Recent updates on targeting the molecular mediators of NAFLD
AbstractNonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common disease worldwide in an era of rapid economic growth. NAFLD is a multifactorial disease, involving multiple genetic, metabolic, and environmental factors, and is closely associated with metabolic syndrome, obesity, and cardiovascular disease. NAFLD can be classified into nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH), which can both progress to cirrhosis and even hepatocellular carcinoma (HCC). Due to the enormous burden of NAFLD and its complications, no FDA-approved drugs for the treatment of NAFLD are on...
Source: Journal of Molecular Medicine - February 16, 2023 Category: Molecular Biology Source Type: research
Simultaneous targeting of mitochondrial Kv1.3 and lysosomal acid sphingomyelinase amplifies killing of pancreatic ductal adenocarcinoma cells in vitro and in vivo
AbstractPancreas ductal adenocarcinoma (PDAC) remains a malignant tumor with very poor prognosis and low 5-year overall survival. Here, we aimed to simultaneously target mitochondria and lysosomes as a new treatment paradigm of malignant pancreas cancer in vitro and in vivo. We demonstrate that the clinically used sphingosine analog FTY-720 together with PAPTP, an inhibitor of mitochondrial Kv1.3, induce death of pancreas cancer cells in vitro and in vivo. The combination of both drugs results in a marked inhibition of the acid sphingomyelinase and accumulation of cellular sphingomyelin in vitro and in vivo in orthotopic a...
Source: Journal of Molecular Medicine - February 15, 2023 Category: Molecular Biology Source Type: research
The PER3rs772027021 SNP induces pigmentation phenotypes of dyschromatosis universalis hereditaria
In this study, whole-exome sequencing, data analysis, and Sanger sequencing were utilized for a four-generation extended Chinese family with DUH. A single-nucleotide polymorphism (SNP) (c. 517C > T (p.P173S), rs772027021) variant in exon 5 ofPeriod Circadian Regulator 3 (PER3) (NM_001289861) was detected in each affected individual of the DUH family; the c. 517C > T SNP ofPER3 (PER3rs772027021 SNP) and a novel mutation in exon 14 ofSASH1 (c. 1574C > G (p.T525R)) were both found in the proband. The affected individuals carryingPER3rs772027021 SNP in this family demonstrated mild-pigmented phenotyp...
Source: Journal of Molecular Medicine - February 15, 2023 Category: Molecular Biology Source Type: research
Endotoxin tolerance and low activation of TLR-4/NF- κB axis in monocytes of COVID-19 patients
AbstractHigher endotoxin in the circulation may indicate a compromised state of host immune response against coinfections in severe COVID-19 patients. We evaluated the inflammatory response of monocytes from COVID-19 patients after lipopolysaccharide (LPS) challenge. Whole blood samples of healthy controls, patients with mild COVID-19, and patients with severe COVID-19 were incubated with LPS for 2 h. Severe COVID-19 patients presented higher LPS and sCD14 levels in the plasma than healthy controls and mild COVID-19 patients. In non-stimulated in vitro condition, severe COVID-19 patients presented higher inflammatory cyt...
Source: Journal of Molecular Medicine - February 15, 2023 Category: Molecular Biology Source Type: research
Ectodomain shedding of proteins important for SARS-CoV-2 pathogenesis in plasma of tobacco cigarette smokers compared to electronic cigarette vapers: a cross-sectional study
AbstractThe impact of tobacco cigarette (TCIG) smoking and electronic cigarette (ECIG) vaping on the risk of development of severe COVID-19 is controversial. The present study investigated levels of proteins important for SARS-CoV-2 pathogenesis present in plasma because of ectodomain shedding in smokers, ECIG vapers, and non-smokers (NSs). Protein levels of soluble angiotensin-converting enzyme 2 (ACE2), angiotensin (Ang) II (the ligand of ACE2), Ang 1 –7 (the main peptide generated from Ang II by ACE2 activity), furin (a protease that increases the affinity of the SARS-CoV-2 spike protein for ACE2), and products of ADA...
Source: Journal of Molecular Medicine - February 10, 2023 Category: Molecular Biology Source Type: research
Activation of aryl hydrocarbon receptor (AhR) in Alzheimer ’s disease: role of tryptophan metabolites generated by gut host-microbiota
AbstractGut microbiota in interaction with intestinal host tissues influences many brain functions and microbial dysbiosis has been linked with brain disorders, such as neuropsychiatric conditions and Alzheimer ’s disease (AD).l-tryptophan metabolites and short-chained fatty acids (SCFA) are major messengers in the microbiota-brain axis. Aryl hydrocarbon receptors (AhR) are main targets of tryptophan metabolites in brain microvessels which possess an enriched expression of AhR protein. The Ah receptor is an evolutionarily conserved, ligand-activated transcription factor which is not only a sensor of xenobiotic toxins but...
Source: Journal of Molecular Medicine - February 9, 2023 Category: Molecular Biology Source Type: research
Correction to: PRMT4 drives post-ischemic angiogenesis via YB1/VEGF signaling
(Source: Journal of Molecular Medicine)
Source: Journal of Molecular Medicine - February 7, 2023 Category: Molecular Biology Source Type: research
Antiangiogenic activity of the penicillin derivative TAP7f in melanoma
AbstractPreviously
, we demonstrated that the non-antibiotic penicillin derivative TAP7f inhibited melanoma metastasis in vitro and in vivo through the downregulation of β-catenin and integrin αVβ3. As angiogenesis is required for tumor growth and metastasis, we decided to explore the possible antiangiogenic effect of TAP7f. We found that TAP7f inhibited proliferation, migration, tube formation, and actin cytoskeleton organization of human endothelial cells. In a gel plug assay, an in vivo model for angiogenesis, TAP7f also blocked vascular formation induced by fibroblast growth factor 2. Furthermore, when murine B16...
Source: Journal of Molecular Medicine - January 23, 2023 Category: Molecular Biology Source Type: research
The CRL4DCAF6 E3 ligase ubiquitinates CtBP1/2 to induce apoptotic signalling and promote intervertebral disc degeneration
AbstractInflammation and apoptosis are two important pathological causes of intervertebral disc degeneration (IDD). The crosstalk between these two biological processes during IDD pathogenesis remains elusive. Herein, we discovered that chronic inflammation induced apoptosis through a cullin –RING E3 ligase (CRL)-dependent mechanism. Two cullin proteins, CUL4A and 4B, recruited DNA damage-binding protein 1 (DDB1), RING-box protein 1 (RBX1) and DDB1- and CUL4-associated factor 6 (DCAF6) to assemble a CRL4DCAF6 E3 ligase in intervertebral discs (IVDs) derived from IDD patients. The CRL4DCAF6 E3 ligase ubiquitinated and deg...
Source: Journal of Molecular Medicine - January 23, 2023 Category: Molecular Biology Source Type: research
Inhibition of ERK/CREB signaling contributes to postoperative learning and memory dysfunction in neonatal rats
AbstractExposure to surgery with anesthesia early in life may lead to abnormal behavior, learning, and memory in humans. Pre-clinical studies have suggested a critical role of glial cell-derived neurotrophic factor (GDNF) in these effects. We hypothesize that the inhibition of extracellular signal-regulated kinase (ERK)-cAMP response element-binding protein (CREB) pathway contributes to GDNF decrease and the dysfunction of learning and memory. To address this hypothesis, 7-day-old Sprague –Dawley male and female rats were subjected to right carotid artery exposure (surgery) under sevoflurane anesthesia. Their learning an...
Source: Journal of Molecular Medicine - January 23, 2023 Category: Molecular Biology Source Type: research
ADAMTS-7 deficiency attenuates thoracic aortic aneurysm and dissection in mice
AbstractThoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular disease with severe extracellular matrix (ECM) remodeling that lacks efficient early stage diagnosis and nonsurgical therapy. A disintegrin and metalloproteinase with thrombospondin motif 7 (ADAMTS-7) is recognized as a novel locus for human coronary artery atherosclerosis. Previous work by us and others showed that ADAMTS-7 promoted atherosclerosis, postinjury neointima formation, and vascular calcification. However, whether ADAMTS-7 is involved in TAAD pathogenesis is unknown. We aimed to explore the alterations in ADAMTS-7 expres...
Source: Journal of Molecular Medicine - January 20, 2023 Category: Molecular Biology Source Type: research
Expression of PKM2 in wound keratinocytes is coupled to angiogenesis during skin repair in vivo and in HaCaT keratinocytes in vitro
AbstractAn injured skin is rapidly restored in a manner of wound healing. We have previously shown that intact insulin signaling and glucose uptake are fundamental to proper wound closure. Consequently, under exacerbated inflammation, compromised insulin action and glucose uptake lead to impaired healing. However, in spite of the increased attention to cell metabolism during tissue regeneration, metabolic mediators that govern cellular and physiological processes throughout skin repair remained largely elusive. Through assessment of mRNA using real-time PCR and protein blot analysis, we report that healing of cutaneous wou...
Source: Journal of Molecular Medicine - January 12, 2023 Category: Molecular Biology Source Type: research
Elevation of hsa-miR-7-5p level mediated by CtBP1-p300-AP1 complex targets ATXN1 to trigger NF- κB-dependent inflammation response
AbstractNuclear factor- κB (NF-κB)–mediated inflammation is a major cause of acute respiratory distress syndrome (ARDS). However, the regulatory mechanisms by which NF-κB transactivates proinflammatory cytokines remain unclear in the pathogenesis of ARDS. Herein, we report that the activating protein 1 (AP1) transcrip tion factor recruits a histone acetyltransferase p300 and a transcriptional regulator C-terminal binding protein 1 (CtBP1) to assemble the CtBP1-p300-AP1 complex, which transactivates the expression of hsa-miR-7-5p in ARDS biopsies. Overexpressed hsa-miR-7-5p binds to the three prime untranslated re gion...
Source: Journal of Molecular Medicine - January 11, 2023 Category: Molecular Biology Source Type: research
FoxO3 and oxidative stress: a multifaceted role in cellular adaptation
AbstractOxidative stress is a major cause of morbidity and mortality in human health and disease. In this review, we focus on the Forkhead Box (Fox) subclass O3 (FoxO3), an extensively studied transcription factor that plays a pleiotropic role in a wide range of physiological and pathological processes by regulating multiple gene regulatory networks involved in the modulation of numerous aspects of cellular metabolism, including fuel metabolism, cell death, and stress resistance. This review will also focus on regulatory mechanisms of FoxO3 expression and activity, such as crucial post-translational modifications and non-c...
Source: Journal of Molecular Medicine - January 4, 2023 Category: Molecular Biology Source Type: research
Are there foetal extracellular vesicles in maternal blood? Prospects for diagnostic biomarker discovery
AbstractPrenatal diagnosis of congenital disease improves clinical outcomes; however, as many as 50% of congenital heart disease cases are missed by current ultrasound screening methods. This indicates a need for improved screening technology. Extracellular vesicles (EVs) have attracted enormous interest in recent years for their potential in diagnostics. EVs mediate endocrine signalling in health and disease and are known to regulate aspects of embryonic development. Here, we critically evaluate recent evidence suggesting that EVs released from the foetus are able to cross the placenta and enter the maternal circulation. ...
Source: Journal of Molecular Medicine - December 20, 2022 Category: Molecular Biology Source Type: research
