Subject(s)
COVID-19 , Self-Injurious Behavior , Humans , Adolescent , Pandemics , Self-Injurious Behavior/epidemiology , Risk Factors , China/epidemiology , Students , Suicidal IdeationABSTRACT
Valproic acid (VPA) is a first-line antiepileptic drug with broad efficacy. Due to significant individual differences in its metabolism, therapeutic drug monitoring is commonly used. However, the recommended therapeutic range (50-100 µg/mL) is inadequate for predicting clinical outcomes. Additionally, the relationship between VPA metabolites and clinical outcomes remains unclear. In this retrospective study, 485 Chinese Southern Han epilepsy patients receiving VPA monotherapy were analyzed after reaching steady-state levels. Plasma concentrations of VPA and its five main metabolites were determined by liquid chromatography-mass spectrometry (LC-MS). We assessed the relevance of the recommended therapeutic VPA range for clinical outcomes and explored the association between VPA/metabolites levels and treatment efficacy/adverse effects. Vitro experiments were conducted to assess 4-ene-VPA hepatotoxicity. The therapeutic range of VPA exhibited no significant correlation with clinical outcomes, and plasma concentrations of VPA failed to serve as predictive indicators for treatment response/adverse effects. Treatment responders had higher 2-PGA concentrations (median, 26.39 ng/mL versus 13.68 ng/mL), with a threshold of 36.5 ng/mL for optimal epilepsy treatment. Patients with abnormal liver function had a higher 4-ene-VPA median concentration (6.41 µg/mL versus 4.83 µg/mL), and the ratio of 4-ene-VPA to VPA better predicted VPA-induced hepatotoxicity (area under the curve, 0.718) than 4-ene-VPA concentration. Vitro experiments revealed that 4-ene-VPA was more hepatotoxic than VPA in HepaRG and L02 cell lines. Total plasma VPA concentration does not serve as a predictor of clinical outcomes. 2-PGA concentrations may be associated with efficacy, whereas the ratio of 4-ene-VPA to VPA may be considered a better biomarker (threshold 10.03%) for VPA-induced hepatotoxicity. SIGNIFICANCE STATEMENT: This was the first and largest observational cohort in China to explore the relationship between patients' parent and metabolites concentrations of VPA and clinical outcomes during the maintenance of VPA monotherapy in epileptic patients. This study provided feasible references of VPA for epilepsy clinical treatment with a larger sample of patients compared with previous studies for a more definitive conclusion based on real-world situations. We found two potential biomarkers in predicting efficacy and liver injury, respectively. This breakthrough has the potential to assist in the rational use of VPA.
Subject(s)
Chemical and Drug Induced Liver Injury , Drug-Related Side Effects and Adverse Reactions , Epilepsy , Humans , Anticonvulsants/adverse effects , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/drug therapy , Drug Monitoring , Epilepsy/drug therapy , Retrospective Studies , Valproic Acid/adverse effectsABSTRACT
Omega-3 polyunsaturated fatty acids (PUFAs) can play important roles in maintaining mental health and resistance to stress, and omega-3 PUFAs supplementation can display beneficial effects on both the prevention and treatment of depressive disorders. Although the underlying mechanisms are still unclear, accumulated evidence indicates that omega-3 PUFAs can exhibit pleiotropic effects on the neural structure and function. Thus, they play fundamental roles in brain activities involved in the mood regulation. Since depressive symptoms have been assumed to be of central origin, this review aims to summarize the recently published studies to identify the potential neurobiological mechanisms underlying the anti-depressant effects of omega-3 PUFAs. These include that of (1) anti-neuroinflammatory; (2) hypothalamus-pituitary-adrenal (HPA) axis; (3) anti-oxidative stress; (4) anti-neurodegeneration; (5) neuroplasticity and synaptic plasticity; and (6) modulation of neurotransmitter systems. Despite many lines of evidence have hinted that these mechanisms may co-exist and work in concert to produce anti-depressive effects, the potentially multiple sites of action of omega-3 PUFAs need to be fully established. We also discussed the limitations of current studies and suggest future directions for preclinical and translational research in this field.
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AIMS: Fibrotic scars composed of a dense extracellular matrix are the major obstacles for axonal regeneration. Previous studies have reported that antitumor drugs promote neurofunctional recovery. METHODS: We investigated the effects of 5-fluorouracil (5-FU), a classical antitumor drug with a high therapeutic index, on fibrotic scar formation, axonal regeneration, and functional recovery after spinal cord injury (SCI). RESULTS: 5-FU administration after hemisection SCI improved hind limb sensorimotor function of the ipsilateral hind paws. 5-FU application also significantly reduced the fibrotic scar formation labeled with aggrecan and fibronectin-positive components, Iba1+ /CD11b+ macrophages/microglia, vimentin, chondroitin sulfate proteoglycan 4 (NG2/CSPG4), and platelet-derived growth factor receptor beta (PDGFRß)+ pericytes. Moreover, 5-FU treatment promoted stromal cells apoptosis and inhibited fibroblast proliferation and migration by abrogating the polarity of these cells and reducing matrix metalloproteinase 9 expression and promoted axonal growth of spinal neurons via the neuron-specific protein doublecortin-like kinase 1 (DCLK1). Therefore, 5-FU administration impedes the formation of fibrotic scars and promotes axonal regeneration to further restore sensorimotor function after SCI.
Subject(s)
Cicatrix , Spinal Cord Injuries , Animals , Cicatrix/pathology , Matrix Metalloproteinase 9/pharmacology , Matrix Metalloproteinase 9/therapeutic use , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Disease Models, Animal , Spinal Cord Injuries/pathology , Microtubules/metabolism , Microtubules/pathology , Spinal Cord/pathology , Nerve Regeneration/physiology , AxonsABSTRACT
To characterize human leukocyte antigen (HLA) loci as risk factors in aromatic antiepileptic drug-induced maculopapular exanthema (AED-MPE). A case-control study was performed to investigate HLA loci involved in AED-MPE in a southern Han Chinese population. Between January 2007 and June 2019, 267 patients with carbamazepine (CBZ), oxcarbazepine (OXC), or lamotrigine (LTG) associated MPE and 387 matched drug-tolerant controls from six centers were enrolled. HLA-A/B/C/DRB1 genotypes were determined using sequence-based typing. Potential risk alleles were validated by meta-analysis using data from different populations and in silico analysis of protein-drug interactions. HLA-DRB1*04:06 was significantly associated with OXC-MPE (p = 0.002, p c = 0.04). HLA-B*38:02 was associated with CBZ-MPE (p = 0.03). When pooled, HLA-A*24:02, HLA-A*30:01, and HLA-B*35:01 additionally revealed significant association with AED-MPE. Logistic regression analysis showed a multiplicative interaction between HLA-A*24:02 and HLA-B*38:02 in CBZ-MPE. Meta-analysis of data from different populations revealed that HLA-24*:02 and HLA-A*30:01 were associated with AED-MPE (p = 0.02 and p = 0.04, respectively). In silico analysis of protein-drug interaction demonstrated that HLA-A*24:02 and HLA-A*30:01 had higher affinities with the three aromatic AEDs than the risk-free HLA-A allele. HLA-DRB1*04:06 showed relatively specific high affinity with S-monohydroxy derivative of OXC. HLA-DRB1*04:06 is a specific risk allele for OXC-induced MPE in the Southern Han Chinese. HLA-A*24:02, possibly HLA-A*30:01, are common risk factors for AED-MPE. The multiplicative risk potential between HLA-A*24:02 and HLA-B*38:02 suggests that patients with two risk alleles are at greater risk than those with one risk allele. Inclusion of these HLA alleles in pre-treatment screening would help estimating the risk of AED-MPE.
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MicroRNAs (miRNAs) have emerged as key mediators of posttranscriptional gene silencing in both pathogenic and pathological aspects of ischemic stroke biology. Therefore, the purpose of present study was to explore the effect of microRNA-199b-3p (miR-199b-3p) on the cerebral microvascular endothelial cells (CMECs) in middle cerebral artery occlusion-reperfusion (MCAO-R) mice by regulating MAPK/ERK/EGR1 axis. Mice were used to establish MCAO-R models and to measure the expression of miR-199b-3p and the MAPK/ERK/EGR1 axis-related genes. CMECs were extracted from the MCAO-R mice. A series of mimic or inhibitor for miR-199b-3p, or U0126 (an inhibitor for the MAPK/ERK/EGR1 axis) were introduced to treat these CMECs. The levels of miR-199b-3p and MAPK/ERK/EGR1 axis-related genes in tissues and cells were detected. The effects miR-199b-3p on the process of CMECs, including cell viability, cell cycle and cell apoptosis were evaluated. miR-199b-3p expressed poorly in the brain tissues after MCAO-R, along with activated MAPK/ERK/EGR1 axis and increased CMECs apoptosis. CMECs transfected with miR-199b-3p mimics and U0126 manifested with increased cell viability, more cells arrested at the S stage, and inhibited apoptosis of CMECs. In conclusion, these key results demonstrated up-regulated miR-199b-3p could protect mice against ischemic stroke by inhibiting the apoptosis of CMECs through blockade of MAPK/ERK/EGR1 axis.
Subject(s)
Apoptosis/genetics , Brain Ischemia/metabolism , Cerebrum/pathology , Early Growth Response Protein 1/metabolism , Endothelial Cells/metabolism , MAP Kinase Signaling System/genetics , MicroRNAs/metabolism , Mitogen-Activated Protein Kinases/metabolism , Stroke/metabolism , Animals , Cell Survival/genetics , Disease Models, Animal , Down-Regulation/genetics , Mice , Mice, Inbred BALB C , MicroRNAs/genetics , S Phase Cell Cycle Checkpoints/genetics , Up-Regulation/geneticsABSTRACT
BACKGROUND: The prognostic roles of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported in head and neck squamous cell carcinoma (HNSCC), but their results remain controversial. METHODS: A total of 25 literatures with 28 cohorts involving 6847 HNSCC patients were included. The hazard ratio (HR) was pooled with 95% confidence interval (CI) using fixed-effects or random-effects models. RESULTS: High pretreatment NLR predicted poor overall survival (OS: HR = 1.68; 95% CI = 1.39-2.03; P < .001), disease-free survival (DFS: HR = 1.76; 95% CI = 1.42-2.17; P < .001), progression-free survival (PFS: HR = 1.53; 95% CI = 1.09-2.14; P = .014), and cancer-specific survival (CSS: HR = 1.45; 95% CI = 1.23-1.71; P < .001) in HNSCC. However, the association between PLR and OS or DFS was not statistically significant. CONCLUSION: The NLR can serve as a potential prognostic biomarker for patients with HNSCC.
Subject(s)
Biomarkers, Tumor/blood , Head and Neck Neoplasms/blood , Head and Neck Neoplasms/mortality , Neoadjuvant Therapy/methods , Squamous Cell Carcinoma of Head and Neck/blood , Squamous Cell Carcinoma of Head and Neck/mortality , Disease-Free Survival , Female , Head and Neck Neoplasms/therapy , Humans , Lymphocyte Count , Male , Neutrophils/pathology , Prognosis , Squamous Cell Carcinoma of Head and Neck/therapy , Survival AnalysisABSTRACT
Valproic acid (VPA), a widely used antiepileptic drug, is characterized by intensive inter-individual variability in concentration. Both efflux and influx transporters are reported to play important roles in the disposition of VPA, however, no comprehensive investigation into the association of the single nucleotide polymorphism (SNP) in ABC/SLC families with VPA concentration are reported. In the present study, we investigated the association of 12 SNPs in ABCC2, ABCC4, ABCG2, MCT1, MCT2, and OATP2B1 in 187 Chinese patients with epilepsy on VPA monotherapy with the trough concentrations of VPA. The data showed that VPA concentration in patients with ABCC2 rs2273697 AA genotype was significantly higher than that in those with GA+GG genotypes (p=0.000). The findings of the present study suggest that ABCC2 polymorphisms influence VPA concentrations in patients with epilepsy on VPA monotherapy, which may affect the treatment outcomes.
Subject(s)
Anticonvulsants/pharmacokinetics , Epilepsy/genetics , Multidrug Resistance-Associated Proteins/genetics , Valproic Acid/pharmacokinetics , Adult , Anticonvulsants/administration & dosage , Asian People/genetics , Epilepsy/drug therapy , Epilepsy/metabolism , Female , Genotype , Humans , Male , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/metabolism , Polymorphism, Single Nucleotide , Treatment Outcome , Valproic Acid/administration & dosage , Young AdultABSTRACT
SmI2-mediated reductive cyclization of ß-arylthio ketones to generate thiochroman derivatives is not a generally observed process and the reported examples are limited to geminal disubstitution in the substrates. The results of the current study show that the cyclization also occurs when other substitution patterns are present, affording a general approach to dihydrothiochroman-ols in good yields and high degrees of diastereoselectivity. Besides, the halogen substitution on ß-aryl is tolerated in most cases here although reductive dehalogenation has been reported to predominate in the reductive cyclization process. Dihydrothiochroman-4-ols were readily oxidized to thiochroman-4-ols in almost quantitative yields.
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OBJECTIVE: To investigate the involvement of human leukocyte antigen (HLA) loci in aromatic antiepileptic drug-induced cutaneous adverse reactions. METHODS: A case-control study was performed to detect HLA loci involved in aromatic antiepileptic drug-induced Stevens-Johnson syndrome in a southern Han Chinese population. Between January 1, 2006, and December 31, 2015, 91 cases of Stevens-Johnson syndrome induced by aromatic antiepileptic drugs and 322 matched drug-tolerant controls were enrolled from 8 centers. Important genotypes were replicated in cases with maculopapular eruption and in the meta-analyses of data from other populations. Sequence-based typing determined the HLA-A, HLA-B, HLA-C, and HLA-DRB1 genotypes. RESULTS: HLA-B*15:02 was confirmed as strongly associated with carbamazepine-induced Stevens-Johnson syndrome (p = 5.63 × 10-15). In addition, HLA-A*24:02 was associated significantly with Stevens-Johnson syndrome induced by the aromatic antiepileptic drugs as a group (p = 1.02 × 10-5) and by individual drugs (carbamazepine p = 0.015, lamotrigine p = 0.005, phenytoin p = 0.027). Logistic regression analysis revealed a multiplicative interaction between HLA-B*15:02 and HLA-A*24:02. Positivity for HLA-A*24:02 and/or HLA-B*15:02 showed a sensitivity of 72.5% and a specificity of 69.0%. The presence of HLA-A*24:02 in cases with maculopapular exanthema was also significantly higher than in controls (p = 0.023). Meta-analysis of data from Japan, Korea, Malaysia, Mexico, Norway, and China revealed a similar association. CONCLUSIONS: HLA-A*24:02 is a common genetic risk factor for cutaneous adverse reactions induced by aromatic antiepileptic drugs in the southern Han Chinese and possibly other ethnic populations. Pretreatment screening is recommended for people in southern China.
Subject(s)
Anticonvulsants/adverse effects , Genetic Predisposition to Disease , HLA-A24 Antigen/genetics , Stevens-Johnson Syndrome/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Anticonvulsants/therapeutic use , Asian People/genetics , Case-Control Studies , Child , Child, Preschool , China , Female , Follow-Up Studies , HLA-B15 Antigen/genetics , Humans , Infant , Male , Middle Aged , Stevens-Johnson Syndrome/ethnology , Young AdultABSTRACT
To investigate the effects of carbamazepine (CBZ) on the plasma concentrations of valproic acid (VPA) and its toxic metabolite 2-propyl-4-pentenoic acid (4-ene VPA) in epileptic patients, the plasma concentrations of VPA and 4-ene VPA were determined, and the effect of CBZ on pharmacokinetics of VPA was evaluated. All patients had been divided into two groups (VPA group, n = 87; and VPA+CBZ group, n = 19). As compared to VPA group, the combination of CBZ significantly (P < 0.01) decreased the trough concentration of VPA [VPA group, (69.5 +/- 28.8) microg x mL(-1); VPA+CBZ group, (46.3 +/- 25.6) microg x mL(-1)] and does-adjusted VPA trough concentration [VPA group, (4.89 +/- 2.21) microg x mL(-1) x mg(-1) x kg(-1); VPA+CBZ group, (3.14 +/- 1.74) microg x mL(-1) x mg(-1) x kg(-1)]. However, the addition of CBZ did not influence the concentration of 4-ene VPA. The present study revealed that coadministration of CBZ can reduce VPA plasma concentration and may impact VPA clinical effect, therefore therapeutic drug mornitoring of VPA should be used when combined use of CBZ and VPA.
Subject(s)
Anticonvulsants , Carbamazepine , Epilepsy/blood , Valproic Acid , Adolescent , Adult , Anticonvulsants/blood , Anticonvulsants/pharmacokinetics , Anticonvulsants/therapeutic use , Carbamazepine/blood , Carbamazepine/pharmacokinetics , Carbamazepine/therapeutic use , Drug Interactions , Drug Therapy, Combination , Epilepsy/drug therapy , Fatty Acids, Monounsaturated/blood , Female , Humans , Male , Valproic Acid/blood , Valproic Acid/pharmacokinetics , Valproic Acid/therapeutic use , Young AdultABSTRACT
PURPOSE: The incidence of polycystic ovary syndrome (PCOS) increases in women with epilepsy (WWE), which appears to vary with ethnicity. This study was conducted to determine the incidence and risk factors of PCOS in Chinese WWE. METHODS: The study was carried out in 102 of 139 Chinese WWE at reproductive ages, with 32 receiving valproic acid (VPA), 40 receiving other antiepileptic drugs (AEDs), and 30 without AEDs therapy. PCOS was defined as having 2 or more of the following components: polycystic ovaries, hyperandrogenism, and amenorrhoea or oligomenorrhoea (a/oligomenorrhoea). RESULTS: One or more isolated components of PCOS were found in 56 (54.9%) patients, with 29 (28.4%) having polycystic ovaries, 20 (19.6%) with a/oligomenorrhea, 7 (6.9%) with hyperandrogenism, and 13 (12.7%) with defined PCOS. Their average age at the start of seizure was 13.8±6.5 years, younger than that of patients without these disorders (16.9±8.6 years, p<0.05). VPA therapy increased the incidence of PCOS (11/32, 34.4%), in addition to increased blood levels of testosterone and luteinizing hormone (LH) as well as LH to FSH (follicle-stimulating hormone) ratio. No significant relationship was found between the incidence of PCOS and the type, duration, or frequency of seizures in these WWE. CONCLUSION: There is an increased incidence of PCOS in Chinese WWE at reproductive ages, by more than 2 times of that in the general population. Risk factors include seizures starting at a young age and VPA therapy.
Subject(s)
Asian People/ethnology , Epilepsy/ethnology , Polycystic Ovary Syndrome/chemically induced , Polycystic Ovary Syndrome/ethnology , Valproic Acid/adverse effects , Adolescent , Adult , Biomarkers/blood , Child , Epilepsy/blood , Epilepsy/drug therapy , Female , Follicle Stimulating Hormone/blood , Humans , Luteinizing Hormone/blood , Middle Aged , Polycystic Ovary Syndrome/blood , Risk Factors , Testosterone/blood , Young AdultABSTRACT
Valproic acid (VPA) is a well-established anticonvulsant drug that has been increasingly used in the treatment of many forms of generalized epilepsy. Although there are many reports of adverse effects of VPA, studies focusing on the concentration-response relationships of VPA and its metabolites in patients with epilepsy are extremely limited. In this study, a rapid and specific high performance liquid chromatography-ultraviolet (HPLC-UV) method to simultaneously detect the concentrations of VPA and its major hepatotoxic metabolite 2-propyl-4-pentenoic acid (4-ene VPA) in human plasma has been established, using 2,4'-dibromoacetophenone and octanoic acid as the derivatization reagent and internal standard, respectively. This method was used to analyze plasma samples (n=64) of Chinese patients with epilepsy. The results revealed that 4-ene VPA concentrations in Chinese patients were much higher than those in patients in other countries such as United States and Iran. Significant correlations between aspartate aminotransferase (AST), alanine aminotransferase (ALT) and 4-ene VPA concentration suggest that the simultaneous determination of VPA and 4-ene VPA is an effective tool for the prediction of clinical hepatotoxicity in epileptic patients. Furthermore, the present study describes a less costly and complex technique for the clinical monitoring of VPA plasma levels and the risk of hepatotoxicity which may be of particular interest in developing countries like China.
Subject(s)
Anticonvulsants/adverse effects , Anticonvulsants/blood , Chromatography, High Pressure Liquid/methods , Epilepsy/drug therapy , Fatty Acids, Monounsaturated/blood , Valproic Acid/adverse effects , Valproic Acid/blood , Adolescent , Adult , Anticonvulsants/chemistry , Child , China , Epilepsy/blood , Fatty Acids, Monounsaturated/chemistry , Female , Humans , Iran , Male , United States , Valproic Acid/chemistry , Young AdultABSTRACT
The classification, clinical and electrophysiological characteristics, treatment outcome and pathogenesis of paroxysmal dyskinesia were summarized and analyzed. Paroxysmal dyskinesia was classified into three types. Different types had different incentives in clinical practice. Patients were mostly male adolescents, and the attacks, which were in various forms, manifested as dysmyotonia of choreoathetosis, body torsion and facemaking; no disturbance of consciousness during attacks. Electroencephalogram and other examinations showed no specific abnormalities during both the attacks and interictal period. Paroxysmal dyskinesia was an independent disease and different from epilepsy.
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Previous studies have found a strong association between HLA-B*1502 and carbamazepine-induced Stevens-Johnson syndrome in Asian areas including Taiwan, Hongkong and Thailand. This study explores the association between HLA-B*1502 allele and carbamazepine-induced cutaneous adverse reactions in Han Chinese of southern China mainland, and find the genetic marker that can predict carbamazepine-induced cutaneous adverse reactions. HLA-B*1502 allele genotyping was performed by a polymerase chain reaction-sequence specific primers (PCR-SSP) method in 48 Han Chinese subjects who had carbamazepine-induced cutaneous adverse reactions, including 9 severe cutaneous adverse reaction patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) and 39 cutaneous adverse reaction patients with maculopapular eruption (MPE). Meanwhile 80 carbamazepine-tolerant controls and 62 healthy individuals were also tested. The frequency of HLA-B*1502 allele among SJS/TEN patients (100%) is significantly higher than carbamazepine-tolerant controls (13.75%, P<0.001) and healthy individuals (17.74%, P<0.001). But the frequency between MPE patients and carbamazepine-tolerant controls (25.64% vs.13.75%, P=0.110) did not have any significant difference. The data showed that HLA-B*1502 allele is strongly associated with carbamazepine-induced SJS/TEN but not MPE in Han Chinese of southern China mainland.
Subject(s)
Anticonvulsants/adverse effects , Carbamazepine/adverse effects , Drug Eruptions/genetics , HLA-B Antigens/genetics , Adult , Anticonvulsants/therapeutic use , Carbamazepine/therapeutic use , China/epidemiology , DNA/genetics , Drug Eruptions/ethnology , Drug Eruptions/pathology , Female , Genotype , HLA-B15 Antigen , Humans , Male , Middle Aged , Reverse Transcriptase Polymerase Chain Reaction , Skin/pathology , Stevens-Johnson Syndrome/complications , Stevens-Johnson Syndrome/ethnology , Stevens-Johnson Syndrome/geneticsABSTRACT
The silkworm, Bombyx mori, was used to produce recombinant endo-beta-glucanase II (rEGII). The EGII gene (egl2) was cloned from the cellulolytic fungus Trichoderma reesei and inserted into B. mori nucleopolyhedrovirus (BmNPV) genome using BmNPV/Bac-to-Bac expression vector. For expression of rEGII, both the BmN cells and B. mori larvae were infected with the recombinant virus. The putative rEGII yield was about 386 microg per larva and the enzyme activity of the purified rEGII was approx 352 U/mg of rEGII. The optimal activity of this purified protein was observed at 55 degrees C and pH 4, respectively.