In plants, there is a complex and multilevel network of the antioxidative system (AOS) operating to counteract harmful reactive species (RS), the foremost important of which are reactive oxygen ...species (ROS), and maintain homeostasis within the cell. Specific AOSs for plant cells are, first and foremost, enzymes of the glutathione-ascorbate cycle (Asc-GSH), followed by phenolic compounds and lipophilic antioxidants like carotenoids and tocopherols. Evidence that plant cells have excellent antioxidative defense systems is their ability to survive at H
O
concentrations incompatible with animal cell life. For the survival of stressed plants, it is of particular importance that AOS cooperate and participate in redox reactions, therefore, providing better protection and regeneration of the active reduced forms. Considering that plants abound in antioxidant compounds, and humans are not predisposed to synthesize the majority of them, new fields of research have emerged. Antioxidant potential of plant compounds has been exploited for anti-aging formulations preparation, food fortification and preservation but also in designing new therapies for diseases with oxidative stress implicated in etiology.
Antimicrobial Peptides (AMPs) are one of the most common components of the innate immune system that protect multicellular organisms against microbial invasion. The vast majority of AMPs are isolated ...from the frog skin. Anuran (frogs and toads) skin contains abundant AMPs that can be developed therapeutically. Such peptides are a unique but diverse group of molecules. In general, more than 50% of the amino acid residues form the hydrophobic part of the molecule. Normally, there are no conserved structural motifs responsible for activity, although the vast majority of the AMPs are cationic due to the presence of multiple lysine residues; this cationicity has a close relationship with antibacterial activity. Notably, recent evidence suggests that synthesis of AMPs in frog skin may confer an advantage on a particular species, although they are not essential for survival. Frog skin AMPs exert potent activity against antibiotic-resistant bacteria, protozoa, yeasts, and fungi by permeating and destroying the plasma membrane and inactivating intracellular targets. Importantly, since they do not bind to a specific receptor, AMPs are less likely to induce resistance mechanisms. Currently, the best known amphibian AMPs are esculentins, brevinins, ranacyclins, ranatuerins, nigrocin-2, magainins, dermaseptins, bombinins, temporins, and japonicins-1 and -2, and palustrin-2. This review focuses on these frog skin AMPs and the mechanisms underlying their antimicrobial activity. We hope that this review will provide further information that will facilitate further study of AMPs and cast new light on novel and safer microbicides.
Cyclosporine A (CsA) is a widely used immunosuppressive agent that greatly reduces the rates of kidney-, heart-, and liver-transplant rejection. However, CsA nephrotoxicity is a serious side effect ...that limits the clinical use of CsA. While the mechanisms underlying CsA nephrotoxicity are still not fully understood, increasing lines of evidence suggest that oxidative stress plays an important role in this phenomenon. Specifically, CsA induces endoplasmic reticulum stress and increases mitochondrial reactive oxygen species production: this modifies the redox balance, which causes lipid peroxidation and thereby induces nephrotoxicity. Recent studies on the pathogenesis of CsA nephrotoxicity suggest that CsA-induced autophagy can alleviate the deleterious effects of CsA-induced endoplasmic reticulum stress, thereby preventing nephrotoxicant-induced renal injury. A variety of signaling pathways participate in the pathogenesis of CsA nephrotoxicity. Specifically, the p38, ERK, and JNK MAPK subfamilies are all involved in CsA nephrotoxicity, while NF-κB is a target molecule of CsA. Moreover, the fibrogenic cytokine TGF-β1 contributes to CsA-induced renal fibrosis, while Nrf2 modulates CsA-induced cellular oxidative stress. In addition, CsA generally inhibits nitric oxide synthesis and impairs endothelium-dependent relaxation in the renal artery. However, some reports also suggest that nitric oxide synthesis is enhanced in the kidney cortex during CsA nephrotoxicity. Notably, the biomarkers of CsA nephrotoxicity associated with CsA have not been reviewed previously. Therefore, in this review, we will first provide an update on CsA nephrotoxicity in humans and describe the potential biomarkers of CsA nephrotoxicity. The molecular and cellular mechanisms that underlie CsA nephrotoxicity and the roles played by oxidative stress, autophagy, and signaling pathways will then be comprehensively summarized and discussed. Finally, the current therapeutical strategies for CsA nephrotoxcixity are summarized. We hope this review will provide a better understanding of CsA nephrotoxicity, thereby improving the management of patients who are treated with CsA.
•Biomarkers of CsA nephrotoxicity were summarized for the first time.•Mechanisms of oxidative stress and autophagy in CsA nephrotoxicity.•Signaling pathways that participate in CsA nephrotoxicity.
The adamantane moiety is the structural backbone of numerous compounds and its discovery launched a new field of chemistry studying the approaches to the synthesis as well as the physicochemical and ...biological properties of organic polyhedral compounds with practical application in the pharmaceutical industry. Adamantane derivatives have proven to be very potent compounds in a wide range of applications from systemic to topical therapy. This review summarizes the currently available adamantane derivatives in clinical practice (amantadine, memantine, rimantadine, tromantadine, adapalene, saxagliptin, vildagliptin), focusing on mechanisms of action, pharmacokinetics, pharmacodynamics and clinical trials. The adamantane-based compounds presented in this manuscript have been approved for a wide spectrum of indications (antivirals, antidiabetics and against Alzheimer's and Parkinson's disease). Each of the compounds proved to be of vital importance in their therapeutic indication for numerous patients worldwide. This review also considers the mechanisms of side effects to deliver a complete perspective on current treatment options.
The role of mTOR in age-related diseases Chrienova, Zofia; Nepovimova, Eugenie; Kuca, Kamil
Journal of enzyme inhibition and medicinal chemistry,
01/2021, Letnik:
36, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The ageing population is becoming a significant socio-economic issue. To address the expanding health gap, it is important to deepen our understanding of the mechanisms underlying ageing in various ...organisms at the single-cell level. The discovery of the antifungal, immunosuppressive, and anticancer drug rapamycin, which possesses the ability to extend the lifespan of several species, has prompted extensive research in the areas of cell metabolic regulation, development, and senescence. At the centre of this research is the mTOR pathway, with key roles in cell growth, proteosynthesis, ribosomal biogenesis, transcriptional regulation, glucose and lipid metabolism, and autophagy. Recently, it has become obvious that mTOR dysregulation is involved in several age-related diseases, such as cancer, neurodegenerative diseases, and type 2 diabetes mellitus. Additionally, mTOR hyperactivation affects the process of ageing per se. In this review, we provide an overview of recent insights into the mTOR signalling pathway, including its regulation and its influence on various hallmarks of ageing at the cellular level.
Beauvericin (BEA) is an emerging
mycotoxin that contaminates food and feeds globally. BEA biosynthesis is rapidly catalyzed by BEA synthetase through a nonribosomal, thiol-templated mechanism. This ...mycotoxin has cytotoxicity and is capable of increasing oxidative stress to induce cell apoptosis. Recently, large evidence further shows that this mycotoxin has a variety of biological activities and is being considered a potential candidate for medicinal and pesticide research. It is noteworthy that BEA is a potential anticancer agent since it can increase the intracellular Ca
levels and induce the cancer cell death through oxidative stress and apoptosis. BEA has exhibited effective antibacterial activities against both pathogenic Gram-positive and Gram-negative bacteria. Importantly, BEA exhibits an effective capacity to inhibit the human immunodeficiency virus type-1 integrase. Moreover, BEA can simultaneously target drug resistance and morphogenesis which provides a promising strategy to combat life-threatening fungal infections. Thus, in this review, the synthesis and the biological activities of BEA, as well as, the underlying mechanisms, are fully analyzed. The risk assessment of BEA in food and feed are also discussed. We hope this review will help to further understand the biological activities of BEA and cast some new light on drug discovery.
Role of hypoxia in cellular senescence Gao, Haoyu; Nepovimova, Eugenie; Heger, Zbynek ...
Pharmacological research,
08/2023, Letnik:
194
Journal Article
Recenzirano
Odprti dostop
Senescent cells persist and continuously secrete proinflammatory and tissue-remodeling molecules that poison surrounding cells, leading to various age-related diseases, including diabetes, ...atherosclerosis, and Alzheimer’s disease. The underlying mechanism of cellular senescence has not yet been fully explored. Emerging evidence indicates that hypoxia is involved in the regulation of cellular senescence. Hypoxia-inducible factor (HIF)− 1α accumulates under hypoxic conditions and regulates cellular senescence by modulating the levels of the senescence markers p16, p53, lamin B1, and cyclin D1. Hypoxia is a critical condition for maintaining tumor immune evasion, which is promoted by driving the expression of genetic factors (such as p53 and CD47) while triggering immunosenescence. Under hypoxic conditions, autophagy is activated by targeting BCL-2/adenovirus E1B 19-kDa interacting protein 3, which subsequently induces p21WAF1/CIP1 as well as p16Ink4a and increases β-galactosidase (β-gal) activity, thereby inducing cellular senescence. Deletion of the p21 gene increases the activity of the hypoxia response regulator poly (ADP-ribose) polymerase-1 (PARP-1) and the level of nonhomologous end joining (NHEJ) proteins, repairs DNA double-strand breaks, and alleviates cellular senescence. Moreover, cellular senescence is associated with intestinal dysbiosis and an accumulation of D-galactose derived from the gut microbiota. Chronic hypoxia leads to a striking reduction in the amount of Lactobacillus and D-galactose-degrading enzymes in the gut, producing excess reactive oxygen species (ROS) and inducing senescence in bone marrow mesenchymal stem cells. Exosomal microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play important roles in cellular senescence. miR-424–5p levels are decreased under hypoxia, whereas lncRNA-MALAT1 levels are increased, both of which induce cellular senescence. The present review focuses on recent advances in understanding the role of hypoxia in cellular senescence. The effects of HIFs, immune evasion, PARP-1, gut microbiota, and exosomal mRNA in hypoxia-mediated cell senescence are specifically discussed. This review increases our understanding of the mechanism of hypoxia-mediated cellular senescence and provides new clues for anti-aging processes and the treatment of aging-related diseases.
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Fruits and vegetables are the highly used food products amongst the horticultural crops. These items are consumed uncooked, nominally cooked or fully cooked, according to their nature and cooking ...process. With the change in diet habits and rising population, the production, as well as the processing of horticultural crops, has exponentially improved to meet its increasing demand. A large amount of peel waste is generated from fruit and vegetable-based industries and household kitchen and has led to a big nutritional and economic loss and environmental problems. Processing of fruits and vegetables alone generates a significant waste, which amounts to 25-30% of the total product. Most common wastes include pomace, peels, rind and seeds, which are highly rich in valuable bioactive compounds such as carotenoids, enzymes, polyphenols, oils, vitamins and many other compounds. These bioactive compounds show their application in various industries such as food to develop edible films, food industries for probiotics and other industries for valuable products. The utilization of these low-cost waste horticultural wastes for producing the value-added product is a novel step in its sustainable utilization. The present review intends to summarize the different types of waste originating from fruits as well as vegetables peels and highlight their potential in developing edible films, probiotics, nanoparticles, carbon dots, microbial media, biochar and biosorbents.
Mycotoxin contamination causes significant economic loss to food and feed industries and seriously threatens human health. Aflatoxins (AFs) are one of the most harmful mycotoxins, which are produced ...by
,
, and other fungi that are commonly found in the production and preservation of grain and feed. AFs can cause harm to animal and human health due to their toxic (carcinogenic, teratogenic, and mutagenic) effects. How to remove AF has become a major problem: biological methods cause no contamination, have high specificity, and work at high temperature, affording environmental protection. In the present research, microorganisms with detoxification effects researched in recent years are reviewed, the detoxification mechanism of microbes on AFs, the safety of degrading enzymes and reaction products formed in the degradation process, and the application of microorganisms as detoxification strategies for AFs were investigated. One of the main aims of the work is to provide a reliable reference strategy for biological detoxification of AFs.
T-2 toxin is the most toxic trichothecene mycotoxin, and it exerts potent toxic effects, including immunotoxicity, neurotoxicity, and reproductive toxicity. Recently, several novel metabolites, ...including 3′,4′-dihydroxy-T-2 toxin and 4′,4′-dihydroxy-T-2 toxin, have been uncovered. The enzymes CYP3A4 and carboxylesterase contribute to T-2 toxin metabolism, with 3′-hydroxy-T-2 toxin and HT-2 toxin as the corresponding primary products. Modified forms of T-2 toxin, including T-2–3-glucoside, exert their immunotoxic effects by signaling through JAK/STAT but not MAPK. T-2–3-glucoside results from hydrolyzation of the corresponding parent mycotoxin and other metabolites by the intestinal microbiota, which leads to enhanced toxicity. Increasing evidence has shown that autophagy, hypoxia-inducible factors, and exosomes are involved in T-2 toxin-induced immunotoxicity. Autophagy promotes the immunosuppression induced by T-2 toxin, and a complex crosstalk between apoptosis and autophagy exists. Very recently, “immune evasion” activity was reported to be associated with this toxin; this activity is initiated inside cells and allows pathogens to escape the host immune response. Moreover, T-2 toxin has the potential to trigger hypoxia in cells, which is related to activation of hypoxia-inducible factor and the release of exosomes, leading to immunotoxicity. Based on the data from a series of human exposure studies, free T-2 toxin, HT-2 toxin, and HT-2–4-glucuronide should be considered human T-2 toxin biomarkers in the urine. The present review focuses on novel findings related to the metabolism, immunotoxicity, and human exposure assessment of T-2 toxin and its modified forms. In particular, the immunotoxicity mechanisms of T-2 toxin and the toxicity mechanism of its modified form, as well as human T-2 toxin biomarkers, are discussed. This work will contribute to an improved understanding of the immunotoxicity mechanism of T-2 toxin and its modified forms.
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