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PloS One 2024DNA barcoding is used to identify cryptic species, survey environmental samples, and estimate phyletic and genetic diversity. Armored scale insects are phytophagous...
DNA barcoding is used to identify cryptic species, survey environmental samples, and estimate phyletic and genetic diversity. Armored scale insects are phytophagous insects and are the most species-rich taxa in the Coccoidea superfamily. This study developed a DNA barcode library for armored scale insect species collected from southern China during 2021-2022. We sequenced a total of 239 specimens, recognized as 50 morphological species, representing two subfamilies and 21 genera. Sequencing analysis revealed that the average G + C content of the cytochrome oxidase subunit I (COI) gene sequence was very low (~18.06%) and that the average interspecific divergence was 10.07% while intraspecific divergence was 3.20%. The intraspecific divergence value was inflated by the high intraspecific divergence in ten taxa, which may indicate novel species overlooked by current taxonomic treatments. All the Automated Barcode Gap Discovery, Assemble Species by Automatic Partitioning, Taxon DNA analysis and Bayesian Poisson Tree Process methods yielded largely consistent results, indicating a robust and credible species delimitation. Based on these results, an intergeneric distance threshold of ≤ 5% was deemed appropriate for the differentiation of armored scale insect species in China. This study establishes a comprehensive barcode library for the identification of armored scale insects, future research, and application.
Topics: Animals; DNA Barcoding, Taxonomic; China; Hemiptera; Phylogeny; Electron Transport Complex IV; Genetic Variation; Gene Library; Bayes Theorem
PubMed: 38814962
DOI: 10.1371/journal.pone.0301499 -
Kidney360 May 2024
Topics: Kidney Transplantation; Humans; Proteasome Endopeptidase Complex; Organ Preservation; Kidney; Cold Temperature
PubMed: 38814755
DOI: 10.34067/KID.0000000000000436 -
Journal of Experimental & Clinical... May 2024Intrahepatic cholangiocarcinoma (ICCA) is a heterogeneous group of malignant tumors characterized by high recurrence rate and poor prognosis. Heterochromatin Protein 1α...
BACKGROUND
Intrahepatic cholangiocarcinoma (ICCA) is a heterogeneous group of malignant tumors characterized by high recurrence rate and poor prognosis. Heterochromatin Protein 1α (HP1α) is one of the most important nonhistone chromosomal proteins involved in transcriptional silencing via heterochromatin formation and structural maintenance. The effect of HP1α on the progression of ICCA remained unclear.
METHODS
The effect on the proliferation of ICCA was detected by experiments in two cell lines and two ICCA mouse models. The interaction between HP1α and Histone Deacetylase 1 (HDAC1) was determined using Electrospray Ionization Mass Spectrometry (ESI-MS) and the binding mechanism was studied using immunoprecipitation assays (co-IP). The target gene was screened out by RNA sequencing (RNA-seq). The occupation of DNA binding proteins and histone modifications were predicted by bioinformatic methods and evaluated by Cleavage Under Targets and Tagmentation (CUT & Tag) and Chromatin immunoprecipitation (ChIP).
RESULTS
HP1α was upregulated in intrahepatic cholangiocarcinoma (ICCA) tissues and regulated the proliferation of ICCA cells by inhibiting the interferon pathway in a Signal Transducer and Activator of Transcription 1 (STAT1)-dependent manner. Mechanistically, STAT1 is transcriptionally regulated by the HP1α-HDAC1 complex directly and epigenetically via promoter binding and changes in different histone modifications, as validated by high-throughput sequencing. Broad-spectrum HDAC inhibitor (HDACi) activates the interferon pathway and inhibits the proliferation of ICCA cells by downregulating HP1α and targeting the heterodimer. Broad-spectrum HDACi plus interferon preparation regimen was found to improve the antiproliferative effects and delay ICCA development in vivo and in vitro, which took advantage of basal activation as well as direct activation of the interferon pathway. HP1α participates in mediating the cellular resistance to both agents.
CONCLUSIONS
HP1α-HDAC1 complex influences interferon pathway activation by directly and epigenetically regulating STAT1 in transcriptional level. The broad-spectrum HDACi plus interferon preparation regimen inhibits ICCA development, providing feasible strategies for ICCA treatment. Targeting the HP1α-HDAC1-STAT1 axis is a possible strategy for treating ICCA, especially HP1α-positive cases.
Topics: Cholangiocarcinoma; Humans; Chromobox Protein Homolog 5; Histone Deacetylase 1; Mice; Animals; STAT1 Transcription Factor; Bile Duct Neoplasms; Chromosomal Proteins, Non-Histone; Cell Line, Tumor; Cell Proliferation; Male; Gene Expression Regulation, Neoplastic; Female
PubMed: 38812060
DOI: 10.1186/s13046-024-03070-3 -
Scientific Reports May 2024The loss of biodiversity in marine populations is one of the consequences of the increased events of extreme environmental conditions in the oceans, which can condition...
The loss of biodiversity in marine populations is one of the consequences of the increased events of extreme environmental conditions in the oceans, which can condition the persistence of populations to future scenarios of climate change. Therefore, it is extremely necessary to explore and monitor the genetic diversity of natural populations. In the Southeast Pacific Ocean (SEPO), specifically on the coast of Chile, the presence of the copepod Acartia tonsa has been indicated solely using morphological evidence, due to the absence of genetic information. In the present work, the genetic diversity, population structure and phylogenetic position within the genus Acartia, of populations identified morphologically as A. tonsa, was evaluated by amplification of the mitochondrial cytochrome c oxidase subunit I and nuclear marker 18 s. Our results showed that the populations identified as A. tonsa correspond to a new monophyletic group endemic to SEPO (GMYC = 1.00; PTP = 0.95). The populations showed moderate to high genetic diversity with an incipient structuring between populations and biogeographic zones. Our results suggest that despite the homogenizing effect of the Humboldt Current, isolation by distance and contrasting environmental conditions at different geographic scales have an important influence on the genetic diversity of zooplankton in the SEPO region.
Topics: Animals; Copepoda; Pacific Ocean; Phylogeny; Genetic Variation; Electron Transport Complex IV; Chile; Biodiversity; Zooplankton
PubMed: 38811606
DOI: 10.1038/s41598-024-62080-5 -
Nature Communications May 2024Stimulator of interferon genes (STING) is a central component of the cytosolic nucleic acids sensing pathway and as such master regulator of the type I interferon...
Stimulator of interferon genes (STING) is a central component of the cytosolic nucleic acids sensing pathway and as such master regulator of the type I interferon response. Due to its critical role in physiology and its' involvement in a variety of diseases, STING has been a focus for drug discovery. Targeted protein degradation (TPD) has emerged as a promising pharmacology for targeting previously considered undruggable proteins by hijacking the cellular ubiquitin proteasome system (UPS) with small molecules. Here, we identify AK59 as a STING degrader leveraging HERC4, a HECT-domain E3 ligase. Additionally, our data reveals that AK59 is effective on the common pathological STING mutations, suggesting a potential clinical application of this mechanism. Thus, these findings introduce HERC4 to the fields of TPD and of compound-induced degradation of STING, suggesting potential therapeutic applications.
Topics: Ubiquitin-Protein Ligases; Humans; Membrane Proteins; Proteolysis; HEK293 Cells; Animals; Mutation; Proteasome Endopeptidase Complex; Ubiquitination
PubMed: 38811577
DOI: 10.1038/s41467-024-48922-w -
Cell Death & Disease May 2024The targeted elimination of radio- or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as...
The targeted elimination of radio- or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as well as therapeutic side effects such as fibrosis. We screened an in-house library of 178 substances derived from marine sponges, endophytic fungi, and higher plants, and determined their senolytic activities towards DNA damage-induced senescent HCT116 colon carcinoma cells. The Pan-PI3K-inhibitor wortmannin and its clinical derivative, PX-866, were identified to act as senolytics. PX-866 potently induced apoptotic cell death in senescent HCT116, MCF-7 mammary carcinoma, and A549 lung carcinoma cells, independently of whether senescence was induced by ionizing radiation or by chemotherapeutics, but not in proliferating cells. Other Pan-PI3K inhibitors, such as the FDA-approved drug BAY80-6946 (Copanlisib, Aliqopa®), also efficiently and specifically eliminated senescent cells. Interestingly, only the simultaneous inhibition of both PI3K class I alpha (with BYL-719 (Alpelisib, Piqray®)) and delta (with CAL-101 (Idelalisib, Zydelig®)) isoforms was sufficient to induce senolysis, whereas single application of these inhibitors had no effect. On the molecular level, inhibition of PI3Ks resulted in an increased proteasomal degradation of the CDK inhibitor p21 in all tumor cell lines analyzed. This led to a timely induction of apoptosis in senescent tumor cells. Taken together, the senolytic properties of PI3K-inhibitors reveal a novel dimension of these promising compounds, which holds particular potential when employed alongside DNA damaging agents in combination tumor therapies.
Topics: Humans; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p21; HCT116 Cells; Proteasome Endopeptidase Complex; Apoptosis; Phosphoinositide-3 Kinase Inhibitors; MCF-7 Cells; Proteolysis; A549 Cells; Wortmannin; Senotherapeutics; Class I Phosphatidylinositol 3-Kinases; DNA Damage; Pyrimidines; Quinazolines
PubMed: 38811535
DOI: 10.1038/s41419-024-06755-x -
Molecular Plant Pathology Jun 2024F-box protein is a subunit of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex, which plays a critical role in regulating different pathways in plant...
F-box protein is a subunit of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex, which plays a critical role in regulating different pathways in plant immunity. In this study, we identified the rice (Oryza sativa) F-box protein OsFBX156, which targets the heat shock protein 70 (OsHSP71.1) to regulate resistance to the rice blast fungus Magnaporthe oryzae. Overexpression of OsFBX156 or knockout of OsHSP71.1 in rice resulted in the elevation of pathogenesis-related (PR) genes and an induction burst of reactive oxygen species (ROS) after flg22 and chitin treatments, thereby enhancing resistance to M. oryzae. Furthermore, OsFBX156 can promote the degradation of OsHSP71.1 through the 26S proteasome pathway. This study sheds lights on a novel mechanism wherein the F-box protein OsFBX156 targets OsHSP71.1 for degradation to promote ROS production and PR gene expression, thereby positively regulating rice innate immunity.
Topics: Oryza; Plant Diseases; Plant Proteins; Ubiquitination; Disease Resistance; F-Box Proteins; Reactive Oxygen Species; Gene Expression Regulation, Plant; Proteasome Endopeptidase Complex; Proteolysis; Plant Immunity; Ascomycota
PubMed: 38808386
DOI: 10.1111/mpp.13459 -
Scientific Reports May 2024Tuberculosis (TB) continues to be a global health crisis, necessitating urgent interventions to address drug resistance and improve treatment efficacy. In this study, we...
Tuberculosis (TB) continues to be a global health crisis, necessitating urgent interventions to address drug resistance and improve treatment efficacy. In this study, we validate lumazine synthase (RibH), a vital enzyme in the riboflavin biosynthetic pathway, as a potential drug target against Mycobacterium tuberculosis (M. tb) using a CRISPRi-based conditional gene knockdown strategy. We employ a high-throughput molecular docking approach to screen ~ 600,000 compounds targeting RibH. Through in vitro screening of 55 shortlisted compounds, we discover 3 compounds that exhibit potent antimycobacterial activity. These compounds also reduce intracellular burden of M. tb during macrophage infection and prevent the resuscitation of the nutrient-starved persister bacteria. Moreover, these three compounds enhance the bactericidal effect of first-line anti-TB drugs, isoniazid and rifampicin. Corroborating with the in silico predicted high docking scores along with favourable ADME and toxicity profiles, all three compounds demonstrate binding affinity towards purified lumazine synthase enzyme in vitro, in addition these compounds exhibit riboflavin displacement in an in vitro assay with purified lumazine synthase indicative of specificity of these compounds to the active site. Further, treatment of M. tb with these compounds indicate reduced production of flavin adenine dinucleotide (FAD), the ultimate end product of the riboflavin biosynthetic pathway suggesting the action of these drugs on riboflavin biosynthesis. These compounds also show acceptable safety profile in mammalian cells, with a high selective index. Hence, our study validates RibH as an important drug target against M. tb and identifies potent antimycobacterial agents.
Topics: Mycobacterium tuberculosis; Antitubercular Agents; Molecular Docking Simulation; Multienzyme Complexes; Drug Discovery; Bacterial Proteins; Humans; Tuberculosis; Microbial Sensitivity Tests; Animals
PubMed: 38806590
DOI: 10.1038/s41598-024-63051-6 -
Nature Communications May 2024Cryptophyte algae are an evolutionarily distinct and ecologically important group of photosynthetic unicellular eukaryotes. Photosystem II (PSII) of cryptophyte algae...
Cryptophyte algae are an evolutionarily distinct and ecologically important group of photosynthetic unicellular eukaryotes. Photosystem II (PSII) of cryptophyte algae associates with alloxanthin chlorophyll a/c-binding proteins (ACPs) to act as the peripheral light-harvesting system, whose supramolecular organization is unknown. Here, we purify the PSII-ACPII supercomplex from a cryptophyte alga Chroomonas placoidea (C. placoidea), and analyze its structure at a resolution of 2.47 Å using cryo-electron microscopy. This structure reveals a dimeric organization of PSII-ACPII containing two PSII core monomers flanked by six symmetrically arranged ACPII subunits. The PSII core is conserved whereas the organization of ACPII subunits exhibits a distinct pattern, different from those observed so far in PSII of other algae and higher plants. Furthermore, we find a Chl a-binding antenna subunit, CCPII-S, which mediates interaction of ACPII with the PSII core. These results provide a structural basis for the assembly of antennas within the supercomplex and possible excitation energy transfer pathways in cryptophyte algal PSII, shedding light on the diversity of supramolecular organization of photosynthetic machinery.
Topics: Photosystem II Protein Complex; Cryptophyta; Cryoelectron Microscopy; Chlorophyll; Chlorophyll Binding Proteins; Protein Multimerization; Chlorophyll A; Models, Molecular; Light-Harvesting Protein Complexes
PubMed: 38806516
DOI: 10.1038/s41467-024-48878-x -
Clinical and Translational Medicine Jun 2024Although numerous studies have indicated that activated pyroptosis can enhance the efficacy of antitumour therapy in several tumours, the precise mechanism of pyroptosis...
BACKGROUND
Although numerous studies have indicated that activated pyroptosis can enhance the efficacy of antitumour therapy in several tumours, the precise mechanism of pyroptosis in colorectal cancer (CRC) remains unclear.
METHODS
Pyroptosis in CRC cells treated with antitumour agents was assessed using various techniques, including Western blotting, lactate dehydrogenase release assay and microscopy analysis. To uncover the epigenetic mechanisms that regulate NLRP3, chromatin changes and NLRP3 promoter histone modifications were assessed using Assay for Transposase-Accessible Chromatin using sequencing and RNA sequencing. Chromatin immunoprecipitation‒quantitative polymerase chain reaction was used to investigate the NLRP3 transcriptional regulatory mechanism. Additionally, xenograft and patient-derived xenograft models were constructed to validate the effects of the drug combinations.
RESULTS
As the core molecule of the inflammasome, NLRP3 expression was silenced in CRC, thereby limiting gasdermin D (GSDMD)-mediated pyroptosis. Supplementation with NLRP3 can rescue pyroptosis induced by antitumour therapy. Overexpression of HDAC2 in CRC silences NLRP3 via epigenetic regulation. Mechanistically, HDAC2 suppressed chromatin accessibility by eliminating H3K27 acetylation. HDAC2 knockout promotes H3K27ac-mediated recruitment of the BRD4-p-P65 complex to enhance NLRP3 transcription. Inhibiting HDAC2 by Santacruzamate A in combination with classic antitumour agents (5-fluorouracil or regorafenib) in CRC xenograft-bearing animals markedly activated pyroptosis and achieved a significant therapeutic effect. Clinically, HDAC2 is inversely correlated with H3K27ac/p-P65/NLRP3 and is a prognostic factor for CRC patients.
CONCLUSION
Collectively, our data revealed a crucial role for HDAC2 in inhibiting NLRP3/GSDMD-mediated pyroptosis in CRC cells and highlighted HDAC2 as a potential therapeutic target for antitumour therapy.
HIGHLIGHTS
Silencing of NLRP3 limits the GSDMD-dependent pyroptosis in colorectal cancer. HDAC2-mediated histone deacetylation leads to epigenetic silencing of NLRP3. HDAC2 suppresses the NLRP3 transcription by inhibiting the formation of H3K27ac/BRD4/p-P65 complex. Targeting HDAC2 activates pyroptosis and enhances therapeutic effect.
Topics: Pyroptosis; Colorectal Neoplasms; Humans; NLR Family, Pyrin Domain-Containing 3 Protein; Histone Deacetylase 2; Mice; Animals; Intracellular Signaling Peptides and Proteins; Antineoplastic Agents; Cell Line, Tumor; Gasdermins; Phosphate-Binding Proteins
PubMed: 38804602
DOI: 10.1002/ctm2.1692