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Cancer immunotherapy involves blocking the interactions between the PD-1/PD-L1 immune checkpoints with antibodies. This has shown unprecedented positive outcomes in clinics. Particularly, the PD-L1 antibody therapy has shown the efficiency in blocking membrane PD-L1 and efficacy in treating some advanced carcinoma. However, this therapy has limited effects on many solid tumors, suspecting to be relevant to PD-L1 located in other cellular compartments, where they play additional roles and are associated with poor prognosis. In this review, we highlight the advances of 3 current strategies on PD-1/PD-L1 based immunotherapy, summarize cellular distribution of PD-L1, and review the versatile functions of intracellular PD-L1. The intracellular distribution and function of PD-L1 may indicate why not all antibody blockade is able to fully stop PD-L1 biological functions and effectively inhibit tumor growth. In this regard, gene silencing may have advantages over antibody blockade on suppression of PD-L1 sources and functions. Apart from cancer cells, PD-L1 silencing on host immune cells such as APC and DC can also enhance T cell immunity, leading to tumor clearance. Moreover, the molecular regulation of PD-L1 expression in cells is being elucidated, which helps identify potential therapeutic molecules to target PD-L1 production and improve clinical outcomes. Based on our understandings of PD-L1 distribution, regulation, and function, we prospect that the more effective PD-L1-based cancer immunotherapy will be combination therapies.

With the changes in modern life, hyperuricemia (HUA) has become a serious universal health issue, leading to rising morbidity and mortality. Characterized by elevated levels of UA, HUA has become an independent risk factor for gout, chronic kidney disease, insulin resistance, cardiovascular disease, nonalcoholic fatty liver disease, etc. As HUA is a metabolic syndrome, the immune response is likely to play an active role throughout the whole process. Moreover, macrophages, as an indispensable component of the immune system, may serve as a promising target for addressing hyperuricemia-induced inflammation. Along with their precursor cells, monocytes, macrophages play a key role in the pathogenesis of HUA, primarily through three specific aspects, all of which are associated with inflammatory cytokines. The first mechanism involves direct action on urate transporters, such as URAT1 and ABCG2. The second mechanism is the modulation of inflammation, including targeting toll-like receptors (TLRs) and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. The third mechanism pertains to the effects on oxidative stress mediators. In this review, we summarize the underlying mechanisms of hyperuricemia, focusing on the effects of macrophages, therapeutic approaches, and clinical trials addressing hyperuricemia-caused dysfunction. Additionally, we highlight directions for future development, aiming to support future theoretical studies.

Colorectal cancer is one of the most common malignant tumors, and its drug resistance poses a huge challenge and a serious threat to people’s health. In previous studies, we have found that the combination of paclitaxel and BEZ235 has synergistic anti-colon cancer effects, particularly in drug-resistant colorectal cancer, demonstrating excellent anti-tumor effects. Therefore, this study aims to investigate the preparation of the nanoemulsification of paclitaxel and BEZ235 (NEs-PTX-BEZ235) and to explore the potential key parameters for its clinical translation. This study aims to provide a new therapeutic strategy for colorectal cancer, especially for drug-resistant colorectal cancer. The nanomaterials were prepared by low energy self-emulsification method, and analyzed by Malvern laser particle size analyzer. Cell drug uptake was observed under fluorescence microscope. CCK8, Western blot and flow cytometry were used to compare the anti-cancer effects and mechanisms of different experimental groups on ordinary and drug-resistant colon cancer cells. Human colon cancer primary cells were extracted to verify the anti-tumor effect of drugs. Finally, we found that NEs-PTX-BEZ235 significantly killed colon cancer cells, especially drug-resistant cells, and performed better than Nab-PTX. It may play a synergistic role in reducing drug resistance, inhibiting tumor stemness and inducing apoptosis of colon cancer cells by inhibiting drug resistance proteins.

Background Previous studies reported that emodin extracted from Rheum palmatum L. exerts antiproliferation and antimetastatic effects in a variety of human cancer types. However, the role of emodin in hepatocellular carcinoma (HCC) remain unknown. Methods EdU and colony formation assays were performed to evaluate the effects of emodin on proliferation. The mobility capacities of HCC treated with emodin were evaluated using wound healing assay. Transwell invasion and migration assays were performed to evaluate anti-migratory and anti-invasive effects of emodin on HCC. Annexin V-FITC/PI was performed to analyze the apoptosis. PI stain was performed to analyze cell cycle. RNA sequencing technology was used to identify the differentially expressed genes (DEGs) induced by emodin in HCC. The impact of emodin on autophagic flux in HepG2 cells was examined by mCherry-GFP-LC3 analysis. Western blot was used to assess the protein expressions of epithelial-mesenchymal transition (EMT), autophagy, PI3K/AKT/mTOR and Wnt/β-catenin signaling pathway. Results We found that emodin inhibited the growth of HepG2 cells in a dose- and time-dependent manner. In addition, emodin inhibited cell proliferation, induced S and G2/M phases arrest, and promoted apoptosis in HepG2 cells. The migration and invasion of HepG2 cells were also suppressed by emodin. Enrichment analysis revealed that DEGs involved in cell adhesion, cancer metastasis and cell cycle arrest. Moreover, western bolt results show that emodin-induced autophagy promotes Snail and β-catenin degradation. We also found that blocking autophagic flux after emodin treatment caused EMT reversal. Furthermore, the PI3K agonist Y-P 740 significantly reversed the phosphorylation levels of GSK3β and mTOR. These results indicated that emodin induced autophagy and inhibited the EMT in part through suppression of the PI3K/AKT/mTOR and Wnt/β-catenin pathways. Conclusion Our study indicated that emodin inhibited cell metastasis in HCC via the crosstalk between autophagy and EMT.

Background Programmed cell death ligand 1 (PD-L1) is an important immune-inhibitory protein expressed on cancer cells to mediate cancer escape through interaction with PD-1 expressed on activated T lymphocytes (T cells). Previously, we reported that colon and breast cancer stem cells (CSCs) expressed much higher levels of PD-L1 than their parental cells, suggesting they will be more resistant to immune attack. Methods We investigated the underlining mechanism of PD-L1 increase in colon CSCs, with a special focus on the effect of insulin and epithelial growth factor (EGF), the two fundamental components to sustain the metabolism and stemness in the culture of CSCs. Results We found that insulin increased the total and surface PD-L1 levels through PI3K/Akt/mTOR pathway as the increase could be inhibited by the dual inhibitor of the pathway, BEZ235. EGF didn’t affect the total PD-L1 levels of CSCs but increased the cell surface protein levels by flow cytometry analysis, indicating EGF promotes the transport of PD-L1 to the cell surface. Blocking cell surface PD-L1 with a specific antibody resulted in a significant reduction of tumour sphere formation but didn’t interfere with the sphere growth, suggesting that cell surface PD-L1 may act as an adhering molecule for CSCs. Conclusions Apart from the essential roles in metabolism and stemness, insulin and EGF involve in up-regulation of PD-L1 expression in colon CSCs, therefore the inhibition of insulin and EGF/EGFR pathways can be considered for cancer immunotherapy or combined with PD-1/PD-L1 antibody-based cancer immunotherapy to eliminate CSCs.

There are currently no targeted delivery systems to satisfactorily treat bone-related disorders. Many clinical drugs consisting of small organic molecules have a short circulation half-life and do not effectively reach the diseased tissue site. This coupled with repeatedly high dose usage that leads to severe side effects. With the advance in nanotechnology, drugs contained within a nano-delivery device or drugs aggregated into nanoparticles (nano-drugs) have shown promises in targeted drug delivery. The ability to design nanoparticles to target bone has attracted many researchers to develop new systems for treating bone related diseases and even repurposing current drug therapies. In this review, we shall summarise the latest progress in this area and present a perspective for future development in the field. We will focus on calcium-based nanoparticle systems that modulate calcium metabolism and consequently, the bone microenvironment to inhibit disease progression (including cancer). We shall also review the bone affinity drug family, bisphosphonates, as both a nano-drug and nano-delivery system for bone targeted therapy. The ability to target and release the drug in a controlled manner at the disease site represents a promising safe therapy to treat bone diseases in the future.

In this work a novel strategy has been developed to prepare well-dispersed amine-functionalized SiO2 nanodot-coated layered double hydroxide nano- composite （NH2-SiO2@LDH） via electrostatic interactions and condensation of （3-aminopropyl）triethoxysilane （APTES）. This nanocomposite system is well dispersed in culture media and phosphate buffered saline, and exhibits low cytotoxicity and good biocompatibility. The fluorescence microscopy images and flow cytometry data indicate that such an NH2-SiO2@LDH nanocomposite is able to efficiently deliver small interfering RNA （siRNA） into the U2OS cell line to inhibit cell proliferation. Thus, NH2-SiOR@LDH nanocomposite has a great potential as a nanocarrier for efficient gene delivery.

Background Esophageal squamous cell carcinoma (ESCC) is a deadly gastrointestinal malignancy, and chemotherapy resistance is a key factor leading to its poor prognosis. M2 tumor-associated macrophages (M2-TAMs) may be an important cause of chemoresistance in ESCC, but its exact mechanism is still unclear. Methods In order to study the role of M2-TAMs in ESCC chemoresistance, CCK-8, clone formation assay, flow cytometric apoptosis assay, qRT-PCR, western blotting, and serum-free sphere formation assays were used. In vivo animal experiments and human ESCC tissues were used to confirm the findings. Results In vitro and in vivo animal experiments, M2-TAMs reduced the sensitivity of ESCC cells to cisplatin. Mechanistically, M2-TAMs highly secreted TGF-β1 which activated the TGFβR1-smad2/3 pathway to promote and maintain the stemness characteristic of ESCC cells, which could inhibit the sensitivity to cisplatin. Using TGFβ signaling inhibitor SB431542 or knockdown of TGFβR1 could reverse the cisplatin resistance of ESCC cells. In 92 cases of human ESCC tissues, individuals with a high density of M2-TAMs had considerably higher levels of TGF-β1. These patients also had worse prognoses and richer stemness markers. Conclusion TGF-β1 secreted from M2-TAMs promoted and maintained the stemness characteristic to induce cisplatin resistance in ESCC by activating the TGFβ1-Smad2/3 pathway.

ObjectiveTo clarify whether the high-density lipoprotein cholesterol/C reactive protein (HDL-C/CRP) ratio can be used as a new prognosticator of all-cause mortality in patients with chronic heart failure (CHF) (New York Heart Association (NYHA) cardiac class III/IV).DesignRetrospective study.BackgroundSeveral papers have revealed that HDL-C and CRP can act as anti-inflammatory and pro-inflammatory factors, respectively, to affect disease progression in patients with heart failure, and the balance of the two has been shown to affect the prognosis of patients with heart failure with preserved ejection fraction (HFpEF), but none of the above studies involved patients with the more severe forms of heart failure with mildly reduced ejection fraction and heart failure with reduced ejection fraction; therefore, the present study is to extend the balance of HDL-C and CRP to the whole range of types of patients CHF to further confirm its importance.SettingThis study is from a single centre in Yunnan Province, China.ParticipantsAfter excluding ineligible patients, we finally included 1192 patients with CHF from January 2017 to October 2021.Primary and secondary measuresThe primary outcome was all-cause mortality in patients with CHF between January 2017 and October 2021. No secondary outcome measures were performed.ResultsAll patients were divided into four groups according to the quartiles of the HDL-C/CRP ratio. Using the Kaplan-Meier analysis, the risk of all-cause mortality was always the highest for Q1 (HDL-C/CRP<0.395) and the lowest for group Q4 (HDL-C/CRP≥3.4163). Cox univariate and multivariate regression analyses showed that HDL-C/CRP was consistently an independent risk factor for death from CHF. Based on the receiver operating characteristic curve, the area under the curve for HDL-C/CRP was 0.7254 (p<0.001), with a sensitivity of 65.5% and a specificity of 69.6%.ConclusionsThe HDL-C/CRP ratio is an independent prognostic indicator of all-cause mortality in patients with CHF in NYHA cardiac function class III/IV, which has good specificity and sensitivity. Patients with lower levels of the HDL-C/CRP ratio are at a greater risk of death than patients with higher levels of the HDL-C/CRP ratio.