Angiogenesis-related lncRNAs index: A predictor for CESC prognosis, immunotherapy efficacy, and chemosensitivity.

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) is a common gynecologic tumor and patients with advanced and recurrent disease usually have a poor clinical outcome. Angiogenesis is involved in the biological processes of tumors and can promote tumor growth and invasion. In this paper, we created a signature for predicting prognosis based on angiogenesis-related lncRNAs (ARLs). This provides a prospective direction for enhancing the efficacy of immunotherapy in CESC patients. We screened seven OS-related ARLs by univariate and multivariate regression analyses and Lasso analysis and developed a prognostic signature at the same time. Then, we performed an internal validation in the TCGA-CESC cohort to increase the precision of the study. In addition, we performed a series of analyses based on ARLs, including immune cell infiltration, immune function, immune checkpoint, tumor mutation load, and drug sensitivity analysis. Our created signature based on ARLs can effectively predict the prognosis of CESC patients. To strengthen the prediction accuracy of the signature, we built a nomogram by combining signature and clinical features.

Unraveling the role of the circadian clock genes in cervical squamous cell carcinoma and endocervical adenocarcinoma: A prognostic indicator for prognostic, immunotherapy response, and chemotherapy sensitivity.

Background: Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) account for a significant proportion of gynecological malignancies and represent a major global health concern. Globally, CESC is ranked as the fourth most common cancer among women. Conventional treatment of this disease has a less favorable prognosis for most patients. However, the discovery of early molecular biomarkers is therefore important for the diagnosis of CESC, as well as for slowing down their progression process. Methods: To identify differentially expressed genes strongly associated with prognosis, univariate Cox proportional hazard analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were used. Using multiple Cox proportional hazard regression, a multifactorial model for prognostic risk assessment was then created. Results: The expression of biological clock-related genes, which varied considerably among distinct subtypes and were associated with significantly diverse prognoses, was used to categorize CESC patients. These findings demonstrate how the nomogram developed based on the 7-CRGs signature may assist physicians in creating more precise, accurate, and successful treatment plans that can aid CESC patients at 1, 3, and 5 years. Conclusions: By using machine learning techniques, we thoroughly investigated the impact of CRGs on the prognosis of CESC patients in this study. By creating a unique nomogram, we were able to accurately predict patient prognosis. At the same time, we showed new perspectives on the development of CESC and its treatment by analyzing the associations of the prognostic model with immunity, enrichment pathways, chemotherapy sensitivity, and so on. This research provides a new direction for clinical treatment.

Uncovering the Impact of Aggrephagy in the Development of Alzheimer's Disease: Insights Into Diagnostic and Therapeutic Approaches from Machine Learning Analysis.

BACKGROUND: Alzheimer's disease (AD) stands as a widespread neurodegenerative disorder marked by the gradual onset of memory impairment, predominantly impacting the elderly. With projections indicating a substantial surge in AD diagnoses, exceeding 13.8 million individuals by 2050, there arises an urgent imperative to discern novel biomarkers for AD. METHODS: To accomplish these objectives, we explored immune cell infiltration and the expression patterns of immune cells and immune function-related genes of AD patients. Furthermore, we utilized the consensus clustering method combined with aggrephagy-related genes (ARGs) for typing AD patients and categorized AD specimens into distinct clusters (C1, C2). A total of 272 candidate genes were meticulously identified through a combination of differential analysis and Weighted Gene Co-Expression Network Analysis (WGCNA). Subsequently, we applied three machine learning algorithms-namely random forest (RF), support vector machine (SVM), and generalized linear model (GLM)-to pinpoint a pathogenic signature comprising five genes associated with AD. To validate the predictive accuracy of these identified genes in discerning AD progression, we constructed nomograms. RESULTS: Our analyses uncovered that cluster C2 exhibits a higher immune expression than C1. Based on the ROC(0.956). We identified five characteristic genes (PFKFB4, PDK3, KIAA0319L, CEBPD, and PHC2T) associated with AD immune cells and function. The nomograms constructed on the basis of these five diagnostic genes demonstrated effectiveness. In the validation group, the ROC values were found to be 0.760 and 0.838, respectively. These results validate the robustness and reliability of the diagnostic model, affirming its potential for accurate identification of AD. CONCLUSION: Our findings not only contribute to a deeper understanding of the molecular mechanisms underlying AD but also offer valuable insights for drug development and clinical analysis. The limitation of our study is the limited sample size, and although AD-related genes were identified and some of the mechanisms elucidated, further experiments are needed to elucidate the more in-depth mechanisms of these characterized genes in the disease.

Platelet-membrane camouflaged cerium nanoparticle-embedded gelatin methacryloyl hydrogel for accelerated diabetic wound healing.

Impaired angiogenesis and excessive inflammation are major factors contributing to delayed wound healing in diabetic patients. This study presents the development of a novel multifunctional hydrogel, Pltm@CNPs/Gel, which incorporates platelet membrane camouflaged cerium nanoparticles into a gelatin methacryloyl matrix. The Pltm@CNPs/Gel nanocomposite hydrogel was characterized and tested for its effects on platelet activation, coagulation, cell viability, anti-oxidation, and anti-inflammation in vitro. Moreover, we evaluated the wound healing potential of the hydrogel in a diabetic rat model. Our findings demonstrate that the Pltm@CNPs/Gel hydrogel possesses anti-oxidative and anti-inflammatory properties. Furthermore, it accelerates diabetic wound healing by promoting neovascularization, cell proliferation, and collagen fiber organization. This study highlights the potential of the Pltm@CNPs/Gel hydrogel as a therapeutic option for diabetic wound healing and its promising applications as a diabetic wound dressing candidate.

Effects of Solid Fermentation on Polygonatum cyrtonema Polysaccharides: Isolation, Characterization and Bioactivities.

Polygonati Rhizoma is a widely used traditional Chinese medicine (TCM) with complex pre-processing steps. Fermentation is a common method for processing TCM to reduce herb toxicity and enhance their properties and/or produce new effects. Here, in this study, using Bacillus subtilis and Saccharomyces cerevisiae, we aimed to evaluate the potential application of solid fermentation in isolating different functional polysaccharides from Polygonatum cyrtonema Hua. With hot water extraction, ethanol precipitation, DEAE anion exchange chromatography and gel filtration, multiple neutral and acidic polysaccharides were obtained, showing different yields, content, compositions and functional groups after fermentation. Combining in vitro experiments and in vivo aging and immunosuppressed mouse models, we further compared the antioxidant and immunomodulating bioactivities of these polysaccharides and found a prominent role of a natural polysaccharide (BNP) from fermented P. cyrtonema via Bacillus subtilis in regulating intestinal antioxidant defense and immune function, which may be a consequence of the ability of BNP to modulate the homeostasis of gut microbiota. Thus, this work provides evidence for the further development and utilization of P. cyrtonema with fermentation, and reveals the potential values of BNP in the treatment of intestinal disorders.

Bioengineered stem cell membrane functionalized nanoparticles combine anti-inflammatory and antimicrobial properties for sepsis treatment.

BACKGROUND: Sepsis is a syndrome of physiological, pathological and biochemical abnormalities caused by infection. Although the mortality rate is lower than before, many survivors have persistent infection, which means sepsis calls for new treatment. After infection, inflammatory mediators were largely released into the blood, leading to multiple organ dysfunction. Therefore, anti-infection and anti-inflammation are critical issues in sepsis management. RESULTS: Here, we successfully constructed a novel nanometer drug loading system for sepsis management, FZ/MER-AgMOF@Bm. The nanoparticles were modified with LPS-treated bone marrow mesenchymal stem cell (BMSC) membrane, and silver metal organic framework (AgMOF) was used as the nanocore for loading FPS-ZM1 and meropenem which was delivery to the infectious microenvironments (IMEs) to exert dual anti-inflammatory and antibacterial effects. FZ/MER-AgMOF@Bm effectively alleviated excessive inflammatory response and eliminated bacteria. FZ/MER-AgMOF@Bm also played an anti-inflammatory role by promoting the polarization of macrophages to M2. When sepsis induced by cecal ligation and puncture (CLP) challenged mice was treated, FZ/MER-AgMOF@Bm could not only reduce the levels of pro-inflammatory factors and lung injury, but also help to improve hypothermia caused by septic shock and prolong survival time. CONCLUSIONS: Together, the nanoparticles played a role in combined anti-inflammatory and antimicrobial properties, alleviating cytokine storm and protecting vital organ functions, could be a potential new strategy for sepsis management.

Study on the Role of an Erythrocyte Membrane-Coated Nanotheranostic System in Targeted Immune Regulation of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in the elderly population. Despite significant advances in studies of the pathobiology on AD, there is still no effective treatment. Here, an erythrocyte membrane-camouflaged nanodrug delivery system (TR-ZRA) modified with transferrin receptor aptamers that can be targeted across the blood-brain barrier to ameliorate AD immune environment is established. Based on metal-organic framework (Zn-CA), TR-ZRA is loaded with CD22shRNA plasmid to silence the abnormally high expression molecule CD22 in aging microglia. Most importantly, TR-ZRA can enhance the ability of microglia to phagocytose Aß and alleviate complement activation, which can promote neuronal activity and decrease inflammation level in the AD brain. Moreover, TR-ZRA is also loaded with Aß aptamers, which allow rapid and low-cost monitoring of Aß plaques in vitro. After treatment with TR-ZRA, learning, and memory abilities are enhanced in AD mice. In conclusion, the biomimetic delivery nanosystem TR-ZRA in this study provides a promising strategy and novel immune targets for AD therapy.

An Aggrephagy-Related LncRNA Signature for the Prognosis of Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is a common, highly malignant, and aggressive gastrointestinal tumor. The conventional treatment of PAAD shows poor results, and patients have poor prognosis. The synthesis and degradation of proteins are essential for the occurrence and development of tumors. Aggrephagy is a type of autophagy that selectively degrades aggregated proteins. It decreases the formation of aggregates by degrading proteins, thus reducing the harm to cells. By breaking down proteins, it decreases the formation of aggregates; thus, minimizing damage to cells. For evaluating the response to immunotherapy and prognosis in PAAD patients, in this study, we developed a reliable signature based on aggrephagy-related genes (ARGs). We obtained 298 AGGLncRNAs. Based on the results of one-way Cox and LASSO analyses, the lncRNA signature was constructed. In the risk model, the prognosis of patients in the low-risk group was noticeably better than that of the patients in the high-risk group. Additionally, the ROC curves and nomograms validated the capacity of the risk model to predict the prognosis of PAAD. The patients in the low-risk and high-risk groups showed considerable variations in functional enrichment and immunological analysis. Regarding drug sensitivity, the low-risk and high-risk groups had different half-maximal inhibitory concentrations (IC50).

Simiao pill inhibits epithelial mesenchymal transition in a mouse model of chronic hyperuricemic nephropathy by inhibiting NLRP3 inflammasome activation.

BACKGROUND: Simiao pill module (SMM), a traditional Chinese medicine formula, has been widely used to treat gout and gouty arthritis. The goal of this study was to investigate the effects of SMM on epithelial-mesenchymal transition (EMT) and activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome in a mouse model of potassium oxonate (PO)-induced chronic hyperuricemic nephropathy (HN). METHODS: Mice were randomly divided into the following four groups: control, HN model (PO), febuxostat (FEB)-treated (PO + FEB), and SMM-treated (PO + SMM) groups. Following 6 weeks of treatment, blood samples were collected and mice were sacrificed to collect kidney samples to study the biochemical parameters associated with renal function and histopathological changes associated with HN, respectively. The samples were analyzed for the expression of markers of EMT (collagen type 3, α-smooth muscle actin [α-SMA], fibronectin, vimentin and E-cadherin) and activation of NLRP3 inflammasome (NLRP3, apoptosis-associated speck-like protein [ASC], caspase-1, interleukin [IL]-1ß, and IL-18). RESULTS: Our results showed that hyperuricemia, impaired kidney function, and renal pathological characteristics induced by PO treatment were improved following treatment with SMM and FEB. Additionally, treatment with SMM and FEB decreased the expression of vimentin, collagen 3, fibronectin, and α-SMA, and increased the expression of E-cadherin. Moreover, NLRP3 inflammasome activation, as assessed by the increased expression of NLRP3, ASC, and caspase-1, and secretion of IL-1ß and IL-18, was inhibited by treatment with SMM and FEB. CONCLUSION: These results suggest that SMM inhibited EMT and NLRP3 inflammasome activation in chronic HN mice, and the beneficial effect of SMM was compared with a standard drug, FEB.

Multi-center Retrospective Study of Factors Affecting Perioperative Transfusion of Packed Red Blood Cells for Pelvic Fracture Patients.

OBJECTIVE: To analyze the use of packed red blood cells (PRBCs) for patients with pelvic fracture and evaluate factors associated with PRBC transfusion for patients with pelvic fracture. METHODS: This retrospective cohort study collected 551 patients with pelvic fractures from six hospitals between September 1, 2012, and June 31, 2019. The age span of patients varied from 10 to 95 years old, and they were classified into two groups based on high-energy pelvic fractures (HE-PFs) or low-energy pelvic fractures (LE-PFs). The study's outcome was the use of PRBCs, fresh frozen plasma (FFP), and albumin. Demographic data, characteristics, laboratory tests, clinical treatment details, and clinical outcomes were compared between the two groups. Factors that were statistically associated with perioperative PRBCs in univariate analyses were included to conduct an optimal scale regression to determine the independent factors for perioperative PRBCs. RESULTS: A total of 551 patients were screened from six hospitals, and after inclusion and exclusion, 319 were finally included and finished the follow-up from admission to discharge, while four patients died during hospitalization. Three hundred and nineteen patients were classified into two groups by their injury mechanisms. A total of 230/319 (72.1%) patients were classified into the HE-PF group, and 89/319 (27.8%) patients were classified into the LE-PF group. Patients in the HE-PF group were transfused with 4.5 (3-8) units of PRBCs, 300 (0-600) ml of FFP, and 0 (0-30) g of albumin, while patients in the LE-PF group were transfused with 3.5 (2-4.5) units of PRBCs, 0 (0-295) ml of FFP, and 0 (0-0) g of albumin (all P < 0.001). There were higher proportions of male patients and patients under 65 in the HE-PF group (all P < 0.001). HE-PF group patients were more severely injured and likely to take external fixation. The optimal scale regression revealed four significant factors associated with perioperative transfused PRBCs, which were patients on admission with hemorrhagic shock (importance = 0.283, P = 0.004), followed by fracture types identified by Tile classification (importance = 0.156, P < 0.001), hemoglobin levels below 70 g/L on admission (importance = 0.283, P = 0.004), followed by fracture types identified by Tile classification (importance = 0.156, P < 0.001), hemoglobin levels below 70 g/L on admission (importance = 0.148, P = 0.039), and methods of pelvic fixation (importance = 0.008, P = 0.026), ranked by the importance. CONCLUSION: Patients with HE-PFs had increased transfusions of PRBCs, FFP, and albumin, and hemorrhagic shock on admission, Tile classification, Hb levels, and stabilization methods were found to be associated with perioperative PRBCs.

Ability of a Machine Learning Algorithm to Predict the Need for Perioperative Red Blood Cells Transfusion in Pelvic Fracture Patients: A Multicenter Cohort Study in China.

Background: Predicting the perioperative requirement for red blood cells (RBCs) transfusion in patients with the pelvic fracture may be challenging. In this study, we constructed a perioperative RBCs transfusion predictive model (ternary classifications) based on a machine learning algorithm. Materials and Methods: This study included perioperative adult patients with pelvic trauma hospitalized across six Chinese centers between September 2012 and June 2019. An extreme gradient boosting (XGBoost) algorithm was used to predict the need for perioperative RBCs transfusion, with data being split into training test (80%), which was subjected to 5-fold cross-validation, and test set (20%). The ability of the predictive transfusion model was compared with blood preparation based on surgeons' experience and other predictive models, including random forest, gradient boosting decision tree, K-nearest neighbor, logistic regression, and Gaussian naïve Bayes classifier models. Data of 33 patients from one of the hospitals were prospectively collected for model validation. Results: Among 510 patients, 192 (37.65%) have not received any perioperative RBCs transfusion, 127 (24.90%) received less-transfusion (RBCs < 4U), and 191 (37.45%) received more-transfusion (RBCs ≥ 4U). Machine learning-based transfusion predictive model produced the best performance with the accuracy of 83.34%, and Kappa coefficient of 0.7967 compared with other methods (blood preparation based on surgeons' experience with the accuracy of 65.94%, and Kappa coefficient of 0.5704; the random forest method with an accuracy of 82.35%, and Kappa coefficient of 0.7858; the gradient boosting decision tree with an accuracy of 79.41%, and Kappa coefficient of 0.7742; the K-nearest neighbor with an accuracy of 53.92%, and Kappa coefficient of 0.3341). In the prospective dataset, it also had a food performance with accuracy 81.82%. Conclusion: This multicenter retrospective cohort study described the construction of an accurate model that could predict perioperative RBCs transfusion in patients with pelvic fractures.

Zirconia Nanoparticles Induce HeLa Cell Death Through Mitochondrial Apoptosis and Autophagy Pathways Mediated by ROS.

Zirconia nanoparticles (ZrO2 NPs) are commonly used in the field of biomedical materials, but their antitumor activity and mechanism is unclear. Herein, we evaluated the anti-tumor activity of ZrO2 NPs and explored the anti-tumor mechanism. The results of in vitro and in vivo experiments showed that the level of intracellular reactive oxygen species (ROS) in HeLa cells was elevated after ZrO2 NPs treatment. Transmission electron microscopy (TEM) showed that after treatment with ZrO2 NPs, the mitochondria of HeLa cells were swollen, accompanied with the induction of autophagic vacuoles. In addition, flow cytometry analysis showed that the apoptotic rate of HeLa cells increased significantly by Annexin staining after treatment with ZrO2 NPs, and the mitochondrial membrane potential (MMP) was reduced significantly. The proliferation of HeLa cells decreased as indicated by reduced Ki-67 labeling. In contrast, TUNEL-positive cells in tumor tissues increased after treatment with ZrO2 NPs, which is accompanied by increased expression of mitochondrial apoptotic proteins including Bax, Caspase-3, Caspase-9, and Cytochrome C (Cyt C) and increased expression of autophagy-related proteins including Atg5, Atg12, Beclin-1, and LC3-II. Treating HeLa cells with N-acetyl-L-cysteine (NAC) significantly reduced ROS, rate of apoptosis, MMP, and in vivo anti-tumor activity. In addition, apoptosis- and autophagy-related protein expressions were also suppressed. Based on these observations, we conclude that ZrO2 NPs induce HeLa cell death through ROS mediated mitochondrial apoptosis and autophagy.

Construction of homologous cancer cell membrane camouflage in a nano-drug delivery system for the treatment of lymphoma.

BACKGROUND: Non-Hodgkin's lymphoma (NHL) possesses great heterogeneity in cytogenetics, immunophenotype and clinical features, and chemotherapy currently serves as the main treatment modality. Although employing monoclonal antibody targeted drugs has significantly improved its overall efficacy, various patients continue to suffer from drug resistance or recurrence. Chinese medicine has long been used in the treatment of malignant tumors. Therefore, we constructed a low pH value sensitivity drug delivery system based on the cancer cell membrane modified mesoporous silica nanoparticles loaded with traditional Chinese medicine, which can reduce systemic toxicity and improve the therapeutic effect for the targeted drug delivery of tumor cells. RESULTS: Accordingly, this study put forward the construction of a nano-platform based on mesoporous silica nanoparticles (MSNs) loaded with the traditional Chinese medicine isoimperatorin (ISOIM), which was camouflaged by the cancer cell membrane (CCM) called CCM@MSNs-ISOIM. The proposed nano-platform has characteristics of immune escape, anti-phagocytosis, high drug loading rate, low pH value sensitivity, good biocompatibility and active targeting of the tumor site, blocking the lymphoma cell cycle and promoting mitochondrial-mediated apoptosis. CONCLUSIONS: Furthermore, this study provides a theoretical basis in finding novel clinical treatments for lymphoma.

Construction of biomimetic silver nanoparticles in the treatment of lymphoma.

Lymphoma is a well-known malignant tumor in the human body. Although many anticancer drugs have been developed to improve the survival rate of patients, about 40% of patients continue to be recurrent or refractory, a key issue needing remedy. Therefore, it is necessary to identify alternative treatments to reduce the disease's mortality. To this effect, a new type of anti-lymphoma nanocomplex FA@RBCm-AgNPs was prepared using AgNPs as the core of nanoparticles along with the targeting molecule folic acid inserted erythrocyte membrane as the shell. The biomimetic properties of red blood cell membrane (RBCm) endow F-RAN with good biocompatibility as well as the ability to evade clearance of the reticuloendothelial system. In addition, F-RAN was modified with folic acid to actively and selectively identify tumor cells. In vivo and in vitro experiments demonstrate that F-RAN can inhibit lymphoma cells and induce apoptosis of stem cells while promoting apoptosis of lymphoma with no obvious side effects. Hence, F-RAN may serve as a new treatment for lymphoma.

A Nano-Traditional Chinese Medicine Against Lymphoma That Regulates the Level of Reactive Oxygen Species.

Jolkinolide B (JB) is a bioactive compound isolated from a Chinese herbal medicine that exerts antitumor activity. However, the anti-lymphoma effect of JB and its mechanism are yet to be revealed. Because free JB has poor pharmacokinetics and weak antitumor efficacy, we opted to use black phosphorus quantum dot (BPQD) nanomaterials as a drug loading platform to synthesize a nano-traditional Chinese medicine (nano-TCM) called BPQDs@JB. Compared with free JB, Raji cells administrated with BPQDs@JB exhibited the cell viability of 19.85 ± 1.02%, and the production of intracellular reactive oxygen species (ROS) was promoted. Likewise, BPQDs@JB was capable of rising the apoptosis rate of Raji cells to 34.98 ± 1.76%. In nude mice transplanted tumor model administrated with BPQDs@JB, the tumor tissue sections administrated with BPQDS@JB achieved a conspicuous red fluorescence, demonstrating the presence of most ROS production in the BPQDS@JB. TUNEL achieved a number of positive (brown) nuclei in vivo, revealing that BPQDS@JB could significantly induce tumor tissue apoptosis. As revealed from the mentioned results, BPQDs@JB can generate considerable ROS and interfere with the redox state to inhibit tumor. In brief, BPQDs@JB may be adopted as a treatment option for lymphoma.

Platelet-Membrane-Camouflaged Zirconia Nanoparticles Inhibit the Invasion and Metastasis of Hela Cells.

Zirconia nanoparticles (ZrO2 NPs) are widely applied in the field of biomedicine. In this study, we constructed a nanoplatform of ZrO2 NPs coated with a platelet membrane (PLTm), named PLT@ZrO2. PLTm nanovesicles camouflage ZrO2 NPs, prevent nanoparticles from being cleared by macrophage, and target tumor sites. Compared to ZrO2 alone, PLT@ZrO2 is better at inhibiting the invasion and metastasis of Hela cells in vitro and in vivo. In vitro, PLT@ZrO2 inhibited the growth and proliferation of Hela cells. Scratch-wound healing recovery assay demonstrated that PLT@ZrO2 inhibited Hela cells migration. Transwell migration and invasion assays showed that PLT@ZrO2 inhibited Hela cells migration and invasion. In vivo, PLT@ZrO2 inhibited the tumor growth of Xenograft mice and inhibited the lung and liver metastasis of Hela cells. Immunofluorescence and Western blotting results showed that anti-metastasis protein (E-cadherin) was upregulated and pro-metastasis proteins (N-cadherin, Smad4, Vimentin, E-cadherin,ß-catenin, Fibronectin, Snail, Slug, MMP2, Smad2) were down-regulated. Our study indicated that PLT@ZrO2 significantly inhibits tumor growth, invasion, and metastasis.

Smart Biomimetic Nanocomposites Mediate Mitochondrial Outcome through Aerobic Glycolysis Reprogramming: A Promising Treatment for Lymphoma.

Toxicity and drug resistance caused by chemotherapeutic drugs have become bottlenecks in treating tumors. The delivery of anticancer drugs based on nanocarriers is regarded as an ideal way to solve the aforementioned problems. In this study, a new antilymphoma nanodrug CD20 aptamer-RBCm@Ag-MOFs/PFK15 (A-RAMP) is designed and constructed, and it consists of two parts: (1) metal-organic frameworks Ag-MOFs (AM) loaded with tumor aerobic glycolysis inhibitor PFK15 (P), forming a core part (AMP); (2) targeted molecule CD20 aptamer (A) is inserted into the red blood cell membrane (RBCm) to form the shell part (A-R). A-RAMP under the guidance of CD20 aptamer actively targets B-cell lymphoma both in vitro and in vivo. As a result, A-RAMP not only significantly inhibits the effect on tumor growth but also shows no obvious side effects on the treated nude mice, indicating that A-RAMP can accurately target tumor cells, reprogram aerobic glycolysis, and exert synergistic antitumor effect by Ag+ and PFK 15. Furthermore, the antitumor mechanism of A-RAMP in vivo by apoptotic pathway and targeting metabonomics are explored. These results suggest that A-RAMP has a promising application prospect as an smart, safe, effective, and synergistic antilymphoma agent.

The Acetone Indigo Red Dehydrating Agent IF203 Induces HepG2 Cell Death Through Cell Cycle Arrest, Autophagy and Apoptosis.

BACKGROUND: Isatin derivatives have extensive biological activities, such as antitumor. IF203, a novel isatin derivative, has not previously been reported to have antitumor activity. METHODS: Acid phosphatase assays (APAs) and Ki-67 immunohistochemistry were used to detect the proliferation of HepG2 cells. Transmission electron microscope (TEM) was applied to detect ultrastructural changes. Flow cytometry (FCM) was used to detect cell cycle, apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) of HepG2 cells in vitro. TUNEL, MMP and ROS immunofluorescence assays were applied to assess apoptosis, MMP, and ROS of HepG2 cells in vivo. Western Blotting was applied to assess the levels of apoptosis- and autophagy-related proteins. RESULTS: In this study, in vivo and in vitro experiments showed that IF203 possesses antitumor activity. The results of APAs and Ki-67 immunohistochemistry demonstrated that IF203 could inhibit the proliferation of HepG2 cells. Cell cycle assays, downregulation of Cyclin B1 and Cdc2, and upregulation of P53 suggested that IF203 could lead to G2/M cell cycle arrest. In addition, ultrastructural changes, apoptosis assays, TUNEL immunofluorescence results, upregulated expression of Bax, and downregulated expression of Bcl-2 suggest that IF203 can induce apoptosis in HepG2 cells. After IF203 treatment, intracellular ROS levels increased, MMP decreased, JC-1 green fluorescence was enhanced, and the levels of Caspase-9, Caspase-3 and Cytochrome C expression were upregulated, suggesting that IF203 could induce apoptosis of HepG2 cells through the mitochondrial apoptosis pathway. Moreover, characteristic apoptotic ultrastructural changes were accompanied by the appearance of many autophagy bubbles and upregulation of Atg5, Atg12, ULK1, Beclin-1 and LC3-II proteins, suggesting that IF203 could induce autophagy in HepG2 cells. CONCLUSION: This study showed that IF203 leads to the death of HepG2 cells through cell cycle arrest, apoptotic induction, and autophagy promotion.

Attenuation of diabetic cardiomyopathy by relying on kirenol to suppress inflammation in a diabetic rat model.

Diabetic cardiomyopathy is characterized by diabetes-induced myocardial abnormalities, accompanied by inflammatory response and alterations in inflammation-related signalling pathways. Kirenol, isolated from Herba Siegesbeckiae, has potent anti-inflammatory properties. In this study, we aimed to investigate the cardioprotective effect of kirenol against DCM and underlying the potential mechanisms in a type 2 diabetes mellitus model. Kirenol treatment significantly decreased high glucose-induced cardiofibroblasts proliferation and increased the cardiomyocytes viability, prevented the loss of mitochondrial membrane potential and further attenuated cardiomyocytes apoptosis, accompanied by a reduction in apoptosis-related protein expression. Kirenol gavage could affect the expression of pro-inflammatory cytokines in a dose-dependent manner but not lower lipid profiles, and only decrease fasting plasma glucose, fasting plasma insulin and mean HbA1c levels in high-dose kirenol-treated group at some time-points. Left ventricular dysfunction, hypertrophy, fibrosis and cell apoptosis, as structural and functional abnormalities, were ameliorated by kirenol administration. Moreover, in diabetic hearts, oral kirenol significantly attenuated activation of mitogen-activated protein kinase subfamily and nuclear translocation of NF-κB and Smad2/3 and decreased phosphorylation of IκBα and both fibrosis-related and apoptosis-related proteins. In an Electrophoretic mobility shift assay, the binding activities of NF-κB, Smad3/4, SP1 and AP-1 in the nucleus of diabetic myocardium were significantly down-regulated by kirenol treatment. Additionally, high dose significantly enhanced myocardial Akt phosphorylation without intraperitoneal injection of insulin. Kirenol may have potent cardioprotective effects on treating for the established diabetic cardiomyopathy, which involves the inhibition of inflammation and fibrosis-related signalling pathways and is independent of lowering hyperglycaemia, hyperinsulinemia and lipid profiles.

Establishment of the Normal Reference Range of Thrombelastogram among the Healthy Population and Pregnants in China.

BACKGROUND: We aimed to establish the reference range of thrombelastogram (TEG) for Chinese healthy volunteers and pregnant women and analyze the influence factors. METHODS: Blood samples were collected from healthy volunteers and pregnant women at five tertiary hospitals (the Third Xiangya Hospital of Central South University, the Second Xiangya Hospital of Central South University, Hunan Provincial People's Hospital, Hunan Cancer Hospital and Changsha Central Hospital) in 2016. The effects of age, gender, blood type, and full-term pregnancy on the reference range of normal TEG for healthy volunteers and pregnant women were studied. The specificity of TEG in detecting coagulation disorder. RESULTS: For healthy volunteers, the normal ranges of TEG parameters were as follows: R, 4.3-9.3 min; K, 1.2-3.2 min; α, 50.2-71.2°; MA, 54.1-71.3 mm; LY30: 0%-2.2%; CI, -3.8-2.4. At least one parameter exceeded the normal range specified by the manufacturer in 20.3% of the healthy volunteers; about 7.6% healthy volunteers were diagnosed as coagulation disorder by the above standards; the specificity of detection was 79.7%. There were significant differences in R, K, α, MA and CI between males and females (P<0.01). For pregnant women, the normal ranges of TEG were as follows: R, 3.9-7.5 min; K, 1.0-2.4 min; α, 57.6-74.9°; MA, 55.7-75.7 mm; LY30, 0%-0.56%; CI, -0.97-3.6. Pregnant women having O blood group had a dramatically prolonged R. Full-term pregnancy had no significant impact on TEG results. CONCLUSION: Compared with pregnant women having non-O blood group, those having O blood group had a dramatically prolonged R and showed greater tendency to hemorrhage during and after parturition.