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The aim of this work is to develop and evaluate self-nanoemulsifying drug delivery systems (SNEDDS) containing simvastatin to increase its oral bioavailability. Formulation EO 5 (Ethyl oleate 9.3% w/w: Tween 80 49.4% w/w: Propylene glycol 39.3% w/w) and Formulation CL 14 (Clove oil 54.3% w/w: Tween 80 34.4% w/w: Transcutol-P 9.3% w/w) were thoroughly studied. They showed emulsification time less than 1 min, droplet size in the nanometric range, and almost a complete drug release after 2 h. The in-vitro dissolution profile of both formulations was found to be significant in comparison to the pure drug in pH 1.2 and 7.4 buffers (P < 0.0001). Furthermore, they demonstrated superior anti-hyperlipidemic activity in comparison to simvastatin suspension (10 mg/kg/day). In order to investigate the impact of oil type on oral bioavailability, the selected formulations have been examined in terms of the in-vivo pharmacokinetic study, and formulation EO 5 was found to have higher bioavailability. After oral administration of a single dose (40 mg/kg) of simvastatin-loaded SNEDDS (CL14 and EO 5), a 1.5-fold and 1.95-fold increase in bioavailability were observed, respectively, as compared to simvastatin suspension. Hence, the results indicated that the developed SNEDDS could enhance the therapeutic efficacy and oral bioavailability of simvastatin. [ABSTRACT FROM AUTHOR]

Background: The infamous multidrug-resistant (MDR) bacterium Acinetobacter baumannii is becoming a nightmare in intensive care units across the globe. Since there are now very few effective antimicrobial agents, it is necessary to explore unconventional resources for novel antimicrobials. This study investigated the potential antimicrobial activity of Origanum majorana L. against A. baumannii employing multiple approaches including antimicrobial susceptibility, fractionation, ultra-performance liquid chromatography–high-resolution mass spectrometry (UPLC-HRMS) dereplication, and in silico analysis for target/ligand identification. Results: On the extremely pathogenic MDR strain A. baumannii AB5075, O. majorana L. has shown a significant growth inhibitory effect (MIC = 0.675 mg/mL). The polar 50% methanol fraction was the most active (MIC = 0.5 mg/mL). The UPLC-HRMS dereplication of the bioactive fraction detected 29 metabolites belonging to different chemical classes. Justicidin B, one of the identified metabolites, was projected by preliminary in silico analysis to be the most highly scoring metabolite for binding with molecular targets in A. baumannii with a Fit score = 8.56 for enoyl-ACP reductase (FabI) (PDB ID: 6AHE), suggesting it to be its potential target. Additionally, docking, molecular dynamics simulation, and bioinformatics analysis suggested that this interaction is similar to a well-known FabI inhibitor. The amino acids involved in the interaction are conserved among different MDR A. baumannii strains and the effectiveness could extend to Gram-negative pathogens within the ESKAPE group. Conclusions: Origanum majorana L. extract exhibits antimicrobial activity against A. baumannii using one or more metabolites in its 50% methanol fraction. The characterized active metabolite is hypothesized to be justicidin B which inhibits the growth of A. baumannii AB5075 via targeting its fatty acid synthesis. [ABSTRACT FROM AUTHOR]

Recent advancements in the field of biomedical engineering have underscored the pivotal role of biodegradable materials in addressing the challenges associated with tissue regeneration therapies. The spectrum of biodegradable materials presently encompasses ceramics, polymers, metals, and composites, each offering distinct advantages for the replacement or repair of compromised human tissues. Despite their utility, these biomaterials are not devoid of limitations, with issues such as suboptimal tissue integration, potential cytotoxicity, and mechanical mismatch (stress shielding) emerging as significant concerns. To mitigate these drawbacks, our research collective has embarked on the development of protein-based composite materials, showcasing enhanced biodegradability and biocompatibility. This study is dedicated to the elaboration and characterization of an innovative suture fabricated from human serum albumin through an extrusion methodology. Employing a suite of analytical techniques—namely tensile testing, scanning electron microscopy (SEM), and thermal gravimetric analysis (TGA)—we endeavored to elucidate the physicochemical attributes of the engineered suture. Additionally, the investigation extends to assessing the influence of integrating biodegradable organic modifiers on the suture's mechanical performance. Preliminary tensile testing has delineated the mechanical profile of the Filament Suture (FS), delineating tensile strengths spanning 1.3 to 9.616 MPa and elongation at break percentages ranging from 11.5 to 146.64%. These findings illuminate the mechanical versatility of the suture, hinting at its applicability across a broad spectrum of medical interventions. Subsequent analyses via SEM and TGA are anticipated to further delineate the suture's morphological features and thermal resilience, thereby enriching our comprehension of its overall performance characteristics. Moreover, the investigation delves into the ramifications of incorporating biodegradable organic constituents on the suture's mechanical integrity. Collectively, the study not only sheds light on the mechanical and thermal dynamics of a novel suture material derived from human serum albumin but also explores the prospective enhancements afforded by the amalgamation of biodegradable organic compounds, thereby broadening the horizon for future biomedical applications. [ABSTRACT FROM AUTHOR]

New 3-substituted oxindole derivatives were designed and synthesized as antiproliferative agents. The antiproliferative activity of compounds 6a–j was evaluated against 60 NCI cell lines. Among these tested compounds, compounds 6f and 6g showed remarkable antiproliferative activity, specifically against leukemia and breast cancer cell lines. Compound 6f was the most promising antiproliferative agent against MCF-7 (human breast cancer) with an IC50 value of 14.77 µM compared to 5-fluorouracil (5FU) (IC50 = 2.02 µM). Notably, compound 6f hampered receptor tyrosine EGFR fundamentally with an IC50 value of 1.38 µM, compared to the reference sunitinib with an IC50 value of 0.08 µM. Moreover, compound 6f afforded anti-tubulin polymerization activity with an IC50 value of 7.99 µM as an outstanding observable activity compared with the reference combretastatin A4 with an IC50 value of 2.64 µM. In silico molecular-docking results of compound 6f in the ATP-binding site of EGFR agreed with the in vitro results. Besides, the investigation of the physicochemical properties of compound 6f via the egg-boiled method clarified good lipophilicity, GIT absorption, and blood–brain barrier penetration properties. [ABSTRACT FROM AUTHOR]

Phytochemical investigation of Key lime (Citrus aurantifolia L., F. Rutaceae) peels afforded six metabolites, known as methyl isolimonate acetate (1), limonin (2), luteolin (3), 3ˋ-hydroxygenkwanin (4), myricetin (5), and europetin (6). The structures of the isolated compounds were assigned by 1D NMR. In the case of limonin (2), further 1- and 2D NMR experiments were done to further confirm the structure of this most active metabolite. The antiplasmodial properties of the obtained compounds against the pathogenic NF54 strain of Plasmodium falciparum were assessed in vitro. According to antiplasmodial screening, only limonin (2), luteolin (3), and myricetin (5) were effective (IC50 values of 0.2, 3.4, and 5.9 µM, respectively). We explored the antiplasmodial potential of phytochemicals from C. aurantifolia peels using a stepwise in silico-based analysis. We first identified the unique proteins of P. falciparum that have no homolog in the human proteome, and then performed inverse docking, ΔGBinding calculation, and molecular dynamics simulation to predict the binding affinity and stability of the isolated compounds with these proteins. We found that limonin (2), luteolin (3), and myricetin (5) could interact with 20S a proteasome, choline kinase, and phosphocholine cytidylyltransferase, respectively, which are important enzymes for the survival and growth of the parasite. According to our findings, phytochemicals from C. aurantifolia peels can be considered as potential leads for the development of new safe and effective antiplasmodial agents. [ABSTRACT FROM AUTHOR]

The current study investigated the scabicidal potential of Egyptian mandarin peel oil (Citrus reticulata Blanco, F. Rutaceae) against sarcoptic mange-in-rabbits. Analysis of the oil's GC–MS identified a total of 20 compounds, accounting for 98.91% of all compounds found. Mandarin peel oil topical application improved all signs of infection, causing a scabicidal effect three days later, whereas in vitro application caused complete mite mortality one day later. In comparison to ivermectin, histopathological analysis showed that the epidermis' inflammatory-infiltration/hyperkeratosis-had disappeared. In addition to TIMP-1, the results of the mRNA gene expression analysis showed upregulation of I-CAM-1-and-KGF and downregulation of ILs-1, 6, 10, VEGF, MMP-9, and MCP-1. The scabies network was constructed and subjected to a comprehensive bioinformatic evaluation. TNF-, IL-1B, and IL-6, the top three hub protein-coding genes, have been identified as key therapeutic targets for scabies. From molecular docking data, compounds 15 and 16 acquired sufficient affinity towards the three screened proteins, particularly both possessing higher affinity towards the IL-6 receptor. Interestingly, it achieved a higher binding energy score than the ligand of the docked protein rather than displaying proper binding interactions like those of the ligand. Meanwhile, geraniol (15) showed the highest affinity towards the GST protein, suggesting its contribution to the acaricidal effect of the extract. The subsequent, MD simulations revealed that geraniol can achieve stable binding inside the binding site of both GST and IL-6. Our findings collectively revealed the scabicidal ability of mandarin peel extract for the first time, paving the way for an efficient, economical, and environmentally friendly herbal alternative for treating rabbits with Sarcoptes mange. [ABSTRACT FROM AUTHOR]

Introduction: One of the most robust global challenges and difficulties in the 21st century is cancer. Treating cancer is a goal which continues to motivate researchers to innovate in design and development of new treatments to help battle the disease. Objectives: Our objective was developing new antiapoptotic hybrids based on biologically active heterocyclic motifs "benzimidazole?oxadiazole-chalcone hybrids'' that had shown promising ability to inhibit EGFR and induce apoptosis. We expected these scaffolds to display anticancer activity via inhibition of BRAF, EGFR, and Bcl-2 and induction of apoptosis through activation of caspases. Methods: The new hybrids 7a-x were evaluated for their anti-proliferative, EGFR & BRAFV600E inhibitory, and apoptosis induction activities were detected. Docking study & dynamic stimulation into EGFR and BRAFV600E were studied. Results: All hybrids exhibited remarkable cell growth inhibition on the four tested cell lines with IC50 ranging from 0.95 μM to 12.50 μM. which was comparable to Doxorubicin. Compounds 7k-m had the most potent EGFR inhibitory activity. While, compounds 7e, 7g, 7k and 7l showed good inhibitory activities against BRAFV600E. Furthermore, Compounds 7k, 7l, and 7m increased Caspases 3,8 & 9, Cytochrome C and Bax levels and decreased Bcl-2 protein levels. Compounds 7k-m received the best binding scores and showed binding modes that were almost identical to each other and comparable with that of the co-crystalized Erlotinib in EGFR and BRAF active sites. Conclusion: Compounds 7k-m could be used as potential apoptotic anti-proliferative agents upon further optimization. [ABSTRACT FROM AUTHOR]

The present study was designed to evaluate the potential renoprotective impacts of apocynin (APC) against nephrotoxicity induced by methotrexate (MTX) administration. To fulfill this aim, rats were allocated into four groups: control; APC (100 mg/kg/day; orally); MTX (20 mg/kg; single intraperitoneal dose at the end of the 5th day of the experiment); and APC +MTX (APC was given orally for 5 days before and 5 days after induction of renal toxicity by MTX). On the 11th day, samples were collected to estimate kidney function biomarkers, oxidative stress, pro-inflammatory cytokines, and other molecular targets. Compared to the MTX control group, treatment with APC significantly decreased urea, creatinine, and KIM-1 levels and improved kidney histological alterations. Furthermore, APC restored oxidant/antioxidant balance, as evidenced by a remarkable alleviation of MDA, GSH, SOD, and MPO levels. Additionally, the iNOS, NO, p-NF-κB-p65, Ace-NF-κB-p65, TLR4, p-p38-MAPK, p-JAK1, and p-STAT-3 expressions were reduced, while the IκBα, PPAR-γ, SIRT1, and FOXO3 expressions were significantly increased. In NRK-52E cells, MTX-induced cytotoxicity was protected by APC in a concentration-dependent manner. In addition, increased expression of p-STAT-3 and p-JAK1/2 levels were reduced in MTX-treated NRK-52E cells by APC. The in vitro experiments revealed that APC-protected MTX-mediated renal tubular epithelial cells were damaged by inhibiting the JAK/STAT3 pathway. Besides, our in vivo and in vitro results were confirmed by predicting computational pharmacology results using molecular docking and network pharmacology analysis. In conclusion, our findings proved that APC could be a good candidate for MTX-induced renal damage due to its strong antioxidative and anti-inflammatory bioactivities. [ABSTRACT FROM AUTHOR]

In this study, we utilized pomegranate peel and marine algae Ulva lactuca (U. lactuca) as rich and sustained sources of bioactive compounds to combat tomato-black spot disease. n-Hexane extracts from the peel of pomegranate (Punica granatum) (PPE) and the marine algal biomass U. lactuca (ULE) were used alone and in combinations to verify their impact against Alternaria alternata (A. alternata). The applied extracts exhibited severe destructive effects on both fungal growth and structure such as mycelia malformation, underdeveloped conidia, cell wall deformation, and shrinkage. Moreover, increased deformations and protrusions, and notch-like structures, were noticed in A. alternata mycelia treated with mixed extracts (PPE and ULE) compared to all other treatments. The protein and reduced sugar contents in tomato fruits were significantly increased in the infected fruits with A. alternata. The highest enzyme activities of pectinase, cellulase, catalase (CAT), and ascorbate peroxidase (APX) were recorded in infected tomatoes in comparison with the healthy ones. Molecular docking studies showed that each extract is rich with bioactive compounds that have a promising inhibition effect on A. alternata cellulases. Pomegranate and Ulva extract showed promising antifungal activity against A. alternata which revealed their feasibility and applicability as biocontrol agents in postharvest disease management and food preservation against fungal pathogens. [ABSTRACT FROM AUTHOR]

Chemotherapeutic drugs are used effectively to manage wide types of malignancies, but their therapeutic use is limited due to their associated hepatic intoxication. The current study sheds light on the effect of phytochemicals berberine (BBR) and umbelliferone (UMB) on methotrexate (MTX)–induced hepatic intoxication. Forty-eight rats were allocated to normal, BBR (50 mg/kg orally for 10 days), UMB (30 mg/kg orally for 10 days), MTX (20 mg/kg at the 5th day), BBR+MTX, and UMB+MTX. With regard to MTX, the results of this investigation reveal potent amelioration of MTX hepatotoxicity by BBR and UMB through reduction of the elevated serum levels of ALT, ALP, AST, and LDH confirmed by the attenuation of histopathological abrasion in liver tissues. BBR and UMB markedly restored antioxidant status. More importantly, BBR resulted in reducing P38 mitogen–activated protein kinase (P38MAPK), nuclear factor kappa-B (NF-κB), and Kelch-like ECH-associated protein 1 (Keap-1) genes and enhanced mRNA expression of Nrf-2 (P < 0.05). Interestingly, in silico studies via molecular docking pinpointed the binding modes of BBR and UMB to the binding pocket residues of P38MAPK, NF-κB, and Keap-1 and demonstrated a promising inhibition of Keap-1, P38MAPK, and NF-κB. BBR and UMB reduced the expression of pro-apoptotic protein Bax and apoptotic protein caspase-3 as well as increased the expression of anti-apoptotic protein Bcl-2. Therefore, BBR and UMB may denote promising therapeutic agents that can avert hepatic intoxication in patients receiving MTX. [ABSTRACT FROM AUTHOR]

Fungal endophytes are a major source of anti-infective agents and other medically relevant compounds. However, their classical blinded-chemical investigation is a challenging process due to their highly complex chemical makeup. Thus, utilizing cheminformatics tools such as metabolomics and computer-aided modelling is of great help deal with such complexity and select the most probable bioactive candidates. In the present study, we have explored the fungal endophytes associated with the well-known antimalarial medicinal plant Artemisia annua for their production of further antimalarial agents. Based on the preliminary antimalarial screening of these endophytes and using LC-HRMS-based metabolomics and multivariate analyses, we suggested different potentially active metabolites (compounds 1–8). Further in silico investigation using the neural-network-based prediction software PASS led to the selection of a group of quinone derivatives (compounds 1–5) as the most possible active hits. Subsequent in vitro validation revealed emodin (1) and physcion (2) to be potent antimalarial candidates with IC50 values of 0.9 and 1.9 µM, respectively. Our approach in the present investigation therefore can be applied as a preliminary evaluation step in the natural products drug discovery, which in turn can facilitate the isolation of selected metabolites notably the biologically active ones. [ABSTRACT FROM AUTHOR]

In this paper we are interested in studying the effect of the fractional-order damping in the forced Duffing oscillator before and after applying a discretization process to it. Fixed points and their stability are discussed for the discrete system obtained. Finally, numerical simulations using Matlab are carried out to investigate the dynamic behavior such as bifurcation, chaos, and chaotic attractors. We note that on increasing the value of the fractional-order parameter, the resulting discrete system is stabilized. [ABSTRACT FROM AUTHOR]

Study design:Review article.Objectives:To provide an overview of free radical biology, particularly with respect to muscle physiology, as well as the potential effects of muscle morphological changes, physical capacity and nutritional status on oxidative stress in people with chronic spinal cord injury (SCI). The potential implications of these factors for determining the optimal dosage of rehabilitation training interventions in people with chronic SCI will also be presented.Setting:Vancouver, BC, Canada.Methods:Literature review.Results:Not applicable.Conclusion:There has been a great deal of focus on rehabilitation exercise interventions providing intensive practice of movements to enhance functional recovery and physical capacity following SCI. However, there is still much to be understood about the appropriate dosage of training parameters (e.g. frequency, duration). It has been known for several decades that exercise increases free radical production, leading to oxidative stress. To date, there has been little consideration of the potential interaction of oxidative stress with training parameters on functional outcomes in chronic SCI. Furthermore, individuals with chronic SCI face many secondary consequences of their injury, such as muscle atrophy, change in muscle fiber type, general deconditioning and nutritional status, that are known to influence free radical production and antioxidant capacity. Better understanding of the potential confounding effects of oxidative stress associated with exercise will improve our ability to determine the optimal 'dose' of rehabilitation training to maximize functional recovery following SCI. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the efficacy of the chemokine CCL19 (ELC) as an adjuvant for intradermal gene gun delivery of Her2/neu DNA and to investigate the role of B cells in CCL19-mediated enhancement of immune responses. Balb/c mice were immunized intramuscularly (i.m.) on days 1 and 15 with plasmid DNA (pDNA) (100 μg DNA) or intradermally (i.d.) by gene gun delivery (1-2 μg DNA). Administration of pDNA encoding Her2/neu (pDNA(Her2/neu) was compared with pDNA(Her2/neu) plus pDNA(CCL19), pDNA(CCL19), mock vector or uncoated gold particles/phosphate-buffered saline (PBS). Tumor challenge was performed subcutaneously on day 25 with syngeneic Her2/neu+ tumor cells (D2F2/E2). Intradermal immunization by gene gun led to an enhancement of tumor protection by the DNA vaccine as compared with i.m. immunization. The protective effect of the vaccine was further enhanced by coadministration of pDNA(CCL19) both after i.m. and i.d. immunization. Tumor protection was associated with Her2/neu-specific T cell and humoral immune responses. Experiments in B-cell-deficient μMT mice showed that B cells are crucial for CCL19-mediated enhancement of tumor rejection, most likely as antigen-presenting B cells. DNA vaccines against Her2/neu may play a future role in the treatment of Her2/neu-positive breast cancer patients in a clinical situation of minimal residual disease. [ABSTRACT FROM AUTHOR]

Secondary lymphoid-tissue chemokine (SLC/CCL21) is a CC chemokine that is constitutively expressed in various lymphoid tissues and binds to chemokine receptor CCR7 on mature dendritic cells (DCs) and distinct T-and B-cell sub-populations. In vivo, CCL21 regulates the encounters between DC and T cells and thus is a key regulator of adaptive immune responses. We asked whether CCL21 is able to augment immunogenicity of a DNA-based vaccine against Her2/neu in a Balb/c mouse model with syngeneic Her2/neu+ tumor cells (D2F2/E2). Mice were vaccinated intramuscularly with plasmid DNA (pDNA) on day 1 and boosted on day 15; tumor challenge was performed subcutaneously on day 25. Coexpression of CCL21 and Her-2/neu resulted in induction of a TH1-polarized immune response and substantial improvement of the protective effect of the DNA vaccine. Coexpression of tumor antigen pDNA(Her2/neu) with both pDNA(GM-CSF) and pDNA(CCL21) as adjuvants led to further improvement of protection by the vaccine (70% tumor-free mice on day 35 vs 40% with either adjuvant alone vs 5-10% with tumor antigen alone). Our results show that CCL21 is a potent adjuvant for DNA vaccination, particularly in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). Clinical use of a pDNA(Her2/neu/CCL21/GM-CSF) vaccine might be particularly promising in minimal residual Her2/neu+ breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: To study the value of pretreatment testing of P53 overexpression in selection of candidates for pelvic lymphadenectomy in clinical stage I endometrial carcinoma. Patients and methods: This prospective randomized clinical study included 38 patients with histologically confirmed endometrial carcinoma and staged clinically as stage I. Immunohistochemical staining of the tumor specimens obtained by dilatation and curettage with P53 monoclonal antibodies was done. The patients were randomized into two groups according to the planned surgical treatment: hysterectomy group and hysterectomy plus pelvic lymphadenectomy group. Results: There was no significant difference in mean age, parity, medical status, surgical stage, histologic types, grade of differentiation, and myometrial invasion between the two groups. The survival rate in the hysterectomy group in our study was 82.4% and the recurrence rate was 17.6%, while in hysterectomy and lymphadenectomy group the survival rate was 81.0% and the recurrence rate was 19%. Adding pelvic lymphadenectomy was found to be associated with prolonged recurrence time in the P53-positive patients (24.07 vs. 17.8 months for group A). Conclusion: Pretreatment testing of P53 expression is recommended to help with other prognostic factors in the selection of candidates for pelvic lymphadenectomy in clinical stage I endometrial carcinoma. [ABSTRACT FROM AUTHOR]

Laminar flow and forced convection heat transfer of the time independent non–Newtonian fluid obeying power law stress-strain relation have been investigated numerically in the annular space between two coaxial rotating cylinders. The problem is considered when the inner cylinder rotates about the common axis with constant angular velocity and the outer cylinder is at rest. The viscosity of the fluid and thermal conductivity are assumed to vary with the temperature. The outer surface of the annulus is considered to be adiabatic, while the inner surface has a uniform temperature. The tangential and axial momentum equations and energy equation have been solved iteratively by using a finite difference method. For the steady fully developed flow, the velocity distributions, temperature profiles, the volumetric flow rate, torque and the average Nusselt number have been obtained for different values of the radius ratio and model parameters. [ABSTRACT FROM AUTHOR]

The fractional order evolutionary integral equations have been considered by the first author in [6], the existence, uniqueness and some other properties of the solution have been proved. Here we study the continuation of the solution and its fractional order derivative. Also we study the generality of this problem and prove that the fractional order diffusion problem, the fractional order wave problem and the initial value problem of the equation of evolution are special cases of it. The abstract diffusion-wave problem will be given also as an application. [ABSTRACT FROM AUTHOR]

This study presents a detailed experimental program for reinforced concrete T-beams strengthened in shear with near-surface mounted (NSM) basalt fiber-reinforced polymer (BFRP) bars. This paper aims to introduce and evaluate a nonmechanical anchorage technique for shear strengthening using NSM-BFRP bars. T-beams were strengthened using manually manufactured closed or U-shaped hybrid BFRP stirrups (BFRP bars and BFRP sheets). The experimental program was developed to study the effects of these anchorage techniques. The results showed that the shear capacity increased by 8%–46% for beams strengthened with NSM-BFRP bars without anchorage. However, the presence of the proposed anchorage system increased the shear capacity of the strengthened beams by 39.6%–81.6%. Moreover, the maximum strains induced in the BFRP bars ranged from 27 to 59% of their ultimate strains according to the spacing between the NSM and the presence of the anchorage. The proposed anchorage technique prevented the premature debonding of the NSM-BFRP bars. [ABSTRACT FROM AUTHOR]

We investigate the existence and uniqueness of a solution for a Sturm-Liouville fractional differential equation with a multi-point boundary condition via the Caputo derivative; existence and uniqueness results for the given problem are obtained via the Banach fixed point theorem. Also we study its continuous dependence on coefficients of the nonlocal condition. We discuss our results for more general boundary conditions, we present the existence of solutions under nonlocal integral conditions and also extend our results to an ordinary Sturm-Liouville problem. Two examples illustrating the main results are also presented. [ABSTRACT FROM AUTHOR]

Introduction: One of the most robust global challenges and difficulties in the 21st century is cancer. Treating cancer is a goal which continues to motivate researchers to innovate in design and development of new treatments to help battle the disease. Objectives: Our objective was developing new antiapoptotic hybrids based on biologically active heterocyclic motifs "benzimidazole?oxadiazole-chalcone hybrids'' that had shown promising ability to inhibit EGFR and induce apoptosis. We expected these scaffolds to display anticancer activity via inhibition of BRAF, EGFR, and Bcl-2 and induction of apoptosis through activation of caspases. Methods: The new hybrids 7a-x were evaluated for their anti-proliferative, EGFR & BRAFV600E inhibitory, and apoptosis induction activities were detected. Docking study & dynamic stimulation into EGFR and BRAFV600E were studied. Results: All hybrids exhibited remarkable cell growth inhibition on the four tested cell lines with IC50 ranging from 0.95 μM to 12.50 μM. which was comparable to Doxorubicin. Compounds 7k-m had the most potent EGFR inhibitory activity. While, compounds 7e, 7g, 7k and 7l showed good inhibitory activities against BRAFV600E. Furthermore, Compounds 7k, 7l, and 7m increased Caspases 3,8 & 9, Cytochrome C and Bax levels and decreased Bcl-2 protein levels. Compounds 7k-m received the best binding scores and showed binding modes that were almost identical to each other and comparable with that of the co-crystalized Erlotinib in EGFR and BRAF active sites. Conclusion: Compounds 7k-m could be used as potential apoptotic anti-proliferative agents upon further optimization. [ABSTRACT FROM AUTHOR]

Introduction: One of the most robust global challenges and difficulties in the 21st century is cancer. Treating cancer is a goal which continues to motivate researchers to innovate in design and development of new treatments to help battle the disease., Objectives: Our objective was developing new antiapoptotic hybrids based on biologically active heterocyclic motifs "benzimidazole?oxadiazole-chalcone hybrids'' that had shown promising ability to inhibit EGFR and induce apoptosis. We expected these scaffolds to display anticancer activity via inhibition of BRAF, EGFR, and Bcl-2 and induction of apoptosis through activation of caspases., Methods: The new hybrids 7a-x were evaluated for their anti-proliferative, EGFR & BRAF V600E inhibitory, and apoptosis induction activities were detected. Docking study & dynamic stimulation into EGFR and BRAF V600E were studied., Results: All hybrids exhibited remarkable cell growth inhibition on the four tested cell lines with IC 50 ranging from 0.95 μM to 12.50 μM. which was comparable to Doxorubicin. Compounds 7k-m had the most potent EGFR inhibitory activity. While, compounds 7e, 7g, 7k and 7l showed good inhibitory activities against BRAF V600E . Furthermore, Compounds 7k, 7l, and 7m increased Caspases 3,8 & 9, Cytochrome C and Bax levels and decreased Bcl-2 protein levels. Compounds 7k-m received the best binding scores and showed binding modes that were almost identical to each other and comparable with that of the co-crystalized Erlotinib in EGFR and BRAF active sites., Conclusion: Compounds 7k-m could be used as potential apoptotic anti-proliferative agents upon further optimization., (© 2023. Springer Nature Switzerland AG.)