Hypoxic Area Research Articles

Effect of PACAP on Hypoxia-Induced Angiogenesis and Epithelial-Mesenchymal Transition in Glioblastoma.

Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts different effects in various human cancer. In glioblastoma (GBM), PACAP has been shown to interfere with the hypoxic micro-environment through the modulation of hypoxia-inducible factors via PI3K/AKT and MAPK/ERK pathways inhibition. Considering that hypoxic tumor micro-environment is strictly linked to angiogenesis and Epithelial–Mesenchymal transition (EMT), in the present study, we have investigated the ability of PACAP to regulate these events. Results have demonstrated that PACAP and its related receptor, PAC1R, are expressed in hypoxic area of human GBM colocalizing either in epithelial or mesenchymal cells. By using an in vitro model of GBM cells, we have observed that PACAP interferes with hypoxic/angiogenic pathway by reducing vascular-endothelial growth factor (VEGF) release and inhibiting formation of vessel-like structures in H5V endothelial cells cultured with GBM-conditioned medium. Moreover, PACAP treatment decreased the expression of mesenchymal markers such as vimentin, matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) as well as CD44 in GBM cells by affecting their invasiveness. In conclusion, our study provides new insights regarding the multimodal role of PACAP in GBM malignancy.

Recent regime of persistent hypoxia in the Baltic Sea

Oxygen deficiency, in the form of hypoxia and anoxia, is a direct consequence of the eutrophication of the Baltic Sea. There is ongoing debate concerning the increasing extent of hypoxia. We analyse the integral metrics of hypoxia and anoxia: (1) temporal evolution of the hypoxic and anoxic area and volume, (2) the spatial distribution of the probabilities of hypoxia and anoxia occurrence in the Baltic Sea. The results are based on the state-of-the-art coupled physical and biogeochemical numerical model reanalysis data from Copernicus Marine Environment Monitoring Service for the period of 1993–2017. Statistical analysis showed that the variability of hypoxic and anoxic areas since the year 2000 represents stationary processes around their respective mean levels. From 2000 to 2017, the hypoxic area varies between 50000 and 80000 km2 and the anoxic area varies between 10000 and 50000 km2. Different methods and data sources indicate that the uncertainties of the estimates account for about 10000 km2. We suggest that the loss of stationarity of the time series of the hypoxic area would be an indication of the regime change of hypoxia development in the Baltic Sea. Probability distribution maps of hypoxia and anoxia provide detailed information about the persistency of hypoxia and anoxia in different parts of the Baltic Sea. The probability of hypoxia exceeds 0.9 in the eastern and western Gotland basins and in the deep area of the Bornholm basin. The Gulf of Finland and the shallower areas that connect different deep basins of the Baltic Sea exhibit seasonal and episodic hypoxia. The 80 m and 120 m isobaths are the approximate bathymetry limits of hypoxia and anoxia occurrence, respectively. Our study supports previous knowledge that hypoxia development is controlled to a large degree by the depth of the permanent halocline.

Oxygen-Based Nanocarriers to Modulate Tumor Hypoxia for Ameliorated Anti-Tumor Therapy: Fabrications, Properties, and Future Directions.

Over the past five years, oxygen-based nanocarriers (NCs) to boost anti-tumor therapy attracted tremendous attention from basic research and clinical practice. Indeed, tumor hypoxia, caused by elevated proliferative activity and dysfunctional vasculature, is directly responsible for the less effectiveness or ineffective of many conventional therapeutic modalities. Undeniably, oxygen-generating NCs and oxygen-carrying NCs can increase oxygen concentration in the hypoxic area of tumors and have also been shown to have the ability to decrease the expression of drug efflux pumps (e.g., P-gp); to increase uptake by tumor cells; to facilitate the generation of cytotoxic reactive oxide species (ROS); and to evoke systematic anti-tumor immune responses. However, there are still many challenges and limitations that need to be further improved. In this review, we first discussed the mechanisms of tumor hypoxia and how it severely restricts the therapeutic efficacy of clinical treatments. Then an up-to-date account of recent progress in the fabrications of oxygen-generating NCs and oxygen-carrying NCs are systematically introduced. The improved physicochemical and surface properties of hypoxia alleviating NCs for increasing the targeting ability to hypoxic cells are also elaborated with special attention to the latest nano-technologies. Finally, the future directions of these NCs, especially towards clinical translation, are proposed. Therefore, we expect to provide some valued enlightenments and proposals in engineering more effective oxygen-based NCs in this promising field in this comprehensive overview.

Hypoxic Effects on the Radiocarbon in DIC of the ECS Subsurface Water

AbstractDissolved inorganic carbon (DIC) in the East China Sea (ECS) is physically and chemically affected by the northward intrusion of the Kuroshio Branch Current (KBC) and the Changjiang River (CR) outflow. We trace these processes using dual DIC isotopic compositions (Δ14C and δ13C) along transects that begin in the CR and estuary, and extend out into middle shelf waters of the ECS. We especially focus on frequently occurred nearshore hypoxia, as they appeared in the summer of 2017. The Δ14C values (28.8‰–35.3‰) from the ECS mid‐shelf water were comparable to the reported value from the Kuroshio Current (KC) at the continental slope (34.4‰ ± 7.4‰), but Δ14C values in the CR (−173.6‰ & −162.3‰) were substantially lower than observations made in 2014. We also found that the Δ14C of DIC in the bottom waters along the inner shelf, including hypoxic area, decreased from 25.0‰ to 18.5‰, from south to north. Water masses mixing between the CR and the ECS mid‐shelf waters with and without organic carbon degradation can be identified in plots of Δ14C versus DIC‐1. With simple mixing calculations, we show that the northward decreasing Δ14C of inner shelf bottom water is caused by downward transport of DIC with low Δ14C value mediated by biological process from the surface, as opposed to simple physical mixing.

Implication of O2 dynamics for both N2O and CH4 emissions from soil during biological soil disinfestation

Soil O2 dynamics have significant influences on greenhouse gas emissions during soil management practice. In this study, we deployed O2-specific planar optodes to visualize spatiotemporal distribution of O2 in soils treated with biological soil disinfestation (BSD). This study aimed to reveal the role of anoxia development on emissions of N2O and CH4 from soil amended with crop residues during BSD period. The incorporation of crop residues includes wheat straw only, wheat straw with biochar and early straw incorporation. The anoxia in soil developed very fast within 3 days, while the O2 in headspace decreased much slower and it became anaerobic after 5 days, which was significantly affected by straw and biochar additions. The N2O emissions were positively correlated with soil hypoxic fraction. The CH4 emissions were not significant until the anoxia dominated in both soil and headspace. The co-application of biochar with straw delayed the anoxia development and extended the hypoxic area in soil, resulting in lower emissions of N2O and CH4. Those results highlight that the soil O2 dynamic was the key variable triggering the N2O and CH4 productions. Therefore, detailed information of soil O2 availability could be highly beneficial for optimizing the strategies of organic amendments incorporation in the BSD technique.

Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model

BackgroundPatients with metastatic HER2/neu-positive (HER2/neu +) breast cancer (BC) often experience treatment resistance, disease recurrences and metastases. Thus, new approaches for improving the treatment of HER2/neu + BC to prevent metastatic dissemination are urgently needed. Our previous studies have shown that losartan, an angiotensin receptor blocker, increases tumor perfusion and decreases hypoxia in a number of tumor models. Hypoxia reduces the efficacy of radiation and increases metastases. We therefore hypothesized that by modifying tumor stroma and increasing oxygenation, losartan will improve the outcome of radiotherapy and inhibit disease progression in a highly metastatic HER2/neu + murine BC model.MethodsWe established a metastatic HER2/neu + murine BC line (MCa-M3C) and used it to generate mammary fat pad isografts in syngeneic female FVB/N mice. Starting on day 3 after orthotopic tumor implantation, we administered a 7-day losartan treatment (40 mg/kg BW, gavage daily); or a 7-day losartan treatment followed by 20 Gy single dose local irradiation (S-IR) on day 10 (tumor size ~ 100 mm3), or 20 Gy local fractionated (5 × 4 Gy daily) irradiation (F-IR) on days 10–14. We analyzed tumor-growth delay (TGD), development of spontaneous lung metastases, animal survival, tumor vascular density, and tumor hypoxia.ResultsTreatments with S-IR, F-IR, Losartan + S-IR, or Losartan + F-IR resulted in a significantly increased TGD (8–16 days) in MCa-M3C tumors versus controls. However, the combination of Losartan + S-IR and Losartan + F-IR further enhanced tumor response to radiation alone by increasing TGD an additional 5 to 8 days for both single and fractionated dose irradiation (P < 0.01), decreasing lung metastasis (Losartan + IR vs. Control, P < 0.025), and increasing animal survival (Losartan + IR vs. Control, P = 0.0303). In addition, losartan treatment significantly increased tumor vascularity (P = 0.0314) and decreased pimonidazole positive (hypoxic) area (P = 0.0002).ConclusionsCombining losartan with local irradiation significantly enhanced tumor response, at least in part via reduced tumor hypoxia presumably due to increased tumor perfusion. Our findings suggest that combining losartan with radiotherapy is a potential new treatment strategy for local control and inhibiting metastasis in HER2 + BC.

Natural variability is a large source of uncertainty in future projections of hypoxia in the Baltic Sea

Coastal seas worldwide suffer from increasing human impact. One of the most severe environmental threats is excessive nutrient pollution from land, which causes oxygen depletion and harmful algal blooms. In 2018, the semi-enclosed Baltic Sea was determined to contain the largest hypoxic area among the world’s coastal seas, with a size equal to the Republic of Ireland. In this study, ensemble modelling was used to investigate whether climate change will intensify hypoxia in the Baltic Sea and whether nutrient load abatement strategies would counteract this scenario. We analysed the largest ensemble of scenario simulations for the Baltic Sea currently available (including different boundary conditions) and estimated the magnitude of various sources of uncertainty. The results showed that natural variability was a larger source of uncertainty than previously considered. The earliest time and appropriate location to detect a trend above the background noise were estimated. A significant decrease in hypoxia can be achieved by further reductions in nutrient loads implemented in combination with existing measures.

Sanguinarine combats hypoxia-induced activation of EphB4 and HIF-1α pathways in breast cancer

BackgroundBreast cancer is the most common female cancer worldwide. Large hypoxic area is one of the features of tumor microenvironment. Highly activated hypoxia-induced pathways positively correlate with poor clinical response to chemo- and radiotherapy and high mortality in breast cancer patients. PurposeWe explore the effect of sanguinarine on hypoxia-induced activation of Ephrin type-B receptor 4 (EphB4) and hypoxia inducible factor-1α (HIF-1α) pathways in breast cancer. ResultsHypoxia-induced expression of a receptor tyrosine kinase EphB4 was observed in hypoxic breast cancer cell models. Sanguinarine, a natural alkaloid, could effectively combat hypoxia-induced EphB4 and HIF-1α expression. Sanguinarine inhibited the activation of downstream protein signal transducer and activator of transcription-3 (STAT3), thereby blocking hypoxia-induced HIF-1α/STAT3 interaction and downregulating the mRNA levels of their target genes. Mechanically, sanguinarine attenuated HIF-1α protein levels via inhibition of MAPK/ERK pathways and promotion of HIF-1α proteasome degradation. Sanguinarine inhibited STAT3 activation through targeting its upstream EphB4 and accelerating STAT3 dephosphorylation. Correspondingly, xenograft models confirmed that sanguinarine treatment disrupted hypoxia-induced pathways and inhibited tumor growth in vivo. ConclusionsOur results may bring insights to the hypoxia-induced pathways in breast cancers, and suggest sanguinarine as a promising candidate for EphB4 and HIF-1α-targeted inhibition.

LinTT1 peptide-functionalized liposomes for targeted breast cancer therapy

Breast cancer, with around 2 million new cases in 2019, is the second most common cancer worldwide and the second leading cause of cancer death among females. The aim of this work is to prepare a targeting nanoparticle through the conjugation of LinTT1 peptide, a specific molecule targeting p32 protein overexpressed by breast cancer and cancer associated cells, on liposomes’ surface. This approach increases the cytotoxic effects of doxorubicin (DOX) and sorafenib (SRF) co-loaded in therapeutic liposomes on both 2D and 3D breast cancer cellular models. The liposome functionalization leads to a higher interaction with 3D breast cancer spheroids than bare ones. Moreover, interaction studies between LinTT1-functionalized liposomes and M2 primary human macrophages show an internalization of 50% of the total nanovesicles that interact with these cells, while the other 50% results only associated to cell surface. This finding suggests the possibility to use the amount of associated liposomes to enrich the hypoxic tumor area, exploiting the ability of M2 macrophages to accumulate in the central core of tumor mass. These promising results highlight the potential use of DOX and SRF co-loaded LinTT1-functionalized liposomes as nanomedicines for the treatment of breast cancer, especially in triple negative cancer cells.

Reducing Hypoxia in an Urban Estuary Despite Climate Warming.

Seasonal hypoxia is a serious threat to coastal ecosystems. This study on hypoxia in Long Island Sound (LIS), a large urbanized estuary, focuses on responses to managed nitrogen load reductions and climate change. At the analyzed station in western LIS, warming in bottom waters (0.8 °C per decade) favors hypoxia. Total nitrogen concentrations have decreased (0.06 mg L-1 per decade) with load reductions, but no linear temporal trend in chlorophyll is discernible. Bottom dissolved oxygen has increased (0.48 mg L-1 per decade), despite warming-induced solubility decreases (0.13 mg L-1 per decade). Decreasing trends in hypoxic area and volume (100 km2 and 1 km3 per decade) reflect improved conditions and are coincident with reducing loads. Regressions link hypoxic extent to nitrogen loads, chlorophyll, salinity, and winds. Though mitigation has reduced hypoxia, these improvements will not be sustained in the warming climate without continued intervention. The warming-induced oxygen solubility decrease forecasted for 2099 (0.4 mg L-1) would erode 35% of the observed oxygen gains. Implementing a nitrogen load reduction of 1.2 × 106 kg year-1 before the century's end would offset the oxygen solubility decline. This overall approach is applicable to areas experiencing warming and continued development that complicate efforts to reign in hypoxia.

Three-dimensional collagen-based scaffold model to study the microenvironment and drug-resistance mechanisms of oropharyngeal squamous cell carcinomas.

Objective:Squamous cell carcinoma (SCC) represents the most common histotype of all head and neck malignancies and includes oropharyngeal squamous cell carcinoma (OSCC), a tumor associated with different clinical outcomes and linked to human papilloma virus (HPV) status. Translational research has few available in vitro models with which to study the different pathophysiological behavior of OSCCs. The present study proposes a 3-dimensional (3D) biomimetic collagen-based scaffold to mimic the tumor microenvironment and the crosstalk between the extracellular matrix (ECM) and cancer cells.Methods:We compared the phenotypic and genetic features of HPV-positive and HPV-negative OSCC cell lines cultured on common monolayer supports and on scaffolds. We also explored cancer cell adaptation to the 3D microenvironment and its impact on the efficacy of drugs tested on cell lines and primary cultures.Results:HPV-positive and HPV-negative cell lines were successfully grown in the 3D model and displayed different collagen fiber organization. The 3D cultures induced an increased expression of markers related to epithelial–mesenchymal transition (EMT) and to matrix interactions and showed different migration behavior, as confirmed by zebrafish embryo xenografts. The expression of hypoxia-inducible factor 1α (1α) and glycolysis markers were indicative of the development of a hypoxic microenvironment inside the scaffold area. Furthermore, the 3D cultures activated drug-resistance signaling pathways in both cell lines and primary cultures.Conclusions:Our results suggest that collagen-based scaffolds could be a suitable model for the reproduction of the pathophysiological features of OSCCs. Moreover, 3D architecture appears capable of inducing drug-resistance processes that can be studied to better our understanding of the different clinical outcomes of HPV-positive and HPV-negative patients with OSCCs.

Sequential Magneto‐Actuated and Optics‐Triggered Biomicrorobots for Targeted Cancer Therapy

AbstractMicro/nanorobots have the potential to be remotely propelled and manipulated in complex biological fluid and organ tissue. However, the combination of the sophisticated physiological barriers, remote‐controlled navigation, real‐time motion tracking, and diagnostic/therapeutic effects are tremendous challenges for application and translation. An unique sequential magneto‐actuated and optics‐triggered biomicrorobot (AI microrobot) for actively targeted cancer treatment is prepared. The AI microrobot consists of two components, magnetospirillum magneticum (AMB‐1), providing the ability to autonomously swim toward the tumor site via internal hypoxia‐driven effects and an external applied magnetic field, and indocyanine green nanoparticles, acting as a fluorescence imaging agent and photothermal therapy. The AI microrobots are tracked in vivo by fluorescence and magnetic resonance imaging. It is found that the AI microrobots can sequentially migrate to the hypoxic internal area of tumors and then effectively eradicate solid tumors through photothermal therapy under NIR laser irradiation. The sequential magneto‐actuated and optics‐triggered AI microrobots platform described here presents a bioinspired strategy toward remotely controlled propulsion, actively targeted cargo delivery, and satisfactory therapeutic performance in the circulatory system.

Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases.

The cerebral hypoxia-ischemia can induce a wide spectrum of biologic responses that include depolarization, excitotoxicity, oxidative stress, inflammation, and apoptosis, and result in neurodegeneration. Several adaptive and survival endogenous mechanisms can also be activated giving an opportunity for the affected cells to remain alive, waiting for helper signals that avoid apoptosis. These signals appear to help cells, depending on intensity, chronicity, and proximity to the central hypoxic area of the affected tissue. These mechanisms are present not only in a large list of brain pathologies affecting commonly older individuals, but also in other pathologies such as refractory epilepsies, encephalopathies, or brain trauma, where neurodegenerative features such as cognitive and/or motor deficits sequelae can be developed. The hypoxia inducible factor 1α (HIF-1α) is a master transcription factor driving a wide spectrum cellular response. HIF-1α may induce erythropoietin (EPO) receptor overexpression, which provides the therapeutic opportunity to administer pharmacological doses of EPO to rescue and/or repair affected brain tissue. Intranasal administration of EPO combined with other antioxidant and anti-inflammatory compounds could become an effective therapeutic alternative, to avoid and/or slow down neurodegenerative deterioration without producing adverse peripheral effects.

Increasing heart vascularisation after myocardial infarction using brain natriuretic peptide stimulation of endothelial and WT1+ epicardial cells.

Brain natriuretic peptide (BNP) treatment increases heart function and decreases heart dilation after myocardial infarction (MI). Here, we investigated whether part of the cardioprotective effect of BNP in infarcted hearts related to improved neovascularisation. Infarcted mice were treated with saline or BNP for 10 days. BNP treatment increased vascularisation and the number of endothelial cells in all areas of infarcted hearts. Endothelial cell lineage tracing showed that BNP directly stimulated the proliferation of resident endothelial cells via NPR-A binding and p38 MAP kinase activation. BNP also stimulated the proliferation of WT1+ epicardium-derived cells but only in the hypoxic area of infarcted hearts. Our results demonstrated that these immature cells have a natural capacity to differentiate into endothelial cells in infarcted hearts. BNP treatment increased their proliferation but not their differentiation capacity. We identified new roles for BNP that hold potential for new therapeutic strategies to improve recovery and clinical outcome after MI.

Anti-tumor efficacy of CKD-516 in combination with radiation in xenograft mouse model of lung squamous cell carcinoma

BackgroundHypoxic tumors are known to be highly resistant to radiotherapy and cause poor prognosis in non-small cell lung cancer (NSCLC) patients. CKD-516, a novel vascular disrupting agent (VDA), mainly affects blood vessels in the central area of the tumor and blocks tubulin polymerization, thereby destroying the aberrant tumor vasculature with a rapid decrease in blood, resulting in rapid tumor cell death. Therefore, we evaluated the anti-tumor efficacy of CKD-516 in combination with irradiation (IR) and examined tumor necrosis, delayed tumor growth, and expression of proteins involved in hypoxia and angiogenesis in this study.MethodsA xenograft mouse model of lung squamous cell carcinoma was established, and the tumor was exposed to IR 5 days per week. CKD-516 was administered with two treatment schedules (day 1 or days 1 and 5) 1 h after IR. After treatment, tumor tissues were stained with hematoxylin and eosin, and pimonidazole. HIF-1α, Glut-1, VEGF, CD31, and Ki-67 expression levels were evaluated using immunohistochemical staining.ResultsShort-term treatment with IR alone and CKD-516 + IR (d1) significantly reduced tumor volume (p = 0.006 and p = 0.048, respectively). Treatment with CKD-516 + IR (d1 and d1, 5) resulted in a marked reduction in the number of blood vessels (p < 0.005). More specifically, CKD-516 + IR (d1) caused the most extensive tumor necrosis, which resulted in a significantly large hypoxic area (p = 0.02) and decreased HIF-1α, Glut-1, VEGF, and Ki-67 expression. Long-term administration of CKD-516 + IR reduced tumor volume and delayed tumor growth. This combination also greatly reduced the number of blood vessels (p = 0.0006) and significantly enhanced tumor necrosis (p = 0.004). CKD-516 + IR significantly increased HIF-1α expression (p = 0.0047), but significantly reduced VEGF expression (p = 0.0046).ConclusionsTaken together, our data show that when used in combination, CKD-516 and IR can significantly enhance anti-tumor efficacy compared to monotherapy in lung cancer xenograft mice.

Targeting Hypoxia Using Evofosfamide and Companion Hypoxia Imaging of FMISO-PET in Advanced Biliary Tract Cancer.

PurposeHypoxia is widely known as one of the mechanisms of chemoresistance and as an environmental condition which triggers invasion and metastasis of cancer. Evofosfamide is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard conjugated with 2-nitroimidazole. Biliary tract cancer (BTC) is known to contain large hypoxic area. This study evaluated the efficacy and safety of evofosfamide as a second-line treatment of advanced BTC.Materials and MethodsPatients received evofosfamide at a dose of 340 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Primary end-point was progression-free survival (PFS) rate at 4-months (4m-PFSR). Secondary end-points included overall survival (OS), PFS, disease control rate (DCR), metabolic response by 18F-fluorodeoxyglucose positron emission tomography (PET), hypoxic parameters evaluated by 18F-fluoromisonidazole (FMISO) PET and toxicity.ResultsTwenty patients were treated with evofosfamide, with 16 response-evaluable patients. There was no objective response; stable disease was observed in nine patients, with a DCR of 56.25%. 4m-PFSR was 40.6%. Median PFS was 3.60 months (95% confidence interval [CI], 1.68 to 5.52). Median OS was 6.37 months (95% CI, 3.94 to 8.79). Reduction of tumor metabolic activity was observed in eight of 15 patients (53.3%). High baseline hypoxic parameters were associated with poor PFS. Change of hypoxic parameters between pretreatment and post-treatment reflected hypoxic-activated drug response. There was no treatment-related death.ConclusionEvofosfamide as second-line treatment of advanced BTC showed acceptable safety and comparable efficacy to other agents. Changes in volumetric parameters measured with FMISO PET, showing the degree of tumor hypoxia, reflected the response to evofosfamide based on the mode of action.

Hypoxia-Induced Glioma-Derived Exosomal miRNA-199a-3p Promotes Ischemic Injury of Peritumoral Neurons by Inhibiting the mTOR Pathway.

The underlying molecular mechanisms that the hypoxic microenvironment could aggravate neuronal injury are still not clear. In this study, we hypothesized that the exosomes, exosomal miRNAs, and the mTOR signaling pathway might be involved in hypoxic peritumoral neuronal injury in glioma. Multimodal radiological images, HE, and HIF-1α staining of high-grade glioma (HGG) samples revealed that the peritumoral hypoxic area overlapped with the cytotoxic edema region and directly contacted with normal neurons. In either direct or indirect coculture system, hypoxia could promote normal mouse hippocampal neuronal cell (HT22) injury, and the growth of HT22 cells was suppressed by C6 glioma cells under hypoxic condition. For administrating hypoxia-induced glioma-derived exosomes (HIGDE) that could aggravate oxygen-glucose deprivation (OGD)/reperfusion neuronal injury, we identified that exosomes may be the communication medium between glioma cells and peritumoral neurons, and we furtherly found that exosomal miR-199a-3p mediated the OGD/reperfusion neuronal injury process by suppressing the mTOR signaling pathway. Moreover, the upregulation of miRNA-199a-3p in exosomes from glioma cells was induced by hypoxia-related HIF-1α activation. To sum up, hypoxia-induced glioma-derived exosomal miRNA-199a-3p can be upregulated by the activation of HIF-1α and is able to increase the ischemic injury of peritumoral neurons by inhibiting the mTOR pathway.

Contribution of the offshore detached Changjiang (Yangtze River) Diluted Water to the formation of hypoxia in summer

The Changjiang (Yangtze River) Diluted Water (CDW) plume substantially impacts the biogeochemical processes off the estuary and its adjacent area, resulting in considerable environmental and ecological effects. Based on survey data in the northeastern area off the Changjiang Estuary (CE) obtained in the summers of 2008 and 2013, the hypoxia induced by the offshore detached CDW plume and the associated controlling mechanisms were investigated. The results show that the offshore transport of the CDW plume caused a dispersed low-salinity area in the northeastern area off the CE during summer, in sharp contrast with the surrounding high-salinity and high-density waters. There was a hypoxic area with low-pH (i.e., acidification) near the 40-m isobath in bottom waters in the northeastern area off the CE, and its position generally corresponded to the surface offshore CDW plume. In the area affected by the offshore low-salinity water, the surface patch-like phytoplankton bloom and the organic debris produced in situ were the material drivers of the bottom oxygen consumption and led to the corresponding relationship between the bottom hypoxic zone and the high chlorophyll-a (Chl-a) area at the surface. We consider that the local stratification caused by the offshore low-salinity water and the stable environment within the detached CDW plume constituted the external dynamic conditions for maintaining the bottom hypoxia. Our results demonstrate that the offshore detached CDW plume in the northeastern area off the CE may contribute to the formation of a local hypoxic center with low pH. This study would provide basis for understanding of the physical-biogeochemical processes and environmental responses in the offshore areas of the CDW plume.

Intrusion of Kuroshio Helps to Diminish Coastal Hypoxia in the Coast of Northern South China Sea

Since half century ago, the number and area of dead zones (dissolved oxygen (DO) < 2 mg L-1 or 30% saturation) in the coastal oceans have increased dramatically. As is widely recognized the increased terrestrial nutrient and organic matter inputs are the two main factors causing the eutrophication of many coastal oceans. Here we show with decadal observed time series data from stations off the Pearl River Estuary and in the northern South China Sea (nSCS) that a strong intrusion into the nSCS of the West Philippine Sea (WPS) seawater in the form of Kuroshio branch occurred during the warm phase of the Pacific Decadal Oscillation (PDO) around 2003–2004 and 2015–2016 (also a strong El Nino event). Consequently, the DO concentration increased but NO3- and PO43- concentrations decreased in the subsurface layers of the nSCS. The WPS seawater was observed to reach the hypoxic area off the Pearl River Estuary in 2003–2004. Likely, due to the oxygen supply carried by the Kuroshio, little hypoxia developed. Yet, anoxic condition developed in the cold phase of PDO or strong La Nina years with weak Kuroshio intrusions.

Fusion-Based Hypoxia Estimates: Combining Geostatistical and Mechanistic Models of Dissolved Oxygen Variability.

The need to characterize and track coastal hypoxia has led to the development of geostatistical models based on in situ observations of dissolved oxygen (DO) and mechanistic models based on a representation of biophysical processes. To integrate the benefits of these two distinct modeling approaches, we develop a space-time geostatistical framework for synthesizing DO observations with hydrodynamic-biogeochemical model simulations and meteorological time series (as covariates). This fusion-based approach is used to estimate hypoxia in the northern Gulf of Mexico across summers from 1985 to 2017. Deterministic trends with dynamic covariates explain over 35% of the variability in DO. Moreover, cross-validation results indicate that 58% of DO variability is explained when combining these trends with spatiotemporal interpolation, which is substantially better than mechanistic or conventional geostatistical hypoxia modeling alone. The fusion-based approach also reduces hypoxic area uncertainties by 11% on average and up to 40% in months with sparse sampling. Moreover, our new estimates of mean summer hypoxic area changed by >10% in a majority of years, relative to previous geostatistical estimates. These fusion-based estimates can be a valuable resource when assessing the influence of hypoxia on the coastal ecosystem.