Role of hypoxia in cellular senescence

This work was supported by the National Natural Science Foundation of China (Grant no. 31972741) ; MH CZ-DRO (UHHK, 00179906) ; Grant Agency of the Czech Republic (20-22037S) ; Research Program of University of Granada; and Scientific Grant Agency (VEGA Project 1/0482/20).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)-1 alpha 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 19kDa interacting protein 3, which subsequently induces p21(WAF1/CIP1) as well as p16(Ink4a) and increases beta-galactosidase (beta-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.National Natural Science Foundation of China (NSFC) 31972741MH CZ-DRO (UHHK) 00179906Grant Agency of the Czech Republic Norwegian Agency for Development Cooperation - NORAD 20-22037SResearch Program of University of GranadaVedecka grantova agentura MSVVaS SR a SAV (VEGA) 1/0482/2

Anti-oxidant potential of plants and probiotic spp. in alleviating oxidative stress induced by H2O2

Cells produce reactive oxygen species (ROS) as a metabolic by-product. ROS molecules trigger oxidative stress as a feedback response that significantly initiates biological processes such as autophagy, apoptosis, and necrosis. Furthermore, extensive research has revealed that hydrogen peroxide (H2O2) is an important ROS entity and plays a crucial role in several physiological processes, including cell differentiation, cell signalling, and apoptosis. However, excessive production of H2O2 has been shown to disrupt biomolecules and cell organelles, leading to an inflammatory response and contributing to the development of health complications such as collagen deposition, aging, liver fibrosis, sepsis, ulcerative colitis, etc. Extracts of different plant species, phytochemicals, and Lactobacillus sp (probiotic) have been reported for their anti-oxidant potential. In this view, the researchers have gained significant interest in exploring the potential plants spp., their phytochemicals, and the potential of Lactobacillus sp. strains that exhibit anti-oxidant properties and health benefits. Thus, the current review focuses on comprehending the information related to the formation of H2O2, the factors influencing it, and their pathophysiology imposed on human health. Moreover, this review also discussed the anti-oxidant potential and role of different extract of plants, Lactobacillus sp. and their fermented products in curbing H2O2‑induced oxidative stress in both in-vitro and in-vivo models via boosting the anti-oxidative activity, inhibiting of important enzyme release and downregulation of cytochrome c, cleaved caspases-3, − 8, and − 9 expression. In particular, this knowledge will assist R&D sections in biopharmaceutical and food industries in developing herbal medicine and probiotics-based or derived food products that can effectively alleviate oxidative stress issues induced by H2O2 generation.UHK PrF Excellence project 2208/2023-2024, MH CZ - DRO (UHHK, 00179906)King Saud University Researchers Supporting Project Number (RSP2023R35) and by Scientific Grant Agency (VEGA Project 1/0482/20

Non-edible fruit seeds: nutritional profile, clinical aspects, and enrichment in functional foods and feeds

Nowadays, fruits are gaining high demand due to their promising advantages on human health. Astonishingly, their by-products, that is, seeds and peels, account for 10–35% of fruit weight and are usually thrown as waste after consumption or processing. But it is neglected that fruit seeds also have functional properties and nutritional value, and thus could be utilized for dietary and therapeutic purposes, ultimately reducing the waste burden on the environment. Owing to these benefits, researchers have started to assess the nutritional value of different fruits seeds, in addition to the chemical composition in various bioactive constituents, like carotenoids (lycopene), flavonoids, proteins (bioactive peptides), vitamins, etc., that have substantial health benefits and can be used in formulating different types of food products with noteworthy functional and nutraceutical potential. The current review aims to comprehend the known information of nutritional and phytochemical profiling of non-edible fruits seeds, viz. apple, apricot, avocado, cherry, date, jamun, litchi, longan, mango, and papaya. Additionally, clinical studies conducted on these selected non-edible fruit seed extracts, their safety issues and their enrichment in food products as well as animal feed has also been discussed. This review aims to highlight the potential applications of the non-edible fruit seeds in developing new food products and also provide a viable alternative to reduce the waste disposal issue faced by agro-based industriesPrF UHK 2217/2022-2023 Czech RepublicResearch program of University of Granad

Formulation of pH-responsive highly swellable hydrogel scaffolds for controlled release of tramadol HCl: characterization and biocompatibility evaluation

Introduction: The objective of current project was to formulate a system for controlled delivery of Tramadol HCl (TRD), an opioid analgesic used in the treatment of moderate to severe pain. Methods: For this purpose, a pH responsive AvT-co-poly hydrogel network was formulated through free radical polymerization by incorporating natural polymers i.e., aloe vera gel and tamarind gum, monomer and crosslinker. Formulated hydrogels were loaded with Tramadol HCl (TRD) and evaluated for percent drug loading, sol-gel fraction, dynamic and equilibrium swelling, morphological characteristics, structural features and in-vitro release of Tramadol HCl. Results and Discussions: Hydrogels were proved to be pH sensitive as remarkable dynamic swelling response ranging within 2.94g/g-10.81g/g was noticed at pH 7.4 as compared to pH 1.2. Percent drug loading was in the range of 70.28%-90.64% for all formulations. Thermal stability and compatibility of hydrogel components were validated by DSC analysis and FTIR spectroscopy. Controlled release pattern of Tramadol HCl from the polymeric network was confirmed as maximum release of 92.22% was observed for over a period of 24 hours at pH 7.4. Moreover, oral toxicity studies were also conducted in rabbits to investigate the safety of hydrogels. No evidence of any toxicity, lesions and degeneration was reported, confirming the biocompatibility and safety of grafted systemProject (2216/2023-2024), Scholars Visiting Program (University of Granada)Researchers Supporting Project (number RSP 2023R35), King Saud Universit

Botulinum Toxin; Bioterror and Biomedicinal Agent

Botulinum toxin is a group of seven homologous, highly poisonous proteins isolated fromfermentation of the anaerobic bacterium Clostridium botulinum, which naturally occurs in soiland can grow on many meats and vegetables. Botulinum toxin causes neuromuscular disordercalled botulism, which is a potentially lethal disease. There are three types of botulism: Food,wound, and infant botulism. It can lead to death unless appropriate therapy is done. Due to theseverity and potency of botulinum toxin, its importance as a biological weapon is of majorconcern to public health officials. Nevertheless, botulinum toxin is also medicament

Sarin Assay using Acetylcholinesterases and Electrochemical Sensor Strip

An electrochemical sensor strip was used for sarin assay. Three different acetylcholinesterases (AChEs) were chosen as promising recognition elements. viz., human recombinant, electric eel, and bovine erythrocytes origin. Human recombinant AChE seems to be the most sensitive to inhibition by sarin when the achieved limit of detection (0.45×10-8 mol/l) and IC50 [(9.77± 8.08)×10-6 mol/l] are considered. On the contrary, AChE from bovine erythrocytes proved to reach highest IC50 (5.37± 4.52)×10-7 mol/l and the one from electric eel reached the highest limit of detection 0.93×10-8 mol/l. From the AChEs tested as biorecognition element, human recombinant seems to be the best for construction of new ChE detectors.Defence Science Journal, 2009, 59(3), pp.300-304, DOI:http://dx.doi.org/10.14429/dsj.59.152

Prophylaxis Against Nerve Agent Intoxications

The acute toxicity of organophosphates is usually attributed to their irreversible inhibitionof an enzyme acetylcholinesterase that hydrolyses the neurotransmitter acetylcholine. Theresultant increase in concentration of acetylcholine at the cholinergic synapses of the peripheraland central nervous system, and neuromuscular junction is manifested by over-stimulation ofthe cholinergic neurotransmission. Current antidotal regimens for organophosphate poisoningconsisting of a post-exposure therapy with anticholinergics such as atropine, acetylcholinesterasereactivators (oximes), benzodiazepines have some limitations. Therefore, effective prophylaxisbefore intoxication is of a special interest. Four fundamental prophylactic methods are: (i)protection of acetylcholinesterase against irreversible inhibition by organophosphates usingdifferent reversible inhibitors, (ii) protection against neurotoxic effect of organophosphates usingbenzodiazepines, memantine, NMDA receptor blockers, (iii) administration of cholinesterasepreparations of different sources (sometimes commercially available at present) acting asbioscavengers, and (iv) gene therapy being a new treatment modality under intensive researchusing enzymes hydrolysing/splitting organophosphates with the aim to eliminate toxic agentbefore it is transported to the target organs

Multi-Target-Directed Ligands in Alzheimer’s Disease Therapy

So far, the only clinically approved drugs that are effective in Alzheimer’s disease (AD) are those neurotransmitters oriented in their mode of action and focus, in particular, on the functional significance of acetylcholine or glutamate in the brain. Current AD drugs can, therefore, reduce the severity of cognitive symptoms, improve the quality of life, and stabilize the symptoms for some years, but they are not able to significantly modify the course of the disease. Complex disorders such as neurodegenerative diseases tend to result from multiple molecular abnormalities, not from a single defect. Moreover, a single target is unlikely to help in such cases because the cells can often find ways to compensate for a protein whose activity is affected by a drug. Thus, these limitations of the conventional “one-target, one-molecule” paradigm have triggered a recent shift in efforts to create drugs that hit more than one target simultaneously. The term multi-target-directed ligands (MTDLs) have been proposed to describe these hybrid molecules that are effective in treating complex diseases. Within our contribution, we would like to present general overview of MTDL design strategy in AD therapy, its positives and negatives, and finally summary of such multipotent compounds evaluated in clinical trials

Are we facing NOVICHOK nerve agent threat?

In the short history, at least four similar attacks by nerve agents were committed. In this short communication, we wanted to interlink some important insights into nerve agents and novichoks and point out that the latest assault by novichoks is not the only attack with prohibited chemical warfare agents and, unfortunately, probably not the last, as these substances can easily be synthesized in a well-equipped chemical laboratory

Are the current methods for the distribution of public funds in secondary education effective? Multiple criteria model in the Czech Republic

The aim of the paper is to analyse the current financing system for schools in the Czech Republic and the subsequent formulation of criteria for improving the redistribution of funds from public sources. First, the method of retrospective analysis of expenditures on education financing at European level and the developed countries of the OECD. Second, the multiple criteria model for the distribution of funds is established using Expert Choice. Finally, a method of guided interviews will be exploited in order to detect attitudes, priorities of representatives from the education department and the economic department in the Czech Republic. In the analysis of secondary school finance decision-making, individual solution options and key criteria were specified. The criteria include justice, motivation, stability, controllability and simplicity. Based on the multi-criteria evaluation output, it is possible to recommend the inclusion of three elements in the current financing system of secondary education in the Czech Republic. These are the tracking of graduates in the labour market, assessment of schools and teacher