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    Beyond the Hayflick limit: How microbes influence cellular aging
    (Elsevier Ireland Ltd, 2025) Abavisani, Mohammad; Faraji, Saba; Ebadpour, Negar; Karav, Sercan; Sahebkar, Amirhossein
    Cellular senescence, a complex biological process resulting in permanent cell-cycle arrest, is central to aging and age-related diseases. A key concept in understanding cellular senescence is the Hayflick Limit, which refers to the limited capacity of normal human cells to divide, after which they become senescent. Senescent cells (SC) accumulate with age, releasing pro-inflammatory and tissue-remodeling factors collectively known as the senescence-associated secretory phenotype (SASP). The causes of senescence are multifaceted, including telomere attrition, oxidative stress, and genotoxic damage, and they extend to influences from microbial sources. Research increasingly emphasizes the role of the microbiome, especially gut microbiota (GM), in modulating host senescence processes. Beneficial microbial metabolites, such as short-chain fatty acids (SCFAs), support host health by maintaining antioxidant defenses and reducing inflammation, potentially mitigating senescence onset. Conversely, pathogenic bacteria like Pseudomonas aeruginosa and Helicobacter pylori introduce factors that damage host DNA or increase ROS, accelerating senescence via pathways such as NF-?B and p53-p21. This review explores the impact of bacterial factors on cellular senescence, highlighting the role of specific bacterial toxins in promoting senescence. Additionally, it discusses how dysbiosis and the loss of beneficial microbial species further contribute to age-related cellular deterioration. Modulating the gut microbiome to delay cellular senescence opens a path toward targeted anti-aging strategies. This work underscores the need for deeper investigation into microbial influence on aging, supporting innovative interventions to manage and potentially reverse cellular senescence. © 2025 Elsevier B.V.
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    Decoy oligodeoxynucleotides: A promising therapeutic strategy for inflammatory skin disorders
    (Elsevier Science Inc, 2024) Mahjoubin-Tehran, Maryam; Rezaei, Samaneh; Karav, Sercan; Kesharwani, Prashant; Sahebkar, Amirhossein
    Chronic inflammatory skin conditions such as psoriasis and atopic dermatitis (AD) impose a significant burden on both the skin and the overall well-being of individuals, leading to a diminished quality of life. Despite the use of conventional treatments like topical steroids, there remains a need for more effective and safer therapeutic options to improve the lives of patients with severe skin conditions. Molecular therapy has emerged as a promising approach to address disorders such as atopic dermatitis, psoriasis, and contact hypersensitivity. One strategy to counteract the disease processes involves targeting the transcriptional process. A novel form of gene therapy utilizes double-stranded oligodeoxynucleotides (ODNs), also known as decoys, that contain cis-elements. By introducing these decoy ODNs through transfection, the cis-trans interactions are disrupted, leading to the inhibition of trans-factors from binding to the intrinsic cis-elements and thus regulating gene expression. In this review, we have summarized studies investigating the therapeutic effects of decoy ODNs on inflammatory skin diseases. Various transcription factors, including NF-kB, STAT6, HIF-1 alpha/STAT5, STAT1, and Smad, have been targeted and inhibited using designed decoy ODNs for the treatment of atopic dermatitis, psoriasis, hypertrophic scarring, and contact hypersensitivity. The findings of these studies confirm the significant potential of the decoy approach in the treatment of inflammatory skin diseases.
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    Exploring the antioxidant properties of semaglutide: A comprehensive review
    (Elsevier Science Inc, 2024) Yaribeygi, Habib; Maleki, Mina; Forouzanmehr, Behina; Kesharwani, Prashant; Jamialahmadi, Tannaz; Karav, Sercan; Sahebkar, Amirhossein
    Patients with diabetes commonly experience an aberrant production of free radicals and weakened antioxidative defenses, making them highly susceptible to oxidative stress development. This, in turn, can induce and promote diabetic complications. Therefore, utilizing antidiabetic agents with antioxidative properties can offer dual benefits by addressing hyperglycemia and reducing oxidative damage. Semaglutide, a recently approved oral form of glucagon-like peptide-1 (GLP-1) analogues, has shown potent antidiabetic effects. Additionally, recent studies have suggested that it possesses antioxidative properties. However, the exact effects and the molecular pathways involved are not well understood. In this review, we present the latest findings on the antioxidative impacts of semaglutide and draw conclusions about the mechanisms involved.
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    Impact of statin therapy on CD40:CD40L signaling: mechanistic insights and therapeutic opportunities
    (Springer Heidelberg, 2024) Askarizadeh, Fatemeh; Karav, Sercan; Jamialahmadi, Tannaz; Sahebkar, Amirhossein
    Statins are widely utilized to reduce cholesterol levels, particularly in cardiovascular diseases. They interface with cholesterol synthesis by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase enzyme. Besides their primary effect, statins demonstrate anti-inflammatory and immune-modulating properties in various diseases, highlighting the pleiotropic effect of these drugs. The CD40:CD40L signaling pathway is considered a prominent inflammatory pathway in multiple diseases, including autoimmune, inflammatory, and cardiovascular diseases. The findings from clinical trials and in vitro and in vivo studies suggest the potential anti-inflammatory effect of statins in modulating the CD40 signaling pathway and downstream inflammatory mediator. Accordingly, as its classic ligand, statins can suppress immune responses in autoimmune diseases by inhibiting CD40 expression and blocking its interaction with CD40L. Additionally, statins affect intracellular signaling and inhibit inflammatory mediator secretion in chronic inflammatory diseases like asthma and autoimmune disorders such as myasthenia gravis, multiple sclerosis, systemic lupus erymanthus, and cardiovascular diseases like atherosclerosis. However, it is essential to note that the anti-inflammatory effect of statins may vary depending on the specific type of statin used. In this study, we aim to explore the potential anti-inflammatory effects of statins in treating inflammatory diseases by examining their role in regulating immune responses, particularly their impact on the CD40:CD40L signaling pathway, through a comprehensive review of existing literature.
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    Lipid nanoparticle-based delivery of small interfering RNAs: New possibilities in the treatment of diverse diseases
    (Pergamon-Elsevier Science Ltd, 2025) Askarizadeh, Anis; Vahdat-Lasemi, Fatemeh; Karav, Sercan; Kesharwani, Prashant; Sahebkar, Amirhossein
    RNA interference (RNAi) is a well-known post-transcriptional gene-silencing mechanism that has garnered significant attention as a potentially powerful therapeutic procedure for combating recalcitrant diseases. Small interfering RNA (siRNA) as an effective RNAi tool mediates gene silencing pathway by mRNA degradation in cells and presents a unique strategy for the treatment of rebellious diseases. However, the low stability and suboptimal pharmacokinetic behavior of naked siRNAs have made it necessary to employ a delivery vehicle to protect siRNA against degradation and allow for its intracellular delivery. Among a plethora of available delivery platforms, lipid nanoparticles (LNPs) have received significant research attention and are currently recognized as the most advanced delivery system for RNA-based therapeutic agents. This is exemplified by the approval of Onpattro (R) for treating amyloidosis in the US and the European Union in 2018, as well as the development of COVID-19 mRNA vaccines. This review aims to provide a comprehensive evaluation of the potential effectiveness of lipid-based nanoparticles as a delivery system for siRNA in treating a wide array of diseases.
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    Modulation of the ubiquitin-proteasome system by curcumin: Therapeutic implications in cancer
    (2025) Torghabe, Shima Yahoo; Alavi, Parisa; Rostami, Sara; Davies, Neal M.; Kesharwani, Prashant; Karav, Sercan; Sahebkar, Amirhossein
    By the ubiquitin-proteasomes, cellular proteins are structurally degraded and turnover. Many essential functions and regulations of cells are regulated and controlled by these proteins. Recent studies indicated that many cancer types have been associated with aberrations in the ubiquitination pathway, which involves three enzymatic steps. Dietary phytochemicals have been identified as having the potential to inhibit carcinogenesis recently. As part of this group of phytochemicals, curcumin can play a crucial role in suppressing carcinogenesis by changing many reactions affected by the ubiquitin-proteasome pathway. Due to its ability to change some biological processes such as NF-?B, inhibit some cyclins, and induce apoptosis, it can be used as a drug in cancer treatment. Copyright © 2024 Elsevier GmbH. All rights reserved.
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    Nutritional factors and physical frailty: Highlighting the role of functional nutrients in the prevention and treatment
    (Elsevier Ireland Ltd, 2024) Ziaei, Rahele; Shahdadian, Farnaz; Bagherniya, Mohammad; Karav, Sercan; Sahebkar, Amirhossein
    Physical frailty, an age-related decline in the physiological capacity and function of various organs, is associated with higher vulnerability to unfavorable health outcomes. The mechanisms proposed for physical frailty including increased inflammation and oxidative stress are closely related to nutritional status. In addition to traditional nutritional factors such as protein malnutrition and nutrient deficiencies, emerging evidence has focused on the role of functional nutrients including polyphenols, carotenoids, probiotics, prebiotics, omega-3 long-chain polyunsaturated fatty acids (n-3 PUFAs), (3-hydroxy-(3-methylbutyrate (HMB), coenzyme Q10 (CoQ10), and L-carnitine in modifying the risk of physical frailty syndrome. Although several clinical trials have suggested the beneficial effects of supplementation with polyphenols, HMB, and prebiotics on frailty indices, the current evidence is still not robust to support recommendations on the routine clinical use of such functional nutrients for the management of frailty. Similarly, the association between CoQ10 and frailty was mainly assessed in observational studies, and more randomized controlled trials are needed in this regard. A limited number of studies have reported the beneficial effect of L-carnitine supplementation on frailty indices. Since carnitine is mainly found in skeletal muscle and its measurement is thus challenging due to ethical constraints, it is necessary to examine the effect of different doses of L-carnitine on frailty and its indices in future studies. A large number of interventional studies evaluated the impact of n-3 PUFA supplementation on physical frailty in the elderly and many of them reported improved physical performance following supplementation, especially when combined with resistance training programs. Although promising findings from experimental and observational studies have been reported on functional nutrients, high-quality evidence from randomized controlled trials as well as detailed mechanistic studies are still required to affirm their role in the prevention and/or treatment of physical frailty. This review aims to describe the current state of research on functional nutrients that may modify the development or prognosis of frailty syndrome.
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    Overcoming antibiotic resistance: the potential and pitfalls of drug repurposing
    (Taylor & Francis Ltd, 2024) Abavisani, Mohammad; Khoshrou, Alireza; Eshaghian, Souzan; Karav, Sercan; Sahebkar, Amirhossein
    Since its emergence shortly after the discovery of penicillin, antibiotic resistance has escalated dramatically, posing a significant health threat and economic burden. Drug repositioning, or drug repurposing, involves identifying new therapeutic applications for existing drugs, utilising their established safety profiles and pharmacological data to swiftly provide effective treatments against resistant pathogens. Several drugs, including otilonium bromide, penfluridol, eltrombopag, ibuprofen, and ceritinib, have demonstrated potent antibacterial activity against multidrug-resistant (MDR) bacteria. These drugs can disrupt biofilms, damage bacterial membranes, and inhibit bacterial growth. The combination of repurposed drugs with conventional antibiotics can reduce the required dosage of individual drugs, mitigate side effects, and delay the development of resistance, making it a promising strategy against MDR bacteria such as Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. Despite its promise, drug repurposing faces challenges such as potential off-target effects, toxicity, and regulatory and intellectual property issues, necessitating rigorous evaluations and strategic solutions. This article aims to explore the potential of drug repurposing as a strategy to combat antibiotic resistance, examining its benefits, challenges, and future prospects. We address the legal, economic, and practical challenges associated with repurposing existing drugs, highlight successful examples, and propose solutions to enhance the efficacy and viability of this approach in combating MDR bacterial infections.
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    Regulatory effects of statins on CCL2/CCR2 axis in cardiovascular diseases: new insight into pleiotropic effects of statins
    (BMC, 2024) Gholamalizadeh, Hanieh; Ensan, Behzad; Karav, Sercan; Jamialahmadi, Tannaz; Sahebkar, Amirhossein
    BackgroundHMG-CoA reductase inhibitors are well-known medications in the treatment of cardiovascular disorders due to their pleiotropic and lipid-lowering properties. Herein, we reviewed the effects of statins on the CCL2/CCR2 axis.MethodScopus and Pubmed databases were systematically searched using the following keywords: Hydroxymethylglutaryl CoA Reductase Inhibitors, HMG-CoA Reductase Inhibitors, Statins, CCL2, Chemokine, Monocyte Chemoattractant Protein-1 and Chemokine (C-C Motif) Ligand 2. Evidence investigating the role of statin on MCP-1 in CVD was identified and bibliographies were completely evaluated to gather further related studies.ResultsThe anti-inflammatory effects of statins on the CCL2/CCR2 pathway have been widely investigated. Despite inconclusive results, a great body of research supports the regulatory roles of statins on this pathway due to their pleiotropic effects. By disrupting the CCL2/CCR2 axis, statins attenuate the infiltration of monocytes and macrophages into the zone of inflammation and hence down-regulate the inflammatory cascades in various CVDs including atherosclerosis, cardiac remodeling, and stroke, among others.ConclusionCCL2 plays a major role in the pathogenesis of cardiovascular disorders. Down-regulation of CCL2 is proposed as one of the pleiotropic properties of statins. However, more investigations are required to elucidate which statin in what dose exerts a more potent effect on CCL2/CCR2 pathway.
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    Utilizing ionic liquids as eco-friendly and sustainable carriers for delivering nucleic acids: A review on the revolutionary advancement in nano delivery systems
    (Elsevier B.V., 2024) Mirhadi, Elaheh; Kesharwani, Prashant; Jha, Saurav Kumar; Karav, Sercan; Sahebkar, Amirhossein
    Ionic liquids (ILs) are an extremely versatile class of chemicals. It has been shown that they can effectively pass through many biological barriers in the human body to deliver medications. ILs are solvents noted for their ecological friendliness; they contain equal amounts of cations and anions and remain liquid at temperatures below 100 °C. Hence, these are ideal for biomedical applications owing to their advantageous properties such as biocompatibility, solubility, and adaptability. ILs are widely reported to improve the solubility and stability of nucleic acids (DNA and RNA) in aqueous conditions, allowing for more effective delivery. Certain ILs have shown the ability to enhance the absorption of nucleic acids into cells. In addition, ILs can also be used to create vectors for gene delivery, such as liposomes and nanoparticles, thereby improving the transfection efficiency of plasmid DNA and siRNA. Subsequently, the application of ILs for nucleic acid delivery has increased significantly in recent years. In this context, we believe that using ILs to enhance the transport of nucleic acids will have a considerable effect as a novel and crucial therapeutic method in the upcoming decades. The use of ILs as solvents to preserve the natural structure of DNA and RNA shows promise for a variety of biotechnological and medical applications. Notably, ILs may be utilized for a variety of functions, including extracting, concentrating, stabilizing, and spreading nucleic acids inside cells. Our review emphasizes the key findings of research works published in this domain, wherein outstanding effectiveness of delivering RNA to the desired areas was achieved, and was made possible through the utilization of ILs. © 2024 Elsevier B.V.