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Zhengyu Fang,1,* Peihong Lin,1,* Rui Gao,1,* Wenjing Yang,1 Aizhen Zhou,2 Wenying Yu1,3 1School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, People’s Republic of China; 2Department of Traditional Chinese Medicine, Zhejiang Pharmaceutical University, Ningbo, 315500, People’s Republic of China; 3Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310013, People’s Republic of China*These authors contributed equally to this workCorrespondence: Aizhen Zhou; Wenying Yu, Tel +86 571 88215623, Email zhouaz@zjpc.net.cn; zjyuwenying@163.comBackground: Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, is a potential candidate for cancer chemotherapy. However, Tet has poor aqueous solubility and a short half-life, which limits its bioavailability and efficacy. Liposomes have been widely utilized to enhance the bioavailability and efficacy of drugs.Methods: In this study, Tet-loaded stealth liposomes (S-LPs@Tet) were prepared by ethanol injection method. Furthermore, physicochemical characterisation, biopharmaceutical behaviour, therapeutic efficacy, and biocompatibility of S-LPs@Tet were assessed.Results: The prepared S-LPs@Tet had an average particle size of 65.57 ± 1.60 nm, a surface charge of − 0.61 ± 0.10 mV, and an encapsulation efficiency of 87.20% ± 1.30%. The S-LPs@Tet released Tet in a sustained manner, and the results demonstrated that the formulation remained stable for one month. More importantly, S-LPs significantly enhanced the inhibitory ability of Tet on the proliferation and migration of lung cancer cells, and enabled Tet to escape phagocytosis by immune cells. Furthermore, in vivo studies confirmed the potential for long-circulation and potent tumor-suppressive effects of S-LPs@Tet. Moreover, ex vivo and in vivo safety experiments demonstrated that the carrier material S-LPs exhibited superior biocompatibility.Conclusion: Our research suggested that

We aimed to develop an improved version of the diagnostic model predicting the risk of malignant esophageal lesions in opportunistic screening and validate it in external populations. The development set involved 10,595 outpatients receiving endoscopy from a hospital in Hua County, a high-risk region for esophageal squamous cell carcinoma in northern China. Validation set A enrolled 9453 outpatients receiving endoscopy in a non-high-risk region in southern China. Validation set B involved 17,511 residents in Hua County. The improved diagnostic model consisted of seven predictors including age, gender, family history of esophageal squamous cell carcinoma, smoking, body mass index, dysphagia, and retrosternal pain, with an area under the receiver operating characteristic curve (AUC) of 0.860 (95% confidence interval: 0.835–0.886) in the development set. Ideal discrimination ability was achieved in external validations (AUC validation set A: 0.892, 95% confidence interval: 0.858–0.926; AUC validation set B: 0.799, 95% confidence interval: 0.705–0.894). This improved model also markedly increased the detection rate of malignant esophageal lesions compared with universal screening, demonstrating great potential for use in opportunistic screening of malignant esophageal lesions in heterogeneous populations. © 2022 by the authors.

Tumor suppressor protein P53 induces cycle arrest and apoptosis by mediating the transcriptional expression of its target genes. Mutations causing conformational abnormalities and post-translational modifications that promote degradation are the main reasons for the loss of P53 function in tumor cells. Reporter gene assays that can scientifically reflect the biological function can help discover the mechanism and therapeutic strategies that restore P53 function. In the reporter gene system of this work, tetracycline-inducible expression of wild-type P53 was used to provide a fully activated state as a 100% activity reference for the objective measurement of biological function. It was confirmed by RT-qPCR, cell viability assay, immunofluorescence, and Western blot analysis that the above-mentioned reporter gene system could correctly reflect the differences in biological activity between the wild-type and mutants. After that, the system was tentatively used for related mechanism research and compound activity evaluation. Through the tetracycline-induced co-expression of wild-type P53 and mutant P53 in exact proportion, it was observed that the response modes of typical transcriptional response elements (TREs) to dominant negative P53 mutation effect were not exactly the same. Compared to the relative multiple-to-solvent control, the activity percentage relative to the 100% activity reference of wild-type P53 can better reflect the actual influence of the so-called P53 mutant reactivator. Similarly, relative to the 100% activity reference, it can objectively reflect the biological effects caused by the inhibitor of P53 negative factors, such as MDM2. In conclusion, this study provides a 100% activity reference and a reliable calculation model for relevant basic research and drug development.

Objective:To evaluate the biological effect and mechanisms of C-reactive protein (CRP) on the activation of fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA). Study design:To understand if CRP is involved in RA, expression of CRP and its receptors CD32/64 was examined in synovial tissues from RA patients and normal controls.In vitro, the potential role and mechanisms of CRP in FLS proliferation and invasion, expression of pro-inflammatory cytokines, and activation of signaling pathways were investigated in both RA - FLS and a normal human fibroblast-like synoviocyte line (HFLS). Results:Compared to normal controls, synovial tissues from 21 RA patients exhibited highly activated CRP signaling, particularly by FLSs as identified by 65% of CRP-expressing cells being CRP+vimentin+ and CD32/64+vimentin+ cells.In vitro, FLSs from RA patients, but not HFLS, showed highly reactive to CRP by largely increasing proliferative and invasive activities and expressing pro-inflammatory cytokines and chemokines, including CCL2, CXCL8, IL-6, and MMP2/9. All these changes were blocked largely by a neutralizing antibody to CD32 and, to a less extent by the anti-CD64 antibody, revealing CD32 as a primary mechanism of CRP signaling during synovial inflammation. Further studies revealed that CRP also induced synovial inflammation differentially via CD32/CD64- NF-kappa B or p38 pathways as blockade of CRP-CD32-NF-kappa B signaling inhibited CXCL8, CCL2, IL-6, whereas CRP induced RA-FLS invasiveness through CD32-p38 and MMP9 expression via the CD64-p38-dependent mechanism. Conclusions:CRP signaling is highly activated in synovial FLSs from patients with RA. CRP can induce synovial inflammation via mechanisms associated with activation of CD32/64-p38 and NF-kappa B signaling.