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1.
Cell ; 182(5): 1341-1359.e19, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32763154

RESUMO

Antitumoral immunity requires organized, spatially nuanced interactions between components of the immune tumor microenvironment (iTME). Understanding this coordinated behavior in effective versus ineffective tumor control will advance immunotherapies. We re-engineered co-detection by indexing (CODEX) for paraffin-embedded tissue microarrays, enabling simultaneous profiling of 140 tissue regions from 35 advanced-stage colorectal cancer (CRC) patients with 56 protein markers. We identified nine conserved, distinct cellular neighborhoods (CNs)-a collection of components characteristic of the CRC iTME. Enrichment of PD-1+CD4+ T cells only within a granulocyte CN positively correlated with survival in a high-risk patient subset. Coupling of tumor and immune CNs, fragmentation of T cell and macrophage CNs, and disruption of inter-CN communication was associated with inferior outcomes. This study provides a framework for interrogating how complex biological processes, such as antitumoral immunity, occur through concerted actions of cells and spatial domains.


Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Invasividade Neoplásica/imunologia , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Imunoterapia/métodos , Masculino , Microambiente Tumoral/imunologia
2.
Mar Drugs ; 22(4)2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38667784

RESUMO

Halophilic archaea, also termed haloarchaea, are a group of moderate and extreme halophilic microorganisms that constitute the major microbial populations in hypersaline environments. In these ecosystems, mainly aquatic, haloarchaea are constantly exposed to ionic and oxidative stress due to saturated salt concentrations and high incidences of UV radiation (mainly in summer). To survive under these harsh conditions, haloarchaea have developed molecular adaptations including hyperpigmentation. Regarding pigmentation, haloarchaeal species mainly synthesise the rare C50 carotenoid called bacterioruberin (BR) and its derivatives, monoanhydrobacterioruberin and bisanhydrobacterioruberin. Due to their colours and extraordinary antioxidant properties, BR and its derivatives have been the aim of research in several research groups all over the world during the last decade. This review aims to summarise the most relevant characteristics of BR and its derivatives as well as describe their reported antitumoral, immunomodulatory, and antioxidant biological activities. Based on their biological activities, these carotenoids can be considered promising natural biomolecules that could be used as tools to design new strategies and/or pharmaceutical formulas to fight against cancer, promote immunomodulation, or preserve skin health, among other potential uses.


Assuntos
Antineoplásicos , Antioxidantes , Carotenoides , Neoplasias , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Humanos , Carotenoides/farmacologia , Carotenoides/química , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Animais , Archaea/metabolismo
3.
Mar Drugs ; 22(2)2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38393023

RESUMO

Mycalin A (MA) is a polybrominated C-15 acetogenin isolated from the marine sponge Mycale rotalis. Since this substance displays a strong antiproliferative bioactivity towards some tumour cells, we have now directed our studies towards the elucidation of the MA interactome through functional proteomic approaches, (DARTS and t-LIP-MS). DARTS experiments were performed on Hela cell lysates with the purpose of identifying MA main target protein(s); t-LiP-MS was then applied for an in-depth investigation of the MA-target protein interaction. Both these techniques exploit limited proteolysis coupled with MS analysis. To corroborate LiP data, molecular docking studies were performed on the complexes. Finally, biological and SPR analysis were conducted to explore the effect of the binding. Mortalin (GRP75) was identified as the MA's main interactor. This protein belongs to the Hsp70 family and has garnered significant attention due to its involvement in certain forms of cancer. Specifically, its overexpression in cancer cells appears to hinder the pro-apoptotic function of p53, one of its client proteins, because it becomes sequestered in the cytoplasm. Our research, therefore, has been focused on the possibility that MA might prevent this sequestration, promoting the re-localization of p53 to the nucleus and facilitating the apoptosis of tumor cells.


Assuntos
Acetogeninas , Proteínas de Choque Térmico HSP70 , Poríferos , Animais , Humanos , Acetogeninas/farmacologia , Poríferos/metabolismo , Simulação de Acoplamento Molecular , Células HeLa , Proteômica , Proteína Supressora de Tumor p53/metabolismo
4.
Int J Mol Sci ; 25(4)2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38396837

RESUMO

Antineoplastic therapies for prostate cancer (PCa) have traditionally centered around the androgen receptor (AR) pathway, which has demonstrated a significant role in oncogenesis. Nevertheless, it is becoming progressively apparent that therapeutic strategies must diversify their focus due to the emergence of resistance mechanisms that the tumor employs when subjected to monomolecular treatments. This review illustrates how the dysregulation of the lipid metabolic pathway constitutes a survival strategy adopted by tumors to evade eradication efforts. Integrating this aspect into oncological management could prove valuable in combating PCa.


Assuntos
Antineoplásicos , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , Ácido Mevalônico , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
5.
Int J Mol Sci ; 25(8)2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38673967

RESUMO

Breast cancer is one of the leading causes of death in the female population because of the resistance of cancer cells to many anticancer drugs used. Curcumin has cytotoxic activities against breast cancer cells, although it has limited use due to its poor bioavailability and rapid metabolic elimination. The synthesis of metal complexes of curcumin and curcuminoids is a relevant topic in the search for more active and selective derivatives of these molecular scaffolds. However, solubility and bioavailability are concomitant disadvantages of these types of molecules. To overcome such drawbacks, the preparation of inclusion complexes offers a chemical and pharmacologically safe option for improving the aqueous solubility of organic molecules. Herein, we describe the preparation of the inclusion complex of dimethoxycurcumin magnesium complex (DiMeOC-Mg, (4)) with beta-cyclodextrin (DiMeOC-Mg-BCD, (5)) in the stoichiometric relationship 1:1. This new inclusion complex's solubility in aqueous media phosphate buffer saline (PBS) was improved by a factor of 6x over the free metal complex (4). Furthermore, 5 affects cell metabolic rate, cell morphology, cell migration, induced apoptosis, and downregulation of the matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6), and signal transducer and activator of transcription-3 (STAT3) expression levels on MD Anderson metastasis breast-231 cancer (MDA-MB-231) cell lines. Results of an antitumor assay in an in ovo model showed up to 30% inhibition of tumor growth for breast cancer (MDA-MB-231) when using (5) (0.650 mg/kg dose) and 17.29% inhibition with the free homoleptic metal complex (1.5 mg/kg dose, (4)). While the formulation of inclusion complexes from metal complexes of curcuminoids demonstrates its usefulness in improving the solubility and bioavailability of these metallodrugs, the new compound (5) exhibits excellent potential for use as a therapeutic agent in the battle against breast cancer.


Assuntos
Antineoplásicos , Curcumina , Curcumina/análogos & derivados , Magnésio , beta-Ciclodextrinas , beta-Ciclodextrinas/química , Curcumina/farmacologia , Curcumina/química , Curcumina/farmacocinética , Humanos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Magnésio/química , Apoptose/efeitos dos fármacos , Feminino , Linhagem Celular Tumoral , Fator de Transcrição STAT3/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Movimento Celular/efeitos dos fármacos , Solubilidade , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Embrião de Galinha , Metaloproteinase 9 da Matriz/metabolismo
6.
Molecules ; 29(8)2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38675640

RESUMO

Chalcones are polyphenols that belong to the flavonoids family, known for their broad pharmacological properties. They have thus attracted the attention of chemists for their obtention and potential activities. In our study, a library of compounds from 2'-hydroxychalcone's family was first synthesized. A one-step mechanochemical synthesis via Claisen-Schmidt condensation reaction under ball mill conditions was studied, first in a model reaction between a 5'-fluoro-2'-hydroxyacetophenone and 3,4-dimethoxybenzaldehyde. The reaction was optimized in terms of catalysts, ratio of reagents, reaction time, and influence of additives. Among all assays, we retained the best one, which gave the highest yield of 96% when operating in the presence of 1 + 1 eq. of substituted benzaldehyde and 2 eq. of KOH under two grinding cycles of 30 min. Thus, this protocol was adopted for the synthesis of the selected library of 2'-hydroxychalcones derivatives. The biological activities of 17 compounds were then assessed against Plasmodium falciparum, Leishmania donovani parasite development, as well as IGR-39 melanoma cell lines by inhibiting their viability and proliferation. Compounds 6 and 11 are the most potent against L. donovani, exhibiting IC50 values of 2.33 µM and 2.82 µM, respectively, better than the reference drug Miltefosine (3.66 µM). Compound 15 presented the most interesting antimalarial activity against the 3D7 strain, with IC50 = 3.21 µM. Finally, chalcone 12 gave the best result against IGR-39 melanoma cell lines, with an IC50 value of 12 µM better than the reference drug Dacarbazine (IC50 = 25 µM).


Assuntos
Chalconas , Plasmodium falciparum , Chalconas/farmacologia , Chalconas/química , Chalconas/síntese química , Humanos , Linhagem Celular Tumoral , Plasmodium falciparum/efeitos dos fármacos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/crescimento & desenvolvimento , Antimaláricos/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estrutura Molecular
7.
Gastroenterol Hepatol ; 47(1): 51-62, 2024 Jan.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-37062500

RESUMO

OBJECTIVE: Data on anti-tumor necrosis factor (anti-TNF) treatment and suboptimal response (SOR) among patients with inflammatory bowel diseases (IBD) in Latin America (LATAM) are scarce. This study evaluated the incidence and indicators of SOR to anti-TNF therapy in patients with ulcerative colitis (UC) and Crohn's disease (CD) from Argentina, Colombia and Mexico. PATIENTS AND METHODS: We performed retrospective analysis of data from LATAM patients of the EXPLORE study (NCT03090139) including adult patients with IBD who initiated anti-TNF therapy between March 2010 to March 2015. The cumulative incidence of SOR to first-line anti-TNF therapy was assessed. A physician survey to assess barriers to anti-TNF therapies was also carried out. RESULTS: We included 185 IBD patients (UC/CD: 99/86) treated with first-line anti-TNF from Argentina (38 UC; 40 CD), Colombia (21 UC; 25 CD) and Mexico (40 UC; 21 CD). 36.4% of patients with UC and 46.5% of patients with CD experienced SOR to anti-TNF therapy during the median (interquartile range) observational period: 49.0 months (37.2-60.1) in UC, and 50.0 months (40.9-60.1) in CD. The most common indicator of SOR among patients was augmentation of non-biologic therapy (UC: 41.7%; CD: 35.0%). Affordability and late referral to IBD specialist care centers were the most common barriers to anti-TNF therapies. CONCLUSIONS: SOR to anti-TNF therapy was common in LATAM IBD patients, where augmentation with non-biologic therapy represented the most frequent indicator of SOR across indications. Our findings contribute to the current evidence on the unmet needs associated with anti-TNF in LATAM.


Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Adulto , Humanos , Colite Ulcerativa/complicações , Doença de Crohn/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/complicações , América Latina , Estudos Retrospectivos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa
8.
Glia ; 71(1): 127-138, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35322459

RESUMO

High-grade gliomas constitute the most frequent and aggressive form of primary brain cancer in adults. These tumors express cannabinoid CB1 and CB2 receptors, as well as other elements of the endocannabinoid system. Accruing preclinical evidence supports that pharmacological activation of cannabinoid receptors located on glioma cells exerts overt anti-tumoral effects by modulating key intracellular signaling pathways. The mechanism of this cannabinoid receptor-evoked anti-tumoral activity in experimental models of glioma is intricate and may involve an inhibition not only of cancer cell survival/proliferation, but also of invasiveness, angiogenesis, and the stem cell-like properties of cancer cells, thereby affecting the complex tumor microenvironment. However, the precise biological role of the endocannabinoid system in the generation and progression of glioma seems very context-dependent and remains largely unknown. Increasing our basic knowledge on how (endo)cannabinoids act on glioma cells could help to optimize experimental cannabinoid-based anti-tumoral therapies, as well as the preliminary clinical testing that is currently underway.


Assuntos
Canabinoides , Glioma , Humanos , Adulto , Endocanabinoides/farmacologia , Glioma/patologia , Receptores de Canabinoides/metabolismo , Receptores de Canabinoides/uso terapêutico , Canabinoides/farmacologia , Transdução de Sinais , Microambiente Tumoral
9.
Toxicol Appl Pharmacol ; 475: 116630, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37473966

RESUMO

Gastric cancer (GC) is among the most-diagnosed and deadly malignancies worldwide. Deregulation in cellular bioenergetics is a hallmark of cancer. Based on the importance of metabolic reprogramming for the development and cancer progression, inhibitors of cell metabolism have been studied as potential candidates for chemotherapy in oncology. Mebendazole (MBZ), an antihelminthic approved by FDA, has shown antitumoral activity against cancer cell lines. However, its potential in the modulation of tumoral metabolism remains unclear. Results evidenced that the antitumoral and cytotoxic mechanism of MBZ in GC cells is related to the modulation of the mRNA expression of glycolic targets SLC2A1, HK1, GAPDH, and LDHA. Moreover, in silico analysis has shown that these genes are overexpressed in GC samples, and this increase in expression is related to decreased overall survival rates. Molecular docking revealed that MBZ modifies the protein structure of these targets, which may lead to changes in their protein function. In vitro studies also showed that MBZ induces alterations in glucose uptake, LDH's enzymatic activity, and ATP production. Furthermore, MBZ induced morphologic and intracellular alterations typical of the apoptotic cell death pathway. Thus, this data indicated that the cytotoxic mechanism of MBZ is related to an initial modulation of the tumoral metabolism in the GC cell line. Altogether, our results provide more evidence about the antitumoral mechanism of action of MBZ towards GC cells and reveal metabolic reprogramming as a potential area in the discovery of new pharmacological targets for GC chemotherapy.


Assuntos
Antineoplásicos , Neoplasias Gástricas , Humanos , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Glucose
10.
Cell Biol Int ; 47(9): 1638-1649, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37337926

RESUMO

The activation of the nuclear factor-κB (NF-κB) pathway has been associated with the development and progression of colorectal cancer (CRC). Parthenolide (PTL), a well-known inhibitor of the NF-κB pathway, has emerged as an alternative treatment. However, whether PTL activity is tumor cell-specific and dependent on the mutational background has not been defined. This study investigated the antitumor role of PTL after tumor necrosis factor-α (TNF-α) stimulation in various CRC cell lines with different mutational statuses of TP53. We observed that CRC cells displayed different patterns of basal p-IκBα levels; PTL reduced cell viability according to p-IκBα levels and p-IκBα levels varied among the cell lines according to the time of TNF-α stimulation. High concentrations of PTL reduced more effectively p-IκBα levels than low doses of PTL. However, PTL increased total IκBα levels in Caco-2 and HT-29 cells. In addition, PTL treatment downregulated p-p65 levels in HT-29 and HCT-116 cells stimulated by TNF-α in a dose-dependent manner. Moreover, PTL induced cell death via apoptosis and reduced the proliferation rate of TNF-α-treated HT-29 cells. Finally, PTL downregulated the messenger RNA levels of interleukin-1ß, a downstream cytokine of NF-κB, reverted the E-cadherin-mediated disorganization of cell-cell contacts, and decreased the invasion of HT-29 cells. Together, these results suggest a differential antitumoral activity of PTL on CRC cells with different mutational statuses of TP53, modulating cell death, survival, and proliferation underlying the NF-κB pathway TNF-α-induced. Therefore, PTL has emerged as a potential treatment for CRC in an inflammatory NF-κB-dependent manner.


Assuntos
Neoplasias Colorretais , NF-kappa B , Humanos , NF-kappa B/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Baixo , Adesão Celular , Células CACO-2 , Apoptose , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico
11.
Prostaglandins Other Lipid Mediat ; 166: 106731, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37001725

RESUMO

One of the chemotherapeutic agents widely used in the treatment of non-small cell lung cancer (NSCLC) is cisplatin. However, the resistance of cancer cells to cisplatin and additionally serious side effects from cisplatin limit its use. Conjugated linoleic acid (CLA) has been shown to suppress the development of carcinogenesis in vitro and in vivo studies and has antitumoral activity in many cancers. The study aimed to investigate the potential effect of using cisplatin, the first-line treatment for NSCLC, in combination with CLA to increase its efficacy in low-dose use. MTT cytotoxicity assay was performed to determine the effects of CLA in combination with cisplatin on cell viability of NSCLC cell lines. The apoptotic effect of this combination on NSCLC cell lines and cell cycle distribution was determined by flow cytometry. At the same time, apoptosis and cell cycle-related gene expression levels were determined by Real-Time PCR. Combination treatment of low-dose cisplatin with CLA resulted in a significant decrease in cell viability compared to cisplatin alone, and an increase in the rate of apoptotic cells was observed. While cisplatin caused G1 phase arrest in cancer cells, there was an increase in cell percentages in S and G2 phases after combined application with CLA. In high-dose cisplatin administration, it was observed that the efficiency of the decrease in anti-apoptotic BCL2 expression related to resistance to chemotherapeutic agents was less than that of low-dose cisplatin administration. Combined administration of high-dose cisplatin with CLA significantly recovered BCL2 downregulation.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Ácidos Linoleicos Conjugados , Neoplasias Pulmonares , Humanos , Cisplatino/farmacologia , Células A549 , Antineoplásicos/farmacologia , Ácidos Linoleicos Conjugados/farmacologia , Neoplasias Pulmonares/genética , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células
12.
Acta Oncol ; 62(4): 358-363, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37021781

RESUMO

BACKGROUND: Breast cancer is the most prevalent neoplasm in women in North American and European countries. Data about intensive care unit (ICU) requirements and the related outcomes are scarce. Furthermore, long-term outcome after ICU discharge has not been described. MATERIAL AND METHODS: We conducted a retrospective monocenter study including patients with breast cancer requiring unplanned ICU admission over a 14-year period (2007-2020). RESULTS: 177 patients (age = 65[57-75] years) were analyzed. Breast cancer was at a metastatic stage for 122 (68.9%) patients, recently diagnosed in 25 (14.1%) patients or in progression under treatment in 76 (42.9%) patients. Admissions were related to sepsis in 56 (31.6%) patients, to iatrogenic/procedural complication in 19 (10.7%) patients and to specific oncological complications in 47 (26.6%) patients. Seventy-two (40.7%) patients required invasive mechanical ventilation, 57 (32.2%) vasopressors/inotropes, and 26 (14.7%) renal replacement therapy. In-ICU and one-year mortality rates were 20.9% and 57.1%, respectively. Independent factors associated with in-ICU mortality were invasive mechanical ventilation and impaired performance status. One-year mortality in ICU survivors was independently associated with specific complications, triple negative cancer, and impaired performance status. After hospital discharge, most patients (77.4%) were able to continue or initiate antitumoral treatment. CONCLUSION: ICU admission was linked to the underlying malignancy in one-quarter of breast cancer patients. Despite the low in-ICU mortality rate (20.9%) and thereafter continuation of cancer treatment in most survivors (77.4%), one-year mortality reached 57.1%. Impaired performance status prior to the acute complication was a potent predictor of both short-term and long-term outcomes.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Idoso , Neoplasias da Mama/terapia , Estudos Retrospectivos , Prognóstico , Mortalidade Hospitalar , Unidades de Terapia Intensiva
13.
J Nanobiotechnology ; 21(1): 431, 2023 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-37978538

RESUMO

BACKGROUND: Tumor treatment still remains a clinical challenge, requiring the development of biocompatible and efficient anti-tumor nanodrugs. Carbon dots (CDs) has become promising nanomedicines for cancer therapy due to its low cytotoxicity and easy customization. RESULTS: Herein, we introduced a novel type of "green" nanodrug for multi-level cancer therapy utilizing Fe-doped carbon dots (Fe-CDs) derived from iron nutrient supplement. With no requirement for target moieties or external stimuli, the sole intravenous administration of Fe-CDs demonstrated unexpected anti-tumor activity, completely suppressing tumor growth in mice. Continuous administration of Fe-CDs for several weeks showed no toxic effects in vivo, highlighting its exceptional biocompatibility. The as-synthesized Fe-CDs could selectively induce tumor cells apoptosis by BAX/Caspase 9/Caspase 3/PARP signal pathways and activate antitumoral macrophages by inhibiting the IL-10/Arg-1 axis, contributing to its significant tumor immunotherapy effect. Additionally, the epithelial-mesenchymal transition (EMT) process was inhibited under the treatment of Fe-CDs by MAPK/Snail pathways, indicating the capacity of Fe-CDs to inhibit tumor recurrence and metastasis. CONCLUSIONS: A three-level tumor treatment strategy from direct killing to activating immunity to inhibiting metastasis was achieved based on "green" Fe-CDs. Our findings reveal the broad clinical potential of Fe-CDs as a novel candidate for anti-tumor nanodrugs and nanoplatform.


Assuntos
Neoplasias , Pontos Quânticos , Animais , Camundongos , Carbono/farmacologia , Neoplasias/tratamento farmacológico
14.
Mar Drugs ; 22(1)2023 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-38248641

RESUMO

The extract obtained by pressurized hot water extraction from Sargassum muticum, to recover the bioactive compound known as fucoidan, was fractionated using membranes of 100, 50, 30, 10, and 5 kDa, obtaining five retentates and the final permeate. These fractions were characterized for phloroglucinol content, protein content, sulfate content, and trolox equivalent antioxidant capacity (TEAC); apart from oligosaccharides, FTIR and molar mass distribution were also evaluated. Retentates of 100 and 50 kDa showed higher values for phloroglucinol, TEAC, and sulfate content. The rheology of the alginate fraction was also evaluated. Regarding the potential antitumoral activity, all fractions were assessed in MCF-7 cells using a metabolic activity assay based on the reduction of a tetrazolium compound, the most efficient being R100 and R50. Based on the results, these fractions were compared with commercial fucoidans at the same concentrations, and similar results were found. In addition, synergistic cytotoxic effects using two drugs commonly used in breast cancer, cis-Platinum (cis-Pt) and 5-fluorouracil (5-FU), were tested in combination with R100 and R50. Promising results were obtained when the retentate and the drugs were mixed, showing an improvement in the cytotoxicity induced by the chemotherapy.


Assuntos
Sargassum , Peso Molecular , Polissacarídeos/farmacologia , Antioxidantes/farmacologia , Fluoruracila , Floroglucinol , Sulfatos
15.
Arch Pharm (Weinheim) ; 356(3): e2200305, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36481876

RESUMO

We present the preparation of a series of novel natural product-like homobarrelenones, norcaranes, and dihydrofluorenones through a diversity-oriented synthetic (DOS) strategy that combines Diels-Alder reactions and phototransformations, as well as their biological evaluation against MCF-7, HT-29, and NCI-H460 human tumor cells. Six of these demonstrated activities in the micromolar range against the three cell lines, and none were predicted as cytotoxic against human nontumor cells according to in silico studies. In addition, within the set of active derivatives, three exhibited low unspecific cytotoxicity in a sperm motility assay. The rich functionality of the new compounds makes them ideal candidates for exhaustive structure-activity relationship studies.


Assuntos
Antineoplásicos , Biflavonoides , Masculino , Humanos , Relação Estrutura-Atividade , Tropolona/farmacologia , Motilidade dos Espermatozoides , Biflavonoides/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Estrutura Molecular , Proliferação de Células
16.
Int J Mol Sci ; 24(22)2023 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-38003414

RESUMO

Bioactive peptides have emerged as promising therapeutic agents with antimicrobial, antifungal, antiparasitic, and, recently, antitumoral properties with a mechanism of action based on membrane destabilization and cell death, often involving a conformational change in the peptide. This biophysical study aims to provide preliminary insights into the membrane-level antitumoral mode of action of crotalicidin, a cationic host defense peptide from rattlesnake venom, toward breast cancer cell lines. The lipid composition of breast cancer cell lines was obtained after lipid extraction and quantification to prepare representative cell membrane models. Membrane-peptide interaction studies were performed using differential scanning calorimetry and Fourier-transform infrared spectroscopy. The outcome evidences the potential antitumoral activity and selectivity of crotalicidin toward breast cancer cell lines and suggests a mechanism initiated by the electrostatic interaction of the peptide with the lipid bilayer surface and posterior conformation change with membrane intercalation between the acyl chains in negatively charged lipid systems. This research provides valuable information that clears up the antitumoral mode of action of crotalicidin.


Assuntos
Anti-Infecciosos , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Bicamadas Lipídicas/química , Anti-Infecciosos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Varredura Diferencial de Calorimetria
17.
Molecules ; 28(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36615553

RESUMO

Liquidambar styraciflua L. is an aromatic species, popularly used in traditional Chinese medicine to treat diarrhea, dysentery, coughs, and skin sores. The present study was designed to investigate the chemical composition and biological potential of extracts obtained from the fruits of this plant. For the chemical evaluation, it was used mainly liquid and gas chromatography, plus NMR, and colorimetric methods. The aqueous extract (EA) originated two other fractions: an aqueous (P-EA) and an ethanolic (S-EA). The three extracts were composed of proteins, phenolic compounds, and carbohydrates in different proportions. The analyses showed that the polysaccharide extract (P-EA) contained pectic polysaccharides, such as acetylated and methyl esterified homogalacturonans together with arabinogalactan, while the fraction S-EA presented phenolic acids and terpenes such as gallic acid, protocathecuic acid, liquidambaric acid, combretastatin, and atractyloside A. EA, P-EA, and S-EA showed antioxidant activity, with IC50 values of 4.64 µg/mL, 16.45 µg/mL, and 3.67 µg/mL, respectively. The cytotoxicity followed the sequence S-EA > EA > P-EA, demonstrating that the toxic compounds were separated from the non-toxic ones by ethanol precipitation. While the fraction S-EA is very toxic to any cell line, the fraction P-EA is a promising candidate for studies against cancer due to its high toxicity to tumoral cells and low toxicity to normal cells.


Assuntos
Antineoplásicos , Liquidambar , Frutas , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Liquidambar/química , Antioxidantes/farmacologia , Antioxidantes/química , Antineoplásicos/farmacologia
18.
Molecules ; 28(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36615543

RESUMO

The genus Ulex comprises thirteen accepted species of perennial shrubs in the family Fabaceae. In Galicia (Spain) many of these are considered spontaneous colonizing species, which are easy to establish and maintain. Among them, Ulex gallii Planch. is used in traditional medicine for the same anti-infective, hypotensive and diuretic purposes as Ulex europaeus L., which is the most studied species. Likewise, some studies have described the antitumoral properties of several species. However, there are few scientific studies that justify the use of Ulex gallii Planch. and nothing has been reported about its composition to date. In our study, the entire plant was extracted with methanol and the crude extract was subjected to liquid phase extraction with distinct solvents, yielding three fractions: hexane (H), dichloromethane (D) and methanol (M), which were subsequently fractionated. The dichloromethane (D5, D7 and D8) and methanol (M4) sub-fractions showed antiproliferative activity on A549 (lung cancer) and AGS (stomach cancer) cell lines, and caspase 3/7 activity assessment and DNA quantification were also performed. Targeted analysis via UHPLC-QToF, in combination with untargeted analysis via MS-Dial, MS-Finder and Global Natural Products Social Molecular Networking (GNPS), allowed us to tentatively identify different metabolites in these sub-fractions, mostly flavonoids, that might be involved in their antiproliferative activity.


Assuntos
Fabaceae , Plantas Medicinais , Plantas Medicinais/química , Ulex , Fabaceae/química , Metanol/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Espanha , Cloreto de Metileno , Compostos Fitoquímicos/farmacologia
19.
Molecules ; 28(9)2023 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-37175327

RESUMO

A series of new [1,2,4]triazolo[4,3-a]pyrimidine derivatives was prepared using a one-pot three-component synthesis from 5-amino-1-phenyl-1H-1,2,4-triazoles, aromatic aldehydes and ethyl acetoacetate. The compound structures were confirmed by IR, 1H-NMR, 13C-NMR, HRMS and X-ray analyses. The biological activity of these compounds as antitumor agents was evaluated. Their antitumor activities against cancer cell lines (MDA-MB-231 and MCF-7) were tested by the MTT in vitro method. Among them, compounds 4c and 4j displayed the best antitumor activity with IC50 values of 17.83 µM and 19.73 µM against MDA-MB-231 and MCF-7 cell lines, respectively, compared to the Cisplatin reference.


Assuntos
Antineoplásicos , Pirimidinas , Humanos , Pirimidinas/química , Antineoplásicos/química , Cisplatino/farmacologia , Células MCF-7 , Espectroscopia de Ressonância Magnética , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade , Proliferação de Células , Linhagem Celular Tumoral , Estrutura Molecular
20.
Molecules ; 28(12)2023 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-37375393

RESUMO

Nanotechnology is an innovative field of study that has made significant progress due to its potential versatility and wide range of applications, precisely because of the development of metal nanoparticles such as copper. Nanoparticles are bodies composed of a nanometric cluster of atoms (1-100 nm). Biogenic alternatives have replaced their chemical synthesis due to their environmental friendliness, dependability, sustainability, and low energy demand. This ecofriendly option has medical, pharmaceutical, food, and agricultural applications. When compared to their chemical counterparts, using biological agents, such as micro-organisms and plant extracts, as reducing and stabilizing agents has shown viability and acceptance. Therefore, it is a feasible alternative for rapid synthesis and scaling-up processes. Several research articles on the biogenic synthesis of copper nanoparticles have been published over the past decade. Still, none provided an organized, comprehensive overview of their properties and potential applications. Thus, this systematic review aims to assess research articles published over the past decade regarding the antioxidant, antitumor, antimicrobial, dye removal, and catalytic activities of biogenically synthesized copper nanoparticles using the scientific methodology of big data analytics. Plant extract and micro-organisms (bacteria and fungi) are addressed as biological agents. We intend to assist the scientific community in comprehending and locating helpful information for future research or application development.


Assuntos
Anti-Infecciosos , Nanopartículas Metálicas , Cobre/química , Nanopartículas Metálicas/química , Bactérias , Anti-Infecciosos/farmacologia , Extratos Vegetais/química , Antioxidantes/química , Antibacterianos/química
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