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Annals of Translational Medicine Jan 2023The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes novel coronavirus disease 2019 (COVID-19), which is characterized by pneumonia, cytokine...
BACKGROUND
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes novel coronavirus disease 2019 (COVID-19), which is characterized by pneumonia, cytokine storms, and lymphopenia. Due to immunosuppression, cancer patients may be more susceptible to SARS-CoV-2 and have more serious complications. According to recent research, cyclic GMP-AMP synthase () could be a potential SARS-CoV-2 sensor. However, at present, no studies have been conducted on gene alterations in pan-cancer. This study aimed to discover therapeutic implications for COVID-19-infected tumor patients by performing a comprehensive analysis of in malignant tumors.
METHODS
expression matrices were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases, which were used to evaluate expression in various tumors, its prognostic value, and its relationship to the immune microenvironment, microsatellite instability (MSI), immune neoantigens, gene mutations, immune checkpoints, MSI, tumor mutational burden (TMB), mismatch repair (MMR) genes, and DNA methyltransferases (DNMT). We also used the cBioPortal, Human Protein Atlas (HPA), and GeneMANIA databases to explore the types of changes, gene networks and immunofluorescence localization, and protein expression of these genes.
RESULTS
Compared to normal tissues, was highly expressed in 13 types of cancer (e.g., lung cancer) and lowly expressed in other cancers (e.g., pancreatic cancer). expression was associated with prognosis in nine cancers, such as renal clear cell carcinoma (P<0.05). Furthermore, deep deletion was the most common type of genomic mutation. DNMT, immune infiltration levels, TMB, MSI, MMR genes, neoantigens, and immune checkpoints were all correlated with expression. Moreover, we used the GSE30589 dataset to investigate the post-SARS-CoV infection changes in expression . Finally, mithramycin, MI219, AFP464, aminoflavone, kahalide F, AT13387, doxorubicin, and other drugs increased the sensitivity of expression. According to the evidence presented above, may become an important target for cancer therapy.
CONCLUSIONS
This study discovered that SARS-CoV-2-infected cancer patients might experience changes in their tumor environment as a result of , making patients with tumors expressing high more susceptible to COVID-19 and possibly a worsening prognosis. Furthermore, may be a novel biomarker for diagnosing and treating COVID-19-infected tumor patients.
PubMed: 36819495
DOI: 10.21037/atm-22-6318 -
Frontiers in Genetics 2022Head and neck squamous cell carcinoma (HNSCC), the most common malignancy of the head and neck, has an overall 5-year survival rate of <50%. Genes associated with...
Head and neck squamous cell carcinoma (HNSCC), the most common malignancy of the head and neck, has an overall 5-year survival rate of <50%. Genes associated with cuproptosis, a newly identified copper-dependent form of cell death, are aberrantly expressed in various tumours. However, their role in HNSCC remains unknown. In this study, bioinformatic analysis revealed that the cuproptosis-related gene CDKN2A was correlated with the malignant behaviour of HNSCC. Kaplan-Meier (KM) curves showed that patients with high CDKN2A expression had a better prognosis. Multiomic analysis revealed that CDKN2A may be associated with cell cycle and immune cell infiltration in the tumour microenvironment and is important for maintaining systemic homeostasis in the body. Furthermore, molecular docking and molecular dynamics simulations suggested strong binding between plicamycin and CDKN2A. And plicamycin inhibits the progression of HNSCC in cellular assays. In conclusion, this study elucidated a potential mechanism of action of the cuproptosis-associated gene CDKN2A in HNSCC and revealed that plicamycin targets CDKN2A to improve the prognosis of patients.
PubMed: 36699463
DOI: 10.3389/fgene.2022.1036408 -
Immunological Investigations Feb 2023Interleukin-34 (IL-34) is a cytokine that plays important roles at steady state and in diseases. The induced or inhibited expression of IL-34 by stimuli has been deeply...
Interleukin-34 (IL-34) is a cytokine that plays important roles at steady state and in diseases. The induced or inhibited expression of IL-34 by stimuli has been deeply investigated. However, the regulation of IL-34 basal expression is largely unknown. The aim of this study is to investigate whether IL-34 expression is regulated by a general transcription factor Specificity Protein 1 (Sp1) at transcription level. By using bioinformatic software, four putative Sp1-binding sites overlapping GC boxes were found in the core promoter region of IL-34. Alignment of the core promoter sequences of mammalian IL-34 showed GC box-C (-62/-57) and D (-11/-6) were conserved in some mammals. Luciferase assay results showed that only deletion of GC box-C (-62/-57) significantly reduced luciferase activities of IL-34 core promoter in SH-SY5Y cells. By using electrophoretic mobility shift assay (EMSA), it was found that Sp1 specifically interacted with GC box-C sequence CCCGCC (-62/-57) in the core promoter of IL-34. By using chromatin immunoprecipitation (ChIP), it was discovered that Sp1 bound to the core promoter of IL-34 in living cells. In addition, silencing of Sp1 expression by its specific siRNA reduced IL-34 mRNA and protein levels significantly in SH-SY5Y cells. Likewise, IL-34 expression was inhibited in a dose-dependent manner by a Sp1 inhibitor Plicamycin. Furthermore, silencing of Sp1 also downregulated mRNA and protein expression of IL-34 in GES-1 and 293T cell lines, suggesting that IL-34 transcription regulated by Sp1 was not cell-type specific. Taken together, these results indicate that Sp1 controls the basal level of IL-34 transcription.
Topics: Animals; Humans; Neuroblastoma; Promoter Regions, Genetic; Binding Sites; Interleukins; RNA, Messenger; Luciferases; Sp1 Transcription Factor; Gene Expression Regulation; Mammals
PubMed: 36562687
DOI: 10.1080/08820139.2022.2157283 -
International Journal of Molecular... Dec 2022Pemetrexed is a folic acid inhibitor used as a second-line chemotherapeutic agent for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC),...
Pemetrexed is a folic acid inhibitor used as a second-line chemotherapeutic agent for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), which accounts for 85% of lung cancers. However, prolonged treatment with pemetrexed may cause cancer cells to develop resistance. In this study, we found increased expressions of BMI1 (B Lymphoma Mo-MLV insertion region 1 homolog) and Sp1 and a decreased expression of miR-145-5p was found in pemetrexed-resistant A400 cells than in A549 cells. Direct Sp1 targeting activity of miR-145-5p was demonstrated by a luciferase based Sp1 3'-UTR reporter. Changed expression of miR-145-5p in A400 or A549 cells by transfection of miR-145-5p mimic or inhibitor affected the sensitivity of the cells to pemetrexed. On the other hand, the overexpression of Sp1 in A549 cells caused the decreased sensitivity to pemetrexed, induced cell migratory capability, and epithelial-mesenchymal transition (EMT) related transcription factors such as Snail Family Transcriptional Repressor 1 and Zinc Finger E-Box Binding Homeobox 1. In addition, the overexpression of BMI1 in the A549 cells resulted in an increase in Sp1 and a decrease in miR-145-5p accompanied by the elevations of cell proliferation and EMT transcription factors, which could be reduced by the overexpression of miR-145-5p or by treatment with the Sp1 inhibitor of mithramycin A. In conclusion, the results of this study suggest that the downregulation of miR-145-5p by BMI1 overexpression could lead to the enhanced expression of Sp1 to induce the EMT process in pemetrexed-resistant NSCLC cells. These results suggest that increasing miR-145-5p expression by delivering RNA drugs may serve as a sensitizing agent for pemetrexed-resistant NSCLC patients.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Epithelial-Mesenchymal Transition; Pemetrexed; Lung Neoplasms; MicroRNAs; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Zinc Finger E-box-Binding Homeobox 1; Cell Proliferation; Polycomb Repressive Complex 1; Sp1 Transcription Factor
PubMed: 36499676
DOI: 10.3390/ijms232315352 -
Journal of Pharmaceutical Sciences Apr 2023Traditional chemotherapies target rapidly developing cells in the human body resulting in harsh side effects including fatigue, immune system suppression, and nausea,...
Traditional chemotherapies target rapidly developing cells in the human body resulting in harsh side effects including fatigue, immune system suppression, and nausea, among others. Delivery systems to focus the active pharmaceutical ingredients (APIs) to the diseased tissue can diminish the negative side effects while improving treatment outcomes. Gold nanoparticles (AuNP) offer many unique advantages as drug delivery vehicles, including being biologically inert, easily adaptable to various shapes and sizes, able to create a strong Au-thiol bond, and able to generate heat upon the absorption of near-infrared light. To this end, a AuNP delivery vehicle was engineered to load and release two DNA binding anti-cancer drugs, mithramycin and doxorubicin, in a controlled fashion. The drugs were loaded onto the surface of the AuNP with temperature sensitive linkages. The amount of heat generated, and subsequent release of the drugs was controlled by the irradiation time with a near-infrared laser. By modulating the linkage used to load the drugs three different release profiles were able to be achieved, indicating the feasibility of such a system for combinational therapy requiring sequential release of APIs.
Topics: Humans; Gold; Delayed-Action Preparations; Metal Nanoparticles; Antineoplastic Agents; Drug Delivery Systems; Doxorubicin; Infrared Rays; DNA
PubMed: 36493881
DOI: 10.1016/j.xphs.2022.12.001 -
Microbial Biotechnology Dec 2022Coelimycin P1 and argimycins P are two types of polyketide alkaloids produced by Streptomyces coelicolor and Streptomyces argillaceus, respectively. Their biosynthesis...
Coelimycin P1 and argimycins P are two types of polyketide alkaloids produced by Streptomyces coelicolor and Streptomyces argillaceus, respectively. Their biosynthesis pathways share some early steps that render very similar aminated polyketide chains, diverging the pathways afterwards. By expressing the putative isomerase cpkE and/or the putative epoxidase/dehydrogenase cpkD from the coelimycin P1 gene cluster into S. argillaceus wild type and in argimycin mutant strains, five novel hybrid argimycins were generated. Chemical characterization of those compounds revealed that four of them show unprecedented scaffolds (quinolizidine and pyranopyridine) never found before in the argimycin family of compounds. One of these compounds (argimycin DM104) shows improved antibiotic activity. Noticeable, biosynthesis of these quinolizidine argimycins results from a hybrid pathway created by combining enzymes from two different pathways, which utilizes an aminated polyketide chain as precursor instead of lysine as it occurs for other quinolizidines.
Topics: Plicamycin; Streptomyces; Multigene Family; Anti-Bacterial Agents
PubMed: 36346129
DOI: 10.1111/1751-7915.14167 -
ChemMedChem Feb 2023DNA coordinating platinum (Pt) containing compounds cisplatin and carboplatin have been used for the treatment of ovarian cancer therapy for four decades. However,...
DNA coordinating platinum (Pt) containing compounds cisplatin and carboplatin have been used for the treatment of ovarian cancer therapy for four decades. However, recurrent Pt-resistant cancers are a major cause of mortality. To combat Pt-resistant ovarian cancers, we designed and synthesized a conjugate of an anticancer drug mithramycin with a reactive Pt(II) bearing moiety, which we termed mithplatin. The conjugates displayed both the Mg -dependent noncovalent DNA binding characteristic of mithramycin and the covalent crosslinking to DNA of the Pt. The conjugate was three times as potent as cisplatin against ovarian cancer cells. The DNA lesions caused by the conjugate led to the generation of DNA double-strand breaks, as also observed with cisplatin. Nevertheless, the conjugate was highly active against both Pt-sensitive and Pt-resistant ovarian cancer cells. This study paves the way to developing mithplatins to combat Pt-resistant ovarian cancers.
Topics: Humans; Female; Cisplatin; Plicamycin; Antineoplastic Agents; Ovarian Neoplasms; DNA; Cell Line, Tumor; Drug Resistance, Neoplasm
PubMed: 36342449
DOI: 10.1002/cmdc.202200368 -
Antioxidants (Basel, Switzerland) Sep 2022Clasmatodendrosis is an autophagic astroglial degeneration (a non-apoptotic (type II) programmed cell death) whose underlying mechanisms are fully understood....
Clasmatodendrosis is an autophagic astroglial degeneration (a non-apoptotic (type II) programmed cell death) whose underlying mechanisms are fully understood. Peroxiredoxin-6 (Prdx6), the "non-selenium glutathione peroxidase (NSGPx)", is the only member of the 1-cysteine peroxiredoxin family. Unlike the other Prdx family, Prdx6 has multiple functions as glutathione peroxidase (GPx) and acidic calcium-independent phospholipase (aiPLA2). The present study shows that Prdx6 was upregulated in CA1 astrocytes in chronic epilepsy rats. 2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) and N-acetylcysteine (NAC, a precursor of glutathione) ameliorated clasmatodendrosis accompanied by reduced Prdx6 level in CA1 astrocytes. Specificity protein 1 (Sp1) expression was upregulated in CA1 astrocyte, which was inhibited by mithramycin A (MMA). MMA alleviated clasmatodendrosis and Prdx6 upregulation. Sp1 expression was also downregulated by CDDO-Me and NAC. Furthermore, 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) attenuated clasmatodendrosis without affecting Prdx6 expression. All chemicals shortened spontaneous seizure duration but not seizure frequency and behavioral seizure severity in chronic epilepsy rats. Therefore, our findings suggest that Sp1 activation may upregulate Prdx6, whose aiPLA2 activity would dominate over GPx activity in CA1 astrocytes and may lead to prolonged seizure activity due to autophagic astroglial degeneration.
PubMed: 36290607
DOI: 10.3390/antiox11101883 -
Gels (Basel, Switzerland) Sep 2022Gelatin is a popular biopolymer for biomedical applications due to its harmless impact with a negligible inflammatory response in the host organism. Gelatin interacts...
Gelatin is a popular biopolymer for biomedical applications due to its harmless impact with a negligible inflammatory response in the host organism. Gelatin interacts with soluble molecules in aqueous media as ionic counterparts such as ionic liquids (ILs) to be used as cosolvents to generate the so-called Ionogels. The perfluorinated IL (FIL), 1-ethyl-3-methylpyridinium perfluorobutanesulfonate, has been selected as co-hydrosolvent for fish gelatin due to its low cytotoxicity and hydrophobicity aprotic polar structure to improve the drug aqueous solubility. A series of FIL/water emulsions with different FIL content and their corresponding shark gelatin/FIL Ionogel has been designed to enhance the drug solubility whilst retaining the mechanical structure and their nanostructure was probed by simultaneous SAXS/WAXS, FTIR and Raman spectroscopy, DSC and rheological experiments. Likewise, the FIL assisted the solubility of the antitumoural Doxorubicin whilst retaining the performing mechanical properties of the drug delivery system network for the drug storage as well as the local administration by a syringe. In addition, the different controlled release mechanisms of two different antitumoral such as Doxorubicin and Mithramycin from two different Ionogels formulations were compared to previous gelatin hydrogels which proved the key structure correlation required to attain specific therapeutic dosages.
PubMed: 36135306
DOI: 10.3390/gels8090594 -
ACS Pharmacology & Translational Science Sep 2022Drug resistance is a leading cause for the failure of cancer treatments. Plasticity of cancer cells to acquire stem cell-like properties enables them to escape drug...
Drug resistance is a leading cause for the failure of cancer treatments. Plasticity of cancer cells to acquire stem cell-like properties enables them to escape drug toxicity through different adaptive mechanisms. Eliminating cancer stem cells (CSCs) can potentially improve treatment outcomes for patients. To determine the role of CSCs in resistance of colorectal cancer cells to targeted therapies and identify treatment strategies, we treated spheroids of BRAF and KRAS colorectal cancer cells with inhibitors of the mitogen-activated protein kinase pathway and studied resistance mechanisms through gene and protein expression analyses. We found that treatments activated several oncogenic pathways and expression of CSC markers CD166 and ALDH1A3. We identified a specific combination treatment using trametinib and mithramycin A to simultaneously inhibit the CSC phenotype and activities of several pathways in cancer cells. This study demonstrates the feasibility of therapeutic targeting of CSCs as a strategy to block tumorigenic activities of cancer cells.
PubMed: 36110381
DOI: 10.1021/acsptsci.1c00257