Thyroid Hormone Signaling Pathway Research Articles

Candidate genes for litter size in Xinjiang sheep identified by Specific Locus Amplified Fragment (SLAF) sequencing

The aim of this study was to investigate the selection signatures at a genome-wide level in ‘Pishan’ sheep using Specific Locus Amplified Fragment (SLAF)-seq. Blood samples from 126 ewes were sequenced using SLAF tags, and the ovarian tissues from 8 ewes (Bashbay sheep, a single litter size group (SG group); ‘Pishan’ sheep, double litter size group (DG group)) were collected to detect expression levels by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Selection signature analysis was performed using global fixation index (Fst) and nucleotide diversity (π) ratio. A total of 1,192,168 high-quality SLAFs were identified. Notably, 2380 candidate regions under selection using two approaches were identified. A total of 2069 genes were identified, which were involved in dopaminergic synapses, thyroid hormone synthesis, ovarian steroidogenesis and thyroid hormone signalling pathways. Furthermore, Growth Differentiation Factor 9 (GDF9), Period Circadian Regulator 2 (PER2), Thyroid Stimulating Hormone Receptor (TSHR), and Nuclear Receptor Coactivator 1 (NCOA1) reside within these regions and pathways. The expression levels of GDF9 and PER2 genes in sheep tissue of the DG group were significantly higher than those in the SG group. These genes are interesting candidates for litter size and provide a starting point for further identification of conservation strategies for ‘Pishan’ sheep.

Elucidation of the potential antioxidant compound and mechanism of mung bean using network pharmacology and in vitro anti-oxidative activity

Mung bean is rich in bioactive components, but the main compound and pharmacological mechanism in reducing oxidative and free radical damage are unclear. Network pharmacology and 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) radical scavenging activities were employed to uncover the antioxidant mechanism of potentially active compounds, considering the interactions between mung bean targets and oxidative and free radical damage. These key targets were analyzed by protein–protein interactions (PPIs), and key genes were used to find the biological pathway and therapeutic mechanism by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The results showed that five antioxidant components and 18 mung bean targets were screened. β-carotene and vitexin both played a crucial role in mung bean against oxidative and free radical damage, and the ABTS radical scavenging activities of β-carotene and vitexin were 94.84 and 87.79%, which were equivalent to those of vitamin C. Key targets may be AR, HSP90AA1, MYC, and CASP3 for mung bean to exert antioxidant activity. GO and KEGG indicated that mung bean may mainly act on thyroid hormone signaling pathway, estrogen signaling pathway, p53 signaling pathway, etc. In vitro antioxidant activity tests showed that the bioactive ingredients of mung beans had great antioxidant activity. Network pharmacology analysis also revealed the underlying molecular mechanisms of oxidative and free radical damage. This study provides new insights and evidence to explore the bioactive compounds and biological functions of food cereals and legumes, as well as a reference for the functional evaluation of food ingredients and the development of functional foods.

Screening of key biomarkers in osteoporosis: Evidence from bioinformatic analysis.

To analyze the expression characteristics of osteoporosis-related genes by bioinformatics and elucidate the pathogenesis of osteoporosis. The differentially expressed genes (DEGs), microRNA (miRNA), and genes with differentially methylated regions (DMRS) in promoters were identified. The protein-protein interaction (PPI) network was constructed and performed. The Clue Gene Ontology analysis and miRNA-mRNA (messenger RNA) regulatory network were constructed using Cytoscape. Fifty-nine DEGs, 10 differential miRNAs, and 2083 genes with DMRs were screened out. The Proteasome-Modulator (PSMD) family proteins and estrogen receptor 1 (ESR1) are vital for the PPI analysis of DEGs. The interaction network of the Smad3 protein showed that the degree of connection to ESR1, PSMD11, and transcription factor 4 (TCF4) is very high. Homo sapiens (hsa)-miR-106b-5p was differential and regulated TCF4 through building the miRNA-mRNA regulatory network. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment of DEGs focused on vascular smooth muscle contraction, thyroid hormone signaling pathway, and estrogen signaling pathway. The Gene Ontology (GO) function analysis of genes with DMRs in promoters was primarily concentrated in the cell differentiation, positive regulation of CDP-diacylglycerol-serine O-phosphatidyltransferase activity, and positive regulation of C-palmitoyltransferase activity. The KEGG enrichment of genes with DMRs in promoters largely focused on glycerol phospholipid metabolism, histidine metabolism, Adenosine 5'-monophosphate-activated protein kinase signaling pathway, Hedgehog signaling pathway, and mRNA surveillance pathway. Hsa-miRNA-106b-5p regulates bone formation and the pathogenesis of osteoporosis by controlling TCF4, and methylation modification of TCF4 can also affect the pathogenesis of osteoporosis.

TSH-SPP1/TRβ-TSH positive feedback loop mediates fat deposition of hepatocyte: Crosstalk between thyroid and liver.

AimsWe conducted this study with two aims: (1) whether TRβ could be damaged by NAFLD, thereby represent thyroid hormone resistance-like manifestation and (2) to analyze the potential role of SPP1 in TH signaling pathway on the process of NAFLD. This study is expected to provide a new perspective on the therapeutic mechanism in the pathological course of NAFLD.MethodsA total of 166 patients diagnosed with type 2 diabetes mellitus (T2DM) were enrolled in this study. All patients had a BMI above 24 kg/m2 and were stratified into two groups: NAFLD and Non-NAFLD groups. Ages, gender, BMI, duration of diabetes and biochemical markers were obtained from participants’ records. We downloaded the dataset GSE48452 from GEO. The Pathview library was used to make the thyroid hormone signaling pathway visualization. The CIBERSORT algorithm was applied to calculate the infiltrated immune cells in obese NAFLD patients. C57BL/6 mice were randomly selected to constitute the normal control (NC) group and were fed a normal chow diet; the rest of the mice were fed a high-fat diet (HFD). After 12 weeks HFD feeding, the mice were sacrificed by cervical dislocation, and blood samples were collected. Mouse livers were also collected; one part of each liver was fixed in 10% formalin for histological analysis, and the other part was snap-frozen for subsequent molecular analyses. To explore the relationship between SPP1, TRβ and lipid deposition in hepatocytes, HepG2 cells were treated with 50 μ M concentration of PA and/or 20 ng/ml concentration of rh-SPP1 for 48h. In addition, the PC3.1-TRβ plasmid was constructed for further validation in HepG2 cells. We used THP-1 cells to construct an M1 macrophage model in vitro. We then analyzed THP-1 cells treated with various concentrations of PA or TSH.Results(1) After adjusting for all factors that appeared P value less than 0.1 in the univariate analysis, BMI, TSH, and FT3 were significant independent risk factors of NAFLD (ORs were 1.218, 1.694, and 2.259, respectively); (2) A further analysis with BMI stratification indiacted that both FT3 and TSH had a significant change between individuals with NAFLD and Non-NAFLD in obesity subgroup; however, there was no statistic difference in over-weight group; (3) Bioinformatics analysis of GSE48452 had shown that several key molecular (including TRβ) of thyroid hormone pathway affected by NAFLD induced transcriptomic changes and the expression levels of SPP1, FABP4 and RPS4Y1 were significantly higher, while the expression levels of PZP and VIL1 were significantly decreased in NAFLD patients(adjusted p < 0.05, |logFC| > 1.0). The CIBERSORT algorithm showed increased M0 and M1, decreased M2 macrophage infiltration in NAFLD with comparison to healthy obese group; (4) After 12 weeks of HFD-feeding, the obesity mice had significantly higher serum TSH and In IHC-stained liver sections of obesity group, the intensity of SPP1 had a significantly increased, while TRβ reduced; (5) In vitro studies have shown SPP1 aggravated lipid deposition in hepatic cells dependent on down-regulating the expression of TRβ and TSH acts to promote secretion of SPP1 in M1 macrophage cells.ConclusionsSPP1 secretion induced by M1 macrophage polarization, which may down-regulates TRβ in hepatocytes via paracrine manner, on the one hand, the lipid deposition aggravating in liver, on the other hand, a compensatory increase of TSH in serum. The increased TSH can further lead to the following SPP1 secretion of M1 macrophage. The positive feedback crosstalk between thyroid and liver, may be plays an important role in maintaining and amplifying pathological process of NAFLD.

Exploring the Anti-Inflammatory Mechanism of Tieguanyin (TGY) Volatile Compounds Based on Gas Chromatography-Mass Spectrometry (GCMS)- Network Pharmacology.

Inflammation is a common disease which can induce many diseases. There are unique advantages of Traditional Chinese Medicine (TCM) to anti-inflammation. Tieguanyin (TGY) is a well-known beverage; the quality is determined by aroma, taste, liquor color, and shape. The volatile compounds produce the flavor of tea, which can be lost with the increase of storage time. TGY has an excellent antiinflammatory effect; its volatile compounds also have an anti-inflammatory impact that is unclear. This study aimed to identify volatile compounds and anti-inflammatory mechanisms within the validity period (TGY1) and the out-of-date (TGY2). The volatile compounds of TGY1 and TGY2 were analyzed with headspace solid-phase microextraction (HS-PME) and identified by Gas chromatography-mass spectrometry (GC-MS). The percentage of volatile compounds was calculated by the peak area normalization method. The compounds of the targets were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP), PubChem Database, and Swiss Target Prediction database. Next, the disease potential targets were screened by the GeneCards database, Online Mendelian Inheritance in Man (OMM) database, and Therapeutic Target Database (TTD). Furthermore, core targets were screened by the Search Tool for the Retrieval of Inter-acting Genes/Proteins (STRING) database. Then, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of core targets was performed by the ClueGo plugin Cytoscape 3.7.1 software. At last, Autodock vina software performed molecular docking between the main compounds and core targets. Significant differences in volatile compounds and percentage contents in TGY were observed; the 61 volatile compounds in TGY1 and 57 volatile compounds in TGY2 were identified. After excluding the unidentified compounds, a total of 47 volatile compounds were obtained from TGY1 and TGY2. With the use of network pharmacology, 34 core targets and 23 signaling pathways from TGY1, 28 core targets, and 19 signaling pathways from TGY2 were screened. The main common core targets of TGY1 and TGY2 contained MAPK3, TNF, MAPK1, SRC, etc., while the main different core targets included PTGS2, CAT, etc. A total of 12 biological processes are shared by TGY1 and TGY2, among which the cellular response to oxidative stress is the primary biological process. The different biological processes of TGY1 and TGY2 include cellular response to lipopolysaccharide, androgen receptor signaling pathway, etc. There were 14 common signaling pathways in TGY1 and TGY2, among which the thyroid hormone signaling pathway is the main common signaling pathway. The differential signaling pathways in TGY1 and TGY2 included the erbB signaling pathway, Chagas disease, etc. Molecular docking results showed that the ordinand and differential volatile compounds of TGY1 and TGY2 had different binding forces with the core targets. The GC-MS experiment showed significant differences in volatile compounds and percentage contents in TGY1 and TGY2. Network pharmacology indicated that they have anti-inflammatory effects. Besides, they were different in core targets, biological processes, and signaling pathways but shared similar anti-inflammatory mechanisms. Molecular docking results showed that the binding force of the TGY1 compounds to the core target is greater than that of the TGY2. Therefore, expired TGY affects volatile compounds, resulting in differences in the anti-inflammatory mechanism. The study provided a theoretical framework for further development and application of used medicinal and edible species. In addition, the application of expired TGY under safe conditions can also have anti-inflammatory effects. These results shed new light on the rational use of resources.

Metformin is Protective Against the Development of Mood Disorders.

Mood disorders are a major cause of disability, and current treatment options are inadequate for reducing the burden on a global scale. The aim of this project was to identify drugs suitable for repurposing to treat mood disorders. This mixed-method study utilized gene expression signature technology and pharmacoepidemiology to investigate drugs that may be suitable for repurposing to treat mood disorders. The transcriptional effects of a combination of drugs commonly used to treat mood disorders included regulation of the steroid and terpenoid backbone biosynthesis pathways, suggesting a mechanism involving cholesterol biosynthesis, and effects on the thyroid hormone signaling pathway. Connectivity Map analysis highlighted metformin, an FDA-approved treatment for type 2 diabetes, as a drug having global transcriptional effects similar to the mood disorder drug combination investigated. In a retrospective cohort study, we found evidence that metformin is protective against the onset of mood disorders. These results provide proof-of-principle of combining gene expression signature technology with pharmacoepidemiology to identify potential novel drugs for treating mood disorders. Importantly, metformin may have utility in the treatment of mood disorders, warranting future randomized controlled trials to test its efficacy.

Network Toxicology Guided Mechanism Study on the Association between Thyroid Function and Exposures to Polychlorinated Biphenyls Mixture.

Polychlorinated biphenyls (PCBs) are persistent and highly toxic pollutants, which can accumulate in organisms and produce toxic effects, especially damaging the function of thyroid hormones. So far, the molecular mechanism of PCBs mixture and their metabolites interfering with thyroid hormones has not been studied thoroughly except for individual compounds. In this study, PubMed, Web of Science, and STITCH databases were used to search PCBs and their corresponding target proteins. The intersection of PCBs and thyroid hormone dysfunction target proteins was obtained from GeneCards. The “compounds-targets-pathways” network was constructed by Cytoscape software. And KEGG and Go analyses were performed for key targets. Finally, molecular docking was used to verify the binding effect. Four major active components, five key targets, and 10 kernel pathways were successfully screened by constructing the network. Functional enrichment analysis showed that the interference was mediated by cancer, proteoglycans, PI3K-Akt, thyroid hormone, and FoxO signaling pathways. The molecular docking results showed that the binding energies were less than -5 kcal·mol−1. PCBs and their metabolites may act on the key targets of MAPK3, MAPK1, RXRA, PIK3R1, and TP53. The toxic effect of sulfated and methyl sulfone PCBs is greater. The method of screening targets based on the simultaneous action of multiple PCBs can provide a reference for other research. The targets were not found in previous metabolite toxicity studies. It also provides a bridge for the toxic effects and experimental research of PCBs and their metabolites in the future.

Mechanisms of Intervertebral Disc Degeneration Treatment with Deer Antlers Based on Network Pharmacology and Molecular Docking.

Background With the aging of the population, the prevalence of IVDD increases preoperatively. How to better treat IVDD has become an important clinical issue. Deer antlers proved to have a great effect on the treatment of IVDD in many studies, but the molecular mechanism has not been clarified. Objective To investigate the molecular mechanism and target of deer antlers in the treatment of IVDD. Methods Compounds from deer antlers were collected and targets were predicted using HERB, TCMSP, TCMID, SwissADME, and SwissTargetPrediction. Collection of disease targets for IVDD was done using GeneCards, TTD, DrugBank, DisGeNET, and OMIM. Cytoscape 3.7.2, AutoDock Vina (v1.1.2), and R software were used for data analysis and the construction of network diagrams. Results A total of 5 active compounds from deer antlers were screened and 104 therapeutic targets were predicted. A total of 1023 IVDD disease targets were collected. Subsequently, PPI network prediction analysis was performed for disease and treatment targets, and 112 core targets were collected after screening. After obtaining the core target, we used the clusterProfiler software package of R software to carry out GO and KEGG enrichment analyses for the core target and plot the bubble maps. According to the GO enrichment results, the main biological processes of IVDD treatment by deer antlers lie in the rhythmic process, mRNA catabolic process, and G1/S transition of the mitotic cell cycle. KEGG results were mainly related to the PI3K-Akt signaling pathway, thyroid hormone signaling pathway, and Notch signaling pathway. Molecular docking results showed that estrone had the best docking results on ESR1. Conclusion Deer antlers are rich in various compounds that can prevent the development of IVDD by upregulating the PI3K-Akt signaling pathway and Notch signaling pathway. Its key compounds estradiol and estrone can reduce the inflammatory response and oxidative stress in tissues and organs, thus slowing down the progression of IVDD. Estrone, the active compound in deer antlers, was found by molecular docking to have good results against ESR1, the target of the disease, which may be a potential site for drug therapy.

The potential toxicity of polystyrene nanoplastics to human trophoblasts in vitro

Nanoplastics (NPs), the emerging contaminants in recent years, widely distributed in the environment and are bioaccumulated and biomagnified in organisms through food chain. A growing number of studies have detected plastic particulates in human placenta and blood. However, few studies have focused on their effects during human pregnancy. Herein, human trophoblast HTR-8/Svneo cells were used to evaluate the effects and the possible mechanism of 100-nm polystyrene NPs on placental trophoblasts at the maternal-fetal interface. The results showed that NPs entered the trophoblastic cytoplasm, decreased cell viability, caused cell cycle arrest, reduced the cell migration and invasion abilities, increased level of intracellular reactive oxygen species and the production of proinflammatory cytokines (TNF-α and IFN-γ) in a dose-dependent manner. Furthermore, global transcriptome sequencing (RNA-Seq) was performed on HTR-8/Svneo cells with or without 100 μg/mL PS-NP exposure for 24 h. A total of 344 differentially expressed genes were detected. The gene functions for regulation of leukocyte differentiation, response to stimulus, cell cycle, apoptotic process, and cell adhesion were enriched. Thyroid hormone, Hippo, TGF-β and FoxO signaling pathways were activated. Collectively, our data provided evidences for the adverse consequences of NPs on the biological functions of trophoblasts, which provided new insights into the potential trophoblast toxicity of NPs in mammals.

Dissecting the potential mechanism of antihypertensive effects of RVPSL on spontaneously hypertensive rats via widely targeted kidney metabolomics.

Our previous study has demonstrated that the egg-white-derived peptide RVPSL can lower blood pressure in spontaneously hypertensive rats (SHRs), but its potential action mechanism remains unclear. In this work, the underlying mechanism of the antihypertensive effects of RVPSL in SHRs was elucidated using the widely targeted kidney metabolomics approach. Ten SHRs were divided into two groups: SHR-Untreated group (0.9% saline) and SHR-RVPSL group (50 mg kg-1 body weight RVPSL) for 4 weeks. After 4 weeks, kidney samples were collected and widely targeted (liquid chromatography-electrospray ionization-tandem mass spectrometry) metabolomics was used to detect metabolites. Fifty-six biomarkers were identified that may be associated with hypertension. Among them, 17 biomarkers were upregulated and 39 biomarkers were downregulated. The results suggested that eight potential biomarkers were identified in kidney samples: O-phospho-l-serine, tyramine, citric acid, 3-hydroxybutyrate, O-acetyl-l-serine, 15-oxo-5Z,8Z,11Z,13E-eicosatetraenoic acid (15-oxoETE), dopaquinone and 3,3',5-triiodo-l-thyronine. These potential biomarkers mainly involved carbon metabolism, thyroid hormone signaling pathway, tyrosine metabolism and arachidonic acid metabolism. The study suggested that RVPSL may exert antihypertensive effects through upregulation of O-phospho-l-serine, 3-hydroxybutyrate and 15-oxoETE, and downregulation of tyramine, citric acid, O-acetyl-l-serine, 3,3',5-triiodo-l-thyronine and dopaquinone. The antihypertensive effects of RVPSL may be related to carbon metabolism, thyroid hormone signaling pathway, tyrosine metabolism and arachidonic acid metabolism. RVPSL exhibited a potent antihypertensive effect, and the antihypertensive effects were associated with inhibition of vascular smooth muscle cell proliferation, vascular remodeling, vascular endothelium dysfunction, restoring reactive oxygen species, oxidative stress, inflammation and immune reaction. © 2022 Society of Chemical Industry.

Characterization of somatic mutations and pathway alterations during hepatocellular carcinoma vascular invasion using next-generation sequencing.

BackgroundVascular invasion is an independent risk factors for recurrence and poor prognosis in patients with hepatocellular carcinoma (HCC). However, the molecular mechanisms of HCC vascular invasion are largely unknown. Deciphering the molecular changes associated with the vascular invasion process will aid in the identification of therapeutic targets and treatment for patients with HCC.MethodsDNA was extracted from tumor specimens and blood samples collected from 50 patients with HCC. Next-generation sequencing (NGS) was performed to detect HCC gene variants. Bioinformatics methods were used to comprehensively analyze the three sets of sequencing data grouped by vascular invasion, including differences in tumor mutation burden (TMB), mutation characteristics, and alterations in signaling pathways.ResultsBioinformatics analysis detected a total of 762 single nucleotide variants (SNVs). The TMB was not significantly different between patients with macrovascular invasion, microvascular invasion (MVI), or avascular invasion. Ten genes related to prognosis or recurrence, and one oncogene related to vascular invasion were screened. Compared with the avascular invasion cluster, the variant genes in the macrovascular and MVI clusters were mainly enriched in the thyroid hormone signaling pathway. In addition, macrovascular invasion variant genes were also enriched in the insulin signaling pathway and the Fanconi anemia pathway.ConclusionsSomatic mutations and pathway changes associated with vascular invasion in HCC were identified. The discovery of the molecular drivers of vascular invasion in HCC provides novel insights that can help guide further patient diagnosis and personalized therapy.

Microarray analysis of mRNA expression profiles in liver of ob/ob mice with real-time atmospheric PM2.5 exposure.

Epidemiological studies have demonstrated the association between exposure to fine particulate matter (PM2.5) and the onset of non-alcoholic fatty liver disease (NAFLD). However, the potential biological mechanism is largely unknown. Our study was aimed to explore the impact of PM2.5 on the transcriptome level in the liver of ob/ob mice by atmosphere PM2.5 whole-body dynamic exposure system, and meanwhile preliminarily investigated the effects of metformin intervention in this process. More than three thousand differentially expressed genes (DEGs) was screened out by microarray analysis (p < 0.05, |FC|> 1.5). KEGG pathway enrichment analysis showed that these DEGs were mainly enriched in cancers, infectious diseases, and signal transduction, and the most significant pathways were thyroid hormone signaling pathway, chronic myeloid leukemia and metabolic pathways. Then, 12 hub genes were gained through weighted gene correlation network analysis (WGCNA) and verified by qRT-PCR. The expression of 5 genes in darkslateblue module (cd53, fcer1g, cd68, ctss, laptm5) increased after PM2.5 exposure and decreased after metformin intervention. They were related to insulin resistance, glucose and lipid metabolism and other liver metabolism, and also neurodegenerative diseases. This study provided valuable clues and possible protective measures to the liver damage in ob/ob mice caused by PM2.5 exposure, and further research is needed to explore the related mechanism in detail.

Biological networks in gestational diabetes mellitus: insights into the mechanism of crosstalk between long non-coding RNA and N6-methyladenine modification

BackgroundGestational diabetes mellitus (GDM) is one of the most common complications of pregnancy. The mechanism underlying the crosstalk between long non-coding RNAs (lncRNAs) and N6-methyladenine (m6A) modification in GDM remain unclear.MethodsWe generated a lncRNA-mediated competitive endogenous RNA (ceRNA) network using comprehensive data from the Gene Expression Omnibus database, published data, and our preliminary findings. m6A-related lncRNAs were identified based on Pearson correlation coefficient (PCC) analysis using our previous profiles. An integrated pipeline was established to constructed a m6A-related subnetwork thereby predicting the potential effects of the m6A-related lncRNAs.ResultsThe ceRNA network was composed of 16 lncRNAs, 17 microRNAs, 184 mRNAs, and 338 edges. Analysis with the Kyoto Encyclopedia of Genes and Genomes database demonstrated that genes in the ceRNA network were primarily involved in the development and adverse outcomes of GDM, such as those in the fatty acid-metabolism pathway, the peroxisome proliferator-activated receptor signaling pathway, and thyroid hormone signaling pathway. Four m6A-related lncRNAs were involved in the ceRNA network, including LINC00667, LINC01087, AP000350.6, and CARMN. The m6A-related subnetwork was generated based on these four lncRNAs, their ceRNAs, and their related m6A regulators. Genes in the subnetwork were enriched in certain GDM-associated hormone (thyroid hormone and oxytocin) signaling pathways. LINC00667 was positively correlated with an m6A “reader” (YTHDF3; PCC = 0.95) and exhibited the highest node degree in the ceRNA network. RIP assays showed that YTHDF3 directly bind LINC00667. We further found that MYC possessed the highest node degree in a protein–protein interaction network and competed with LINC00667 for miR-33a-5p. qPCR analysis indicated that LINC00667, YTHDF3 and MYC levels were upregulated in the GDM placentas, while miR-33a-5p was downregulated. In a support-vector machine classifier, an m6A-related module composed of LINC00667, YTHDF3, MYC, and miR-33a-5p showed excellent classifying power for GDM in both the training and the testing dataset, with an accuracy of 76.19 and 71.43%, respectively.ConclusionsOur results shed insights into the potential role of m6A-related lncRNAs in GDM and have implications in terms of novel therapeutic targets for GDM.

Therapeutic Potential of Berberine for Osteoporosis and its Underlying Mechanisms: A Bioinformatics, Network Pharmacology, Molecular Dynamics Simulation Study

Osteoporosis is a systemic skeletal disease that can easily lead to bone fractures. Berberine has been shown to be effective in treating osteoporosis. This study was conducted to identify the potential mechanism of berberine in treating this complaint. We screened potential targets of berberine and identified the osteoporosis-related differentially expressed genes (DEGs) in the microarray dataset GSE56815. Protein–protein interaction (PPI) network construction, hub targets identification, and pathway enrichment were carried out to find the potential targets. Molecular docking and molecular dynamics studies were performed to verify the combination of berberine with its treatment-related central targets. In addition, SwissADME preliminarily evaluated the physicochemical properties of berberine. Through data mining, 23 osteoporosis-related targets of berberine were selected. PPI and module analyses suggested that AKT1, MAPK1, ESR1, AR, TP53, and PTGS2 are the core targets of berberine. Docking and molecular dynamics studies showed that berberine could stably bind to core proteins to form a protein–ligand complex. The enrichment analysis showed that the estrogen signaling pathway and thyroid hormone signaling pathway play important roles in curing osteoporosis. To sum up, berberine primarily acts on AKT1, MAPK1, ESR1, AR, TP53, and PTGS2, mainly regulating the estrogen and thyroid hormone signaling pathways to treat osteoporosis in a multi-target, multi-pathway, and multi-system manner.

The potential role of eyestalk in the immunity of Litopenaeus vannamei to Vibrio parahaemolyticus infection II. From the perspective of long non-coding RNA

Long non-coding RNAs (lncRNAs) have been linked to immunological modulation. Unfortunately, little is known about the processes of immune control in shrimp. In crustaceans such as Litopenaeus vannamei, a prominent aquaculture species, the X-organ-sinus gland complex (XO-SG) in the eyestalk is an essential neuroendocrine regulatory organ. Eyestalk ablation is commonly employed in aquaculture to accelerate ovarian maturation in shrimp. It does, however, have a negative impact on the shrimps' immunocompetence and causes death. As a result, we used RNA-seq to profile the transcriptomes of L. vannamei hemocytes infected with Vibrio parahaemolyticus after the eyestalk ablation. Following strict transcript screening procedures, 2307 lncRNAs were identified from L. vannamei hemocytes in this study. Pearson correlation analysis was finally used to uncover 535 DElncRNAs and 1566 DEmRNA targets. According to the Venn diagram analysis, 326 non-eyestalk regulatory lncRNAs (NElncRNAs) with a target of 1014 non-eyestalk regulatory genes (NEmRNAs), 47 eyestalk negative regulatory lncRNAs (ENRlncRNAs) with a target of 95 eyestalk negative regulatory genes (ENRmRNAs), and 162 eyestalk positive regulatory lncRNAs (EPRlncRNAs) with a target of 457 eyestalk positive regulatory genes (EPRmRNAs) were screened. The bioinformatics analysis revealed that lncRNAs were associated with Axon regeneration, Rap1 signaling pathway, Thyroid hormone signaling pathway, TGF-beta signaling pathway, and PI3K-Akt signaling pathway, implying that lncRNAs may play a role in the regulation of the neuroendocrine-immune (NEI) system. Furthermore, several lncRNAs targeting HSP70, YWHAZ, FER2, HIF1α, and Notch were discovered and verified by qRT-PCR. These findings showed that regulation of lncRNAs in hemocytes which were controlled by the eyestalk might be one of the impact variables in controlling the differential expression of mRNAs associated with immune response in L. vannamei infected with V. parahaemolyticus.

Identification of Potential Core Genes for the Rupture of Intracranial Aneurysms by a Bioinformatics Analysis.

Background: Previous studies, using autopsy and angiography, have shown that 3.6–6% of the population have intracranial aneurysms, and the rupture of aneurysm can lead to brain dysfunction or even death in patients. Methods: To explore potential preventional target genes for the ruptured of aneurysm, we analyze three gene expression datasets (GSE13353, GSE15629 and GSE54083) derived from the GEO database. We confirm DEGs associated with the unrupture of aneurysms by R package. DAVID version provides functional classification and annotation analyses of associated genes, including GO and KEGG pathway. PPI of these DEGs is analyzed based on the string database and visualized by Cytoscape software. DEGs are verified by qRT-PCR using samples isolated from the patients. Results: 249 overlapping DEGs, including 96 up-regulated genes and 153 down-regulated genes are screened using the Venn diagram webtool. The GO term and KEGG pathways analysis results indicate that these DEGs are mainly enriched in protein phosphorylation, apoptotic process and inflammatory response in the BP term and focal adhesion, thyroid hormone signaling pathway, ErbB signaling pathway, cytokine-cytokine receptor interaction and some disease processes in the KEGG pathways. 6 candidates are confirmed by Cytoscape software and qRT-PCR, including APP, JUN, GSK3B, ErbB2, PPBP and THBS1. Conclusions: Our data and previous studies show that ErbB2 and THBS1 are crucial to prevent aneurysm rupture, while APP, JUN, GSK3B and PPBP performs the opposite role, and further experiments are needed to verify these findings.

Comparison between Traditional Chinese Medicine Constitution and Blood Biochemical Markers Associated with Left and Right Mammary Hyperplasia in Rural Areas of Southwest China.

Background Hyperplasia of mammary glands (HMG) is the breast disease with the highest clinical incidence. Many traditional Chinese medicine (TCM) doctors suggest that the treatment of HMG should be based on the left and right breast pain difference. However, these views are based on case reports, and an objective basis has not been established for treatment according to left-side and right-side differences. Methods We enrolled 150 patients who met the clinical diagnostic criteria of HMG. The incidence bias was determined according to the score difference between bilateral breast pain and mass in patients with HMG. A left group, right group, and bilateral group were included, and TCM constitution was investigated in each group. Blood biochemical indicators were measured for 120 fasting patients. We conducted a network pharmacology study of the key herb qingpi and chenpi, which are used by TCM doctors to treat different lateral HMG. Results In patients with biased onset of HMG, the results showed that the frequency and constitution score of stagnant blood in the L group were higher than those of the R group, and the frequency and constitution score of phlegm-dampness in the R group were higher than those of the L group. Both the L and R groups had high proportion of stagnant Qi. The results indicated that the concentration of coagulation factor VIII (FVIII) was higher in the L group than that in the R group, and the concentration of lipoprotein a (Lp-α) was higher in the R group than that in the L group. The results showed that sinensetin and neohesperidin contained in qingpi might interfere with platelet activation, thrombogenesis, prolactin signaling pathway, and atherosclerosis process, in removing “blood stasis” and eventually treating the left-leaning group of HMG patients. Sitosterol and citromitin contained in chenpi could regulate lipid metabolism by interfering with regulation of lipolysis in adipocytes, salivary secretion, estrogen signaling pathway, and thyroid hormone signaling pathway. Chenpi could eliminate “phlegm turbidity” and treat HMG patients in the right-leaning group. Conclusions We preliminarily confirmed that the clinical pathogenesis of HMG is not a left-right equilibrium and TCM constitution, coagulation function, and lipid metabolism may be used as the objective basis for the difference between the left and right in HMG pathogenesis. For left-sided HMG patients, the doctor can consider qingpi, herb of activating blood and removing stasis, to treat HMG. However, for right-sided HMG, we think doctors should apply herb of activating Qi and eliminating phlegm, such as chenpi.

Changes in Transcriptome and Ultrastructure Reveal Salinity Tolerance of Obscure Puffer Takifugu obscurus

Fish can maintain a stable intracellular concentration of ions in environments of variable salinities through osmoregulation. In this study, we focused on obscure puffer Takifugu obscurus (T. obscurus), an anadromous fish with high commercial value and rapid depression of wide populations, to investigate changes at molecular and physiological levels underlying salinity tolerance through multifaceted analyses integrating transcriptomics and micrography. We found that with the increase of salinity, the structure of the three main osmoregulation organs, i.e., gill, intestine, and kidney had remarkable changes. The results of transcriptome demonstrated that the ATP-binding box transporter and cyclic adenosine monophosphate (cAMP) signaling pathway in the gill and kidney were significantly reduced. Growth hormone, prolactin, and cortisol regulated more transporters of body composition and stimulated chloride cell proliferation and differentiation, which change the capacity for membrane transport between ion and water molecules. Adenosine-activating protein kinase and thyroid hormone signaling pathway were also significantly upregulated. These transcriptional levels changes of T. obscurus combined with ultrastructure in response to salinity increase indicated that osmoregulation is a complex process involving multiple organs and signaling pathways. Overall, this study can deepen the understanding of osmotic regulation during fish migration.

Expression and Regulation Network of HDAC3 in Acute Myeloid Leukemia and the Implication for Targeted Therapy Based on Multidataset Data Mining.

Background Histone deacetylase 3 (HDAC3) plays an important role in the development and progression of a variety of cancers, but its regulatory mechanism in acute myeloid leukemia (LAML) is not entirely understood. Methods We analyzed the expression of HDAC3 in normal and cancerous tissues using Oncomine, UALCAN, and GEO databases. Changes of the HDAC3 gene were analyzed by cBioPortal. The genes coexpressed with HDAC3 were analyzed by WebGestalt, and the predicted signaling pathways in KEGG were discussed. Results We discovered that the expression of HDAC3 was elevated in some types of acute myeloid leukemia. The HDAC3 gene has a strong positive correlation with SLC25A5, NDUFA2, Cox4I1, and EIF3K, which regulate cell growth and development. HDAC3 transcription is higher in patients with FLT3 mutation than in healthy people. HDAC3 can be directly involved in regulating the thyroid hormone signaling pathway. MEF2D is directly involved in the cGMP-PKG signaling pathway, and the HDAC3 gene has a strong synergistic relationship with MEF2D. HDAC3 is indirectly involved in the cGMP-PKG signaling pathway, thereby indirectly regulating the expression levels of p53 and p21 genes in patients with LAML. Genomics of Drug Sensitivity in Cancer (GDSC) database analysis revealed that the application of the HDAC3 inhibitor can inhibit the proliferation of leukemia cells. Conclusions Therefore, our data suggest that HDAC3 may be a possible therapeutic target for acute myeloid leukemia.

Comprehensive Analysis of the Differential Expression and Prognostic Value of Histone Deacetylases in Glioma.

Gliomas are the most common and aggressive malignancies of the central nervous system. Histone deacetylases (HDACs) are important targets in cancer treatment. They regulate complex cellular mechanisms that influence tumor biology and immunogenicity. However, little is known about the function of HDACs in glioma. The Oncomine, Human Protein Atlas, Gene Expression Profiling Interactive Analysis, Broad Institute Cancer Cell Line Encyclopedia, Chinese Glioma Genome Atlas, OmicShare, cBioPortal, GeneMANIA, STRING, and TIMER databases were utilized to analyze the differential expression, prognostic value, and genetic alteration of HDAC and immune cell infiltration in patients with glioma. HDAC1/2 were considerable upregulated whereas HDAC11 was significantly downregulated in cancer tissues. HDAC1/2/3/4/5/7/8/11 were significantly correlated with the clinical glioma stage. HDAC1/2/3/10 were strongly upregulated in 11 glioma cell lines. High HDCA1/3/7 and low HDAC4/5/11 mRNA levels were significantly associated with overall survival and disease-free survival in glioma. HDAC1/2/3/4/5/7/9/10/11 are potential useful biomarkers for predicting the survival of patients with glioma. The functions of HDACs and 50 neighboring genes were primarily related to transcriptional dysregulation in cancers and the Notch, cGMP-PKG, and thyroid hormone signaling pathways. HDAC expression was significantly correlated with the infiltration of B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells in glioma. Our study indicated that HDACs are putative precision therapy targets and prognostic biomarkers of survival in glioma patients.