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1.
bioRxiv ; 2024 Apr 28.
Article in English | MEDLINE | ID: mdl-38712036

ABSTRACT

Antigen specificity is the central trait distinguishing adaptive from innate immune function. Assembly of antigen-specific T cell and B cell receptors occurs through V(D)J recombination mediated by the Recombinase Activating Gene endonucleases RAG1 and RAG2 (collectively called RAG). In the absence of RAG, mature T and B cells do not develop and thus RAG is critically associated with adaptive immune function. In addition to adaptive T helper 2 (Th2) cells, group 2 innate lymphoid cells (ILC2s) contribute to type 2 immune responses by producing cytokines like Interleukin-5 (IL-5) and IL-13. Although it has been reported that RAG expression modulates the function of innate natural killer (NK) cells, whether other innate immune cells such as ILC2s are affected by RAG remains unclear. We find that in RAG-deficient mice, ILC2 populations expand and produce increased IL-5 and IL-13 at steady state and contribute to increased inflammation in atopic dermatitis (AD)-like disease. Further, we show that RAG modulates ILC2 function in a cell-intrinsic manner independent of the absence or presence of adaptive T and B lymphocytes. Lastly, employing multiomic single cell analyses of RAG1 lineage-traced cells, we identify key transcriptional and epigenomic ILC2 functional programs that are suppressed by a history of RAG expression. Collectively, our data reveal a novel role for RAG in modulating innate type 2 immunity through suppression of ILC2s.

2.
Int J Mol Sci ; 25(4)2024 Feb 08.
Article in English | MEDLINE | ID: mdl-38396774

ABSTRACT

Platelets assume a pivotal role in the pathogenesis of cardiovascular diseases (CVDs), emphasizing their significance in disease progression. Consequently, addressing CVDs necessitates a targeted approach focused on mitigating platelet activation. Eugenol, predominantly derived from clove oil, is recognized for its antibacterial, anticancer, and anti-inflammatory properties, rendering it a valuable medicinal agent. This investigation delves into the intricate mechanisms through which eugenol influences human platelets. At a low concentration of 2 µM, eugenol demonstrates inhibition of collagen and arachidonic acid (AA)-induced platelet aggregation. Notably, thrombin and U46619 remain unaffected by eugenol. Its modulatory effects extend to ATP release, P-selectin expression, and intracellular calcium levels ([Ca2+]i). Eugenol significantly inhibits various signaling cascades, including phospholipase Cγ2 (PLCγ2)/protein kinase C (PKC), phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3ß, mitogen-activated protein kinases, and cytosolic phospholipase A2 (cPLA2)/thromboxane A2 (TxA2) formation induced by collagen. Eugenol selectively inhibited cPLA2/TxA2 phosphorylation induced by AA, not affecting p38 MAPK. In ADP-treated mice, eugenol reduced occluded lung vessels by platelet thrombi without extending bleeding time. In conclusion, eugenol exerts a potent inhibitory effect on platelet activation, achieved through the inhibition of the PLCγ2-PKC and cPLA2-TxA2 cascade, consequently suppressing platelet aggregation. These findings underscore the potential therapeutic applications of eugenol in CVDs.


Subject(s)
Eugenol , Pulmonary Embolism , Humans , Mice , Animals , Eugenol/pharmacology , Eugenol/therapeutic use , Eugenol/metabolism , Phospholipase C gamma/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Disease Models, Animal , Platelet Activation , Platelet Aggregation , Blood Platelets/metabolism , Phosphorylation , Protein Kinase C/metabolism , Thromboxane A2/metabolism , Collagen/metabolism , Pulmonary Embolism/drug therapy , Pulmonary Embolism/metabolism , Phospholipases A2, Cytosolic/metabolism
3.
J Cell Mol Med ; 28(4): e18139, 2024 02.
Article in English | MEDLINE | ID: mdl-38334198

ABSTRACT

Platelets assume a pivotal role in the cardiovascular diseases (CVDs). Thus, targeting platelet activation is imperative for mitigating CVDs. Ginkgetin (GK), from Ginkgo biloba L, renowned for its anticancer and neuroprotective properties, remains unexplored concerning its impact on platelet activation, particularly in humans. In this investigation, we delved into the intricate mechanisms through which GK influences human platelets. At low concentrations (0.5-1 µM), GK exhibited robust inhibition of collagen and arachidonic acid (AA)-induced platelet aggregation. Intriguingly, thrombin and U46619 remained impervious to GK's influence. GK's modulatory effect extended to ATP release, P-selectin expression, intracellular calcium ([Ca2+ ]i) levels and thromboxane A2 formation. It significantly curtailed the activation of various signaling cascades, encompassing phospholipase Cγ2 (PLCγ2)/protein kinase C (PKC), phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3ß and mitogen-activated protein kinases. GK's antiplatelet effect was not reversed by SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor), and GK had no effect on the phosphorylation of vasodilator-stimulated phosphoproteinSer157 or Ser239 . Moreover, neither cyclic AMP nor cyclic GMP levels were significantly increased after GK treatment. In mouse studies, GK notably extended occlusion time in mesenteric vessels, while sparing bleeding time. In conclusion, GK's profound impact on platelet activation, achieved through inhibiting PLCγ2-PKC cascade, culminates in the suppression of downstream signaling and, ultimately, the inhibition of platelet aggregation. These findings underscore the promising therapeutic potential of GK in the CVDs.


Subject(s)
Biflavonoids , Nucleotides, Cyclic , Phospholipases , Humans , Animals , Mice , Nucleotides, Cyclic/metabolism , Nucleotides, Cyclic/pharmacology , Phospholipase C gamma/metabolism , Arachidonic Acid/pharmacology , Arachidonic Acid/metabolism , Phospholipases/metabolism , Phospholipases/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Platelet Aggregation Inhibitors/pharmacology , Platelet Activation , Blood Platelets/metabolism , Platelet Aggregation , Protein Kinase C/metabolism , Phosphorylation , Collagen/metabolism
4.
Expert Rev Clin Pharmacol ; 17(2): 157-164, 2024.
Article in English | MEDLINE | ID: mdl-38224017

ABSTRACT

BACKGROUND: This study aimed to evaluate the effectiveness and safety of fixed-dose combination (FDC) inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA) in bronchiectasis. RESEARCH DESIGN AND METHODS: A retrospective cohort study analyzed electronic medical records of bronchiectasis patients initiating ICS/LABA FDC or LAMA between 2007 and 2021. All bronchiectasis diagnoses were made by radiologists using high-resolution computed tomography. RESULTS: Of the 1,736 patients, 1,281 took ICS/LABA FDC and 455 LAMA. Among the 694 propensity score matched patients, ICS/LABA FDC had comparable outcomes to LAMA, with HRs of 1.22 (95% CI 0.81-1.83) for hospitalized respiratory infection, 1.06 (95% CI 0.84-1.33) for acute exacerbation, and 1.06 (95% CI 0.66-1.02) for all-cause hospitalization. Beclomethasone/formoterol (BEC/FOR) or budesonide/formoterol (BUD/FOR) led to a lower risk of acute exacerbation compared to fluticasone/salmeterol (FLU/SAL) (BEC/FOR HR 0.59, 95% CI 0.43-0.81; BUD/FOR HR 0.68, 95% CI 0.50-0.93). BEC/FOR resulted in lower risks of hospitalized respiratory infection (HR 0.48, 95% 0.26-0.86) and all-cause hospitalization (HR 0.55, 95% 0.37-0.80) compared to FLU/SAL. CONCLUSION: Our findings provide important evidence on the effectiveness and safety of ICS/LABA FDC compared with LAMA for bronchiectasis. BEC/FOR and BUD/FOR were associated with better outcomes than FLU/SAL.


Subject(s)
Bronchiectasis , Pulmonary Disease, Chronic Obstructive , Humans , Muscarinic Antagonists/adverse effects , Retrospective Studies , Adrenergic beta-2 Receptor Agonists/adverse effects , Pulmonary Disease, Chronic Obstructive/drug therapy , Formoterol Fumarate , Adrenal Cortex Hormones , Fluticasone-Salmeterol Drug Combination/therapeutic use , Bronchiectasis/drug therapy , Administration, Inhalation , Bronchodilator Agents , Drug Therapy, Combination
5.
Int J Nanomedicine ; 19: 327-345, 2024.
Article in English | MEDLINE | ID: mdl-38229707

ABSTRACT

Ischemic stroke, a condition that often leads to severe nerve damage, induces complex pathological and physiological changes in nerve tissue. The mature central nervous system (CNS) lacks intrinsic regenerative capacity, resulting in a poor prognosis and long-term neurological impairments. There is no available therapy that can fully restore CNS functionality. However, the utilization of injectable hydrogels has emerged as a promising strategy for nerve repair and regeneration. Injectable hydrogels possess exceptional properties, such as biocompatibility, tunable mechanical properties, and the ability to provide a supportive environment for cell growth and tissue regeneration. Recently, various hydrogel-based tissue engineering approaches, including cell encapsulation, controlled release of therapeutic factors, and incorporation of bioactive molecules, have demonstrated great potential in the treatment of CNS injuries caused by ischemic stroke. This article aims to provide a comprehensive review of the application and development of injectable hydrogels for the treatment of ischemic stroke-induced CNS injuries, shedding light on their therapeutic prospects, challenges, recent advancements, and future directions. Additionally, it will discuss the underlying mechanisms involved in hydrogel-mediated nerve repair and regeneration, as well as the need for further preclinical and clinical studies to validate their efficacy and safety.


Subject(s)
Ischemic Stroke , Plastic Surgery Procedures , Humans , Hydrogels/pharmacology , Ischemic Stroke/therapy , Tissue Engineering/methods , Central Nervous System , Nerve Regeneration
6.
Eur Radiol ; 34(1): 126-135, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37572194

ABSTRACT

OBJECTIVE: To explore the neuroimage change in Parkinson's disease (PD) patients with cognitive impairments, this study investigated the correlation between plasma biomarkers and morphological brain changes in patients with normal cognition and mild cognitive impairment. The objective was to identify the potential target deposition regions of the plasma biomarkers and to search for the relevant early neuroimaging biomarkers on the basis of different cognitive domains. METHODS: Structural brain MRI and diffusion weighted images were analyzed from 49 eligible PD participants (male/female: 27/22; mean age: 73.4 ± 8.5 years) from a retrospective analysis. Plasma levels of α-synuclein, amyloid beta peptide, and total tau were collected. A comprehensive neuropsychological assessment of the general and specific cognitive domains was performed. Difference between PD patients with normal cognition and impairment was examined. Regression analysis was performed to evaluate the correlation between image-derived index and plasma biomarkers or neuropsychological assessments. RESULTS: Significant correlation was found between plasma Aß-42 level and fractional anisotropy of the middle occipital, angular, and middle temporal gyri of the left brain, as well as plasma T-tau level and the surface area of the isthmus or the average thickness of the posterior part of right cingulate gyrus. Visuospatial and executive function is positively correlated with axial diffusivity in bilateral cingulate gyri. CONCLUSION: In nondemented PD patients, the target regions for plasma deposition might be located in the cingulate, middle occipital, angular, and middle temporal gyri. Changes from multiple brain regions can be correlated to the performance of different cognitive domains. CLINICAL RELEVANCE STATEMENT: Cognitive impairment in Parkinson's disease is primarily linked to biomarkers associated with Alzheimer's disease rather than those related to Parkinson's disease and resembles the frontal variant of Alzheimer's disease, which may guide management strategies for cognitive impairment in Parkinson's disease. KEY POINTS: • Fractional anisotropy, surface area, and thickness in the cingulate, middle occipital, angular, and middle temporal gyri can be significantly correlated with plasma Aß-42 and T-tau level. • Axial diffusivity in the cingulate gyri was correlated with visuospatial and executive function. • The pattern of cognitive impairment in Parkinson's disease can be similar to the frontal variant than typical Alzheimer's disease.


Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Parkinson Disease , Humans , Male , Female , Middle Aged , Aged , Aged, 80 and over , Parkinson Disease/complications , Parkinson Disease/diagnostic imaging , Alzheimer Disease/complications , Amyloid beta-Peptides , Retrospective Studies , Cognitive Dysfunction/complications , Cognitive Dysfunction/diagnostic imaging , Magnetic Resonance Imaging/methods , Neuropsychological Tests , Biomarkers
7.
Chinese Pharmacological Bulletin ; (12): 133-138, 2024.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-1013616

ABSTRACT

Aim To explore the effect of exogenous hydrogen sulfide ( H2 S ) on hypoxia/reoxygenation ( H/R) injury in glomerular mesangial cells and elucidate its relevant mechanism. Methods H/R induced mouse mesangial cell line ( SV40MES13 ) to establish cell damage model. Cell viability was detected by cell proliferation kit ( CCK8 ), the content of H

8.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-1013606

ABSTRACT

Pyroptosis is the programmed death of cells accompanied by an inflammatory response and is widely involved in the development of a variety of diseases, such as infectious diseases, cardiovascular diseases, and neurodegeneration. It has been shown that cellular scorching is involved in the pathogenesis of pulmonary arterial hypertension ( PAH) in cardiovascular diseases. Patients with PAH have perivascular inflammatory infiltrates in lungs, pulmonary vasculopathy exists in an extremely inflam-matory microenvironment, and pro-inflammatory factors in cellular scorching drive pulmonary vascular remodelling in PAH patients. This article reviews the role of cellular scorch in the pathogenesis of PAH and the related research on drugs for the treatment of PAH, with the aim of providing new ideas for clinical treatment of PAH.

9.
Cell ; 187(1): 44-61.e17, 2024 01 04.
Article in English | MEDLINE | ID: mdl-38134932

ABSTRACT

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPß was dependent on JAK1 in the vagus nerve, and CGRPß suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.


Subject(s)
Dermatitis, Atopic , Immunity, Innate , Lung , Sensory Receptor Cells , Animals , Humans , Mice , Cytokines , Dermatitis, Atopic/immunology , Inflammation , Lung/immunology , Lymphocytes , Sensory Receptor Cells/enzymology
10.
Int J Nanomedicine ; 18: 7441-7468, 2023.
Article in English | MEDLINE | ID: mdl-38090364

ABSTRACT

Current therapies for Alzheimer's disease used in the clinic predominantly focus on reducing symptoms with limited capability to control disease progression; thus, novel drugs are urgently needed. While nanoparticles (liposomes, high-density lipoprotein-based nanoparticles) constructed with synthetic biomembranes have shown great potential in AD therapy due to their excellent biocompatibility, multifunctionality and ability to penetrate the BBB, nanoparticles derived from natural biomembranes (extracellular vesicles, cell membrane-based nanoparticles) display inherent biocompatibility, stability, homing ability and ability to penetrate the BBB, which may present a safer and more effective treatment for AD. In this paper, we reviewed the synthetic and natural biomembrane-derived nanoparticles that are used in AD therapy. The challenges associated with the clinical translation of biomembrane-derived nanoparticles and future perspectives are also discussed.


Subject(s)
Alzheimer Disease , Nanoparticles , Humans , Alzheimer Disease/drug therapy , Liposomes/pharmacology , Blood-Brain Barrier
11.
PLoS Genet ; 19(11): e1011021, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37917726

ABSTRACT

Small nuclear RNAs (snRNAs) are structural and functional cores of the spliceosome. In metazoan genomes, each snRNA has multiple copies/variants, up to hundreds in mammals. However, the expressions and functions of each copy/variant in one organism have not been systematically studied. Focus on U1 snRNA genes, we investigated all five copies in Drosophila melanogaster using two series of constructed strains. Analyses of transgenic flies that each have a U1 promoter-driven gfp revealed that U1:21D is the major and ubiquitously expressed copy, and the other four copies have specificities in developmental stages and tissues. Mutant strains that each have a precisely deleted copy of U1-gene exhibited various extents of defects in fly morphology or mobility, especially deletion of U1:82Eb. Interestingly, splicing was changed at limited levels in the deletion strains, while large amounts of differentially-expressed genes and alternative polyadenylation events were identified, showing preferences in the down-regulation of genes with 1-2 introns and selection of proximal sites for 3'-end polyadenylation. In vitro assays suggested that Drosophila U1 variants pulled down fewer SmD2 proteins compared to the canonical U1. This study demonstrates that all five U1-genes in Drosophila have physiological functions in development and play regulatory roles in transcription and 3'-end formation.


Subject(s)
Drosophila melanogaster , RNA, Small Nuclear , Animals , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , RNA, Small Nuclear/genetics , RNA, Small Nuclear/metabolism , RNA Splicing/genetics , Drosophila/genetics , Drosophila/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Mammals/genetics
12.
Heliyon ; 9(10): e20286, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37767484

ABSTRACT

Platelets play a vital role in the formation of dangerous arterial thrombosis. Platelets are activated by adhesive proteins or soluble agonists through their specific receptors. The receptor-mediated signaling pathways lead to common signaling events, which result in shape changes and inside-out signaling, leading fibrinogen binding to glycoprotein IIb/IIIa complex (integrin αIIbß3). This interaction initiates integrin αIIbß3-mediated outside-in signaling, subsequently culminating in granule secretion and aggregation. Myricetin is a flavonoid that occurs in a variety of plants. Although myricetin has been demonstrated to have several bioactive properties, its role in platelet activation has not been extensively studied. The present study demonstrated the ability of myricetin to inhibit platelet aggregation stimulated by collagen, thrombin, and U46619. Myricetin reduced the ATP-release, cytosolic Ca2+ mobilization, and P-selectin expression and the activation of PLCγ2/PKC, PI3K/Akt/GSK3ß, and MAPK. Myricetin exerted a direct inhibitory effect on the activation of integrin αIIbß3 by disrupting the binding between FITC-PAC-1 and the integrin. Moreover, myricetin suppressed integrin αIIbß3-mediated outside-in signaling, such as integrin ß3, Src, and Syk phosphorylation on immobilized fibrinogen. In animal studies, myricetin significantly prolonged the occlusion time of thrombotic platelet plug formation in mesenteric microvessels without extending bleeding time. This study concludes that myricetin is a natural integrin αIIbß3 inhibitor and a novel antithrombotic agent.

13.
Mol Neurobiol ; 60(9): 5199-5213, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37277682

ABSTRACT

Epilepsy is one of the most common neurological disorders. The pro-epileptic and antiepileptic roles of microglia have recently garnered significant attention. Interleukin-1 receptor-associated kinase (IRAK)-M, an important kinase in the innate immune response, is mainly expressed in microglia and acts as a negative regulator of the TLR4 signaling pathway that mediates the anti-inflammatory effect. However, whether IRAK-M exerts a protective role in epileptogenesis as well as the molecular and cellular mechanisms underlying these processes are yet to be elucidated. An epilepsy mouse model induced by pilocarpine was used in this study. Real-time quantitative polymerase chain reaction and western blot analysis were used to analyze mRNA and protein expression levels, respectively. Whole-cell voltage-clamp recordings were employed to evaluate the glutamatergic synaptic transmission in hippocampal neurons. Immunofluorescence was utilized to show the glial cell activation and neuronal loss. Furthermore, the proportion of microglia was analyzed using flow cytometry. Seizure dynamics influenced the expression of IRAK-M. Its knockout dramatically exacerbated the seizures and the pathology in epilepsy and increased the N-methyl-d-aspartate receptor (NMDAR) expression, thereby enhancing glutamatergic synaptic transmission in hippocampal CA1 pyramidal neurons in mice. Furthermore, IRAK-M deficiency augmented hippocampal neuronal loss via a possible mechanism of NMDAR-mediated excitotoxicity. IRAK-M deletion promotes microglia toward the M1 phenotype, which resulted in high levels of proinflammatory cytokines and was accompanied by a visible increase in the expressions of key microglial polarization-related proteins, including p-STAT1, TRAF6, and SOCS1. The findings demonstrate that IRAK-M dysfunction contributes to the progression of epilepsy by increasing M1 microglial polarization and glutamatergic synaptic transmission. This is possibly related to NMDARs, particularly Grin2A and Grin2B, which suggests that IRAK-M could serve as a novel therapeutic target for the direct alleviation of epilepsy.


Subject(s)
Epilepsy , Status Epilepticus , Mice , Animals , Microglia/metabolism , Neuroinflammatory Diseases , Interleukin-1 Receptor-Associated Kinases/metabolism , Status Epilepticus/metabolism , Seizures/metabolism , Epilepsy/metabolism
14.
Chin Med ; 18(1): 71, 2023 Jun 10.
Article in English | MEDLINE | ID: mdl-37301823

ABSTRACT

BACKGROUND: Platelets play a crucial role in cardiovascular diseases (CVDs) and are activated by endogenous agonists like collagen. These agonists initiate signal transduction through specific platelet receptors, resulting in platelet aggregation. Glabridin, a prenylated isoflavonoid found in licorice root, is known for its significance in metabolic abnormalities. Glabridin has been observed to inhibit collagen-induced platelet aggregation, but the precise mechanisms, specifically concerning NF-κB activation and integrin αIIbß3 signaling, are not yet fully understood. METHODS: In this study, platelet suspensions were prepared from healthy human blood donors, and the aggregation ability was observed using a lumi-aggregometer. The inhibitory mechanisms of glabridin in human platelets were evaluated through immunoblotting and confocal microscopy. The anti-thrombotic effects of glabridin were assessed by histological analysis of lung sections in acute pulmonary thromboembolism and by examining fluorescein-induced platelet plug formation in mesenteric microvessels in mice. RESULTS: Glabridin inhibited integrin αIIbß3 inside-out signals such as Lyn, Fyn, Syk, and integrin ß3 activation and NF-κB-mediated signal events, with similar potency to classical inhibitors BAY11-7082 and Ro106-9920. Glabridin and BAY11-7082 inhibited IKK, IκBα, and p65 phosphorylation and reversed IκBα degradation, while Ro106-9920 only reduced p65 phosphorylation and reversed IκBα degradation. BAY11-7082 reduced Lyn, Fyn, Syk, integrin ß3, phospholipase Cγ2 and protein kinase C activation. Glabridin reduced platelet plug formation in mesenteric microvessels and occluded vessels in thromboembolic lungs of mice. CONCLUSION: Our study revealed a new pathway for activating integrin αIIbß3 inside-out signals and NF-κB, which contributes to the antiplatelet aggregation effect of glabridin. Glabridin could be a valuable prophylactic or clinical treatment option for CVDs.

15.
Life Sci ; 326: 121791, 2023 Aug 01.
Article in English | MEDLINE | ID: mdl-37211346

ABSTRACT

AIMS: Platelet activation plays a central role in arterial thrombosis. Platelets are activated by adhesive proteins (i.e., collagen) or soluble agonists (i.e., thrombin), the respective receptor-specific signaling cause inside-out signaling, leading to the binding of fibrinogen to integrin αIIbß3. This binding triggers outside-in signaling, resulting in platelet aggregation. Garcinol, a polyisoprenylated benzophenone, is extracted from the fruit rind of Garcinia indica. Although garcinol exhibits considerable bioactivities, few studies have investigated the effect of garcinol on platelet activation. MAIN METHODS: Aggregometry, immunoblotting, flow cytometer, confocal microscopic analysis, fibrin clot retraction, animal studies such as fluorescein-induced platelet plug formation in mesenteric microvessels, acute pulmonary thromboembolism, and tail bleeding time were performed in this study. KEY FINDINGS: This study indicates that garcinol inhibited platelet aggregation stimulated by collagen, thrombin, arachidonic acid, and U46619. Garcinol reduced integrin αIIbß3 inside-out signaling, including ATP release; cytosolic Ca2+ mobilization; P-selectin expression; and Syk, PLCγ2/PKC, PI3K/Akt/GSK3ß, MAPKs, and NF-κB activation stimulated by collagen. Garcinol directly inhibited integrin αIIbß3 activation by interfering with FITC-PAC-1 and FITC-triflavin by collagen. Additionally, garcinol affected integrin αIIbß3-mediated outside-in signaling, such as decreasing platelet adhesion and the single-platelet spreading area; suppressing integrin ß3, Src, FAK, and Syk phosphorylation on immobilized fibrinogen; and inhibiting thrombin-stimulated fibrin clot retraction. Garcinol substantially reduced mortality caused by pulmonary thromboembolism and prolonged the occlusion time of thrombotic platelet plug formation without extending bleeding time in mice. SIGNIFICANCE: This study identified that garcinol, a novel antithrombotic agent, acts as a naturally occurring integrin αIIbß3 inhibitor.


Subject(s)
Pulmonary Embolism , Thrombosis , Humans , Mice , Animals , Blood Platelets/metabolism , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Fluorescein-5-isothiocyanate/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Thrombin/metabolism , Platelet Activation , Platelet Aggregation , Thrombosis/metabolism , Phosphorylation , Collagen/metabolism , Fibrinogen/metabolism , Pulmonary Embolism/metabolism
16.
BMC Geriatr ; 23(1): 256, 2023 04 28.
Article in English | MEDLINE | ID: mdl-37118686

ABSTRACT

BACKGROUND: Older adults with chronic diseases require long-term medication. However, due to lack of drug knowledge and hypomnesia, older adults with chronic diseases are prone to adverse drug events and increased medical costs. This study aimed to explore the status and influencing factors of home-based medication safety among community-dwelling older adults with chronic diseases in China to provide a basis for follow-up to conduct targeted health education. METHODS: Overall, 427 community-dwelling older adults with chronic diseases participated in this study. The Knowledge, Attitude, and Behaviour of Medication Safety among Older Adults with Chronic Diseases Questionnaire was used to assess their home-based medication safety. Multivariate linear regression was used to identify the factors influencing knowledge, attitude, and behaviour regarding medication safety. RESULTS: The average score of home-based medication safety among older adults with chronic diseases was 68.26 ± 8.96, indicating that they had a moderate grasp of medication safety. The scoring rate of each subscale was ranked from high to low as follows: behaviour (84.51%), knowledge (63.33%), and attitude (47.39%). Stepwise linear regression analysis showed that medication safety knowledge, attitudes, and behaviours were significantly associated with higher monthly income, adverse drug events, and taking medicine several times a day (p < 0.05). Additional influencing factors included having fewer chronic diseases, being female, higher educational attainment, taking medicines multiple kinds a day, better self-care ability, and non-hospitalisation for chronic illnesses (p < 0.05). CONCLUSION: Medical staff and community workers should pay attention to the drug safety of older adults with different characteristics and mobilise their enthusiasm for participation to improve their medication self-management ability. TRIAL REGISTRATION: Chinese Clinical Trial Register: ChiCTR2200060987 ; reg. date: 15/06/2022.


Subject(s)
Drug-Related Side Effects and Adverse Reactions , Independent Living , Humans , Female , Aged , Male , Cross-Sectional Studies , Health Knowledge, Attitudes, Practice , Chronic Disease , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/prevention & control
17.
Huan Jing Ke Xue ; 44(3): 1452-1464, 2023 Mar 08.
Article in Chinese | MEDLINE | ID: mdl-36922206

ABSTRACT

Seasonal algal blooms produce a high risk for water supply safety. To explore the mechanism of seasonal algal blooms in northern eutrophic stratified reservoirs, the combination of taxonomic and functional classifications, local weighted regression (LOWESS), and Boundary line analysis (BLA) were employed to obtain the succession features and environmental thresholds of seasonal (e.g., spring and summer) algal blooms, based on the long-term and high-frequency monitoring from 2017 to 2020 in Lijiahe Reservoir. The results showed that:① the succession and response mechanisms of algal blooms were different in spring and summer. In detail, Chlorophyta, Bacillariophyta, and Dinoflagellates (e.g., low-temperature, small, high surface-to-volume genera) dominated in spring, whereas Chlorophyta, Bacillariophyta, and Cyanobacteria (e.g., high-temperature, large or colonial, low surface-to-volume genera) dominated in summer. The differences in physiological and morphological characteristics of algae were the internal cause triggering seasonal algal blooms. ② The main drivers of algal blooms were different in spring and summer. Spring blooms were controlled by water temperature (WT), mixing depth (i.e., Zmix), and light availability (i.e., Zeu/Zmix), whereas summer blooms were jointly influenced by WT, Zmix, Zeu/Zmix, and total phosphorus (TP). The differences in the changes of the major drivers were external causes triggering seasonal algal blooms. ③ The water environment thresholds starting seasonal algal blooms were different in spring and summer. The thresholds of WT, Zmix, and Zeu/Zmix in spring were>9.4℃, <10.9 m, and>0.24, respectively, whereas the thresholds of WT, Zmix, Zeu/Zmix, and TP in summer were>16.0℃, <11.6 m, >0.16, and>0.011 mg·L-1, respectively. Based on the research on the mechanism of seasonal algal blooms and related thresholds, this work will provide a reference for the control of subsequent algal blooms.


Subject(s)
Eutrophication , Fresh Water , Seasons , Temperature , Sunlight , Phosphorus/analysis , China , Fresh Water/chemistry , Environmental Monitoring
18.
Antioxidants (Basel) ; 12(2)2023 Jan 17.
Article in English | MEDLINE | ID: mdl-36829776

ABSTRACT

The incidence of traumatic brain injury (TBI) increases dramatically with advanced age and accumulating evidence indicates that age is one of the important predictors of an unfavorable prognosis after brain trauma. Unfortunately, thus far, evidence-based effective therapeutics for geriatric TBI is limited. By using middle-aged animals, we first confirm that there is an age-related change in TBI susceptibility manifested by increased inflammatory events, neuronal death and impaired functional outcomes in motor and cognitive behaviors. Since thyroid hormones function as endogenous regulators of oxidative stress, we postulate that age-related thyroid dysfunction could be a crucial pathology in the increased TBI severity. By surgically removing the thyroid glands, which recapitulates the age-related increase in TBI-susceptible phenotypes, we provide direct evidence showing that endogenous thyroid hormone-dependent compensatory regulation of antioxidant events modulates individual TBI susceptibility, which is abolished in aged or thyroidectomized individuals. The antioxidant capacity of melatonin is well-known, and we found acute melatonin treatment but not liothyronine (T3) supplementation improved the TBI-susceptible phenotypes of oxidative stress, excitotoxic neuronal loss and promotes functional recovery in the aged individuals with thyroid dysfunction. Our study suggests that monitoring thyroid function and acute administration of melatonin could be feasible therapeutics in the management of geriatric-TBI in clinic.

19.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-988731

ABSTRACT

ObjectiveThe aim of this study is to investigate change of platelet count in red blood cell (RBC) units at different storage periods and explore the efficiency of platelet removal by leukocyte filter. MethodsA total of 58 RBC units were divided into four groups according to different storage periods: 1 week Group (16), 2 weeks Group (16), 3 weeks Group (14) and 4 weeks Group (12). RBC units in the four groups were filtered through leukocyte filter. The RBC samples before and after filtration were obtained. The platelet count was detected by automatic blood cell counter and the efficiency of platelet removal was calculated. RBC samples before filtration were made into blood cell smears. The blood cell smears were dyed with Wright-Giemsa stain, and the morphology of platelets was observed through a microscope. ResultsThe platelet count in RBC units stored for 1, 2, 3 and 4 weeks was (286.5±62.34)×109/L, (238.0±57.37)×109/L, (193.6±56.21)×109/L and (167.8±24.76)×109/L, respectively. Platelet count in blood stored for 3 weeks (P<0.01) and 4 weeks (P <0.000 1) were significantly lower than those stored for 1 weeks. When observed in the blood smears of RBC units at different storage periods, platelets with normal morphology were distributed in clump and scattered style. The platelet removal rates of the four groups were (80.13±9.06) %, (76.41±10.13) %, (77.78±9.30) % and (70.63±9.39) %, respectively, with no significant difference (P >0.05). ConclusionsPlatelet count in RBC units decreases gradually as the storage period increases, but most platelets still remain in RBC units of late storage periods (3 weeks and 4 weeks). The leukocyte filter is able to remove most of the platelets, and the removal efficiency is similar among the groups.

20.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-998169

ABSTRACT

ObjectiveTo investigate the effect and underlying molecular mechanism of astragaloside-Ⅳ (AS-Ⅳ) on autophagy and apoptosis of nasopharyngeal carcinoma cells. MethodIn experiments in vitro, the effect of AS-Ⅳ on the autophagy of nasopharyngeal carcinoma cells was observed by monodansylcadaverine (MDC) staining and transmission electron microscopy (TEM). In experiments in vivo, immunofluorescence (IF) and Western blot were used to detect the changes in autophagy and apoptosis and the expression of key proteins in the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway after the establishment of a xenograft tumor model in nude mice. ResultAfter 5-8F cells were treated with AS-Ⅳ of different doses (5, 10, 20 μmol·L-1), the fluorescence intensity of autophagy in AS-Ⅳ groups significantly increased as compared with that in the blank group. The fluorescence expression of autophagy in AS-Ⅳ groups was the strongest after intervention for 24 hours, and the fluorescence expression in the 10 μmol·L-1 AS-Ⅳ group was the most obvious. The autophagy activator rapamycin (RAPA) induced more autophagosomes in 5-8F cells under the transmission electron microscope, and 3-methyladenine (3-MA), an autophagy inhibitor, did not induce autophagosome formation in 5-8F cells under the transmission electron microscope as compared with the results in the blank group. In the 10 μmol·L-1 AS-Ⅳ group, the intracellular structure and cell membrane were intact and clear, and autophagosome formation was observed. Compared with the blank group, the AS-Ⅳ groups showed inhibited tumor volume (P<0.05, P<0.01), potentiated fluorescence signals of microtubule-associated protein l light chain 3 type Ⅱ/microtubule-associated protein l light chain 3 type Ⅰ (LC3 Ⅱ/Ⅰ) and cleaved Caspase-3 (P<0.05, P<0.01), increased expression levels of the mammalian homolog of yeast ATG6 (Beclin-1), LC3 Ⅱ/Ⅰ, cleaved Caspase-3, and cleaved PARP (P<0.05, P<0.01), down-regulated expression of ubiquitin-binding protein (p62) (P<0.05, P<0.01), and reduced protein expression levels of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), and phosphorylated mTOR (p-mTOR) (P<0.05, P<0.01). ConclusionAS-Ⅳ can induce autophagy and apoptosis of nasopharyngeal carcinoma cells, and the mechanism is presumably attributed to the activation of the PI3K/Akt/mTOR signaling pathway.

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