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In this study, double enzyme hydrolysis significantly enhanced the DPP-IV inhibition rate compared to single enzyme. The α + K enzymes exhibited the highest inhibition rate. Ultrasonic pretreatment for 30 min improved the hydrolysis efficiency and DPP-IV inhibition rate, potentially due to the structural changes in hydrolysates, such as the increased surface hydrophobicity, and reduced particle size, α-helix and ß-turn. Six peptides were screened and verified in vitro. QPY, WPEYL, and YPPQVM displayed competitive inhibition, while LPAAP and IPAPSFPRL displayed mixed competitive/non-competitive inhibition. The interactions between these six peptides and DPP-IV primarily occurred through hydrogen bonds, electrostatic and hydrophobic interactions. Network pharmacological analysis indicated that LPAAP might inhibit DPP-IV activity trough interactions with diabetes-related targets such as CASP3, HSP90AA1, MMP9, and MMP9. These results uncover the potential mechanism of regulating blood glucose by camel milk hydrolysates, establishing camel milk peptide as a source of DPP-IV inhibitory peptide.
Assuntos
Camelus , Dipeptidil Peptidase 4 , Inibidores da Dipeptidil Peptidase IV , Leite , Peptídeos , Animais , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Leite/química , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Hidrólise , Interações Hidrofóbicas e Hidrofílicas , Sequência de Aminoácidos , HumanosRESUMO
Purpose: Tumor-associated macrophages (TAMs) play a crucial role in solid tumors and display varying characteristics depending on the specific tumor microenvironment (TME). The study investigated the presence and characteristics of TAMs in renal clear cell carcinoma (ccRCC) and assessed their influence on patient prognosis. Methods: Immunohistochemistry (IHC) was used to identify CD204+ TAMs in a cohort of 72 patients with ccRCC. Kaplan-Meier survival analysis and log-rank test were used to evaluate the prognostic significance of CD204+ TAMs in each group. The TCGA-KIRC cohort was used to analyze the relationship between CD204 and immunity. The functions of CD204+ TAMs in the TCGA-KIRC cohort were analyzed through GO enrichment analysis. Immunofluorescence (IF) was conducted to confirm the positive effects of CD204 on regulatory T (Treg) cells and exhausted T (Tex) cells. Results: There was a negative relation between high infiltration of CD204+ TAMs and both overall survival (OS) and progression-free survival (PFS) in ccRCC. A positive correlation was found between high-infiltrating CD204+ TAMs and distant organ metastasis, as well as lymph node metastasis. In the TCGA-KIRC cohort, the group with high expression of CD204 exhibited significant up-regulation of 120 genes as well as enrichment in the negative regulation of immunity. CD204 high-expression group showed up-regulation of Treg cells and Tex cells. Conclusion: The presence of CD204+ TAMs in ccRCC is associated with a negative prognosis in patients. The high infiltration of CD204 promotes distant organ metastasis by aggerating Treg cells and Tex cells.
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Background: Lymphangiogenesis represents a key event in the progression and metastasis of patients with clear cell renal cell carcinoma (ccRCC). Nevertheless, the prognostic value of lymphangiogenesis-related genes (LRGs) in ccRCC patients remains unknown. Method: Differential analyses were performed to identify differentially expressed LRGs between normal and tumor tissues. A univariate Cox analysis was performed to identify differently expressed LRGs associated with overall survival (OS). LASSO and multivariate Cox analyses were performed to construct and optimize the LRG signature. To further explore the molecular characterization of the LRG signature, a functional enrichment analysis, immune signature, somatic mutations, and drug sensitivity were assessed. Immunohistochemistry (IHC) and immunofluorescence staining were performed to validate the relationship between lymphangiogenesis and immunity using our ccRCC samples. Results: Four candidate genes (IL4, CSF2, PROX1, and TEK) were eventually available to construct the LRG signature in the training set. Patients in the high-risk group had a shorter survival than those in the low-risk group. The LRG signature was an independent prognostic factor of OS. These results were confirmed in the validation group. The LRG signature was correlated with immunosuppressive cell infiltration, T cell exhaustion markers, somatic mutations, and drug sensitivity. The IHC and immunofluorescence staining results confirmed the correlation between lymphangiogenesis and CD163+ macrophages, exhausted CD8+PD-1+, and CD8+ LAG3+ T cells. Conclusion: A novel prognostic signature based on LRGs could provide insight into the prognostic evaluation and treatment of ccRCC patients.
Assuntos
Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Linfangiogênese/genética , Prognóstico , Complexo CD3 , Imunossupressores , Neoplasias Renais/genética , Microambiente Tumoral/genéticaRESUMO
Lycii Cortex, a popular herb medicine in traditional Chinese medicine, is used to treat different inflammation-related diseases. The aim of our work is to find the key constituents inhibiting NF-kappaB, a key regulator of inflammation. In the investigations of cell-based in vitro assays of extracts, we found that both ethyl acetate extract and methanol extract of Lycii Cortex inhibited the TNF-alpha-induced activation of NF-kappaB. Through bioassay-guided fractionation, we identified 4 phenolic amides including trans-N-(p-coumaroyl) tyramine (1), trans-N-feruloyltyramine (2), trans-N-caffeoyltyramine (3), and dihydro-N-caffeoyltyramine (4). Four phenolic amides showed differently inhibitory activities on TNF-alpha-induced NF-kappaB activation. Trans-N-caffeoyltyramine (3) was identified as the key component with an IC50 of 18.41 micromol x L(-1). It was suggested that the hydroxyl group at C-3 in trans-N-caffeoyltyramine might be a key binding site and its C-7,8-double bond might play an important role on NF-kappaB inhibitory activities as the link of the conjugation of pi electrons leading to a partial planar conformation. It might be inferred that the biological activity of compound 3 is attributed to the structure of Michael reaction acceptor containing alpha, beta-unsaturated ketones and benzene along with hydroxyl group in o-diphenol.
Assuntos
Medicamentos de Ervas Chinesas/química , Mediadores da Inflamação/antagonistas & inibidores , Lycium/química , NF-kappa B/antagonistas & inibidores , Bioensaio , Linhagem Celular , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Mediadores da Inflamação/imunologia , Estrutura Molecular , NF-kappa B/imunologiaRESUMO
A new route was created for the preparation of AgCl-polyacrylamide (AgCl-PAM) composite microspheres with patterned surface structures. The route is a combination of a polymer microgel template method and a reverse micelle technique. The size of the AgCl nanoparticles existing on the surfaces of the composite microspheres and the clearness of the surface patterns of the composite microspheres can be altered by simply adjusting the amount of precipitated AgCl and the rate of the deposition reaction. The route can be also used for the preparation of other water-insoluble salt-polymer composite microspheres, such as BaSO(4)-PAM. It is expected that the composite microspheres with patterned surface structures may not only combine the advantages of polymers and those of inorganic compounds, but also combine the advantages of microspheres in the micrometer size range and those in the nanometer size range.