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Molecules (Basel, Switzerland) Apr 2024The cannabinoid-type I (CB1) receptor functions as a double-edged sword to decide cell fate: apoptosis/survival. Elevated CB1 receptor expression is shown to cause acute...
A Novel Non-Psychoactive Fatty Acid from a Marine Snail, , Signals Cannabinoid Receptor 1 (CB1) to Accumulate Apoptotic C16:0 and C18:0 Ceramides in Teratocarcinoma Cell Line PA1.
The cannabinoid-type I (CB1) receptor functions as a double-edged sword to decide cell fate: apoptosis/survival. Elevated CB1 receptor expression is shown to cause acute ceramide accumulation to meet the energy requirements of fast-growing cancers. However, the flip side of continual CB1 activation is the initiation of a second ceramide peak that leads to cell death. In this study, we used ovarian cancer cells, PA1, which expressed CB1, which increased threefold when treated with a natural compound, bis(palmitoleic acid) ester of a glycerol (). This novel compound is isolated from a marine snail, using hexane and the structural details are available in the public domain PubChem database (ID: 14275348). The compound induced two acute ceramide pools to cause G0/G1 arrest and killed cells by apoptosis. The compound increased intracellular ceramides (C:16 to 7 times and C:18 to 10 times), both of which are apoptotic inducers in response to CB1 signaling and thus the compound is a potent CB1 agonist. The compound is not genotoxic because it did not induce micronuclei formation in non-cancerous Chinese hamster ovarian (CHO) cells. Since the compound induced the cannabinoid pathway, we tested if there was a psychotropic effect in zebrafish models, however, it was evident that there were no observable neurobehavioral changes in the treatment groups. With the available data, we propose that this marine compound is safe to be used in non-cancerous cells as well as zebrafish. Thus, this anticancer compound is non-toxic and triggers the CB1 pathway without causing psychotropic effects.
Topics: Animals; Female; Humans; Apoptosis; Cell Line, Tumor; Ceramides; Fatty Acids; Receptor, Cannabinoid, CB1; Signal Transduction; Conus Snail
PubMed: 38675558
DOI: 10.3390/molecules29081737 -
Surgical Case Reports Mar 2024Epipericardial fat necrosis (EFN) is a rare disease in which local inflammation and necrosis occur in the adipose tissue surrounding the heart, particularly epicardial...
BACKGROUND
Epipericardial fat necrosis (EFN) is a rare disease in which local inflammation and necrosis occur in the adipose tissue surrounding the heart, particularly epicardial fat. Few cases of EFN in which surgical resection was performed have been reported. We report a case of EFN after surgical resection of a right extrapulmonary tumor, in which a malignant disease could not be excluded.
CASE PRESENTATION
A 75-year-old male patient presented with fever and chest pain. A contrast-enhanced computed tomography scan of the chest revealed a lesion, 53 × 48 mm in size, with mixed fatty density spanning the middle and lower lobes of the right lung. Thoracic magnetic resonance imaging (MRI) revealed a mass with mixed fat and soft tissue density in the same area; the lesion was contiguous with pericardial fatty tissue. The tumor was diagnosed as a liposarcoma or teratocarcinoma based on imaging results; however, the possibility of lung cancer could not be excluded. Finally, EFN was diagnosed based on the postoperative histopathological examination. The patient underwent surgical resection of the suspected right extrapulmonary tumor. The intraoperative findings revealed a mediastinal mass contiguous with pericardial fat located between the middle and lower lobes. Intraoperative pathological examination of the lesion was performed using a needle biopsy; however, no definitive diagnosis was made. The tumor may have invaded the middle lobe of the right lung, and partial resection of the right lower lobe was performed in addition to resection of the middle lobe of the right lung. The patient was followed up every 3 months without adjuvant therapy. No recurrence was reported at 1 year after surgery.
CONCLUSION
EFN should be considered in the differential diagnosis of an extrapulmonary tumor when continuity with the pericardial space is observed on MRI or other imaging studies. Surgical resection is useful in the diagnosis and treatment of EFNs. Preoperative three-dimensional reconstructive imaging and MRI should be used to identify vascular structures and confirm the continuity of the lesion with the surrounding tissues to ensure safe and rapid tumor removal.
PubMed: 38453823
DOI: 10.1186/s40792-024-01859-0 -
Redox Biology May 2024Peroxidasin (PXDN) is a secreted heme peroxidase that catalyzes the oxidative crosslinking of collagen IV within the extracellular matrix (ECM) via intermediate...
Peroxidasin (PXDN) is a secreted heme peroxidase that catalyzes the oxidative crosslinking of collagen IV within the extracellular matrix (ECM) via intermediate hypobromous acid (HOBr) synthesis from hydrogen peroxide and bromide, but recent findings have also suggested alternative ECM protein modifications by PXDN, including incorporation of bromide into tyrosine residues. In this work, we sought to identify the major target proteins for tyrosine bromination by HOBr or by PXDN-mediated oxidation in ECM from mouse teratocarcinoma PFHR9 cells. We detected 61 bromotyrosine (BrY)-containing peptides representing 23 proteins in HOBr-modified ECM from PFHR9 cells, among which laminins displayed the most prominent bromotyrosine incorporation. Moreover, we also found that laminin α1, laminin β1, and tubulointerstitial nephritis antigen-like (TINAGL1) contained BrY in untreated PFHR9 cells, which depended on PXDN. We extended these analyses to lung tissues from both healthy mice and mice with experimental lung fibrosis, and in lung tissues obtained from human subjects. Analysis of ECM-enriched mouse lung tissue extracts showed that 83 ECM proteins were elevated in bleomycin-induced fibrosis, which included various collagens and laminins, and PXDN. Similarly, mRNA and protein expression of PXDN and laminin α/β1 were enhanced in fibrotic mouse lung tissues, and also in mouse bone-marrow-derived macrophages or human fibroblasts stimulated with transforming growth factor β1, a profibrotic growth factor. We identified 11 BrY-containing ECM proteins, including collagen IV α2, collagen VI α1, TINAGL1, and various laminins, in both healthy and mouse fibrotic lung tissues, although the relative extent of tyrosine bromination of laminins was not significantly increased during fibrosis. Finally, we also identified 7 BrY-containing ECM proteins in human lung tissues, again including collagen IV α2, collagen VI α1, and TINAGL1. Altogether, this work demonstrates the presence of several bromotyrosine-modified ECM proteins, likely involving PXDN, even in normal lung tissues, suggesting a potential biological function for these modifications.
Topics: Humans; Animals; Mice; Extracellular Matrix Proteins; Bromides; Laminin; Extracellular Matrix; Lung; Peroxidasin; Collagen Type IV; Pulmonary Fibrosis; Tyrosine; Bromates
PubMed: 38430684
DOI: 10.1016/j.redox.2024.103102 -
In Vitro Cellular & Developmental... Feb 2024The notion of using pluripotent stem cells (PSCs) as a source of differentiated cell types for replacement of disease or damaged tissues in regenerative medicine is now... (Review)
Review
The notion of using pluripotent stem cells (PSCs) as a source of differentiated cell types for replacement of disease or damaged tissues in regenerative medicine is now an active area of research, with approaches to treating eye diseases such as age-related macular degeneration or Parkinson's disease now on the horizon. But the foundations for this research lie in a quite different area of science, namely the role of genetics of cancer. In this review, we trace the evolution of ideas starting with the discovery that strain 129 mice are particularly subject to develop germ cell tumors, through the identification of embryonal carcinoma (EC) cells as the stem cells of the teratocarcinoma manifestation of these tumors, to the recognition of their relationship to pluripotent cells of the early embryo, and eventually their role in the derivation of embryonic stem cells, first from mouse embryos and then from primates including humans. This is a story that illustrates how science commonly develops through the interests and insights of individual investigators, often with unexpected and unintended outcomes.
PubMed: 38396072
DOI: 10.1007/s11626-024-00865-8 -
Microorganisms Oct 2023Natural metabolites from beneficial fungi were recognized for their potential to inhibit multidrug-resistant human and plant fungal pathogens. The present study...
Natural metabolites from beneficial fungi were recognized for their potential to inhibit multidrug-resistant human and plant fungal pathogens. The present study describes the isolation, metabolite profiling, antibacterial, and antifungal, antioxidant, and anticancer activities of soil fungi. Among the 17 isolates, the AK-7 isolate was selected based on the primary screening. Further, the identification of isolate AK-7 was performed by 18S rRNA sequencing and identified as (with 99.90% similarity). Additionally, the ethyl acetate extract of the strain AK-7 (AK-7 extract) was characterized by Fourier Transform Infrared Spectroscopy (FTIR) and a Gas Chromatography-Mass Spectroscopy (GC-MS) analysis, and the results showed different functional groups and bioactive metabolites. Consequently, a secondary screening of antibacterial activity by the agar well diffusion method showed significant antibacterial activity against Gram-negative and Gram-positive bacterial pathogens. The AK-7 extract exhibited notable antifungal activity by a food poisoning method and showed maximum inhibition of 77.84 ± 1.62%, 56.42 ± 1.27%, and 37.96 ± 1.84% against , and phytopathogens. Consequently, the AK-7 extract showed significant antioxidant activity against DPPH and ABTS free radicals with IC values of 59.084 μg/mL and 73.36 μg/mL. Further, the anticancer activity of the AK-7 extract against the human ovarian teratocarcinoma (PA-1) cell line was tested by MTT and Annexin V flow cytometry. The results showed a dose-dependent reduction in cell viability and exhibited apoptosis with an IC value of 82.04 μg/mL. The study highlights the potential of the strain AK-7 as a source of active metabolites and natural antibacterial, antifungal, antioxidant, and anticancer agent, and it could be an excellent alternative for pharmaceutical and agricultural sectors.
PubMed: 37894138
DOI: 10.3390/microorganisms11102480 -
Current Issues in Molecular Biology Oct 2023The spatial organization of euchromatin (EC) and heterochromatin (HC) appears as a cell-type specific network, which seems to have an impact on gene regulation and cell...
The spatial organization of euchromatin (EC) and heterochromatin (HC) appears as a cell-type specific network, which seems to have an impact on gene regulation and cell fate. The spatial organization of cohesin should thus also be characteristic for a cell type since it is involved in a TAD (topologically associating domain) formation, and thus in gene regulation or DNA repair processes. Based on the previous hypotheses and results on the general importance of heterochromatin organization on genome functions in particular, the configurations of these organizational units (EC represented by H3K4me3-positive regions, HC represented by H3K9me3-positive regions, cohesins) are investigated in the cell nuclei of different cancer and non-cancerous cell types and under different anti-cancer treatments. Confocal microscopic images of the model cell systems were used and analyzed using analytical processes of quantification created in Fiji, an imaging tool box well established in different fields of science. Human fibroblasts, breast cancer and glioblastoma cells as well as murine embryonal terato-carcinoma cells were used as these cell models and compared according to the different parameters of spatial arrangements. In addition, proliferating, quiescent and from the quiescent state reactivated fibroblasts were analyzed. In some selected cases, the cells were treated with X-rays or azacitidine. Heterogeneous results were obtained by the analyses of the configurations of the three different organizational units: granulation and a loss of H3K4me3-positive regions (EC) occurred after irradiation with 4 Gy or azacitidine treatment. While fibroblasts responded to irradiation with an increase in cohesin and granulation, in breast cancer cells, it resulted in decreases in cohesin and changes in granulation. H3K9me3-positive regions (HC) in fibroblasts experienced increased granulation, whereas in breast cancer cells, the amount of such regions increased. After azacitidine treatment, murine stem cells showed losses of cohesin and granulation and an increase in the granulation of H3K9me3-positive regions. Fibroblasts that were irradiated with 2 Gy only showed irregularities in structural amounts and granulation. Quiescent fibroblasts contained less euchromatin-related H3K4me3-positive signals and cohesin levels as well as higher heterochromatin-related H3K9me3-positive signals than non-quiescent ones. In general, fibroblasts responded more intensely to X-ray irradiation than breast cancer cells. The results indicate the usefulness of model cell systems and show that, in general, characteristic differences initially existing in chromatin and cohesin organizations result in specific responses to anti-cancer treatment.
PubMed: 37886958
DOI: 10.3390/cimb45100515 -
Biomedical and Environmental Sciences :... Sep 2023Circular RNAs (circRNAs) participate in several important pathological processes and have been used in the diagnosis and treatment of various diseases. This study aimed...
OBJECTIVE
Circular RNAs (circRNAs) participate in several important pathological processes and have been used in the diagnosis and treatment of various diseases. This study aimed to investigate the role of circRNAs in neural tube defects (NTDs).
METHOD
We characterized circRNA-associated competitive endogenous RNA (ceRNA) networks in brain tissue of low folate -induced NTDs mouse at embryonic day 13.5 by high-throughput sequencing. The expression levels of Circzfp644, miR-20-5p and were detected by RT-PCR. and Circzfp644 functions were determined by miRNA-mimics and inhibitors in mouse teratocarcinoma cells (F9 cells), and luciferase gene reporter assay was assessed in the F9 cells. In addition, the expression levels of Circzfp644, miR-20-5p and were determined by Nanostring in human NTDs tissues.
RESULTS
We detected 57 circRNA transcripts, 16 miRNAs, and 148 mRNAs that were significantly dysregulated in NTDs brain tissues compared with their expression levels in control (normal) tissues. Circzfp644 shared miRNA response elements with the growth arrest specific 7 ( ) gene and competitively bound with miR-20-5p to increase the expression of . Downregulation of Circzfp644 and and upregulation of miR-20-5p were found in human NTD tissue.
CONCLUSION
This study provides new perspectives on the role of circRNAs in nervous system development and the pathogenesis of NTDs.
Topics: Humans; Animals; Mice; RNA, Circular; MicroRNAs; Down-Regulation; Neural Tube Defects; Folic Acid
PubMed: 37803896
DOI: 10.3967/bes2023.071 -
International Journal of Molecular... Jul 2023During cardiac differentiation, numerous factors contribute to the development of the heart. Understanding the molecular mechanisms underlying cardiac development will...
During cardiac differentiation, numerous factors contribute to the development of the heart. Understanding the molecular mechanisms underlying cardiac development will help combat cardiovascular disorders, among the leading causes of morbidity and mortality worldwide. Among the main mechanisms, we indeed find Cripto. Cripto is found in both the syncytiotrophoblast of ampullary pregnancies and the inner cell mass along the primitive streak as the second epithelial-mesenchymal transformation event occurs to form the mesoderm and the developing myocardium. At the same time, it is now known that cardiac signaling pathways are intimately intertwined with the expression of myomiRNAs, including miR-1. This miR-1 is one of the muscle-specific miRs; aberrant expression of miR-1 plays an essential role in cardiac diseases. Given this scenario, our study aimed to evaluate the inverse correlation between Cripto and miR-1 during heart development. We used in vitro models of the heart, represented by embryoid bodies (EBs) and embryonic carcinoma cell lines derived from an embryo-derived teratocarcinoma in mice (P19 cells), respectively. First, through a luciferase assay, we demonstrated that Cripto is a target of miR-1. Following this result, we observed that as the days of differentiation increased, the Cripto gene expression decreased, while the level of miR-1 increased; furthermore, after silencing miR-1 in P19 cells, there was an increase in Cripto expression. Moreover, inducing damage with a cobra cardiotoxin (CTX) in post-differentiation cells, we noted a decreased miR-1 expression and increased Cripto. Finally, in mouse cardiac biopsies, we observed by monitoring gene expression the distribution of Cripto and miR-1 in the right and left ventricles. These results allowed us to detect an inverse correlation between miR-1 and Cripto that could represent a new pharmacological target for identifying new therapies.
Topics: Animals; Mice; Cell Differentiation; Epidermal Growth Factor; Heart; MicroRNAs; Myocardium
PubMed: 37569627
DOI: 10.3390/ijms241512251 -
Pharmaceuticals (Basel, Switzerland) Jul 2023Quaternary ammonium palmitoyl glycol chitosan (GCPQ) has already shown beneficial drug delivery properties and has been studied as a carrier for anticancer agents....
Quaternary ammonium palmitoyl glycol chitosan (GCPQ) has already shown beneficial drug delivery properties and has been studied as a carrier for anticancer agents. Consequently, we synthesised cytotoxic platinum(IV) conjugates of cisplatin, carboplatin and oxaliplatin by coupling via amide bonds to five GCPQ polymers differing in their degree of palmitoylation and quaternisation. The conjugates were characterised by H and Pt NMR spectroscopy as well as inductively coupled plasma mass spectrometry (ICP-MS), the latter to determine the amount of platinum(IV) units per GCPQ polymer. Cytotoxicity was evaluated by the MTT assay in three human cancer cell lines (A549, non-small-cell lung carcinoma; CH1/PA-1, ovarian teratocarcinoma; SW480, colon adenocarcinoma). All conjugates displayed a high increase in their cytotoxic activity by factors of up to 286 times compared to their corresponding platinum(IV) complexes and mostly outperformed the respective platinum(II) counterparts by factors of up to 20 times, also taking into account the respective loading of platinum(IV) units per GCPQ polymer. Finally, a biodistribution experiment was performed with an oxaliplatin-based GCPQ conjugate in non-tumour-bearing BALB/c mice revealing an increased accumulation in lung tissue. These findings open promising opportunities for further tumouricidal activity studies especially focusing on lung tissue.
PubMed: 37513938
DOI: 10.3390/ph16071027 -
Frontiers in Genetics 2023Testicular teratomas and teratocarcinomas are the most common testicular germ cell tumors in early childhood and young men, and they are frequently found unilaterally in...
Testicular teratomas and teratocarcinomas are the most common testicular germ cell tumors in early childhood and young men, and they are frequently found unilaterally in the left testis. In 129/SvJ mice carrying a heterozygous copy of the potent modifier of tumor incidence , a point mutation in the dead-end homolog one gene ( ), ∼70% of the unilateral teratomas arise in the left testis. We previously showed that in mice, left/right differences in vascular architecture are associated with reduced hemoglobin saturation and increased levels of the hypoxia inducible factor-1 alpha (HIF-1α) in the left compared to the right testis. To test the hypothesis that systemic reduction of oxygen availability in mice would lead to an increased incidence of bilateral tumors, we placed pregnant females from 129/SvJ intercross matings in a hypobaric chamber for 12-h intervals. Our results show that in 129/SvJ male gonads, the incidence of bilateral teratoma increased from 3.3% to 64% when fetuses were exposed to acute low oxygen conditions for 12-h between E13.8 and E14.3. The increase in tumor incidence correlated with the maintenance of high expression of pluripotency genes , and , elevated activity of the Nodal signaling pathway, and suppression of germ cell mitotic arrest. We propose that the combination of heterozygosity for the mutation and hypoxia causes a delay in male germ cell differentiation that promotes teratoma initiation.
PubMed: 37180974
DOI: 10.3389/fgene.2023.1179256