A novel SpaSA based hyper-parameter optimized FCEDN with adaptive CNN classification for skin cancer detection.

Skin cancer is the most prevalent kind of cancer in people. It is estimated that more than 1 million people get skin cancer every year in the world. The effectiveness of the disease's therapy is significantly impacted by early identification of this illness. Preprocessing is the initial detecting stage in enhancing the quality of skin images by removing undesired background noise and objects. This study aims is to compile preprocessing techniques for skin cancer imaging that are currently accessible. Researchers looking into automated skin cancer diagnosis might use this article as an excellent place to start. The fully convolutional encoder-decoder network and Sparrow search algorithm (FCEDN-SpaSA) are proposed in this study for the segmentation of dermoscopic images. The individual wolf method and the ensemble ghosting technique are integrated to generate a neighbour-based search strategy in SpaSA for stressing the correct balance between navigation and exploitation. The classification procedure is accomplished by using an adaptive CNN technique to discriminate between normal skin and malignant skin lesions suggestive of disease. Our method provides classification accuracies comparable to commonly used incremental learning techniques while using less energy, storage space, memory access, and training time (only network updates with new training samples, no network sharing). In a simulation, the segmentation performance of the proposed technique on the ISBI 2017, ISIC 2018, and PH2 datasets reached accuracies of 95.28%, 95.89%, 92.70%, and 98.78%, respectively, on the same dataset and assessed the classification performance. It is accurate 91.67% of the time. The efficiency of the suggested strategy is demonstrated through comparisons with cutting-edge methodologies.

Exploring the potential of Ziziphus nummularia and luteolin-7-O-glucoside as tubulin inhibitors in cancer therapy and survival.

Cancer is responsible for approximately 10 million deaths worldwide, with 70% of the deaths occurring in low- and middle-income countries; as such safer and more effective anti-cancer drugs are required. Therefore, the potential benefits of Ziziphus nummularia and Ziziphus spina-christi as sources of anti-cancer agents were investigated. Z. nummularia and Z. spina-christi extracts were prepared using chloroform, ethanol, ethyl acetate, and water. The extracts' anti-cancer properties were determined using the MTT Cell Viability Assay in four cancer cell lines: breast (KAIMRC2 and MDA-MB-231), colorectal (HCT8), and liver (HepG2). The ApoTox-Glo Triplex Assay and high-content imaging (HCI)-Apoptosis Assay were used to assess KAIMRC2 and HCT8 cells further. In addition, KAIMRC2 cells were tested for microtubule staining, and AKT/mTOR protein expression was determined by western blot analysis. Liquid chromatography-mass spectrometry (LC-MS) was performed to identify the secondary metabolites in the ethanol and ethyl acetate extracts, followed by in silico techniques to predict molecular targets and interactions, safety, and pharmacokinetic profile for identified metabolites. Out of the eight extracts, the ethanolic extract of Z. nummularia, exhibited the most potent activity against KAIMRC2 cells with an IC50 value of 29.2 µg/ml. Cancer cell treatment with the ethanolic extract of Z. nummularia resulted in a dose-dependent decrease in cell viability with increased apoptosis and cytotoxic effects. Microtubule staining showed a disrupted microtubular network. The ethanolic extract treatment of KAIMRC2 cells led to upregulated expression of pAKT and pmTOR. In silico studies predicted luteolin-7-O-glucoside to be a ligand for tubulin with the highest docking score (- 7.686) and similar binding interactions relative to the native ligand. Further computational analysis of the metabolites showed acceptable pharmacokinetic and safety profiles, although ethanolic extract metabolites were predicted to have cardiotoxic effects. Ethanolic extraction is optimal for solubilizing active anticancer metabolites from Z. nummularia, which may act by causing M-phase arrest via inhibition of tubulin polymerization. Luteolin-7-O-glucoside is the lead candidate for further research and development as an anti-cancer agent. In addition, this study suggests that herbal treatment could switch on mechanisms of adaptation and survival in cancer cells.

The effect of novel antihypertensive drug valsartan on lysozyme aggregation: A combined in situ and in silico study.

Protein misfolding can result in amyloid fiber aggregation, which is associated with various types of diseases. Therefore, preventing or treating abnormally folded proteins may provide therapeutic intervention for these diseases. Valsartan (VAL) is an angiotensin II receptor blocker (ARB) that is used to treat hypertension. In this study, we examine the anti-aggregating effect of VAL against hen egg-white lysozyme (HEWL) amyloid fibrils through spectroscopy, docking, and microscopic analysis. In vitro formation of HEWL amyloid fibrils was indicated by increased turbidity, RLS (Rayleigh light scattering), and ThT fluorescence intensity. 10 µM VAL, amyloid/aggregation was inhibited up to 83% and 72% as measured by ThT and RLS respectively. In contrast, 100 µM VAL significantly increases the fibril aggregation of HEWL. CD spectroscopy results show a stabilization of HEWL α-helical structures in the presence of 10 µM VAL while the increase in ß-sheet was detected at 100 µM concentration of VAL. The hydrophobicity of HEWL was increased at 100 µM VAL, suggesting the promotion of aggregation via its self-association. Steady-state quenching revealed that VAL and HEWL interact spontaneously via hydrogen bonds and van der Waals forces. Transmission electron microscopy (TEM) images illustrate that the needle-like fibers of HEWL amyloid were reduced at 10 µM VAL, while at 100 µM the fibrils of amyloid were increased. Additionally, our computational studies showed that VAL could bind to two binding sites within HEWL. In the BS-1 domain of HEWL, VAL binds to ASN59, ILE98, ILE58, TRP108, VAL109, SER50, ASP52, ASN59, ALA107, and TRP108 residues with a binding energy of -9.72 kcal mol-1. Also, it binds to GLU7, ALA10, ALA11, CYS6, ARG128, and ARG14 in the BS-2 domain with a binding energy of -5.89 kcal mol-1. VAL, therefore, appears to have dual effect against HEWL aggregation. We suggest that VAL stabilizes HEWL's aggregation-prone region (APR) at 10 µM, preventing aggregation. Also, we assume that at 100 µM, VAL occupies BS-2 beside BS-1 and destabilizes the folding structure of HEWL, resulting in aggregation. Further studies are needed to investigate the mechanism of action and determine its potential side effects.

Integration of in vitro and in-silico analysis of Caulerpa racemosa against antioxidant, antidiabetic, and anticancer activities.

Marine algae are found to be excellent in their nutritional and potential therapeutic properties. This study explores the antidiabetic and anticancer potential of fractionated polyphenolic extract of Caulerpa racemosa, green macroalgae. Crude polyphenolic extract (CPE) of C. racemosa and its fractions (n-hexane, ethyl acetate, chloroform, and distilled water) were tested for its total phenol and flavonoid contents and antioxidant potential. The ethyl acetate fraction was subjected to gas chromatography/mass spectrometry (GC/MS). The in vitro antidiabetic activity was assessed by alpha-amylase, glucosidase inhibition and anti-glycation assays. Also, in-silico studies were conducted to test the binding affinities between caulerpin with alpha-glucosidase enzyme and estrogen receptor (ER) active sites. Each fraction was tested for its in vitroin vitroanticancer activity by CellTiter-Glo and MTT cell proliferation assays. The total phenolic and flavonoid contents and the antioxidant potential of the crude extract were observed to be dose dependent. The GC/MS analysis of the ethyl acetate fraction yielded 47 peaks, whereas n-hexadecanoic acid and hexadecanoic acid methyl ester showed the highest compatibility percentages of 99% and 96%, respectively. The CPE exhibited a higher potential in both alpha-amylase inhibitory and anti-glycation activities. The ethyl acetate fraction was more effective against alpha-glucosidase inhibition. Molecular docking revealed a high binding affinity between the alpha-glucosidase enzyme and caulerpin and showed high binding affinity toward caulerpin, with H-bond interactions. The in vitro anticancer analyses revealed that chloroform fraction and CPE exhibited moderate activity on the KAIMRC1 cell line. Also, the CPE exhibited high specificity compared to the standard drug in anticancer studies. Our findings evidence the pharmacological potential of the CPE of C. racemosa, and bioactive compounds of the species may be utilized as lead molecules to develop anti-diabetic and anti-cancer drugs.

Surfactant modified waste ash for the removal of chloro and nitro group substituted benzene from wastewater.

A surfactant-modified coal fly ash was developed as a multifunctional adsorbent for the removal of organic pollutants from wastewater. Sodium dodecyl sulfate (SDS) was used to modify the surface of coal fly ash (CFA). The modified CFA was characterized using scanning electron microscopy (SEM), surface porosity analyzer, thermogravimetric analysis (TGA) and Fourier transform infrared (FTIR) spectroscopy. The results showed that loading CFA with SDS not only improved the functionality and surface morphology of the raw ash for the adsorption of organic pollutants, but also enhanced its thermal stability. The efficiency of the modified fly ash was tested in terms of removal of two non-polar organic pollutants namely chlorobenzene (CB) and nitrobenzene (NB) from aqueous phase. The maximum uptake capacity of chlorobenzene and nitrobenzene with SDS-modified coal fly ash (SCFA) was 225 mg/g and 90 mg/g, respectively. The kinetic analysis was done by controlled kinetic models, i.e., pseudo first and second order kinetic models. The results showed that adsorption of CB and NB onto SCFA followed a pseudo second order kinetic model. The adsorption of chlorobenzene was exothermic over the modified adsorbent while nitrobenzene showed an endothermic behavior. The isotherm analysis depicted the multilayer adsorption of both pollutants onto the surface of the surfactant modified adsorbent. This work has shown that surface modification using surfactants can be a viable option to enhance the adsorption capacity of fly ash for pollutants removal.

Achillea fragrantissima (Forssk.) Sch.Bip Flower Dichloromethane Extract Exerts Anti-Proliferative and Pro-Apoptotic Properties in Human Triple-Negative Breast Cancer (MDA-MB-231) Cells: In Vitro and In Silico Studies.

The aggressive triple-negative breast cancer (TNBC) is a challenging disease due to the absence of tailored therapy. The search for new therapies involves intensive research focusing on natural sources. Achillea fragrantissima (A. fragrantissima) is a traditional medicine from the Middle East region. Various solvent extracts from different A. fragrantissima plant parts, including flowers, leaves, and roots, were tested on TNBC MDA-MB-231 cells. Using liquid chromatography, the fingerprinting revealed rich and diverse compositions for A. fragrantissima plant parts using polar to non-polar solvent extracts indicating possible differences in bioactivities. Using the CellTiter-Glo™ viability assay, the half-maximal inhibitory concentration (IC50) values were determined for each extract and ranged from 32.4 to 161.7 µg/mL. The A. fragrantissima flower dichloromethane extract had the lowest mean IC50 value and was chosen for further investigation. Upon treatment with increasing A. fragrantissima flower dichloromethane extract concentrations, the MDA-MB-231 cells displayed, in a dose-dependent manner, enhanced morphological and biochemical hallmarks of apoptosis, including cell shrinkage, phosphatidylserine exposure, caspase activity, and mitochondrial outer membrane permeabilization, assessed using phase-contrast microscopy, fluorescence-activated single-cell sorting analysis, Image-iT™ live caspase, and mitochondrial transition pore opening activity, respectively. Anticancer target prediction and molecular docking studies revealed the inhibitory activity of a few A. fragrantissima flower dichloromethane extract-derived metabolites against carbonic anhydrase IX, an enzyme reported for its anti-apoptotic properties. In conclusion, these findings suggest promising therapeutic values of the A. fragrantissima flower dichloromethane extract against TNBC development.

The Role of Myrrh Metabolites in Cancer, Inflammation, and Wound Healing: Prospects for a Multi-Targeted Drug Therapy.

BACKGROUND: Myrrh extract is a well-known medicinal plant with significant therapeutic benefits attributed to the activity of its diverse metabolites. It has promising activity against cancer and inflammatory diseases, and could serve as a potential therapeutic alternative since most therapeutic agents have severe side effects that impair quality of life. METHOD: The current study identified the active metabolites from the myrrh resin methanolic extract. Then, the extracts were tested for in vitro anti-inflammatory and anti-cancer activity using cancer cell lines and Tamm-Horsfall Protein 1 (Thp-1)-like macrophage cell lines. Furthermore, using an in vivo rat model, the extracts' anti-inflammatory and wound-healing activity was investigated. In addition, in silico predictions of the myrrh constituents highlighted the pharmacokinetic properties, molecular targets, and safety profile, including cytochrome P 450 (CYP) inhibition and organ toxicity. RESULTS: Nine secondary metabolites were identified, and computational predictions suggested a good absorption profile, anticancer, anti-inflammatory, and wound-healing effects. The myrrh extract had moderate cytotoxic activity against both HL60 and K562 leukemia cell lines and the KAIMRC1 breast cancer cell line. Myrrh caused a dose-dependent effect on macrophages to increase the reactive oxygen species (ROS) levels, promote their polarization to classically activated macrophages (M1) and alternatively activated macrophages (M2) phenotypes, and consequently induce apoptosis, highlighting its ability to modulate macrophage function, which could potentially aid in several desired therapeutic processes, including the resolution of inflammation, and autophagy which is an important aspect to consider in cancer treatment. The topical application of myrrh improved wound healing, with no delayed inflammatory response, and promoted complete re-epithelization of the skin, similar to the positive control. In conclusion, we provide evidence for the methanolic extract of myrrh having cytotoxic activity against cancer cells and anti-inflammatory wound-healing properties, which may be attributed to its role in modulating macrophage function. Furthermore, we suggest the active constituents responsible for these properties, which warrants further studies focusing on the precise roles of the active metabolites.

Cranio-maxillofacial post-operative face prediction by deep spatial multiband VGG-NET CNN.

Current plastic and reconstructive surgery computational techniques are not precise and take a long time to perform. Therefore, these limitations reduced the adoption of computational techniques. Although computer-aided surgical preparation systems may help to enhance clinical results, minimize operating time and costs, they are too complicated and require detailed manual information, which restricts their usage in doctor-patient communication and clinical decision-making. In order to obtain the optimal aesthetic and reconstruction treatment results, these techniques must be designed and implemented carefully. Computer-aided modeling, planning, and simulation techniques enable the preoperational evaluation of various therapeutic strategies based on the 3D patient models. We offer the new deep-learning architecture for diagnostics, risk stratification, and post-operative simulation for face prediction. Initially, preprocessing was done by using the weighted adaptive median filter and Laplacian partial differential equation-based histogram equalization. Then the target area was converted to 3D for clear visualization by using the Smart restorative frustum model. Finally, the post-operative face prediction was constructed by using the deep spatial Multiband VGG NET CNN. We obtained a face dataset of 313,318 CT and their clinical records from different centers. The algorithms were developed by 21,095 scans (Qure25k data set). In addition, CQ500 datasets from various centers were compiled in two batches, B1 and B2, to validate the algorithms clinically. Four hundred ninety-one scans used the CQ500 dataset. Initially, we reconstructed the input image and then devised the post-operative face computationally. The suggested deep spatial Multiband VGG NET CNN showed the high range of post-operative face prediction accuracy. Therefore, successful metrics such as the Jaccard and dice scores have shown accurate outcomes compared to other traditional methods. MATLAB was used to obtain the output of proposed work. With the help of the suggested classifier, the prediction accuracy was 93.7%, sensitivity was 99.9%, and specificity was 99.8%, all of which were higher than traditional approaches. Here, the suggested method provides better results for post-operative face prediction to the applied dataset than any other existing mechanisms. It is a generalized attempt that can apply to other similar datasets as well.

Distinct Mechanisms of Cytotoxicity in Novel Nitrogenous Heterocycles: Future Directions for a New Anti-Cancer Agent.

Electron-rich, nitrogenous heteroaromatic compounds interact more with biological/cellular components than their non-nitrogenous counterparts. The strong intermolecular interactions with proteins, enzymes, and receptors confer significant biological and therapeutic properties to the imidazole derivatives, giving rise to a well-known and extensively used range of therapeutic drugs used for infections, inflammation, and cancer, to name a few. The current study investigates the anti-cancer properties of fourteen previously synthesized nitrogenous heterocycles, derivatives of imidazole and oxazolone, on a panel of cancer cell lines and, in addition, predicts the molecular interactions, pharmacokinetic and safety profiles of these compounds. METHOD: The MTT and CellTiter-Glo® assays were used to screen the imidazole and oxazolone derivatives on six cancer cell lines: HL60, MDA-MB-321, KAIMRC1, KMIRC2, MCF-10A, and HCT8. Subsequently, in vitro tubulin staining and imaging were performed, and the level of apoptosis was measured using the Promega ApoTox-Glo® triplex assay. Furthermore, several computational tools were utilized to investigate the pharmacokinetics and safety profile, including PASS Online, SEA Search, the QikProp tool, SwissADME, ProTox-II, and an in silico molecular docking study on tubulin to identify the critical molecular interactions. RESULTS: In vitro analysis identified compounds 8 and 9 to possess the most significant potent cytotoxic activity on the HL60 and MDA-MB-231 cell lines, supported by PASS Online anti-cancer predictions with pa scores of 0.413 and 0.434, respectively. In addition, compound 9 induced caspase 3/7 dependent-apoptosis and interfered with tubulin polymerization in the MDA-MB-231 cell line, consistent with in silico docking results, identifying binding similarity to the native ligand colchicine. All the derivatives, including compounds 8 and 9, had acceptable pharmacokinetics; however, the safety profile was suboptimal for all the tested derivates except compound 4. CONCLUSION: The imidazole derivative compound 9 is a promising anti-cancer agent that switches on caspase-dependent apoptotic cell death and modulates microtubule function. Therefore, it could be a lead compound for further drug optimization and development.

An easy, fast and inexpensive method of preparing a biological specimen for scanning electron microscopy (SEM).

Biological samples usually require cumbersome preparation steps before SEM imaging. Here we propose a simple, fast and inexpensive method to prepare and visualize biological cell culture samples in a few easy steps. We have tested this method with success on several adherent breast cancer and non-adherent leukemia cell lines. This method gives results comparable to other well-established techniques, and it can be convenient in day-to-day biological sample preparation for SEM imaging.•An easy and rapid method to visualize biological specimens under SEM.•Cells are grown on carbon tapes and gold coated.•Air drying without compromising the image quality.

Discovery of a novel potentially transforming somatic mutation in CSF2RB gene in breast cancer.

The colony stimulating factor 2 receptor subunit beta (CSF2RB) is the common signaling subunit of the cytokine receptors for IL-3, IL-5, and GM-CSF. Several studies have shown that spontaneous and random mutants of CSF2RB can lead to ligand independence in vitro. To date, no report(s) have been shown for the presence of potentially transforming and oncogenic CSF2RB mutation(s) clinically in cancer patients until the first reported case of a leukemia patient in 2016 harboring a germline-activating mutation (R461C). We combined exome sequencing, pathway analyses, and functional assays to identify novel somatic mutations in KAIMRC1 cells and breast tumor specimen. The patient's peripheral blood mononuclear cell (PBMC) exome served as a germline control in the identification of somatic mutations. Here, we report the discovery of a novel potentially transforming and oncogenic somatic mutation (S230I) in the CSF2RB gene of a breast cancer patient and the cell line, KAIMRC1 established from her breast tumor tissue. KAIMRC1 cells are immortalized and shown to survive and proliferate in ligand starvation condition. Immunoblot analysis showed that mutant CSF2RB signals through JAK2/STAT and PI3K/mTOR pathways in ligand starvation conditions. Screening a small molecule kinase inhibitor library revealed potent JAK2 inhibitors against KAIMRC1 cells. We, for the first time, identified a somatic, potentially transforming, and oncogenic CSF2RB mutation (S230I) in breast cancer patients that seem to be an actionable mutation leading to the development of new therapeutics for breast cancer.

Novel Anti-Tubulin Compounds from Trigonella foenum-graecum Seeds; Insights into In-vitro and Molecular Docking Studies.

BACKGROUND: Fenugreek, also known as Trigonella foenum-graecum L, is a natural plant that belongs to the Fabaceae family and has been known as a promising source of bioactive compounds. It has been widely used as traditional medicine since it has shown to lower blood glucose, manage cholesterol levels and further aid in the prevention and treatment of cancer. Herein, we aim to evaluate the anticancer activity of methanolic fenugreek seed extract against several cancer cell lines. METHODS: We sought to investigate the phytochemical classes present in multiple fenugreek seeds extracts using HPLC-DAD followed by LC/MS, predict and investigate anticancer activity using PASS online webserver, the CellTiter-Glo assay, evaluate ADME properties, and perform molecular docking for all bioactive compounds via Maestro software. RESULTS: Multiple extracts exhibited distinct phytochemical classes that demonstrated different biological activities. Fenugreek methanolic extract contains flavonoid chemical class, which showed the highest anticancer activity against the HCT8 cell line of colorectal cancer (IC50 of 8.83 µg/mL), followed by KAIMRC1 breast cancer cell line (IC50 of 35.06 µg/mL), HL60 leukemia cell line (37.80 µg/mL), MDA-MB-231 breast cancer cell line (38.51 µg/mL), and lastly, HCT116 colorectal cancer cell line with IC50 of 56.03 µg/mL. In contrast, the chloroform extract was inactive. The molecular docking study for all the bioactive compounds suggested that flavonoids F6 (-9.713 and -12.132), F7 (-10.166 and -12.411), and F11 (-10.084 and -13.516) possess the highest docking scores through SP and XP scores, respectively. CONCLUSION: The obtained results confirm that the bioactive compounds present in fenugreek seeds exhibit anticancer activity against several cancer cells that can mediate via tubulin polymerization inhibition. Although our study has evaluated the anticancer potential of Trigonella foenum-graecum as a promising natural source for new anticancer agents, fenugreek biological activity needs further research and investigations on their mechanism of action and toxicity profile.

Isolation and Establishment of a Highly Proliferative, Cancer Stem Cell-Like, and Naturally Immortalized Triple-Negative Breast Cancer Cell Line, KAIMRC2.

In vitro studies of a disease are key to any in vivo investigation in understanding the disease and developing new therapy regimens. Immortalized cancer cell lines are the best and easiest model for studying cancer in vitro. Here, we report the establishment of a naturally immortalized highly tumorigenic and triple-negative breast cancer cell line, KAIMRC2. This cell line is derived from a Saudi Arabian female breast cancer patient with invasive ductal carcinoma. Immunocytochemistry showed a significant ratio of the KAIMRC2 cells' expressing key breast epithelial and cancer stem cells (CSCs) markers, including CD47, CD133, CD49f, CD44, and ALDH-1A1. Gene and protein expression analysis showed overexpression of ABC transporter and AKT-PI3Kinase as well as JAK/STAT signaling pathways. In contrast, the absence of the tumor suppressor genes p53 and p73 may explain their high proliferative index. The mice model also confirmed the tumorigenic potential of the KAIMRC2 cell line, and drug tolerance studies revealed few very potent candidates. Our results confirmed an aggressive phenotype with metastatic potential and cancer stem cell-like characteristics of the KAIMR2 cell line. Furthermore, we have also presented potent small molecule inhibitors, especially Ryuvidine, that can be further developed, alone or in synergy with other potent inhibitors, to target multiple cancer-related pathways.

Metabolites Profiling, In Vitro, In Vivo, Computational Pharmacokinetics and Biological Predictions of Aloe perryi Resins Methanolic Extract.

BACKGROUND: Aloe perryi is a traditional herb that has various biological and pharmacological properties such as anti-inflammatory, laxative, antiviral, antidiabetic, and antitumor effects, which have not been deliberated before. The current investigation aims to evaluate in vitro cytotoxicity against several cancer cell lines in addition to in vivo anti-inflammatory activities of Aloe perryi extract using a rat animal model. Moreover, the pharmacokinetic properties of bioactive constituents and possible biological targets were assessed and evaluated. The methanolic extract of Aloe perryi was prepared by maceration, to tentatively identify the biomolecules of the Aloe perryi extract, analytical LC-QTOF-MS method was employed for Aloe perryi methanolic extract. The cytotoxic activity was examined in six cancer cell lines using Titer-Glo assay and the IC50s were calculated in addition to in silico target predictions and in vivo anti-inflammatory activity assessment. Subsequently, the pharmacokinetics of the identified active components of Aloe perryi were predicted using SwissADME, and target prediction using the Molinspiration webserver. The cytotoxic activity on HL60 and MDA-MB-231 was moderately affected by the Aloe perryi extract with IC50 of 63.81, and 89.85 µg/ml, respectively, with no activity on other cells lines. Moreover, the Aloe perryi extract exhibited a significant increase in wound contraction, hair growth, and complete re-epithelization when compared with the negative control. The pharmacokinetic properties of the bioactive constituents suggested a good pharmaceutical profile for the active compounds and nuclear receptors and enzymes were the two main possible targets for these active compounds. Our results demonstrated the promising activity of Aloe perryi extract with cytotoxic and anti-inflammatory properties, indicating a potential therapeutic utility of this plant in various disease conditions.

Iron Oxide Mesoporous Magnetic Nanostructures with High Surface Area for Enhanced and Selective Drug Delivery to Metastatic Cancer Cells.

This work reports the fabrication of iron oxide mesoporous magnetic nanostructures (IO-MMNs) via the nano-replication method using acid-prepared mesoporous spheres (APMS) as the rigid silica host and iron (III) nitrate as the iron precursor. The obtained nanosized mesostructures were fully characterized by SEM, TEM, DLS, FTIR, XRD, VSM, and nitrogen physisorption. IO-MMNs exhibited relatively high surface areas and large pore volumes (SBET = 70-120 m2/g and Vpore = 0.25-0.45 cm3/g), small sizes (~300 nm), good crystallinity and magnetization, and excellent biocompatibility. With their intrinsic porosities, high drug loading efficiencies (up to 70%) were achieved and the drug release rates were found to be pH-dependent. Cytotoxicity, confocal microscopy, and flow cytometry experiments against different types of cancerous cells indicated that Dox-loaded IO-MMNs reduced the viability of metastatic MCF-7 and KAIMRC-1 breast as well as HT-29 colon cancer cells, with the least uptake and toxicity towards normal primary cells (up to 4-fold enhancement). These results strongly suggest the potential use of IO-MMNs as promising agents for enhanced and effective drug delivery in cancer theranostics.

Role of receptor tyrosine kinases mediated signal transduction pathways in tumor growth and angiogenesis-New insight and futuristic vision.

In the past two decades, significant progress has been made in the past two decades towards the understanding of the basic mechanisms underlying cancer growth and angiogenesis. In this context, receptor tyrosine kinases (RTKs) play a pivotal role in cell proliferation, differentiation, growth, motility, invasion, and angiogenesis, all of which contribute to tumor growth and progression. Mutations in RTKs lead to abnormal signal transductions in several pathways such as Ras-Raf, MEK-MAPK, PI3K-AKT and mTOR pathways, affecting a wide range of biological functions including cell proliferation, survival, migration and vascular permeability. Increasing evidence demonstrates that multiple kinases are involved in angiogenesis including RTKs such as vascular endothelial growth factor, platelet derived growth factor, epidermal growth factor, insulin-like growth factor-1, macrophage colony-stimulating factor, nerve growth factor, fibroblast growth factor, Hepatocyte Growth factor, Tie 1 & 2, Tek, Flt-3, Flt-4 and Eph receptors. Overactivation of RTKs and its downstream regulation is implicated in tumor initiation and angiogenesis, representing one of the hallmarks of cancer. This review discusses the role of RTKs, PI3K, and mTOR, their involvement, and their implication in pro-oncogenic cellular processes and angiogenesis with effective approaches and newly approved drugs to inhibit their unrestrained action.

Investigation of biological activity of soil fungal extracts and LC/MS-QTOF based metabolite profiling.

Soil is considered an extensively explored ecological niche for microorganisms that produce useful biologically active natural products suitable for pharmaceutical applications. The current study aimed at investigating biological activities and metabolic profiles of three fungal strains identified from different desert sites in Saudi Arabia. Soil fungal isolates were collected from AlQasab, Tabuk, and Almuzahimiyah in Saudi Arabia and identified. Furthermore, their antibacterial activity was investigated against Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumonia, and Escherichia coli in blood, nutrient, and Sabouraud dextrose agars. Moreover, fungal extracts were evaluated on cell viability/proliferation against human breast carcinoma and colorectal adenocarcinoma cells. To identify the biomolecules of the fungal extracts, High-performance liquid chromatography HPLC-DAD coupled to analytical LC-QTOF-MS method was employed for fungal ethyl acetate crude extract. Identified fungal isolates, Chaetomium sp. Bipolaris sp. and Fusarium venenatum showed varied inhibitory activity against tested microbes in relation to crude extract, microbial strain tested, and growth media. F. venenatum showed higher anticancer activity compared to Chaetomium sp. and Bipolaris sp. extracts against four of the tested cancer cell lines. Screening by HPLC and LC/MS-QTOF identified nine compounds from Chaetomium sp. and three from Bipolaris sp. however, for F. venenatum extracts compounds were not fully identified. In light of the present findings, some biological activities of fungal extracts were approved in vitro, suggesting that such extracts could be a useful starting point to find compounds that possess promising agents for medical applications. Further investigations to identify exact biomolecules from F. venenatum extracts are needed.

New Born Calf Serum Can Induce Spheroid Formation in Breast Cancer KAIMRC1 Cell Line.

Three-dimensional (3D) cell culture systems have become very popular in the field of drug screening and discovery. There is an immense demand for highly efficient and easy methods to produce 3D spheroids in any cell format. We have developed a novel and easy method to produce spheroids from the newly isolated KAIMRC1 cell line in vitro. It can be used as a 3D model to study proliferation, differentiation, cell death, and drug response of cancer cells. Our procedure requires growth media supplemented with 10% new born calf serum (NBCS) and regular cell culture plates to generate KAIMRC1 spheroids without the need for any specialized 3D cell culture system. This procedure generates multiple spheroids within a 12-24-h culture. KAIMRC1 spheroids are compact, homogeneous in size and morphology with a mean size of 55.8 µm (±3.5). High content imaging (HCI) of KAIMRC1 spheroids treated with a panel of 240 compounds resulted in the identification of several highly specific compounds towards spheroids. Immunophenotyping of KAIMRC1 spheroids revealed phosphorylation of FAK, cJUN, and E-cadherin, which suggests the involvement of JNK/JUN pathway in the KAIMRC1 spheroids formation. Gene expression analysis showed upregulation of cell junction genes, GJB3, DSC1, CLDN5, CLDN8, and PLAU. Furthermore, co-culture of KAIMRC1 cells with primary cancer-associated-fibroblasts (CAFs) showcased the potential of these cells in drug discovery application.

Optimized Polyethylene Glycolylated Polymer-Lipid Hybrid Nanoparticles as a Potential Breast Cancer Treatment.

PURPOSE: The aim of this work is to optimize a polyethylene glycolated (PEGylated) polymer-lipid hybrid nanoparticulate system for the delivery of anastrozole (ANS) to enhance its biopharmaceutical attributes and overall efficacy. METHODS: ANS loaded PEGylated polymer-lipid hybrid nanoparticles (PLNPs) were prepared by a direct emulsification solvent evaporation method. The physical incorporation of PEG was optimized using variable ratios. The produced particles were evaluated to discern their particle size and shape, zeta-potential, entrapment efficiency, and physical stability. The drug-release profiles were studied, and the kinetic model was analyzed. The anticancer activity of the ANS PLNPs on estrogen-positive breast cancer cell lines was determined using flow cytometry. RESULTS: The prepared ANS-PLNPs showed particle sizes in the range of 193.6 ± 2.9 to 218.2 ± 1.9 nm, with good particle size uniformity (i.e., poly-dispersity index of around 0.1). Furthermore, they exhibited relatively low zeta-potential values ranging from -0.50 ± 0.52 to 6.01 ± 4.74. The transmission electron microscopy images showed spherical shape of ANS-PLNPs and the compliance with the sizes were revealed by light scattering. The differential scanning calorimetry DSC patterns of the ANS PLNPs revealed a disappearance of the characteristic sharp melting peak of pure ANS, supporting the incorporation of the drug into the polymeric matrices of the nanoparticles. Flow cytometry showed the apoptosis of MCF-7 cell lines in the presence of ANS-PLNPs. CONCLUSION: PEGylated polymeric nanoparticles presented a stable encapsulated system with which to incorporate an anticancer drug (ANS) with a high percentage of entrapment efficiency (around 80%), good size uniformity, and induction of apoptosis in MCF-7 cells.