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Journal of Advanced Research Jan 2022Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer's disease (AD), but the poor dissolution hampers its bioavailability and therapeutic...
INTRODUCTION
Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer's disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy.
OBJECTIVES
A novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. The anti-AD effects of Nano-HO was determined.
METHODS
Male TgCRND8 mice were daily orally administered Nano-HO or HO at the same dosage (20 mg/kg) for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions using the Morris Water Maze test (MWMT).
RESULTS
Our pharmacokinetic study indicated that the oral bioavailability was greatly improved by Nano-HO. In addition, Nano-HO significantly improved cognitive deficits and inhibited neuroinflammation via suppressing the levels of TNF-α, IL-6 and IL-1β in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing β-amyloid (Aβ) deposition in the cortex and hippocampus of TgCRND8 mice. Moreover, Nano-HO was more effective than HO in modulating amyloid precursor protein (APP) processing via suppressing β-secretase, as well as enhancing Aβ-degrading enzymes like neprilysin (NEP). Furthermore, Nano-HO more markedly inhibited tau hyperphosphorylation via decreasing the ratio of p-Tau (Thr 205)/tau and regulating tau-related apoptosis proteins (caspase-3 and Bcl-2). In addition, Nano-HO more markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3β (Ser9)/GSK-3β. Finally, Nano-HO prevented the gut microflora dysbiosis in TgCRND8 mice in a more potent manner than free HO.
CONCLUSION
Nano-HO was more potent than free HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aβ deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3β signaling pathway. Nano-HO also more potently modulated the gut microbiota community to protect its stability than free HO. These results suggest that Nano-HO has good potential for further development into therapeutic agent for AD treatment.
Topics: Alzheimer Disease; Animals; Biphenyl Compounds; Cognition; Cognitive Dysfunction; Gastrointestinal Microbiome; Glycogen Synthase Kinase 3 beta; Lignans; Male; Mice; Neuroinflammatory Diseases
PubMed: 35024199
DOI: 10.1016/j.jare.2021.03.012 -
Frontiers in Immunology 2021Tonsil hyperplasia is the most common cause of pediatric obstructive sleep apnea (OSA). Despite the growing knowledge in tissue immunology of tonsils, the...
Tonsil hyperplasia is the most common cause of pediatric obstructive sleep apnea (OSA). Despite the growing knowledge in tissue immunology of tonsils, the immunopathology driving tonsil hyperplasia and OSA remains unknown. Here we used multi-parametric flow cytometry to analyze the composition and phenotype of tonsillar innate lymphoid cells (ILCs), T cells, and B cells from pediatric patients with OSA, who had previous polysomnography. Unbiased clustering analysis was used to delineate and compare lymphocyte heterogeneity between two patient groups: children with small tonsils and moderate OSA (n = 6) or large tonsils and very severe OSA (n = 13). We detected disturbed ILC and B cell proportions in patients with large tonsils, characterized by an increase in the frequency of naïve CD27CD21 B cells and a relative reduction of ILCs. The enrichment of naïve B cells was not commensurate with elevated Ki67 expression, suggesting defective differentiation and/or migration rather than cellular proliferation to be the causative mechanism. Finally, yet importantly, we provide the flow cytometry data to be used as a resource for additional translational studies aimed at investigating the immunological mechanisms of pediatric tonsil hyperplasia and OSA.
Topics: Child, Preschool; Female; Flow Cytometry; Humans; Hyperplasia; Immunity, Innate; Lymphocytes; Male; Memory B Cells; Palatine Tonsil; Receptors, CXCR5; Sleep Apnea, Obstructive; Tumor Necrosis Factor Receptor Superfamily, Member 7
PubMed: 34745084
DOI: 10.3389/fimmu.2021.674080 -
Radiation Oncology (London, England) Jan 2022To define the clinical characteristics of irradiation-induced nasopharyngeal necrosis (INN) after intensity-modulated radiotherapy (IMRT) and identify the influence of...
Irradiation-induced nasopharyngeal necrosis (INN) in newly diagnosed nasopharyngeal carcinoma treated by intensity-modulated radiation therapy: clinical characteristics and the influence of treatment strategies.
PURPOSE
To define the clinical characteristics of irradiation-induced nasopharyngeal necrosis (INN) after intensity-modulated radiotherapy (IMRT) and identify the influence of treatment strategies on INN in primary nasopharyngeal carcinoma (NPC) patients.
PATIENTS AND METHODS
From 2008 to 2019, NPC patients pathologically diagnosed with INN after primary IMRT were reviewed. Those patients were matched with propensity scores for patients without INN in our center. The impact of treatment strategies on INN occurrence was assessed using univariate and multivariate logistic regression analysis.
RESULTS
The incidence rate of INN was 1.9% among the primary NPC population, and 53 patients with INN were enrolled. Headache and foul odor were the main symptoms, and 71.7% of cases had pseudomembrane during or at the end of radiotherapy. All patients were in early or middle stage INN, and no one presented with skull-based osteoradionecrosis. Then 212 non-INN patients were included based on propensity scores match. Overall survival (p = 0.248) and progression-free survival (p = 0.266) curves were similar between the INN and non-INN groups. Treatment strategies including combining chemotherapy or molecular targeted therapy with radiotherapy were not associated with INN occurrence, while boost dose (OR 7.360; 95% CI 2.301-23.547; p = 0.001) was a predictor factor for it. However, the optimal threshold for an accumulated dose to predict INN's occurrence was failed to determine.
CONCLUSION
In the IMRT era, the severity of INN in primary NPC patients is lessened. This study showed that treatment strategies contributed little to develop INN, while the accumulated dose of radiation may relate to its occurrence.
Topics: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Nasopharynx; Necrosis; Radiation Injuries; Radiotherapy, Intensity-Modulated; Retrospective Studies; Young Adult
PubMed: 35062991
DOI: 10.1186/s13014-022-01980-0 -
Cleveland Clinic Journal of Medicine Aug 2023
Topics: Humans; Infectious Mononucleosis; Splenic Infarction; Palatine Tonsil
PubMed: 37527871
DOI: 10.3949/ccjm.90a.22079 -
Circulation Aug 2020Supplemental Digital Content is available in the text.
Supplemental Digital Content is available in the text.
Topics: Adult; Antiviral Agents; Betacoronavirus; C-Reactive Protein; COVID-19; Cobicistat; Coronavirus Infections; Darunavir; Electrocardiography; Female; Humans; Hypokinesia; Hypotension; International Normalized Ratio; Myocardium; Nasopharynx; Pandemics; Platelet Count; Pneumonia, Viral; SARS-CoV-2; ST Elevation Myocardial Infarction; Thrombosis; Troponin I; Ventricular Dysfunction, Left
PubMed: 32677840
DOI: 10.1161/CIRCULATIONAHA.120.049294 -
BMJ Case Reports Nov 2019Nasopharyngeal carcinoma (NPC), an uncommon malignancy in Western Countries and Radiotherapy, remains an effective treatment. Its side effects are classified as either...
Nasopharyngeal carcinoma (NPC), an uncommon malignancy in Western Countries and Radiotherapy, remains an effective treatment. Its side effects are classified as either immediate or late; postradiation necrosis is as an important late side effect with a strong impact on the prognosis in patients with NPC. We report the case of 65-year-old Caucasian man presenting with a deep necrotic ulcer of the nasopharynx and osteoradionecrosis of the skull base that appeared 3 months after radiotherapy for nasopharyngeal carcinoma. Conservative treatment was applied with surgical management of the ulcer. Clinical and radiological outcomes are presented. Radiotherapy remains a good treatment option with varying degrees of side effects, in particular, postradiation necrosis and ulcer. Multiple options of treatment have been described. However, the surgical management could be indicated in cases of deep ulcer with life-threatening prognosis.
Topics: Aged; Endoscopy; Humans; Male; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Nasopharynx; Osteoradionecrosis; Radiation Injuries; Skull Base; Treatment Outcome; Ulcer
PubMed: 31694827
DOI: 10.1136/bcr-2019-230700 -
FEBS Open Bio May 2020Adenoidal hypertrophy (AH) is a common disorder in the pediatric population, with common symptoms including mouth breathing, nasal congestion, hyponasal speech, snoring...
Adenoidal hypertrophy (AH) is a common disorder in the pediatric population, with common symptoms including mouth breathing, nasal congestion, hyponasal speech, snoring and obstructive sleep apnea. Although the pathogenesis of AH has not been fully elucidated, recent studies have indicated that immune responses may play an important role in AH. Tumor necrosis factor-alpha (TNF-α)-induced protein-8 like-2 (TIPE2) is a newly identified protein that negatively regulates the activation of inflammatory pathways. Here, we investigated the effect of TIPE2 in AH in children. We observed that the levels of TNF-α and interleukin-6 were greater in the adenoid tissue of AH children than in healthy control subjects (P < 0.01), and this increase was positively correlated with the severity of AH. The level of TIPE2 expression was decreased compared with control and was negatively correlated with AH. TIPE2 overexpression in primary human monocytes (isolated from adenoid tissue of children with AH) inhibited the activation of nuclear factor-κB and the expression of TNF-α and interleukin-6. These results suggest that overexpression of TIPE2 may attenuate AH through inactivation of the nuclear factor-κB signaling pathway.
Topics: Adenoids; Child; Child, Preschool; China; Female; Humans; Hypertrophy; Inflammation; Interleukin-6; Intracellular Signaling Peptides and Proteins; Male; Monocytes; RNA, Messenger; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 32100476
DOI: 10.1002/2211-5463.12821 -
Brazilian Journal of Otorhinolaryngology 2020Obstrutive sleep apnea syndrome is characterized by repeated episodes of upper airway obstruction, associated with intermittent hypoxia and hypercapnia, and the main...
INTRODUCTION
Obstrutive sleep apnea syndrome is characterized by repeated episodes of upper airway obstruction, associated with intermittent hypoxia and hypercapnia, and the main risk factor in childhood is adenotonsillar hypertrophy. The lymphocytes in these structures are responsible for local and systemic immune responses.
OBJECTIVE
Verify the levels of the inflammatory markers, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-15, TNF-α, CRP and α1-GP, in the tonsils of children with and without obstructive sleep apnea syndrome.
METHODS
This cross-sectional prospective study included 34 children with complains of snoring, difficulty breathing during sleep or recurrent tonsillitis. Patients underwent to a complete otorhinolaryngological examination, nasal endoscopy and polysomnography and were divided into two groups with 17 children each: obstructive sleep apnea syndrome group and control group. All underwent an adenotonsillectomy. Cytokines were measured in the collected tonsils (ELISA and Multiplex methods).
RESULTS
Statistically significant increasing were observed between IL-8 and IL-10 cytokines of patients with obstructive sleep apnea when compared to the control group; also between c-reactive protein and α1-GP of the tonsils cortical region in children with obstructive sleep apnea syndrome when compared with the medullary region. There were no statistically significant differences for the remaining inflammatory mediators.
CONCLUSION
After the analysis of the levels of pro and anti-inflammatory markers (IL-1β, IL-4, IL-6, IL-8, IL-10, Il-15, TNF-α, CRP, α1-GP) in the tonsils, we observed higher levels of markers IL-8 and IL-10 in pediatric patients with obstructive sleep apnea syndrome.
Topics: Biomarkers; C-Reactive Protein; Child; Child, Preschool; Cross-Sectional Studies; Cytokines; Female; Humans; Inflammation; Interleukins; Male; Orosomucoid; Palatine Tonsil; Prospective Studies; Sleep Apnea, Obstructive; Tonsillectomy; Tumor Necrosis Factor-alpha
PubMed: 30213594
DOI: 10.1016/j.bjorl.2018.08.001 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Dec 2023To explore the mechanism of in treatment of Alzheimer's Disease (AD).
OBJECTIVES
To explore the mechanism of in treatment of Alzheimer's Disease (AD).
METHODS
The active ingredients and targets of for treatment of AD were screened with network pharmacology methods, the protein-protein interaction (PPI) network was constructed and the core targets were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriching analysis was performed. The peripheral blood lymphocytes were extracted and lymphoblastoid cell lines (LCL) were constructed and an cell model of LCL-SKNMC was established. MTT and CCK-8 methods were used to quantify SKNMC/LCL cells, 2 ´, 7 ´-dichlorodihydrofluorescein diacetate (DCFH-DA) probe was used to detect reactive oxygen species (ROS), and immunofluorescence staining was used to detect the generation of Aβ in a co-cultured model. Western blotting was used to detect protein expression in the co-culture model. The lifespan of N2 nematodes was observed under oxidative stress, normal state, and heat stress; ROS generated by N2 nematodes was detected by DCFH-DA probes. The paralysis time of CL4176 N2 nematodes was evaluated by paralysis assay, and Aβ deposition in the pharynx was detected by Thioflavin S staining.
RESULTS
Through network pharmacology, 15 potential active ingredients and 103 drug-disease targets were identified. PPI analysis showed that the might play anti-AD roles through albumin, Akt1, tumor necrosis factor, epidermal growth factor receptor (EGFR), vascular endothelial growth factor A (VEGFA), mammalian target of rapamycin (mTOR), amyloid precursor protein (APP) and other related targets. KEGG analysis showed that the pharmacological effects of might involve the biological processes of Alzheimer's disease, endocrine resistance, insulin resistance; and neuroactive ligand-receptor interaction, phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway, calcium signaling pathway, AGE-RAGE signaling pathway in diabetes complications, neurotrophic factor signaling pathway and others. The cell experiments showed that was able to reduce the production of ROS and Aβ (both <0.01), inhibit the expression of β-secretase 1 (BACE1), APP and Aβ proteins (all <0.05), up-regulate the expression of p-PI3K/PI3K, p-AKT/AKT, p-GSK3β/GSK3β in SKNMC cells (all <0.05). The studies further confirmed that prolonged the lifespan of under stress and normal conditions, reduced the accumulation of ROS and the toxicity of Aβ deposition.
CONCLUSIONS
may reduce the production of Aβ in AD and inhibit its induced oxidative stress, which may be achieved by regulating the PI3K/Akt/GSK-3β pathway.
Topics: Animals; Alzheimer Disease; Amyloid Precursor Protein Secretases; Drugs, Chinese Herbal; Glycogen Synthase Kinase 3 beta; Proto-Oncogene Proteins c-akt; Vascular Endothelial Growth Factor A; Caenorhabditis elegans; Network Pharmacology; Phosphatidylinositol 3-Kinases; Reactive Oxygen Species; Aspartic Acid Endopeptidases; Amyloid beta-Protein Precursor; Paralysis; Mammals; Fluoresceins
PubMed: 38105702
DOI: 10.3724/zdxbyxb-2023-0362 -
EBioMedicine May 2021Coronavirus-2 (SARS-CoV-2) infection causes an acute respiratory syndrome accompanied by multi-organ damage that implicates a prothrombotic state leading to widespread...
BACKGROUND
Coronavirus-2 (SARS-CoV-2) infection causes an acute respiratory syndrome accompanied by multi-organ damage that implicates a prothrombotic state leading to widespread microvascular clots. The causes of such coagulation abnormalities are unknown. The receptor tissue factor, also known as CD142, is often associated with cell-released extracellular vesicles (EV). In this study, we aimed to characterize surface antigens profile of circulating EV in COVID-19 patients and their potential implication as procoagulant agents.
METHODS
We analyzed serum-derived EV from 67 participants who underwent nasopharyngeal swabs molecular test for suspected SARS-CoV-2 infection (34 positives and 33 negatives) and from 16 healthy controls (HC), as referral. A sub-analysis was performed on subjects who developed pneumonia (n = 28). Serum-derived EV were characterized for their surface antigen profile and tested for their procoagulant activity. A validation experiment was performed pre-treating EV with anti-CD142 antibody or with recombinant FVIIa. Serum TNF-α levels were measured by ELISA.
FINDINGS
Profiling of EV antigens revealed a surface marker signature that defines circulating EV in COVID-19. A combination of seven surface molecules (CD49e, CD209, CD86, CD133/1, CD69, CD142, and CD20) clustered COVID (+) versus COVID (-) patients and HC. CD142 showed the highest discriminating performance at both multivariate models and ROC curve analysis. Noteworthy, we found that CD142 exposed onto surface of EV was biologically active. CD142 activity was higher in COVID (+) patients and correlated with TNF-α serum levels.
INTERPRETATION
In SARS-CoV-2 infection the systemic inflammatory response results in cell-release of substantial amounts of procoagulant EV that may act as clotting initiation agents, contributing to disease severity.
FUNDING
Cardiocentro Ticino Institute, Ente ospedaliero Cantonale, Lugano-Switzerland.
Topics: Adult; Aged; Aged, 80 and over; Antigens, Surface; Biomarkers; COVID-19; Case-Control Studies; Diagnosis, Differential; Extracellular Vesicles; Female; Humans; Male; Middle Aged; Nasopharynx; SARS-CoV-2; Switzerland; Thromboplastin; Thrombosis; Tumor Necrosis Factor-alpha
PubMed: 33971404
DOI: 10.1016/j.ebiom.2021.103369