TAT-beclin1 treatment accelerates the development of atherosclerotic lesions in ApoE-deficient mice.

The importance of autophagy in atherosclerosis has garnered significant attention regarding the potential applications of autophagy inducers. However, the impact of TAT-Beclin1, a peptide inducer of autophagy, on the development of atherosclerotic plaques remains unclear. Single-cell omics analysis indicates a notable reduction in GAPR1 levels within fibroblasts, stromal cells, and macrophages during atherosclerosis. Tat-beclin1 (T-B), an autophagy-inducing peptide derived from Beclin1, could selectively bind to GAPR1, relieving its inhibition on Beclin1 and thereby augmenting autophagosome formation. To investigate its impact on atherosclerosic plaque progression, we established the ApoE-/- mouse model of carotid atherosclerotic plaques. Surprisingly, intravenous administration of Tat-beclin1 dramatically accelerated the development of carotid artery plaques. Immunofluorescence analysis suggested that macrophage aggregation and autophagosome formation within atherosclerotic plaques were significantly increased upon T-B treatment. However, immunofluorescence and transmission electron microscopy (TEM) analysis revealed a reduction in autophagy flux through lysosomes. In vitro, the interaction between T-B and GAPR1 was confirmed in RAW264.7 cells, resulting in the increased accumulation of p62/SQSTM1 and LC3-II in the presence of ox-LDL. Additionally, T-B treatment elevated the protein levels of p62/SQSTM1, LC3-II, and cleaved caspase 1, along with the secretion of IL-1ß in response to ox-LDL exposure. In summary, our study underscores that T-B treatment amplifies abnormal autophagy and inflammation, consequently exacerbating atherosclerotic plaque development in ApoE-/- mice.

Backstepping Sliding Mode Control for Radar Seeker Servo System Considering Guidance and Control System.

This paper investigates the design of a missile seeker servo system combined with a guidance and control system. Firstly, a complete model containing a missile seeker servo system, missile guidance system, and missile control system (SGCS) was creatively proposed. Secondly, a designed high-order tracking differentiator (HTD) was used to estimate states of systems in real time, which guarantees the feasibility of the designed algorithm. To guarantee tracking precision and robustness, backstepping sliding-mode control was adopted. Aiming at the main problem of projectile motion disturbance, an adaptive radial basis function neural network (RBFNN) was proposed to compensate for disturbance. Adaptive RBFNN especially achieves online adjustment of residual error, which promotes estimation precision and eliminates the "chattering phenomenon". The boundedness of all signals, including estimation error of high-order tracking differentiator, was especially proved via the Lyapunov stability theory, which is more rigorous. Finally, in considered scenarios, line of sight angle (LOSA)-tracking simulations were carried out to verify the tracking performance, and a Monte Carlo miss-distance simulation is presented to validate the effectiveness of the proposed method.

Concanavalin-conjugated zinc-metal-organic framework drug for pH-controlled and targeted therapy of wound bacterial infection.

Wounds are prone to infection which may be fatal to the life of the patient. The use of antibiotics is essential for managing bacterial infections in wounds, but the long-term use of high doses of antibiotics may lead to bacterial drug resistance and even to creation of superbacteria. Therefore, the development of targeted antimicrobial treatment strategies and the reduction in antibiotic usage are of utmost urgency. In this study, a multifunctional nanodrug delivery system (Cef-rhEGF@ZIF-8@ConA) for the treatment of bacteriostatic infection was synthesized through self-assembly of Zn2+, cefradine (Cef) and recombinant human epidermal growth factor (rhEGF), then conjugated with concanavalin (ConA), which undergoes pH-responsive degradation to release the drugs. First, ConA can specifically combine with bacteria and inhibit the rapid release of Zn2+ ions, thus achieving a long-acting antibacterial effect. Cef exerts its antibacterial effect by inhibiting the synthesis of bacterial membrane proteins. Finally, Zn2+ ions released from the Zn-metal-organic framework (MOF) demonstrate bacteriostatic properties by enhancing the permeability of the bacterial cell membrane. Furthermore, rhEGF upregulates angiogenesis-associated genes, thereby promoting angiogenesis, re-epithelialization and wound healing processes. The results showed that Cef-rhEGF@ZIF-8@ConA has good biocompatibility, with antibacterial efficacy against Staphylococcus aureus and Escherichia coli of 99.61 % and 99.75 %, respectively. These nanomaterials can inhibit the release of inflammatory cytokines and promote the release of anti-inflammatory cytokines, while also stimulating the proliferation of fibroblasts to facilitate wound healing. Taken together, the Cef-rhEGF@ZIF-8@ConA nanosystem is an excellent candidate in clinical therapeutics for bacteriostatic infection and wound healing.

MAPKAPK5-AS1 drives the progression of hepatocellular carcinoma via regulating miR-429/ZEB1 axis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignancy. Long non-coding RNAs (lncRNAs) partake in the progression of HCC. However, the role of lncRNA MAPKAPK5-AS1 in the development of HCC has not been fully clarified. METHODS: RNA sequencing data and quantitative real-time polymerase chain reaction (qRT-PCR) were adopted to analyze MAPKAPK5-AS1, miR-429 and ZEB1 mRNA expressions in HCC tissues and cell lines. Western blot was used to detect ZEB1, E-cadherin and N-cadherin protein expressions. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Transwell and flow cytometry assays were adopted to analyze the effects of MAPKAPK5-AS1 on cell proliferation, migration, invasion and apoptosis. Besides, luciferase reporter assay was used to detect the targeting relationship between miR-429 and MAPKAPK5-AS1 or ZEB1 3'UTR. The xenograft tumor mouse models were used to explore the effect of MAPKAPK5-AS1 on lung metastasis of HCC cells. RESULTS: MAPKAPK5-AS1 and ZEB1 expressions were up-regulated in HCC tissues, and miR-429 expression is down-regulated in HCC tissues. MAPKAPK5-AS1 knockdown could significantly impede HCC cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), as well as promote cell apoptosis. MAPKAPK5-AS1 overexpression could enhance L02 cell proliferation, migration, invasion and EMT, and inhibit cell apoptosis. MiR-429 was validated to be the target of MAPKAPK5-AS1, and miR-429 inhibitors could partially offset the effects of knocking down MAPKAPK5-AS1 on HCC cells. MAPKAPK5-AS1 could positively regulate ZEB1 expression through repressing miR-429. Moreover, fewer lung metastatic nodules were observed in the lung tissues of nude mice when the MAPKAPK5-AS1 was knocked down in HCC cells. CONCLUSION: MAPKAPK5-AS1 can adsorb miR-429 to promote ZEB1 expression to participate in the development of HCC.

[Correlation between expression of vascular endothelial growth factor and prognosis of patients with esophageal squamous cell carcinoma].

BACKGROUND & OBJECTIVES: Angiogenesis plays an essential role in tumor growth, invasion, and metastasis. Vascular endothelial growth factor(VEGF) is regarded the most important angiogenetic growth factor and it has been found in many kinds of tumors that its high expression can promote tumor progression and effect prognosis. However, there was few reports about the relationship between the VEGF expression and the progression and prognosis of the patients with esophageal carcinoma. The current study was designed to investigate the relationship between VEGF expression and the prognosis of patients with esophageal squamous cell carcinoma. METHODS: The expression of VEGF protein in 72 resected specimens from the patients with esophageal squamous cell carcinoma were examined immunohistochemically, and its effects on postoperative recurrence and survival of the patients were analyzed retrospectively. RESULTS: Fourty-five out of 72 (62.5%) samples were positive for VEGF expression. The VEGF-positive patients tend to occur postoperative recurrence than VEGF-negative patients (P < 0.001). The median survival time and 1, 3, 5-year survival rate of VEGF-positive patients was lower than those of VEGF-negative patients. And the Kaplan-Meier survival curve was worse in VEGF-positive groups than in VEGF-negtive groups(Log rank test, P = 0.021). Multivariate analysis revealed that VEGF was not an independent factor that impact on the prognosis (P > 0.05). CONCLUSIONS: The high expression of VEGF in esophageal squamous cell carcinoma may promote the tumor progression and lead to dismal prognosis. However, the value of VEGF expression for judging prognosis need further study.