Search Results (2,114)

Colorectal cancer (CRC) is the third most prevalent cancer globally. TASK-1, encoded by the KCNK3 gene, is emerging as a putative target in cancer; it regulates resting membrane potential, cell proliferation, and apoptosis. A series of 27 novel xanthene derivatives, modified at position 9, were synthesized via azide coupling of 2-(9H-xanthen-9-yl)acetohydrazide with selected amines and amino acids, followed by hydrazine-mediated conversion to the corresponding hydrazides. The cytotoxic activity of selected compounds (5a–5g, 6a–6h, 7b, 7f–7h) was evaluated against the HCT-116 cell line in vitro. In addition, molecular docking and molecular dynamics simulations were performed to investigate binding interactions and assess the stability of the protein–ligand complexes. Several compounds (5f, 5g, 6c, 6d, 6f, 6g, 7b, 7f, and 7h) exhibited moderate cytotoxic activity against HCT-116 cells (IC₅₀: 66.97–99.62 µM), compared to cisplatin (IC₅₀: 18.25 µM). Compound 7h demonstrated pronounced antiproliferative effects, evidenced by DAPI staining showing chromatin condensation and apoptotic body formation, along with a marked reduction in cell count and coverage. Molecular docking indicated favorable binding within the TASK-1 potassium channel, and molecular dynamics simulations confirmed the stability of the protein–ligand complex, with consistent interactions, including a key hydrogen bond with Asn240. These findings support 7h as a promising lead candidate. These findings identify xanthene-based derivatives as promising lead compounds for further optimization as TASK-1-targeted therapeutic candidates in colorectal cancer Full article

Soil salinization severely restricts rice growth and global grain production, posing a serious threat to food security. Dongxiang wild rice serves as an important genetic resource for improving salt tolerance in rice. In this study, a backcross inbred line (BIL) population derived from Dongxiang wild rice DY80 and an indica restorer line R974 were used to detect QTLs for salt tolerance at the germination and seedling stages. Four QTLs related to germination-stage salt tolerance and three QTLs for seedling-stage salt tolerance were identified, among which qSTS5 on chromosome 5 showed the largest effect with a LOD score of 8.0 and a phenotypic contribution rate of 14.8%. An F_2:3 population was further constructed to validate qSTS5, which increased its LOD value to 10.4 and phenotypic variation explanation rate to 18.5%, and the locus was finally delimited to a 2.3 Mb interval. Transcriptome analysis identified eight differentially expressed genes (DEGs) within the qSTS5 region under salt stress. Sequence comparison between the parents revealed that three DEGs had no coding-region variations, while the other five showed nucleotide polymorphisms leading to amino acid changes. Among them, Os05g0349800 encodes a LEA protein, a typical stress-responsive gene, and harbors a frameshift mutation in DY80. Combined with its induced expression pattern under salt stress, this gene was considered the most promising candidate for qSTS5. This study not only provides a stable major QTL for rice breeding for salt tolerance but also lays a foundation for dissecting the molecular mechanism of salt tolerance in Dongxiang wild rice. Full article

The heat shock transcription factor (HSF) family is a core regulatory component for plants in response to adversity stress and plays a pivotal role in regulating plant reactions to abiotic stress. Lanzhou lily (Lilium davidii var. unicolor) is an economically and horticulturally important bulbous crop widely cultivated in Northwest China, and its growth and yield are severely threatened by high-temperature stress during the growing season. Although HSF genes have been extensively and thoroughly investigated in other plant species, their functional characterization in lilies remains elusive. In this study, a total of 41 LdHSF genes were identified from the genome of Lilium davidii var. unicolor using bioinformatics approaches. The proteins encoded by these genes exhibited considerable variations in the number of amino acids (aa), as well as distinct isoelectric points (pI) and instability indices. Phylogenetic analysis classified these 41 LdHSF genes into three subfamilies (A, B and C). Promoter analysis revealed that the promoters of most LdHSF genes were rich in light-responsive cis-elements. Meanwhile, the promoters of some genes were highly abundant in hormone-responsive cis-elements, whereas those of other genes were enriched in stress-responsive cis-elements. Gene expression heatmaps and transcriptomic data demonstrated that the expression patterns of LdHSF genes showed significant differences in various tissues and under heat treatment. Based on transcriptomic and RT-qPCR data, we further screened out LdHSF10 and LdHSF40 as the major genes responding to heat stress. Functional experiments verified that these two genes encoded nuclear-localized proteins with transcriptional activity. Collectively, these findings lay a solid foundation for elucidating the molecular mechanisms underlying the regulation of heat tolerance by HSF transcription factors (TFs) in lilies in future research. Full article

Amino acids play a dual role in milk protein synthesis, functioning as both metabolic precursors and signaling molecules. This study aimed to elucidate the molecular mechanism by which glycine regulates α-casein production in bovine mammary epithelial cells (MAC-T). Under serum-free conditions, MAC-T cells were exposed to graded concentrations of glycine (1.105, 2.209, 4.418, 8.836, 17.673, and 35.345 mM) for 24 h. α-Casein levels in cell lysates and culture supernatants were quantified by ELISA. Transcriptional activity of casein-encoding genes (CSN1S1, CSN1S2) and PI3K-AKT-mTOR pathway components was assessed by RT-qPCR. Phosphorylation status of pathway proteins was analyzed by Western blot. The functional involvement of the PI3K-AKT-mTOR pathway was validated using the specific inhibitor LY294002. Glycine stimulated α-casein synthesis and secretion in a concentration-dependent manner, with maximal efficacy at 4.418 mM. At this concentration, glycine upregulated CSN1S1, CSN1S2, and PI3K-AKT-mTOR pathway gene expression, and enhanced phosphorylation of the corresponding proteins. Inhibition of PI3K-AKT-mTOR signaling by LY294002 abolished glycine-induced α-casein synthesis, and this effect was reversed by glycine co-treatment. These findings demonstrate that glycine enhances α-casein synthesis through activation of the PI3K-AKT-mTOR pathway. Full article

This work introduces an approach to evolutionary analysis in which information encoded in amino-acid sequences is converted into a specific type of image, termed a genetic image. Genetic images derived from the amino-acid sequences of cytochrome b and cytochrome c oxidase subunit I are shown to be suitable for identifying evolutionary similarities between organisms. Furthermore, artificial neural networks are demonstrated to recognize these genetic images, enabling identification of species evolution. The results indicate the similarity of the genetic images of organisms belonging to species that emerged earlier during Earth’s evolutionary history to the genetic images of organisms belonging to species that emerged later. This finding indicates that genetic images are inherited and undergo gradual modification during evolutionary processes. The phenomenon of inheritance and modification of genetic images suggests that evolution tends to change the already existing functionalities of organisms, which allows for the ordering of organisms belonging to different species from ancient forms, through species that appeared successively during evolution, to those belonging to species that have developed more recently, up to Homo sapiens. Moreover, unlike analyses based on phylogenetic trees, the method presented in this article does not require computing hypothetical taxonomic units to study evolution. Combined with analyses of the inheritance of genetic images, it can support the interpretations of phylogenetic trees and evolutionary research. Full article

Pathogenesis-related protein 1 (PR1) plays important roles in plant responses to both biotic and abiotic stresses; however, its role in mediating defense against pine wood nematode in Pinus massoniana remains unclear. In this study, a total of 63 PR1 family members were identified in P. massoniana using bioinformatics approaches and were named PmPR1-1 to PmPR1-63 based on their phylogenetic relationships. Phylogenetic analysis showed that these members were distributed among four of the six subfamilies. Most of the encoded proteins were hydrophilic, with lengths ranging from 131 to 406 amino acids. Their promoter regions contained multiple cis-acting elements associated with phytohormone signaling and stress responses, and some members formed gene clusters on chromosomes 2, 5, and 9. qRT-PCR (quantitative reverse transcription polymerase chain reaction) analysis showed that the clustered genes PmPR1-46, PmPR1-55, PmPR1-56, and PmPR1-61 were significantly upregulated in the early stage of pine wood nematode inoculation in both resistant and susceptible P. massoniana plants, with higher expression levels in resistant plants. Transient overexpression of PmPR1-61 increased SOD and PPO activities as well as proline content while decreasing CAT activity. These results suggest that the PmPR1 family may be involved in the defense response of P. massoniana against pine wood nematode. Among them, PmPR1-55, PmPR1-56, and PmPR1-61 represent candidate resistance genes worthy of further investigation and provide valuable gene resources for elucidating resistance mechanisms and supporting molecular breeding in P. massoniana. Full article

Background:Pinellia ternata is a major medicinal herb widely utilized in traditional medicine, but is sensitive to high temperature, which often triggers a severe “sprout tumble” phenomenon. Methods: To elucidate the molecular mechanisms of heat tolerance in P. ternata, we screened two contrasting germplasms: the heat-tolerant JBX1 and the heat-sensitive XBX4. In the present study, a combined analysis of physiology, transcriptome, and metabolome was performed on JBX1 and XBX4 under heat stress at 40 °C. Results: JBX1 exhibited significantly greater leaf thickness, higher basal chlorophyll content, more stable antioxidant enzyme activities, and lower oxidative damage than XBX4 under heat stress. Transcriptomically, JBX1 maintained elevated basal expression of genes encoding key enzymes in carbon fixation, amino acid metabolism, and phenylpropanoid biosynthesis, as well as those encoding heat shock transcription factors (HSFs), heat shock proteins (HSPs), and the thermosensor Thermo-With ABA-Response 1 (TWA1). Metabolomically, JBX1 accumulated higher levels of key primary metabolites, antioxidants, and protective phenylpropanoids under both control and heat conditions. Notably, a “polarity reversal” emerged in nitrogen metabolism, where core amino acids accumulated in JBX1 but were depleted in XBX4. Integrated analysis revealed a more coordinated gene–metabolite network in JBX1 involving the phenylpropanoid, ATP-binding cassette (ABC) transporter, and glutathione pathways. Conclusions: Our findings demonstrate that JBX1 possessed stronger basal thermotolerance, which is derived from coordinated establishment of higher constitutive metabolic reserves and efficient dynamic metabolic reprogramming. This study provides insights into the molecular mechanisms of heat stress in P. ternata. Full article

TEA domain transcription factors are critical regulators of tissue development and regeneration in mammals, yet their roles in aquatic invertebrate regeneration remain poorly understood. Here, a full-length cDNA encoding a putative transcriptional enhanced associate domain protein 1 (TEAD1) ortholog in Apostichopus japonicus (AjTEAD1) was cloned and characterized. The open reading frame (ORF) of AjTEAD1 is 1344 bp, encoding a polypeptide of 447 amino acids with a conserved TEA domain (Asp⁴⁰–Leu¹¹¹) and a protein-binding domain (Gly²³¹–Asp⁴⁴⁶). Function analysis demonstrates that AjTEAD1 is essential for intestinal regeneration. AjTEAD1 expression was significantly upregulated during the regeneration process. Functional impairment of AjTEAD1 suppressed intestinal regeneration and attenuated cell proliferation. At the molecular level, we identified the cell cycle gene in A. japonicus (AjCyclin E), whose expression pattern coincided with that of AjTEAD1 and was downregulated following AjTEAD1 knockdown. Dual-luciferase reporter assays further confirmed that AjTEAD1 binds to specific sites in the AjCyclin E promoter and transcriptionally activates its expression. In summary, our study reveals that AjTEAD1 promotes cell proliferation and drives intestinal regeneration in A. japonicus by directly upregulating AjCyclin E transcription. These findings identify the TEAD–Cyclin E axis as a key regulator of echinoderm regeneration, shedding new light on the regenerative processes and cytological mechanisms in economically important species. Full article

One of the most puzzling and unsolved challenges in molecular biology is understanding how proteins fold. Despite having advanced predictive tools that can accurately estimate the native structures of proteins, we still lack a comprehensive model that explains how amino acid sequences dictate folding pathways and trajectories. This manuscript introduces a novel treatment for the issue by employing the “principle of least action.” This approach enables us to explore an intriguing question: how does a protein achieve its native state at a constant folding rate and within a biologically plausible time frame? A response to this inquiry will help us understand why proteins must fold along specific pathways and identify the boundary conditions that limit their availability. Furthermore, the principle of least action—together with the effective trajectory conjecture—enables us to explain why different proteins could exhibit the same folding rate. Finally, it will enable us to provide an in-depth description of the genesis and solution of Levinthal’s paradox. Our results are expected to pave the way for a more profound understanding of how proteins fold, shedding light on how the amino acid sequence and its surrounding environment encode the protein’s folding pathways and, consequently, the protein’s three-dimensional structure. Full article

Jasmonate ZIM-domain (JAZ) proteins, as core negative regulatory factors of the jasmonic acid (JA) signaling pathway, play a key role in the growth and development of plants and the response to biotic and abiotic stress. In this study, 11 flax JAZ members were identified, all of which contain a ZIM domain and a Jas domain. LuJAZs comprise 3–16 exons, encoding 187–808 amino acids (aa) with molecular weights ranging from 20.24 to 88.76 kDa and isoelectric points (PI) of 5.68–9.77. They are all hydrophilic proteins located in the nucleus. These 11 LuJAZ genes are divided into five subfamilies and are unevenly distributed on chromosomes. Transcriptome and qRT-PCR analyses revealed that six LuJAZ genes, including LUSG00004384, LUSG00030782, LUSG00016742, LUSG00004390, LUSG00010997, and LUSG00029783, are significantly induced by JA. The protein–protein interaction (PPI) prediction and analysis of differential expression genes (DEGs) suggest that the MYC2 gene (LUSG00028070) may play a role in the JA-induced response. This study provides a theoretical basis for further exploring the function of the JAZ family in flax. Full article

Selenium (Se) is an essential trace element. The bioactivity of Se arises from its incorporation into the 21st amino acid, selenocysteine (Sec). Twenty-five human genes have been identified that encode selenoproteins, each of which contains at least one Sec residue. Selenoprotein functions include antioxidant responses, thyroid hormone synthesis, and maintenance of cellular redox homeostasis. Due to its role in critical cellular functions, Se deficiency is associated with morbidities of the cardiovascular system and connective tissue in regions of countries with low soil Se content. While these morbidities are geography-specific and have been mitigated in adults through public health interventions, preterm infants remain susceptible to Se deficiency worldwide. Infants born preterm are deprived of fetal Se accrual in the 3rd trimester of pregnancy, a deficiency compounded by higher Se needs than term infants and older infants and dependence on parenteral nutrition (PN) and fortification. In addition, the composition of selenoproteins and selenometabolites in human milk is different from that in formula and PN, yet little is known about the biological impact of these differences. The knowledge gap in optimal Se supplementation is reflected in discrepant guidelines between North American and European/Chinese nutrition societies, whose recommended Se supplementation in preterm infants differs by more than 2-fold. In this review, we describe the biosynthesis, metabolism, and maternal-fetal transfer of Se. In addition, we address how developmentally regulated aspects of metabolism may impact how preterm infants respond to supplementation with different forms of Se. Lastly, we highlight current challenges and recommendations for optimizing Se levels in neonates based on available data. Full article

The homeodomain-leucine zipper (HD-Zip) transcription factor family is conserved in land plants and is critical for regulating growth, development, and stress responses. Flax (Linum usitatissimum L.) is an economically valuable dual-purpose crop valued for its high nutrition and notable drought tolerance; however, its HD-Zip gene family has not been systematically characterized. In this study, a comprehensive genome-wide analysis was performed to identify and characterize the HD-Zip family in flax. A total of 34 LuHD-Zip genes were identified, which were unevenly distributed across 15 chromosomes and exhibited substantial variation in physicochemical properties. The encoded proteins ranged from 200 to 372 amino acids in length, with molecular weights of 22.7–40.3 kDa and theoretical isoelectric points (pI) of 4.49–9.46. All LuHD-Zip proteins were predicted to be hydrophilic and localized to the nucleus. Phylogenetic analysis divided these proteins into two major subfamilies (Group 1 and Group 2), a classification strongly supported by conserved gene structures and motif compositions, implying potential functional redundancy within each group. Gene duplication analysis revealed that segmental duplication events (29 pairs) were the primary drivers of family expansion. Comparative syntenic analysis further indicated that the LuHD-Zip gene family has remained relatively conserved throughout evolution. Promoter cis-element analysis identified multiple regulatory elements associated with hormone signaling and abiotic stress responses, suggesting complex transcriptional control in response to environmental stimuli. Expression profiling via quantitative real-time PCR (qRT-PCR) demonstrated that LuHD-Zip genes exhibit tissue-specific expression patterns and are differentially regulated by various phytohormone treatments and abiotic stresses. This study provides the first genome-wide characterization of the HD-Zip gene family in flax, offering valuable insights into its evolution and potential functions. These findings establish a solid foundation for future functional investigations of the LuHD-Zip gene family. Full article

Sterol Carrier Protein X (SCP-x) is an evolutionarily conserved lipid transport protein that plays important roles in sterol metabolism. In insects, cholesterol is an essential component of cellular membranes and the precursor of ecdysteroids, yet insects cannot synthesize cholesterol de novo and must obtain it from dietary sources. However, the functional role of SCP-x in cholesterol absorption and transport in insects remains poorly understood. In this study, the SCP-x gene from the migratory locust Locusta migratoria was identified and characterized using transcriptomic data from the midgut and fat body. The full-length LmSCP-x encodes a 404-amino-acid protein containing both the 3-oxoacyl-CoA thiolase domain and the sterol carrier protein-2 domain. Expression analysis revealed that LmSCP-x is predominantly expressed in the midgut and fat body, and subcellular localization experiments showed that the protein is mainly distributed in the cytoplasm. RNA interference-mediated knockdown of LmSCP-x significantly reduced cholesterol levels in the fat body and delayed nymphal development. Structural prediction using AlphaFold 3 further revealed a conserved three-dimensional structure of the SCP-2 domain, and molecular docking identified key amino acid residues involved in cholesterol binding, which were subsequently validated by bio-layer interferometry assays. Together, these results demonstrate that LmSCP-x plays a crucial role in cholesterol transport in L. migratoria and provide new insights into sterol metabolism in insects, offering potential targets for the development of novel pest management strategies. Full article

Streptococcus parauberis is a major pathogen responsible for streptococcosis in both marine and freshwater fish species, causing substantial economic losses in aquaculture. The increasing prevalence of multidrug resistance has highlighted the urgent need for alternative disease control strategies. Interference with bacterial quorum sensing (QS) systems represents a promising approach. This study aimed to identify and biochemically characterize an Rgg-family transcriptional regulator and evaluate its potential as a target for quorum sensing-related regulatory interference in vitro. We hypothesized that this Rgg regulator may function as a quorum sensing-associated transcription factor capable of promoter binding and modulation by small molecules. Bioinformatic analyses were used to identify the rgg gene encoding an Rgg-family transcriptional regulator and predict its structural features. The gene was cloned, heterologously expressed, and purified. Promoter binding activity was examined using electrophoretic mobility shift assay (EMSA), and key amino acid residues were identified through site-directed mutagenesis. The inhibitory effect of the cyclic peptide cyclosporin A (CsA) on Rgg-promoter binding was further assessed. The rgg gene (864 bp) encoding a 287-amino-acid protein (34.1 kDa) was successfully identified and expressed. Purified Rgg specifically bound to its own promoter region in a concentration-dependent manner. Mutations at conserved arginine residues R12 and R15 within the helix-turn-helix DNA-binding domain abolished promoter binding activity. Furthermore, CsA disturbed Rgg-promoter binding in a dose-dependent manner. This study provides the first in vitro characterization of an Rgg-family transcriptional regulator in fish-derived S. parauberis. The findings expand current understanding of Rgg-family regulators potentially associated with quorum sensing in aquatic streptococci and provide a preliminary basis for further investigation of quorum sensing-related regulatory interference strategies for controlling streptococcal diseases in aquaculture. Full article

Bovine leukemia virus (BLV) is an oncogenic retrovirus and the etiological agent of enzootic bovine leukosis (EBL), which is spread worldwide. This study presents data on the genetic diversity of BLV in the Novosibirsk region of Russia. ELISA-positive samples were selected from six districts of the Novosibirsk region (Dovolnoye, Barabinsk, Tatarsk, Toguchin, Bolotnoye, and Kochenyovo districts). To assess the diversity of circulating BLV genotypes, samples were collected from settlements and districts that were geographically distant from each other and had no shared pasture lands. In total, 1410 bp fragments encoding the env gene region were obtained from 417 BLV-positive samples. Phylogenetic analysis classified 325 BLV strains (77.9%) as genotype 4 (G4) and 92 strains (22.1%) as genotype 7 (G7). A pairwise identity matrix was constructed for 268 amino acid residues. Pairwise identity of BLV amino acid sequences in the gp51 region ranged from 96.6% to 100% for G4 and from 97.4% to 100% for G7. Multiple alignment of the amino acid sequences identified 74 mutations found in the Russian BLV variants. Through the addition of 417 novel env BLV sequences to GenBank, this study significantly expands the foundational data and knowledge of BLV molecular epidemiology in Russia. Full article