Search Results (2,974)

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality, despite advances in pharmacological prevention and treatment. The burden of CVD necessitates implementing the treatment of risk factors including dyslipidemia. Pharmaceutical advancements and in depth understanding of pathophysiology have enabled innovative therapies targeting pathways underlying lipoprotein metabolism disorders. Angiopoietin protein-like 3 (ANGPTL3) plays a crucial role in the regulation of lipoprotein metabolism, therefore being a potential therapeutic target. Inhibition of ANGPTL3 has emerged as a new therapeutic strategy to reduce LDL-cholesterol levels independent of the LDL receptor function. Therapeutic approaches for ANGPTL3 inhibition range from monoclonal antibodies to nucleic acid therapeutics including antisense oligonucleotides and small interfering RNAs. In this review, we briefly explain the structure and mechanism of action of ANGPTL3 and discuss the therapeutic approaches for targeting ANGPTL3 in the clinical setting. We also discuss Evinacumab, a monoclonal antibody, its structure, mechanism of action, safety, tolerability, pharmacokinetics, and pharmacodynamics, as well as its clinical trial-derived results. The antisense oligonucleotides modify ANGPTL3 mRNA to inhibit protein production, and small interfering RNAs induce mRNA degradation; results from clinical trials were reviewed in detail. Finally, we discuss promising gene editing approaches including clustered regularly interspaced short palindromic repeats (CRISPR)/Cas systems. Full article

Staphylococcus aureus (S. aureus) is a common pathogen that threatens healthcare and food safety. Vine tea extract (VTE) and its major active component, dihydromyricetin (DMY), show antibacterial activity. However, their mechanisms of action are not fully understood. In this study, we combined proteomics and lipidomics, with RT–qPCR validation of selected differentially expressed genes, to investigate how DMY and VTE affect S. aureus. Proteomics identified 210 and 535 differentially expressed proteins (DEPs) in the DMY-treated and VTE-treated groups, respectively. These DEPs were mainly enriched in cell wall- and membrane-associated pathways. DMY markedly increased proteins involved in fatty acid degradation, glyceride metabolism, and cell wall synthesis. In contrast, VTE increased proteins related to heme/iron acquisition and cell wall degradation. In addition, VTE altered proteins involved in pyrimidine metabolism and aminoacyl-tRNA biosynthesis, suggesting that non-DMY components in VTE may contribute to the antibacterial activity through additional pathways. Lipidomics further indicated membrane lipid remodeling, including increased fatty acid unsaturation and shorter acyl chain length. Collectively, DMY and VTE may inhibit S. aureus growth by remodeling membrane lipids and disturbing cell wall–cell membrane homeostasis. These findings provide mechanistic support for further development of DMY and VTE as natural antimicrobial candidates. Full article

MicroRNAs (miRNAs) are small non-coding RNA molecules approximately 20–22 nucleotides in length that regulate gene expression at the post-transcriptional level. By binding to target messenger RNAs (mRNAs), miRNAs inhibit translation or induce degradation, thus influencing a wide array of biological processes including development, inflammation, apoptosis, and tissue remodeling. Owing to their remarkable stability and tissue specificity, miRNAs have emerged as promising biomarkers in both clinical and forensic settings. In recent years, increasing evidence has demonstrated their utility in cardiovascular diseases, where they may serve as diagnostic, prognostic, and therapeutic tools. This systematic review aims to comprehensively summarize the role of miRNAs in cardiovascular pathology, focusing on their diagnostic potential in myocardial infarction, sudden cardiac death (SCD), and cardiomyopathies, and their applicability in post-mortem investigations. Following PRISMA guidelines, we screened PubMed, Scopus, and Web of Science databases for studies up to December 2024. The results highlight several miRNAs—including miR-1, miR-133a, miR-208b, miR-499a, and miR-486-5p—as robust markers for ischemic injury and sudden death, even in degraded or formalin-fixed autopsy samples. The high stability of miRNAs under extreme post-mortem conditions reinforces their potential as molecular tools in forensic pathology. Nevertheless, methodological heterogeneity and limited standardization currently hinder their routine application. Future studies should aim to harmonize analytical protocols and validate diagnostic thresholds across larger, well-characterized cohorts to fully exploit miRNAs as reliable molecular biomarkers in both clinical cardiology and forensic medicine. Full article

Background/Objectives: This review integrates evolutionary, metabolic, genetic, and nutritional perspectives to explain how sterol-derived vitamin D pathways shape human physiology and inter-individual variability in vitamin D status. Methods: The literature on sterol and vitamin D metabolism across animals, plants, fungi, and algae was synthesized with data from metabolomics databases, genome-wide association studies, RNA-seq resources (including GTEx), structural biology, and functional genomics. Results: Vitamin D₂ and vitamin D₃ likely emerged early in evolution as non-enzymatic photochemical sterol derivatives and were later co-opted into a tightly regulated endocrine system in vertebrates. In humans, cytochrome P450 enzymes coordinate vitamin D activation and degradation and intersect with oxysterol production, thereby linking vitamin D signaling to cholesterol and bile acid metabolism. Tissue-specific gene expression and regulatory genetic variants, particularly in the genes DHCR7, CYP2R1, CYP27B1, and CYP27A1, contribute to population-level differences in vitamin D status and metabolic outcomes. Structural analyses reveal selective, high-affinity binding of 1,25-dihydroxyvitamin D₃ to VDR, contrasted with broader, lower-affinity ligand recognition by LXRs. Dietary patterns modulate nuclear receptor signaling through distinct yet convergent ligand sources, including cholesterol-derived oxysterols, oxidized phytosterols, and vitamin D₂ versus vitamin D₃. Conclusions: Sterol and vitamin D metabolism constitute an evolutionarily conserved, adaptable network shaped by UV exposure, enzymatic control, genetic variation, and diet. This framework explains inter-individual variability in vitamin D biology and illustrates how evolutionary and dietary modulation of sterol-derived ligands confers functional flexibility to nuclear receptor signaling in human health. Full article

Background: Proteasomes are protein complexes that mediate proteolysis to degrade unneeded or damaged proteins, and they play an indispensable role in plant growth and development. However, their regulatory effects on tomato fruit quality and the underlying metabolic mechanisms remain largely elusive. This study aimed to elucidate the metabolic regulatory mechanisms of proteasomes in tomato fruits through untargeted metabolome analysis. Methods: An untargeted metabolomics approach was employed to profile the metabolic changes in tomato fruits. Metabolites were detected and identified under both positive and negative ion modes. Metabolic profiles were compared between wild-type (WT) tomato fruits and SlPBB2 RNA interference (SlPBB2-RNAi) lines. Specifically, the SlPBB2-RNAi line refers to a transgenic tomato line constructed via Agrobacterium-mediated transformation, where the expression of the proteasome component gene SlPBB2 was stably downregulated by RNA interference technology to clarify its regulatory role in fruit metabolism. KEGG enrichment analysis was performed to annotate the functions of differential metabolites. Results: A total of 568 and 333 metabolites were identified in positive and negative ion modes, respectively. Comparative analysis revealed 43 differentially abundant metabolites between WT and SlPBB2-RNAi fruits, including D-glucose, pyruvic acid, leucine, and naringenin. KEGG enrichment analysis further identified key metabolites involved in the carbon fixation pathway of photosynthetic organisms, with L-malic acid being a prominent representative. Reduced accumulation of D-glucose and pyruvic acid in SlPBB2-RNAi fruits suggested the inhibition of the citrate cycle, a core pathway in cellular energy metabolism. This metabolic perturbation was associated with decreased chlorophyll content in SlPBB2-RNAi plants, implying impaired photosynthetic carbon fixation and energy metabolism. Conclusions: This study uncovers the metabolic regulatory role of SlPBB2-mediated proteasome function in tomato fruits, providing novel insights into the link between proteasomal activity and fruit metabolic homeostasis from a metabolomic perspective. These findings offer new theoretical foundations for developing strategies to improve tomato nutritional quality. Full article

The development of RNA-based drugs for MAFLD-related fibrosis is severely hampered by the poor oral bioavailability of nucleic acids. This study employed a novel, patent-protected LNP formulation to orally deliver plant-derived miR-55 and investigate its therapeutic potential, focusing on its novel mechanism of action via the CK2α/SMO interaction. In a rat model established with a methionine-choline-deficient diet, orally administered miR-55 markedly improved liver injury, lipid dysregulation, oxidative stress, and pathological collagen deposition. The anti-fibrotic efficacy was quantitatively confirmed by a significant reduction in hepatic hydroxyproline content and downregulation of key fibrogenic genes (Col1a1, Col3a1, TIMP-1, TGF-β1, CTGF) and pro-inflammatory cytokines (TNF-α, IL-6), achieving effects comparable to the full Ge Xia Zhu Yu Decoction. Mechanistically, both bioinformatic prediction and in vivo validation indicated that miR-55 is predicted to target CK2α. This targeting suppressed CK2α expression and disrupted the endogenous CK2α-SMO complex, thereby promoting the ubiquitin-mediated degradation of SMO—a previously unreported mechanism. This cascade inhibited the downstream Gli1 pathway and downregulated pro-fibrotic and pro-angiogenic factors (VEGF, PDGF), thereby providing a comprehensive mechanistic basis for the therapeutic effects. This study is the first to provide evidence that orally delivered, plant-derived miR-55 may act as a natural modulator that potentially through disrupting the CK2α/SMO interaction via a unique complex disruption-promoted degradation mechanism, attenuating Hedgehog signaling and alleviating liver fibrosis. These findings offer important insights into cross-kingdom regulation and highlight miR-55 as a potential targeted therapeutic candidate. Full article

Arid and semi-arid soils represent extreme habitats where microbial life is constrained by high temperature, low water availability, salinity, and nutrient limitation, yet these ecosystems harbor unique bacterial communities that sustain key ecological processes. To explore the diversity and functional potential of prokaryotic assemblages in Algerian drylands, we compared soils from three contrasting sites: The Oasis of Djanet (RM1), the hyper-arid Tassili of Djanet desert (RM2), and the semi-arid El Ouricia forest in Sétif (RM3). Physicochemical analyses revealed strong environmental gradients: RM2 exhibited the highest pH (8.66), electrical conductivity (11.7 dS/m), and sand fraction (56%), whereas RM3 displayed the greatest moisture (10.9%), organic matter (7.6%), and calcium carbonate (20.7%) content, with RM1 generally showing intermediate levels. High-throughput 16S rRNA gene sequencing generated >60,000 effective reads per sample with sufficient coverage (>0.99). Alpha diversity indices indicated the highest bacterial richness and diversity in RM2 (Chao1 = 3144, Shannon = 10.0), while RM3 showed lower evenness and the dominance of a few taxa. Across sites, 66 phyla and 551 genera were detected, dominated by Actinobacteriota (38–45%) and Chloroflexi (13–44%), with Proteobacteria declining from RM1 (17.5%) to RM3 (3.3%). Venn analysis revealed limited overlap, with only 58 operational taxonomic units shared among all sites, suggesting highly habitat-specific communities. Predictive functional profiling (PICRUSt2, Tax4Fun, FAPROTAX) indicated metabolism as the dominant functional category (≈50% of KEGG Level-1), with carbohydrate and amino acid metabolism forming the metabolic backbone. Notably, transport functions (ABC transporters), lipid metabolism, and amino acid degradation pathways were enriched in RM2–RM3, consistent with adaptation to osmotic stress, nutrient limitation, and energy conservation under aridity. Collectively, these findings demonstrate that Algerian arid and semi-arid soils host diverse, site-specific bacterial communities whose functional repertoires are strongly shaped by soil chemistry and climate, highlighting their ecological and biotechnological potential. Full article

Upon RNA virus infection, viral RNA is sensed by the RIG-I-like receptors (RLRs), which signal through the adaptor protein VISA/MAVS to induce an innate antiviral response. How the VISA-mediated innate antiviral response is regulated and whether it can be targeted for drug development against diseases caused by RNA virus infection needs to be further investigated. Here we report that physalin F, a natural secosteroid isolated from Physalis angulata L., inhibits innate immune response to RNA virus. Mechanistically, physalin F binds to and promotes the activation of the mitochondrial m-AAA protease AFG3L2, which subsequently mediates the degradation of VISA. Knockdown of AFG3L2 promotes RLR-mediated innate antiviral signaling, whereas physalin F inhibits innate immune response to RNA virus both in cells and mice. Our study discovers physalin F as an inhibitor of VISA-mediated innate antiviral response as well as a candidate compound for the treatment of related diseases. More importantly, our findings suggest that AFG3L2 constitutively mediates degradation of VISA under physiological conditions, which represents a novel negative regulatory mechanism of RLR-mediated innate antiviral response. Full article

Inflammation plays a central role in the pathogenesis of numerous diseases through the excessive production of nitric oxide (NO), prostaglandins, and pro-inflammatory cytokines. Although bromophenols from marine algae and various phenolic compounds exhibit strong anti-inflammatory activity, the biological properties of brominated vanillin derivatives remain largely unexplored. This study aimed to investigate the anti-inflammatory effects of 2-bromo-5-hydroxy-4-methoxybenzaldehyde (2B5H4M), a brominated vanillin derivative structurally similar to marine bromophenols, in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. 2B5H4M significantly reduced LPS-induced NO and PGE₂ production by suppressing the protein and mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). It also downregulated the expression of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. Mechanistically, 2B5H4M inhibited the phosphorylation and degradation of IκB-α, thereby preventing NF-κB nuclear translocation, and reduced the phosphorylation of ERK and JNK. These findings demonstrate that 2B5H4M exerts potent anti-inflammatory effects by simultaneously blocking NF-κB and MAPK signaling pathways. Although not algae-derived, the structural resemblance of 2B5H4M to marine bromophenols highlights its potential as a marine-inspired reference compound. This work suggests that 2B5H4M may serve as a promising lead scaffold for developing new phenolic anti-inflammatory agents and provides a foundation for future mechanistic and in vivo studies. Full article

Contamination of agricultural products such as maize by fungi is a significant concern worldwide, as it can compromise food safety and quality. In recent years, the use of microorganisms as natural food preservatives has gained interest. Probiotic lactic acid bacteria (LAB) and their metabolites are considered a promising strategy to reduce fungal growth and limit other food contaminants. This study aimed to characterize, screen and compare the probiotic properties and antifungal activity of LAB of maize origin. A total of 23 LAB isolates obtained from untreated maize grains were identified through 16S rRNA gene sequencing as Weissella viridenscens (34.7%), Pediococcus pentosaceus (34.7%), Enterococcus durans (17.4%), Leuconostoc citreum (9%), and Enterococcus faecium (4.3%). All isolates demonstrated acid, phenol, and bile salt tolerance; surface hydrophobicity; and antagonistic activity against selected bacterial foodborne pathogens. Notably, Enterococcus sp. showed the strongest inhibitory activity against Escherichia coli ATCC 5211 (21 mm inhibition zone) and Staphylococcus aureus (17 mm inhibition zone), whereas Pediococcus sp. exhibited the highest antagonistic effect against Listeria monocytogenes (18.7 mm inhibition zone). Furthermore, E. durans and P. pentosaceus demonstrated the strongest antifungal activity, effectively inhibiting the growth of Alternaria tenuissima (F22FR) and Fusarium oxysporum (F44FR), respectively. Overall, all the LAB strains isolated from this study showed considerable potential for use in the food industry as probiotics, starter cultures for functional food fermentations, bio-preservatives and biocontrol agents against toxigenic fungi and pathogenic bacteria, with E. durans standing out for its exceptional performance. Future research will explore the ability of these isolates and/or their enzymes to degrade mycotoxins commonly found in maize, a staple food in many African countries. Full article

Background/Objectives: Chimeric antigen receptor (CAR) T cells are a powerful cancer therapy, but their function depends heavily on internal signaling domains and metabolic adaptability. Most studies evaluate CAR behavior upon antigen exposure, yet intrinsic signaling properties may pre-program CAR T cell states even in the absence of stimulation. This study investigates how CAR design and metabolic support shape baseline transcriptional programs, focusing on tonic signaling and NF-κB-related pathways. Methods: We engineered CAR T cells targeting HER2 or GPC3 antigens, incorporating either 4-1BB or CD28 co-stimulatory domains, respectively. A subset of cells was further modified with adenosine deaminase 1 (ADA1) and CD26 to degrade extracellular adenosine and supply inosine, a metabolic strategy termed metabolic refueling (MR). Bulk RNA-seq was performed on resting T cells without antigen stimulation. We analyzed differential gene expression, gene set enrichment (GO, KEGG, Hallmarks), and transcription factor activity (DoRothEA) to assess the impact of CAR design and MR on T cell programming. Results: All CAR T cells exhibited activation of NF-κB–centered inflammatory programs at baseline, indicating tonic signaling. GPC3 CAR T cells showed stronger baseline activation than HER2 CAR T cells. Metabolic refueling amplified these programs without altering their directionality, enhancing inflammatory, survival, and effector modules. Transcription factor activity scores mirrored these trends, highlighting RELA, FOS, and STATs as key regulatory nodes. Conclusions: CAR-intrinsic features, notably co-stimulatory domain choice, define the tonic NF-κB activation tone in resting CAR T cells. Metabolic refueling boosts these baseline states without overstimulation, suggesting it may be especially valuable for weaker CAR constructs. These findings provide a framework for tuning CAR T cell function through combinatorial design strategies targeting signaling and metabolism. Full article

Concrete is the most widely used construction material worldwide, yet its production and disposal pose significant environmental challenges due to high carbon emissions and limited recyclability. While microbial colonization of concrete is often associated with structural deterioration, recent research has highlighted the potential of microorganisms to contribute positively to concrete recycling and self-healing. In this study, we investigated the bacterial and fungal communities inhabiting urban concrete samples using amplicon-based taxonomic profiling targeting the 16S rRNA gene and internal transcribed spacer (ITS) region. Our analyses revealed a diverse assemblage of microbial taxa capable of surviving the extreme physicochemical conditions of concrete. Several taxa were associated with known metabolic functions relevant to concrete degradation, such as acid and sulphate production, as well as biomineralization processes that may support crack repair and surface sealing. These findings suggest that concrete-associated microbiomes may serve as a reservoir of biological functions with potential applications in sustainable construction, including targeted biodegradation for recycling and biogenic mineral formation for structural healing. This work provides a foundation for developing microbial solutions to reduce the environmental footprint of concrete infrastructure. Full article

Background: Evidence on non-restrictive MIND pattern interventions in Alzheimer’s (ALZ) disease remains limited. Methods: In an observational case–control study, 60 participants (ALZ, n = 30; cognitively healthy controls, n = 30) completed baseline (T0) and follow-up (T1) after structured MIND counseling. Adherence was assessed via the MEDAS questionnaire. Stool samples (16S rRNA profiling) were taken and anthropometry and cognitive/functional measures were recorded at T0/T1. Results: In the ALZ group, MEDAS improved as adherence to the Mediterranean diet increased (increasing the use of vegetables ≥ 2/day, p < 0.01; and lowering butter adoption ≤ 1/day, p = 0.02), with a shift from low to moderate/high adherence; in controls, baseline Mediterranean diet adherence was already high, and changes in MEDAS categories were modest (low adherence from 13.8% to 3.6%, high adherence from 37.9% to 50.0%), with no statistically significant overall change (p = 0.39). Regarding gut microbiota (GM), in the ALZ group, alpha diversity increased significantly and Bray–Curtis PCoA separated T0 from T1. Species-level analysis showed increases in SCFA-linked taxa (e.g., Anaerobutyricum hallii, Blautia luti, Eubacterium coprostanoligenes) and reductions in dysbiosis/mucin-degrading taxa (e.g., Mediterraneibacter torques, M. gnavus, Agathobacter rectalis). Between-group Δ(T1 − T0) comparisons at the genus level indicated larger positive shifts in ALZ for Anaerobutyricum, Oscillibacter, Faecalicatena, Romboutsia, Mediterraneibacter, and Blautia, and more negative Δ for Gemmiger, Subdoligranulum, Bifidobacterium, Clostridium, and Collinsella. sPLS-DA showed partial separation (first two components ≈ 9% variance). Conclusions: A structured, non-restrictive MIND intervention was feasible, improved dietary adherence, and accompanied higher diversity and compositional remodeling of the GM in ALZ’s disease. Larger randomized mechanistic studies are warranted. Full article

Acinetobacter baumannii represents a critical-priority organism due to its multidrug resistance. The emergence of carbapenem-resistant strains poses a major clinical challenge, underscoring the urgent need for novel antibacterial agents with alternative mechanisms. As peptide nucleic acids (PNAs) have recently gained attention as antisense therapeutics, we aimed to validate their potential as novel antimicrobial strategies against multidrug-resistant A. baumannii. We synthesized a cell-penetrating peptide (CPP)–PNA conjugate targeting pdxA, an essential gene involved in vitamin B6 biosynthesis. Among several candidate genes tested, the pdxA-targeting PNA exhibited the strongest inhibitory activity, achieving complete growth suppression of A. baumannii at 1.56 μM. Although quantitative real-time polymerase chain reaction did not reveal significant reductions in pdxA transcript levels, ELISA quantification revealed an approximately 80% reduction in intracellular vitamin B6, indicating translational inhibition rather than mRNA degradation. The pdxA-targeting CPP–PNA showed negligible activity against other Gram-negative or Gram-positive species, indicating high target specificity; no detectable cytotoxicity in human cells was observed even at relatively high concentrations. CPP–PNA conjugates targeting pdxA interfere with vitamin B6 biosynthesis, leading to growth inhibition of A. baumannii. These findings support PNA as a promising antisense antimicrobial platform that inhibits multidrug-resistant A. baumannii by blocking vitamin B6 biosynthesis. Full article

Abdominal aortic aneurysm (AAA) is a life-threatening disease. Although AAA is generally asymptomatic, the mortality rate remains very high once rupture occurs, even with successful treatment. The pathophysiology of AAA involves inflammatory cell infiltration, smooth muscle cell apoptosis, and extracellular matrix degradation. However, there are various unclear aspects of pathophysiology due to cellular heterogeneity and multifactorial disease. Moreover, there are no blood biomarkers or available pharmacological drugs for AAA. Extracellular vesicles (EVs) are lipid bilayer particles released from every type of cell for intercellular communication. EVs include proteins, DNA, RNA (mRNA, microRNA), and lipids. EV cargos are delivered to recipient cells and modulate their biological effects. Although fewer studies have investigated EVs in AAA than in other cardiovascular diseases with similar molecular mechanisms, recent research indicates that EVs play a significant role in AAA development. Further research on EVs and AAA will contribute to the elucidation of AAA pathophysiology and the development of novel pharmacological drugs. In this review, we summarize the EV-associated pathophysiology, EV-based biomarkers, and EV-based treatment strategies in AAA. We also discuss the prospects for EVs research in AAA. Full article