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Photoacoustic microscopy reveals the hemodynamic basis of sphingosine 1-phosphate-induced neuroprotection against ischemic stroke
摘要： Rationale: Emerging evidence has suggested that sphingosine 1-phosphate (S1P), a bioactive metabolite of sphingolipids, may play an important role in the pathophysiological processes of cerebral hypoxia and ischemia. However, the influence of S1P on cerebral hemodynamics and metabolism remains unclear. Material and Methods: Uniquely capable of high-resolution, label-free, and comprehensive imaging of hemodynamics and oxygen metabolism in the mouse brain without the influence of general anesthesia, our newly developed head-restrained multi-parametric photoacoustic microscopy (PAM) is well suited for this mechanistic study. Here, combining the cutting-edge PAM and a selective inhibitor of sphingosine kinase 2 (SphK2) that can increase the blood S1P level, we investigated the role of S1P in cerebral oxygen supply-demand and its neuroprotective effects on global brain hypoxia induced by nitrogen gas inhalation and focal brain ischemia induced by transient middle cerebral artery occlusion (tMCAO). Results: Inhibition of SphK2, which increased the blood S1P, resulted in the elevation of both arterial and venous sO2 in the hypoxic mouse brain, while the cerebral blood flow remained unchanged. As a result, it gradually and significantly reduced the metabolic rate of oxygen. Furthermore, pre-treatment of the mice subject to tMCAO with the SphK2 inhibitor led to decreased infarct volume, improved motor function, and reduced neurological deficit, compared to the control treatment with a less potent R-enantiomer. In contrast, post-treatment with the inhibitor showed no improvement in the stroke outcomes. The failure for the post-treatment to induce neuroprotection was likely due to the relatively slow hemodynamic responses to the SphK2 inhibitor-evoked S1P intervention, which did not take effect before the brain injury was induced. Conclusions: Our results reveal that elevated blood S1P significantly changes cerebral hemodynamics and oxygen metabolism under hypoxia but not normoxia. The improved blood oxygenation and reduced oxygen demand in the hypoxic brain may underlie the neuroprotective effect of S1P against ischemic stroke.
关键词： Sphingosine 1-phosphate,Photoacoustic microscopy,Neuroprotection,Hypoxia,Ischemic stroke
更新于2025-09-23 15:22:29
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Synthesis and Evaluation of Multifunctional Fluorescent Inhibitors with Synergistic Interaction of PSMA and Hypoxia for Prostate Cancer
摘要： Prostate cancer is one of the most common cancers in the world. It is widely known that prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer, and hypoxia is a common characteristic of many solid tumors, including prostate cancer. In this study, we designed multifunctional fluorescent inhibitors to target PSMA and tumor hypoxia in order to increase the tumor uptake of inhibitors. Novel PSMA inhibitors were prepared using lysine as the backbone to connect three different functional groups: the glutamate-urea-lysine (GUL) structure for inhibiting PSMA, 2-nitroimidazole for the hypoxia-sensitive moiety, and a near-infrared fluorophore (sulfo-Cyanine 5.5). According to the in vitro PSMA binding assay, novel fluorescent inhibitors were demonstrated to have nanomolar binding affinities. Multifunctional inhibitor 2 with one 2-nitroimidazole had a similar inhibitory activity to inhibitor 1 that did not contain the hypoxia targeting moiety, but multifunctional inhibitor 3 with two 2-nitroimidazoles showed lower inhibitory activity than inhibitor 1 due to the bulky structure of the hypoxia-sensitive group. However, in vivo optical imaging and ex vivo biodistribution studies indicated that both multifunctional inhibitors 2 and 3 had higher accumulation in tumors than inhibitor 1 due to a synergistic combination of PSMA and hypoxia targeting moieties. These observations suggest that this novel multifunctional strategy might be a promising approach to improve the diagnosis and therapy of prostate cancer.
关键词： multifunctional inhibitors,hypoxia,near-infrared fluorophore,Prostate cancer,2-nitroimidazole,PSMA
更新于2025-09-23 15:21:21
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Acute physiological responses to combined blood flow restriction and low-level laser
摘要： Purpose Blood flow restriction (BFR) is an innovation in fitness to train muscles with low loads at low oxygen levels. Low-level laser therapy (LLLT) is a bio-energetic approach to alleviate muscle fatigue during resistance training. This study investigated the immediate effect of LLLT pre-conditioning on BFR that accelerates muscle fatigue due to ischemia. Methods Fifteen young adults participated in this study of a crossover randomized design. They completed a low-load contraction with various pre-conditioning (blood flow restriction with low-level laser therapy (LLLT + BFR), blood flow restriction with sham low-level laser therapy (BFR), and control). Force fluctuation dynamics, muscle oxygen saturation of hemoglobin and myoglobin (SmO2), and discharge patterns of motor units (MU) were compared. Results Normalized SmO2 during low-load contractions significantly varied with the pre-contraction protocols (Control (83.6 ± 3.0%) > LLLT + BFR (70.3 ± 2.8%) > BFR (55.4 ± 2.4%). Also, force fluctuations and MU discharge varied with the pre-contraction protocols. Multi-scale entropy and mean frequency of force fluctuations were greater in the LLLT + BFR condition (31.95 ± 0.67) than in the BFR condition (29.47 ± 0.73). The mean inter-spike interval of MUs was greater in the LLLT + BFR condition (53.32 ± 2.70 ms) than in the BFR condition (45.04 ± 1.08 ms). In particular, MUs with higher recruitment thresholds exhibited greater LLLT-related discharge complexity (LLLT + BFR (0.201 ± 0.012) > BFR (0.154 ± 0.006)). Conclusions LLLT pre-conditioning can minimize the BFR-related decline in muscle oxygen saturation, leading to force gradation and MU discharge in a cost-effective and complex manner.
关键词： Myoglobin,Motor unit,Force fluctuations,Electromyography,Photobiomodulation,Hypoxia
更新于2025-09-23 15:19:57
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Light-Triggered Dual-Modality Drug Release of Self-Assembled Prodrug-Nanoparticles for Synergistic Photodynamic and Hypoxia-Activated Therapy
摘要： Photodynamic therapy (PDT) leads to tumor hypoxia which could be utilized for the activation of hypoxia-activated prodrugs (HAPs). However, conventional photosensitizer-loaded nanoformulations suffer from aggregation-caused quenching (ACQ) effect, which limits the efficiency of PDT and synergistic therapy. Herein, prodrug-nanoparticles (NPs) are prepared by the self-assembly of heterodimeric prodrugs composed of pyropheophorbide a (PPa), hypoxia-activated prodrug PR104A, and a thioether or thioketal linkage. In addition, a novel dual-modality drug release pattern is proposed on the basis of the structural states of prodrug-NPs. Under light irradiation, PR104A is released via photoinduced electron transfer (PET) due to the aggregating state of prodrugs. With the disassembly of prodrug-NPs, ACQ effect relieves, PPa produces singlet oxygen which further promotes the reactive oxygen species (ROS)-sensitive release of PR104A. Such prodrug-NPs turn the disadvantage of the ACQ effect to facilitate drug release, demonstrating high-efficiency synergy in combination with PDT and hypoxia-activated therapy.
关键词： aggregation-caused quenching,Photodynamic therapy,drug release,photoinduced electron transfer,hypoxia-activated prodrugs,reactive oxygen species
更新于2025-09-23 15:19:57
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Non-Recurring Circuit Nanozymatic Enhancement of Hypoxic Pancreatic Cancer Phototherapy Using Speckled Ru-Te Hollow Nanorods
摘要： Nanozymatic reactions that produce or consume oxygen (O2) or reactive oxygen species (ROS) consist of oxidase, peroxidase, superoxide dismutase (SOD), and catalase-type activity. Although extensive studies were conducted to overcome hypoxia through nanozymatic reactions, the construction of an ideal system is challenging, given that the reactants and products are arranged in a recurring structure for continuous consumption in a full cycle. In this study, speckled Ru-Te hollow nanorods were prepared through solvothermal galvanic replacement against Te nanorod templates with high yield and robustness. From their multi-compositional characteristics, non-recurring peroxidase-SOD-catalase-type nanozymatic properties were identified with photothermal and photodynamic feasibility over a wide range of laser irradiation wavelengths. Owing to the excellent colloidal stability and biocompatibility, the proposed Ru-Te based nanozymatic platform was highly effective in hypoxic pancreatic cancer phototherapy in vitro and in vivo by near infrared laser irradiation mediated photothermal and photodynamic combination treatment.
关键词： nanozyme,galvanic replacement,phototherapy,hypoxia,ruthenium
更新于2025-09-23 15:19:57
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Fluorine-18 click radiosynthesis and MicroPET/CT evaluation of a small peptide-a potential PET probe for carbonic anhydrase IX
摘要： Carbonic anhydrase IX (CA IX) is the first carbonic anhydrase found to be associated with cancer that is over-expressed in a variety of human solid tumors. As a surrogate marker for hypoxia, the expression of CA IX is strongly upregulated in hypoxic tumors by hypoxia and hypoxia-inducible factor 1a (HIF-1a). In our pursuit of a CA IX-specific PET probe, we designed and synthesized a peptide-based CA IX imaging probe by the efficient click reaction of 1,3-dipolar cycloaddition of terminal alkynes and organic azides. The probe 18F-CA IX-P1-4-10 was obtained with a radiochemical yield of 35-45% (n = 5) and radiochemical purity of >99% in 70-80 min (HPLC purification time included). 18F-CAIX-P1-4-10 had good stability in phosphate buffered saline (PBS), but about 51% peptide degradation was detected in new-born calf serum (NBCS) after incubation. Preliminary microPET/CT experiments demonstrated a specific uptake of 18F-CA IX-P1-4-10 in HT29 tumor and the uptake of 18F-CA IX-P1-4-10 was blocked by peptide CA IX-P1-4-10-Yne pretreatment. Immunohistochemical staining and western blotting studies confirmed the HT29 tumor was CA IX-positive which further proved tumor accumulation of 18F-CA IX-P1-4-10 was correlated with CA IX expression. The results suggest that 18F-CA IX-P1-4-10 is a promising PET tracer for the specific imaging of CA IX-expressing tumors at the molecular level.
关键词： peptide,tumor hypoxia,18F-labeling,Carbonic anhydrase IX,PET imaging
更新于2025-09-19 17:15:36
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Modulation of Intracellular Oxygen Pressure by Dual-Drug Nanoparticles to Enhance Photodynamic Therapy
摘要： Oxygen plays an essential role in the photodynamic therapy (PDT) of cancer. However, hypoxia inside tumors severely attenuates the therapeutic effect of PDT. To address this issue, a novel strategy is reported for cutting off the oxygen consumption pathway by using sub-50 nm dual-drug nanoparticles (NPs) to attenuate the hypoxia-induced resistance to PDT and to enhance PDT efficiency. Specifically, dual-drug NPs that encapsulate photosensitizer (PS) verteporfin (VER) and oxygen-regulator atovaquone (ATO) with sub-50 nm diameters can penetrate deep into the interior regions of tumors and effectively deliver dual-drug into tumor tissues. Then, ATO released from NPs efficiently reduce in advance cellular oxygen consumption by inhibition of mitochondria respiratory chain and further heighten VER to generate greater amounts of 1O2 in hypoxic tumor. As a result, accompanied with the upregulated oxygen content in tumor cells and laser irradiation, the dual-drug NPs exhibit powerful and overall antitumor PDT effects both in vitro and in vivo, and even tumor elimination. This study presents a potential appealing clinical strategy in photodynamic eradication of tumors.
关键词： atovaquone,verteporfin,hypoxia,oxygen consumption rate,photodynamic therapy
更新于2025-09-19 17:15:36
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[IEEE 2018 IEEE Asian Solid-State Circuits Conference (A-SSCC) - Tainan, Taiwan (2018.11.5-2018.11.7)] 2018 IEEE Asian Solid-State Circuits Conference (A-SSCC) - Design of a 2.45-GHz RF Energy Harvester for SWIPT IoT smart sensors
摘要： The aim of this study is to investigate the effects of chronic hypoxia and hypercapnia on learning and memory function of mice and the expression of neurotensin (NT) and calcitonin gene–related peptide (CGRP) in mice brain. A total of 30 C57BL/6J male mice were randomly divided into normoxia control group (control group, n = 15) and chronic hypoxia and hypercapnia stress group (experimental group, n = 15). The control group was kept under normal temperature and pressure conditions, while the experimental group was kept in a chamber at normal pressure, hypoxia and hypercapnia for 8 h daily and 6 days a week for 4 weeks. On the 28th day, the learning and memory ability of mice was examined by 8-arm maze. The content of 8-hydroxy-deoxyguanosine (8-OHdG) in brain was detected by enzyme-linked immunosorbent assay (ELISA) analysis. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were determined by spectrophotometry, and the derangement of hippocampal ultrastructures and numbers of apoptotic neurons were observed by microscope. The expression of NT and CGRP in brain tissue was observed by immunochemistry. Compared to control group, the content of 8-OHdG in hippocampal and serum MDA were significantly increased by 1.3 and 1.78 times, while the activity of SOD in serum was decreased by 27.28% in experimental group. Besides, the cellular structure of the hippocampus was disorderly arranged, the shape is irregular and the quantity is markedly reduced obviously in experimental group. In addition, the content of NT and CGRP in brain tissue was higher in experimental group than in control group (P < 0.05). The stress of chronic hypoxia and hypercapnia not only can induce learning and memory disorders in mice which may be related to increased neuronal apoptosis and oxidative stress injury but also can increase the expression of NT and CGRP in brain tissue which may have some impact on gastrointestinal motility in mice.
关键词： chronic hypoxia and hypercapnia,calcitonin gene–related peptide,learning and memory function,neurotensin,mice
更新于2025-09-19 17:15:36
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Development of rhodamine-based fluorescent probes for sensitive detection of Fe <sup>3+</sup> in water: spectroscopic and computational investigations
摘要： The aim of this study was to investigate the expression of hypoxia-inducible factor-1α (HIF-1α) in keloids and its correlation with inflammatory responses and apoptosis. The keloid specimens resected in our hospital from November 2015 to February 2017 were selected as the pathological group, and the normal skin tissues from our hospital during the same period were selected as the control group. The expression of HIF-1α, inflammatory response cytokines, and apoptotic molecules in the tissues of two groups were detected. The messenger RNA (mRNA) expression of HIF-1α in the keloids in the pathological group was significantly higher than that in the control group, and the mRNA expression of interleukin (IL)-1β, IL-2, IL-6, and tumor necrosis factor (TNF)-α in the pathological group was significantly higher than those in the control group. The mRNA expression of Bax in the pathological group was significantly higher than that in the control group. The mRNA expression of Bcl-2, livin, and hPEBP4 in the pathological group was significantly lower than that in the control group. Pearson test showed that there was a positive correlation between the mRNA expression of HIF-1α and inflammatory cytokines including IL-1β, IL-2, IL-6, and TNF-α. There were also a positive correlation between the mRNA expression of HIF-1α and Bax and a negative correlation between the mRNA expression of HIF-1α and Bcl-2, livin, and hPEBP4. In conclusion, HIF-1α was highly expressed in keloids and closely related to inflammatory response cytokines and apoptosis molecules. Increased expression of HIF-1α in keloids may be an important factor in inflammatory responses and increased apoptosis in skin tissues.
关键词： inflammatory responses,hypoxia-inducible factor-1α,apoptosis,keloids
更新于2025-09-19 17:15:36
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Inhibitor of growth 4 affects hypoxia-induced migration and angiogenesis regulation in retinal pigment epithelial cells
摘要： Inhibitor of growth 4 (ING4), a potential tumor suppressor, is implicated in cell migration and angiogenesis. However, its effects on diabetic retinopathy (DR) have not been elucidated. In this study, we aimed to evaluate ING4 expression in normal and diabetic rats and clarify its effects on hypoxia‐induced dysfunction in human retinal pigment epithelial (ARPE‐19) cells. A Type 1 diabetic model was generated by injecting rats intraperitoneally with streptozotocin and then killed them 4, 8, or 12 weeks later. ING4 expression in retinal tissue was detected using western blot analysis, reverse transcription quantitative real‐time polymerase chain reaction (RT‐qPCR), and immunohistochemistry assays. After transfection with an ING4 overexpression lentiviral vector or small interfering RNA (siRNA), ARPE‐19 migration under hypoxia was tested using wound healing and transwell assays. The angiogenic effect of conditioned medium (CM) from ARPE‐19 cells was examined by assessing human retinal endothelial cell (HREC) capillary tube formation. Additionally, western blot analysis and RT‐qPCR were performed to investigate the signaling pathways in which ING4, specificity protein 1 (Sp1), matrix metalloproteinase 2 (MMP‐2), MMP‐9, and vascular endothelial growth factor A (VEGF‐A) were involved. Here, we found that ING4 expression was significantly reduced in the diabetic rats’ retinal tissue. Silencing ING4 aggravated hypoxia‐induced ARPE‐19 cell migration. CM collected from ING4 siRNA‐transfected ARPE‐19 cells under hypoxia promoted HREC angiogenesis. These effects were reversed by ING4 overexpression. Furthermore, ING4 suppressed MMP‐2, MMP‐9, and VEGF‐A expression in an Sp1‐dependent manner in hypoxia‐conditioned ARPE‐19 cells. Overall, our results provide valuable mechanistic insights into the protective effects of ING4 on hypoxia‐induced migration and angiogenesis regulation in ARPE‐19 cells. Restoring ING4 may be a novel strategy for treating DR.
关键词： migration,angiogenesis,diabetic retinopathy,retinal pigment epithelium cells,hypoxia,inhibitor of growth 4
更新于2025-09-19 17:15:36