Normal Human Fibroblast Cells Research Articles

Bis(1-methylimidazol-2-yl) diselenide and its evaluation as a chemical radio-protector: role of kinetic rate constants for ROS scavenging and glutathione peroxidase like activity

Bis(1-methylimidazol-2-yl) diselenide (MeImSe), a derivative of selenoneine, has been examined for bimolecular rate constants for scavenging of various radiolytically and non-radiolytically generated reactive oxygen species (ROS). Further, its potential to show glutathione peroxidase (GPx)-like activity and to protect in vitro models of DNA and lipid against radiation induced strand breakage and lipid peroxidation, respectively were studied. The results confirmed that MeImSe scavenged all major short-lived (hydroxyl radical) and long-lived (peroxyl radical, carbonate radical, nitrogen dioxide radical, hypochlorite and hydrogen peroxide) oxidants involved in the radiation toxicity either directly or through GPx-like catalytic mechanism. The rate constants of MeImSe for these oxidants were found to be comparable to analogous sulfur and selenium-based compounds. The enzyme kinetics study established that MeImSe took part in the GPx cycle through the reductive pathway. Further, MeImSe inhibited the radiation induced DNA strand cleavage and lipid peroxidation with half maximal inhibitory concentration (IC50) of ∼ 60 μM and ∼100 μM, respectively. Interestingly, MeImSe treatment in the above concentration range (>100 μM) did not show any significant toxicity in normal human lung fibroblast (WI26) cells. The balance between efficacy and toxicity of MeImSe as a chemical radioprotector was attributed to the formation of less reactive intermediates during its oxidation/reduction reactions as evidenced from NMR studies. Highlights MeImSe, a derivative of selenoneine protects DNA and lipid from radiation damage MeImSe scavenges all major short- and long-lived oxidants involved in radiation toxicity Rate constants of MeImSe for ROS scavenging determined by pulse radiolysis technique First organoselenium compound reported to scavenge nitrogen dioxide radical MeImSe exhibits GPx-like activity through reductive pathway

Sacha Inchi: The Promising Source of Functional Oil for Anti-Aging Product.

Sacha inchi (Plukenetia volubilis) oil is constituted with macronutrients and the health benefit fatty acids. In this context, the efficient of Sacha inchi oil for anti-aging product is presented. The light-clear yellowish seed oil of Sacha inchi was revealed on its physicochemical properties that are in the same range of the commercializing plant-oil supplied for topical products. The oil was GC/MS exhibited to be constituted with α-linolenic (51.72%) and linoleic (24.3%) acids, with unsaturated/saturated fatty acids ratio of 21.26. The oil was noted onto its potent in vitro antioxidant activity assessed by ABTS, DPPH and FRAP assays. In addition, the oil (1-3%) was proved to be safe in normal human fibroblast cells. Furthermore, the oil exhibited cellular antioxidant with inhibitory effect against MMP-2. Sacha inchi oil is therefore highlighted as a potential source of nutraceutical especially for anti-aging product. The oil is specified for the product development in terms of physicochemical, chemical and biological profiles. Innovative processing of Sacha inchi is therefore encouraged as the promising plant for anti-aging product.

Toosendanin Restrains Idiopathic Pulmonary Fibrosis by Inhibiting ZEB1/CTBP1 Interaction.

Extensive deposition of extracellular matrix (ECM) in idiopathic pulmonary fibrosis (IPF) is due to hyperactivation and proliferation of pulmonary fibroblasts. However, the exact mechanism is not clear. This study focused on the role of CTBP1 in lung fibroblast function, elaborated its regulation mechanism, and analyzed the relationship between CTBP1 and ZEB1. Meanwhile, the antipulmonary fibrosis effect and its molecular mechanism of Toosendanin were studied. Human IPF fibroblast cell lines (LL-97A and LL-29) and normal fibroblast cell lines (LL-24) were cultured in vitro. The cells were stimulated with FCS, PDGF-BB, IGF-1, and TGF-β1, respectively. BrdU detected cell proliferation. The mRNA expression of CTBP1 and ZEB1 was detected by QRT-PCR. Western blotting was used to detect the expression of COL1A1, COL3A1, LN, FN, and α-SMA proteins. An animal model of pulmonary fibrosis was established to analyze the effects of CTBP1 silencing on pulmonary fibrosis and lung function in mice. CTBP1 was up-regulated in IPF lung fibroblasts. Silencing CTBP1 inhibits growth factor-driven proliferation and activation of lung fibroblasts. Overexpression of CTBP1 promotes growth factor-driven proliferation and activation of lung fibroblasts. Silencing CTBP1 reduced the degree of pulmonary fibrosis in mice with pulmonary fibrosis. Western blot, CO-IP, and BrdU assays confirmed that CTBP1 interacts with ZEB1 and promotes the activation of lung fibroblasts. Toosendanin can inhibit the ZEB1/CTBP1protein interaction and further inhibit the progression of pulmonary fibrosis. CTBP1 can promote the activation and proliferation of lung fibroblasts through ZEB1. CTBP1 promotes lung fibroblast activation through ZEB1, thereby increasing excessive deposition of ECM and aggravating IPF. Toosendanin may be a potential treatment for pulmonary fibrosis. The results of this study provide a new basis for clarifying the molecular mechanism of pulmonary fibrosis and developing new therapeutic targets.

A Combination of Curcumin and Lactobacillus rhamnosus GG Inhibits Viability and Induces Apoptosis in SCC-9 Human Oral Squamous Cell Carcinoma Cells.

The aim of this study was to evaluate the effect of curcumin combined with Lactobacillus rhamnosus GG cell-free supernatant (LGG CFS) on the proliferation and induction of apoptosis in SCC-9 oral squamous cell carcinoma (OSCC) cells. Curcumin (40 µg/ml) and 25% v/v LGG CFS (108 CFU/ml), both alone and in a combination regimen, significantly decreased the viability of SCC-9 cells and normal human gingival fibroblast (HGF) cells. Interestingly, the combination of low doses of curcumin (5 µg/ml) and 25% v/v LGG CFS (106 CFU/ml) had no effect on the HGF cells but significantly inhibited the viability of SCC-9 cells (p < 0.05). Flow cytometric analysis revealed that SCC-9 cells treated with the combination of low-dose curcumin and low-dose LGG CFS had a higher apoptotic rate than the cells in the control group and the single treatment groups (p < 0.05). The combined treatment also significantly increased the Bax/Bcl2 mRNA and protein expression in SCC-9 cells (p < 0.05) but not in HGF cells, indicating the underlying mechanism of the combination regimen. There was no significant difference in caspase-3 protein expression or the Bcl-xL/Bak and Mcl-1/Bak ratios between the treatment and control groups in both cell lines. These findings suggested that the coadministration of curcumin and LGG could exhibit anticancer effects in SCC-9 cells without causing toxicity to normal fibroblast cells.

Design, synthesis and biological evaluation of rhein-piperazine-furanone hybrids as potential anticancer agents.

Novel rhein-piperazine-furanone hybrids, 5, were designed and synthesized efficiently from rhein. Cytotoxicity of all hybrids 5a-j against A549 human lung cancer cells was superior to the parent rhein and the reference cytarabine (CAR). Hybrid 5e (IC50 = 5.74 μM), the most potent compound, was 46- and 35-fold more toxic against A549 cells than rhein (IC50 = 265.59 μM) and CAR (IC50 = 202.57 μM), respectively. Moreover, hybrid 5e (IC50 = 69.28 μM) was less toxic to normal WI-38 human lung fibroblast cells with good selectivity (WI-38/A549, SI ≈ 12), being much higher than rhein (SI ≈ 1) and CAR (SI ≈ 2). Structure-activity relationship (SAR) analysis showed that cytotoxicity and selectivity against A549 lung cancer cells were greatly enhanced when methoxy-containing furanone was introduced to the hybrids (5e and 5h). Further, hybrid 5e showed better cytotoxicity against four types of human lung cancer cells (H460, A549, PC-9, and Calu-1; IC50 = 4.35-15.39 μM) than six other types of human cancer cells (SK-BR-3, SK-OV-3, 786-O, Huh-7, HCT116, and HeLa; IC50 = 13.77-60.45 μM), showing specificity. In particular, hybrid 5e showed the highest cytotoxicity (IC50 = 4.35 μM) and the highest selectivity (WI-38/H460, SI ≈ 16) against H460 human lung cancer cells. Flow cytometric analysis showed that hybrid 5e induced apoptosis in a concentration-dependent manner in H460 cells. The results show that the cytotoxicity and selectivity of rhein can be greatly enhanced by hybridization with furanone. Hybrid 5e is expected to be a leading candidate for anti-lung cancer drugs.

Cytotoxic constituents of Cymbidium tracyanum L.Castle

Three phenanthrene derivatives, cymbisamoquinone (1), calanquinone B (6), and 3,7-dihydroxy-2,4,6- trimethoxyphenanthrene (2), and two bibenzyls, Tristin (3) and gigantic (4), together with the lignan (+)-pinoresinol (5), were isolated from the whole plants of Cymbidium tracyanum L.Castle (Orchidaceae). Their structures were determined through spectroscopic analysis as well as a comparison of the spectral data with literature values. The phytochemical constituents of this plant have been reported for the first time. All isolated compounds were evaluated for in vitro cytotoxic activity against human colon (Caco-2) and breast (MCF-7) cancer cell lines, doxorubicin-resistant (MCF-7/DOX) and mitoxantrone-resistant (MCF-7/MX) MCF-7 sublines, together with normal human fibroblast (NIH/3T3) cell line. Among the isolated compounds, 1 exhibited the strongest and relatively selective activity on MCF-7/DOX cells. The results obtained from the molecular docking study suggested that the cytotoxicity of 1 on MCF-7/DOX cells was possibly due to the induction of apoptosis via suppression of the cell survival systems mediated by the mitogen-activated protein kinases and protein kinase B/glycogen synthase kinase-3β/nuclear factor erythroid 2-related factor 2 signalling pathways.

In-vitro Cytotoxicity Investigations for Phytoconstituents of Saudi Medicinal Plants With Putative Ocular Effects.

Metastatic secondary ocular tumors spread from systemic malignancies, including breast cancer. This study aimed to evaluate the cytotoxicity of extracts from 5 medicinal plants native to Saudi Arabia. For preliminary activity screening, cytotoxicity using the MTT assay and selectivity index determinations were made for medicinal plant extracts against various cancer cell-lines. The most promising extract was subjected to GC-MS analysis to determine the phytochemical composition. Clonogenic assays were performed using the most promising extract to confirm the initial results. Finally, western blot analysis was used to determine the modulation in expression of survivin and P27 suppressor genes in the human breast adenocarcinoma (MCF7) cell-line to understand the potential mechanistic properties of the active plant extract. The 5 plant extracts showed various cytotoxic activity levels using IC50. The most active extract was found to be the leaves of Capparis spinosa L. (BEP-07 extract) against the MCF7 breast cancer cell-line (IC50 = 3.61 ± 0.99 μg/ml) and selectivity index of 1.17 compared to the normal human fetal lung fibroblast (MRC5) cells. BEP-07 extract showed a dose dependent clonogenic effect against the MCF7 colonies which was comparable with the effect of doxorubicin. BEP-07 extract caused a significant decrease of survivin and increase in P27 expression compared to control GAPDH at its highest dose (14 µg/ml). The GC-MS chromatogram of Capparis spinosa L. (BEP-07 extract) revealed the existence of 145 compounds, belonging to the diverse classes of phytoconstituents. Fatty acids and their derivatives represent 15.4%, whilst octadecanoic acid, 2,3-dihydroxypropyl ester was the principal component (7.9%) detected. Leaves of Capparis spinosa L. (BEP-07 extract) exhibited a significant cytotoxic effect particularly against breast cancer cells. It exhibited this effect through survivin inhibition and via P27 upregulation. The detected phytoconstituents in the plant extract might be involved in tested cytotoxic activity, while further investigations are required to complete the drug candidate profile.

Bio-response of copper-magnesium co-substituted mesoporous bioactive glass for bone tissue regeneration.

Mesoporous bioactive glass (MBG) is widely acknowledged in bone tissue engineering due to its mesoporous structure, large surface area, and bioactivity. Recent research indicates that introduction of metallic ions has beneficial impacts on bone metabolism and angiogenesis. Thus, the features of MBG can be modified by incorporating combinations of ions, such as magnesium (Mg) and copper (Cu), which can play a considerable role in bone formation, influencing angiogenesis, osteogenesis, as well as antibacterial properties. In this study, Mg and Cu were co-doped for the first time (in a ratio of 1 : 1) in 80SiO2-5P2O5-(15 - 2x)CaO-xMgO-xCuO glass composition with x = 0, 0.5, 1, and 2 mol%, synthesized using the sol-gel and evaporation-induced self-assembly method. X-ray diffraction analysis confirmed the amorphous nature of the powders, while inductively coupled plasma-optical emission spectrometry verified the existence of dopant ions in the respective amounts. The nitrogen sorption method indicated the formation of uniform cylindrical mesopores which are open at both ends and a high surface area of the powders. TEM images show fringes, indicating an ordered mesoporous structure in all MgCu co-doped systems. In vitro bioactivity was observed in all MBG powders, confirmed by the formation of an apatite phase when placed in simulated body fluid (SBF). Flake-like microstructure characteristics of HAp crystals found on the surface of MBG powders were visualized using FESEM. Cytotoxicity tests at lower concentrations (0.1 and 1 wt/vol%) of co-doped 2MC MBG (co-doping up to 2 mol%) showed cell proliferation and viability of osteoblast-like MG-63 cells and normal human dermal fibroblast (NHDF) cells similar to the basic glass 80S. Antibacterial study of MBG pellets showed an increment in the zone of inhibition with the sequential addition of doping ions. The turbidity measurement of bacterial cultures revealed that the optimal concentration for effectively inhibiting bacterial growth was 1 wt/vol% (i.e., 10 mg mL-1) concentration of MBG extracts. The result suggested that the incorporation of Mg and Cu ions in MBG in lower concentrations of up to 2 mol% can be useful in bone regeneration owing to bioactivity, cell proliferation, and antibacterial characteristics.

In vitro pro-apoptotic and anti-metastatic potentials of harmaline-silver containing folate-linked chitosan nano-drug delivery system.

Harmaline and green-synthesized silver nanoparticles were encapsulated by folate-linked chitosan molecules as a receptor-mediated drug delivery system to evaluate its pro-apoptotic and anti-metastatic potentials on human ovarian (A2780) and epithelioid (PANC) cancer cells. The Ag nanoparticles (AgNP) were synthesized utilizing an herbal bio-platform (Bistorta officinalis) and embedded with harmalin. The Harmaline-ag containing folate-linked chitosan nanoparticles (HA-fCNP) were synthesized utilizing the ionic gelation method. Both the AgNP and HA-fCNP nanoparticles were characterized by DLS, FESEM, and Zeta potential analysis. Moreover, the chemical properties of HA-fCNP and the crystallinity of AgNPs were determined by applying FTIR and XRD methods, respectively. The HA-fCNP cytotoxicity was analyzed on A2780, PANC, and HFF cell lines. Moreover, pro-apoptotic and anti-metastatic potentials of HA-fCNP were studied by analyzing the BAX-BCL2 and MMP2-MMP9 gene expression profiles, respectively. The A2780 cellular death was determined by AO/PI and flow cytometry methods. The HA-fCNP significantly exhibited a selective cytotoxic impact on A2780 and PANC cancerous cell lines compared with normal human foreskin fibroblast (HFF) cells. The increased SubG1-arrested A2780 cells and up-regulated BAX gene expression following the increased treatment concentrations of hA-fCNP indicated its selective pro-apoptotic activity on A2780 cells. Also, the notable down-regulated expressions of MMP2 and MMP9 metastatic genes following the increasing doses of HA-fCNP treatment on A2780 cells confirmed its anti-metastatic activity. The cancer-selective cytotoxicity, apoptotic, and anti-metastatic properties of HA-fCNP are considered the appropriate properties of an anticancer compound.

Nutritional Profiling, Antioxidant Potential and Collagen Building Properties of Lacto-Fermented, Microencapsulated Guava Juice Powder

Fermented products consist beneficial probiotics, which makes these products render improved nutritional properties and health effects. There is a need for research to explore and establish the use of commonly existing fruits in fermented forms for application in skincare and as anti aging solutions.This study has been conducted to establish collagen building and antioxidant potential of fermented guava fruit juice powder.The human dermal fibroblast cells were used to determine the collagen building potential while chemical enzymatic assays were used to evaluate antioxidant properties of fermented guava juice powder (FGJP) . The antioxidant activity evaluated by the ability to scavenge DPPH radicals showed very high anti-oxidative capacity (IC50 = 0.015 mg/ml) comparable to ascorbic acid (IC50 = 0.018 mg/ml). This antioxidant potential can be attributed to the presence of various phytonutrients, primarily flavonoid (quercetin equivalent) at a concentration of 38 mcg/mg of the powder. The Collagen building potential was evaluated on the normal human fibroblast cell line . The levels of Collagen IV involved in skin cell migration, regeneration, and wound healing were estimated. FGJP imparted proliferation ability in NHDF cells at the concentrations of 0.025, 0.05, and 0.1mg/ml,which is 31% collagen synthesis against untreated cell control. This explains that fermented guava juice powder has a collagen building potential along with antioxidant properties. Such product would be helpful in providing a plant based anti aging solutions especially for vegan consumers.The optimized fermented guava juice powder has a shelf life of 45 days when stored at refrigerated conditions with a potential for combating oxidative stress and supporting in alleviating the aging symptoms like fine-line, wrinkle through collagen building.

Imidazole derivatives as novel and potent antifungal agents: Synthesis, biological evaluation, molecular docking study, molecular dynamic simulation and ADME prediction

Fungal infections have become a serious threat to human health due to their high incidence and mortality. In this study, a new set of imidazole derivatives (7a-f) were synthesized and their chemical structures were characterized using spectroscopic techniques including IR, 1H-NMR, 13C-NMR and Mass. In the following, the antifungal activities of these derivatives were evaluated against several yeasts, aspergillus and dermatophyte species using the CLSI method. In addition, to check the safety of the synthesized compounds, the in vitro cytotoxicity activity of these compounds was investigated towards normal human fibroblasts cell line (MRC-5) using MTT assay. The obtained biological results indicated that these compounds acted as the most potential antifungal agents. In particular, compounds 7c, 7d and 7f exhibited excellent activity against Candida albicans, Candida tropicalis, Candida glabrata, Candida krusei, Candida dubliniensis, Candida parapsilosis, and Cryptococcus neoformans species with MIC50 values in the range of 0.5-16 µg/ml. The cytotoxicity results showed that these compounds have low toxicity against normal human fibroblasts cell line (MRC-5). Additionally, molecular modelling studies and molecular dynamic simulation were carried out to predict the binding energy and possible interaction mode of these compounds in the binding site of lanosterol 14α-demethylase (CYP51) as a conventional target for azole derivatives. In silico ADME study was also performed to investigate the physicochemical features of the synthesized imidazole derivatives. According to the results, these compounds can be considered as promising antifungal candidates for further development.

Preparation of protein nanoparticles using diselenide functionalized gelatin for redox responsive release of doxorubicin

The present study demonstrates the fabrication of a nanocarrier system using diselenide conjugated gelatin (G-Se-Se-G) for the redox responsive delivery of a wide spectrum anticancer drug, doxorubicin (Dox). The method involves nanoprecipitation of the aqueous solution of G-Se-Se-G employing ethanol and F68 as the desolvating and stabilizing agents respectively. The drug, Dox is loaded within the nanocarrier by entrapment method during the nanoparticle synthesis. The physico-chemical characterizations confirm the formation of nanoparticles of regular spherical shape with hydrodynamic size, surface charge and loading efficiency of 181 ± 12.6 nm, -13.10 ± 0.83 mV and ∼9 % respectively. Notably, Dox loaded G-Se-Se-G carrier shows significantly higher drug release in response to acidic (pH = ∼5.5) and reducing (10 mM glutathione) sink conditions. Dox release kinetic data fitted to a universal Korsmeyer–Peppas model suggests that irrespective of the nature of stimuli, the release of Dox from G-Se-Se-G carrier follows non-Fickian mechanism which is attributed to the diffusion and erosion. The cytotoxicity studies employing human lung adenocarcinoma (A549) and human normal lung fibroblast (WI38) cells confirm the potency as well as selectively of Dox loaded G-Se-Se-G carrier towards cancer cells. The intracellular drug release studies through fluorescence imaging indeed corroborate the redox (reducing environment) mediated preferential release of Dox from G-Se-Se-G carrier in A549 cells as compared to WI38 cells. Finally, in vivo studies using A549 derived xenograft tumor model establishes that Dox loaded G-Se-Se-G nanocarrier is better tolerable than free Dox with almost similar efficacy.

Multi-functionalization of reduced graphene oxide nanosheets for tumor theragnosis: Synthesis, characterization, enzyme assay, in-silico study, radiolabeling and in vivo targeting evaluation

BackgroundIn this study, a combination of nanotechnology, organic synthesis and radiochemistry were utilized in order to design an efficient nano-system conjugated with a suitable radionuclide and an antitumor agent for possible application as tumor theragnostic agent.MethodFour novel compounds (3 and 4a-c) bearing tetrahydroquinazoline-7-sulfonohydrazide or 1,2,3,4-tetrahydroquinazoline-7-sulfonamide scaffold were designed. Then, docking study predicted that the compounds can be considered as potential inhibitors for PARP-1. Following that; the four compounds were synthesized and properly characterized using 1HNMR, 13CNMR, IR and Mass spectroscopy. The cytotoxic effect of the four compounds was evaluated against breast cancer cell line (MDA-MB-436), where compound 3 showed the most promising cytotoxic effect. The inhibitory effect of the four compounds was evaluated in vitro against PARP-1.ResultCarboxylated graphene oxide nanosheets (NGO-COOH) were synthesized by a modified Hummer's method and has size of range 40 nm. The NGO-COOH nanosheets were proven to be safe and biocompatible when tested in vitro against normal human lung fibroblast cells (MRC-5). The prepared NGO-COOH nanosheets were conjugated with compound 3 then radiolabeled with 99mTc to yield 99mTc-NGO-COOH-3 with a radiochemical yield of 98.5.0 ± 0.5%. 99mTc-NGO-COOH-3 was injected intravenously in solid tumor bearing mice to study the degree of localization of the nano-system at tumor tissue. The results of the study revealed, excellent localization and retention of the designed nano-system at tumor tissues with targeting ratio of 9.0.ConclusionStirred a new candidate tumor theragnostic agent that is safe, selective and stable.Graphical abstract

Evaluation of the Antitumor Activity of Quaternary Ammonium Surfactants.

Quaternary ammonium surfactants, due to their diverse chemical structure and their biological properties, can be used in medicine as DNA carriers, disinfectants, and antimicrobial and antitumor agents. In this study, using melanoma A375, colon adenocarcinoma HT-29 and normal human dermal fibroblast (NHDF) cells, we tested the hypothesis that the quaternary ammonium surfactants 2-dodecanoyloxyethyl)trimethylammonium bromide (DMM-11), 2-dodecanoyloxypropyl)trimethylammonium bromide (DMPM-11) and 2-pentadecanoyloxymethyl)trimethylammonium bromide (DMGM-14) act selectively against cancer cells. The results showed that these compounds led to the initiation of the apoptotic process of programmed cell death, as evidenced by the ratio of the relative expression of Bax protein to Bcl-2. The encapsulation of surfactants in liposomes allowed lower concentrations to be used. Moreover, encapsulation reduced their toxicity towards non-cancerous cells. The anticancer efficiency and apoptotic effect of the liposomal formulations with surfactants (DMM-11, DMPM-11 and DMGM-14) were higher than those of surfactant-free liposomes. Therefore, quaternary ammonium surfactant-loaded liposomes show significant potential as delivery vehicles for the treatment of melanoma and colon cancers. The use of nano-formulations offers the advantage of optimizing quaternary ammonium surfactant delivery for improved anticancer therapy.

Anticancer Activities of Zinc Oxide Nanoparticles Synthesized Using Guava Leaf extract.

AbstractIn this study, we report on the green synthesis, characterization, and anticancer activity of zinc oxide nanoparticles (ZnO NPs) prepared using extracts of guava leaves. The ZnO NPs were successfully synthesized using a simple and eco‐friendly method. Then, the synthesized NPs were characterized using various techniques including Fourier‐transform infrared spectroscopy, X‐ray diffraction, scanning electron microscopy, and transmission electron microscopy. The results confirmed the formation of ZnO NPs with an average size of approximately 20 nm, along with a spherical morphology and well‐defined boundaries. The anticancer activity of the synthesized NPs was evaluated against different cancer cell lines, including A549 (lung cancer), HeLa (cervical cancer), and MCF7 (breast cancer), as well as normal human dermal fibroblast (HDF) cells. The analysis showed that the ZnO NPs exhibited significant anticancer activity, especially against the MCF7 and HeLa cancer cell lines, along with relatively low toxicity toward HDF cells. These findings highlight the potential of ZnO NPs synthesized using guava leaf extract as promising candidates for biomedical applications, particularly in cancer therapy.

The Novel CDK9/CDK4/6/PI3K Triple Inhibitor LCI139 for the Treatment of MYC-Driven Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an aggressive B cell malignancy with characteristic t(11;14)(q13;q32) translocation juxtaposing IGH and CCND1 gene loci. This chromosomal rearrangement leads to Cyclin D1 overexpression and cell cycle dysregulation at the G1/S phase transition. MCL is generally diagnosed at advanced stages and follows an aggressive course of disease. Although chemotherapy-based combination regimens are initially effective, most patients relapse with a median survival of only 2.5-5 years. While novel targeted therapeutics have shown promising activity in relapsed/refractory patients, inevitable relapse associated with progressively declining efficacy and increasing resistance to single agent targeted therapy is a major concern. To overcome this barrier, we designed in-silico based a novel multitarget small molecule inhibitor LCI139 which simultaneously blocks three oncogenic targets: cyclin-dependent kinase 9 (CDK9), CDK4/6, and phosphatidylinositol-3 kinase (PI3K). LCI139 is a potent CDK9/CDK4/6/PI3K inhibitor with IC 50s of 0.000039µM (CDK9), 0.0015µM/0.0036µM (CDK4/6) 0.070µM (p110α), 0.461µM (p110γ), and 0.214 (p110δ), as determined by cell free assay alpha screens. Dose-dependent screening of LCI139 against a panel of MCL cell lines revealed robust cytotoxic effects with maximal IC 50 of 86.67 nM in JeKo-1 cells, 64.8 nM in Mino cells, and 202.5 nM in Rec-1 cells. Compared with clinical single agent CDK9 inhibitor AZD4573, LCI139 is less toxic to normal human stromal cells (HS-5), whereas both LCI139 and AZD4573 have no significant cytotoxic effect on normal human foreskin fibroblast cells (Hs68). LCI139 treatment at various concentrations for 24hrs induced significant apoptotic response in two MCL cell lines, JeKo-1 (p&amp;lt;0.001 DMSO vs LCI139 100 nM, p&amp;lt;0.0001 DMSO vs LCI139 200 nM) and Mino (p&amp;lt;0.05 DMSO vs LCI139 100 nM, p&amp;lt;0.0001 DMSO vs LCI139 200 nM) as determined by Annexin V/7-AAD apoptosis staining. Similarly, LCI139-induced apoptotic cell death was further confirmed by increasing cl-PARP protein levels compared to control as assessed by Western blot analysis. LCI139 induced robust G2/M cell cycle arrest in JeKo-1 cells and G1 arrest in Mino cells. The mechanism of action of pan-CDK inhibitors has been associated with downregulation of the anti-apoptotic protein MCL-1 through inhibition of transcriptional CDKs. Our results show that short-term exposure of LCI139 (1hr and 3hr) significantly suppressed MCL-1 and MYC mRNA expression in JeKo-1 (p&amp;lt;0.00001 DMSO vs LCI139) and Mino cells (p&amp;lt;0.00001 DMSO vs LCI139). LCI139 suppressed pRpb1 (Ser2), MCL-1 and cMYC protein expression in IgM-stimulated JeKo-1 and Mino cells in a dose-dependent manner. Treatment with LCI139 had no significant effect on pAKT (Ser473) in Jeko-1 cells, whereas pAKT (Ser473) was completely abolished in Mino cells at 500nM of LCI139. Mechanistically, our findings also demonstrate that LCI139 decreased MCL-1 and cMYC protein stability and reduced half-life as accessed by cycloheximide chase assay. This decrease in cMYC stability is associated with decreased of cMYC phosphorylation at Ser62. Adaptive kinome remodeling via drug-induced transcriptional reprogramming is a known contributor to ibrutinib resistant (IR) MCL. RNA-sequencing analysis of JeKo-1 vs Jeko-1 IR cells revealed a total of 3468 differentially expressed genes (FC &amp;gt; 1.5 and FDR &amp;lt; 0.05) where 110 kinases display altered expression in JeKo-1 IR cells. Finally, we show that LCI139 overcomes chronic ibrutinib resistance by decreasing viability in JeKO-1 IR and Mino IR cells with an IC 50 of 79 nM and 89 nM, respectively. Therefore, the multitarget small molecule inhibitor LCI139 has superior potency against IR MCL cell lines and overcomes ibrutinib-resistance at nanomolar doses.

Cytotoxic Activity of Some Half‐sandwich Rhodium(III) Complexes Containing 4,4’‐disubstituted‐2,2’‐bipyridine Ligands

AbstractThe synthesis and characterization of three compounds [Rh(η5‐C5Me5)Cl(N^N)]PF6 (N^N=4,4’‐disubstituted‐2,2’‐bipyridines, 1–3) are described. The cationic complexes contain the bidentate ligands N^N=4,4'‐di‐tert‐butyl‐2,2'‐bipyridine (1), N^N=4,4'‐dinonyl‐2,2'‐bipyridine (2) and N^N=4,4'‐diamino‐2,2'‐bipyridine (3). The complex salts were obtained by the bridge‐splitting reaction from the precursor [{Rh(η5‐C5Me5)(μ‐Cl)Cl}2] and subsequent salt metathesis affording their corresponding hexafluorido phosphate salts. All compounds were characterized by elemental analysis and spectroscopic means. Additionally, the molecular structure of compound 3 in the solid was determined by a single‐crystal X‐ray diffraction study. The cytotoxicity of all three compounds was examined by MTT assay against two cancer cell lines – HT‐29 (colon adenocarcinoma) and MCF‐7 (human breast adenocarcinoma) ‐ and normal human fibroblast cells (GM5657T). Compound 1 has moderate cytotoxicity against both cell lines, while compound 2 is seven to nine times more cytotoxic than cisplatin against MCF‐7 and HT‐29, respectively. In contrast to cisplatin, both compounds are more active against cancer cells than fibroblasts, thus showing some cancer selectivity.

Exploring NiFe2O4 nanoparticles: Electrochemical analysis and evaluation of cytotoxic effects on normal human dermal fibroblasts (HDF) and mouse melanoma (B16-F10) cell lines

Nanobiotechnology facilitates the development of novel materials with potential applications in human health, the environment, and a variety of industries. We used X-ray diffraction (XRD) to characterize NiFe2O4 nanoparticles (NPs), confirming a cubic crystal structure with crystallite sizes of 19 nm and 21 nm. Synthesized NPs spherical shape morphology was confirmed by field emission-scanning electron microscopy (FE-SEM) and an average diameter (prepared NPs) of 20 nm and 23 nm was revealed by Transmission electron microscopy (TEM). The chemical state was determined using X-ray photoelectron spectroscopy (XPS). A vibrating sample magnetometer (VSM) was used to measure the magnetic characteristics. The electrochemical characteristics of prepared electrodes could be useful for supercapacitor applications. Changing the surfactants, reaction temperature, and heating duration considerably enhanced electrochemical performance, according to our findings. At 700 °C, specific capacitance (Cs) attained an outstanding value of 67.2 F/g. The prepared NPs cytotoxicity was performed on normal human dermal fibroblast (HDF) and mouse melanoma (B16-F10) cell lines. The current findings show that these NPs are non-toxic at concentrations ranging from 0 to 1000 µg/mL. These findings point to prospective biomedical uses for NiFe2O4 NPs.

Cysteine-Silver-Polymer Systems for the Preparation of Hydrogels and Films with Potential Applications in Regenerative Medicine.

Herein, the problem concerning the poorer mechanical properties of gels based on low molecular weight gelators (LMWGs)-L-cysteine and silver nitrate-was solved by the addition of various polymers-polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP) and polyethylene glycol (PEG)-to the initial cysteine-silver sol (CSS). The physicochemical methods of analysis-viscosimetry, UV spectroscopy, DLS, and SEM-identified that cysteine-silver hydrogels (CSG) based on PVA possess the best rheological properties and porous microstructure (the average pore size is 2-10 µm) compared to gels without the polymer or with PVP or PEG. Such gels are able to form cysteine-silver cryogels (CSC) and then porous cysteine-silver films (CSF) with an average pore size of 10-20 µm and good mechanical, swelling, and adhesion to skin characteristics as long as the structure of CSS particles remains stable. In vitro experiments have shown that hydrogels are non-toxic to normal human fibroblast cells. The obtained materials could potentially be applied to regenerative medicine.

Synthesis and Biological Evaluation of 12-Aryl-11-hydroxy-5,6-dihydropyrrolo[2″,1″:3',4']pyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-8(9H)-one Derivatives as Potential Cytotoxic Agents.

In the present paper, a facile and efficient synthetic procedure has been applied to obtain dihydrodipyrrolo[1,2-a:2',1'-c]pyrazine-2,3-dicarboxylates (5a-s), which have subsequently gone through the cyclization in the presence of hydrazine hydrate to afford 12-aryl-11-hydroxy-5,6-dihydropyrrolo[2″,1″:3',4']pyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-8(9H)-ones (7a-q). The molecular structures of these novel compounds were extensively examined through the analysis of spectroscopic data in combination with X-ray crystallography techniques. Following that, the in vitro cytotoxic activities of all derivatives against three human cancer cell lines (Panc-1, PC3, and MDA-MB-231) were comprehensively evaluated alongside the assessment on normal human dermal fibroblast (HDF) cells using the MTT assay. Among the compounds, the 3-nitrophenyl derivative (7m) from the second series showed the best antiproliferative activity against all tested cell lines, particularly against Panc-1 cell line, (IC50 = 12.54 μM), being nearly twice as potent as the standard drug etoposide. The induction of apoptosis and sub-G1 cell cycle arrest in Panc-1 cancer cells by compound 7m was confirmed through further assessment. Moreover, the inhibition of kinases and the induction of cellular apoptosis by compound 7m in Panc-1 cancer cells were validated using the Western blotting assay.