Peptide-based radiopharmaceuticals targeting integrin α5β1 show promise for precise tumor diagnosis and treatment. However, current peptide-based radioligands that target α5β1 demonstrate inadequate in vivo performance owing to limited tumor retention. The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity. Therefore, a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed. Here, we developed a PEGylation-enabled peptide multidisplay platform (PEGibody) for PR_b, an α5β1 targeting peptide. PEGibody generation involved PEGylation and self-assembly. [⁶⁴Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter. Compared with non-PEGylated radioligands, [⁶⁴Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability. Importantly, the biodistribution analysis confirmed rapid clearance of [⁶⁴Cu]QM-2303 from the bloodstream. Administration of a single dose of [¹⁷⁷Lu]QM-2303 led to robust antitumor efficacy. Furthermore, [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice. Therefore, this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime. The PEGibody-based radiopharmaceutical [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy for α5β1-overexpressing tumors.

This study investigated the mechanism by which kaempferol(KAE) affected intervertebral disc degeneration(IDD) through the p38 mitogen-activated protein kinase(p38 MAPK) signaling pathway. Rats were randomly divided into five groups: control group, model group, low-dose KAE group, medium-dose KAE group, and high-dose KAE group. An IDD model was established by needle puncture of the caudal intervertebral discs. Four weeks post-surgery, the rats were administered KAE via gavage for 8 consecutive weeks. Magnetic resonance imaging(MRI) was performed, and samples were collected. In vitro, an inflammation model of nucleus pulposus cells(NPCs) induced by tumor necrosis factor-alpha(TNF-α) was constructed. Anisomycin was used to activate the p38 MAPK signaling pathway. NPCs were divided into blank, model, KAE, agonist, and KAE + agonist groups. After 1 day of treatment, cell proliferation activity was assessed using the CCK-8. Protein expression levels were determined by Western blot, and mRNA expression was measured by real-time quantitative polymerase chain reaction. Cell apoptosis was detected by TUNEL staining, and immunofluorescence staining was used to detect type Ⅱ collagen and matrix metalloproteinase 3(MMP3). In vivo results indicated significant improvement in the degree of IDD in the treatment groups compared to the model group, with the medium-dose group showing more pronounced therapeutic effects than the low-and high-dose groups. In vitro results demonstrated that KAE treatment significantly enhanced NPC proliferation activity, down-regulated the expression levels of Bcl-2-associated X protein(Bax), interleukin-6(IL-6), interleukin-17A(IL-17A), MMP3, and a disintegrin and metalloproteinase with thrombospondin motifs 5, and inhibited the phosphorylation of p38 MAPK pathway-related proteins. Activation of the p38 MAPK signaling pathway by anisomycin reduced the therapeutic effects of KAE. The study concluded that KAE could improve the proliferation activity of degenerated NPCs, reduce inflammation levels, and slow the progression of IDD in rats, and the mechanism was likely related to the regulation of the p38 MAPK signaling pathway.
Animals ; p38 Mitogen-Activated Protein Kinases/genetics* ; Kaempferols/pharmacology* ; Intervertebral Disc Degeneration/genetics* ; Rats ; Rats, Sprague-Dawley ; Male ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Nucleus Pulposus/drug effects* ; Signal Transduction/drug effects* ; Humans ; MAP Kinase Signaling System/drug effects*

Lu Dangshen, a traditional authentic medicinal material of Codonopsis Radix is mainly produced in Shangdang (Changzhi) area of Shanxi Province. Baitiao Dangshen is mainly produced in Gansu Province. Codonopsis Radix contains many kinds of components such as phenylpropanoids, polyalkynes, alkaloids, terpenes, fatty acids, flavonoids, and so on. At present, the effect of producing areas on its chemical compositions has not been systematically studied. This study analyzed the differences of metabolites among Codonopsis pilosula from different producing areas by UPLC-HRMS. PCA, OPLS-DA coupled with Thermo mzcloud online and local databases were used to compare the overall differences of metabolites among Codonopsis pilosula from different producing areas, and the chemical constituents were identified to further screen and find out the different metabolites and analyze the metabolic pathways by information retrieval in HMDB, PubChem, Chemspider and KEGG databases. The results showed that 72 differential metabolites were identified in this study. There were 15 kinds of up-regulated and 57 kinds of down-regulated metabolites of Lu Dangshen compared with Baitiao Dangshen. The top 30 metabolic pathways were analyzed by KEGG enrichment, and the most important metabolic pathways were phenylpropanoid biosynthesis, which was demonstrated that phenylpropanoid biosynthesis pathway and related intermediate metabolites could be used as the characteristics of distinguishing Lu Dangshen from different habitats of Codonopsis pilosula. The present study provided a basis for analyzing the influence of producing areas on the chemical components of Codonopsis pilosula and reasonably evaluating the quality of Codonopsis Radix, and also provided a new idea for expounding the authenticity of Lu Dangshen.

OBJECTIVE: Physiologic cardiac pacing is a novel technique which has been largely popularized in recent decades. His bundle pacing (HBP) has been long considered the most physiologic pacing method; however, with the widespread implementation of this method, its disadvantages have become apparent. In this context, left bundle branch pacing (LBBP)-directly engaged in the His-Purkinje system-has been foreseen as the best pacing method to mimic physiologic activation patterns. This review aimed to summarize recent approaches to physiologic cardiac pacing. DATA SOURCES: This review included fully peer reviewed publications up to July 2018, found in the PubMed database using the keywords "His bundle branch pacing," "right ventricular pacing," and "physiologic pacing." STUDY SELECTION: All selected articles were in English, with no restriction on study design. RESULTS: The HBP has been studied worldwide, and is currently considered the most physiologic pacing method. However, it has disadvantages, such as high pacing threshold, unsatisfactory sensing and long procedure times, among others. Although LBBP is theoretically superior to HBP, the clinical relevance of this difference remains under debate, as few large randomized clinical trials with LBBP have been published. CONCLUSIONS Although HBP indeed appears to be the most physiologic pacing method, it has certain shortcomings, such as high pacing threshold, difficult implantation due to specific anatomic features, and others. Further studies are required to clarify the clinical significance of LBBP.
Cardiac Catheterization ; Cardiac Pacing, Artificial ; Cardiac Resynchronization Therapy ; Humans ; Randomized Controlled Trials as Topic

BACKGROUND: Currently, there are few studies about prostaglandin E1 in the paracrine and migration of bone marrow mesenchymal stem cells. OBJECTIVE: To explore the effects of prostaglandin E1 in the paracrine and migration of bone marrow mesenchymal stem cells. METHODS: Bone marrow mesenchymal stem cells isolated from Sprague Dawley rats were cultured in vitro. Passage 3 cells were co-cultured with prostaglandin E1 at concentrations of 10 μg/L, and then culture supernatant was collected at 3, 6, 9, 12, 24, 48, and 72 hours after co-culture. The level of vascular endothelial growth factor was detected by enzyme-linked immunosorbent assay. Effects of prostaglandin E1 on the migration of bone marrow mesenchymal stem cells were detected by Transwell assay and cell scratch assay. RESULTS AND CONCLUSION: After treatment with prostaglandin E1 for 3 hours, bone marrow mesenchymal stem cells began to secrete vascular endothelial growth factors, and the secretion level was peaked at 24 hours and then gradually decreased. Results from the Transwell assay and cell scratch assay showed that the migration ability of bone marrow mesenchymal stem cells was significantly promoted by prostaglandin E1 (P < 0.05). Overall findings reveal that prostaglandin E1 promotes the secretion of vascular endothelial growth factor from bone marrow mesenchymal stem cells and enhances cell migration.

S-phase kinase-associated protein 2 (Skp2) belongs to the F-box protein family. It is a component of the SCF E3 ubiquitin ligase complex. Skp2 has been shown to regulate cellular proliferation by targeting several cell cycle-regulated proteins for ubiquitination and degradation, including cyclin-dependent kinase inhibitor p27. Skp2 has also been demonstrated to display an oncogenic function since its overexpression has been observed in many human cancers. This review discusses the recent discoveries on the novel roles of Skp2 in regulating cellular senescence, cancer progression, and metastasis, as well as the therapeutic potential of targeting Skp2 for human cancer treatment.
Animals ; Cell Movement ; Cellular Senescence ; Cyclopentanes ; pharmacology ; Disease Progression ; Drug Delivery Systems ; methods ; Gene Expression Regulation, Neoplastic ; Humans ; Neoplasms ; metabolism ; pathology ; therapy ; Pyrimidines ; pharmacology ; S-Phase Kinase-Associated Proteins ; antagonists & inhibitors ; metabolism ; physiology ; Ubiquitination

OBJECTIVETo evaluate the value of modified acute physiologic and chronic health score (APACHE II score) in predicting postoperative complications in patients with acute obstructing colorectal carcinoma.

METHODSPostoperative complications in 92 patients with acute obstructing colorectal carcinoma were evaluated by APACHE II score and modified APACHE II score (severe organ dysfunction and immune damage in chronic health indicators were replaced by the duration and degree of obstruction, which were considered as the severity of intestinal obstruction). The sensitivity, specificity, and Youden index were compared with regard to complication prediction. Receiver operating characteristic curves were plotted to calculate area under the curve(AUC).

RESULTSTwenty-five patients developed postoperative complications including 3 deaths. The APACHE-II score(13.72±4.24), modified APACHE II score (19.28±4.92), intestinal obstruction severity score (5.56±2.20) were significantly higher in patients with complications than those in patients without complications (10.58±3.44, 14.69±3.73, 4.10±1.52, all P<0.01). The sensitivity, specificity, accuracy, Youden index, and AUC were 0.640, 0.940, 0.859, 0.580, and 0.839 for the modified APACHE-II score with 20 being the optimal cut-off point, respectively, and were 0.560, 0.896, 0.804, 0.456, and 0.784 for APACHE-II (14 was the optimal cut-off point), respectively.

CONCLUSIONThe modified APACHE-II score system with the intestinal obstruction severity score is a better prediction method for the occurrence of postoperative complications in patients with acute obstructing colorectal carcinoma.

APACHE ; Adult ; Aged ; Aged, 80 and over ; Area Under Curve ; Colorectal Neoplasms ; complications ; surgery ; Female ; Humans ; Intestinal Obstruction ; etiology ; surgery ; Male ; Middle Aged ; Postoperative Complications ; Retrospective Studies ; Sensitivity and Specificity