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Medicina (Kaunas, Lithuania) Jun 2024Despite the decreased rates in inflammatory bowel disease (IBD) colectomies due to high advances in therapeutic options, a significant number of patients still require... (Review)
Review
Despite the decreased rates in inflammatory bowel disease (IBD) colectomies due to high advances in therapeutic options, a significant number of patients still require proctocolectomy with ileal pouch-anal anastomosis (IPPA) for ulcerative colitis (UC). Pouchitis is the most common complication in these patients, where up to 60% develop one episode of pouchitis in the first two years after UC surgery with IPAA with severe negative impact on their quality of life. Acute cases usually respond well to antibiotics, but 15% of patients will still develop a refractory disease that requires the initiation of advanced immunosuppressive therapies. For chronic idiopathic pouchitis, current recommendations suggest using the same therapeutic options as for IBD in terms of biologics and small molecules. However, the available data are limited regarding the effectiveness of different biologics or small molecules for the management of this condition, and all evidences arise from case series and small studies. Vedolizumab is the only biologic agent that has received approval for the treatment of adult patients with moderately to severely active chronic refractory pouchitis. Despite the fact that IBD treatment is rapidly evolving with the development of novel molecules, the presence of pouchitis represents an exclusion criterion in these trials. Recommendations for the approach of these conditions range from low to very low certainty of evidence, resulting from small randomized controlled trials and case series studies. The current review focuses on the therapeutic management of idiopathic pouchitis.
Topics: Humans; Pouchitis; Inflammatory Bowel Diseases; Chronic Disease; Proctocolectomy, Restorative; Acute Disease; Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Anti-Bacterial Agents
PubMed: 38929596
DOI: 10.3390/medicina60060979 -
Antioxidants (Basel, Switzerland) Jun 2024Semaphorin 3A (SEMA3A), a nerve-repellent factor produced by keratinocytes, has an inhibitory effect on nerve extension to the epidermis. Epidermal innervation is...
Semaphorin 3A (SEMA3A), a nerve-repellent factor produced by keratinocytes, has an inhibitory effect on nerve extension to the epidermis. Epidermal innervation is involved in pruritus in inflammatory skin diseases such as atopic dermatitis (AD) and dry skin. We previously reported that tapinarof, a stilbene molecule, upregulates SEMA3A in human keratinocytes. We also showed that this mechanism is mediated via the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, and the nuclear factor erythroid 2-related factor 2 (NRF2) axis. Since some stilbenes activate AHR and NRF2, we attempted to identify other stilbenes that upregulate SEMA3A. We analyzed normal human epidermal keratinocytes (NHEKs) treated with 11 types of stilbenes and examined SEMA3A expression. We found that resveratrol and pinostilbene, antioxidant polyphenols, upregulated SEMA3A and increased nuclear AHR and NRF2 expression. In addition, AHR knockdown by small interfering RNA (siRNA) transfection abolished the NRF2 nuclear expression. Furthermore, AHR and NRF2 knockdown by siRNA transfection abrogated resveratrol- and pinostilbene-induced SEMA3A upregulation. Finally, we confirmed that resveratrol and pinostilbene increased SEMA3A promoter activity through NRF2 binding using ChIP-qPCR analysis. These results suggest that resveratrol and pinostilbene upregulate SEMA3A via the AHR-NRF2 axis in human keratinocytes.
PubMed: 38929171
DOI: 10.3390/antiox13060732 -
Antioxidants (Basel, Switzerland) Jun 2024Oxidative stress can damage tissues and cells, and their resilience or susceptibility depends on the robustness of their antioxidant mechanisms. The latter include small... (Review)
Review
Oxidative stress can damage tissues and cells, and their resilience or susceptibility depends on the robustness of their antioxidant mechanisms. The latter include small molecules, proteins, and enzymes, which are linked together in metabolic pathways. Red blood cells are particularly susceptible to oxidative stress due to their large number of hemoglobin molecules, which can undergo auto-oxidation. This yields reactive oxygen species that participate in Fenton chemistry, ultimately damaging their membranes and cytosolic constituents. Fortunately, red blood cells contain robust antioxidant systems to enable them to circulate and perform their physiological functions, particularly delivering oxygen and removing carbon dioxide. Nonetheless, if red blood cells have insufficient antioxidant reserves (e.g., due to genetics, diet, disease, or toxin exposure), this can induce hemolysis in vivo or enhance susceptibility to a "storage lesion" in vitro, when blood donations are refrigerator-stored for transfusion purposes. Ergothioneine, a small molecule not synthesized by mammals, is obtained only through the diet. It is absorbed from the gut and enters cells using a highly specific transporter (i.e., SLC22A4). Certain cells and tissues, particularly red blood cells, contain high ergothioneine levels. Although no deficiency-related disease has been identified, evidence suggests ergothioneine may be a beneficial "nutraceutical." Given the requirements of red blood cells to resist oxidative stress and their high ergothioneine content, this review discusses ergothioneine's potential importance in protecting these cells and identifies knowledge gaps regarding its relevance in enhancing red blood cell circulatory, storage, and transfusion quality.
PubMed: 38929156
DOI: 10.3390/antiox13060717 -
Antioxidants (Basel, Switzerland) May 2024Imbalances in the redox state of the liver arise during metabolic processes, inflammatory injuries, and proliferative liver disorders. Acute exposure to intracellular... (Review)
Review
The Coming Age of Antisense Oligos for the Treatment of Hepatic Ischemia/Reperfusion (IRI) and Other Liver Disorders: Role of Oxidative Stress and Potential Antioxidant Effect.
Imbalances in the redox state of the liver arise during metabolic processes, inflammatory injuries, and proliferative liver disorders. Acute exposure to intracellular reactive oxygen species (ROS) results from high levels of oxidative stress (OxS) that occur in response to hepatic ischemia/reperfusion injury (IRI) and metabolic diseases of the liver. Antisense oligonucleotides (ASOs) are an emerging class of gene expression modulators that target RNA molecules by Watson-Crick binding specificity, leading to RNA degradation, splicing modulation, and/or translation interference. Here, we review ASO inhibitor/activator strategies to modulate transcription and translation that control the expression of enzymes, transcription factors, and intracellular sensors of DNA damage. Several small-interfering RNA (siRNA) drugs with N-acetyl galactosamine moieties for the liver have recently been approved. Preclinical studies using short-activating RNAs (saRNAs), phosphorodiamidate morpholino oligomers (PMOs), and locked nucleic acids (LNAs) are at the forefront of proof-in-concept therapeutics. Future research targeting intracellular OxS-related pathways in the liver may help realize the promise of precision medicine, revolutionizing the customary approach to caring for and treating individuals afflicted with liver-specific conditions.
PubMed: 38929116
DOI: 10.3390/antiox13060678 -
Antioxidants (Basel, Switzerland) May 2024Aquaporins are membrane pores regulating the transport of water, glycerol, and other small molecules across membranes. Among 13 human aquaporins, six have been shown to...
Aquaporins are membrane pores regulating the transport of water, glycerol, and other small molecules across membranes. Among 13 human aquaporins, six have been shown to transport HO and are therefore called peroxiporins. Peroxiporins are implicated in cancer development and progression, partly due to their involvement in HO transport. Oxidative stress is linked to breast cancer development but is also a mechanism of action for conventional chemotherapy. The aim of this study is to investigate the effects of prolonged oxidative stress on Aquaporin 3 (AQP3), Aquaporin 5 (AQP5), and signaling pathways in breast cancer cell lines of different malignancies alongside a non-tumorigenic breast cell line. The prolonged oxidative stress caused responses in viability only in the cancer cell lines, while it affected cell migration in the MCF7 cell line. Changes in the localization of NRF2, a transcription factor involved in oxidative stress response, were observed only in the cancer cell lines, and no effects were recorded on its downstream target proteins. Moreover, the prolonged oxidative stress caused changes in AQP3 and AQP5 expression only in the cancer cell lines, in contrast to their non-malignant counterparts. These results suggest peroxiporins are potential therapeutic targets in cancer treatment. However, further research is needed to elucidate their role in the modulation of therapy response, highlighting the importance of research on this topic.
PubMed: 38929065
DOI: 10.3390/antiox13060626 -
International Journal of Molecular... Jun 2024Salt stress seriously affects crop growth, leading to a decline in crop quality and yield. Application of exogenous substances to improve the salt tolerance of crops and...
Salt stress seriously affects crop growth, leading to a decline in crop quality and yield. Application of exogenous substances to improve the salt tolerance of crops and promote their growth under salt stress has become a widespread and effective means. Eugenol is a small molecule of plant origin with medicinal properties such as antibacterial, antiviral, and antioxidant properties. In this study, tobacco seedlings were placed in Hoagland's solution containing NaCl in the presence or absence of eugenol, and physiological indices related to stress tolerance were measured along with transcriptome sequencing. The results showed that eugenol improved the growth of tobacco seedlings under salt stress. It promoted carbon and nitrogen metabolism, increased the activities of nitrate reductase (NR), sucrose synthase (SS), and glutamine synthetase (GS) by 31.03, 5.80, and 51.06%. It also activated the enzymatic and non-enzymatic antioxidant systems, reduced the accumulation of reactive oxygen species in the tobacco seedlings, and increased the activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) by 24.38%, 18.22%, 21.60%, and 28.8%, respectively. The content of glutathione (GSH) was increased by 29.49%, and the content of superoxide anion (O) and malondialdehyde (MDA) were reduced by 29.83 and 33.86%, respectively. Promoted osmoregulation, the content of Na decreased by 34.34, K increased by 41.25%, and starch and soluble sugar increased by 7.72% and 25.42%, respectively. It coordinated hormone signaling in seedlings; the content of abscisic acid (ABA) and gibberellic acid 3 (GA) increased by 51.93% and 266.28%, respectively. The transcriptome data indicated that the differentially expressed genes were mainly enriched in phenylpropanoid biosynthesis, the MAPK signaling pathway, and phytohormone signal transduction pathways. The results of this study revealed the novel role of eugenol in regulating plant resistance and provided a reference for the use of exogenous substances to alleviate salt stress.
Topics: Nicotiana; Seedlings; Antioxidants; Signal Transduction; Eugenol; Gene Expression Regulation, Plant; Salt Stress; Plant Growth Regulators; Salt Tolerance; Reactive Oxygen Species
PubMed: 38928476
DOI: 10.3390/ijms25126771 -
International Journal of Molecular... Jun 2024Chitosan is a natural polymer with numerous biomedical applications. The cellular activity of chitosan has been studied in various types of cancer, including melanoma,...
Chitosan is a natural polymer with numerous biomedical applications. The cellular activity of chitosan has been studied in various types of cancer, including melanoma, and indicates that these molecules can open new perspectives on antiproliferative action and anticancer therapy. This study analyzes how different chitosan conformations, such as α-chitosan (CH) or β-oligochitosan (CO), with various degrees of deacetylation (DDA) and molar mass (MM), both in different concentrations and in CH-CO mixtures, influence the cellular processes of SK-MEL-28 melanocytes, to estimate the reactivity of these cells to the applied treatments. The in vitro evaluation was carried out, aiming at the cellular metabolism (MTT assay), cellular morphology, and chitinase-like glycoprotein YKL-40 expression. The in vitro effect of the CH-CO mixture application on melanocytes is obvious at low concentrations of α-chitosan/β-oligochitosan (1:2 ratio), with the cell's response supporting the hypothesis that β-oligo-chitosan amplifies the effect. This oligochitosan mixture, favored by the β conformation and its small size, penetrates faster into the cells, being more reactive when interacting with some cellular components. Morphological effects expressed by the loss of cell adhesion and the depletion of YKL-40 synthesis are significant responses of melanocytes. β-oligochitosan (1.5 kDa) induces an extension of cytophysiological effects and limits the cell viability compared to α-chitosan (400-900 kDa). Statistical analysis using multivariate techniques showed differences between the CH samples and CH-CO mixtures.
Topics: Chitosan; Melanocytes; Humans; Chitin; Oligosaccharides; Chitinase-3-Like Protein 1; Cell Survival; Cell Proliferation; Cell Line, Tumor; Melanoma
PubMed: 38928474
DOI: 10.3390/ijms25126768 -
A Quantitative Human Red Blood Cell Agglutination Assay for Characterisation of Galectin Inhibitors.International Journal of Molecular... Jun 2024Galectins are a family of beta-galactoside-binding proteins that are characterised by their carbohydrate recognition domain (CRD) and include galectin-1 and galectin-3....
Galectins are a family of beta-galactoside-binding proteins that are characterised by their carbohydrate recognition domain (CRD) and include galectin-1 and galectin-3. These galectins have been implicated in numerous diseases due to their pleiotropic nature, including cancer and fibrosis, with therapeutic inhibitors being clinically developed to block the CRD. One of the early methods developed to characterise these galectins was the hemagglutination of red blood cells. Although it is insightful, this approach has been hampered by a lack of sensitivity and accurate quantification of the agglutination observed. In this study, we aimed to validate a more precise and quantitative method to enable the further investigation of differences between galectins in respect to agglutination induction in different blood groups, as well as the characterisation of small molecule inhibitors. Quantification of hemagglutination was shown to be optimal using U-bottom plates imaged and analysed with FIJI ImageJ rather than flat-bottom plates read for absorbance on an optical density plate reader. Galectin-3-induced red blood cell agglutination efficacy increased significantly from blood group O to A to B. However, for both the galectin-1 monomer and concatemer, a more comparable effect was observed between blood group B and O, but with more potent effects than in blood group A. Inhibition assays for both galectin-3 and galectin-1 induced-hemagglutination were able to demonstrate clear concentration responses and expected selectivity profiles for a set of small-molecule glycomimetics, confirming the historical profiles obtained in biochemical binding and functional cellular assays.
Topics: Humans; Erythrocytes; Hemagglutination; Galectins; Galectin 1; Galectin 3; Agglutination Tests; Hemagglutination Tests; Agglutination
PubMed: 38928462
DOI: 10.3390/ijms25126756 -
International Journal of Molecular... Jun 2024Affinity reagents, or target-binding molecules, are quite versatile and are major workhorses in molecular biology and medicine. Antibodies are the most famous and... (Review)
Review
Affinity reagents, or target-binding molecules, are quite versatile and are major workhorses in molecular biology and medicine. Antibodies are the most famous and frequently used type and they have been used for a wide range of applications, including laboratory techniques, diagnostics, and therapeutics. However, antibodies are not the only available affinity reagents and they do have significant drawbacks, including laborious and costly production. Aptamers are one potential alternative that have a variety of unique advantages. They are single stranded DNA or RNA molecules that can be selected for binding to many targets including proteins, carbohydrates, and small molecules-for which antibodies typically have low affinity. There are also a variety of cost-effective methods for producing and modifying nucleic acids in vitro without cells, whereas antibodies typically require cells or even whole animals. While there are also significant drawbacks to using aptamers in therapeutic applications, including low in vivo stability, aptamers have had success in clinical trials for treating a variety of diseases and two aptamer-based drugs have gained FDA approval. Aptamer development is still ongoing, which could lead to additional applications of aptamer therapeutics, including antitoxins, and combinatorial approaches with nanoparticles and other nucleic acid therapeutics that could improve efficacy.
Topics: Aptamers, Nucleotide; Humans; Animals; SELEX Aptamer Technique
PubMed: 38928448
DOI: 10.3390/ijms25126742 -
International Journal of Molecular... Jun 2024Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic...
Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in "primary human ATC cells" (pATCs) with transforming striatin (STRN)-ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN-ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN-ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN-ALK), particularly in those with STRN-ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.
Topics: Humans; Crizotinib; Thyroid Carcinoma, Anaplastic; Anaplastic Lymphoma Kinase; Cell Proliferation; Protein Kinase Inhibitors; Apoptosis; Thyroid Neoplasms; Male; Female; Antineoplastic Agents; Middle Aged; Cell Movement; Aged; Oncogene Proteins, Fusion; Tumor Cells, Cultured; Cell Line, Tumor; Calmodulin-Binding Proteins; Membrane Proteins; Nerve Tissue Proteins
PubMed: 38928438
DOI: 10.3390/ijms25126734