Exploring the interconnected between type 2 diabetes mellitus and nonalcoholic fatty liver disease: Genetic correlation and Mendelian randomization analysis.

Epidemiological and clinical studies have indicated a higher risk of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), implying a potentially shared genetic etiology, which is still less explored. Genetic links between T2DM and NAFLD were assessed using linkage disequilibrium score regression and pleiotropic analysis under composite null hypothesis. European GWAS data have identified shared genes, whereas SNP-level pleiotropic analysis under composite null hypothesis has explored pleiotropic loci. generalized gene-set analysis of GWAS data determines pleiotropic pathways and tissue enrichment using eQTL mapping to identify associated genes. Mendelian randomization analysis was used to investigate the causal relationship between NAFLD and T2DM. Linkage disequilibrium score regression analysis revealed a strong genetic correlation between T2DM and NAFLD, and identified 24 pleiotropic loci. These single-nucleotide polymorphisms are primarily involved in biosynthetic regulation, RNA biosynthesis, and pancreatic development. generalized gene-set analysis of GWAS data analysis revealed significant enrichment in multiple brain tissues. Gene mapping using these 3 methods led to the identification of numerous pleiotropic genes, with differences observed in liver and kidney tissues. These genes were mainly enriched in pancreas, brain, and liver tissues. The Mendelian randomization method indicated a significantly positive unidirectional causal relationship between T2DM and NAFLD. Our study identified a shared genetic structure between NAFLD and T2DM, providing new insights into the genetic pathogenesis and mechanisms of NAFLD and T2DM comorbidities.

A case of primary aldosteronism with rhabdomyolysis in which the first symptoms were thyrotoxicosis and peripheral paralysis and literature review.

Background: Primary aldosteronism (PA) is one of the main causes of secondary endocrine hypertension, especially refractory hypertension. Increased autonomous secretion leads to increased blood pressure and proinflammatory effects on different organ systems, including the cardiovascular system. However, because of its diverse clinical manifestations or the combination of other conditions, it sometimes causes problems for correct diagnosis. Therefore, we report and review the characteristics of some atypical and uncommon special case cases related to proaldosterone to provide clinical ideas for correct diagnosis and decision-making of proaldosterone. Case Description: A 38-year-old male patient with fatigue and bilateral lower extremity pain came to the clinic and was found to have abnormal thyroid function, low blood potassium, elevated blood pressure, and also combined with rhabdomyolysis (RM) after further improvement of functional tests and imaging tests was diagnosed with an adrenal cortical adenoma (aldosteronism), hypertension secondary to PA, hypokalemia secondary to PA, RM, and subacute thyroiditis. After laparoscopic resection of a unilateral adrenal adenoma, the patient's blood pressure and blood potassium gradually returned to normal, and thyroid function returned to normal without additional intervention. Conclusions: Early screening should be performed for the high-risk population of PA to prevent the occurrence of RM and other serious complications caused by the progression of the disease. For patients with RM, the primary disease should be approached radically and should be based on symptomatic treatment. For RM syndrome associated with thyroid dysfunction, the etiology of the thyroid dysfunction should be actively identified to guide appropriate clinical management.

Programmed cell death 10 can be used as a potential biomarker for ankylosing spondylitis diagnosis and treatment.

STUDY DESIGN: Diagnostic study. OBJECTIVE: Programmed cell death 10 (PDCD10) is a new versatile molecule involved in signal transduction regulation in angiogenesis and tumors. The potential of using it as a biomarker for the diagnosis of ankylosing spondylitis (AS) is still unknown. SETTING: University laboratory in Gannan Medical University, China. METHODS: Expression of PDCD10 was analyzed using clinical samples of patients with AS and Gene Expression Omnibus (GEO) data GDS5231. To explore its function, PDCD10 was upregulated and downregulated in synovial cells. Spearman analysis was used to study the association between PDCD10 and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). The Receiver operating characteristic (ROC) curve was applied to evaluate the sensitivity and specificity of PDCD10. RESULTS: Expression of PDCD10 was upregulated in patients with AS and it is capable of promoting the calcification of synovial cells. A positive association between PDCD10 and the BASDAI and the mSASSS was observed. The area under the ROC curve (AUC) of PDCD10 was 82% with a 95% confidence interval of [0.772, 0.868]. CONCLUSIONS: PDCD10 is upregulated in patients with AS and it can promote the calcification of synovial cells in vitro. PDCD10 is positively associated with outcome parameters of AS. ROC analysis of PDCD10 suggests that it can be used as a biomarker for the diagnosis and treatment of AS.

Molecular-Assisted Breeding of Cadmium Pollution-Safe Cultivars.

Cadmium (Cd) contamination in edible agricultural products, especially in crops intended for consumption, has raised worldwide concerns regarding food safety. Breeding of Cd pollution-safe cultivars (Cd-PSCs) is an effective solution to preventing the entry of Cd into the food chain from contaminated agricultural soil. Molecular-assisted breeding methods, based on molecular mechanisms for cultivar-dependent Cd accumulation and bioinformatic tools, have been developed to accelerate and facilitate the breeding of Cd-PSCs. This review summarizes the recent progress in the research of the low Cd accumulation traits of Cd-PSCs in different crops. Furthermore, the application of molecular-assisted breeding methods, including transgenic approaches, genome editing, marker-assisted selection, whole genome-wide association analysis, and transcriptome, has been highlighted to outline the breeding of Cd-PSCs by identifying critical genes and molecular biomarkers. This review provides a comprehensive overview of the development of Cd-PSCs and the potential future for breeding Cd-PSC using modern molecular technologies.

Circular RNAs in osteosarcoma: An update of recent studies (Review).

Osteosarcoma (OS) prevailing in children and adolescents mainly occurs at the metaphysis of long bones. As it is associated with a high invasive and metastatic ability, resistance to chemotherapy, and a low 5­year survival rate, the diagnosis and treatment of OS post a global healthy issue. Over the past decades, RNA biology has shed new light onto the pathogenesis of OS. As a type of non­coding RNAs, circular RNAs (circRNAs) have been found to play crucial roles in cellular activities. Recently, a large number of circRNAs have been identified in OS and some of them have been validated to be functional in OS. In the present review, abnormally expressed and different types of circRNAs in OS are summarized. Functional studies on circRNAs have revealed that circRNAs can regulate gene expression at different levels, such as gene transcription, precursor mRNA splicing, miRNA sponges and translation into proteins/peptides. Mechanistic analyses on circRNAs show that circRNAs can regulate JAK­STAT3, NF­κB, PI3K­AKT, Wnt/ß­catenin signaling pathways during the occurrence and development of OS. Furthermore, the potential clinical applications of circRNAs are also emphasized. The present review focus on the current knowledge on the functions and mechanisms of circRNAs in the pathogenesis of OS, aiming to provide new insight into the OS diagnosis and treatment of OS.

[Potential components and mechanism of Liangxue Tuezi Mixture in treating Henoch-Schönlein purpura based on network pharmacology and metabolomics].

Ultra-performance liquid chromatography-quadrupole time of fight/mass spectrometry(UPLC-Q-TOF-MS) and UNIFI were employed to rapidly determine the content of the components in Liangxue Tuizi Mixture. The targets of the active components and Henoch-Schönlein purpura(HSP) were obtained from SwissTargetPrediction, Online Mendelian Inheritance in Man(OMIM), and GeneCards. A "component-target-disease" network and a protein-protein interaction(PPI) network were constructed. Gene Ontology(GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were performed for the targets by Omishare. The interactions between the potential active components and the core targets were verified by molecular docking. Furthermore, rats were randomly assigned into a normal group, a model group, and low-, medium-, and high-dose Liangxue Tuizi Mixture groups. Non-targeted metabolomics was employed to screen the differential metabolites in the serum, analyze possible metabolic pathways, and construct the "component-target-differential metabolite" network. A total of 45 components of Liangxue Tuizi Mixture were identified, and 145 potential targets for the treatment of HSP were predicted. The main signaling pathways enriched included resistance to epidermal growth factor receptor tyrosine kinase inhibitors, phosphatidylinositol 3-kinase/protein kinase B(PI3K-AKT), and T cell receptor. The results of molecular docking showed that the active components in Liangxue Tuizi Mixture had strong binding ability with the key target proteins. A total of 13 differential metabolites in the serum were screened out, which shared 27 common targets with active components. The progression of HSP was related to metabolic abnormalities of glycerophospholipid and sphingolipid. The results indicate that the components in Liangxue Tuizi Mixture mainly treats HSP by regulating inflammation and immunity, providing a scientific basis for rational drug use in clinical practice.

Lipopolysaccharide-induced depression is associated with estrogen receptor-α/SIRT1/NF-κB signaling pathway in old female mice.

The present study aims to investigate the influence of sex/age on depressive-like behaviors in lipopolysaccharide (LPS)-challenged mice model, and explore the underlying mechanisms. Tail suspension test and forced swimming test were used to evaluate the depressive-like behaviors. SIRT1 mRNA expression was assessed by PCR. Levels of 17ß-estradiol (E2), SIRT1, NF-κB, tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) were detected by enzyme linked immunosorbent assay (ELISA). In the behavior tests, under the same LPS stimulation, significant depressive-like behavior was observed in young male mice but not in young female mice, however, female mice were more likely to be depressed than male mice in the old age. Moreover, we found age-related depression difference existed only in female mice. In the experiments of mechanism exploration in old female mice, E2 improved LPS-induced depressive-like behavior, and simultaneously elevated SIRT1 levels and downregulated expressions of NF-κB and inflammatory cytokines in the hippocampus and frontal cortex. Interestingly, ERα inhibition, not ERß inhibition, abolished E2's function. Additionally, SIRT1 antagonist also reversed E2's effects on depressive-like behavior and the expressions of NF-κB and inflammatory cytokines. These results suggested that E2 could protect the old female mice from depression via E2/ERα/SIRT1/NF-κB signaling pathway. In other words, LPS-induced depression was associated with ER-α/SIRT1/NF-κB signaling pathway in old female mice. By comparing the results of mechanism exploration in old male mice and old female mice and the different expression levels of E2, SIRT1, NF-κB and inflammatory cytokines in young female mice and old female mice, we speculate that the age or gender-related depression difference may be associated with the different activation levels of the ERα/SIRT1/NF-κB signaling pathway.

Irisin protects female mice with LPS-induced endometritis through the AMPK/NF-κB pathway.

OBJECTIVES: This research was designed to determine the role of irisin in lipopolysaccharide (LPS)-induced endometritis in female mice. MATERIALS AND METHODS: Animals were randomly assigned into sham, sham + irisin, LPS, LPS + irisin (0.1, 1, 10 µg/kg), and LPS + irisin + compound C groups. Histological features and expression of AMPK, NF-κB, inflammatory mediators, and oxidative stress markers were compared among different groups. RESULTS: The results showed that LPS resulted in obvious uterus damage, meanwhile, the inflammatory mediators (COX-2, iNOS, IL-1ß, IL-6, and TNF-α), as well as NF-κB in the uterine tissue, were significantly increased and the level of adenosine monophosphate-activated protein kinase (AMPK) was reduced. Nevertheless, pretreatment with irisin reversed the phenomena caused by LPS. Interestingly, compound C (AMPK inhibitor) abolished irisin's effects on the uterus, which suggested that irisin's beneficial function was achieved through regulating the AMPK-NF-κB pathway. Moreover, LPS-induced alterations of oxidative factors (MnSOD, GSH, and MDA) were reversed significantly by pretreatment with irisin. This data indicated irisin's beneficial function was also related to antioxidation besides anti-inflammation. CONCLUSION: Our study implies that irisin is a potential therapeutic agent for endometritis.

Irisin Protects Against Motor Dysfunction of Rats with Spinal Cord Injury via Adenosine 5'-Monophosphate (AMP)-Activated Protein Kinase-Nuclear Factor Kappa-B Pathway.

The aim of the present research was to investigate the effects of irisin, a skeletal muscle-derived myokine, on spinal cord injury (SCI) in rats and explore the possible mechanisms. SCI model was constructed in male SD rats. The effects of irisin on SCI rats were assessed via behavior tests including Basso, Beattie, and Bresnahan (BBB) scoring method and inclined plane test, followed by histomorphology tests including HE staining, Nissl staining, and transmission electron microscope examination. Biochemical analyses including PCR, Western blots and ELISA were employed to further evaluate the changes at molecular level of SCI rats. In addition, lipopolysaccharide (LPS)-induced cell damage model was established in PC12 cells to verify the mechanism of irisin's effect on nerve cells in vitro. Results showed that the BBB score and the angle of incline significantly decreased after SCI surgery, however, chronic irisin treatment improved SCI-induced motor dysfunction. HE and Nissl staining assays showed that SCI surgery induced histological injury of spinal cord, which could be reversed by irisin treatment. Morphological abnormality of nerve cells caused by SCI also could be alleviated by irisin. Further biochemical analyses showed that irisin inhibited SCI-induced overexpression of Interleukin-1ß (IL-1ß), Interleukin- 6 (IL-6), tumor necrosis factor alpha (TNF-α), inducible nitricoxidesynthase (iNOS) and Cyclooxygenase-2 (COX-2)], as well as nuclear factor kappa-B (NF-κB)p65 in rats, and the positive function of irisin could be reversed by Compound C treatment. In our in vitro study, LPS-induced declines of cell viability and neurite length of PC12 cell were inhibited by irisin treatment, and irisin inhibited LPS-induced overexpression of NF-κBp65, IL-1ß, IL-6, TNF-α, iNOS and COX-2. These changes could be reversed by activated protein kinase (AMPK) siRNA pre-treatment. Taken together, irisin could protect the rats from SCI, and its protection is associated with the regulation of adenosine 5'-monophosphate-activated protein kinase (AMPK)- NF-κB signaling pathway.

Terminus-Associated Non-coding RNAs: Trash or Treasure?

3' untranslated regions (3' UTRs) of protein-coding genes are well known for their important roles in determining the fate of mRNAs in diverse processes, including trafficking, stabilization, translation, and RNA-protein interactions. However, non-coding RNAs (ncRNAs) scattered around 3' termini of the protein-coding genes, here referred to as terminus-associated non-coding RNAs (TANRs), have not attracted wide attention in RNA research. Indeed, whether TANRs are transcriptional noise, degraded mRNA products, alternative 3' UTRs, or functional molecules has remained unclear for a long time. As a new category of ncRNAs, TANRs are widespread, abundant, and conserved in diverse eukaryotes. The biogenesis of TANRs mainly follows the same promoter model, the RNA-dependent RNA polymerase activity-dependent model, or the independent promoter model. Functional studies of TANRs suggested that they are significantly involved in the versatile regulation of gene expression. For instance, at the transcriptional level, they can lead to transcriptional interference, induce the formation of gene loops, and participate in transcriptional termination. Furthermore, at the posttranscriptional level, they can act as microRNA sponges, and guide cleavage or modification of target RNAs. Here, we review current knowledge of the potential role of TANRs in the modulation of gene expression. In this review, we comprehensively summarize the current state of knowledge about TANRs, and discuss TANR nomenclature, relation to ncRNAs, cross-talk biogenesis pathways and potential functions. We further outline directions of future studies of TANRs, to promote investigations of this emerging and enigmatic category of RNA.

Down-regulated miR-495 can target programmed cell death 10 in ankylosing spondylitis.

BACKGROUND: MicroRNAs (miRNAs) play crucial roles in regulating eukaryotic gene expression. Recent studies indicated that aberrantly expressed miRNAs are involved in the pathogenesis of ankylosing spondylitis (AS). Indeed, hsa-miR-495-3p (miR-495) has been reported as an anti-oncogene in different cancers. However, the role of miR-495 in AS is still unknown. METHODS: In this study, quantitative real-time polymerase chain reaction (PCR) was used to detect the expression of miR-495 in the peripheral blood mononuclear cells (PBMCs), whole blood, and serum of patients with AS. Bisulfite-specific PCR sequencing and methylated DNA immunoprecipitation were used to detect the methylation in the promoter region of miR-495. To determine the influence of miR-495 expression on the target gene, programmed cell death 10 (PDCD10), dual luciferase reporter assays together with an adenoviral vector containing the miR-495 locus were used. Receiver operating characteristic (ROC) curves were used to evaluate the efficacy of miR-495 as a diagnostic biomarker of AS. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and western blotting were used to explore the potential role of miR-495 in AS pathogenesis and the mechanism by which it facilitates AS pathogenesis. RESULTS: miR-495 is down-regulated and the promoter region of miR-495 is highly methylated in AS. The expression of miR-495 is negatively associated with PDCD10 expression in both patients with AS and healthy controls. Further experiments showed that PDCD10 can be targeted by miR-495. The ROC curves of miR-495 suggested that it is a very specific and sensitive biomarker for AS diagnosis. Bioinformatics analysis and signal pathway studies indicated that miR-495 can down-regulate ß-catenin and transforming growth factor-ß1. CONCLUSIONS: Our studies indicated that down-regulation of miR-495 can be used as a potential molecular marker for the diagnosis and treatment of AS, thus providing new insights into the role of miRNAs in AS pathology.

Role of AMPK/SIRT1-SIRT3 signaling pathway in affective disorders in unpredictable chronic mild stress mice.

OBJECTIVES: To explore the role of 5' adenosine monophosphate-activated protein kinase/sirtuin1-sirtuin3 (AMPK/SIRT1-SIRT3) signaling pathway in behavioral and neuroinflammation/oxidative stress alterations in unpredictable chronic mild stress (UCMS) model mice. METHODS: Male ICR mice weighing 20-22 g were used in this study. Behavior performance was evaluated from the 14th day of drug treatment. Expression levels of AMPK, SIRT1, SIRT3, and NF-κBp65 were tested by immuno-blot analysis. Contents of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) were detected by enzyme linked immunosorbent assay (ELISA). Reactive oxygen species (ROS), superoxide dismutase (SOD) and glutathione (GSH) expressions were tested by neurochemical and biochemical assays. RESULTS: Behavioral disorders and decreases of AMPK, SIRT1 and SIRT3 induced by UCMS were all reversed by AICA Riboside (AICAR) treatment. These effects were correlated with alterations of oxidative stress (ROS, GSH, SOD) and inflammation (pNF-κBp65, TNF-α, IL-1ß, IL-6) status. Co-treatment with SIRT3 inhibitor (3-TYP) in addition to AICAR abolished AICAR's effects on behavior and expression level of inflammation/oxidative stress-related factors of mice, without affecting the content of SIRT1. Contrarily, combining use of AICAR and SIRT1 inhibitor (Sirtinol or EX-527) increased SIRT3 level, which led to better alleviation of behavioral disorders, compared with single AICAR treatment. Interestingly, in normal or UCMS mice, up or down regulation of SIRT1 did not affect SIRT3 level. CONCLUSION: Provided that AMPK is activated, SIRT1 inhibition could induce the increase of SIRT3, and SIRT3 exerts more beneficial function in alleviation of consequences of chronic stress than SIRT1.

Withdrawal Notice: Renoprotective Effect of Curcumin Labelled on Mesoscale Nanoparticles (MNPs) in Renal Ischemia-Reperfusion Injury (RIRI) via the miR-146a/nNOS/NO/cGMP/PKG Signaling Pathway

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Noncoding RNAs in Calcific Aortic Valve Disease: A Review of Recent Studies.

Calcific aortic valve disease (CAVD) is the most common heart valve disorder in human populations. Nevertheless, there are presently no effective means for its prevention and treatment. It is therefore critical to comprehensively define key mechanisms of the disease. A major focus of cardiovascular research has been characterization of how regulation of gene expression maintains healthy physiologic status of the component tissues of the system and how derangements of gene regulation may become pathological. Recently, substantial evidence has emerged that noncoding RNAs, which are an enormous and versatile class of regulatory elements, such as microRNAs and long noncoding RNAs, have roles in onset and prognosis of CAVD. Authors of the present report have therefore here provided a summary of the current understanding of contributions made by noncoding RNAs major features of CAVD. It is anticipated that this article will serve as a valuable guide to research strategy in this field and may additionally provide both researchers and clinicians with an expanded range of CAVD-associated biomarkers.

Administration of Curcumin Protects Kidney Tubules Against Renal Ischemia-Reperfusion Injury (RIRI) by Modulating Nitric Oxide (NO) Signaling Pathway.

BACKGROUND/AIMS: To explore the protective effect of curcumin on renal ischemia-reperfusion injury (RIRI) in rats, and its influence on nephridial tissue's NO and cGMP levels as well as downstream signaling pathway, to elucidate the possible mechanism of curcumin on RIRI. METHODS: 36 Sprague Dawley rats (SD rats) were randomly divided into Sham group, Model group, curcumin (CUR +) Model group, 12 rats per group. They were all given RIRI model preparation by unilateral artery occlusion method. All groups' ß2-MG in urine in 24h, serum Cr and BUN were compared, and UAER were calculated. Nitric oxide synthase (NOS), cGMP-dependent protein kinase (PKG), Caspase-3 expression were all determined by western blot. Nitric oxide (NO), NOS and cGMP levels were also examined by using ELISA. All groups' nephridial histomorphology and kidney tubules score were evaluated and compared. RESULTS: ß2-MG and UAER in urine, serum Cr and BUN, in renal tissue were all elevated in Model of RIRI, indicating the success of animal model of RIRI establishment, and above index in CUR + Model group were all lower than those in Model group. Furthermore, iNOS, NO, cGMP, PKG and Caspase-3 in renal tissue were all increased in Model of RIRI, indicating the NO signaling pathway was activated, which is one of the pathogenesis of RIRI, and above index in CUR + Model group were all lower than those in Model group, suggesting that inactivation of iNOS/NO/cGMP/PKG signaling pathway is one of the reasons that explain the protective effect of curcumin in RIRI. CONCLUSION: The activation of iNOS/NO/cGMP/PKG signaling pathway and the consequent promoted apoptosis of renal tubules are significantly involved in the pathogenesis of development of RIRI, and curcumin treatment could protect renal tubules against RIRI, at least partially, by suppressing the activated iNOS/NO/cGMP/PKG signaling pathway.

miRNA-Dependent Activation of mRNA Translation.

MicroRNAs (miRNAs) are small and important RNA molecules. They can regulate gene expression at different levels. Although their biogenesis has been well documented, elucidation of miRNA-dependent activation of mRNA translation has just begun. Here, we highlighted different patterns of miRNA-dependent activation of mRNA translation: miRNA can activate mRNA translation through binding different target sites; in different sub-cellular locations; under different cellular circumstances. MiRNA-dependent activation of mRNA translation suggests unexpected functions of miRNA, that could provide new clues in functional studies of other ncRNAs.

Dynamic miRNA-mRNA paradigms: New faces of miRNAs.

More and more evidences suggested that the flow of genetic information can be spatially and temporally regulated by non-coding RNAs (ncRNAs), such as microRNAs (miRNAs). Although biogenesis and function of miRNAs have been well detailed, elucidation of the dynamic interplays between miRNAs and mRNAs have just begun. Here, we highlighted that the miRNA-mRNA interactions which could take place in different cellular locations. During dynamic interactions, miRNA binding sites included not only 3'UTRs, but also 5'UTRs and CDSs. Under different physiological or pathological conditions, miRNAs could switch from translational inhibition to activation. Dynamic miRNA-mRNA paradigms which suggested a novel tip of the iceberg beneath the gene regulation network will provide clues for function studies of other ncRNAs.