👤 Xi Jing

The interleukin (IL) plays a role in the development of acute pancreatitis (AP). However, the specific IL in AP has not been fully revealed. Therefore, the association between prospective IL and AP was studied via Mendelian randomization (MR). The HUGO Gene nomenclature committee (HGNC) database provided 47 interleukin related genes (ILRGs). ILRGs and differentially expressed genes (DEGs) from GSE194331 were overlapped to create differently expressed ILRGs (DE-ILRGs). The integrative epidemiology unit (IEU) open genome-wide association study (GWAS) database provided exposure and outcome datasets. Univariate MR (UVMR) analysis using MR-Egger, IVW, simple mode, and weighted mode was done. UVMR results were verified using sensitivity analysis. Drug prediction, MVMR analysis, and PPI network development were also performed. Six DE-ILRGs were obtained. IL27 and IL1RN were substantially causally linked with AP by UVMR analysis (OR = 0.926, P < 0.001 and OR = 1.031, P = 0.023). Our sensitivity analysis showed the dependability of our results. Direct effect of IL27 was suggested by MVMR analysis. In the cytokine receptor binding pathway, IL27 and IL1RN interacted with IL36G and IL1R2. TAE-684, ARQ-680, and 12 other IL1RN and 14 IL27 medications were predicted. IL1RN was identified as a risk factor for acute pancreatitis (AP), but IL27 was found to be a protective factor for AP. Show less

Subsurface dams have been recognized as one of the most effective measures for preventing saltwater intrusion. However, it may result in large amounts of residual saltwater being trapped upstream of the dam and take years to decades to remove, which may limit the utilization of fresh groundwater in coastal areas. In this study, field-scale numerical simulations were used to investigate the mechanisms of residual saltwater removal from a typical stratified aquifer, where an intermediate low-permeability layer (LPL) exists between two high-permeability layers, under the effect of seasonal sea level fluctuations. The study quantifies and compares the time of residual saltwater removal (Tre) for constant sea level (CSL) and seasonally varying sea level (FSL) scenarios. The modelling results indicate that, in most cases, seasonal fluctuations in sea level facilitate the dilution of residual saltwater and thus accelerate residual saltwater removal compared to a static sea level scenario. However, accounting for seasonal sea level variations may increase the required critical dam height (the minimum dam height required to achieve complete residual saltwater removal). Sensitivity analyses show that Tre decreases with increasing height of subsurface dam (Hd) under CSL or weaker sea level fluctuation scenarios; however, when the magnitude of sea level fluctuation is large, Tre changes non-monotonically with Hd. Tre decreases with increasing distance between subsurface dam and ocean for both CSL and FSL scenarios. We also found that stratification model had a significant effect on Tre. The increase in LPL thickness for both CSL and FSL scenarios leads to a decrease in Tre and critical dam height. Tre generally shows a non-monotonically decreasing trend as LPL elevation increases. These quantitative analyses provide valuable insights into the design of subsurface dams in complex situations. Show less

The application of rituximab has significantly enhanced the overall survival rates in patients with diffuse large B-cell lymphoma (DLBCL). Regrettably, a significant number of patients still progress to relapse/refractory DLBCL (rrDLBCL). Herein, we employed targeted sequencing of 55 genes to investigate if gene mutations could predict the progression to rrDLBCL. Additionally, we compared the mutation profiles at the time of DLBCL diagnosis with those found in rrDLBCL cases. Our findings highlighted significantly elevated mutation frequencies of Collectively, this study elucidates some of the genetic mechanisms contributing to the progression of rrDLBCL and suggests that the presence of Show less

Microplastics can enter the human body via direct body contact or the food chain, increasing the likelihood of adverse impacts on pregnancy and fetal development. We investigated the potential effects and modes of action of polystyrene nanoplastics (PS-NPs) in placenta and fetus using mice as a model species. Maternal PS-NP exposure (100 nm; 1 and 10 mg/L) via drinking water induced a significant decline in fetal weights at the higher exposure concentration. Abnormal morphologies of cells in the placenta and fetus were observed after exposure. For the placenta, transcriptomic analyses indicated that PS-NPs significantly disturbed cholesterol metabolism and complement and coagulation cascades pathways. Metabolomics showed appreciable metabolic disorders, particularly affecting sucrose and daidzein concentrations. For the fetal skeletal muscle, transcriptomics identified many significantly regulated genes, involving muscle tissue development, lipid metabolism, and skin formation. Transcriptomic analysis of the placenta and fetal skeletal muscle at the high PS-NP concentration showed that APOA4 and its transcriptional factors, facilitating cholesterol transportation, were significantly regulated in both tissues. Our study revealed that PS-NPs caused fetal growth restriction and significantly disturbed cholesterol metabolism in both placenta and fetus, offering new insights into the mechanisms underlying the placental and fetal effects in mice exposed to PS-NPs. Show less

As Alzheimer's disease (AD) is a neurodegenerative disease with a complex pathogenesis, the exploration of multi-target drugs may be an effective strategy for AD treatment. Multifunctional small molecular agents can be obtained by connecting two or more active drugs or privileged pharmacophores by multicomponent reactions (MCRs). In this paper, two series of polysubstituted pyrazine derivatives with multifunctional moieties were designed as anti-AD agents and synthesized by Passerini-3CR and Ugi-4CR. Since the oxidative stress plays an important role in the pathological process of AD, the antioxidant activities of the newly synthesized compounds were first evaluated. Subsequently, selected active compounds were further screened in a series of AD-related bioassays, including Aβ Show less

Observational studies have suggested an association between lipid-lowering drugs and inflammatory bowel disease (IBD) risk. This study aimed to assess the causal influence of lipid-lowering agents on IBD risk using Mendelian randomization analysis. In a population of 173,082 individuals of European ancestry, 55 single-nucleotide polymorphisms were identified as instrumental variables for 6 lipid-lowering drug targets (HMGCR, NPC1LC, PCSK9, LDLR, CETP and APOB). Summary statistics for the genome-wide association study of IBD, ulcerative colitis (UC) and Crohn's disease (CD) were obtained from the FinnGen consortium, Program in Complex Trait Genomics and UK Biobank. Inverse-variance weighted was employed as the primary MR method, and odds ratios (ORs) with 95% confidence intervals were reported as the results. Sensitivity analyses using conventional MR methods were conducted to assess result robustness. Gene-proxied inhibition of Niemann-Pick C1-like 1 (NPC1L1) was associated with an increased IBD risk (OR [95% CI]: 2.31 [1.38, 3.85]; p = .001), particularly in UC (OR [95% CI]: 2.40 [1.21, 4.74], p = .012), but not in CD. This finding was replicated in the validation cohort. Additionally, gene-proxied inhibition of low-density lipoprotein receptor was associated with reduced IBD (OR [95% CI]: .72 [.60, .87], p < .001) and UC risk (OR [95% CI]: .74 [.59, .92], p = .006), although this result was not replicated in the validation cohort. Other drug targets did not show significant associations with IBD, UC or CD risk. Inhibition of the lipid-lowering drug-target NPC1L1 leads to an increased IBD risk, mainly in the UC population. Show less

Tumor protein 53 (TP53) mutation in bladder carcinoma (BC), upregulates the transcription of carbamoyl phosphate synthetase 1 (CPS1), to reduce intracellular ammonia toxicity. To leverage ammonia combating BC, here, an intravesically perfusable nanoporter-encased hydrogel system is reported. A biomimetic fusogenic liposomalized nanoporter (FLNP) that is decorated with urea transporter-B (UT-B) is first synthesized with protonated chitosan oligosaccharide for bladder tumor-targeted co-delivery of urease and small interfering RNA targeting CPS1 (siCPS1). Mussel-inspired hydrogel featured with dual functions of bio-adhesion and injectability is then fabricated as the reservoir for intravesical immobilization of FLNP. It is found that FLNP-mediated UT-B immobilization dramatically induces urea transportation into tumor cells, and co-delivery of urease and siCPS1 significantly boosts ammonia accumulation in tumor inducing cell apoptosis. Treatment with hybrid system exhibits superior anti-tumor effect in orthotopic bladder tumor mouse model and patient-derived xenograft model, respectively. Combined with high-protein diet, the production of urinary urea increases, leading to an augmented intracellular deposition of ammonia in BC cells, and ultimately an enhanced tumor inhibition. Together, the work establishes that cascade modulation of ammonia in tumor cells could induce tumor apoptosis and may be a practical strategy for eradication of TP53-mutated bladder cancer. Show less

Nucleolar prominence is a biomarker of prostate cancer (CaP), and the nucleolar protein block of proliferation 1 (BOP1) participates in the development of CaP, which has great significance for CaP therapy. Thus, this study explored the mechanism of BOP1 in CaP development. BOP1 expression levels in the tumor tissues of CaP patients and in PC3 tumor cells were determined. The viability, apoptosis rate of PC3 cells, and apoptosis-related proteins levels were determined to explore the effect of BOP1 on tumor-cell growth BOP1 expression was upregulated in the tumor tissues and PC3 cells of CaP patients. BOP1 knockout reduced the activity of PC3 cells and induced apoptosis, significantly inhibiting the metastasis of PC3 cells. DUSP6 was overexpressed in tumor tissues and PC3 cells. BOP1 knockout inhibited DUSP6 expression and the MAPK pathway. DUSP6 overexpression reversed the inhibition of BOP1 siRNA (si-BOP1) on PC3 cells and the activated MAPK signaling pathway. This finding demonstrated that BOP1 promoted CaP progression by regulating the DUSP6/MAPK pathway. Show less

The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and ageing in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in ageing vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and ageing phenotypes. Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature ageing characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature ageing of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and ageing. Show less

Increasing evidence implicates endothelial dysfunction in the pathogenesis of Alzheimer's disease (AD). Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is essential in maintaining cerebrovascular function and can modulate the production and clearance of amyloid beta (Aβ). APPswe/PSdE1 (APP/PS1) mice display age-related Aβ accumulation and memory deficits. In order to make the model more clinically relevant with an element of endothelial dysfunction, we generated APP/PS1/eNOS Show less

Heterogeneous nuclear ribonucleoprotein (HnRNP) F is a member of HnRNP family proteins that participate in splicing of cellular newly synthesized mRNAs by specifically recognizing tandem guanine-tracts (G-tracts) RNA sequences. Whether HnRNP F could recognize viral-derived tandem G-tracts and affect virus replication remain poorly defined. The effect of HnRNP F on porcine reproductive and respiratory syndrome virus (PRRSV) propagation was evaluated by real-time PCR, western blotting, and plaque-forming unit assay. The association between HnRNP F and PRRSV guanine-rich segments (GRS) were analyzed by RNA pulldown and RNA immunoprecipitation. The expression pattern of HnRNP F was investigated by western blotting and nuclear and cytoplasmic fractionation. Knockdown of endogenous HnRNP F effectively blocks the synthesis of viral RNA and nucleocapsid (N) protein. Conversely, overexpression of porcine HnRNP F has the opposite effect. Moreover, RNA pulldown and RNA immunoprecipitation assays reveal that the qRMM1 and qRRM2 domains of HnRNP F recognize the GRS in PRRSV antigenomic RNA. Finally, HnRNP F is redistributed into the cytoplasm and forms a complex with guanine-quadruplex (G4) helicase DHX36 during PRRSV infection. These findings elucidate the potential functions of HnRNP F in regulating the proliferation of PRRSV and contribute to a better molecular understanding of host-PRRSV interactions. Show less

In China there are approximately 100 pig breeds, which show great diversity in their appearance. However, information on genome selection signatures, such as spine curvature, is scarce. Therefore, we used the fixation index (F Show less

Renal fibrosis is the final common result of a variety of progressive injuries leading to chronic renal failure. However, there are no effective clinical available drugs for the treatment. Notoginsenoside from Panax notoginseng could ameliorate renal fibrosis. We hypothesized that polysaccharide from this herb might have similar bioactivity. Here, we elucidated structure of a novel pectin-like polysaccharide designed SQD4S2 with a netty antenna backbone of glucogalacturonan substituted by glucoarabinan, glucurogalactan and galactose residues from this herb. Interestingly, SQD4S2 could reverse the morphological changes of human renal tubular HK-2 cells induced by TGF-β. Mechanism study suggested that this bioactivity might associate with N-cadherin (CDH2), Snail (SNAI1), Slug (SNAI2) depression and E-cadherin (CDH1) enhancement. In addition, SQD4S2 could impede critical fibrogenesis associated molecules such as α-SMA, fibronectin, vimentin, COL1A1, COL3A1, FN1 and ACTA2 expression induced by TGF-β in HK-2 cells. Current findings outline a novel leading polysaccharide for against renal fibrosis new drug development. Show less

PCBP-1, a multifunctional RNA binding protein, is expressed in various human cell/tissue types and involved in post-transcriptional gene regulation. PCBP-1 has important roles in cellular Iron homeostasis, mitochondrial stability, and other cellular activities involved in the pathophysiological process of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). However, it remains enigmatic whether PCPB-1 is associated with the pathogenesis of PD. In this study, we cloned and constitutively overexpressed PCBP-1 in rat PC12 cells (PC12 cell is the common cell line studying neurodegenerative disease include PD). RNA-seq was performed to analyze PCBP-1-regulated differentially expressed genes (DEGs) and alternative splicing events (ASEs) between control and PCBP1-overexpressed cells. GO and KEGG pathway analyses were performed to identify functional DEGs and alternatively spliced genes. Consequently, we validated PCBP-1-regulated genes using RT-qPCR. Finally, we downloaded CLIP-seq data from GEO (GSE84700) to analyze the mechanisms of PCBP-1's regulation of gene expression and ASEs by revealing the binding profile of PCBP-1 on its target pre-mRNAs. Overexpression of PCBP-1 partially regulated the ASE and expression of genes enriched in neuroinflammation and protein ubiquitination, which were also associated with PD pathogenesis. Moreover, RT-qPCR assay verified the PCBP-1-modulated expression of neuroinflammatory genes, like Show less

The melanocortin receptors (MC1R-MC5R) belong to class A G-protein-coupled receptors (GPCRs) and are known to have receptor-specific roles in normal and diseased states. Selectivity for MC4R is of particular interest due to its involvement in various metabolic disorders, including obesity, feeding regulation, and sexual dysfunctions. To further improve the potency and selectivity of MC4R (ant)agonist peptide ligands, we designed and synthesized a series of cyclic peptides based on the recent crystal structure of MC4R in complex with the well-characterized antagonist Show less

Intestinal barrier breakdown, a frequent complication of intestinal ischemia-reperfusion (I/R) including dysfunction and the structure changes of the intestine, is characterized by a loss of tight junction and enhanced permeability of the intestinal barrier and increased mortality. To develop effective and novel therapeutics is important for the improvement of outcome of patients with intestinal barrier deterioration. Recombinant human angiopoietin-like protein 4 (rhANGPTL4) is reported to protect the blood-brain barrier when administered exogenously, and endogenous ANGPTL4 deficiency deteriorates radiation-induced intestinal injury. To identify whether rhANGPTL4 may protect intestinal barrier breakdown induced by I/R. Intestinal I/R injury was elicited through clamping the superior mesenteric artery for 60 min followed by 240 min reperfusion. Intestinal epithelial (Caco-2) cells and human umbilical vein endothelial cells were challenged by hypoxia/ reoxygenation to mimic I/R Indicators including fluorescein isothiocyanate-conjugated dextran (4 kilodaltons; FD-4) clearance, ratio of phosphorylated myosin light chain/total myosin light chain, myosin light chain kinase and loss of zonula occludens-1, claudin-2 and VE-cadherin were significantly increased after intestinal I/R or cell hypoxia/reoxygenation. rhANGPTL4 treatment significantly reversed these indicators, which were associated with inhibiting the inflammatory and oxidative cascade, excessive activation of cellular autophagy and apoptosis and improvement of survival rate. Similar results were observed rhANGPTL4 can function as a protective agent against intestinal injury induced by intestinal I/R and improve survival Show less

Here, we investigate the role of SmERF73, a group VII ETHYLENE RESPONSE FACTOR stress response transcription factor, in the regulation of post-modification of the skeleton precursors of diterpene tanshinones in Salvia miltiorrhiza. Most genes found to be involved in tanshinone biosynthesis are located on chromosome 6, and five of these genes comprise a large gene cluster in S. miltiorrhiza. We found that SmERF73 overexpression in S. miltiorrhiza coordinately up-regulated the transcription of seven tanshinone biosynthetic genes, four of which were located in the tanshinone gene cluster, consequently increasing tanshinone accumulation, while SmERF73 silencing reduced corresponding gene transcription and tanshinone accumulation. SmERF73 recognizes GCC-box promoter elements of four tanshinone-associated genes (DXR1, CPS1, KSL1 and CYP76AH3) and activates their expression. Moreover, SmERF73 and its targets were up-regulated by stress elicitors; SmERF73 appears to be at least partly mediated by the jasmonic acid (JA) signaling pathway via interaction with SmJAZ3. SmERF73 coordinately regulates tanshinone biosynthetic gene expression, suggesting a potential link between tanshinone production and plant stress responses. Show less

Many psychiatric disorders are characterized by a strong sex difference, but the mechanisms behind sex-bias are not fully understood. DNA methylation plays important roles in regulating gene expression, ultimately impacting sexually different characteristics of the human brain. Most previous literature focused on DNA methylation alone without considering the regulatory network and its contribution to sex-bias of psychiatric disorders. Since DNA methylation acts in a complex regulatory network to connect genetic and environmental factors with high-order brain functions, we investigated the regulatory networks associated with different DNA methylation and assessed their contribution to the risks of psychiatric disorders. We compiled data from 1408 postmortem brain samples in 3 collections to identify sex-differentially methylated positions (DMPs) and regions (DMRs). We identified and replicated thousands of DMPs and DMRs. The DMR genes were enriched in neuronal related pathways. We extended the regulatory networks related to sex-differential methylation and psychiatric disorders by integrating methylation quantitative trait loci (meQTLs), gene expression, and protein-protein interaction data. We observed significant enrichment of sex-associated genes in psychiatric disorder-associated gene sets. We prioritized 2080 genes that were sex-biased and associated with psychiatric disorders, such as NRXN1, NRXN2, NRXN3, FDE4A, and SHANK2. These genes are enriched in synapse-related pathways and signaling pathways, suggesting that sex-differential genes of these neuronal pathways may cause the sex-bias of psychiatric disorders. Show less

Orf virus (ORFV) is a member of the genus Parapoxvirus and family Poxviridae. The virus has a worldwide distribution and infects sheep, goats, humans, and wild animals. However, due to the complex structure of the poxvirus, the underlying mechanism of the entry and infection by ORFV remains largely unknown. ORFV ORF047 encodes a protein named L1R. Poxviral L1R serves as the receptor-binding protein and blocks virus binding and entry independently of glycosaminoglycans (GAGs). The study aimed to identify the host interaction partners of ORFV ORF047. Yeast two-hybrid cDNA library of sheep testicular cells was applied to screen the host targets with ORF047 as the bait. ORF047 was cloned into a pBT3-N vector and expressed in the NMY51 yeast strain. Then, the expression of bait proteins was validated by Western blot analysis. Sheep SERP1and PABPC4 were identified as host target proteins of ORFV ORF047, and a Co-IP assay further verified their interaction. New host cell proteins SERP1and PABPC4 were found to interact with ORFV ORF047 and might involve viral mRNA translation and replication. Show less

Our daily life depends on muscle contraction, a process that is controlled by the neuromuscular junction (NMJ). However, the mechanisms of NMJ assembly remain unclear. Here we show that Rapsn, a protein critical for NMJ formation, undergoes liquid-liquid phase separation (LLPS) and condensates into liquid-like assemblies. Such assemblies can recruit acetylcholine receptors (AChRs), cytoskeletal proteins, and signaling proteins for postsynaptic differentiation. Rapsn LLPS requires multivalent binding of tetratricopeptide repeats (TPRs) and is increased by Musk signaling. The capacity of Rapsn to condensate and co-condensate with interaction proteins is compromised by mutations of congenital myasthenic syndromes (CMSs). NMJ formation is impaired in mutant mice carrying a CMS-associated, LLPS-deficient mutation. These results reveal a critical role of Rapsn LLPS in forming a synaptic semi-membraneless compartment for NMJ formation. Show less

Metastasis and chemoresistance are major causes of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC), manipulated by multiple factors including deubiquitinating enzyme (DUB). DUB PSMD14 is reported to be a promising therapeutic target in various cancers. Here, we explored the antitumor activity of Thiolutin (THL), the PSMD14 inhibitor, as a new therapy strategy in ESCC. Show less

Esophageal squamous cell carcinoma (ESCC) is one of the most common lethal cancers in the world. Dysregulation of purine-rich element binding protein alpha (PURα), which contributes to the initiation of PURΑ syndrome, is reportedly involved in the progression of multiple cancers, but its function and underlying mechanisms in ESCC progression remain unclear. Here, we first demonstrated that PURα promoted cell growth, migration and invasion in ESCC both in vitro and in vivo. An immunohistochemistry assay was then performed on 225 ESCC tissues, showing that high PURα expression was positively associated with lymph node metastasis and the AJCC stage, and the ESCC patients with positive PURα expression had worse survival. In addition, RNA sequencing implied that PURα induced epithelial-mesenchymal transition (EMT) in ESCC, which was further confirmed by qPCR, Western blotting and immunofluorescence analyses. Mechanistically, PURα enhanced the transcription of Snail2 by binding to its promoter region. Knockdown of Snail2 reversed PURα-induced EMT and inhibited the migration and invasion of ESCC cells. In conclusion, this study indicated that PURα promotes Snail2 transcriptional activity to induce EMT during ESCC progression. Show less

Selenium (Se) is an essential trace element for living organisms and plays diverse biological roles. Endometritis is a common reproductive disorder in dairy cows, causing huge economic losses. In this study, we explored the effects of Se on lipopolysaccharide (LPS)-induced endometritis in mice and expounded its underlying mechanism of action. We validated the anti-inflammatory effects of Se in vivo by establishing a mouse model of endometriosis induced by LPS. Se significantly reversed the LPS-induced uterine histopathological changes, MPO activity and inflammatory cytokine levels in vivo. Simultaneously, TLR4 and its downstream signaling pathways, lipid rafts and cholesterol levels in the tissues were also attenuated by Se under LPS stimulation. In addition, the molecular mechanism of the Se anti-inflammatory effect was clarified in mouse endometrial epithelial cells. Se inhibited TLR4-mediated NF-κB and IRF3 signal transduction pathways to reduce the production of inflammatory factors. We found that Se promoted the consumption of cholesterol to suppress the lipid rafts coming into being and inhibited the TLR4 positioning to the lipid raft to prevent the inflammatory response caused by LPS. Meanwhile, Se activated the LxRα-ABCA1 pathway to cause the outflow of cholesterol in cells. The anti-inflammatory effect of Se was disrupted by silencing LxRα. In conclusion, Se exerted anti-inflammatory effects most likely by the LxRα-ABCA1 pathway activation, which inhibited lipid rafts by depleting cholesterol and ultimately impeded the migration of TLR4 to lipid rafts. Show less

Reprogramming of the tumor immune microenvironment is a salient feature during metastasis in LUAD. miR-24-3p and KLF8, which are key regulators of the tumor immune microenvironment, had been proved to show metastasis-promoting property in LUAD. However, whether miR-24-3p could regulate LUAD metastasis by targeting KLF8 remains unclear. This study explored the functions and mechanisms of miR-24-3p/KLF8 signaling in advanced LUAD. The expression level of miR-24-3p and KLF8 were tested in LUAD patients, and the corelation of miR-24-3p and KLF8 was evaluated. The interaction of miR-24-3p and KLF8 was demonstrated by luciferase reporter activity assay, Show less

Valproic acid (VPA) as a widely used primary medication in the treatment of epilepsy is associated with reversible or irreversible hepatotoxicity. Long-term VPA therapy is also related to increased risk for the development of non-alcoholic fatty liver disease (NAFLD). In this review, metabolic elimination pathways of VPA in the liver and underlying mechanisms of VPA-induced hepatotoxicity are discussed. We searched in PubMed for manuscripts published in English, combining terms such as "Valproic acid", "hepatotoxicity", "liver injury", and "mechanisms". The data of screened papers were analyzed and summarized. The formation of VPA reactive metabolites, inhibition of fatty acid β-oxidation, excessive oxidative stress and genetic variants of some enzymes, such as CPS1, POLG, GSTs, SOD2, UGTs and CYPs genes, have been reported to be associated with VPA hepatotoxicity. Furthermore, carnitine supplementation and antioxidants administration proved to be positive treatment strategies for VPA-induced hepatotoxicity. Therapeutic drug monitoring (TDM) and routine liver biochemistry monitoring during VPA-therapy, as well as genotype screening for certain patients before VPA administration, could improve the safety profile of this antiepileptic drug. Show less

Chronic apical periodontitis (CAP) is defined as chronic inflammation of the dental pulp and root canal system. Porphyromonas endodontalis lipopolysaccharide ( P. endodontalis LPS) plays an important role in inducing an inflammatory response in CAP. microRNA-146a (miR-146a) is a key regulator of inflammation and is induced by LPS. Hairy and enhancer-of-split related with YRPW motif 2 (Hey2) has been confirmed to be induced by the Notch signaling pathway, which is involved in tooth development, pulp regeneration, and repair after injury. Our study aimed to investigate the functional role of miR-146a via the targeting of Hey2 in CAP as well as the underlying mechanism. Compared with 13 healthy controls, miR-146a and Hey2 expressions were significantly higher in 20 patients with CAP. In addition, miR-146a, Hey2, interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α expressions were significantly increased in MC3T3-E1 cells stimulated with different concentrations (0-20 μg/mL) of P. endodontalis LPS for different amounts of time (0-48 hours). Moreover, miR-146a, which acts as an anti-inflammatory mediator, negatively regulated the expression of IL-6, IL-1β, and TNF-α, and Hey2 was confirmed as a target gene of miR-146a by a luciferase reporter assay. Hey2 also negatively regulated miR-146a, IL-6, IL-1β, and TNF-α expressions, and P. endodontalis LPS strongly induced Hey2 recruitment to the IL-6 promoter (-400 ~ -200 bp). These findings suggest that miR-146a and Hey2 form a mutual negative feedback regulatory loop, demonstrating a novel mechanism that regulates inflammatory responses in CAP. Show less

Spinal cord injury (SCI) is a common demyelinating disorder of the central nervous system. The differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs), which induce myelination, plays a critical role in the functional recovery following SCI. In this study, the effect of low frequency pulsed electromagnetic field (PEMF) on the differentiation of OPCs and the potential underlying mechanisms were investigated. OPCs were randomly divided into the PEMF and non-PEMF (NPEMF) groups. Immunofluorescence and western blot assays were performed to assess the expression levels of OLs stage-specific markers after 3, 7, 14, and 21 days of PEMF or NPEMF exposure. qRT-PCR was used to further assess the expression levels of miR-219-5p, miR-338, miR-138, and miR-9, which are associated with OPCs differentiation, and the expression levels of genes associated with miR-219-5p. Finally, following PEMF or NPEMF exposure, qRT-PCR and western blot assays were performed to explore the relationship between miR-219-5p and Lingo1 and between miR-219-5p and PEMF in promoting OPCs differentiation. PEMF promoted the differentiation of OPCs. PEMF upregulated the expression level of miR-219-5p and downregulated the expression level of Lingo1 during the differentiation of OPCs. Under PEMF exposure, miR-219-5p targeted Lingo1 and reversed the inhibitory effect of miR-219-5p inhibitor on OPCs differentiation. In addition, PEMF synergized with miR-219-5p to promote OPCs differentiation. Our results, for the first time, indicated that PEMF promoted OPCs differentiation by regulating miR-219-5p activity in vitro. Show less