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1.
Brain Behav ; 14(7): e3621, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38970239

ABSTRACT

INTRODUCTION: Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver diseases characterized by neuroinflammation. The efficacies of nonabsorbable rifaximin (RIF) and lactulose (LAC) have been well documented in the treatment of HE. [18F]PBR146 is a translocator protein (TSPO) radiotracer used for in vivo neuroinflammation imaging. This study investigated anti-neuroinflammation effect of RIF or/and LAC in chronic HE rats by [18F]PBR146 micro-PET/CT. METHODS: Bile duct ligation (BDL) operation induced chronic HE models, and this study included Sham+normal saline (NS), BDL+NS, BDL+RIF, BDL+LAC, and BDL+RIF+LAC groups. Behavioral assessment was performed to analyze the motor function, and fecal samples were collected after successfully established the chronic HE model (more than 28 days post-surgery). In addition, fecal samples collection and micro-PET/CT scans were performed sequentially. And we also collected the blood plasma, liver, intestinal, and brain samples after sacrificing the rats for further biochemical and pathological analyses. RESULTS: The RIF- and/or LAC-treated BDL rats showed similar behavioral results with Sham+NS group, while the treatment could not reverse the biliary obstruction resulting in sustained liver injury. The RIF or/and LAC treatments can inhibit IFN-γ and IL-10 productions. The global brain uptake values of [18F]PBR146 in BDL+NS group was significantly higher than other groups (p < .0001). The brain regions analysis showed that the basal ganglia, hippocampus, and cingulate cortex had radiotracer uptake differences among groups (all p < .05), which were consistent with the brain immunohistochemistry results. Sham+NS group was mainly enriched in Christensenella, Coprobacillus, and Pseudoflavonifractor. BDL+NS group was mainly enriched in Barnesiella, Alloprevotella, Enterococcus, and Enterorhabdus. BDL+RIF+LAC group was enriched in Parabacteroides, Bacteroides, Allobaculum, Bifidobacterium, and Parasutterella. CONCLUSIONS: RIF or/and LAC had anti-neuroinflammation in BDL-induced chronic HE rats with gut microbiota alterations. The [18F]PBR146 could be used for monitoring RIF or/and LAC treatment efficacy of chronic HE rats.


Subject(s)
Hepatic Encephalopathy , Lactulose , Rats, Sprague-Dawley , Rifaximin , Animals , Hepatic Encephalopathy/drug therapy , Hepatic Encephalopathy/diagnostic imaging , Hepatic Encephalopathy/metabolism , Rifaximin/pharmacology , Rats , Male , Lactulose/pharmacology , Positron Emission Tomography Computed Tomography , Disease Models, Animal , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/diagnostic imaging , Gastrointestinal Agents/pharmacology , Gastrointestinal Agents/administration & dosage , Brain/diagnostic imaging , Brain/drug effects , Brain/metabolism , Fluorine Radioisotopes , Carrier Proteins , Receptors, GABA-A
2.
PeerJ Comput Sci ; 10: e2108, 2024.
Article in English | MEDLINE | ID: mdl-38983233

ABSTRACT

With the development of technology, more and more devices are connected to the Internet. According to statistics, Internet of Things (IoT) devices have reached tens of billions of units, which forms a massive Internet of Things system. Social Internet of Things (SIoT) is an essential extension of the IoT system. Because of the heterogeneity present in the SIoT system and the limited resources available, it is facing increasing security issues, which hinders the interaction of SIoT information. Consortium chain combined with the trust problem in SIoT systems has gradually become an important goal to improve the security of SIoT data interaction. Detection of malicious nodes is one of the key points to solve the trust problem. In this article, we focus on the consortium chain network. According to the information characteristics of nodes on the consortium chain, it can be analyzed that the SIoT malicious node detection combined with the consortium chain network should have the privacy protection, subjectivity, uncertainty, lightweight, dynamic timeliness and so on. In response to the features above and the concerns of existing malicious node detection methods, we propose an algorithm based on inter-block delay. We employ unsupervised clustering algorithms, including K-means and DBSCAN, to analyze and compare the data set intercepted from the consortium chain. The results indicate that DBSCAN exhibits the best clustering performance. Finally, we transmit the acquired data onto the chain. We conclude that the proposed algorithm is highly effective in detecting malicious nodes on the combination of SIoT and consortium chain networks.

3.
CNS Neurosci Ther ; 30(6): e14692, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38872258

ABSTRACT

AIM: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A-1, a derivative of arctigenin with AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated. METHODS: A-1 at 33.3 mg/kg was administrated in SOD1G93A transgenic mice orally from the 13th week for a 6-week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. RESULTS: A-1 administration in SOD1G93A mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A-1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial-related proteins. The A-1 treatment group showed decreased levels of IL-1ß, pIκBα/IκBα, and pNF-κB/NF-κB. CONCLUSIONS: A-1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC-1α pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL-1ß/NF-κB pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A-1 as a promising therapeutic approach for ALS.


Subject(s)
AMP-Activated Protein Kinases , Amyotrophic Lateral Sclerosis , Furans , Interleukin-1beta , Mice, Transgenic , NF-kappa B , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Sirtuin 1 , Animals , Sirtuin 1/metabolism , Mice , NF-kappa B/metabolism , AMP-Activated Protein Kinases/metabolism , Furans/pharmacology , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/pathology , Amyotrophic Lateral Sclerosis/metabolism , Interleukin-1beta/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Lignans/pharmacology , Lignans/therapeutic use , Signal Transduction/drug effects , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism , Male , Motor Neurons/drug effects , Motor Neurons/pathology , Motor Neurons/metabolism , Spinal Cord/drug effects , Spinal Cord/pathology , Spinal Cord/metabolism
4.
J Org Chem ; 89(11): 7821-7827, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38805614

ABSTRACT

Total synthesis of simonsol C has been achieved, focusing on the postdearomatization transformations. Our methodology integrates an efficient combination of dearomatization and Zn/AcOH reduction to introduce an allyl group, followed by oxo-Michael addition, to construct the 6/5/6 benzofuran skeleton. It offers a novel method for synthesizing allyl-containing quaternary carbon atoms in a straightforward manner.

5.
Transl Neurosci ; 15(1): 20220340, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-38708097

ABSTRACT

Objectives: The FT4-to-FT3 ratio (FFR) variations in patients with subacute combined spinal cord degeneration (SCSD) as a potentially useful prognostic indicator are still unknown. This study aimed to investigate the changes of FFR as a potentially valuable prognostic predictor in patients with SCSD. Methods: This study included 144 consecutive SCSD patients who received standard diagnostic and therapeutic procedures between January 2015 and December 2021 and were admitted to the Department of Neurology at the First Affiliated Hospital of Bengbu Medical University. At the time of admission, we gathered data on all patients' demographics, daily routines, previous chronic conditions, medication histories, and other clinical details. For the purpose of measuring FFR, blood samples were specifically taken within 48 h of admission. The degree of neurological impairment of patients was assessed using the functional disability scale at the time of admission. At 6 months following discharge, the Modified Rankin Scale (mRS) was used to evaluate the clinical prognosis. To evaluate the relationship between the FFR and the risks of a poor outcome (mRS > 2), univariate and multivariate logistic regression analysis was utilized. The significance of the FT4/FT3 ratio in predicting the clinical outcomes in SCSD patients 6 months after discharge was assessed using the area under curve-receiver operating characteristic (AUC-ROC). Results: About 90 patients (62.5%) of the 144 patients had poor outcomes, while 54 (37.5%) had favorable outcomes. Higher FFR at admission was independently linked to higher odds of a poor outcome, according to a logistic analysis. With an optimized cutoff value of >2.843, the FFR exhibited the maximum accuracy for predicting a poor outcome, according to the AUC‒ROC curve (AUC 0.731, P < 0.001; sensitivity, 77.8%; specificity, 83.3%). FFR was identified as an independent predictor of poor outcomes by multivariate logistic regression (OR, 2.244; 95% CI, 1.74-2.90; P < 0.001). Conclusions: We discovered that in patients who had a bad result 6 months after discharge, the FFR had dramatically increased at the time of admission, providing a unique prognostic marker in patients with SCSD.

6.
Phys Chem Chem Phys ; 26(15): 11414-11428, 2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38591159

ABSTRACT

The ongoing evolution of the Omicron lineage of SARS-CoV-2 has led to the emergence of subvariants that pose challenges to antibody neutralization. Understanding the binding dynamics between the receptor-binding domains (RBD) of these subvariants spike and monoclonal antibodies (mAbs) is pivotal for elucidating the mechanisms of immune escape and for advancing the development of therapeutic antibodies. This study focused on the RBD regions of Omicron subvariants BA.2, BA.5, BF.7, and XBB.1.5, employing molecular dynamics simulations to unravel their binding mechanisms with a panel of six mAbs, and subsequently analyzing the origins of immune escape from energetic and structural perspectives. Our results indicated that the antibody LY-COV1404 maintained binding affinities across all studied systems, suggesting the resilience of certain antibodies against variant-induced immune escape, as seen with the mAb 1D1-Fab. The newly identified mAb 002-S21F2 showed a similar efficacy profile to LY-COV1404, though with a slightly reduced binding to BF.7. In parallel, mAb REGN-10933 emerged as a potential therapeutic candidate against BF.7 and XBB.1.5, reflecting the importance of identifying variant-specific antibody interactions, akin to the binding optimization observed in BA.4/5 and XBB.1.5. And key residues that facilitate RBD-mAb binding were identified (T345, L441, K444, V445, and T500), alongside residues that hinder protein-protein interactions (D420, L455, K440, and S446). Particularly noteworthy was the inhibited binding of V445 and R509 with mAbs in the presence of mAb 002-S21F2, suggesting a mechanism for immune escape, especially through the reduction of V445 hydrophobicity. These findings enhance our comprehension of the binding interactions between mAbs and RBDs, contributing to the understanding of immune escape mechanisms. They also lay the groundwork for the design and optimization of antiviral drugs and have significant implications for the development of treatments against current and future coronaviruses.


Subject(s)
Antibodies, Monoclonal , Antibodies, Neutralizing , Antiviral Agents , Molecular Dynamics Simulation , SARS-CoV-2
7.
Chem Asian J ; 19(10): e202400237, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38563626

ABSTRACT

Herein, we report a rare example of cationic three-dimensional (3D) metal-organic framework (MOF) of [Cu5Cl3(TMPP)]Cl5 ⋅ xSol (denoted as Cu-TMPP; H2TMPP=meso-tetrakis (6-methylpyridin-3-yl) porphyrin; xSol=encapsulated solvates) supported by [Cu8Cl6]10+ cluster secondary building units (SBUs) wherein the eight faces of the Cl--based octahedron are capped by eight Cu2+. Surface-area analysis indicated that Cu-TMPP features a mesoporous structure and its solvate-like Cl- counterions can be exchanged by BF4 -, PF6 -, and NO3 -. The polyvinylpyrrolidone (PVP) coated Cu-TMPP (denoted as Cu-TMPP-PVP) demonstrated good ROS generating ability, producing ⋅OH in the absence of light (peroxidase-like activity) and 1O2 on light irradiation (650 nm; 25 mW cm-2). This work highlights the potential of Cu-TMPP as a functional carrier of anionic guests such as drugs, for the combination therapy of cancer and other diseases.

8.
Int J Biol Macromol ; 265(Pt 1): 130921, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38492688

ABSTRACT

The design of small molecule inhibitors that target the programmed death ligand-1 (PD-L1) is a forefront issue in immune checkpoint blocking therapy. Small-molecule inhibitors have been shown to exert therapeutic effects by inducing dimerization of the PD-L1 protein, however, the specific mechanisms underlying this dimerization process remain largely unexplored. Furthermore, there is a notable lack of comparative studies examining the binding modes of structurally diverse inhibitors. In view of the research gaps, this work employed molecular dynamics simulations to meticulously examine the interactions between two distinct types of inhibitors and PD-L1 in both monomeric and dimeric forms, and predicted the dimerization mechanism. The results revealed that inhibitors initially bind to a PD-L1 monomer, subsequently attracting another monomer to form a dimer. Notably, symmetric inhibitors observed superior binding efficiency compared to other inhibitors. Key residues, including Ile54, Tyr56, Met115 and Tyr123 played a leading role in binding. Structurally, symmetric inhibitors were capable of thoroughly engaging the binding pocket, promoting a more symmetrical formation of PD-L1 dimers. Furthermore, symmetric inhibitors formed more extensive hydrophobic interactions with protein residues. The insights garnered from this research are expected to significantly contribute to the rational design and optimization of small molecule inhibitors targeting PD-L1.


Subject(s)
B7-H1 Antigen , Programmed Cell Death 1 Receptor , Dimerization , B7-H1 Antigen/metabolism , Programmed Cell Death 1 Receptor/metabolism , Small Molecule Libraries/chemistry , Molecular Dynamics Simulation
9.
J Thorac Imaging ; 39(2): 86-92, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38270475

ABSTRACT

PURPOSE: To investigate intraindividual cardiac structural and functional changes before and after COVID-19 infection in a previously healthy population with a 3T cardiac magnetic resonance (CMR). MATERIALS AND METHODS: A total of 39 unhospitalized patients with COVID-19 were recruited. They participated in our previous study as non-COVID-19 healthy volunteers undergoing baseline CMR examination and were recruited to perform a repeated CMR examination after confirmed COVID-19 infection in December 2022. The CMR parameters were measured and compared between before and after COVID-19 infection with paired t tests. The laboratory measures including myocardial enzymes and inflammatory indicators were also collected when performing repeated CMR. RESULTS: The median duration was 393 days from the first to second CMR and 26 days from clinical symptoms onset to the second CMR. Four patients (10.3%, 4/39) had the same late gadolinium enhancement pattern at baseline and repeated CMR and 5 female patients (12.8%, 5/39) had myocardial T2 ratio >2 (2.07 to 2.27) but with normal T2 value in post-COVID-19 CMR. All other CMR parameters were in normal ranges before and after COVID-19 infection. Between before and after the COVID-19 infection, there were no significant differences in cardiac structure, function, and tissue characterization, no matter with or without symptoms (fatigue, chest discomfort, palpitations, shortness of breath, and insomnia/sleep disorders) (all P >0.05). The laboratory measures at repeated CMR were in normal ranges in all participants. CONCLUSIONS: These intraindividual CMR studies showed unhospitalized patients with COVID-19 with normal myocardial enzymes had no measurable CMR abnormalities, which can help alleviate wide social concerns about COVID-19-related myocarditis.


Subject(s)
COVID-19 , Myocarditis , Humans , Female , Contrast Media , COVID-19/diagnostic imaging , COVID-19/pathology , Magnetic Resonance Imaging, Cine , Gadolinium , Magnetic Resonance Imaging , Myocardium/pathology , Magnetic Resonance Spectroscopy , Predictive Value of Tests
10.
J Cell Mol Med ; 28(3): e18097, 2024 02.
Article in English | MEDLINE | ID: mdl-38164738

ABSTRACT

Current studies have indicated that insufficient trophoblast epithelial-mesenchymal transition (EMT), migration and invasion are crucial for spontaneous abortion (SA) occurrence and development. Exosomal miRNAs play significant roles in embryonic development and cellular communication. Hereon, we explored the roles of serum exosomes derived from SA patients on trophoblast EMT, migration and invasion. Exosomes were isolated from normal control (NC) patients with abortion for unplanned pregnancy and SA patients, then characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting. Exosomal miRNA profiles were identified by miRNA sequencing. The effects of serum exosomes on trophoblast migration and invasion were detected by scratch wound healing and transwell assays, and other potential mechanisms were revealed by quantitative real-time PCR (RT-PCR), western blotting and dual-luciferase reporter assay. Finally, animal experiments were used to explore the effects of exosomal miR-410-3p on embryo absorption in mice. The serum exosomes from SA patients inhibited trophoblast EMT and reduced their migration and invasion ability in vitro. The miRNA sequencing showed that miR-410-3p was upregulated in SA serum exosomes. The functional experiments showed that SA serum exosomes restrained trophoblast EMT, migration and invasion by releasing miR-410-3p. Mechanistically, SA serum exosomal miR-410-3p inhibited trophoblast cell EMT, migration and invasion by targeting TNF receptor-associated factor 6 (TRAF6) at the post-transcriptional level. Besides, SA serum exosomal miR-410-3p inhibited the p38 MAPK signalling pathway by targeting TRAF6 in trophoblasts. Moreover, milk exosomes loaded with miR-410-3p mimic reached the maternal-fetal interface and aggravated embryo absorption in female mice. Clinically, miR-410-3p and TRAF6 expression were abnormal and negatively correlated in the placental villi of SA patients. Our findings indicated that exosome-derived miR-410-3p plays an important role between SA serum and trophoblasts in intercellular communication, suggesting a novel mechanism by which serum exosomal miRNA regulates trophoblasts in SA patients.


Subject(s)
Abortion, Spontaneous , Exosomes , MicroRNAs , Humans , Female , Pregnancy , Mice , Animals , Exosomes/metabolism , TNF Receptor-Associated Factor 6/metabolism , Placenta/metabolism , MicroRNAs/genetics , Trophoblasts/metabolism , Epithelial-Mesenchymal Transition/genetics , Cell Proliferation , Cell Movement/genetics
11.
Phys Chem Chem Phys ; 26(6): 4989-5001, 2024 Feb 07.
Article in English | MEDLINE | ID: mdl-38258432

ABSTRACT

HIV-1 protease (PR) plays a crucial role in the treatment of HIV as a key target. The global issue of emerging drug resistance is escalating, and PR mutations pose a substantial challenge to the effectiveness of inhibitors. HIV-1 PR is an ideal model for studying drug resistance to inhibitors. The inhibitor, darunavir (DRV), exhibits a high genetic barrier to viral resistance, but with mutations of residues in the PR, there is also some resistance to DRV. Inhibitors can impede PR in two ways: one involves binding to the active site of the dimerization protease, and the other involves binding to the PR monomer, thereby preventing dimerization. In this study, we aimed to investigate the inhibitory effect of DRV with a modified inhibitor on PR, comparing the differences between wild-type and mutated PR, using molecular dynamics simulations. The inhibitory effect of the inhibitors on PR monomers was subsequently investigated. And molecular mechanics Poisson-Boltzmann surface area evaluated the binding free energy. The energy contribution of individual residues in the complex was accurately calculated by the alanine scanning binding interaction entropy method. The results showed that these inhibitors had strong inhibitory effects against PR mutations, with GRL-142 exhibiting potent inhibition of both the PR monomer and dimer. Improved inhibitors could strengthen hydrogen bonds and interactions with PR, thereby boosting inhibition efficacy. The binding of the inhibitor and mutation of the PR affected the distance between D25 and I50, preventing their dimerization and the development of drug resistance. This study could accelerate research targeting HIV-1 PR inhibitors and help to further facilitate drug design targeting both mechanisms.


Subject(s)
HIV Protease Inhibitors , Darunavir , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , Dimerization , HIV Protease/chemistry , Molecular Dynamics Simulation , Mutation
12.
Heliyon ; 9(12): e22155, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38125500

ABSTRACT

Background: Polycystic ovary syndrome (PCOS) is a multifaceted endocrine and metabolic syndrome with complex origins and pathogenesis that has not yet been fully elucidated. Recently, the interconnection between gut microbiota and metabolic diseases has gained prominence in research, generating new insights into the correlation between PCOS and gut microbiota composition. However, the causal link between PCOS and gut microbiota remains relatively unexplored, indicating a crucial gap in current research. Methods: We conducted a two-sample Mendelian randomization analysis using summary statistics obtained from the MiBioGen Consortium's extensive genome-wide association studies (GWAS) meta-analysis, focusing on the gut microbiota. Summary statistics for PCOS were acquired from the FinnGen Consortium R7 release data. Various statistical approaches, including inverse variance weighted, MR-Egger, maximum likelihood, weighted model, and weighted median, have been employed to investigate the causal association between the gut microbiota and PCOS. Additionally, we performed a reverse causal analysis. Cochran's Q statistic was used to assess the heterogeneity of the instrumental variables. Regarding the relationships between PCOS and specific genera within the gut microbiota, a significance level of P < 0.05 was observed, but only when q ≥ 0.1. Results: Our analysis revealed that specific microbial genera, namely Bilophila (P = 4.62 × 10-3), Blautia (P = 0.02), and Holdemania (P = 0.04), displayed a protective effect against PCOS. Conversely, the presence of the Lachnospiraceae family of bacteria was associated with a detrimental effect on PCOS (P = 0.04). Furthermore, reverse Mendelian randomization analysis confirmed the significant influence of Lachnospiraceae on PCOS. No significant variations in instrumental variables or evidence of horizontal pleiotropy were observed. Conclusions: The results revealed a definitive causal link between PCOS and the presence of Bilophila, Blautia, Holdemania, and Lachnospiraceae in the gut microbiota. This discovery could provide pivotal insights, leading to novel preventive and therapeutic approaches for PCOS.

13.
Cell Mol Biol (Noisy-le-grand) ; 69(13): 156-161, 2023 Dec 10.
Article in English | MEDLINE | ID: mdl-38158673

ABSTRACT

Neurodegenerative illnesses have long been handled clinically by traditional Chinese medicine. This study is the first time to explore the pharmacological basis of application in amyotrophic lateral sclerosis (ALS) through network pharmacology and molecular docking techniques. In the present investigation, the TCMSP database and HIT2 database were examined for 9 TCM constituents of Sheng Ji Yu Sui Decoction (SJYSD), and the desired sites for the components were searched in the Drugbank database. and the Sjysd-target network was constructed. Associated targets for Amyotrophic lateral sclerosis (ALS) were then retrieved and collected in the OMIM, TTD, Genecards and DisGeNET databases. Protein-protein interaction and enrichment analysis were performed for the common targets of drugs and diseases, and molecular anchoring for the chosen core targets and related molecules was carried out. The results showed that SJYSD had 100 active compounds corresponding to 598 targets. ALS has a total of 5,325 genes. SJYSD and ALS share 163 genes, and these targets involve PI3K-AKT signaling, p53 signaling and IL-17 signaling, etc. The core components of luteolin and quercetin were discovered and may be used to treat ALS by regulating PI3K-AKT signaling pathway by HSP90AB1 protein.


Subject(s)
Amyotrophic Lateral Sclerosis , Drugs, Chinese Herbal , Humans , Network Pharmacology , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/genetics , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt , Medicine, Chinese Traditional , Technology , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use
14.
Toxicology ; 499: 153654, 2023 11.
Article in English | MEDLINE | ID: mdl-37866543

ABSTRACT

Lead (Pb), as a heavy metal that is easily exposed in daily life, can cause damage to various systems of body. Apoptosis is an autonomous cell death process regulated by genes in order to maintain the stability of internal environment, which plays an important role in the development of nervous system. RB binding protein 4 (RBBP4) is one of the core histone binding subunits and is closely related to the apoptosis process of nervous system cells. However, it is not known whether RBBP4 can regulate neuronal apoptosis in lead-exposed environments. We exposed PC12 cells to 0 µM (control group), 1 µM, and 100 µM PbAc for 24 h to obtain cell samples. The female rats ingested drinking water containing 0, 0.5 g/L, and 2.0 g/L PbAc from the first day of pregnancy to three weeks after delivery to obtain hippocampal tissue samples from mammary rats. The results of TUNEL showed that lead exposure promoted the onset of apoptosis in cells and hippocampus. The mRNA and protein levels of the apoptosis-related protein Survivin were significantly reduced in the lead-exposed group compared to the control group. In addition, we found that lead exposure reduces the mRNA and protein levels of RBBP4 in PC12 cells and hippocampus, and increases the mRNA and protein levels of NFκB p65. Moreover, inhibiting NFκB p65 can reverse the decrease in RBBP4 expression in the lead exposure model. Overexpression of RBBP4 increased Survivin expression and reduced apoptosis induced by lead exposure. This suggests that lead exposure induces apoptosis through the NFκB p65/RBBP4/Survivin signaling pathway.


Subject(s)
Apoptosis , Lead , Pregnancy , Female , Rats , Animals , Survivin/metabolism , Lead/toxicity , Signal Transduction , PC12 Cells , RNA, Messenger/metabolism , NF-kappa B/metabolism
15.
Kidney Dis (Basel) ; 9(4): 277-284, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37900003

ABSTRACT

Introduction: The aim of the study was to investigate biventricular structural and functional abnormalities in pre-dialysis patients across stages of chronic kidney disease (CKD) by cardiac magnetic resonance (CMR). Methods: Fifty-one CKD patients with CMR exams were retrospectively analyzed. Patients were divided into three groups according to estimated glomerular filtration rate (eGFR): CKD 1 group (patients with normal eGFR≥90 mL/min/1.73 m2, n = 20), CKD 2-3 group (patients with eGFR< 90 to ≥30 mL/min/1.73 m2, n = 14), and CKD 4-5 group (patients with eGFR<30 mL/min/1.73 m2, n = 17). Twenty-one age- and sex-matched healthy controls (HC) were recruited. CMR-derived left ventricular (LV) and right ventricular (RV) structural and functional measures were compared. Association between CMR parameters and clinical measures was assessed. Results: There was an increasing trend in RV mass index (RVMi) and LV mass index (LVMi) with the occurrence and development of CKD from HC group to CKD 4-5 group although no significant difference was observed between CKD 1 group and HC group. LV global radial strain and LV global circumferential strain dropped and native T1 value elevated significantly in CKD 4-5 group compared with the other three groups (all p < 0.05), while RV strain measures, RV ejection fraction, and LV ejection fraction showed no significant difference among 4 groups (all p > 0.05). Elevated LV end-diastolic volume index (ß = 0.356, p = 0.016) and RV end-systolic volume index (ß = 0.488, p = 0.001) were independently associated with RVMi. Increased systolic blood pressure (ß = 0.309, p = 0.004), LV end-systolic volume index (ß = 0.633, p < 0.001), and uric acid (ß = 0.261, p = 0.013) were independently associated with LVMi. Meanwhile, serum phosphorus (ß = 0.519, p = 0.001) was independently associated with native T1 value. Conclusion: In pre-dialysis CKD patients, left and right ventricular remolding has occurred. RVMi and LVMi were the first changed CMR indexes in the development of CKD when eGFR began to drop. Because fluid volume overload was the independent risk factor for RVMi and LVMi increase, reasonable controlling fluid volume overload may slow down the progression of biventricular remolding and may reduce related cardiovascular disease risk.

16.
Cell Mol Life Sci ; 80(11): 313, 2023 Oct 05.
Article in English | MEDLINE | ID: mdl-37796323

ABSTRACT

Papain-like protease (PLpro), a non-structural protein encoded by SARS-CoV-2, is an important therapeutic target. Regions 1 and 5 of an existing drug, GRL0617, can be optimized to produce cooperativity with PLpro binding, resulting in stronger binding affinity. This work investigated the origin of the cooperativity using molecular dynamics simulations combined with the interaction entropy (IE) method. The regions' improvement exhibits cooperativity by calculating the binding free energies between the complex of PLpro-inhibitor. The thermodynamic integration method further verified the cooperativity generated in the drug improvement. To further determine the specific source of cooperativity, enthalpy and entropy in the complexes were calculated using molecular mechanics/generalized Born surface area and IE. The results show that the entropic change is an important contributor to the cooperativity. Our study also identified residues P248, Q269, and T301 that play a significant role in cooperativity. The optimization of the inhibitor stabilizes these residues and minimizes the entropic loss, and the cooperativity observed in the binding free energy can be attributed to the change in the entropic contribution of these residues. Based on our research, the application of cooperativity can facilitate drug optimization, and provide theoretical ideas for drug development that leverage cooperativity by reducing the contribution of entropy through multi-locus binding.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Entropy , Molecular Dynamics Simulation
18.
Phys Chem Chem Phys ; 25(34): 22941-22951, 2023 Aug 30.
Article in English | MEDLINE | ID: mdl-37593785

ABSTRACT

Recent studies have shown that DNA methylation is an important epigenetic marker. Two prominent forms are methylation of the C5 position of cytosine and methylation of the C6 position of adenine. Given the vital significance of DNA methylation, investigating the mechanisms that influence protein binding remains a compelling pursuit. This study used molecular dynamics simulations to investigate the binding patterns of R2R3 protein and four differentially methylated DNAs. The alanine scanning combined with interaction entropy method was used to identify key residues that respond to different methylation patterns. The order of protein binding ability to DNA is as follows: unmethylated DNA > A11 methylation (5'-A6mAC-3') (6m2A system) > A10 methylation (5'-6mAAC-3') (6m1A system) > both A10 and A11 methylation (5'-6mA6mAC-3') (6mAA system) > C12 methylation (5'-AA5mC-3') (5mC system). All methylation systems lead to the sixth α helix (H6) (residues D105 to L116) moving away from the binding interface, and in the 5mC and 6m1A systems, the third α helix (H3) (residues G54 to L65) exhibits a similar trend. When the positively charged amino acids in H3 and H6 move away from the binding interface, their electrostatic and van der Waals interactions with the negatively charged DNA are weakened. Structural changes induced by methylation contributed to the destabilization of the hydrogen bond network near the original binding site, except for the 6m2A system. Moreover, there is a positive correlation between the number of methylated sites and the probability of distorting the DNA structure. Our study explores how different methylation patterns affect binding and structural adaptability, and have implications for drug discovery and understanding diseases related to abnormal methylation.


Subject(s)
5-Methylcytosine , DNA , Kinetics , Adenine
19.
Int J Biol Macromol ; 247: 125690, 2023 Aug 30.
Article in English | MEDLINE | ID: mdl-37423448

ABSTRACT

DNA methylation as an important epigenetic marker, has gained attention for the significance of three oxidative modifications (hydroxymethyl-C (hmC), formyl-C (fC), and carboxyl-C (caC)). Mutations occurring in the methyl-CpG-binding domain (MBD) of MeCP2 result in Rett. However, uncertainties persist regarding DNA modification and MBD mutation-induced interaction changes. Here, molecular dynamics simulations were used to investigate the underlying mechanisms behind changes due to different modifications of DNA and MBD mutations. Alanine scanning combined with the interaction entropy method was employed to accurately evaluate the binding free energy. The results show that MBD has the strongest binding ability for mCDNA, followed by caC, hmC, and fCDNA, with the weakest binding ability observed for CDNA. Further analysis revealed that mC modification induces DNA bending, causing residues R91 and R162 closer to the DNA. This proximity enhances van der Waals and electrostatic interactions. Conversely, the caC/hmC and fC modifications lead to two loop regions (near K112 and K130) closer to DNA, respectively. Furthermore, DNA modifications promote the formation of stable hydrogen bond networks, however mutations in the MBD significantly reduce the binding free energy. This study provides detailed insight into the effects of DNA modifications and MBD mutations on binding ability. It emphasizes the necessity for research and development of targeted Rett compounds that induce conformational compatibility between MBD and DNA, enhancing the stability and strength of their interactions.


Subject(s)
Rett Syndrome , Humans , Rett Syndrome/genetics , Rett Syndrome/metabolism , Methyl-CpG-Binding Protein 2/chemistry , DNA/chemistry , Mutation , DNA Methylation , Protein Binding
20.
BMC Oral Health ; 23(1): 351, 2023 06 02.
Article in English | MEDLINE | ID: mdl-37268939

ABSTRACT

OBJECTIVE: The aim was to investigate the prevalence and clinical and 3-dimensional (3D) radiographic characteristics of supernumerary teeth (ST) in a paediatric dental population. The factors associated with ST eruption potential were analysed, and the optimal extraction time for nonerupted ST was discussed. METHODS: A retrospective study was performed in a 13,336-participant baseline population aged 3-12 years for whom panoramic radiographs had been obtained in the hospital from 2019 to 2021. The medical records and radiographic data were reviewed to identify patients with ST. Both the demographic variables and ST characteristics were recorded and analysed . RESULTS: In total, 890 patients with 1,180 ST were screened from the 13,336 baseline population. The ratio of males (679) to females (211) was approximately 3.2:1. Generally, ST occurred singularly and were frequently found in the maxilla (98.1%). A total of 40.8% of ST were erupted, and the 6-year-old age group presented the highest eruption rate (57.8%). The eruption rate of ST was highly negatively correlated with age. A total of 598 patients additionally underwent cone- beam computed tomography (CBCT). According to the CBCT images, the majority of ST were conical, normally oriented, palatally situated, nonerupted and symptomatic. The most common ST-associated complication was failed eruption of adjacent teeth. In addition, symptomatic ST were more common in the 7- to 8- and 9- to 10-year-old age groups. The eruption rate of ST was 25.3% among the patients who had undergone CBCT. A normal orientation and the labial position were significant protective factors for ST eruption, with odds ratios (ORs) of 0.004 (0.000-0.046) and 0.086 (0.007-1.002), respectively. Age and the palatal position were significant risk factors, with ORs of 1.193 (1.065-1.337) and 2.352 (1.377-4.02), respectively. CONCLUSIONS: This study provides a detailed analysis of ST characteristics in 3-12 year old children. Age as well as the position and orientation of ST were reliable predictors of the ST eruption. An age of 6 years old may be the optimal time for extraction of nonerupted ST to maximize the utilization of eruption potential and reduce the incidence of ST-associated complications.


Subject(s)
Tooth, Supernumerary , Male , Child , Female , Humans , Child, Preschool , Tooth, Supernumerary/diagnostic imaging , Tooth, Supernumerary/epidemiology , Retrospective Studies , Prevalence , Cone-Beam Computed Tomography/methods , Maxilla/diagnostic imaging , China/epidemiology
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