Search Results (6,973)

Nuclear factor erythroid 2-related factor 2 (NRF2) serves as a master transcriptional regulator of cellular antioxidant responses through orchestration of cytoprotective gene expression, establishing its significance as a therapeutic target in cerebral pathophysiology. Classical electrophilic NRF2 activators, despite potent activation potential, exhibit paradoxically reduced therapeutic efficacy relative to single antioxidants, attributable to concurrent oxidative stress generation, glutathione depletion, mitochondrial impairment, and systemic toxicity. Although emerging non-electrophilic pharmacological activators offer therapeutic potential, their utility remains limited by bioavailability and suboptimal potency, underscoring the imperative for innovative therapeutic strategies to harness this cytoprotective pathway. Non-pharmacological interventions, including neuromodulation, physical exercise, and lifestyle modifications, activate NRF2 through non-canonical, non-electrophilic pathways involving protein–protein interaction inhibition, KEAP1 degradation, post-translational and transcriptional modulation, and protein stabilization, though mechanistic characterization remains incomplete. Such interventions utilize multi-mechanistic approaches that synergistically integrate multiple non-electrophilic NRF2 pathways or judiciously combine electrophilic and non-electrophilic mechanisms while mitigating electrophile-induced toxicity. This strategy confers neuroprotective effects without the contraindications characteristic of classical electrophilic activators. This review comprehensively examines the mechanistic underpinnings of non-pharmacological NRF2 modulation, highlighting non-electrophilic activation pathways that bypass the limitations inherent to electrophilic activators. The evidence presented herein positions non-pharmacological interventions as viable therapeutic approaches for achieving non-electrophilic NRF2 activation in the treatment of cerebrovascular and neurodegenerative pathologies. Full article

The associations between sialylated anti-cyclic citrullinated peptide (anti-CCP) antibodies bearing α-2,6-sialic acid (SIA), ST6Gal1 and Neu1 enzymes, and clinical disease activity measures such as disease activity score 28 (DAS28), the Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) are unknown in rheumatoid arthritis (RA). To address this gap, this study included 97 patients with RA evaluated at baseline (month 0) and at 6 and 12 months. At each visit, blood cells were analyzed for B-cell ST6Gal1 and Neu1 expressions, and plasma samples were assessed for ST6Gal1 and Neu1 levels. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), monocyte chemotactic protein-1 (MCP-1), and IgG anti-CCP with its α-2,6-SIA modification were measured. Disease activity measures, namely DAS28-ESR, DAS28-CRP, DAS28-MCP-1, SDAI, and CDAI, were calculated. Correlations and Receiver Operating Characteristics among ST6Gal, Neu1, SIA/anti-CCP ratios, and disease activity measures were assessed. Multivariate regression analyses were performed to reveal confounding factors in such correlations. The total SIA content of anti-CCP antibodies was inversely correlated with B-cell Neu1 levels (ρ = −0.317 with p = 0.013. Plasma (free-form) Neu1 levels were inversely correlated with SIA/IgG anti-CCP ratios (ρ = −0.361, p = 0.001) in the DAS28-MCP-1 < 2.2 (remission) subgroup. No such correlation was observed for the DAS28-ESR, DAS28-CRP, SDAI, or CDAI subgroups. B-cell ST6Gal1 levels correlated inversely with SDAI ≤ 11 and DAS28-MCP-1 ≤ 3.6 combined remission and low-disease-activity subgroups (ρ = −0.315 with p = 0.001 and ρ = −0.237 with p = 0.008, respectively). The same was observed for B-cell ST6Gal1/Neu1 ratios correlating with the SDAI ≤ 11 subgroup (ρ = −0.261, p = 0.009). Nevertheless, B-cell ST6Gal1/Neu1 ratios against SDAI ≤ 11 and DAS28-MCP-1 ≤ 3.6 subgroups produced significant area-under-curve (AUC) values of 0.616 and 0.600, respectively (asymptotic p-Values 0.004 and 0.018, respectively). Through multivariate regression analyses, we found that biologics (a confounding factor) interfered with p-Values related to the B-cell ST6Gal1 enzyme but did not interfere with p-Values related to the pure B-cell Neu1 enzyme. In addition, disease duration interfered with p-Values related to the pure Neu1 enzyme on B-cells or in plasma. Moreover, plasma ST6Gal1/Neu1 ratios against the DAS28-MCP-1 < 2.2 remission subgroup produced an AUC of 0.628 and asymptotic p = 0.003. Therefore, it is suggested that B-cell ST6Gal1/Neu1 ratios can be used as clinical indicators for the combined remission and low-disease-activity subgroup of SDAI and DAS28-MCP-1 formulae. Plasma ST6Gal1/Neu1 ratios are also good indicators of DAS28-MCP-1 remission. Full article

Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS) are multifactorial and progressive neurodegenerative diseases (ND), which cause a functional capacity decline. Both diseases etiology remains unclear. They may have a hereditary genetic architecture, but they can also be due to a combination of genetic and environmental factors. Heat shock proteins (HSPs) play a crucial role in protein quality control, avoiding protein dysfunction and, consequently, cell apoptosis, which are well-known pathogenic mechanisms of ND. There are studies about chaperones physiology. However, research on their pathophysiology is scarce. Especially when it comes to their associated dysfunctions with Single nucleotide variants (SNV) on HSPs in ND. Thus, this review aimed to examine the role of genetic variants in genes encoding HSPs and their contribution to the pathophysiology of these sclerosis. We performed a qualitative and descriptive literature review, searching by the indexed terms “amyotrophic lateral sclerosis,” “genetic variants,” “heat shock proteins,” “Hsp40”, “Hsp70”, Hsp90”, “DNAJC7”, “multiple sclerosis,” “neurodegenerative diseases,” “protein quality control”, and “SNV” in the PubMed/NCBI, EMBASE and SciELo databases. Results described by a qualitative synthesis of the most significant studies. Despite the existence of studies with genetic variants in HSPs in patients with ND, we realize in this review the need for more specific research on this topic to demonstrate a significance as to the responsibility for deleterious effects in the modification in genes HSPs linked to sclerosis. Full article

Isoegomaketone [(E)-1-(furan-3-yl)-4-methylpent-2-en-1-one; 1] is abundant in the essential oil of Perilla species and exhibits various biological activities, such as anticancer and anti-inflammatory effects. In order to discover compounds with reduced toxicity or enhanced biological activity through structural modification of natural product-derived components, isoegomaketone was irradiated with an electron beam at five different doses, and (±)-8-methoxy-perilla ketone (2) was obtained with the highest yield of 3.8% (w/w) at 80 kGy. Its structure was identified by one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy and high-resolution chemical ionization mass spectrometry. Compound 2 inhibited nitric oxide production and inducible nitric oxide synthase mRNA expression in a dose-dependent manner in lipopolysaccharide-stimulated RAW 264.7 cells. It also dose-dependently suppressed the mRNA expression of pro-inflammatory mediators such as IL-1β, IFN-β, and MCP-1, while having no significant effect on IL-6 mRNA levels. Furthermore, ELISA analysis demonstrated that 2 reduced MCP-1 protein expression but did not affect the protein level of TNF-α or IL-6. This study provides a reference for the structural analysis of compounds related to 2 by presenting NMR data acquired with chloroform-d, and is the first to report the anti-inflammatory properties of 2. Full article

Intrinsically disordered regions (IDRs) are present in nearly all proteins, often accounting for more than 40% of their amino acid sequence. Unlike structured domains, IDRs lack sequence or structural conservation across species while maintaining conserved biological functions. Here, we discovered that the previously uncharacterized disordered tail region of Poly(ADP-ribose) glycohydrolase (PARG) controls its localization and activity. Despite its structural divergence, this domain supports conserved regulatory functions across species. Deletion of the disordered tail results in cytoplasmic mislocalization, aberrant accumulation in the nucleolus, impaired chromatin association, and reduced enzymatic activity. Mass spectrometry analysis reveals that this disordered region mediates interactions with nuclear transport factors, post-translational modification enzymes, and chromatin-associated complexes. Together, these results demonstrate that the disordered tail region of PARG acts as a regulatory hub that integrates multiple layers of control to ensure proper subcellular localization and chromatin function. Full article

Nuclear processes are fundamental to the regulation of cellular, tissue, and organismal function, especially in complex multicellular systems. Central to these processes are lamins and lamin-associated proteins, which contribute to nuclear structure, gene expression, and chromatin organization. The discovery that mutations in genes coding for lamins and lamina-associated proteins give rise to rare disorders—collectively called laminopathies—has intensified interest in this field among cell biologists and medical scientists. While many practical and clinically relevant questions about phenotype development and potential treatments require mammalian models, key molecular mechanisms and interactions have also been effectively studied in both vertebrate and invertebrate systems. This review focuses on a discussion of Drosophila lamins, their major properties, functions, interactions and post-translational modifications, with comparison to mammalian lamins, and a discussion of the value of fly models in studies of lamins in muscle tissue development and function in comparison to mammalian lamin B-type and A/C-type. In this paper, we have discussed the overall impact of lamin Dm and lamin C level manipulations on overall phenotype, especially on larval and adult muscles. We have thoroughly discussed the conclusions, which may have been drawn from experiments with overexpression of lamin C mutants mimicking lamin A laminopathy mutations. We have presented and discussed the suggestion that the mechanisms underlying Drosophila muscle phenotype development are similar not only to human dystrophic laminopathies but also to classical human muscular dystrophies such as Duchenne muscular dystrophy and Hutchison–Gilford Progeria syndrome. We suggest that the activation of the stress response contributes to the laminopathic phenotype detected in Drosophila. Finely, this review discusses in depth the lamin Dm and lamin C interactomes, discrepancies between String-based interactome networks, and our map of interactomes based on manual verification of experimental data on Drosophila lamin interactions. Full article

Somatic embryogenesis (SE) is a key plant regeneration technique involving the reprogramming of somatic cells into embryogenic structures. This developmental transition is regulated by complex genetic and epigenetic mechanisms, including post-translational modifications such as SUMOylation—the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to target proteins, influencing their function, stability, and interactions. While SUMOylation is known to regulate plant development and stress responses, its role in SE has remained unknown. In this study, we investigated the involvement of the SUMOylation pathway in SE induction in Medicago truncatula. Using BLASTp analysis with known SUMO pathway proteins from Arabidopsis thaliana and Glycine max, we identified 10 homologous genes in M. truncatula. Phylogenetic relationships, gene structure, and conserved motif analyses confirmed their evolutionary conservation and characteristic domains. Expression profiling revealed significant upregulation of SUMO pathway genes—including Mt SUMO2, Mt SAE1-2, Mt SCE1a-b, Mt MMS21, and Mt PIAL2—in embryogenic cell lines during early SE induction. Additionally, in silico prediction of SUMOylation sites and SUMO-interacting motifs (SIMs) in 12 key SE regulatory proteins indicated a broad potential for SUMO-mediated regulation. These findings suggest that SUMOylation may contribute to the acquisition of embryogenic competence during somatic cell reprogramming in plants. Full article

Rice bran protein (RBP) is an important plant protein, but its functional properties are reduced due to the presence of disulfide bonds in the structure. Polyphenol modification is an effective strategy to improve protein functional properties. However, the interactions between quercetin (Que) and RBP have not been well-studied. In this study, we explored the mechanism of non-covalent interactions between RBP and Que and systematically evaluated the improvement of functional properties of the RBP–Que complex. The results revealed that the addition of Que can significantly affect the particle size, ζ-potential and protein flexibility of the RBP–Que complex, and the non-covalent interactions significantly altered the secondary structure (α-helix content decreased to 20.28%, β-sheet decreased to 22.02%, β-turn increased to 29.30% and random coil increased to 28.40%) and the tertiary conformation of RBP. Spectroscopic data showed that static quenching occurred. Thermodynamic parameters showed that ΔG, ΔH, and ΔS were negative, revealing that the binding process was spontaneous and exothermic and the main reactive bonds were the hydrogen bond and the van der Waals force. When the Que concentration was 120 μmol/g, the emulsifying and foaming properties were improved by 57.72% and 71.88% compared with the RBP, respectively. The study will expand the application of RBP in the food and beverage processing industry. Full article

The giant squid (Dosidicus gigas) is an abundant marine species with high protein content, making it a promising resource for the food and biomaterial industries. This study aimed to investigate the effect of temperature (25–100 °C) on the structural changes in sarcoplasmic, myofibrillar, and stromal proteins isolated from squid mantle. Fourier-transform infrared spectroscopy (FT-IR) and circular dichroism (CD) were employed to monitor modifications in secondary structure, while field emission scanning electron microscopy (FE-SEM) was used to examine morphological characteristics. The FT-IR analysis revealed temperature-induced transitions in amide I, II, and A bands, indicating unfolding and aggregation processes, particularly in myofibrillar and stromal proteins. CD results confirmed a loss of α-helix content and an increase in β-sheet structures with rising temperature, especially above 60 °C, suggesting progressive denaturation. FE-SEM micrographs illustrated clear morphological differences: sarcoplasmic proteins displayed smooth, amorphous structures; myofibrillar proteins exhibited fibrous, porous networks; and stromal proteins presented dense and layered morphologies. These findings highlight the different thermal sensitivities and structural behaviors of squid muscle proteins and provide insight into their potential functional applications in thermally processed foods and bio-based materials. Full article

Transglutaminase (TGase) improves protein structure by facilitating cross-linking reactions. However, the effects of TGase on the physicochemical properties of whey protein isolate (WPI)–soymilk complexes and their applications in yuba remain unclear. Therefore, the impacts of TGase concentration on the free sulfhydryl content, free amino content, particle size, and structure of WPI–soymilk complexes and their film-forming properties were studied. The results showed that the physicochemical properties of the composite soymilk were changed by the TGase-induced cross-linking reaction of protein. Compared with the composite soymilk without TGase modification, the particle size of the WPI–soymilk complexes increased from 707.99 ± 9.47 nm to 914.41 ± 2.8 nm as the TGase concentration increased, and the complexes remained relatively stable at low TGase concentrations. TGase modification changed the tertiary structure of the WPI–soymilk complexes. The composite yuba with 0.01% and 0.03% levels of TGase had a higher β-sheet content than composite yuba without addition of TGase. The surface hydrophobicity of composite soymilk was decreased by all the addition levels of TGase. Meanwhile, the TGase-modified composite protein with 0.03% TGase had the lowest free sulfhydryl (35.92 μg/g) and amino groups (0.46). Additionally, the tensile strength of the composite yuba with 0.05% TGase addition reached a peak of 1.66 ± 0.02 MPa, which was 7.8% higher than that of the composite yuba without TGase addition. The SEM results revealed that the composite yuba with 0.01–0.03% TGase addition exhibited a dense and non-porous film structure. Moreover, all the composite yuba with TGase addition had a reduced rate of yuba cooking loss. This study contributes to enhancing the yield and mechanical properties of traditional yuba. Full article

N, as plants’ most essential nutrient, profoundly shapes root system architecture (RSA), with LRs being preferentially regulated. This review synthesizes the intricate molecular mechanisms underpinning N sensing, signaling, and its integration into developmental pathways governing LR initiation, primordium formation, emergence, and elongation. We delve deeply into the roles of specific transporters (NRT1.1, nitrate transporter 2.1 (NRT2.1)), transcription factors (Arabidopsis nitrate regulated 1 (ANR1), NLP7, TGACG motif-binding factor (TGA), squamosa promoter-binding protein-like 9 (SPL9)) and intricate hormone signaling networks (auxin, abscisic acid, cytokinins, ethylene) modulated by varying N availability (deficiency, sufficiency, excess) and chemical forms (NO₃⁻, NH₄⁺, organic N). Emphasis is placed on the systemic signaling pathways, including peptide-mediated long-distance communication (CEP—C-terminally encoded peptide receptor 1 (CEPR1)) and the critical role of the shoot in modulating root responses. Furthermore, we explore the emerging significance of carbon–nitrogen (C/N) balance, post-translational modifications (ubiquitination, phosphorylation), epigenetic regulation, and the complex interplay with other nutrients (phosphorus (P), sulfur (S)) and environmental factors in shaping N-dependent LR plasticity. Recent advances utilizing single-cell transcriptomics and advanced imaging reveal unprecedented cellular heterogeneity in LR responses to N. Understanding this sophisticated regulatory network is paramount for developing strategies to enhance nitrogen use efficiency (NUE) in crops. This synthesis underscores how N acts as a master regulator, dynamically rewiring developmental programs through molecular hubs that synchronize nutrient sensing with root morphogenesis—a key adaptive strategy for resource acquisition in heterogeneous soils. Full article

Magnesium (Mg) alloys, particularly Mg AZ31, have emerged as promising biomaterials for orthopedic applications due to their biodegradability and favorable mechanical characteristics. Among these, the Mg AZ31+SPF alloy, subjected to hydrothermal (HT) treatment, has demonstrated enhanced bioactivity. Our previous research established that this surface modification supports the osteogenic differentiation of human mesenchymal stem cells (hMSCs) by modulating both canonical and non-canonical signaling pathways, including those implicated in osteogenesis, hypoxic response, exosome biogenesis, and lipid metabolism. In the present study, we extended our investigation to assess the effects of Mg AZ31+SPF+HT and Mg AZ31+SPF extracts on murine pre-osteoclasts (RAW 264.7 cells) over 3- and 6-day treatment periods. The primary objectives were to evaluate biocompatibility and to investigate potential impacts on osteoclastogenesis induction and miRNA expression profiles. Methods: To assess cytocompatibility, metabolic activity, DNA integrity, and morphological alterations in RAW 264.7 cells were evaluated. Osteoclast differentiation was quantified using TRAP staining, alongside the assessment of osteoclastogenic marker expression by qRT-PCR and ELISA. The immunomodulatory properties of the extracts were examined using multiplex BioPlex assays to quantify soluble factors involved in bone healing. Additionally, global miRNA expression profiling was performed using a specialized panel targeting 82 microRNAs implicated in bone remodeling and inflammatory signaling. Results: Mg AZ31+SPF+HT extract exhibited high biocompatibility, with no observable adverse effects on cell viability. Notably, a significant reduction in the number of TRAP-positive and multinucleated cells was observed relative to the Mg AZ31+SPF group. This effect was corroborated by the downregulation of osteoclast-specific gene expression and decreased MMP9 protein levels. Cytokine profiling indicated that Mg AZ31+SPF+HT extract promoted an earlier release of key cytokines involved in maintaining the balance between bone formation and resorption, suggesting a beneficial role in bone healing. Furthermore, miRNA profiling revealed a distinct regulatory signature in Mg AZ31+SPF+HT-treated cells, with differentially expressed miRNAs associated with inflammation, osteoclast differentiation, apoptosis, bone resorption, hypoxic response, and metabolic processes compared to Mg AZ31+SPF-treated cells. Conclusions: Collectively, these findings indicate that hydrothermal treatment of Mg AZ31+SPF (resulting in Mg AZ31+SPF+HT) attenuates pre-osteoclast activation by influencing cellular morphology, gene and protein expression, as well as post-transcriptional regulation via modulation of miRNAs. The preliminary identification of miRNAs and the activation of their regulatory networks in pre-osteoclasts exposed to hydrothermally treated Mg alloy are described herein. In the context of orthopedic surgery—where balanced bone remodeling is imperative—our results emphasize the dual significance of promoting bone formation while modulating bone resorption to achieve optimal implant integration and ensure long-term bone health. Full article

Currently, there is an increasing demand for plant-based and low-fat snacks. Non-conventional starch and grains are alternative ingredients. Environmentally friendly processing, such as liquid nitrogen and microwaves, can be used to obtain modified starch, as well as hot air frying to cook snacks. The aim of this work was to evaluate the impact of eco-friendly physical modification of starch from Oxalis tuberosa in a low-fat snack processed by hot air frying. First, native starch (NS) was treated with liquid nitrogen (LNS) and liquid nitrogen/microwaves (LNMS), and the amylose/amylopectin content and functional properties were determined. The snacks were formulated with NS or modified starches, amaranth flour, quinoa flour, corn, onion powder, salt, and water; the ingredients were mixed and placed in an electric pasta maker and cooked by hot air frying. The hardness, hedonic test, colorimetric parameters, acrylamide, proximal composition, and fatty acid profile were analyzed. All starches showed similar values of amylose and amylopectin content. LNMS starch had the lowest water solubility index as compared to NS and LNS. The snacks with the starch modified with liquid nitrogen showed the highest values of hardness as well as the highest score for the texture from a hedonic test. The snacks with modified starches showed a lower browning index than the snack formulated with NS. Acrylamide was not detected in any snacks. The lipid value of the snacks with modified starch was 1.9–2.70 g/100 g of sample, providing ω-9, ω-6, and ω-3 fatty acids. All snacks contained 7.7 g of protein/100 g of sample. These low-fat and plant-based snacks are a healthy option made by environmentally friendly technologies. Full article

Glycosylation, the enzymatic addition of glycans to proteins and lipids, is a critical post-translational modification that influences protein folding, stability, trafficking, immune modulation, and cell signaling. The vast structural diversity of glycans arising from differences in monosaccharide composition, branching, and terminal modifications such as sialylation, fucosylation, and sulfation underpins their functional specificity and regulatory capacity. This review provides a comprehensive overview of glycan biosynthesis, with a focus on N-glycans, O-glycans, glycosaminoglycans (GAGs), and glycolipids. It explores their essential roles in maintaining cellular homeostasis, development, and immune surveillance. In health, glycans mediate cell–cell communication, protein interactions, and immune responses. In disease, however, aberrant glycosylation is increasingly recognized as a hallmark of numerous pathological conditions, including cancer, neurodegenerative disorders, autoimmune diseases, and a wide range of infectious diseases. Glycomic alterations contribute to tumor progression, immune evasion, therapy resistance, neuroinflammation, and synaptic dysfunction. Tumor-associated carbohydrate antigens (TACAs) and disease-specific glycoforms present novel opportunities for biomarker discovery and therapeutic targeting. Moreover, glycan-mediated host–pathogen interactions are central to microbial adhesion, immune escape, and virulence. This review highlights current advances in glycomics technologies, including mass spectrometry, lectin microarrays, and glycoengineering, which have enabled the high-resolution profiling of the glycome. It also highlights the emerging potential of single-cell glycomics and multi-omics integration in precision medicine. Understanding glycome and its dynamic regulation is essential for uncovering the molecular mechanisms of disease and translating glycomic insights into innovative diagnostic and therapeutic strategies. Full article

Background: A trilayered collagen/collagen–magnesium–hydroxyapatite (Col/Col-Mg-HA) scaffold is used in clinical practice to treat osteochondral lesions, but the regeneration of the subchondral bone is still not satisfactory. Objective: The aim of this study was to test, in vitro, the osteoinductivity induced by the addition of bone morphogenetic protein-2 (BMP-2) or amorphous calcium phosphate granules with strontium ions (Sr-ACP), in order to improve the clinical regeneration of subchondral bone, still incomplete. Methodology: Normal human osteoblasts (NHOsts) were seeded on the scaffolds and grown for 14 days in the presence of human osteoclasts and conditioned medium of human endothelial cells. NHOst adhesion and morphology were observed with transmission electron microscopy, and metabolic activity was tested by Alamar blue assay. The expression of osteoblast- and osteoclast-typical markers was evaluated by RT-PCR on scaffolds modified by enrichment with BPM-2 or Sr-ACP, as well as on unmodified material used as a control. Results: NHOsts adhered well to all types of scaffolds, maintained their typical morphology, and secreted abundant extracellular matrix. On the modified materials, COL1A1, SPARC, SPP1, and BGLAP were more expressed than on the unmodified ones, showing the highest expression in the presence of BMP-2. On Sr-ACP-enriched scaffolds, NHOsts had a lower proliferation rate and a lower expression of RUNX2, SP7, and ALPL compared to the other materials. The modified scaffolds, particularly the one containing Sr-ACP, increased the expression of the osteoclasts’ typical markers and decreased the OPG/RANKL ratio. Both types of scaffold modification were able to increase the osteoinductivity with respect to the original scaffold used in clinical practice. BMP-2 modification seemed to be more slightly oriented to sustain NHOst activity, and Sr-ACP seemed to be more slightly oriented to sustain the osteoclast activity. These could provide a concerted action toward better regeneration of the entire osteochondral unit. Full article