Fetal programming effects of pentaerythritol tetranitrate in a rat model of superimposed preeclampsia
In conclusion, maternal PETN treatment in DSSR shows both beneficial and unfavorable effects. It improve s fetal growth and ameliorates glucose tolerance in the offspring. Although maternal PETN treatment has no effect on blood pressure in offspring fed with normal chow or high-salt diet, the offspring is at higher risk to develop HFD-induced hypertension. PETN may potentiate the blood pressure respons e to HFD by epigenetic modifications of EDHF genes.Key messagesThe core findings of this article suggest that maternal PETN treatment of DSSR, a rat model of a spontaneous superimposed preeclampsia, leads to•Improvement...
Source: Journal of Molecular Medicine - August 3, 2020 Category: Molecular Biology Source Type: research

Gut microbiota and atherosclerosis: role of B cell for atherosclerosis focusing on the gut-immune-B2 cell axis
AbstractAtherosclerosis is the leading cause of cardiovascular mortality and morbidity worldwide and is described as a complex disease involving several different cell types and their molecular products. Recent studies have revealed that atherosclerosis arises from a systemic inflammatory process, including the accumulation and activities of various immune cells. However, the immune system is a complicated network made up of many cell types, hundreds of bioactive cytokines, and millions of different antigens, making it challenging to readily define the associated mechanism of atherosclerosis. Nevertheless, we previously re...
Source: Journal of Molecular Medicine - July 31, 2020 Category: Molecular Biology Source Type: research

Microparticles expressing myeloperoxidase as potential biomarkers in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV)
AbstractTo investigate presence of circulating myeloperoxidase-positive microparticles (MPO+MPs) in relation to disease activity in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Forty-six patients with AAV and 23 age- and sex-matched healthy controls were included. Vasculitis disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). MPs were analyzed in citrate plasma by flow cytometry and phenotyped based on MPO expression and co-expression of pentraxin-3 (PTX3), high mobility group box 1 protein (HMGB1), and tumor necrosis factor-like weak inducer of apo...
Source: Journal of Molecular Medicine - July 30, 2020 Category: Molecular Biology Source Type: research

Interaction with p53 explains a pro-proliferative function for VHL in cancer
AbstractThe von Hippel-Lindau (VHL) protein binds and degrades hypoxia-inducible factors (HIF) hydroxylated by prolyl-hydroxylases under normoxia. Although originally described as a tumor suppressor, there is growing evidence that VHL may paradoxically promote tumor growth. The significance of its described interactions with many other proteins remains unclear. We found that VHL interacts with p53, preventing its tetramerization, promoter  binding and expression of its target genes p21, PUMA, and Bax. VHL limited the decrease in proliferation and increase in apoptosis caused by p53 activation, independent of prolyl-hy...
Source: Journal of Molecular Medicine - July 28, 2020 Category: Molecular Biology Source Type: research

Phenotypic characteristics of commonly used inbred mouse strains
AbstractThe laboratory mouse is the most commonly used mammalian model for biomedical research. An enormous number of mouse models, such as gene knockout, knockin, and overexpression transgenic mice, have been created over the years. A common practice to maintain a genetically modified mouse line is backcrossing with standard inbred mice over several generations. However, the choice of inbred mouse for backcrossing is critical to phenotypic characterization because phenotypic variabilities are often observed between mice with different genetic backgrounds. In this review, the major features of commonly used inbred mouse li...
Source: Journal of Molecular Medicine - July 25, 2020 Category: Molecular Biology Source Type: research

SCFAs induce autophagy in intestinal epithelial cells and relieve colitis by stabilizing HIF-1 α
In this study, we investigated the relationship between HIF-1α and autophagy in healthy and inflammatory states using transgenic mice, colitis models, and cel l culture models. We confirmed that the absence of intestinal epithelial HIF-1α changed the composition of the intestinal microbes and increased the susceptibility of mice to dextran sodium sulfate (DSS)-induced colitis. In addition, autophagy levels in the intestinal epithelial cells (IECs) were s ignificantly reduced in IEC-specific HIF-1α-deficient (HIF-1α∆IEC) mice. Moreover, in the cell culture models, butyrate treatment significantly i...
Source: Journal of Molecular Medicine - July 22, 2020 Category: Molecular Biology Source Type: research

TNFSF13 upregulation confers chemotherapeutic resistance via triggering autophagy initiation in triple-negative breast cancer
AbstractSince chemotherapy is a main strategy to treat triple-negative breast cancer (TNBC) patients currently, identifying a biomarker to predict chemotherapeutic responses is urgently needed for patients to avoid suffering through unnecessary chemotherapeutic treatments. Here, we found that the endogenous expression ofTNFSF13 in a panel of TNBC cell lines highly correlates with paclitaxel (PTX) and doxorubicin IC50 concentrations. Whereas knocking downTNFSF13 enhances PTX effectiveness in PTX-insensitive MDA-MB231 cells, recombinant TNFSF13 (recTNFSF13) desensitizes PTX-sensitive HCC1806 cells to PTX treatment. Moreover,...
Source: Journal of Molecular Medicine - July 15, 2020 Category: Molecular Biology Source Type: research

Metabolism of N-nitrosodimethylamine, methylation of macromolecules, and development of hepatic fibrosis in rodent models
AbstractHepatic fibrosis and cirrhosis are chronic diseases affecting liver and a major health problem throughout the world. The hallmark of fibrosis and cirrhosis is inordinate synthesis and deposition of fibril forming collagens in the extracellular matrix of the liver leading to nodule formation and loss of normal architecture. Hepatic stellate cells play a crucial role in the pathogenesis and progression of liver fibrosis through secretion of several potent fibrogenic factors that trigger hepatocytes, portal fibrocytes, and bone marrow –derived fibroblasts to synthesize and deposit several connective tissue prote...
Source: Journal of Molecular Medicine - July 14, 2020 Category: Molecular Biology Source Type: research

Genetic contribution of endoplasmic reticulum aminopeptidase 1 polymorphisms to liver fibrosis progression in patients with HCV infection
AbstractThe endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses, trimming peptides and loading onto HLA class I molecules. Coding single nucleotide polymorphisms within ERAP1 are associated with autoimmune diseases, viral infections, and cancer development. Our purpose was to analyze the influence of ERAP1 variants on fibrogenesis in hepatitis C virus (HCV) –infected patients. A range of ERAP1 polymorphisms were genotyped in 722 unrelated Caucasian patients diagnosed with chronic HCV from two Spanish cohorts. Patients were classified according to their fibrosis stage. Paraffin-em...
Source: Journal of Molecular Medicine - July 9, 2020 Category: Molecular Biology Source Type: research

Synergistic effects of pazopanib and hyperthermia against uterine leiomyosarcoma growth mediated by downregulation of histone acetyltransferase 1
AbstractPazopanib —a multitargeted tyrosine kinase inhibitor with prominent antiangiogenic effects—has shown promise in the treatment of soft-tissue sarcomas. Hyperthermia has been also applied as an adjunctive treatment to chemotherapy for these malignancies. Here, we show that pazopanib and hyperthermia act syn ergistically in inhibiting uterine leiomyosarcoma (LMS) cell growth. Compared with either treatment alone, the combination of pazopanib and hyperthermia exerted the highest antitumor activity in a xenograft model. Mechanistically, we found that combined treatment with pazopanib and hyperthermia inhi bi...
Source: Journal of Molecular Medicine - July 7, 2020 Category: Molecular Biology Source Type: research

The novel protein homeostatic modulator BTX306 is active in myeloma and overcomes bortezomib and lenalidomide resistance
AbstractSmall molecules targeting the cereblon-containing E3 ubiquitin ligase including thalidomide, lenalidomide, and pomalidomide modulate turnover of downstream client proteins and demonstrate pre-clinical and clinical anti-myeloma activity. Different drugs that engage with cereblon hold the potential of unique phenotypic effects, and we therefore studied the novel protein homeostatic modulator (PHM ™) BTX306 with a unique thiophene-fused scaffold bearing a substituted phenylurea and glutarimide. This agent much more potently reduced human-derived myeloma cell line viability, with median inhibitory concentrations ...
Source: Journal of Molecular Medicine - July 6, 2020 Category: Molecular Biology Source Type: research

Vascular K ATP channels protect from cardiac dysfunction and preserve cardiac metabolism during endotoxemia
AbstractKATP channels in the vasculature composed of Kir6.1 regulate vascular tone and may contribute to the pathogenesis of endotoxemia. We used mice with cell-specific deletion of Kir6.1 in smooth muscle (smKO) and endothelium (eKO) to investigate this question. We found that smKO mice had a significant survival disadvantage compared with their littermate controls when treated with a sub-lethal dose of lipopolysaccharide (LPS). All cohorts of mice became hypotensive following bacterial LPS administration; however, mean arterial pressure in WT mice recovered to normal levels, whereas smKO struggled to overcome LPS-induced...
Source: Journal of Molecular Medicine - July 6, 2020 Category: Molecular Biology Source Type: research

Genetically programmed changes in transcription of the novel progranulin regulator
AbstractProgranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggestedPSRC1 (proline and serine rich coiled-coil 1) to be a target of genetic variants associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation ofPSRC1. Phylogenetic module complexity analysis (PMCA) prioritized four polymorphisms (rs12740374, rs629301, rs660240, rs7528419) altering transcription factor binding sites with an overall score for potential regulatory function ofSall >  7.0. The effects of these var...
Source: Journal of Molecular Medicine - July 3, 2020 Category: Molecular Biology Source Type: research

A comprehensive review of genetic alterations and molecular targeted therapies for the implementation of personalized medicine in acute myeloid leukemia
AbstractAcute myeloid leukemia (AML) is an extremely heterogeneous disease defined by the clonal growth of myeloblasts/promyelocytes not only in the bone marrow but also in peripheral blood and/or tissues. Gene mutations and chromosomal abnormalities are usually associated with aberrant proliferation and/or block in the normal differentiation of hematopoietic cells. So far, the combination of cytogenetic profiling and molecular and gene mutation analyses remains an essential tool for the classification, diagnosis, prognosis, and treatment for AML. This review gives an overview on how the development of novel innovative tec...
Source: Journal of Molecular Medicine - July 3, 2020 Category: Molecular Biology Source Type: research

Translation of curative therapy concepts with T cell and cytokine antibody combinations for type 1 diabetes reversal in the IDDM rat
AbstractProinflammatory cytokines released from the pancreatic islet immune cell infiltrate in type 1 diabetes (T1D) cause insulinopenia as a result of severe beta cell loss due to apoptosis. Diabetes prevention strategies targeting different cytokines with antibodies in combination with a T cell antibody, anti-TCR, have been assessed for therapy success in the LEW.1AR1-iddm (IDDM) rat, an animal model of human T1D. Immediately after diabetes manifestation, antibody combination therapies were initiated over 5 days with anti-TNF- α (tumour necrosis factor), anti-IL-1β (interleukin), or anti-IFN-γ (interfero...
Source: Journal of Molecular Medicine - June 30, 2020 Category: Molecular Biology Source Type: research

Sars-Cov-2 interference in HEME production: is it the time for an early predictive biomarker?
(Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - June 29, 2020 Category: Molecular Biology Source Type: research

Molecular karyotyping and gene expression analysis in childhood cancer patients
AbstractThe genetic etiology of sporadic childhood cancer cases remains unclear. We recruited a cohort of 20 patients who survived a childhood malignancy and then developed a second primary cancer (2N), and 20 carefully matched patients who survived a childhood cancer without developing a second malignancy (1N). Twenty matched cancer-free (0N) and additional 1000 (0N) GHS participants served as controls. Aiming to identify new candidate loci for cancer predisposition, we compared the genome-wide DNA copy number variations (CNV) with the RNA-expression data obtained after in vitro irradiation of primary fibroblasts. In 2N p...
Source: Journal of Molecular Medicine - June 23, 2020 Category: Molecular Biology Source Type: research

MESP2 variants contribute to conotruncal heart defects by inhibiting cardiac neural crest cell proliferation
This study first analyzedMESP2 variants identified in sporadic nonsyndromic CTD patients.MESP2 is expressed in the OFT of different stages of human and mouse embryos.MESP2 regulates the transcriptional activities of downstream CTD-related genes and promotes CNCC proliferation by regulating cell cycle factorp21cip1 orCdk4. (Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - June 22, 2020 Category: Molecular Biology Source Type: research

Comprehensive characterization of hepatocyte-derived extracellular vesicles identifies direct miRNA-based regulation of hepatic stellate cells and DAMP-based hepatic macrophage IL-1 β and IL-17 upregulation in alcoholic hepatitis mice
AbstractExtracellular vesicles (EVs) have been growingly recognized as biomarkers and mediators of alcoholic liver disease (ALD) in human and mice. Here we characterized hepatocyte-derived EVs (HC-EVs) and their cargo for their biological functions in a novel murine model that closely resembles liver pathology observed in patients with alcoholic hepatitis (AH), the most severe spectrum of ALD. The numbers of circulating EVs and HC-EVs were significantly increased by 10-fold in AH mice compared with control mice. The miRNA (miR) –seq analysis detected 20 upregulated and 4 downregulated miRNAs (P 
Source: Journal of Molecular Medicine - June 18, 2020 Category: Molecular Biology Source Type: research

Transcriptional signature of resting-memory CD4 T cells differentiates spontaneous from treatment-induced HIV control
AbstractThe HIV reservoir is the main barrier to eradicating HIV infection, and resting memory CD4 T (Trm) cells are one of the most relevant cellular component harboring latent proviruses. This is the first study analyzing the transcriptional profile of Trm cells, in two well-characterized groups of HIV patients with distinct mechanisms of viral replication control (spontaneous versus treatment-induced). We use a systems biology approach to unravel subtle but important differences in the molecular mechanisms operating at the cellular level that could be associated with the host ’s ability to control virus replicatio...
Source: Journal of Molecular Medicine - June 17, 2020 Category: Molecular Biology Source Type: research

TCF21: a critical transcription factor in health and cancer
AbstractTranscription factor 21 (TCF21) is a member of the basic helix-loop-helix (bHLH) transcription factors that mediate cell fate and differentiation by orchestrating temporal and spatial gene expression during the development of various organs. It plays a crucial role in a wide spectrum of biological processes, including organogenesis, epithelial-mesenchymal transition (EMT), cell cycle, autophagy, proliferation, differentiation, specification, maturation, and survival of cells, as well as invasion and metastasis of cancer cells. Controlled expression and activity of TCF21 provide a balanced transcriptional program th...
Source: Journal of Molecular Medicine - June 15, 2020 Category: Molecular Biology Source Type: research

COVID-19: molecular diagnostics overview
AbstractThe last day of 2019 delivered the first report to the World Health Organization (WHO) about a group of cases of pneumonia of unknown etiology in Wuhan, China. Subsequent investigations identified the new comer, a novel coronavirus related to severe acute respiratory syndrome coronavirus (SARS-CoV) and thus was termed as SARS-CoV-2. Being very contagious, the new virus led the era of “COVID-19” which is the acronym of “coronavirus disease 2019,” evoking an imminent threat to global health security with unprecedented devastating challenges to human kind. In this article, we provide a molecula...
Source: Journal of Molecular Medicine - June 13, 2020 Category: Molecular Biology Source Type: research

Gene-environment regulation of chamber-specific maturation during hypoxemic perinatal circulatory transition
AbstractChamber-specific and temporally regulated perinatal cardiac growth and maturation is critical for functional adaptation of the heart and may be altered significantly in response to perinatal stress, such as systemic hypoxia (hypoxemia), leading to significant pathology, even mortality. Understanding transcriptome regulation of neonatal heart chambers in response to hypoxemia is necessary to develop chamber-specific therapies for infants with cyanotic congenital heart defects (CHDs). We sought to determine chamber-specific transcriptome programming during hypoxemic perinatal circulatory transition. We performed tran...
Source: Journal of Molecular Medicine - June 12, 2020 Category: Molecular Biology Source Type: research

Lysosomal storage diseases: current therapies and future alternatives
AbstractLysosomal storage disorders (LSDs) are a group of monogenic diseases characterized by progressive accumulation of undegraded substrates into the lysosome, due to mutations in genes that encode for proteins involved in normal lysosomal function. In recent years, several approaches have been explored to find effective and successful therapies, including enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, hematopoietic stem cell transplantation, and gene therapy. In the case of gene therapy, genome editing technologies have opened new horizons to accelerate the development of novel tre...
Source: Journal of Molecular Medicine - June 11, 2020 Category: Molecular Biology Source Type: research

Correction to: Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein
The correct name of the 17th Author is presented in this paper. (Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - June 11, 2020 Category: Molecular Biology Source Type: research

Correction to: Signaling lipids as diagnostic biomarkers for ocular surface cicatrizing conjunctivitis
The correct name of the 11th Author and the missing Acknowledgment is presented in this paper. (Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - June 10, 2020 Category: Molecular Biology Source Type: research

Arginine derivatives in atrial fibrillation progression phenotypes
AbstractArginine, homoarginine (hArg), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) affect nitric oxide metabolism and altered concentrations are associated with cardiovascular morbidity and mortality. We analyzed these metabolites using liquid chromatography –tandem mass spectrometry in patients with atrial fibrillation (AF) (n = 241) with a focus on heart rhythm at blood withdrawal, AF progression phenotypes, and successful sinus rhythm (SR) restoration (n = 22). AF progression phenotypes were defined as paroxysmal AF with/without low voltage areas (LVA) and ...
Source: Journal of Molecular Medicine - June 6, 2020 Category: Molecular Biology Source Type: research

Novel therapeutic approaches for treatment of COVID-19
AbstractTo date, there is no licensed treatment or approved vaccine to combat the coronavirus disease of 2019 (COVID-19), and the number of new cases and mortality multiplies every day. Therefore, it is essential to develop an effective treatment strategy to control the virus spread and prevent the disease. Here, we summarized the therapeutic approaches that are used to treat this infection. Although it seems that antiviral drugs are effective in improving clinical manifestation, there is no definite treatment protocol. Lymphocytopenia, excessive inflammation, and cytokine storm followed by acute respiratory distress syndr...
Source: Journal of Molecular Medicine - June 3, 2020 Category: Molecular Biology Source Type: research

Impact of β-glycerophosphate on the bioenergetic profile of vascular smooth muscle cells
In conclusion, β-glycerophosphate modifies key parameters of mitochondrial function and cellular bioenergetics in VSMCs that may contribute to the onset of phenotypical transdifferentiation and calcification. These observations advance the unde rstanding of the role of energy metabolism in VSMC physiology and pathophysiology of vascular calcification during hyperphosphatemia.Key messagesβ-Glycerophosphate modifies key parameters of mitochondrial respiration in VSMCs.β-Glycerophosphate induces changes in mitochondrial fuel choice in VSMCs.β-Glycerophosphate promotes a more oxidative and less glycoly...
Source: Journal of Molecular Medicine - June 2, 2020 Category: Molecular Biology Source Type: research

Cell-specific conditional deletion of interleukin-1 (IL-1) ligands and its receptors: a new toolbox to study the role of IL-1 in health and disease
AbstractThe pro-inflammatory cytokine interleukin-1 (IL-1) plays a key role in many physiological processes and during the inflammatory and immune response to most common diseases. IL-1 exists as two agonists, IL-1 α and IL-1β that bind to the only signaling IL-1 type 1 receptor (IL-1R1), while a second decoy IL-1 type 2 receptor (IL-1R2) binds both forms of IL-1 without inducing cell signaling. The field of immunology and inflammation research has, over the past 35 years, unraveled many mechanisms of IL-1 actions, through in vitro manipulation of the IL-1 system or by using genetically engineered mouse mod...
Source: Journal of Molecular Medicine - May 29, 2020 Category: Molecular Biology Source Type: research

Oxidized LDL induces vimentin secretion by macrophages and contributes to atherosclerotic inflammation
AbstractActivated macrophages show increased expression of vimentin, an intermediate filament protein. Macrophages secrete vimentin into extracellular space; however, the functions of extracellular vimentin and the process of vimentin secretion are not clearly defined. We found that oxidized low-density lipoproteins (oxLDL) via CD36 induced vimentin secretion in macrophages. We also revealed that extracellular vimentin induced macrophages to release inflammatory cytokines and augmented oxLDL-induced release of TNF- α and IL-6. Extracellular vimentin activated NF-κB signaling via phosphorylation of focal adhesio...
Source: Journal of Molecular Medicine - May 25, 2020 Category: Molecular Biology Source Type: research

Stabilization of the histone acetyltransferase Tip60 by deubiquitinating enzyme USP7 stimulates the release of pro-inflammatory mediators in acute lung injury
Abstract Acute lung injury (ALI) is often associated with inflammation. Increasing evidence has identified the role for ubiquitin-specific protease 7 (USP7) in activating the expression of inflammatory factors in macrophages. The present study evaluated whether USP7 also mediates histone acetyltransferase Tat-interactive protein 60 (Tip60) in the development of ALI inflammation. An ALI mouse model was induced by intratracheal lipopolysaccharide (LPS) administration. Next, lung myeloperoxidase (MPO) activity and the ratio of dry weight/wet weight of lung were examined to evaluate tissue damage. In addition, RAW 264.7 cells ...
Source: Journal of Molecular Medicine - May 22, 2020 Category: Molecular Biology Source Type: research

GSTM1 null and GSTT1 null: predictors of cisplatin-caused acute ototoxicity measured by DPOAEs
AbstractPreventing the ototoxicity caused by cisplatin is a major issue yet to be overcome. Useful preventive treatments will soon be available. Consequently, the next step is to filter out those patients who are more prone to develop ototoxicity. The aim of this study was to prospectively evaluate potential predictive markers of acute ototoxicity as determined by measures of distortion product otoacoustic emissions (DPOAEs). A total of 118 patients from our previous DPOAE analysis were put under evaluation. Ototoxic cases were divided according to unilateral (n = 45) or bilateral (n = 23) involvement. The clinicopathologi...
Source: Journal of Molecular Medicine - May 20, 2020 Category: Molecular Biology Source Type: research

A new potential mode of cardiorenal protection of KLOTHO gene variability in type 1 diabetic adolescents
AbstractAs the KL-VS haplotype alters secretion and activity of KLOTHO and uric acid (UA) is associated with endothelial dysfunction and inflammation, their mutual links may contribute to microalbuminuria (MA) in patients with type 1 diabetes (T1D). Therefore, we hypothesize that KL-VS polymorphism could be associated with the prevalence of MA in T1D patients, and KL-VS polymorphism could modify physiological functions and pathogenic potential of UA. We have examined 350 patients with T1D. The analysis concerned KL-VS polymorphism along with the concentrations of serum inflammatory markers, indicators of renal function, bl...
Source: Journal of Molecular Medicine - May 20, 2020 Category: Molecular Biology Source Type: research

Opposite regulation of piRNAs, rRNAs and miRNAs in the blood after subarachnoid hemorrhage
This report, although preliminary and largely proof-of-concept, is the first to describe alterations in sRNAs abundance levels in response to IA rupture in humans. The obtained results indicate novel mechanisms that may constitute another level of control of the inflammatory response.Key messagesA total of 542 sRNAs were differentially expressed after aneurysmal SAH comparing with controlspiRNAs and rRNAs were upregulated and miRNAs were downregulated after IA ruptureThe regulated sRNA showed an enrichment in the representation of some transcription factor binding sitespiRNAs, tRNAs, and rRNAs showed an overrepresentation ...
Source: Journal of Molecular Medicine - May 18, 2020 Category: Molecular Biology Source Type: research

Local Wnt3a treatment restores bone regeneration in large osseous defects after surgical debridement of osteomyelitis
In this study, we investigated the positive effects of Wnt-pathway modulation on bone regeneration in our previous established mouse model. This was achieved by local application of Wnt3a, a recombinant activator of the canonical Wnt-pathway. Application of Wnt3a could enhance new bone formation, which was verified by histological and μ-CT analysis. Moreover, histology and western blots revealed enhanced osteoblastogenesis and downregulated osteoclasts in a RANKL-dependent manner. Further analysis of Wnt-pathway showed downregulation after bone infections were reconstituted by application of Wnt3a. Interestingly, Wnt-in...
Source: Journal of Molecular Medicine - May 18, 2020 Category: Molecular Biology Source Type: research

CU06-1004 (endothelial dysfunction blocker) ameliorates astrocyte end-feet swelling by stabilizing endothelial cell junctions in cerebral ischemia/reperfusion injury
AbstractCerebral ischemia, or stroke, is widespread leading cause of death and disability. Surgical and pharmacological interventions that recover blood flow are the most effective treatment strategies for stroke patients. However, restoring the blood supply is accompanied by severe reperfusion injury, with edema and astrocyte end-feet disruption. Here, we report that the oral administration of CU06-1004 (previously Sac-1004), immediately after onset of ischemia/reperfusion (I/R), ameliorated cerebral damage. CU06-1004 stabilized blood ‑brain barrier by inhibiting the disruption of the tight junction-related protein zona...
Source: Journal of Molecular Medicine - May 16, 2020 Category: Molecular Biology Source Type: research

Legumain promotes fibrogenesis in chronic pancreatitis via activation of transforming growth factor β1
AbstractChronic pancreatitis (CP) is a major risk factor for pancreatic cancer; however, little is known about the pathogenic mechanisms underlying the development of CP. Legumain (Lgmn) has been linked to some chronic inflammatory diseases. The present study investigated the role of legumain in pancreatic fibrogenesis. We induced CP in wild type C57BL6 (WT), Lgmn-deficient (Lgmn−/−), Lgmnflox/flox and Lgmnflox/flox× LysMCre mice by intraperitoneal injection of caerulein for 4  weeks. Pancreata were collected and analyzed by quantitative reverse transcription polymerase chain reaction, Western blotti...
Source: Journal of Molecular Medicine - May 15, 2020 Category: Molecular Biology Source Type: research

Bax inhibitor-1 deficiency leads to obesity by increasing Ca 2+ -dependent insulin secretion
AbstractTransmembrane BAX inhibitor motif containing 6 (TMBIM6), also known as Bax inhibitor-1, is an evolutionarily conserved protein involved in endoplasmic reticulum (ER) function. TMBIM6 is an ER Ca2+ leak channel and its deficiency enhances susceptibility to ER stress due to inhibition of the ER stress sensor IRE1 α. It was previously shown that TMBIM6 overexpression improves glucose metabolism and that TMBIM6 knockout mice develop obesity. We here examined the metabolic alterations underlying the obese phenotype and subjected TMBIM6 knockout mice to indirect calorimetry and euglycemic-hyperinsulinemic tests wit...
Source: Journal of Molecular Medicine - May 11, 2020 Category: Molecular Biology Source Type: research

Microglial-specific depletion of TAK1 is neuroprotective in the acute phase after ischemic stroke
AbstractTransforming growth factor- β-activated kinase 1 (TAK1) is upregulated after cerebral ischemia and contributes to an aggravation of brain injury. TAK1 acts as a key regulator of NF-ΚB and the MAP kinases JNK and p38 and modulates post-ischemic neuroinflammation and apoptosis. Microglia are the main TAK1-expressing immunocomp etent cells of the brain. However, little is known about the function and regulation of microglial TAK1 after cerebral ischemia. Tamoxifen-dependent conditional depletion of TAK1 in microglial cells was induced inCx3cr1creER-Tak1fl/fl mice. ThecreER-negativeTak1fl/fl mice and vehicle...
Source: Journal of Molecular Medicine - May 7, 2020 Category: Molecular Biology Source Type: research

Eukaryotic elongation factor-2 kinase (eEF2K) signaling in tumor and microenvironment as a novel molecular target
AbstractEukaryotic elongation factor-2 kinase (eEF2K), an atypical member of alpha-kinase family, is highly overexpressed in breast, pancreatic, brain, and lung cancers, and associated with poor survival in patients. eEF2K promotes cell proliferation, survival, and aggressive tumor characteristics, leading to tumor growth and progression. While initial studies indicated that eEF2K acts as a negative regulator of protein synthesis by suppressing peptide elongation phase, later studies demonstrated that it has multiple functions and promotes cell cycle, angiogenesis, migration, and invasion as well as induction of epithelial...
Source: Journal of Molecular Medicine - May 7, 2020 Category: Molecular Biology Source Type: research

Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein
AbstractStimulation of monocytes with microbial and non-microbial products, including oxidized low-density lipoprotein (oxLDL), induces a protracted pro-inflammatory, atherogenic phenotype sustained by metabolic and epigenetic reprogramming via a process calledtrained immunity. We investigated the intracellular metabolic mechanisms driving oxLDL-induced trained immunity in human primary monocytes and observed concomitant upregulation of glycolytic activity and oxygen consumption. In two separate cohorts of healthy volunteers, we assessed the impact of genetic variation in glycolytic genes on the training capacity of monocy...
Source: Journal of Molecular Medicine - April 30, 2020 Category: Molecular Biology Source Type: research

Correction to: Paracrine signaling in islet function and survival
The corrected References in Table 1 are presented in this paper. (Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - April 28, 2020 Category: Molecular Biology Source Type: research

Neutralization of extracellular NAMPT (nicotinamide phosphoribosyltransferase) ameliorates experimental murine colitis
AbstractExtracellular nicotinamide phosphoribosyltransferase (eNAMPT) is increased in inflammatory bowel disease (IBD) patients, and its serum levels correlate with a worse prognosis. In the present manuscript, we show that eNAMPT serum levels are increased in IBD patients that fail to respond to anti-TNF α therapy (infliximab or adalimumab) and that its levels drop in patients that are responsive to these therapies, with values comparable with healthy subjects. Furthermore, eNAMPT administration in dinitrobenzene sulfonic acid (DNBS)-treated mice exacerbates the symptoms of colitis, suggesting a ca usative role of t...
Source: Journal of Molecular Medicine - April 27, 2020 Category: Molecular Biology Source Type: research

Immune landscape and a novel immunotherapy-related gene signature associated with clinical outcome in early-stage lung adenocarcinoma
AbstractPatients with early-stage lung adenocarcinoma (LUAD) exhibit different overall survival (OS) rates and immunotherapy responses. Understanding the immune landscape facilitates the personalized treatment of LUAD. The immune cell populations in tumour tissues were quantified to depict the immune landscape in early-stage LUAD patients in The Cancer Genome Atlas (TCGA). Early-stage LUAD patients in three immune clusters identified by the immune landscape exhibited different survival potentials. A prognostic immune-related gene signature was built to predict the survival of early-stage LUAD patients. Several machine lear...
Source: Journal of Molecular Medicine - April 25, 2020 Category: Molecular Biology Source Type: research

Targeting TJP1 attenuates cell –cell aggregation and modulates chemosensitivity against doxorubicin in leiomyosarcoma
AbstractTight junction protein 1 (TJP1) is a membrane-associated cytosolic protein important for cell –cell communication in intercellular barriers in epithelial and non-epithelial cells. Here, we explored the functional involvement of TJP1 in non-epithelial tumors such as soft tissue sarcoma, especially in leiomyosarcoma (LMS). TJP1 expression in soft tissue sarcoma was analyzed in normal and tum or tissues as well as from public datasets such as the TCGA provisional dataset, in which TJP1 expression was compared with other subtypes such as undifferentiated sarcomas, and myxofibrosarcomas. SK-LMS-1 cell lines with r...
Source: Journal of Molecular Medicine - April 21, 2020 Category: Molecular Biology Source Type: research

Fructose metabolism by the guts cuts liver fat
(Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - April 21, 2020 Category: Molecular Biology Source Type: research

Stress-mediated generation of deleterious ROS in healthy individuals - role of cytochrome c oxidase
AbstractPsychosocial stress is known to cause an increased incidence of coronary heart disease. In addition, multiple other diseases like cancer and diabetes mellitus have been related to stress and are mainly based on excessive formation of reactive oxygen species (ROS) in mitochondria. The molecular interactions between stress and ROS, however, are still unknown. Here we describe the missing molecular link between stress and an increased cellular ROS, based on the regulation of cytochrome c oxidase (COX). In normal healthy cells, the “allosteric ATP inhibition of COX” decreases the oxygen uptake of mitochondr...
Source: Journal of Molecular Medicine - April 20, 2020 Category: Molecular Biology Source Type: research

Signaling lipids as diagnostic biomarkers for ocular surface cicatrizing conjunctivitis
AbstractMetabolomics has been applied to diagnose diseases, predict disease progression, and design therapeutic strategies in various areas of medicine. However, it remains to be applied to the ocular surface diseases, where biological samples are often of limited quantities. We successfully performed proof-of-concept metabolomics assessment of volume-limited cytology samples from a clinical form of chronic inflammatory cicatrizing conjunctivitis, i.e., ocular MMP and discovered metabolic changes of signaling lipid mediators upon disease onset and progression. The metabolomics assessment revealed active oxylipins, lysophos...
Source: Journal of Molecular Medicine - April 20, 2020 Category: Molecular Biology Source Type: research

HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD
AbstractNon-alcoholic fatty liver disease (NAFLD) parallels the global obesity epidemic with unmet therapeutic needs. We investigated whether inhibition of hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2), a key cellular oxygen sensor whose inhibition stabilizes HIF, would protect from NAFLD by subjecting HIF-P4H-2-deficient (Hif-p4h-2gt/gt) mice to a high-fat, high-fructose (HFHF) or high-fat, methionine-choline-deficient (HF-MCD) diet. On both diets, theHif-p4h-2gt/gt mice gained less weight and had less white adipose tissue (WAT) and its inflammation, lower serum cholesterol levels, and lighter livers with le...
Source: Journal of Molecular Medicine - April 15, 2020 Category: Molecular Biology Source Type: research