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Veterinary Medicine and Science Jul 2024A 10-year-old, neutered male, Golden Retriever dog presented for surgical correction of a descemetocele. Acepromazine (0.02 mg/kg) and methadone (0.5 mg/kg) were...
A 10-year-old, neutered male, Golden Retriever dog presented for surgical correction of a descemetocele. Acepromazine (0.02 mg/kg) and methadone (0.5 mg/kg) were administered intramuscularly for sedation, propofol (2 mg/kg) and midazolam (0.2 mg/kg) were administered intravenously for anaesthetic induction and isoflurane in oxygen was utilised for anaesthetic maintenance. Rocuronium (0.5 mg/kg), a neuromuscular blocking agent, was administered intravenously to facilitate central positioning of the eye for surgery. Within 10 min of rocuronium administration, the dog became tachycardic and hypotensive. Hemodynamic aberrations did not resolve with initial interventions but were successfully mitigated with the administration of diphenhydramine (0.8 mg/kg) intravenously. The dog remained stable throughout the remainder of the procedure and experienced a smooth and uneventful recovery. While it is difficult to confirm that the hemodynamic changes observed in this clinical case resulted solely from administration of rocuronium, the observance of the cardiovascular changes, timing of events and response to therapy suggest that rocuronium elicited a histamine response that was successfully treated with diphenhydramine.
Topics: Animals; Rocuronium; Dogs; Male; Neuromuscular Nondepolarizing Agents; Hemodynamics; Androstanols; Dog Diseases; Diphenhydramine
PubMed: 38952251
DOI: 10.1002/vms3.1531 -
British Journal of Pharmacology Jul 2024Pulmonary hypertension (PH) results from pulmonary vasculopathy, initially leading to a compensatory right ventricular (RV) hypertrophy, and eventually to RV failure....
BACKGROUND AND PURPOSE
Pulmonary hypertension (PH) results from pulmonary vasculopathy, initially leading to a compensatory right ventricular (RV) hypertrophy, and eventually to RV failure. Hypoxia can trigger both pulmonary vasculopathy and RV failure. Therefore, we tested if myo-inositol trispyrophosphate (ITPP), which facilitates oxygen dissociation from haemoglobin, can relieve pulmonary vasculopathy and RV hypoxia, and eventually prevent RV failure and mortality in the rat model of monocrotaline-induced PH.
EXPERIMENTAL APPROACH
Rats were injected with monocrotaline (PH) or saline (control) and received ITPP or placebo for 5 weeks. Serial echocardiograms were obtained to monitor the disease, pressure-volume loops were recorded and evaluated, myocardial pO was measured using a fluorescent probe, and histological and molecular analyses were conducted at the conclusion of the experiment.
KEY RESULTS AND CONCLUSIONS
ITPP reduced PH-related mortality. It had no effect on progressive increase in pulmonary vascular resistance, yet significantly relieved intramyocardial RV hypoxia, which was associated with improvement of RV function and reduction of RV wall stress. ITPP also tended to prevent increased hypoxia inducible factor-1α expression in RV cardiac myocytes but did not affect RV capillary density.
IMPLICATIONS
Our study suggests that strategies aimed at increasing oxygen delivery to hypoxic RV in PH could potentially be used as adjuncts to other therapies that target pulmonary vessels, thus increasing the ability of the RV to withstand increased afterload and reducing mortality. ITPP may be one such potential therapy.
PubMed: 38952183
DOI: 10.1111/bph.16482 -
Journal of Biochemical and Molecular... Jul 2024Non-small cell cancer (NSCLC) is the most common cancer in the world, but its effective therapeutic methods are limited. Tilianin and sufentanil alleviate various human...
Non-small cell cancer (NSCLC) is the most common cancer in the world, but its effective therapeutic methods are limited. Tilianin and sufentanil alleviate various human tumors. This research aimed to clarify the functions and mechanisms of Tilianin and sufentanil in NSCLC. The functions of Tilianin and sufentanil on NSCLC cell viability, apoptosis, mitochondrial dysfunction, and immunity in vitro were examined using Cell Counting Kit-8 assay, flow cytometry, reactive oxygen species level analysis, CD8+ T cell percentage analysis, Western blot, and enzyme-linked immunosorbent assay, respectively. The molecular mechanism regulated by Tilianin and sufentanil in NSCLC was assessed using Western blot, and immunofluorescence assays. Meanwhile, the roles of Tilianin and sufentanil in NSCLC tumor growth, apoptosis, and immunity in vivo were determined by establishing a tumor xenograft mouse model, immunohistochemistry, and Western blot assays. When sufentanil concentration was proximity 2 nM, the inhibition rate of NSCLC cell viability was 50%. The IC50 for A549 cells was 2.36 nM, and the IC50 for H1299 cells was 2.18 nM. The IC50 of Tilianin for A549 cells was 38.7 μM, and the IC50 of Tilianin for H1299 cells was 44.6 μM. Functionally, 0.5 nM sufentanil and 10 μM Tilianin reduced NSCLC cell (A549 and H1299) viability in a dose-dependent manner. Also, 0.5 nM sufentanil and 10 μM Tilianin enhanced NSCLC cell apoptosis, yet this impact was strengthened after a combination of Tilianin and Sufentanil. Furthermore, 0.5 nM sufentanil and 10 μM Tilianin repressed NSCLC cell mitochondrial dysfunction and immunity, and these impacts were enhanced after a combination of Tilianin and Sufentanil. Mechanistically, 0.5 nM sufentanil and 10 μM Tilianin repressed the NF-κB pathway in NSCLC cells, while this repression was strengthened after a combination of Tilianin and Sufentanil. In vivo experimental data further clarified that 1 µg/kg sufentanil and 10 mg/kg Tilianin reduced NSCLC growth, immunity, and NF-κB pathway-related protein levels, yet these trends were enhanced after a combination of Tilianin and Sufentanil. Tilianin strengthened the antitumor effect of sufentanil in NSCLC.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Sufentanil; Lung Neoplasms; Animals; Mice; Apoptosis; Xenograft Model Antitumor Assays; A549 Cells; Mice, Nude; Drug Synergism; Cell Line, Tumor; Mice, Inbred BALB C; Antineoplastic Agents; Chondroitin Sulfates; Amphibian Venoms
PubMed: 38952040
DOI: 10.1002/jbt.23761 -
Cancer & Metabolism Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease without meaningful therapeutic options beyond the first salvage therapy. Targeting PDAC metabolism...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease without meaningful therapeutic options beyond the first salvage therapy. Targeting PDAC metabolism through amino acid restriction has emerged as a promising new strategy, with asparaginases, enzymes that deplete plasma glutamine and asparagine, reaching clinical trials. In this study, we investigated the anti-PDAC activity of the asparaginase formulation Pegcrisantaspase (PegC) alone and in combination with standard-of-care chemotherapeutics.
METHODS
Using mouse and human PDAC cell lines, we assessed the impact of PegC on cell proliferation, cell death, and cell cycle progression. We further characterized the in vitro effect of PegC on protein synthesis as well as the generation of reactive oxygen species and levels of glutathione, a major cellular antioxidant. Additional cell line studies examined the effect of the combination of PegC with standard-of-care chemotherapeutics. In vivo, the tolerability and efficacy of PegC, as well as the impact on plasma amino acid levels, was assessed using the C57BL/6-derived KPC syngeneic mouse model.
RESULTS
Here we report that PegC demonstrated potent anti-proliferative activity in a panel of human and murine PDAC cell lines. This decrease in proliferation was accompanied by inhibited protein synthesis and decreased levels of glutathione. In vivo, PegC was tolerable and effectively reduced plasma levels of glutamine and asparagine, leading to a statistically significant inhibition of tumor growth in a syngeneic mouse model of PDAC. There was no observable in vitro or in vivo benefit to combining PegC with standard-of-care chemotherapeutics, including oxaliplatin, irinotecan, 5-fluorouracil, paclitaxel, and gemcitabine. Notably, PegC treatment increased tumor expression of asparagine and serine biosynthetic enzymes.
CONCLUSIONS
Taken together, our results demonstrate the potential therapeutic use of PegC in PDAC and highlight the importance of identifying candidates for combination regimens that could improve cytotoxicity and/or reduce the induction of resistance pathways.
PubMed: 38951899
DOI: 10.1186/s40170-024-00346-2 -
Journal of Nanobiotechnology Jul 2024Reperfusion therapy is critical for saving heart muscle after myocardial infarction, but the process of restoring blood flow can itself exacerbate injury to the...
Targeting delivery of miR-146a via IMTP modified milk exosomes exerted cardioprotective effects by inhibiting NF-κB signaling pathway after myocardial ischemia-reperfusion injury.
Reperfusion therapy is critical for saving heart muscle after myocardial infarction, but the process of restoring blood flow can itself exacerbate injury to the myocardium. This phenomenon is known as myocardial ischemia-reperfusion injury (MIRI), which includes oxidative stress, inflammation, and further cell death. microRNA-146a (miR-146a) is known to play a significant role in regulating the immune response and inflammation, and has been studied for its potential impact on the improvement of heart function after myocardial injury. However, the delivery of miR-146a to the heart in a specific and efficient manner remains a challenge as extracellular RNAs are unstable and rapidly degraded. Milk exosomes (MEs) have been proposed as ideal delivery platform for miRNA-based therapy as they can protect miRNAs from RNase degradation. In this study, the effects of miR-146a containing MEs (MEs-miR-146a) on improvement of cardiac function were examined in a rat model of MIRI. To enhance the targeting delivery of MEs-miR-146a to the site of myocardial injury, the ischemic myocardium-targeted peptide IMTP was modified onto the surfaces, and whether the modified MEs-miR-146a could exert a better therapeutic role was examined by echocardiography, myocardial injury indicators and the levels of inflammatory factors. Furthermore, the expressions of miR-146a mediated NF-κB signaling pathway-related proteins were detected by western blotting and qRT-PCR to further elucidate its mechanisms. MiR-146 mimics were successfully loaded into the MEs by electroporation at a square wave 1000 V voltage and 0.1 ms pulse duration. MEs-miR-146a can be up-taken by cardiomyocytes and protected the cells from oxygen glucose deprivation/reperfusion induced damage in vitro. Oral administration of MEs-miR-146a decreased myocardial tissue apoptosis and the expression of inflammatory factors and improved cardiac function after MIRI. The miR-146a level in myocardium tissues was significantly increased after the administration IMTP modified MEs-miR-146a, which was higher than that of the MEs-miR-146a group. In addition, intravenous injection of IMTP modified MEs-miR-146a enhanced the targeting to heart, improved cardiac function, reduced myocardial tissue apoptosis and suppressed inflammation after MIRI, which was more effective than the MEs-miR-146a treatment. Moreover, IMTP modified MEs-miR-146a reduced the protein levels of IRAK1, TRAF6 and p-p65. Therefore, IMTP modified MEs-miR-146a exerted their anti-inflammatory effect by inhibiting the IRAK1/TRAF6/NF-κB signaling pathway. Taken together, our findings suggested miR-146a containing MEs may be a promising strategy for the treatment of MIRI with better outcome after modification with ischemic myocardium-targeted peptide, which was expected to be applied in clinical practice in future.
Topics: Animals; MicroRNAs; Myocardial Reperfusion Injury; Exosomes; NF-kappa B; Signal Transduction; Rats; Rats, Sprague-Dawley; Male; Milk; Myocardium; Cardiotonic Agents; Myocytes, Cardiac
PubMed: 38951872
DOI: 10.1186/s12951-024-02631-0 -
Journal of Nanobiotechnology Jul 2024Numerous studies have confirmed the involvement of extracellular vesicles (EVs) in various physiological processes, including cellular death and tissue damage. Recently,...
BACKGROUND
Numerous studies have confirmed the involvement of extracellular vesicles (EVs) in various physiological processes, including cellular death and tissue damage. Recently, we reported that EVs derived from ischemia-reperfusion heart exacerbate cardiac injury. However, the role of EVs from healthy heart tissue (heart-derived EVs, or cEVs) on myocardial ischemia-reperfusion (MI/R) injury remains unclear.
RESULTS
Here, we demonstrated that intramyocardial administration of cEVs significantly enhanced cardiac function and reduced cardiac damage in murine MI/R injury models. cEVs treatment effectively inhibited ferroptosis and maintained mitochondrial homeostasis in cardiomyocytes subjected to ischemia-reperfusion injury. Further results revealed that cEVs can transfer ATP5a1 into cardiomyocytes, thereby suppressing mitochondrial ROS production, alleviating mitochondrial damage, and inhibiting cardiomyocyte ferroptosis. Knockdown of ATP5a1 abolished the protective effects of cEVs. Furthermore, we found that the majority of cEVs are derived from cardiomyocytes, and ATP5a1 in cEVs primarily originates from cardiomyocytes of the healthy murine heart. Moreover, we demonstrated that adipose-derived stem cells (ADSC)-derived EVs with ATP5a1 overexpression showed much better efficacy on the therapy of MI/R injury compared to control ADSC-derived EVs.
CONCLUSIONS
These findings emphasized the protective role of cEVs in cardiac injury and highlighted the therapeutic potential of targeting ATP5a1 as an important approach for managing myocardial damage induced by MI/R injury.
Topics: Animals; Extracellular Vesicles; Mice; Myocardial Reperfusion Injury; Myocytes, Cardiac; Male; Mice, Inbred C57BL; Mitochondrial Proton-Translocating ATPases; Mitochondria; Myocardium; Reactive Oxygen Species; Ferroptosis; Disease Models, Animal
PubMed: 38951822
DOI: 10.1186/s12951-024-02618-x -
Molecular and Cellular Biochemistry Jun 2024Despite the implementation of novel therapeutic regimens and extensive research efforts, chemoresistance remains a formidable challenge in the treatment of acute myeloid...
Despite the implementation of novel therapeutic regimens and extensive research efforts, chemoresistance remains a formidable challenge in the treatment of acute myeloid leukemia (AML). Notably, the involvement of lysosomes in chemoresistance has sparked interest in developing lysosome-targeted therapies to sensitize tumor cells to currently approved chemotherapy or as innovative pharmacological approaches. Moreover, as ion channels on the lysosomal membrane are critical regulators of lysosomal function, they present potential as novel targets for enhancing chemosensitivity. Here, we discovered that the expression of a lysosomal cation channel, namely transient receptor potential mucolipin 1 (TRPML1), was elevated in AML cells. Inhibiting TRPML1 individually does not impact the proliferation and apoptosis of AML cells. Importantly, inhibition of TRPML1 demonstrated the potential to modulate the sensitivity of AML cells to chemotherapeutic agents. Exploration of the underlying mechanisms revealed that suppression of TRPML1 impaired autophagy while concurrently increasing the production of reactive oxygen species (ROS) and ROS-mediated lipid peroxidation (Lipid-ROS) in AML cells. Finally, the knockdown of TRPML1 significantly reduced OCI-AML3 tumor growth following chemotherapy in a mouse model of human leukemia. In summary, targeting TRPML1 represents a promising approach for combination therapy aimed at enhancing chemosensitivity in treating AML.
PubMed: 38951379
DOI: 10.1007/s11010-024-05054-5 -
Nature Communications Jun 2024Keratoconus, a disorder characterized by corneal thinning and weakening, results in vision loss. Corneal crosslinking (CXL) can halt the progression of keratoconus. The...
Keratoconus, a disorder characterized by corneal thinning and weakening, results in vision loss. Corneal crosslinking (CXL) can halt the progression of keratoconus. The development of accelerated corneal crosslinking (A-CXL) protocols to shorten the treatment time has been hampered by the rapid depletion of stromal oxygen when higher UVA intensities are used, resulting in a reduced cross-linking effect. It is therefore imperative to develop better methods to increase the oxygen concentration within the corneal stroma during the A-CXL process. Photocatalytic oxygen-generating nanomaterials are promising candidates to solve the hypoxia problem during A-CXL. Biocompatible graphitic carbon nitride (g-CN) quantum dots (QDs)-based oxygen self-sufficient platforms including g-CN QDs and riboflavin/g-CN QDs composites (RF@g-CN QDs) have been developed in this study. Both display excellent photocatalytic oxygen generation ability, high reactive oxygen species (ROS) yield, and excellent biosafety. More importantly, the A-CXL effect of the g-CN QDs or RF@g-CN QDs composite on male New Zealand white rabbits is better than that of the riboflavin 5'-phosphate sodium (RF) A-CXL protocol under the same conditions, indicating excellent strengthening of the cornea after A-CXL treatments. These lead us to suggest the potential application of g-CN QDs in A-CXL for corneal ectasias and other corneal diseases.
Topics: Quantum Dots; Animals; Graphite; Oxygen; Riboflavin; Rabbits; Male; Cross-Linking Reagents; Nitrogen Compounds; Reactive Oxygen Species; Keratoconus; Ultraviolet Rays; Cornea; Humans; Photosensitizing Agents; Corneal Stroma
PubMed: 38951161
DOI: 10.1038/s41467-024-49645-8 -
Accuracy of the defining characteristics of respiratory nursing diagnoses in patients with COVID-19.International Journal of Nursing... Jul 2024To analyze the accuracy of the defining characteristics of four respiratory nursing diagnoses (ND) in patients with COVID-19 and on oxygen therapy.
OBJECTIVE
To analyze the accuracy of the defining characteristics of four respiratory nursing diagnoses (ND) in patients with COVID-19 and on oxygen therapy.
METHODS
This is a cross-sectional study conducted in four Brazilian public hospitals in two regions of the country. A total of 474 patients with COVID-19 receiving oxygen therapy were assessed. Latent-adjusted class analysis with random effects was used to establish the sensitivity (Se) and specificity (Sp) of the defining characteristics evaluated for each ND.
RESULTS
Among the ND that constituted the study (impaired spontaneous ventilatory, impaired gas exchange, ineffective airway clearance, and dysfunctional ventilatory weaning response), the following defining characteristics had the highest simultaneous Se and Sp (>0.8): decrease in tidal volume, confusion, irritability, dyspnea, decreased breath sounds, orthopnea, impaired ability to cooperate and respond to coaching, and decrease in the level of consciousness.
CONCLUSIONS
Recognizing the clinical signs that predict respiratory ND in patients affected by COVID-19 can contribute to the nurse's accurate diagnostic inference and designate the appropriate nursing interventions to achieve the desired results and avoid complications.
PubMed: 38951045
DOI: 10.1111/2047-3095.12481 -
BMJ Open Jul 2024Acute hypoxaemic respiratory failure (AHRF) is associated with high mortality in sub-Saharan Africa. This is at least in part due to critical care-related resource...
Respiratory support with standard low-flow oxygen therapy, high-flow oxygen therapy or continuous positive airway pressure in adults with acute hypoxaemic respiratory failure in a resource-limited setting: protocol for a randomised, open-label, clinical trial - the Acute Respiratory Intervention...
RATIONALE
Acute hypoxaemic respiratory failure (AHRF) is associated with high mortality in sub-Saharan Africa. This is at least in part due to critical care-related resource constraints including limited access to invasive mechanical ventilation and/or highly skilled acute care workers. Continuous positive airway pressure (CPAP) and high-flow oxygen by nasal cannula (HFNC) may prove useful to reduce intubation, and therefore, improve survival outcomes among critically ill patients, particularly in resource-limited settings, but data in such settings are lacking. The aim of this study is to determine whether CPAP or HFNC as compared with standard oxygen therapy, could reduce mortality among adults presenting with AHRF in a resource-limited setting.
METHODS
This is a prospective, multicentre, randomised, controlled, stepped wedge trial, in which patients presenting with AHRF in Uganda will be randomly assigned to standard oxygen therapy delivered through a face mask, HFNC oxygen or CPAP. The primary outcome is all-cause mortality at 28 days. Secondary outcomes include the number of patients with criteria for intubation at day 7, the number of patients intubated at day 28, ventilator-free days at day 28 and tolerance of each respiratory support.
ETHICS AND DISSEMINATION
The study has obtained ethical approval from the Research and Ethics Committee, School of Biomedical Sciences, College of Health Sciences, Makerere University as well as the Uganda National Council for Science and Technology. Patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals.
TRIAL REGISTRATION NUMBER
NCT04693403.
PROTOCOL VERSION
8 September 2023; version 5.
Topics: Humans; Continuous Positive Airway Pressure; Oxygen Inhalation Therapy; Respiratory Insufficiency; Prospective Studies; Uganda; Adult; Hypoxia; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Acute Disease; Resource-Limited Settings
PubMed: 38951007
DOI: 10.1136/bmjopen-2023-082223