Search Results (189)

Polymethyl methacrylate nanoparticles functionalized with three different compounds, acrylic acid (AA), curcumin (CUR), and fumaramide (FA), were tested in a two-step solid–liquid extraction process (extraction and stripping) for yttrium recovery. In both stages, the best conditions were determined: pH, solid–liquid ratio and the compound with the highest affinity for yttrium recovery, obtaining 90% of efficiency for both stages in a single work cycle. The results obtained by SEM ruled out the growing of nanoparticles by swelling and confirmed the formation of structural arrangements by the addition of the metal to the system. In addition, there is evidence that the recovery process can be selective considering the mixing of rare earth elements through changes in pH. Using isothermal titration calorimetry (ITC), the thermodynamic properties of the extraction process were calculated, understanding the system as the union of a macromolecule and a ligand. The results showed that the extraction process was spontaneous and highly entropic. Full article

Folic acid (FA) is used as a targeting ligand for targeted drug delivery to tumor cells, some types of which overexpress folate receptors on their surface. However, while the preparation of conjugates containing FA may comprise a multi-step process, FA presents low photostability under UV irradiation. In addition, FA undergoes radiolysis under the action of ionizing radiation, which is utilized for drug sterilization. In this study, we investigate the stability of FA in a conjugate (FA-PVP-C₆₀) with fullerene C₆₀ and polyvinylpyrrolidone under the action of UV (205–400 nm) and electron irradiation (doses from 2 to 8 kGy) at different pH (4.5, 7.2, 10.7). The degradation of FA is studied using fluorescence and UV–Vis spectroscopy. It is found that the fullerene C₆₀ in the FA-PVP-C₆₀ conjugate suppresses the degradation of FA during both photolysis and radiolysis, which is confirmed by the decrease in the quantum yield of fluorescence and the radiation chemical yield of FA destruction accompanied by increasing fullerene content in the conjugate (from 2.8 to 10 wt.%). Full article

Background/Objectives: Cellular aging represents a crucial element in the progression of musculoskeletal diseases, contributing to muscle atrophy, functional decline, and alterations in bone turnover, which promote fragility fractures. However, knowledge about expression patterns of factors potentially involved in aging and senescence at the tissue level remains limited. Our pilot study aimed to characterize the expression profile of cell cycle regulators, factors released by aged cells, and sirtuin 1 (SIRT1) in the muscle tissue of 26 elderly patients undergoing hip arthroplasty, including 13 with low-energy fracture and 13 with osteoarthritis (OA). Methods: The mRNA expression levels of cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin-dependent kinase inhibitor 1B (CDKN1B), cyclin-dependent kinase inhibitor 2A (CDKN2A), p53, tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-15 (IL-15), chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 3 (CCL3), growth differentiation factor 15 (GDF15), and SIRT1 were evaluated in muscle tissue by qRT-PCR. In addition, immunohistochemistry and Western blotting analysis were conducted to measure the protein levels of SIRT1. Results: A marked muscle atrophy was observed in fractured patients compared to the OA group, in association with an up-regulation of cell cycle regulators and factors released by the aged cells. The expression of matrix metallopeptidase 3 (MMP3), plasminogen activator inhibitor 1 (PAI-1), and fas cell surface death receptor (FAS) was also investigated, although no significant differences were observed between the two experimental groups. Notably, SIRT1 expression was significantly higher in OA patients, confirming its role in maintaining muscle health during aging. Conclusions: Further studies will be needed to clarify the role of SIRT1 in the senescence characteristic of age-related musculoskeletal disorders, counteracting the muscle atrophy that predisposes to fragility fractures. Full article

Kujigamberol, a dinorlabdane compound isolated from Kuji amber, exerts multiple biological effects, including anti-allergic and anti-inflammatory activities. The present study demonstrated that kujigamberol inhibited cytokine production by T cells. In response to a phorbol 12-myristate 13-acetate (PMA) and ionomycin (IM) stimulation, kujigamberol suppressed interferon-γ (IFN-γ) and interleukin-2 (IL-2) mRNA expression in murine T-cell lymphoma BW5147 cells stably transfected with the T-box transcription factor eomesodermin. IL-4 and Fas ligand mRNA expression was also inhibited by kujigamberol. In the murine cytotoxic T-cell line CTLL-2, kujigamberol more strongly decreased IFN-γ mRNA expression induced by IM alone than that induced by the combination of PMA and IM. A luciferase reporter assay showed that kujigamberol preferentially reduced nuclear factor of activated T cell (NFAT)-dependent transcription in human embryonic kidney 293T cells. Unlike the calcineurin inhibitor FK506, kujigamberol did not markedly affect NFATc2 protein levels in BW5147 cells but interfered with the binding of NFATc2 to the IFN-γ and IL-2 promoters. These results indicate that kujigamberol inhibited IFN-γ and IL-2 mRNA expression by preventing the binding of NFATc2 to their promoters; therefore, it has potential as an immunosuppressive agent. Full article

Obesity and cardiometabolic diseases (CMDs) have reached epidemic levels. Dysregulation of lipid metabolism is a risk factor for obesity and CMDs. Lipids are energy substrates, essential components of cell membranes, and signaling molecules. Fatty acids (FAs) are the major components of lipids and are classified based on carbon chain length and number, position, and stereochemistry of double bonds. They exert differential impacts on CMDs, such that saturated fat increases risks while very-long-chain n-3 FAs provide benefits. The functionalities of FAs, modulating membrane properties, acting as ligands for receptors, and serving as precursors for lipid mediators, are vital for insulin signaling, lipid metabolism, oxidative stress, and inflammatory response, collectively contributing to cardiometabolic health. This review examines recent advances in the characteristics and functional properties of different FAs in lipid structures, signaling pathways, and cellular metabolism to better understand the differential roles of different types of FAs in obesity and cardiometabolic health. Full article

Ocular graft versus host disease (oGVHD) is a common complication of allogeneic hematopoietic stem cell transplantation and may be associated with dry eye disease and chronic inflammation and fibrosis. Immune dysregulation, particularly the Th1/Th2 imbalance, plays a key role in the progression of oGVHD. This case study presents two oGVHD patients (a 20-year-old with acute oGVHD and a 59-year-old with chronic oGVHD), analyzing clinical dry eye parameters (Schirmer test I, tear film break-up time, Ocular Surface Disease Index (OSDI), and kerato-conjunctival staining) alongside tear biomarkers. A 27-plex tear cytokine analysis was performed using the Luminex200 platform, assessing various biomarkers against a control group-defined normal range. Key biomarkers included beta2-microglobulin (β2-MG), complement components, chemokines, growth factors, and both pro-inflammatory and anti-inflammatory cytokines, as well a series of soluble ligand and receptors. The study identified distinct biomarker progression patterns during topical corticosteroid treatment in the acute oGHVD patient, suggesting potential shifts in Th1/Th2 responses as the disease progressed. Notably, the soluble CD27, TNF-related apoptosis-inducing ligand (TRAIL) receptor 2 (TRAIL-R2), chemokine ligand 2 (CCL2), and IL-1β, initially elevated, normalized during treatment, while tear-soluble Fas remained highly elevated (>400-fold). Conversely, soluble TRAIL, which was initially at very low levels (100-fold lower), increased during treatment and reached normal tear levels, coinciding with improvements in the clinical ocular inflammation symptoms and OSDI score. This case study also highlights potential differences between acute and chronic oGVHD, particularly in the distinct patterns of novel tear biomarkers such as CD27, TRAIL/TRAIL-R2, and CCL2. Enhancing our understanding of biomarker dynamics may improve disease monitoring and pave the way for personalized management strategies to improve patient outcomes. Full article

Fusidic acid (FA), a tetracyclic triterpenoid, has been approved to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. However, there are few reports about FA derivatives with high efficacy superior to FA, manifesting the difficulty of discovering the derivatives based on experience-based drug design. In this study, we employed a stepwise method to discover novel FA derivatives. First, molecular dynamics (MD) simulations were performed to identify the molecular mechanism of FA against elongation factor G (EF-G) and drug resistance. Then, we utilized a scaffold decorator to design novel FA derivatives at the 3- and 21-positions of FA. The ligand-based and structure-based screening models, including Chemprop and RTMScore, were employed to identify promising hits from the generated set. Ten generated FA derivatives with high efficacy in the Chemprop and RTMScore models were synthesized for in vitro testing. Compounds 4 and 10 demonstrated a 2-fold increase in potency against MRSA strains compared to FA. This study highlights the significant impact of AI-based methods on the design of novel FA derivatives with drug efficacy, which provides a new approach for drug discovery. Full article

Manganese (Mn) is widely used in many industries but is also biologically harmful when abundant in the environment. While there are several commercially available methods for manganese removal from water, efficient and cost-effective solutions for addressing manganese contamination in diverse environmental matrices remain limited. In this study, we developed a new method for removing Mn from contaminated lakes using an aptamer. The Seo-Gok Reservoir was selected as the study area due to its significant levels of Mn contamination. We first screened aptamers that bind to Mn through systematic evolution of ligands by exponential enrichment (SELEX). Among 6 aptamers (from FA-M1 to FA-M6), the FA-M1 aptamer exhibited the highest binding affinity to Mn with the lowest Kd value of 4.56 × 10⁻⁹ M. Potential Mn-binding sites in aptamers were predicted by analyzing the secondary structures. To confirm the binding of Mn to the proposed region, we evaluated the sequence homology of the screened aptamers. Aptamer specificity was evaluated against diverse metals. We demonstrated that FA-M1 could remove more than 95% of Mn from an aqueous sample; 99.9% of this Mn could then be recovered. FA-M1 removed more than 90% of Mn from a sample of the Mn-contaminated Seo-Gok Reservoir, indicating that aptamers can be utilized to remove Mn ions from the environment. Full article

Background/Objectives: Kidneys are fatty acid (FA)-consuming organs that use adenosine triphosphate (ATP) for tubular functions, including endocytosis for protein reabsorption to prevent urinary protein loss. Peroxisome proliferator-activated receptor α (PPARα) is a master regulator of FA metabolism and energy production, with high renal expression. Although polyunsaturated fatty acids (PUFAs) are essential nutrients that are natural PPARα ligands, their role in tubular protein reabsorption remains unclear. As clinical PUFA deficiency occurs in humans under various conditions, we used a mouse model that mimics these conditions. Methods: We administered a 2-week intraperitoneal protein-overload (PO) treatment to mice that had been continuously fed a PUFA-deficient diet. We compared the phenotypic changes with those in mice fed a standard diet and those in mice fed a PUFA-deficient diet with PUFA supplementation. Results: In the absence of PO, the PUFA-deficient diet induced increased lysosomal autophagy activation; however, other phenotypic differences were not detected among the diet groups. In the PO experimental condition, the PUFA-deficient diet increased daily urinary protein excretion and tubular lysosomes; suppressed adaptive endocytosis activation, which was probably enhanced by continuous autophagy activation; and worsened FA metabolism and PPARα-mediated responses to PO, which disrupted renal energy homeostasis. However, these changes were attenuated by PUFA supplementation at the physiological intake level. Conclusions: PUFAs are essential nutrients for the tubular adaptive reabsorption response against urinary protein loss. Therefore, active PUFA intake may be important for patients with kidney disease-associated proteinuria, especially those with various PUFA deficiency-inducing conditions. Full article

In celiac disease (CeD), interleukin 15 (IL-15) affects the epithelial barrier by acting on intraepithelial lymphocytes, promoting interferon γ (IFN-γ) production and inducing strong cytotoxic activity as well as eliciting apoptotic death of enterocytes by the Fas/Fas ligand system. This study investigates the effects of a monoclonal antibody neutralizing the effects of IL-15 (aIL-15) on tissue-damaging immune response in untreated CeD patients by using an organ culture system. Jejunal biopsies from 10 untreated CeD patients were cultured ex vivo with or without aIL-15. Epithelial expressions of CD95/Fas, HLA-E and perforin were analyzed by immunohistochemistry. Apoptosis was detected in the epithelium by using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Additionally, the surface epithelium compartment of ex vivo cultured biopsy samples was isolated by laser capture microdissection (LCM). RNA from each LCM sample was extracted and the relative expression of IFN-γ was evaluated by quantitative reverse transcriptase-PCR (qRT-PCR). Biopsies cultured with the aIL-15 antibody showed a reduction in Fas, HLA-E and perforin epithelial expression, as well as a decrease in epithelial TUNEL+ cells compared to biopsies cultured without the aIL-15 antibody. Moreover, downregulation of epithelial IFN-γ expression was recorded in biopsies incubated with aIL-15, compared to those cultured without aIL-15. Our findings suggest that neutralizing the effects of IL-15 in ex vivo cultured untreated CeD intestinal mucosa could block apoptosis by downregulating Fas and HLA-E expression and the release of cytotoxic proteins, such as perforin. Furthermore, it can dampen the hyperactive immune response by reducing IFN-γ expression. More generally, our study provides new evidence for the effects of anti-IL-15 neutralizing monoclonal antibodies in preventing or repairing epithelial damage and further supports the concept that IL-15 is a meaningful therapeutic target in CeD, or inflammatory diseases associated with the upregulation of IL-15. Full article

Two Fe-based hybrids, [SiO₂@NP(Ph)₂/Fe^II/PP₃] and [SiO₂@NP(t-Bu)₂/Fe^II/PP₃], were synthesized using the double-ligand approach by covalently grafting NP ligands onto the surface of SiO₂. Both catalytic systems were evaluated for H₂ production through formic acid dehydrogenation (FADH), revealing important efficiency without requiring additional additives and/or co-catalysts. During the continuous addition of FA, [SiO₂@NP(Ph)₂/Fe^II/PP₃] and [SiO₂@NP(t-Bu)₂/Fe^II/PP₃] demonstrated great stability, achieving total TONs = 20,636 and 20,854, respectively. FT-IR and Raman spectroscopy provided insights into the role of NP ligands, such as NP(Ph)₂ and NP(t-Bu)₂, on the assembly and structural configuration of active hybrid Fe catalysts and their ability to dehydrogenate formic acid. Additional studies, including in situ mapping of the solution potential (E_h) of the catalytic reaction and an Arrhenius study of the activation energy (E_a), revealed a correlation between E_a and H₂ production rates: the system [SiO₂@NP(Ph)₂/Fe^II/PP₃] with an E_a = 29.4 KJ/mol shows an H₂ production rate of 58 mL-H₂/min, while [SiO₂@NP(t-Bu)₂/Fe^II/PP₃] with a E_a = 50.6 KJ/mol shows an H₂ production rate of 55 mL-H₂/min. This is the first example of a heterogeneous FADH system where the original strategy of a “double-ligand” has been demonstrated for homogeneous FADH catalytic systems. Herein we demonstrate that we can engineer a decrease in the activation barrier Ea via two synergistic steps: (i) via grafting of the NP ligand onto SiO₂ and (ii) using PP₃ as double ligand. This strategy leads to a boost in the H₂ production efficiency of [SiO₂@NP(Ph)₂/Fe^II/PP₃] as a heterogeneous catalyst, which for the first time has been shown to be able to outperform the parental reference/homogenous catalyst [Fe^II/PP₃]. Full article

The apoptotic molecule Fas and its ligand FasL are involved in the process of T-lymphocyte death, which may lead to lymphopenia, a characteristic of severe coronavirus disease 2019 (COVID-19). In this study, we investigated the influence of polymorphisms in the FAS and FASL genes, FAS and FASL gene expression, and plasma cytokine levels on COVID-19 severity and long COVID occurrence. A total of 116 individuals with severe COVID-19 and 254 with the non-severe form of the disease were evaluated. In the post-COVID-19 period, samples from 196 individuals with long COVID and 67 from people who did not have long COVID were included. Genotyping and quantification of gene expression were performed via real-time PCR, and cytokine measurement was performed via flow cytometry. The AA genotype for FAS rs1800682 (A/G) and the TT genotype for FASL rs763110 (C/T) were associated with increased FAS and FASL gene expression, respectively (p < 0.005). Higher plasma IFN-γ levels were associated with higher FAS and FASL gene expression (p < 0.05). Among individuals with non-severe COVID-19, carriers of the AA genotype for FAS rs1800682 (A/G) had higher levels of FAS expression, more symptoms, and higher IFN-γ levels (p < 0.05). No association of the evaluated markers with long COVID were observed. The AA genotype of FAS rs1800682 (A/G) and the TT genotype of FASL rs763110 (C/T) influence the levels of FAS and FASL gene expression. Higher gene expression of FAS and FASL may lead to greater inflammation in COVID-19 patients, with higher levels of IFN-γ and T lymphocyte death. Full article

Bone marrow transplantation (BMT) is mainly performed to restore an anti-tumor immune response, called the graft-versus-tumor (GVT) effect, against leukemia, myeloma and lymphoma. This GVT reactivity is driven by donor T cells, and it can also cause lethal graft-versus-host disease (GVHD). We previously demonstrated that the colonization of mice with helminths preserves the GVT response while suppressing GVHD. As the T helper-2 (Th2) pathway is critical to helminthic immune regulation, we asked whether the genetic induction of Th2 signaling in donor T cells can restore helminthic immune regulation after BMT. Our studies utilized transgenic donor T lymphocytes that overexpress a constitutively active form of the Th2-associated transcription factor STAT6. Constitutively active STAT6 sustained the GVT response without causing severe acute GVHD, where transgenic T cells generated robust quantities of cytotoxic proteins important in GVT response, such as granzymes A and B, interferon-γ and Fas ligand, in addition to generating high quantities of Th2/regulatory cytokines. Bioinformatic analysis based on chromosome immune precipitation experiments indicated that STAT6 stimulates the expression of granzymes directly. Thus, in preserving the GVT response without causing GVHD mortality, our results indicate the therapeutic potential of restoring helminthic immune modulation by targeting STAT6 and STAT6-dependent T cell maturation. Full article

Background/Objectives: Perillyl alcohol (POH), a plant-derived compound, has demonstrated anti-tumor activity across various human cancers. Understanding the regulatory pathways through which POH exerts its effects is crucial for identifying new therapeutic opportunities and exploring potential drug repositioning strategies. Therefore, this scoping review aims to provide a comprehensive overview of the metabolic and regulatory pathways involved in the anticancer effects of POH, based on in vitro evidence. Methods: Following the PRISMA-ScR 2018 guidelines, a systematic search was conducted in the PUBMED, Web of Science, and Scopus databases. Results: A total of 39 studies were included, revealing that POH exerts its biological effects by modulating several pathways, including the regulation of cyclins, CDKs, and p21, thereby affecting cell cycle progression. It inhibits growth and promotes cell death by attenuating AKT phosphorylation, reducing PARP-1 activity, increasing caspase activity and the FAS receptor and its ligand FASL. Additionally, POH reduces ERK phosphorylation, inhibits RAS protein isoprenylation, and decreases Na/K-ATPase activity. Conclusions: In conclusion, this review delineates the key regulatory pathways responsible for mediating the biological effects of POH in cancer. Full article

Cell survival and death are intricately governed by apoptosis, a meticulously controlled programmed cell death. Apoptosis is vital in facilitating embryonic development and maintaining tissue homeostasis and immunological functioning. It is a complex interplay of intrinsic and extrinsic signaling pathways that ultimately converges on executing the apoptotic program. The extrinsic pathway is initiated by the binding of death ligands such as TNF-α and Fas to their respective receptors on the cell surface. In contrast, the intrinsic pathway leads to increased permeability of the outer mitochondrial membrane and the release of apoptogenic factors like cytochrome c, which is regulated by the Bcl-2 family of proteins. Once activated, these pathways lead to a cascade of biochemical events, including caspase activation, DNA fragmentation, and the dismantling of cellular components. Dysregulation of apoptosis is implicated in various disorders, such as cancer, autoimmune diseases, neurodegenerative disorders, and cardiovascular diseases. This article focuses on elucidating the molecular mechanisms underlying apoptosis regulation, to develop targeted therapeutic strategies. Modulating apoptotic pathways holds immense potential in cancer treatment, where promoting apoptosis in malignant cells could lead to tumor regression. This article demonstrates the therapeutic potential of targeting apoptosis, providing options for treating cancer and neurological illnesses. The safety and effectiveness of apoptosis-targeting drugs are being assessed in ongoing preclinical and clinical trials (phase I–III), opening the door for more effective therapeutic approaches and better patient outcomes. Full article