalassemia Centre, Department of Hematology and Oncology, Bangladesh Shishu Hospital &amp; Institute, from December 2019 to November 2020. The study included 140 children with thalassemia, aged 5 to 16 years, who were receiving blood transfusions. Data were collected using a structured questionnaire with participant consent. Statistical analysis was performed using SPSS version 23.0. Results: In this study, hypothyroidism was observed in 26.2% of patients, with 23.5% having subclinical and 2.9% overt hypothyroidism. In most of the patients (n=85), aged 11-16 years, 58.3% had normal thyroid function, 36.5% had subclinical, and 4.7% had overt hypothyroidism, which was statistically significant (p&lt;0.05). Of the 91 patients with hemoglobin levels below 11.5 g/dL, 85.7% had normal thyroid function, 13.2% had subclinical hypothyroidism, and 1.1% had overt hypothyroidism, also significant (p&lt;0.05). In the group with ferritin levels of 1200-2000 ng/mL, 78.1% had normal thyroid function, 18.8% had subclinical hypothyroidism, and 3.1% had overt hypothyroidism, which was not statistically significant (p&gt;0.05). Conclusion: Subclinical hypothyroidism is commonly seen in thalassemia patients aged 5 to 16 years who undergo regular blood transfusions. Regular physical exams and thyroid function assessments are crucial to detect overt hypothyroidism early. Timely hormone replacement can

Obstructive sleep apnoea is independently associated with non-alcoholic fatty pancreatic disease

Purpose This study investigated the prevalence of non-alcoholic fatty pancreatic disease (NAFPD) in patients with obstructive sleep apnoea (OSA) and analysed the correlation between them. Materials and methods Patients who underwent polysomnography and modified abdominal ultrasound examinations were continuously enrolled and divided into OSA and control groups. The OSA group was further divided into NAFPD and non-NAFPD groups. Differences in various indicators were compared. Binary logistic regression analyses were conducted to identify factors influencing NAFPD. Results A total of 210 participants were included in the study, including 178 in the OSA group and 32 in the control group. The prevalence of NAFPD, weight, body mass index (BMI), and other indicators were significantly higher in the OSA group than that in the control group (p < 0.05). The above indices, prevalence of hypertension and metabolic associated steatotic liver disease (MASLD), and severity of sleep apnoea were higher in the NAFPD group than that in the non-NAFPD group (p < 0.05). Binary logistic regression analysis showed a 4.4% increased risk of NAFPD for each unit increase in apnea-hypopnea index (AHI) after adjusting for BMI and hypertension. Conclusion The prevalence of NAFPD was higher in the OSA group than that in the control group, and chronic intermittent hypoxia was strongly associated with pancreatic fat infiltration; AHI, BMI, and hypertension were independent risk factors for NAFPD. The NAFPD group had a higher prevalence of obesity and some other diseases.

The burden of suicide across different altitudes: 11-year geodemographic analysis conducted in 221 cantons in Ecuador ranging from 0 to 4300 m of elevation.

The World Health Organization and the Global Burden of Disease study estimate that almost 800 000 people die from suicide yearly. The role of non-traditional risk factors such as climate and high-altitude exposure are poorly understood. This study aims to determine a potential relationship between altitude exposure and suicide rates among 221 cantons located at different altitudes ranging from 0 to 4300 m. We conducted an 11-year, country-wide, population-based analysis on age- and gender-standardised suicide rates in Ecuador, based on the official data from the National Institute of Statistics, using all available self-harm death codes (ICD-10 codes X60-X84). A total of 11 280 cases of suicide were reported during 2011-2021. Suicide rates were higher among men (11.48/100 000). In terms of elevation, suicide rates were significantly higher among people from high-altitude cantons (3.7/100 000) versus those from low-altitude cantons. When applying the International Society Mountain Medicine categorisation, suicide rates were significantly higher at moderate- (4.3/100 000), high- (3.6/100 000) and very-high-altitude cantons (4.4/100 000) when compared with low-altitude locations (2.5/100 000). Ecuador is one of the few countries that has a vast range of cantons located at different altitudes. We found that living at higher elevations is positively associated with greater suicide rates. Although the rates are significantly greater as elevation increases, a clear linear relationship is not apparent, likely because of the interplay of socioeconomic factors, including urbanicity. The effect of chronic hypobaric hypoxia on mood cannot be ruled out, although the existence of causal mechanisms remains to be elucidated.

GLP-1 analogue liraglutide attenuates CIH-induced cognitive deficits by inhibiting oxidative stress, neuroinflammation, and apoptosis via the Nrf2/HO-1 and MAPK/NF-κB signaling pathways

Obstructive sleep apnea (OSA) is a common clinical condition linked to cognitive impairment, mainly characterized by chronic intermittent hypoxia (CIH). GLP-1 receptor agonist, known for promoting insulin secretion and reducing glucose levels, has demonstrated neuroprotective effects in various experimental models such as stroke, Alzheimer’s disease, and Parkinson’s disease. This study aims to investigate the potential role and mechanisms of the GLP-1 receptor agonist liraglutide in ameliorating OSA-induced cognitive deficits. CIH exposure, a well-established and mature OSA pathological model, was used both in vitro and in vivo. In vitro, CIH significantly activated oxidative stress, inflammation, and apoptosis in SH-SY5Y cells. Liraglutide enhanced the nuclear translocation of Nrf2, activating its downstream pathways, thereby mitigating CIH-induced injury in SH-SY5Y cells. Additionally, liraglutide modulated the MAPK/NF-κB signaling pathway, reducing the expression of inflammatory factors and proteins. In vivo, we subjected mice to an intermittent hypoxia incubator to mimic the pathogenesis of human OSA. The Morris water maze test revealed that CIH exposure substantially impaired spatial memory. Subsequent western blot analyses and histopathological examinations indicated that liraglutide could activate the Nrf2/HO-1 axis and inhibit the MAPK/NF-κB signaling pathway, thereby alleviating OSA-associated cognitive dysfunction in mice. These findings suggest that GLP-1 receptor agonists may offer a promising preventive strategy for OSA-associated cognitive impairment. By refining these findings, we provide new insights into GLP-1’s protective mechanisms in combating cognitive deficits associated with CIH, underscoring its potential as a therapeutic agent for conditions linked to OSA.

Understanding and Managing Adenotonsillar Hypertrophy in Pediatric Otolaryngology

Adenotonsillar hypertrophy (ATH) is a common pediatric condition marked by the growth of lymphoid tissues within the Waldeyer’s ring, which includes adenoids, palatine tonsils, and lingual tonsils. These tissues surround the upper airway and food passage, and play an immunological role, enlarging until about age 12, before gradually reducing during adolescence and adulthood. Untreated or poorly managed ATH can severely impact multiple health aspects of children. It is the primary cause of upper airway obstruction and obstructive sleep apnea (OSA) syndrome in children, which disrupts sleep and can severely impair cognitive development, school performance and behaviour. Chronic mouth breathing from ATH can alter dental arches and facial growth, known as adenoid facies. More severe outcomes include increased pulmonary pressures and the potential development of pulmonary hypertension and cor pulmonale due to chronic hypoxia and CO2 retention. As a result, tonsillectomy, with or without adenoidectomy (T&amp;A), has become one of the most frequently performed surgeries in North America, with over 530,000 operations performed annually on children under age 15. This paper discusses the significant impact of ATH on pediatric health and the frequent need for surgical intervention. It covers the immunophysiology, influence of atopy, community-based assessments prior to specialist referrals, and an overview of available medical and surgical treatment options. Additionally, it outlines general indications for referring patients to otolaryngology.

Magnesium Sulfate, Rosuvastatin, Sildenafil and Their Combination in Chronic Hypoxia-Induced Pulmonary Hypertension in Male Rats.

Previous experimental findings have led to considerable interest in the beneficial effects on pulmonary hypertension (PH) produced by sildenafil and in the pleiotropic effects of rosuvastatin and their positive role in the process of pulmonary angiogenesis. However, magnesium sulfate, the most abundant intracellular cation, is essential in vascular endothelial functionality due to its anti-inflammatory and vasodilatory effects. Therefore, the present study aims to assess these treatment regimens and how they could potentially provide some additional benefits in PH therapy. Fourteen days after chronic-hypoxia PH was induced, rosuvastatin, sildenafil and magnesium sulfate were administered for an additional fourteen days to male Wistar rats. The Fulton Index, right ventricle (RV) anterior wall thickness, RV internal diameter and pulmonary arterial (PA) acceleration time/ejection time were evaluated, and another four biochemical parameters were calculated: brain natriuretic peptide, vascular endothelial growth factor, nitric oxide metabolites and endothelin 1. The present study demonstrates that sildenafil and rosuvastatin have modest effects in reducing RV hypertrophy and RV systolic pressure. The drug combination of sildenafil + rosuvastatin + magnesium sulfate recorded statistically very highly significant results on all parameters; through their positive synergistic effects on vascular endothelial function, oxidative stress and pathological RV remodeling, they attenuated PH in the chronic hypoxia pulmonary hypertension (CHPH) rat model.

Ndufs4 inactivation in glutamatergic neurons reveals swallow-breathing discoordination in a mouse model of Leigh Syndrome.

Swallowing, both nutritive and non-nutritive, is highly dysfunctional in children with Leigh Syndrome (LS) and contributes to the need for both gastrostomy and tracheostomy tube placement. Without these interventions aspiration of food, liquid, and mucus occur resulting in repeated bouts of respiratory infection. No study has investigated whether mouse models of LS, a neurometabolic disorder, exhibit dysfunctions in neuromuscular activity of swallow and breathing integration. We used a genetic mouse model of LS in which the NDUFS4 gene is knocked out (KO) specifically in Vglut2 or Gad2 neurons. We found increased variability of the swallow motor pattern, disruption in breathing regeneration post swallow, and water-induced apneas only in Vglut2 KO mice. These physiological changes likely contribute to weight loss and premature death seen in this mouse model. Following chronic hypoxia (CH) exposure, swallow motor pattern, breathing regeneration, weight, and life expectancy were not changed in the Vglut2-Ndufs4-KO CH mice compared to control, indicating a rescue of phenotypes. These findings show that like patients with LS, Ndufs4 mouse models of LS exhibit swallow impairments as well as swallow-breathing dyscoordination alongside the other phenotypic traits described in previous studies. Understanding this aspect of LS will open roads for the development of future more efficacious therapeutic intervention for this illness.

The Influence of Experimental Chronic Antenatal and Acute Postnatal Hypoxia on the Morphological State of the Liver Stromal Component

BACKGROUND: At present, the asymptomatic course of liver pathology in early childhood remains an urgent problem. AIMS: The objective of the study was the detection of morphological features of the stromal component of the liver of rats, which were at different stages of postnatal ontogenesis and were exposed to chronic antenatal and acute postnatal hypoxia (APH). MATERIALS AND METHODS: The study material was rat liver tissue of the control group, the APH group, and the chronic antenatal hypoxia (CAH) group. RESULTS: From day 1 to day 35, CAH leads to an increase and growth of the stromal component in the liver of offsprings due to the development of sclerotic changes caused by activation of collagen formation with a predominance of mature collagen Type I over immature collagen Type III on day 1 and day 14 of the experiment and predominance of collagen Type III over collagen Type I on day 35 of the experiment, increasing the expression of fibronectin. Starting from day 14, APH leads to the development of sclerotic changes in this organ which increase to day 35, less pronounced compared to the detected sclerotic changes in CAH, and manifest in increased expression of fibronectin, activation of collagen formation with a predominance of collagen Type I over collagen Type III on days 14 and 35 of the experiment. CONCLUSION: CAH from day 1 and APH from day 14 of postnatal life lead to the development of sclerotic changes in the liver of offsprings, which are more pronounced in cases of simulation of CAH and increase with age.

The context-dependent epigenetic and organogenesis programs determine 3D vs. 2D cellular fitness of MYC-driven murine liver cancer cells.

3D cellular-specific epigenetic and transcriptomic reprogramming is critical to organogenesis and tumorigenesis. Here we dissect the distinct cell fitness in 2D (normoxia vs. chronic hypoxia) vs 3D (normoxia) culture conditions for a MYC-driven murine liver cancer model. We identify over 600 shared essential genes and additional context-specific fitness genes and pathways. Knockout of the VHL-HIF1 pathway results in incompatible fitness defects under normoxia vs. 1% oxygen or 3D culture conditions. Moreover, deletion of each of the mitochondrial respiratory electron transport chain complex has distinct fitness outcomes. Notably, multicellular organogenesis signaling pathways including TGFb-SMAD specifically constrict the uncontrolled cell proliferation in 3D while inactivation of epigenetic modifiers (Bcor, Kmt2d, Mettl3 and Mettl14) has opposite outcomes in 2D vs. 3D. We further identify a 3D-dependent synthetic lethality with partial loss of Prmt5 due to a reduction of Mtap expression resulting from 3D-specific epigenetic reprogramming. Our study highlights unique epigenetic, metabolic and organogenesis signaling dependencies under different cellular settings.