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Aging Jun 2024Chronic atrophic gastritis (CAG) is a chronic inflammatory disease and precancerous lesion in stomach cancer. Abnormal activation cellular ferroptosis further damages...
Chronic atrophic gastritis (CAG) is a chronic inflammatory disease and precancerous lesion in stomach cancer. Abnormal activation cellular ferroptosis further damages gastric tissue, which is susceptible to inflammation. Luteolin has powerful anti-inflammatory and regulatory potential for cellular ferroptosis. We aimed to clarify the involvement of luteolin in inflammation and ferroptosis during CAG. Luteolin targets were searched to identify intersecting genes in the chronic atrophic gastritis disease database. The AGE-RAGE pathway is a potential target of luteolin for the treatment of chronic atrophic gastritis and a binding site between luteolin and RAGE was predicted through a computer simulation of molecular docking. We established a CAG rat model using N-methyl-N-nitro-N-nitroguanidine. The therapeutic effect of luteolin on CAG was detected using western blotting, qPCR, hematoxylin and eosin staining, lipid oxidation (MDA), and Fe assays. Luteolin inhibited the AGE-RAGE signaling pathway and reduced the inflammatory response in gastric tissues. Additionally, luteolin downregulated the concentration of (MDA) and Fe, and CAG downregulated the expression levels of ACSL4 and NOX1 and upregulated the expression levels of FIH1 and GPX4 ferroptosis-related proteins, thus inhibiting the ferroptosis of gastric tissue cells, which had a therapeutic effect on CAG.
PubMed: 38917486
DOI: 10.18632/aging.205969 -
Nucleic Acids Research Jun 2024Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that causes severe outbreaks in human populations. ZIKV infection leads to the accumulation of small...
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that causes severe outbreaks in human populations. ZIKV infection leads to the accumulation of small non-coding viral RNAs (known as sfRNAs) that are crucial for evasion of antiviral responses and for viral pathogenesis. However, the mechanistic understanding of how sfRNAs function remains incomplete. Here, we use recombinant ZIKVs and ribosome profiling of infected human cells to show that sfRNAs block translation of antiviral genes. Mechanistically, we demonstrate that specific RNA structures present in sfRNAs trigger PKR activation, which instead of limiting viral replication, enhances viral particle production. Although ZIKV infection induces mRNA expression of antiviral genes, translation efficiency of type I interferon and interferon stimulated genes were significantly downregulated by PKR activation. Our results reveal a novel viral adaptation mechanism mediated by sfRNAs, where ZIKV increases its fitness by repurposing the antiviral role of PKR into a proviral factor.
PubMed: 38917323
DOI: 10.1093/nar/gkae507 -
Rhode Island Medical Journal (2013) Jul 2024The molecular pathogenesis of exocrine pancreatic cancer involves mutations K-RAS, TP53, CDKN2A, and SMAD4. The KRAS oncogene leads to constitutively active tumor cell... (Review)
Review
The molecular pathogenesis of exocrine pancreatic cancer involves mutations K-RAS, TP53, CDKN2A, and SMAD4. The KRAS oncogene leads to constitutively active tumor cell proliferation and is present in 90% of unresectable or metastatic pancreatic adenocarcinomas. Of these, the G12C variant of K-RAS genes accounts for 1-2% of mutations. A 65-year-old woman initially diagnosed with T3N0M0 pancreatic adenocarcinoma, underwent six cycles of neoadjuvant chemotherapy with mFOLFIRINOX followed by Whipple procedure. Her pathological stage was T4N2. She then received adjuvant mFOLFIRINOX but unfortunately her disease progressed through multiple lines of chemotherapy. Molecular analysis by Next Generation Sequence(NGS) panel revealed KRAS G12C mutation. Based on this mutational status, she was started on Sotorasib to which she had clinical response lasting for about 11 months prior to disease progression. Off-label use of Sotorasib as fourth-line treatment in our patient with KRAS G12C mutated pancreatic cancer was efficacious and relatively well tolerated.
Topics: Humans; Pancreatic Neoplasms; Female; Aged; Adenocarcinoma; Triazoles; Antineoplastic Combined Chemotherapy Protocols; Proto-Oncogene Proteins p21(ras); Pyrimidines; Mutation; Antineoplastic Agents; Irinotecan; Oxaliplatin; Fluorouracil; Leucovorin; Off-Label Use; Piperazines; Pyridines
PubMed: 38917307
DOI: No ID Found -
The Plant Cell Jun 2024Although the strigolactone (SL) signaling pathway and SL-mediated anthocyanin biosynthesis have been reported, the molecular association between SL signaling and...
Although the strigolactone (SL) signaling pathway and SL-mediated anthocyanin biosynthesis have been reported, the molecular association between SL signaling and anthocyanin biosynthesis remains unclear. In this study, we identified the SL signal transduction pathway associated with anthocyanin biosynthesis and the crosstalk between gibberellin (GA) and SL signaling in apple (Malus × domestica). ELONGATED HYPOCOTYL5 (HY5) acts as a key node integrating SL signaling and anthocyanin biosynthesis, and the SL response factor AGAMOUS-LIKE MADS-BOX9 (AGL9) promotes anthocyanin biosynthesis by activating HY5 transcription. The SL signaling repressor SUPPRESSOR OF MAX2 1-LIKE8 (SMXL8) interacts with AGL9 to form a complex that inhibits anthocyanin biosynthesis by downregulating HY5 expression. Moreover, the E3 ubiquitin ligase PROTEOLYSIS1 (PRT1) mediates the ubiquitination-mediated degradation of SMXL8, which is a key part of the SL signal transduction pathway associated with anthocyanin biosynthesis. In addition, the GA signaling repressor REPRESSOR-of-ga1-3-LIKE2a (RGL2a) mediates the crosstalk between GA and SL by disrupting the SMXL8-AGL9 interaction that represses HY5 transcription. Taken together, our study reveals the regulatory mechanism of SL-mediated anthocyanin biosynthesis and uncovers the role of SL-GA crosstalk in regulating anthocyanin biosynthesis in apple.
PubMed: 38917246
DOI: 10.1093/plcell/koae191 -
The Plant Cell Jun 2024Plants generally enhance their root growth in the form of greater biomass and/or root length to boost nutrient uptake in response to short-term low nitrogen (LN)....
Plants generally enhance their root growth in the form of greater biomass and/or root length to boost nutrient uptake in response to short-term low nitrogen (LN). However, the underlying mechanisms of short-term LN-mediated root growth remain largely elusive. Our genome-wide association study, haplotype analysis, and phenotyping of transgenic plants showed that the crucial nitrate signaling component NIN-LIKE PROTEIN3.2 (ZmNLP3.2), a positive regulator of root biomass, is associated with natural variations in root biomass of maize (Zea mays L.) seedlings under LN. The monocot-specific gene AUXIN/INDOLE-3-ACETIC ACID14 (ZmAux/IAA14) exhibited opposite expression patterns to ZmNLP3.2 in ZmNLP3.2 knockout and overexpression lines, suggesting that ZmNLP3.2 hampers ZmAux/IAA14 transcription. Importantly, ZmAux/IAA14 knockout seedlings showed a greater root dry weight (RDW), whereas ZmAux/IAA14 overexpression reduced RDW under LN compared with wild-type plants, indicating that ZmAux/IAA14 negatively regulates the RDW of LN-grown seedlings. Moreover, in vitro and vivo assays indicated that AUXIN RESPONSE FACTOR19 (ZmARF19) binds to and transcriptionally activates ZmAux/IAA14, which was weakened by the ZmNLP3.2-ZmARF19 interaction. The zmnlp3.2 ZmAux/IAA14-OE seedlings exhibited further reduced RDW compared to ZmAux/IAA14 overexpression lines when subjected to LN treatment, corroborating the ZmNLP3.2-ZmAux/IAA14 interaction. Thus, our study reveals a ZmNLP3.2-ZmARF19-ZmAux/IAA14 module regulating root biomass in response to nitrogen limitation in maize.
PubMed: 38917216
DOI: 10.1093/plcell/koae184 -
PloS One 2024Prostate stem cell antigen (PSCA) is associated with disease progression, promotion of angiogenesis, invasion, metastasis and immune evasion in cancer. However, its...
Prostate stem cell antigen (PSCA) is associated with disease progression, promotion of angiogenesis, invasion, metastasis and immune evasion in cancer. However, its expression pattern and diagnostic and prognostic potential have not been thoroughly analysed from a pan-cancer perspective. This study aimed to examine the effects of PSCA on the prognosis and inflammatory cell infiltration patterns of various cancer types. We analysed the relationship between PSCA expression and immunological subtypes in tumor microenvironment (TME) and the role of molecular subtypes, potentially promising immune biomarkers and tumour-infiltrating lymphocytes (TILs) in various cancer types, especially lung adenocarcinoma (LUAD). In addition, we investigated the prognostic significance of PSCA expression in LUAD. The co-expression network of PSCA was found to be mainly involved in the regulation of immune responses and antigen processing and expression and was significantly enriched in pathological and substance metabolism-related pathways in cancer. Altogether, this study reveals that PSCA is a promising target for immunotherapy in patients with cancer.
Topics: Humans; Antigens, Neoplasm; Prognosis; Tumor Microenvironment; Lymphocytes, Tumor-Infiltrating; Neoplasm Proteins; GPI-Linked Proteins; Biomarkers, Tumor; Neoplasms; Adenocarcinoma of Lung; Lung Neoplasms; Gene Expression Regulation, Neoplastic; Male
PubMed: 38917176
DOI: 10.1371/journal.pone.0298469 -
PloS One 2024The aim of the present work is to explore the impact of the COVID-19 pandemic on research activities in a vast multidisciplinary academic community to identify the most...
PURPOSE
The aim of the present work is to explore the impact of the COVID-19 pandemic on research activities in a vast multidisciplinary academic community to identify the most critical issues.
METHOD
To this purpose we planned a survey addressed to the entire academic research staff at "Sapienza" University of Rome, which represents the largest Italian academic community. A questionnaire consisting of both open and closed-ended questions was delivered to 4118 individuals in April 2021.
RESULTS
A total of 544 responses were collected. All academic roles were sufficiently represented in the study cohort. The median number of critical issues experienced by academic research staff was three. Among these, the three most frequently reported were related to: "Access to libraries / laboratories / research sites" (21.9%), "Limitation to stay abroad / study / research periods" (17.6%), "Progress of experimental work" (14.7%), with variable prevalence according to academic position and gender. Older subjects reported issues with "Projects' financial reporting" and "Expiration of acquired consumable material more frequently". The most common critical aspects reported in relation to the economic burden were: being "Unable to allocate funds" (31.4%), a "Reduction in clinical and scientific activity" (26.3%) and experiencing "Increased expenses (comprising private costs)" (21.2%) with no differences between genders. Researchers in Applied Sciences and Natural Sciences reported a higher frequency of problems in clinical and scientific activities, whereas increased expenses were reported also by researchers operating in the Humanities field. As a possible solution aimed at improving these issues, most subjects, especially those aged >45 years, indicated "Economic aid" (22.6%), "Reduction in bureaucracy" (19.9%) or "Enhancement of the scientific and clinical activities", whereas those aged ≤45 years felt that an increased duration and better access to PhD programs were to be prioritized.
CONCLUSION
Our findings highlight the most critical issues related to research activities during the COVID-19 pandemic in a large academic community. The information achieved may be useful to identify researchers' needs and to design appropriate policies aimed at preparing research institutions for unexpected catastrophic events and limiting the negative impact on academic research activities.
Topics: Humans; COVID-19; Male; Female; Surveys and Questionnaires; Middle Aged; Adult; Italy; Pandemics; SARS-CoV-2; Universities; Aged; Biomedical Research; Research Personnel
PubMed: 38917126
DOI: 10.1371/journal.pone.0304078 -
PloS One 2024Increasing the yield of maize F1 hybrid is one of the most important target for breeders. However, as a result of the genetic complexity and extremely low heritability,...
Increasing the yield of maize F1 hybrid is one of the most important target for breeders. However, as a result of the genetic complexity and extremely low heritability, it is very difficult to directly dissect the genetic basis and molecular mechanisms of yield, and reports on genetic analysis of F1 hybrid yield are rare. Taking F1 hybrid as the research object and dividing the yield into different affect factors, this approach may be the best strategy for clarifying the genetic mechanism of yield. Therefore, in this study, a maize F1 population consisting of 300 hybrids with 17,652 single nucleotide polymorphisms (SNPs) markers was used for genome-wide association study (GWAS) to filtrate candidate genes associated with the four yield-related traits, i.e., kernel row number (KRN), kernel number per row (KNPR), ear tip-barrenness (ETB), and hundred kernel weight (HKW). Combined with the results of previous studies and functional annotation information of candidate genes, a total of six candidate genes were identified as being associated with the four traits, which were involved in plant growth and development, protein synthesis response, phytohormone biosynthesis and signal transduction. Our results improve the understanding of the genetic basis of the four yield-related traits and may be provide a new strategy for the genetic basis of maize yield.
Topics: Zea mays; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Phenotype; Quantitative Trait Loci; Genes, Plant
PubMed: 38917065
DOI: 10.1371/journal.pone.0305357 -
Proceedings of the National Academy of... Jul 2024To survive adverse environments, many animals enter a dormant state such as hibernation, dauer, or diapause. Various species undergo adult reproductive diapause in...
To survive adverse environments, many animals enter a dormant state such as hibernation, dauer, or diapause. Various species undergo adult reproductive diapause in response to cool temperatures and/or short day-length. While flies are less active during diapause, it is unclear how adverse environmental conditions affect circadian rhythms and sleep. Here we show that in diapause-inducing cool temperatures, exhibit altered circadian activity profiles, including severely reduced morning activity and an advanced evening activity peak. Consequently, the flies have a single activity peak at a time similar to when nondiapausing flies take a siesta. Temperatures ≤15 °C, rather than photoperiod, primarily drive this behavior. At cool temperatures, flies rapidly enter a deep-sleep state that lacks the sleep cycles of flies at higher temperatures and require high levels of stimulation for arousal. Furthermore, we show that at 25 °C, flies prefer to siesta in the shade, a preference that is virtually eliminated at 10 °C. Resting in the shade is driven by an aversion to blue light that is sensed by Rhodopsin 7 outside of the eyes. Flies at 10 °C show neuronal markers of elevated sleep pressure, including increased expression of Bruchpilot and elevated Ca in the R5 ellipsoid body neurons. Therefore, sleep pressure might overcome blue light aversion. Thus, at the same temperatures that cause reproductive arrest, preserve germline stem cells, and extend lifespan, are prone to deep sleep and exhibit dramatically altered, yet rhythmic, daily activity patterns.
Topics: Animals; Drosophila melanogaster; Sleep; Circadian Rhythm; Rhodopsin; Drosophila Proteins; Photoperiod; Temperature; Light; Diapause, Insect
PubMed: 38917005
DOI: 10.1073/pnas.2400964121 -
Proceedings of the National Academy of... Jul 2024Chronic inflammation is epidemiologically linked to the pathogenesis of gastrointestinal diseases, including inflammatory bowel disease (IBD) and colorectal cancer...
Chronic inflammation is epidemiologically linked to the pathogenesis of gastrointestinal diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, our understanding of the molecular mechanisms controlling gut inflammation remains insufficient, hindering the development of targeted therapies for IBD and CRC. In this study, we uncovered as a negative regulator of gut inflammation, operating through the modulation of epithelial cell metabolism. encodes two molecular products, C15ORF48 protein and miR-147-3p microRNA, which are predominantly expressed in the intestinal epithelium. ablation leads to gut dysbiosis and exacerbates chemically induced colitis in mice. C15ORF48 and miR-147-3p work together to suppress colonocyte metabolism and inflammation by silencing , a subunit of mitochondrial complex IV (CIV). Interestingly, the C15ORF48 protein, a structural paralog of NDUFA4, contains a unique C-terminal α-helical domain crucial for displacing NDUFA4 from CIV and its subsequent degradation. silencing hinders NF-κB signaling activation and consequently attenuates inflammatory responses. Collectively, our findings have established the - molecular axis as an indispensable regulator of gut homeostasis, bridging mitochondrial metabolism and inflammation.
Topics: Animals; MicroRNAs; Mice; Gastrointestinal Microbiome; Energy Metabolism; Humans; Inflammation; Intestinal Mucosa; Colitis; NF-kappa B; Dysbiosis; Signal Transduction; Mice, Inbred C57BL; Inflammatory Bowel Diseases
PubMed: 38917002
DOI: 10.1073/pnas.2315944121