RESUMO
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
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.
RESUMO
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
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
Cancer, one of the deadliest diseases for both sexes, has always demanded updated treatment strategies with time. Breast cancer is responsible for the highest mortality rate among females worldwide and requires treatment with advanced regimens due to the higher probability of breast cancer cells to develop drug cytotoxicity followed by resistance. Covalent organic framework (COF) materials with ordered nanoscale porosity can serve as drug delivery vehicles due to their biocompatible nature and large internal void spaces. In this research work, we have employed a novel biocompatible COF, TRIPTA, as a drug delivery carrier towards breast cancer cells. It served as a drug delivery vehicle for cisplatin in triple negative breast cancer (TNBC) cells. We have checked the potency of TRIPTA in combating the proliferation of metastatic TNBC cells. Our results revealed that cisplatin loaded over TRIPTA-COF exhibited a greater impact on the CD44+/CD24- cancer stem cell niche of breast cancer. Retarded migration of cancer cells has also been observed with the dual treatment of TRIPTA and cisplatin compared to that of cisplatin alone. Epithelial-mesenchymal transition (EMT) has also been minimized by the combinatorial treatment of cisplatin carried by the carrier material in comparison to cisplatin alone. The epithelial marker E-cadherin is significantly increased in cells treated with cisplatin together with the carrier COF, and the expression of mesenchymal markers such as N-cadherin is lower. The transcriptional factor Snail has been observed under the same treatment. The carrier material is also internalized by the cancer cells in a time-dependent manner, suggesting that the organic carrier can serve as a specific drug delivery vehicle. Our experimental results suggested that TRIPTA-COF can serve as a potent nanocarrier for cisplatin, showing higher detrimental effects on the proliferation and migration of TNBC cells by increasing the cytotoxicity of cisplatin.
RESUMO
Background: Ovarian cancer (OvCa), the deadliest gynaecological malignancy, is associated with poor prognosis and high mortality rate. Ovarian cancer has been related with CA-125 and metabolic reprogramming by SIRT1 leading to metastasis with the involvement of exosomes. Methods: Clinicopathological data of OvCa patients were collected to perform the analysis. Patients' samples were collected during surgery for immunohistochemistry and flow cytometric analysis of SIRT1, HIF-1α, exosomal markers (CD81 and CD63), ki-67, and PAS staining for glycogen deposition. Adjacent normal and tumor tissues were collected as per the CA-125 levels. Results: CA-125, a vital diagnostic marker, has shown significant correlation with body mass index (BMI) (P = 0.0153), tumor type (P = 0.0029), ascites level, ascites malignancy, degree of dissemination, tumor differentiation, FIGO stage, TNM stage, laterality, and tumor size at P < 0.0001. Since significant correlation was associated with BMI and degree of dissemination, as disclosed by IHC analysis, metabolic marker SIRT1 (P = 0.0003), HIF-1α (P < 0.0001), exosomal marker CD81 (P < 0.0001), ki-67 status (P = 0.0034), and glycogen deposition (P <0.0001) were expressed more in tumor tissues as compared to the normal ones. ROC analysis of CA-125 had shown 327.7 U/ml has the best cutoff point with 82.4% sensitivity and specificity of 52.3%. In addition, Kaplan-Meier plots of CA-125 (P < 0.0001), BMI (P = 0.001), degree of dissemination (P < 0.0001), and ascites level (P <0.0001) reflected significant correlation with overall survival (OS). Upon multivariate Cox-regression analysis for overall survival (OS), BMI (P = 0.008, HR 1.759, 95% CI 1.156-2.677), ascites malignancy (P = 0.032, HR 0.336, 95% CI 0.124-0.911), and degree of dissemination (P = 0.004, HR 1.994, 95% CI 1.251-3.178) were significant proving to be independent indicators of the disease. Conclusion: Clinicopathological parameters like BMI, degree of dissemination, and ascites level along with CA-125 can be prognostic factors for the disease. Levels of CA-125 can depict the metabolic and metastatic factors. Thus, by targeting SIRT1 and assessing exosomal concentrations to overcome metastasis and glycogen deposition, individualized treatment strategy could be designed. In-depth studies are still required.
Assuntos
Exossomos , Neoplasias Ovarianas , Ascite , Antígeno Ca-125 , Carcinoma Epitelial do Ovário , Exossomos/metabolismo , Feminino , Glicogênio , Humanos , Antígeno Ki-67 , Mucinas , Prognóstico , Sirtuína 1/metabolismoRESUMO
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
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.
Assuntos
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
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.
Assuntos
Anestésicos Inalatórios , Isoflurano , Propofol , Humanos , Recidiva Local de Neoplasia , Propofol/farmacologia , Estudos ProspectivosRESUMO
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
Exosomes, the endosome-derived bilayered extracellular nanovesicles with their contribution in many aspects of cancer biology, have become one of the prime foci of research. Exosomes derived from various cells carry cargoes similar to their originator cells and their mode of generation is different compared to other extracellular vesicles. This review has tried to cover all aspects of exosome biogenesis, including cargo, Rab-dependent and Rab-independent secretion of endosomes and exosomal internalization. The bioactive molecules of the tumor-derived exosomes, by virtue of their ubiquitous presence and small size, can migrate to distal parts and propagate oncogenic signaling and epigenetic regulation, modulate tumor microenvironment and facilitate immune escape, tumor progression and drug resistance responsible for cancer progression. Strategies improvised against tumor-derived exosomes include suppression of exosome uptake, modulation of exosomal cargo and removal of exosomes. Apart from the protumorigenic role, exosomal cargoes have been selectively manipulated for diagnosis, immune therapy, vaccine development, RNA therapy, stem cell therapy, drug delivery and reversal of chemoresistance against cancer. However, several challenges, including in-depth knowledge of exosome biogenesis and protein sorting, perfect and pure isolation of exosomes, large-scale production, better loading efficiency, and targeted delivery of exosomes, have to be confronted before the successful implementation of exosomes becomes possible for the diagnosis and therapy of cancer.
RESUMO
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
Triple-negative breast cancer (TNBC), defined as loss of estrogen, progesterone, and Her2 receptors, is a subtype of highly aggressive breast cancer with worse prognosis and poor survival rate. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine aberrantly expressed in many solid tumors and known to promote tumor progression and metastasis. However, its role in TNBC progression and metastasis is unexplored. Here we have shown that in TNBC patients, MIF expression was significantly enriched in the tumor compared to adjacent normal tissue. Using publically available patient datasets, we showed that MIF overexpression correlates with worse survival in TNBC compared to other hormonal status. Orthotopic implantation of TNBC cells into MIF knockout mice showed reduced tumor growth compared to wild-type mice. In addition, we have shown that MIF downregulation inhibits TNBC growth and progression in a syngeneic mouse model. We further showed that CPSI-1306, a small-molecule MIF inhibitor, inhibits the growth of TNBC cells in vitro. Mechanistic studies revealed that CPSI-1306 induces intrinsic apoptosis by alteration in mitochondrial membrane potential, cytochrome c (Cyt c) release, and activation of different caspases. In addition, CPSI-1306 inhibits the activation of cell survival and proliferation-related molecules. CPSI-1306 treatment also reduced the tumor growth and metastasis in orthotopic mouse models of mammary carcinoma. CPSI-1306 treatment of tumor-bearing mice significantly inhibited TNBC growth and pulmonary metastasis in a dose-dependent manner. Histological analysis of xenograft tumors revealed a higher number of apoptotic cells in CPSI-1306-treated tumors compared to vehicle controls. Our studies, for the first time, show that MIF overexpression in TNBC enhances growth and metastasis. Taken together, our results indicate that using small molecular weight MIF inhibitors could be a promising strategy to inhibit TNBC progression and metastasis.
Assuntos
Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose , Caspases/metabolismo , Movimento Celular , Sobrevivência Celular , Citocromos c/metabolismo , Progressão da Doença , Ativação Enzimática , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas In Vitro , Inflamação , Oxirredutases Intramoleculares/antagonistas & inibidores , Isoxazóis/farmacologia , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Morfolinas/farmacologia , Metástase Neoplásica , Transplante de Neoplasias , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/patologia , CicatrizaçãoRESUMO
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
The hydrogenation of carbon dioxide (CO2) to formic acid is of great importance due to its useful properties in the chemical industry. In this work, we have prepared a novel metal-organic framework (MOF), JMS-1, using bipyridyl dicarboxylate linkers, with molecular formula [La2(bpdc)3(DMF)3] n . Network analysis of JMS-1 revealed a new 7-connected topology (zaz). The MOF backbone of the activated phase (JMS-1a) was functionalized by cyclometalation using [RuCl2(p-cymene)]2 to produce Ru(ii)@JMS-1a. Both JMS-1a and Ru(ii)@JMS-1a were able to convert CO2 in the presence of hydrogen to formate. Ru(ii)@JMS-1a displayed outstanding conversion evidenced by a yield of 98% of formate under optimized conditions of total pressure 50 bar (CO2/H2 = 1 : 4, temperature 110 °C, time 24 h, 5 mmol KOH, 8 mL ethanol). This work is significant in providing new strategies of incorporating active catalytic centres in MOFs for efficient and selective conversion of CO2 to formate.
RESUMO
Lipid droplets (LD) are newly characterized dynamic cytoplasmic organelle which is the storehouse of different immunosuppressive cytokines and enzymes like cyclooxygenase and lipoxygenase. Tumors are known to modulate the immune system by immune-editing the microenvironment. Immuno-editing comprises of three steps namely cancer immune-surveillance, tumor dormancy and finally escape leading to tumor development. The latency of the tumor microenvironment is greatly contributed by the M2 polarized macrophages and TGF-ß is a prime culprit. Modulating M2 macrophages to M1 can be a strategy against tumor progression. We found that tumor-conditioned medium or recombinant TGF-ß was efficient to induce LD formation in Raw264.7 cells and the inhibition of LD was associated with the switch of M2 to M1 phenotype involving MEK1/2 axis. Signature molecules of M2 polarized macrophages like CD206 were also downregulated while co-stimulatory molecules like CD80, CD86 were up-regulated along with enhanced surface expression of MHCII when these macrophages were subjected to C75 treatment to reduce the LD formation. The level of pro-inflammatory cytokine, as well as ROS and NO generation, were also increased when TGF-ß treated macrophages were subjected to C75 treatment. This study is probably the first report of this kind and can be used in the future in cancer treatment.
Assuntos
Citocinas/imunologia , Gotículas Lipídicas/imunologia , Macrófagos/imunologia , Neoplasias/imunologia , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Fenótipo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Células THP-1 , Microambiente Tumoral/imunologiaRESUMO
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
The natural anti-cancer agent bromelain is found to be beneficial for either single or multi-targeted therapy in gastric and skin carcinoma, by inhibiting cancer cell growth. Importantly, the presence of peroxidase enhances its biological efficiency. We have now evaluated a panel of cancer cell lines with bromelain in presence or absence of peroxidase to identify that the combination has higher apoptosis inducing potential in all those cell lines. Bromelain plus peroxidase (BM-PR) inhibited acute myeloid (K562) cell proliferation and altered the morphological features. Incidence of apoptosis was established by using annexin V exposure and this was confirmed that the cell cycle was arrested at G0/G1 phase in a concentration-dependent manner. BM-PR increased the intracellular ROS level and altered the mitochondrial membrane potential, as detected using dichlorofluores cin diacetate (DCFDA). It also regulated the expression of apoptosis-related proteins like Bax, Bcl2, caspase-3 and cytochrome besides causing up-regulation of p53 as determined by western blot analysis. These results suggest that BM-PR from pineapple induces apoptosis better than only bromelain in acute myeloid leukemia cells possibly via mitochondria dependent pathway.
Assuntos
Antineoplásicos/farmacologia , Bromelaínas/farmacologia , Leucemia/tratamento farmacológico , Peroxidase/farmacologia , Ananas , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Espécies Reativas de Oxigênio/metabolismoRESUMO
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.