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HDAC8 is a therapeutic target with great promise for breast cancer. Here, we reported a novel compound corallorazine D from Nocardiopsis sp. XZB108, selectively inhibited HDAC8 (IC50 = 0.90 ± 0.014 µM), suggesting that it may be a promising nonhydroxamate HDAC8 inhibitor. Upon additional modifications of corallorazine D, a candidate compound 5k, demonstrated remarkable inhibitory potency against HDAC8 (IC50 = 0.12 ± 0.01 nM), 89-fold superior to PCI-34051. The selectivity of 5k was at least 439-fold, superior to corallorazine D, confirming the efficacy of our modifications. In an orthotopic mouse model of breast cancer, 5k displayed nearly 4-fold superior antitumor activity than SAHA. Furthermore, 5k triggered antitumor immunity by activating T cells. Treatment with 5k significantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). 5k represents a promising compound for further investigation as a potential treatment for breast cancer.
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Antineoplásicos , Neoplasias de la Mama , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Animales , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Humanos , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/uso terapéutico , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Histona Desacetilasas/metabolismo , Línea Celular Tumoral , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/metabolismo , Relación Estructura-Actividad , Ratones Endogámicos BALB C , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Based on the structure of caerulomycin A, 90 novel bipyridine derivatives were designed and synthesized. Among these, compound B19 exerted strong antitumor effects in vivo and in vitro. Importantly, NOP2/Sun RNA methyltransferase 3 (NSUN3) protein was identified as the target specific binding to B19, which inhibits oxidative phosphorylation of mitochondrial energy metabolism and enhances glycolytic activity by binding to NSUN3. Knockdown of NSUN3 inhibited both proliferation and migration of colorectal cancer (CRC) cells by activating AMPK-related signaling and inhibiting downstream STAT3 signaling to exert antiproliferative and pro-apoptotic effects. Our findings support the use of NSUN3 inhibitors as promising therapeutic strategies against CRC.
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Antineoplásicos , Proliferación Celular , Neoplasias Colorrectales , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Ratones , Línea Celular Tumoral , Metiltransferasas/antagonistas & inhibidores , Metiltransferasas/metabolismo , Apoptosis/efectos de los fármacos , Piridinas/farmacología , Piridinas/química , Piridinas/síntesis química , Ratones Desnudos , Relación Estructura-Actividad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/uso terapéutico , Ratones Endogámicos BALB C , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Movimiento Celular/efectos de los fármacosRESUMEN
BACKGROUND: Complete pathological response (pCR) and major pathological response (MPR) have been proven to have a close association with improved event-free survival (EFS) and overall survival (OS) for patients accepting chemotherapy or chemoradiotherapy. However, further study focusing on neoadjuvant immunotherapy is limited. Here we provided an updated and comprehensive evaluation of the association between pathological response and long-term survival outcomes at patient level and trial level for neoadjuvant immunotherapy. METHODS: We systematically searched and assessed studies in PubMed, Embase, the Cochrane Library and relevant conference abstracts from inception to June 1, 2023. Studies reported EFS/OS results by pCR/MPR status were eligible. RESULTS: Forty-three studies comprising a total of 4100 patients were eligible for the analysis, which included 39 studies for the patient-level analysis and 5 randomized controlled trials for the trial-level analysis. Our results highlighted that pCR was associated with improved EFS (HR, 0.48 [95 % CI, 0.39-0.60]) and OS (HR, 0.55 [95 % CI, 0.41-0.74]). The magnitude of HRs by MPR status were similar to the results by pCR status (EFS HR, 0.31 [95 % CI, 0.18-0.53]) and OS HR, 0.43 [95 % CI, 0.19-0.96]). However, no association between pCR and EFS at trial level was found (P = 0.8, R2 = 0). CONCLUSION: Our meta-analysis demonstrates a strong association between pathological response and long-term survival outcomes at patient level across studies applying neoadjuvant immunotherapy in most solid tumors but we fail to validate the relationship at trial level. Therefore, an accepted surrogate endpoint applied to both patient and trial levels are waited for further search.
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Inmunoterapia , Terapia Neoadyuvante , Humanos , Terapia Neoadyuvante/métodos , Inmunoterapia/métodos , Neoplasias/terapia , Neoplasias/mortalidad , Neoplasias/inmunología , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Proteolysis targeting chimera (PROTAC) is a protein degradation technique that has been increasingly used in the development of new drugs in recent years. Akt is a classical serine/threonine kinase, and its role outside of the kinase has gradually gained attention in recent years, making it one of the proteins targeted by PROTACs. Currently, there are many methods used for the evaluation of intracellular protein degradation, but each has its own advantages or disadvantages. This study aimed to investigate the feasibility of evaluating the degradation of pan-Akt proteins in cells by PROTACs (MS21 and MS170) using the NanoLuc luciferase method. After conducting a thorough comparison between this method and the classical western blot assay in various cells, as well as testing the stability of the experiments between multiple batches, we found that NanoLuc luciferase is a highly accurate, stable, low-cost and easy-to-operate method for the evaluation of intracellular pan-Akt degradation by PROTACs with a short cycle time and high cellular expandability. Given the numerous advantages of this method, it is hypothesized that it could be extended to evaluate the degradation of more target proteins of PROTACs. In summary, the NanoLuc luciferase is a suitable method for early protein degradation screening of PROTAC compounds.
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Iron phthalocyanine (FePc) has attracted widespread attention for its tunable electronic structure. However, the Fe-N sites suffer from undesirable oxygen reduction activity due to the symmetric geometries. A suitable substrate was thus needed to induce electron redistribution around Fe-N to improve the activity. Herein, ultrathin nitrogen-doped carbon nanosheets (N-CNSs) were prepared by a simple high temperature pyrolysis. Then iron phthalocyanine was loaded on the ultrathin nitrogen-doped carbon nanosheets (FePc@N-CNSs) by a low-cost and simple solution method. This composite catalyst shows an excellent ORR activity with a half potential of 0.88 V, an onset potential of 0.99 V and durability superior to commercial Pt/C. When used as an air cathode catalyst for rechargeable zinc-air batteries, FePc@N-CNS modified batteries outperform Pt/C + RuO2 modified batteries with higher power density and superior constant current charge-discharge cycling stability of 37 hours. The regulated electronic structure of FePc by the N-CNS substrate was revealed further by DFT calculations, which explained the enhanced adsorption of the active center to the intermediates and the increased ORR performance.
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Psoriasis, a prevalent chronic skin disorder, remains a significant therapeutic obstacle. This study centers on rho-associated coiled-coil-containing kinase2 (ROCK2) as an advantageous target for treating psoriasis and identifies five potent and selective ROCK2 inhibitors (A31-35). Notably, A32-35 outperform KD025 in ROCK2/ROCK1 selectivity by up to 216-fold. Among these candidates, A31 emerged as an exceedingly promising molecule, showcasing remarkable inhibitory potency (IC50 = 3.7 ± 0.8 nM), 19-fold ROCK2/ROCK1 selectivity, and favorable pharmacokinetics. Insights from the binding mode study further underscored the pivotal role of interactions with Phe103 on the P-loop in determining the selectivity between ROCK1 and ROCK2. In an imiquimod-induced psoriasis-like mouse model, oral administration of A31 notably ameliorated symptoms by targeting the IL-23/Th17 axis. Based on these compelling findings, A31 was selected as a highly promising compound for further investigation as a potential treatment for psoriasis.
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Psoriasis , Animales , Ratones , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Quinasas Asociadas a rhoRESUMEN
Nine new compounds, including streptothiomycin A-E (1-5), two cyclopentenones (6, 7), one α-pyrone (8), wailupemycin Q (20), along with sixteen known compounds were identified from a rhizosphere strain Streptomyces sp. DS-27 derived from the marine cordgrass Spartina alterniflora under two different culture conditions. All of the structures were elucidated by extensive analysis of 1D/2D NMR and HR-ESI-MS data. The absolute configurations were determined by NOESY analysis, ECD, specific rotation and GIAO NMR calculations, and DP4+ probability analysis. Bioactivity investigation showed that compounds 5 and 7 exhibited significant inhibitory effects on LPS-induced NO production in a dose-dependent manner, which indicates their anti-inflammatory potential.
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Antineoplásicos , Streptomyces , Antineoplásicos/farmacología , Streptomyces/química , Espectroscopía de Resonancia Magnética , Pironas/química , Estructura MolecularRESUMEN
Streptomyces sp. HNA39 is a promising candidate for the production of antineoplastic metabolites screened from a collection of 448 actinomycetes derived from coastal sediments. The complete genome sequence of HNA39 comprises a 7,351,753-bp linear chromosome with a GC content of 71.94%. Whole genome analysis reveals the presence of 29 putative biosynthetic gene clusters (BGCs) encoding secondary metabolites. Among them, a type I PKS BGC shows an 82% similarity with the cyclizidine (CLD) BGC identified from Streptomyces NCIB 11649. LC-MS profiles further supported the production of new CLD congeners. Bafilomycins were also found produced in abundance, corresponding to another type I PKS BGC highly homologous to that of bafilomycin B1 from S. lohii. CLDs are indolizidine alkaloids consisting a fused five- and six-membered ring system with an intriguing cyclopropane terminal linked by a trans-dienic chain. The cyclization mechanism of the cylopropyl ring, one of its pharmacophores, is still unknown. Genome sequencing of the new CLD producer and subsequent comparative analysis of their gene clusters would further our understanding of the chemistry behind cyclopropane formation.
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Streptomyces , Streptomyces/genética , Secuencia de Bases , Mapeo Cromosómico , China , Familia de MultigenesRESUMEN
Alpiniamides E-G, three previously unreported linear polyketide derivatives, along with two known compounds, were isolated from Streptomyces sp. QHA48, which was isolated from the saline lakes of Qinghai-Tibet Plateau. The structures of these compounds were determined through analysis of their spectroscopic data, as well as density functional theory prediction of NMR chemical shifts, application of the DP4+ algorithm and electronic circular dichroism (ECD) calculations. In a cell-based lipid-lowering assay, all five alpiniamides exhibited significant inhibition of lipid accumulation in HepG2 cells without inducing cytotoxic effects at a concentration of 27â µM.
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Lagos , Streptomyces , Streptomyces/química , Dicroismo Circular , Espectroscopía de Resonancia Magnética , Lípidos/farmacología , Estructura MolecularRESUMEN
Polychlorinated biphenyls (PCBs) and microplastics (MPs) commonly co-exist in various environments. MPs inevitably start aging once they enter environment. In this study, the effect of photo-aged polystyrene MPs on microbial PCB dechlorination was investigated. After a UV aging treatment, the proportion of oxygen-containing groups in MPs increased. Photo-aging promoted the inhibitory effect of MPs on microbial reductive dechlorination of PCBs, mainly attributed to the inhibition of meta-chlorine removal. The inhibitory effects on hydrogenase and adenosine triphosphatase activity by MPs increased with increasing aging degree, which may be attributed to electron transfer chain inhibition. PERMANOVA showed significant differences in microbial community structure between culturing systems with and without MPs (p < 0.05). Co-occurrence network showed a simpler structure and higher proportion of negative correlation in the presence of MPs, especially for biofilms, resulting in increased potential for competition among bacteria. MP addition altered microbial community diversity, structure, interactions, and assembly processes, which was more deterministic in biofilms than in suspension cultures, especially regarding the bins of Dehalococcoides. This study sheds light on the microbial reductive dechlorination metabolisms and mechanisms where PCBs and MPs co-exist and provides theoretical guidance for in situ application of PCB bioremediation technology.
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Bifenilos Policlorados , Envejecimiento de la Piel , Bifenilos Policlorados/metabolismo , Microplásticos , Plásticos , Poliestirenos , Biodegradación Ambiental , Cloro/farmacología , Cloro/metabolismo , Sedimentos Geológicos/microbiologíaRESUMEN
Breast cancer metastasis is a major challenge in clinical therapy because of the absence of effective treatments. Rho-associated coiled-coil kinase (ROCK), which is essential for cell invasion and migration, has recently been suggested as a potential target for the treatment of cancer metastasis. Herein, we report the structure-activity relationships (SAR) of indolocarbazoles against ROCK2 and reveal the crucial role of the C-3 hydroxyl for ROCK2 inhibition. The most potent unglycosylated aglycone THK01 was demonstrated to bind to and stabilize ROCK2 with potent anti-metastatic effects in breast cancer in vitro and in vivo with no obvious toxicities. Further mechanistic studies revealed that the anti-metastatic effect of THK01 was closely related to the suppression of STAT3Y705 activation. Moreover, THK01 exhibited excellent selectivity over the isoform protein ROCK1 (>100-fold). Taken together, with low toxicity, the ROCK2 inhibitor THK01 potently inhibited breast cancer metastasis through the ROCK2-STAT3 signaling pathway, which offers a new opportunity for the treatment of metastatic breast cancer.
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Neoplasias de la Mama , Neoplasias Cutáneas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Quinasas Asociadas a rho , Isoformas de Proteínas , Melanoma Cutáneo MalignoRESUMEN
Lipid-lowering is one of the most effective methods of prevention and treatment for cardiovascular diseases. However, most clinical lipid-lowering drugs have adverse effects and cannot achieve the desired efficacy in some complex hyperlipidemia patients, so it is of great significance to develop safe and effective novel lipid-lowering drugs. In the course of our project aimed at discovering the chemical novelty and bioactive natural products of marine-derived actinomycetes, we found that the organic crude extracts (OCEs) of Nocardiopsis sp. ZHD001 exhibited strong in vivo efficacies in reducing weight gain, lowering LDL-C, TC, and TG levels, and improving HDL-C levels in high-fat-diet-fed mice models. Chemical investigations of the active OCEs led to identifying two new sphydrofuran-derived compounds (1-2) and one known 2-methyl-4-(1-glycerol)-furan (3). Their structures were elucidated by the analysis of HRESIMS, 1D and 2D NMR spectroscopic data, and ECD calculations. Among these compounds, compound 1 represents a novel rearranged sphydrofuran-derived derivative. Bioactivity evaluations of these pure compounds showed that all the compounds exhibited significant lipid-lowering activity with lower cytotoxicity in vitro compared to simvastatin. Our results demonstrate that sphydrofuran-derived derivatives might be promising candidates for lipid-lowering drugs.
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Glicerol , Nocardiopsis , Ratones , Animales , Hipolipemiantes/uso terapéutico , Extractos Vegetales/química , LípidosRESUMEN
A new SEK15-derived polyketide compound, strepolyketide D (1), was isolated from salt-lake-derived Streptomyces sp. DBC5, together with two known analogues (2-3). Their structures were elucidated based on spectroscopic analysis of IR, MS, 1 D and 2 D NMR. Compound 2 elicited moderate antioxidation with IC50 value of 39.26 µg/ml. The results of the study revealed that salt-lake actinomycetes of Lake Dabancheng appear to have immense potential as a source of polyketide compounds.
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Policétidos , Streptomyces , Streptomyces/química , Lagos , Espectroscopía de Resonancia MagnéticaRESUMEN
The consensus tracking problem means that a group of followers tracks the desired trajectory with local communication. In this article, partial components of cluster consensus have been considered. In this scenario, the p components of the followers in different clusters track the leader at different lag times, while p components of each agent in the same cluster reach a consensus, which is called p components of cluster-lag (PCCL) consensus. By using a seminorm ||xi||2,p and a Lyapunov-Krasovskii functional, PCCL consensus for second-order multiagent systems with homogeneous nonlinear systems on cooperative-competitive networks has been considered. For the case that the communication network graph is undirected, a decentralized adaptive controller, which is based on the exchanged neighbors' information from the same cluster, is designed such that all the agents reach PCCL consensus. For the directed graph case, an adaptive protocol based on the intracoupling strength is constructed for each cluster to achieve PCCL consensus. Finally, two simulation examples are illustrated to show the effectiveness of the proposed control protocols.
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In this paper, we present a new microfluidic microwave sensor loaded with a star-slotted patch for detecting the quality of edible oil. The relative dielectric permittivity and the quality of edible oil will change after being heated at a high temperature. Therefore, the quality of edible oil can be detected by measuring the relative dielectric permittivity of edible oil. The sensor is used to determine the edible oil with different dielectric permittivity by measuring the resonance frequency offset of the input reflection coefficient, which operates at 2.68 GHz. This sensor is designed based on a resonant approach to provide the best sensing accuracy and is implemented using a substrate integrated waveguide structure combined with a pentagonal slot antenna operating at 2.3~2.9 GHz. It can detect greasy liquids with the real part of the complex permittivity ranging from two to three.
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Microfluídica , MicroondasRESUMEN
Two new p-methoxyphenyl-type derivatives cytchloramol (1) and cytoxazinanone (2), along with six known compounds (3-8) were identified from the chemical investigations of a saline lake actinomycete, Streptomyces sp. XZB32. The structures of the new compounds were elucidated by extensive NMR spectroscopic analysis, HRESIMS data, GIAO (gauge-including atomic orbitals) NMR, specific optical rotation (SOR) and electronic circular dichroism (ECD) calculations. Cytotoxicity evaluation of the two new compounds showed that compound 1 exhibited significant activity against HCT-116 and MDA-MB-231 human cancer cell line with IC50 values of 2.7 ± 0.07 µM and 1.54 ± 0.14 µM, respectively.
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Thirteen new compounds, including suncheonosides E-M (1-9), four benzothioate derivatives (10-13), and one known compound (14), were identified from the marine-derived Streptomyces sp. ZSN77. Suncheonosides E-M incorporate ß-d-glucose, while the reported suncheonosides (A-D) incorporate only l-rhamnose. All of the structures were determined by extensive analysis of NMR spectroscopic and HRESIMS data. Bioactivity evaluation of these compounds showed that 6 had significant activity against PC3 cells with an IC50 value of 4.1 ± 0.1 µM, while compounds 12 and 14 exhibited cytotoxicity against HCT116 cells with IC50 values of 7.3 ± 0.4 and 3.9 ± 0.3 µM, respectively. In addition, compounds 1, 2, 6, 10, and 14 displayed potent in vivo anti-inflammatory efficacy with inhibition of NO production in a dose-dependent manner.
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Streptomyces , Células HCT116 , Humanos , Espectroscopía de Resonancia Magnética/métodos , Estructura Molecular , Células PC-3 , Streptomyces/químicaRESUMEN
Immunotherapy represented by immune checkpoint inhibitors has gradually entered a new era of precision medicine. In view of the limited clinical benefits of immunotherapy in patients with digestive system cancers, as well as the side-effects and high treatment costs, development of biomarkers to predict the efficacy of immune therapy is a key imperative. In this article, we review the available evidence of the value of microsatellite mismatch repair, tumor mutation burden, specific mutated genes or pathways, PD-L1 expression, immune-related adverse reactions, blood biomarkers, and patient-related biomarkers in predicting the efficacy of immunotherapy against digestive system cancers. Establishment of dynamic personalized prediction models based on multiple biomarkers is a promising area for future research.
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Neoplasias del Sistema Digestivo , Inhibidores de Puntos de Control Inmunológico , Biomarcadores de Tumor/metabolismo , Reparación de la Incompatibilidad de ADN , Neoplasias del Sistema Digestivo/tratamiento farmacológico , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Factores Inmunológicos/uso terapéutico , InmunoterapiaRESUMEN
This work developed a composite (Pe-FeLs) which loaded ferric lignin on polyethylene film (PE film) by chemical modification and physico-chemically characterized by Microscope, FESEM with elemental mapping analysis, and XRD. Microscope pictures showed that chemical modification did not destroy the appearance of PE film. The FESEM images of Pe-FeLs showed the well-distributed clusters could be clearly seen and most of the particles were spherical morphology. Elemental mapping of individual element on Pe-FeLs clearly indicated the existing of iron. The XRD pattern showed the amorphous hydroxides of iron on Pe-FeLs. In arsenic solution, the total arsenic adsorption capacity of Pe-FeLs was much higher than that of ferric lignin and PE, which showed Pe-FeLs had the ability to adsorb arsenic. For making Pe-FeLs work well in the soil, a Pe-FeLs system was set up with plastic grid plate, PE film with holes, Pe-FeLs, PE film, and plastic grid plate from the upper to bottom in order. With applying Pe-FeLs system under the soil, arsenic was significantly reduced by 25.5 ~ 53.4% in heavily, moderately, and lower arsenic-polluted soils, the biomass of the romaine lettuce increased and arsenic accumulation in the romaine lettuce decreased.
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Arsénico , Contaminantes del Suelo , Arsénico/análisis , Hierro/análisis , Lactuca , Lignina , Polietileno , Suelo/química , Contaminantes del Suelo/análisisRESUMEN
In nature and human society, successive lag synchronization (SLS) is an important synchronization phenomenon. Compared with other synchronization patterns, the control theory of SLS is very lacking. To this end, we first introduce a complex dynamical network model with distributed delayed couplings, and design both the linear feedback pinning control and adaptive feedback pinning control to push SLS to the desired trajectories. Second, we obtain a series of sufficient conditions to achieve SLS to a desired trajectory with global stability. What is more, the control flow of SLS is given to show how to pick the pinned nodes accurately and set the feedback gains as well. Finally, since time-varying delay is common, we extend the constant time delay in SLS to be time varying. We find that the proposed pinning control schemes are still feasible if the coupling terms are appropriately adjusted. The theoretical results are verified on a neural network and the coupled Chua's circuits.