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Asian Pacific Journal of Cancer... Jun 2024This study examined the morphological changes in the colonic mucosa and the presence of inflammation in rats induced with 1,2-dimethylhydrazine (DMH) 30 mg/kg BW over 9,...
OBJECTIVE
This study examined the morphological changes in the colonic mucosa and the presence of inflammation in rats induced with 1,2-dimethylhydrazine (DMH) 30 mg/kg BW over 9, 11, and 13 weeks without a latency period.
METHODS
Hematoxylin and eosin staining was performed to assess the morphology and characteristic alteration of the epitheliocytes in the colon. Immunohistochemistry was employed to assess the expression of tumor necrosis factor (TNF)-α and cyclooxygenase-2 (COX-2). The difference in the severity of inflammation and COX-2 expression was examined using one-way analysis of variance. The correlation of COX-2 expression with the severity of inflammation was analyzed using Spearman's rank correlation test.
RESULT
Until week 13, chronic inflammation and non-hyperplastic and hyperplastic aberrant crypt foci occurred. The severity of inflammation gradually shifted from high moderate to low moderate. TNF-α expression was high in all groups; however, COX-2 expression was gradually lower with longer duration of induction, which corresponded with the severity of inflammation.
CONCLUSION
DMH induction until week 13 without a latency period caused chronic inflammation without the formation of adenoma or adenocarcinoma. A very strong correlation was established between COX-2 expression and inflammation.
Topics: Animals; 1,2-Dimethylhydrazine; Rats; Colorectal Neoplasms; Cyclooxygenase 2; Inflammation; Male; Tumor Necrosis Factor-alpha; Intestinal Mucosa; Carcinogens; Rats, Sprague-Dawley; Aberrant Crypt Foci; Colon; Adenocarcinoma
PubMed: 38918668
DOI: 10.31557/APJCP.2024.25.6.2059 -
Scientific Reports Jun 2024Bivalves are an extraordinary class of animals in which species with a doubly uniparental inheritance (DUI) of mitochondrial DNA have been described. DUI is...
Bivalves are an extraordinary class of animals in which species with a doubly uniparental inheritance (DUI) of mitochondrial DNA have been described. DUI is characterized as a mitochondrial homoplasmy of females and heteroplasmy of male individuals where F-type mitogenomes are passed to the progeny with mother egg cells and divergent M-type mitogenomes are inherited with fathers sperm cells. However, in most cases only male individuals retain divergent mitogenome inherited with spermatozoa. Additionally, in many of bivalves, unique mitochondrial features, like additional genes, gene duplication, gene extensions, mitochondrial introns, and recombination, were observed. In this study, we sequenced and assembled male-type mitogenomes of three Donax species. Comparative analysis of mitochondrial sequences revealed a lack of all seven NADH dehydrogenase subunits as well as the presence of three long additional open reading frames lacking identifiable homology to any of the existing genes.
Topics: Animals; Male; Genome, Mitochondrial; Electron Transport Complex I; DNA, Mitochondrial; Female; Spermatozoa; Phylogeny; Open Reading Frames
PubMed: 38914611
DOI: 10.1038/s41598-024-63764-8 -
JCI Insight May 2024Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators...
Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.
Topics: Animals; Membrane Proteins; Mice; Female; Signal Transduction; T-Lymphocytes, Cytotoxic; Triple Negative Breast Neoplasms; Indomethacin; Cell Line, Tumor; Humans; Lung Neoplasms; Cyclooxygenase Inhibitors; Nucleotidyltransferases; Interferon Type I; Cyclooxygenase 2; Lymphocytes, Tumor-Infiltrating; Mice, Inbred BALB C
PubMed: 38912586
DOI: 10.1172/jci.insight.165356 -
Frontiers in Endocrinology 2024Paragangliomas (PGL) are rare neuroendocrine tumors derived from the autonomic nervous system paraganglia. Urinary bladder paragangliomas (UBPGL) originate from the...
BACKGROUND
Paragangliomas (PGL) are rare neuroendocrine tumors derived from the autonomic nervous system paraganglia. Urinary bladder paragangliomas (UBPGL) originate from the sympathetic neurons of the urinary bladder wall and represent 0.7% of all paragangliomas and <0.05% of all bladder tumors. PGL and UBPGL can be associated with gene variants, with the most common germline alterations found in and .
CASE REPORT
We report a case of a 42-year-old woman who presented with menorrhagia/hematuria, uterine leiomyomas, as well as cardiac and bladder masses. The cardiac mass was favored to be a myxoma based on clinical findings, while the bladder mass was diagnosed as UBPGL. A novel mutation (c.642G>A, p Q214Q), detected in the UBPGL, was proven to be somatic. Although this variant was seemingly synonymous, it was predicted to have a loss of function due to the splice site effect, which was further supported by the immunohistochemical loss of .
CONCLUSION
This case highlights the challenges of diagnosing an extremely rare entity, bladder paraganglioma, with an emphasis on the multidisciplinary approach to navigate various clinical and imaging findings that may initially be misleading. In addition, a novel loss of function variant that could have been overlooked as a synonymous variant is herein reported, while also illustrating the importance of both germline and somatic mutation testing.
Topics: Humans; Female; Adult; Urinary Bladder Neoplasms; Paraganglioma; Succinate Dehydrogenase; Mutation
PubMed: 38911036
DOI: 10.3389/fendo.2024.1386285 -
Scientific Reports Jun 2024Metabolites exploration of the ethyl acetate extract of Fusarium solani culture broth that was isolated from Euphorbia tirucalli root afforded five compounds;...
Metabolites exploration of the ethyl acetate extract of Fusarium solani culture broth that was isolated from Euphorbia tirucalli root afforded five compounds; 4-hydroxybenzaldehyde (1), 4-hydroxybenzoic acid (2), tyrosol (3), azelaic acid (4), malic acid (5), and fusaric acid (6). Fungal extract as well as its metabolites were evaluated for their anti-inflammatory and anti-hyperpigmentation potential via in vitro cyclooxygenases and tyrosinase inhibition assays, respectively. Azelaic acid (4) exhibited powerful and selective COX-2 inhibition followed by fusaric acid (6) with IC values (2.21 ± 0.06 and 4.81 ± 0.14 μM, respectively). As well, azelaic acid (4) had the most impressive tyrosinase inhibitory effect with IC value of 8.75 ± 0.18 μM compared to kojic acid (IC = 9.27 ± 0.19 μM). Exclusive computational studies of azelaic acid and fusaric acid with COX-2 were in good accord with the in vitro results. Interestingly, this is the first time to investigate and report the potential of compounds 3-6 to inhibit cyclooxygenase enzymes. One of the most invasive forms of skin cancer is melanoma, a molecular docking study using a set of enzymes related to melanoma suggested pirin to be therapeutic target for azelaic acid and fusaric acid as a plausible mechanism for their anti-melanoma activity.
Topics: Fusarium; Anti-Inflammatory Agents; Dicarboxylic Acids; Molecular Docking Simulation; Melanoma; Humans; Cyclooxygenase 2; Fusaric Acid; Monophenol Monooxygenase; Computer Simulation; Cyclooxygenase Inhibitors
PubMed: 38909081
DOI: 10.1038/s41598-024-63958-0 -
Systematic Parasitology Jun 2024Eight species of Pandarus Leach, 1816 collected from hosts caught off South Africa are reported. These species include P. bicolor Leach, 1816, P. niger Kirtisinghe, 1950...
Eight species of Pandarus Leach, 1816 collected from hosts caught off South Africa are reported. These species include P. bicolor Leach, 1816, P. niger Kirtisinghe, 1950 and P. carcharhini Ho, 1963 belonging to the "bicolor" group and P. cranchii Leach, 1819, P. satyrus Dana, 1849, P. smithii Rathbun, 1886 and P. sinuatus Say, 1818 belonging to the "cranchii" group. Notes on previous and new distinguishing features are provided with illustrations, specifically the relative lengths of the dorsal plates and caudal rami as well as the structure of the distomedial spine on the second segment of leg 1 exopod. Additionally, illustrated re-descriptions are provided for P. satyrus and P. sinuatus. Furthermore, a new species Pandarus echinifer n. sp., also belonging to the "cranchii" group, collected from the snaggletooth shark Hemipristis elongata (Klunzinger) is described. This species is most similar to P. sinuatus but can be distinguished from it by the heavily spinulated distomedial spine on the last segment of the first leg exopod. Molecular analysis of the cytochrome oxidase I partial gene is used to calculate sequence divergences amongst different individuals and species. According to the results (as well as based on morphological characters) P. rhincodonicus Norman, Newbound & Knott, 2000 is a synonym of P. cranchii. New hosts and geographic localities from South Africa (and Ningaloo Park, Western Australia) are reported.
Topics: Animals; South Africa; Species Specificity; Elasmobranchii; Copepoda; Phylogeny; Electron Transport Complex IV; Male; Female
PubMed: 38907944
DOI: 10.1007/s11230-024-10167-y -
International Journal of Medical... 2024Gastric cancer (GC) is a prevalent malignancy characterized by significant morbidity and mortality, yet its underlying pathogenesis remains elusive. The etiology of GC... (Review)
Review
Gastric cancer (GC) is a prevalent malignancy characterized by significant morbidity and mortality, yet its underlying pathogenesis remains elusive. The etiology of GC is multifaceted, involving the activation of oncogenes and the inactivation of antioncogenes. The ubiquitin-proteasome system (UPS), responsible for protein degradation and the regulation of physiological and pathological processes, emerges as a pivotal player in GC development. Specifically, the F-box protein (FBP), an integral component of the SKP1-Cullin1-F-box protein (SCF) E3 ligase complex within the UPS, has garnered attention for its prominent role in carcinogenesis, tumor progression, and drug resistance. Dysregulation of several FBPs has recently been observed in GC, underscoring their significance in disease progression. This comprehensive review aims to elucidate the distinctive characteristics of FBPs involved in GC, encompassing their impact on cell proliferation, apoptosis, invasive metastasis, and chemoresistance. Furthermore, we delve into the emerging role of FBPs as downstream target proteins of non-coding RNAs(ncRNAs) in the regulation of gastric carcinogenesis, outlining the potential utility of FBPs as direct therapeutic targets or advanced therapies for GC.
Topics: Stomach Neoplasms; Humans; F-Box Proteins; Gene Expression Regulation, Neoplastic; Drug Resistance, Neoplasm; Cell Proliferation; Apoptosis; Proteasome Endopeptidase Complex; Carcinogenesis
PubMed: 38903918
DOI: 10.7150/ijms.91584 -
Cell Death & Disease Jun 2024Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, necessitating the identification of novel therapeutic targets. Lysosome...
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, necessitating the identification of novel therapeutic targets. Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is involved in biological processes critical to cancer progression, such as regulation of solute carrier transporter proteins and metabolic pathways, including mTORC1. However, the metabolic processes governed by LAPTM4B and its role in oncogenesis remain unknown. In this study, we conducted unbiased metabolomic screens to uncover the metabolic landscape regulated by LAPTM4B. We observed common metabolic changes in several knockout cell models suggesting of a role for LAPTM4B in suppressing ferroptosis. Through a series of cell-based assays and animal experiments, we demonstrate that LAPTM4B protects tumor cells from erastin-induced ferroptosis both in vitro and in vivo. Mechanistically, LAPTM4B suppresses ferroptosis by inhibiting NEDD4L/ZRANB1 mediated ubiquitination and subsequent proteasomal degradation of the cystine-glutamate antiporter SLC7A11. Furthermore, metabolomic profiling of cancer cells revealed that LAPTM4B knockout leads to a significant enrichment of ferroptosis and associated metabolic alterations. By integrating results from cellular assays, patient tissue samples, an animal model, and cancer databases, this study highlights the clinical relevance of the LAPTM4B-SLC7A11-ferroptosis signaling axis in NSCLC progression and identifies it as a potential target for the development of cancer therapeutics.
Topics: Ferroptosis; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Animals; Proteasome Endopeptidase Complex; Ubiquitin; Mice; Amino Acid Transport System y+; Oncogene Proteins; Membrane Proteins; Cell Line, Tumor; Ubiquitination; Mice, Nude; Proteolysis
PubMed: 38902268
DOI: 10.1038/s41419-024-06836-x -
Nature Communications Jun 2024Aerobic life is powered by membrane-bound redox enzymes that shuttle electrons to oxygen and transfer protons across a biological membrane. Structural studies suggest...
Aerobic life is powered by membrane-bound redox enzymes that shuttle electrons to oxygen and transfer protons across a biological membrane. Structural studies suggest that these energy-transducing enzymes operate as higher-order supercomplexes, but their functional role remains poorly understood and highly debated. Here we resolve the functional dynamics of the 0.7 MDa IIIIV obligate supercomplex from Mycobacterium smegmatis, a close relative of M. tuberculosis, the causative agent of tuberculosis. By combining computational, biochemical, and high-resolution (2.3 Å) cryo-electron microscopy experiments, we show how the mycobacterial supercomplex catalyses long-range charge transport from its menaquinol oxidation site to the binuclear active site for oxygen reduction. Our data reveal proton and electron pathways responsible for the charge transfer reactions, mechanistic principles of the quinone catalysis, and how unique molecular adaptations, water molecules, and lipid interactions enable the proton-coupled electron transfer (PCET) reactions. Our combined findings provide a mechanistic blueprint of mycobacterial supercomplexes and a basis for developing drugs against pathogenic bacteria.
Topics: Mycobacterium smegmatis; Electron Transport; Cryoelectron Microscopy; Oxidation-Reduction; Bacterial Proteins; Protons; Electron Transport Complex III; Oxygen; Electron Transport Complex IV; Catalytic Domain; Models, Molecular
PubMed: 38902248
DOI: 10.1038/s41467-024-49628-9 -
Clinics (Sao Paulo, Brazil) 2024Cuproptosis is known to regulate diverse physiological functions in many diseases, but its role in regulating Myocardial Ischemia-Reperfusion Injury (MI/RI) remains...
BACKGROUND
Cuproptosis is known to regulate diverse physiological functions in many diseases, but its role in regulating Myocardial Ischemia-Reperfusion Injury (MI/RI) remains unclear.
METHODS
For this purpose, the MI/RI microarray datasets GSE61592 were downloaded from the Gene Expression Omnibus (GEO) database, and the Differently Expressed Genes (DEGs) in MI/RI were identified using R software. Moreover, the MI/RI mice model was established to confirm further the diagnostic value of Pyruvate Dehydrogenase B (Pdhb), Dihydrolipoamide S-acetyltransferase (Dlat), and Pyruvate dehydrogenase E1 subunit alpha 1 (Pdhα1).
RESULTS
The analysis of microarray datasets GSE61592 revealed that 798 genes were upregulated and 768 were downregulated in the myocardial tissue of the ischemia-reperfusion injury mice. Furthermore, Dlat, Pdhb, Pdhα1, and cuproptosis-related genes belonged to the downregulated genes. The receiver operating characteristics curve analysis results indicated that the Dlat, Pdhb, and Pdhα1 levels were downregulated in MI/RI and were found to be potential biomarkers for MI/RI diagnosis and prognosis. Similarly, analysis of Dlat, Pdhb, and Pdhα1 levels in the MI/RI mice revealed Pdhb being the key diagnostic marker.
CONCLUSIONS
This study demonstrated the prognostic value of cuproptosis-related genes (Dlat, Pdhb, and Pdhα1), especially Pdhb, MI/RI, providing new insight into the MI/RI treatment.
Topics: Animals; Myocardial Reperfusion Injury; Computational Biology; Mice; Down-Regulation; Male; Disease Models, Animal; Up-Regulation; Mice, Inbred C57BL; Gene Expression Profiling; Pyruvate Dehydrogenase (Lipoamide); Biomarkers; Acetyltransferases
PubMed: 38901133
DOI: 10.1016/j.clinsp.2024.100410