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Lipids in Health and Disease Jun 2024Overweight, often known as obesity, is the abnormal and excessive accumulation of fat that exposes the health of a person at risk by increasing the likelihood that they...
BACKGROUND
Overweight, often known as obesity, is the abnormal and excessive accumulation of fat that exposes the health of a person at risk by increasing the likelihood that they may experience many chronic conditions. Consequently, obesity has become a global health threat, presenting serious health issues, and attracting a lot of attention in the healthcare profession and the scientific community.
METHOD
This study aims to explore the anti-adipogenic properties of 7-MEGA™ in an attempt to address obesity, using both in vitro and in vivo research. The effects of 7MEGA™ at three distinct concentrations were investigated in obese mice who were given a high-fat diet (HFD) and 3T3-L1 adipocytes.
RESULTS
7MEGA™ decreased the total fat mass, overall body weight, and the perirenal and subcutaneous white adipose tissue (PWAT and SWAT) contents in HFD mice. Additionally, 7MEGA™ showed promise in improving the metabolic health of individuals with obesity and regulate the levels of insulin hormone, pro-inflammatory cytokines and adipokines. Furthermore, Peroxisome proliferator-activated receptors (PPAR) α and γ, Uncoupling Protein 1 (UCP-1), Sterol Regulatory Element-Binding Protein 1 (SREBP-1), Fatty Acid-Binding Protein 4 (FABP4), Fatty Acid Synthase (FAS), Acetyl-CoA Carboxylase (ACC), Stearoyl-CoA Desaturase-1 (SCD-1) and CCAAT/Enhancer-Binding Protein (C/EBPα) were among the adipogenic regulators that 7MEGA™ could regulate.
CONCLUSION
In summary, this study uncovered that 7MEGA™ demonstrates anti-adipogenic and anti-obesity effects, suggesting its potential in combating obesity.
Topics: Animals; Diet, High-Fat; Adipogenesis; Obesity; Mice; 3T3-L1 Cells; Adipocytes; Mice, Inbred C57BL; Male; PPAR gamma; Sterol Regulatory Element Binding Protein 1; Stearoyl-CoA Desaturase; Mice, Obese; Fatty Acid-Binding Proteins; Adipokines; Anti-Obesity Agents; Uncoupling Protein 1; Adipose Tissue, White; CCAAT-Enhancer-Binding Proteins
PubMed: 38909257
DOI: 10.1186/s12944-024-02175-0 -
Medicina 2024Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a late onset neurodegenerative disorder. Its genetic basis has recently been identified in...
Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a late onset neurodegenerative disorder. Its genetic basis has recently been identified in the gene encoding a subunit of the Replication Factor C (RFC1). We present the case of a 62-year-old woman who experienced a history of a biphasic presentation of imbalance and gait disorders, with rapid onset of symptoms followed by slow and progressive neurological deterioration. The diagnostic process was challenging, and numerous tests were conducted to rule out acquired and genetic causes of ataxia, leading to a diagnosis of late-onset idiopathic cerebellar ataxia. Subsequently, vestibular function tests identified severe bilateral vestibulopathy. This led to considering CANVAS among the diagnoses, which was ultimately confirmed through genetic testing (biallelic expansion of the pentanucleotide AAGGG in the RFC1 gene). This case highlights the importance of this new described genetic disease and its subacute presentation variant, emphasizing the relevance of objective vestibular function tests in idiopathic ataxias to achieve proper diagnosis and eventual genetic counseling for offspring.
Topics: Humans; Female; Middle Aged; Cerebellar Ataxia; Bilateral Vestibulopathy; Syndrome; Replication Protein C; Vestibular Function Tests
PubMed: 38907973
DOI: No ID Found -
Science Advances Jun 2024The central nervous system coordinates peripheral cellular stress responses, including the unfolded protein response of the mitochondria (UPR); however, the contexts for...
The central nervous system coordinates peripheral cellular stress responses, including the unfolded protein response of the mitochondria (UPR); however, the contexts for which this regulatory capability evolved are unknown. UPR is up-regulated upon pathogenic infection and in metabolic flux, and the olfactory nervous system has been shown to regulate pathogen resistance and peripheral metabolic activity. Therefore, we asked whether the olfactory nervous system in controls the UPR cell nonautonomously. We found that silencing a single inhibitory olfactory neuron pair, AWC, led to robust induction of UPR and reduction of oxidative phosphorylation dependent on serotonin signaling and -mediated mitophagy. Further, AWC ablation confers resistance to the pathogenic bacteria partially dependent on the UPR transcription factor and fully dependent on mitophagy machinery. These data illustrate a role for the olfactory nervous system in regulating whole-organism mitochondrial dynamics, perhaps in preparation for postprandial metabolic stress or pathogenic infection.
Topics: Animals; Caenorhabditis elegans; Mitophagy; Mitochondria; Caenorhabditis elegans Proteins; Smell; Unfolded Protein Response; Pseudomonas aeruginosa; Ubiquitin-Protein Ligases; Oxidative Phosphorylation; Signal Transduction; Serotonin; Transcription Factors
PubMed: 38905346
DOI: 10.1126/sciadv.adn0014 -
Surgical Case Reports Jun 2024Anticoagulant therapy with heparin is the first-line treatment for acute mesenteric vein thrombosis and is effective in improving outcomes. Conversely, patients with...
BACKGROUND
Anticoagulant therapy with heparin is the first-line treatment for acute mesenteric vein thrombosis and is effective in improving outcomes. Conversely, patients with failed early anticoagulant therapy occasionally develop bowel infarction requiring surgery. The efficacy of long-term anticoagulant therapy on recanalizing mesenteric vein thrombosis in patients with failed early anticoagulant therapy remains unclear. Herein, we report a patient who achieved recanalization of port-superior mesenteric vein thrombosis treated with anticoagulant therapy for 10 years after failed early anticoagulant therapy, followed by bowel resection.
CASE PRESENTATION
A 38-year-old male patient visited an outpatient clinic due to acute exacerbation of abdominal pain that had persisted for a month. He was diagnosed with port-superior mesenteric vein thrombosis on contrast-enhanced computed tomography (CT) scan and was transferred to our institution. Although he presented with abdominal pain, his respiration and circulation were stable upon hospital arrival. Anticoagulant therapy with heparin was started, and the patient was admitted to the intensive care unit. However, the patient's abdominal pain worsened, and he began to develop signs of peritonitis. Repeat CT scan revealed bowel infarction. Thus, the patient underwent bowel resection 6 h after admission. The initial surgery was completed with open abdomen management. Bowel anastomosis was performed on the second-look surgery on the first postoperative day. Finally, the abdomen was closed on the third postoperative day after confirming the absence of bowel ischemia progression. The patient had prolonged impaired bowel function with paralytic ileus, but was discharged on the 60th postoperative day. He was then diagnosed with protein C and S deficiency based on the tests performed. Anticoagulant therapy with warfarin was initiated. He also received anticoagulant therapy in the outpatient setting. The patient's port-superior mesenteric vein thrombosis had improved gradually with warfarin during the follow-up period. At 10 years after surgery, total occlusion of the port-superior mesenteric vein was recanalized with improvement of the portal collateral vessels. In addition, no gastric or esophageal varices were observed.
CONCLUSIONS
Long-term anticoagulation therapy could affect the recanalization of extensive thrombus in multiple segments in patients with mesenteric venous thrombosis.
PubMed: 38900377
DOI: 10.1186/s40792-024-01948-0 -
Cureus May 2024We report structural changes in the retina of an adolescent diagnosed with the concomitant two temporal cilioretinal artery occlusion (CLRAO) with impending central...
Concomitant Two-Temporal Cilioretinal Artery Occlusion (CLRAO) With Impending Central Retinal Vein Occlusion (CRVO) in a Young Adolescent With Protein C Deficiency: A Rare Case.
We report structural changes in the retina of an adolescent diagnosed with the concomitant two temporal cilioretinal artery occlusion (CLRAO) with impending central retinal vein occlusion (CRVO) along with mild protein C deficiency. An 18-year-old girl came to the emergency room with sudden onset painless loss of vision in her right eye. On comprehensive ophthalmic examination, she had a pale superior-temporal retina with spongy macular edema corresponding to two temporal CLRAO and blurred disc margins with mild disc swelling and mild tortuosity of retinal veins all over the retina with few superficial hemorrhages in the right eye corresponding to impending CRVO. Optimal coherence tomography (OCT) showed thickening of the nerve fiber layer in the superior-temporal quadrant involving some part of the macula in the right eye. Perimetry showed a right eye visual field defect in the inferior nasal quadrant. Her coagulation profile was normal but her autoimmune profile was suggestive of mild protein C deficiency. Immediately she was started on anticoagulants. After one month, her visual acuity improved from finger counting close to face to 6/9 with treatment. Over a period of one month, retinal and OCT changes recovered with the same perimetry findings as earlier. This case shows how prompt treatment resulted in dramatic improvement in the form of good visual outcomes.
PubMed: 38894807
DOI: 10.7759/cureus.60615 -
Molecules (Basel, Switzerland) Jun 2024Transient receptor potential melastatin-8 (TRPM8) is a cation channel that is activated by cold and "cooling agents" such as menthol and icilin, which induce a cold...
Transient receptor potential melastatin-8 (TRPM8) is a cation channel that is activated by cold and "cooling agents" such as menthol and icilin, which induce a cold sensation. The stimulation of TRPM8 activates an intracellular signaling cascade that ultimately leads to a change in the gene expression pattern of the cells. Here, we investigate the TRPM8-induced signaling pathway that links TRPM8 channel activation to gene transcription. Using a pharmacological approach, we show that the inhibition of phosphatidylinositol 4-phosphate 5 kinase α (PIP5K), an enzyme essential for the biosynthesis of phosphatidylinositol 4,5-bisphosphate, attenuates TRPM8-induced gene transcription. Analyzing the link between TRPM8 and Gq proteins, we show that the pharmacological inhibition of the βγ subunits impairs TRPM8 signaling. In addition, genetic studies show that TRPM8 requires an activated Gα subunit for signaling. In the nucleus, the TRPM8-induced signaling cascade triggers the activation of the transcription factor AP-1, a complex consisting of a dimer of basic region leucine zipper (bZIP) transcription factors. Here, we identify the bZIP protein c-Jun as an essential component of AP-1 within the TRPM8-induced signaling cascade. In summary, with PIP5K, Gq subunits, and c-Jun, we identified key molecules in TRPM8-induced signaling from the plasma membrane to the nucleus.
Topics: TRPM Cation Channels; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Signal Transduction; Phosphotransferases (Alcohol Group Acceptor); Transcription Factor AP-1; HEK293 Cells; Proto-Oncogene Proteins c-jun; Animals
PubMed: 38893478
DOI: 10.3390/molecules29112602 -
International Journal of Molecular... May 2024The tumor suppressor gene F-box and WD repeat domain-containing (FBXW) 7 reduces cancer stemness properties by promoting the protein degradation of pluripotent stem cell...
The tumor suppressor gene F-box and WD repeat domain-containing (FBXW) 7 reduces cancer stemness properties by promoting the protein degradation of pluripotent stem cell markers. We recently demonstrated the transcriptional repression of FBXW7 by the three-dimensional (3D) spheroid formation of several cancer cells. In the present study, we found that the transcriptional activity of FBXW7 was promoted by the inhibition of the Ca-activated K channel, K1.1, in a 3D spheroid model of human prostate cancer LNCaP cells through the Akt-Nrf2 signaling pathway. The transcriptional activity of FBXW7 was reduced by the siRNA-mediated inhibition of the CCAAT-enhancer-binding protein C/EBP δ (CEBPD) after the transfection of miR223 mimics in the LNCaP spheroid model, suggesting the transcriptional regulation of FBXW7 through the Akt-Nrf2-CEBPD-miR223 transcriptional axis in the LNCaP spheroid model. Furthermore, the K1.1 inhibition-induced activation of FBXW7 reduced (1) K1.1 activity and protein levels in the plasma membrane and (2) the protein level of the cancer stem cell (CSC) markers, c-Myc, which is a molecule degraded by FBXW7, in the LNCaP spheroid model, indicating that K1.1 inhibition-induced FBXW7 activation suppressed CSC conversion in K1.1-positive cancer cells.
Topics: Humans; F-Box-WD Repeat-Containing Protein 7; Male; NF-E2-Related Factor 2; Prostatic Neoplasms; Signal Transduction; Spheroids, Cellular; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Up-Regulation; Intermediate-Conductance Calcium-Activated Potassium Channels; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; MicroRNAs; Proto-Oncogene Proteins c-akt
PubMed: 38892210
DOI: 10.3390/ijms25116019 -
International Journal of Molecular... May 2024Capmatinib and savolitinib, selective inhibitors, are widely used to treat various -positive cancers. In this study, we aimed to determine the effects of these...
Capmatinib and savolitinib, selective inhibitors, are widely used to treat various -positive cancers. In this study, we aimed to determine the effects of these inhibitors on -amplified gastric cancer (GC) cells. Methods: After screening 37 GC cell lines, the following cell lines were found to be -positive with copy number variation >10: SNU-620, ESO51, MKN-45, SNU-5, and OE33 cell lines. Next, we assessed the cytotoxic response of these cell lines to capmatinib or savolitinib alone using cell counting kit-8 and clonogenic cell survival assays. Western blotting was performed to assess the effects of capmatinib and savolitinib on the signaling pathway. Xenograft studies were performed to evaluate the in vivo therapeutic efficacy of savolitinib in MKN-45 cells. Savolitinib and capmatinib exerted anti-proliferative effects on MET-amplified GC cell lines in a dose-dependent manner. Savolitinib inhibited the phosphorylation of and downstream signaling pathways, such as the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways, in -amplified GC cells. Additionally, savolitinib significantly decreased the number of colonies formed on the soft agar and exerted dose-dependent anti-tumor effects in an MKN-45 GC cell xenograft model. Furthermore, a combination of trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in human epidermal growth factor receptor-2 ()- and -positive OE33 cells. Targeting MET with savolitinib and capmatinib efficiently suppressed the growth of -amplified GC cells. Moreover, these MET inhibitors exerted synergistic effects with trastuzumab on - and -amplified GC cells.
Topics: Humans; Proto-Oncogene Proteins c-met; Stomach Neoplasms; Cell Line, Tumor; Animals; Triazines; Mice; Xenograft Model Antitumor Assays; Benzamides; Cell Proliferation; Esophageal Neoplasms; Signal Transduction; Mice, Nude; Protein Kinase Inhibitors; Antineoplastic Agents; Molecular Targeted Therapy; Female; Imidazoles
PubMed: 38892160
DOI: 10.3390/ijms25115975 -
Cells Jun 2024Precise control of neuronal activity is crucial for the proper functioning of neurons. How lipid homeostasis contributes to neuronal activity and how much of it is...
Precise control of neuronal activity is crucial for the proper functioning of neurons. How lipid homeostasis contributes to neuronal activity and how much of it is regulated by cells autonomously is unclear. In this study, we discovered that absence of the lipid regulator , a functional ortholog of the peroxisome proliferator-activated receptor (PPAR) in , resulted in defective pathogen avoidance behavior against (PA14). Functional NHR-49 was required in the neurons, and more specifically, in a set of oxygen-sensing body cavity neurons, URX, AQR, and PQR. We found that lowering the neuronal activity of the body cavity neurons improved avoidance in mutants. Calcium imaging in URX neurons showed that mutants displayed longer-lasting calcium transients in response to an O upshift, suggesting that excess neuronal activity leads to avoidance defects. Cell-specific rescue of NHR-49 in the body cavity neurons was sufficient to improve pathogen avoidance, as well as URX neuron calcium kinetics. Supplementation with oleic acid also improved avoidance behavior and URX calcium kinetics, suggesting that the defective calcium response in the neuron is due to lipid dysfunction. These findings highlight the role of cell-autonomous lipid regulation in neuronal physiology and immune behavior.
Topics: Animals; Caenorhabditis elegans; Lipid Metabolism; Caenorhabditis elegans Proteins; Neurons; Pseudomonas aeruginosa; Calcium; Mutation; Avoidance Learning; Receptors, Cytoplasmic and Nuclear
PubMed: 38891110
DOI: 10.3390/cells13110978 -
Scientific Reports Jun 2024Familial platelet disorder with associated myeloid malignancies (FPDMM) is an autosomal dominant disease caused by heterozygous germline mutations in RUNX1. It is...
Familial platelet disorder with associated myeloid malignancies (FPDMM) is an autosomal dominant disease caused by heterozygous germline mutations in RUNX1. It is characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematological malignancies. Although FPDMM is a precursor for diseases involving abnormal DNA methylation, the DNA methylation status in FPDMM remains unknown, largely due to a lack of animal models and challenges in obtaining patient-derived samples. Here, using genome editing techniques, we established two lines of human induced pluripotent stem cells (iPSCs) with different FPDMM-mimicking heterozygous RUNX1 mutations. These iPSCs showed defective differentiation of hematopoietic progenitor cells (HPCs) and megakaryocytes (Mks), consistent with FPDMM. The FPDMM-mimicking HPCs showed DNA methylation patterns distinct from those of wild-type HPCs, with hypermethylated regions showing the enrichment of ETS transcription factor (TF) motifs. We found that the expression of FLI1, an ETS family member, was significantly downregulated in FPDMM-mimicking HPCs with a RUNX1 transactivation domain (TAD) mutation. We demonstrated that FLI1 promoted binding-site-directed DNA demethylation, and that overexpression of FLI1 restored their megakaryocytic differentiation efficiency and hypermethylation status. These findings suggest that FLI1 plays a crucial role in regulating DNA methylation and correcting defective megakaryocytic differentiation in FPDMM-mimicking HPCs with a RUNX1 TAD mutation.
Topics: Core Binding Factor Alpha 2 Subunit; Humans; DNA Methylation; Megakaryocytes; Proto-Oncogene Protein c-fli-1; Cell Differentiation; Induced Pluripotent Stem Cells; Mutation; Blood Platelet Disorders; Transcriptional Activation; Hematopoietic Stem Cells; Leukemia, Myeloid, Acute; Blood Coagulation Disorders, Inherited
PubMed: 38890442
DOI: 10.1038/s41598-024-64829-4