Hypoxic Sites Research Articles

Lactate/Cysteine Dual-Consuming Probiotic-Nanomedicine Biohybrid System for Enhanced Cancer Chemo-Immunotherapy.

Immunotherapy is revolutionizing oncology, but its therapeutic efficiency is still limited by the off-target toxicities and poor antitumor immune responses. By integrating the drug-loaded nanoparticles (DMnSH) with the unique metabolic traits of Veillonella parvula (Vei), a probiotic-nanomedicine conjugate Vei@DMnSH biohybrid is elaborately designed for enhanced cancer chemo-immunotherapy. Specifically, Vei@DMnSH can accumulate in hypoxic tumor sites and simultaneously consume lactate and cysteine to reverse the lactate-associated immunosuppression and impede the biosynthesis of GSH. In addition, the DMnSH nanoparticles will rapidly deplete intracellular GSH and disassemble to release DOX and Mn2+. Accompanied by the two-pronged GSH depletion, the Mn2+-mediated Fenton-like reaction can effectively generate oxidative hydroxyl radicals to induce heavy redox imbalance. Combined with the therapeutic effect of DOX, robust immunogenic cell death is provoked and subsequently activates antitumor adaptive immunity with a tumor suppression rate over 82%, synergistically enhancing the therapeutic outcomes of cancer chemo-immunotherapy.

Engineered Mesenchymal Stem Cells as Treatment for Cancers: Opportunities, Clinical Applications and Challenges.

The insufficient and unspecific target of classical chemotherapies often leads to therapy resistance and cancer recurrence. Over the past decades, discoveries about mesenchymal stem cell (MSC) biology have provided new potential approaches to improve cancer therapy. Researchers have utilised the multipotent, regenerative and immunosuppressive qualities of MSCs and tropisms towards inflammatory, hypoxic and malignant sites in various therapeutic applications. Although MSC-based therapies have generally been demonstrated safe, their effectiveness remains limited when these cells are used alone. However, through genetic engineering, researchers have proven that MSCs can be modified to have specialised delivery roles to increase their therapeutic efficacy in cancer treatment. They can be made to overexpress therapeutic proteins through viral or non-viral genetic modification, which enhances their innate properties. Nevertheless, these engineering strategies must be optimised to increase therapeutic efficacy and targeting effectiveness while minimising any loss of MSC function. This review underscores the cutting-edge methods for engineering MSCs, discusses their promise and the difficulties in translating them into clinical settings, and offers some prospective suggestions for the future on achieving their full therapeutic potential.

Characteristics of demersal fish community structure during summer hypoxia in the Pearl River Estuary, China.

In recent decades, hypoxic areas have rapidly expanded worldwide in estuaries and coastal zones. The Pearl River Estuary (PRE), one of China's largest estuaries, experiences frequent seasonal hypoxia due to intense human activities and eutrophication. However, the ecological effects of hypoxia in the PRE, particularly on fish communities, remain unclear. To explore these effects, we collected fish community and environmental data in July 2021 during the summer hypoxia development period. The results revealed that bottom-layer dissolved oxygen (DO) in the PRE ranged from 0.08 to 5.71 mg/L, with extensive hypoxic zones (DO ≤ 2 mg/L) observed. Hypoxia has varied effects on fish community composition, distribution, species, and functional diversity in the PRE. A total of 104 fish species were collected in this study, with approximately 30 species (28.6%) exclusively found in hypoxic areas. Species responses to hypoxia varied: species such as Sardinella zunasi, Coilia mystus, and Nuchequula nuchalis were sensitive, while Decapterus maruadsi, Siganus fuscescens, and Lagocephalus spadiceus showed higher tolerance. Within the hypoxia area, dissolved oxygen was the main limiting factor for fish community diversity. Functional diversity (FDiv) decreased with higher dissolved oxygen levels, indicating a potential shift in the functional traits and ecological roles of fish species in response to changing oxygen conditions. Further analysis demonstrated that dissolved oxygen had a significantly stronger effect on fish community structure at hypoxic sites than in the whole PRE. Moreover, other environmental variables also had significant effects on the fish community structure and interacted with dissolved oxygen in the hypoxia area. These findings suggest that maintaining sufficient dissolved oxygen levels is essential for sustaining fish communities and ecosystem health in the PRE. This study provides novel insights into the effects of hypoxia on fish communities in estuarine ecosystems and has significant implications for the ecological health and management of the PRE.

Impact of summer hypoxia on macrobenthic communities in a semi-enclosed bay: A long-term observation in the North Yellow sea of China

The O2 content of the global ocean has been declining progressively over the past decades, mainly because of human activities and global warming. Despite this situation, the responses of macrobenthos under hypoxic conditions remain poorly understood. In this study, we conducted a long-term observation (2015–2022) to investigate the intricate impact of summer hypoxia on macrobenthic communities in a semi-enclosed bay of the North Yellow Sea. Comparative analyses revealed higher macrobenthos abundance (1956.8 ± 1507.5 ind./m2 vs. 871.8 ± 636.9 ind./m2) and biomass (8.2 ± 4.1 g/m2 vs. 5.6 ± 3.2 g/m2) at hypoxic sites compared to normoxic sites during hypoxic years. Notably, polychaete species demonstrated remarkable adaptability, dominating hypoxic sites, and shaping community structure. The decline in biodiversity underscored the vulnerability and diminished resilience of macrobenthic communities to hypoxic stressors. Stable isotope analysis provided valuable insights into food web structures. The average trophic level of macrobenthos measured 2.84 ± 0.70 at hypoxic sites, contrasting with the higher value of 3.14 ± 0.74 observed at normoxic sites, indicating the absence of predators at high trophic levels under hypoxic conditions. Moreover, trophic interactions were significantly altered, resulting in a simplified and more vulnerable macrobenthic trophic structure. The findings underscored the importance of comprehensive research to understand the complex responses of macrobenthic communities to hypoxia, thereby informing future conservation efforts in impacted ecosystems.

Upconversion dual-photosensitizer-expressing bacteria for near-infrared monochromatically excitable synergistic phototherapy.

Synergistic phototherapy stands for superior treatment prospects than a single phototherapeutic modality. However, the combined photosensitizers often suffer from incompatible excitation mode, limited irradiation penetration depth, and lack of specificity. We describe the development of upconversion dual-photosensitizer-expressing bacteria (UDPB) for near-infrared monochromatically excitable combination phototherapy. UDPB are prepared by integrating genetic engineering and surface modification, in which bacteria are encoded to simultaneously express photothermal melanin and phototoxic KillerRed protein and the surface primary amino groups are derived to free thiols for biorthogonal conjugation of upconversion nanoparticles. UDPB exhibit a near-infrared monochromatic irradiation-mediated dual-activation characteristic as the photothermal conversion of melanin can be initiated directly, while the photodynamic effect of KillerRed can be stimulated indirectly by upconverted visible light emission. UDPB also show living features to colonize hypoxic lesion sites and inhibit pathogens via bacterial community competition. In two murine models of solid tumor and skin wound infection, UDPB separately induce robust antitumor response and a rapid wound healing effect.

Electrogenic sulfur oxidation by cable bacteria in two seasonally hypoxic coastal systems

Cable bacteria can reach high densities in coastal sediments, and as a result of their unusual electrogenic lifestyle and intense metabolic activity, exert a major and distinct impact on biogeochemical cycling, both locally in sediments and at the ecosystem level. This appears to be particularly true for seasonally hypoxic systems, but the driving force behind the proliferation of cable bacteria in these systems is not well understood. Moreover, the metabolism of cable bacteria induces strong acid production, which can be buffered through carbonate dissolution in sediments. A strong depletion of alkalinity in the pore water is therefore expected in carbonate-poor sediments. To evaluate the impact of cable bacteria metabolism on sediment geochemistry, we performed field sampling and laboratory sediment incubations in two seasonally hypoxic sites: one carbonate-poor site with low levels of free sulfide in pore water (Yarra Estuary, Australia) and one carbonate-rich site with high free sulfide (Lake Grevelingen, The Netherlands). Active cable bacteria populations were found in both field locations, with higher abundance and activity observed in spring compared to autumn. The sediment incubations tracked the metabolic activity of cable bacteria over time (maximum 84 days), and confirmed the fast development of an electric network (cell doubling time: ∼19 h). These results suggest that cable bacteria are widespread in seasonally hypoxic systems, supporting previous findings. Cable bacteria acidified the sediment by > 1.5 pH units in 6–13 days (differing per site) and their activity accounted for >70% of the oxygen uptake. A clear subsurface accumulation of Fe2+ was observed after 8 days of Yarra sediment incubations, indicative of increased FeS dissolution as e-SOx developed. The increased availability of sulfide from FeS dissolution promotes a positive-feedback loop that we infer allowed for a faster development of cable bacteria in the carbonate-poor sediments. A depletion of total alkalinity was observed in the deeper Yarra sediment, whereas, a higher alkalinity efflux was previously observed in the carbonate-rich sediments from Lake Grevelingen. These results suggest a differential pH and alkalinity dynamic due to the interaction between the local carbonate content of the sediment and cable bacteria activity.

Potentiating light-harvesting tactics through an A-D-A structure: repolarization of tumor-associated macrophages through phototherapy.

Aiming to decrease the recurrence of tumors and achieve patient satisfaction, the elicitation of immunotherapy and its integrated synergistic employment is a bright new direction in oncotherapy, yet an emergently challenging task. In particular, tumor-associated macrophage (TAM) regulation though light-induced photodynamic and photothermal therapy (PDT and PTT) is regarded as a powerful approach, which focuses on the systemic immune system instead of the tumor itself. Herein, this study reports an acceptor-donor-acceptor (A-D-A) aggregation-induced emission luminogen (AIEgen), named TPA-2CN, which was applied as a photosensitizer (PS) and photothermal agent (PTA). Attributed to its A-D-A structure and AIE properties, TPA-2CN exhibits a high molar absorption coefficient and acts as a perfect template in regulating radiative and nonradiative transitions, which mainly utilize excited energy. The generation of type I reactive oxygen promoted its application in hypoxic tumor sites and the combination of hyperpyrexia forcefully induces macrophages to polarize towards the immune response M1 phenotype. In in vitro and in vivo, the successful reversion and reprogramming of the immune microenvironment was impressively proved. This method optimally concentrated immune therapy, PDT and PTT as one and exhibited excellent synergistic therapeutic effects with good biosafety.

Light-Enhanced Hypoxia-Responsive Gene Editing for Hypoxia-Resistant Photodynamic and Immunotherapy.

Hypoxia is a key hallmark of solid tumors and can cause resistance to various treatments such as photodynamics and immunotherapy. Microenvironment-responsive gene editing provides a powerful tool to overcome hypoxia resistance and remodel hypoxic microenvironments for enhanced tumor therapy. Here, a light-enhanced hypoxia-responsive multifunctional nanocarrier is developed to perform spatiotemporal specific dual gene editing for enhanced photodynamic and immunotherapy in breast cancer. As a gated molecule of nanocarrier, the degradation of azobenzene moieties under hypoxic conditions triggers controllable release of Cas9 ribonucleoprotein in hypoxic site of the tumor. Hyaluronic acid is conjugated with chloramine e6 to coat mesoporous silica nanoparticles for targeted delivery in tumors and generation of high levels of reactive oxygen species, which can result in increased hypoxia levels for effective cleavage of azobenzene bonds to improve gene editing efficiency and reduce toxic side effects with light irradiation. Moreover, dual targeting HIF-1α and PD-L1 in the anoxic microenvironments can overcome hypoxia resistance and remodel immune microenvironments, which reduces tumor plasticity and resistance to photodynamic and immunotherapy. In summary, a light-enhanced hypoxia responsive nanocomposite is developed for controllable gene editing which holds great promise for synergistic hypoxia-resistant photodynamic and immunotherapy.

ROS-mediated Therapeutics Combined with Metal-based Porphyrin Nanoparticles and their Applications in Tumor Treatment.

High concentrations of reactive oxygen species (ROS) can disrupt cell structure and induce apoptosis and necrosis of tumor cells. Photodynamic therapy (PDT) and chemodynamic therapy (CDT) are two cancer treatments mediated by reactive oxygen species. Oxygen molecules (O2 ) are one of the indispensable factors in PDT and hypoxic tumor sites limit its application. However, another ROS-mediated method, CDT, can generate •OH and O2 in situ by Fenton reaction or Fenton-like reaction. Synergistic PDT/CDT therapy is a strategy to overcome the limitations of tumor microenvironment therapy. In this review, PDT and CDT therapies are briefly introduced, with an emphasis on metal-basrd porphyrin nanoparticles constructed in different ways for PDT/CDT dual-mode therapy. By introducing the history and latest design schemes of the treatment model, it provides ideas for researchers engaged in ROS-mediated cancer therapies.

Hypoxia diversifies molecular composition of dissolved organic matter and enhances preservation of terrestrial organic carbon in the Yangtze River Estuary

Dissolved organic matter (DOM) is an essential component of the global carbon cycle, and estuaries link the rivers and the oceans, thus playing important roles in land-ocean DOM transformation and transport. However, the effects of hypoxia on DOM transport and fate in estuaries and coastal oceans remains poorly understood. To address this gap, we characterized the molecular composition of DOM in bottom water (BW) and sediment porewater (PW) at hypoxic and non-hypoxic sites in the Yangtze River Estuary (YRE) using ultra-high-resolution Fourier transform ion cyclotron resonance mass spectrometry. Our results showed significant differences in DOM molecular composition between hypoxic and non-hypoxic areas for both BW and PW. Specifically, DOM in hypoxic sites was more recalcitrant than that in non-hypoxic areas for both BW and PW, with lower H/C, and higher O/C, double bond equivalent, and modified aromaticity index. The presence of higher polyphenols, and black carbon in hypoxic areas suggested that hypoxic conditions could facilitate the preservation of terrestrial organic matter. Furthermore, we identified a much higher number of hypoxia-unique formulas than ocean-non-hypoxia-unique formulas, indicating that hypoxia could diversify the DOM pool. Within hypoxia-unique formulas for PW, both biologically labile (unsaturated aliphatic compounds and peptides) and recalcitrant formulas (carboxyl-rich alicyclic molecules) were found, suggesting that hypoxia could facilitate the preservation of labile formulas and the production of recalcitrant formulas. In addition, we formulated that the sulfurization is more important in PW than BW in hypoxic areas based on the higher dissolved organic sulfur (DOS) abundance and larger number of hypoxia-only formulas in hypoxic PW, and also the precursor analysis results. Overall, our study provides insights into the effect of hypoxia on the molecular characteristics and preservation of DOM in estuaries and coastal oceans, highlighting the importance of considering hypoxia in understanding the biogeochemical processes of these ecosystems.

Hypoxia-targeted and spatial-selective tumor suppression by near infrared nanoantenna sensitized engineered bacteria

It is an active research area in the development of engineered bacteria to address the bottleneck issue of hypoxic tumors, which otherwisely possess resistance to chemotherapies, radiotherapies, and photodynamic therapies. Here we report a new method to ablate hypoxic tumors with NIR-nanoantenna sensitized engineered bacteria (NASEB) in a highly effective and dual selective manner. It features engineered E. coli MG1655 (EB) with coatings of lanthanide upconversion nanoparticles (UCNPs) as external antennas on bacterial surface (MG1655/HlyE-sfGFP@UCNP@PEG), enabling NIR laser-switchable generation/secretion of HlyE perforin to kill cancer cells. We have demonstrated that NASEB enrichment on hypoxic tumor sites via their innate chemotactic tendency, in assistance of localized NIR laser irradiation, can suppress tumors with improved efficacy and selectivity, thus minimizing potential side effects in cancer treatment. The NIR-responsive nanoantenna sensitized switching in engineering bacteria is distinct from the previous reports, promising conceptually new development of therapeutics against hypoxic tumors. Statement of significanceTumor hypoxia exacerbates tumor progression, but also reduces the efficacy of conventional chemotherapies, radiotherapies, or photodynamic therapies. Here we develop near infrared Nano Antenna Sensitized Engineered Bacteria (NASEB) to treat hypoxic tumors. NASEB can accumulate and proliferate on hypoxic tumor sites via their innate chemotactic tendency. After receiving NIR laser signals, the upconversion nanoparticles on NASEB surface as antennas can transduce them to blue light for activation of HlyE perforin in the protein factory of EB. Our method features dual selectivity on the tumor sites, contributed by hypoxic tumor homing of anaerobic bacteria and spatial confinement through selective NIR laser irradiation. The concept of NASEB promises to address the challenges of tumor hypoxia for cancer therapies.

Uridine as a novel fuel for cancer cells

Cancer cells are known to have an enormous appetite for calorie. This is something they are addicted to sustain their unrestricted growth and rapid proliferation. In order to accomplish this feat, cancer cells has evolved multiple mechanisms, rewiring their metabolic circuitry such that metabolic fuels are preferentially diverted to meet their energy demands. A classic example (Warburg effect) of this is aerobic glycolysis and preferential production of lactate to produce ATP (without relying on mitochondrial oxidative phosphorylation). Further, rapid proliferation of cancer cells, exhausts the nutrient and oxygen supply derived from the existing vasculature, making them hypoxic. In turn triggers the upregulation of pro angiogenic factors from the hypoxic tumor sites( HIF), which in turn re-vascularizes the tumor mass, bringing in metabolic cargo.
 When it comes to cancer metabolism, cancer cells are highly innovative to devise novel mechanisms to bypass metabolic regulations and In a recent article published in Nature Metabolism, Skinner et al. identified an unusual source of glucose in cancer cells. Ribose moiety of uridine can be repurposed to replenish the energy requirements in cancer cells thorough the uridine phosphorylase UPP1/UPP2 mediated cleavage of uridine into its constituents , uracil and ribose-1-phosphate (R1P). R1P is then utilized to convert into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the HMP shunt back to glycolysis and ATP production.
 These findings are novel and intuitive. It means that the cancer cells has the ability to salvage glucose from uridine, when needed. This also indicates that cutting off Uridine supply to cancer cells maybe a mechanism to target cancer cells .

Intraspecific patterns of mortality and cardiac response to hypoxia in the eastern oyster, Crassostrea virginica

Hypoxia is a naturally occurring phenomenon in coastal and estuarine waters that is increasing in frequency and extent due largely to human activities. Elucidating how organisms differentially tolerate hypoxia as a consequence of prior exposure can yield insights into their capacity for adaptation or acclimatization to changing oxygen availability. The eastern oyster, Crassostrea virginica, is an ecologically significant bivalve that inhabits estuarine environments with highly variable oxygen conditions. This study aims to increase knowledge on intraspecific variability in oyster hypoxia tolerance and how prior exposure affects this tolerance. Survival and heart rate in response to hypoxia exposure were measured in oysters sourced from reefs with differing frequency of exposure to low oxygen. Regardless of the source site, oysters showed significantly greater mortality, particularly for large oysters, and significantly reduced heart rate upon hypoxic exposure. Additionally, oysters from normoxic versus hypoxic reefs showed no significant differences in survival upon experimental hypoxia exposure. In contrast, heart rate reduction upon hypoxia exposure differed between oysters from hypoxic versus normoxic sites, with significantly less reduction in heart rate observed for oysters from one hypoxic site, and a trend towards smaller reduction in a second site. Results indicate that oysters with prior hypoxia exposure show no difference in survival in hypoxia but show some physiological difference in tolerance, particularly for oysters with greater frequency of prior hypoxia exposure. Overall, these results suggest that hypoxia has negative effects on oyster physiology, and underscore the importance of continued research into oyster's capacity to tolerate future intensification of coastal hypoxia.

Effective drug and shRNA delivery for synergistic treatment of triple-negative breast cancer by sequentially targeting tumor hypoxia

Clinical treatment of TNBC remains challenging, due to the lack of targeted therapies. As TNBC is highly hypoxic with higher HIF-1α expression than other subtypes, we fabricated hypoxia-responsive polymeric micelles co-loading drug and shRNA to treat TNBC by targeting hypoxic tumor microenvironment and subsequently targeting overexpressed HIF-1α under hypoxia. The micelles were assembled from methoxy-polyethylene glycol (mPEG) and poly-L-lysine (PLL) copolymer with AZO as a hypoxia-responsive bridge of mPEG and PLL. Once exposed to hypoxia, AZO bridge was cleaved, resulting in the disassembly of the micelles for rapid release. In vitro and in vivo results showed that the micelles enabled simultaneous delivery of drug and shRNA to hypoxic sites for site-specific rapid release, facilitated by sensitive response to hypoxia; hypoxia-responsive shRNA delivery effectively silenced HIF-1α and its downstream genes, which not only ameliorated the response of hypoxic tumor to drug, but also modulated tumor microenvironment for further improved drug and shRNA delivery; as a result, synergistic treatment of chemotherapy and HIF-1α targeted gene therapy inhibited the growth of primary TNBC tumor and its distant metastasis in a murine model of orthotopic TNBC. Together with their good biocompatibility, hypoxia-responsive polymeric micelles thus emerged as a safe, effective, and universally applicable drug and gene carrier for treatment of TNBC as well as other hypoxic tumors.

Tumour suppressor PTEN activity is differentially inducible by myo-inositol phosphates.

Tumour evolution and efficacy of treatments are controlled by the microenvironment, the composition of which is primarily dependent on the angiogenic reaction to hypoxic stress. Tumour angiogenesis normalization is a challenge for adjuvant therapy strategies to chemo-, radio- and immunotherapeutics. Myo-inositol trispyrophosphate (ITPP) appears to provide the means to alleviate hypoxia in the tumour site by a double molecular mechanism. First, it modifies the properties of red blood cells (RBC) to release oxygen (O2 ) in the hypoxic sites more easily, leading to a rapid and stable increase in the partial pressure of oxygen (pO2 ). And second, it activates the endothelial phosphatase and tensin homologue deleted on Chromosome 10 (PTEN). The hypothesis that stable normalization of the vascular system is due to the PTEN, a tumour suppressor and phosphatase which controls the proper angiogenic reaction was ascertained. Here, by direct biochemical measurements of PTEN competitive activity in relation to PIP2 production, we show that the kinetics are complex in terms of the activation/inhibition effects of ITPP with an inverted consequence towards the kinase PI3K. The use of the surface plasmon resonance (SPR) technique allowed us to demonstrate that PTEN binds inositol derivatives differently but weakly. This method permitted us to reveal that PTEN is highly sensitive to the local concentration conditions, especially that ITPP increases the PTEN activity towards PIP3, and importantly, that PTEN affinity for ITPP is considerably increased by the presence of PIP3, as occurs in vivo. Our approach demonstrates the validity of using ITPP to activate PTEN for stable vessel normalization strategies.

Transitions in nitrogen and organic matter form and concentration correspond to bacterial population dynamics in a hypoxic urban estuary.

The online version contains supplementary material available at 10.1007/s10533-023-01021-2.

Live bio-nano-sonosensitizer targets malignant tumors in synergistic therapy.

Sonosensitizers that can increase the concentration of reactive oxygen species (ROS) within a tumor microenvironment is a high priority for sonodynamic therapy (SDT). In this study, a functionalized, smart nanosonosensitizer based on Au-RuO2 nanoparticles (NPs) and selenium nanoparticles (Se NPs) that were electrostatically self-assembled onto the surface of Listeria innocua (LI) was used to create Bac@ARS. Au NPs provided the core in which RuO2 was deposited to form Au-RuO2 NPs. Additionally, the underlying properties of the Au NPs and Se NPs were used to optimize the sonosensitivity performance. Compared with pristine RuO2 NPs, Bac@ARS exhibits highly efficient ROS-producing activity. Furthermore, Bac@ARS remodeled the hypoxic tumor microenvironment, enabling overproduction of ROS. Importantly, Bac@ARS exploits the natural tropism of LI to selectively accumulate in tumors, which improved the treatment precision at hypoxic tumor sites after sonodynamic activation. However, the activity of LI was greatly reduced after ultrasound (US) irradiation, ensuring the biosafety of Bac@ARS. Bac@ARS was also used to monitor tumors, in real time, using photoacoustic imaging of the gold-based nanoparticles. Therefore, Bac@ARS is a promising microbial sonosensitizer providing a new platform for the optimization of sonosensitizers for tumor treatment. STATEMENT OF SIGNIFICANCE: A bio-nano-sonosensitizer was designed using a Au nanoparticle (NP) core modified with RuO2 NPs. The Au-RuO2 NPs together with Se-NPs are attached via electrostatic adsorption to a live bacterium Listeria innocua (LI), creating Bac@ARS. The role of the NPs was to optimize the sonosensitivity performance at the target tumor site. Bac@ARS reshaped the tumor microenvironment and overcame tumor hypoxia leading to ROS overproduction. This activated a potent ICD-mediated cellular immunity and anti-tumor activity. Importantly, Bac@ARS exploited the natural tropism of LI to selectively accumulate in tumors, resulting in more precise delivery of the therapeutic effect while exhibiting reduced effects on healthy tissues.

ПРИМЕНЕНИЕ ГИПЕРБАРИЧЕСКОЙ ОКСИГЕНОТЕРАПИИ В КОМПЛЕКСНОМ ЛЕЧЕНИИ ЖЕЛЕЗОДЕФИЦИТНОЙ ПОСЛЕРОДОВОЙ АНЕМИИ

Iron deficiency is the most common cause of postpartum anemia due to food habits, insufficient maternal iron reserves at the beginning of pregnancy, in-creased iron requirements associated with pregnancy, and blood loss during childbirth. As a non-drug treatment the use of hyperbaric oxygen therapy (HBO) is proposed. The main essence of the action of HBO is reduced to a rapid in-crease in oxygen tension in tissues due to an increase in the amount of dissolved oxygen in the blood, an increase in its diffusion rate between the blood and the hypoxic tissue site. Non-specific adaptive reactions developing during the use of HBO provide a wide range of therapeutic effects. At the same time, along with the beneficial effect, hyperoxia can also have a toxic effect, the clinic of which de-pends on the duration of exposure, individual sensitivity to oxygen, on the influ-ence of concomitant factors: temperature environment, physical activity, density of the gas mixture. The implementation of the compensatory capabilities of HBO is promising only with timely optimal use of the method.

Dynamic mobilization of redox sensitive elements Mo, U and V in seasonal hypoxic sediments off the Changjiang Estuary

The coastal waters off the Changjiang Estuary are a seasonal hypoxic region, offering an ideal system for studying the geochemical cycles of redox sensitive elements (RSEs) at the sediment-water interface (SWI) and their response potential to redox changes. The profiles of porewater and solid RSEs and their chemical speciation and diffusive fluxes at five sites in two seasons were studied to evaluate the migration and removal of RSEs at the SWI off the Changjiang Estuary. Results showed that porewater and solid RSEs displayed the corresponding profile variations. The porewater Mo and U concentrations generally decreased with depth, attributed to the reductive removal. Particularly, the removal of Mo may be mediated by the Fe–S phase, and the removal of U appears to be via the microbially-mediated reduction. Porewater V, U and Mo were removed successively with depth, corresponding to the peaks of dissolved nitrate, Fe2+ and acid volatile sulfur (AVS). However, porewater V increased again in the deep layers due to its complexation with dissolved organic matter. The upward shift of RSE peaks in porewater and transformation depths of their oxidation states based on the model from spring to summer reflected the occurrence of hypoxia in summer. The downward diffusive fluxes of RSEs at hypoxic site in summer indicated their hypoxia-induced enrichment. The Mo–U covariation suggested that the seasonal hypoxic sites off the Changjiang Estuary were more favorable for the accumulation of authigenic U.

Erythrocyte Sphingosine 1 Phosphate Is Essential to Combat HIF1α-Dependent Creatine Shuttle, Macrophage Polarization and Fibrosis

Erythrocytes have long been considered as the major reservoir and supplier for plasma sphingosine 1 phosphate (S1P), which is a potent biolipid signaling via its specific receptors responsible for immune cell trafficking and polarization of tissue macrophages. Currently, emerging evidence has revealed that erythrocyte intracellular S1P has its own function to promote oxygen (O2) delivery to counteract tissue hypoxia. However, whether O2 delivery mediated by erythrocyte S1P is involved in tissue macrophage polarization, inflammation and fibrosis remains unrecognized. Here we report that genetic ablation of erythrocyte SphK1 (the only enzyme to generate S1P in erythrocyte eSphK1-/-) resulted in less O2 delivery from erythrocytes, thus leading to severe hypoxic tissue microenvironment, kidney damage and fibrosis in a well-accepted pathological hypoxic model infused with angiotensin II (a potent vasoconstrictor known to be elevated in hypertensive patients). Surprisingly, although plasma S1P levels were reduced to 50% in Ang II-infused eSphK1-/- mice, these mice displayed preferentially elevated pro-fibrosis M2 macrophages surrounding the hypoxic renal tubules (one of the most hypoxic sites with Ang II infusion). Metabolically, untargeted high-throughput metabolic profiling in macrophages purified from mouse kidney revealed a substantial reduction of amino acids (AAs) and fatty acids (FAs) but increased creatine. Further studies demonstrated that no significant differences of S1P level in either kidney or renal macrophages between Ang II-infused controls and eSphK1-/- mice, ruling out the possibility of difference of kidney or macrophage S1P levels responsible for renal M2 macrophage polarization in Ang II-infused eSphK1-/- mice. Instead, we revealed that reduced O2 offload from erythrocytes was previously unrecognized but essential to promote tissue M2 polarization and fibrosis by upregulating creatine shuttle to meet rapid intracellular energy needs when FAs, AAs and O2 were insufficient due to hypoxia in Ang II-infused eSphK1-/- mice. At cellular and molecular level, we demonstrated that hypoxia signaling via HIF-1a directly induced M2 polarization as well as expression of Slc6a8 (a gene encoding creatine transport), M2 specific marker gene and fibrotic marker gene in cultured murine BMDMs. Overall, our work has revealed that erythrocyte S1P combats HIF1α-dependent creatine shuttle, tissue macrophage polarization and fibrosis and highlighted potential diagnostic and therapeutic possibilities for macrophage polarization and tissue fibrosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal