IUBMB Life最新文献

Targeting the influencing factors in tumor growth and expansion in the tumor microenvironment is one of the key approaches to cancer immunotherapy. Various factors in the tumor microenvironment can in cooperation stimulate tumor growth, suppress anti-tumor immune responses, promote drug resistance, and ultimately enhance tumor recurrence. Therefore, due to the dependence and close cooperation of these axes, their combined targeting can have a greater effect compared to their individual targeting. Among the important factors affecting tumor growth in the tumor region, CD73 and EGFR play an important role in tumor growth by stimulating each other's expression and function. Therefore, we intended to use the nanocarriers that we had previously produced and characterized to deliver anti-CD73 and EGFR siRNAs to murine breast cancer 4T1 cells. Silencing CD73 and EGFR could significantly induce cell death in cancer cells. Downregulation of the CD73/EGFR axis also suppressed the migratory and proliferative potential of cancer cells. This therapeutic strategy also inhibited tumor growth in in ovo model. These findings imply that simultaneous targeting of CD73 and EGFR in breast cancer can be considered a novel immunotherapeutic approach that needs further investigation in future studies.

Keratinocytes exosome participates in the pathogenesis of psoriasis and exosomes always carry long non-coding RNAs (lncRNAs) into target cells to function as an essential immune regulator in psoriasis-related diseases. LncRNA LOC285194 is closely associated with the occurrence of psoriasis. However, whether keratinocyte exosomal LOC285194 participates in the process of psoriasis remains vague. Exosomes were authenticated by transmission electron microscope and nanoparticle tracking analysis (NTA). Relative gene expression was determined by reverse transcription-polymerase chain reaction (RT-PCR). Flow cytometry was used to monitor the proportion of immune cells. Fluorescence in situ hybridization was employed to determine the colocalization of lncRNA and miRNA. Keratinocyte exosomal LOC285194 was reduced in psoriasis patients and had a negative association with Th17 cell infiltration in psoriasis patients. LOC285194-downregulation contributed to the differentiation of CD4⁺T cells to Th17 cells. Cytokine cocktail treatment reduced LOC285194 expression in keratinocytes and keratinocyte exosome, subsequently promoted the differentiation of CD4⁺T cells to Th17 cells and Th17 cells-related molecular levels including IL-17A, IL-22 and TNF-α, which were notably abrogated by LOC285194-upregulation in keratinocytes. As a sponge of LOC285194, miR-211-5p inhibition induced the increase of Th17 cell proportion in CD4⁺T cells, while exosomes treatment isolated from cytokine cocktail-exposed keratinocytes further enhanced Th17 cell proportion, which were abolished by LOC285194 overexpressed-exosome treatment. Furthermore, silent information regulator 1 (SIRT1) mediated the regulation role of miR-211-5p on Th17 cell production. Combined with the imiquimod-induced psoriasis animal model, exosomes isolated from LOC285194-overexpressing keratinocytes relieved psoriasis symptom through regulating miR-211-5p/SIRT1 axis. LOC285194 upregulation in keratinocytes promoted the keratinocyte exosomal LOC285194, that could be absorbed by CD4⁺T cells, leading to the inhibition of Th17 cell differentiation through targeting miR-211-5p/SIRT1 axis. This study provides a novel molecular mechanism of Th17 cell accumulation-mediated psoriasis.

Parkinson's disease (PD), characterized by progressive degeneration of dopaminergic neurons in substantia nigra, has no disease-modifying therapy. Mesenchymal stem cell (MSC) therapy has shown great promise as a disease-modifying solution for PD. Induced pluripotent stem cell-derived MSC (iMSC) not only has stronger neural repair function, but also helps solve the problem of MSC heterogeneity. So we evaluated the therapeutic effects of iMSCs on PD. iMSCs were administered by tail vein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD models of C57BL/6 mice. The results showed iMSCs increased body weights, inhibited the prolongation of latencies to descend in pole tests, the decrease of grip strength in grip strength tests and increase of open arm entries in elevated plus maze test, and showed a trend to alleviate striatal dopamine loss. They indicate iMSCs might improve functions partially by preserving striatal dopamine in PD. We for the first time (1) found that iMSC has therapeutic effects on PD; (2) tested specifically muscle strength in cell therapy for PD and found it increases muscle strength; (3) found cell therapy alleviated the increase of entries into the open arms in PD. It suggests iMSC is a promising candidate for clinical investigations and drug development for PD.

Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended to treat moderate-to-severe pain. Previous studies suggest that NSAIDs can suppress cellular proliferation and elevate apoptosis in different cancer cells. Ketorolac is an NSAID and can reduce the cancer cells' viability. However, molecular mechanisms by which Ketorolac can induce apoptosis and be helpful as an anti-tumor agent against carcinogenesis are unclear. Here, we observed treatment with Ketorolac disturbs proteasome functions, which induces aggregation of aberrant ubiquitinated proteins. Ketorolac exposure also induced the aggregation of expanded polyglutamine proteins, results cellular proteostasis disturbance. We found that the treatment of Ketorolac aggravates the accumulation of various cell cycle-linked proteins, which results in pro-apoptotic induction in cells. Ketorolac-mediated proteasome disturbance leads to mitochondrial abnormalities. Finally, we have observed that Ketorolac treatment depolarized mitochondrial membrane potential, released cytochrome c into cytoplasm, and induced apoptosis in cells, which could be due to proteasome functional depletion. Perhaps more in-depth research is required to understand the details of NSAID-based anti-proliferative molecular mechanisms that can elevate apoptosis in cancer cells and generate anti-tumor potential with the combination of putative cancer drugs.

Antimicrobial resistance (AMR) has been declared one of the top 10 global public health challenges of our age by the World Health Organization, and the World Bank describes AMR as a crisis affecting the finance, health, and agriculture sectors and a major threat to the attainment of Sustainable Development Goals. But what is AMR? It is a phenotype that evolves in microbes exposed to antimicrobial molecules and causes dangerous infections. This suggests that scientists and healthcare workers should be on the frontline in the search for sustainable solutions to AMR. Yet AMR is also a societal problem to be understood by everyone. This review aims to explore the need to address the problem of AMR through a coherent, international strategy with buy-in from all sectors of society. As reviewed here, the sustainable solutions to AMR will be driven by better understanding of AMR biology but will require more than this alone to succeed. Some advances on the horizon, such as the use of bacteriophage (phage) to treat AMR infections. However, many of the new technologies and new therapeutics to address AMR require access to biodiversity, where the custodians of that biodiversity—and the traditional knowledge required to access it—are needed as key partners in the scientific, clinical, biotechnological, and international ventures that would treat the problem of AMR and ultimately prevent its further evolution. Many of these advances will be built on microbial assessments to understand the extent of AMR in our environments and bioprospecting to identify microbes that may have beneficial uses. Genuine partnerships for access to this biodiversity and sharing of benefits accrued require a consideration of ethical practice and behavior. Behavior change is needed across all sectors of culturally diverse societies so that rapid deployment of solutions can be implemented for maximum effect against the impacts of AMR.

Lichens are mutualistic associations consisting of a primary fungal host, and one to few primary phototrophic symbiont(s), usually a green alga and/or a cyanobacterium. They form complex thallus structures, which provide unique and stable habitats for many other microorganisms. Frequently isolated from lichens are the so-called black fungi, or black yeasts, which are mainly characterized by melanized cell walls and extremophilic lifestyles. It is presently unclear in which ways these fungi interact with other members of the lichen symbiosis. Genomic resources of lichen-associated black fungi are needed to better understand the physiological potential of these fungi and shed light on the complexity of the lichen consortium. Here, we present high-quality genomes of 14 black fungal lineages, isolated from lichens of the rock-dwelling genus Umbilicaria. Nine of the lineages belong to the Eurotiomycetes (Chaetothyriales), four to the Dothideomycetes, and one to the Arthoniomycetes, representing the first genome of a black fungus in this class. The PacBio-based assemblies are highly contiguous (5–42 contigs per genome, mean coverage of 79–502, N50 of 1.0–7.3 mega-base-pair (Mb), Benchmarking Universal Single-Copy Orthologs (BUSCO) completeness generally ≥95.4%). Most contigs are flanked by a telomere sequence, suggesting we achieved near chromosome-level assemblies. Genome sizes range between 26 and 44 Mb. Transcriptome-based annotations yielded ~11,000–18,000 genes per genome. We analyzed genome content with respect to repetitive elements, biosynthetic genes, and effector genes. Each genome contained a polyketide synthase gene related to the dihydroxynaphthalene-melanin pathway. This research provides insights into genome content and metabolic potential of these relatively unknown, but frequently encountered lichen associates.

All life depends on accurate and efficient protein synthesis. The aminoacyl-tRNA synthetases (aaRSs) are a family of proteins that play an essential role in protein translation, as they catalyze the esterification reaction that charges a transfer RNA (tRNA) with its cognate amino acid. However, new domains added to the aaRSs over the course of evolution in eukaryotes confer novel functions unrelated to protein translation. To date, damaging variants that affect aaRS-encoding genes have been linked to over 50 human diseases. In this study, we leverage the evolutionary history of the aaRS proteins to better understand the distribution of disease-causing missense variants in human cytosolic aaRSs. We hypothesized that disease-causing missense variants in human aaRSs were more likely to be located in the ancient domains of the aaRS, essential for the aminoacylation reaction, rather than in the evolutionarily more recent domains found in eukaryotes. We determined the locations of the modern and ancient domains in each aaRS protein found in humans. We then statistically assessed the positional conservation across each domain and examined the distribution of pathogenic and benign/unknown missense human genetic variants across these domains. We establish that pathogenic missense variants in the human aaRS proteins are enriched in the evolutionarily ancient domains while benign/unknown missense variants are enriched in the modern domains. In addition to defining the evolutionary history of human aaRS proteins through domain identification, we anticipate that this work will improve the ability to diagnose patients affected by damaging genetic variants in the aaRS protein family.

Gefitinib resistance (GR) presents a significant challenge in treating lung adenocarcinoma (LUAD), highlighting the need for alternative therapies. This study explores the genetic basis of GR to improve prediction, prevention, and treatment strategies. We utilized public databases to obtain GR gene sets, single-cell data, and transcriptome data, applying univariate and multivariate regression analyses alongside machine learning to identify key genes and develop a predictive signature. The signature's performance was evaluated using survival analysis and time-dependent ROC curves on internal and external datasets. Enrichment and tumor immune microenvironment analyses were conducted to understand the mechanistic roles of the signature genes in GR. Our analysis identified a robust 22-gene signature with strong predictive performance across validation datasets. This signature was significantly associated with chromosomal processes, DNA replication, immune cell infiltration, and various immune scores based on enrichment and tumor microenvironment analyses. Importantly, the signature also showed potential in predicting the efficacy of immunotherapy in LUAD patients. Moreover, we identified alternative agents to gefitinib that could offer improved therapeutic outcomes for high-risk and low-risk patient groups, thereby guiding treatment strategies for gefitinib-resistant patients. In conclusion, the 22-gene signature not only predicts prognosis and immunotherapy efficacy in gefitinib-resistant LUAD patients but also provides novel insights into non-immunotherapy treatment options.

Initiation factors play critical roles in fine-tuning translation initiation, which is the first and the rate-limiting step in protein synthesis. In bacteria, initiation factors, IF1, IF2 and IF3 work in concert to accurately position the initiator tRNA (i-tRNA) in its formyl-aminoacyl form, and the mRNA start codon at the ribosomal P-site, setting the stage for accommodation of the aminoacyl-tRNA in response to the second codon, and formation of the first peptide bond. Among these, IF3 is particularly crucial in ensuring the fidelity of translation initiation as it is involved in the accuracy of the selection of i-tRNA and the start codon. The two-domains (N- and C-terminal) dumbbell shaped structure and dynamics of IF3 significantly influence its fidelity function. This review explores how the N- and C-terminal domains of IF3 communicate with each other and how their interaction with i-tRNA helps to maintain the fidelity of translation initiation.

Neuroblastoma (NB), a rare childhood cancer originating in nerve tissue. YTHDF3, a member of the YTH domain protein family, is involved in RNA m6A modification and cancer progression. Polymorphisms in YTHDF3 may influence its expression and biological function. Herein, this study estimated the association between YTHDF3 polymorphisms (rs2241753, rs2241754, and rs7464) and NB susceptibility in a multicenter study comprising 898 cases and 1734 controls. We genotyped YTHDF3 candidate polymorphisms by the TaqMan assay. Logistic regression analysis was applied to indicate the possible relationships between these polymorphisms and NB susceptibility, using odds ratios (ORs) and 95% confidence intervals (CIs). Logistic regression analysis revealed that the rs2241753 GA versus GG decreased NB risk (Adjusted OR = 0.84, 95% CI = 0.71–0.997, p = .047), while the rs7464 GG versus AA enhanced NB risk (Adjusted OR = 1.62, 95% CI = 1.20–2.18, p = .002). Additionally, rs7464 GG versus AA/AG showed a higher risk (Adjusted OR = 1.66, 95% CI = 1.24–2.22, p = .0006). Combination analysis showed that having 1–3 risk genotypes versus 0 was associated with increased NB risk (Adjusted OR = 1.28, 95%CI = 1.09–1.51, p = .003). The significance of rs7464 and the risk genotypes combination persisted across multiple subgroups, whereas rs2241754 was significant only in mediastinal NB. False-positive report probability (FPRP) confirmed the reliability of results. Notably, the interaction between rs7464 and rs2241754 may increase NB risk dramatically. Our study demonstrated that YTHDF3 rs7464 A > G significantly affected NB susceptibility, warranting validation in larger sample sizes.