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Daljeet Singh Dhanjal,1,* Parul Mehra,2,* Sonali Bhardwaj,1,* Reena Singh,1 Parvarish Sharma,3 Eugenie Nepovimova,4 Chirag Chopra,1 Kamil Kuca4,5 1School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India; 2Central Research Institute, Kasauli, Himachal Pradesh, India; 3School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India; 4Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, 50003, Czech Republic; 5Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, 50005, Czech Republic*These authors contributed equally to this workCorrespondence: Kamil Kuca, Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, 50003, Czech Republic, Tel +420 603 289 166, Email kamil.kuca@uhk.cz Chirag Chopra, School of Bioengineering and Biosciences, Lovely Professional University, Jalandhar-Delhi GT Road, Phagwara, Punjab, 144411, India, +91-7837815676, Email chirag.18298@lpu.co.inAbstract: In today’s time, nanotechnology is being utilized to develop efficient products in the cosmetic and pharmaceutical industries. The application of nanotechnology in transforming bioactive material into nanoscale products substantially improves their biocompatibility and enhances their effectiveness, even when used in lower quantities. There is a significant global market potential for these nanoparticles because of which research teams around the world are interested in the advancements in nanotechnology. These recent advances have shown that fungi can synthesize metallic nanoparticles via extra- and intracellular mechanisms. Moreover, the chemical and physical properties of novel metallic nanoparticles synthesised by fungi are improved by regulating the surface chemistry, size, and surface morphology of the nanoparticles. Compared to chemical synthesis, the green synthesis of nanoparticles offers a safe and sustainable approach for developing nanoparticles. Biosynthesised nanoparticles can potentially enhance the bioactivities of different cellular fractions, such as plant extracts, fungal extracts, and metabolites. The nanoparticles synthesised by fungi offer a wide range of applications. Recently, the biosynthesis of nanoparticles using fungi has become popular, and various ways are being explored to maximize nanoparticles synthesis. This manuscript reviews the characteristics and applications of the nanoparticles synthesised using the different taxa of fungi. The key focus is given to the applications of these nanoparticles in medicine and cosmetology.Keywords: fungi, biological application, biosynthesis, nanoparticles, nanotechnology

Kamil Kuca,1,2 Jana Zdarova Karasova,2,3 Ondrej Soukup,2 Jiri Kassa,3 Eva Novotna,2 Vendula Sepsova,2,3 Anna Horova,2 Jaroslav Pejchal,3 Martina Hrabinova,2,3 Eva Vodakova,2 Daniel Jun,2,3 Eugenie Nepovimova,1,2 Martin Valis,4 Kamil Musilek1,2 1Department of Chemistry, Faculty of Science, University of Hradec Kralove, 2Biomedical Research Center, University Hospital Hradec Kralove, 3Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, 4Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic Background: Intoxication by nerve agents could be prevented by using small acetylcholinesterase inhibitors (eg, pyridostigmine) for potentially exposed personnel. However, the serious side effects of currently used drugs led to research of novel potent molecules for prophylaxis of organophosphorus intoxication. Methods: The molecular design, molecular docking, chemical synthesis, in vitro methods (enzyme inhibition, cytotoxicity, and nicotinic receptors modulation), and in vivo methods (acute toxicity and prophylactic effect) were used to study bispyridinium, bisquinolinium, bisisoquinolinium, and pyridinium-quinolinium/isoquinolinium molecules presented in this study. Results: The studied molecules showed non-competitive inhibitory ability towards human acetylcholinesterase in vitro that was further confirmed by molecular modelling studies. Several compounds were selected for further studies. First, their cytotoxicity, nicotinic receptors modulation, and acute toxicity (lethal dose for 50% of laboratory animals [LD50]; mice and rats) were tested to evaluate their safety with promising results. Furthermore, their blood levels were measured to select the appropriate time for prophylactic administration. Finally, the protective ratio of selected compounds against soman-induced toxicity was determined when selected compounds were found similarly potent or only slightly better to standard pyridostigmine. Conclusion: The presented small bisquaternary molecules did not show overall benefit in prophylaxis of soman-induced in vivo toxicity. Keywords: AChE inhibitors, prophylaxis, pre-treatment, nerve agents, toxicity, soman

Oxidative stress status, as a disruption of redox homeostasis, in the blood sera of Wistar rats caused by repeated application of selected acetylcholinesterase reactivators - asoxime, obidoxime, K027, K048, K074, and K075 were evaluated. Throughout this study, each oxime in a dose of 0.1 of LD 50 /kg im was given 2x/week for 4 weeks. Then, seven days after the last oximes' application, markers of lipid peroxidation (malondialdehyde, MDA), and protein oxidation (advanced oxidation protein products, AOPP), as well as the activity of antioxidant enzymes (catalase, CAT, superoxide dismutase, SOD, reduced glutathione, GSH, and oxidized glutathione, GSSG), were determined. Oxidative stress parameters, MDA and AOPP were significantly highest in the K048-, K074- and K075-treated groups (p < 0.001). The activity of CAT was significantly elevated in the obidoxime-treated group (p < 0.05), while treatment with K027, K048, and K074 induced high elevation in SOD levels (p < 0.01, p < 0.001). Interestingly, the activity of GSH in each oxime-treated group was significantly elevated. Unlike, treatment with obidoxime caused elevation in GSSG levels (p < 0.01). As a continuation of our previously published data, these results assure that applied oximes following subacute treatment ameliorated the oxidative status and further adverse systemic toxic effects in rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing for financial interests or personal relationships that could have appeared to influence the work reported in this paper. None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Postoperative distant metastasis and high recurrence rate causes a dilemma in treating triple-negative breast cancer (TNBC) owing to its unforeseeable invasion into various organs or tissues. The wealth of nutrition provided by vascular may facilitate the proliferation and angiogenesis of cancer cells, which further enhance the rates of postoperative metastasis and recurrence. Chemotherapy, as a systemic postoperative adjuvant therapy, is generally applied to diminish recurrence and metastasis of TNBC. Herein, an halofuginone-silver nano thermosensitive hydrogel (HTPM&AgNPs-gel) was prepared via a physical swelling method. The in vitro anticancer efficacy of HTPM&AgNPs-gel was analyzed by investigating cell proliferation, migration, invasion, and angiogenesis capacity. Furthermore, the in vivo anti-cancer activity of HTPM&AgNPs-gel was further appraised through the tumor suppression, anti-metastatic, anti-angiogenic, and anti-inflammatory ability. The optimized HTPM&AgNPs-gel, a thermosensitive hydrogel, showed excellent properties, including syringeability, swelling behavior, and a sustained release effect without hemolysis. In addition, HTPM&AgNPs-gel was confirmed to effectively inhibit the proliferation, migration, invasion, and angiogenesis of MDA-MB-231 cells. An evaluation of the in vivo anti-tumor efficacy demonstrated that HTPM&AgNPs-gel showed a stronger tumor inhibition rate (68.17%) than did HTPM-gel or AgNPs-gel used alone and exhibited outstanding biocompatibility. Notably, HTPM&AgNPs-gel also inhibited lung metastasis induced by residual tumor tissue after surgery and further blocked angiogenesis-related inflammatory responses. Taken together, the suppression of inflammation by interdicting the blood vessels adjoining the tumor and inhibiting angiogenesis is a potential strategy to attenuate the recurrence and metastasis of TNBC. HTPM&AgNPs-gel is a promising anticancer agent for TNBC as a local postoperative treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Biodiversity conservation amidst the uncertainty of climate change presents unique challenges that necessitate precise management strategies. The study reported here was aimed at refining understanding of these challenges and to propose specific, actionable management strategies. Employing a quantitative literature analysis, we meticulously examined 1268 research articles from the Web of Science database between 2005 and 2023. Through Cite Spaces and VOS viewer software, we conducted a bibliometric analysis and thematic synthesis to pinpoint emerging trends, key themes, and the geographical distribution of research efforts. Our methodology involved identifying patterns within the data, such as frequency of keywords, co-authorship networks, and citation analysis, to discern the primary focus areas within the field. This approach allowed us to distinguish between research concentration areas, specifically highlighting a predominant interest in Environmental Sciences Ecology (67.59 %) and Biodiversity Conservation (22.63 %). The identification of adaptive management practices and ecosystem services maintenance are central themes in the research from 2005 to 2023. Moreover, challenges such as understanding phenological shifts, invasive species dynamics, and anthropogenic pressures critically impact biodiversity conservation efforts. Our findings underscore the urgent need for precise, data-driven decision-making processes in the face of these challenges. Addressing the gaps identified, our study proposes targeted solutions, including the establishment of germplasm banks for at-risk species, the development of advanced genomic and microclimate models, and scenario analysis to predict and mitigate future conservation challenges. These strategies are aimed at enhancing the resilience of biodiversity against the backdrop of climate change through integrated, evidence-based approaches. By leveraging the compiled and analyzed data, this study offers a foundational framework for future research and practical action in biodiversity conservation strategies, demonstrating a path forward through detailed analysis and specified solutions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Increasing evidence has revealed that cellular senescence drives NDs, including Alzheimer's disease (AD) and Parkinson's disease. Different senescent cell populations secrete senescence-associated secretory phenotypes (SASP), including matrix metalloproteinase-3, interleukin (IL)-1α, IL-6, and IL-8, which can harm adjacent microglia. Moreover, these cells possess high expression levels of senescence hallmarks (p16 and p21) and elevated senescence-associated β-galactosidase activity in in vitro and in vivo ND models. These senescence phenotypes contribute to the deposition of β-amyloid and tau-protein tangles. Selective clearance of senescent cells and SASP regulation by inhibiting p38/mitogen-activated protein kinase and nuclear factor kappa B signaling attenuate β-amyloid load and prevent tau-protein tangle deposition, thereby improving cognitive performance in AD mouse models. In addition, telomere shortening, a cellular senescence biomarker, is associated with increased ND risks. Telomere dysfunction causes cellular senescence, stimulating IL-6, tumor necrosis factor-α, and IL-1β secretions. The forced expression of telomerase activators prevents cellular senescence, yielding considerable neuroprotective effects. This review elucidates the mechanism of cellular senescence in ND pathogenesis, suggesting strategies to eliminate or restore senescent cells to a normal phenotype for treating such diseases., (© 2024. The Author(s).)

Deoxynivalenol (DON), a potent mycotoxin, exhibits strong immunotoxicity and poses a significant threat to human and animal health. Cell senescence has been implicated in the immunomodulatory effects of DON; however, the potential of DON to induce cell senescence remains inadequately explored. Emerging evidence suggests that hypoxia-inducible factor-1α (HIF-1α) serves as a crucial target of mycotoxins and is closely involved in cell senescence. To investigate this potential, we employed the RAW264.7 macrophage model and treated the cells with varying concentrations of DON (2-8 μM) for 24 h. Transcriptome analysis revealed that 2365 genes were significantly upregulation while 2405 genes were significantly decreased after exposure to DON. KEGG pathway enrichment analysis demonstrated substantial enrichment in pathways associated with cellular senescence and hypoxia. Remarkably, we observed a rapid and sustained increase in HIF-1α expression following DON treatment. DON induced cell senescence through the activation of the p53/p21 WAF1/CIP1 (p21) and p16 INK4A (p16) pathways, while also upregulating the expression of nuclear factor-κB, leading to the secretion of senescence-associated secretory phenotype (SASP) factors, including IL-6, IL-8, and CCL2. Crucially, HIF-1α positively regulated the expression of p53, p21, and p16, as well as the secretion of SASP factors. Additionally, DON induced cell cycle arrest at the S phase, enhanced the activity of the senescence biomarker senescence-associated β-galactosidase, and disrupted cell morphology, characterized by mitochondrial damage. Our study elucidates that DON induces cell senescence in RAW264.7 macrophages by modulating the HIF-1α/p53/p21 pathway. These findings provide valuable insights for the accurate prevention of DON-induced immunotoxicity and associated diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024. Published by Elsevier B.V.)

The liver is a vital organ in human physiology positioned in the upper right quadrant of the peritoneal cavity, which plats a critical role in metabolic processes, detoxification of various substances and overall homeostasis. Along with these critical functions, hepatic diseases impose as significant global health threat. Liver illness is the cause of two million fatalities every year, or 4% of all deaths. Traditionally, healthcare providers have prescribed antibacterial and antiviral medications to address liver illness. Nephrotoxicity is a frequently observed negative reaction to drugs, with the majority of such events happening in individuals who have advanced cirrhosis. Thus, recognizing this gap, there is a dire need of exploration of pharmaceutical alterative for hepatic diseases, with special focus on their efficacy and reduced toxicity. Fruits have long been known to therapeutic impact on human health, thus exploration of fruits components namely pulp, seeds and peels containing phytochemicals have emerged as a promising avenue for hepatoprotective interventions. Thus, review comprehends the information about worldwide burden of chemical induced toxicity and injuries as well as highlight the on-going challenges in hepatic disease management. It also shed light on the valuable contributions fruit parts and their phytocompounds obtained from different components of fruits. Fruit pulp, especially when rich in flavonoids, has demonstrated significant potential in animal model studies. It has been observed to enhance the activity of antioxidant enzymes and reduce the expression of pro-inflammatory markers. The methanolic and ethanolic extracts have demonstrated the most favorable outcomes. Further, this review also discusses about the safety assessments of fruits extracts for their utilization as hepatoprotective agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The utmost objective of every nation is to achieve zero hunger and ensure the health and well-being of its population. However, in impoverished nations, particularly in rural areas, such issues persist on a daily basis. Currently, there is a growing demand for fruit consumption due to their potential health benefits. Surprisingly, their most prevalent by-product is pomace, which is produced in millions of tonnes and is usually discarded as waste after processing or consumption. Even food produced with these kinds of raw resources can contribute to the objective of eradicating world hunger. Owing to these advantages, scientists have begun evaluating the nutritional content of various fruit pomace varieties as well as the chemical composition in different bioactive constituents, which have significant health benefits and can be used to formulate a variety of food products with notable nutraceutical and functional potential. So, the purpose of this review is to understand the existing familiarity of nutritional and phytochemical composition of selected fruit pomaces, those derived from pineapple, orange, grape, apple, and tomato. Furthermore, this article covers pre-clinical and clinical investigations conducted on the selected fruit pomace extracts and/or powder forms and its incorporation into food products and animal feed. Adding fruit pomaces reduces the glycemic index, increases the fibre content and total polyphenolic contents, and reduces the cooking loss, etc. In animal feeds, incorporating fruit pomaces improves the antioxidant enzyme activities, humoral immune system, and growth performance and reduces methane emission., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

This review systematically compiles sports-related drugs, substances, and methodologies based on the most frequently detected findings from prohibited lists published annually by the World Anti-Doping Agency (WADA) between 2003 and 2021. Aligned with structure of the 2023 prohibited list, it covers all proscribed items and details the pharmacokinetics and pharmacodynamics of five representatives from each section. Notably, it explores significant metabolites and metabolic pathways associated with these substances. Adverse analytical findings are summarized in tables for clarity, and the prevalence is visually represented through charts. The review includes a concise historical overview of doping and WADA's role, examining modifications in the prohibited list for an understanding of evolving anti-doping measures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neutrophils play a Janus-faced role in the complex landscape of cancer pathogenesis and immunotherapy. As immune defense cells, neutrophils release toxic substances, including reactive oxygen species and matrix metalloproteinase 9, within the tumor microenvironment. They also modulate the expression of tumor necrosis factor-related apoptosis-inducing ligand and Fas ligand, augmenting their capacity to induce tumor cell apoptosis. Their involvement in antitumor immune regulation synergistically activates a network of immune cells, bolstering anticancer effects. Paradoxically, neutrophils can succumb to the influence of tumors, triggering signaling cascades such as JAK/STAT, which deactivate the immune system network, thereby promoting immune evasion by malignant cells. Additionally, neutrophil granular constituents, such as neutrophil elastase and vascular endothelial growth factor, intricately fuel tumor cell proliferation, metastasis, and angiogenesis. Understanding the mechanisms that guide neutrophils to collaborate with other immune cells for comprehensive tumor eradication is crucial to enhancing the efficacy of cancer therapeutics. In this review, we illuminate the underlying mechanisms governing neutrophil-mediated support or inhibition of tumor progression, with a particular focus on elucidating the internal and external factors that influence neutrophil polarization. We provide an overview of recent advances in clinical research regarding the involvement of neutrophils in cancer therapy. Moreover, the future prospects and limitations of neutrophil research are discussed, aiming to provide fresh insights for the development of innovative cancer treatment strategies targeting neutrophils., (© 2024. The Author(s).)

Mycobacterium leprae is the causative agent responsible for the chronic disease known as leprosy. This condition is characterized by dermal involvement, often leading to peripheral nerve damage, sensory-motor loss, and related abnormalities. Both innate and acquired immunological responses play a role in the disease, and even in individuals with lepromatous leprosy, there can be a transient increase in T cell immunity during lepromatous reactions. Diagnosing of early-stage leprosy poses significant challenges. In this context, nanoparticles have emerged as a promising avenue for addressing various crucial issues related to leprosy. These include combatting drug resistance, mitigating adverse effects of conventional medications, and enhancing targeted drug delivery. This review serves as a comprehensive compilation, encompassing aspects of pathology, immunology, and adverse effects of multidrug delivery systems in the context of leprosy treatment. Furthermore, the review underscores the significance of ethnomedicinal plants, bioactive secondary metabolites, and nanotherapeutics in the management of leprosy. It emphasizes the potential to bridge the gap between existing literature and ongoing research efforts, with a profound scope for validating traditional claims, developing herbal medicines, and formulating nanoscale drug delivery systems that are safe, effective, and widely accepted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kimta, Majdalawieh, Nasrallah, Puri, Nepovimova, Jomova and Kuča.)

Mycotoxins have been shown to activate multiple mechanisms that may potentially lead to the progression of Alzheimer's disease (AD). Overexpression/aberrant cleavage of amyloid precursor protein (APP) and hyperphosphorylation of tau (P-tau) is hallmark pathologies of AD. Recent advances suggest that the neurotoxic effects of mycotoxins involve c-Jun N-terminal kinase (JNK) and hypoxia-inducible factor-1α (HIF-1α) signaling, which are closely linked to the pathogenesis of AD. Due to the high toxicity and broad contamination of T-2 toxin, we assessed how T-2 toxin exposure alters APP and P-tau formation in BV2 cells and determined the underlying roles of HIF-1α and JNK signaling. The findings revealed that T-2 toxin stimulated the expression of HIF-1α and hypoxic stress factors in addition to increasing the expression of APP and P-tau. Additionally, HIF-1α acted as a "brake" on the induction of APP and P-tau expression by negatively regulating these proteins. Notably, T-2 toxin activated JNK signaling, which broke this "brake" to promote the formation of APP and P-tau. Furthermore, the cytoskeleton was an essential target for T-2 toxin to exert cytotoxicity, and JNK/HIF-1α participated in this damage. Collectively, when the T-2 toxin induces the production of APP and P-tau, JNK might interfere with HIF-1α's protective function. This study will provide clues for further research on the neurotoxicity of mycotoxins., (© 2024. The Author(s) under exclusive licence to Society for Mycotoxin (Research Gesellschaft für Mykotoxinforschung e.V.) and Springer-Verlag GmbH Germany, part of Springer Nature.)

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are well recognized for playing a dual role, since they can be either deleterious or beneficial to biological systems. An imbalance between ROS production and elimination is termed oxidative stress, a critical factor and common denominator of many chronic diseases such as cancer, cardiovascular diseases, metabolic diseases, neurological disorders (Alzheimer's and Parkinson's diseases), and other disorders. To counteract the harmful effects of ROS, organisms have evolved a complex, three-line antioxidant defense system. The first-line defense mechanism is the most efficient and involves antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). This line of defense plays an irreplaceable role in the dismutation of superoxide radicals (O 2 •- ) and hydrogen peroxide (H 2 O 2 ). The removal of superoxide radicals by SOD prevents the formation of the much more damaging peroxynitrite ONOO - (O 2 •-  + NO • ), an important molecule in neurotransmission, inflammation, and vasodilation. The second-line antioxidant defense pathway involves exogenous diet-derived small-molecule antioxidants. The third-line antioxidant defense is ensured by the repair or removal of oxidized proteins and other biomolecules by a variety of enzyme systems. This review briefly discusses the endogenous (mitochondria, NADPH, xanthine oxidase (XO), Fenton reaction) and exogenous (e.g., smoking, radiation, drugs, pollution) sources of ROS (superoxide radical, hydrogen peroxide, hydroxyl radical, peroxyl radical, hypochlorous acid, peroxynitrite). Attention has been given to the first-line antioxidant defense system provided by SOD, CAT, and GPx. The chemical and molecular mechanisms of antioxidant enzymes, enzyme-related diseases (cancer, cardiovascular, lung, metabolic, and neurological diseases), and the role of enzymes (e.g., GPx4) in cellular processes such as ferroptosis are discussed. Potential therapeutic applications of enzyme mimics and recent progress in metal-based (copper, iron, cobalt, molybdenum, cerium) and nonmetal (carbon)-based nanomaterials with enzyme-like activities (nanozymes) are also discussed. Moreover, attention has been given to the mechanisms of action of low-molecular-weight antioxidants (vitamin C (ascorbate), vitamin E (alpha-tocopherol), carotenoids (e.g., β-carotene, lycopene, lutein), flavonoids (e.g., quercetin, anthocyanins, epicatechin), and glutathione (GSH)), the activation of transcription factors such as Nrf2, and the protection against chronic diseases. Given that there is a discrepancy between preclinical and clinical studies, approaches that may result in greater pharmacological and clinical success of low-molecular-weight antioxidant therapies are also subject to discussion.- ) and maintains the physiologically relevant level of nitric oxide (NO • ), an important molecule in neurotransmission, inflammation, and vasodilation. The second-line antioxidant defense pathway involves exogenous diet-derived small-molecule antioxidants. The third-line antioxidant defense is ensured by the repair or removal of oxidized proteins and other biomolecules by a variety of enzyme systems. This review briefly discusses the endogenous (mitochondria, NADPH, xanthine oxidase (XO), Fenton reaction) and exogenous (e.g., smoking, radiation, drugs, pollution) sources of ROS (superoxide radical, hydrogen peroxide, hydroxyl radical, peroxyl radical, hypochlorous acid, peroxynitrite). Attention has been given to the first-line antioxidant defense system provided by SOD, CAT, and GPx. The chemical and molecular mechanisms of antioxidant enzymes, enzyme-related diseases (cancer, cardiovascular, lung, metabolic, and neurological diseases), and the role of enzymes (e.g., GPx4) in cellular processes such as ferroptosis are discussed. Potential therapeutic applications of enzyme mimics and recent progress in metal-based (copper, iron, cobalt, molybdenum, cerium) and nonmetal (carbon)-based nanomaterials with enzyme-like activities (nanozymes) are also discussed. Moreover, attention has been given to the mechanisms of action of low-molecular-weight antioxidants (vitamin C (ascorbate), vitamin E (alpha-tocopherol), carotenoids (e.g., β-carotene, lycopene, lutein), flavonoids (e.g., quercetin, anthocyanins, epicatechin), and glutathione (GSH)), the activation of transcription factors such as Nrf2, and the protection against chronic diseases. Given that there is a discrepancy between preclinical and clinical studies, approaches that may result in greater pharmacological and clinical success of low-molecular-weight antioxidant therapies are also subject to discussion., (© 2024. The Author(s).)

Fentanyl is a synthetic μ-opioid receptor agonist approved to treat severe to moderate pain with faster onset of action and about 100 times more potent than morphine. Over last two decades, abuse of fentanyl and its derivatives has an increased trend, globally. Currently, the United States (US) faces the most serious situation related to fentanyl overdose, commonly referred to as the opioid epidemic. Nowadays, fentanyl is considered as the number one cause of death for adults aged 18-45 in the US. Synthesis and derivatization of fentanyl is inexpensive to manufacture and easily achievable. Indeed, more than 1400 fentanyl derivatives have been described in the scientific literature and patents. In addition, accessibility and efficacy of fentanyl and its derivatives can play a potential role in misuse of these compounds as a chemical weapon. In this review, the properties, general pharmacology, and overdose death cases associated with fentanyl and selected derivatives are presented. Moreover, current opioid epidemic in the US, Moscow theatre hostage crisis, and potential misuse of fentanyl and its derivatives as a chemical weapon are disclosed., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Soil contamination with heavy metals has emerged as a global environmental threat, compromising agricultural productivity, ecosystem integrity, and human health. Conventional remediation techniques often fall short due to high costs, operational complexities, and environmental drawbacks. Plant-based disposal technologies, including biochar, phytometallurgy, and phrolysis, have emerged as promising solutions in this regard. Grounded in a novel experimental framework, biochar is studied for its dual role as soil amendment and metal adsorbent, while phytometallurgy is explored for its potential in resource recovery and economic benefits derived from harvested metal-rich plant biomass. Pyrolysis, in turn, is assessed for transforming contaminated biomass into value-added products, thereby minimizing waste. These plant disposal technologies create a circular model of remediation and resource utilization that holds the potential for application in large-scale soil recovery projects, development of environmentally friendly agro-industries, and advancement in sustainable waste management practices. This review mainly discussed cutting-edge plant disposal technologies-biochar application, phytometallurgy, and pyrolysis-as revolutionary approaches to soil heavy metal remediation. The efficacy, cost-effectiveness, and environmental impact of these innovative technologies are especially evaluated in comparison with traditional methods. The success of these applications could signal a paradigm shift in how we approach both environmental remediation and resource recovery, with profound implications for sustainable development and circular economy strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The foundations of cell reprogramming were laid by Yamanaka and co-workers, who showed that somatic cells can be reprogrammed into pluripotent cells (induced pluripotency). Since this discovery, the field of regenerative medicine has seen advancements. For example, because they can differentiate into multiple cell types, pluripotent stem cells are considered vital components in regenerative medicine aimed at the functional restoration of damaged tissue. Despite years of research, both replacement and restoration of failed organs/ tissues have remained elusive scientific feats. However, with the inception of cell engineering and nuclear reprogramming, useful solutions have been identified to counter the need for compatible and sustainable organs. By combining the science underlying genetic engineering and nuclear reprogramming with regenerative medicine, scientists have engineered cells to make gene and stem cell therapies applicable and effective. These approaches have enabled the targeting of various pathways to reprogramme cells, i.e., make them behave in beneficial ways in a patient-specific manner. Technological advancements have clearly supported the concept and realization of regenerative medicine. Genetic engineering is used for tissue engineering and nuclear reprogramming and has led to advances in regenerative medicine. Targeted therapies and replacement of traumatized , damaged, or aged organs can be realized through genetic engineering. Furthermore, the success of these therapies has been validated through thousands of clinical trials. Scientists are currently evaluating induced tissue-specific stem cells (iTSCs), which may lead to tumour-free applications of pluripotency induction. In this review, we present state-of-the-art genetic engineering that has been used in regenerative medicine. We also focus on ways that genetic engineering and nuclear reprogramming have transformed regenerative medicine and have become unique therapeutic niches., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Sarcoma is a heterogeneous group of malignancies often resistant to conventional chemotherapy and radiation therapy. The phosphatidylinositol-3-kinase/ protein kinase B /mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway has emerged as a critical cancer target due to its central role in regulating key cellular processes such as cell growth, proliferation, survival, and metabolism. Dysregulation of this pathway has been implicated in the development and progression of bone sarcomas (BS) and soft tissue sarcomas (STS). PI3K/Akt/mTOR inhibitors have shown promising preclinical and clinical activity in various cancers. These agents can inhibit the activation of PI3K, Akt, and mTOR, thereby reducing the downstream signaling events that promote tumor growth and survival. In addition, PI3K/Akt/mTOR inhibitors have been shown to enhance the efficacy of other anticancer therapies, such as chemotherapy and radiation therapy. The different types of PI3K/Akt/mTOR inhibitors vary in their specificity, potency, and side effect profiles and may be effective depending on the specific sarcoma type and stage. The molecular targeting of PI3K/Akt/mToR pathway using drugs, phytochemicals, nanomaterials (NMs), and microbe-derived molecules as Pan-PI3K inhibitors, selective PI3K inhibitors, and dual PI3K/mTOR inhibitors have been delineated. While there are still challenges to be addressed, the preclinical and clinical evidence suggests that these inhibitors may significantly improve patient outcomes. Further research is needed to understand the potential of these inhibitors as sarcoma therapeutics and to continue developing more selective and effective agents to meet the clinical needs of sarcoma patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment.

In all living organisms, ferritins are a group of proteins important for maintaining iron homeostasis. Increasing amount of studies has shown that recombinant ferritins can be widely used in multimodal nanomedicine, especially for anticancer treatment and vaccination. Recombinant particles prepared by fusing viral proteins and ferritin subunits produce a better immune response and higher antibody titres. Moreover, actively-targeted ferritin nanoparticles can recognise receptors and deliver natural or chemical drugs specifically to the tumour tissue. In addition, ferritin-linked or loaded with contrast agents or fluorescent dyes can be used as multimodal particles useful cancer theranostics. In this review, we fully summarised the unitisation of recombinant ferritins in multimodal nanomedicine. The research progress of using recombinant ferritins as nanovaccines, nanozymes, and bioengineered nanocarriers for targeted therapy and bioimaging is emphasised.

Understanding the role of the mitogen-activated protein kinases (MAPKs) signalling pathway is essential in advancing treatments for neurodegenerative disorders like Alzheimer's. In this study, we investigate in-silico techniques involving computer-based methods to extract the MAPK1 sequence. Our applied methods enable us to analyze the protein's structure, evaluate its properties, establish its evolutionary relationships, and assess its prevalence in populations. We also predict epitopes, assess their ability to trigger immune responses, and check for allergenicity using advanced computational tools to understand their immunological properties comprehensively. We apply virtual screening, docking, and structure modelling to identify promising drug candidates, analyze their interactions, and enhance drug design processes. We identified a total of 30 cell-targeting molecules against the MAPK1 protein, where we selected top 10 CTL epitopes (PAGGGPNPG, GGGPNPGSG, SAPAGGGPN, AVSAPAGGG, AGGGPNPGS, ATAAVSAPA, TAAVSAPAG, ENIIGINDI, INDIIRTPT, and NDIIRTPTI) for further evaluation to determine their potential efficacy, safety, and suitability for vaccine design based on strong binding potential. The potential to cover a large portion of the world's population with these vaccines is substantial-88.5 % for one type and 99.99 % for another. In exploring the molecular docking analyses, we examined a library of compounds from the ZINC database. Among them, we identified twelve compounds with the lowest binding energy. Critical residues in the MAPK1 protein, such as VAL48, LYS63, CYS175, ASP176, LYS160, ALA61, LEU165, TYR45, SER162, ARG33, PRO365, PHE363, ILE40, ASN163, and GLU42, are pivotal for interactions with these compounds. Our result suggests that these compounds could influence the protein's behaviour. Moreover, our docking analyses revealed that the predicted peptides have a strong affinity for the MAPK1 protein. These peptides form stable complexes, indicating their potential as potent inhibitors. This study contributes to the identification of new drug compounds and the screening of their desired properties. These compounds could potentially help reduce the excessive activity of MAPK1, which is linked to Alzheimer's disease., Competing Interests: The authors declare no conflict of interest, financial or otherwise., (© 2023 The Authors.)

Frentizole is immunosuppressive drug with low acute toxicity and lifespan-prolonging effect. Recently, frentizole´s potential to disrupt toxic amyloid β (Aβ) - Aβ-binding alcohol dehydrogenase (ABAD) interaction in mitochondria in Alzheimer´s brains has been revealed. Another broadly studied drug with anti-aging and immunosuppressive properties is an mTOR inhibitor - rapamycin. Since we do not yet precisely know what is behind the lifespan-prolonging effect of rapamycin and frentizole, whether it is the ability to inhibit the mTOR signaling pathway, reduction in mitochondrial toxicity, immunosuppressive effect, or a combination of all of them, we have decided within our previous work to dock the entire in-house library of almost 240 Aβ-ABAD modulators into the FKBP-rapamycin-binding (FRB) domain of mTOR in order to interlink mTOR-centric and mitochondrial free radical-centric theories of aging and thus to increase the chances of success. Based on the results of the docking study, molecular dynamic simulation and MM-PBSA calculations, we have selected nine frentizole-like compounds (1 - 9). Subsequently, we have determined their real physical-chemical properties (logP, logD, pKa and solubility in water and buffer), cytotoxic/cytostatic, mTOR inhibitory, and in vitro anti-senescence (senolytic and senomorphic) effects. Finally, the three best candidates (4, 8, and 9) have been forwarded for in vivo safety studies to assess their acute toxicity and pharmacokinetic properties. Based on obtained results, only compound 4 demonstrated the best results within in vitro testing, the ability to cross the blood-brain barrier and the lowest acute toxicity (LD 50 in male mice 559 mg/kg; LD 50 in female mice 575 mg/kg)., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Acetylcholinesterase (AChE, EC 3.1.1.7) reactivators (2-PAM, trimedoxime, obidoxime, asoxime) have become an integral part of antidotal treatment in cases of nerve agent and organophosphorus (OP) pesticide poisonings. They are often referred to as specific antidotes due to their ability to restore AChE function when it has been covalently inhibited by an OP compound. Currently available commercial reactivators exhibit limited ability to penetrate the blood-brain barrier, where reactivation of inhibited AChE is crucial. Consequently, there have been numerous efforts to discover more brain-penetrating AChE reactivators. In this study, we examined a derivative of 2-PAM designed to possess increased lipophilicity. This enhanced lipophilicity was achieved through the incorporation of a benzyl group into its molecular structure. Initially, a molecular modeling study was conducted, followed by a comparison of its reactivation efficacy with that of 2-PAM against 10 different AChE inhibitors in vitro. Unfortunately, this relatively significant structural modification of 2-PAM resulted in a decrease in its reactivation potency. Consequently, this derivative cannot be considered as a broad-spectrum AChE reactivator., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or "good stress" and is characterized by low to mild levels of oxidants involved in the regulation of various biochemical transformations such as carboxylation, hydroxylation, peroxidation, or modulation of signal transduction pathways such as Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2-related factor 2 (Nrf2) and other processes. Increased levels of ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result in a harmful condition termed oxidative stress ("bad stress"). Although it is widely accepted, that many chronic diseases are multifactorial in origin, they share oxidative stress as a common denominator. Here we review the importance of oxidative stress and the mechanisms through which oxidative stress contributes to the pathological states of an organism. Attention is focused on the chemistry of ROS and RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl radicals, nitric oxide, peroxynitrite), and their role in oxidative damage of DNA, proteins, and membrane lipids. Quantitative and qualitative assessment of oxidative stress biomarkers is also discussed. Oxidative stress contributes to the pathology of cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer's and Parkinson's diseases, Down syndrome), psychiatric diseases (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, lung cancer), and aging. The concerted action of antioxidants to ameliorate the harmful effect of oxidative stress is achieved by antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), and small molecular weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others). Perhaps one of the most effective low molecular weight antioxidants is vitamin E, the first line of defense against the peroxidation of lipids. A promising approach appears to be the use of certain antioxidants (e.g. flavonoids), showing weak prooxidant properties that may boost cellular antioxidant systems and thus act as preventive anticancer agents. Redox metal-based enzyme mimetic compounds as potential pharmaceutical interventions and sirtuins as promising therapeutic targets for age-related diseases and anti-aging strategies are discussed., (© 2023. The Author(s).)

Oxidative stress status and morphological injuries in the brain of Wistar rats induced by repeated application of selected acetylcholinesterase reactivators - asoxime, obidoxime, K027, K048, K074, and K075 were evaluated. Each oxime in a dose of 0.1 of LD 50 /kg im was given 2x/week for 4 weeks. Markers of lipid peroxidation (malondialdehyde, MDA), and protein oxidation (advanced oxidation protein products, AOPP), as well as the activity of antioxidant enzymes (catalase, CAT, superoxide dismutase, SOD, glutathione reductase, GR, and glutathione peroxidase, GPx), were estimated in the brain tissue homogenates on day 35 of the study. Brain alterations were carefully quantified by semiquantitative grading scales - brain damage score (BDS). Oxidative stress parameters, MDA and AOPP were significantly highest in the asoxime-, obidoxime- and K075-treated groups (p < 0.001). The activity of SOD and CAT was significantly elevated in the obidoxime-, K048-, and K075-treated groups (p < 0.001). Besides, GR was markedly decreased in the obidoxime- and K074-treated groups (p < 0.01), while treatment with K048, K074 and K075 induced extremely high elevation in GPx levels (p < 0.001). In the same groups of rats, brain alterations associated with polymorphonuclear cell infiltrate were significantly more severe than those observed in animals receiving only asoxime or K027 (p < 0.001). The presented results confirmed that treatment with different oximes significantly improved the oxidative status and attenuated signs of inflammation in rats' brains. Presented results, together with our previously published data can help to predict likely adverse systemic toxic effects, and target organ systems, which are crucial for establishing risk categories, as well as in dose selection of K-oximes as drug candidates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing for financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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 (H 2 O 2 ) 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 H 2 O 2 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 H 2 O 2, 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 H 2 O 2 ‑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 H 2 O 2 generation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Trichothecene mycotoxin deoxynivalenol (DON) negatively regulates immune response by damaging host immune system and harming the organism's health. We hypothesized that DON can initiate an active immunosuppressive mechanism similar to "immune evasion" to alter the cellular microenvironment and evade immune surveillance. We tested this hypothesis using the RAW264.7 macrophage model. DON rapidly increased the expression of immune checkpoints PD-1 and PD-L1, inflammatory cytokine TGF-β, and key immune evasion factors STAT3, VEGF, and TLR-4, and caused cellular hypoxia. Importantly, hypoxia-inducible factor-1α (HIF-1α) acts as a key regulator of DON-induced immunosuppression. HIF-1α accumulated in the cytoplasm and was gradually transferred to the nucleus following DON treatment. Moreover, DON activated HIF-1α through STAT3 signaling to upregulate downstream signaling, including PD-1/PD-L1. Under DON treatment, immunosuppressive miR-210-3p, lncRNA PVT1, lncRNA H19, and lncRNA HOTAIR were upregulated by the STAT3/HIF-1α axis. Moreover, DON damaged mitochondrial function, causing mitophagy, and suppressed immune defenses. Collectively, DON triggered RAW264.7 intracellular hypoxia and rapidly activated HIF-1α via STAT3 signaling, activating immune evasion signals, miRNAs, and lncRNAs, thereby initiating the key link of immune evasion. This study offers further clues for accurate prevention and treatment of immune diseases caused by mycotoxins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cellular senescence leads to decreased tissue regeneration and inflammation and is associated with diabetes, neurodegenerative diseases, and tumorigenesis. However, the mechanisms of cellular senescence are not fully understood. Emerging evidence has indicated that c-Jun N-terminal kinase (JNK) signaling is involved in the regulation of cellular senescence. JNK can downregulate hypoxia inducible factor-1α to accelerate hypoxia-induced neuronal cell senescence. The activation of JNK inhibits mTOR activity and triggers autophagy, which promotes cellular senescence. JNK can upregulate the expression of p53 and Bcl-2 and accelerates cancer cell senescence; however, this signaling also mediates the expression of amphiregulin and PD-LI to achieve cancer cell immune evasion and prevents their senescence. The activation of JNK further triggers forkhead box O expression and its target gene Jafrac1 to extend the lifespan of Drosophila. JNK can also upregulate the expression of DNA repair protein poly ADP-ribose polymerase 1 and heat shock protein to delay cellular senescence. This review discusses recent advances in understanding the function of JNK signaling in cellular senescence and includes a comprehensive analysis of the molecular mechanisms underlying JNK-mediated senescence evasion and oncogene-induced cellular senescence. We also summarize the research progress in anti-aging agents that target JNK signaling. This study will contribute to a better understanding of the molecular targets of cellular senescence and provides insights into anti-aging, which may be used to develop drugs for the treatment of aging-related diseases., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The antioxidant properties of flavonoids are mediated by their functional hydroxyl groups, which are capable of both chelating redox active metals such as iron, copper and scavenging free radicals. In this paper, the antioxidant vs. prooxidant and DNA protecting properties of baicalein and Cu(II)-baicalein complexes were studied under the conditions of the Copper-Fenton reaction and of the Copper-Ascorbate system. From the relevant EPR spectra, the interaction of baicalein with Cu(II) ions was confirmed, while UV-vis spectroscopy demonstrated a greater stability over time of Cu(II)-baicalein complexes in DMSO than in methanol and PBS and Phosphate buffers. An ABTS study confirmed a moderate ROS scavenging efficiency, at around 37%, for both free baicalein and Cu(II)-baicalein complexes (in the ratios 1:1 and 1:2). The results from absorption titrations are in agreement with those from viscometric studies and confirmed that the binding mode between DNA and both free baicalein and Cu-baicalein complexes, involves hydrogen bonds and van der Waals interactions. The DNA protective effect of baicalein has been investigated by means of gel electrophoresis under the conditions of the Cu-catalyzed Fenton reaction and of the Cu-Ascorbate system. In both cases, it was found that, at sufficiently high concentrations, baicalein offers some protection to cells from DNA damage caused by ROS (singlet oxygen, hydroxyl radicals and superoxide radical anions). Accordingly, baicalein may be useful as a therapeutic agent in diseases with a disturbed metabolism of redox metals such as copper, for example Alzheimer's disease, Wilson's disease and various cancers. While therapeutically sufficient concentrations of baicalein may protect neuronal cells from Cu-Fenton-induced DNA damage in regard to neurological conditions, conversely, in the case of cancers, low concentrations of baicalein do not inhibit the pro-oxidant effect of copper ions and ascorbate, which can, in turn, deliver an effective damage to DNA in tumour cells., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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 p21 WAF1/CIP1 as well as p16 Ink4a 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mycotoxins result in immune dysfunction and cause immune diseases in animals and humans. However, the mechanisms of immunotoxicity involved in mycotoxins have not been fully explored, and emerging evidence suggests that these toxins may promote their immunotoxicity via cellular senescence. Mycotoxins induce cell senescence after DNA damage, and activate signaling via the NF-κB and JNK pathways to promote the secretion of senescence-associated secretory phenotype (SASP) cytokines including IL-6, IL-8, and TNF-α. DNA damage can also over-activate or cleave poly (ADP-ribose) polymerase-1 (PARP-1), increase the expression of cell cycle inhibitory proteins p21, and p53, and induce cell cycle arrest and then senescence. These senescent cells further down-regulate proliferation-related genes and overexpress inflammatory factors resulting in chronic inflammation and eventual immune exhaustion. Here we review the underlying mechanisms by which mycotoxins trigger cell senescence and the potential roles of SASP and PARP in these pathways. This work will help to further understand the mechanisms of immunotoxicity involved in mycotoxins., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Fluoride is one of the abundant elements found in the Earth's crust and is a global environmental issue. The present work aimed to find the impact of chronic consumption of fluoride contained groundwater on human subjects. Five hundred and twelve volunteers from different areas of Pakistan were recruited. Cholinergic status, acetylcholinesterase and butyrylcholinesterase gene SNPs and pro-inflammatory cytokines were examined. Association analysis, regression and other standard statistical analyses were performed. Physical examination of the fluoride endemic areas' participants revealed the symptoms of dental and skeletal fluorosis. Cholinergic enzymes (AChE and BChE) were significantly increased among different exposure groups. ACHE gene 3'-UTR variant and BCHE K-variant showed a significant association with risk of fluorosis. Pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) were found to be increased and have a significant correlation in response to fluoride exposure and cholinergic enzymes. The study concludes that chronic consumption of high fluoride-contained water is a risk factor for developing low-grade systemic inflammation through the cholinergic pathway and the studied cholinergic gene SNPs were identified to be associated with the risk of flurosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Serious health risks associated with the consumption of food products contaminated with aflatoxins (AFs) are worldwide recognized and depend predominantly on consumed AF concentration by diet. A low concentration of aflatoxins in cereals and related food commodities is unavoidable, especially in subtropic and tropic regions. Accordingly, risk assessment guidelines established by regulatory bodies in different countries help in the prevention of aflatoxin intoxication and the protection of public health. By assessing the maximal levels of aflatoxins in food products which are a potential risk to human health, it's possible to establish appropriate risk management strategies. Regarding, a few factors are crucial for making a rational risk management decision, such as toxicological profile, adequate information concerning the exposure duration, availability of routine and some novel analytical techniques, socioeconomic factors, food intake patterns, and maximal allowed levels of each aflatoxin in different food products which may be varied between countries., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing for financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The genetic variant A2 β-casein integrates the casein protein group in milk and has been often associated with positive health outcomes. Therefore, this review explores the present understanding of A2 β-casein, including detection methods and the market trends for dairy from A2 milk. Also, the interaction of A2 β-casein with αs 1 -casein and κ-casein genotypes was examined in terms of technological impacts on A2 milk. A limited number of preliminary studies has aimed to investigate the sensorial and technological impacts of β-casein variants in milk matrices, for instance, in yogurt and other derivatives. Nevertheless, considering studies carried out so far, it is concluded that the manufacture of dairy products from A2 milk is perfectly feasible, as the products presented slight differences when compared to those derived from traditional milk. In one of the works, sensitive drops in rennet coagulation time and curd firmness values were observed in cheese traits. However, it is relevant to point out that variant A of κ-casein plays a negative role in the coagulation features of milk. Therefore, alterations in the pattern of cheese-making properties are not uniquely related to β-casein variants. Attempts to produce A2 β-casein in laboratory (non-natural source), through biosynthesis, for example, have not been found so far. This knowledge gap offers a promising area for future studies concerning proteins and bioactive peptide production., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Main Conclusion: EF have been explored for its beneficial impact on environment and for its commercial applications. It has proved its worth in these sectors and showed an impact on biological properties of plants by producing various bioactive molecules and enzymes. Endophytes are plant mutualists that live asymptomatically within plant tissues and exist in almost every plant species. Endophytic fungi benefit from the host plant nutrition, and the host plant gains improved competitive abilities and tolerance against pathogens, herbivores, and various abiotic stresses. Endophytic fungi are one of the most inventive classes which produce secondary metabolites and play a crucial role in human health and other biotic aspects. This review is focused on systematic study on the biodiversity of endophytic fungi in plants, and their role in enhancing various properties of plants such as antimicrobial, antimycobacterial, antioxidant, cytotoxic, anticancer, and biological activity of secondary metabolites produced by various fungal endophytes in host plants reported from 1994 to 2021. This review emphasizes the endophytic fungal population shaped by host genotype, environment, and endophytic fungi genotype affecting host plant. The impact of endophytic fungi has been discussed in detail which influences the commercial properties of plants. Endophytes also have an influence on plant productivity by increasing parameters such as nutrient recycling and phytostimulation. Studies focusing on mechanisms that regulate attenuation of secondary metabolite production in EF would provide much needed impetus on ensuring continued production of bioactive molecules from a indubitable source. If this knowledge is further extensively explored regarding fungal endophytes in plants for production of potential phytochemicals, then it will help in exploring a keen area of interest for pharmacognosy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: People in different occupations are exposed to a variety of xenobiotics which affect the health and physiological processes of the body. Butyrylcholinesterase (BChE), has been reported to play neuronal and non-neuronal roles, though its exact function is yet to be established. This study aimed to find the status and role of BChE in seven different occupational groups; gasoline fillers, auto-mechanics, carpenters, textile shop workers, furniture shop workers, electricians, and office workers., Methods: A total of 400 samples were screened. BChE activity was determined by Worek et al. method based on Ellman's principle. Pro-inflammatory cytokines were determined by ELISA. Genotypic analysis of the K-variant of BCHE gene SNP was carried out by standard molecular methods. Among seven groups, office workers were taken as a control to compare the results with all other occupational groups., Results: The results revealed a significant decrease in BChE activity in gasoline fillers (79.52%) followed by carpenters (73.49%), auto mechanics (39.76%), textile shop workers (18.07%), electricians (10.84%), and furniture shop workers (7.23%). TNF-α, IL-6, and IL1-β were elevated in all groups. IL-6 and IL1-β in gasoline fillers, and electricians were not statistically significantly increased. Binomial regression to determine the odd ratio was found to be significant (p < 0.05) in all groups. However, correlation (Pearson) did not reveal significance between different biochemical parameters. Genotypic analysis of the K-variant SNP of the BCHE gene showed a significant association with occupational groups when compared with control which indicates a possible association with xenobiotics exposure and the physiological role of K-variant in understudied occupational groups., Conclusion: The study concluded that BChE and its gene SNP rs 1803274 and proinflammatory cytokines significantly dysregulates under the exposure to cumulative multiple xenobiotics in different occupational groups which may lead to pathophysiological conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Mycotoxins induce oxidative stress, hypoxia, and cause immunosuppressive effects. Moreover, emerging evidence show that mycotoxins have a potential of inducing cellular senescence, which are involved in their immunomodulatory effects. Mycotoxins upregulate the expression of senescence markers γ-H2AX, senescence-associated β-galactosidase, p53, p16, and senescence-associated secretory phenotype (SASP) inflammatory factors. Moreover, mycotoxins cause senescence-associated cell cycle arrest by diminishing cyclin D 1 and Cdk4 pathways, as well as increasing the expression of p53, p21, and CDK6. Mycotoxins may induce cellular senescence by activating reactive oxygen species (ROS)-induced oxidative stress. In addition, hypoxia acts as a double-edged sword on cell senescence; it could both act as the stress-induced senescence and also hinder the onset of cellular senescence. The SASP inflammatory factors have the ability to induce an immunosuppressive environment, while mycotoxins directly cause immunosuppression. Therefore, there is a potential relationship between mycotoxins and cellular senescence that synergistically cause immunosuppression. However, most of the current studies have involved the effect of mycotoxins on cell cycle arrest, but only limited in-depth research has been carried out to link the occurrence of this condition (cell cycle arrest) with cellular senescence., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The main objective of the current research work was to synthesize mesoporous silica nanoparticles for controlled delivery of mometasone furoate for potential nasal delivery. The optimized sol-gel method was used for the synthesis of mesoporous silica nanoparticles. Synthesized nanoparticles were processed through Zeta sizer, SEM, TEM, FTIR, TGA, DSC, XRD, and BET analysis for structural characterization. The in vitro dissolution test was performed for the inclusion compound, while the Franz diffusion experiment was performed for permeability of formulation. For the determination of expression levels of anti-inflammatory cytokines IL-4 and IL-5, RNA extraction, reverse transcription, and polymerase chain reaction (RT-PCR) were performed. The MTT assay was also performed to determine cell viability. Synthesized and functionalized mesoporous silica nanoparticles showed controlled release of drugs. FT-IR spectroscopy confirmed the presence of the corresponding functional groups of drugs within mesoporous silica nanoparticles. Zeta sizer and thermal analysis confirmed the delivery system was in nano size and thermally stable. Moreover, a highly porous system was observed during SEM and TEM evaluation, and further it was confirmed by BET analysis. Greater cellular uptake with improved permeability characteristics was also observed. As compared to the crystalline drug, a significant improvement in the dissolution rate was observed. It was concluded that stable mesoporous silica nanoparticles with significant porosity were synthesized, efficiently delivering the loaded drug without any toxic effect., Competing Interests: YM and HS were employed by Saffron Pharmaceuticals (Pvt.) Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer VS declared a shared affiliation with the author RS to the handling editor at the time of review., (Copyright © 2023 Mehmood, Shahid, Barkat, Ibraheem, Riaz, Badshah, Chopra, Sharma, Nepovimova, Kuca, Valis and Emran.)

Probiotics consumption has been associated with various health promoting benefits, including disease prevention and even treatment by modulating gut microbiota. Contrary to this, probiotics may also overstimulate the immune system, trigger systemic infections, harmful metabolic activities, and promote gene transfer. In children, the fragile immune system and impaired intestinal barrier may boost the occurrence of adverse effects following probiotics' consumption. To overcome these health challenges, the key focus has been shifted toward non-viable probiotics, also called paraprobiotics. Cell wall polysaccharides, peptidoglycans, surface proteins and teichoic acid present on cell's surface are involved in the interaction of paraprobiotics with the host, ultimately providing health benefits. Among other benefits, paraprobiotics possess the ability to regulate innate and adaptive immunity, exert anti-adhesion, anti-biofilm, anti-hypertensive, anti-inflammatory, antioxidant, anti-proliferative, and antagonistic effects against pathogens, while also enhance clinical impact and general safety when administered in children in comparison to probiotics. Clinical evidence have underlined the paraprobiotics impact in children and young infants against atopic dermatitis, respiratory and gastrointestinal infections, in addition to be useful for immunocompromised individuals. Therefore, this review focuses on probiotics-related issues in children's health and also discusses the Lactobacillus and Bifidobacterium spp. qualities for qualifying as paraprobiotics and their role in promoting the children's health.

The mammalian target of rapamycin (mTOR) is an important biological target for development of novel anticancer drugs and potential antiageing agents. Therefore, many scientific groups search for mTOR kinase inhibitors. Herein, we present structure-based approach which could be helpful in the studies on new bioactive compounds. Method validation was preceded by structural analysis of ATP catalytic cleft and FRB domain. In silico studies allowed us to point crucial amino acid residues for ligand binding and develop optimal docking protocols. The presented methodology could be applied for design and development of potential mTOR kinase inhibitors., (© 2022 John Wiley & Sons Ltd.)

To date, the most studied drug in anti-aging research is the mTOR inhibitor - rapamycin. Despite its almost perfect anti-aging profile, rapamycin exerts one significant limitation - inappropriate physicochemical properties. Therefore, we have decided to utilize virtual high-throughput screening and fragment-based design in search of novel mTOR inhibiting scaffolds with suitable physicochemical parameters. Seven lead compounds were selected from the list of obtained hits that were commercially available ( 4, 5, and 7 ) or their synthesis was feasible ( 1, 2, 3, and 6 ) and evaluated in vitro and subsequently in vivo . Of all these substances, only compound 3 demonstrated a significant cytotoxic, senolytic, and senomorphic effect on normal and cancerous cells. Further, it has been confirmed that compound 3 is a direct mTORC1 inhibitor. Last but not least, compound 3 was found to exhibit anti-SASP activity concurrently being relatively safe within the test of in vivo tolerability. All these outstanding results highlight compound 3 as a scaffold worthy of further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chrienova, Rysanek, Oleksak, Stary, Bajda, Reinis, Mikyskova, Novotny, Andrys, Skarka, Vasicova, Novak, Valis, Kuca, Hodny and Nepovimova.)