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Saponins, consisting of sapogenins as their aglycones and carbohydrate chains, are widely found in plants and some marine organisms. Due to the complexity of the structure of saponins, involving different types of sapogenins and sugar moieties, investigation of their absorption and metabolism is limited, which further hinders the explanation of their bioactivities. Large molecular weight and complex structures limit the direct absorption of saponins rendering their low bioavailability. As such, their major modes of action may be due to interaction with the gastrointestinal environment, such as enzymes and nutrients, and interaction with the gut microbiota. Many studies have reported the interaction between saponins and gut microbiota, that is, the effects of saponins on changing the composition of gut microbiota, and gut microbiota playing an indispensable role in the biotransformation of saponins into sapogenins. However, the metabolic routes of saponins by gut microbiota and their mutual interactions are still sparse. Thus, this review summarizes the chemistry, absorption, and metabolic pathways of saponins, as well as their interactions with gut microbiota and impacts on gut health, to better understand how saponins exert their health-promoting functions.
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Deoxyshikonin, a natural naphthoquinone compound extracted from Lithospermum erythrorhizon Sieb. et Zucc (Boraginaceae), has a wide range of pharmacological activities, including anti-tumor, anti-bacterial and wound healing effects. However, the inhibitory effect of deoxyshikonin on cytochrome P450 (CYP) remains unclear. This study investigated the potential inhibitory effects of deoxyshikonin on CYP1A2, 2B1/6, 2C9/11, 2D1/6, 2E1 and 3A2/4 enzymes in human and rat liver microsomes (HLMs and RLMs) by the cocktail approach in vitro. The single-point inactivation experiment showed that deoxyshikonin presented no time-dependent inhibition on CYP activities in HLMs and RLMs. Enzyme inhibition kinetics indicated that in HLMs, deoxyshikonin was not only a competitive inhibitor of CYP1A2 and 2E1, but also a mixed inhibitor of CYP2B6, 2C9, 2D6 and 3A4, with Ki of 2.21, 1.78, 1.68, 0.20, 4.08 and 0.44 µM, respectively. In RLMs, deoxyshikonin not only competitively inhibited CYP2B1 and 2E1, but also exhibited mixed inhibition on CYP1A2, 2C11, 2D1 and 3A2, with Ki values of no more than 18.66 µM. In conclusion, due to the low Ki values of deoxythiokonin on CYP enzymes in HLMs, this may lead to drug-drug interactions (DDI) and potential toxicity.
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Paris saponins, also known as polyphyllins, are natural compounds extracted from Paris polyphylla, which have many pharmacological activities, such as anti-inflammation and anti-cancer. In particular, paris saponin I, II, VII and polyphyllin VI are the components of the quality standard for Paris polyphylla. However, the inhibition risk of polyphyllins on cytochrome P450 (CYP) and UDP-glucuronosyltransferases (UGT) remains unclear. Therefore, this report investigated the potential inhibitory effects of paris saponin I, II, VII and polyphyllin VI on the activities of CYP (CYP1A2, CYP2B1, CYP2C11, CYP2D1, CYP2E1 and CYP3A2) and UGT (UGT1A1, UGT1A3, UGT1A6, PROG and AZTG) through cocktail inhibition assays in vitro. In the study of CYP, polyphyllin VI exhibited weak inhibition on CYP2D1 activity in rat liver microsomes with IC50 value at 45.2 µM, while paris saponin VII weakly inhibited CYP2C11 and CYP2E1 activities with IC50 value at 42.0 and 67.7 µM, respectively. In the study of UGT, none of the four steroidal saponins showed significant inhibition risk. In conclusion, paris saponin I, II, VII and polyphyllin VI have very low potential to cause the possible toxicity and drug interactions involving CYP and UGT enzymes, indicating that they are safe enough to take with drugs.
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Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Microssomos Hepáticos/efeitos dos fármacos , Saponinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Glucuronosiltransferase/metabolismo , Humanos , Masculino , Microssomos Hepáticos/enzimologia , Conformação Molecular , Ratos , Ratos Sprague-Dawley , Medição de Risco , Saponinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Tumor-associated macrophages (TAMs) and angiogenesis are increasingly considered as the pivotal factors that affect tumor progress. Herein, we developed the paclitaxel (PTX)-loaded nanoparticles (NP/PTX) and decorated it with an innovative peptide YI (YINP/PTX) for simultaneously targeting delivery of drug to TAMs and angiogenesis. We demonstrated that the modification of YI peptide significantly enhanced the internalization of nanoparticles by cells and accumulation of nanoparticles in tumor tissues, but down regulated the distribution of them in normal tissues especially the liver. We also made a confirmation that the YI peptide decorated nanoparticles had an excellent co-localization with TAMs and angiogenesis in vivo. Finally, in the HT-26 colorectal tumor-bearing mice, a pharmacodynamic evaluation was performed and results showed that the YINP/PTX was more effective than other PTX formulations in anti-tumor growth. These results together suggested that the prepared nanoparticles are promising in targeting delivery of chemotherapeutics to tumor microenvironment for enhancing tumor therapy effect.
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Neoplasias do Colo/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Macrófagos/patologia , Nanopartículas/administração & dosagem , Neovascularização Patológica , Paclitaxel/farmacologia , Fragmentos de Peptídeos/química , Animais , Anexina A1/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/irrigação sanguínea , Neoplasias do Colo/patologia , Humanos , Camundongos , Camundongos Nus , Nanopartículas/química , Paclitaxel/administração & dosagem , Paclitaxel/química , Células Tumorais Cultivadas , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Angiotensin I converting enzyme (ACE) plays an important role in regulating blood pressure in the human body. ACE inhibitory peptides derived from food proteins could exert antihypertensive effects without side effects. Jellyfish (Rhopilema esculentum) is an important fishery resource suitable for production of ACE inhibitory peptides. The objective of this study was to optimize the hydrolysis conditions for production of protein hydrolysate from R. esculentum (RPH) with ACE inhibitory activity, and to isolate and identify the ACE inhibitory peptides from RPH. RESULTS: Rhopilema esculentum protein was hydrolyzed with Compound proteinase AQ to produce protein hydrolysate with ACE inhibitory activity, and the hydrolysis conditions were optimized using response surface methodology. The optimum parameters for producing peptides with the highest ACE inhibitory activity were as follows: hydrolysis time 3.90 h, hydrolysis temperature 58 °C, enzyme:substrate ratio 2.8% and pH 7.60. Under these conditions, the ACE inhibitory rate reached 32.21%. In addition, four novel ACE inhibitory peptides were isolated, and their amino acids sequences were identified as Val-Gly-Pro-Tyr, Phe-Thr-Tyr-Val-Pro-Gly, Phe-Thr-Tyr-Val-Pro-Gly-Ala and Phe-Gln-Ala-Val-Trp-Ala-Gly, respectively. The IC50 value of the purified peptides for ACE inhibitory activity was 8.40, 23.42, 21.15 and 19.11 µmol L(-1) . CONCLUSION: These results indicate that the protein hydrolysate prepared from R. esculentum might be a commercial competitive source of ACE inhibitory ingredients to be used in functional foods. © 2015 Society of Chemical Industry.
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Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Peptídeos/isolamento & purificação , Peptídeos/metabolismo , Hidrolisados de Proteína/isolamento & purificação , Hidrolisados de Proteína/metabolismo , Cifozoários/química , Sequência de Aminoácidos , Animais , Cromatografia Líquida de Alta Pressão , Ativação Enzimática , Ensaios Enzimáticos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Peptídeos/química , Hidrolisados de Proteína/antagonistas & inibidores , Hidrolisados de Proteína/química , TemperaturaRESUMO
This study describes the extraction, preliminary characterization and evaluation of the in vitro antitumor and antioxidant activities of polysaccharides extracted from Mentha piperita (MPP). The optimal parameters for the extraction of MPP were obtained by Box-Behnken experimental design and response surface methodology (RSM) at the ratio of water to raw material of 20, extraction time of 1.5 h and extraction temperature at 80 °C. Chemical composition analysis showed that MPP was mainly composed of glucuronic acid, galacturonic acid, glucose, galactose and arabinose, and the molecular weight of its two major fractions were estimated to be about 2.843 and 1.139 kDa, respectively. In vitro bioactivity experiments showed that MPP not only inhibited the growth of A549 cells but possessed potent inhibitory action against DNA topoisomerase I (topo I), and an appreciative antioxidant action as well. These results indicate that MPP may be useful for developing safe natural health products.
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Antioxidantes/química , Mentha piperita/metabolismo , Polissacarídeos/química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Antioxidantes/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/metabolismo , Humanos , Radical Hidroxila/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Superóxidos/química , TemperaturaRESUMO
Resistant starch from rice was prepared using high-pressure homogenization and branched chain amylase treatment. The yield, starch external structure, thermal properties, and crystal structure of rice-resistant starch prepared in different ways were investigated. The results showed that the optimum homogenizing pressure was 90 MPa, the optimum digestion time was 4 h, the optimum concentration of branched-chain amylase was 50 U/g and the yield of resistant starch was 38.58 %. Scanning electron microscopy results showed a rougher surface and more complete debranching of the homogenized coenzyme rice-resistant starch granules. FT-IR and X-ray diffraction results showed that the homogenization treatment exhibited a spiral downward trend on rice starch relative crystallinity and a spiral upward trend on starch debranching and recrystallization. The 4-week dietary intervention in db/db type 2 diabetic mice showed that homogeneous coenzyme rice-resistant starch had a better glycemic modulating effect than normal debranched starch and had a tendency to interfere with the index of liver damage in T2DM mice. Additionally, homogeneous coenzyme rice-resistant starch proved more effective in improving intestinal flora disorders and enhancing the abundance of probiotics in T2DM mice.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Oryza , Camundongos , Animais , Amido Resistente , Glicemia , Oryza/química , Espectroscopia de Infravermelho com Transformada de Fourier , Amido/química , Difração de Raios X , AmilasesRESUMO
Heat shock factor 1 (HSF1), an essential transcription factor for stress response, is exploited by various tumors to facilitate their initiation, progression, invasion, and migration. Amplification of HSF1 is widely regarded as an indicator in predicting cancer severity, the likelihood of treatment failure and reduced patient survival. Notably, HSF1 is markedly amplified in 40% of pancreatic cancer (PC), which typically have limited treatment options. HSF1 has been proven to be a promising therapeutic target for multiple cancers. However, a direct small molecule HSF1 inhibitor with sufficient bioactivity and reliable safety has not been developed clinically. In this study, we successfully established a high-throughput screening system utilizing luciferase reporter assay specifically designed for HSF1, which leads to the discovery of a potent small molecule inhibitor targeting HSF1. Homoharringtonine (HHT) selectively inhibited PC cell viability with high HSF1 expression and induced a markedly stronger tumor regression effect in the subcutaneous xenograft model than the comparator drug KRIBB11, known for its direct action on HSF1. Moreover, HHT shows promise in countering the resistance encountered with HSP90 inhibitors, which have been observed to increase heat shock response intensity in clinical trials. Mechanistically, HHT directly bound to HSF1, suppressing its expression and thereby inhibiting transcription of HSF1 target genes. In conclusion, our work presents a preclinical discovery and validation for HHT as a HSF1 inhibitor for PC treatment.
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Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Unfortunately, targeting STAT3 with small molecules has proven to be very challenging, and for full activation of STAT3, the cooperative phosphorylation of both tyrosine 705 (Tyr705) and serine 727 (Ser727) is needed. Further, a selective inhibitor of STAT3 dual phosphorylation has not been developed. Here, we identified a low nanomolar potency and highly selective small-molecule STAT3 inhibitor that simultaneously inhibits both STAT3 Tyr705 and Ser727 phosphorylation. YY002 potently inhibited STAT3-dependent tumor cell growth in vitro and achieved potent suppression of tumor growth and metastasis in vivo. More importantly, YY002 exhibited favorable pharmacokinetics, an acceptable safety profile, and superior antitumor efficacy compared to BBI608 (STAT3 inhibitor that has advanced into phase III trials). For the mechanism, YY002 is selectively bound to the STAT3 Src Homology 2 (SH2) domain over other STAT members, which strongly suppressed STAT3 nuclear and mitochondrial functions in STAT3-dependent cells. Collectively, this study suggests the potential of small-molecule STAT3 inhibitors as possible anticancer therapeutic agents.
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The discovery of adult cardiac progenitor cells (CPCs) provides a promising way for treating heart disease; however, their surface characteristics that play a critical role in regulating their maintenance, self-renewal, migration, and differentiation have not been fully investigated. One subpopulation of Dolichos biflorus agglutinin (DBA)-positive cells was identified in the heart of adult mice. Flow cytometry showed that 3.7% of heart cells could be labeled by FITC conjugated DBA. BrdU pulse-chase showed that 55-75% of DBA(+) cells were CPCs. Evidences from 5-FU-induced myelosuppression along with BrdU pulse-chasing suggests that DBA-positive cells are proliferative. Furthermore, DBA positive cells display a cologenic appearance in vivo. Our findings suggest that DBA-positive cells in the heart of adult mouse contained a subset of CPCs, and DBA reactivity is one novel surface characteristic on CPCs.
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Epitopos/imunologia , Miocárdio/citologia , Lectinas de Plantas/imunologia , Polissacarídeos/imunologia , Células-Tronco/citologia , Células-Tronco/imunologia , Animais , Bromodesoxiuridina/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Clonais , Fluoruracila/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Proteínas Proto-Oncogênicas c-kit/metabolismo , Coloração e Rotulagem , Células-Tronco/efeitos dos fármacosRESUMO
Acute myeloid leukemia (AML) is a common type of acute leukemia in adults and relapse is one of the main reasons for treatment failure. FLT3ITD mutations are associated with poor prognosis, short diseasefree progression survival and high relapse rates in patients with AML. STAT5 is activated by FLT3ITD and drives the pathogenesis of AML. STAT5 activation is usually a hallmark of hematologic malignancies and occurs in ~70% of patients with AML. Moreover, STAT5 is a key molecule which regulates hematopoiesis, and its high expression is closely associated with drug resistance, thus direct targeting of STAT5 for AML is of great clinical value. The present study introduces a new smallmolecule inhibitor that targets STAT5, presenting a promising approach for AML therapy. A high throughput fluorescence polarization (FP) screening system for STAT5 was designed and established, and used to screen an existing compound library to obtain the highly active small molecule inhibitor, topotecan hydrochloride. Topotecan hydrochloride was demonstrated to be an effective inhibitor of STAT5 by molecular docking prediction and cellular thermal shift assay. Topotecan hydrochloride bound to STAT5, inhibiting its dimerization, phosphorylation and transcription of specific target genes. The compound exhibits cellular activity at the nanomolar level and significantly inhibits the proliferation of human AML cell lines and FLT3ITD+ AML cells. Furthermore, topotecan hydrochloride has the potential to exert an antitumor effect in vivo. Overall, topotecan hydrochloride offers a new opportunity for the treatment of AML and other hematologic malignancies by directly targeting STAT5.
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Neoplasias Hematológicas , Leucemia Mieloide Aguda , Humanos , Topotecan/farmacologia , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Simulação de Acoplamento Molecular , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , RecidivaRESUMO
Tyrosine kinase 2 (TYK2) as a member of Janus kinase (JAK) family, mainly mediates the signaling of type I interferons (IFN), interleukin-12 (IL-12) and interleukin-23 (IL-23), which has become an attractive target for treatment of immune and inflammatory diseases. However, the development of selective TYK2 inhibitors is challenging due to the high homology of the catalytic kinase domain among the JAK family members. Here, we report a novel and potent allosteric inhibitor, WD-890, which binds to the pseudokinase domain of TYK2 with high selectivity and inhibits its function. We accomplished a series of preclinical studies to demonstrate the therapeutic efficacy of WD-890 in four animal models: systemic lupus erythematosus (SLE), psoriasis, psoriatic arthritis (PsA), and inflammatory bowel disease (IBD). The pharmacokinetic and toxicology results further indicate that WD-890 has favorable absorption, distribution, metabolism, and excretion (ADME) properties and tolerable toxicity. In conclusion, our study shows that WD-890 could be a promising oral TYK2 inhibitor for future treatment of autoimmune diseases.
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Artrite Psoriásica , Doenças Autoimunes , Animais , TYK2 Quinase/metabolismo , Doenças Autoimunes/tratamento farmacológico , Janus Quinases , Interleucina-12RESUMO
Cholecystokinin (CCK) can make the human body feel full and has neurotrophic and anti-inflammatory effects. It is beneficial in treating obesity, Parkinson's disease, pancreatic cancer, and cholangiocarcinoma. Traditional biological experiments are costly and time-consuming when it comes to finding and identifying novel CCK-secretory peptides, and there is an urgent need to develop a new computational method to predict new CCK-secretory peptides. This study combines the transfer learning method with the SMILES enumeration data augmentation strategy to solve the data scarcity problem. It establishes a fusion model of the hierarchical attention network (HAN) and bidirectional long short-term memory (BiLSTM), which fully extracts peptide chain features to predict CCK-secretory peptides efficiently. The average accuracy of the proposed method in this study is 95.99%, with an AUC of 98.07%. The experimental results show that the proposed method is significantly superior to other comparative methods in accuracy and robustness. Therefore, this method is expected to be applied to the preliminary screening of CCK-secretory peptides.
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Colecistocinina , Aprendizado de Máquina , Humanos , Peptídeos/farmacologia , Receptores da ColecistocininaRESUMO
Background: As a common fragrance ingredient, α-ionone is widely used in cosmetics, perfume, and hygiene products. Nevertheless, little information is available for its biological activities on the skin. In this study, we investigated the effect of α-ionone on keratinocyte functions associated with skin barrier repair and further evaluated its skin barrier recovery capacity to explore its therapeutic potential for the treatment of skin barrier disruption. Methods: The effect of α-ionone on the keratinocyte functions including cell proliferation, migration, and production of hyaluronic acid (HA) and human ß-defensin-2 (HBD-2) were examined in vitro using human immortalized keratinocytes (HaCaT cells) as experimental model. The barrier recovery effects of topical hydrogels containing 0.1% or 1% α-ionone were tested on the volar forearm of 31 healthy volunteers by measuring transepidermal water loss (TEWL) and stratum corneum (SC) hydration following barrier disruption induced by repeated tape-stripping. The statistical significance was evaluated by one-way analysis of variance (ANOVA) followed by a Dunnett's post-hoc test. Results: α-ionone promoted HaCaT cell proliferation (P<0.01) dose-dependently in the 10 to 50 µM range. Meanwhile, it also increased the intracellular cyclic adenosine monophosphate (cAMP) levels (P<0.05). Furthermore, HaCaT cells treated with α-ionone (10, 25, 50 µM) showed enhanced cell migration (P<0.05), up-regulated gene expression of hyaluronic acid synthases 2 (HAS2) (P<0.05), HAS3 (P<0.01), and HBD-2 (P<0.05), and enhanced production of HA (P<0.01) and HBD-2 (P<0.05) in the culture supernatant. These beneficial actions of α-ionone were abrogated by cAMP inhibitor, suggesting that its effects are cAMP-mediated in HaCaT cells. In vivo study showed that topical application of α-ionone-containing hydrogels accelerated the epidermal barrier recovery of human skin after barrier disruption by tape stripping. Treatment with hydrogel containing 1% α-ionone resulted in a significant increase of above 15% in the barrier recovery rate at day 7 post-treatment when compared to the vehicle control (P<0.01). Conclusions: These results demonstrated the role of α-ionone in the improvement of keratinocyte functions and the epidermal barrier recovery. These findings suggest possible therapeutic application of α-ionone in the treatment of skin barrier disruption.
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MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.
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Satiety hormone cholecystokinin (CCK) plays a vital role in appetite inhibition. Its secretion is regulated by dietary components. The search for bioactive compounds that stimulate CCK secretion is currently an active area of research. The objective of this study was to evaluate the ability of buckwheat (Fagopyrum esculentum Moench) protein digest (BPD) to stimulate CCK secretion in vitro and in vivo and clarify the structural characteristics of peptides stimulating CCK secretion. BPD was prepared by an in vitro gastrointestinal digestion model. The relative molecular weight of BPD was <10 000 Da, and peptides with <3000 Da accounted for 70%. BPD was rich in essential amino acids Lys, Leu, and Val but lacked sulfur amino acids Met and Cys. It had a stimulatory effect on CCK secretion in vitro and in vivo. Chromatographic separation was performed to isolate peptide fractions involved in CCK secretion, and five novel CCK-releasing peptides including QFDLDD, PAFKEEHL, SFHFPI, IPPLFP, and RVTVQPDS were successfully identified. A sequence length range of 6-8 and marked hydrophobicity (18-28) were observed among the most CCK-releasing peptides. The present study demonstrated for the first time that BPD could stimulate CCK secretion and clarify the structural characteristics of bioactive peptides having CCK secretagogue activity in BPD.
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Colecistocinina , Fagopyrum , Colecistocinina/metabolismo , Fagopyrum/metabolismo , Peptídeos , Proteínas , DigestãoRESUMO
In this research, oat resistant starch (ORS) was prepared by autoclaving-retrogradation cycle (ORS-A), enzymatic hydrolysis (ORS-B), and ultrasound combined enzymatic hydrolysis (ORS-C). Differences in their structural features, physicochemical properties and digestive properties were studied. Results of particle size distribution, XRD, DSC, FTIR, SEM and in vitro digestion showed that ORS-C was a B + C-crystal, and ORS-C had a larger particle size, the smallest span value, the highest relative crystallinity, the most ordered and stable double helix structure, the roughest surface shape and strongest digestion resistance compared to ORS-A and ORS-B. Correlation analysis revealed that the digestion resistance of ORS-C was strongly positively correlated with RS content, amylose content, relative crystallinity and absorption peak intensity ratio of 1047/1022 cm-1 (R1047/1022), and weakly positively correlated with average particle size. These results provided theoretical support for the application of ORS-C with strong digestion resistance prepared by ultrasound combined enzymatic hydrolysis in the low GI food application.
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Avena , Amido , Hidrólise , Amido/química , Amido Resistente , Amilose/química , DigestãoRESUMO
PURPOSE: Pancreatic cancer is the worst prognosis among all human cancers, and novel effective treatments are urgently needed. Signal transducer and activator of transcription 3 (STAT3) has been demonstrated as a promising target for pancreatic cancer. Meanwhile, selectively targeted STAT3 with small molecule remains been challenging. EXPERIMENTAL DESIGN: To specifically identify STAT3 inhibitors, more than 1.3 million compounds were screened by structure-based virtual screening and confirmed with the direct binding assay. The amino acid residues that WB436B bound to were verified by induced-fit molecular docking simulation, RosettaLigand computations, and site-directed mutagenesis. On-target effects of WB436B were examined by microscale thermophoresis, surface plasmon resonance, in vitro kinase assay, RNA sequencing, and selective cell growth inhibition assessment. In vivo studies were performed in four animal models to evaluate effects of WB436B on tumor growth and metastasis. Kaplan-Meier analyses were used to assess survival. RESULTS: WB436B selectively bound to STAT3 over other STAT families protein, and in vitro antitumor activities were improved by 10 to 1,000 fold than the representative STAT3 inhibitors. WB436B selectively inhibits STAT3-Tyr705 phosphorylation, STAT3 target gene expression, and the viability of STAT3-dependent pancreatic cancer cells. WB436B significantly suppresses tumor growth and metastasis in vivo and prolongs survival of tumor-bearing mice. Mechanistic studies showed that WB436B have unique binding sites located in STAT3 Src homology 2 domain. CONCLUSIONS: Our work presents the first-in-class selective STAT3 inhibitor WB436B as a potential therapeutic candidate for the treatment of pancreatic cancer.
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Neoplasias Pancreáticas , Fator de Transcrição STAT3 , Humanos , Animais , Camundongos , Fator de Transcrição STAT3/metabolismo , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Domínios de Homologia de src , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fosforilação , Proliferação de Células , Apoptose , Neoplasias PancreáticasRESUMO
Prostate cancer is one of the most lethal malignancies, and androgen deprivation therapy remains the mainstay of treatment for prostate cancer patients. Although androgen deprivation can initially come to remission, the disease often develops into castration-resistant prostate cancer (CRPC), which is still dependent on androgen receptor (AR) signaling and is related to a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance uninterrupted emerges, and new therapies are urgently needed. In this study, we identified a potent small molecule compound, ZY-444, that suppressed PCa cells proliferation and metastasis, and inhibited tumor growth both in subcutaneous. Transcriptome sequencing analysis showed that TNFAIP3 was significantly elevated in prostate cancer cells after ZY-444 treatment. Further studies through overexpression of TNFAIP3 confirmed that TNFAIP3, as a direct target gene of ZY-444, contributes to the functions of ZY-444. In addition, we demonstrated the effects of TNFAIP3 on prostate cancer cell apoptosis, migration and proliferation to elucidate the mechanism of ZY-444. We found that TNFAIP3 inhibited the TNF signaling pathway, which could inhibit cell migration and proliferation and contribute to apoptosis. Overall, these findings highlighted TNFAIP3 as a tumor suppressor gene in the regulation of the progression and metastatic potential of prostate cancer and that targeting TNFAIP3 by ZY-444 might be a promising strategy for prostate cancer treatment.