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International Journal of Molecular... Jun 2024The interaction of programmed death-1 (PD-1) on T lymphocytes with its ligands Programmed Death Ligand 1 (PD-L1) and Programmed Death Ligand 2 (PD-L2) on tumor cells... (Review)
Review
The interaction of programmed death-1 (PD-1) on T lymphocytes with its ligands Programmed Death Ligand 1 (PD-L1) and Programmed Death Ligand 2 (PD-L2) on tumor cells and/or tumor-associated macrophages results in inhibitory signals to the T-cell receptor pathway, consequently causing tumor immune escape. PD-L1/PD-L2 are currently used as predictive tissue biomarkers in clinical practice. Virtually PD-L1 levels expressed by tumor cells are associated with a good response to immune checkpoint blockade therapies targeting the PD-1/PD-L1 axis. These therapies restore T-cell antitumor immune response by releasing T-lymphocytes from the inhibitory effects of tumor cells. Immune checkpoint therapies have completely changed the management of patients with solid cancers. This therapeutic strategy is less used in hematological malignancies, although good results have been achieved in some settings, such as refractory/relapsed classic Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Variable results have been obtained in diffuse large B-cell lymphoma and T-cell lymphomas. Immunohistochemistry represents the main technique for assessing PD-L1 expression on tumor cells. This review aims to describe the current knowledge of PD-L1 expression in various types of lymphomas, focusing on the principal mechanisms underlying PD-L1 overexpression, its prognostic significance and practical issues concerning the evaluation of PD-L1 immunohistochemical results in lymphomas.
Topics: Humans; B7-H1 Antigen; Lymphoma; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Immune Checkpoint Inhibitors
PubMed: 38928153
DOI: 10.3390/ijms25126447 -
International Journal of Molecular... Jun 2024Nicotinamide adenine dinucleotide (NAD) is involved in renal physiology and is synthesized by nicotinamide mononucleotide adenylyltransferase (NMNAT). NMNAT exists as...
Nicotinamide adenine dinucleotide (NAD) is involved in renal physiology and is synthesized by nicotinamide mononucleotide adenylyltransferase (NMNAT). NMNAT exists as three isoforms, namely, NMNAT1, NMNAT2, and NMNAT3, encoded by , , and , respectively. In diabetic nephropathy (DN), NAD levels decrease, aggravating renal fibrosis. Conversely, sodium-glucose cotransporter-2 inhibitors increase NAD levels, mitigating renal fibrosis. In this regard, renal NAD synthesis has recently gained attention. However, the renal role of in DN remains uncertain. Therefore, we investigated the role of by establishing genetically engineered mice. Among the three isoforms, NMNAT1 levels were markedly reduced in the proximal tubules (PTs) of db/db mice. We examined the phenotypic changes in PT-specific conditional knockout (CKO) mice. In CKO mice, expression in PTs was downregulated when the tubules exhibited albuminuria, peritubular type IV collagen deposition, and mitochondrial ribosome (mitoribosome) excess. In CKO mice, deficiency-induced mitoribosome excess hindered mitoribosomal translation of mitochondrial inner membrane-associated oxidative phosphorylation complex I (CI), CIII, CIV, and CV proteins and mitoribosomal dysfunction. Furthermore, the expression of hypermethylated in cancer 1, a transcription repressor, was downregulated in CKO mice, causing mitoribosome excess. overexpression preserved mitoribosomal function, suggesting its protective role in DN.
Topics: Animals; Diabetic Nephropathies; Mice; Nicotinamide-Nucleotide Adenylyltransferase; Mice, Knockout; Kidney Tubules, Proximal; Male; Mitochondria; Mice, Inbred C57BL
PubMed: 38928090
DOI: 10.3390/ijms25126384 -
International Journal of Molecular... Jun 2024Proteasome 26S Subunit, Non-ATPase 9 () plays an important role in the balance of protamine and the stability of the nucleolar structure during spermatogenesis. In this...
Proteasome 26S Subunit, Non-ATPase 9 () plays an important role in the balance of protamine and the stability of the nucleolar structure during spermatogenesis. In this study, we cloned the of and analyzed its expression pattern. was identified on the Z chromosome of , which is considered an interesting candidate gene for spermatogenesis. qRT-PCR and FISH experiments showed that the gene was significantly highly expressed in the testes. It is worth noting that the expression level of in male fish testes is significantly higher than that in pseudomales. In order to further explore the role of in spermatogenesis, a male testicular cell line was used as the experimental material. The results of the -RNAi and overexpression experiments showed that had a synergistic effect with spermatogenesis-related genes , , and , but had an antagonistic effect with . Our findings offer a scientific foundation for comprehending the role of in the spermatogenesis regulatory network of .
Topics: Animals; Spermatogenesis; Male; Testis; Sex Chromosomes; Fish Proteins; Proteasome Endopeptidase Complex; Cloning, Molecular
PubMed: 38928079
DOI: 10.3390/ijms25126372 -
International Journal of Molecular... Jun 2024Metabolic engineering enables oilseed crops to be more competitive by having more attractive properties for oleochemical industrial applications. The aim of this study...
Metabolic engineering enables oilseed crops to be more competitive by having more attractive properties for oleochemical industrial applications. The aim of this study was to increase the erucic acid level and to produce wax ester (WE) in seed oil by genetic transformation to enhance the industrial applications of . Six transgenic lines for high erucic acid and fifteen transgenic lines for wax esters were obtained. The integration of the target genes for high erucic acid ( and ) and for WEs ( and ) in the genome of cv. 'Derash' was confirmed by PCR analysis. The qRT-PCR results showed overexpression of and and downregulation of RNAi- in the seeds of the transgenic lines. The fatty acid profile and WE content and profile in the seed oil of the transgenic lines and wild type grown in biotron were analyzed using gas chromatography and nanoelectrospray coupled with tandem mass spectrometry. A significant increase in erucic acid was observed in some transgenic lines ranging from 19% to 29% in relation to the wild type, with a level of erucic acid reaching up to 52.7%. Likewise, the transgenic lines harboring and genes produced up to 25% WE content, and the most abundant WE species were 22:1/20:1 and 22:1/22:1. This study demonstrated that metabolic engineering is an effective biotechnological approach for developing into an industrial crop.
Topics: Erucic Acids; Metabolic Engineering; Plants, Genetically Modified; Waxes; Esters; Seeds; Brassica; Fatty Acids; Plant Oils; Gene Expression Regulation, Plant; Plant Proteins
PubMed: 38928029
DOI: 10.3390/ijms25126322 -
International Journal of Molecular... Jun 2024Oxidative stress represents a critical facet of the array of abiotic stresses affecting crop growth and yield. In this paper, we investigated the potential differences...
Oxidative stress represents a critical facet of the array of abiotic stresses affecting crop growth and yield. In this paper, we investigated the potential differences in the functions of two highly homologous Arabidopsis DSS1 proteins in terms of maintaining genome integrity and response to oxidative stress. In the context of homologous recombination (HR), it was shown that overexpressing AtDSS1(I) using a functional complementation test increases the resistance of the Δ mutant of to genotoxic agents. This indicates its conserved role in DNA repair via HR. To investigate the global transcriptome changes occurring in plant mutant lines, gene expression analysis was conducted using Illumina RNA sequencing technology. Individual RNA libraries were constructed from three total RNA samples isolated from , , and wild-type (WT) plants under hydrogen peroxide-induced stress. RNA-Seq data analysis and real-time PCR identification revealed major changes in gene expression between mutant lines and WT, while the and mutant lines exhibited analogous transcription profiles. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed significantly enriched metabolic pathways. Notably, genes associated with HR were upregulated in mutants compared to the WT. Otherwise, genes of the metabolic pathway responsible for the synthesis of secondary metabolites were downregulated in both mutant lines. These findings highlight the importance of understanding the molecular mechanisms of plant responses to oxidative stress.
Topics: Oxidative Stress; Arabidopsis; Seedlings; Transcriptome; Arabidopsis Proteins; Gene Expression Regulation, Plant; Gene Knockout Techniques; Gene Expression Profiling; Mutation; Hydrogen Peroxide
PubMed: 38927997
DOI: 10.3390/ijms25126291 -
Cancers Jun 2024Raf Kinase Inhibitor Protein (RKIP) is recognized as a bona fide tumor suppressor gene, and its diminished expression or loss is associated with the progression and poor...
Raf Kinase Inhibitor Protein (RKIP) is recognized as a bona fide tumor suppressor gene, and its diminished expression or loss is associated with the progression and poor prognosis of various solid tumors. It exerts multifaceted roles in carcinogenesis by modulating diverse intracellular signaling pathways, including those governed by HER receptors such as MAPK. Given the significance of HER receptor overexpression in numerous tumor types, we investigated the potential oncogenic relationship between RKIP and HER receptors in solid tumors. Through a comprehensive in silico analysis of 30 TCGA PanCancer Atlas studies encompassing solid tumors (10,719 samples), we uncovered compelling evidence of an inverse correlation between RKIP and EGFR expression in solid tumors observed in 25 out of 30 studies. Conversely, a predominantly positive association was noted for the other HER receptors (ERBB2, ERBB3, and ERBB4). In particular, cervical cancer (CC) emerged as a tumor type exhibiting a robust inverse association between RKIP and EGFR expression, a finding that was further validated in a cohort of 202 patient samples. Subsequent in vitro experiments involving pharmacological and genetic modulation of EGFR and RKIP showed that RKIP depletion led to significant upregulation of EGFR mRNA levels and induction of EGFR phosphorylation. Conversely, EGFR overactivation decreased RKIP expression in CC cell lines. Additionally, we identified a common molecular signature among patients depicting low RKIP and high EGFR expression and demonstrated the prognostic value of this inverse correlation in CC patients. In conclusion, our findings reveal an inverse association between RKIP and EGFR expression across various solid tumors, shedding new light on the underlying molecular mechanisms contributing to the aggressive phenotype associated with RKIP and EGFR in cervical cancer.
PubMed: 38927888
DOI: 10.3390/cancers16122182 -
Genes Jun 2024Ionizing radiation (IR) and chemotherapy with DNA-damaging drugs such as cisplatin are vital cancer treatment options. These treatments induce double-strand breaks...
Ionizing radiation (IR) and chemotherapy with DNA-damaging drugs such as cisplatin are vital cancer treatment options. These treatments induce double-strand breaks (DSBs) as cytotoxic DNA damage; thus, the DSB repair activity in each cancer cell significantly influences the efficacy of the treatments. Pancreatic cancers are known to be resistant to these treatments, and the overexpression of MUC1, a member of the glycoprotein mucins, is associated with IR- and chemo-resistance. Therefore, we investigated the impact of MUC1 on DSB repair. This report examined the effect of the overexpression of MUC1 on homologous recombination (HR) and non-homologous end-joining (NHEJ) using cell-based DSB repair assays. In addition, the therapeutic potential of NHEJ inhibitors including HDAC inhibitors was also studied using pancreatic cancer cell lines. The MUC1-overexpression enhances NHEJ, while partially suppressing HR. Also, MUC1-overexpressed cancer cell lines are preferentially killed by a DNA-PK inhibitor and HDAC1/2 inhibitors. Altogether, MUC1 induces metabolic changes that create an imbalance between NHEJ and HR activities, and this imbalance can be a target for selective killing by HDAC inhibitors. This is a novel mechanism of MUC1-mediated IR-resistance and will form the basis for targeting MUC1-overexpressed pancreatic cancer.
Topics: Humans; Mucin-1; DNA End-Joining Repair; Cell Line, Tumor; DNA Breaks, Double-Stranded; Pancreatic Neoplasms; Up-Regulation; Homologous Recombination; Histone Deacetylase Inhibitors; Gene Expression Regulation, Neoplastic
PubMed: 38927743
DOI: 10.3390/genes15060808 -
Genes Jun 2024Peroxisome proliferator-activated receptor γ (PPARG) has various splicing variants and plays essential roles in the regulation of adipocyte differentiation and...
Peroxisome proliferator-activated receptor γ (PPARG) has various splicing variants and plays essential roles in the regulation of adipocyte differentiation and lipogenesis. However, little is known about the expression pattern and effect of the PPARG on milk fat synthesis in the buffalo mammary gland. In this study, we found that only and of the splicing variant were expressed in the buffalo mammary gland. Amino acid sequence characterization showed that the proteins encoded by and are endonuclear non-secreted hydrophilic proteins. Protein domain prediction found that only the -encoded protein had PPAR ligand-binding domains (NR_LBD_PPAR), which may lead to functional differences between the two splices. RNA interference (RNAi) and the overexpression of and in buffalo mammary epithelial cells (BMECs) were performed. Results showed that the expression of fatty acid synthesis-related genes (, , , , , ) was significantly modified ( < 0.05) by the RNAi and overexpression of and . All kinds of FAs detected in this study were significantly decreased ( < 0.05) after RNAi of or . Overexpression of or significantly decreased ( < 0.05) the SFA content, while significantly increased ( < 0.05) the UFA, especially the MUFA in the BMECs. In conclusion, there are two splicing variants expressed in the BMECs that can regulate FA synthesis by altering the expression of diverse fatty acid synthesis-related genes. This study revealed the expression characteristics and functions of the gene in buffalo mammary glands and provided a reference for further understanding of fat synthesis in buffalo milk.
Topics: Animals; Buffaloes; PPAR gamma; Mammary Glands, Animal; Female; Epithelial Cells; Alternative Splicing; Fatty Acids; Protein Isoforms; Milk
PubMed: 38927715
DOI: 10.3390/genes15060779 -
Genes Jun 2024Small auxin-upregulated RNAs (), as the largest family of early auxin-responsive genes, play important roles in plant growth and development processes, such as auxin...
Small auxin-upregulated RNAs (), as the largest family of early auxin-responsive genes, play important roles in plant growth and development processes, such as auxin signaling and transport, hypocotyl development, and tolerance to environmental stresses. However, the functions of few genes are known in the root development of sweet potatoes. In this study, an gene was cloned and functionally analyzed. The IbSAUR36 protein was localized to the nucleus and plasma membrane. The transcriptional level of this gene was significantly higher in the pencil root and leaf.This gene was strongly induced by indole-3-acetic acid (IAA), but it was downregulated under methyl-jasmonate(MeJA) treatment. The promoter of contained the core -elements for phytohormone responsiveness. Promoter β-glucuronidase (GUS) analysis in showed that is highly expressed in the young tissues of plants, such as young leaves, roots, and buds. -overexpressing sweet potato roots were obtained by an efficient -mediated root transgenic system. We demonstrated that overexpression of promoted the accumulation of IAA, upregulated the genes encoding IAA synthesis and its signaling pathways, and downregulated the genes encoding lignin synthesis and JA signaling pathways. Taken together, these results show that plays an important role in adventitious root (AR) development by regulating IAA signaling, lignin synthesis, and JA signaling pathways in transgenic sweet potatoes.
Topics: Ipomoea batatas; Plant Roots; Plants, Genetically Modified; Indoleacetic Acids; Gene Expression Regulation, Plant; Plant Proteins; Plant Growth Regulators; Promoter Regions, Genetic; Cyclopentanes
PubMed: 38927696
DOI: 10.3390/genes15060760 -
Genes May 2024Soil salinization is a major abiotic stress factor that negatively impacts plant growth, development, and crop yield, severely limiting agricultural production and...
Soil salinization is a major abiotic stress factor that negatively impacts plant growth, development, and crop yield, severely limiting agricultural production and economic development. Cotton, a key cash crop, is commonly cultivated as a pioneer crop in regions with saline-alkali soil due to its relatively strong tolerance to salt. This characteristic renders it a valuable subject for investigating the molecular mechanisms underlying plant salt tolerance and for identifying genes that confer salt tolerance. In this study, focus was placed on examining a salt-tolerant variety, E991, and a salt-sensitive variety, ZM24. A combined analysis of transcriptomic data from these cotton varieties led to the identification of potential salt stress-responsive genes within the glutathione S-transferase (GST) family. These versatile enzyme proteins, prevalent in animals, plants, and microorganisms, were demonstrated to be involved in various abiotic stress responses. Our findings indicate that suppressing in cotton led to a notably salt-sensitive phenotype, whereas heterologous overexpression in Arabidopsis plants decreases the accumulation of reactive oxygen species under salt stress, thereby enhancing salt stress tolerance. This suggests that serves as a positive regulator in cotton's response to salt stress. These results offer new target genes for developing salt-tolerant cotton varieties.
Topics: Arabidopsis; Gossypium; Plants, Genetically Modified; Salt Tolerance; Gene Expression Regulation, Plant; Plant Proteins; Salt Stress; Reactive Oxygen Species; Glutathione Transferase; Stress, Physiological; Salt-Tolerant Plants
PubMed: 38927631
DOI: 10.3390/genes15060695