Hypoxia and overexpression of glutathione (GSH) are typical characteristics of the tumor microenvironment, which severely hinders cancer treatments. Here, we design a novel biodegradable therapeutic ...system, O2–Cu/ZIF-8@Ce6/ZIF-8@F127 (OCZCF), to simultaneously achieve GSH depletion and O2-enhanced combination therapy. Notably, the doped Cu2+ doubles the O2 storage capacity of the ZIF-8 matrix, which makes OCZCF an excellent pH-sensitive O2 reservoir for conquering tumor hypoxia, enhancing the photodynamic therapy (PDT) efficiency of chlorin e6 (Ce6) under 650 nm laser irradiation. Moreover, the released Cu2+ can act as a smart reactive oxygen species protector by consuming intracellular GSH. The byproduct Cu+ will undergo highly efficient Fenton-like reaction to achieve chemodynamic therapy (CDT) in the presence of abundant H2O2. The accompanying O2 will further alleviate hypoxia. The in vitro and in vivo experimental data indicate that OCZCF could cause remarkable tumor inhibition through enhanced synergetic PDT and CDT, which may open up a new path for cancer therapy.
Premenopausal women express reduced blood pressure and risk of cardiovascular disease relative to age-matched men. This purportedly relates to elevated estrogen levels increasing nitric oxide ...synthase (NOS) activity and NO-mediated vasorelaxation. We tested the hypotheses that female rat skeletal muscle would:
1
) evince a higher O
2
delivery-to-utilization ratio (Q̇
o
2
/V̇
o
2
) during contractions; and
2
) express greater modulation of Q̇
o
2
/V̇
o
2
with changes to NO bioavailability compared with male rats. The spinotrapezius muscle of Sprague-Dawley rats (females = 8, males = 8) was surgically exposed and electrically-stimulated (180 s, 1 Hz, 6 V). OxyphorG4 was injected into the muscle and phosphorescence quenching employed to determine the temporal profile of interstitial P
o
2
(P
o
2is
, determined by Q̇
o
2
/V̇
o
2
). This was performed under three conditions: control (CON), 300 µM sodium nitroprusside (SNP; NO donor), and 1.5 mM
N
ω
-nitro-
l
-arginine methyl ester (
l
-NAME; NOS blockade) superfusion. No sex differences were found for the P
o
2is
kinetics parameters in CON or
l
-NAME (
P
> 0.05), but females elicited a lower baseline following SNP (males 42 ± 3 vs. females 36 ± 2 mmHg,
P
< 0.05). Females had a lower ΔP
o
2is
during contractions following SNP (males 22 ± 3 vs. females 17 ± 2 mmHg,
P
< 0.05), but there were no sex differences for the temporal response to contractions (
P
> 0.05). The total NO effect (SNP minus
l
-NAME) on P
o
2is
was not different between sexes. However, the spread across both conditions was shifted to a lower absolute range for females (reduced SNP baseline and greater reduction following
l
-NAME). These data support that females have a greater reliance on basal NO bioavailability and males have a greater responsiveness to exogenous NO and less responsiveness to reduced endogenous NO.
NEW & NOTEWORTHY
Interstitial P
o
2
(P
o
2is
; determined by O
2
delivery-to-utilization matching) plays an important role for O
2
flux into skeletal muscle. We show that both sexes regulate P
o
2is
at similar levels at rest and during skeletal muscle contractions. However, modulating NO bioavailability exposes sex differences in this regulation with females potentially having a greater reliance on basal NO bioavailability and males having a greater responsiveness to exogenous NO and less responsiveness to reduced endogenous NO.
Despite its clinical promise, photodynamic therapy (PDT) suffers from a key drawback associated with its oxygen‐dependent nature, which limits its effective use against hypoxic tumors. Moreover, both ...PDT‐mediated oxygen consumption and microvascular damage further increase tumor hypoxia and, thus, impede therapeutic outcomes. In recent years, numerous investigations have focused on strategies for overcoming this drawback of PDT. These efforts, which are summarized in this review, have produced many innovative methods to avoid the limits of PDT associated with hypoxia.
PDT beats hypoxia: Novel and robust strategies, which can improve the therapeutic efficacy of photodynamic therapy (PDT) for hypoxic tumors, have been widely investigated in recent years. These efforts have led to the development of new approaches that have changed the paradigm of PDT and provided solutions to some key problems.
Hypoxic microenvironments emerge as tumor grow, leading to the over-expression and stabilization of hypoxia-inducible factor 1-alpha (HIF-1α). HIF-1α lowers the sensitization against chemotherapy, ...radiation therapy and photodynamic therapy in cancer. In this study, nano-sized oxygen carrier, namely oxygen dissolved nanoliposome (ODL) was synthesized, and oxygen was efficiently delivered to different types of mammalian cells to help relieve hypoxia. ODL confirmed that oxygen was released without inducing toxicity to cells. After artificially creating hypoxia in cancer cells, normal cells, and immune cells; various parameters such as cell morphology, HIF-1α expression, and degree of hypoxia were examined. The cellular environment was found to be altered by treatment with the ODL. Under hypoxia, the shape of the cells changed, and the cells began to die. After treatment with the ODL, the degree of hypoxia was reduced, indicating that HIF-1α expression and the rate of cell death decreased. Furthermore, bacteria proliferation was observed with the ODL. Therefore, ODL can be used for oxygen delivery platform in cancer therapy. ODL has a potential application in other microorganisms which needs future research.
The complex cellular interactions that underlie pathologies related to reduced oxygen delivery after surgery are poorly defined and difficult to measure. Heywood and colleagues explored the patterns ...of protein expression in skin biopsies taken from a subgroup of patients enrolled in a randomised trial designed to evaluate perioperative goal-directed therapy. One of their key findings was that a failure of participants to maintain preoperative systemic oxygen delivery was associated with an upregulation of intracellular proteins involved in counteracting oxidative stress. Their study highlights the importance of oxidative stress in the perioperative setting and suggests that maintenance of baseline oxygen delivery might be an important regulator of redox balance.
The recent years have witnessed the blooming of cancer immunotherapy, as well as their combinational use together with other existing cancer treatment techniques including radiotherapy. However, ...hypoxia is one of several causes of the immunosuppressive tumor microenvironment (TME). Herein, we develop an innovative strategy to relieve tumor hypoxia by delivering exogenous H2O2 into tumors and the subsequent catalase-triggered H2O2 decomposition. In our experiment, H2O2 and catalase are separately loaded within stealthy liposomes. After intravenous (iv) preinjection of CAT@liposome, another dose of H2O2@liposome is injected 4 h later. The sustainably released H2O2 could be decomposed by CAT@liposome, resulting in a long lasting effect in tumor oxygenation enhancement. As the result, the combination treatment by CAT@liposome plus H2O2@liposome offers remarkably enhanced therapeutic effects in cancer radiotherapy as observed in a mouse tumor model as well as a more clinically relevant patient-derived xenograft tumor model. Moreover, the relieved tumor hypoxia would reverse the immunosuppressive TME to favor antitumor immunities, further enhancing the combined radio-immunotherapy with cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade. This work presents a simple yet effective strategy to promote tumor oxygenation via sequential delivering catalase and exogenous H2O2 into tumors using well-established liposomal carriers, showing great potential for clinical translation in radio-immunotherapy of cancer.
Aim
To determine if the use of closed‐loop automated oxygen control (CLAC) reduced the incidence and duration of hypoxemic episodes (SpO2 < 92%) in ventilated infants born at or above 34 weeks of ...gestation.
Methods
Infants were studied on two consecutive days for 6 h each day. They were randomised to receive standard care (manual oxygen control) or standard care with a CLAC system (automated oxygen control) first.
Results
Sixteen infants with a median (IQR) gestational age of 37.4 (36.6–38.8) weeks were studied at a median (IQR) postmenstrual age of 38.8 (37.4–39.8) weeks. During the automated oxygen control period, infants spent less time in hypoxemia (SpO2 < 92%) (p = 0.033), episodes of desaturation were shorter (p = 0.001), the time spent within target SpO2 range (92%–96%) was increased (p = 0.001), and the FiO2 delivery was lower (p = 0.018). The time spent in hyperoxemia (SpO2 > 96%) was reduced during automated oxygen control (p = 0.011), the episodes of hyperoxemia were of shorter duration (p = 0.008) and fewer manual adjustments were made to the FiO2 (p = 0.005).
Conclusions
Closed‐loop automated oxygen control in ventilated infants born at or near term was associated with a reduction in the incidence and duration of hypoxemic episodes with more time spent in the target oxygen range.
Hypoxic ischemic brain injury (HIBI) after cardiac arrest (CA) is a leading cause of mortality and long-term neurologic disability in survivors. The pathophysiology of HIBI encompasses a ...heterogeneous cascade that culminates in secondary brain injury and neuronal cell death. This begins with primary injury to the brain caused by the immediate cessation of cerebral blood flow following CA. Thereafter, the secondary injury of HIBI takes place in the hours and days following the initial CA and reperfusion. Among factors that may be implicated in this secondary injury include reperfusion injury, microcirculatory dysfunction, impaired cerebral autoregulation, hypoxemia, hyperoxia, hyperthermia, fluctuations in arterial carbon dioxide, and concomitant anemia.Clarifying the underlying pathophysiology of HIBI is imperative and has been the focus of considerable research to identify therapeutic targets. Most notably, targeted temperature management has been studied rigorously in preventing secondary injury after HIBI and is associated with improved outcome compared with hyperthermia. Recent advances point to important roles of anemia, carbon dioxide perturbations, hypoxemia, hyperoxia, and cerebral edema as contributing to secondary injury after HIBI and adverse outcomes. Furthermore, breakthroughs in the individualization of perfusion targets for patients with HIBI using cerebral autoregulation monitoring represent an attractive area of future work with therapeutic implications.We provide an in-depth review of the pathophysiology of HIBI to critically evaluate current approaches for the early treatment of HIBI secondary to CA. Potential therapeutic targets and future research directions are summarized.
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