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1.
Int J Mol Sci ; 25(8)2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38674060

RESUMO

Mandarin peel, a main by-product from the processing of citrus juice, has been highlighted for its various bioactivities and functional ingredients. Our previous study proved the inhibitory effects of Celluclast extract from mandarin peel (MPCE) on lipid accumulation and differentiation in 3T3-L1 adipocytes. Therefore, the current study aimed to evaluate the anti-obesity effect of MPCE in high-fat diet (HFD)-induced obese mice. The high-performance liquid chromatography (HPLC) analysis exhibited that narirutin and hesperidin are the main active components of MPCE. Our current results showed that MPCE supplementation decreased adiposity by reducing body and organ weights in HFD-induced obese mice. MPCE also reduced triglyceride (TG), alanine transaminase (ALT), aspartate transaminase (AST), and leptin contents in the serum of HFD-fed mice. Moreover, MPCE significantly inhibited hepatic lipid accumulation by regulating the expression levels of proteins associated with lipid metabolism, including sterol regulatory element-binding protein (SREBP1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). Furthermore, MPCE administration significantly inhibited both adipogenesis and lipogenesis, with modulation of energy metabolism by activating 5' adenosine monophosphate-activated protein kinase (AMPK) and lipolytic enzymes such as hormone-sensitive lipase (HSL) in the white adipose tissue (WAT). Altogether, our findings indicate that MPCE improves HFD-induced obesity and can be used as a curative agent in pharmaceuticals and nutraceuticals to alleviate obesity and related disorders.


Assuntos
Adipogenia , Citrus , Dieta Hiperlipídica , Dissacarídeos , Metabolismo Energético , Flavanonas , Camundongos Endogâmicos C57BL , Obesidade , Extratos Vegetais , Animais , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Obesidade/tratamento farmacológico , Obesidade/etiologia , Citrus/química , Camundongos , Metabolismo Energético/efeitos dos fármacos , Extratos Vegetais/farmacologia , Masculino , Adipogenia/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Células 3T3-L1 , Fármacos Antiobesidade/farmacologia , Fígado/metabolismo , Fígado/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Triglicerídeos/metabolismo , Triglicerídeos/sangue
2.
FEMS Microbiol Lett ; 3702023 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-37777836

RESUMO

Bacterial population exposed to stressful antibiotic conditions consists of various subpopulations such as tolerant, persister, and resistant cells. The aim of this study was to evaluate the phenotypic heterogeneity of Salmonella Typhimurium preadapted to sublethal concentrations of antibiotics. Salmonella Typhimurium cells were treated with 1/2 × MIC of antibiotics for the first 48 h and successively 1 × MIC for the second 24 h at 37°C, including untreated control (CON), no antibiotic and 1 × MIC ciprofloxacin (NON-CIP), 1/2 × MIC ciprofloxacin and 1 × MIC ciprofloxacin (CIP-CIP), 1/2 × MIC tetracycline and 1 × MIC ciprofloxacin (TET-CIP), no antibiotic and 1 × MIC tetracycline (NON-TET), 1/2 × MIC ciprofloxacin and 1 × MIC tetracycline (CIP-TET), and 1/2 × MIC tetracycline and 1 × MIC tetracycline (TET-TET). All treatments were evaluated by antibiotic susceptibility, ATP level, relative fitness, cross-resistance, and persistence. S. Typhimurium cells were more susceptible to non-adapted NON-CIP and NON-TET (>3-log reduction) than pre-adapted CIP-CIP, TET-CIP, CIP-TET, and TET-TET. CON exhibited the highest ATP level, corresponding to the viable cell number. The relative fitness levels were more than 0.95 for all treatments, except for NON-CIP (0.78). The resistance to ciprofloxacin and tetracycline was increased at all treatments with the exception of NON-TET. The persister cells were noticeably induced at CIP-TET treatment, showing more than 5 log CFU mL-1. The results suggest that the antibiotic preadaptation led to heterogeneous populations including persisters that can develop to resistance. This study provides new insight in the bacterial persistence associated with their potential risk and paves the way to design antibiotic therapy targeting dormant bacteria.


Assuntos
Ciprofloxacina , Salmonella typhimurium , Ciprofloxacina/farmacologia , Salmonella typhimurium/genética , Antibacterianos/farmacologia , Tetraciclina/farmacologia , Trifosfato de Adenosina , Testes de Sensibilidade Microbiana
3.
Front Pharmacol ; 14: 1163970, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37274097

RESUMO

Anoctamin 1 (ANO1), a drug target for various cancers, including prostate and oral cancers, is an intracellular calcium-activated chloride ion channel that plays various physiopathological roles, especially in the induction of cancer growth and metastasis. In this study, we tested a novel compound isolated from Schisandra sphenanthera, known as schisandrathera D, for its inhibitory effect on ANO1. Schisandrathera D dose-dependently suppressed the ANO1 activation-mediated decrease in fluorescence of yellow fluorescent protein; however, it did not affect the adenosine triphosphate-induced increase in the intracellular calcium concentration or forskolin-induced cystic fibrosis transmembrane conductance regulator activity. Specifically, schisandrathera D gradually decreased the levels of ANO1 protein and significantly reduced the cell viability in ANO1-expressing cells when compared to those in ANO1-knockout cells. These effects could be attributed to the fact that schisandrathera D displayed better binding capacity to ANO1 protein than the previously known ANO1 inhibitor, Ani9. Finally, schisandrathera D increased the levels of caspase-3 and cleaved poly (ADP-ribose) polymerase 1, thereby indicating that its anticancer effect is mediated through apoptosis. Thus, this study highlights that schisandrathera D, which reduces ANO1 protein levels, has apoptosis-mediated anticancer effects in prostate and oral cancers, and thus, can be further developed into an anticancer agent.

4.
Life Sci ; 307: 120912, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36037872

RESUMO

Menaquinone (MK)-7 is a vitamin K2 analog that functions as a cofactor of γ-glutamyl carboxylase involved in the activation of vitamin K (VK)-dependent proteins. The present study aimed to evaluate the effect of MK-7 on memory and cognitive function in aged C57BL/6 mice. Eighteen-month-old mice were raised for a further 4 months, fed on a standard or calcium-rich diet (3 % [w/w]), and were orally given MK-7 (40 and 400 µg/day/mouse) five times per week during the same period. The Morris water maze (MWM) test was performed at 19 and 22 months. The aged mice showed noticeable memory declines in the MWM test at all time points compared with 6-week-old mice, and this memory loss was significantly restored by the daily administration of high-dose MK-7 for 4 months. MK-7 administration also improved micro-computed tomography-based cerebrovascular calcification and aging-associated declines in growth arrest-specific 6, total and carboxylated matrix Gla proteins, and ganglioside levels in the brain of aged mice. It serologically reduced phosphorous levels in the blood, but not the urea, cholesterol, and calcium. Taken together, the long-term administration of MK-7 significantly improved age-related memory and cognitive impairments, possibly through inhibition of cerebrovascular calcification in aged mice, indicating that it can be used to develop new drugs for improving memory and cognitive function in older adults.


Assuntos
Calcinose , Cálcio , Animais , Colesterol , Gangliosídeos , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Ureia , Vitamina K , Vitamina K 2/análogos & derivados , Vitamina K 2/farmacologia , Vitamina K 2/uso terapêutico , Microtomografia por Raio-X
5.
Pharmaceutics ; 14(5)2022 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-35631513

RESUMO

Herein, we designed a nanocarrier to deliver the LO specifically to HER2+ breast cancer (BC) cells, where functionalization of mAb (anti-HER2+) with PEGylated chitosan enabled it to target the HER2+ BC cells. Taking advantage of overexpression of HER2+ in cancer cells, our nanocarrier (CS-LO-PEG-HER NPs) exhibited promising potency and selectivity against HER2+ BC cells (BT474). The CS-LO-PEG-HER NPs demonstrated the cytotoxicity in BT474 cells by promoting reactive oxygen species, mitochondrial membrane potential loss, and nucleus damage. The biocompatibility of CS-LO-PEG-HER NPs was evidenced by the hemolysis assay and H & E staining of major organs. The CS-LO-PEG-HER NPs showed anticancer potency against the BT474-xenograft tumor-bearing mice, as evident by the reduction of tumor size and cell density. These results indicate that CS-LO-PEG-HER NPs are biocompatible with mice while inhibiting tumor growth through alter the oxidative stress. Overall, this work provides a promising approach for the delivery of LO for good therapeutic effect in combination with mAb.

6.
Biosensors (Basel) ; 11(12)2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34940228

RESUMO

Tumor angiogenesis is enhanced in all types of tumors to supply oxygen and nutrients for their growth and metastasis. With the development of anti-angiogenic drugs, the importance of technology that closely monitors tumor angiogenesis has also been emerging. However, to date, the technology for observing blood vessels requires specialized skills with expensive equipment, thereby limiting its applicability only to the laboratory setting. Here, we used a preclinical optical imaging system for small animals and, for the first time, observed, in real time, the entire process of blood vessel development in tumor-bearing mice injected with indocyanine green. Time-lapse sequential imaging revealed blood vessel volume and blood flow dynamics on a microscopic scale. Upon analyzing fluorescence dynamics at each stage of tumor progression, vessel volume and blood flow were found to increase as the tumor developed. Conversely, these vascular parameters decreased when the mice were treated with angiogenesis inhibitors, which suggests that the effects of drugs targeting angiogenesis can be rapidly and easily screened. The results of this study may help evaluate the efficacy of angiogenesis-targeting drugs by facilitating the observation of tumor blood vessels easily in a laboratory unit without large and complex equipment.


Assuntos
Neoplasias , Preparações Farmacêuticas , Inibidores da Angiogênese/uso terapêutico , Animais , Camundongos , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/tratamento farmacológico , Imagem Óptica
7.
iScience ; 24(2): 102104, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33615202

RESUMO

Systematic control of in vivo behavior of protein-based therapeutics is considered highly desirable for improving their clinical outcomes. Modulation of biochemical properties including molecular weight, surface charge, and binding affinity has thus been suggested to enhance their therapeutic effects. However, establishing a relationship between the binding affinity and tumor localization remains a debated issue. Here we investigate the influence of the binding affinity of proteins on tumor localization by using four repebodies having different affinities to EGFR. Biochemical analysis and molecular imaging provided direct evidence that optimal affinity with balanced target binding and dissociation can facilitate deep penetration and accumulation of protein binders in tumors by overcoming the binding-site-barrier effect. Our findings suggest that binding kinetics-based protein design can be implicated in the development of fine-tuned protein therapeutics for cancers.

8.
Int J Mol Sci ; 21(20)2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33053881

RESUMO

Acute myeloid leukemia (AML) is an aggressive type of human leukemia with a low survival rate, and its complete remission remains challenging. Although chemotherapy is the first-line treatment of AML, it exerts toxicity in noncancerous cells when used in high doses, thus necessitating the development of novel compounds with a high therapeutic window. This study aimed to investigate the anticancer effects of several compounds derived from the fruits of Melia azedarach (a tree with medicinal properties). Among them, 1-cinnamoyltrichilinin (CT) was found to strongly suppress the viability of HL-60 human leukemia cells. CT treatment induced apoptosis and increased nuclear fragmentation and fractional DNA content in HL-60 cells in a dose-dependent manner. CT induced phosphorylation of p38 mitogen-activated protein kinases (p38), though not of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), and activated Bcl-2 family proteins towards the proapoptosis and cleavage of caspase-3 and poly (ADP-ribose) polymerase. Both CT-mediated apoptosis and apoptotic protein expression were reversed by treatment with the p38 inhibitor, thereby indicating the p38 pathway to be critical in CT-stimulated apoptosis. The results collectively indicated CT to suppress HL-60 survival by activating the p38 pathway and inducing apoptosis, hence being a novel potential therapeutic agent for AML.


Assuntos
Apoptose/efeitos dos fármacos , Limoninas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melia azedarach/química , Extratos Vegetais/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células HL-60 , Humanos , Limoninas/química , Estrutura Molecular , Extratos Vegetais/química
9.
Small ; 14(52): e1802618, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30398698

RESUMO

With a growing number of intracellular drug targets and the high efficacy of protein therapeutics, the targeted delivery of active proteins with negligible toxicity is a challenging issue in the field of precision medicine. Herein, a programed assembly of nucleoprotein nanoparticles (NNPs) using DNA and zinc fingers (ZnFs) for targeted protein delivery is presented. Two types of ZnFs with different sequence specificities are genetically fused to a targeting moiety and a protein cargo, respectively. Double-stranded DNA with multiple ZnF-binding sequences is grafted onto inorganic nanoparticles, followed by conjugation with the ZnF-fused proteins, generating the assembly of NNPs with a uniform size distribution and high stability. The approach enables controlled loading of a protein cargo on the NNPs, offering a high cytosolic delivery efficiency and target specificity. The utility and potential of the assembly as a versatile protein delivery vehicle is demonstrated based on their remarkable antitumor activity and target specificity with negligible toxicity in a xenograft mice model.


Assuntos
DNA/química , Nanopartículas/química , Nucleoproteínas/química , Proteínas/química , Animais , Sistemas de Liberação de Medicamentos , Humanos , Camundongos , Ligação Proteica , Dedos de Zinco
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