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Molecular Medicine Reports Aug 2024Elevated levels of blood glucose in patients with ischemic stroke are associated with a worse prognosis. The present study aimed to explore whether hyperglycemia...
Elevated levels of blood glucose in patients with ischemic stroke are associated with a worse prognosis. The present study aimed to explore whether hyperglycemia promotes microglial pyroptosis by increasing the oxygen extraction rate in an acute ischemic stroke model. C57BL/6 mice that underwent middle cerebral artery occlusion were used for assessment of blood glucose level and neurological function. The cerebral oxygen extraction ratio (CERO), oxygen consumption rate (OCR) and partial pressure of brain tissue oxygen (PbtO) were measured. To investigate the significance of the NOD‑like receptor protein 3 (NLRP3) inflammasome, NLRP3 mice were used, and the expression levels of NLRP3, caspase‑1, full‑length gasdermin D (GSDMD‑FL), GSDMD‑N domain (GSDMD‑N), IL‑1β and IL‑18 were evaluated. In addition, Z‑YVAD‑FMK, a caspase‑1 inhibitor, was used to treat microglia to determine whether activation of the NLRP3 inflammasome was required for the enhancing effect of hyperglycemia on pyroptosis. It was revealed that hyperglycemia accelerated cerebral injury in the acute ischemic stroke model, as evidenced by decreased latency to fall and the percentage of foot fault. Hyperglycemia aggravated hypoxia by increasing the oxygen extraction rate, as evidenced by increased CERO and OCR, and decreased PbtO in response to high glucose treatment. Furthermore, hyperglycemia‑induced microglial pyroptosis was confirmed by detection of increased levels of caspase‑1, GSDMD‑N, IL‑1β and IL‑18 and a decreased level of GSDMD‑FL. However, the knockout of NLRP3 attenuated these effects. Pharmacological inhibition of caspase‑1 also reduced the expression levels of GSDMD‑N, IL‑1β and IL‑18 in microglial cells. These results suggested that hyperglycemia stimulated NLRP3 inflammasome activation by increasing the oxygen extraction rate, thus leading to the aggravation of pyroptosis following ischemic stroke.
Topics: Animals; Pyroptosis; Microglia; Ischemic Stroke; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Oxygen; Male; Hyperglycemia; Inflammasomes; Mice, Inbred C57BL; Caspase 1; Disease Models, Animal; Mice, Knockout; Interleukin-1beta; Phosphate-Binding Proteins; Oxygen Consumption; Gasdermins
PubMed: 38940333
DOI: 10.3892/mmr.2024.13270 -
Muscle & Nerve Jun 2024The impact of treatment expectations on active treatment outcomes has not been specifically investigated in neuromuscular disorders. We thus explored in myasthenia...
INTRODUCTION/AIMS
The impact of treatment expectations on active treatment outcomes has not been specifically investigated in neuromuscular disorders. We thus explored in myasthenia gravis (MG) the contribution of patients' pre-treatment expectations combined with an immunosuppressant drug on treatment outcomes.
METHODS
This pilot correlational study involved 17 patients with generalized MG, scheduled to start immunosuppressant azathioprine. At baseline, a healthcare professional administered: (i) the Stanford Expectations of Treatment Scale; (ii) a structured checklist paper form asking patients which side-effects they expected to develop after starting azathioprine, coupled with a standardized framing of statements. Quantitative Myasthenia Gravis (QMG) score and daily dose of concomitant drugs were assessed by neurologists as clinical outcomes. Clinical outcomes and side-effects were re-assessed at 3 and 6 months, and clinical outcomes were monitored at 18 months.
RESULTS
Clinically significant improvement in the QMG scores was achieved at 3 or 6 months. The level of state anxiety appeared to act as moderator of pre-treatment negative expectations (strong, positive, indicative correlation, rs = .733, p = .001). The latter were, in turn, associated with the fulfillment of side-effects that patients expected to develop with the new treatment (moderate, positive, indicative correlation, rs = .699, p = .002). No significant correlation emerged between positive and negative expectations.
DISCUSSION
Our findings show a very quick clinical response and also suggest that patients' expectations and anxiety contributed to treatment outcomes, highlighting the importance of promoting safety messages and education strategies around newly introduced treatments. Future goals include evaluating a larger cohort that includes a matched control group.
PubMed: 38940302
DOI: 10.1002/mus.28189 -
Current Medicinal Chemistry Jun 2024The formation of fibrotic bands in female reproductive system, including the uterus, after abdominal and pelvic surgeries, is an important medical challenge associated...
Lysyl Oxidase-like 2 Dysregulation Increases the Risk of Post-Operative Fibrotic Scars Formation in the Female Reproductive Tract: A Novel Therapeutic Target to Reduce Fibrogenesis.
The formation of fibrotic bands in female reproductive system, including the uterus, after abdominal and pelvic surgeries, is an important medical challenge associated with many complications, including infertility and pain. Investigating the role of different molecules involved in fibrosis and adhesion formation may help in the development of new drugs to prevent this disorder. Lysyl oxidase-like 2 (LoxL2) is a copper-dependent enzyme that catalyzes the cross-linking of collagen and elastin fibers in the extracellular matrix (ECM) to stabilize ECM. Dysregulation of LoxL2 activity resulting from tissue hypoxia and inflammation after gynecological surgeries in the female reproductive tract increases collagen fibers cross-linking and promotes fibrosis. It has been shown that targeting LoxL2 by Lox inhibitors may reduce fibrosis. Considering the expression of LoxL2 in female reproductive organs and its dysregulation in hypoxia and inflammation, it is possible that LoxL2 has therapeutic potential as a drug target in the prevention of adhesions. In this review, we discuss the role of LoxL2 in the promotion of fibrotic processes focusing on its link with inflammatory and hypoxic conditions. We also justify the use of anti- LoxL2 agents as a potential therapeutic strategy for the prevention of post-surgical scar formation.
PubMed: 38939993
DOI: 10.2174/0109298673306240240612055116 -
Current Drug Delivery Jun 2024Drug transporters are critical factors influencing the pharmacokinetics of drugs under hypoxic conditions. Studies have shown significant changes in drug transporter...
Drug transporters are critical factors influencing the pharmacokinetics of drugs under hypoxic conditions. Studies have shown significant changes in drug transporter levels in the hypoxic environment. In addition to being regulated by HIF-1, nuclear receptors, and inflammatory factors, hypoxia can also regulate transporters through epigenetic modifications, thereby affecting drug absorption, distribution, metabolism, and excretion. In recent years, increasing attention has been paid to the role of epigenetic modifications in regulating drug transporters under hypoxic conditions at high altitude. In this paper, we comprehensively review the effects of hypoxia on drug transporters and epigenetic modifications and explore the regulatory mechanism of epigenetic modifications on drug transporter expression under hypoxic conditions. The aim is to provide a reference for exploring the epigenetic regulation mechanism of drug transporter expression in the hypoxic environment at high altitude, and then guide the study of pharmacokinetics and promote effective and safe medication at high altitude.
PubMed: 38939986
DOI: 10.2174/0115672018295087240620061102 -
Frontiers in Oncology 2024This study aims to elucidate the clinical features observed in cases of pediatric acute myeloid leukemia (AML) initially presenting with cardiac tamponade and to share...
OBJECTIVE
This study aims to elucidate the clinical features observed in cases of pediatric acute myeloid leukemia (AML) initially presenting with cardiac tamponade and to share treatment experiences.
MATERIALS AND METHODS
Five pediatric patients were initially diagnosed with AML accompanied by cardiac myeloid sarcoma (MS). The diagnosis was established by examining our hospital records and reviewing pertinent literature from 1990 to July 2023, accessible through MEDLINE/PubMed. We comprehensively assessed the clinical characteristics and treatment modalities employed for these patients.
RESULT
Five pediatric patients presented with acute symptoms, including shortness of breath, malaise, cough, and fever, leading to their hospitalization. Physical examination revealed irritability, hypoxia, tachypnea, tachycardia, and hypotension. Initial detection utilized chest X-ray or echocardiogram, leading to subsequent diagnoses based on pericardial effusion and/or bone marrow examination. Two patients received chemotherapy at the time of initial diagnosis, one with cytarabine and etoposide, and the other with cytarabine and cladribine. Post-treatment, their bone marrow achieved remission, and over a 2.5-year follow-up, their cardiac function remained favorable. Unfortunately, the remaining three patients succumbed within two weeks after diagnosis, either due to receiving alternative drugs or without undergoing chemotherapy.
CONCLUSION
This is the first and largest case series of pediatric AML patients with cardiac MS, manifesting initially with cardiac tamponade. It highlights the rarity and high mortality associated with this condition. The critical factors for reducing mortality include identifying clinical manifestations, conducting thorough physical examinations, performing echocardiography promptly, initiating early and timely pericardial drainage, and avoiding cardiotoxic chemotherapy medications.
PubMed: 38939339
DOI: 10.3389/fonc.2024.1391768 -
IScience Jun 2024The hemoglobinless Antarctic icefish develop large hearts to compensate for reduced oxygen-carrying capacity, which serves as a naturally occurred model to explore the...
The hemoglobinless Antarctic icefish develop large hearts to compensate for reduced oxygen-carrying capacity, which serves as a naturally occurred model to explore the factors regulating cardiogenesis. Through miRNAome and microRNAome comparisons between an icefish () and two red-blooded notothenioids, we discovered significant upregulation of factors in the BMP signaling pathways and altered expression of many miRNAs, including downregulation of 14 miRNAs in the icefish heart. Through knocking down of these miRNAs, we identified two of them, miR-458-3p and miR-144-5p, involved in enlarged heart development. The two miRNAs were found to regulate cardiomyocyte proliferation by targeting bone morphogenetic protein-2 (). We further validated that activation of the miRNA- signaling in the fish heart could be triggered by hypoxic exposure. Our study suggested that a few miRNAs play important roles in the hypoxia-induced cardiac remodeling of the icefish which shed new light on the mechanisms regulating cardiomyocyte proliferation in heart.
PubMed: 38939105
DOI: 10.1016/j.isci.2024.110128 -
Frontiers in Physiology 2024Although compartmentalization of the eye seems to promote its experimental manipulation, drug penetration to its posterior part is severely limited by hard barriers thus... (Review)
Review
Although compartmentalization of the eye seems to promote its experimental manipulation, drug penetration to its posterior part is severely limited by hard barriers thus hindering drug development for eye diseases. In particular, angiogenesis-related retinal diseases share common mechanisms and are responsible for the majority of cases of blindness. Their prevalence is globally increasing mostly because of the increased incidence of systemic pathologies in the adult. Despite the number of preclinical findings demonstrating the efficacy of novel treatments, therapy of retinal neovascular diseases still remains confined to intravitreal anti-vascular endothelial growth factor treatments with some extension to anti-inflammatory therapy. In the of preclinical findings aimed to develop novel avenues for future therapies, most compounds, despite their efficacy in experimental models, do not seem to meet the criteria for their therapeutic application. In particular, the groove between preclinical findings and their clinical application increases instead of decreasing and the attempt to bridging the gap between them creates intense frustration and a sense of defeat. In this complex scenario, we will discuss here the role that overactivation of the sympathetic system plays in retinal vessel proliferation in response to hypoxia using the oxygen-induced retinopathy (OIR) model. The potential application of the beta-adrenoceptor (β-AR) blockade with propranolol to the treatment of retinopathy of prematurity will be also discussed in light of preclinical findings in the OIR model and clinical trials using propranolol in preterm infants either or as eye drops.
PubMed: 38938747
DOI: 10.3389/fphys.2024.1408605 -
F1000Research 2021
Topics: Humans; Mesenchymal Stem Cells; Biomarkers; Adipose Tissue; Cell Survival; Cell Hypoxia; Neovascularization, Physiologic; Ischemic Preconditioning
PubMed: 38938689
DOI: 10.12688/f1000research.55351.3 -
Frontiers in Immunology 2024Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumor entities worldwide, with human papillomavirus (HPV) infection contributing to cancer...
Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumor entities worldwide, with human papillomavirus (HPV) infection contributing to cancer development. Conventional therapies achieve only limited efficiency, especially in recurrent or metastatic HNSCC. As the immune landscape decisively impacts the survival of patients and treatment efficacy, this study comprehensively investigated the immunological tumor microenvironment (TME) and its association with patient outcome, with special focus on several dendritic cell (DC) and T lymphocyte subpopulations. Therefore, formalin-fixed paraffin-embedded tumor samples of 56 HNSCC patients, who have undergone resection and adjuvant radiotherapy, were analyzed by multiplex immunohistochemistry focusing on the detailed phenotypic characterization and spatial distribution of DCs, CD8 T cells, and T-helper cell subsets in different tumor compartments. Immune cell densities and proportions were correlated with clinical characteristics of the whole HNSCC cohort and different HPV- or hypoxia-associated subcohorts. Tumor stroma was highly infiltrated by plasmacytoid DCs and T lymphocytes. Among the T-helper cells and CD8 T cells, stromal regulatory T cells and intraepithelial exhausted CD8 T cells expressing programmed cell death protein-1 (PD-1) and/or lymphocyte-activation gene-3 (LAG-3) were the predominant phenotypes, indicating an immunosuppressive TME. HPV-associated tumors showed significantly higher infiltration of type I and type II conventional DCs (cDC1, cDC2) as well as several CD8 T cell phenotypes including exhausted, activated, and proliferating T cells. On the contrary, tumors with hypoxia-associated gene signatures exhibited reduced infiltration for these immune cells. By multivariate Cox regression, immune-related prognostic factors were identified. Patient clusters defined by high infiltration of DCs and T lymphocytes combined with HPV positivity or low hypoxia showed significantly prolonged survival. Thereby, cDC1 and CD8 T cells emerged as independent prognostic factors for local and distant recurrence. These results might contribute to the implementation of an immune cell infiltration score predicting HNSCC patients' survival and such patient stratification might improve the design of future individualized radiochemo-(immuno)therapies.
Topics: Humans; Dendritic Cells; Squamous Cell Carcinoma of Head and Neck; Male; Female; CD8-Positive T-Lymphocytes; Middle Aged; Tumor Microenvironment; Head and Neck Neoplasms; Aged; Lymphocytes, Tumor-Infiltrating; Prognosis; Adult; Papillomavirus Infections
PubMed: 38938577
DOI: 10.3389/fimmu.2024.1414298 -
Open Veterinary Journal May 2024Oxygen deprivation (OD) is a critical condition that can lead to brain damage and even death. Current hypoxia management approaches are limited in effectiveness. (CA),...
BACKGROUND
Oxygen deprivation (OD) is a critical condition that can lead to brain damage and even death. Current hypoxia management approaches are limited in effectiveness. (CA), known for its neuroprotective properties, offers a potential alternative for OD treatment.
AIMS
This study aims to investigate the neuroprotective effects of CA on the expression of brain-derived neurotrophic factor (BDNF) and vesicular glutamate transporter 1 (VGLUT1) in zebrafish larvae under oxygen-deficient conditions.
METHODS
Zebrafish embryos were subjected to low oxygen levels (1.5 mg/l) 0-2 hours post-fertilization (hpf) until 3 days post-fertilization (dpf), simulating the early stages of OD. Subsequent treatment involved varying concentrations of CA (1.25-5 µg/ml) up to 9 days post-fertilization. The expression levels of BDNF and VGLUT1 were measured using PCR methods. Statistical analysis was conducted using a two-way analysis of variance to evaluate the impact of CA on the expression of BDNF and VGLUT1 in zebrafish larvae aged 3 and 9 dpf in oxygen-deprived conditions.
RESULTS
CA significantly influenced the expression of BDNF and VGLUT1 under OD ( < 0.001). An increase in BDNF expression ( < 0.001) and a decrease in VGLUT1 ( < 0.01) were observed in zebrafish larvae experiencing OD and treated with CA. There was no significant difference in BDNF and VGLUT1 expression across age variations in zebrafish larvae at 3 dpf and 9 dpf in the treatment groups ( > 0.05). CA concentration of 2.5 µg/ml effectively enhanced BDNF and reduced VGLUT1 in 3-9 dpf zebrafish larvae.
CONCLUSION
CA demonstrates potential as a neuroprotective agent, modulating increased BDNF expression and reduced VGLUT1 under OD conditions. These findings lay a foundation for further research in developing therapies for oxygen deficiency.
Topics: Animals; Zebrafish; Centella; Plant Extracts; Larva; Triterpenes; Brain-Derived Neurotrophic Factor; Neuroprotective Agents; Oxygen; Fish Diseases; Hypoxia
PubMed: 38938421
DOI: 10.5455/OVJ.2024.v14.i5.9