Levels Of Hypoxia Research Articles

Biodegradable nanotherapeutic with simultaneously GSH depletion and H2O2 supplying for enhanced synergistic chemotherapy/chemodynamic therapy

Chemodynamic therapy (CDT) has been exploited as an emerging therapeutic modality for cancer treatment. However, insufficient intracellular H2O2 levels and ultrahigh glutathione (GSH) in the tumor microenvironment (TME) severely restrict CDT efficacy. To address these concerns, in this work, a self-reinforcing biodegradable nanotherapeutic was developed to modulate the TME to amplify CDT. The nanotherapeutic (GOD-FeCaP@TPZ, abbreviated GFCT) was fabricated through a mild one-step biomineralization process using the enzyme catalyst glucose oxidase (GOD) as a template to form biodegradable iron-doped calcium phosphate nanoparticles, followed by the loading of the prodrug tirapazamine (TPZ). When GFCT decomposes and releases Fe3+ in the acidic TME, the delivered GOD can effectively catalyze the oxidization of glucose to enhance the subsequent Fenton-like reaction by promoting intracellular acidity (via the production of gluconic acid) and improving the generation of H2O2. Moreover, the released iron constantly depletes GSH by self-cyclic valence alterations in Fe(III) and Fe(II) and then triggers H2O2 to produce •OH through an Fe(II)-mediated Fenton-like reaction. Moreover, the elevated level of hypoxia induced by GOD-mediated glucose oxidization can activate the prodrug TPZ for effective chemotherapy, thus achieving remarkable synergistic therapeutic outcomes. This work provides another paradigm to augment antitumor efficacy via modulation of the TME.

Comparing Sleep Patterns and Clinical Features between Preschool and School-Age Children with OSA.

This study aimed to evaluate sleep patterns and investigate differences in clinical features among young individuals with snoring and obstructive sleep apnea (OSA). Data from 213 children and adolescents who underwent polysomnography (PSG) for primary snoring or OSA were collected between July 2017 and December 2021. To analyze differences in sleep architecture, hypoxia levels, and other clinical features, the participants were divided into two age groups: a preschool group and a school-age group. The school-age group had significantly higher apnea-hypopnea index, obstructive apnea index, oxygen desaturation index, and body mass index than the preschool group. Both the lowest and average oxygen saturation levels were lower in the school-age group. Adenoid hypertrophy was more prevalent in the preschool group. The rate of overweight or obesity was 35.6% in the preschool group and even 94.2% in the school-age group. There were higher percentages of N1 and N2 sleep stages, and lower percentages of N3 and REM sleep stages in the school-age group. The groups exhibiting moderate to severe OSA demonstrated significant alterations in the difference between sleeping and waking diastolic blood pressure. There is a higher frequency of respiratory events among school-age children compared with their preschool peers. Moreover, alterations in sleep structure are more prominent in the school-age group. Adenoid hypertrophy may serve as the primary instigator of OSA in preschool children, whereas the predominant causes in school-age children may be obesity or excessive weight. Retrospective chart review, 3 Laryngoscope, 134:1472-1478, 2024.

Peroxide-Simulating and GSH-Depleting Nanozyme for Enhanced Chemodynamic/Photodynamic Therapy via Induction of Multisource ROS.

Reactive oxygen species (ROS) generation, using photodynamic therapy (PDT) and chemodynamic therapy (CDT), is a promising strategy for cancer treatment. However, the production of ROS in tumor cells is often limited by hypoxia, insufficient substrates, and high level of ROS scavengers in a tumor microenvironment, which seriously affects the efficacy of ROS-related tumor therapies. Herein, we report a lipid-supported manganese oxide nanozyme, MLP@DHA&Ce6, by decorating a MnO2 nano-shell on the liposome loaded with dihydroartemisinin (DHA) and photosensitizer Ce6 for generating multisource ROS to enhance cancer therapy. MLP@DHA&Ce6 can be accumulated in tumors and can release active components, Mn2+ ions, and O2. The conjugate generates ROS via nanozyme-catalyzed CDT using DHA as a substrate, PDT through Ce6, and the Fenton reaction catalyzed by Mn2+ ions. The production of O2 from MnO2 enhanced Ce6-mediated PDT under near-infrared light irradiation. Meanwhile, MLP@DHA&Ce6 showed prominent glutathione depletion, which allowed ROS to retain high activity in tumor cells. In addition, the release of Mn2+ ions and DHA in tumor cells induced ferroptosis. This multisource ROS generation and ferroptosis effect of MLP@DHA&Ce6 led to enhanced therapeutic effects in vivo.

Depletion of slow-cycling PDGFRα+ADAM12+ mesenchymal cells promotes antitumor immunity by restricting macrophage efferocytosis

The capacity to survive and thrive in conditions of limited resources and high inflammation is a major driver of tumor malignancy. Here we identified slow-cycling ADAM12+PDGFRα+ mesenchymal stromal cells (MSCs) induced at the tumor margins in mouse models of melanoma, pancreatic cancer and prostate cancer. Using inducible lineage tracing and transcriptomics, we demonstrated that metabolically altered ADAM12+ MSCs induced pathological angiogenesis and immunosuppression by promoting macrophage efferocytosis and polarization through overexpression of genes such as Gas6, Lgals3 and Csf1. Genetic depletion of ADAM12+ cells restored a functional tumor vasculature, reduced hypoxia and acidosis and normalized CAFs, inducing infiltration of effector T cells and growth inhibition of melanomas and pancreatic neuroendocrine cancer, in a process dependent on TGF-β. In human cancer, ADAM12 stratifies patients with high levels of hypoxia and innate resistance mechanisms, as well as factors associated with a poor prognosis and drug resistance such as AXL. Altogether, our data show that depletion of tumor-induced slow-cycling PDGFRα+ MSCs through ADAM12 restores antitumor immunity.

Maternal high-fat diet changes breathing pattern and causes excessive sympathetic discharge in juvenile offspring rat.

Early life over-nutrition, as experienced in maternal obesity, is a risk factor for developing cardiorespiratory and metabolic diseases. Here we investigated the effects of high-fat diet (HFD) consumption on the breathing pattern and sympathetic discharge to blood vessels in juvenile offspring from dams fed with HFD (O-HFD). Adult female Holtzman rats were given a standard diet (SD) or HFD from 6 wk before gestation to weaning. At weaning (P21), the male offspring from SD dams (O-SD) and O-HFD received SD until the experimental day (P28-P45). Nerve recordings performed in decerebrated in situ preparations demonstrated that O-HFD animals presented abdominal expiratory hyperactivity under resting conditions and higher vasoconstrictor sympathetic activity levels. The latter was associated with blunted respiratory-related oscillations in sympathetic activity, especially in control animals. When exposed to elevated hypercapnia or hypoxia levels, the O-HFD animals mounted similar ventilatory and respiratory motor responses as the control animals. Hypercapnia and hypoxia exposure also increased sympathetic activity in both groups but did not reinstate the respiratory-sympathetic coupling in the O-HFD rats. In freely behaving conditions, O-HFD animals exhibited higher resting pulmonary ventilation and larger variability of arterial pressure levels than the O-SD animals due to augmented sympathetic modulation of blood vessel diameter. Maternal obesity modified the functioning of cardiorespiratory systems in offspring at a young age, inducing active expiration and sympathetic overactivity under resting conditions. These observations represent new evidence about pregnancy-related complications that lead to the development of respiratory distress and hypertension in children of obese mothers.NEW & NOTEWORTHY Maternal obesity is a risk factor for developing cardiorespiratory and metabolic diseases. This study highlights the changes on the breathing pattern and sympathetic discharge to blood vessels in juvenile offspring from dams fed with HFD. Maternal obesity modified the functioning of cardiorespiratory systems in offspring, inducing active expiration and sympathetic overactivity. These observations represent new evidence about pregnancy-related complications that lead to the development of respiratory distress and hypertension in children of obese mothers.

Perivascular nanocarrier aggregation as a drug reservoir augments tumor drug delivery and treatment efficacy

Anticancer nanomedicines must overcome a series of physiological and pathological barriers to reach the site of action, and this often leads to low overall therapeutic efficiency. Herein, we present tumor acidity regulated rapid aggregation of nanocarriers around tumor blood vessels to construct drug reservoirs for on-demand drug delivery. We designed two nanocarriers, one that protonates extremely quickly to expose click reactive groups on its surface and that subsequently reacted with the other noncarrier via click chemistry to rapidly form agglomerates as drug reservoirs. In proof-of-concept experiments, vascular disrupting agent combretastatin A4 (CA4) and hypoxia-activated prodrug PR-104A were loaded into the two nanocarriers, respectively. CA4 was enriched near blood vessels while PR-104A diffused deep into tumors and was activated by profound hypoxia levels induced by CA4. This combination produced effective adaptive therapy for tumors with different hypoxia levels.

Oxygen Imaging of a Rabbit Tumor Using a Human-Sized Pulse Electron Paramagnetic Resonance Imager.

Spatial heterogeneity in tumor hypoxia is one of the most important factors regulating tumor growth, development, aggressiveness, metastasis, and affecting treatment outcome. Most solid tumors are known to have hypoxia or low oxygen levels (pO2 ≤10 torr). Electron paramagnetic resonance oxygen imaging (EPROI) is an emerging oxygen mapping technology. EPROI utilizes the linear relationship between the relaxation rates of the injectable OX071 trityl spin probe and the partial oxygen pressure (pO2). However, most of the EPROI studies have been limited to mouse models of solid tumors because of the instrument-size limitations. The purpose of this work was to develop a human-sized 9-mT (250 MHz resonance frequency, 60 cm bore size) pulse EPROI instrument and evaluate its performance with rabbit VX-2 tumor oxygen imaging. A New Zealand white rabbit with a 3.2-cm VX-2 tumor in the calf muscle was imaged using the human-sized EPROI instrument and a 2.25-in. ID volume coil. The animal received a ~8-min intravenous injection of OX071 (5.2 mL total volume at 72 mM concentration) and, after 75 min, an intratumoral injection (120 μL total at 5 mM OX071 concentration) and underwent EPROI. At the end of the experiments, MRI was performed using a preclinical 9.4-T MRI system to outline the tumor boundaries. For the first time, a human-sized pulse EPROI instrument with a 60-cm bore size/250-MHz frequency was built and evaluated using rabbit tumor oxygen imaging. For the first time, the systemic IV injection of the oxygen-sensitive trityl OX071 spin probe was used for an animal of this size. The resulting EPROI image from the IV injection showed complete tumor coverage. The image obtained after intratumoral injection showed localized coverage in the upper lobe of the tumor, demonstrating the need for improved intratumoral injection protocol. This study demonstrates the performance of the world's first human-sized pulse EPROI instrument. It also demonstrates that the EPROI of larger animals can be performed using the systemic injection of a manageable amount of the spin probe. This brings EPROI one step closer to clinical applications in cancer therapies. Oxygen imaging is a platform technology, and the instrument and techniques developed here will also be useful for other clinical applications.

Hypoxia-induced HIF-1α promotes Listeria monocytogenes invasion into tilapia.

HIF-1α is a nuclear transcription factor, and its activity is tightly regulated by the level of available oxygen in cells. Here, we investigated the roles of HIF-1α in the invasion of Listeria monocytogenes into tilapia under hypoxic environments. We found that the expression levels of HIF-1α in examined tissues of hypoxic tilapia were significantly upregulated, indicating that the tissue cells have been in hypoxic conditions. After 24-h infection with L. monocytogenes, we found that bacterial burden counts increased significantly in all examined tissues of hypoxic fish. To explore why the bacterial count increased significantly in the tissues of hypoxic fish, we modulated HIF-1α expression through RNAi technology. The results indicated that c-Met expression levels were positively related to HIF-1α expression. Since c-Met is the receptor of InlB that plays critical roles in the adhesion and invasion of L. monocytogenes, the ∆InlB strain was used to further explore the reason for the significant increase in bacterial counts in hypoxic fish. As expected, the decrease in the adhesion ability of ∆InlB suggested that InlB mediates L. monocytogenes infection in tilapia. After being infected with ∆InlB strain, we found that the bacterial counts in hypoxic fish were not affected by hypoxic conditions or HIF-1α expression levels. These findings indicate that HIF-1α may promote the internalization of InlB by upregulating c-Met expression and therefore contributes to the invasion of L. monocytogenes into hypoxic tilapia. IMPORTANCE Listeria monocytogenes is a zoonotic food-borne bacterial pathogen with a solid pathogenicity for humans. After ingestion of highly contaminated food, L. monocytogenes is able to cross the intestine invading phagocytic and nonphagocytic cells and causes listeriosis. China is the world's largest supplier of tilapia. The contamination rate of L. monocytogenes to tilapia products was as high as 2.81%, causing a severe threat to public health. This study revealed the underlying regulatory mechanisms of HIF-1α in the invasion of L. monocytogenes into tilapia under hypoxic environments. This study will be helpful for better understanding the molecular mechanisms of hypoxic environments in L. monocytogenes infection to tilapia. More importantly, our data will provide novel insights into the prevention and control of this pathogen in aquaculture.

NIR diagnostic imaging of triple-negative breast cancer and its lymph node metastasis for high-efficiency hypoxia-activated multimodal therapy

BackgroundTriple-negative breast cancer (TNBC) possesses special biological behavior and clinicopathological characteristics, which is highly invasive and propensity to metastasize to lymph nodes, leading to a worse prognosis than other types of breast cancer. Thus, the development of an effective therapeutic method is significant to improve the survival rate of TNBC patients.ResultsIn this work, a liposome-based theranostic nanosystem (ILA@Lip) was successfully prepared by simultaneously encapsulating IR 780 as the photosensitizer and lenvatinib as an anti-angiogenic agent, together with banoxantrone (AQ4N) molecule as the hypoxia-activated prodrug. The ILA@Lip can be applied for the near-infrared (NIR) fluorescence diagnostic imaging of TNBC and its lymph node metastasis for multimodal therapy. Lenvatinib in ILA@Lip can inhibit angiogenesis by cutting oxygen supply, thereby leading to enhanced hypoxia levels. Meanwhile, large amounts of reactive oxygen species (ROS) were produced while IR 780 was irradiated by an 808 nm laser, which also rapidly exhausted oxygen in tumor cells to worsen tumor hypoxia. Through creating an extremely hypoxic in TNBC, the conversion of non-toxic AQ4N to toxic AQ4 was much more efficiency for hypoxia-activated chemotherapy. Cytotoxicity assay of ILA@Lip indicated excellent biocompatibility with normal cells and tissues, but showed high toxicity in hypoxic breast cancer cells. Also, the in vivo tumors treated by the ILA@Lip with laser irradiation were admirably suppressed in both subcutaneous tumor model and orthotopic tumor models.ConclusionUtilizing ILA@Lip is a profound strategy to create an extremely hypoxic tumor microenvironment for higher therapeutic efficacy of hypoxia-activated chemotherapy, which realized collective suppression of tumor growth and has promising potential for clinical translation.

Debunking the lethal triad and delineating damage control surgery.

The last three decades of literature in trauma have been erroneously hammered by the belief the lethal triad (LT) of acidosis, hypothermia and coagulopathy was, as claimed originally, the statutory rationale underlying for the application of damage control surgery (DCS) strategy. As a matter of fact, the LT is not all lethal: only acidosis is lethal and a reliable hard sign for DCS, indicating severe levels of hypoxemia and tissues hypoxia. The mainstream flow of events leading to exitus in hemorragic shock pass through macro and microcirculation dynamics, oxygen, acidosis, and ischemia-reperfusion toxemia. It is solely by interfering or manipulating these variables dynamics that we can decrease morbidity and mortality. A solid synoptic list of the indications and timing of DCS has been elaborated.

Analysis of microRNA expression in rat kidneys after VEGF inhibitor treatment under different degrees of hypoxia.

Previously, we found that the incidence of kidney injury in patients with chronic hypoxia was related to the partial pressure of arterial oxygen. However, at oxygen concentrations that contribute to kidney injury, the changes in the relationship between microRNAs (miRNAs) and the hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) axis and the key miRNAs involved in this process have not been elucidated. Therefore, we elucidated the relationship between VEGF and kidney injury at different oxygen concentrations and the mechanisms mediated by miRNAs. Sprague-Dawley rats were exposed to normobaric hypoxia and categorized into six groups based on the concentration of the oxygen inhaled and injection of the angiogenesis inhibitor bevacizumab, a humanized anti-VEGF monoclonal antibody. Renal tissue samples were processed to determine pathological and morphological changes and HIF-1α, VEGF, and miRNA expression. We performed a clustering analysis of high-risk pathways and key hub genes. The results were validated using two Gene Expression Omnibus datasets (GSE94717 and GSE30718). As inhaled oxygen concentration decreased, destructive changes in the kidney tissues became more severe. Although the kidney possesses a self-protective mechanism under an intermediate degree of hypoxia (10% O2), bevacizumab injections disrupted this mechanism, and VEGF expression was associated with the ability of the kidney to repair itself. rno-miR-124-3p was identified as a crucial miRNA; a key gene target, Mapk14, was identified during this process. VEGF plays an important role in kidney protection from injury under different hypoxia levels. Specific miRNAs and their target genes may serve as biomarkers that provide new insights into kidney injury treatment.NEW & NOTEWORTHY Renal tolerance to hypoxic environments is limited, and the degree of hypoxia does not show a linear relationship with angiogenesis. VEGF plays an important role in the kidney's self-protective mechanism under different levels of hypoxia. miR-124-3p may be particularly important in kidney repair, and it may modulate VEGF expression through the miR-124-3p/Mapk14 signaling pathway. These microRNAs may serve as biomarkers that provide new insights into kidney injury treatment.

Prostate cancer radiogenomics reveals proliferative gene expression programs associated with distinct MRI-based hypoxia levels

Background and purposeThe biology behind individual hypoxia levels in patient tumors is poorly understood. Here, we used radiogenomics to identify associations between magnetic resonance imaging (MRI)-based hypoxia levels and biological processes derived from gene expression data in prostate cancer. Materials and methodsFor 85 prostate cancer patients, MRI-based hypoxia images were constructed by combining diffusion-weighted images reflecting oxygen consumption and supply. The ability to differentiate hypoxia levels in these images was verified by comparison with matched biopsy sections stained for the hypoxia marker pimonidazole. For MRI-defined hypoxia levels, corresponding hypoxic fractions were calculated and correlated with biopsy gene expression profiles. Biological processes were predicted by gene set enrichment analysis (GSEA) and validated by immunohistochemistry (Ki67 proliferation marker, reactive stroma grade) and RT-PCR (MYC). ResultsGenes with correlation between expression level and hypoxic fraction were identified for 56 MRI-based hypoxia levels. At all levels, GSEA identified proliferation as the predominant biological process enriched among the correlating genes. Two independent proliferative gene signatures were developed. The Peak1 signature, upregulated at moderate/severe hypoxia, reflected MYC upregulation and high Ki67-proliferation index of cancer cells in pimonidazole-positive regions. The Peak2 signature, upregulated at mild to non-hypoxic levels, was associated with fibroblast gene signature and reactive stroma grade. High scores of both Peak1 and Peak2 indicated elevated risk of biochemical recurrence in multiple cohorts. ConclusionRadiogenomics identified two gene expression programs activated at different hypoxia levels, reflecting proliferation of cancer cells and stroma cells. Genes involved in these programs could be candidate targets for intervention.

A novel nitroreductase-responsive turn-off fluorescent probe based on AIEgen and its bioimaging application

Nitroreductase (NTR) is frequently employed as a biomarker to assess the level of hypoxia in tumor tissues. To date, the majority of NTR-reactive probes have focused on the luminescence "turn on" characteristic, which has been plagued by background interferences. In this study, we present the first report of an NTR-responsive "turn-off" fluorescent probe, TPEDCH-PBN, based on AIEgen. This probe exhibits typical aggregation-induced emission (AIE) properties in high PBS fraction, which may be attributed to the restriction of intramolecular motions (RIM) effect. DFT/TD-DFT calculations were employed to determine the discrepancies in structure and electron density distribution among TPEDCH, TPEDCH-PBNOH and TPEDCH-PBN. Additionally, docking calculations were utilized to elucidate the structure-function relationship between the probe and NTR, revealing a favorable structural and spatial match. Photophysical investigations demonstrated the probe's high selectivity towards NTR with the detection limit of 0.68 μg/mL. The dynamic quenching process of TPEDCH-PBN upon NTR was examined, and the quenching constant Ksv was determined to be 53.6 g−1.L. In addition, the NTR detection ability of probe TPEDCH-PBN as well as its time-dependent fluorescence quenching behaviors were confirmed by cell imaging of probe in A549 cells. Overall, this study proposed a novel molecular design approach for the biomarker detection probe, which may prove to be more extensively applicable.

In vivo real-time monitoring of the development of hypoxia and angiogenesis in cervical cancer

The growth of solid tumors is inevitably accompanied by hypoxia and angiogenesis. Understanding the true state of tissue hypoxia and angiogenesis during tumor progression will help further comprehend the tumor microenvironment and cancer therapy. Here, we provided a novel strategy for the long-term tracking of tumor hypoxia and angiogenesis in cervical cancer. The hypoxia response elements (HRE)-driven luciferase (LUC) reporter gene transfected cervical cancer cell lines were constructed for hypoxia visualization. The hypoxia response activity of HRE-driven LUC was verified in HeLa cells and then monitored via the HeLa-HRE-LUC tumor-bearing mouse models by bioluminescence imaging (BLI). An oxygen-sensitive nanoparticle was constructed for glycerol monooleate cubic liquid crystal material loaded with Ir(piq)3/IR780 and could be used for phosphorescence-fluorescence imaging. The imaging result showed that the nanoparticles labeled the low oxygen region overlapped with the BLI signal region detected by HRE-driven LUC in vivo, which confirmed that the hypoxia visualization platform could genuinely reflect the hypoxia level in vivo. The angiogenesis in vivo was reflected by changes in deoxygenated/oxygenated hemoglobin detected by photoacoustic imaging. Besides these, anticancer drug apigenin down-regulated HIF-1α and VEGF under hypoxia conditions and inhibited the tube formation in vitro. Then, the inhibition effects were verified in the hypoxia and angiogenesis visualization model in vivo. This study confirmed a novel in vivo real-time monitoring of tumor hypoxia and angiogenesis strategy, which can provide useful information for further research on cancer progression and anticancer therapy.

Unraveling the transcriptome-based network of tfh cells in primary sjogren syndrome: insights from a systems biology approach.

Primary Sjogren Syndrome (pSS) is an autoimmune disease characterized by immune cell infiltration. While the presence of follicular T helper (Tfh) cells in the glandular microenvironment has been observed, their biological functions and clinical significance remain poorly understood. We enrolled a total of 106 patients with pSS and 46 patients without pSS for this study. Clinical data and labial salivary gland (LSG) biopsies were collected from all participants. Histological staining was performed to assess the distribution of Tfh cells and B cells. Transcriptome analysis using RNA-sequencing (RNA-seq) was conducted on 56 patients with pSS and 26 patients without pSS to uncover the underlying molecular mechanisms of Tfh cells. To categorize patients, we employed the single-sample gene set enrichment analysis (ssGSEA) algorithm, dividing them into low- and high-Tfh groups. We then utilized gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and deconvolution tools to explore functional and immune infiltration differences between the low- and high-Tfh groups. Patients with pSS had a higher positive rate of the antinuclear antibody (ANA), anti-Ro52, anti-SSA, anti-SSB and hypergammaglobulinaemia and higher levels of serum IgG compared to the non-pSS. Histopathologic analyses revealed the presence of Tfh cells (CD4+CXCR5+ICOS+) in germinal centers (GC) within the labial glands of pSS patients. GSEA, WGCNA, and correlation analysis indicated that the high-Tfh group was associated with an immune response related to virus-mediated IFN response and metabolic processes, primarily characterized by hypoxia, elevated glycolysis, and oxidative phosphorylation levels. In pSS, most immune cell types exhibited significantly higher infiltration levels in the high-Tfh group compared to the low-Tfh group. Additionally, patients in the Tfh-high group demonstrated a higher positive rate of the ANA, rheumatoid factor (RF), and hypergammaglobulinaemia, as well as higher serum IgG levels. Our study suggests that Tfh cells may play a crucial role in the pathogenesis of pSS and could serve as potential therapeutic targets in pSS patients.

Unveiling the hypoxia-induced mitophagy process through two-channel real-time imaging of NTR and viscosity under the same excitation

Mitophagy is an essential physiological process that eliminates damaged mitochondria via lysosomes. It is reported that hypoxia, inflammatory stimuli or other stress conditions could lead to mitochondrial damage and mitochondrial dysfunction, which induces the process of mitophagy. Herein, we report a novel fluorescent probe PC-NTR for imaging hypoxia-induced mitophagy by monitoring the change of nitroreductase and viscosity simultaneously. To our delight, PC-NTR could respond simultaneously to nitroreductase and viscosity at different fluorescence channels with no mutual interference under the same excitation wavelength. The fluorescence emission around 535 nm was enhanced dramatically after addition of nitroreductase while the fluorescence emission around 635 nm heightened as the viscosity increased. The probe would be able to selectively targeting of mitochondria in cells because of the positively charged pyridine salt structure of PC-NTR. The probe was successfully applied to assess the different levels of hypoxia and real-time imaging of mitochondrial autophagy in live cells. More importantly, using dual channel imaging, PC-NTR could be used to distinguish cancer cells from normal cells and was successfully applied to imaging experiments in HeLa-derived tumor-bearing nude mice. Therefore, PC-NTR would be an important molecular tool for hypoxia imaging and detecting solid tumors in vivo.

Effect of long-term hypoxia on the reproductive systems of female and male yellow catfish (Pelteobagrus fulvidraco).

This study investigated the effects of different levels of hypoxia on the reproductive system of yellow catfish. Yellow catfish (Pelteobagrus fulvidraco) were exposed to three dissolved oxygen concentration levels: normoxia (6.5 ± 0.2 mg/L), moderate hypoxia (MH, 3.8 ± 0.3 mg/L) and severe hypoxia (SH, 1.9 ± 0.2 mg/L) for 30 days. The gonadosomatic index of males, not females, significantly decreased in the SH group. In the SH group, for the females, the ratio of vitellogenic follicles significantly decreased, whereas the number of atretic follicles significantly increased. In male fish, a significantly reduced number of spermatozoa was observed in both the MH and SH groups. Elevated apoptosis levels in the testes and ovaries were observed only in the SH group. Serum 17β-estradiol and vitellogenin levels in females and testosterone levels in males significantly decreased in the SH group. The concentration of 11-ketotestosterone in males significantly decreased in both the MH and SH groups. In female fish, dysregulated expression of the hypothalamic-pituitary-gonadal (HPG) axis, steroidogenesis genes, and hepatic genes related to vitellogenesis were observed only in the SH group. However, in male fish, moderate hypoxia altered the expression of HPG genes, including gnrh1, lhcgr, and amh. Moreover, the MH group significantly altered the expression of steroidogenesis genes like star, 17β-hsd, and cyp17a1. The results of this study suggest that severe hypoxia can cause reproductive defects in female and male yellow catfish. Moreover, the reproductive system of male yellow catfish is more sensitive to moderate hypoxia than that of female catfish. Our findings contribute to our understanding of the response of the teleost reproductive system to long-term hypoxia.

Consuming intracellular glucose and regulating the levels of O2/H2O2 via the closed cascade catalysis system of Cu-CeO2 nanozyme and glucose oxidase

Imbalances in the intracellular environment caused by high levels of glucose, H2O2, and hypoxia can greatly impact cancer development and treatment. However, there is limited research on regulating the levels of these species simultaneously in tumor cells. Here, a pH-responsive nanozyme-enzyme hybrid system was developed to regulate intracellular glucose, H2O2 and O2. The system, named DMSN@Cu-CeO2@GOx, consists of Cu-CeO2 nanoparticles and glucose oxidase (GOx) immobilized in dendritic mesoporous silica (DMSN) spheres. GOx efficiently consumes glucose in tumor cells, causing a drop in pH and producing a significant amount of H2O2. Cu-CeO2 then catalyzes the conversion of H2O2 to O2 due to its high catalase-like (CAT) activity in weakly acidic conditions. The process was monitored by fluorescence probes, and the mechanism was investigated through fluorescence spectroscopy and confocal laser scanning microscopy. The cascade catalytic system with excellent biocompatibility continuously consumes glucose and elevates the level of O2 in cells. This hybrid nanomaterial offers a means to regulate the glucose/H2O2/O2 levels in cells and may provide insights into starvation therapy by modulating reactive species within cells.

Validation of a Smart Ring Oximeter in Individuals With Dark Skin Pigment

ObjectiveTo evaluate a ring wearable’s accuracy in the measurement of oxyhemoglobin saturation measured by pulse oximeter (SpO2) compared to a simultaneous SaO2 obtained from arterial blood gases (ABGs) because oximeters may overestimate oxyhemoglobin saturation in darkly pigmented individuals resulting in occult hypoxemia. Patients and MethodsCircul+ (Bodimetrics), with a form factor of a ring, measures several variables for cardiorespiratory assessment (SpO2, movement, and heart rate). The design ensures that measurements are made on the palmar surface of the digit, where there is generally less pigment. Twenty-four healthy participants (8 Black, 16 non-Black) had catheters inserted into their radial arteries during the timeframe between August 2020 and January 2022. They were administered nitrogen-rich air that made them hypoxic in steps to an SaO2 of 70%. ABGs was sampled at various levels of hypoxia, and simultaneous readings were obtained from the Circul+. We compared SpO2 from Circul with measurement of ABGs by a medical grade blood gas analyzer. ResultsThere was excellent correlation between SaO2 measured by the ring oximeter and ABGs in both Black (y = 1.0174x − 1.573; R2 = 0.9414) and Non-Black (y = 1.0209x − 2.5607; R2 = 0.9207) participants. No differences were found in comparing the intercept and slopes of the regressions. At ABG of 70% and 100%, the SaO2 measured by the ring was calculated to be 69.6% and 100.2% for the Black participants and 68.9% and 99.5% for the non-Black participants. Bland-Altman analysis found a bias (deviation from the mean) of 0.0 for the Black participants and −0.7% for the non-Black participants. ConclusionResults from this study confirmed that Circul+ oximetry accuracy seems to be independent of skin tone, perhaps because measurements are made on the palmar surface of the digit, where there is generally less pigment.

Chemodynamic therapy agent optimized mesoporous TiO2 nanoparticles for Glutathione-Enhanced and Hypoxia-Tolerant synergistic Chemo-Sonodynamic therapy

Sonodynamic therapy (SDT) can generate reactive oxygen species to kill cancer cells by activating sonosensitizers under ultrasound (US) irradiation. Nevertheless, its application is greatly limited by low quantum yield of sonosensitizers, high levels of endogenous glutathione (GSH) and tumor hypoxia. Herein, a GSH-activated sonosensitizers with synergistic therapy effect (chemodynamic therapy (CDT) and SDT) are developed by depositing Fe(III)-artemisinin infinite coordination polymers (Fe(III)-ART CPs) in pores of mesoporous TiO2 nanoparticles (NPs). The formed Fe(III)-ART-TiO2 NPs have high sono-induced electron-hole separation efficiency because the deposited Fe(III)-ART CPs can provide isolated intermediate bands to capture sono-induced electrons in TiO2 NPs. Meanwhile, Fe3+ in Fe(III)-ART-TiO2 NPs are reduced to Fe2+ by GSH with oxygen-deficient sites generated to further capture sono-induced electrons in TiO2 NPs. Based on this, the reaction efficiency between water molecules and sono-induced holes is high enough to generate numerous hydroxyl radicals (•OH) without oxygen participated for overcoming tumor hypoxia. Additionally, through consuming GSH, the generated Fe2+ can catalyze ART to produce C-centered free radicals for CDT. Owing to these characteristics, Fe(III)-ART-TiO2 NPs show significant tumor suppression ability and good biocompatibility in vivo. The strategy of using CDT agent to modify sonosensitizers offers new options to improve SDT effect without introducing harmful substances.