Biyang floral mushroom-derived exosome-like nanovesicles: characterization, absorption stability and ionizing radiation protection.

Diet-derived exosome-like nanovesicles are a class of natural active substances that have similar structures and functions to mammalian exosomes. Biyang floral mushrooms and their active extracts have been found to possess radioprotective effects and to deeply explore their novel active substances, the radioprotective effects of Biyang floral mushroom-derived exosome-like nanovesicles (BFMELNs) were investigated in this study. Results showed that these surface-negatively charged vesicles possessed an ideal size and good stability against environmental changes such as temperature and gastrointestinal digestion. Furthermore, BFMELNs could effectively be taken up by HL-7702 cells and Caco-2 cells through cellular phagocytosis mediated by clathrin and dynein. Emphatically, BFMELNs with an exosome-like morphology contained RNA, proteins, lipids, polyphenols and flavonoids to exert good antioxidant and radioprotective effects in vitro. Meanwhile, BFMELNs also exhibited good radioprotective effects by restoring peripheral blood indexes, mitigating damage to organs, and regulating the redox state in mice. Collectively, BFMELNs showed promise as novel and natural radioprotective nano-agents for preventing IR-induced oxidative stress damage.

Machine learning algorithms for identifying contralateral central lymph node metastasis in unilateral cN0 papillary thyroid cancer.

Purpose: The incidence of thyroid cancer is growing fast and surgery is the most significant treatment of it. For patients with unilateral cN0 papillary thyroid cancer whether to dissect contralateral central lymph node is still under debating. Here, we aim to provide a machine learning based prediction model of contralateral central lymph node metastasis using demographic and clinical data. Methods: 2225 patients with unilateral cN0 papillary thyroid cancer from Wuhan Union Hospital were retrospectively studied. Clinical and pathological features were compared between patients with contralateral central lymph node metastasis and without. Six machine learning models were constructed based on these patients and compared using accuracy, sensitivity, specificity, area under the receiver operating characteristic and decision curve analysis. The selected models were then verified using data from Differentiated Thyroid Cancer in China study. All statistical analysis and model construction were performed by R software. Results: Male, maximum diameter larger than 1cm, multifocality, ipsilateral central lymph node metastasis and younger than 50 years were independent risk factors of contralateral central lymph node metastasis. Random forest model performed better than others, and were verified in external validation cohort. A web calculator was constructed. Conclusions: Gender, maximum diameter, multifocality, ipsilateral central lymph node metastasis and age should be considered for contralateral central lymph node dissection. The web calculator based on random forest model may be helpful in clinical decision.

[Effectiveness analysis of revision surgery after total hip arthroplasty assisted by artificial intelligence preoperative planning system].

Objective: To explore the short-term effectiveness of hip revision surgery guided by artificial intelligence preoperative planning (AIHIP) system. Methods: The clinical data of 22 patients (23 hips) who were admitted between June 2019 and March 2023 and met the selection criteria were retrospectively analyzed. There were 12 males and 10 females with an average age of 69.7 years (range, 44-90 years). There were 19 hips in the first revision, 3 hips in the second revision, and 1 hip in the third revision. The causes of revision included 12 hips with prosthesis loosening, 4 hips with acetabular cup loosening, 3 hips with osteolysis, 2 hips with acetabular dislocation, 1 hip with postoperative infection, and 1 hip with prosthesis wear. There were 6 hips in stage ⅡA, 9 hips in stage ⅡB, 4 hips in stage ⅡC, 3 hips in stage ⅢA, and 1 hip in stage ⅢB according to Paprosky staging of acetabular bone defect. The replacement of prosthesis type, operation time, hospitalization stay, ground active condition, and postoperative infection, fracture, prosthesis loosening, and other adverse events were recorded. The function of the affected limb was evaluated by Harris score before operation, at 1 week and 6 months after operation, and the range of motion of the hip joint was compared before operation and at 6 months after operation. Results: The operation time was 85-510 minutes, with an average of 241.8 minutes; the hospitalization stay was 7-35 days, with an average of 15.2 days; the time of disassociation from the walker was 2-108 days, with an average of 42.2 days. All the 22 patients were followed up 8-53 months (mean, 21.7 months). No adverse events such as prosthesis loosening or infection occurred in the rest of the patients, except for postoperative hematoma of the thigh in 1 patient and dislocation of the hip in 1 hip. The matching degree of acetabular cup was completely matched in 22 hips and mismatched in 1 hip (+2), the matching rate was 95.65%. The matching degree of femoral stem was completely matched in 22 hips and generally matched in 1 hip (-1), and the matching rate was 100%. The Harris scores were 55.3±9.8 and 89.6±7.2 at 1 week and 6 months after operation, respectively, which significantly improved when compared with before operation (33.0±8.6, P<0.05), and further improved at 6 months after operation than at 1 week after operation ( P<0.05). The function of hip joint was evaluated by Harris score at 6 months after operation, and 21 hips were good and 2 hips were moderate, which could meet the needs of daily life. The range of motion of hip joint was (111.09±10.11)° at 6 months after operation, which was significantly different from (79.13±18.50)° before operation ( t=-7.269, P<0.001). Conclusion: AIHIP system can improve the accuracy of revision surgery, reduce the difficulty of surgery, and achieve good postoperative recovery and satisfactory short-term effectiveness.

The clinical progress and challenges of mRNA vaccines.

Owing to the breakthroughs in the prevention and control of the COVID-19 pandemic, messenger RNA (mRNA)-based vaccines have emerged as promising alternatives to conventional vaccine approaches for infectious disease prevention and anticancer treatments. Advantages of mRNA vaccines include flexibility in designing and manipulating antigens of interest, scalability in rapid response to new variants, ability to induce both humoral and cell-mediated immune responses, and ease of industrialization. This review article presents the latest advances and innovations in mRNA-based vaccines and their clinical translations in the prevention and treatment of infectious diseases or cancers. We also highlight various nanoparticle delivery platforms that contribute to their success in clinical translation. Current challenges related to mRNA immunogenicity, stability, and in vivo delivery and the strategies for addressing them are also discussed. Finally, we provide our perspectives on future considerations and opportunities for applying mRNA vaccines to fight against major infectious diseases and cancers. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Biology-Inspired Nanomaterials > Lipid-Based Structures.

Protective effect of coix seed seedling extract on 60 Co-γ radiation-induced oxidative stress in mice.

Exposure to ionizing radiation (IR) can cause oxidative damage to human body, leading to various diseases and even death. In this study, the potential radioprotective effect of coix seed seedling extract (CSS-E) was studied through a model of 60 Co-γ radiation-induced oxidative stress in mice. Overall radioprotective effect of CSS-E against radiation-induced damage was evaluated by biochemical analysis and histopathological analysis. The results showed that CSS-E could significantly reduce the IR-induced damage to the hematopoietic system. CSS-E-M (200 mg/kg BW) pretreatment could increase the activities of superoxide dismutase in serum, liver, and spleen increased by 31.68%, 45.10%, and 56.67%, respectively, and the glutathione peroxidase levels in serum, liver, and spleen of mice were improved by 19.17%, 41.97%, and 130.56%, respectively. Meanwhile, the glutathione levels of serum, liver, and spleen in CSS-E-M group were increased by 17.10%, 35.06%, and 40.71%, respectively. The contents of MDA in different tissues and serum could be reduced by CSS-E-M treatment to the normal level. Moreover, CSS-E could markedly reduce the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in radiation mice, among which CSS-E-M group showed maximum restoration with decreased AST and ALT levels by 20.13% and 32.76% as compared against IR group. In conclusion, these results indicated that CSS-E could be used as a potential natural radioprotectant against IR-induced damage.

60Coγ induction improves the protective effect of Acetobacter pasteurianus against ionizing radiation in mice.

Exposure to ionizing radiation (IR) tends to cause serious health concerns. Thus, radioprotective agents are vital for the population exposed to radiation. As microorganisms have the advantages of fast reproduction and no geographical restrictions, direct microbe-based and environmental induction compounds are thriving radioprotectants resources. Oxidative system and oxidase in Acetobacter pasteurianus are unique and intriguing, the radioprotective effect of the cell-free extract from A. pasteurianus (APE) and 60Coγ-treated extract (IRE) were comparatively investigated in the present study. The survival rate of A. pasteurianus with IRE addition was 149.1% in H2O2 damage test, while that with APE was only 10.4%. The viability of 60Coγ-treated AML-12 cells was increased by 18.8% with IRE addition, yet APE showed no significant radioprotective effect. Moreover, in 60Coγ-treated mice, IRE could significantly protect the white blood cell, improve the liver index, and attenuate the injuries of immune organs in mice. Administration of IRE significantly raised the activities of superoxide dismutase (SOD) and reduced the products of lipid peroxidation. These results clarified that gavage with APE and IRE presented notable antioxidant and radioprotective efficacy. A. pasteurianus showed appealing potential to be novel radioprotective bioagents and 60Coγ treatment on microbe could be a new method for the development of better radioprotectant. KEY POINTS: • 60Coγ induction could improve the radioprotective effect of APE. • IRE protected white blood cell in mice under IR. • IRE products have broad application prospects in radioprotection based on microbes.

Radioprotective effect of radiation-induced Lactococcus lactis cell-free extract against 60Coγ injury in mice.

Ionizing radiation (IR) is widely used in the diagnosis and treatment of various cancers. However, IR can cause damage to human health by producing reactive oxygen species. Lactococcus lactis is a type of microorganism that is beneficial to human health and has a strong antioxidant capacity. In this study, the protective effect of normal and IR-induced L. lactis IL1403 cell-free extracts (CFE and IR-CFE, respectively) against oxidative damage in vitro and the radioprotective effect of IR-CFE in vivo was evaluated using 60Coγ-induced oxidative damage model in mice. Results showed that IR-CFE exhibited a stronger oxidative damage-protective effect than CFE for L. lactis IL1403 under H2O2 in vitro. Moreover, IR-CFE also showed strong radioprotective effect on hepatocyte cells (AML-12) under radiation condition, and the effect was better than that of CFE. Animal experiment indicated that IR-CFE could reduce the IR-induced damage to the hematopoietic system by increasing the number of white blood cells and red blood cells in peripheral blood of irradiated mice. It was also observed that IR-CFE could markedly alleviate the 60Coγ-induced oxidative stress via increasing the activities of superoxide dismutase and glutathione peroxidase, enhancing the levels of glutathione, and decreasing the contents of malondialdehyde in serum, liver, and spleen. In addition, IR-CFE also could reduce the activities of alanine transaminase and aspartate aminotransferase in serum, thereby reducing radiation damage to the liver. These results suggested that IR-CFE could be considered as potential candidates for natural radioprotective agents. This study provides a theoretical basis for improving the application of lactic acid bacteria.

Potential of natural products as radioprotectors and radiosensitizers: opportunities and challenges.

Natural products can be used as natural radiosensitizers and radioprotectors, showing promising effects in cancer treatments in combination with radiotherapy, while reducing ionizing radiation (IR) damage to normal cells/tissues. The different effects of natural products on irradiated normal and tumor cells/tissues have attracted more and more researchers' interest. Nonetheless, the clinical applications of natural products in radiotherapy are few, which may be related to their low bioavailability in the human body. Here, we displayed the radiation protection and radiation sensitization of major natural products, highlighted the related molecular mechanisms of these bioactive substances combined with radiotherapy to treat cancer, and critically reviewed their deficiency and improved measures. Lastly, several clinical trials were presented to verify the clinical application of natural products as radiosensitizers and radioprotectors. Further clinical evaluation is still needed. This review provides a reference for the utilization of natural products as radiosensitizers and radioprotectors.

Comparative study on the bioactive components and in vitro biological activities of three green seedlings.

To explore functional food ingredients from green seedlings, the bioactive components (phenolic compounds and γ-aminobutyric acid) and antioxidant activities (DPPH radical scavenging ability, ABTS radical scavenging ability and reducing power) of three green seedlings, including coix seed seedling (CSS), highland barely seedling (HBS) and naked oats seedling (NOS) cultivars were respectively measured and deeply compared. Results indicated that CSS showed the highest contents of the total polyphenol (183.35 mg/100 g), total flavonoid (348.68 mg/100 g), and γ-aminobutyric acid (54.17 mg/100 g). As expected, CSS also exerted the highest level of antioxidant activity, followed by HBS and NOS. Moreover, CSS possessed the potential of stimulating immune responses, including promoting proliferation and strengthening phagocytosis function of RAW264.7 cells. Taken together, all results suggested that the three green seedlings, especially CSS could be used as natural ingredients for functional food.

Coordinated targeting of CK2 and KIT in gastrointestinal stromal tumours.

BACKGROUND: Most gastrointestinal stromal tumours (GIST) are driven by activating oncogenic mutations of KIT/PDGFRA, which provide a compelling therapeutic target. Our previous studies showed that CDC37, regulated by casein kinase 2 (CK2), is a crucial HSP90 cofactor for KIT oncogenic function and a promising and more selective therapeutic target in GIST. METHODS: Biologic mechanisms of CK2-mediated CDC37 regulation were assessed in GISTs by immunoblotting, immunoprecipitations, knockdown and inactivation assays. The effects of a combination of KIT and CK2 inhibition were assessed by immunoblotting, cell viability, colony growth, cell cycle analysis, apoptosis, migration and invasiveness. RESULTS: CK2 overexpression was demonstrated by immunoblotting in GIST cell lines and patient biopsies. Treatment with a specific CK2 inhibitor, CX4945, leads to CDC37 dephosphorylation and inhibits KIT signalling in imatinib-sensitive and in imatinib-resistant GIST cell lines. Immunoprecipitation demonstrated that CK2 inhibition blocks KIT:HSP90:CDC37 interaction in GIST cells. Coordinated inhibition of CK2 and KIT by CX4945 (or CK2 shRNA) and imatinib, respectively, leads to increased apoptosis, anti-proliferative effects and cell cycle arrest and decreased p-AKT and p-S6 expression, migration and invasiveness in all GIST cell lines compared with either intervention alone, indicating additive effects of inhibiting these two important regulators of GIST biology. CONCLUSION: Our findings suggest that combinatorial inhibition of CK2 and KIT warrants evaluation as a novel therapeutic strategy in GIST, especially in imatinib-resistant GIST.

NLRC5 deficiency protects against acute kidney injury in mice by mediating carcinoembryonic antigen-related cell adhesion molecule 1 signaling.

There is significant progress in understanding the structure and function of NLRC5, a member of the nucleotide oligomerization domain-like receptor family. However, in the context of MHC class I gene expression, the functions of NLRC5 in innate and adaptive immune responses beyond the regulation of MHC class I genes remain controversial and unresolved. In particular, the role of NLRC5 in the kidney is unknown. NLRC5 was significantly upregulated in the kidney from mice with renal ischemia/reperfusion injury. NLRC5 deficient mice significantly ameliorated renal injury as evidenced by decreased serum creatinine levels, improved morphological injuries, and reduced inflammatory responses versus wild type mice. Similar protective effects were also observed in cisplatin-induced acute kidney injury. Mechanistically, NLRC5 contributed to renal injury by promoting tubular epithelial cell apoptosis and reducing inflammatory responses were, at least in part, associated with the negative regulation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). To determine the relative contribution of NLRC5 expression by parenchymal cells or leukocytes to renal damage during ischemia/reperfusion injury, we generated bone marrow chimeric mice. NLRC5 deficient mice engrafted with wild type hematopoietic cells had significantly lower serum creatinine and less tubular damage than wild type mice reconstituted with NLRC5 deficient bone marrow. This suggests that NLRC5 signaling in renal parenchymal cells plays the dominant role in mediating renal damage. Thus, modulation of the NLRC5-mediated pathway may have important therapeutic implications for patients with acute kidney injury.

ß-Arrestin-1 deficiency ameliorates renal interstitial fibrosis by blocking Wnt1/ß-catenin signaling in mice.

Despite substantial progress being made in understanding the mechanisms contributing to the pathogenesis of renal fibrosis, there are only a few therapies available to treat or prevent renal fibrosis in clinical use today. Therefore, identifying the key cellular and molecular mediators involved in the pathogenesis of renal fibrosis will provide new therapeutic strategy for treating patients with chronic kidney disease (CKD). ß-Arrestin-1, a member of ß-arrestin family, not only is a negative adaptor of G protein-coupled receptors (GPCRs), but also acts as a scaffold protein and regulates a diverse array of cellular functions independent of GPCR activation. In this study, we identified for the first time that ß-arrestin-1 was upregulated in the kidney from mice with unilateral ureteral obstruction nephropathy as well as in the paraffin-embedded sections of human kidneys from the patients with diabetic nephropathy, polycystic kidney, or uronephrosis, which normally causes renal fibrosis. Deficiency of ß-arrestin-1 in mice significantly alleviated renal fibrosis by the regulation of inflammatory responses, kidney fibroblast activation, and epithelial-mesenchymal transition (EMT) in both in vivo and in vitro studies. Furthermore, we found that among the major isoforms of Wnts, Wnt1 was regulated by ß-arrestin-1 and gene silencing of Wnt1 inhibited the activation of ß-catenin and suppressed ß-arrestin-1-mediated renal fibrosis. Collectively, our results indicate that ß-arrestin-1 is one of the critical components of signal transduction pathways in the development of renal fibrosis. Modulation of these pathways may be an innovative therapeutic strategy for treating patients with renal fibrosis. KEY MESSAGES: ß-Arrestin-1 was upregulated in the kidney from mice with UUO nephropathy. ß-Arrestin-1 regulated kidney fibroblast activation and epithelial-mesenchymal transition. ß-Arrestin-1 exacerbated renal fibrosis via mediating Wnt1/ß-catenin signaling.

HDACi inhibits liposarcoma via targeting of the MDM2-p53 signaling axis and PTEN, irrespective of p53 mutational status.

The MDM2-p53 pathway plays a prominent role in well-differentiated liposarcoma (LPS) pathogenesis. Here, we explore the importance of MDM2 amplification and p53 mutation in LPS independently, to determine whether HDACi are therapeutically useful in LPS. We demonstrated that simultaneous knockdown of MDM2 and p53 in p53-mutant LPS lines resulted in increased apoptosis, anti-proliferative effects, and cell cycle arrest, as compared to either intervention alone. HDACi treatment resulted in the dephosphorylation and depletion of MDM2 and p53 without affecting CDK4 and JUN expression, irrespective of p53 mutational status in MDM2-amplified LPS. In control mesothelioma cell lines, HDACi treatment resulted in down-regulation of p53 in the p53 mutant cell line JMN1B, but resulted in no changes of MDM2 and p53 in two mesothelioma lines with normal MDM2 and wild-type p53. HDACi treatment substantially decreased LPS and mesothelioma proliferation and survival, and was associated with upregulation of PTEN and p21, and inactivation of AKT. Our findings indicate that wild-type p53 depletion by HDACi is MDM2 amplification-dependent. These findings underscore the importance of targeting both MDM2 and p53 in LPS and other cancers harboring p53 mutations. Moreover, the pro-apoptotic and anti-proliferative effect of HDACi warrants further evaluation as a therapeutic strategy in MDM2-amplified LPS.