Diabetes mellitus (DM) is a major world health problem and one of the most studied diseases, which are highly prevalent in the whole world, it is frequently associated with severe clinical ...complications, such as diabetic cardiomyopathy, nephropathy, retinopathy, neuropathy etc. Scientific research is continuously casting about for new monomer molecules from Chinese herbal medicine that could be invoked as candidate drugs for fighting against diabetes and its complications. Resveratrol (RES), a polyphenol phytoalexin, possesses diverse biochemical and physiological actions, including antiplatelet, estrogenic, and anti-inflammatory properties. It is recently gaining scientific interest for RES in controlling blood sugar and fighting against diabetes and its complications properties in various types of diabetic models. These beneficial effects seem to be due to the multiple actions of RES on cellular functions, which make RES become a promising molecule for the treatment of diabetes and diabetic complications. Here, we review the mechanism of action and potential therapeutic use of RES in prevention and mitigation of these diseases in recent ten years to provide a reference for further research and development of RES.
The pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has had a profound impact on the global health and economy. While mass vaccination for herd immunity is effective, ...emerging SARS-CoV-2 variants can evade spike protein-based COVID-19 vaccines. In this study, we develop a new immunization strategy by utilizing a nanocarrier, dendritic mesoporous silica nanoparticle (DMSN), to deliver the receptor-binding domain (RBD) and conserved T-cell epitope peptides (DMSN-P-R), aiming to activate both humoral and cellular immune responses in the host. The synthesized DMSN had good uniformity and dispersion and showed a strong ability to load the RBD and peptide antigens, enhancing their uptake by antigen-presenting cells (APCs) and promoting antigen delivery to lymph nodes. The DMSN-P-R vaccine elicited potent humoral immunity, characterized by highly specific RBD antibodies. Neutralization tests demonstrated significant antibody-mediated neutralizing activity against live SARS-CoV-2. Crucially, the DMSN-P-R vaccine also induced robust T-cell responses that were specifically stimulated by the RBD and conserved T-cell epitope peptides of SARS-CoV-2. The DMSN demonstrated excellent biocompatibility and biosafety in vitro and in vivo, along with degradability. Our study introduces a promising vaccine strategy that utilizes nanocarriers to deliver a range of antigens, effectively enhancing both humoral and cellular immune responses to prevent virus transmission.
Enzalutamide (ENZ) is a second-generation androgen receptor (AR) antagonist used for the treatment of castration-resistant prostate cancer (CRPC) and reportedly prolongs survival time within a year ...of starting therapy. However, CRPC patients can develop ENZ resistance (ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR (ARfl) or dominantly active androgen receptor splice variant 7 (ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood–brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.
LLU-206 is a novel ARfl/ARv7 inhibitor that can suppress PCa cell proliferation and ENZR tumor growth via dual-targeting of ARfl/ARv7 heterodimers and protein degradation. Display omitted
Background and Aims
Therapeutic blockade of the programmed cell death protein‐1 (PD‐1) immune checkpoint pathways has resulted in significant reactivation of T cell–mediated antitumor immunity and is ...a promising clinical anticancer treatment modality in several tumor types, but the durable response rate remains relatively low (15%–20%) in most patients with HCC for unknown reasons. Evidence reveals that the interferon signaling pathway plays a critical role in modulating the efficacy and sensitivity of anti–PD‐1 therapy against multiple tumor types, but the mechanisms are unclear.
Approach and Results
Using Kaplan‐Meier survival analysis based on HCC databases, we found that deceased expression of interferon regulatory factor (IRF) 8 in HCC, among all the nine IRF members that regulate interferon signals, was associated with poor prognosis of patients with HCC. Moreover, gene set enrichment analysis identified the interferon‐gamma and PD‐1 signaling signatures as the top suppressed pathways in patients with IRF8‐low HCC. Contrarily, overexpression of IRF8 in HCC cells significantly enhanced antitumor effects in immune‐competent mice, modulating infiltration of tumor‐associated macrophages (TAMs) and T cell exhaustion in tumor microenvironment. We further demonstrated that IRF8 regulated recruitment of TAMs by inhibiting the expression of chemokine (C‐C motif) ligand 20 (CCL20). Mechanically, IRF8‐mediated repression of c‐fos transcription resulted in decreased expression of CCL20, rather than directly bound to CCL20 promoter region. Importantly, adeno‐associated virus 8–mediated hepatic IRF8 rescue significantly suppressed HCC progression and enhanced the response to anti–PD‐1 therapy.
Conclusions
This work identified IRF8 as an important prognostic biomarker in patients with HCC that predicted the response and sensitivity to anti–PD‐1 therapy and uncovered it as a therapeutic target for enhancing the efficacy of immune therapy.
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Hepatic ischemia/reperfusion (I/R) injury is an inevitable complication of hepatic surgery occasioned by liver transplantation and resection. The progression from liver ischemia to ...reperfusion injury is accompanied by abnormal metabolism, Kupffer cell activation, neutrophil recruitment and the release of cytokines. Activation of several interferon regulatory factors (IRFs) has been reported to either enhance or restrict I/R progression, but the role of IRF8 in the regulation of I/R injury progression is still unknown. In this study, we explore the IRF8 function in the I/R-mediated liver injury using overexpressed hepatic IRF8 and knockout mice. According to our results, IRF8 knockout mice had significantly lower inflammatory cells infiltration, inflammatory cytokines release and serum aspartate aminotransferase/alanine aminotransferase levels that improved the necrotic injury after I/R, unlike the control mice. Conversely, the overexpression of IRF8 in WT mice markedly aggravated the liver structure damage and its abnormal function. We further showed that IRF8-mediated inflammatory cells infiltration were partly dependent on early autophagy and NF-κΒ signal pathway during I/R. AAV8-IRF8-I/R mice pretreated with autophagy inhibitor hydroxychloroquine and NF-κΒ signal pathway inhibitor secukinumab could drastically reverse the IRF8-mediated increase of neutrophil infiltration and chemokine release at different degrees. This work uncovered a critical role of IRF8 in the modulation of the hepatic microenvironment and as a potential target in the initial treatment of I/R injury.
In incurable castration-resistant prostate cancer (CRPC), resistance to the novel androgen receptor (AR) antagonist enzalutamide is driven mainly by AR overexpression. Here we report that the ...expression of interferon regulatory factor 8 (IRF8) is increased in primary prostate cancer but decreased in CRPC compared with normal prostate tissue. Decreased expression of IRF8 positively associated with CRPC progression and enzalutamide resistance. IRF8 interacted with AR and promoted its degradation via activation of the ubiquitin/proteasome systems. Epigenetic knockdown of IRF8 promoted AR-mediated prostate cancer progression and enzalutamide resistance
and
. Furthermore, IFNα increased expression of IRF8 and improved the efficacy of enzalutamide in CRPC by targeting the IRF8-AR axis. We also provide preliminary evidence for the efficacy of IFNα with hormonotherapy in a clinical study. Collectively, this study identifies IRF8 both as a tumor suppressor in prostate cancer pathogenesis and a potential alternative therapeutic option to overcome enzalutamide resistance. SIGNIFICANCE: These findings identify IRF8-mediated AR degradation as a mechanism of resistance to AR-targeted therapy, highlighting the therapeutic potential of IFNα in targeting IRF8-AR axis in CRPC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2927/F1.large.jpg.
Therapeutic blockade of the programmed cell death protein-1 (PD-1) immune checkpoint pathways has resulted in significant reactivation of T-cell mediated antitumor immunity and is a promising ...clinical anticancer treatment modality in several tumor types, but the durable response rate remains relatively low (15–20%) in most hepatocellular carcinoma (HCC) patients for unknown reasons. Evidences reveal that the interferon signaling pathway plays a critical role in modulating the efficacy and sensitivity of anti-PD-1 therapy against multiple tumor types, but the mechanisms are unclear. Using Kaplan-Meier survival analysis based on HCC databases, we found that deceased expression of interferon regulatory factor (IRF8) in HCC, among all the nine IRF members which regulate interferon signals, was associated with the poor prognosis of HCC patients. Moreover, gene set enrichment analysis identified the IFN-gama and PD-1 signaling signatures as the top suppressed pathways in IRF8 low HCC patients. Contrarily, overexpression of IRF8 in HCC cells significantly enhanced antitumor effects in immune-competent mice, modulating infiltration of tumor associated macrophages (TAMs) and T cells exhaustion in tumor microenvironment. We further demonstrated that IRF8 regulated recruitment of TAMs by inhibiting the expression of CCL20. Mechanically, IRF8-mediated repression of c-fos transcription resulted in decreased expression of CCL20, rather than directly bound to CCL20 promoter region. Importantly, adeno-associated virus 8-mediated hepatic IRF8 rescue significantly suppressed HCC progression and enhanced the response to anti-PD-1 therapy.
In conclusion:
This work identified IRF8 as an important prognostic biomarker in HCC patients which predicted the response and sensitivity to anti-PD-1 therapy and uncovered it as a new therapeutic target for enhancing the efficacy of immune therapy.
Objective
Breast cancer has become the most common cancer in women in China, and the clinicopathological features differ from those in Western patients. This study was performed to investigate the ...distribution of programmed cell death protein 1 (PD-1)+/PD-1− tumor-infiltrating lymphocytes (TILs) and its association with clinicopathological features among Chinese patients with breast cancer.
Methods
In total, 133 consecutive patients with primary breast cancer were recruited into this cross-sectional study from 2012 to 2013. TILs were measured by cell counts under high-power fields (HPFs). Immunohistochemistry was used to detect PD-1 expression on tumor-infiltrating lymphocytes in the microenvironment.
Results
The median cell counts of the overall TILs, PD-1+ TILs, and PD-1− TILs were 80, 18, and 55/HPF, respectively. The number of PD-1− TILs was significantly lower in older than younger patients (50 vs. 60/HPF). Patients with positive E-cadherin expression had more PD-1− TILs than patients with negative E-cadherin expression (57 vs. 27/HPF). The Ki-67 index was positively correlated with the cell counts of PD-1+ TILs, and the correlation coefficient was 0.29.
Conclusions
PD-1 expression on TILs had different clinicopathological features in Chinese patients with breast cancer. E-Cadherin expression was associated with PD-1− TILs; however, Ki-67 expression was associated with PD-1+ TILs.
Objective. This study is aimed at investigating the association of exhausted CD8+ tumor-infiltrating lymphocytes with clinic-pathological factors. Methods. 133 patients diagnosed with primary ...invasive ductal breast cancer were recruited into the cross-sectional study consecutively. Immunohistochemistry was used to detect biomarker expression on formalin-fixed and paraffin-embedded sections. Double staining of CD8 and PD-1 was conducted on lymphocytes. Results. The proportion of CD8+/PD-1- TILs was 16% among patients with axillary lymph node metastasis, significantly lower than those without metastasis (24%). The expression of CK7, CK20, or Ki-67 was not related with the proportion of phenotypes of CD8/PD-1 TILs. Younger patients had more cell counts of CD8+/PD-1- TILs than elderly patients (18/HPF vs. 9/HPF, p<0.05). Patients with axillary lymph node metastasis had less CD8+/PD-1- TILs than those without metastasis (11/HPF vs. 27/HPF, p<0.05). Median counts of CD8+/PD-1- TILs among patients with CK20 and E-Cad expression were 33/HPF and 14/HPF, significantly higher than those among patients with negative CK20 (16/HPF) and E-Cad expression (6/HPF). Ki-67 index had a significant correlation with cell counts of CD8+/PD-1+ TILs and CD8+/PD-1- TILs, and the correlation coefficients were 0.19 and 0.21 (p<0.05), respectively. Conclusion. The proportion of CD8+/PD-1- TILs was related with metastatic status of the axillary lymph node but cell counts of CD8+/PD-1- TILs were related with metastatic status of the axillary lymph node and expression of CK7, CK20, E-Cad, and Ki-67. Absolute cell counts, not proportion of CD8/PD-1 TILs, were more likely to distinguish clinic and pathologic characteristics of breast cancer.
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