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The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is well recognized as a critical regulator of redox, metabolic, and protein homeostasis, as well as the regulation of inflammation. An age-associated decline in NRF2 activity may allow oxidative stress to remain unmitigated and affect key features associated with the aging phenotype, including telomere shortening. Telomeres, the protective caps of eukaryotic chromosomes, are highly susceptible to oxidative DNA damage, which can accelerate telomere shortening and, consequently, lead to premature senescence and genomic instability. In this review, we explore how the dysregulation of NRF2, coupled with an increase in oxidative stress, might be a major determinant of telomere shortening and age-related diseases. We discuss the relevance of the connection between NRF2 deficiency in aging and telomere attrition, emphasizing the importance of studying this functional link to enhance our understanding of aging pathologies. Finally, we present a number of compounds that possess the ability to restore NRF2 function, maintain a proper redox balance, and preserve telomere length during aging., (© 2023. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) is associated with one of the most unfavorable prognoses across all malignancies. In this review, we investigate the role of inhibitors targeting crucial regulators of DNA damage response (DDR) pathways, either as single treatments or in combination with chemotherapeutic agents and targeted therapies in PDAC. The most prominent clinical benefit of PARP inhibitors' monotherapy is related to the principle of synthetic lethality in individuals harboring BRCA1/2 and other DDR gene mutations as predictive biomarkers. Moreover, induction of BRCAness with inhibitors of RTKs, including VEGFR and c-MET and their downstream signaling pathways, RAS/RAF/MEK/ERK and PI3K/AKT/mTOR in order to expand the application of PARP inhibitors in patients without DDR mutations, has also been addressed. Other DDR-targeting agents beyond PARP inhibitors, including inhibitors of ATM, ATR, CHEK1/2, and WEE1 have also demonstrated their potential in preclinical models of PDAC and may hold promise in future studies., Competing Interests: Declaration of competing interest The authors declare that they do not possess any identifiable competing financial interests or personal relationships that might be perceived to have impacted the research presented in this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neuropathic pain, a chronic condition resulting from nerve injury or dysfunction, presents significant therapeutic challenges and is closely associated with oxidative stress and inflammation, both of which can lead to mitochondrial dysfunction. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a critical cellular defense mechanism against oxidative stress, has emerged as a promising target for neuropathic pain management. Nrf2 modulators enhance the expression of antioxidant and cytoprotective genes, thereby reducing oxidative damage, inflammation, and mitochondrial impairment. This review explores the antinociceptive effects of Nrf2, highlighting how pharmacological agents and natural compounds may be used as potential therapeutic strategies against neuropathic pain. Although preclinical studies demonstrate significant pain reduction and improved nerve function through Nrf2 activation, several clinical challenges need to be addressed. However, emerging clinical evidence suggests potential benefits of Nrf2 modulators in several conditions, such as diabetic neuropathy and multiple sclerosis. Future research should focus on further elucidating the molecular role of Nrf2 in neuropathic pain to optimize its modulation efficacy and maximize clinical utility.

The influenza virus (IFV) imposes a considerable health and economic burden globally, requiring a comprehensive understanding of its pathogenic mechanisms. Ferroptosis, an iron-dependent lipid peroxidation cell death pathway, holds unique implications for the antioxidant defense system, with possible contributions to inflammation. This exploration focuses on the dynamic interplay between ferroptosis and the host defense against viruses, emphasizing the influence of IFV infections on the activation of the ferroptosis pathway. IFV causes different types of cell death, including apoptosis, necrosis, and ferroptosis. IFV-induced ferroptotic cell death is mediated by alterations in iron homeostasis, intensifying the accumulation of reactive oxygen species and promoting lipid peroxidation. A comprehensive investigation into the mechanism of ferroptosis in viral infections, specifically IFV, has great potential to identify therapeutic strategies. This understanding may pave the way for the development of drugs using ferroptosis inhibitors, presenting an effective approach to suppress viral infections., (© 2024. The Author(s).)

The tumor suppressor proteins are key transcription factors involved in the regulation of various cellular processes, such as apoptosis, DNA repair, cell cycle, senescence, and metabolism. The tumor suppressor protein p53 responds to different type of stress signaling, such as hypoxia, DNA damage, nutrient deprivation, oncogene activation, by activating or repressing the expression of different genes that target processes mentioned earlier. p53 has the ability to modulate the activity of many other proteins and signaling pathway through protein-protein interaction, post-translational modifications, or non-coding RNAs. In many cancers the p53 is found to be mutated or inactivated, resulting in the loss of its tumor suppressor function and acquisition of new oncogenic properties. The tumor suppressor protein p53 also plays a role in the development of other metabolic disorders such as diabetes, obesity, and fatty liver disease. In this review, we will summarize the current data and knowledge on the molecular mechanisms and the functions of p53 in different pathways and processes at the cellular level and discuss the its implications for human health and disease., 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 Inc. All rights reserved.)

The marine environment has been recognized as a prolific source of potent bioactive compounds with significant anticancer properties. Among these, heteronemin, a sesterterpenoid-type natural product, has shown promise. This study delves into the potential of heteronemin as a ferroptotic agent against pancreatic cancer, using the Panc-1 cell line as a model. The cytotoxic potential of heteronemin was assessed using cell viability assays. Furthermore, its effect on lipid peroxidation was determined spectrophotometrically, while the changes it induced in autophagy- and ferritin-related protein expressions were evaluated using immunoblotting techniques. Various cell-based tests were employed to scrutinize its anticancer efficacy. Heteronemin displayed a notable cytotoxic effect, reducing cell viability by 50% at a concentration of 55 nM. This cytotoxicity was discernibly linked to ferroptosis, as evidenced by the reversal of cell death upon treatment with the ferroptosis inhibitor, ferrostatin-1. Heteronemin treatment led to a marked increase in ferroptosis markers and malondialdehyde (MDA) levels. Conversely, the expression of glutathione peroxidase-4 (GPX4), a key anti-ferroptotic protein, was suppressed. Furthermore, significant modulations in the expression of ferritinophagy- and iron-related proteins such as Atg5, Atg7, FTL, STEAP3, and DMT-1 were evident post-treatment (p < 0.05). This study underscores the potential of heteronemin as a ferroptosis inducer in pancreatic cancer cells. Given its robust cytotoxicity, heteronemin emerges as a promising lead compound for further exploration in cancer therapeutics., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Alzheimer's disease is the primary neurodegenerative disease affecting the elderly population. Despite the first description of its pathology over a century ago, its precise cause and molecular mechanism remain unknown. Numerous factors, including beta-amyloid, tau protein, the APOEε4 gene, and different metals, have been extensively investigated in relation to this disease. However, none of them have been proven to have a decisive causal relationship. Furthermore, no single theory has successfully integrated these puzzle pieces thus far. In this review article, we propose the most probable molecular mechanism for AD, which clearly shows the relationship between the main aspects of the disease, and addresses fundamental questions such as: Why is aging the major risk factor for the disease? Are amyloid plaques and tau tangles the causes or consequences of AD? Why are the distributions of senile plaques and tau tangles in the brain different and independent of each other? Why is the APOEε4 gene a risk factor for AD? Finally, why is the disease more prevalent in women?

Obesity is a multifactorial pathophysiological condition with an imbalance in biochemical, immunochemical, redox status and genetic parameters values. We aimed to estimate the connection between relative leucocyte telomere lengths (rLTL) - biomarker of cellular ageing with metabolic and redox status biomarkers values in a group of obese and lean children. The study includes 110 obese and 42 lean children and adolescents, both sexes. The results suggested that rLTL are significantly shorter in obese, compared with lean group ( P < 0·01). Negative correlation of rLTL with total oxidant status (TOS) (Spearman's ρ = -0·365, P < 0·001) as well as with C-reactive protein (Spearman's ρ = -0·363, P < 0·001) were observed. Principal component analysis (PCA) extracted three distinct factors (i.e. principal components) entitled as: prooxidant factor with 35 % of total variability; antioxidant factor with 30 % of total variability and lipid antioxidant - biological ageing factor with 12 % of the total variability. The most important predictor of BMI > 30 kg/m 2 according to logistic regression analysis was PCA-derived antioxidant factor's score (OR: 1·66, 95th Cl 1·05-2·6, P = 0·029). PCA analysis confirmed that oxidative stress importance in biological ageing is caused by obesity and its multiple consequences related to prooxidants augmentation and antioxidants exhaustion and gave us clear signs of disturbed cellular homoeostasis deepness, even before any overt disease occurrence.

Sex differences may play a role in the etiopathogenesis and severity of metabolic dysfunction-associated steatotic liver disease (MASLD), a disorder characterized by excessive fat accumulation associated with increased inflammation and oxidative stress. We previously observed the development of steatosis specifically in female rats fed a high-fat diet enriched with liquid fructose (HFHFr) for 12 weeks. The aim of this study was to better characterize the observed sex differences by focusing on the antioxidant and cytoprotective pathways related to the KEAP1/NRF2 axis. The KEAP1/NRF2 signaling pathway, autophagy process (LC3B and LAMP2), and endoplasmic reticulum stress response (XBP1) were analyzed in liver homogenates in male and female rats that were fed a 12-week HFHFr diet. In females, the HFHFr diet resulted in the initial activation of the KEAP1/NRF2 pathway, which was not followed by the modulation of downstream molecular targets; this was possibly due to the increase in KEAP1 levels preventing the nuclear translocation of NRF2 despite its cytosolic increase. Interestingly, while in both sexes the HFHFr diet resulted in an increase in the levels of LC3BII/LC3BI, a marker of autophagosome formation, only males showed a significant upregulation of LAMP2 and XBP1s; this did not occur in females, suggesting impaired autophagic flux in this sex. Overall, our results suggest that males are characterized by a greater ability to cope with an HFHFr metabolic stimulus mainly through an autophagic-mediated proteostatic process while in females, this is impaired. This might depend at least in part upon the fine modulation of the cytoprotective and antioxidant KEAP1/NRF2 pathway resulting in sex differences in the occurrence and severity of MASLD. These results should be considered to design effective therapeutics for MASLD.

The relationship between nuclear factor erythroid 2-related factor 2 (Nrf2) and phytocannabinoids/endocannabinoids (pCBs/eCBs) has been investigated in a variety of models of peripheral illnesses, with little clarification on their interaction within the central nervous system (CNS). In this context, evidence suggests that the Nrf2-pCBs/eCBS interaction is relevant in modulating peroxidation processes and the antioxidant system. Nrf2, one of the regulators of cellular redox homeostasis, appears to have a protective role toward damaging insults to neurons and glia by enhancing those genes involved in the regulation of homeostatic processes. Specifically in microglia and macroglia cells, Nrf2 can be activated, and its signaling pathway modulated, by both pCBs and eCBs. However, the precise effects of pCBs and eCBs on the Nrf2 signaling pathway are not completely elucidated yet, making their potential clinical employment still not fully understood.

The contribution of the human papillomavirus (HPV) to cancer is significant but not exclusive, as carcinogenesis involves complex mechanisms, notably oxidative stress. Oxidative stress and HPV can independently cause genome instability and DNA damage, contributing to tumorigenesis. Oxidative stress-induced DNA damage, especially double-strand breaks, aids in the integration of HPV into the host genome and promotes the overexpression of two viral proteins, E6 and E7. Lifestyle factors, including diet, smoking, alcohol, and psychological stress, along with genetic and epigenetic modifications, and viral oncoproteins may influence oxidative stress, impacting the progression of HPV-related cancers. This review highlights various mechanisms in oxidative-induced HPV-mediated carcinogenesis, including altered mitochondrial morphology and function leading to elevated ROS levels, modulation of antioxidant enzymes like Superoxide Dismutase (SOD), Glutathione (GSH), and Glutathione Peroxidase (GPx), induction of chronic inflammatory environments, and activation of specific cell signaling pathways like the Phosphoinositide 3-kinase, Protein kinase B, Mammalian target of rapamycin (PI3K/AKT/mTOR) and the Extracellular signal-regulated kinase (ERK) signaling pathway. The study highlights the significance of comprehending and controlling oxidative stress in preventing and treating cancer. We suggested that incorporating dietary antioxidants and targeting cancer cells through mechanisms involving ROS could be potential interventions to mitigate the impact of oxidative stress on HPV-related malignancies., (© 2024. The Author(s).)

Numerous natural antioxidants commonly found in our daily diet have demonstrated significant benefits for human health and various diseases by counteracting the impact of reactive oxygen and nitrogen species. Their chemical properties enable a range of biological actions, including antihypertensive, antimicrobial, anti-inflammatory, anti-fibrotic, and anticancer effects. Despite promising outcomes from preclinical studies, ongoing debate persists regarding their reproducibility in human clinical models. This controversy largely stems from a lack of understanding of the pharmacokinetic properties of these compounds, coupled with the predominant focus on monotherapies in research, neglecting potential synergistic effects arising from combining different antioxidants. This study aims to provide an updated overview of natural antioxidants, operating under the hypothesis that a multitherapeutic approach surpasses monotherapy in efficacy. Additionally, this study underscores the importance of integrating these antioxidants into the daily diet, as they have the potential to prevent the onset and progression of various diseases. To reinforce this perspective, clinical findings pertaining to the treatment and prevention of non-alcoholic fatty liver disease and conditions associated with ischemia and reperfusion phenomena, including myocardial infarction, postoperative atrial fibrillation, and stroke, are presented as key references.

It is known that more than 10 % of genetic diseases are caused by a mutation in protein-coding mRNA (premature termination codon; PTC). mRNAs with an early stop codon are degraded by the cellular surveillance process known as nonsense-mediated mRNA decay (NMD), which prevents the synthesis of C-terminally truncated proteins. Up-frameshift-1 (UPF1) has been reported to be involved in the downregulation of various cancers, and low expression of UPF1 was shown to correlate with poor prognosis. It is known that UPF1 is a master regulator of nonsense-mediated mRNA decay (NMD). UPF1 may also function as an E3 ligase and degrade target proteins without using mRNA decay mechanisms. Increasing evidence indicates that UPF1 could serve as a good biomarker for cancer diagnosis and treatment for future therapeutic applications. Long non-coding RNAs (lncRNAs) have the ability to bind different proteins and regulate gene expression; this role in cancer cells has already been identified by different studies. This article provides an overview of the aberrant expression of UPF1, its functional properties, and molecular processes during cancer for clinical applications in cancer. We also discussed the interactions of lncRNA with UPF1 for cell growth during tumorigenesis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

By controlling several antioxidant and detoxifying genes at the transcriptional level, including NAD(P)H quinone oxidoreductase 1 (NQO1), multidrug resistance-associated proteins (MRPs), UDP-glucuronosyltransferase (UGT), glutamate-cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits, glutathione S-transferase (GST), sulfiredoxin1 (SRXN1), and heme-oxygenase-1 (HMOX1), the KEAP1/NRF2 pathway plays a crucial role in the oxidative stress response. Accordingly, the discovery of modulators of this pathway, activating cellular signaling through NRF2, and targeting the antioxidant response element (ARE) genes is pivotal for the development of effective antioxidant agents. In this context, natural products could represent promising drug candidates for supplementation to provide antioxidant capacity to human cells. In recent decades, by coupling in silico and experimental methods, several natural products have been characterized to exert antioxidant effects by targeting the KEAP1/NRF2 pathway. In this review article, we analyze several natural products that were investigated experimentally and in silico for their ability to modulate KEAP1/NRF2 by non-covalent and covalent mechanisms. These latter represent the two main sections of this article. For each class of inhibitors, we reviewed their antioxidant effects and potential therapeutic applications, and where possible, we analyzed the structure-activity relationship (SAR). Moreover, the main computational techniques used for the most promising identified compounds are detailed in this survey, providing an updated view on the development of natural products as antioxidant agents., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Significance: The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) system is a master regulator of redox homeostasis and cell adaptation to a variety of exogenous and endogenous stressors. Accumulating evidence from the last decade indicates that the impairment of the redox balance leads to oxidative stress (OS), a common alteration occurring in many human acute and chronic inflammatory diseases, such as cancer, diabetes, neurodegeneration, and metabolic disorders, and aging. Recent Advances: Being located at the intersection of crucial signaling pathways, NRF2 can influence several cellular functions, which extend beyond the maintenance of the redox balance and include cellular metabolism, proteostasis, mitochondrial function and inflammation. For this reason, there is a growing interest in the pharmacologic manipulation of NRF2 for therapeutic purposes, which requires the accurate knowledge of the cell context and the specific time frame both of NRF2 activation and inhibition. This appears to be an important prerequisite and reflects the extreme complexity of the NRF2 signaling, characterized by an intrinsic dualism that mediates beneficial or detrimental effects even in the same biological process. Critical Issues: Of crucial importance will be to understand whether the NRF2 activity modulation might be exploited to exert beneficial outcomes in patients suffering from pathological conditions, in which the OS and the deregulation of inflammatory processes play a crucial role. Future Directions: In this review, we discuss the dual involvement of NRF2 in aging, neurodegeneration, metabolic diseases, long-COVID-19, and carcinogenesis and we present an overview of the most recent therapeutic modulators of NRF2, particularly emphasizing on those selected for clinical trials. Antioxid. Redox Signal. 40, 636-662.

The central nervous system is essential for maintaining homeostasis and controlling the body's physiological functions. However, its biochemical characteristics make it highly vulnerable to oxidative damage, which is a common factor in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). ALS is a leading cause of motor neuron disease, characterized by a rapidly progressing and incurable condition. ALS often results in death from respiratory failure within 3-5 years from the onset of the first symptoms, underscoring the urgent need to address this medical challenge. The aim of this study is to present available data supporting the role of oxidative stress in the mechanisms underlying ALS and to discuss potential antioxidant therapies currently in development. These therapies aim to improve the quality of life and life expectancy for patients affected by this devastating disease., Competing Interests: Conflict of interest: Authors state no conflict of interest., (© 2024 the author(s), published by De Gruyter.)

Adrenergic pathways represent the main channel of communication between the nervous system and the immune system. During inflammation, blood monocytes migrate within tissue and differentiate into macrophages, which polarize to M1 or M2 macrophages with tissue-damaging or -reparative properties, respectively. This study investigates whether the β-adrenergic receptor (β-AR)-blocking drug propranolol modulates the monocyte-to-macrophage differentiation process and further influences macrophages in their polarization toward M1- and M2-like phenotypes. Six-day-human monocytes were cultured with M-CSF in the presence or absence of propranolol and then activated toward an M1 pro-inflammatory state or an M2 anti-inflammatory state. The chronic exposure of monocytes to propranolol during their differentiation into macrophages promoted the increase in the M1 marker CD16 and in the M2 markers CD206 and CD163 and peroxisome proliferator-activated receptor ɣ expression. It also increased endocytosis and the release of IL-10, whereas it reduced physiological reactive oxygen species. Exposure to the pro-inflammatory conditions of propranolol-differentiated macrophages resulted in an anti-inflammatory promoting effect. At the molecular level, propranolol upregulated the expression of the oxidative stress regulators NRF2, heme oxygenase-1 and NQO1. By contributing to regulating macrophage activities, propranolol may represent a novel anti-inflammatory and immunomodulating compound with relevant therapeutic potential in several inflammatory diseases.

Oxidative stress can affect the protein, lipids, and DNA of the cells and thus, play a crucial role in several pathophysiological conditions. It has already been established that oxidative stress has a close association with inflammation via nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway. Amino acids are notably the building block of proteins and constitute the major class of nitrogen-containing natural products of medicinal importance. They exhibit a broad spectrum of biological activities, including the ability to activate NRF2, a transcription factor that regulates endogenous antioxidant responses. Moreover, amino acids may act as synergistic antioxidants as part of our dietary supplementations. This has aroused research interest in the NRF2-inducing activity of amino acids. Interestingly, amino acids' activation of NRF2-Kelch-like ECH-associated protein 1 (KEAP1) signaling pathway exerts therapeutic effects in several diseases. Therefore, the present review will discuss the relationship between different amino acids and activation of NRF2-KEAP1 signaling pathway pinning their anti-inflammatory and antioxidant properties. We also discussed amino acids formulations and their applications as therapeutics. This will broaden the prospect of the therapeutic applications of amino acids in a myriad of inflammation and oxidative stress-related diseases. This will provide an insight for designing and developing new chemical entities as NRF2 activators., (© 2024. The Author(s).)

In recent years, research on the discovery of natural compounds with potent antioxidant properties has resulted in growing interest in these compounds due to their potential therapeutic applications in oxidative-stress-related diseases. Argan oil, derived from the kernels of a native tree from Morocco, Argania spinosa , is renowned for its rich composition of bioactive compounds, prominently tocopherols, polyphenols, and fatty acids. Interestingly, a large body of data has shown that several components of argan oil activate the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, playing a crucial role in the cellular defense against oxidative stress. Activation of this Nrf2 pathway by argan oil components leads to the increased expression of downstream target proteins like NAD(P)H quinone oxidoreductase (NQO1), superoxide dismutase (SOD), heme oxygenase 1 (HO-1), and catalase (CAT). Such Nrf2 activation accounts for several health benefits related to antioxidant defense, anti-inflammatory effects, cardiovascular health, and neuroprotection in organisms. Furthermore, the synergistic action of the bioactive compounds in argan oil enhances the Nrf2 pathway. Accordingly, the modulation of the Kelch-like ECH associated protein 1 (Keap1)/Nrf2 signaling pathway by these components highlights the potential of argan oil in protecting cells from oxidative stress and underlines its relevance in dietetic prevention and therapeutic applications. This review aims to provide an overview of how major compounds in argan oil activate the Nrf2 pathway, updating our knowledge on their mechanisms of action and associated health benefits.

Phenothiazines (PTZs) are an emerging group of molecules showing effectiveness toward redox signaling and reduction of oxidative injury to cells, via the activation on Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Nrf2). Although several electrophilic and indirect Nrf2 activators have been reported, the risk of "off-target" effect due to the complexity of their molecular mechanisms of action, has aroused research interest toward non-electrophilic and direct modulators of Nrf2 pathway, such as PTZs. This review represents the first overview on the roles of PTZs as non-electrophilic Nrf2 activator and free radical scavengers, as well as on their potential therapeutic effects in oxidative stress-mediated diseases. Here, we provide a collective and comprehensive information on the PTZs ability to scavenge free radicals and activate the Nrf2 signaling pathway, with the aim to broaden the knowledge of their therapeutic potentials and to stimulate innovative research ideas., (© 2024 Wiley Periodicals LLC.)

Background: ABC transporter-mediated multidrug resistance (MDR) remains a major obstacle for cancer pharmacological treatment. Some tyrosine kinase inhibitors (TKIs) have been shown to reverse MDR. The present study was designed to evaluate for the first time whether foretinib, a multitargeted TKI, can circumvent ABCB1 and ABCG2-mediated MDR in treatment-resistant cancer models., Methods: Accumulation of fluorescent substrates of ABCB1 and ABCG2 in ABCB1-overexpressing MES-SA/DX5 and ABCG2-overexpressing MCF-7/MX and their parenteral cells was evaluated by flow cytometry. The growth inhibitory activity of single and combination therapy of foretinib and chemotherapeutic drugs on MDR cells was examined by MTT assay. Analysis of combined interaction effects was performed using CalcuSyn software., Results: It was firstly proved that foretinib increased the intracellular accumulation of rhodamine 123 and mitoxantrone in MES-SA/DX5 and MCF-7/MX cancer cells, with accumulation ratios of 12 and 2.2 at 25 μM concentration, respectively. However, it did not affect the accumulation of fluorescent substrates in the parental cells. Moreover, foretinib synergistically improved the cytotoxic effects of doxorubicin and mitoxantrone. The means of combination index (CI) values at fraction affected (Fa) values of 0.5, 0.75, and 0.9 were 0.64 ± 0.08 and 0.47 ± 0.09, in MES-SA/DX5 and MCF-7/MX cancer cells, respectively. In silico analysis also suggested that the drug-binding domain of ABCB1 and ABCG2 transporters could be considered as potential target for foretinib., Conclusion: Overall, our results suggest that foretinib can target MDR-linked ABCB1 and ABCG2 transporters in clinical cancer therapy., 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 Inc.)

Ferroptosis has been characterized as a form of iron-dependent regulated cell death accompanied by an accumulation of reactive oxygen species and lipid oxidation products along with typical morphological alterations in mitochondria. Ferroptosis is activated by diverse triggers and inhibited by ferrostatin-1 and liproxstatin-1, apart from iron chelators and several antioxidants, and the process is implicated in multiple pathological conditions. There are, however, certain ambiguities about ferroptosis, especially regarding the final executioner of cell death subsequent to the accumulation of ROS. This study uses a typical inducer of ferroptosis such as erastin on SH-SY5Y cells, and shows clearly that ferroptotic death of cells is accompanied by the loss of mitochondrial membrane potential and intracellular ATP content along with an accumulation of oxidative stress markers. All these are prevented by ferrostatin-1 and liproxstatin-1. Additionally, cyclosporine A prevents mitochondrial alterations and cell death induced by erastin implying the crucial role of mitochondrial permeability transition pore (mPTP) activation in ferroptotic death. Furthermore, an accumulation of α-synuclein occurs during erastin induced ferroptosis which can be inhibited by ferrostatin-1 and liproxstatin-1. When the knock-down of α-synuclein expression is performed by specific siRNA treatment of SH-SY5Y cells, the mitochondrial impairment and ferroptotic death of the cells induced by erastin are markedly prevented. Thus, α-synuclein through the involvement of mPTP appears to be the key executioner protein of ferroptosis induced by erastin, but it needs to be verified if it is a generalized mechanism of ferroptosis by using other inducers and cell lines.

Oxidative stress is characterized by the deregulation of the redox state in the cells, which plays a role in the initiation of various types of cancers. The activity of galectin-1 (Gal-1) depends on the cell redox state and the redox state of the microenvironment. Gal-1 expression has been related to many different tumor types, as it plays important roles in several processes involved in cancer progression, such as apoptosis, cell migration, adhesion, and immune response. The erythroid-2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway is a crucial mechanism involved in both cell survival and cell defense against oxidative stress. In this review, we delve into the cellular and molecular roles played by Gal-1 in the context of oxidative stress onset in cancer cells, particularly focusing on its involvement in activating the Nrf2/Keap1 signaling pathway. The emerging evidence concerning the anti-apoptotic effect of Gal-1, together with its ability to sustain the activation of the Nrf2 pathway in counteracting oxidative stress, supports the role of Gal-1 in the promotion of tumor cells proliferation, immuno-suppression, and anti-tumor drug resistance, thus highlighting that the inhibition of Gal-1 emerges as a potential strategy for the restraint and regression of tumor progression. Overall, a deeper understanding of the multi-functionality and disease-specific expression profiling of Gal-1 will be crucial for the design and development of novel Gal-1 inhibitors as anticancer agents. Excitingly, although it is still understudied, the ever-growing knowledge of the sophisticated interplay between Gal-1 and Nrf2/Keap1 will enable researchers to gain valuable insights into the underlying causes of carcinogenesis and metastasis., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2024.)

Stroke is a major contributor to global mortality and disability. While reperfusion is essential for preventing neuronal death in the penumbra, it also triggers cerebral ischemia-reperfusion injury, a paradoxical injury primarily caused by oxidative stress, inflammation, and blood-brain barrier disruption. An oxidative burst inflicts marked cellular damage, ranging from alterations in mitochondrial function to lipid peroxidation and the activation of intricate signalling pathways that can even lead to cell death. Thus, given the pivotal role of oxidative stress in the mechanisms of cerebral ischemia-reperfusion injury, the reinforcement of the antioxidant defence system has been proposed as a protective approach. Although this strategy has proven to be successful in experimental models, its translation into clinical practice has yielded inconsistent results. However, it should be considered that the availability of numerous antioxidant molecules with a wide range of chemical properties can affect the extent of injury; several groups of antioxidant molecules, including polyphenols, carotenoids, and vitamins, among other antioxidant compounds, can mitigate this damage by intervening in multiple signalling pathways at various stages. Multiple clinical trials have previously been conducted to evaluate these properties using melatonin, acetyl-L-carnitine, chrysanthemum extract, edaravone dexborneol, saffron, coenzyme Q10, and oleoylethanolamide, among other treatments. Therefore, multi-antioxidant therapy emerges as a promising novel therapeutic option due to the potential synergistic effect provided by the simultaneous roles of the individual compounds.

Stilbenes are phytoalexins, and their biosynthesis can occur through a natural route (shikimate precursor) or an alternative route (in microorganism cultures). The latter is a metabolic engineering strategy to enhance production due to stilbenes recognized pharmacological and medicinal potential. It is believed that in the human body, these potential activities can be modulated by the regulation of the nuclear factor erythroid derived 2 (Nrf2), which increases the expression of antioxidant enzymes. Given this, our review aims to critically analyze evidence regarding E -stilbenes in human metabolism and the Nrf2 activation pathway, with an emphasis on inflammatory and oxidative stress aspects related to the pathophysiology of chronic and metabolic diseases. In this comprehensive literature review, it can be observed that despite the broad number of stilbenes, those most frequently explored in clinical trials and preclinical studies (in vitro and in vivo) were resveratrol, piceatannol, pterostilbene, polydatin, stilbestrol, and pinosylvin. In some cases, depending on the dose/concentration and chemical nature of the stilbene, it was possible to identify activation of the Nrf2 pathway. Furthermore, the use of some experimental models presented a challenge in comparing results. In view of the above, it can be suggested that E -stilbenes have a relationship with the Nrf2 pathway, whether directly or indirectly, through different biological pathways, and in different diseases or conditions that are mainly related to inflammation and oxidative stress.

Infertility represents a significant global health challenge, affecting more than 12% of couples worldwide, and most cases of infertility are caused by male factors. Several pathological pathways are implicated in male infertility. The main mechanisms involved are driven by the loss of reduction-oxidation (redox) homeostasis and the resulting oxidative damage as well as the chronic inflammatory process. Increased or severe oxidative stress leads to sperm plasma membrane and DNA oxidative damage, dysregulated RNA processing, and telomere destruction. The signaling pathways of these molecular events are also regulated by Nuclear factor-E2-related factor 2 (Nrf2). The causes of male infertility, the role of oxidative stress in male infertility and the Keap1-Nrf2 antioxidant pathway are reviewed. This review highlights the regulatory role of Nrf2 in the balance between oxidants and antioxidants as relevant mechanisms to male fertility. Nrf2 is involved in the regulation of spermatogenesis and sperm quality. Establishing a link between Nrf2 signaling pathways and the regulation of male fertility provides the basis for molecular modulation of inflammatory processes, reactive oxygen species generation, and the antioxidant molecular network, including the Nrf2-regulated antioxidant response, to improve male reproductive outcomes.

The understanding that humans are exposed to a low level of toxic metals and metalloids in their lifetime has resulted in a shift in scientific and regulatory perspectives from the traditional evaluation of single metal toxicity to complex mixtures, relevant to real-life exposure. Therefore, the aim of this study was to examine the impact of real-life, 90-days exposure to mixture of toxic metal(oid)s, Cd, Pb, Ni, Cr, As and Hg, on the nuclear factor erythroid 2-related factor 2 and hemoxygenase-1 (Nrf2/HO-1) signalling and redox status by assessing total sulfhydryl groups (SH), glutathione (GSH), superoxide dismutase activity (SOD), malondialdehyde (MDA), and ischemia modified albumin (IMA) in the liver and kidney of Wistar rats. Animals (20 males and 20 females) were randomized in 2 control and 6 treated groups that received by oral gavage mixture of metal(oid)s solutions in doses that reflect blood metal(oid) levels determined in previous human biomonitoring study as benchmark dose (F/M &#95;BMD), median (F/M &#95;MED), and 95th percentile (F/M &#95;95). Our results have shown that metal(oid)s mixture impaired the activation of the Nrf2/HO-1 pathway in the kidney and liver of male rats and kidney of female rats, followed by depletion of GSH levels in males. Additionally, in males elevated levels of IMA in the liver were observed, while in both genders increased MDA levels were observed in the kidney. Interestingly, the effects were more pronounced in male than in female rats. This study is among the first that examined hepato-renal toxic mechanisms of real-life metal mixture exposure, while our results might be of immense importance for assessing the risk of exposure to mixtures of toxic substances., 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.)

Glioblastoma multiforme (GBM) is a highly aggressive malignant primary tumor in the central nervous system. Despite extensive efforts in radiotherapy, chemotherapy, and neurosurgery, there remains an inadequate level of improvement in treatment outcomes. The development of large-scale genomic and proteomic analysis suggests that GBMs are characterized by transcriptional heterogeneity, which is responsible for therapy resistance. Hence, knowledge about the genetic and epigenetic heterogeneity of GBM is crucial for developing effective treatments for this aggressive form of brain cancer. Tyrosine kinases (TKs) can act as signal transducers, regulate important cellular processes like differentiation, proliferation, apoptosis and metabolism. Therefore, TK inhibitors (TKIs) have been developed to specifically target these kinases. TKIs are categorized into allosteric and non-allosteric inhibitors. Irreversible inhibitors form covalent bonds, which can lead to longer-lasting effects. However, this can also increase the risk of off-target effects and toxicity. The development of TKIs as therapeutics through computer-aided drug design (CADD) and bioinformatic techniques enhance the potential to improve patients' survival rates. Therefore, the continued exploration of TKIs as drug targets is expected to lead to even more effective and specific therapeutics in the future., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rahban, Joushi, Bashiri, Saso and Sheibani.)

Background: Cancer management faces multiple obstacles, including resistance to current therapeutic approaches. In the face of challenging microenvironments, cancer cells adapt metabolically to maintain their supply of energy and precursor molecules for biosynthesis and thus sustain rapid proliferation and tumor growth. Among the various metabolic adaptations observed in cancer cells, the altered glucose metabolism is the most widely studied. The aberrant glycolytic modification in cancer cells has been associated with rapid cell division, tumor growth, cancer progression, and drug resistance. The higher rates of glycolysis in cancer cells, as a hallmark of cancer progression, is modulated by the transcription factor hypoxia inducible factor 1 alpha (HIF-1α), a downstream target of the PI3K/Akt signaling, the most deregulated pathway in cancer., Aim of Review: We provide a detailed overview of current, primarily experimental, evidence on the potential effectiveness of flavonoids to combat aberrant glycolysis-induced resistance of cancer cells to conventional and targeted therapies. The manuscript focuses primarily on flavonoids reducing cancer resistance via affecting PI3K/Akt, HIF-1α (as the transcription factor critical for glucose metabolism of cancer cells that is regulated by PI3K/Akt pathway), and key glycolytic mediators downstream of PI3K/Akt/HIF-1α signaling (glucose transporters and key glycolytic enzymes)., Key Scientific Concepts of Review: The working hypothesis of the manuscript proposes HIF-1α - the transcription factor critical for glucose metabolism of cancer cells regulated by PI3K/Akt pathway as an attractive target for application of flavonoids to mitigate cancer resistance. Phytochemicals represent a source of promising substances for cancer management applicable to primary, secondary, and tertiary care. However, accurate patient stratification and individualized patient profiling represent crucial steps in the paradigm shift from reactive to predictive, preventive, and personalized medicine (PPPM / 3PM). The article is focused on targeting molecular patterns by natural substances and provides evidence-based recommendations for the 3PM relevant implementation., 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. Production and hosting by Elsevier B.V.)

Neurodegenerative disorders are characterized by neuronal degradation, dysfunction, or death within the CNS. Oxidative and inflammatory stress play crucial roles in the pathogenesis of various neurodegenerative diseases. The interplay between these stressors and dysregulated cellular signaling pathways contributes to neurodegeneration. Downregulation of NRF-2 compromises antioxidant defense, exacerbating neuronal damage, while increased TLR-4/MAPK and TLR-4/NF-κB signaling promotes neuroinflammation. Excessive ROS production by NADPH oxidase leads to oxidative damage and neuronal apoptosis. The strategies targeting NRF-2, TLR-4-mediated inflammatory stress, and NADPH oxidase activity promise to mitigate neuronal damage and halt the progression of the disease. Kaempferol is a flavonoid polyphenol antioxidant found abundantly in various fruits and vegetables, including apples, grapes, tomatoes, and broccoli. It is widely found in medicinal plants including Equisetum spp., Sophora japonica, Ginkgo biloba, and Euphorbia pekinensis (Rupr.). A substantial body of in vitro and in vivo evidences have demonstrated the neuroprotective potential of kaempferol against neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Kaempferol demonstrates multifaceted potential in mitigating neuroinflammation, apoptosis, and oxidative stress in different neurodegenerative diseases through the modulation of various pathways including NRF-2, NADPH oxidase, TLR-4/MAPK, and TLR-4/NF-κB. This review article was developed through a comprehensive analysis and interpretation of research published between 2009 and 2024, sourced from multiple scientific databases, including PubMed, Scopus, ScienceDirect, and Web of Science. This review aims to provide an in-depth overview of the neuroprotective effects of kaempferol, focusing on its underlying molecular mechanisms. A total of 24 research evidence were included to elucidate the molecular pathways by which kaempferol exerts its protective effects against neurodegenerative diseases., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Brain cancer is regarded as one of the most life-threatening forms of cancer worldwide. Oxidative stress acts to derange normal brain homeostasis, thus is involved in carcinogenesis in brain. The Nrf2/Keap1/ARE pathway is an important signaling cascade responsible for the maintenance of redox homeostasis, and regulation of anti-inflammatory and anticancer activities by multiple downstream pathways. Interestingly, Nrf2 plays a somewhat, contradictory role in cancers, including brain cancer. Nrf2 has traditionally been regarded as a tumor suppressor since its cytoprotective functions are considered to be the principle cellular defense mechanism against exogenous and endogenous insults, such as xenobiotics and oxidative stress. However, hyperactivation of the Nrf2 pathway supports the survival of normal as well as malignant cells, protecting them against oxidative stress, and therapeutic agents. Plants possess a pool of secondary metabolites with potential chemotherapeutic/chemopreventive actions. Modulation of Nrf2/ARE and downstream activities in a Keap1-dependant manner, with the aid of plant-derived secondary metabolites exhibits promise in the management of brain tumors. Current article highlights the effects of Nrf2/Keap1/ARE cascade on brain tumors, and the potential role of secondary metabolites regarding the management of the same., (© 2024. The Author(s).)

Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder affecting individuals worldwide. It is characterized by progressive motor dysfunction, cognitive decline, and psychiatric disturbances. The pathogenesis of HD involves oxidative stress, neuroinflammation, and mitochondrial dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor regulating cellular responses to redox imbalance and inflammation, has emerged as a potential target for therapeutic intervention., Methods: Through the use of a number of different search engines like Scopus, PubMed, Elsevier and Bentham, a literature review was carried out with the keywords 'Huntington's Disease, 'Pathology of HD' and 'Nrf2 signalling pathway'. Using the keywords that were given above, this review was carried out in order to collect the most recent publications and gain an understanding of the breadth of the extensive research that has been conducted on the role of Nrf2 in HD pathogenesis., Results: Oxidative stress and neuroinflammation significantly contribute to HD progression. Activation of Nrf2 offers neuroprotection by enhancing anti-oxidant defense mechanisms. Furthermore, several signaling pathways, play crucial roles in HD pathophysiology. Pharmacological modulation of these pathways through selective inhibitors or agonists shows promise for the development of new therapeutic strategies., Conclusion: The various downstream pathways such as extracellular signal-related kinase (ERK), phosphoinositide 3-Kinase (PI3-K), 5'-AMP-activated protein kinase (AMPK), Sirtuins, Mitogen-activated protein kinases (MAPK) plays a role in alleviating pathophysiology of HD. Diverse reports of these studies demonstrated PI3-K/AMPK/ERK/Sirtuins activators and MAPK inhibitors as encouraging targets in alleviating HD pathophysiology., (© 2024. Fondazione Società Italiana di Neurologia.)

Lewy bodies (LBs), α-synuclein-enriched intracellular inclusions, are a hallmark of Parkinson's disease (PD) pathology, yet a cellular model for LB formation remains elusive. Recent evidence indicates that immune dysfunction may contribute to the development of PD. In this study, we found that induced pluripotent stem cell (iPSC)-derived human dopaminergic (DA) neurons form LB-like inclusions after treatment with α-synuclein preformed fibrils (PFFs) but only when coupled to a model of immune challenge (interferon-γ or interleukin-1β treatment) or when co-cultured with activated microglia-like cells. Exposure to interferon-γ impairs lysosome function in DA neurons, contributing to LB formation. The knockdown of LAMP2 or the knockout of GBA in conjunction with PFF administration is sufficient for inclusion formation. Finally, we observed that the LB-like inclusions in iPSC-derived DA neurons are membrane bound, suggesting that they are not limited to the cytoplasmic compartment but may be formed due to dysfunctions in autophagy. Together, these data indicate that immune-triggered lysosomal dysfunction may contribute to the development of PD pathology., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Neurological conditions encompassing a wide range of disorders pose significant challenges globally. The complex interactions among signaling pathways and molecular elements play pivotal roles in the initiation and progression of neurodegenerative diseases. Isoflavones have emerged as a promising candidate to fight against neurodegenerative diseases. Daidzein, a 7-hydroxy-3-(4-hydroxyphenyl)-chromen-4-one, belongs to the isoflavone class and exhibits a diverse pharmacological profile. It is found primarily in soybeans and soy products, as well as in some other legumes and herbs. Investigations into daidzein have revealed that it confers neuroprotection by inhibiting oxidative stress, inflammation, and apoptosis, which are key contributors to neuronal damage and degeneration. Activating pathways like PI3K/Akt/mTOR and promoting neurotrophic factors like BDNF by daidzein underscore its potential in supporting neuronal function and combating neurodegeneration. Daidzein's effects on dopamine provide further avenues for intervention in conditions like Parkinson's disease. Additionally, the modulation of inflammatory and NRF-2-antioxidant signaling by daidzein reinforces its neuroprotective role. Moreover, daidzein's interaction with receptors and cellular processes like ER-β, GPR30, MAO, VEGF, and GnRH highlights its multifaceted effects across multiple pathways involved in neuroprotection and neuronal function. This review article delves into the mechanistic interplay of various mediators in mediating the neuroprotective effects of daidzein. The review article consolidates and analyzes research published over nearly two decades (2005-2024) from various databases, including PubMed, Scopus, ScienceDirect, and Web of Science, to provide a comprehensive understanding of daidzein's effects and mechanisms in neuroprotection., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Sporadic Alzheimer's disease (SAD) represents a major health concern especially among elderly. Noteworthy, neuroinflammation and oxidative stress are highly implicated in AD pathogenesis resulting in enhanced disease progression. Moreover, most of the available anti-Alzheimer drugs have several adverse effects with variable efficacy, therefore new strategies, including agents with anti-inflammatory and antioxidant effects, are encouraged. Along these lines, canagliflozin (CAN), with its anti-inflammatory and anti-apoptotic activities, presents a promising candidate for AD treatment. Therefore, this study aimed to evaluate the therapeutic potential of CAN via regulation of AMPK/SIRT-1/BDNF/GSK-3β signaling pathway in SAD. SAD model was induced by intracerebroventricular streptozotocin injection (ICV-STZ;3 mg/kg, once), while CAN was administered (10 mg/kg/day, orally) to STZ-treated mice for 21 days. Behavioral tests, novel object recognition (NOR), Y-Maze, and Morris Water Maze (MWM) tests, histopathological examination, total adenosine monophosphate-activated protein kinase (T-AMPK) expression, p-AMPK, and silent information regulator-1 (SIRT-1) were evaluated. Furthermore, brain-derived neurotrophic factor (BDNF), glycogen synthase kinase-3β (GSK-3β), acetylcholinesterase (AChE), Tau protein, insulin-degrading enzyme (IDE), nuclear factor erythroid-2 (Nrf-2), interleukin-6 (IL-6), nuclear factor kappa-B-p65 (NFκB-p65), beta-site APP cleaving enzyme 1 (BACE-1), and amyloid beta (Aβ) plaque were assessed. CAN restored STZ-induced cognitive deficits, confirmed by improved behavioral tests and histopathological examination. Besides, CAN halted STZ-induced neurotoxicity through activation of p-AMPK/SIRT-1/BDNF pathway, subsequently reduction of GSK-3β, Tau protein, AChE, NFκB-p65, IL-6, BACE-1, and Aβ plaque associated with increased IDE and Nrf-2. Consequentially, our findings assumed that CAN, via targeting p-AMPK/SIRT-1 pathway, combated neuroinflammation and oxidative stress in STZ-induced AD. Thus, this study highlighted the promising effect of CAN for treating AD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The emergence of diverse infections worldwide, which is a serious global threat to human existence, necessitates the urgent development of novel therapeutic candidates that can combat these diseases with efficacy. Molecular hybridization has been established as an efficient technique in designing bioactive molecules capable of fighting infections. Isatin, a core nucleus of an array of compounds with diverse biological properties can be modified at different positions leading to the creation of novel drug targets, is an active area of medicinal chemistry. This review containing published articles from 2005 to 2022 highlights isatin hybrids which have been synthesized and reported in the literature alongside a discussion on their biological properties. The enriched structure-activity relationship studies discussed provides insights for the rational design of novel isatin hybrids with tailored biological properties as effective therapeutic candidates inspired by nature., (© 2024. The Author(s).)

Neuropsychiatric disorders such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are considered a public health problem since it interferes in personal relationships and at work. The pathophysiological mechanisms of these mental disorders are still not completely understood. The variety and heterogeneity of symptoms, as well as the absence of biomarkers, make the diagnosis, prognosis, and treatment of these disorders difficult. However, oxidative stress appears to play a role in the pathophysiology of these diseases. In this context, advanced oxidation protein products (AOPPs) are considered a biomarker of protein oxidative damage and have been associated with neuroinflammatory diseases. In patients with neuropsychiatric disorders, increased levels of AOPPs were associated with the severity of symptoms and decreased quality of life. Thus, the objective of this integrative review is to investigate and discuss the relationship between AOPPs levels and MDD, BD, and SZ. Different databases were consulted and approximately 112 scientific articles were found relating AOPPs and psychiatric disorders. In the majority of studies, the blood levels of AOPPs were increased in MDD, BD, and SZ and associated with the severity of the disorders. Although the association of this marker with the risk of developing one of these mental disorders is more uncertain, some studies have suggested this relationship. Of the twenty-four studies highlighted, only four did not find significant differences in AOPPs levels in patients with the disorders mentioned. In summary, it may be suggested that the assessment of AOPPs levels can be a useful tool in the evaluation of neuropsychiatric disorders, at least for prognostic evaluation. However, the role of this biomarker in the pathophysiology of mental disorders is still unclear, as well as whether reducing its levels represents a potential therapeutic strategy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Since the role of Nrf2 in cancer cell survival has been highlighted, the pharmacological modulation of the Nrf2-Keap1 pathway may provide new opportunities for cancer treatment. This study purposed to use ubiquinone (Q10) as an antioxidant and catharanthine alkaloid as a cAMP inducer suppressing HepG2 cells by reducing Nrf2 level. The effects of Q10 and catharanthine on HepG2 cells in terms of viability were analyzed by MTT test. MTT results were used to determine the effective concentration of both drugs for the subsequent treatment and analysis. Subsequently, the effects of Q10 and catharanthine in a single and combined manner on oxidant/antioxidant status, apoptosis, metastasis, and drug resistance of HepG2 cells were investigated by related methods. Both Q10 and catharanthine decreased the level of oxidative stress products and increased antioxidant capacity in HepG2 cells. Nrf2 gene expression decreased by Q10, but catharanthine unexpectedly increased it. Following Nrf2 alterations, the expression levels of MMP-9 and MRP1 involved in metastasis and drug resistance were significantly and dose-dependently decreased by Q10, while catharanthine slightly increased both. However, both drugs increased caspase 3/7 activity and apoptosis rate, and the effect of Q10 on apoptosis was stronger than that of catharanthine. Most of the effects of the combination treatments were similar to those of the Q10 single treatment and indicated the dominant effect over the catharanthine component. Despite the antioxidant and apoptotic properties of both agents, Q10 was better than catharanthine in inducing apoptosis, counteracting drug resistance, and metastasis in HepG2 cells., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cancer is one of the main causes of death among humans, second only to cardiovascular diseases. In recent years, numerous studies have been conducted on the pathophysiology of cancer, and it has been established that this disease is developed by a group of stem cells known as cancer stem cells (CSCs). Thus, cancer is considered a stem cell disease; however, there is no comprehensive consensus about the characteristics of these cells. Several different signaling pathways including Notch, Hedgehog, transforming growth factor-β (TGF-β), and WNT/β-catenin pathways cause the self-renewal of CSCs. CSCs change their metabolic pathways in order to access easy energy. Therefore, one of the key objectives of researchers in cancer treatment is to destroy CSCs. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays an essential role in the protection of CSCs from reactive oxygen species (ROS) and chemotherapeutic agents by regulating antioxidants and detoxification enzymes. Human epidermal growth factor receptor 2 (HER2) is a member of the tyrosine kinase receptor family, which contributes to the protection of cancer cells against treatment and implicated in the invasion, epithelial-mesenchymal transition (EMT), and tumorigenesis. Aldehyde dehydrogenases (ALDHs) are highly active in CSCs and protect the cells against damage caused by active aldehydes through the regulation of aldehyde metabolism. On the other hand, ALDHs promote the formation and maintenance of tumor cells and lead to drug resistance in tumors through the activation of various signaling pathways, such as the ALDH1A1/HIF-1α/VEGF axis and Wnt/β-catenin, as well as changing the intracellular pH value. Given the growing body of information in this field, in the present narrative review, we attempted to shed light on the function of Nrf2, HER2, and ALDH in CSCs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This article provides an overview of the background knowledge of ferroptosis in the nervous system, as well as the key role of nuclear factor E2-related factor 2 (Nrf2) in regulating ferroptosis. The article takes Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as the starting point to explore the close association between Nrf2 and ferroptosis, which is of clear and significant importance for understanding the mechanism of neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links ferroptosis to the pathogenesis of NDs. As the disease progresses, damage to the antioxidant system, excessive OS, and altered Nrf2 expression levels, especially the inhibition of ferroptosis by lipid peroxidation inhibitors and adaptive enhancement of Nrf2 signaling, demonstrate the potential clinical significance of Nrf2 in detecting and identifying ferroptosis, as well as targeted therapy for neuronal loss and mitochondrial dysfunction. These findings provide new insights and possibilities for the treatment and prevention of NDs., (© 2024. The Author(s).)

Background: Demethylnobiletin (DN), with a variety of biological activities, is a polymethoxy-flavanone (PMF) found in citrus. In the present study, we explored the biological activities and potential mechanism of DN to improve cerebral ischemia reperfusion injury (CIRI) in rats, and identified DN as a novel neuroprotective agent for patients with ischemic brain injury., Methods: Rat CIRI models were established via middle cerebral artery occlusion (MCAO). Primary nerve cells were isolated and cultured in fetal rat cerebral cortex in vitro, and oxygen-glucose deprivation/reperfusion (OGD/R) models of primary nerve cells were induced. After intervention with DN with different concentrations in MCAO rats and OGD/R nerve cells, 2,3,5-triphenyltetrazolium chloride staining was used to quantify cerebral infarction size in CIRI rats. Modified neurological severity score was utilized to assess neurological performance. Histopathologic staining and live/dead cell-viability staining was used to observe apoptosis. Levels of glutathione (GSH), superoxide dismutase (SOD), reactive oxygen species (ROS) and malondialdehyde (MDA) in tissues and cells were detected using commercial kits. DN level in serum and cerebrospinal fluid of MCAO rats were measured by liquid chromatography tandem mass spectrometry. In addition, expression levels of proteins like Kelch like ECH associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nfr2) and heme oxygenase 1 (HO-1) in the Nrf2/HO-1 pathway, and apoptosis-related proteins like Cleaved caspase-3, BCL-2-associated X protein (Bax) and B-cell lymphoma-2 (Bcl-2) were determined by Western blot and immunofluorescence., Results: DN can significantly enhance neurological function recovery by reducing cerebral infarction size and weakening neurocytes apoptosis in MCAO rats. It was further found that DN could improve oxidative stress (OS) injury of nerve cells by bringing down MDA and ROS levels and increasing SOD and GSH levels. Notably, DN exerts its pharmacological influences through entering blood-brain barrier. Mechanically, DN can reduce Keap1 expression while activate Nrf2 and HO-1 expression in neurocytes., Conclusions: The protective effect of DN on neurocytes have been demonstrated in both in vitro and in vivo circumstances. It deserves to be developed as a potential neuroprotective agent through regulating the Nrf2/HO-1 signaling pathway to ameliorate neurocytes impairment caused by OS., (© 2023 The Authors. Environmental Toxicology published by Wiley Periodicals LLC.)

Multiple sclerosis (MS) is an autoimmune debilitating disease of the central nervous system caused by a mosaic of interactions between genetic predisposition and environmental factors. The pathological hallmarks of MS are chronic inflammation, demyelination, and neurodegeneration. Oxidative stress, a state of imbalance between the production of reactive species and antioxidant defense mechanisms, is considered one of the key contributors in the pathophysiology of MS. This review is a comprehensive overview of the cellular and molecular mechanisms by which oxidant species contribute to the initiation and progression of MS including mitochondrial dysfunction, disruption of various signaling pathways, and autoimmune response activation. The detrimental effects of oxidative stress on neurons, oligodendrocytes, and astrocytes, as well as the role of oxidants in promoting and perpetuating inflammation, demyelination, and axonal damage, are discussed. Finally, this review also points out the therapeutic potential of various synthetic antioxidants that must be evaluated in clinical trials in patients with MS., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Facile synthetic procedures and broad spectrum of biological activities are special attributes of sulfonamides. Sulfonamide derivatives have demonstrated potential as a class of compounds for the treatment of Alzheimer's disease (AD). Recent sulfonamide derivatives have been reported as prospective anti-AD agents, with a focus on analogues that significantly inhibit the function of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes and exhibit remarkable antioxidant and anti-inflammatory properties, all of which are critical for the treatment of AD. Sulfonamide- mediated activation of nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of the endogenous antioxidant response, has also been suggested as a potential therapeutic approach in AD. Additionally, it has been discovered that a number of sulfonamide derivatives show selectivity for the β- and γ-secretase enzymes and a significant reduction of amyloid B (Aβ) aggregation, which have been implicated in AD. The comparative molecular docking of benzenesulfonamide and donepezil, an AD reference drug showed comparable anti-AD activities. These suggest that sulfonamide derivatives may represent a new class of drugs for the treatment of AD. Thus, the current review will focus on recent studies on the chemical synthesis and evaluation of the anti-AD properties, molecular docking, pharmacological profile, and structure-activity relationship (SAR) of sulfonamide derivatives, as well as their potential anti-AD mechanisms of action. This paper offers a thorough assessment of the state of the art in this field of study and emphasizes the potential of sulfonamide derivatives synthesized during the 2012-2023 period as a new class of compounds for the treatment of AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Atherosclerosis is a major cardiovascular complication of diseases associated with elevated oxidative stress such as type 2 diabetes and metabolic syndrome. In these situations, low-density lipoproteins (LDL) undergo oxidation. Oxidized LDL displays proatherogenic activities through multiple and complex mechanisms which lead to dysfunctions of vascular cells (endothelial cells, smooth muscle cells, and macrophages). Oxidized LDLs are enriched in oxidized products of cholesterol called oxysterols formed either by autoxidation, enzymatically, or by both mechanisms. Several oxysterols have been shown to accumulate in atheroma plaques and to play a key role in atherogenesis. Depending on the type of oxysterols, various biological effects are exerted on vascular cells to regulate the formation of macrophage foam cells, endothelial integrity, adhesion and transmigration of monocytes, plaque progression, and instability. Most of these effects are linked to the ability of oxysterols to induce cellular oxidative stress and cytotoxicity mainly through apoptosis and proinflammatory mediators. Like for excess cholesterol, high-density lipoproteins (HDL) can exert antiatherogenic activity by stimulating the efflux of oxysterols that have accumulated in foamy macrophages., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Neurological disorders, characterized by oxidative stress (OS) and inflammation, have become a major global health concern. Redox reactions play a vital role in regulating the balance of the neuronal microenvironment. Specifically, the imbalance leads to a significant weakening of the organism's natural defensive mechanisms. This, in turn, causes the development of harmful oxidative stress, which plays a crucial role in the onset and progression of neurodegenerative diseases. The quest for effective therapeutic agents has led to significant advancements in the synthesis of antioxidant derivatives. This review provides a comprehensive overview of the recent developments in the use of novel antioxidant compounds with potential pharmacological applications in the management of neurological disorders. The discussed compounds encompass a diverse range of chemical structures, including polyphenols, vitamins, flavonoids, and hybrid molecules, highlighting their varied mechanisms of action. This review also focuses on the mechanism of oxidative stress in developing neurodegenerative disease. The neuroprotective effects of these antioxidant derivatives are explored in the context of specific neurological disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. The ultimate goal is to provide effective treatments for these debilitating conditions and improve the quality of life for patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Flavonoids are a widespread category of naturally occurring polyphenols distinguished by the flavan nucleus in plant-based foods and beverages, known for their various health benefits. Studies have suggested that consuming 150-500 mg of flavonoids daily is beneficial for health. Recent studies suggest that flavonoids are involved in maintaining mitochondrial activity and preventing impairment of mitochondrial dynamics by oxidative stress., Objective: This review emphasized the significance of studying the impact of flavonoids on mitochondrial dynamics, oxidative stress, and inflammatory response., Methods: This review analysed and summarised the findings related to the impact of flavonoids on mitochondria from publicly available search engines namely Pubmed, Scopus, and Web of Science., Description: Any disruption in mitochondrial dynamics can contribute to cellular dysfunction and diseases, including cancer, cardiac conditions, and neurodegeneration. Flavonoids have been shown to modulate mitochondrial dynamics by regulating protein expression involved in fission and fusion events. Furthermore, flavonoids exhibit potent antioxidant properties by lowering the production of ROS and boosting the performance of antioxidant enzymes. Persistent inflammation is a characteristic of many different disorders. This is because flavonoids also alter the inflammatory response by controlling the expression of numerous cytokines and chemokines involved in the inflammatory process. Flavonoids exhibit an impressive array of significant health effects, making them an effective therapeutic agent for managing various disorders. Further this review summarised available mechanisms underlying flavonoids' actions on mitochondrial dynamics and oxidative stress to recognize the optimal dose and duration of flavonoid intake for therapeutic purposes., Conclusion: This review may provide a solid foundation for developing targeted therapeutic interventions utilizing flavonoids, ultimately benefiting individuals afflicted with various disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The medicinal importance, natural rarity, and challenges associated with the synthesis of C3-functionalized 1 H -indazoles have propelled the development of novel and practical 1 H -indazole N-oxides for the production of diverse arrays of C3-functionalized 1 H -indazoles. The use of 1 H -indazole N-oxides has been remarkably effective for the selective introduction of diverse functional groups, including amino (NHAr), chloro (Cl), hydroxy (OH), sulfonyl (SO2 Ar), aromatic (Ar), olefin, alkyl, and N-formyl (NRCHO) groups, to indazole pharmacophore molecules. This review offers a concise overview of the synthetic approaches and practical applications of 1 H -indazole N-oxides, including recent studies conducted by the authors. Transformative reactions involving 1 H -indazole N-oxides not only offer strategies for synthesizing C3-functionalized 1 H -indazoles but also hold significant potential in medicinal chemistry. 1 Introduction 2 Synthetic Approaches and Applications of 1 H -Indazole N -Oxides 3 Summary and Outlook [ABSTRACT FROM AUTHOR]

With the increasing prevalence of diabetes mellitus worldwide, type 2 diabetes mellitus (T2D) combined with cognitive impairment and aging has become one of the common and important complications of diabetes mellitus, which seriously affects the quality of life of the patients, and imposes a heavy burden on the patients’ families and the society. Currently, there are no special measures for the treatment of cognitive impairment and aging in type 2 diabetes mellitus. Therefore, the search for potential biological markers of type 2 diabetes mellitus combined with cognitive impairment and aging is of great significance for future precisive treatment. We downloaded three gene expression datasets from the GEO database: GSE161355 (related to T2D with cognitive impairment and aging), GSE122063, and GSE5281 (related to Alzheimer’s disease). Differentially expressed genes (DEGs) were identified, followed by gene set enrichment analysis (GSEA). A protein-protein interaction (PPI) network was constructed using the STRING database, and the top 15 hub genes were identified using the CytoHubba plugin in Cytoscape. Core genes were ultimately determined using three machine learning methods: LASSO regression, Support Vector Machine Recursive Feature Elimination (SVM-RFE), and Linear Discriminant Analysis (LDA). The diagnostic performance of these genes was assessed using ROC curve analysis and validated in an independent dataset (GSE5281). Regulatory genes related to ferroptosis were screened from the FerrDb database, and their biological functions were further explored through GO and KEGG enrichment analyses. Finally, the CIBERSORT algorithm was used to analyze immune cell infiltration, and the correlation between core genes and immune cell infiltration levels was calculated, leading to the construction of an mRNA-miRNA regulatory network. In the GSE161355 and GSE122063 datasets, 217 common DEGs were identified. GSEA analysis revealed their enrichment in the PI3K-PLC-TRK signaling pathway, TP53 regulation of metabolic genes pathway, Notch signaling pathway, among others. PPI network analysis identified 15 candidate core genes, and further selection using LASSO, LDA, and SVM-RFE machine learning algorithms resulted in 6 core genes: BCL6, TP53, HSP90AA1, CRYAB, IL1B, and DNAJB1. ROC curve analysis indicated that these genes had good diagnostic performance in the GSE161355 dataset, with TP53 and IL1B achieving an AUC of 0.9, indicating the highest predictive accuracy. BCL6, HSP90AA1, CRYAB, and DNAJB1 also had AUCs greater than 0.8, demonstrating moderate predictive accuracy. Validation in the independent dataset GSE5281 showed that these core genes also had good diagnostic performance in Alzheimer’s disease samples (AUC > 0.6). Ferroptosis-related analysis revealed that IL1B and TP53 play significant roles in apoptosis and immune response. Immune cell infiltration analysis showed that IL1B is significantly positively correlated with infiltration levels of monocytes and NK cells, while TP53 is significantly negatively correlated with infiltration levels of follicular helper T cells. The construction of the miRNA-mRNA regulatory network suggested that miR-150a-5p might play a key role in the regulation of T2D-associated cognitive impairment and aging by TP53. This study, by integrating bioinformatics and machine learning methods, identified BCL6, TP53, HSP90AA1, CRYAB, IL1B, and DNAJB1 as potential diagnostic biomarkers for T2D with cognitive impairment and aging, with a particular emphasis on the significance of TP53 and IL1B in immune cell infiltration. These findings not only enhance our understanding of the molecular mechanisms linking type 2 diabetes to cognitive impairment and aging, providing new targets for early diagnosis and treatment, but also offer new directions and targets for basic research. [ABSTRACT FROM AUTHOR]