traditional treatment modalities in the clinic. [1,2] Macrophages are a significant constituent of innate immune system and have an indispensable impact in activating body's first-line defense against infection and cancer. [3] Effectively activating macrophage-mediated immunity holds great potential in cancer immunotherapy. [4] However, cancer cells are masters of immunomodulation and express "don't eat me" signal CD47 on the cellular surface, protecting them from the phagocytosis via binding to signal regulatory protein alpha (SIRPα) receptor on macrophages. [5,6] Blockade of CD47-SIRPα signaling pathway has been widely studied and dozens of CD47 antagonists are being actively tested in clinical trials. [7,8] CD47 checkpoint inhibitors have been demonstrated to not only promote macrophages to directly "eat" cancer cells but also trigger potent T-cell immune responses. [9] Although promising, systemic infusion of these CD47 inhibitors can cause significant side effects, such as thrombocytopenia and anemia. [2,10] Meanwhile, similar to other checkpoint inhibitors, the clinical benefit rate and objective response rate of these antagonists need to be further improved. [10] Thus, addressing these concerns are Immunomodulation of macrophages against cancer has emerged as an encouraging therapeutic strategy. However, there exist two major challenges in effectively activating macrophages for antitumor immunotherapy. First, ligation of signal regulatory protein alpha (SIRPα) on macrophages to CD47, a "don't eat me" signal on cancer cells, prevents macrophage phagocytosis of cancer cells. Second, colony stimulating factors, secreted by cancer cells, polarize tumor-associated macrophages (TAMs) to a tumorigenic M2 phenotype. Here, it is reported that genetically engineered cell-membrane-coated magnetic nanoparticles (gCM-MNs) can disable both mechanisms. The gCM shell genetically overexpressing SIRPα variants with remarkable affinity efficiently blocks the CD47-SIRPα pathway while the MN core promotes M2 TAM repolarization, synergistically triggering potent macrophage immune responses. Moreover, the gCM shell protects the MNs from immune clearance; and in turn, the MN core delivers the gCMs into tumor tissues under magnetic navigation, effectively promoting their systemic circulation and tumor accumulation. In melanoma and breast cancer models, it is shown that gCM-MNs significantly prolong overall mouse survival by controlling both local tumor growth and distant tumor metastasis. The combination of cell-membrane-coating nanotechnology and genetic editing technique offers a safe and robust strategy in activating the body's immune responses for cancer immunotherapy.
DNA methylation is closely related to the occurrence and development of many diseases, but its role in obesity is still unclear. This study aimed to find the potential differentially methylated genes associated with obesity occurrence and development. By combining methylation and transcriptome analysis, we identified the key genes in adipose tissue affecting the occurrence and development of obesity and revealed the possible molecular mechanisms involved in obesity pathogenesis. We first screened 14 methylation-related differential genes and verified their expression in adipose tissue by quantitative polymerase chain reaction (qPCR). Seven genes with the same expression pattern were identified as key genes, namely, CCRL2, GPT, LGALS12, PC, SLC27A2, SLC4A4, and TTC36. Then, the immune microenvironment of adipose tissue was quantified by CIBERSORT, and we found that the content of M0 macrophages and T follicular helper cells in adipose tissue was significantly increased and decreased, respectively, in the obese group. Furthermore, the relationship between key genes and the immune microenvironment was analyzed. Additionally, the metabolic pathway activity of each sample was calculated based on the ssGSEA algorithm, and the key gene–metabolic network was constructed. Moreover, we performed a CMAP analysis based on the differential genes in adipose tissue to screen out drugs potentially effective in obesity treatment. In conclusion, we identified seven methylation-related key genes closely related to obesity pathogenesis and explored the potential mechanism of their role in obesity. This study provided novel insights into the molecular mechanisms and management of obesity.
Background Despite the synergy of immune checkpoint blockade (ICB) therapy and photodynamic therapy (PDT) holds great promise as countermeasures against breast cancer, exploring long-term or flexible short-time therapeutic strategies in “cold” tumors remains great challenge. Methods Programmed death-ligand 1 antibody (αPD-L1) and photosensitizer chlorin e6 (Ce6) were loaded in polyunsaturated fatty acid-doped liposomal hydrogel Lp(DHA)@CP Gel for flexible local photoimmunotherapy with merely single-dosed administration. Phototriggered drug release and ROS generation of Lp(DHA)@CP Gel were evaluated in vitro. To investigate tumor therapeutic effect, NIR laser of 671 nm was used to irradiate tumor site after a single dose of peritumoral administration of Lp(DHA)@CP Gel of 4T1-bearing mice. Results With syringe-injectable and self-healing property, Lp(DHA)@CP Gel showed a photo-triggered release of αPD-L1 repeatedly induced to in situ in response to PDT for at least 11 days. Additionally, Lp(DHA)@CP Gel exhibited prominent antitumor efficacy both in vitro and in vivo. The on-demand treatment can maximize the patient compliance and safety by adjusting therapeutic behaviors via a photo on-off switch. Furthermore, the immunogenic cell death (ICD) effect of PDT evoked “cold” breast tumor to “hot” one, and then assisted the cascade released αPD-L1 to synergistically boost the immunotherapy. Conclusion Lp(DHA)@CP Gel is a flexible medication platform, showing promise in improving the objective response rate of ICB therapy and minimizing its systemic toxicity.
Introduction Diabetic kidney disease (DKD) has become the leading cause of end-stage kidney disease (ESKD) in most countries. Recently, long noncoding RNA XIST has been found involved in the development of DKD. Methods A total of 1184 hospitalized patients with diabetes were included and divided into four groups based on their estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR): normal control group (nDKD), DKD with normoalbuminuric and reduced eGFR (NA-DKD), DKD with albuminuria but without reduced eGFR (A-DKD), and DKD with albuminuria and reduced eGFR (Mixed), and then their clinical characteristics were analyzed. Peripheral blood mononuclear cells (PBMCs) of patients with DKD were isolated, and lncRNA XIST expression was detected by real-time quantitative PCR. Results The prevalence of DKD in hospitalized patients with diabetes mellutus (DM) was 39.9%, and the prevalence of albuminuria and decreased eGFR was 36.6% and 16.2%, respectively. NA-DKD, A-DKD, and Mixed groups accounted for 3.3%,23.7%, and 12.9%, respectively. Women with DKD had considerably lower levels of lncRNA XIST expression in their PBMCs compared to nDKD. There was a significant correlation between eGFR level and lncRNA XIST expression ( R = 0.390, P = 0.036) as well as a negative correlation between HbA1c and lncRNA XIST expression ( R = − 0.425, P = 0.027) in female patients with DKD. Conclusions Our study revealed that 39.9% of DM inpatients who were admitted to the hospital had DKD. Importantly, lncRNA XIST expression in PBMCs of female patients with DKD was significantly correlated with eGFR and HbA1c. Supplementary Information The online version contains supplementary material available at 10.1007/s13300-023-01439-9.
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