RESUMO
Eosinophilic esophagitis (EoE) and gastroesophageal reflux disease (GERD) share many histopathological features; therefore, markers for differentiation are of diagnostic interest and may add to the understanding of the underlying mechanisms. The nitrergic system is upregulated in GERD and probably also in EoE. Esophageal biopsies of patients with EoE (n = 20), GERD (n = 20), and healthy volunteers (HVs) (n = 15) were exposed to antibodies against inducible nitric oxide synthase (iNOS), nitrotyrosine, eosinophilic peroxidase, eotaxin-3, and galectin-3. The stained object glasses were randomized, digitized, and blindly analyzed regarding the expression of DAB (3,3'-diaminobenzidine) by a protocol developed in QuPath software. A statistically significant overexpression of iNOS was observed in patients with any of the two inflammatory diseases compared with that in HVs. Eotaxin-3 could differentiate HVs versus inflammatory states. Gastroesophageal reflux patients displayed the highest levels of nitrotyrosine. Neither iNOS nor nitrotyrosine alone were able to differentiate between the two diseases. For that purpose, eosinophil peroxidase was a better candidate, as the mean levels increased stepwise from HVs via GERD to EoE. iNOS and nitrotyrosine are significantly overexpressed in patients with EoE and GERD compared with healthy controls, but only eosinophil peroxidase could differentiate the two types of esophagitis. The implications of the finding of the highest levels of nitrotyrosine among gastroesophageal reflux patients are discussed.
Assuntos
3,3'-Diaminobenzidina , Quimiocina CCL26 , Peroxidase de Eosinófilo , Esofagite Eosinofílica , Galectina 3 , Refluxo Gastroesofágico , Óxido Nítrico Sintase Tipo II , Tirosina , Humanos , Óxido Nítrico Sintase Tipo II/metabolismo , Refluxo Gastroesofágico/metabolismo , Refluxo Gastroesofágico/patologia , Feminino , Esofagite Eosinofílica/metabolismo , Esofagite Eosinofílica/patologia , Tirosina/análogos & derivados , Tirosina/metabolismo , Tirosina/análise , Masculino , Adulto , Pessoa de Meia-Idade , Biópsia , Peroxidase de Eosinófilo/metabolismo , Peroxidase de Eosinófilo/análise , Quimiocina CCL26/metabolismo , Galectina 3/metabolismo , Galectina 3/análise , Estudos de Casos e Controles , Esôfago/patologia , Esôfago/metabolismo , Biomarcadores/análise , Biomarcadores/metabolismo , Quimiocina CCL24/metabolismo , Adulto Jovem , Idoso , Imuno-HistoquímicaRESUMO
Krüppel-like factor 8 (KLF8) is a transcription factor expressed abnormally in various cancer types and promotes oncogenic transformation. However, the role of KLF8 in ovarian cancer (OC) progression remains unclear. This study reports that transforming growth factor-ß1 (TGF-ß1)/Smad2/KLF8 axis regulates epithelial-mesenchymal transition (EMT) and contributes to OC progression. We analyzed the KLF8 expression in OC cells and tissues, wherein a significant overexpression of KLF8 was observed. Increased KLF8 expressions were correlated with higher cell proliferation, EMT, migration, and invasion and conferred poor clinical outcomes in OC patients. Overexpressed KLF8 increases F-actin polymerization and induces cytoskeleton remodeling of OC cells. Furthermore, a dissection of the molecular mechanism defined that TGF-ß1 triggers KLF8 through the Smad2 pathway and regulates EMT. Pharmacological and genetic inhibition of Smad2 followed by TGF-ß1 treatment failed to activate KLF8 expression and induction of EMT. Using promoter-luciferase reporter assays, we defined that upon TGF-ß1 activation, phosphorylated Smad2 binds and promotes the KLF8 promoter activity, and knockdown of Smad2 inhibits KLF8 promoter activation. Together, these results demonstrate that TGF-ß1 activates KLF8 expression by the Smad2 pathway, and KLF8 contributes to OC progression and may serve as a potential therapeutic strategy for treating OC patients.
Assuntos
Neoplasias Ovarianas , Fator de Crescimento Transformador beta1 , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias Ovarianas/genética , Proteína Smad2/genética , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Four two-dimensional (2D), fluorinated metal-organic frameworks (MOFs), [Cu(hfipbb)(DMF)]n·0.5(DMF)n (1), [Cu(hfipbb)(DEF)]n (2), [Cu3(hfipbb)3(DMA)3]n·6(DMA)n·2(H2O)n (3), and [Cu2(hfipbb)2(DEA)2]n·2(DEA)n·2(H2O)n (4), have been synthesized where hfipbb = 4,4'-(hexafluoroisopropylidene)bis(benzoate), DMF = N,N'-dimethylformamide, DEF = N,N'-diethylformamide, DMA = N,N'-dimethylacetamide, and DEA = N,N'-diethylacetamide. The choice of either a formamide or acetamide solvent ligand leads to a 2D, doubly interpenetrated (1 and 2) or noninterpenetrated (3 and 4) MOF structure. Despite their lower potential void spaces, the doubly interpenetrated structures have superior carbon dioxide and hydrogen sorption properties. Their 195 K CO2 sorption isotherms display inflection points, followed by â¼3-fold increases in their sorption capacities and very large extents of hysteretic behavior. This shows that small changes in the identity of the ligated solvent ligand can affect whether the resulting MOF is interpenetrated or noninterpenetrated and so drastically affect the sorption properties. In addition, the activated phase of a fifth MOF, synthesized through DMF ligand exchange with water in 1 (1W), does not display an inflection point and subsequent increased CO2 sorption at 195 K, despite having the same degree of interpenetration, showing that even more subtle differences in the desolvated phases can lead to marked differences in their sorption behavior.
RESUMO
In December 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a novel variant of coronavirus has emerged from Wuhan in China and has created havoc impulses across the world with a larger number of fatalities. At the same time, studies are on roll to discover potent vaccine against it or repurposing of approved drugs which are widely adopted are under trial to eradicate the SARS-CoV-2 causing COVID-19 pandemic. Reports have also shown that there are asymptomatic carriers of COVID-19 disease who can transmit the disease to others too. However, the first line defense of the viral attack is body's strong and well-coordinated immune response producing excessive inflammatory innate reaction, thus impaired adaptive host immune defense which lead to death upon the malfunctioning. Considerable works are going on to establish the relation between immune parameters and viral replication that, might alter both the innate and adaptive immune system of COVID-19 patient by up riding a massive cytokines and chemokines secretion. This review mainly gives an account on how SARS-CoV-2 interacts with our immune system and how does our immune system responds to it, along with that drugs which are being used or can be used in fighting COVID-19 disease. The curative therapies as treatment for it have also been addressed in the perspective of adaptive immunity of the patients.
Assuntos
COVID-19/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Imunidade Adaptativa , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Mapeamento de Epitopos , Humanos , Imunidade CelularRESUMO
Two Cu(II)-based metal-organic frameworks (MOFs) having paddle-wheel secondary building units (SBUs), namely, 1Me and 1ipr, were synthesized solvothermally using two new bent di-isophthalate ligands incorporating different substituents. The MOFs showed high porosity (BET surface area, 2191 m2/g for 1Me and 1402 m2/g for 1ipr). For 1Me, very high CO2 adsorption (98.5 wt % at 195 K, 42.9 wt % at 273 K, 23.3 wt % at 298 K) at 1 bar was found, while for 1ipr, it was significantly less (14.3 wt % at 298 K and 1 bar, 54.4 wt % at 298 K at 50 bar). 1Me exhibited H2 uptake of 3.2 wt % at 77 K and 1 bar of pressure, which compares well with other benchmark MOFs. For 1ipr, the H2 uptake was found to be 2.54 wt % under similar experimental conditions. The significant adsorption of H2 and CO2 for 1Me could be due to the presence of micropores as well as unsaturated metal sites in these MOFs besides the presence of substituents that interact with the gas molecules. The experimental adsorption behavior of the MOFs could be justified by theoretical calculations. Additionally, catalytic conversions of CO2 and CS2 into useful chemicals like cyclic carbonates, cyclic trithiocarbonates, and cyclic dithiocarbonates could be achieved.
RESUMO
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders that exist on a symptomological spectrum and share both genetic underpinnings and pathophysiological hallmarks. Functional abnormality of TAR DNA-binding protein 43 (TDP-43), an aggregation-prone RNA and DNA binding protein, is observed in the vast majority of both familial and sporadic ALS cases and in ~40% of FTLD cases, but the cascade of events leading to cell death are not understood. We have expressed human TDP-43 (hTDP-43) in Drosophila neurons and glia, a model that recapitulates many of the characteristics of TDP-43-linked human disease including protein aggregation pathology, locomotor impairment, and premature death. We report that such expression of hTDP-43 impairs small interfering RNA (siRNA) silencing, which is the major post-transcriptional mechanism of retrotransposable element (RTE) control in somatic tissue. This is accompanied by de-repression of a panel of both LINE and LTR families of RTEs, with somewhat different elements being active in response to hTDP-43 expression in glia versus neurons. hTDP-43 expression in glia causes an early and severe loss of control of a specific RTE, the endogenous retrovirus (ERV) gypsy. We demonstrate that gypsy causes the degenerative phenotypes in these flies because we are able to rescue the toxicity of glial hTDP-43 either by genetically blocking expression of this RTE or by pharmacologically inhibiting RTE reverse transcriptase activity. Moreover, we provide evidence that activation of DNA damage-mediated programmed cell death underlies both neuronal and glial hTDP-43 toxicity, consistent with RTE-mediated effects in both cell types. Our findings suggest a novel mechanism in which RTE activity contributes to neurodegeneration in TDP-43-mediated diseases such as ALS and FTLD.
Assuntos
Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Drosophila melanogaster/genética , Doenças Neurodegenerativas/genética , Retroelementos/genética , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas de Ligação a DNA/metabolismo , Drosophila melanogaster/metabolismo , Drosophila melanogaster/ultraestrutura , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/metabolismo , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Doenças Neurodegenerativas/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Emerging shreds of evidence suggest that tumor-associated macrophages (TAMs) modulate various hallmarks of cancer during tumor progression. Tumor microenvironment (TME) prime TAMs to execute important roles in cancer development and progression, including angiogenesis, matrix metalloproteinases (MMPs) secretion, and extracellular matrix (ECM) disruption. MicroRNAs (miRNAs) are critical epigenetic regulators, which modulate various functions in diverse types of cells, including macrophages associated with TME. In this review article, we provide an update on miRNAs regulating differentiation, maturation, activation, polarization, and recruitment of macrophages in the TME. Furthermore, extracellular miRNAs are secreted from cancerous cells, which control macrophages phenotypic plasticity to support tumor growth. In return, TAMs also secrete various miRNAs that regulate tumor growth. Herein, we also describe the recent updates on the molecular connection between tumor cells and macrophages. A better understanding of the interaction between miRNAs and TAMs will provide new pharmacological targets to combat cancer.
Assuntos
MicroRNAs/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Polaridade Celular/genética , Polaridade Celular/imunologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , MicroRNAs/genética , Neoplasias/genéticaRESUMO
We report the synthesis of two isoreticular mixed-ligand metal-organic frameworks (MOFs), namely, [Zn(µ2-ia)(µ2-bpe)] n· nDMF (1) and [Zn(µ2-mia)(µ2-bpe)] n· nDMF (2), where ia = isophthalate, mia = 5-methoxyisophthalate, bpe = 1,2-bis(4-pyridyl)ethane, and DMF = N, N'-dimethylformamide. Single-crystal X-ray diffraction studies revealed that the structures of 1 and 2 consist of a 2-periodic, layer sql motif. Structures exhibit entanglement through interpenetration of neighboring frameworks to form a two-dimensional bilayer. Variable-temperature powder X-ray diffraction studies confirmed both structures retain crystallinity upon desolvation up to â¼500 K. Although structurally similar, activated samples of 1 and 2 showed differing gas and vapor sorption capabilities. Despite activated 2 having the higher actual void space, activated 1 showed significantly higher sorption for carbon dioxide at 195 K, as well as significant hysteresis upon desorption. Empirical evidence points toward weaker bilayer···bilayer interactions, which allow the separation of the bilayers, illustrating that small changes in functional groups within an isoreticular pair of MOFs may have a large tuning effect on sorption properties.
RESUMO
BACKGROUND/AIMS: Cytotoxic effect of attenuated Leishmania on liver cancer cells by inducing ROS generation. METHODS: Spectrophotometric study to analyze cell death and levels of different active caspases. Flow cytometric study was done to analyze apoptosis induction and ROS generation and levels of different protein. Western blot analysis was performed to study the levels of protein. Confocal microscopy was done to ascertain the expression of different apoptotic markers. RESULTS: We have now observed that attenuated Leishmania donovani UR6 also has potentiality towards growth inhibition of HepG2 cells and investigated the mechanism of action. The effect is associated with increased DNA fragmentation, rise in number of annexinV positive cells, and cell cycle arrest at G1 phase. The detection of unregulated levels of active PARP, cleaved caspases 3 and 9, cytosolic cytochrome C, Bax, and Bad, along with the observed downregulation of Bcl-2 and loss of mitochondrial membrane potential suggested the involvement of mitochondrial pathway. Enhanced ROS and p53 levels regulate the apoptosis of HepG2 cells. NAC was found to inhibit p53 production but PFT-α has no effect on ROS generation. In conclusion, Leishmania donovani UR6 efficiently induces apoptosis in HepG2 cells through ROS mediated p53 dependent mitochondrial pathway. CONCLUSION: It has been reported earlier that some parasites show prominent cytotoxic effect and prevent tumor growth. From our study we found that Leishmania donovani UR6 efficiently induced apoptosis in HepG2 cells through ROS mediated p53 dependent mitochondrial pathway. This study has rejuvenated the age old idea of bio-therapy.
Assuntos
Apoptose , Leishmania/patogenicidade , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Acetilcisteína/farmacologia , Cálcio/metabolismo , Caspase 3/análise , Caspase 3/metabolismo , Caspase 9/análise , Caspase 9/metabolismo , Citocromos c/metabolismo , Fragmentação do DNA , Regulação para Baixo , Pontos de Checagem da Fase G1 do Ciclo Celular , Células Hep G2 , Temperatura Alta , Humanos , Potencial da Membrana Mitocondrial , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
The linker [1,1':3',1â³-terphenyl]-4,4',4â³,6'-tetracarboxylic acid (H4L) was used to construct two three-dimensional (3D) metal-organic frameworks (MOFs), namely, {[Cd2(L)(L1)(DMF)(H2O)](2DMF)(3H2O)}n (1) and {[Cd4(L)2(L2)3(H2O)2](8DMF)(8H2O)}n (2) (DMF = N,N'-dimethylformamide) in the presence of colinkers 4,4'-bipyridine (L1) and 2-amino-4,4'-bipyridine (L2), respectively, under solvothermal condition. A small change in the colinker leads to significant differences in the overall structure of the MOFs. Topological analysis reveals that the framework 1 exhibits 6,4-connected forbidden sub-configuration (FSC) topology, while the framework 2 exhibits twofold interpenetrated and (3,4,4)-connected new network topology with Schläfli point symbol {4.6(2)}{4.6(4).8}{4(2).6(2).8(2)}. The crystallographic investigation reveals the framework 2 having single helix structure, which is further coiled through noncovalent interaction, afforded a double-helix structure similar to DNA. These double helices are further connected through the colinker L2 to form an overall 3D structure. Besides framework 2 exhibits remarkable fluorescence intensity compared to 1. Framework 2 displayed a strong emission at 457 nm when a sample of 2 was dispersed in ethanol and excited at 334 nm. This emission is selectively and completely quenched in the presence of 2,4,6-trinitrophenol (TNP) allowing its detection in the presence of other nitroaromatic compounds. The quenching constant for TNP was found to be 3.89 × 10(4) M(-1), which is 26 times higher than that of TNT demonstrating greater and selective quenching ability. The emission is restored to its original value when the sample after collected by filtration is dispersed in fresh ethanol for 1 d. Interestingly, when solid 2 is exposed to different nitroaromatic compounds, its emission is quenched selectively in the presence of nitrobenzene. In this case, the emission is restored upon heating the sample to 150 °C for 2 h.
RESUMO
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.
Assuntos
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
Sphingolipids are membrane and intracellular lipids that typically modulate cellular processes to cause cell death. Exogenous administration of sphingolipids may cause restriction of tumour growth and several alternative strategies are being used to control the cell growth. The microbes, their cellular component(s) or metabolites like DHA, EPA and also FTY720 have been employed as new therapeutic entities to regulate the disease condition. The therapeutic efficacy of lipids from Leishmania donovani in rheumatoid arthritis and also in sepsis condition associated with inflammatory diseases is well established. In this study, we explored the apoptotic effect of LSPL-1 (leishmanial sphingolipid-1) in Sarcoma 180 cells towards the regulation of tumour growth. The study using a panel of cancer cell lines revealed that LSPL-1 induces cell death in Sarcoma 180. The apoptotic changes were assessed by annexin exposure and DNA content analysis using flow cytometry. LSPL-1 appears to activate several pro- and anti-apoptotic molecules through reactive oxygen species (ROS) generation and also caspase activation, as determined by Western blot and ELISA analyses. Simultaneously, it may improve the survival rate of mice bearing tumour induced by Sarcoma 180 cells, with pathological changes. LSPL-1 may also suppress the cancer-associated inflammatory responses with the expression of matrix metalloproteinase having inhibitory role. It may regulate several angiogenic factors including VEGF, Ang-2 and CD34 in angiogenic events generated in Sarcoma 180 cell-induced tumour. These studies underline the significance of anti-neoplastic potential of LSPL-1 through apoptosis induction and abrogation of angiogenic responses in Sarcoma 180 cell-associated tumour.
Assuntos
Proliferação de Células/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Sarcoma 180/tratamento farmacológico , Esfingolipídeos/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Caspase 3/biossíntese , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Leishmania donovani/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Neovascularização Patológica/patologia , Espécies Reativas de Oxigênio/metabolismo , Sarcoma 180/patologia , Transdução de Sinais/efeitos dos fármacos , Esfingolipídeos/química , Esfingolipídeos/isolamento & purificação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
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
Anticancer drugs are often associated with limitations such as poor stability in aqueous solutions, limited cell membrane permeability, nonspecific targeting, and irregular drug release when taken orally. One possible solution to these problems is the use of nanocarriers of drug molecules, particularly those with targeting ability, stimuli-responsive properties, and high drug loading capacity. These nanocarriers can improve drug stability, increase cellular uptake, allow specific targeting of cancer cells, and provide controlled drug release. While improving the therapeutic efficacy of cancer drugs, contemporary researchers also aim to reduce their associated side effects, such that cancer patients are offered with a more effective and targeted treatment strategy. Herein, a set of nine porous covalent organic frameworks (COFs) were tested as drug delivery nanocarriers. Among these, paclitaxel loaded in COF-3 was most effective against the proliferation of ovarian cancer cells. This study highlights the emerging potential of COFs in the field of therapeutic drug delivery. Due to their biocompatibility, these porous COFs provide a viable substrate for controlled drug release, making them attractive candidates for improving drug delivery systems. This work also demonstrates the potential of COFs as efficient drug delivery agents, thereby opening up new opportunities in the field of sarcoma therapy.
Assuntos
Antineoplásicos , Portadores de Fármacos , Estruturas Metalorgânicas , Neoplasias Ovarianas , Paclitaxel , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Portadores de Fármacos/química , Feminino , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Paclitaxel/uso terapêutico , Paclitaxel/química , Paclitaxel/farmacologia , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/uso terapêutico , Estruturas Metalorgânicas/farmacologia , Linhagem Celular Tumoral , Porosidade , Liberação Controlada de FármacosRESUMO
The diversified impacts of mitochondrial function vs. dysfunction have been observed in almost all disease conditions including cancers. Mitochondria play crucial roles in cellular homeostasis and integrity, however, mitochondrial dysfunctions influenced by alterations in the mtDNA can disrupt cellular balance. Many external stimuli or cellular defects that cause cellular integrity abnormalities, also impact mitochondrial functions. Imbalances in mitochondrial activity can initiate and lead to accumulations of genetic mutations and can promote the processes of tumorigenesis, progression, and survival. This comprehensive review summarizes epigenetic and genetic alterations that affect the functionality of the mitochondria, with considerations of cellular metabolism, and as influenced by ethnicity. We have also reviewed recent insights regarding mitochondrial dynamics, miRNAs, exosomes that play pivotal roles in cancer promotion, and the impact of mitochondrial dynamics on immune cell mechanisms. The review also summarizes recent therapeutic approaches targeting mitochondria in anti-cancer treatment strategies.
Assuntos
Mitocôndrias , Dinâmica Mitocondrial , Mutação , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mutação/genética , Dinâmica Mitocondrial/genética , Progressão da Doença , DNA Mitocondrial/genética , Animais , MicroRNAs/genéticaRESUMO
Corchorusin-D (COR-D), isolated from Corchorus acutangulus, was reported to induce apoptosis in leukemic cells. However, no studies concerning its activity on melanoma cells have been reported. We have evaluated its in vitro anti-cancer activity on melanoma cells (B16F10, SK-MEL-28, and A375). The results demonstrate that COR-D showed maximum inhibition of B16F10 cells in vitro. COR-D induced mitochondrial dysfunction and altered the Bax/Bcl-2 ratio with down regulation of pro-caspases 9 and activation of caspase 3 in B16F10 cells, triggering intrinsic pathway of apoptosis. Moreover, it inhibited the in vivo B16F10 tumor growth and increased the survival rate of mice. Greater number of Annexin V-FITC and propidium iodide (PI)-positive tumor cells signified that COR-D induced apoptosis in vivo also. The reduction in tumor growth is well correlated with decreased microvascular density of the tumor cells in treated mice. In conclusion, this study reveals that COR-D-induced mitochondrial dysfunction is responsible for the induction of apoptotic cell death.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Corchorus/química , Glicosídeos/farmacologia , Triterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Caspase 9/metabolismo , Glicosídeos/química , Glicosídeos/isolamento & purificação , Humanos , Melanoma/metabolismo , Melanoma/patologia , Melanoma/fisiopatologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Estrutura Molecular , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Saponinas/farmacologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Triterpenos/química , Triterpenos/isolamento & purificação , Proteína X Associada a bcl-2/metabolismoRESUMO
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.
Assuntos
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
Inflammation is a protective immune response against harmful stimuli whose long time continuation results in host disease. Quinazolinones are nitrogen containing heterocyclic compounds with wide spectrum of biological activities. The anticancer effect of a 3-(arylideneamino)-phenylquinazoline-4(3H)-one derivative was reported earlier. The anti-inflammatory effect of these quinazolinone derivatives has now been examined in endotoxin stimulated macrophages and in different in vivo models of inflammation by measuring the proinflammatory cytokines (TNF-α, IL-1ß and IL-6), mediators NO and NF-κB (by ELISA and western blot), and translocation of the nuclear factor kB (by immunocytochemical analysis). To elucidate the in vivo effect, mice endotoxin model was and the various levels of edema, inflammatory pain and vascular permeability were studied. One of the quinazolinone derivatives showed significant anti-inflammatory activity in stimulated macrophage cells by inhibiting the expression of TNF-α, IL-1ß, IL-6, iNOS, COX-2, p-IκB and NF-κBp65. Significant (P<0.01) improvement was observed in the mortality of endotoxemic mice. The carrageenan and formalin-induced paw edema thicknesses were found to be reduced significantly (P<0.01) along with the reduction of pain, vascular permeability and edema induced by complete Freund's adjuvant (P<0.01). These findings indicate that 3-(arylideneamino)-phenylquinazoline-4(3H)-one derivative as a potential anti-inflammatory agent.
Assuntos
Anti-Inflamatórios não Esteroides , Inflamação/tratamento farmacológico , Quinazolinas/farmacologia , Animais , Western Blotting , Permeabilidade Capilar/efeitos dos fármacos , Carragenina , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/sangue , Dinoprostona/metabolismo , Feminino , Formaldeído , Inflamação/induzido quimicamente , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Fígado/patologia , Testes de Função Hepática , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Microscopia de Fluorescência , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Quinazolinas/síntese química , Quinazolinas/toxicidade , Choque Séptico/patologia , SobrevidaRESUMO
A previously-reported cadmium-based two-periodic metal-organic framework [Cd1.5(BTC)(H2O)4.5] n ·nH2O (CP1) has been re-synthesized, where H3BTC = 1,3,5-benzenetricarboxylic acid. CP1 was characterized with single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD) followed by various thermal analyses such as thermogravimetric analysis (TGA), hot stage microscopy (HSM) and differential scanning calorimetry (DSC). CP1 is composed of 2-periodic layers, which are interdigitated. Heating can effectively remove the uncoordinated and coordinated water molecules resulting in an amorphous product CP1'. The original framework can be regenerated by readsorption of water from the atmosphere, indicating that the dehydration is reversible.
RESUMO
Propofol as an intravenous anesthetic and isoflurane as an inhalational/volatile anesthetic continue to be an important part of surgical anesthetic interventions worldwide. The impact of these anesthetics on tumor progression, immune modulation, and survival rates of cancer patients has been widely investigated. Although most of the preclinical studies have provided a beneficial effect of propofol over isoflurane or other volatile anesthetics, several investigations have shown contradictory results, which warrant more preclinical and clinical studies. Propofol mostly exhibits antitumor properties, whereas isoflurane being a cost-effective anesthetic is frequently used. However, isoflurane has been also reported with protumorigenic activity. This review provides an overall perspective on the network of signaling pathways that may modulate several steps of tumor progression from inflammation, immunomodulation, epithelial-mesenchymal transition (EMT) to invasion, metastasis, angiogenesis, and cancer stemness and extracellular vesicles along with chemotherapeutic applications and clinical status of these anesthetics. A clear understanding of the mechanistic viewpoints of these anesthetics may pave the way for more prospective clinical trials with the ultimate goal of obtaining a safe and optimal anesthetic intervention that would prevent cancer recurrence and may influence better postoperative survival.