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Lung cancer has become progressively widespread, posing a challenge to traditional chemotherapeutic drugs such as platinum compounds and paclitaxel owing to growing resistance. Along with that, the chemotherapeutic drugs infer major side effects. The usage of natural compounds as chemosensitizers to boost the efficacy of these chemotherapeutic drugs and minimizing their toxicity is a plausible approach. In our investigation, we employed paclitaxel as the standard chemotherapeutic agent and utilized Chrysin-functionalized gold nanoparticles (CHR-AuNP) to augment its cytotoxicity. Gold nanoparticles were chosen for their inherent cytotoxic properties and ability to enhance Chrysin's bioavailability and solubility.Characterization of CHR-AuNP revealed spherical nanoparticles within the nano-size range (35-70 nm) with a stable negative zeta potential of -22 mV, confirmed by physicochemical analyses including UV-Vis spectroscopy, FT-IR, and visual observation of the wine-red coloration. MTT assay cytotoxicity studies demonstrated CHR-AuNP's superior efficacy compared to CHR alone, with synergistic effects observed in combination with paclitaxel, validated by Compusyn software. Morphological changes indicative of apoptosis were more pronounced with combined treatment, corroborated by AO/ETBr staining and Annexin V assays. Furthermore, the combination treatment amplified ROS production and destabilized mitochondrial membrane potential, while altering the expression of pro-apoptotic and anti-apoptotic proteins. Exploring the mechanistic pathways, we found that the drugs upregulated PPAR-γ expression while suppressing Akt and overexpressing PTEN, thereby impeding the Wnt/ß-catenin pathway commonly dysregulated in lung cancer. This highlights the potential of low-dose combination therapy with paclitaxel and CHR-AuNP as a promising strategy for addressing lung cancer's challenges.
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Current drugs are inefficient for the treatment of visceral leishmaniasis an immunosuppressive ailment caused by Leishmania donovani. Regrettably, there is no plant-origin antileishmanial drug present. P2X7R is constitutively present on macrophage surfaces and can be a putative therapeutic target in intra-macrophage pathogens with function attributes towards inflammation, host cell apoptosis, altered redox, and phagolysosomal maturation by activating p38MAPK. Here we demonstrated that the initial interaction of Spergulin-A (Sp A), a triterpenoid saponin with RAW 264.7 macrophages was mediated through P2X7R involving the signaling cascade intermediates Ca++, p38MAPK, and NF-κß. Phospho (P)-p38MAPK involvement is shown to have specific and firm importance in leishmanial killing with increased NF-κßp65. Phago-lysosomal maturation by Sp A also campaigns for another contribution of P2X7R. In vivo evaluation of the anti-leishmanial activity of Sp A was monitored through expression analyses of P2X7R, P-p38MAPK, and NF-κßp65 in murine spleen and bone-marrow macrophages and supported Sp A being a natural compound of leishmanicidal functions which acted through the P2X7R-p38MAPK axis.
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Proteínas de Transporte/metabolismo , Leishmania donovani , Leishmaniose Visceral , Animais , Leishmania donovani/metabolismo , Leishmaniose Visceral/tratamento farmacológico , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Receptores Purinérgicos P2X7/metabolismo , Transdução de Sinais , Baço/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
In this study, we have designed and synthesized a new hybrid ligand (SCG) that can selectively detect cysteine in the free and protein-bound states within minutes at the subnanomolar level. Photoinduced electron transfer was responsible for the visible color change as well as a large increase in steady state fluorescence. This detection was validated by using multiple model protein systems with differing cysteine environments and spatial arrangements. SCG was able to monitor the early events of the folding/aggregation kinetics of α-synuclein, a protein involved in the pathology of Parkinson's disease. The early events consisted of conformational fluctuations between different forms of the protein and oligomer formation. SCG was found to be effective in detecting early isomers of α-syn in vitro and in live cell environments.
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Proliferação de Células , Cisteína/química , Corantes Fluorescentes/química , Neuroblastoma/patologia , Multimerização Proteica , Bibliotecas de Moléculas Pequenas/química , alfa-Sinucleína/química , Humanos , Neuroblastoma/metabolismo , Células Tumorais Cultivadas , alfa-Sinucleína/metabolismoRESUMO
Very often conventional therapy, i.e. chemotherapeutic treatment, develops resistance in cancer cells and fails to be effective against disease states. An alternative strategy or a new entity may resolve the problem. Interestingly, the microbial world has begun to be explored in medicinal research as a potential new source to deliver bio-active molecules such as sphingolipids for efficacious cancer treatment. A sphingolipid of microbial origin, especially from Leishmania donovani (LSPL), is a novel entity which may exert anti-cancer activity by regulating cellular growth. The present study reveals that among a range of cancer cells evaluated, LSPL-1 (a component of LSPL) reduces cell viability, annexin exposures and arrests cell cycle in B16F10 cells in a concentration and time dependent manner. Flowcytometric analysis showed that it alters mitochondrial membrane potential and generates a number of ROS positive melanoma cells. It activates p53 at serine anchor region via up-regulation of p21 subunit along with PUMA and NOXA. It also exerts activity in vivo by reducing tumor micro vessel and mitotic index while simultaneously improving the survival rate. The inflammatory responses including elevated level of cytokine-chemokine and increased expression of PCNA and F480 are subdued by LSPL-1 treatment in tumour bearing mice. Besides, it reduces the metastatic outburst of angiogenic factors like VEGF, Ang-2, and CD34 through the involvement of several growth promoting factors. These findings indicate that LSPL-1 may be explored as a potent entity against melanoma growth and the associated angiogenic promotion.
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Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Leishmania donovani/química , Neovascularização Patológica/metabolismo , Esfingolipídeos/farmacologia , Animais , Linhagem Celular Tumoral , Feminino , Inflamação/metabolismo , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Sepsis is the reflection of systemic immune response that manifests in the sequential inflammatory process in presence of infection. This may occur as a result of gram-negative bacterial sepsis including Escherichia coli infection that gives rise to excessive production of inflammatory mediators and causes severe tissue injuries. We have reported earlier that the lipid of attenuated Leishmania donovani suppresses the inflammatory responses in arthritis patients. Using heat killed E. coli stimulated macrophages, we have now investigated the effect of leishmanial total lipid (LTL) isolated from Leishmania donovani (MHO/IN/1978/UR6) for amelioration of the inflammatory mediators and transcriptional factor with suppression of TLR4-CD14 expression. To evaluate the in vivo effect, E. coli induced murine sepsis model was used focusing on the changes in different parameter(s) of lung injury caused by sepsis, namely, edema, vascular permeability, and pathophysiology, and the status of different cytokine-chemokine(s) and adhesion molecule(s). Due to the effect of LTL, E. coli induced inflammatory cytokine-chemokine(s) levels were significantly reduced in serum and bronchoalveolar lavage fluid simultaneously. LTL also improved the lung injury and suppressed the cell adhesion molecules in lung tissue. These findings indicate that LTL may prove to be a potential anti-inflammatory agent and provide protection against gram-negative bacterial sepsis with pulmonary impairment.
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Escherichia coli/patogenicidade , Inflamação/tratamento farmacológico , Leishmania donovani/química , Lipídeos/uso terapêutico , Sepse/tratamento farmacológico , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Escherichia coli/efeitos dos fármacos , Feminino , Lipídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Microscopia de FluorescênciaRESUMO
(-)-Epigallocatechin-3-gallate (EGCG), a bioactive polyphenol of green tea, has chemo-preventive effects against various cancer cells. Nanoparticles (NPs) carrying different ligands are able to specifically interact with their receptors on different cancer cells that can provide effective release of cytotoxic drugs. In the present study, we have prepared EGCG entrapped NPs using PLGA (poly(d,l-lactide-co-glycolide)). Polyethylene glycol (PEG) and folic acid (FA) via double emulsion solvent evaporation (DESE) method obtained PLGA-EGCG (P-E), PLGA-PEG-EGCG (PP-E), and PLGA-PEG-FA-EGCG (PPF-E). Nanoformulations had been characterized with 1H NMR and FT-IR techniques, AFM, and DLS. PPF-E NPs showed an average size of 220 nm. Analysis of zeta potential confirmed the stability of NPs. HCT-116, HT-29, HCT-15, and HEK 293 cells were treated with both the prepared NPs and free EGCG (0-140 µM). Result showed PPF-E NPs had improved delivery, uptake and cell cytotoxicity toward human folic acid receptor-positive (FR+) colorectal cancer (CRC) cells as mainly on HCT-116 compared to HT-29, but not on the folic acid-negative cells (FR-) as HCT-15. PPF-E NPs enhanced intracellular reactive oxygen species (ROS) level in absence of N-acetyl-l-cysteine (NAC), elevated DNA fragmentation level, and increased apoptotic cell death at higher doses compared to other two NPs and free EGCG. In conclusion, PPF-E NPs exerted greater efficacy than PP-E, P-E, and free EGCG in HCT-116 cells.
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Nanoparticles (NPs) are encapsulating agents that exist in the nanometer range. They can be classified into different classes based on their properties, shapes, or sizes. Metal NPs, fullerenes, polymeric NPs, ceramic NPs, and luminescent nanoporous hybrid materials are only a few examples. This study explored the anticancer potential of quercetin and 5-fluorouracil-encapsulated chitosan nanoparticles (CS-5-FU-QCT NPs). The nanoparticles were prepared by ionic gelation, and their efficacy and mechanism of action were examined. CS-5-FU-QCT NPs were characterized using dynamic light scattering (DLS), atomic force microscopy (AFM), UV-visible spectroscopy, and Fourier transform infrared spectroscopy (FTIR); cytotoxicity was analyzed using an MTT assay. Cells were treated with CS-5-FU-QCT NPs and incubated for 12, 24, and 36 h, and apoptosis analysis (using Annexin V/FITC), cell-cycle analysis, Western blotting, and confocal microscopic analysis were performed. Biophysical analysis revealed that the CS-5-FU-QCT NPs fall in the range of 300-400 nm with a near-spherical shape. The in vitro drug release profile indicates sustained release of drugs over a period of about 36 h. The cytotoxicity of CS-5-FU-QCT NPs was more prominent in HCT116 cells than in other cancer cells. This particular nanoformulation caused G0/G1 phase cell-cycle arrest in HCT116 cells and induced intracellular ROS generation, thereby causing apoptosis. It also downregulated Bcl2, cyclin D1, and Cdk4 and upregulated BAX, p53, and p21, causing cell-cycle arrest and apoptosis. In summary, CS-5-FU-QCT NPs hindered proliferation of HCT116 cells via ROS generation and altered the expression of key proteins in the p53/p21 axis and apoptotic machinery in a time-dependent manner.
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Objective: Grape Seed Extract is a natural source of various polyphenols, which have been shown to possess potent antioxidant and free radical-scavenging activities. The earlier studies have reported that grape seed extract exhibits broad-spectrum pharmacological activities. Therefore, studying the hepatoprotective effects and elucidation of mechanisms of action of the Indian Variety, Manjari Medika grape seed extract (GSE), may give an insight into therapeutic benefits. Methotrexate (MTX) is the first-line pharmacological therapy for different rheumatic diseases. The major adverse events such as hepatotoxicity are evident even in the low doses used for the treatment. The present study investigated the role of MTX on hepatic damage in murine liver and the plausible protective effects of the Indian grape variety, Manjari Medika grape seed extract, in ameliorating it. Methods and Results: To assess the hepatological modulation, mice were divided into eight groups to investigate the ameliorative potential of this GSE (75 and 125 mg/kg) and correlate the experimental findings. The active components of the extract were assessed through UPLC-(ESI)-QToF-MS analysis. On the other hand, various biochemical and immunological indices were carried out to correlate the experimental data. The result demonstrated that the prophylactic administration of GSE reduced MTX-induced hepatic toxicity indices, which subsequently restored the hepatic morphological architecture. Moreover, the application of GSE in a dual dosage (75 and 125 mg/kg) suppressed MTX-induced reactive oxygen species generation, followed by lipid peroxidation and cellular nitrite formation. MTX-induced inflammasome activation through the redox-assisted cascade of TLR4/NF-κB signaling was further reduced by applying the GSE. The results showed that the activation of cytoprotective transcription factor Nrf2 enhanced the level of endogenous antioxidants. Furthermore, through the regulation of TLR4/NF-κB and Nrf2/HO-1 axis, this extract could reduce the MTX-mediated hepatic damage. Conclusion: Our findings suggest that Manjari Medika seed extract could be used as a therapeutic agent to relieve the side effects of MTX and other hepatic disorders.
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Different quinazoline derivatives have showed wide spectrum of pharmacological activities. Some 3-(arylideneamino)-phenylquinazoline-4(3H)-ones have been reported to possess antimicrobial activity. The present study has been undertaken to evaluate the anticancer effect of these quinazolinone derivatives. The quinazolinone derivatives were synthesized as reported earlier. Compounds containing NO(2), OH, OCH(3), or OH and OCH(3) as substituent(s) on the arylideneamino group were named as P(3a), P(3b), P(3c), and P(3d) respectively. Out of these, P(3a) and P(3d) showed better cytotoxic activity than P(3b) and P(3c) on a panel of six cancer cell lines of different origin, namely, B16F10, MiaPaCa-2, HCT116, HeLa, MCF7, and HepG2, though the effect was higher in B16F10, HCT116, and MCF7 cells. P(3a) and P(3d) induced death of B16F10 and HCT116 cells was associated with characteristic apoptotic changes like cell shrinkage, nuclear condensation, DNA fragmentation, and annexin V binding. Also, cell cycle arrest at G1 phase, alteration of caspase-3, caspase-9, Bcl-2 and PARP levels, loss of mitochondrial membrane potential, and enhanced level of cytosolic cytochrome c were observed in treated B16F10 cells. Treatment with multiple doses of P(3a) significantly increased the survival rate of B16F10 tumor bearing BALB/c mice by suppressing the volume of tumor while decreasing microvascular density and mitotic index of the tumor cells.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Quinazolinas/farmacologia , Animais , Anexina A5/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Citocromos c/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Células HCT116 , Células HeLa , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Neoplasias/tratamento farmacológico , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quinazolinas/química , Quinazolinas/uso terapêutico , Transplante HeterólogoRESUMO
Background: NLRP3 inflammasome activation plays a critical role in mediating inflammation and NASH (non-alcoholic steatohepatitis) progression that ultimately leads to cirrhosis and hepatocellular carcinoma. Melatonin (MLT) controls high-fat diet-induced NASH in the murine model by modulating NLRP3 mediated inflammation. P2X7R-mediated inflammasome activation is reported in several inflammatory models including NASH. Objective: The role of MLT in P2X7R-mediated inflammation in the NASH model has not yet been explored. The present study investigated the role of MLT in amending high-fat diet-induced nonalcoholic steatohepatitis in the murine liver. Methods: To evaluate the hepatological changes, mice were divided into four groups to investigate the improvement potential of this MLT (10 and 20 mg/kg) and to assess the experimental findings. Histology, biochemical assays, ELISA, FACS analysis, Western blotting, and IF were performed to assess the physical and molecular changes upon melatonin treatment. Results: The result demonstrated that MLT administration reduced HFD (high-fat diet)-induced non-alcoholic steatohepatitic indices, which successively restored the hepatic morphological architecture and other pathophysiological features too. Moreover, the application of MLT suppressed HFD-induced activation of the inflammasome and through TLR4/NF-κB signaling. Herein, we report that MLT significantly suppresses P2X7R expression and calcium influx along with inflammasome in both in vitro and in vivo. The docking study revealed a strong binding affinity of MLT with P2X7R. Moreover, the results also showed that the Nrf2 level was boosted which may normalize the expression of antioxidant proteins that safeguard against oxidative damage triggered by inflammation. Furthermore, some matrix metalloproteinases like MMP 2 and MMP 9 were repressed and TIMP-1 level was increased, which also signifies that MLT could improve liver fibrosis in this model. Conclusion: Based on our findings, this study may conclude that MLT could be used as a therapeutic agent in the high-fat diet-induced NASH model as it has persuasive anti-inflammatory potential.
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Recently unfolded mechanisms showed lipid droplet helps in pathogen survival and paralyzes host immune response. In the present study, we showed the extent of lipid droplet(LD) generation in Leishmania donovani infection, the signaling involved, and their function concerning pathogenicity. RAW 264.7 and J774A.1 cells were used to infect with L. donovani and then flow cytometry and confocal microscopy were used to detect lipid droplet generation and subsequent assays. In this study, we showed that L. donovani AG83 (AG83/MHOM/1983) triggers lipid droplet formation in macrophages in a time-dependent manner. We provide novel insight into the signaling molecules which is responsible for LD accumulation. Interestingly, LPG deficient attenuated Leishmania strain UR6 (UR6/MHOM/1978) failed to fuel LD generation. But inhibition of phagosome maturation drastically stimulates LD accumulation in UR6 infected MΦs. Aspirin treatment in AG83 infected MΦs does not only lower LD load but also favors phagolysosome biogenesis and corrects cytokine balance. Employing strategies to circumvent halt in phagosome maturation using drugs that manipulate lipid droplet generation could be used as a therapeutic tool to resist parasite growth in the early hour of infection.
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Leishmania donovani/patogenicidade , Leishmaniose Visceral/metabolismo , Gotículas Lipídicas/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Macrófagos/metabolismo , Animais , Linhagem Celular , Citocinas/metabolismo , Camundongos , Fagocitose/fisiologia , Células RAW 264.7RESUMO
Colon cancer is the second highest contributor of cancer-related deaths throughout the world. Treatment strategies with tannic acid and vitamin E are envisaged as desirable and safe owing to their robust antioxidative and anti-inflammatory potential. In the present report, these bioactives have been nanoencapsulated in poly(d,l-lactide-co-glycolic acid) (PLGA) formulations for maintaining sustained release and ensuring enhanced bioavailability. Capping of nanoparticles (NPs) with chitosan was done for enhanced anticancer efficacy and tumor targeting. CS-PLGA-TA-E, administered intraperitoneally, significantly inhibited tumor number and tumor volume and normalized colon histology in the colon cancer. Tissue distribution studies showed that TA/E content from CS-PLGA-TA-E was present in a higher concentration in the tumor tissue than the concentration of TA/E content from PLGA-TA-E or free TA or free E. Also, the TA/E content from all of the treatment groups showed its highest concentration in the tumor compared to other organs. Antioxidant enzymes and proinflammatory cytokines (TNF-α, IL-1ß, IL-6) were inhibited by CS-PLGA-TA-E. CS-PLGA-TA-E inhibited markers for tumor growth (EGFR-PI3K-AKT), inflammation (NF-κB/Stat3), ß-catenin signaling (ß-catenin, c-myc, cyclin D1), EMT (E-cadherin, N-cadherin, vimentin), and apoptosis (Bcl-2) in a significantly greater way as compared with PLGA-TA-E, TA, or E. CS-PLGA-TA-E NPs can be considered promising anticancer drugs for colon cancer.
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Andrographis paniculata (Burm. f.) Nees and Andrographis nallamalayana J.L.Ellis have traditionally been used to treat various ailments such as mouth ulcers, intermittent fever, inflammation, snake bite. This study compares the comparative in vitro cytotoxic activity, and phytochemical profiling of methanol extract of A. nallamalayana (ANM) and A. paniculata (APM). UPLC-ESI-QTOF-MS/MS analysis has been performed. The cytotoxic activity of crude methanol extracts were evaluated against three different cancer cell lines (HCT 116, HepG2, and A549 cell line). Both plants' extract exhibited significant cytotoxic activity against tested cell lines in a dose-dependent manner. IC50 of ANM and APM in HCT 116 cell was 11.71 ± 2.48 µg ml-1 and 45.32 ± 0.86 µg ml-1 and in HepG2 cell line was 15.65 ± 2.25 µg ml-1 and 60.32 ± 1.05 µg ml-1 respectively. Cytotoxicity of these two extracts was comparatively similar in A549 cells. ANM induced cytotoxicity involved programmed cell death, externalisation of phosphatidylserine, ROS generation, up-regulation and down-regulation of major apoptotic markers. HRMS analysis of ANM and APM resulted in the identification of 59 and 42 compounds, respectively. Further, using the MS/MS fragmentation approach, 20 compounds, of which 18 compounds were identified for the first time from ANM, which belongs to phenolic acids, flavonoids, and their glycosides. Three known compounds, echioidinin, skullcapflavone I and 5,2',6'-trihydroxy-7-methoxyflavone 2'-O-ß-d-glucopyranoside, were isolated from A. nallamalayana and their crystal structures were reported for the first time. Subsequently, seven major compounds were identified in A. nallamalayana by direct comparison (retention time and UV-spectra) with authentic commercial standards and isolated compounds using HPLC-UV analysis. The cytotoxicity of phytochemicals from both the plants using in silico tools also justify their in vitro cytotoxic activity. It is the first report on the comparative characterisation of phytochemicals present in the methanolic extract of both the species of Andrographis, along with the cytotoxic activity of A. nallamalayana.
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Aim: Tannic acid and vitamin E loaded-poly D, L-lactide-co-glycolic acid (PLGA) nanoparticles (NP) were developed to achieve hepatoprotection in alcoholic liver disease mice model. Materials & methods: PLGA NPs were formed by emulsion solvent evaporation and characterized and delivered to mice. Histology studies were performed, serum enzyme levels of AST, ALT and inflammatory cytokines were checked using ELISA kits. Confocal microscopy and western blot analysis were utilized to determine protein expression levels, and docking studies were performed for interaction analysis. Results: PLGA NPs provided hepatoprotection by reducing inflammatory load, preventing reactive oxygen species generation and apoptosis, as well as by inhibiting the EGFR-AKT-STAT3 pathway. Conclusion: PLGA NPs of tannic acid and vitamin E could be a future medication for alcoholic liver disease treatment.
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Hepatopatias Alcoólicas/tratamento farmacológico , Fígado/efeitos dos fármacos , Proteína Oncogênica v-akt/genética , Fator de Transcrição STAT3/genética , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos/efeitos dos fármacos , Receptores ErbB/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/patologia , Hepatopatias Alcoólicas/patologia , Camundongos , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Taninos/química , Taninos/farmacologia , Vitamina E/química , Vitamina E/farmacologiaRESUMO
Three asymmetric tridentate acyl hydrazone Schiff base ligands namely L1, L2 and L3 were prepared via condensation of 4-methoxybenzohydrazide with picolinaldehyde, 1-(pyridin-2-yl)ethanone and phenyl(pyridin-2-yl)methanone respectively. Three bio-relevant mononuclear zinc(ii) complexes [Zn(L1)Cl2]·2H2O (1), [Zn(L2)Cl2] (2) and [Zn(L3)Cl2] (3) were synthesized by treatment of zinc(ii) chloride with the corresponding Schiff base ligands and characterised by the usual physicochemical techniques. The solid state structures of complexes 1 and 3 were evaluated by single crystal X-ray analysis. All complexes were able to hydrolyse the P-O bond of the phosphate monoester in 90% (v/v) DMSO-water medium using 4-nitrophenylphosphate (4-NPP) as the model substrate and the trend in their activity is 1≈2 > 3. On considering the highly efficient hydrolysis properties, complexes 1-3 were tested as potential therapeutic agents for cancer using HCT116 (human colorectal carcinoma), HepG2 (human hepatocellular carcinoma) and A549 (human non-small lung carcinoma) cells. Complex 2 showed the highest IC50 values for anti-cancer activity towards all three cell lines among the three complexes and complex 3 showed the least activity as observed in the phosphatase activity study. The internucleosomal degradation of DNA during apoptosis can be detected by cell death detection ELISA. DNA fragmentation that leads to cell death was examined and when induced by complex 2 in HepG2 cells a significant level of DNA fragmentation was observed at regular intervals of time.
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Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Hidrazonas/química , Monoéster Fosfórico Hidrolases/metabolismo , Zinco/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Humanos , Cinética , Bases de Schiff/químicaRESUMO
The development of drug carriers based on nanomaterials that can selectively carry chemotherapeutic agents to cancer cells has become a major focus in biomedical research. A novel pH-sensitive multifunctional envelope-type mesoporous silica nanoparticle (SBA-15) was fabricated for targeted drug delivery to human colorectal carcinoma cells (HCT-116). SBA-15 was functionalized with folic acid (FA), and the material was loaded with the water-insoluble flavonoid, quercetin (QN). Additionally, acid-labile magnetite Fe3O4 nanoparticles were embedded over the FA-functionalized QN-loaded monodisperse SBA-15 to prepare the highly orchestrated material FA-FE-SBA15QN. The in vitro and in vivo anti-carcinogenic efficacy of FA-FE-SBA15QN was carried out to explore the pH-sensitive QN release with putative mechanistic aspects. FA-FE-SBA15QN caused a marked tumor suppression, and triggered mitochondrial-dependent apoptosis through a redox-regulated cellular signaling system. Furthermore, FA-IO-SBA-15-QN initiated the c-Jun N-terminal Kinase (JNK)-guided H2AX phosphorylation, which relayed the downstream apoptotic signal to the phosphorylate tumor suppressor protein, p53. On the other hand, the selective inhibition of heat shock protein-27 (HSP-27) by FA-FE-SBA15QN augmented the apoptotic fate through JNK/H2AX/p53 axis. The in vitro and in vivo magnetic resonance imaging (MRI) studies have indicated the theranostic perspective of the composite. Thus, the result suggested that the newly synthesized FA-FE-SBA15QN could be used as a promising chemo theranostic material for the management of carcinoma.
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A set of unique triptycene-based and organic Schiff-base-linked polymers (TBOSBLs) are conveniently synthesized in which triptycene motifs are connected with 1,3,5-triformylphloroglucinol units via Schiff-base linkages. TBOSBLs are amorphous, thermally stable with a reasonable surface area (SABET up to 649 m2/g), and have abundant nanopores (pore size < 100 nm). TBOSBLs are good sorbents for small gas molecules (such as CO2, H2, and N2) and they can selectively capture CO2 over N2. Additionally, TBOSBLs show superior antiproliferative activity against human colorectal cancer cells relative to previously reported covalent organic frameworks (COFs). The mechanism of cell death is also studied elaborately.
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We report here the preparation of an aminoxy amide-based pseudopeptide-derived building block using furanoid sugar molecules. Through the cyclo-oligomerization reaction, we generate a hybrid triazole/aminoxy amide macrocycle using the as-prepared building block. The novel conformation of the macrocycle has been characterized using NMR and molecular modeling studies, which show a strong resemblance of our synthesized compound to d-,l-α-aminoxy acid-based cyclic peptides that contain uniform backbone chirality. We observe that the macrocycle can efficiently and selectively bind Cl- ion and transport Cl- ion across a lipid bilayer. 1H NMR anion binding studies suggest a coherent relationship between the acidity of aminoxy amide N-H and triazole C-H proton binding strength. Using time-based fluorescence assay, we show that the macrocycle acts as a mobile transporter and follows an antiport mechanism. Our synthesized macrocycle imposes cancer cell death by disrupting ionic homeostasis through Cl- ion transport. The macrocycle induced cytochrome c leakage and changes in mitochondrial membrane potential along with activation of family of caspases, suggesting that the cellular apoptosis occurs through a caspase-dependent intrinsic pathway. The present results suggest the possibility of using the macrocycle as a biological tool of high therapeutic value.
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BACKGROUND: Many of present chemotherapeutics are inadequate and also resistant against visceral leishmaniasis (VL), an immunosuppressive ailment caused by Leishmania donovani. Despite the interest in plant-based drug development, no antileishmanial drugs from plant source are currently available. Glinus oppositifolius had been reported in favor of being immune modulators along with other traditional uses. Novel anti-VL therapies can rely on host immune-modulation with associated leishmanicidal action. OBJECTIVE: Discovery of novel plant-based antileishmanial compound from G. oppositifolius having permissible side effects. METHODS: With this rationale, an n-BuOH fraction of the methanolic extract of the plant and obtained triterpenoid saponin Spergulin-A were evaluated against acellular and intracellular L. donovani. Immunostimulatory activity of them was confirmed by elevated TNF-α and extracellular NO production from treated MФs and was found nontoxic to the host cells. Identification and structure confirmation for isolated Spergulin-A was performed by ESI-MS,13C, and 1H NMR. RESULTS: Spergulin-A was found ineffective against the acellular forms while, against the intracellular parasites at 30 µg/mL, the reduction was 92.6% after 72 hrs. Spergulin-A enhanced ROS and nitric oxide (NO) release and changes in Gp91-phox, i-NOS, and pro and anti-inflammatory cytokines elaborated its intracellular anti-leishmanial activity. CONCLUSION: The results supported that G. oppositifolius and Spergulin-A can potentiate new lead molecules for the development of alternative drugs against VL.
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A bolaamphiphilic cross-linked nanoassembly endowed with pH responsive degradation features has been designed and fabricated for stable noncovalent guest encapsulation and controlled release. The self-assembled bolaamphiphile is utilized to prepare cross-linked nanoassemblies to further stabilize the noncovalent guest encapsulation at a concentration below its critical aggregation concentration (CAC) in a large volume of water or serum for drug delivery applications. Thus, this system can simultaneously address premature drug release and safety issues. The nanoassemblies integrated with a ß-thioester linker, which can be hydrolyzed selectively under mildly acidic conditions (pH â¼ 5.3) at a slow rate, thus enable controlled release of guest molecules. Biological evaluation revealed that doxorubicin loaded cross-linked nanoassemblies (CNs-DOX) are nontoxic to normal cells such as HEK-293 or PBMC, but in contrast, showed a robust apoptotic effect on colon cancer cells, HCT-116, indicating excellent specificity. Thus, the fabrication reproducibility, robust stability, triggered drug release and cell selective toxicity behavior make this small molecular system very promising in the field of chemotherapeutic applications.