Search Results (107)

Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a proto-oncogene that serves as a nuclear and cytoplasmic scaffolding protein. PELP1 plays a critical role in nuclear receptor signaling, ribosome biogenesis, chromatin modifications, cell cycle progression, non-genomic signaling, and DNA damage response. PELP1 expression is upregulated in a variety of cancers, including breast, ovarian, endometrial, prostate, and liver cancers and serves as a prognostic factor for poor survival. PELP1’s structural motifs, unique scaffolding function, and oncogenic activity make it a potential target for a range of therapeutic approaches. This review summarizes the most recent advancements in PELP1 biology, with a particular focus on the emergent oncogenic functions of PELP1 and its inhibitors for the treatment of cancer. Full article

As a globally popular crop, strawberry is highly susceptible to cold stress, which significantly limits its cultivation and yield. This review synthesizes current knowledge on the morphological, physiological, and molecular responses of strawberry plants to cold stress. Morphologically, cold stress induces chlorosis, necrosis, and growth retardation, while physiologically, it impairs photosynthesis and membrane integrity and triggers oxidative stress. At the molecular level, the cold acclimation process in plants is orchestrated by a sophisticated regulatory network centered on the ICE-CBF/DREB signaling pathway and incorporating transcription factors, epigenetic modifications, and non-coding RNAs. The accumulation of protective compounds like proline, anthocyanins, and antioxidants is a key metabolic adaptation. Finally, we discuss integrative management practices and future breeding strategies, including genetic engineering, marker-assisted selection, and the use of plant growth-promoting rhizobacteria to enhance cold tolerance. This comprehensive overview provides valuable insights for developing resilient strawberry varieties in the face of unpredictable climate events. Full article

Traditional anticoagulants used in atrial fibrillation (AF) are being increasingly replaced by novel oral anticoagulants such as rivaroxaban, improving patient outcomes. Although rivaroxaban 20 mg/1× daily is approved to reduce stroke and systemic embolism risk in AF, some patients still develop thrombus in the left atrial appendage (LAA). A previous study demonstrated thrombus lysis with a modified regimen of rivaroxaban 15 mg/2× daily, yet over 50% of patients remained unresponsive despite therapeutic plasma levels. This study compared metabolic profiles of responders and non-responders to identify predictive markers of treatment efficacy. From the RIVA-TWICE study cohort (n = 249), 15 AF patients with LAA thrombus despite standard dosing were switched to 2 × 15 mg rivaroxaban. Plasma samples collected prior to dose modification underwent untargeted and targeted LC-MS analysis, focusing on acylcarnitines (ACs), carnitine, and its precursors. Thrombus resolution occurred in 7 (46.7%) patients, who showed differential abundance of metabolites related to alpha-linolenic acid and fatty acid metabolism, carnitine synthesis, and arginine/proline pathways. Targeted analysis confirmed elevated levels of ACs, carnitine, and precursors. Findings suggest that a patient phenotype, including carnitine, its precursors, and ACs, may predict rivaroxaban efficacy in thrombus lysis. While these metabolites may not directly mediate lysis, their elevated levels represent potential biomarkers of treatment response. Full article

The novel hybrid fish BTB, derived from crossing blunt snout bream (Megalobrama amblycephala, BSB) and topmouth culter (Culter alburnus, TC), exhibits markedly hypoxia tolerance in aquaculture. In this study, hypoxic treatment experiments confirmed that, comparing to its original parent BSB, the tolerance to low oxygen of BTB increased by 20.0%. Furthermore, a comparative analysis of the transcriptome and metabolome was performed using gill tissues from BTB exposed to normoxic and hypoxic conditions. Under hypoxic conditions, BTB displayed adaptive modifications in gill lamellae and hemocytes. Transcriptomic profiling identified 789 differentially expressed genes (DEGs), with 298 upregulated and 491 downregulated, enriched in pathways including apoptosis, NK cell-mediated cytotoxicity, MAPK/TNF/Toll-like receptor signaling, and HIF-1/FoXO signaling pathways. Twelve hypoxia-related candidate genes (egln3, im_7150988, znf395a, hif-1an, mknk2b, pck2, ero1a, igfbp-1a, vhl, bpifcl, egln1a, and ccna1) were screened and validated as potential contributors to hypoxia tolerance. Metabolomics analysis revealed a total of 108 differential metabolites (78 upregulated and 30 downregulated), predominantly linked to Arginine and proline metabolism, Ether lipid metabolism, Arachidonic acid metabolism, and Glycerophospholipid metabolism. Association analysis of transcriptomics and metabolomics revealed that the DEGs and DMs were enriched in the pathways of glycerophospholipid metabolism, ether lipid metabolism, arachidonic acid metabolism, and arginine and proline metabolism. In summary, BTB exhibited relatively high hypoxia tolerance, and 12 candidate genes related to hypoxia tolerance were identified. These findings laid a foundation for further investigation into the mechanisms of hypoxia tolerance improvement in hybrid fish. Full article

Seed priming has become a promising technique in agriculture and crop-stress management. Several authors have shown that the positive effects of seed priming are associated with various metabolic, physiological, and biochemical modifications (enzyme activation, membrane repair, initiation of DNA/RNA, and protein synthesis) that enhance the speed, uniformity, and vigor of germination. However, the mechanisms underlying seed priming are not yet well understood. The aim of our work was to study the quantitative and qualitative metabolic changes in the embryonic axes (radicle and plumule) and cotyledons of Vigna unguiculata (L.) Walp. Seeds were subjected to osmopriming with polyethylene glycol (PEG), simple hydropriming, and double hydropriming (a novel treatment). Results indicated that all types of priming, particularly double hydropriming, strongly stimulated the hydrolysis of protein and carbohydrate reserves. This resulted in a decrease in soluble proteins and starch contents and an increase in amino acids and soluble sugars contents. Moreover, the priming promoted the biosynthesis of osmolytes such as proline and induced qualitative changes in the composition of amino acids and soluble sugars. These biochemical changes depend on the organ and treatment method applied to the seeds. It is worth noting that double hydropriming induces metabolic modifications to a greater extent than single hydropriming. Full article

A reassessment of the risk-benefit balance of the two lipid nanoparticle (LNP)-based vaccines, Pfizer’s Comirnaty and Moderna’s Spikevax, is currently underway. While the FDA has approved updated products, their administration is recommended only for individuals aged 65 years or older and for those aged 6 months or older who have at least one underlying medical condition associated with an increased risk of severe COVID-19. Among other factors, this change in guidelines reflect an expanded spectrum and increased incidence of adverse events (AEs) and complications relative to other vaccines. Although severe AEs are relatively rare (occurring in <0.5%) in vaccinated individuals, the sheer scale of global vaccination has resulted in millions of vaccine injuries, rendering post-vaccination syndrome (PVS) both clinically significant and scientifically intriguing. Nevertheless, the cellular and molecular mechanisms of these AEs are poorly understood. To better understand the phenomenon and to identify research needs, this review aims to highlight some theoretically plausible connections between the manifestations of PVS and some unique structural properties of mRNA-LNPs. The latter include (i) ribosomal synthesis of the antigenic spike protein (SP) without natural control over mRNA translation, diversifying antigen processing and presentation; (ii) stabilization of the mRNA by multiple chemical modification, abnormally increasing translation efficiency and frameshift mutation risk; (iii) encoding for SP, a protein with multiple toxic effects; (iv) promotion of innate immune activation and mRNA transfection in off-target tissues by the LNP, leading to systemic inflammation with autoimmune phenomena; (v) short post-reconstitution stability of vaccine nanoparticles contributing to whole-body distribution and mRNA transfection; (vi) immune reactivity and immunogenicity of PEG on the LNP surface increasing the risk of complement activation with LNP disintegration and anaphylaxis; (vii) GC enrichment and double proline modifications stabilize SP mRNA and prefusion SP, respectively; and (viii) contaminations with plasmid DNA and other organic and inorganic elements entailing toxicity with cancer risk. The collateral immune anomalies considered are innate immune activation, T-cell- and antibody-mediated cytotoxicities, dissemination of pseudo virus-like hybrid exosomes, somatic hypermutation, insertion mutagenesis, frameshift mutation, and reverse transcription. Lessons from mRNA-LNP vaccine-associated AEs may guide strategies for the prediction, prevention, and treatment of AEs, while informing the design of safer next-generation mRNA vaccines and therapeutics. Full article

The document is an updated review, starting from the Special Issue “Molecular Breeding for Abiotic Stress Tolerance in Crops” published in the Int. J. Mol. Sci. It reviews molecular breeding strategies to enhance abiotic stress tolerance in crops, addressing challenges like drought, salinity, temperature extremes, and waterlogging, which threaten global food security. Climate change intensifies these stresses, making it critical to develop resilient crop varieties. Plants adapt to stress through mechanisms such as hormonal regulation (e.g., ABA, ethylene), antioxidant defense (e.g., SOD, CAT), osmotic adjustment (e.g., proline accumulation), and gene expression regulation via transcription factors like MYB and WRKY. Advanced tools, such as CRISPR/Cas9 genome editing, enable precise modifications of stress-related genes, improving tolerance without compromising yield. Examples include rice (OsRR22, OsDST) and wheat (TaERF3, TaHKT1;5). Epigenetic regulation, including DNA methylation and histone modifications, also plays a role in stress adaptation. Specific studies focused on polyamine seed priming for improved germination and stress resistance, cadmium detoxification mechanisms, and genome-wide association studies (GWAS) to identify genetic markers for salt tolerance and yield. Research on salinity tolerance in wheat emphasizes sodium exclusion and tissue tolerance mechanisms. Future perspectives focus on genetic engineering, molecular markers, epigenetic studies, and functional validation to address environmental stress challenges, including the use of AI and machine learning to manage the large amount of data. The review underscores the importance of translating molecular findings into practical applications to ensure sustainable crop production under changing climates. Full article

Nitric esters are among the compounds that can liberate nitrogen monoxide (NO) in the organism. Due to the vasodilatation caused by nitrogen monoxide, NO-donors have been shown to protect endothelial function, acting as vasodilators, promoting efficient oxygen supply to tissues, to lower blood pressure, and to inhibit platelet aggregation. Incorporation of a NO-liberating moiety in the structure of non-steroidal anti-inflammatory drugs results in anti-inflammatory agents that are safer for the gastrointestinal system. In this research, ibuprofen and naproxen, two commonly applied non-steroidal anti-inflammatory drugs (NSAID), non-selective inhibitors of cyclooxygenases, were used to design novel anti-inflammatory agents able to release NO in the organism. Thus, the NSAIDs were amidated with beta-alanine and L-proline, which were able to incorporate the 2-nitro-oxyethyl moiety as the NO donor. The resulting compounds were anti-inflammatory agents, found to be more potent than the mother drugs, demonstrating remarkable inhibition of cyclooxygenase-2 over cyclooxygenase-1 and the ability to release NO in vitro. Furthermore, two of the most active anti-inflammatory compounds proved to be effective hypolipidemic agents, decreasing plasma total cholesterol, triglycerides, and LDL-cholesterol in hyperlipidemic rats significantly. The most effective compound in all the above tests was the ibuprofen derivative 5, which inhibited COX-2 by 95%, decreased inflammation by 73%, and reduced all lipidemic indices by more than 50%. Furthermore, docking experiments of compound 5 on the active sites of COX-1 and COX-2 showed that it interacts intensely with the binding site of COX-2, and the binding energy is equivalent to that of the relevant to celecoxib selective COX-2 inhibitor 4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide (SC-5580). In conclusion, the performed structural modifications resulted not only in the improvement of the anti-inflammatory activity, compared with the parent NSAID, but also acquired strong hypolipidemic activity. Thus, the combination of structural characteristics resulting in a decrease in lipidemia, with possible inhibition of atherosclerosis, due to their anti-inflammatory activity and vasodilatation ability, via the liberated NO, may constitute a useful rationale for new compounds. Full article

Many vertebrates have evolved resistance to snake venom as a result of coevolutionary chemical arms races. In Australian skinks (family Scincidae), who often encounter venomous elapid snakes, the frequency, diversity, and molecular basis of venom resistance have been unexplored. This study investigated the evolution of neurotoxin resistance in Australian skinks, focusing on mutations in the muscle nicotinic acetylcholine receptor (nAChR) α1 subunit’s orthosteric site that prevent pathophysiological binding by α-neurotoxins. We sampled a broad taxonomic range of Australian skinks and sequenced the nAChR α1 subunit gene. Key resistance-conferring mutations at the toxin-binding site (N-glycosylation motifs, proline substitutions, arginine insertions, changes in the electrochemical state of the receptor, and novel cysteines) were identified and mapped onto the skink organismal phylogeny. Comparisons with other venom-resistant taxa (amphibians, mammals, and reptiles) were performed, and structural modelling and binding assays were used to evaluate the impact of these mutations. Multiple independent origins of α-neurotoxin resistance were found across diverse skink lineages. Thirteen lineages evolved at least one resistance motif and twelve additional motifs evolved within these lineages, for a total of twenty-five times of α-neurotoxic venoms resistance. These changes sterically or electrostatically inhibit neurotoxin binding. Convergent mutations at the orthosteric site include the introduction of N-linked glycosylation sites previously known from animals as diverse as cobras and mongooses. However, an arginine (R) substitution at position 187 was also shown to have evolved on multiple occasions in Australian skinks, a modification previously shown to be responsible for the Honey Badger’s iconic resistance to cobra venom. Functional testing confirmed this mode of resistance in skinks. Our findings reveal that venom resistance has evolved extensively and convergently in Australian skinks through repeated molecular adaptations of the nAChR in response to the enormous selection pressure exerted by elapid snakes subsequent to their arrival and continent-wide dispersal in Australia. These toxicological findings highlight a remarkable example of convergent evolution across vertebrates and provide insight into the adaptive significance of toxin resistance in snake–lizard ecological interactions. Full article

The stability of collagen, the most abundant protein in humans and many animals, is related to the hydroxylation of L-proline, a post-translational modification occurring at carbon 3 and 4 on its pyrrolidine ring. Collagens of different origins have shown different proline hydroxylation levels, making hydroxyprolines useful biomarkers in structure characterizations. The presence of two chiral carbon atoms, 3-hydroxyproline and 4-hydroxyproline, results in eight stereoisomers (four pairs of enantiomers) whose quantitation in collagen hydrolysates requires enantioselective analytical methods. Capillary electrophoresis was applied for the separation and quantitation of the eight stereoisomers of 3- and 4-hydroxyproline and D,L-proline in collagen hydrolysates. The developed method is based on the derivatization with the chiral reagent (R)-(-)-4-(3-Isothiocyanatopyrrolidin-yl)-7-nitro-2,1,3-benzoxadiazole, enabling the use of a light-emitting diode-induced fluorescence detector for high sensitivity. The separation of the considered compounds was accomplished in less than 10 min, using a 500 mM acetate buffer pH 3.5 supplemented with 5 mM of heptakis(2,6-di-O-methyl)-β-cyclodextrin as the chiral selector. The method was fully validated and showed the adequate sensitivity for the application to samples of collagen hydrolysates. The analysis of samples extracted from chicken Pectoralis major muscles affected by growth-related myopathies showed different stereoisomer patterns compared to those from the unaffected control samples. Full article

Background: High temperatures during the early generative stage significantly threaten maize productivity, yet the molecular basis of heat tolerance remains unclear. Methods: To elucidate the molecular mechanisms of heat tolerance in maize, two hybrids—ZD309 (heat-tolerant) and XY335 (heat-sensitive)—were selected for integrated transcriptomic and physiological analyses. The plants were subjected to high-temperature treatments (3–5 °C above ambient field temperature) for 0, 1, 3, 5, and 7 days, with controls grown under natural conditions. Physiological indices, including Superoxide dismutase (SOD) activity, and proline (PRO), malondialdehyde (MDA), soluble sugar, and protein content, were measured. Results: Transcriptome analysis identified 1595 differentially expressed genes (DEGs) in XY335 (509 up- and 1086 down-regulated) and 1526 DEGs in ZD309 (863 up- and 663 down-regulated), with the most pronounced changes occurring on day 5. Key DEGs in XY335 were enriched in galactose metabolism and carbohydrate catabolism, whereas ZD309 exhibited rapid activation of oxidative stress and cell wall integrity pathways. Mfuzz time-series analysis categorized DEGs from XY335 and ZD309 into six clusters each. Weighted gene co-expression network analysis (WGCNA) identified 10 hub genes involved in ubiquitin thioesterase activity and RNA modification, suggesting protein-level regulatory roles. Conclusions: This study reveals distinct transcriptional dynamics between heat-tolerant and heat-sensitive varieties, providing candidate genes for breeding thermotolerant maize and advancing our understanding of heat stress responses during critical reproductive stages. Full article

This study was the first report regarding the application of barley malt (BM) for diets of aquaculture species. Triplicate groups of grass carp Ctenopharyngodon idellus with an initial size of about 1.2 kg were selected and fed with either BM or commercial feed (CF) to apparent satiation for 8 weeks in outdoor ponds connected with a flow-through aquaculture system. The results showed that the final body weight (1651 g) was lower in the BM fish than in the CF fish (1791 g). The edible part was lower in the BM fish than in the CF fish as indicated by the viscerosomatic index. Except for ash levels, which were lower in the fillet of the BM fish than for that of the CF fish, moisture, protein, and lipid levels were not impacted by the application of BM. Water-holding capacity indicators (drop loss, frozen exudation rate, and cooking loss) of grass carp muscle were not relevant to dietary modifications. Hematoxylin-eosin (HE) staining showed that the diameter of the myofibers was decreased while density was increased in response to the application of BM, which contributed to the improvement in textural properties (hardness, gumminess, and chewiness) in the muscle of the BM fish as compared to the CF fish. Glutamic acid level was highest, followed by aspartic acid, lysine, leucine, alanine, and arginine in grass carp muscle. Except three amino acids (proline, phenylalanine, and histidine), the amounts of the other 15 amino acids, essential amino acids, semi-essential amino acids, nonessential amino acids, and delicious amino acids were not impacted by different treatments, suggesting that the application of BM had a minor effect on the amino acid composition of grass carp muscle. Oleic acid (C18:1n-9), linoleic acid (C18:2n-6), and palmitic acid (C16:0) were the most abundant fatty acids in grass carp muscle. The amounts of poly-unsaturated fatty acid (PUFA) in the muscle decreased in response to the application of BM as the diet of grass carp, and n-6 PUFAs (C18:2n-6 and C20:2n-6) rather than n-3 PUFAs accounted for this change, which is beneficial for human health. In conclusion, the application of BM had minor impacts on the proximate composition and amino acid composition but improved textural properties and decreased n-6 PUFAs in the fillet of grass carp. Full article

Background: Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe respiratory illness in humans and currently lacks an approved vaccine. The Newcastle disease virus (NDV) vector is a well-established, safe, and effective platform for vaccine development. With recent advancements in stabilizing coronavirus spike proteins to enhance their antigenicity, this study aimed to determine whether modifications to the MERS-CoV spike protein could improve its presentation on NDV particles, allowing the resulting virus to be used as an inactivated vaccine. Methods: We codon-optimized the gene encoding the ectodomain of the MERS-CoV spike protein and incorporated modifications at the S1/S2 and S2’ cleavage sites, along with a proline substitution at residues V1060-L1061. This modified spike gene was inserted into the NDV genome to create the NDV-S_MERS virus. After purification and inactivation, the vaccine’s immunogenicity was assessed in mice. Results: Mice immunized with the inactivated NDV-S_MERS vaccine developed robust anti-spike IgGs, neutralizing antibodies, and cellular immune responses. The study demonstrated that modifications to the MERS-CoV spike protein were essential for its effective presentation on NDV particles. Additionally, the spike gene insert remained stable through five egg passages, confirming the vector’s stability. Conclusions: Engineering the MERS-CoV spike protein is crucial for its successful display on NDV particles. The strong immune responses elicited by the NDV-S_MERS vaccine in mice highlight that NDV is a promising, safe, and effective platform for MERS-CoV vaccination. Full article

Majusculamide D, isolated from the marine cyanobacterium Moorea producens, is an anticancer lipopentapeptide consisting of fatty acid, tripeptide, and pyrrolyl proline moieties. In this work, by utilizing a convergent synthetic approach, late-stage modification, and bioisostere strategy, 26 majusculamide D analogues were synthesized, and two (1i and 1j) demonstrated IC₅₀ values < 1 nM against PANC-1 cancer cells. The results summarized a preliminary structure-activity relationship mainly at the C23, C4, C34, and C10 sites. A series of in vitro assays, including wound healing, transwell, clone formation, EdU, and western blot, confirmed that majusculamide D inhibited the migration, invasion, and proliferation of pancreatic cancer cells. The optimized fluorinated analogue 1n demonstrated a notable enhancement in stability during the mouse plasma assay (>50% left after 24 h), exhibited tumor-suppressive effects (51.5% at a dosage of 5 mg/kg), and successfully mitigated the severe toxicity (no mouse dead) observed in the group treated with majusculamide D (3 mice dead) in a xenografted mouse model. Full article

The production of chips is an increasing part of the potato market. While the potato tubers are stored at low temperatures to minimize storage problems, they tend to accumulate reducing sugars, which negatively impact the quality and color of fried products. The goal of this study was to analyze the impact of cytoplasm type on chip color after harvest and after cold storage at 4 °C, as well as on proline content in cold-stressed potato tubers in a diploid potato population obtained from reciprocal crossing of parents with T- and D-type cytoplasm. Using 224 F1 progeny clones genotyped with Diversity Array Technology (DArTseq™), we mapped the Quantitative Trait Loci (QTL), treating cytoplasm type as a covariate. We detected five QTLs for chip color after harvest and six after cold storage, with the strongest QTL for both traits overlapping on chromosome III. Five QTL for proline content were detected on chromosomes V, X and XII, with the most significant one located on chromosome X. Although the progeny clones with T-type cytoplasm produced significantly lighter chips after cold storage, the cytoplasm type used as a covariate caused only minor modifications to the obtained QTL landscapes for chip color and proline content. Full article