A combination of two novel VARS2 variants causes a mitochondrial disorder associated with failure to thrive and pulmonary hypertension
We present a case of an infant with lactic acidosis, failure to thrive, and severe primary pulmonary hypertension who was found to be a compound heterozygote for two novelVARS2 variants (c.1940C>T, p.(Thr647Met) and c.2318G>A, p.(Arg773Gln)). The patient was treated with vitamin supplements and a carbohydrate-restricted diet. The lactic acidosis and failure to thrive resolved, and he showed good growth and development. Functional studies and molecular analysis employed a yeast model system and theVAS1 gene (yeast homolog ofVARS2).VAS1 genes harboring either one of two mutations corresponding to the two novel variants...
Source: Journal of Molecular Medicine - September 16, 2019 Category: Molecular Biology Source Type: research

Clinical relevance of circadian melatonin release in relapsing-remitting multiple sclerosis
This report addresses the potential clinical relevance of circadian MT rhythms in relapsing-remitting MS (RRMS) patients. The study sample comprised of fifty-five RRMS patients and fifty age- and sex-matched healthy control (HC) subjects. Circadian salivary MT was measured non-invasively at 12 time points over day in participants ’ home environment. 6-Hydroxy-melatoninsulfate (MT sulfate) concentration in night-time urine was assessed as an estimate for nocturnal MT. Ratings for neurological disability, health-related quality of life (HrQoL), fatigue, depressive symptoms and sleep patterns were additionally obtained....
Source: Journal of Molecular Medicine - August 30, 2019 Category: Molecular Biology Source Type: research

METTL1 overexpression is correlated with poor prognosis and promotes hepatocellular carcinoma via PTEN
AbstractRNA methylation is emerging as an important regulator of gene expression. Dysregulation of methyltransferase that is essential for RNA modification contributes to the development and progression of human cancers. Here we show that methyltransferase-like 1 (METTL1) is upregulated in hepatocellular carcinoma (HCC) and exhibits oncogenic activities via PTEN/AKT signaling pathway. High expression of METTL1 is correlated with larger tumor size, higher serum AFP level, tumor vascular invasion, and poor prognosis in two independent cohorts containing 892 patients with HCC. Multivariate analyses suggest METTL1 as an indepe...
Source: Journal of Molecular Medicine - August 28, 2019 Category: Molecular Biology Source Type: research

Connecting sex differences, estrogen signaling, and microRNAs in cardiac fibrosis
AbstractSex differences are evident in the pathophysiology of heart failure (HF). Progression of HF is promoted by cardiac fibrosis and no fibrosis-specific therapies are currently available. The fibrotic response is mediated by cardiac fibroblasts (CFs), and a central event is their phenotypic transition to pro-fibrotic myofibroblasts. These myofibroblasts may arise from various cellular origins including resident CFs and epicardial and endothelial cells. Both female subjects in clinical studies and female animals in experimental studies generally present less cardiac fibrosis compared with males. This difference is at le...
Source: Journal of Molecular Medicine - August 26, 2019 Category: Molecular Biology Source Type: research

Ablation of serum response factor in hepatic stellate cells attenuates liver fibrosis
In conclusion, our data demonstrate that SRF may play an essential role in HSC activation and liver fibrosis.Key messages• SRF deficiency decelerates activation of hepatic stellate cells (HSCs) in vitro.• SRF epigenetically activates pro-fibrogenic transcription to promote HSC maturation.• SRF interacts with MRTF-A and contributes to MRTF-A transcription.• Conditional SRF deletion in HSCs attenuates BDL-induced liver fibrosis in mice.• Conditional SRF ablation in HSCs attenuates CCl4-induced liver fibrosis in mice. (Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - August 21, 2019 Category: Molecular Biology Source Type: research

Progranulin alleviates podocyte injury via regulating CAMKK/AMPK-mediated autophagy under diabetic conditions
This study was to elucidate the role of progranulin (PGRN), a secreted glycoprotein, in the modulation of podocyte autophagic process and podocyte injury under a diabetic condition. PGRN was downregulated in the kidney from diabetic mice and podocytes under a high-glucose (HG) condition. PGRN deficiency exacerbated the renal dysfunction and glomerular structural alterations. In vitro, treatment with recombinant human PGRN (rPGRN) attenuated HG-induced podocyte injury accompanied by enhanced autophagy. Inhibition of autophagy disturbed the protective effects of PGRN in HG-induced podocytotoxicity. Furthermore, PGRN induced ...
Source: Journal of Molecular Medicine - August 11, 2019 Category: Molecular Biology Source Type: research

Adipose-derived stromal cell secretome disrupts autophagy in glioblastoma
AbstractMesenchymal stromal cells (MSCs) are frequently recruited to tumor sites to play a part in the tumor microenvironment (TME). However, their real impact on cancer cell behavior remains obscure. Here we investigated the effects of human adipose-derived stromal cell (hADSC) secretome in autophagy of glioblastoma (GBM), as a way to better comprehend how hADSCs influence the TME. GBM U-87 MG cells were treated with conditioned medium (CM) from hADSCs and autophagic flux was evaluated. hADSC CM treatment blocked the autophagic flux in tumor cells, as indicated by the accumulation of autophagosomes in the cytosol, the hig...
Source: Journal of Molecular Medicine - August 10, 2019 Category: Molecular Biology Source Type: research

Substance P induces fibrotic changes through activation of the RhoA/ROCK pathway in an in vitro human corneal fibrosis model
This study aimed to elucidate the role of substance P (SP), a neuropeptide that has been shown to be involved in corneal wound healing, in ECM production and fibrotic markers expression in quiescent human keratocytes, and during the onset of fibrosis in corneal fibroblasts, in an in vitro human corneal fibrosis model. We report that SP induces keratocyte contraction and upregulates gene expression of collagens I, III, and V, and fibrotic markers: α-SMA and fibronectin, in keratocytes. Using our in vitro human corneal fibrosis model, we show that SP enhances gene expre ssion and secretion of collagens I, III, and V, a...
Source: Journal of Molecular Medicine - August 9, 2019 Category: Molecular Biology Source Type: research

The dichotomous function of interleukin-9 in cancer diseases
AbstractThe pleiotropic function of the cytokine IL-9 is so far described in many inflammation processes and autoimmune diseases. But its role in cancer immunology is rather diverse as it can have a pro-tumorigenic function as well as anti-tumorigenic characteristics. In various disease models of cancer, this cytokine is involved in different signaling pathways triggering the expression of proteins involved in cell growth, migration, and transformation or repressing cells from the adaptive immune system to reject tumor growth. Additionally, there are even therapeutic approaches for IL-9 in cancer development. This review w...
Source: Journal of Molecular Medicine - August 8, 2019 Category: Molecular Biology Source Type: research

Phosphate-induced ORAI1 expression and store-operated Ca 2+ entry in aortic smooth muscle cells
In conclusion, enhanced phosphate upregulates ORAI1 and STIM1 expression and store-operated Ca2+-entry, which participate in the orchestration of osteo-/chondrogenic signaling of VSMCs.Key messages• In aortic SMC, phosphate donor ß-glycerophosphate upregulates Ca2+ channel ORAI1.• In aortic SMC, ß-glycerophosphate upregulates ORAI1-activator STIM1.• In aortic SMC, ß-glycerophosphate upregulates store-operated Ca2+-entry (SOCE).• The effect of ß-glycerophosphate on SOCE is disrupted by ORAI1 inhibitor MRS1845.• Stimulation of osteogenic signaling is disrupted by MRS1845 and O...
Source: Journal of Molecular Medicine - August 5, 2019 Category: Molecular Biology Source Type: research

Novel plasma peptide markers involved in the pathology of CKD identified using mass spectrometric approach
AbstractChronic kidney disease (CKD) may progress to end-stage renal disease (ESRD) at different pace. Early markers of disease progression could facilitate and improve patient management. However, conventional blood and urine chemistry have proven unable to predict the progression of disease at early stages. Therefore, we performed untargeted plasma peptidome analysis to select the peptides involved in progression, which are suitable for long prospective studies in future. The study consists of non-CKD (n = 66) and CKD (n = 106) patients with different stages. We performed plasma peptidomics on...
Source: Journal of Molecular Medicine - August 5, 2019 Category: Molecular Biology Source Type: research

Rewiring of immune-metabolic crosstalk in the liver after viral infection
(Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - August 1, 2019 Category: Molecular Biology Source Type: research

Bone allografts combined with adipose-derived stem cells in an optimized cell/volume ratio showed enhanced osteogenesis and angiogenesis in a murine femur defect model
In this study, we systemically optimized cell/volume ratio of two promising components of tissue engineering: hASCs and human bone allografts. These findings may serve as a basis for future translational studies.Key messagesBone tissue engineering.Mesenchymal stem cells derived from human adipose tissue (hASCs).Optimal cell/volume ratio of cell-seeded scaffolds.Increased osteogenesis and angiogenesis in vivo. (Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - July 31, 2019 Category: Molecular Biology Source Type: research

Hypoxia drives cardiac miRNAs and inflammation in the right and left ventricle
AbstractAlveolar and myocardial hypoxia may be causes or sequelae of pulmonary hypertension (PH) and heart failure. We hypothesized that hypoxia initiates specific epigenetic and transcriptional, pro-inflammatory programs in the right ventricle (RV) and left ventricle (LV). We performed an expression screen of 750 miRNAs by qPCR arrays in the murine RV and LV in normoxia (Nx) and hypoxia (Hx; 10% O2 for 18  h, 48 h, and 5d). Additional validation included single qPCR analysis of miRNA and pro-inflammatory transcripts in murine and human RV/LV, and neonatal rat cardiomyocytes (NRCMs). Differential qPCR-analysis (H...
Source: Journal of Molecular Medicine - July 23, 2019 Category: Molecular Biology Source Type: research

Correction to: PRSS21/testisin inhibits ovarian tumor metastasis and antagonizes proangiogenic angiopoietins ANG2 and ANGPTL4
The affiliation of Erik W. Martin is corrected in this paper. (Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - July 20, 2019 Category: Molecular Biology Source Type: research

Molecular changes in solitary fibrous tumor progression
In this study, using 91 SFT cases, we examined whether fusion variants are associated with clinicopathological parameters and also investigated the molecular mechanism of malignant transformation using whole-exome sequencing. We detected variant 1b (NAB2ex4-STAT6ex2) in 51/91 (56%) cases and variants 2a/2b (NAB2ex6-STAT6ex16/17) in 17/91 (19%) cases. TheNAB2-STAT6 fusion variant types were significantly associated with their primary site (P 
Source: Journal of Molecular Medicine - July 18, 2019 Category: Molecular Biology Source Type: research

S100A4 promotes inflammation but suppresses lipid accumulation via the STAT3 pathway in chronic ethanol-induced fatty liver
In this study, we discovered the special role of S100A4 in alcoholic liver disease. S100A4 deficiency attenuated ethanol-induced hepatitis and promoted hepatic fat accumulation in ethanol-induced liver tissues. Further mechanistic studies have found that S100A4 promotes early alcoholic hepatitis mainly by activating the STAT3 pathway and its downstream proinflammatory gene expression. Interestingly, activation of the STAT3 pathway downregulates lipogenic gene expression, especially SREBP-1c.Key messagesIn this study, we discovered the special role of S100A4 in alcoholic liver disease. S100A4 deficiency attenuated ethanol-i...
Source: Journal of Molecular Medicine - July 18, 2019 Category: Molecular Biology Source Type: research

The orphan nuclear receptor NUR77 promotes trophoblast invasion at early pregnancy through paracrine placental growth factor
In this study, we showed that NUR77 expression was significantly lower in the villi of the recurrent miscarriage (RM) group compared to that in the healthy controls (HCs) group. We used immunohistochemistry and found that NUR77 was highly expressed in human placental villi during early pregnancy, especially in syncytiotrophoblast (STB), and was expressed at a much lower level in STB from the RM group than in those from HC group. Western blotting data further confirmed that NUR77 was highly expressed in primary human term placental STB and the FSK-induced BeWo cell line. Moreover, antibody array screening and ELISA revealed...
Source: Journal of Molecular Medicine - July 16, 2019 Category: Molecular Biology Source Type: research

Targeting non-muscle myosin II promotes corneal endothelial migration through regulating lamellipodial dynamics
AbstractCorneal endothelial cell (CEC) dysfunction causes corneal edema that may lead to blindness. In addition to corneal transplantation, simple descemetorhexis has been proposed to treat centrally located disease with adequate peripheral cell reserve, but promoting the centripetal migration of CECs is pivotal to this strategy. Here, we show that targeting non-muscle myosin II (NMII) activity by Y27632, a ROCK inhibitor, or blebbistatin, a selective NMII inhibitor, promotes directional migration of CECs and accelerates in vitro wound healing. The lamellipodial protrusion persistence is increased, and actin retrograde flo...
Source: Journal of Molecular Medicine - July 13, 2019 Category: Molecular Biology Source Type: research

Exosomes from patients with Parkinson ’s disease are pathological in mice
AbstractCell-to-cell transport of risk molecules is a highly anticipated pathogenic mechanism in the initiation and progression of various neurodegenerative diseases. Extracellular exosome-mediated neuron to neuron transport of α-synuclein (α-syn) is increasingly recognized as a potential etiologic mechanism in Parkinson’s disease (PD). Exosomal inflammation has also been increasingly implicated in PD pathogenesis and could trigger, facilitate, or aggravate disease development. However, these mechanisms have not been v erified systematically, especially in vivo. Since serum contains abundant exosomes, the...
Source: Journal of Molecular Medicine - July 13, 2019 Category: Molecular Biology Source Type: research

Correction to: STIM1 deficiency is linked to Alzheimer ’s disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca 2+ entry
The original publication of this paper contains errors. (Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - July 2, 2019 Category: Molecular Biology Source Type: research

Delayed endometrial decidualisation in polycystic ovary syndrome; the role of AR-MAGEA11
AbstractPolycystic ovary syndrome (PCOS) is a common gynaecological disorder, with a prevalence of up to 12% of women of reproductive age, and is in part characterised by elevated circulating androgens and aberrant expression of androgen receptor (AR) in the endometrium. A high percentage of PCOS patients suffer from infertility, a condition that appears to be linked to mistimed and incomplete decidualisation critically affecting events surrounding embryo implantation. The aim of this study was to examine the involvement of MAGEA11, and the genome-wide role of AR in PCOS. We determined that elevated androgen levels on PCOS...
Source: Journal of Molecular Medicine - June 29, 2019 Category: Molecular Biology Source Type: research

Relevance of VEGFA in rat livers subjected to partial hepatectomy under ischemia-reperfusion
We examined the effects of VEGFA on damage and regeneration in steatotic and non-steatotic livers of rats submitted to PH under I/R, and characterized the underlying mechanisms involved. Our results indicated that VEGFA levels were decreased in both steatotic and non-steatotic livers after surgery. The administration of VEGFA increased VEGFA levels in non-steatotic livers, reducing the incidence of post-operative complications following surgery through the VEGFR2-Wnt2 pathway, independently of Id1. Unexpectedly, administration of VEGFA notably reduced VEGFA levels in steatotic livers, exacerbating damage and regenerative f...
Source: Journal of Molecular Medicine - June 29, 2019 Category: Molecular Biology Source Type: research

A non-beta-lactam antibiotic inhibitor for enterohemorrhagic Escherichia coli O104:H4
AbstractThe overuse of antibiotics has caused an increased prevalence of drug-resistant bacteria. Bacterial resistance inE. coli is regulated via production of β-lactam-hydrolyzing β-lactamases enzymes.Escherichia coli O104: H4 is a multi-drug resistant strain known to resist β-lactam as well as several other antibiotics. Here, we report a molecular dynamic simulation–combined docking approach to identify, screen, and verify active pharmacophores against enterohemorrhagicEscherichia coli (EHEC). Experimental studies revealed a boronic acid cyclic monomer (BACM), a non- β-lactam compound, to inhibi...
Source: Journal of Molecular Medicine - June 28, 2019 Category: Molecular Biology Source Type: research

Critical regulation of atherosclerosis by the KCa3.1 channel and the retargeting of this therapeutic target in in-stent neoatherosclerosis
This article reviews the pathological and physiological roles of the KCa3.1 channel and its roles in the disease prognosis of in-stent neoatherosclerosis. (Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - June 28, 2019 Category: Molecular Biology Source Type: research

UPARANT is an effective antiangiogenic agent in a mouse model of rubeosis iridis
AbstractPuncture-induced iris neovascularization (rubeosis iridis; RI) in mice is associated with upregulation of extracellular matrix (ECM) degradation and inflammatory factors. The anti-angiogenic and anti-inflammatory efficacy of UPARANT in reducing RI was determined by noninvasive, in vivo iris vascular densitometry, and confirmed in vitro by quantitative vascular-specific immunostaining. Intravitreal administration of UPARANT successfully and rapidly reduced RI to non-induced control levels. Molecular analysis revealed that UPARANT inhibits formyl peptide receptors through a predominantly anti-inflammatory response, a...
Source: Journal of Molecular Medicine - June 26, 2019 Category: Molecular Biology Source Type: research

Early central vs. peripheral immunological and neurobiological effects of fingolimod —a longitudinal study
In this study, we evaluated the immunological and neurobiological effects of FTY in MS. Blood and cerebrospinal fluid (CSF) samples were collected from 15 MS patients before first FTY administration and after 4  months of FTY therapy. Immunophenotyping and evaluation of sphingosine-1-phosphate (S1P), neurofilament light chain (NFL), S-100 and neuron-specific enolase (NSE) levels were conducted. After 4 months of FTY therapy, absolute cell count in CSF was decreased from 6.33 to 2.43 MPt/l, accompanied b y decreases of CD3+ (2.22 to 0.65 MPt/l) and of CD4+ counts (1.60 to 0.39 MPt/l). In blood, CD3+...
Source: Journal of Molecular Medicine - June 26, 2019 Category: Molecular Biology Source Type: research

Preclinical studies of a death receptor 5 fusion protein that ameliorates acute liver failure
In this study, we produced a pharmaceutical-grade soluble death receptor 5 (sDR5)-Fc fusion protein for treating ALF and evaluated the pharmacology, safety, pharmacokinetics, efficacy, and mechanisms of sDR5-Fc in mice, rats, and cynomolgus monkeys. sDR5-Fc bound with high affinity to both human and monkey tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively blocked TRAIL-induced apoptosis in vitro and significantly ameliorated ALF induced by concanavalin A (Con A) in mice. Mechanistically, sDR5-Fc inhibited hepatocyte death and reduced inflammation in vivo. Furthermore, sDR5-Fc attenuated the produc...
Source: Journal of Molecular Medicine - June 22, 2019 Category: Molecular Biology Source Type: research

Sphingosine-coating of plastic surfaces prevents ventilator-associated pneumonia
AbstractVentilator-associated pneumonia (VAP) is a major cause of morbidity and mortality in critically ill patients. Here, we employed the broad antibacterial effects of sphingosine to prevent VAP by developing a novel method of coating surfaces of endotracheal tubes with sphingosine and sphingosine analogs. Sphingosine and phytosphingosine coatings of endotracheal tubes prevent adherence and mediate killing ofPseudomonas aeruginosa,Acinetobacter baumannii, andStaphylococcus aureus, even in biofilms. Most importantly, sphingosine-coating of endotracheal tubes also preventedP. aeruginosa andS. aureus pneumonia in vivo. Coa...
Source: Journal of Molecular Medicine - June 20, 2019 Category: Molecular Biology Source Type: research

Correction to: Elevated expression of CST1 promotes breast cancer progression and predicts a poor prognosis
In Figure 7f the panel for c-myc of MDA-MB-468 was erroneously duplicated. The corrected version of the figure is shown in this paper. This correction does not influence the conclusion of the study and we sincerely apologize for this oversight. (Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - June 15, 2019 Category: Molecular Biology Source Type: research

Combination of PARP inhibitor and temozolomide to suppress chordoma progression
AbstractChordoma, a malignant bone cancer, is highly resistant to conventional therapeutic approaches; this greatly limits radio- and chemotherapeutic options and disease management. In the present study, we investigated three patient-derived chordoma cell lines to elucidate the molecular mechanism of resistance to therapeutics. An in vitro high-throughput chemical screening assay and an in vivo xenograft model were used to identify novel chemosensitizers for chordoma. We found that patient-derived chordoma cell lines recapitulated disease phenotypes, which were highlighted by robust resistance to medical therapy manifeste...
Source: Journal of Molecular Medicine - June 14, 2019 Category: Molecular Biology Source Type: research

Improvement of mesenchymal stromal cells and their derivatives for treating acute liver failure
AbstractAfter the death of large numbers of cells in liver tissue is triggered by various hepatotoxic factors, intimidating and life-threatening acute liver failure (ALF) can develop with high mortality and expensive costs. Although liver transplantation and hepatocyte transplantation have become substitutes for improving liver regeneration, their applications are inhibited by scarce tissue and cell resources. Therefore, the transplantation of mesenchymal stromal cells (MSCs) and their derivatives including hepatocyte-like cells (HLCs), conditioned medium (CM), and exosomes (Ex) can help alleviate liver injury in ALF indiv...
Source: Journal of Molecular Medicine - June 13, 2019 Category: Molecular Biology Source Type: research

Radiation-induced glucocorticoid receptor promotes CD44+ prostate cancer stem cell growth through activation of SGK1-Wnt/ β-catenin signaling
AbstractWe observed cancer stem cell (CSC) population increase in radioresistant LNCaP (LNCaPR18) and C4-2 (C4-2R26) prostate cancer (PCa) cells compared with respective parental cells. Since the CD44 level increase was most significant in radioresistant PCa cells compared with parental cells among CSC markers tested, we isolated the CD44+ population from LNCaP/LNCaPR18 and C4-2/C4-2R26 cell sets via the immunomagnetic separation method and used them as CSC sources. We detected lower AR level, but higher glucocorticoid receptor (GR) level in CD44+ CSCs than CD44- non-CSCs. Higher GR level in CD44+ CSCs than CD44- cells was...
Source: Journal of Molecular Medicine - June 11, 2019 Category: Molecular Biology Source Type: research

Heterogeneous intracellular TRAIL-receptor distribution predicts poor outcome in breast cancer patients
AbstractUpon ligand binding, plasma membrane –located TNF-related apoptosis-inducing ligand (TRAIL)–receptors 1 and 2 induce apoptosis as well as cancer-promoting signaling in cancer cells. TRAIL-R3 and TRAIL-R4 are believed to negatively regulate TRAIL-mediated apoptosis. Intracellular localization of TRAIL-receptors, as observed in many tumor cells, has been associated with oncogenic features, which are distinct from membrane-associated TRAIL-R signaling. Here, analyzing a panel of 354 breast cancer specimens, we found that an unfavorable outcome correlating with cancer-promoting properties of TRAIL-R1, TRAIL...
Source: Journal of Molecular Medicine - June 10, 2019 Category: Molecular Biology Source Type: research

Tumor cells endowed with professional antigen-presenting cell functions prime PBLs to generate antitumor CTLs
AbstractIntrinsic genetic instability of tumor cells leads to continuous production of mutated proteins referred to as tumor-specific neoantigens. Generally, they are recognized as nonself products by the host immune system. However, an effective adaptive response clearing neoantigen-expressing cells is lost in tumor diseases. Most advanced therapeutic strategies aim at inducing neoantigen-specific immune activation through personalized approaches. They include tumor cell exome sequencing, human leukocyte antigen (HLA) typing, synthesis, and injection of peptides/RNA with adjuvants. Here, we propose an innovative method to...
Source: Journal of Molecular Medicine - June 3, 2019 Category: Molecular Biology Source Type: research

Dual PPAR α/γ agonist aleglitazar confers stroke protection in a model of mild focal brain ischemia in mice
AbstractPeroxisome proliferator-activated receptors (PPARs) control the expression of genes involved in glucose homeostasis, lipid metabolism, inflammation, and cell differentiation. Here, we analyzed the effects of aleglitazar, a dual PPAR α and PPARγ agonist with balanced affinity for either subtype, on subacute stroke outcome. Healthy young adult mice were subjected to transient 30 min middle cerebral artery occlusion (MCAo)/reperfusion. Daily treatment with aleglitazar was begun on the day of MCAo and continued until sacrifice. Blood glucose measurements and lipid profile did not differ between mice re...
Source: Journal of Molecular Medicine - May 30, 2019 Category: Molecular Biology Source Type: research

Skeletal muscle miR-34a/SIRT1:AMPK axis is activated in experimental and human non-alcoholic steatohepatitis
AbstractNon-alcoholic fatty liver disease (NAFLD) pathogenesis associates with intramyocellular lipid deposition and mitochondrial dysfunction. microRNAs (miRs), including pro-apoptotic miR-34a, are modulated during disease progression in liver tissue and plasma. We aimed to investigate the functional role of the miR-34a/SIRT1:AMP-activated protein kinase (AMPK) pathway in modulating local mitochondrial dysfunction in the skeletal muscle of human and experimental non-alcoholic steatohepatitis. Muscle biopsies were obtained from morbid obese NAFLD patients undergoing bariatric surgery. C57BL/6N mice were fed different NAFLD...
Source: Journal of Molecular Medicine - May 28, 2019 Category: Molecular Biology Source Type: research

Prospect and challenge of detecting dynamic gene copy number increases in stem cells by whole genome sequencing
AbstractGene amplification is an evolutionarily well-conserved and highly efficient mechanism to increase the amount of specific proteins. In humans, gene amplification is a hallmark of cancer and has recently been found during stem cell differentiation. Amplifications in stem cells are restricted to specific tissue areas and time windows, rendering their detection difficult. Here, we report on the performance of deep WGS sequencing (average 82-fold depth of coverage) on the BGISEQ with nanoball technology to detect amplifications in human mesenchymal and neural stem cells. As reference technology, we applied array-based c...
Source: Journal of Molecular Medicine - May 27, 2019 Category: Molecular Biology Source Type: research

The median eminence as the hypothalamic area involved in rapid transfer of glucose to the brain: functional and cellular mechanisms
AbstractOur data proposes that glucose is transferred directly to the cerebrospinal fluid (CSF) of the hypothalamic ventricular cavity through a rapid “fast-track-type mechanism” that would efficiently stimulate the glucosensing areas. This mechanism would occur at the level of the median eminence (ME), a periventricular hypothalamic zone with no blood-brain barrier. This “fast-track” mechanism would involve specific glial cells of the ME known as β2 tanycytes that could function as “inverted enterocytes,” expressing low-affinity glucose transporters GLUT2 and GLUT6 in order to rapi...
Source: Journal of Molecular Medicine - May 26, 2019 Category: Molecular Biology Source Type: research

The protean world of non-coding RNAs in glioblastoma
AbstractNon-coding ribonucleic acids (ncRNAs) are a diverse group of RNA molecules that are mostly not translated into proteins following transcription. We review the role of ncRNAs in the pathobiology of glioblastoma (GBM), and their potential applications for GBM therapy. Significant advances in our understanding of the protean manifestations of ncRNAs have been made, allowing us to better decipher the molecular complexity of GBM. A large number of regulatory ncRNAs appear to have a greater influence on the molecular pathology of GBM than thought previously. Importantly, also, a range of therapeutic approaches are emergi...
Source: Journal of Molecular Medicine - May 25, 2019 Category: Molecular Biology Source Type: research

AMPK activation inhibits the functions of myeloid-derived suppressor cells (MDSC): impact on cancer and aging
AbstractAMP-activated protein kinase (AMPK) has a crucial role not only in the regulation of tissue energy metabolism but it can also control immune responses through its cooperation with immune signaling pathways, thus affecting immunometabolism and the functions of immune cells. It is known that AMPK signaling inhibits the activity of the NF- κB system and thus suppresses pro-inflammatory responses. Interestingly, AMPK activation can inhibit several major immune signaling pathways, e.g., the JAK-STAT, NF-κB, C/EBPβ, CHOP, and HIF-1α pathways, which induce the expansion and activation of myeloid-der...
Source: Journal of Molecular Medicine - May 25, 2019 Category: Molecular Biology Source Type: research

Correction to: Critical role of interleukin-23 in development of asthma promoted by cigarette smoke
The original publication of this paper contains a mistake. (Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - May 22, 2019 Category: Molecular Biology Source Type: research

Therapeutic potential of AAV9-S15D-RLC gene delivery in humanized MYL2 mouse model of HCM
This study is focused on aspartic acid-to-valine (D166V) mutation in the myosin regulatory light chain, RLC (MYL2 gene), associated with a malignant form of HCM. Since myosin RLC phosphorylation is critical for normal cardiac function, we aimed to exploit this post-translational modification via phosphomimetic-RLC gene therapy. We hypothesized that mimicking/modulating cardiac RLC phosphorylation in non-phosphorylatable D166V myocardium would improve heart function of HCM-D166V mice. Adeno-associated virus, serotype-9 (AAV9) was used to deliver phosphomimetic human RLC variant with serine-to-aspartic acid substitution at S...
Source: Journal of Molecular Medicine - May 17, 2019 Category: Molecular Biology Source Type: research

RPSAP52 lncRNA is overexpressed in pituitary tumors and promotes cell proliferation by acting as miRNA sponge for HMGA proteins
In this study, we aimed to identify lncRNAs associated with pituitary tumorigenesis. We have analyzed the lncRNA expression profile of a panel of gonadotroph pituitary adenomas in comparison with normal pituitaries. Then, we focused on RPSAP52, a novel lncRNA antisense for theHMGA2 gene, whose overexpression plays a critical role in the development of pituitary adenomas. We report that RPSAP52 expression is highly upregulated in gonadotroph and prolactin-secreting pituitary adenomas, where it correlates with that of HMGA2, compared with normal pituitary tissues. Conversely, its expression showed a variable behavior in soma...
Source: Journal of Molecular Medicine - May 10, 2019 Category: Molecular Biology Source Type: research

Pathological cardiac hypertrophy: the synergy of adenylyl cyclases inhibition in cardiac and immune cells during chronic catecholamine stress
AbstractResponse to stressors in our environment and daily lives is an adaptation conserved through evolution as it is beneficial in enhancing the survival and continuity of humans. Although stressors have evolved, the drastic physiological response they elicit still remains unchanged. The chronic secretion and circulation of catecholamines to produce physical responses when they are not required may result in pathological consequences which affect cardiac function drastically. This review seeks to point out the probable implication of chronic stress in inducing an inflammation disorder in the heart. We discussed the likel...
Source: Journal of Molecular Medicine - May 6, 2019 Category: Molecular Biology Source Type: research

Regulation of osteoblast behaviors via cross-talk between Hippo/YAP and MAPK signaling pathway under fluoride exposure
This study evaluated the role of Hippo/YAP and MAPK signaling pathway in osteoblast behaviors under excessive fluoride exposure in vitro and in vivo. Commercially pure Ti (cp-Ti) samples were exposed to fluoride (0, 0.1, and 1.0  mM NaF) for 7 days. Cell adhesion was observed using a laser scanning confocal microscope. Cell viability and apoptosis were evaluated by CCK-8 assay and flow cytometry, respectively. The expressions of osteoblast markers and key molecules in MAPK and YAP pathway were detected by Western blot. In vivo studies were evaluated by histology methods in C57/BL6 mice model. Our results showed t...
Source: Journal of Molecular Medicine - May 4, 2019 Category: Molecular Biology Source Type: research

Macrophage derived TNF α promotes hepatic reprogramming to Warburg-like metabolism
AbstractDuring infection, hepatocytes must undergo a reprioritization of metabolism, termed metabolic reprogramming. Hepatic metabolic reprogramming in response to infection begins within hours of infection, suggesting a mechanism closely linked to pathogen recognition. Following injection with polyinosinic:polycytidylic acid, a mimic of viral infection, a robust hepatic innate immune response could be seen involving the TNF α pathway at 2 h. Repeated doses led to the adoption of Warburg-like metabolism in the liver as determined by in vivo metabolic imaging, expression analyses, and metabolomics. Hepatic macrop...
Source: Journal of Molecular Medicine - May 3, 2019 Category: Molecular Biology Source Type: research

A rapid, safe, and quantitative in vitro assay for measurement of uracil-DNA glycosylase activity
AbstractBase excision repair (BER) is a frontline repair mechanism that operates through the G1 phase of the cell cycle, which ensures the genome integrity by repairing thousands of DNA lesions due to endogenous and exogenous agents. Its correct functioning is fundamental for cell viability and the health of the organism. Uracil is one of the most prevalent lesions that appears in DNA arising by spontaneous or enzymatic deamination of cytosine or misincorporation of the deoxyuridine 5 ′-triphosphate nucleotide (dUTP) in place of deoxythymidine 5′-triphosphate (dTTP) during DNA replication. In the first pathway,...
Source: Journal of Molecular Medicine - May 1, 2019 Category: Molecular Biology Source Type: research

Bone marrow chimeras —a vital tool in basic and translational research
AbstractBone marrow chimeras are used routinely in immunology research as well as in other fields of biology. Here, we provide a concise state-of-the-art review about the types of chimerisms that can be achieved and the type of information that each model generates. We include separate sections for caveats and future developments. We provide examples from the literature in which different types of chimerism were employed to answer specific questions. While simple bone marrow chimeras allow to dissect the role of genes in distinct cell populations such as the hematopoietic cells versus non-hematopoietic cells, mixed bone ma...
Source: Journal of Molecular Medicine - April 26, 2019 Category: Molecular Biology Source Type: research

Regulation and role of the ER stress transcription factor CHOP in alveolar epithelial type-II cells
AbstractIdiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by type-II alveolar epithelial cell (AECII) injury and fibroblast hyperproliferation. Severe AECII endoplasmic reticulum (ER) stress is thought to underlie IPF, but is yet incompletely understood. We studied the regulation of C/EBP homologous protein (CHOP), a proapoptotic ER-stress-related transcription factor (TF) in AECII-like cells. Interestingly, single or combined overexpression of the active ER stress transducers activating transcription factor-4 (Atf4) and activating transcription factor-6 (p50Atf6) or spliced x-box-binding protein-1 (sXbp...
Source: Journal of Molecular Medicine - April 26, 2019 Category: Molecular Biology Source Type: research