Spectroscopic, biochemical and computational studies of bioactive DNA minor groove binders targeting 5'-WGWWCW-3' motif.

Spectroscopic, biochemical, and computational modelling studies have been used to assess the binding capability of a set of minor groove binding (MGB) ligands against the self-complementary DNA sequences 5'-d(CGCACTAGTGCG)-3' and 5'-d(CGCAGTACTGCG)-3'. The ligands were carefully designed to target the DNA response element, 5'-WGWWCW-3', the binding site for several nuclear receptors. Basic 1D 1H NMR spectra of the DNA samples prepared with three MGB ligands show subtle variations suggestive of how each ligand associates with the double helical structure of both DNA sequences. The variations among the investigated ligands were reflected in the line shape and intensity of 1D 1H and 31P-{1H} NMR spectra. Rapid visual inspection of these 1D NMR spectra proves to be beneficial in providing valuable insights on MGB binding molecules. The NMR results were consistent with the findings from both UV DNA denaturation and molecular modelling studies. Both the NMR spectroscopic and computational analyses indicate that the investigated ligands bind to the minor grooves as antiparallel side-by-side dimers in a head-to-tail fashion. Moreover, comparisons with results from biochemical studies offered valuable insights into the mechanism of action, and antitumor activity of MGBs in relation to their structures, essential pre-requisites for future optimization of MGBs as therapeutic agents.

Deciphering the interplay of histone post-translational modifications in cancer: Co-targeting histone modulators for precision therapy.

Chromatin undergoes dynamic regulation through reversible histone post-translational modifications (PTMs), orchestrated by "writers," "erasers," and "readers" enzymes. Dysregulation of these histone modulators is well implicated in shaping the cancer epigenome and providing avenues for precision therapies. The approval of six drugs for cancer therapy targeting histone modulators, along with the ongoing clinical trials of numerous candidates, represents a significant advancement in the field of precision medicine. Recently, it became apparent that histone PTMs act together in a coordinated manner to control gene expression. The intricate crosstalk of histone PTMs has been reported to be dysregulated in cancer, thus emerging as a critical factor in the complex landscape of cancer development. This formed the foundation of the swift emergence of co-targeting different histone modulators as a new strategy in cancer therapy. This review dissects how histone PTMs, encompassing acetylation, phosphorylation, methylation, SUMOylation and ubiquitination, collaboratively influence the chromatin states and impact cellular processes. Furthermore, we explore the significance of histone modification crosstalk in cancer and discuss the potential of targeting histone modification crosstalk in cancer management. Moreover, we underscore the significant strides made in developing dual epigenetic inhibitors, which hold promise as emerging candidates for effective cancer therapy.

Decoding cell death signalling: Impact on the response of breast cancer cells to approved therapies.

Breast cancer is a principal cause of cancer-related mortality in female worldwide. While many approved therapies have shown promising outcomes in treating breast cancer, understanding the intricate signalling pathways controlling cell death is crucial for optimizing the treatment outcome. A growing body of evidence has unveiled the aberrations in multiple cell death pathways across diverse cancer types, highlighting these pathways as appealing targets for therapeutic interventions. In this review, we provide a comprehensive overview of the current state of knowledge on the cell death signalling mechanisms with a particular focus on their impact on the response of breast cancer cells to approved therapies. Additionally, we discuss the potentials of combination therapies that exploit the synergy between approved drugs and therapeutic agents targeting modulators of cell death pathways.

Design, synthesis and mechanistic anticancer activity of new acetylated 5-aminosalicylate-thiazolinone hybrid derivatives.

The development of hybrid compounds has been widely considered as a promising strategy to circumvent the difficulties that emerge in cancer treatment. The well-established strategy of adding acetyl groups to certain drugs has been demonstrated to enhance their therapeutic efficacy. Based on our previous work, an approach of accommodating two chemical entities into a single structure was implemented to synthesize new acetylated hybrids (HH32 and HH33) from 5-aminosalicylic acid and 4-thiazolinone derivatives. These acetylated hybrids showed potential anticancer activities and distinct metabolomic profile with antiproliferative properties. The in-silico molecular docking predicts a strong binding of HH32 and HH33 to cell cycle regulators, and transcriptomic analysis revealed DNA repair and cell cycle as the main targets of HH33 compounds. These findings were validated using in vitro models. In conclusion, the pleiotropic biological effects of HH32 and HH33 compounds on cancer cells demonstrated a new avenue to develop more potent cancer therapies.

Modulation of the Tumor Microenvironment by Ellagic Acid in Rat Model for Hepatocellular Carcinoma: A Potential Target against Hepatic Cancer Stem Cells.

The resistance to therapy and relapse in hepatocellular carcinoma (HCC) is highly attributed to hepatic cancer stem cells (HCSCs). HCSCs are under microenvironment control. This work aimed to assess the systemic effect of ellagic acid (EA) on the HCC microenvironment to decline HCSCs. Fifty Wistar rats were divided into six groups: negative control (CON), groups 2 and 3 for solvents (DMSO), and (OVO). Group 4 was administered EA only. The (HCC-M) group, utilized as an HCC model, administered CCL4 (0.5 mL/kg in OVO) 1:1 v/v, i.p) for 16 weeks. HCC-M rats were treated orally with EA (EA + HCC) 50 mg/kg bw for five weeks. Biochemical, morphological, histopathological, and immunohistochemical studies, and gene analysis using qRT-PCR were applied. Results revealed elevated liver injury biomarkers ALT, AST, ALP, and tumor biomarkers AFP and GGT, and marked nodularity of livers of HCC-M. EA effectively reduced the biomarkers and restored the altered structure of the livers. At the mRNA level, EA downregulated the expression of TGF-α, TGF-ß, and VEGF, and restored p53 expression. This induced an increase in apoptotic cells immunostained with caspase3 and decreased the CD44 immunostained HCSCs. EA could modulate the tumor microenvironment in the HCC rat model and ultimately target the HCSCs.

The design, synthesis, biological evaluation, and molecular docking of new 5-aminosalicylamide-4-thiazolinone hybrids as anticancer agents.

New 5-aminosalicylamide-4-thiazolinone hybrids (27) were efficiently synthesized, characterized, and evaluated to explore their structure-activity relationship as anticancer agents. The antiproliferative activities of the new hybrids were evaluated against eight cancer cell lines using the sulforhodamine B assay. The most potent compound (24b) possessed high selectivity on the tested cell lines in the low micromolar range, with much lower effects on normal fibroblast cells (IC50 > 50 µM). The cell lines derived from leukemia (Jurkat), cervix (HeLa), and colon (HCT116) cancers appeared to be the most sensitive, with IC50 of 2 µM. 24b is the N-ethylamide derivative with p-dimethylaminobenzylidene at position 5 of the 4-thiazolinone moiety. Other N-substituents or arylidene derivatives showed lower activity. Hybrids with salicylamides showed lower activity than with methyl salicylate. The results clearly show that the modifications of the carboxy group and arylidene moiety greatly affect the activity. Investigating the possible molecular mechanisms of these hybrids revealed that they act through cell-cycle arrest and induction of apoptosis and epidermal growth factor receptor (EGFR) inhibition. Molecular docking studies rationalize the molecular interactions of 24b with EGFR. This work expands our knowledge of the structural requirements to improve the anticancer activity of 5-aminosalicylic-thiazolinone hybrids and pave the way toward multitarget anticancer salicylates.

Epigenetic modulations in cancer: predictive biomarkers and potential targets for overcoming the resistance to topoisomerase I inhibitors.

INTRODUCTION: Altered epigenetic map is frequently observed in cancer and recent investigations have demonstrated a pertinent role of epigenetic modifications in the response to many anticancer drugs including the DNA damaging agents. Topoisomerase I (Top I) is a well-known nuclear enzyme that is critical for DNA function and cell survival and its inhibition causes DNA strand breaks and cell cycle arrest. Inhibitors of human Top I have proven to be a prosperous chemotherapeutic treatment for a vast number of cancer patients. While the treatment is efficacious in many cases, resistance and altered cellular response remain major therapeutic issues. AREAS COVERED: This review highlights the evidence available till date on the influence of different epigenetic modifications on the response to Top I inhibitors as well as the implications of targeting epigenetic alterations for improving the efficacy and safety of Top I inhibitors. EXPERT OPINION: The field of epigenetic research is steadily growing. With its assistance, we could gain better understanding on how drug response and resistance work. Epigenetics can evolve as possible biomarkers and predictors of response to many medications including Top I inhibitors, and could have significant clinical implications that necessitate deeper attention.HIGHLIGHTSEpigenetic alterations, including DNA methylation and histone modifications, play a pertinent role in the response to several anticancer treatments, including DNA damaging agents like Top I inhibitors.Although camptothecin derivatives are used clinically as Top I inhibitors for management of cancer, certain types of cancer have inherent and or acquired resistance that limit the curative potential of them.Epigenetic modifications like DNA hypomethylation can either increase or decrease sensitivity to Top I inhibitors by different mechanisms.The combination of Top I inhibitors with the inhibitors of histone modifying enzymes can result in enhanced cytotoxic effects and sensitization of resistant cells to Top I inhibitors.MicroRNAs were found to directly influence the expression of Top I and other proteins in cancer cells resulting in positive or negative alteration of the response to Top I inhibitors.lncRNAs and their genetic polymorphisms have been found to be associated with Top I function and the response to its inhibitors.Clinical trials of epigenetic drugs in combination with Top I inhibitors are plentiful and some of them showed potentially promising outcomes.

Interaction of an anticancer benzopyrane derivative with DNA: Biophysical, biochemical, and molecular modeling studies.

BACKGROUND: SIMR1281 is a potent anticancer lead candidate with multi- target activity against several proteins; however, its mechanism of action at the molecular level is not fully understood. Revealing the mechanism and the origin of multitarget activity is important for the rational identification and optimization of multitarget drugs. METHODS: We have used a variety of biophysical (circular dichroism, isothermal titration calorimetry, viscosity, and UV DNA melting), biochemical (topoisomerase I & II assays) and computational (molecular docking and MD simulations) methods to study the interaction of SIMR1281 with duplex DNA structures. RESULTS: The biophysical results revealed that SIMR1281 binds to dsDNA via an intercalation-binding mode with an average binding constant of 3.1 × 106 M-1. This binding mode was confirmed by the topoisomerases' inhibition assays and molecular modeling simulations, which showed the intercalation of the benzopyrane moiety between DNA base pairs, while the remaining moieties (thiazole and phenyl rings) sit in the minor groove and interact with the flanking base pairs adjacent to the intercalation site. CONCLUSIONS: The DNA binding characteristics of SIMR1281, which can disrupt/inhibit DNA function as confirmed by the topoisomerases' inhibition assays, indicate that the observed multi-target activity might originate from ligand intervention at nucleic acids level rather than due to direct interactions with multiple biological targets at the protein level. GENERAL SIGNIFICANCE: The findings of this study could be helpful to guide future optimization of benzopyrane-based ligands for therapeutic purposes.

Proteomic and metabolomic signatures of U87 glioblastoma cells treated with cisplatin and/or paclitaxel.

BACKGROUND: Glioblastoma (GBM) is a primary malignancy of the central nervous system and is classified as a grade IV astrocytoma by the World Health Organization (WHO). Although GBM rarely metastasizes, its prognosis remains poor. Moreover, the standard treatment for GBM, temozolomide (TMZ), is associated with chemoresistance, which is a major factor behind GBM-related deaths. Investigating drugs with repurposing potential in the context of GBM is worthwhile to bypass lengthy bench-to-bedside research. The field of omics has garnered significant interest in scientific research because of its potential to delineate the intricate regulatory network underlying tumor development. In particular, proteomic and metabolomic analyses are powerful approaches for the investigation of metabolic enzymes and intermediate metabolites since they represent the functional end of the cancer phenotype. METHODS: We chose two of the most widely prescribed anticancer drugs, cisplatin and paclitaxel. To our knowledge, the current literature lacks studies examining their effects on metabolic and proteomic alterations in GBM. We employed the mass spectrometry technological platform 'UHPLC-Q-TOF-MS/MS' to examine the changes in the proteome and metabolome profiles of the U87 cell line with defined concentrations of cisplatin and/or paclitaxel via an untargeted approach. RESULTS: A total of 1,419 distinct proteins and 90 metabolites were generated, and subsequent analysis was performed. We observed that upon treatment with cisplatin (9.5 µM), U87 cells exhibited apparent efforts to cope with this exogenous stressor, understanding the effect of paclitaxel (5.3 µM) on altering the transport machinery of the cell, and how the combination of cisplatin and/or paclitaxel suggests potential interactions with promising benefits in GBM therapeutics. CONCLUSION: Our research provides a detailed map of alterations in response to cisplatin and paclitaxel treatment, provides crucial insights into the molecular basis of their action, and paves the way for further research to identify molecular targets for this elusive malignancy.

Pharmacophore-based virtual screening approaches to identify novel molecular candidates against EGFR through comprehensive computational approaches and in-vitro studies.

Alterations to the EGFR (epidermal growth factor receptor) gene, which primarily occur in the axon 18-21 position, have been linked to a variety of cancers, including ovarian, breast, colon, and lung cancer. The use of TK inhibitors (gefitinib, erlotinib, lapatinib, and afatinib) and monoclonal antibodies (cetuximab, panitumumab, and matuzumab) in the treatment of advanced-stage cancer is very common. These drugs are becoming less effective in EGFR targeted cancer treatment and developing resistance to cancer cell eradication, which sometimes necessitates stopping treatment due to the side effects. One in silico study has been conducted to identify EGFR antagonists using other compounds, databases without providing the toxicity profile, comparative analyses, or morphological cell death pattern. The goal of our study was to identify potential lead compounds, and we identified seven compounds based on the docking score and four compounds that were chosen for our study, utilizing toxicity analysis. Molecular docking, virtual screening, dynamic simulation, and in-vitro screening indicated that these compounds' effects were superior to those of already marketed medication (gefitinib). The four compounds obtained, ZINC96937394, ZINC14611940, ZINC103239230, and ZINC96933670, demonstrated improved binding affinity (-9.9 kcal/mol, -9.6 kcal/mol, -9.5 kcal/mol, and -9.2 kcal/mol, respectively), interaction stability, and a lower toxicity profile. In silico toxicity analysis showed that our compounds have a lower toxicity profile and a higher LD50 value. At the same time, a selected compound, i.e., ZINC103239230, was revealed to attach to a particular active site and bind more tightly to the protein, as well as show better in-vitro results when compared to our selected gefitinib medication. MTT assay, gene expression analysis (BAX, BCL-2, and ß-catenin), apoptosis analysis, TEM, cell cycle assay, ELISA, and cell migration assays were conducted to perform the cell death analysis of lung cancer and breast cancer, compared to the marketed product. The MTT assay exhibited 80% cell death for 75 µM and 100µM; however, flow cytometry analysis with the IC50 value demonstrated that the selected compound induced higher apoptosis in MCF-7 (30.8%) than in A549.

Plant Flavonoids on Oxidative Stress-Mediated Kidney Inflammation.

The kidney is susceptible to reactive oxygen species-mediated cellular injury resulting in glomerulosclerosis, tubulointerstitial fibrosis, tubular cell apoptosis, and senescence, leading to renal failure, and is a significant cause of death worldwide. Oxidative stress-mediated inflammation is a key player in the pathophysiology of various renal injuries and diseases. Recently, flavonoids' role in alleviating kidney diseases has been reported with an inverse correlation between dietary flavonoids and kidney injuries. Flavonoids are plant polyphenols possessing several health benefits and are distributed in plants from roots to leaves, flowers, and fruits. Dietary flavonoids have potent antioxidant and free-radical scavenging properties and play essential roles in disease prevention. Flavonoids exert a nephroprotective effect by improving antioxidant status, ameliorating excessive reactive oxygen species (ROS) levels, and reducing oxidative stress, by acting as Nrf2 antioxidant response mediators. Moreover, flavonoids play essential roles in reducing chemical toxicity. Several studies have demonstrated the effects of flavonoids in reducing oxidative stress, preventing DNA damage, reducing inflammatory cytokines, and inhibiting apoptosis-mediated cell death, thereby preventing or improving kidney injuries/diseases. This review covers the recent nephroprotective effects of flavonoids against oxidative stress-mediated inflammation in the kidney and their clinical advancements in renal therapy.

Metabolomics Analysis Revealed Significant Metabolic Changes in Brain Cancer Cells Treated with Paclitaxel and/or Etoposide.

Cancer of the central nervous system (CNS) is ranked as the 19th most prevalent form of the disease in 2020. This study aims to identify candidate biomarkers and metabolic pathways affected by paclitaxel and etoposide, which serve as potential treatments for glioblastoma, and are linked to the pathogenesis of glioblastoma. We utilized an untargeted metabolomics approach using the highly sensitive ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS) for identification. In this study, 92 and 94 metabolites in U87 and U373 cell lines were profiled, respectively. The produced metabolites were then analyzed utilizing t-tests, volcano plots, and enrichment analysis modules. Our analysis revealed distinct metabolites to be significantly dysregulated (nutriacholic acid, L-phenylalanine, L-arginine, guanosine, ADP, hypoxanthine, and guanine), and to a lesser extent, mevalonic acid in paclitaxel and/or etoposide treated cells. Furthermore, both urea and citric acid cycles, and metabolism of polyamines and amino acids (aspartate, arginine, and proline) were significantly enriched. These findings can be used to create a map that can be utilized to assess the antitumor effect of paclitaxel and/or etoposide within the studied cancer cells.

Effect of safranal on the response of cancer cells to topoisomerase I inhibitors: Does sequence matter?

Lung and colorectal cancers are among the leading causes of death from cancer worldwide. Although topotecan (TPT), a topoisomerase1 inhibitor, is a first- and second-line drug for lung and colon cancers, the development of drug resistance and toxicity still remain as a major obstacle to chemotherapeutic success. Accumulating evidence indicates increased efficacy and reduced toxicity of chemotherapeutic agents upon combining them with natural products. We aimed to investigate the possible interaction of safranal (SAF), a natural compound obtained from Crocus sativus stigma, with TPT when used in different sequences in colon and lung cancer cell lines. The growth inhibitory effect of the proposed combination given in different sequences was assessed using the colony formation assay. The comet assay, cell cycle distribution, Annexin-V staining, and expression of proteins involved in DNA damage/repair were utilized to understand the mechanism underlying the effect of the combination. SAF enhanced the growth inhibitory effects of TPT particularly when it was added to the cells prior to TPT. This combination increased the double-strand break induction and dysregulated the DNA repair machinery, particularly the tyrosyl-DNA phosphodiesterase 1 enzyme. In addition, the SAF + TPT combination increased the fraction of cells arrested at the G2/M checkpoint as well as enhanced the induction of apoptosis. The current study highlights the status of SAF as a natural product sensitizing the lung and colon cancer cells to the cytotoxic effects of the anticancer drug TPT. In addition, it emphasizes the importance of sequence-dependent interaction which can affect the overall outcome.

The Role of HDACs in the Response of Cancer Cells to Cellular Stress and the Potential for Therapeutic Intervention.

Throughout the process of carcinogenesis, cancer cells develop intricate networks to adapt to a variety of stressful conditions including DNA damage, nutrient deprivation, and hypoxia. These molecular networks encounter genomic instability and mutations coupled with changes in the gene expression programs due to genetic and epigenetic alterations. Histone deacetylases (HDACs) are important modulators of the epigenetic constitution of cancer cells. It has become increasingly known that HDACs have the capacity to regulate various cellular systems through the deacetylation of histone and bounteous nonhistone proteins that are rooted in complex pathways in cancer cells to evade death pathways and immune surveillance. Elucidation of the signaling pathways involved in the adaptive responses to cellular stress and the role of HDACs may lead to the development of novel therapeutic agents. In this article, we overview the dominant stress types including metabolic, oxidative, genotoxic, and proteotoxic stress imposed on cancer cells in the context of HDACs, which guide stress adaptation responses. Next, we expose a closer view on the therapeutic interventions and clinical trials that involve HDACs inhibitors, in addition to highlighting the impact of using HDAC inhibitors in combination with stress-inducing agents for the management of cancer and to overcome the resistance to current cancer therapy.

A Novel Benzopyrane Derivative Targeting Cancer Cell Metabolic and Survival Pathways.

(1) Background: Today, the discovery of novel anticancer agents with multitarget effects and high safety margins represents a high challenge. Drug discovery efforts indicated that benzopyrane scaffolds possess a wide range of pharmacological activities. This spurs on building a skeletally diverse library of benzopyranes to identify an anticancer lead drug candidate. Here, we aim to characterize the anticancer effect of a novel benzopyrane derivative, aiming to develop a promising clinical anticancer candidate. (2) Methods: The anticancer effect of SIMR1281 against a panel of cancer cell lines was tested. In vitro assays were performed to determine the effect of SIMR1281 on GSHR, TrxR, mitochondrial metabolism, DNA damage, cell cycle progression, and the induction of apoptosis. Additionally, SIMR1281 was evaluated in vivo for its safety and in a xenograft mice model. (3) Results: SIMR1281 strongly inhibits GSHR while it moderately inhibits TrxR and modulates the mitochondrial metabolism. SIMR1281 inhibits the cell proliferation of various cancers. The antiproliferative activity of SIMR1281 was mediated through the induction of DNA damage, perturbations in the cell cycle, and the inactivation of Ras/ERK and PI3K/Akt pathways. Furthermore, SIMR1281 induced apoptosis and attenuated cell survival machinery. In addition, SIMR1281 reduced the tumor volume in a xenograft model while maintaining a high in vivo safety profile at a high dose. (4) Conclusions: Our findings demonstrate the anticancer multitarget effect of SIMR1281, including the dual inhibition of glutathione and thioredoxin reductases. These findings support the development of SIMR1281 in preclinical and clinical settings, as it represents a potential lead compound for the treatment of cancer.

Discovery of novel class of histone deacetylase inhibitors as potential anticancer agents.

Selective inhibition of histone deacetylases (HDACs) is an important strategy in the field of anticancer drug discovery. However, lack of inhibitors that possess high selectivity toward certain HDACs isozymes is associated with adverse side effects that limits their clinical applications. We have initiated a collaborative initiatives between multi-institutions aimed at the discovery of novel and selective HDACs inhibitors. To this end, a phenotypic screening of an in-house pilot library of about 70 small molecules against various HDAC isozymes led to the discovery of five compounds that displayed varying degrees of HDAC isozyme selectivity. The anticancer activities of these molecules were validated using various biological assays including transcriptomic studies. Compounds 15, 14, and 19 possessed selective inhibitory activity against HDAC5, while 28 displayed selective inhibition of HDAC1 and HDAC2. Compound 22 was found to be a selective inhibitor for HDAC3 and HDAC9. Importantly, we discovered a none-hydroxamate based HDAC inhibitor, compound 28, representing a distinct chemical probe of HDAC inhibitors. It contains a trifluoromethyloxadiazolyl moiety (TFMO) as a non-chelating metal-binding group. The new compounds showed potent anti-proliferative activity when tested against MCF7 breast cancer cell line, as well as increased acetylation of histones and induce cells apoptosis. The new compounds apoptotic effects were validated through the upregulation of proapoptotic proteins caspases3 and 7 and downregulation of the antiapoptotic biomarkers C-MYC, BCL2, BCL3 and NFĸB genes. Furthermore, the new compounds arrested cell cycle at different phases, which was confirmed through downregulation of the CDK1, 2, 4, 6, E2F1 and RB1 proteins. Taken together, our findings provide the foundation for the development of new chemical probes as potential lead drug candidates for the treatment of cancer.

The impact of CBP expression in estrogen receptor-positive breast cancer.

BACKGROUND: The development of new biomarkers with diagnostic, prognostic and therapeutic prominence will greatly enhance the management of breast cancer (BC). Several reports suggest the involvement of the histone acetyltransferases CREB-binding protein (CBP) and general control non-depressible 5 (GCN5) in tumor formation; however, their clinical significance in BC remains poorly understood. This study aims to investigate the value of CBP and GCN5 as markers and/or targets for BC prognosis and therapy. Expression of CBP, GCN5, estrogen receptor α (ERα), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in BC was analyzed in cell lines by western blot and in patients' tissues by immunohistochemistry. The gene amplification data were also analyzed for CBP and GCN5 using the publicly available data from BC patients. RESULTS: Elevated expression of CBP and GCN5 was detected in BC tissues from patients and cell lines more than normal ones. In particular, CBP was more expressed in luminal A and B subtypes. Using chemical and biological inhibitors for CBP, ERα and HER2 showed a strong association between CBP and the expression of ERα and HER2. Moreover, analysis of the CREBBP (for CBP) and KAT2A (for GCN5) genes in a larger number of patients in publicly available databases showed amplification of both genes in BC patients. Amplification of CREBBP gene was observed in luminal A, luminal B and triple-negative but not in HER2 overexpressing subtypes. Furthermore, patients with high CREBBP or KAT2A gene expression had better 5-year disease-free survival than the low gene expression group (p = 0.0018 and p < 0.00001, respectively). CONCLUSIONS: We conclude that the persistent amplification and overexpression of CBP in ERα- and PR-positive BC highlights the significance of CBP as a new diagnostic marker and therapeutic target in hormone-positive BC.

Current methodologies to refine bioavailability, delivery, and therapeutic efficacy of plant flavonoids in cancer treatment.

Over the last two decades, several advancements have been made to improve the therapeutic efficacy of plant flavonoids, especially in cancer treatment. Factors such as low bioavailability, poor flavonoid stability and solubility, ineffective targeted delivery, and chemo-resistance hinder the application of flavonoids in anti-cancer therapy. Many anti-cancer compounds failed in the clinical trials because of unexpected altered clearance of flavonoids, poor absorption after administration, low efficacy, and/or adverse effects. Hence, the current research strategies are focused on improving the therapeutic efficacy of plant flavonoids, especially by enhancing their bioavailability through combination therapy, engineering gut microbiota, regulating flavonoids interaction with adenosine triphosphate binding cassette efflux transporters, and efficient delivery using nanocrystal and encapsulation technologies. This review aims to discuss different methodologies with examples from reported dietary flavonoids that showed an enhanced anti-cancer efficacy in both in vitro and in vivo models. Further, the review discusses the recent progress in biochemical modifications of flavonoids to improve bioavailability, solubility, and therapeutic efficacy.

Health benefits of cyanidin-3-glucoside as a potent modulator of Nrf2-mediated oxidative stress.

Berries are natural sources of anthocyanins, especially cyanidin-3-glucoside (C3G), and exhibit significant antioxidant, antidiabetic, anti-inflammatory, and cytoprotective effects against various oxidative stress-induced disorders. C3G and its metabolites possess higher absorption and bioavailability, and interaction with gut microbiota may enhance their health benefits. Various in vitro studies have shown the reactive oxygen species (ROS)-mitigating potential of C3G. However, in in vivo models, C3G exerts its cytoprotective properties by regulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant-responsive element (ARE) pathway. Despite existing reports stating various health benefits of C3G, its antioxidant potential by modulating the Nrf2 pathway remains less identified. This review discusses the Nrf2-mediated antioxidant response of C3G in modulating oxidative stress against DNA damage, apoptosis, carcinogen toxicity, and inflammatory conditions. Furthermore, we have reviewed the recent clinical trial data to establish cross talk between a berry-rich diet and disease prevention.

The potential role of pomegranate and its nano-formulations on cerebral neurons in aluminum chloride induced Alzheimer rat model.

The oxidative stress leading to degenerative changes in the brain of Alzheimer's disease (AD) is evident. Our aim was to evaluate the therapeutic and protective effects of pomegranate extract (PE) and pomegranate extract-loaded nanoparticles (PE nano) in an AlCl 3-induced AD rat model. Nanoparticles were synthesized with a PE load of 0.68% w/w, and 70 male Wistar rats were divided into 7 groups: Group I was the control, Group II received PE., Group III received PE nano for 2 weeks, Group IV received AlCl 3 (50 mg/kg) daily orally for 4 weeks, Group V received PE for 2 weeks, Group VI received PE nano for 2 weeks, and Groups V and VI were started after AlCl 3 administration was stopped. Group VII received PE for 2 weeks and was stopped before AlCl 3 was administered. The Results revealed that the discrimination index in the novel object recognition test was the least in AD rat model but increased in cases protected with PE treated with PE nano. Similar results were shown based on calculating the brain weight/body weight percent. The biomarkers of antioxidant activity (catalase, glutathione and total antioxidant activity) in brain homogenate were significantly increased in groups treated with either PE or PE nano. The thiobarbituric acid reactive substance measured to estimate lipid peroxidation was significantly increased in AD rat model and decreased in groups protected with PE or treated with PE nano. Histopathological studies using hematoxylin and eosin, cresyl violet, and silver stains revealed hyaline degeneration, chromatolysis, and hallmarks of AD; neurofibrillary tangles and the senile plaques in brains of AD rat model. Restoration of the histological architecture, Nissl granules, and minimal appearance of hallmarks of AD characterized brains treated with PE or PE nano. In conclusion, PE was more effective as a protectant than a therapeutic measure in alleviating the antioxidant, lipid peroxidative effects and histopathological hallmarks in AD brains. But, the therapeutic PE-loaded nanoparticles increased the efficacy of active components and produced similar results as the protective PE.