Exploring the therapeutic potential of quercetin in cancer treatment: Targeting long non-coding RNAs.

The escalating global incidence of cancer, which results in millions of fatalities annually, underscores the pressing need for effective pharmacological interventions across diverse cancer types. Long noncoding RNAs (lncRNAs), a class of RNA molecules that lack protein-coding capacity but profoundly impact gene expression regulation, have emerged as pivotal players in key cellular processes, including proliferation, apoptosis, metastasis, cellular metabolism, and drug resistance. Among natural compounds, quercetin, a phenolic compound abundantly present in fruits and vegetables has garnered attention due to its significant anticancer properties. Quercetin demonstrates the ability to inhibit cancer cell growth and induce apoptosis-a process often impaired in malignant cells. In this comprehensive review, we delve into the therapeutic potential of quercetin in cancer treatment, with a specific focus on its intricate interactions with lncRNAs. We explore how quercetin modulates lncRNA expression and function to exert its anticancer effects. Notably, quercetin suppresses oncogenic lncRNAs that drive cancer development and progression while enhancing tumor-suppressive lncRNAs that impede cancer growth and dissemination. Additionally, we discuss quercetin's role as a chemopreventive agent, which plays a crucial role in mitigating cancer risk. We address research challenges and future directions, emphasizing the necessity for in-depth mechanistic studies and strategies to enhance quercetin's bioavailability and target specificity. By synthesizing existing knowledge, this review underscores quercetin's promising potential as a novel therapeutic strategy in the ongoing battle against cancer, offering fresh insights and avenues for further investigation in this critical field.

Emerging Insights into the PI3K/AKT/mTOR Signaling Pathway and Non-Coding RNA-mediated Drug Resistance in Glioblastoma.

Glioblastoma multiforme [GBM] is a highly aggressive grade IV central nervous system tumor with a dismal prognosis. Factors such as late detection, treatment limitations due to its aggressive nature, and, notably, drug resistance significantly affect clinical outcomes. Despite the effectiveness of Temozolomide [TMZ], a potent chemotherapy agent, the development of drug resistance remains a major challenge. Given the poor survival rates and chemoresistance, there is an urgent need for novel treatment strategies. Non-coding RNAs, particularly microRNAs [miRNAs], offer a promising approach to GBM diagnosis and treatment. These small non-coding RNAs play crucial roles in tumor progression, either suppressing or promoting oncogenic characteristics. The phosphoinositide-3 kinase [PI3K]/AKT/ mTOR pathway, which regulates essential biological processes like proliferation and survival, is a key target of miRNAs in cancer. Studies have underscored the significance of PI3K/AKT/mTOR signaling in drug resistance development and its interplay with non-coding RNAs as mediators of tumorigenesis. This review aims to outline the involvement of PI3K/AKT/mTOR signaling in miRNA modulation and strategies to overcome chemoresistance in GBM.

Unveiling the potential of FOXO3 in lung cancer: From molecular insights to therapeutic prospects.

Lung cancer poses a significant challenge regarding molecular heterogeneity, as it encompasses a wide range of molecular alterations and cancer-related pathways. Recent discoveries made it feasible to thoroughly investigate the molecular mechanisms underlying lung cancer, giving rise to the possibility of novel therapeutic strategies relying on molecularly targeted drugs. In this context, forkhead box O3 (FOXO3), a member of forkhead transcription factors, has emerged as a crucial protein commonly dysregulated in cancer cells. The regulation of the FOXO3 in reacting to external stimuli plays a key role in maintaining cellular homeostasis as a component of the molecular machinery that determines whether cells will survive or dies. Indeed, various extrinsic cues regulate FOXO3, affecting its subcellular location and transcriptional activity. These regulations are mediated by diverse signaling pathways, non-coding RNAs (ncRNAs), and protein interactions that eventually drive post-transcriptional modification of FOXO3. Nevertheless, while it is no doubt that FOXO3 is implicated in numerous aspects of lung cancer, it is unclear whether they act as tumor suppressors, promotors, or both based on the situation. However, FOXO3 serves as an intriguing possible target in lung cancer therapeutics while widely used anti-cancer chemo drugs can regulate it. In this review, we describe a summary of recent findings on molecular mechanisms of FOXO3 to clarify that targeting its activity might hold promise in lung cancer treatment.

Polyphenols Modulate the miRNAs Expression that Involved in Glioblastoma.

Glioblastoma multiforme (GBM), a solid tumor that develops from astrocytes, is one of the most aggressive types of brain cancer. While there have been improvements in the efficacy of treating GBM, many problems remain, especially with traditional therapy methods. Therefore, recent studies have extensively focused on developing novel therapeutic agents for combating glioblastoma. Natural polyphenols have been studied for their potential as chemopreventive and chemotherapeutic agents due to their wide range of positive qualities, including antioxidant, antiinflammatory, cytotoxic, antineoplastic, and immunomodulatory activities. These natural compounds have been suggested to act via modulated various macromolecules within cells, including microRNAs (miRNAs), which play a crucial role in the molecular milieu. In this article, we focus on how polyphenols may inhibit tumor growth by influencing the expression of key miRNAs that regulate oncogenes and tumor suppressor genes.

Ataxia telangiectasia and Rad3-related (ATR) inhibition by VE-822 potently reversed 5-flourouracil resistance in colorectal cancer cells through targeting DNA damage response.

BACKGROUND: VE-822 is a novel inhibitor of ATR, a key kinase involved in the DNA damage response pathway. The role of ATR inhibition in reversing drug resistance in various cancer types has been investigated. Therefore, this study investigated the effects of ATR inhibition by VE-822 on reversing 5-fluorouracil (5-FU) resistance in colorectal cancer cell line (Caco-2). METHODS: Caco-2 and 5-FU resistance Caco-2 (Caco-2/5-FU) cells were treated with 5-FU and VE-822, alone and in combination. Cell proliferation and viability were assessed by MTT assay and Trypan Blue staining. P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) activities were measured by Rhodamine123 accumulation and uptake assay. The mRNA levels of P-gp, MRP-1, ataxia telangiectasia and Rad3-related (ATR) and checkpoint kinase 1 (CHK1) were measured by qRT-PCR. Western blot was used to measure the protein levels of P-gp, MRP-1, γ-H2AX, ATR and CHK1 in cells. 8-Oxo-2'-deoxyguanosine (8-oxo-dG) levels were determined via ELISA. Apoptosis was evaluated by ELISA death assay, DAPI staining and lactate dehydrogenase (LDH) assay. RESULTS: The Caco-2/5-FU cells showed lower levels of 5-FU mediated proliferation inhibition in comparison to Caco-2 cells. VE-822 decreased the IC50 value of 5-FU on resistant cells. In addition, the expression levels and activity of P-gp and MRP-1 were significantly decreased in resistant cells treated with VE-822 (P < 0.05). The combination of 5-FU and VE-822 increased apoptosis in Caco-2/5-FU cells by downregulating CHK1 and ATR and upregulating γ-H2AX and 8-oxo-dG. CONCLUSION: The simultaneous treatment of resistant colorectal cancer cells with 5-FU and ATR inhibitor, VE-822, was demonstrated to be effective in reversing drug resistance and potentiating 5-FU mediated anticancer effects via targeting DNA damage.

Potential anticancer properties and mechanisms of thymoquinone in colorectal cancer.

Colorectal neoplasms are one of the deadliest diseases among all cancers worldwide. Thymoquinone (TQ) is a natural compound of Nigella sativa that has been used in traditional medicine against a variety of acute/chronic diseases such as asthma, bronchitis, rheumatism, headache, back pain, anorexia, amenorrhea, paralysis, inflammation, mental disability, eczema, obesity, infections, depression, dysentery, hypertension, gastrointestinal, cardiovascular, hepatic, and renal disorders. This review aims to present a detailed report on the studies conducted on the anti-cancer properties of TQ against colorectal cancer, both in vitro and in vivo. TQ stands as a promising natural therapeutic agent that can enhance the efficacy of existing cancer treatments while minimizing the associated adverse effects. The combination of TQ with other anti-neoplastic agents promoted the efficacy of existing cancer treatments. Further research is needed to acquire a more comprehensive understanding of its exact molecular targets and pathways and maximize its clinical usefulness. These investigations may potentially aid in the development of novel techniques to combat drug resistance and surmount the obstacles presented by chemotherapy and radiotherapy.

FOXO1, a tiny protein with intricate interactions: Promising therapeutic candidate in lung cancer.

Nowadays, lung cancer is the most common cause of cancer-related deaths in both men and women globally. Despite the development of extremely efficient targeted agents, lung cancer progression and drug resistance remain serious clinical issues. Increasing knowledge of the molecular mechanisms underlying progression and drug resistance will enable the development of novel therapeutic methods. It has been revealed that transcription factors (TF) dysregulation, which results in considerable expression modifications of genes, is a generally prevalent phenomenon regarding human malignancies. The forkhead box O1 (FOXO1), a member of the forkhead transcription factor family with crucial roles in cell fate decisions, is suggested to play a pivotal role as a tumor suppressor in a variety of malignancies, especially in lung cancer. FOXO1 is involved in diverse cellular processes and also has clinical significance consisting of cell cycle arrest, apoptosis, DNA repair, oxidative stress, cancer prevention, treatment, and chemo/radioresistance. Based on the critical role of FOXO1, this transcription factor appears to be an appropriate target for future drug discovery in lung cancers. This review focused on the signaling pathways, and molecular mechanisms involved in FOXO1 regulation in lung cancer. We also discuss pharmacological compounds that are currently being administered for lung cancer treatment by affecting FOXO1 and also point out the essential role of FOXO1 in drug resistance. Future preclinical research should assess combination drug strategies to stimulate FOXO1 and its upstream regulators as potential strategies to treat resistant or advanced lung cancers.

The Critical Function of microRNAs in Developing Resistance against 5-Fluorouracil in Cancer Cells.

Although there have been significant advancements in cancer treatment, resistance and recurrence in patients make it one of the leading causes of death worldwide. 5-fluorouracil (5-FU), an antimetabolite agent, is widely used in treating a broad range of human malignancies. The cytotoxic effects of 5-FU are mediated by the inhibition of thymidylate synthase (TYMS/TS), resulting in the suppression of essential biosynthetic activity, as well as the misincorporation of its metabolites into RNA and DNA. Despite its huge benefits in cancer therapy, the application of 5-FU in the clinic is restricted due to the occurrence of drug resistance. MicroRNAs (miRNAs) are small, non-coding RNAs that act as negative regulators in many gene expression processes. Research has shown that changes in miRNA play a role in cancer progression and drug resistance. This review examines the role of miRNAs in 5-FU drug resistance in cancers.

Applications of engineered exosomes in drugging noncoding RNAs for cancer therapy.

Noncoding RNAs (ncRNAs) are engaged in key cell biological and pathological events, and their expression alteration is connected to cancer progression both directly and indirectly. A huge number of studies have mentioned the significant role of ncRNAs in cancer prevention and therapy that make them an interesting subject for cancer therapy. However, there are several limitations, including delivery, uptake, and short half-life, in the application of ncRNAs in cancer treatment. Exosomes are introduced as promising options for the delivery of ncRNAs to the target cells. In this review, we will briefly discuss the application and barriers of ncRNAs. After that we will focus on exosome-based ncRNAs delivery and their advantages as well as the latest achievements in drugging ncRNAs with exosomes.

Vitamin D in respiratory viral infections: a key immune modulator?

Respiratory viral infections are common respiratory diseases. Influenza viruses, RSV and SARS-COV2 have the potential to cause severe respiratory infections. Numerous studies have shown that unregulated immune response to these viruses can cause excessive inflammation and tissue damage. Therefore, regulating the antiviral immune response in the respiratory tract is of importance. In this regard, recent years studies have emphasized the importance of vitamin D in respiratory viral infections. Although, the most well-known role of vitamin D is to regulate the metabolism of phosphorus and calcium, it has been shown that this vitamin has other important functions. One of these functions is immune regulation. Vitamin D can regulate the antiviral immune response in the respiratory tract in order to provide an effective defense against respiratory viral infections and prevention from excessive inflammatory response and tissue damage. In addition, this vitamin has preventive effects against respiratory viral infections. Some studies during the COVID-19 pandemic have shown that vitamin D deficiency may be associated with a higher risk of mortality and sever disease in patients with COVID-19. Since, more attention has recently been focused on vitamin D. In this article, after a brief overview of the antiviral immune response in the respiratory system, we will review the role of vitamin D in regulating the antiviral immune response comprehensively. Then we will discuss the importance of this vitamin in influenza, RSV, and COVID-19.

Role of exosomal miRNA in chemotherapy resistance of Colorectal cancer: A systematic review.

The third most common malignancy has been identified as Colorectal cancer (CRC) that conducive to death in most cases. Chemoresistance is a common obstacle to CRC treatment. Circulating exosomal microRNAs (miRNAs) have been shown to reverse chemo-resistance and are promising biomarkers for CRC. The capacity of engineered exosomes to cross biological barriers and deliver functional miRNAs could be used to achieve these proposes. The object of this review is the investigation of the role of exosomal miRNA in the chemo-resistance, diagnosis, and prognosis of CRC. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, electronic databases, PubMed, EMBASE, Web of Science, Scopus were searched from January 1990 to November 2020. Ultimately, eight articles included five in vitro (16 cell lines) and three in vivo examinations. Three studies demonstrated that increasing or decreasing mRNA expression was associated with increasing and decreasing cell proliferation in vitro. The presence of miRNA in two studies increased the sensitivity of the drug and exhibited a considerable growth inhibitory effect on cancer cell proliferation. The apoptotic rate was significantly increased in four studies by increased mRNA expression and reduced mrna expression. Tumor volume of xenograft models in three studies suppressed by antitumor miRNA activity. In contrast, anti-miRNA activity in one study decreased the tumor volume. Exosomal miRNAs can be regulators of chemo-resistance and predict adverse outcomes in CRC patients. In sum, exosomes containing miRNAs can be a promising biomarker for the prognosis and diagnosis of CRC. Subsequent research should be a focus on delineating the function of exosomal miRNA before clinical use.

Interactions of melatonin with various signaling pathways: implications for cancer therapy.

Melatonin is a neuro-hormone with conserved roles in evolution. Initially synthetized as an antioxidant molecule, it has gained prominence as a key molecule in the regulation of the circadian rhythm. Melatonin exerts its effect by binding to cytoplasmic and intra-nuclear receptors, and is able to regulate the expression of key mediators of different signaling pathways. This ability has led scholars to investigate the role of melatonin in reversing the process of carcinogenesis, a process in which many signaling pathways are involved, and regulating these pathways may be of clinical significance. In this review, the role of melatonin in regulating multiple signaling pathways with important roles in cancer progression is discussed, and evidence regarding the beneficence of targeting malignancies with this approach is presented.

The modulatory effects of two bioflavonoids, quercetin and thymoquinone on the expression levels of DNA damage and repair genes in human breast, lung and prostate cancer cell lines.

BACKGROUND: The recent decade has witnessed the increasing potential of various flavonoids such as quercetin and thymoquinone in inhibiting cancer cells proliferation and growth and their therapeutic effects in various cancers. Therefore, in the current study, we aim to evaluate the expression levels of key factors of DNA damage response in human breast, lung and prostate cancer cell lines in response to treatment with quercetin and thymoquinone. METHODS: MTT assay was applied to assess the effects of quercetin and thymoquinone on the viability of MCF-7, A549, and PC3 cancer cells. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate the expression levels of p53, RAD51, Ku70, XRCC1, and H2AX in treated cells. In addition, the expression rate of 8-hydroxy-deoxyguanosine (8-OH-dG) was assessed by ELISA kit. RESULTS: The quercetin and thymoquinone induce cytotoxicity in breast, lung, and prostate cancer cells effectively; MCF-7 cells were the most sensitive cells to quercetin with an IC50 value of 50 µM and PC3 cells were more sensitive to thymoquinone with an IC50 value of 20 µM. The expression levels of DNA damage markers, H2AX, and 8-OH-dG were significantly increased in all cancer cells treated with quercetin and thymoquinone (p < 0.05). Moreover, both flavonoids significantly decreased the expression levels of DNA repair mediators, RAD51, Ku70, XRCC1, in cell lines. P53 was also increased in MCF-7 and A549 cells. CONCLUSION: We concluded that quercetin and thymoquinone may exert their effects through modulation of DNA damage response, increasing DNA damage, and suppressing DNA repair genes.

The role of melatonin in bone regeneration: A review of involved signaling pathways.

Increasing bone resorption followed by decreasing bone mineralization are hallmarks of bone degeneration, which mostly occurs in the elderly population and post-menopausal women. The use of mesenchymal stem cells (MSCs) has raised many promises in the field of bone regeneration due to their high osteoblastic differentiation capacity and easy availability from abundant sources. A variety of compounds, including growth factors, cytokines, and other internal factors, have been combined with MSCs to increase their osteoblastic differentiation capacity. One of these factors is melatonin, whose possible regulatory role in bone metabolism and formation has recently been suggested by many studies. Melatonin also is a potential signaling molecule and can affect many of the signaling pathways involved in MSCs osteoblastic differentiation, such as activation of PI3K/AKT, BMP/Smad, MAPK, NFkB, Nrf2/HO-1, Wnt, SIRT/SOD, PERK/ATF4. Furthermore, melatonin in combination with other components such as strontium, vitamin D3, and vitamin K2 has a synergistic effect on bone microstructure and improves bone mineral density (BMD). In this review article, we aim to summarize the regulatory mechanisms of melatonin in osteoblastic differentiation of MSCs and underling involved signaling pathways as well as the clinical potential of using melatonin in bone degenerative disorders.

Quercetin Augments Cisplatin-Induced Apoptosis, DNA Damage Response, and MiR-22 Expression While It Prevents DNA Repair in Osteosarcoma Cells.

BACKGROUND: Osteosarcoma (OS) patients are commonly treated with chemotherapeutic agents like cisplatin (Cis). Quercetin with fewer side effects can improve the potency of chemotherapy and be used in combinational therapies. Herein, we aimed to evaluate the effects of Cis plus quercetin on DNA damage response (DDR), DNA repair, and apoptosis in Saos-2 cells. METHODS: The effects of Cis and quercetin single or in combination on Saos-2 cell viability and the cytotoxicity of the drugs were measured by MTT assay. The expression of DDR and repair components including P53, ATM, ATR, RAD51, and H2AX, and also miR-22 were analyzed by real-time PCR. The rate of apoptosis was measured by flow cytometry. RESULTS: Quercetin potentiated the cytotoxic effects of Cis in Saos-2 cells. The IC50 of Cis reduced from 6.12 µM to 4.25 µM. The combination of quercetin and Cis was associated with the up-regulation of miR-22 and DDR components, including P53, ATM, ATR, and H2AX as well as the down-regulation of RAD51. Moreover, this combined regimen significantly induced apoptosis in Saos-2 cells compared to mono drugs. CONCLUSION: The co-treatment of quercetin and Cis can accelerate DNA damage, DNA damage response, and apoptosis while interfering with the DNA repair process in Saos-2 cells. Moreover, this combination provokes the tumor suppressor miR-22 expression in these cells.

Molecular mechanisms underlying ameliorative impact of melatonin against age-dependent chronic arsenic toxicity in rats' brains.

Accumulation of random molecular damage such as oxidative DNA damage and inflammation is extremely found to be involved in the aging process. Due to extreme energy requirements and high lipid levels, the brain is more susceptible to oxidative damage during aging especially under exposure to toxic elements such as arsenic. Therefore, this study was aimed to evaluate the ameliorative effects of melatonin, as a neurohormone, on the arsenic-induced behavioral abnormalities, and the underlying mechanisms. Forty-eight rats, as young and old aged groups were exposed to 5.55 g/kg body weight arsenic for 4 weeks and then 10 mg/kg melatonin for 2 weeks. Our results showed that arsenic led to anxiety-like behavioral abnormalities in rats. Increased oxidative stress-induced damage to DNA, lipids and proteins, decreased potential of antioxidant defense system, induced apoptosis, elevated inflammation, and alteration in the histology of cortical region of brains are observed in the rats exposed to arsenic. These effects were more prominent in aged rats in comparison to young rats. Melatonin successfully attenuates arsenic induced adverse effects on the brain in both age groups. In conclusion, our study shows that melatonin has significant ameliorative impact on age-dependent cytotoxicity of arsenic in rats' brains.

Thymoquinone Augments Methotrexate-Induced Apoptosis on Osteosarcoma Cells.

BACKGROUND: Osteosarcoma (OS) as the most frequent primary bone malignancy in children and adolescents has a short survival rate in advanced stages. Alternative herbal medicines with fewer side effects or the potency to protect common therapy's side effects can be helpful in combinational therapies. Herein, we aim to explore the effects of Thymoquinone (TQ) combined with Methotrexate (MTX) on Saos-2 cells apoptosis. METHODS: The effects of TQ and MTX alone or in combination on Saos-2 cell viability were measured by MTT assay. Real-time PCR was applied for the measurement of Bax, BCL-2, and caspase-9 mRNA expression. Apoptosis evaluation was conducted by flow cytometry. RESULTS: TQ improves the cytotoxic effects of MTX on Saos-2 cells proliferation at lower doses. Indeed, the IC50 of MTX decreased from 26 µM to 15 µM when it combined with TQ. TQ and MTX can induce the expression level of pro-apoptotic factors, Bax and caspase-9 while inhibiting anti-apoptotic protein BCL-2. Moreover, the combination of TQ and MTX potentiates apoptosis to 73%, compared to either TQ (48%) or MTX (53%) treated cells. CONCLUSION: The co-treatment of TQ and MTX is associated with the up-regulation of apoptotic factors and down-regulation of anti-apoptotic factors, conducting apoptosis aggravation and OS cell death.

Nanotechnology-based advances in the efficient delivery of melatonin.

N-[2-(5-methoxy-1H-indol-3-yl) ethyl] or simply melatonin is a biogenic amine produced by pineal gland and recently recognized various other organs. Because of a broad range of biological function melatonin is considered as a therapeutic agent with high efficacy in the treatment of multiple disorders, such as cancer, degenerative disorders and immune disease. However, since melatonin can affect receptors on the cellular membrane, in the nucleus and can act as an anti-oxidant molecule, some unwanted effects may be observed after administration. Therefore, the entrapment of melatonin in biocompatible, biodegradable and safe nano-delivery systems can prevent its degradation in circulation; decrease its toxicity with increased half-life, enhanced pharmacokinetic profile leading to improved patient compliance. Because of this, nanoparticles have been used to deliver melatonin in multiple studies, and the present article aims to cumulatively illustrate their findings.

Molecular mechanisms involved in DNA repair in human cancers: An overview of PI3k/Akt signaling and PIKKs crosstalk.

The cellular genome is frequently subjected to abundant endogenous and exogenous factors that induce DNA damage. Most of the Phosphatidylinositol 3-kinase-related kinases (PIKKs) family members are activated in response to DNA damage and are the most important DNA damage response (DDR) proteins. The DDR system protects the cells against the wrecking effects of these genotoxicants and repairs the DNA damage caused by them. If the DNA damage is severe, such as when DNA is the goal of chemo-radiotherapy, the DDR drives cells toward cell cycle arrest and apoptosis. Some intracellular pathways, such as PI3K/Akt, which is overactivated in most cancers, could stimulate the DDR process and failure of chemo-radiotherapy with the increasing repair of damaged DNA. This signaling pathway induces DNA repair through the regulation of proteins that are involved in DDR like BRCA1, HMGB1, and P53. In this review, we will focus on the crosstalk of the PI3K/Akt and PIKKs involved in DDR and then discuss current achievements in the sensitization of cancer cells to chemo-radiotherapy by PI3K/Akt inhibitors.