ABSTRACT
OBJECTIVE: Patients who carry NUP98::NSD1 or FLT3/ITD mutations are reported to have poor prognosis. Previous studies have confidently reported that the poor outcome in younger AML patients is owning to dual NUP98::NSD1 and FLT3/ITD positivity, with a high overlap for those two genetic lesions. In this study, we assessed the prognostic value of the presence of both NUP98::NSD1 and FLT3/ITD in pediatric AML patients. METHODS: We screened a large cohort of 885 pediatric cases from the COG-National Cancer Institute (NCI) TARGET AML cohort and found 57 AML patients with NUP98 rearrangements. RESULTS: The frequency of NUP98 gene fusion was 10.8% in 529 patients. NUP98::NSD1 fusion was the most common NUP98 rearrangement, with a frequency of 59.6%(34 of 57). NUP98::NSD1 -positive patients who carried FLT3/ITD mutations had a decreased CR1 or CR2 rate than those patients carried FLT3/ITD mutation alone (P = 0.0001). Moreover, patients harboring both NUP98::NSD1 fusion and FLT3/ITD mutation exhibited inferior event-free survival (EFS, P < 0.001) and overall survival (OS, P = 0.004) than patients who were dual negative for these two genetic lesions. The presence of only NUP98::NSD1 fusion had no significant impact on EFS or OS. We also found that cases with high FLT3/ITD AR levels ( > = 0.5) with or without NUP98::NSD1 had inferior prognosis. Multivariate analysis demonstrated that the presence of both NUP98::NSD1 and FLT3/ITD was an independent prognostic factors for EFS (hazard ratio: 3.2, P = 0.001) in patients with pediatric AML. However, there was no obvious correlation with OS (hazard ratio: 1.3, P = 0.618). Stem cell transplantation did not improve the survival rate of cases with NUP98 fusion or NUP98::NSD1 AML in terms of EFS or OS. CONCLUSION: Presence of both NUP98::NSD1 and FLT3/ITD was found to be an independent factor for dismal prognosis in pediatric AML patients. Notably, lack of FLT3/ITD mutations in NUP98::NSD1 -positive patients did not retain its prognostic value.
Subject(s)
Leukemia, Myeloid, Acute , Mutation , Nuclear Pore Complex Proteins , fms-Like Tyrosine Kinase 3 , Humans , fms-Like Tyrosine Kinase 3/genetics , Child , Female , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Male , Prognosis , Child, Preschool , Nuclear Pore Complex Proteins/genetics , Adolescent , Infant , Oncogene Proteins, Fusion/genetics , Histone-Lysine N-Methyltransferase/genetics , Nuclear Proteins/genetics , Intracellular Signaling Peptides and Proteins/geneticsABSTRACT
Network Meta-analysis and multi-criteria decision analysis(MCDA) model were performed to evaluate the benefit-risk of Compound Cantharis Capsules, Huisheng Oral Solution, and Jinlong Capsules in the adjuvant treatment of primary liver cancer(PLC). The randomized controlled trial(RCT) of Compound Cantharis Capsules, Huisheng Oral Solution, and Jinlong Capsules in treating PLC were retrieved from CNKI, Wanfang, VIP, Web of Science, PubMed, and Cochrane Library. R 4.2 was employed to conduct a network Meta-analysis, on the basis of which the effect values of the three medicines were obtained by indirect comparison. MCDA was performed to establish the value tree based on the benefit-risk indexes. Hiview 3.2 was used to calculate the benefit values, risk values, and benefit-risk values of the three medicines in treating PLC, and a sensitivity analysis was carried out to evaluate the robustness of the results. Oracle Crystal Ball 11.1 was employed to optimize the evaluation results by Monte Carlo simulation. A total of 39 RCTs were included. The results showed that Compound Cantharis Capsules, Huisheng Oral Solution, and Jinlong Capsules combined with transcatheter arterial chemoembolization(TACE) had the benefit values of 45, 51 and 45, the risk values of 59, 47, and 41, and the benefit-risk values of 52, 49, and 43, respectively. The benefit-risk differences and [95%CI] of Compound Cantharis Capsules vs Huisheng Oral Solution, Compound Cantharis Capsules vs Jinlong Capsules, and Huisheng Oral Solution vs Jinlong Capsules were 3.00[-13.09, 21.82], 9.00[-4.39, 24.62], and 6.00[-8.84, 20.28], respectively. Based on the results of MCDA, Huisheng Oral Solution, Jinlong Capsules, and Compound Cantharis Capsules combined with TACE had the greatest benefit, the greatest risk, and the best overall benefit, respectively. Considering the efficacy and safety, the priority of the three oral Chinese patent medicines combined with TACE for treating PLC followed the trend of Compound Cantharis Capsules, Huisheng Oral Solution, and Jinlong Capsules.
Subject(s)
Drugs, Chinese Herbal , Liver Neoplasms , Humans , Drugs, Chinese Herbal/administration & dosage , Liver Neoplasms/drug therapy , Risk Assessment , Network Meta-Analysis , Administration, Oral , Decision Support Techniques , Randomized Controlled Trials as Topic , Nonprescription DrugsABSTRACT
Seven polyketides, including an undescribed depsidone (1) and six previously reported 3,6,8-trihydroxy-1-methylxanthone (2), 7-hydroxy-2-(2-hydroxypropyl)-5-methylchromone (3), methyl3-chloro-6-hydroxy-2-(4-hy-droxy-2-methoxy-6-methylphenoxy)-4- methoxybenzoate (4), xylarianin A (5), 4,5-dihydroxy-6-(6'-methylsalicyloxy)-2-hydro-xymethyl-2-cyclohexen-1-one (6) and alternariol (7), have been isolated from cultures of the mangrove-derived fungus Penicillium robsamsonii HNNU0006. The structure of compound 1 was elucidated by extensive spectroscopic analysis and X-ray crystallography. Furthermore, all the compounds were evaluated their cytotoxic activities, and compounds 1 and 7 showed weak cytotoxicity against two cell lines Vero and A549 with IC50 values ranging from 95.6 and 296.5 µM, relative to the positive control Etoposide phosphate with IC50 values of 24.5 and 18.7 µM, respectively.
ABSTRACT
BACKGROUND: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare and life-threatening autoimmune disease of the central nervous system. So far, only ten cases of PERM have been reported in children worldwide, including the one in this study. CASE PRESENTATION: We report a case of an 11-year-old boy with PERM with an initial presentation of abdominal pain, skin itching, dysuria, urinary retention, truncal and limb rigidity, spasms of the trunk and limbs during sleep, deep and peripheral sensory disturbances, and dysphagia. A tissue-based assay using peripheral blood was positive, demonstrated by fluorescent staining of mouse cerebellar sections. He showed gradual and persistent clinical improvement after immunotherapy with intravenous immunoglobulin, steroids, plasmapheresis and rituximab. CONCLUSIONS: We summarized the diagnosis and treatment of a patient with PERM and performed a literature review of pediatric PERM to raise awareness among pediatric neurologists. A better comprehension of this disease is required to improve its early diagnosis, treatment, and prognosis.
Subject(s)
Encephalomyelitis , Muscle Rigidity , Myoclonus , Humans , Male , Child , Muscle Rigidity/etiology , Encephalomyelitis/diagnosis , Encephalomyelitis/complications , Myoclonus/etiology , Myoclonus/diagnosisABSTRACT
In this prospective, multicenter, Phase 2 clinical trial (NCT02987244), patients with peripheral T-cell lymphomas (PTCLs) who had responded to first-line chemotherapy with cyclophosphamide, doxorubicin or epirubicin, vincristine or vindesine, etoposide, and prednisone (Chi-CHOEP) were treated by autologous stem cell transplantation (ASCT) or with chidamide maintenance or observation. A total of 85 patients received one of the following interventions: ASCT (n = 15), chidamide maintenance (n = 44), and observation (n = 26). estimated 3 PFS and OS rates were 85.6%, 80.8%, and 49.4% (P = 0.001). The two-year OS rates were 85.6%, 80.8%, and 69.0% (P = 0.075).The ASCT and chidamide maintenance groups had significantly better progression-free survival (PFS) than the observation group (P = 0.001, and P = 0.01, respectively). The overall survival (OS) differed significantly between the chidamide maintenance group and the observation group ( P = 0.041). The multivariate and propensity score matching analyses for PFS revealed better outcomes in the subjects in the chidamide maintenance than observation groups (P = 0.02). The ASCT and chidamide maintenance groups had significant survival advantages over the observation group. In the post-remission stage of the untreated PTCL patients, single-agent chidamide maintenance demonstrated superior PFS and better OS than observation. Our findings highlight the potential benefit of chidamide in this patient subset, warranting further investigation through larger prospective trials. Clinical trial registration: clinicaltrial.gov, NCT02987244. Registered 8 December 2016, http://www.clinicaltrials.gov/ct2/show/NCT02987244 .
Subject(s)
Aminopyridines , Antineoplastic Combined Chemotherapy Protocols , Benzamides , Hematopoietic Stem Cell Transplantation , Lymphoma, T-Cell, Peripheral , Humans , Lymphoma, T-Cell, Peripheral/therapy , Lymphoma, T-Cell, Peripheral/mortality , Lymphoma, T-Cell, Peripheral/drug therapy , Male , Female , Adult , Middle Aged , Aminopyridines/therapeutic use , Benzamides/therapeutic use , Prospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , China/epidemiology , Transplantation, Autologous , Aged , Survival Rate , Young Adult , Maintenance Chemotherapy , Autografts , Remission Induction , AdolescentABSTRACT
OBJECTIVES: To evaluate the effect of external diaphragmatic pacing (EDP) combined with inspiratory muscle training on respiratory function in post-stroke patients. METHODS: Patients with stroke were enrolled from the First Affiliated Hospital of Soochow University in China between 2021 and 2022. The patients were randomized into an EDP treatment group (control group) or an EDP treatment plus inspiratory muscle training group (experimental group). Each therapy was administered once a day for 6 days per week. The peak inspiratory flow (PIF), maximal inspiratory pressure (MIP), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC% ratio, and diaphragm thickness and mobility were measured and compared between the two groups after 4 weeks. RESULTS: After 4 weeks of intervention, respiratory muscle function indicators including PIF (95% CI: 0.21-1.28, p = 0.008) and MIP (95% CI: 6.92-25.44, p = 0.001) significantly improved in the experimental group. Diaphragmatic thickness also significantly increased in the experimental group (p < 0.05), while diaphragmatic excursion showed no significant difference between the two groups. Additionally, FVC (95% CI: 0.14-1.14, p = 0.013) and FEV1 (95% CI: 0.20-1.06, p = 0.005) demonstrated a significant increase in the experimental group, whereas FEV1/FVC% (95% CI: -0.84 to 9.36, p = 0.099) exhibited no significant group difference. CONCLUSION: EDP combined with inspiratory muscle training in individuals with stroke provides greater benefits than EDP alone in terms of respiratory function recovery, except for the parameters of diaphragmatic excursion and FEV1/FVC%.
Subject(s)
Breathing Exercises , Diaphragm , Stroke , Humans , Male , Female , Middle Aged , Diaphragm/physiopathology , Breathing Exercises/methods , Stroke/therapy , Stroke/physiopathology , Aged , Stroke Rehabilitation/methods , Respiratory Muscles/physiopathology , Respiratory Function TestsABSTRACT
Sepsis is a systemic inflammatory response syndrome caused by infection, with high morbidity and mortality. Sepsis-induced liver injury(SILI) is one of the manifestations of sepsis-induced multiple organ syndrome. At present, there is no recommended pharmacological intervention for the treatment of SILI. traditional Chinese medicine(TCM), based on the holism and dialectical treatment concept, shows the therapeutic characteristics of multi-target and multi-pathway and can comprehensively prevent and treat SILI by interfering with inflammatory factors, inflammatory signaling pathways, and anti-oxidative stress and inhibiting apoptosis. This article reviewed the experimental studies on the treatment of SILI with TCM to clarify its pathogenic mechanism and therapeutic characteristics, so as to provide more ideas and directions for the development or preparation of new drugs.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Drugs, Chinese Herbal , Sepsis , Humans , Medicine, Chinese Traditional , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Sepsis/complications , Sepsis/drug therapy , Apoptosis , Signal Transduction , Drugs, Chinese Herbal/therapeutic use , Drugs, Chinese Herbal/pharmacologyABSTRACT
Soil (or plant) water deficit accelerates plant reproduction. However, the underpinning molecular mechanisms remain unknown. By modulating cell division/number, ABSCISIC ACID-INSENSITIVE 5 (ABI5), a key bZIP (basic (region) leucine zippers) transcription factor, regulates both seed development and abiotic stress responses. The KIP-RELATED PROTEIN (KRP) cyclin-dependent kinases (CDKs) play an essential role in controlling cell division, and SHOOT MERISTEMLESS (STM) plays a key role in the specification of flower meristem identity. Here, our findings show that abscisic acid (ABA) signaling and/or metabolism in adjust reproductive outputs (such as rosette leaf number and open flower number) under water-deficient conditions in Arabidopsis (Arabidopsis thaliana) plants. Reproductive outputs increased under water-sufficient conditions but decreased under water-deficient conditions in the ABA signaling/metabolism mutants abscisic acid2-1 (aba2-1), aba2-11, abscisic acid insensitive3-1 (abi3-1), abi4-1, abi5-7, and abi5-8. Further, under water-deficient conditions, ABA induced-ABI5 directly bound to the promoter of KRP1, which encodes a CDK that plays an essential role in controlling cell division, and this binding subsequently activated KRP1 expression. In turn, KRP1 physically interacted with STM, which functions in the specification of flower meristem identity, promoting STM degradation. We further demonstrate that reproductive outputs are adjusted by the ABI5-KRP1-STM molecular module under water-deficient conditions. Together, our findings reveal the molecular mechanism by which ABA signaling and/or metabolism regulate reproductive development under water-deficient conditions. These findings provide insights that may help guide crop yield improvement under water deficiency.
Subject(s)
Abscisic Acid , Arabidopsis Proteins , Arabidopsis , Flowers , Gene Expression Regulation, Plant , Arabidopsis/genetics , Arabidopsis/growth & development , Arabidopsis/metabolism , Arabidopsis/physiology , Arabidopsis Proteins/metabolism , Arabidopsis Proteins/genetics , Abscisic Acid/metabolism , Flowers/genetics , Flowers/growth & development , Flowers/physiology , Basic-Leucine Zipper Transcription Factors/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , Signal Transduction , Meristem/genetics , Meristem/growth & development , Meristem/metabolism , Reproduction , Mutation/genetics , Cyclin-Dependent Kinases/metabolism , Cyclin-Dependent Kinases/genetics , Homeodomain ProteinsABSTRACT
Nine metabolites, including three undescribed alkaloids pyripyropenes VW (1-2), penicioxa A (4), two previously reported pyripyropene A (3), oxaline (5), three grisephenone-type xanthone derivatives (6-8), and a diphenyl ether derivative 4-chloro-7,4'-dihydroxy-5,2'-dimethoxy-2-methylformate-6'-methybenzophone (9), were isolated from cultures of the mangrove-derived fungus Penicillium robsamsonii HNNU0006. Their structures were determined by spectroscopic analysis, ECD calculations, together with DP4+ probability analysis. Furthermore, all the isolated compounds were tested for cytotoxicity and anti-phytopathogenic fungal activities. Compounds 6-8 showed moderate cytotoxicity against tumor cell lines A549, with IC50 values ranging from 5.68 ± 0.21 to 9.71 ± 0.34 µg/mL, respectively.
Subject(s)
Alkaloids , Penicillium , Penicillium/chemistry , Molecular Structure , Humans , Alkaloids/isolation & purification , Alkaloids/pharmacology , Alkaloids/chemistry , A549 Cells , Antineoplastic Agents/pharmacology , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/chemistry , China , Rhizophoraceae/microbiologyABSTRACT
Background: The oncogene IGF2 mRNA binding protein 3 (IGF2BP3) could function as an m6A reader in stabilizing many tumor-associated genes' mRNAs. However, the relevant oncogenic mechanism by which IGF2BP3 promotes ovarian cancer growth is largely unknown. Methods: The IGF2BP3 expression in ovarian cancer was identified by retrieving the datasets from The Cancer Genome Atlas (TCGA). GEO datasets evaluated the relevant signaling pathways in IGF2BP3 knockdown in ovarian cancer cells. IGF2BP3 positive correlation gene in TCGA was calculated. MTS proliferation assay was identified in IGF2BP3 knockdown and rescued by PLAG1 like zinc finger 2 (PLAGL2) overexpression in ES-2 and SKOV3 cells. Bioinformatic analysis and RIP-qPCR were predicted and identified the IGF2BP3 binding site and PLAGL2 mRNA stability. The animal experiment identified IGF2BP3 proliferation inhibition. Results: IGF2BP3 was upregulated in ovarian cancer tissue and cells. The depletion of IGF2BP3 in ovarian cancer cells leads to an enhancement of the pathway involved in cellular proliferation and mRNA stability. IGF2BP3 positive correlation suppressed pro-proliferation gene PLAGL2. IGF2BP3 knockdown suppressed ovarian cancer cell proliferation and was rescued by PLAGL2 overexpression. Luciferase reporter assay confirmed that IGF2BP3 could bind to 3'-UTR of PLAGL2 to maintain the mRNA stability. Further, in in vivo experiments, IGF2BP3 knockdown suppressed ovarian cancer cell proliferation via inhibiting PLAGL2 expression. Conclusion: All of these indicate that PLAGL2 mediates the main function of IGF2BP3 knockdown on ovarian cancer proliferation inhibition through mRNA stability regulation.
ABSTRACT
Single-particle inductively coupled plasma mass spectrometry (spICP-MS) has been used to characterize metallic nanoparticles (NPs) assuming that all NPs are spherical and composed of pure element. However, environmental NPs generally do not meet these criteria, suggesting that spICP-MS may underestimate their true sizes. This study employed a system hyphenating the atomizer (ATM), differential mobility analyzer (DMA), and spICP-MS to characterize metallic NPs in tap water. Its performance was validated by using reference Au nanoparticles (AuNPs) and Ag-shelled AuNPs. The hyphenated system can determine the actual size and metal composition of both NPs with additional heating after ATM, while stand-alone spICP-MS misidentified the Ag-shelled AuNPs as smaller individual AgNPs and AuNPs. Dissolved metal ions could introduce artifact NPs after heating but could be eliminated by centrifugation. The hyphenated system was applied to characterize Fe-containing and Pb-containing NPs resulting from the corrosion of plumbing materials in tap water. The mode sizes of Fe-containing and Pb-containing NPs were determined to be 110 and 100 nm and the particle number concentrations were determined to be 4.99 × 107 and 1.40 × 106 #/mL, respectively. Cautions should be paid to potential changes in particle size induced by heating for metallic NPs with a low melting point or a high organic content.
Subject(s)
Metal Nanoparticles , Metal Nanoparticles/chemistry , Gold/chemistry , Lead , Sanitary Engineering , Corrosion , Nebulizers and Vaporizers , Particle Size , WaterABSTRACT
Intranasal drug delivery is as a noninvasive and efficient approach extensively utilized for treating the local, central nervous system, and systemic diseases. Despite numerous reviews delving into the application of intranasal drug delivery across biomedical fields, a comprehensive analysis of advancements and future perspectives remains elusive. This review elucidates the research progress of intranasal drug delivery through a scientometric analysis. It scrutinizes several challenges to bolster research in this domain, encompassing a thorough exploration of entry and elimination mechanisms specific to intranasal delivery, the identification of drugs compatible with the nasal cavity, the selection of dosage forms to surmount limited drug-loading capacity and poor solubility, and the identification of diseases amenable to the intranasal delivery strategy. Overall, this review furnishes a perspective aimed at galvanizing future research and development concerning intranasal drug delivery.
Subject(s)
Drug Delivery Systems , Nasal Cavity , Administration, Intranasal , Pharmaceutical PreparationsABSTRACT
BACKGROUND: Glycine dehydrogenase (GLDC) plays an important role in the initiation and proliferation of several human cancers. In this study, we aimed to detect the methylation status of GLDC promoter and its diagnostic value for hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC). METHODS: We enrolled 197 patients, 111 with HBV-HCC, 51 with chronic hepatitis B (CHB), and 35 healthy controls (HCs). The methylation status of GLDC promoter in peripheral mononuclear cells (PBMCs) was identified by methylation specific polymerase chain reaction (MSP). The mRNA expression was examined using real-time quantitative polymerase chain reaction (qPCR). RESULTS: The methylation frequency of the GLDC promoter was significantly lower in HBV-HCC patients (27.0%) compared to that in CHB patients (68.6%) and HCs (74.3%) (P < 0.001). The methylated group had lower alanine aminotransferase level (P = 0.035) and lower rates of tumor node metastasis (TNM) III/IV (P = 0.043) and T3/T4 (P = 0.026). TNM stage was identified to be an independent factor for GLDC promoter methylation. GLDC mRNA levels in CHB patients and HCs were significantly lower than those in HBV-HCC patients (P = 0.022 and P < 0.001, respectively). GLDC mRNA levels were significantly higher in HBV-HCC patients with unmethylated GLDC promoters than those with methylated GLDC promoters (P = 0.003). The diagnostic accuracy of alpha-fetoprotein (AFP) combined with GLDC promoter methylation for HBV-HCC was improved compared with that of AFP alone (AUC: 0.782 vs. 0.630, P < 0.001). In addition, GLDC promoter methylation was an independent predictor for overall survival of HBV-HCC patients (P = 0.038). CONCLUSIONS: The methylation frequency of GLDC promoter was lower in PBMCs from HBV-HCC patients than that from patients with CHB and HCs. The combination of AFP and GLDC promoter hypomethylation significantly improved the diagnostic accuracy of HBV-HCC.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis B, Chronic , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/genetics , Hepatitis B virus/genetics , Hepatitis B virus/metabolism , alpha-Fetoproteins/metabolism , Liver Neoplasms/diagnosis , Liver Neoplasms/genetics , Glycine Dehydrogenase , Leukocytes, Mononuclear/chemistry , Leukocytes, Mononuclear/metabolism , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/diagnosis , Hepatitis B, Chronic/genetics , DNA Methylation , Real-Time Polymerase Chain Reaction , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
Chemical investigation of a culture broth from the marine-derived fungus Pyrrhoderma noxium HNNU0524 yielded two new compounds including a drimane-type sesquiterpenoid named pyrrnoxin A (1) and a benzoic acid derivative, pyrrnoxin B (5), together with three related known analogues (2-4). The chemical structures of 1 and 5 were determined by detailed analysis of spectroscopic data, single-crystal X-ray crystallography, quantum mechanics-based DP4+ and ECD calculations. Compounds 2 and 3 moderately inhibited NO production of lipopolysaccharide-induced microglia cells BV2 with IC50 values of 26.6 and 60.5 µM, respectively.
Subject(s)
Basidiomycota , Polycyclic Sesquiterpenes , Sesquiterpenes , Molecular Structure , Sesquiterpenes/chemistry , Anti-Inflammatory Agents/pharmacologyABSTRACT
BACKGROUND: The prevention and treatment of ischaemic stroke is a worldwide challenge, and effective clinical treatment strategies are lacking. Studies have demonstrated the efficacy of Verbena officinalis in managing cerebrovascular disorders. However, the neuroprotective bioactive components and mechanisms remain unclear. PURPOSE: To investigate the pharmacological combinatorial components and mechanism underlying the anti-ischemic stroke effect of the ethanol extract of Verbena officinalis (VO Ex). STUDY DESIGN AND METHODS: The components of VO Ex were identified by HPLC. A middle cerebral artery occlusion (MCAO) induced brain injury model was used to assess the therapeutic effect of VO Ex. The activity of the chemical components of VO Ex was evaluated using a primary astrocyte injury model induced by oxygen-glucose deprivation/reperfusion (OGD/R). RNA sequencing was used to reveal the potential targets of VO Ex against cerebral ischemia-reperfusion injury (CIRI), and the results were verified by qRT-PCR and western blotting. The key components and target binding ability were predicted by molecular docking. Finally, the mechanism of combinatorial components was verified by experiments. RESULTS: The HPLC results indicated that the main ingredients of VO Ex were hastatoside, verbenalin, acteoside, luteolin, apigenin and hispidulin. In vivo experiments showed that VO Ex improved MCAO-induced acute cerebral ischemic injury. Transcriptomic data and biological experiments suggested that VO Ex exerted therapeutic effects through IL17A signalling pathways. The in vitro experiments indicated that verbenalin, acteoside, luteolin, apigenin and hispidulin exhibited neuroprotective activities. The novel formula of VALAH, derived from the aforementioned active ingredients, exhibited superior efficacy compared to each individual component. Molecular docking and mechanistic studies have confirmed that VALAH functions in the treatment of ischaemic stroke by suppressing the activation of the IL17A signalling pathway. CONCLUSION: This work is the first to reveal that VO Ex effectively inhibits the IL17A signaling pathway and mitigates neuroinflammation following ischemic stroke. Moreover, we identified the novel formula VALAH as the bioactive combinatorial components for VO Ex. Further research suggests that the activity of VALAH is associated with IL17A-mediated regulation of neuroinflammation. This finding provides new insights into the efficacious components and mechanisms of traditional Chinese medicine.
Subject(s)
Brain Ischemia , Glucosides , Iridoid Glycosides , Ischemic Stroke , Polyphenols , Reperfusion Injury , Stroke , Verbena , Humans , Infarction, Middle Cerebral Artery/drug therapy , Brain Ischemia/drug therapy , Stroke/drug therapy , Stroke/complications , Neuroinflammatory Diseases , Apigenin , Luteolin/therapeutic use , Molecular Docking Simulation , Ischemic Stroke/drug therapy , Reperfusion Injury/drug therapy , Interleukin-17ABSTRACT
Wearable assistant devices play an important role in daily life for people with disabilities. Those who have hearing impairments may face dangers while walking or driving on the road. The major danger is their inability to hear warning sounds from cars or ambulances. Thus, the aim of this study is to develop a wearable assistant device with edge computing, allowing the hearing impaired to recognize the warning sounds from vehicles on the road. An EfficientNet-based, fuzzy rank-based ensemble model was proposed to classify seven audio sounds, and it was embedded in an Arduino Nano 33 BLE Sense development board. The audio files were obtained from the CREMA-D dataset and the Large-Scale Audio dataset of emergency vehicle sirens on the road, with a total number of 8756 files. The seven audio sounds included four vocalizations and three sirens. The audio signal was converted into a spectrogram by using the short-time Fourier transform for feature extraction. When one of the three sirens was detected, the wearable assistant device presented alarms by vibrating and displaying messages on the OLED panel. The performances of the EfficientNet-based, fuzzy rank-based ensemble model in offline computing achieved an accuracy of 97.1%, precision of 97.79%, sensitivity of 96.8%, and specificity of 97.04%. In edge computing, the results comprised an accuracy of 95.2%, precision of 93.2%, sensitivity of 95.3%, and specificity of 95.1%. Thus, the proposed wearable assistant device has the potential benefit of helping the hearing impaired to avoid traffic accidents.
Subject(s)
Hearing Loss , Wearable Electronic Devices , Humans , Ambulances , Hearing , Accidents, TrafficABSTRACT
Under physiological or pathological conditions, transient receptor potential (TRP) channel vanilloid type 1 (TRPV1) and TRP ankyrin 1 (TRPA1) possess the ability to detect a vast array of stimuli and execute diverse functions. Interestingly, increasing works have reported that activation of TRPV1 and TRPA1 could also be beneficial for ameliorating postoperative ileus (POI). Increasing research has revealed that the gastrointestinal (GI) tract is rich in TRPV1/TRPA1, which can be stimulated by capsaicin, allicin and other compounds. This activation stimulates a variety of neurotransmitters, leading to increased intestinal motility and providing protective effects against GI injury. POI is the most common emergent complication following abdominal and pelvic surgery, and is characterized by postoperative bowel dysfunction, pain, and inflammatory responses. It is noteworthy that natural herbs are gradually gaining recognition as a potential therapeutic option for POI due to the lack of effective pharmacological interventions. Therefore, the focus of this paper is on the TRPV1/TRPA1 channel, and an analysis and summary of the processes and mechanism by which natural herbs activate TRPV1/TRPA1 to enhance GI motility and relieve pain are provided, which will lay the foundation for the development of natural herb treatments for this disease.
Subject(s)
Ileus , Plants, Medicinal , Humans , TRPA1 Cation Channel , Ileus/drug therapy , Pain , Plant Extracts , TRPV Cation Channels/physiologyABSTRACT
Choroid plexus insufficiency or glymphatic stasis are often classified as prequels to harmful accretion of toxic proteins in neurodegenerative disease. Cognitive decline and disordered neuronal signaling subsequently become cardinal features of Alzheimer's disease (AD), typically progressing with amyloid-ß and tau protein accumulation. For Parkinson's disease (PD), α-synuclein deposits and dopamine depletion are linked to impaired movement, resting tremor, and rigidity. Importantly, both diagnoses feature hyperinflammation and intrathecal cytokine changes. Thus far, numerous clinical trials have produced nothing effective for AD or PD, yet the anti-inflammatory and regenerative potential of autologous platelet-rich plasma (PRP) remains largely unexamined in this context. Our report explores a proposed Phase I study on intrathecal condensed plasma growth factors processed from thrombin-activated PRP as monotherapy for AD or PD. The concept gains support from related work where cytokines of platelet origin successfully lowered inflammation, corrected background fibrosis, deactivated abnormal cells, and recovered local tissue function-all desirable outcomes in AD and PD. While PRP-mediated effects on membrane potentials, cellular signaling, electrolyte balance, and water clearance are less well characterized, experimental data suggest these pathways could likewise influence glymphatic drainage to ameliorate proteinopathies. As a well-tolerated 'orthobiologic' with no hypersensitivity risk, intrathecal PRP and its derivatives bring advantages over synthetic pharmaceuticals. If age-associated neuroinflammation in AD and PD is an upstream event inciting or contributing to neural disruption, then dampening local oxidative stress by a patient's own platelet cytokines (successful in other contexts) could offer therapeutic relevance to these neurodegenerative conditions as well.
Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Parkinson Disease , Humans , Alzheimer Disease/therapy , Anti-Inflammatory Agents/therapeutic use , Chronic Disease , Cytokines/metabolism , Neurodegenerative Diseases/therapy , Parkinson Disease/drug therapy , Thrombin/therapeutic use , Clinical Trials, Phase I as TopicABSTRACT
Exposure of dark-grown etiolated seedlings to light triggers the transition from skotomorphogenesis/etiolation to photomorphogenesis/de-etiolation. In the life cycle of plants, de-etiolation is essential for seedling development and plant survival. The mobilization of soluble sugars (glucose [Glc], sucrose, and fructose) derived from stored carbohydrates and lipids to target organs, including cotyledons, hypocotyls, and radicles, underpins de-etiolation. Therefore, dynamic carbohydrate biochemistry is a key feature of this phase transition. However, the molecular mechanisms coordinating carbohydrate status with the cellular machinery orchestrating de-etiolation remain largely opaque. Here, we show that the Glc sensor HEXOKINASE 1 (HXK1) interacts with GROWTH REGULATOR FACTOR5 (GRF5), a transcriptional activator and key plant growth regulator, in Arabidopsis (Arabidopsis thaliana). Subsequently, GRF5 directly binds to the promoter of phytochrome A (phyA), encoding a far-red light (FR) sensor/cotyledon greening inhibitor. We demonstrate that the status of Glc within dark-grown etiolated cotyledons determines the de-etiolation of seedlings when exposed to light irradiation by the HXK1-GRF5-phyA molecular module. Thus, following seed germination, accumulating Glc within dark-grown etiolated cotyledons stimulates a HXK1-dependent increase of GRF5 and an associated decrease of phyA, triggering the perception, amplification, and relay of HXK1-dependent Glc signaling, thereby facilitating the de-etiolation of seedlings following light irradiation. Our findings, therefore, establish how cotyledon carbohydrate signaling under subterranean darkness is sensed, amplified, and relayed, determining the phase transition from skotomorphogenesis to photomorphogenesis on exposure to light irradiation.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Seedlings/metabolism , Cotyledon/metabolism , Etiolation , Glucose/metabolism , Light , Arabidopsis/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Phytochrome A/metabolism , Gene Expression Regulation, PlantABSTRACT
Rare but critical bleeding events in primary immune thrombocytopenia (ITP) present life-threatening complications in patients with ITP, which severely affect their prognosis, quality of life, and treatment decisions. Although several studies have investigated the risk factors related to critical bleeding in ITP, large sample size data, consistent definitions, large-scale multicenter findings, and prediction models for critical bleeding events in patients with ITP are unavailable. For the first time, in this study, we applied the newly proposed critical ITP bleeding criteria by the International Society on Thrombosis and Hemostasis for large sample size data and developed the first machine learning (ML)-based online application for predict critical ITP bleeding. In this research, we developed and externally tested an ML-based model for determining the risk of critical bleeding events in patients with ITP using large multicenter data across China. Retrospective data from 8 medical centers across the country were obtained for model development and prospectively tested in 39 medical centers across the country over a year. This system exhibited good predictive capabilities for training, validation, and test datasets. This convenient web-based tool based on a novel algorithm can rapidly identify the bleeding risk profile of patients with ITP and facilitate clinical decision-making and reduce the occurrence of adversities.