Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 168
Filtrar
1.
Front Pharmacol ; 15: 1330855, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38434709

RESUMO

A mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model links the concentration-time profile of a drug with its therapeutic effects based on the underlying biological or physiological processes. Clinical endpoints play a pivotal role in drug development. Despite the substantial time and effort invested in screening drugs for favourable pharmacokinetic (PK) properties, they may not consistently yield optimal clinical outcomes. Furthermore, in the virtual compound screening phase, researchers cannot observe clinical outcomes in humans directly. These uncertainties prolong the process of drug development. As incorporation of Artificial Intelligence (AI) into the physiologically based pharmacokinetic/pharmacodynamic (PBPK) model can assist in forecasting pharmacodynamic (PD) effects within the human body, we introduce a methodology for utilizing the AI-PBPK platform to predict the PK and PD outcomes of target compounds in the early drug discovery stage. In this integrated platform, machine learning is used to predict the parameters for the model, and the mechanism-based PD model is used to predict the PD outcome through the PK results. This platform enables researchers to align the PK profile of a drug with desired PD effects at the early drug discovery stage. Case studies are presented to assess and compare five potassium-competitive acid blocker (P-CAB) compounds, after calibration and verification using vonoprazan and revaprazan.

2.
Cancer Sci ; 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38487949

RESUMO

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. In this study, we aim to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefit. We retrospective analyzed 69 GBC patients who had received ICI therapy between January 2016 and December 2020. Tumor samples were obtained for genomic sequencing and immunohistochemical analysis. The median progression-free survival (PFS) and overall survival (OS) was 4.4 months and 8.5 months, respectively. Multivariate analysis indicated that alcohol intake history, carcinoma embryonic antigen (CEA) level ≥100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for PFS. CEA level ≥100 U/mL and cutaneous irAEs were independent prognostic factors for OS. The objective response rate and disease control rate (DCR) were 15.9% and 37.7%, respectively. Patients with cutaneous irAEs, high CD8+ T cell infiltrated or immune inflamed GBCs had higher DCR. Patients with high CD8+ T cell infiltrated or immune inflamed GBCs also had a notably improved prognosis. These results suggest that ICIs were effective in patients with GBC. High CEA level, cutaneous irAEs, high CD8+ T cell infiltration, and immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC.

3.
J Transl Med ; 22(1): 176, 2024 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-38369466

RESUMO

BACKGROUND: The need for radiotherapy among the elderly rises with increasing life expectancy and a corresponding increase of elderly cancer patients. Radiation-induced skin injury is one of the most frequent adverse effects in radiotherapy patients, severely limiting their life quality. Re-epithelialization and collagen deposition have essential roles in the recovery of skin injuries induced by high doses of ionizing radiation. At the same time, radiation-induced senescent cells accumulate in irradiated tissues. However, the effects and mechanisms of senescent cells on re-epithelialization and collagen deposition in radiation-induced skin injury have not been fully elucidated. RESULTS: Here, we identified a role for a population of senescent cells expressing p16 in promoting re-epithelialization and collagen deposition in radiation-induced skin injury. Targeted ablation of p16+ senescent cells or treatment with Senolytics resulted in the disruption of collagen structure and the retardation of epidermal coverage. By analyzing a publicly available single-cell sequencing dataset, we identified fibroblasts as a major contributor to the promotion of re-epithelialization and collagen deposition in senescent cells. Notably, our analysis of publicly available transcriptome sequencing data highlighted IL-33 as a key senescence-associated secretory phenotype produced by senescent fibroblasts. Neutralizing IL-33 significantly impedes the healing process. Finally, we found that the effect of IL-33 was partly due to the modulation of macrophage polarization. CONCLUSIONS: In conclusion, our data suggested that senescent fibroblasts accumulated in radiation-induced skin injury sites participated in wound healing mainly by secreting IL-33. This secretion regulated the local immune microenvironment and macrophage polarization, thus emphasizing the importance of precise regulation of senescent cells in a phased manner.


Assuntos
Interleucina-33 , Lesões por Radiação , Humanos , Idoso , Interleucina-33/farmacologia , Pele , Colágeno/farmacologia , Fibroblastos , Macrófagos , Senescência Celular
4.
Artigo em Inglês | MEDLINE | ID: mdl-38286858

RESUMO

OBJECTIVE: The objective of this study was to observe the changes in the levels of indoleamine 2, 3-dioxygenase (IDO) and tryptophan-2, 3-dioxygenase (TDO) in patients with major depressive disorder (MDD) and investigate their potential role as novel biomarkers for diagnosing MDD. METHODS: A total of 55 MDD patients and 55 healthy controls (HC) were enrolled in the study. The severity of MDD was assessed using the 24-item Hamilton Depression Rating Scale (HAMD-24) before and after treatment. The serum concentrations of IDO and TDO were measured at baseline and after treatment. The correlations between the serum levels of IDO and TDO and HAMD-24 scores were evaluated using Pearson's correlation test. Receiver operating characteristic (ROC) curve analysis was used to evaluate the area under the curve (AUC) of serum levels of IDO and TDO for discriminating MDD patients from HC. RESULTS: The serum IDO and TDO concentrations were significantly higher in patients with MDD at baseline than in healthy controls, and decreased significantly after 2 weeks or 1 month of treatment. The levels of IDO and TDO were significantly positively correlated with HAMD-24 scores. Furthermore, the AUC values for IDO and TDO were 0.999 and 0.966, respectively. CONCLUSION: The study suggests that serum IDO and TDO may serve as novel biomarkers for diagnosing MDD. These findings may lead to a better understanding of the pathogenesis of MDD and the development of new therapeutic targets.

5.
J Ethnobiol Ethnomed ; 20(1): 10, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38225656

RESUMO

BACKGROUND: Traditional knowledge associated with medicinal food plants (MFPs) plays a vital role in fighting hidden hunger and safeguarding the health of local people. MFPs resources are abundant in the Gaoligongshan area, a biosphere reserve with the richest biocultural diversity in China. Local people of different linguistic groups also have rich traditional botanical knowledge. However, there are still few comprehensive and systematic studies on MFPs there. METHODS: Ethnobotanical investigation including market survey, semi-structured interviews, free listing and key informant interviews was conducted in the Gaoligongshan area, Western Yunnan, Southwest China. A total of 13 local farmers' markets were selected and information about medicinal food plants, including food categories, medicinal and edible parts, modes of consumption, medicinal effects, and distribution were collected. The relative occurrence frequency (RFO) and cultural food significance index (CFSI) were calculated to identify the culturally significant MFPs. RESULTS: A total of 184 species of MFPs, belonging to 83 families, were collected in the Gaoligongshan area, including vegetables (77), medicinal diets (26), fruits (25), spices (18), herbal tea (13), tea substitutes (11), substitutes for staple food (8), nuts (5), oils and fats (4), and dye material (1). The most frequently used families were Fabaceae, Asteraceae and Apiaceae, with 11, 10, and 9 species, respectively. The most frequently used plant parts were the stems, followed by fruits and leaves. Based on the evaluation results of the CFSI and RFO indices, 18 species of MFPs with magnificent local cultural importance have been screened out, such as Houttuynia cordata, Eryngium foetidum, Sechium edule, Centella asiatica and Pseudocydonia sinensis. CONCLUSION: These findings have guiding significance for conservation of traditional knowledge associated with MFPs and facilitation of scientific utilization of MFPs to meet local people's needs for a healthy life.


Assuntos
Plantas Comestíveis , Plantas Medicinais , Humanos , China , Etnobotânica/métodos , Verduras
6.
Cell Death Dis ; 15(1): 86, 2024 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-38267403

RESUMO

The NLRP3 inflammasome plays an important role in protecting the host from infection and aseptic inflammation, and its regulatory mechanism is not completely understood. Dysregulation of NLRP3 can cause diverse inflammatory diseases. HECTD3 is a E3 ubiquitin ligase of the HECT family that has been reported to participate in autoimmune and infectious diseases. However, the relationship between HECTD3 and the NLRP3 inflammasome has not been well studied. Herein, we show that HECTD3 blocks the interaction between NEK7 and NLRP3 to inhibit NLRP3 inflammasome assembly and activation. In BMDMs, Hectd3 deficiency promotes the assembly and activation of NLRP3 inflammasome and the secretion of IL-1ß, while the overexpression of HECTD3 inhibits these processes. Unexpectedly, HECTD3 functions in an E3 activity independent manner. Mechanically, the DOC domain of HECTD3 interacts with NACHT/LRR domain of NLRP3, which blocks NLRP3-NEK7 interaction and NLRP3 oligomerization. Furthermore, HECTD3 inhibits monosodium urate crystals (MSU)-induced gouty arthritis, a NLRP3-related disease. Thus, we reveal a novel regulatory mechanism of NLRP3 by HECTD3 and suggest HECTD3 could be a potential therapeutic target for NLRP3-dependent pathologies.


Assuntos
Artrite Gotosa , Inflamassomos , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Inflamação , Interleucina-1beta , Quinases Relacionadas a NIMA/genética
7.
ACS Nano ; 17(24): 25419-25438, 2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-38055636

RESUMO

Low-dose radiotherapy (LDR) has shown significant implications for inflaming the immunosuppressive tumor microenvironment (TME). Surprisingly, we identify that FABP-dependent lipid droplet biogenesis in tumor cells is a key determinant of LDR-evoked cytotoxic and immunostimulatory effects and developed a nanointegrated strategy to promote the antitumor efficacy of LDR through cooperative ferroptosis immunotherapy. Specifically, TCPP-TK-PEG-PAMAM-FA, a nanoscale multicomponent functional polymer with self-assembly capability, was synthesized for cooperatively entrapping hafnium ions (Hf4+) and HIF-1α-inhibiting siRNAs (siHIF-1α). The TCPP@Hf-TK-PEG-PAMAM-FA@siHIF-1α nanoassemblies are specifically taken in by folate receptor-overexpressing tumor cells and activated by the elevated cellular ROS stress. siHIF-1α could readily inhibit the FABP3/7 expression in tumor cells via HIF-1α-FABP3/7 signaling and abolish lipid droplet biogenesis for enhancing the peroxidation susceptibility of membrane lipids, which synergizes with the elevated ROS stress in the context of Hf4+-enhanced radiation exposure and evokes pronounced ferroptotic damage in vital membrane structures. Interestingly, TCPP@Hf-TK-PEG-PAMAM-FA@siHIF-1α-enhanced ferroptotic biomembrane damage also facilitates the exposure of tumor-associated antigens (TAAs) to promote post-LDR immunotherapeutic effects, leading to robust tumor regression in vivo. This study offers a nanointegrative approach to boost the antitumor effects of LDR through the utilization of tumor-intrinsic lipid metabolism.


Assuntos
Ferroptose , Neoplasias , Humanos , Espécies Reativas de Oxigênio , Gotículas Lipídicas , Neoplasias/radioterapia , Imunoterapia , Linhagem Celular Tumoral , Microambiente Tumoral
8.
Nat Commun ; 14(1): 7021, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-37919262

RESUMO

Immune-checkpoint inhibitors (ICI) are promising modalities for treating triple negative breast cancer (TNBC). However, hyperglycolysis, a hallmark of TNBC cells, may drive tumor-intrinsic PD-L1 glycosylation and boost regulatory T cell function to impair ICI efficacy. Herein, we report a tumor microenvironment-activatable nanoassembly based on self-assembled aptamer-polymer conjugates for the targeted delivery of glucose transporter 1 inhibitor BAY-876 (DNA-PAE@BAY-876), which remodels the immunosuppressive TME to enhance ICI response. Poly ß-amino ester (PAE)-modified PD-L1 and CTLA-4-antagonizing aptamers (aptPD-L1 and aptCTLA-4) are synthesized and co-assembled into supramolecular nanoassemblies for carrying BAY-876. The acidic tumor microenvironment causes PAE protonation and triggers nanoassembly dissociation to initiate BAY-876 and aptamer release. BAY-876 selectively inhibits TNBC glycolysis to deprive uridine diphosphate N-acetylglucosamine and downregulate PD-L1 N-linked glycosylation, thus facilitating PD-L1 recognition of aptPD-L1 to boost anti-PD-L1 therapy. Meanwhile, BAY-876 treatment also elevates glucose supply to tumor-residing regulatory T cells (Tregs) for metabolically rewiring them into an immunostimulatory state, thus cooperating with aptCTLA-4-mediated immune-checkpoint inhibition to abolish Treg-mediated immunosuppression. DNA-PAE@BAY-876 effectively reprograms the immunosuppressive microenvironment in preclinical models of TNBC in female mice and provides a distinct approach for TNBC immunotherapy in the clinics.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antígeno B7-H1 , Inibidores de Checkpoint Imunológico/uso terapêutico , Terapia de Imunossupressão , DNA , Microambiente Tumoral , Linhagem Celular Tumoral
9.
Ther Adv Respir Dis ; 17: 17534666231208632, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37941347

RESUMO

BACKGROUND: The differential diagnosis of malignant pleural effusion (MPE) and benign pleural effusion (BPE) presents a clinical challenge. In recent years, the use of artificial intelligence (AI) machine learning models for disease diagnosis has increased. OBJECTIVE: This study aimed to develop and validate a diagnostic model for early differentiation between MPE and BPE based on routine laboratory data. DESIGN: This was a retrospective observational cohort study. METHODS: A total of 2352 newly diagnosed patients with pleural effusion (PE), between January 2008 and March 2021, were eventually enrolled. Among them, 1435, 466, and 451 participants were randomly assigned to the training, validation, and testing cohorts in a ratio of 3:1:1. Clinical parameters, including age, sex, and laboratory parameters of PE patients, were abstracted for analysis. Based on 81 candidate laboratory variables, five machine learning models, namely extreme gradient boosting (XGBoost) model, logistic regression (LR) model, random forest (RF) model, support vector machine (SVM) model, and multilayer perceptron (MLP) model were developed. Their respective diagnostic performances for MPE were evaluated by receiver operating characteristic (ROC) curves. RESULTS: Among the five models, the XGBoost model exhibited the best diagnostic performance for MPE (area under the curve (AUC): 0.903, 0.918, and 0.886 in the training, validation, and testing cohorts, respectively). Additionally, the XGBoost model outperformed carcinoembryonic antigen (CEA) levels in pleural fluid (PF), serum, and the PF/serum ratio (AUC: 0.726, 0.699, and 0.692 in the training cohort; 0.763, 0.695, and 0.731 in the validation cohort; and 0.722, 0.729, and 0.693 in the testing cohort, respectively). Furthermore, compared with CEA, the XGBoost model demonstrated greater diagnostic power and sensitivity in diagnosing lung cancer-induced MPE. CONCLUSION: The development of a machine learning model utilizing routine laboratory biomarkers significantly enhances the diagnostic capability for distinguishing between MPE and BPE. The XGBoost model emerges as a valuable tool for the diagnosis of MPE.


Assuntos
Derrame Pleural Maligno , Derrame Pleural , Humanos , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/etiologia , Antígeno Carcinoembrionário/análise , Biomarcadores Tumorais , Inteligência Artificial , Diagnóstico Diferencial , Estudos de Coortes , Derrame Pleural/diagnóstico , Aprendizado de Máquina
10.
Opt Express ; 31(22): 35709-35719, 2023 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-38017736

RESUMO

Cavity solitons are persistent light pulses arising from the externally driven Kerr resonators. Thanks to the passive parametric gain, cavity soliton has been endowed with the natural advantage of the chip-scaled integration since it was first experimentally generated in the fiber-based platform. Deterministic single soliton with smooth spectrum is a preferred state for numerous applications. However, multiple solitons are more common in the resonators with anomalous dispersion. In this condition, adjacent solitons are easily perturbed to attract and collide with each other. Some experimental observations deviated from the aforementioned description have recorded the stable soliton intervals that can last for a long time scale. This phenomenon is known as soliton binding and is attributed to the presence of narrow resonant sidebands in the spectrum. While the stationary configuration of two binding solitons has been investigated, the dynamical evolution remains an area for further exploration. In this paper, we discuss the binding dynamics of the cavity solitons in the presence of high-order dispersion. The proposed theoretical predictions match well with the numerical results, encompassing both the stationary stable intervals and dynamic trajectories. Our research will provide a comprehensive insight into the soliton motion induced by the internal perturbations.

11.
Nat Commun ; 14(1): 7409, 2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-37973985

RESUMO

Ultra-high extinction ratio (ER) optical modulation is crucial for achieving high-performance fiber-optic distributed acoustic sensing (DAS) for various applications. Bulky acousto-optical modulators (AOM) as one of the key devices in DAS have been used for many years, but their relatively large volume and high power consumption are becoming the bottlenecks to hinder the development of ultra-compact and energy-efficient DAS systems that are highly demanded in practice. Here, an on-chip silicon electro-optical modulator (EOM) based on multiple coupled microrings is demonstrated with ultra-high ER of up to 68 dB while the device size and power consumption are only 260 × 185 µm2 and 3.6 mW, respectively, which are at least two orders of magnitude lower than those of a typical AOM. Such an on-chip EOM is successfully applied to DAS with an ultra-high sensitivity of -71.2 dB rad2/Hz (4 pε/√Hz) and a low spatial crosstalk noise of -68.1 dB rad2/Hz, which are very similar to those using an AOM. This work may pave the way for realization of next-generation ultra-compact DAS systems by integration of on-chip opto-electronic devices and modules with the capability of mass-production.

12.
J Ethnobiol Ethnomed ; 19(1): 43, 2023 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-37777741

RESUMO

BACKGROUND: Edible flowers (EFs) represent valuable sources of both food and medicinal resources, holding the promise to enhance human well-being. Unfortunately, their significance is often overlooked. Ethnobotanical studies on the EFs are lacking in comparison with their botanical and phytochemical research. The practice of consuming flowers as food has a rich culture and long history in China, especially among different linguistic groups in Xishuangbanna, Yunnan. However, economic activities have led to a decline of this tradition. Consequently, preserving the traditional knowledge and culture tied to the EFs in Xishuangbanna becomes both essential and pressing. METHODS: The field ethnobotanical survey was conducted in Xishuangbanna during five visits in April 2021 and May 2023, covering 48 villages and 19 local markets of all three county-level areas and 9 different linguistic groups. By conducting a comprehensive literature review and on-site field surveys, relevant information regarding the EFs of Xishuangbanna was systematically collected and documented. Additionally, the relative frequency of citation (RFC) values were calculated from the survey data. RESULTS: A total of 212 taxa (including species and varieties) of EFs from 58 families and 141 genera were documented in the study area. The edible parts of flowers were classified into 13 categories including peduncle, petal, flower buds, inflorescence as a whole, and etc. They were consumed in 21 ways and as 8 types of food. The inflorescence was the most commonly consumed category, accounting for 85 species (40.1%) of the total categories. They always eat flowers as vegetables (184 species, 86.8%). The preparing form of stir-frying was the preferred food preparation method (138, 65.1%). The Xishuangbanna locals had profound knowledge of which EFs required specific processing to remove their toxicity or bitterness. The dishes can be made from either exclusively from the flowers themselves or by incorporating them alongside other plant parts like stems and leaves. Some EFs with high RFC value, such as Musa acuminata and Bauhinia variegata var. candida, showed significant cultural meanings. These edible flowers occupy specific positions in local traditional culture. CONCLUSION: Traditional knowledge regarding edible flowers holds substantial significance and serves as a representative element of the flower-eating culture in Xishuangbanna. Nevertheless, this knowledge and cultural practice are currently decreasing. Serving as a bridge between tradition and modernity, the flower-eating culture, which derives from local people's practical experience, shows the potential of EFs and can be applied to the conservation of biocultural diversity, healthy food systems, and sustainable development.


Assuntos
Etnobotânica , Verduras , Humanos , China , Etnobotânica/métodos , Inquéritos e Questionários , Flores , Plantas Comestíveis
13.
Nano Lett ; 23(18): 8474-8480, 2023 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-37671914

RESUMO

Bottom-up synthesized graphene nanoribbons (GNRs) are increasingly attracting interest due to their atomically controlled structure and customizable physical properties. In recent years, a range of GNR-based field-effect transistors (FETs) has been fabricated, with several demonstrating quantum-dot (QD) behavior at cryogenic temperatures. However, understanding the relationship between the cryogenic charge-transport characteristics and the number of the GNRs in the device is challenging, as the length and location of the GNRs in the junction are not precisely controlled. Here, we present a methodology based on a dual-gate FET that allows us to identify different scenarios, such as single GNRs, double or multiple GNRs in parallel, and a single GNR interacting with charge traps. Our dual-gate FET architecture therefore offers a quantitative approach for comprehending charge transport in atomically precise GNRs.

14.
Adv Sci (Weinh) ; 10(29): e2303958, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37705110

RESUMO

Owing to their mechanical resilience and non-toxicity, titanium implants are widely applied as the major treatment modality for the clinical intervention against bone fractures. However, the intrinsic bioinertness of Ti and its alloys often impedes the effective osseointegration of the implants, leading to severe adverse complications including implant loosening, detachment, and secondary bone damage. Consequently, new Ti implant engineering strategies are urgently needed to improve their osseointegration after implantation. Remarkably, metalorganic frameworks (MOFs) are a class of novel synthetic material consisting of coordinated metal species and organic ligands, which have demonstrated a plethora of favorable properties for modulating the interfacial properties of Ti implants. This review comprehensively summarizes the recent progress in the development of MOF-coated Ti implants and highlights their potential utility for modulating the bio-implant interface to improve implant osseointegration, of which the discussions are outlined according to their physical traits, chemical composition, and drug delivery capacity. A perspective is also provided in this review regarding the current limitations and future opportunities of MOF-coated Ti implants for orthopedic applications. The insights in this review may facilitate the rational design of more advanced Ti implants with enhanced therapeutic performance and safety.


Assuntos
Estruturas Metalorgânicas , Osseointegração , Titânio/química , Próteses e Implantes , Osso e Ossos
15.
Angew Chem Int Ed Engl ; 62(46): e202311533, 2023 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-37767859

RESUMO

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a fascinating group of natural products that exhibit diverse structural features and bioactivities. P450-catalyzed RiPPs stand out as a unique but underexplored family. Herein, we introduce a rule-based genome mining strategy that harnesses the intrinsic biosynthetic principles of RiPPs, including the co-occurrence and co-conservation of precursors and P450s and interactions between them, successfully facilitating the identification of diverse P450-catalyzed RiPPs. Intensive BGC characterization revealed four new P450s, KstB, ScnB, MciB, and SgrB, that can catalyze the formation of Trp-Trp-Tyr (one C-C and two C-N bonds), Tyr-Trp (C-C bond), Trp-Trp (C-N bond), and His-His (ether bond) crosslinks, respectively, within three or four residues. KstB, ScnB, and MciB could accept non-native precursors, suggesting they could be promising starting templates for bioengineering to construct macrocycles. Our study highlights the potential of P450s to expand the chemical diversity of strained macrocyclic peptides and the range of biocatalytic tools available for peptide macrocyclization.


Assuntos
Produtos Biológicos , Peptídeos , Peptídeos/química , Ribossomos/metabolismo , Bactérias/metabolismo , Genoma , Sistema Enzimático do Citocromo P-450/metabolismo , Processamento de Proteína Pós-Traducional , Produtos Biológicos/química
16.
Liver Cancer ; 12(3): 281-288, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37593364

RESUMO

Introduction: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive liver malignancy with poor prognosis. Recently, the development of immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) inhibitors, has emerged as a promising strategy in multiple tumor types, including ICC. Microsatellite instability-high (MSI-H) is an important biomarker for ICIs in solid tumors. The response rate in patients with MSI-H is significantly higher than in those with microsatellite stability/microsatellite instability-low. And approximately 80-90% of the patients with MSI-H could maintain sustained clinical benefits once they had an initial response. However, some patients could have primary resistance at the beginning, and some might have acquired resistance after long-term treatment. Case Presentation: We present the case of an ICC patient with MSI-H who suffered rapid progression after a short-term remission with camrelizumab, a kind of PD-1 inhibitor, as second-line treatment. The patient's genomic and immune features were analyzed by next-generation sequencing and multiplex immunofluorescence staining to explore the possible mechanisms of the rapidly acquired resistance of ICIs in this MSI-H case. Conclusion: The genomic and immunohistochemical analysis showed that TGFBR2 mutation, loss of HLA B44 supertype, carrying B62 supertype, and increased PD-L1+ cells, macrophages, and Tregs in the tumor microenvironment might be related to the nonsustain benefit of ICIs in this MSI-H patient.

17.
Acta Biomater ; 169: 289-305, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37544392

RESUMO

Immunotherapy is an emerging antitumor modality with high specificity and persistence, but its application for resected tumor treatment is impeded by the low availability of tumor-specific antigens and strong immunosuppression in the wound margin. Here a nanoengineered hydrogel is developed for eliciting robust cooperative ferroptosis-immunotherapeutic effect on resected tumors. Specifically, ß-cyclodextrin (ß-CD) is first grafted onto oxidized sodium alginate (OSA) through Schiff base ligation, which could trap cRGD-modified redox-responsive Withaferin prodrugs (WA-cRGD) to obtain the hydrogel building blocks (Gel@WA-cRGD). Under Ca2+-mediated crosslinking, Gel@WA-cRGD rapidly forms physiologically stable hydrogels, of which the porous network is used to deliver programmed cell death ligand 1 antibodies (aPD-L1). After injection into the post-surgical wound cavity, the ß-CD-entrapped WA-cRGD is detached by the local acidity and specifically internalized by residual tumor cells to trigger ferroptosis, thus releasing abundant damage-associated molecular patterns (DAMPs) and tumor-derived antigens for activating the antigen-presenting cell-mediated cross-presentation and downstream cytotoxic T cell (CTL)-mediated antitumor responses. Furthermore, aPD-L1 could block PD-1/PD-L1 interaction and enhance the effector function of CTLs to overcome tumor cell-mediated immunosuppression. This cooperative hydrogel-based antitumor strategy for ferroptosis-immunotherapy may serve as a generally-applicable approach for postoperative tumor management. STATEMENT OF SIGNIFICANCE: To overcome the immunosuppressive microenvironment in resected solid tumors for enhanced patient survival, here we report a nanoengineered hydrogel incorporated supramolecular redox-activatable Withaferin prodrug and PD-L1 antibody, which could elicit robust cooperative ferroptosis-immunotherapeutic effect against residual tumor cells in the surgical bed to prevent tumor relapse, thus offering a generally-applicable approach for postoperative tumor management.


Assuntos
Ferroptose , Pró-Fármacos , Humanos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Antígeno B7-H1 , Hidrogéis/farmacologia , Neoplasia Residual , Recidiva Local de Neoplasia , Imunoterapia , Antígenos de Neoplasias , Microambiente Tumoral , Linhagem Celular Tumoral
18.
J Ethnobiol Ethnomed ; 19(1): 26, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37393284

RESUMO

BACKGROUND: Pu'er Traditional Tea Agroecosystem is one of the projects included in the United Nations' Globally Important Agricultural Heritage Systems (GIAHS) since 2012. Against the background of having rich biodiversity and a long history of tea culture, the ancient tea trees in Pu'er have experienced from wild-transition-cultivation for thousands of years, and the local people's knowledge about the management of ancient teagardens has not been rigorously recorded. For this reason, it is important to study and record the traditional management knowledge of Pu'er ancient teagardens and the influence on the formation of tea trees and communities. This study focuses on the traditional management knowledge of ancient teagardens in Jingmai Mountains, Pu'er, and monoculture teagardens (monoculture and intensively managed planting base for tea cultivation) were used as the control, through the community structure, composition and biodiversity of ancient teagardens to respond to the influence of traditional management, and this work with a view to providing a reference for further research on the stability and sustainable development of tea agroecosystem. METHODS: From 2021 to 2022, information on traditional management of ancient teagardens was obtained through semi-structured interviews with 93 local people in the Jingmai Mountains area of Pu'er. Informed consent was obtained from each participant before conducting the interview process. The communities, tea trees and biodiversity of Jingmai Mountains ancient teagardens (JMATGs) and monoculture teagardens (MTGs) were examined through field surveys, measurements and biodiversity survey methods. The Shannon-Weiner (H), Pielou (E) and Margalef (M) indices were calculated for the biodiversity of the teagardens within the unit sample, using monoculture teagardens as a control. RESULTS: The tea tree morphology, community structure and composition of Pu'er ancient teagardens are significantly different from those of monoculture teagardens, and the biodiversity is significantly higher than that of monoculture teagardens. The local people mainly manage the ancient tea trees mainly using several methods, including weeding (96.8%), pruning (48.4%) and pest control (33.3%). The pest control mainly relies on the removal of diseased branches. JMATGs annual gross output is approximately 6.5 times that of MTGs. The traditional management of ancient teagardens is through setting up forest isolation zones as protected areas, planting tea trees in the understory on the sunny side, keeping tea trees 1.5-7 m apart, as well as consciously protecting forest animals such as spiders, birds and bees, and reasonably rearing livestock in the teagardens. CONCLUSIONS: This study shows that local people have rich traditional knowledge and experience in the management of ancient teagardens in Pu'er, and that this traditional management knowledge has impacted the growth of ancient tea trees, enriched the structure and composition of tea plantation communities and actively protected the biodiversity within ancient teagardens.


Assuntos
Florestas , Árvores , Humanos , Animais , Abelhas , China , Agricultura , Chá
19.
Biomaterials ; 299: 122184, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37276796

RESUMO

Hydrogels are a class of biocompatible materials with versatile functions that have been increasing explored for the localized treatment of ulcerative colitis (UC), but various mechanical stimuli may cause premature hydrogel breakage and detachment, impeding their further clinical translation. Here we report a multifunctional mechanically-resilient self-healing hydrogel for effective UC treatment, which is synthesized through the host-guest interaction between dopamine/ß-cyclodextrin-modified hyaluronic acid (HA-CD-DA) and amantadine-modified carboxymethyl chitosan (CMCS-AD). The excessive ß-CD cavities allow the incorporation of dexamethasone (DEX), while the porous hydrogel network potentiates the encapsulation of basic fibroblast growth factor (bFGF) and L-alanyl-l-glutamine (ALG). DA moieties in HA components allow firm adhesion of the hydrogel to the ulcerative lesions after in-situ implantation, while the reversible host-guest interaction between CD and AD could enhance the persistence of hydrogel. The hydrogel demonstrated favorable biocompatibility and could continuously release DEX to induce M1-to-M2 repolarization of mucosal macrophages through inhibiting the toll-like receptor 4 (TLR4)-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) axis. Furthermore, the co-delivered bFGF and ALG facilitates the regeneration of ulcerative mucosa and restore its barrier functions to ameliorate UC symptoms. The mechanically resilient hydrogel offers an integrative approach for UC therapy in the clinics.


Assuntos
Colite Ulcerativa , Humanos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Hidrogéis/farmacologia , Materiais Biocompatíveis/uso terapêutico , Mucosa/metabolismo , Inflamação/tratamento farmacológico
20.
Materials (Basel) ; 16(10)2023 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-37241427

RESUMO

High-strength press-hardened steels (PHS) are highly desired in the automotive industry to meet the requirement of carbon neutrality. This review aims to provide a systematic study of the relationship between multi-scale microstructural tailoring and the mechanical behavior and other service performance of PHS. It begins with a brief introduction to the background of PHS, followed by an in-depth description of the strategies used to enhance their properties. These strategies are categorized into traditional Mn-B steels and novel PHS. For traditional Mn-B steels, extensive research has verified that the addition of microalloying elements can refine the microstructure of PHS, resulting in improved mechanical properties, hydrogen embrittlement resistance, and other service performance. In the case of novel PHS, recent progress has principally demonstrated that the novel composition of steels coupling with innovative thermomechanical processing can obtain multi-phase structure and superior mechanical properties compared with traditional Mn-B steels, and their effect on oxidation resistance is highlighted. Finally, the review offers an outlook on the future development of PHS from the perspective of academic research and industrial applications.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...