Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 171
Filtrar
1.
J Org Chem ; 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38632865

RESUMO

The photochemistry of noncovalent interactions to promote organic transformations is an emerging approach to providing fresh opportunities in synthetic chemistry. Generally, the external substance is necessary to add as an interaction partner, thereby sacrificing the atom economy of the reaction. Herein, we describe a catalyst-free and noncovalent interaction-mediated strategy to access the olefination of N-tosylhydrazones using acetone as a solvent and an interaction partner. This protocol also features broad substrate scope, excellent functional group compatibility, and mild reaction conditions without transition metals. Moreover, the gram-scale synthesis of olefins and the generation of pharmaceutical intermediates highlighted its practical applicability. Lastly, mechanistic studies indicate that the reaction was initiated via noncovalent interactions between acetone and N-tosylhydrazone anion, which is also supported by density functional theory calculations.

2.
Chemistry ; : e202400021, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38477386

RESUMO

The development of novel and effective drug delivery systems aimed at enhancing therapeutic profile and efficacy of therapeutic agents is a critical challenge in modern medicine. This study presents an intelligent drug delivery system based on self-assembled two-dimensional peptide nanosheets (2D PNSs). Leveraging the tunable properties of amino acid structures and sequences, we design a peptide with the sequence of Fmoc-FKKGSHC, which self-assembles into 2D PNSs with uniform structure, high biocompatibility, and excellent degradability. Covalent attachment of thiol-modified doxorubicin (DOX) drugs to 2D PNSs via disulfide bond results in the peptide-drug conjugates (PDCs), which is denoted as PNS-SS-DOX. Subsequently, the PDCs are encapsulated within the injectable, thermosensitive chitosan (CS) hydrogels for drug delivery. The designed drug delivery system demonstrates outstanding pH-responsiveness and sustained drug release capabilities, which are facilitated by the characteristics of the CS hydrogels. Meanwhile, the covalently linked disulfide bond within the PNS-SS-DOX is responsive to intracellular glutathione (GSH) within tumor cells, enabling controlled drug release and significantly inhibiting the cancer cell growth. This responsive peptide-drug conjugate based on a 2D peptide nanoplatform paves the way for the development of smart drug delivery systems and has bright prospects in the future biomedicine field.

3.
Adv Sci (Weinh) ; : e2307899, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38460164

RESUMO

Gastric cancer (GC) presents a formidable global health challenge, and conventional therapies face efficacy limitations. Ubiquitin-specific protease 7 (USP7) plays pivotal roles in GC development, immune response, and chemo-resistance, making it a promising target. Various USP7 inhibitors have shown selectivity and efficacy in preclinical studies. However, the mechanistic role of USP7 has not been fully elucidated, and currently, no USP7 inhibitors have been approved for clinical use. In this study, DHPO is identified as a potent USP7 inhibitor for GC treatment through in silico screening. DHPO demonstrates significant anti-tumor activity in vitro, inhibiting cell viability and clonogenic ability, and preventing tumor migration and invasion. In vivo studies using orthotopic gastric tumor mouse models validate DHPO's efficacy in suppressing tumor growth and metastasis without significant toxicity. Mechanistically, DHPO inhibition triggers ferroptosis, evidenced by mitochondrial alterations, lipid Reactive Oxygen Species (ROS), Malondialdehyde (MDA) accumulation, and iron overload. Further investigations unveil USP7's regulation of Stearoyl-CoA Desaturase (SCD) through deubiquitination, linking USP7 inhibition to SCD degradation and ferroptosis induction. Overall, this study identifies USP7 as a key player in ferroptosis of GC, elucidates DHPO's inhibitory mechanisms, and highlights its potential for GC treatment by inducing ferroptosis through SCD regulation.

4.
Biochem Pharmacol ; 223: 116141, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38499108

RESUMO

Small Ras homologous guanosine triphosphatase (Rho GTPase) family proteins are highly associated with tumorigenesis and development. As intrinsic exchange activity regulators of Rho GTPases, Rho guanine nucleotide exchange factors (RhoGEFs) have been demonstrated to be closely involved in tumor development and received increasing attention. They mainly contain two families: the diffuse B-cell lymphoma (Dbl) family and the dedicator of cytokinesis (Dock) family. More and more emphasis has been paid to the Dbl family members for their abnormally high expression in various cancers and their correlation to poor prognosis. In this review, the common and distinctive structures of Dbl family members are discussed, and their roles in cancer are summarized with a focus on Ect2, Tiam1/2, P-Rex1/2, Vav1/2/3, Trio, KALRN, and LARG. Significantly, the strategies targeting Dbl family RhoGEFs are highlighted as novel therapeutic opportunities for cancer.


Assuntos
Linfoma de Células B , Neoplasias , Humanos , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Carcinogênese
5.
Artigo em Inglês | MEDLINE | ID: mdl-38425144

RESUMO

OBJECTIVE: Neuromyelitis optica (NMO) was a serious autoimmune inflammatory condition affecting the central nervous system. Currently, there was a lack of diagnostic biomarkers for AQP4-IgG-negative NMO patients. METHODS: A comparative proteomic analysis was conducted on the CSF of 10 patients with NMO and 10 patients with non-inflammatory neurological disorders (NND) using tandem mass tagging technology. Differentially expressed proteins (DEPs) were analyzed using bioinformatic methods. The candidate proteins were then validated through ELISAs in a subsequent cohort of 160 samples, consisting of paired CSF and plasma samples from 50 NMO patients, CSF samples from 30 NND patients, and plasma samples from 30 healthy individuals. RESULTS: We identified 389 proteins via proteomics, screening 79 DEPs. NCAM1, SST and AHSG were selected as candidate molecules for further validation. Compared to NND patients, there were decreased levels of AHSG in CSF and increased levels of NCAM1 and SST in NMO patients. The ELISA results revealed significantly higher levels of AHSG, SST and NCAM1 in the CSF of the NMO group compared to the NND group. Similarly, the serum levels of these three proteins were also higher in the NMO group compared to the healthy control group. It was found that serum NCAM1 levels significantly decreased in patients with non-relapsed NMO compared to patients with relapsed NMO and CSF NCAM1 level increased in patients with bilateral NMO compared to patients with unilateral NMO. Furthermore, CSF SST levels increased in AQP4 antibody-positive NMO patients compared to AQP4 antibody-negative patients. INTERPRETATION: CSF NCAM1, serum NCAM1 and serum SST may serve as potential biomarkers for NMO patients and aid in the diagnosis of AQP4 antibody-negative NMO patients.

6.
J Colloid Interface Sci ; 663: 111-122, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38394816

RESUMO

Fluorescent bioimaging and photothermal therapy (PTT) techniques have potential significance in cancer diagnosis and treatment and have been widely applied in biomedical and practical clinical trials. This study proposes the molecular design and biofabrication of a two-dimensional (2D) nanoplatform, exhibiting promising prospects for synergistic bioimaging and PTT of tumors. First, biocompatible 2D peptide nanosheets (PNSs) were designed and prepared through peptide self-assembly. These served as a support matrix for assembling polyethylene glycol-modified Ag2S quantum dots (PEG-Ag2SQDs) to form a 2D nanoplatform (PNS/PEG-Ag2SQDs) with unique fluorescent and photothermal properties. The designed 2D nanoplatform not only showed improved photothermal efficacy and an elevated photothermal conversion efficiency of 52.46 %, but also demonstrated significant lethality against tumors in both in vitro and in vivo cases. Additionally, it displays excellent imaging effects in the near-infrared II region, making it suitable for synergistic fluorescent imaging-guided PTT of tumors. This study not only provides a facile approach for devising and synthesizing 2D peptide assemblies but also presents new biomimetic strategies to create functional 2D organic/inorganic nanoplatforms for biomedical applications.


Assuntos
Nanopartículas , Neoplasias , Pontos Quânticos , Humanos , Fototerapia/métodos , Terapia Fototérmica , Nanopartículas/química , Biomimética , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Neoplasias/patologia , Peptídeos , Linhagem Celular Tumoral
7.
J Mater Chem B ; 12(9): 2253-2273, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38375592

RESUMO

The injury of both central and peripheral nervous systems can result in neurological disorders and severe nervous diseases, which has been one of the challenges in the medical field. The use of peptide-based hydrogels for nerve repair and regeneration (NRR) provides a promising way for treating these problems, but the effects of the functions of peptide hydrogels on the NRR efficiency have been not understood clearly. In this review, we present recent advances in the material design, matrix fabrication, functional tailoring, and NRR applications of three types of peptide-based hydrogels, including pure peptide hydrogels, other component-functionalized peptide hydrogels, and peptide-modified polymer hydrogels. The case studies on the utilization of various peptide-based hydrogels for NRR are introduced and analyzed, in which the effects and mechanisms of the functions of hydrogels on NRR are illustrated specifically. In addition, the fabrication of medical NRR scaffolds and devices for pre-clinical application is demonstrated. Finally, we provide potential directions on the development of this promising topic. This comprehensive review could be valuable for readers to know the design and synthesis strategies of bioactive peptide hydrogels, as well as their functional tailoring, in order to promote their practical applications in tissue engineering, biomedical engineering, and materials science.


Assuntos
Hidrogéis , Procedimentos de Cirurgia Plástica , Hidrogéis/farmacologia , Hidrogéis/uso terapêutico , Engenharia Tecidual , Peptídeos/farmacologia , Engenharia Biomédica
8.
Biology (Basel) ; 13(2)2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38392302

RESUMO

Several TMED protein family members are overexpressed in malignant tumors and associated with tumor progression. TMED1 belongs to the TMED protein family and is involved in protein vesicular trafficking. However, the expression level and biological role of TMED1 in colorectal cancer (CRC) have yet to be fully elucidated. In this study, the integration of patient survival and multi-omics data (immunohistochemical staining, transcriptomics, and proteomics) revealed that the highly expressed TMED1 was related to the poor prognosis in CRC. Crystal violet staining indicated the cell growth was reduced after knocking down TMED1. Moreover, the flow cytometry results showed that TMED1 knockdown could increase cell apoptosis. The expression of TMED1 was positively correlated with other TMED family members (TMED2, TMED4, TMED9, and TMED10) in CRC, and the protein-protein interaction network suggested its potential impact on immune regulation. Furthermore, TMED1 expression was positively associated with the infiltration levels of regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and endothelial cells and negatively correlated with the infiltration levels of CD4+ T cells, CD8+ T cells, and B cells. At last, the CTRP and GDSC datasets on the GSCA platform were used to analyze the relationship between TMED1 expression and drug sensitivity (IC50). The result found that the elevation of TMED1 was positively correlated with IC50 and implied it could increase the drug resistance of cancer cells. This research revealed that TMED1 is a novel prognostic biomarker in CRC and provided a valuable strategy for analyzing potential therapeutic targets of malignant tumors.

9.
Adv Healthc Mater ; : e2303445, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38290499

RESUMO

The application of oncolytic peptides has become a powerful approach to induce complete and long-lasting remission in multiple types of carcinomas, as affirmed by the appearance of tumor-associated antigens and adenosine triphosphate (ATP) in large quantities, which jumpstarts the cancer-immunity cycle. However, the ATP breakdown product adenosine is a significant contributor to forming the immunosuppressive tumor microenvironment, which substantially weakens peptide-driven oncolytic immunotherapy. In this study, a lipid-coated micelle (CA@TLM) loaded with a stapled oncolytic peptide (PalAno) and an adenosine 2A receptor (A2AR) inhibitor (CPI-444) is devised to enact tumor-targeted oncolytic immunotherapy and to overcome adenosine-mediated immune suppression simultaneously. The CA@TLM micelle accumulates in tumors with high efficiency, and the acidic lysosomal environment prompts the rapid release of PalAno and CPI-444. Subsequently, PalAno induces swift membrane lysis of tumor cells and the release of antigenic materials. Meanwhile, CPI-444 blocks activation of the immunosuppressive adenosine-A2AR signaling pathway. This combined approach exhibit pronounced synergy at stalling tumor growth and metastasis in animal models for triple-negative breast cancer (TNBC) and melanoma, providing a novel strategy for enhanced oncolytic immunotherapy. This article is protected by copyright. All rights reserved.

10.
Med Res Rev ; 44(2): 812-832, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38009264

RESUMO

As a widely considerable target in chemical biology and pharmacological research, rat sarcoma (RAS) gene mutations play a critical driving factor in several fatal cancers. Despite the great progress of RAS subtype-specific inhibitors, rapid acquired drug resistance could limit their further clinical applications. Proteolysis targeting chimera (PROTAC) has emerged as a powerful tool to handle "undruggable" targets and exhibited significant therapeutic benefit for the combat of drug resistance. Owing to unique molecular mechanism and binding kinetics, PROTAC is expected to become a feasible strategy to break the bottleneck of classical RAS inhibitors. This review aims to discuss the current advances of RAS inhibitors and especially focus on PROTAC strategy targeting RAS mutations and their downstream effectors for relevant cancer treatment.


Assuntos
Quimera de Direcionamento de Proteólise , Humanos , Cinética , Mutação
11.
Cell Oncol (Dordr) ; 47(1): 19-35, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37713105

RESUMO

BACKGROUND: Ferroptosis, a newly form of regulated cell death (RCD), is characterized by iron dyshomeostasis and unrestricted lipid peroxidation. Emerging evidence depicts a pivotal role for ferroptosis in driving some pathological processes, especially in cancer. Triggering ferroptosis can suppress tumor growth and induce an anti-tumor immune response, denoting the therapeutic promises for targeting ferroptosis in the management of cancer. As an autophagic phenomenon, ferritinophagy is critical to induce ferroptosis by degradation of ferritin to release intracellular free iron. Recently, a great deal of effort has gone into designing and developing anti-cancer strategies based on targeting ferritinophagy to induce ferroptosis. CONCLUSION: This review delineates the regulatory mechanism of ferritinophagy firstly and summarizes the role of ferritinophagy-induced ferroptosis in cancer. Moreover, the strategies targeting ferritinophagy to induce ferroptosis are highlighted to unveil the therapeutic value of ferritinophagy as a target to manage cancer. Finally, the future research directions on how to cope with the challenges in developing ferritinophagy promoters into clinical therapeutics are discussed.


Assuntos
Ferroptose , Neoplasias , Humanos , Ferro/metabolismo , Ferro/farmacologia , Ferro/uso terapêutico , Ferritinas/metabolismo , Ferritinas/uso terapêutico , Neoplasias/metabolismo , Autofagia
12.
Clin Chim Acta ; 553: 117734, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38128818

RESUMO

BACKGROUND: Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) is a promising stroke biomarker. However, a large study of human serum ASC has not yet to be reported; additionally, the diagnostic value of prehospital concentration and practicality of ASC remains unknown. METHODS: We recruited 774 Chinese stroke patients, including 523 with ischemic stroke (IS) and 251 with hemorrhagic stroke (HS) within 14 days following symptom onset in the emergency department, alongside 481 healthy individuals and 64 cognitive impairment patients as controls. Serum ASC concentrations were determined using automated chemiluminescence immunoassay, exploring the relationship between serum ASC concentration and subtypes, severity, and sampling timepoints of stroke. RESULTS: ASC concentrations were significantly higher in stroke patients compared with all controls (P < 0.001). HS patients had greater ASC concentrations than IS patients (P < 0.05). With increasing ASC concentration, the proportion of severe cases increased. The area under the receiver operating characteristic curve (AUC) for differentiating between healthy individuals and stroke patients in the hyperacute phase was 0.78; this markedly improved (0.90) when considering samples from healthy individuals and patients with subarachnoid hemorrhage (SAH) ≤ 3  h from last-known-well (LKW). CONCLUSIONS: Serum ASC is a valuable biomarker for stroke differentiation and aids in the clinical diagnosis of stroke severity and subtypes.


Assuntos
Proteínas Adaptadoras de Sinalização CARD , Acidente Vascular Cerebral , Humanos , Apoptose , Biomarcadores , Caspases , Acidente Vascular Cerebral/diagnóstico
13.
Small ; : e2308091, 2023 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-38088535

RESUMO

Biomimetic synthesis provides potential guidance for the synthesis of bio-nanomaterials by mimicking the structure, properties and functions of natural materials. Behavioral studies of biological surfaces with specific micro/nano structures are performed to explore the interactions of various molecules or organisms with biological surfaces. These explorations provide valuable inspiration for the development of biomimetic surfaces with similar effects. This work reviews some conventional preparation methods and functional modulation strategies for biomimetic interfaces. It aims to elucidate the important role of biomimetic interfaces with antifouling and low-pollution properties that can replace non-environmentally friendly coatings. Thus, biomimetic antifouling interfaces can be better applied in the field of marine antifouling and antimicrobial. In this review, the commonly used fabrication methods for biomimetic interfaces as well as some practical strategies for functional modulation is present in detail. These methods and strategies modify the physical structure and chemical properties of the biomimetic interfaces, thus improving the wettability, adsorption, drag reduction, etc. that they exhibit. In addition, practical applications are presented of various biomimetic interfaces for antifouling and look ahead to potential biomedical applications. By continuously discovering functional surfaces with biomimetic properties and studying their microstructure and macroscopic properties, more biomimetic interfaces will be developed.

14.
Front Immunol ; 14: 1301577, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38143756

RESUMO

Background: Guillain-Barre syndrome (GBS) is an immune-mediated inflammatory peripheral neuropathy. This study aimed to conduct a systematic analysis of the serum lipids profile in GBS. Methods: We measured the serum lipids profile in 85 GBS patients and compared it with that of 85 healthy controls matched for age and sex. Additionally, we analyzed the correlation between lipids and the severity, subtypes, precursor infections, clinical outcomes, clinical symptoms, immunotherapy, and other laboratory markers of GBS. Results: Compared to the healthy controls, GBS exhibited significantly elevated levels of Apolipoprotein B (APOB), Apolipoprotein C2 (APOC2), Apolipoprotein C3 (APOC3), Apolipoprotein E (APOE), triglycerides (TG), and residual cholesterol (RC). Conversely, Apolipoprotein A1 (APOA1), Apolipoprotein A2 (APOA2), and high-density lipoprotein (HDL) were substantially lower in GBS. Severe GBS displayed noticeably higher levels of APOC3 and total cholesterol (TC) compared to those with mild disease. Regarding different clinical outcomes, readmitted GBS demonstrated higher RC expression than those who were not readmitted. Moreover, GBS who tested positive for neuro-virus antibody IGG in cerebrospinal fluid (CSF) exhibited heightened expression of APOC3 in comparison to those who tested negative. GBS with cranial nerve damage showed significantly reduced expression of HDL and APOA1 than those without such damage. Additionally, GBS experiencing limb pain demonstrated markedly decreased HDL expression. Patients showed a significant reduction in TC after intravenous immunoglobulin therapy. We observed a significant positive correlation between lipids and inflammatory markers, including TNF-α, IL-1ß, erythrocyte sedimentation rate (ESR), white blood cells, monocytes, and neutrophils in GBS. Notably, APOA1 exhibited a negative correlation with ESR. Furthermore, our findings suggest a potential association between lipids and the immune status of GBS. Conclusion: The research demonstrated a strong connection between lipids and the severity, subtypes, clinical outcomes, precursor infections, clinical symptoms, immunotherapy, inflammation, and immune status of GBS. This implies that a low-fat diet or the use of lipid-lowering medications may potentially serve as an approach for managing GBS, offering a fresh viewpoint for clinical treatment of this condition.


Assuntos
Síndrome de Guillain-Barré , Humanos , Síndrome de Guillain-Barré/terapia , Lipídeos , Triglicerídeos , Colesterol , Apolipoproteínas B
15.
Cell Mol Biol (Noisy-le-grand) ; 69(13): 31-35, 2023 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-38158692

RESUMO

The mechanism of gallic acid in improving lipopolysaccharide-induced renal injury in rats was investigated by studying the pro-death and inflammatory response of cells. SPF rats were randomly divided into 4 groups with n=10 in each group. Blank control group: normal saline injection; The model group was injected with LPS induced model (LPS group); Low dose gallic acid group (LPS+L-GA group); Middle dose gallic acid group (LPS+M-GA group). The expression of serum inflammatory factors IL-1, IL-1ß, IL-18, and MCP-1 were detected by Elisa. Western blot assay was used to detect the expression of inflammation-related proteins. The contents of BUN, Scr, SUA, Serum cystatinALB, and ACR were determined by the biochemical analyzer. The pathological tissue sections were used to observe the kidney injury in each group. The renal expressions of NLRP3, Caspase-1, GSDMD, and IL-1ß were detected by immunohistochemistry. The activation of the AMPK/SIRT1 signaling pathway was detected by Western blot assay. The LPS-induced mouse kidney injury model was established successfully. Compared with the model group, different doses of gallic acid can improve the expression of renal biochemical indexes (P<0.05); At the same time, gallic acid can activate AMPK/SIRT1 and reduce kidney injury in mice (P<0.05); Compared with the model group, the expression of pyroptosis gene, the expression of genes related to inflammatory factors and the expression of inflammatory factors were decreased in the gallic acid injection group (P<0.05). By activating the AMPK/SIRT1 signaling pathway, gallic acid can inhibit the scorch death and validation effect in mice, thereby protecting the kidneys of mice.


Assuntos
Lipopolissacarídeos , Sirtuína 1 , Ratos , Camundongos , Animais , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Proteínas Quinases Ativadas por AMP , Rim
16.
Pharmacol Res ; 198: 106996, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37972723

RESUMO

Breast cancer (BC) remains the foremost cause of cancer mortality globally, with neutrophils playing a critical role in its pathogenesis. As an essential tumor microenvironment (TME) component, neutrophils are emerging as pivotal factors in BC progression. Growing evidence has proved that neutrophils play a Janus- role in BC by polarizing into the anti-tumor (N1) or pro-tumor (N2) phenotype. Clinical trials are evaluating neutrophil-targeted therapies, including Reparixin (NCT02370238) and Tigatuzumab (NCT01307891); however, their clinical efficacy remains suboptimal. This review summarizes the evidence regarding the close relationship between neutrophils and BC, emphasizing the critical roles of neutrophils in regulating metabolic and immune pathways. Additionally, we summarize the existing therapeutic approaches that target neutrophils, highlighting the challenges, and affirming the rationale for continuing to explore neutrophils as a viable therapeutic target in BC management.


Assuntos
Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/metabolismo , Neutrófilos/metabolismo , Resultado do Tratamento , Microambiente Tumoral , Ensaios Clínicos como Assunto
17.
Zhongguo Zhong Yao Za Zhi ; 48(18): 4981-4992, 2023 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-37802840

RESUMO

This study constructed a nano-drug delivery system, A3@GMH, by co-delivering the stapled anoplin peptide(Ano-3, A3) with the light-harvesting material graphene oxide(GO), and evaluated its oncolytic immunotherapy effect on triple-negative breast cancer(TNBC). A3@GMH was prepared using an emulsion template method and its physicochemical properties were characterized. The in vivo and in vitro photothermal conversion abilities of A3@GMH were investigated using an infrared thermal imager. The oncoly-tic activity of A3@GMH against TNBC 4T1 cells was evaluated through cell counting kit-8(CCK-8), lactate dehydrogenase(LDH) release, live/dead cell staining, and super-resolution microscopy. The targeting properties of A3@GMH on 4T1 cells were assessed using a high-content imaging system and flow cytometry. In vitro and in vivo studies were conducted to investigate the antitumor mechanism of A3@GMH in combination with photothermal therapy(PTT) through inducing immunogenic cell death(ICD) in 4T1 cells. The results showed that the prepared A3@GMH exhibited distinct mesoporous and coated structures with an average particle size of(308.9±7.5) nm and a surface potential of(-6.79±0.58) mV. The encapsulation efficiency and drug loading of A3 were 23.9%±0.6% and 20.5%±0.5%, respectively. A3@GMH demonstrated excellent photothermal conversion ability and biological safety. A3@GMH actively mediated oncolytic features such as 4T1 cell lysis and LDH release, as well as ICD effects, and showed enhanced in vitro antitumor activity when combined with PTT. In vivo, A3@GMH efficiently induced ICD effects with two rounds of PTT, activated the host's antitumor immune response, and effectively suppressed tumor growth in 4T1 tumor-bearing mice, achieving an 88.9% tumor inhibition rate with no apparent toxic side effects. This study suggests that the combination of stapled anoplin peptide and PTT significantly enhances the oncolytic immunotherapy for TNBC and provides a basis for the innovative application of anti-tumor peptides derived from TCM in TNBC treatment.


Assuntos
Nanopartículas , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Terapia Fototérmica , Neoplasias de Mama Triplo Negativas/terapia , Neoplasias de Mama Triplo Negativas/patologia , Peptídeos Catiônicos Antimicrobianos , Imunoterapia/métodos , Linhagem Celular Tumoral , Fototerapia/métodos , Nanopartículas/química
18.
Clin Transl Med ; 13(10): e1449, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37859535

RESUMO

BACKGROUND: Despite all modern advances in medicine, an effective drug for treating sepsis has yet to be found. The discovery of CMPK2 spurred hopes for the treatment of sepsis. However, CMPK2-untapped target inhibitors are still an enormous obstacle that has hindered the CMPK2-centric treatment of sepsis. METHODS: Here, we found that the CMPK2 gene is highly expressed in the whole blood of sepsis patients by RNA-Seq. First, recombinant CMPK2 was purified by a eukaryotic expression purification system, and the activity of recombinant CMPK2 was detected by the ADP-GLO assay. Second, we developed an affinity MS strategy combined with quantitative lysine reactivity profiling to discover CMPK2 ligands from the active ingredients of Chinese herbs. In addition, the dissociation constant Kd of the ligand and the target protein CMPK2 was further detected by microscale thermophoresis technology. Third, we used this strategy to identify a naturally sourced small molecule, dracorhodin (DP). Using mass spectrometry-based quantitative lysine reactivity profiling combined with a series of mutant tests, the results show that K265 acts as a bright hotspot of DP inhibition of CMPK2. Fourth, immune-histochemical staining, ELISAs, RT-qPCR, flow cytometry and immunoblotting were used to illustrate the potential function and related mechanism of DP in regulating sepsis injury. RESULTS: Our results suggest that DP exerts powerful anti-inflammatory effects by regulating the NLRP3 inflammasome via the lipopolysaccharide (LPS)-induced CMPK2 pathway. Strikingly, DP significantly attenuated LPS-induced sepsis in a mouse model, but its effect was weakened in mice with myeloid-specific Cmpk2 ablation. CONCLUSION: We provide a new framework that provides more valuable information for new therapeutic approaches to sepsis, including the establishment of screening strategies and the development of target drugs to provide a theoretical basis for ultimately improving clinical outcomes for sepsis patients. Collectively, these findings reveal that DP is a promising CMPK2 inhibitor for the treatment of sepsis.


Assuntos
Lipopolissacarídeos , Sepse , Humanos , Animais , Camundongos , Lisina , Inflamação/tratamento farmacológico , Sepse/tratamento farmacológico , Sepse/metabolismo
19.
Signal Transduct Target Ther ; 8(1): 414, 2023 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-37857609

RESUMO

Reversing ventricular remodeling represents a promising treatment for the post-myocardial infarction (MI) heart failure (HF). Here, we report a novel small molecule HHQ16, an optimized derivative of astragaloside IV, which effectively reversed infarction-induced myocardial remodeling and improved cardiac function by directly acting on the cardiomyocyte to reverse hypertrophy. The effect of HHQ16 was associated with a strong inhibition of a newly discovered Egr2-affiliated transcript lnc9456 in the heart. While minimally expressed in normal mouse heart, lnc9456 was dramatically upregulated in the heart subjected to left anterior descending coronary artery ligation (LADL) and in cardiomyocytes subjected to hypertrophic stimulation. The critical role of lnc9456 in cardiomyocyte hypertrophy was confirmed by specific overexpression and knockout in vitro. A physical interaction between lnc9456 and G3BP2 increased NF-κB nuclear translocation, triggering hypertrophy-related cascades. HHQ16 physically bound to lnc9456 with a high-affinity and induced its degradation. Cardiomyocyte-specific lnc9456 overexpression induced, but knockout prevented LADL-induced, cardiac hypertrophy and dysfunction. HHQ16 reversed the effect of lnc9456 overexpression while lost its protective role when lnc9456 was deleted, further confirming lnc9456 as the bona fide target of HHQ16. We further identified the human ortholog of lnc9456, also an Egr2-affiliated transcript, lnc4012. Similarly, lnc4012 was significantly upregulated in hypertrophied failing hearts of patients with dilated cardiomyopathy. HHQ16 also specifically bound to lnc4012 and caused its degradation and antagonized its hypertrophic effects. Targeted degradation of pathological increased lnc4012/lnc9456 by small molecules might serve as a novel promising strategy to regress infarction-induced cardiac hypertrophy and HF.


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Humanos , Camundongos , Animais , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Cardiomegalia/tratamento farmacológico , Cardiomegalia/genética , Cardiomegalia/metabolismo
20.
Brief Bioinform ; 24(6)2023 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-37816138

RESUMO

Immune evasion and metabolism reprogramming have been regarded as two vital hallmarks of the mechanism of carcinogenesis. Thus, targeting the immune microenvironment and the reprogrammed metabolic processes will aid in developing novel anti-cancer drugs. In recent decades, herbal medicine has been widely utilized to treat cancer through the modulation of the immune microenvironment and reprogrammed metabolic processes. However, labor-based herbal ingredient screening is time consuming, laborious and costly. Luckily, some computational approaches have been proposed to screen candidates for drug discovery rapidly. Yet, it has been challenging to develop methods to screen drug candidates exclusively targeting specific pathways, especially for herbal ingredients which exert anti-cancer effects by multiple targets, multiple pathways and synergistic ways. Meanwhile, currently employed approaches cannot quantify the contribution of the specific pathway to the overall curative effect of herbal ingredients. Hence, to address this problem, this study proposes a new computational framework to infer the contribution of the immune microenvironment and metabolic reprogramming (COIMMR) in herbal ingredients against human cancer and specifically screen herbal ingredients targeting the immune microenvironment and metabolic reprogramming. Finally, COIMMR was applied to identify isoliquiritigenin that specifically regulates the T cells in stomach adenocarcinoma and cephaelin hydrochloride that specifically targets metabolic reprogramming in low-grade glioma. The in silico results were further verified using in vitro experiments. Taken together, our approach opens new possibilities for repositioning drugs targeting immune and metabolic dysfunction in human cancer and provides new insights for drug development in other diseases. COIMMR is available at https://github.com/LYN2323/COIMMR.


Assuntos
Antineoplásicos , Neoplasias , Plantas Medicinais , Humanos , Neoplasias/metabolismo , Antineoplásicos/uso terapêutico , Linfócitos T , Medicina Herbária , Microambiente Tumoral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...