Diagnostic value of antibody concentration ratio for treatment-refractory myasthenia gravis.

OBJECTIVE: This study aimed to assess the diagnostic potential of the Antibody concentration ratio in identifying treatment-refractory myasthenia gravis (MG). METHODS: A retrospective analysis was conducted on 116 MG patients who underwent antibody detection at least twice between June 1, 2015, and June 1, 2023. Demographic and clinical characteristics were collated to ascertain their association with refractory MG. The Antibody Concentration Ratio was applied to determine treatment response, using the International Consensus Guidance criteria as the reference standard. The area under nonparametric receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy were calculated to assess the diagnostic efficacy of the Antibody concentration ratio following consecutive immunotherapy relative to initial antibody concentrations for refractory MG. RESULTS: 19 out of 116 patients were unequivocally diagnosed with refractory MG. A significant correlation was found between the Antibody Concentration Ratio and refractory MG status in treatment-refractory and treatment-responsive patients. Subsequently, the AUC demonstrated the robust diagnostic capability of the Antibody concentration ratio for refractory MG, with an AUC of 0.8709 (95% CI: 0.7995-0.9422, p < 0.0001). The optimal cut-off value stood at 0.8903, exhibiting a sensitivity of 94.74% (95% CI: 75.36%-99.73%), a specificity of 68.04% (95% CI: 58.23%-76.48%), and accuracy of 72.41% (95% CI: 64.28%-80.54%). CONCLUSION: Elevated Antibody Concentration Ratio is intrinsically linked with refractory MG and exhibits potential as an diagnostic biomarker for the condition.

Clinical Features and Prognostic Analysis of MuSK-Antibody-Positive Myasthenia Gravis versus Double-Seropositive Myasthenia Gravis: A Single-Center Study from Central South China.

Purpose: To decipher the discrepancies between muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG) and double-seropositive myasthenia gravis (DSP-MG), and to determine prognostic factors for minimal manifestation status (MMS) achievement in MG patients with MuSK autoantibodies (MuSK-Ab). Patients and Methods: A total of 34 MG patients seropositive for MuSK-Ab were enrolled in this study. The demographic and clinical features were compared between MuSK-MG (n = 28) and DSP-MG (n = 6) patients, and factors affecting MMS induction in all patients with MuSK-Ab were identified using Cox regression analysis. Results: Compared to MuSK-MG patients, those with DSP-MG had similar clinical characteristics, except that they had a lower frequency of bulbar muscle involvement at nadir (50% vs 92.9%; P = 0.029) and higher proportions of comorbidities with diabetes mellitus (33.3% vs 0%; P = 0.027) and thymic abnormalities (33.3% vs 0%; P = 0.027). Higher MG Activities of Daily Living (MG-ADL) scores (HR = 0.16, 95% CI: 0.037-0.7, P = 0.015) and axial muscle involvement at nadir (HR = 0.39, 95% CI: 0.16-0.94, P = 0.035) were negative prognostic factors for MMS achievement in patients with MuSK-Ab regardless of acetylcholine receptor antibody (AChR-Ab) positivity. Multivariable Cox regression analysis further established higher MG-ADL scores at the nadir (HR = 0.19, 95% CI: 0.04-0.94; P = 0.042) as an independent risk factor for MMS achievement. Conclusion: DSP-MG was comparable to MuSK-MG and could be considered a single entity in our cohort. In all MG patients with MuSK-Ab, a higher MG-ADL score at nadir may herald a lower chance of MMS achievement, with no observed potential effect of AChR-Ab presence.

Mendelian randomization and colocalization analysis reveal novel drug targets for myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is a complex autoimmune disease affecting the neuromuscular junction with limited drug options, but the field of MG treatment recently benefits from novel biological agents. We performed a drug-targeted Mendelian randomization (MR) study to identify novel therapeutic targets of MG. METHODS: Cis-expression quantitative loci (cis-eQTL), which proxy expression levels for 2176 druggable genes, were used for MR analysis. Causal relationships between genes and disease, identified by eQTL MR analysis, were verified by comprehensive sensitivity, colocalization, and protein quantitative loci (pQTL) MR analyses. The protein-protein interaction (PPI) analysis was also performed to extend targets, followed by enzyme-linked immunosorbent assay (ELISA) to explore the serum level of drug targets in MG patients. A phenome-wide MR analysis was then performed to assess side effects with a clinical trial review assessing druggability. RESULTS: The eQTL MR analysis has identified eight potential targets for MG, one for early-onset MG and seven for late-onset MG. Further colocalization analyses indicated that CD226, CDC42BPB, PRSS36, and TNFSF12 possess evidence for colocalization with MG or late-onset MG. pQTL MR analyses identified the causal relations of TNFSF12 and CD226 with MG and late-onset MG. Furthermore, PPI analysis has revealed the protein interaction between TNFSF12-TNFSF13(APRIL) and TNFSF12-TNFSF13B(BLyS). Elevated TNFSF13 serum level of MG patients was also identified by ELISA experiments. This study has ultimately proposed three promising therapeutic targets (TNFSF12, TNFSF13, TNFSF13B) of MG. CONCLUSIONS: Three drug targets associated with the BLyS/APRIL pathway have been identified. Multiple biological agents, including telitacicept and belimumab, are promising for MG therapy.

Safety, Tolerability, and Pharmacokinetics of the Monoamine Oxidase B Inhibitor, HEC122505, and its Major Metabolite After Single- and Multiple- Ascending Dose, and Food Effect Study in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVES: HEC122505 is a potent and selectively monoamine oxidase B inhibitor that is safe and well-tolerated in preclinical models of Parkinson's disease. The objectives of single ascending dose and multiple dose pharmacokinetic trials of HEC122505 oral tablets were to determine the safety and tolerability of HEC122505, and to examine the food effect on the pharmacokinetic parameters of HEC122505 and its major metabolite HEC129870. METHODS: The phase I study (NCT04625361) consisted of three arms: single ascending dose study (5, 20, 50, 100, 200, 300 or 400 mg HEC122505 tablets or placebo), multiple ascending dose study (20, 50 or 100 mg HEC122505 tablets or placebo once daily), and food effect (100 mg HEC122505 tablets single dose after a high-fat, high-calorie meal). All subjects completed all trial arms and were analyzed as planned. RESULTS: Pharmacokinetic analysis showed that HEC122505 rapidly absorbed with the time to peak plasma concentration (Tmax) ranged from 0.5 to 1.75 h. In addition, maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose proportional manner. Food effect study showed that a high-fat, high-calorie meal had no significant effect on the pharmacokinetics of HEC122505 and its major metabolite HEC129870, suggesting that HEC122505 could be administered in both fasted and fed state in clinical trials. The subsequent multiple-dose study evaluated doses from 20 to 100 mg dose once daily for up to 8 days. HEC122505 reached steady state after approximately 5 days with a once daily dose. In these studies, all dose of HEC122505 was generally safe and well tolerated. No grade ≥ 3 drug related adverse events (AEs) occurred. CONCLUSION: HEC122505 was generally safe and well tolerated in the single ascending dose (ranging from 5 to 400 mg) and multiple ascending dose (50 to 200 mg once daily doses) studies. All the drug related adverse events (AEs) were Grade ≤ 2. There were no deaths, no subjects discontinued the trial due to AEs, and there were no other serious AEs. The safety and pharmacokinetic profile support once daily administration of HEC122505.

Undervalued and novel roles of heterogeneous nuclear ribonucleoproteins in autoimmune diseases: Resurgence as potential biomarkers and targets.

Autoimmune diseases are mainly characterized by the abnormal autoreactivity due to the loss of tolerance to specific autoantigens, though multiple pathways associated with the homeostasis of immune responses are involved in initiating or aggravating the conditions. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a major category of RNA-binding proteins ubiquitously expressed in a multitude of cells and have attracted great attentions especially with their distinctive roles in nucleic acid metabolisms and the pathogenesis in diseases like neurodegenerative disorders and cancers. Nevertheless, the interplay between hnRNPs and autoimmune disorders has not been fully elucidated. Virtually various family members of hnRNPs are increasingly identified as immune players and are pertinent to all kinds of immune-related processes including immune system development and innate or adaptive immune responses. Specifically, hnRNPs have been extensively recognized as autoantigens within and even beyond a myriad of autoimmune diseases, yet their diagnostic and prognostic values are seemingly underestimated. Molecular mimicry, epitope spreading and bystander activation may represent major putative mechanisms underlying the presence of autoantibodies to hnRNPs. Besides, hnRNPs play critical parts in regulating linchpin genes expressions that control genetic susceptibility, disease-linked functional pathways, or immune responses by interacting with other components particularly like microRNAs and long non-coding RNAs, thereby contributing to inflammation and autoimmunity as well as specific disease phenotypes. Therefore, comprehensive unraveling of the roles of hnRNPs is conducive to establishing potential biomarkers and developing better intervention strategies by targeting these hnRNPs in the corresponding disorders. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

Design, synthesis and evaluation of novel monoamine oxidase B (MAO-B) inhibitors with improved pharmacokinetic properties for Parkinson's disease.

A series of novel ((benzofuran-5-yl)methyl)pyrrolidine-2-carboxamide derivatives were designed, synthesized and evaluated as MAO-B inhibitors. SAR studies indicated that cyclizing benzyl ether into benzofuran ring resulted in the most potent MAO-B inhibitor (IC50 = 0.037 µM), (2S,4S)-4-fluoro-1-((2-(4-fluorophenyl) benzofuran-5-yl)methyl)pyrrolidine-2-carboxamide (C14). PK properties of C14 in rats and mice were significantly improved compared to our previous candidate and safinamide, indicating that benzofuran moiety is essential for improving PK properties. Moreover, C14 displayed good metabolic stability and brain-blood barrier permeability, as well as favorable in vitro properties. Finally, C14 significantly inhibited MAO-B in the mouse brain. C14 exhibited a potential efficacy for DA deficits in the MPTP-induced mouse model and significantly increased DA concentration in the striatum. Thus, we identified that C14 may be a promising drug candidate for PD treatment.

Deciphering Nonbioavailable Substructures Improves the Bioavailability of Antidepressants by Serotonin Transporter.

Inadequate bioavailability is one of the most critical reasons for the failure of oral drug development. However, the way that substructures affect bioavailability remains largely unknown. Serotonin transporter (SERT) inhibitors are first-line drugs for major depression disorder, and improving their bioavailability may be able to decrease side-effects by reducing daily dose. Thus, it is an excellent model to probe the relationship between substructures and bioavailability. Here, we proposed the concept of "nonbioavailable substructures", referring to substructures that are unfavorable to bioavailability. A machine learning model was developed to identify nonbioavailable substructures based on their molecular properties and shows the accuracy of 83.5%. A more potent SERT inhibitor DH4 was discovered with a bioavailability of 83.28% in rats by replacing the nonbioavailable substructure of approved drug vilazodone. DH4 exhibits promising anti-depression efficacy in animal experiments. The concept of nonbioavailable substructures may open up a new venue for the improvement of drug bioavailability.

Latent tuberculosis infection in myasthenia gravis patients on immunosuppressive therapy: high incidence yet moderate reactivation rate.

BACKGROUND: Immunosuppressive therapies (ISTs) are mainstays for management of myasthenia gravis (MG). Meanwhile, latent tuberculosis infection (LTBI) is common in the setting of high-burden countries. However, the prevalence of LTBI among MG patients and whether receiving ISTs for MG would aggravate LTBI reactivation remain unknown. METHODS: We retrospectively analyzed the frequency of LTBI via interferon-gamma release assay (IGRA) positivity among hospitalized MG patients from both rural and urban areas in a tertiary hospital, and those receiving ISTs were followed up to investigate the reactivation risk of LTBI. RESULTS: A total of 300 MG patients with determinate IGRA results were enrolled, where the frequency of LTBI was 35.0%. Male (OR = 1.910, 95% CI: 1.181-3.089, p = .008) and elderly (OR = 1.044, 95% CI: 1.027-1.061, p < .001) patients were prone to LTBI. Of those with LTBI, 78 individuals on ISTs were successfully followed up for a median duration of 18.3 (8.5-24.0) months, of which 25 (32.1%) received anti-tuberculosis (TB) treatments. The rate of various degrees of adverse events was 82.1% over the course of the follow-up, but was not different between individuals with and without therapies against TB (χ2 < 0.001, p > .999). Only 1 patient eventually reported lymph node and intestinal TB, with the incidence rate of LTBI reactivation preliminarily estimated to be 0.81 per 100 person years. CONCLUSION: The frequency of LTBI is high in our MG cohort, especially among those with advanced age and males. However, receiving immunosuppressives seems not to increase the risk of LTBI reactivation. LTBI screening is strongly recommended for all MG patients ready to receive ISTs, while preventive anti-TB chemotherapy should be prescribed after weighing potential benefits against the risk of side effects in those with LTBI. In-depth investigation is still entailed to further verify these findings due to the limitation of the retrospective single-center design of our study.

Poor responses and adverse outcomes of myasthenia gravis after thymectomy: Predicting factors and immunological implications.

Myasthenia gravis (MG) has been recognized as a series of heterogeneous but treatable autoimmune conditions. As one of the indispensable therapies, thymectomy can achieve favorable prognosis especially in early-onset generalized MG patients with seropositive acetylcholine receptor antibody. However, poor outcomes, including worsening or relapse of MG, postoperative myasthenic crisis and even post-thymectomy MG, are also observed in certain scenarios. The responses to thymectomy may be associated with the general characteristics of patients, disease conditions of MG, autoantibody profiles, native or ectopic thymic pathologies, surgical-related factors, pharmacotherapy and other adjuvant modalities, and the presence of comorbidities and complications. However, in addition to these variations among individuals, pathological remnants and the abnormal immunological milieu and responses potentially represent major mechanisms that underlie the detrimental neurological outcomes after thymectomy. We underscore these plausible risk factors and discuss the immunological implications therein, which may be conducive to better managing the indications for thymectomy, to avoiding modifiable risk factors of poor responses and adverse outcomes, and to developing post-thymectomy preventive and therapeutic strategies for MG.

Novel difluoromethylated 1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole derivatives as potent 5-HT6 receptor antagonist with AMDE-improving properties: Design, synthesis, and biological evaluation.

Serotonin type 6 receptor (5-HT6R) has been considered as a particularly promising target for treating cognitive deficits due to the positive effects of its antagonists in a wide range of memory impairment paradigms. In this study, we designed, synthesized, and evaluated a series of 3-(difluoromethyl)-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole derivatives as potent 5-HT6R antagonists. Structure-activity relationship study led to the discovery of five compounds (6a, 6m, 6n, 6p and 6q) with potent binding affinity at 5-HT6R. In in vivo pharmacokinetic studies in rats, 6p showed 30-folds higher AUC (267 ng·h/mL) and better bioavailability (34.39 %) than those of 6a (9.37 ng·h/mL and 5.95 %, respectively) by using difluoromethyl group replacing a methyl group. Besides, 6p showed good brain penetration with Cb/Cp ratio ∼6. Based on the pharmacological characteristics and favorable pharmacokinetic properties, 6p was further chosen to evaluate cognition-enhancing property in the preliminary in vivo models. It is identified that 6p not only prevented scopolamine-induced learning deficits in the novel object recognition test but also rescued the recognition barrier caused by scopolamine. Finally, the combination of 6p and donepezil produces synergistic effects on increasing the acetylcholine levels in the intracerebral hippocampus. In light of these findings, we propose 6p as a potential 5-HT6R antagonist for treatment of AD.

Novel difluoromethyl-containing 1-((4-methoxy-3-(piperazin-1-yl)phenyl)sulfonyl)-1H-indole scaffold as potent 5-HT6R antagonists: Design, synthesis, biological evaluation, and early in vivo cognition-enhancing studies.

Herein, a series of novel 1-((4-methoxy-3-(piperazin-1-yl)phenyl)sulfonyl)- 1H-indole derivatives were designed and synthesized via hybridization strategy of idalopirdine and SB-271046. The optimal compound C14 (Ki = 0.085 nM), with difluoromethyl on C3 position on indole scaffold, increased the affinity for the 5-HT6R up to 10-folds than idalopirdine (Ki = 0.83 nM). Additionally, C14 had good pharmacokinetic properties and in vitro metabolic properties. Finally, C14 could efficiently reverse the scopolamine induced emotional memory deficits in novel object recognition assay in rats. Thus, we propose C14 might be considered as a new cognition-enhancing agent and the further studies are now underway in our laboratory.

Enhancing monoamine oxidase B inhibitory activity via chiral fluorination: Structure-activity relationship, biological evaluation, and molecular docking study.

Parkinson's disease (PD) is a common neurodegenerative disease among the elderly. Currently, monoamine oxidase B (MAO-B) inhibitors are extensively used for PD in clinics. In this work, a series of novel chiral fluorinated pyrrolidine derivatives were designed and synthesized. In vitro biological evaluations revealed that compound D5 was the most potent, selective MAO-B inhibitor (IC50 = 0.019 µM, MAO-A/MAO-B selectivity index = 2440), which was 10-fold than that of miracle drug safinamide (IC50 = 0.163 µM, MAO-A/MAO-B selectivity index = 172). It was verified that the enhanced hydrophobic interaction of D5 improved the activity against MAO-B in molecular docking study. Besides, D5 exhibited excellent metabolic properties and pharmacokinetic profiles in monkeys and rats. Moreover, D5 displayed more efficacious than safinamide in vivo models. In the MPTP-induced PD mouse model, D5 significantly alleviated DA deficits and increased the effect of levodopa on dopamine concentration in the striatum. Meanwhile, D5 produced a prominent reduction in tremulous jaw movements induced by galantamine. Accordingly, we present D5 as a novel, highly potent, and selective MAO-B inhibitor for PD therapy.

Environmental enrichment ameliorates high-fat diet induced olfactory deficit and decrease of parvalbumin neurons in the olfactory bulb in mice.

Overweight induced by high-fat diet (HFD) represents one of the major health concerns in modern societies, which can cause lasting peripheral and central metabolic disorders in all age groups. Specifically, childhood obesity could lead to life-long impact on brain development and functioning. On the other hand, environmental enrichment (EE) has been demonstrated to be beneficial for learning and memory. Here, we explored the impact of high-fat diet on olfaction and organization of olfactory bulb cells in adolescent mice, and the effect of EE intervention thereon. Puberty mice (3-week-old) fed with HFD for 10 weeks exhibited poorer odor sensitivity and olfactory memory relative to controls consuming standard chows. The behavioral deficits were rescued in the HFD group with EE intervention. Neuroanatomically, parvalbumin (PV) interneurons in the olfactory bulb (OB) were reduced in the HFD-fed animals relative to control, while EE intervention also normalized this alteration. In contrast, cells expressing calbindin (CB), doublecortin (DCX) in the OB were not altered. Our findings suggest that PV interneurons may play a crucial role in mediating the HFD-induced olfactory deficit in adolescent mice, and can also serve a protective effect of EE against the functional deficit.

The Association between Insomnia-Like Sleep Pattern Changes and Cognitive Dysfunction: Possible Mechanism and Therapeutic Strategy.

The prevalence of sleep disorders and cognitive dysfunction has overwhelmingly increased, with insomnia and Alzheimer's disease (AD) being the most common form. A multitude of studies have linked the alterations in sleep continuity or sleep architecture with cognitive impairment bilaterally, but the management of disrupted sleep patterns in preclinical AD could be more beneficial since there is no cure for AD. This review mainly focuses on the altered sleep patterns in insomnia, and summarizes potential pathways underlying the relationship between insomnia and cognitive impairment, aiming to establish certain sleep pattern changes as biomarkers for cognitive decline and explore potential therapeutic targets based on evidence from research advances.

Design, synthesis and biological evaluation of pyridinylmethylenepiperidine derivatives as potent 5-HT1F receptor agonists for migraine therapy.

Migraine is a common neurovascular disease which has been classified as the sixth most disabling disorder. Current migraine therapy was triptans, however, riptans can cause contraction of blood vessels. Therefore, novel drugs without cardiovascular effects emerged, such as CGRP and selective 5-HT1F receptor agonists. In this work, a series of pyridinylmethylenepiperidine derivatives were designed, synthesized and evaluated for their 5-HT1F receptor agonist activity. The results in vitro showed that compound C1-C6 displayed potent agonist activities compared with positive drug lasmiditan. Pharmacokinetic properties in rat indicated that 2,4,6-trifluoro-N-(6-(fluoro(1-methylpiperidin-4-ylidene)methyl)pyridin-2-yl)benzamide (C5) possessed high AUC and good bioavailability. In two rodent models of migraine, C5 significantly inhibited dural plasma protein extravasation and c-fos expression in the trigeminal nucleus caudalis. Moreover, C5 showed no effect on vasoconstriction. Through these studies, we identified C5 as a potent 5-HT1F receptor agonist for migraine therapy.

The Retrotransposition of L1 is Involved in the Reconsolidation of Contextual Fear Memory in Mice.

BACKGROUND: The long interspersed element-1 (L1) participates in memory formation, and DNA methylation patterns of L1 may suggest resilience or vulnerability factors for Post-Traumatic Stress Disorder (PTSD), of which the principal manifestation is a pathological exacerbation of fear memory. However, the unique roles of L1 in the reconsolidation of fear memory remain poorly understood. OBJECTIVE: The study aimed to investigate the role of L1 in the reconsolidation of context-dependent fear memory. METHODS: Mice underwent fear conditioning and fear recall in the observation chambers. Fear memory was assessed by calculating the percentage of time spent freezing in 5 min. The medial prefrontal cortex (mPFC) and hippocampus were removed for further analysis. Open Reading Frame 1 (ORF1) mRNA and ORF2 mRNA of L1 were analyzed by real-time quantitative polymerase chain reaction. After reactivation of fear memory, lamivudine was administered and its effects on fear memory reconsolidation were observed. RESULTS: ORF1 and ORF2 mRNA expressions in the mPFC and hippocampus after recent (24 h) and remote (14 days) fear memory recall exhibited augmentation via different temporal and spatial patterns. Reconsolidation of fear memory was markedly inhibited in mice treated with lamivudine, which could block L1. DNA methyltransferase mRNA expression declined following lamivudine treatment in remote fear memory recall. CONCLUSION: The retrotransposition of L1 participated in the reconsolidation of fear memory after reactivation of fear memory, and with lamivudine treatment, spontaneous recovery decreased with time after recent and remote fear memory recall, providing clues for understanding the roles of L1 in fear memory.

Hippocampal LASP1 ameliorates chronic stress-mediated behavioral responses in a mouse model of unpredictable chronic mild stress.

Substantial evidence has revealed that abnormalities in synaptic plasticity play important roles during the process of depression. LASP1 (LIM and SH3 domain protein 1), a member of actin-binding proteins, has been shown to be associated with the regulation of synaptic plasticity. However, the role of LASP1 in the regulation of mood is still unclear. Here, using an unpredictable chronic mild stress (UCMS) paradigm, we found that the mRNA and protein levels of LASP1 were decreased in the hippocampus of stressed mice and that UCMS-induced down-regulation of LASP1 was abolished by chronic administration of fluoxetine. Adenosine-associated virus-mediated hippocampal LASP1 overexpression alleviated the UCMS-induced behavioral results of forced swimming test and sucrose preference test in stressed mice. It also restored the dendritic spine density, elevated the levels of AKT (a serine/threonine protein kinase), phosphorylated-AKT, insulin-like growth factor 2, and postsynaptic density protein 95. These findings suggest that LASP1 alleviates UCMS-provoked behavioral defects, which may be mediated by an enhanced dendritic spine density and more activated AKT-dependent LASP1 signaling, pointing to the antidepressant role of LASP1.

Computational Fragment-Based Design Facilitates Discovery of Potent and Selective Monoamine Oxidase-B (MAO-B) Inhibitor.

Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases. Inhibition of monoamine oxidase-B (MAO-B), which is mainly found in the glial cells of the brain, may lead to an elevated level of dopamine (DA) in patients. MAO-B inhibitors have been used extensively for patients with PD. However, the discovery of the selective MAO-B inhibitor is still a challenge. In this study, a computational strategy was designed for the rapid discovery of selective MAO-B inhibitors. A series of (S)-2-(benzylamino)propanamide derivatives were designed. In vitro biological evaluations revealed that (S)-1-(4-((3-fluorobenzyl)oxy)benzyl)azetidine-2-carboxamide (C3) was more potent and selective than safinamide, a promising drug for regulating MAO-B. Further studies revealed that the selectivity mechanism of C3 was due to the steric clash caused by the residue difference of Phe208 (MAO-A) and Ile199 (MAO-B). Animal studies showed that compound C3 could inhibit cerebral MAO-B activity and alleviate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuronal loss.

The alteration of gut microbiome and metabolism in amyotrophic lateral sclerosis patients.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease accompanied with severe paralysis or even death, while the pathogenesis of ALS is still unclear and no effective therapy exists. The accumulating evidence has indicated the association between gut microbiota and various neurological diseases. Thus, to explore the potential role of gut microbiome in ALS, 20 patients diagnosed with probable or definite ALS and 20 healthy controls were enrolled and their fecal excrements were collected. The analysis of fecal community diversity with 16S rDNA sequencing showed an obvious change in microbial structure of ALS patients, where Bacteroidetes at the phylum level and several microbes at the genus level were up-regulated, while Firmicutes at the phylum level and Megamonas at the genus level were down-regulated compared to healthy controls. Additionally, decreased gene function associated with metabolic pathways was observed in ALS patients. The metagenomics further demonstrated the discrepancies in microflora at the species level and relevant metabolites thereof were also revealed when combined with metabolomics. In conclusion, the altered composition of the gut microbiota and metabolic products in ALS patients provided deeper insights into the pathogenesis of ALS, and these biomarkers might be established as potential therapeutic targets which deserve further exploration.

BET proteins inhibitor JQ-1 impaired the extinction of remote auditory fear memory: An effect mediated by insulin like growth factor 2.

Fear extinction is an important preclinical model for behavior therapy in human anxiety disorders, such as post-traumatic stress disorder (PTSD). Histone acetylation is involved in the extinction of fear memory. As the "readers" of histone acetylation markers, the role of the bromodomain and extraterminal domain (BET) proteins in fear extinction is still unclear. In the present study, we found that suppression of BET proteins using small molecule JQ-1 had no effects on the acquisition of auditory fear or on the extinction of recent auditory fear, but it impaired the extinction of remote auditory fear. We found that insulin like growth factor 2 (IGF-2) mRNA and protein were up-regulated in the anterior cingulate cortex (ACC) after the extinction training of remote fear memory, and that this effect was inhibited by JQ-1 administration. Further, the local delivery of IGF-2 protein to the ACC region rescued the impaired extinction of remote memory caused by JQ-1 administration, which suggesting IGF-2 mediates the effects of JQ-1 on remote memory extinction. Gene expression profiling analysis demonstrated that JQ-1 treatment inhibited the up-regulated expression of a key set of neuroplasticity-related genes following remote memory extinction. Together, these findings establish BET proteins as epigenetic mediator for the extinction of remote fear memory. In particular, the findings of this study imply that as a prospective preclinical cancer drug, JQ-1 (or other BET bromodomain inhibitors) should be modified to prevent it from crossing the blood brain barrier and causing neurological side effects.