Background and purpose: Cholesteryl ester transfer protein is a crucial regulator of lipid metabolism and is considered a promising target for treating atherosclerotic cardiovascular disease. Given the clinical limitations and adverse effects of previous cholesteryl ester transfer protein inhibitors, such as torcetrapib, this study aimed to identify safer, more effective alternatives through computational drug discovery. Experimental approach: A diverse set of natural compounds from the ZINC15 database was screened using a multi-step in silico workflow comprising drug-likeness assessment, ADMET profiling, molecular docking, and molecular dynamics simulations. This integrated process narrowed down a large compound library to a refined selection of candidates with favorable safety and pharmacokinetic properties. Findings/Results: Calebin, a bioactive compound derived from turmeric, emerged as the most promising cholesteryl ester transfer protein inhibitor. It demonstrated binding interactions with cholesteryl ester transfer protein (-8.4 Kcal/mol) that were comparable to curcumin (-8.5 kcal/mol) and lower than the reference x-ray inhibitor torcetrapib (-9.4 kcal/mol), along with similar molecular dynamic complex stability (RMSD of 2.515 ± 0.282 Å in comparison to torcetrapib 2.502 ± 0.332 Å). Conclusion and implications: These findings highlight the value of computational drug discovery for identifying natural inhibitors of cholesteryl ester transfer protein and provide a strong foundation for future experimental validation. Calebin A demonstrated a promising binding affinity and interaction stability with cholesteryl ester transfer protein, but proof-of-concept studies are warranted to confirm this potential activity.
Background and purpose: Damage to a specific brain region, in addition to its local effects, can influence brain function by inducing neuroplasticity in remote areas. This study hypothesized that hemorrhage of the medial prefrontal cortex (mPFC) is associated with deficits in shifting attention through structural alterations in the hippocampal CA1 region, an area with known functional connections to the mPFC. Experimental approach: C57BL/6 mice were subjected to intracerebral hemorrhage (ICH) or sham surgery. Neurological function was assessed using the neurological deficit score (NDS) on different days after injury, and cognitive flexibility was evaluated using the attentional set shifting task (AST) over a 17-day protocol. Structural changes were examined by assessing white matter and dendritic spine density using Luxol fast blue (LFB) and Golgi staining techniques on brain tissue. Statistical analysis was performed with SPSS-26. Findings/Results: No significant difference was observed in NDS between the groups. Mice with ICH demonstrated a lower task completion rate, along with an increased number of trials and set-loss errors in the AST. Dendritic spine density in the CA1 region was higher in the ICH group compared to the sham group, particularly in the right hemisphere, but no significant changes were noted in the white matter. Conclusion and implications: The observed results following mPFC injury indicated an association between cortical damage, hippocampal plasticity, and cognitive dysfunction, consequently identifying hippocampal plasticity as a potential target for future therapeutic strategies aimed at improving post-stroke cognitive recovery.
Background and purpose: Leishmaniasis is a parasitic disease prevalent in subtropical and tropical regions, with limited and often toxic treatments ineffective against drug-resistant strains. This study explored 1,013 compounds from algae and corals for potential anti-leishmanial effects. Experimental approach: Three-dimensional structures of Leishmania major proteins, zinc leishmanolysin glycoprotein 63 (GP63), farnesyl diphosphate synthase (FPPS), and N-myristoyltransferase (NMT), as well as 389 coral compounds and 624 algal compounds, were obtained from the PubChem database. Molecular docking analysis was performed using PyRx and AutoDock Vina software for each of the three Leishmania proteins with individual protein-ligand combinations. The properties, including activity, daily carcinogenicity, and absorption, distribution, metabolism, excretion, and toxicity (ADMET), were predicted using SwissADME, Lazar, and Way2Drug tools. Using the GROMACS program, coral and algal compounds with the highest binding scores for each protein were selected for molecular dynamics (MD) simulations. Findings/Results: Alga-utd-01 and Coral-utd-01 exhibited strong affinity for the GP63. Additionally, Alga-utd-05 and Coral-utd-02 showed the highest binding affinity to FPPS, while the top compounds for NMT were Alga-utd-14 and Coral-utd-03. Moreover, Alga-utd-05, Alga-utd-22, and Alga-utd-16 were common algal compounds interacting with all three proteins, and Coral-utd-01, Coral-utd-02, Coral-utd-03, Coral-utd-06, and Coral-utd-12 were common coral compounds. The MD results confirmed relatively stable interactions between the proposed compounds and the three important Leishmania proteins. Conclusion and implications: The algae- and coral-derived compounds exhibited promising anti-parasitic and anti-inflammatory properties, warranting further experimental validation for leishmaniasis treatment.
Background and purpose: Colorectal cancer, a leading cause of mortality, is treated with surgery early and irinotecan (IRI) chemotherapy in advanced stages. Insulin-like growth factor-binding protein 3 (IGFBP-3), regulated by p53, mediates tumor suppression and apoptosis. This study evaluates the combined therapeutic effects of IGFBP-3 and IRI in colorectal cancer. Experimental approach: SW480 colorectal cancer cells were treated with IGFBP-3, IRI, and their combination; IC 50 values were determined by MTT assay, and combination effects were analyzed by CompuSyn. Oxidative stress markers, apoptosis, and cell cycle progression were assessed utilizing flow cytometry. Furthermore, caspase 3/7 activity was measured, and expression levels of Bax, Bcl2 , and β-catenin were determined using RT-PCR. Findings/Results: The MTT assay revealed IC 50 of 8.4 μM for IRI and 43.03 nM for IGFBP-3, with CompuSyn confirming synergistic interaction (CI < 1). Compared to single agents, the combination treatment significantly enhanced apoptosis, induced greater G 2 /M cell cycle arrest, and markedly increased levels of ROS, MDA, and protein carbonyls while significantly depleting GSH. At the molecular level, the combination synergistically upregulated pro-apoptotic Bax and downregulated anti-apoptotic Bcl2 and oncogenic β-catenin . Conclusion and implications: Our results indicated that IRI and IGFBP-3 show cytotoxicity, with IGFBP-3 enhancing IRI effect by inhibiting Wnt/β-catenin and increasing drug uptake, warranting assessment in normal cells.
Background and purpose: Natural products are valuable sources of anticancer agents. This study investigated the phytochemical composition of Diarthron lessertii shoot extract and evaluated the anticancer potential of its isolated phenolic constituents. Experimental approach: Phenolic compounds were isolated using chromatographic techniques and identified by one- and two-dimensional NMR spectroscopy and ESI-MS analysis. Cytotoxicity against HeLa cervical cancer cells was assessed using the MTT assay. A luciferase reporter assay evaluated the effect of the most active compound on FOXO3a was examined through molecular docking. Findings/Results: Nine phenolic compounds were isolated and characterized from D. lessertii , including two lignans (epinortrachelogenin and isolariciresinol), one biflavonoid (stelleranol), one bicoumarin (daphnoretin), and five flavonoids (genkwanin, apigenin 7,4’-dimethyl ether, naringenin, apigenin, and dihydrokaempferol). Among the isolated compounds, epinortrachelogenin (compound 1 ) showed the strongest cytotoxic activity against HeLa cells, with an IC 50 value of 80.37 ± 4.72 μM. In luciferase assays, compound 1 selectively activated FOXO3a, reaching 2274 relative luminescence units at 100 pM. Molecular docking further supported these findings, revealing favorable binding of compound 1 within the FOXO3a binding pocket. Conclusion and implications: Epinortrachelogenin exhibited notable cytotoxicity and selective FOXO3a activation, supported by docking analysis. These findings identify this lignan as a promising lead compound for the development of FOXO3a-targeted anticancer agents.
Background and purpose: Cisplatin, a widely used anticancer agent, has adverse effects on normal tissues during cancer treatment. This study aimed to investigate the use of harmine, a plant β-carboline alkaloid, against pathways associated with ROS-induced apoptosis in the livers of mice administered with cisplatin. Experimental approach: Twenty-four male Balb/c mice were randomly assigned to four groups (n = 6): (1) control group received daily intraperitoneal injections of saline for four days, (2) harmine group (15 mg/kg, intraperitoneally, daily for 4 days), (3) cisplatin group (5.5 mg/kg, intraperitoneally, one injection), and (4) cisplatin + harmine co-administration group. After sacrificing the animals under deep anesthesia, blood and liver tissue samples were collected for biochemical and molecular experiments. Findings/Results: Cisplatin significantly elevated histopathological criteria (both qualitative and quantitative), levels of enzyme activity, malondialdehyde, nitric oxide, ROS, and apoptosis, and decreased glutathione, superoxide dismutase, and total antioxidant capacity. However, these factors were improved in the co-administration group compared to the cisplatin group. Furthermore, cisplatin treatment significantly upregulated caspase-8, BAX, p53, caspase-3, TNF-α , and NF-κB gene expression, while downregulating BCL-2 . Co-administration with harmine led to significant changes in gene expression relative to the cisplatin group. Cisplatin notably increased protein levels of caspase-8, BAX, and TNF-α, but these levels were significantly reduced in the co-treatment group. Conclusion and implications: Harmine effectively ameliorates cisplatin-induced hepatitis by suppressing ROS production, thereby reducing intrinsic, extrinsic, and inflammation-induced apoptosis. These findings suggest that the antioxidant and anti-inflammatory properties of Harmine play a key role in its hepatoprotective actions.
Background and purpose: Breast cancer remains the most commonly diagnosed cancer and the leading cause of cancer-related death among women worldwide. Estrogen receptor alpha (ERα) plays a major role in breast cancer cell proliferation, and approximately 70-80% of breast cancer cases are classified as Erα-positive. This study aims to predict the pinostrobin pentanoate potential against ERα by docking and molecular dynamics, and determine its cytotoxic activity against T47D breast cancer cells and normal cells. Experimental approach: Docking was analyzed using MOE 2022.02. Furthermore, AMBER 20 was used for molecular dynamics. Cytotoxicity was assessed using the MTT assay against T47D breast cancer cells and Vero cells for its selectivity index (SI). Findings/Results: Based on docking results, the binding free energy of pinostrobin pentanoate (-7.682 ± 0.145 kcal/mol) was lower compared to pinostrobin (-6.503 ± 0.153 kcal/mol) against ERα, indicating the stronger binding affinity. In addition, the stability interaction using 100 ns molecular dynamics showed a stable interaction. Moreover, the IC 50 values of pinostrobin and pinostrobin pentanoate against T47D cells were 160 ± 5.30 μM and 32 ± 3.64 μM, respectively, compared to doxorubicin 0.14 ± 0.04 μM. Meanwhile, the CC 50 values of pinostrobin and pinostrobin pentanoate from the cytotoxicity test on Vero cells were estimated to be > 2500 and > 1500 μM, respectively. Therefore, the SI value of pinostrobin (SI > 15.6) is estimated to be smaller than that of pinostrobin pentanoate (SI > 46.8). Additionally, the combination of pinostrobin pentanoate and doxorubicin showed synergistic efficacy. Conclusion and implications: Pinostrobin pentanoate is more selective than pinostrobin, and it can be used as an anti-breast cancer candidate against the ERα for further research.
Background and purpose: Natural compounds combined with human adipose-derived stem cell (hADSCs) transplantation could be considered an effective treatment for multiple sclerosis (MS). In the present study, the effects of bromelain administration in combination with hADSCs transplantation were evaluated for oligodendrocyte differentiation, myelin tissue regeneration, and improvement of motor function. Experimental approach: After inducing an MS mouse model, the mice were randomly divided into 4 groups: MS, MS + bromelain, MS + stem cell, and MS + bromelain + stem cell. Besides, 16 mice were designated for the control and sham groups. Finally, the behavioral test is used to evaluate motor function and motor defects. Furthermore, immunofluorescent staining was used to evaluate the cell markers. The serum levels of IgG, as well as inflammatory and anti-inflammatory factors, were assessed using an ELISA test. Findings/Results: The mean percentages of Olig2- and Mog-positive cells, myelin density, and the serum levels of IL-10 and TGF-β were significantly higher in the treated groups than in the MS group. However, the serum levels of IL-17 and IFN-γ in the MS group were significantly higher compared to the other groups. Also, the serum level of IgG in the MS group was significantly higher than in the other groups. Conclusion and implications: It can be said that hADSCs transplantation, along with bromelain administration, is able to increase myelination and improve balance function. Therefore, the use of these agents could be a fundamental step towards finding a suitable method for the treatment of neurodegenerative diseases.
Background and purpose: Elephantopus mollis Kunth. (EM) is an attractive candidate for cancer treatment research due to its long history of use in traditional cancer remedies. As lung cancer is the most widespread and among the most lethal carcinomas, we assessed the toxicity and anti-metastatic ability of EM extracts on the lung cancer NCI-H1299 cells. Experimental approach: The cytotoxicity of EM extracts was evaluated via the MTT assay. Phytopolyphenol constituents of the potent extract were evaluated by HPLC. The underlying mechanisms of this toxicity were scrutinized by cellular and nuclear morphologies, cleaved caspase-3/8/9 staining, senescence-associated beta-galactosidase activity, and gene expression analysis. The scratch, invasion, adhesion assays, and RT-qPCR were employed for the anti-metastasis study. Findings/Results: The ethyl acetate fraction (EMEA) was the most potent extract against NCI-H1299 cells, with a low IC 50 and an impressive selective effect. Most attractively, this is the very first study showing that EMEA induced both apoptosis and senescence in a cancer cell line. The underlying mechanisms involved the extrinsic apoptotic pathway, DNA damage, p21-dependent cell-cycle arrest, and oxidative stress response. EMEA could also strongly inhibit the migration, invasion, and collagen I adhesion abilities of NCI-H1299 cells. This might stem from the reduction of two crucial metastatic MMP2 and VIM genes. As interesting as the cytotoxic findings, this is among the surprisingly sparse studies on the anti-metastasis activity of EM extracts and compounds. Conclusion and implications: Our research contributed considerably to the knowledge of anticancer properties of EM and cemented its role as a promising source for novel cancer treatment therapies.
Background and purpose: Metabotropic glutamate receptors are class C G-protein-coupled receptors that respond to the neurotransmitter glutamate. In particular, metabotropic glutamate receptor 5 (mGluR5) has been a valuable drug target for the management of psychiatric and neurodegenerative disorders such as fragile X syndrome, autism, depression, anxiety, addiction, and movement disorders through negative allosteric modulators (NAMs). Despite the discovery of several NAMs, limited clinical efficacy was observed, thus preventing them from reaching the clinical stage. Natural products are indispensable, with a plethora of pharmacological actions. This study aimed to identify potential natural compounds as novel natural NAMs modulating mGluR5 using a comprehensive in silico approach. Experimental approach: Utilizing receptor-based pharmacophore modelling, we virtually screened a natural library comprised of ~1.2 million compounds to study their molecular binding behavior against mGluR5. Furthermore, the best hits were evaluated using the end-point method (molecular mechanics Poisson-Boltzmann surface area), molecular dynamics (MD) simulations, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling. Findings/Results: Based on the augmented computational modelling, we identified four promising natural hits-3’-HPS, gigantol, isorhapontigenin, and coclaurine that demonstrated higher affinities than the standard clinical candidate 2-methyl-6-phenylethynyl-pyridine (MPEP), and co-crystal 2-[2-(3-methoxyphenyl)ethynyl]-6-methyl-pyridine (M-MPEP). The top selected hits demonstrated optimal binding energies, molecular interactions, and favorable ADMET properties with a few toxicity liabilities, warranting further lead optimization and experimental validations. MD simulations validated their structural stability through RMSD, RMSF, and principal component analysis. Conclusion and implications: Our findings provided compelling evidence for a structure-based drug design approach in developing potent small-molecule natural modulators for the treatment of neurodegenerative disorders.
Background and purpose: Monoclonal antibodies (MAbs) have revolutionized cancer treatment but are associated with a spectrum of adverse events, including neurological complications. Understanding the mechanism and management of complications is crucial for optimizing patient care. The present systematic review aimed to identify case reports of MAbs used for cancer treatment that resulted in aseptic meningitis (AM). Methods: Databases including Google Scholar, PubMed, and Scopus were searched for studies published until March 2024 (updated in May 2025). The Joanna Briggs Institute (JBI) critical appraisal checklist was used to assess the quality of case report studies, and the methodological quality of the included studies was considered acceptable. Findings/Results: In total, 32 articles were analyzed in the present systematic review. Cetuximab had the highest reported incidence of AM, while rituximab, daratumumab, and apolizumab had the lowest prevalence. The quality of the studies was also acceptable. Conclusion and implications: AM appears to occur more frequently with monoclonal antibodies than with conventional drug structures. Prompt recognition of the underlying mechanisms can help physicians manage these complications more effectively.
Background and purpose:Colorectal cancer (CRC) is a significant global health challenge, necessitating a comprehensive molecular understanding for personalized treatments. Molecular profiling has elucidated key biomarkers that are essential for prognosis, treatment responsiveness, and targeted therapeutic interventions.Experimental approach:This study explored the role of indigenous phytochemicals, using bioinformatics and experimental assays to identify potential CRC-specific therapeutic targets.Findings/Results:A system biology and drug-target network analysis identified four proteins (ANG, DPP4, INSR, and MAPK14) as potential targets for further investigation. Molecular docking studies showed that the cauferoside from Ferula gummosa has a strong binding affinity for these proteins. Molecular dynamics simulations confirmed the stability of the compound-protein complexes. In vitro assays demonstrated the cytotoxic effects of F. gummosa extracts on CRC cells. The leaf extract significantly downregulated the expression of the ANG, DPP4, INSR, and MAPK14 genes, while the root extract exhibited differential effects on gene expression.Conclusion and implications:The findings suggest the potential therapeutic efficacy of F. gummosa against CRC and emphasize the importance of a dual methodology involving bioinformatics and experimental validation in drug discovery. Further in vivo and clinical studies are warranted to validate these findings and facilitate potential therapeutic applications.
Background and purpose: The use of a bispecific antibody engineered as a tandem single-chain fragment variable antibody (scFv-BsAb) offers several advantages over full-length antibodies, including enhanced tissue penetration and the potential for production in bacterial cells. However, production of them in bacteria usually results in the formation of inclusion bodies. The current work aimed to facilitate proper folding and soluble expression of a recombinant scFv-BsAb targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) by co-expression with molecular chaperones. Experimental approach: Escherichia coli BL21(DE3) cells harboring pET28a-scFv-BsAb and pKJE7 plasmids were used as host cells for protein expression. The effect of different temperatures and IPTG concentrations on the expression of soluble protein with or without expression of chaperones was investigated by SDS-PAGE and densitometry analysis. Subsequently, the expressed protein was subjected to native purification using a Ni-NTA affinity column. Then, the binding ability of the scFv-BsAb to the receptors on peripheral blood mononuclear cells (PBMCs) was evaluated by flow cytometry. Findings/Results: Co-expression with chaperones slightly enhanced the expression of soluble scFv-BsAb. The optimal condition for soluble expression of protein is at a temperature of 30 °C and an IPTG concentration of 1 mM when co-expressed with chaperones. The final yield of protein in co-expression with chaperones was 2.9 mg protein per 1 L of culture. Conclusion and implications: Optimization of culture conditions and co-expression with molecular chaperones may be useful for the production of soluble and functionally bioactive scFv antibodies in E. coli.
Background and purpose: Angiogenesis, regulated by vascular endothelial growth factor receptor 2 (VEGFR-2), has a key role in tumor progression, especially in common cancers, including colorectal and renal cancer. Inhibiting VEGFR-2 is a promising therapeutic approach. This research aimed to design, synthesize, and biologically evaluate new 5-(pyridine-3-yl)-1,3,4-oxadiazole derivatives as potential VEGFR-2 inhibitors. Experimental approach: A new series of derivatives (AM3-AM6) was synthesized through S-alkylation of 5-(pyridin-3-yl)-1,3,4-oxadiazole-2-thiol and hydrazinolysis reactions, followed by condensation with aldehydes. The compounds were analyzed using FT-IR,1H-NMR, and 13C-NMR spectroscopy. Molecular modelling studies, including docking (PDB ID: 4ASD), ADMET prediction, and molecular dynamics (MD) simulations, were performed to evaluate binding affinity, pharmacokinetic properties, and complex stability. Cytotoxicity was assessed via MTT assay against HT-29 (colorectal), ACHN (renal), and L929 (normal) cell lines. Findings/Results: Docking results revealed strong binding to VEGFR-2, with compound AM3 showing the best docking score (ΔG = -11.613 kcal/mol). MD simulations confirmed the high stability of the AM3-VEGFR-2 complex with consistent RMSD values and persistent interactions with GLU885 and ASP1046. In vitro, AM4 exhibited a significant cytotoxic effect against HT-29 cells (IC50 = 38.94 μM), compared to sorafenib (IC50 = 9.73), while all compounds were non-toxic toward L929 cells. Conclusions and implications: In silico and in vitro results demonstrated that the new 5-(pyridine-3-yl)-1,3,4-oxadiazole derivatives possess favorable drug-like properties and selective anti-proliferative activity against colorectal and renal cancer cells. These findings suggest that this scaffold is a valuable starting point for developing novel selective VEGFR-2 inhibitors as anticancer agents.
Background and purpose:The expression of Homo sapiens (has)-miR-16-5p and hsa-miR-34a-5p with anti-tumor effects is downregulated in cancer cells. To maintain these gene expressions in cancer cells, we evaluated the effects of pomegranate seed extract (PSE) and ellagic acid (EA) on hsa-miR-16-5p and hsa-miR- 34a-5p expression, cell cycle regulation, and apoptotic induction in the MCF-7 cells encapsulated in the alginate hydrogel, a 3D culture system.Experimental approach:MCF-7 cells were encapsulated in 3-D alginate scaffolds and cultured (experimental groups: EA, PSE, EA and PSE, and the control group). Cell viability (using MTT assay), cell apoptosis (via flow cytometry), the level of malondialdehyde (MDA), and the expression levels of hsa-miR-16-5p, hsa-miR- 34a-5p, B-cell lymphoma 2 (BCL-2), cyclin D1 (CCND1), and sirtuin 1 (SIRT1) were measured (via real-time PCR).Findings/Results:The combination of PSE and EA exhibited the greatest effects on MCF-7 cells. EA and PSE increased the expression of hsa-miR-16-5p and hsa-miR-34a-5p and decreased the expression of the SIRT1 and CCND1 genes. In addition, the antiapoptotic BCL-2 gene was downregulated in the experimental group. Both antioxidants significantly increased the population of MCF-7 cells in the G1 phase. Additionally, antioxidants reduce the level of MDA in cancer cells.Conclusion and implications:EA and PSE antioxidants increased hsa-miR-16-5p and hsa-miR-34a-5p expression, induced apoptosis, decreased cell proliferation, and stopped cancer cells in the G1 phase. Therefore, they can be considered promising compounds for helping the treatment of breast cancer.
Background and purpose: Insulin-like growth factor-binding protein-3 (IGFBP-3), a tumor suppressor and inhibitor of nuclear factor kappa B (NF-kB), has emerged as a promising candidate for therapeutic application across diverse pathological conditions. Given NF-kB’s role in cervical cancer development and cisplatin resistance, this study examines the effects of recombinant human IGFBP-3 (rhIGFBP-3), alone and in combination with cisplatin, on NF-kB levels, inflammatory modulation, and apoptotic response in HeLa cells, and investigates whether rhIGFBP-3 can reduce the cisplatin dose. Experimental approach: The impact of rhIGFBP-3, alone and in combination with cisplatin, on HeLa cells’ viability was evaluated by assessing cell viability (MTT assay); apoptosis (cell cycle analysis, TUNEL, annexin V/PI staining, Bax/Bcl-2 ratio, caspase activity); and NF-kB p65 levels (western blot). Gene expression of inflammatory cytokines and enzymes (IL-6, IL-8, COX-2, iNOS) was analyzed by RT-PCR. Findings/Results: Cisplatin and rhIGFBP-3 inhibited HeLa cell growth in a concentration-dependent manner (IC50 = 6.06 μg/mL and 1.12 μg/mL, respectively). Their combination exhibited synergistic cytotoxicity (combination index < 1), allowing ~2.1-fold reductions in concentration to 2.53 μg/mL cisplatin and 0.46 μg/mL rhIGFBP-3 for 45% growth inhibition. Compared to monotherapy, the combination significantly enhanced apoptosis and DNA fragmentation, sub-G1 accumulation, caspase-8/9/3/7 activation, and BAX/BCL-2 ratio. It also considerably reduced NF-kB p65 and inflammatory markers in comparison with cisplatin alone. Conclusion and implications: Our study demonstrated that rhIGFBP-3 enhanced cisplatin efficacy by promoting apoptosis and attenuating inflammation, highlighting its potential as both a cisplatin adjuvant and a monotherapy in HeLa cells.
Background and purpose: Cancer represents a significant public health challenge and a leading cause of mortality globally. Quinazolinones represent a class of privileged structures that exhibit a broad spectrum of biological activities such as anticancer, antihypertensive, antifungal, antibacterial, and anti-inflammatory properties. In the present study, the synthesis of quinazoline-quinazolinone hybrids as anticancer agents and their cytotoxic evaluation are reported. Experimental approach: Initial studies were done by molecular docking of five analogs of quinazoline- quinazolinone hybrids, erlotinib, and doxorubicin against the epidermal growth factor receptor. Treatment of 3-amino quinazolinone with 4-chloro-2-phenylquinazoline afforded final compounds by the nucleophilic substitution of the chloride with the amine of 3-amino quinazolinone derivatives. The cytotoxic effects of the final compounds were determined in vitro against the MCF-7 cell line using the MTT assay. Findings/Results: Compound 5b (7-hydroxy-2-methyl-3-(2-phenylquinazolin-4-ylamino) quinazolin-4(3H)- one) showed the highest docking score of -10.1 kcal/mol. Additionally, compound 5d (2-methyl-7-nitro-3-(2- phenylquinazolin-4-ylamino) quinazolin-4(3H)-one) exhibited remarkable in-vitro cytotoxic activity at 100 μM against the MCF-7 cells. Conclusion and implications: In the present study, quinazoline-quinazolinone hybrids were synthesized, and their cytotoxic effects on the MCF-7 cell line were evaluated. Among them, compound 5d exhibited the most significant cytotoxic activity. The insertion of a nitro group at the 7 position of quinazolinone enhanced the cytotoxic efficacy against MCF-7 cells, likely attributable to electronic influences. Consequently, this compound could serve as a lead compound in the search for new classes of effective anticancer agents.
Background and purpose: Non-alcoholic fatty liver disease (NAFLD) is the most common liver-related metabolic disorder worldwide, affecting approximately 25% of the global population. Peroxisome proliferator-activated receptor (PPAR) agonists play an important role in NAFLD management through modulation of lipid metabolism and insulin sensitivity. This study compared the effects of fenofibrate (PPARα agonist), pioglitazone (PPARγ agonist), and saroglitazar (dual PPARα/γ agonist) in a high-fat diet (HFD)-induced NAFLD rat model. Experimental approach: NAFLD was induced in Wistar rats by feeding a high-fat diet. Animals were assigned to control, HFD, and HFD-treated groups receiving saroglitazar (3 mg/kg), pioglitazone (30 mg/kg), or fenofibrate (100 mg/kg) for six weeks. Anthropometric parameters, serum liver enzymes, lipid profile, fasting blood glucose, and HOMA-IR were assessed. Histopathological changes were evaluated using H&E and Masson’s trichrome staining. Hepatic expression of FGF21, CPT-1, PPARa, SREBP-1c, and ACC was analyzed by quantitative RT-PCR. Findings/Results: All three PPAR agonists significantly improved hepatic steatosis, inflammation, and fibrosis compared with the HFD group, despite variability in biochemical and metabolic parameters. Among the treatments, saroglitazar demonstrated the most pronounced histological improvement, although systemic metabolic improvements were comparable among all three agents. Conclusion and implications: Fenofibrate, pioglitazone, and saroglitazar exert beneficial effects on NAFLD progression through partially distinct mechanisms. Dual PPARα/γ activation appears to preferentially enhance hepatic histological outcomes, supporting the therapeutic relevance of saroglitazar in NAFLD.
Background and purpose: A seizure is a neurological disorder in the brain that is caused by changes in the function of brain neurons. Caffeic acid phenetyl ester (CAPE), as a polyphenol, has antioxidant, antiinflammatory, and anticancer effects. Since the effects of CAPE on the neurotoxins and neurotoxic medicinal agents have not been widely investigated, this study aimed to investigate the effect of CAPE on the nicotine (NIC)-induced seizures in mice. Experimental approach: Thirty-three male mice were divided into five groups of 6-8 as follows: sham group (normal saline), NIC group (5 mg/kg single dose on day 7), treatment groups (CAPE at 4 and 8 mg/kg for 7 days), and diazepam group (1 mg/kg single dose on day 7). At the end, the animals were anesthetized, and mortality, convulsive behavior, total thiol, thiobarbituric acid reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and the expression of nuclear factor kappa B (NF-kB) protein in the brain frontal cortex were measured, and histological studies were performed. Findings/Results: Treatment with CAPE decreased the levels of TBARS, TNF-α, and NO and increased the levels of total thiol, CAT, SOD, GPx, and NF-kB protein expression compared to the NIC group. Seizure behavioral tests and histopathological investigations confirmed these results. Conclusion and implications: According to the antioxidant effects of CAPE in various studies, it seems that CAPE can improve seizures by reducing inflammation and inhibiting oxidative stress.
Background and purpose: Targeting senescent tumor cells with senotherapeutic agents represents a novel therapeutic strategy in overcoming chemotherapy resistance during 5-fluorouracil (5-FU) treatment of colorectal cancer (CRC). This study aimed to evaluate the senotherapeutic potential of thymoquinone (TQ) and pentoxifylline (PTX) in a 3D spheroid model of CRC subjected to 5-FU-induced senescence. Experimental approach: Caco-2 spheroids were generated via the hanging drop method on Poly-HEMA-coated plates with conditioned medium derived from HFF cells. Spheroids were treated for 24 h with 5-FU (60 μΜ; 50% of IC50), TQ (30 μΜ; 50% of IC50), and PTX (3.5 mM; 50% of IC50). Cell viability was measured using the MTT assay. ROS and IL-8 levels were measured. Cell death and apoptosis were evaluated using Calcein-AM and Annexin V/PI assays, and western blotting was used to assess the expression of SASP and apoptosis-associated proteins. β-galactosidase activity was measured as a marker of senescence. Findings/Results: 5-FU effectively induced senescence and apoptosis in Caco-2 spheroids, as evidenced by an increased expression of p53, p16, p21, and γ-H2AX, as well as an elevated secretion of ROS. Co-treatment with TQ and PTX acted as senotherapeutic agents by enhancing apoptotic cell death through modulation of Bax/Bcl2/cleaved caspase-3 and β-galactosidase activity, and by increasing oxidative stress. Notably, the combination of TQ and PTX was shown to support a greater senotherapeutic effect. Conclusion and implications: Findings indicated that TQ and PTX acted as senotherapeutic agents in 5-FU-induced senescent CRC spheroids and may have potential as adjuvants to enhance CRC therapy.
