Rebooting the Adaptive Immune Response in Immunotherapy-Resistant Lung Adenocarcinoma Using a Supramolecular Albumin.

Despite the availability of immune checkpoint inhibitors (ICBs) significantly prolonging the life expectancy of some lung adenocarcinoma (LUAD) patients, their implementation and long-term effectiveness are hampered by the growing issue of acquired resistance. Herein, the bioinformatics analysis of immunotherapy-resistant LUAD patients and the system analysis of Anti-PD1-resistant mice models once again validate that the resistance-associated Wnt/ß-catenin pathway offers a promising avenue for ICB sensitization. Consequently, a mild and convenient self-assembly between albumin and carnosic acid (CA), a Wnt inhibitor is employed, to develop a supramolecular albumin known as ABCA, serving as a reactivator for ICB. As anticipated, ABCA effectively suppress the Wnt/ß-catenin cascade in vitro and leads to significant inhibition of cell proliferation while promoting apoptosis. Most notably, ABCA restores the anticancer efficacy of Anti-PD1 in immunotherapy-resistant LUAD orthotopic allografting mice models by reinvigorating the adaptive immune response mediated by T lymphocytes. Furthermore, ABCA exhibits minimal adverse effects during treatment and high-dose toxicity tests, underscoring its excellent potential for clinical translation. Collectively, the present work possesses the potential to provide innovative perspectives on the advancement of optimized immunotherapies targeting drug resistance, while also presenting a promising avenue for translating Wnt inhibitors into immunotherapeutic drugs for their clinical application.

Reinvigoration of cytotoxic T lymphocytes in microsatellite instability-high colon adenocarcinoma through lysosomal degradation of PD-L1.

Compensation and intracellular storage of PD-L1 may compromise the efficacy of antibody drugs targeting the conformational blockade of PD1/PD-L1 on the cell surface. Alternative therapies aiming to reduce the overall cellular abundance of PD-L1 thus might overcome resistance to conventional immune checkpoint blockade. Here we show by bioinformatics analysis that colon adenocarcinoma (COAD) with high microsatellite instability (MSI-H) presents the most promising potential for this therapeutic intervention, and that overall PD-L1 abundance could be controlled via HSC70-mediated lysosomal degradation. Proteomic and metabolomic analyses of mice COAD with MSI-H in situ unveil a prominent acidic tumor microenvironment. To harness these properties, an artificial protein, IgP ß, is engineered using pH-responsive peptidic foldamers. This features customized peptide patterns and designed molecular function to facilitate interaction between neoplastic PD-L1 and HSC70. IgP ß effectively reduces neoplastic PD-L1 levels via HSC70-mediated lysosomal degradation, thereby persistently revitalizing the action of tumor-infiltrating CD8 + T cells. Notably, the anti-tumor effect of lysosomal-degradation-based therapy surpasses that of antibody-based immune checkpoint blockade for MSI-H COAD in multiple mouse models. The presented strategy expands the use of peptidic foldamers in discovering artificial protein drugs for targeted cancer immunotherapy.

Rewiring chaperone-mediated autophagy in cancer by a prion-like chemical inducer of proximity to counteract adaptive immune resistance.

Chaperone-mediated autophagy (CMA), a proteolytic system contributing to the degradation of intracellular proteins in lysosomes, is upregulated in tumors for pro-tumorigenic and pro-survival purposes. In this study, bioinformatics analysis revealed the co-occurrence of upregulated CMA and PD-L1 accumulation in metastatic melanoma with adaptive immune resistance (AIR) to anti-PD1 treatment, suggesting the potential therapeutic effects of rewiring CMA for PD-L1 degradation. Furthermore, this co-occurrence is attributed to IFN-γ-mediated compensatory up-regulation of PD-L1 and CMA, accompanied by enhanced macropinocytosis. Drawing inspiration from the cellular uptake of prions via macropinocytosis, a prion-like chemical inducer of proximity called SAP was engineered using self-assembly of the designed chiral peptide PHA. By exploiting sensitized macropinocytosis, SAP clandestinely infiltrates tumor cells and subsequently disintegrates into PHA, which reprograms CMA by inducing PD-L1 close to HSPA8. SAP degrades PD-L1 in a CMA-dependent manner and effectively restores the anti-tumor immune response in both allografting and Hu-PDX melanoma mouse models with AIR while upholding a high safety profile. Collectively, the reported SAP not only presents an immune reactivation strategy with clinical translational potential for overcoming AIR in cutaneous melanomas but serves as a reproducible example of precision-medicine-guided drug development that fully leverages specific cellular indications in pathological states.

α-Glucan derivatives as selective blockers of aldolase A: Computer-aided structure optimization and the effects on HCC.

Aldolase A (ALDOA) promotes hepatocellular carcinoma (HCC) growth and is a potential therapeutic target. A previous study found an α-D-glucan (α-D-(1,6)-Glcp-α-D-(1,4)-Glcp, 10.0:1.0), named HDPS-4II, that could specifically inhibit ALDOA but its activity was not high enough. In this study, the derivatives of α-D-glucan binding to ALDOA were optimized using molecular docking, and its sulfated modification demonstrated the highest affinity with ALDOA among sulfated, carboxylated, and aminated derivatives. Sulfated HDPS-4II and dextrans with different molecular weights (1000 Da, 3000 Da, and 4000 Da) were prepared. Using MST assay, 3-O-sulfated HDPS-4II (SHDPS-4II) and 1000 Da dextran (SDextran1) showed higher affinities to ALDOA with Kd of 1.83 µM and 85.04 µM, respectively. Furthermore, SHDPS-4II and SDextran1 markedly inhibited the proliferation of HCC cells both in vitro and in vivo by blocking ALDOA. These results demonstrate that sulfated modification of α-D-glucans could enhance their affinities with ALDOA and anti-HCC effects.

A d-peptide-based oral nanotherapeutic modulates the PD-1/PD-L1 interaction for tumor immunotherapy.

Background: PD-1/PD-L1 immune checkpoint inhibitors are currently the most commonly utilized agents in clinical practice, which elicit an immunostimulatory response to combat malignancies. However, all these inhibitors are currently administered via injection using antibody-based therapies, while there is a growing need for oral alternatives. Methods: This study has developed and synthesized exosome-wrapped gold-peptide nanocomplexes with low immunogenicity, which can target PD-L1 and activate antitumor immunity in vivo through oral absorption. The SuperPDL1exo was characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared (FTIR), X-ray photoelectron spectroscopy (XPS), and gel silver staining. The transmembrane ability of SuperPDL1exo was evaluated by flow cytometry and immunofluorescence. Cell viability was determined using the Cell Counting Kit-8 (CCK-8) assay. ELISA experiments were conducted to detect serum and tissue inflammatory factors, as well as serum biochemical indicators. Tissue sections were stained with H&E for the evaluation of the safety of SuperPDL1exo. An MC38 colon cancer model was established in immunocompetent C56BL/6 mice to evaluate the effects of SuperPDL1exo on tumor growth in vivo. Immunohistochemistry (IHC) staining was performed to detect cytotoxicity factors such as perforin and granzymes. Results: First, SuperPDL1 was successfully synthesized, and milk exosome membranes were encapsulated through ultrasound, repeated freeze-thaw cycles, and extrusion, resulting in the synthesis of SuperPDL1exo. Multiple characterization results confirmed the successful synthesis of SuperPDL1exo nanoparticles. Furthermore, our data demonstrated that SuperPDL1exo exhibited excellent colloidal stability and superior cell transmembrane ability. In vitro and in vivo experiments revealed that SuperPDL1exo did not cause damage to multiple systemic organs, demonstrating its good biocompatibility. Finally, in the MC38 colon cancer mouse model, it was discovered that SuperPDL1exo could inhibit the progression of colon cancer, and this tumor-suppressive effect was mediated through the activation of tumor-specific cytotoxic T lymphocyte (CTL)-related immune responses. Conclusion: This study has successfully designed and synthesized an oral nanotherapeutic, SuperPDL1exo, which demonstrates small particle size, excellent colloidal stability, transmembrane ability in tumor cells, and biocompatibility. In vivo experiments have shown that it effectively activates T-cell immunity and exerts antitumor effects.

Topic evolution and sentiment comparison of user reviews on an online medical platform in response to COVID-19: taking review data of Haodf.com as an example.

Introduction: Throughout the COVID-19 pandemic, many patients have sought medical advice on online medical platforms. Review data have become an essential reference point for supporting users in selecting doctors. As the research object, this study considered Haodf.com, a well-known e-consultation website in China. Methods: This study examines the topics and sentimental change rules of user review texts from a temporal perspective. We also compared the topics and sentimental change characteristics of user review texts before and after the COVID-19 pandemic. First, 323,519 review data points about 2,122 doctors on Haodf.com were crawled using Python from 2017 to 2022. Subsequently, we employed the latent Dirichlet allocation method to cluster topics and the ROST content mining software to analyze user sentiments. Second, according to the results of the perplexity calculation, we divided text data into five topics: diagnosis and treatment attitude, medical skills and ethics, treatment effect, treatment scheme, and treatment process. Finally, we identified the most important topics and their trends over time. Results: Users primarily focused on diagnosis and treatment attitude, with medical skills and ethics being the second-most important topic among users. As time progressed, the attention paid by users to diagnosis and treatment attitude increased-especially during the COVID-19 outbreak in 2020, when attention to diagnosis and treatment attitude increased significantly. User attention to the topic of medical skills and ethics began to decline during the COVID-19 outbreak, while attention to treatment effect and scheme generally showed a downward trend from 2017 to 2022. User attention to the treatment process exhibited a declining tendency before the COVID-19 outbreak, but increased after. Regarding sentiment analysis, most users exhibited a high degree of satisfaction for online medical services. However, positive user sentiments showed a downward trend over time, especially after the COVID-19 outbreak. Discussion: This study has reference value for assisting user choice regarding medical treatment, decision-making by doctors, and online medical platform design.

Targeting ß-catenin and PD-L1 simultaneously by a racemic supramolecular peptide for the potent immunotherapy of hepatocellular carcinoma.

Objective: The low clinical utility of immune checkpoint inhibitors (ICIs) against PD-1 or PD-L1 has recently been associated with the activation of the Wnt/ß-catenin signaling pathway in hepatocellular carcinoma (HCC), which promotes tumor immune escape and resistance to anti-PD-1/PD-L1 therapy. Hence, we aimed to fabricate a supramolecular peptide which could target the Wnt/ß-catenin signaling pathway coupled with ICIs blockage therapy for optimizing HCC immunotherapy. Methods: A racemic spherical supramolecular peptide termed sBBI&PDP nanoparticle was constructed by hierarchical self-assembly, comprising an L-enantiomeric peptide as an inhibitor of BCL9 and ß-catenin (sBBI) and a D-enantiomeric peptide as an inhibitor of PD-1/PD-L1 (PDP). Results: sBBI&PDP nanoparticle potently suppressed the hyperactivated Wnt/ß-catenin signaling pathway in vitro and in vivo, while blocking endogenous PD-L1 effectively. Furthermore, sBBI&PDP increased the infiltration and action of CD8+ T cells at tumor sites. Notably, compared with the original sBBI and commercial Anti-PD-L1 inhibitors, the designed sBBI&PDP showed stronger antitumor efficacy in an orthotopic homograft mice model of HCC and a PDX HCC model in Hu-PBMC-NSG mice. Moreover, sBBI&PDP possessed a favorable biosafety profile. Conclusion: The successful implementation of this strategy could revitalize ICIs blockage therapy and promote the discovery of artificial peptides for HCC immunotherapy.

[Expression and role of deleted in malignant brain tumor protein 1 in acute respiratory distress syndrome rats induced by sepsis].

OBJECTIVE: To observe the expression of deleted in malignant brain tumor protein 1 (DMBT1) in rat acute respiratory distress syndrome (ARDS) model induced by sepsis and its relationship with ARDS related biomarkers. METHODS: Forty-eight healthy male rats were randomly divided into sham operation group (Sham group) and ARDS model group, and the rats in each group were further divided into three subgroups at 6, 12 and 24 hours after operation, with 8 rats in each subgroup. The rats in the Sham group were exposed to the cecum only, and sepsis induced ARDS model was reproduced by cecal ligation and puncture (CLP) in the ARDS model group. The general performance was observed at 6, 12, 24 hours after operation. Abdominal aortic blood of rats was collected, and the levels of DMBT1, surfactant-associated protein D (SP-D), vascular endothelial growth factor (VEGF), interleukins (IL-6, IL-10) in serum were determined by enzyme-linked immunosorbent assay (ELISA). The lung tissues were collected, and the lung wet/dry weight (W/D) ratio was determined. The lung tissue pathological changes were observed under light microscope after hematoxylin-eosin (HE) staining, and the lung tissue injury score was evaluated. The expression of DMBT1 protein in lung tissue was determined by Western blotting. The relationship between the serum DMBT1 and SP-D, VEGF, IL-6, IL-10, lung tissue injury score were analyzed by Pearson correlation analysis. RESULTS: Rats in the ARDS model group showed obvious pathological manifestations after operation. The alveolar structure destruction, inflammatory cell infiltration, and alveolar hemorrhage were observed under microscope. Compared with the Sham group, the lung tissue injury score and the lung W/D ratio at 12 hours after operation in the ARDS model group were significantly increased (lung tissue injury score: 3.35±0.13 vs. 1.16±0.07, lung W/D ratio: 5.36±0.44 vs. 4.38±0.35, both P < 0.05), and pulmonary edema was present, which suggested that the ARDS model caused by CLP was successfully reproduced. The results of ELISA and Western blotting showed that the levels of serum DMBT1, SP-D, VEGF and IL-6 in the ARDS model group increased gradually with time, while the level of IL-10 increased first and then decreased. Compared with the Sham group, the levels of DMBT1 in serum and the expressions of DMBT1 protein in lung tissue in the ARDS model group were significantly increased from 6 hours after operation [serum (ng/L) : 231.96±19.17 vs. 187.44±10.19, lung tissue (DMBT1/ß-actin): 2.05±0.19 vs. 0.93±0.25, both P < 0.05], and the levels of SP-D, VEGF, IL-6 and IL-10 in serum were significantly increased from 12 hours after operation [SP-D (ng/L): 73.35±8.05 vs. 43.28±5.77, VEGF (ng/L): 89.85±8.47 vs. 43.19±5.11, IL-6 (ng/L): 36.01±2.48 vs. 17.49±1.77, IL-10 (ng/L): 84.55±8.41 vs. 39.83±5.02, all P < 0.05]. Pearson correlation analysis showed that serum DMBT1 was positively correlated with serum SP-D, VEGF, IL-6, IL-10 and lung injury score at 12 hours and 24 hours in the ARDS model group (12 hours: r values were 0.946, 0.942, 0.931, 0.936, 0.748, respectively; 24 hours: r values were 0.892, 0.945, 0.951, 0.918, 0.973, respectively; all P < 0.05). CONCLUSIONS: DMBT1 is a novel early biomarker of ARDS by affecting alveolar epithelial cell, alveolar capillary permeability and inflammatory response.

Elevated Placental microRNA-155 Is a Biomarker of a Preeclamptic Subtype.

BACKGROUND: Preeclampsia is a complicated syndrome with marked heterogeneity. The biomarker-based classification for this syndrome is more constructive to the targeted prevention and treatment of preeclampsia. It has been reported that preeclamptic patients had elevated microRNA-155 (miR-155) in placentas or circulation. Here, we investigated the characteristics of patients with high placental miR-155 (pl-miR-155). METHODS: Based on the 95th percentile (P95) of pl-miR-155 in controls, preeclamptic patients were divided into high miR-155 group (≥P95) and normal miR-155 group (

Signaling effect in social network and charity crowdfunding: Empirical analysis of charity crowdfunding of Sina MicroBlog in China.

With the increasing number of online charity donations, research on the influencing factors of individual donation behavior has become an important topic. Social interaction information in crowdfunding has become an essential basis for potential backers to make decisions. It provides new research space for charity crowdfunding and social capital theory. The primary purpose of this study is to explore the influence of social capital, social recommendation, and other signals on charity crowdfunding performance. We obtain 4,780 project information on the charity crowdfunding of Sina MicroBlog through data collection procedures. Our research found that both external social capital and internal capital can significantly improve the fundraising performance of crowdfunding projects. Projects with more social recommendations are more likely to obtain financial support. In the case of Medical aid crowdfunding projects, the positive promotion effect of social recommendations on project fundraising ability is enhanced. To get more effective support for crowdfunding projects, it is necessary to pay attention to the construction of social capital and the cultivation of its reputation to obtain the recognition of potential backers.

Direct adenylation from 5'-OH-terminated oligonucleotides by a fusion enzyme containing Pfu RNA ligase and T4 polynucleotide kinase.

5'-Adenylated oligonucleotides (AppOligos) are widely used for single-stranded DNA/RNA ligation in next-generation sequencing (NGS) applications such as microRNA (miRNA) profiling. The ligation between an AppOligo adapter and target molecules (such as miRNA) no longer requires ATP, thereby minimizing potential self-ligations and simplifying library preparation procedures. AppOligos can be produced by chemical synthesis or enzymatic modification. However, adenylation via chemical synthesis is inefficient and expensive, while enzymatic modification requires pre-phosphorylated substrate and additional purification. Here we cloned and characterized the Pfu RNA ligase encoded by the PF0353 gene in the hyperthermophilic archaea Pyrococcus furiosus. We further engineered fusion enzymes containing both Pfu RNA ligase and T4 polynucleotide kinase. One fusion enzyme, 8H-AP, was thermostable and can directly catalyze 5'-OH-terminated DNA substrates to adenylated products. The newly discovered Pfu RNA ligase and the engineered fusion enzyme may be useful tools for applications using AppOligos.

Assembling p53 Activating Peptide With CeO2 Nanoparticle to Construct a Metallo-Organic Supermolecule Toward the Synergistic Ferroptosis of Tumor.

Inducing lipid peroxidation and subsequent ferroptosis in cancer cells provides a potential approach for anticancer therapy. However, the clinical translation of such therapeutic agents is often hampered by ferroptosis resistance and acquired drug tolerance in host cells. Emerging nanoplatform-based cascade engineering and ferroptosis sensitization by p53 provides a viable rescue strategy. Herein, a metallo-organic supramolecular (Nano-PMI@CeO2) toward p53 restoration and subsequent synergistic ferroptosis is constructed, in which the radical generating module-CeO2 nanoparticles act as the core, and p53-activator peptide (PMI)-gold precursor polymer is in situ reduced and assembled on the CeO2 surface as the shell. As expected, Nano-PMI@CeO2 effectively reactivated the p53 signaling pathway in vitro and in vivo, thereby downregulating its downstream gene GPX4. As a result, Nano-PMI@CeO2 significantly inhibited tumor progression in the lung cancer allograft model through p53 restoration and sensitized ferroptosis, while maintaining favorable biosafety. Collectively, this work develops a tumor therapeutic with dual functions of inducing ferroptosis and activating p53, demonstrating a potentially viable therapeutic paradigm for sensitizing ferroptosis via p53 activation. It also suggests that metallo-organic supramolecule holds great promise in transforming nanomedicine and treating human diseases.

Psychological experience and social reintegration needs of young stroke patients: a systematic review and meta-aggregation of qualitative studies.

BACKGROUND: The visible physical dysfunction and invisible psychological effects after stroke prevent young patients from returning to their pre-stroke roles and social activities. PURPOSE/AIM: To comprehensively analyze the psychological experience and social reintegration needs of young stroke patients, which may be beneficial for improving quality of life and social reintegration after stroke. METHODS: We conducted a comprehensive literature search of 10 databases. The screening and quality assessment of the included articles were performed by the Qualitative Assessment and Review Instrument (QARI). Meta-aggregation was conducted to synthesize the findings of the included studies. We summarized the certainty of confidence using the Confidence in Evidence from Reviews of Qualitative Research (CERQual) approach. RESULTS: A total of 5506 studies were screened, of which 12 were included. Data synthesis suggested two new themes: (a) the self-growth process from denial of stroke to accepting stroke (high CERQual confidence), and (b) desire to regain pre-stroke normality, but having difficulty in the social reintegration process (high CERQual confidence). CONCLUSION: Stroke, as a traumatic event, disrupts the life structure of young patients, and their needs of reintegration are not adequately considered. Interventions based on the principle of individuation should focus on this issue to restore continuity in life after stroke.

Involvement of blood lncRNA UCA1 in sepsis development and prognosis, and its correlation with multiple inflammatory cytokines.

BACKGROUND: Sepsis is a highly life-threatening disease. Long non-coding RNA urothelial carcinoma associated 1 (lncRNA UCA1) participates in the processes of inflammation and organ injury in several diseases, whereas its role in sepsis patients is still unclear. The aim was to explore the clinical value of lncRNA UCA1 in sepsis patients. METHODS: One hundred seventy-four sepsis patients and 100 age and gender-matched controls were enrolled. LncRNA UCA1 in peripheral blood mononuclear cell samples was examined, and the level of inflammatory cytokines in serum samples was assessed. RESULTS: LncRNA UCA1 was highly expressed in sepsis patients compared with controls. LncRNA UCA1 was positively correlated with tumor necrosis factor-α, interleukin (IL)-6, IL-17, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in sepsis patients, while it was not correlated with these inflammatory cytokines in controls. lncRNA UCA1 upregulation was related to raised APACHE II score and SOFA score in sepsis patients. Moreover, lncRNA UCA1 was increased in sepsis deaths compared with sepsis survivors and was independently correlated with increased 28-day sepsis mortality risk. Further receiver operating characteristic curves presented that lncRNA UCA1 had a good value to predict 28-motality risk, while its combination with other independent factors (including age, history of chronic kidney disease, G+ bacterial infection, Fungus infection, C-reactive protein, and APACHE II score) exerted a great predictive value for 28-day mortality risk. CONCLUSION: LncRNA UCA1 is upregulated and correlates with multiple pro-inflammatory cytokines, terrible disease severity, and poor prognosis in sepsis patients.

The role of junctional adhesion molecule-C in trophoblast differentiation and function during normal pregnancy and preeclampsia.

INTRODUCTION: Junctional adhesion molecule-C (JAM-C) is an important regulator of many physiological processes, ranging from maintenance of tight junction integrity of epithelia to regulation of cell migration, homing and proliferation. Preeclampsia (PE) is a trophoblast-related syndrome with abnormal placentation and insufficient trophoblast invasion. However, the role of JAM-C in normal pregnancy and PE pathogenesis is unknown. METHODS: The expression and location of JAM-C in placentas were determined by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry. The expression of differentiation and invasion markers were detected by qRT-PCR or western blot. The effects of JAM-C on migration and invasion of trophoblasts were examined using wound-healing and invasion assays. Additionally, a mouse model was established by injection of JAM-C-positive adenovirus to explore the effects of JAM-C in vivo. RESULTS: In normal pregnancy, JAM-C was preferentially expressed on cytotrophoblast (CTB) progenitors and progressively decreased when acquiring invasion properties with gestation advance. However, in PE patients, the expression of JAM-C was upregulated in extravillous trophoblasts (EVTs) and syncytiotrophoblasts (SynTs) of placentas. It was also demonstrated that JAM-C suppressed the differentiation of CTBs into EVTs in vitro. Consistently, JAM-C inhibited the migration and invasion capacities of EVTs through GSK3ß/ß-catenin signaling pathway. Importantly, Ad-JAMC-infected mouse model mimicked the phenotype of human PE. DISCUSSION: JAM-C plays an important role in normal placentation and upregulated JAM-C in placentas contributes to PE development.

Synthesis of Antimicrobial Benzo[1,2,4]triazoloazepinium Salts and Tetrahydronaphtho[1,2-e][1,2,4]triazines by Polar [3+ + 2] and [4 + 2]-Cycloaddition Reactions.

Novel annulated azaheterocycles of benzo[1,2,4]triazoloazepine and tetrahydronaphtho[1,2-e][1,2,4]triazine derivatives have been synthesized. Treatment of 2-diazenyl-1,2,3,4-tetrahydronaphthalen-2-yl acetates with BF3·Et2O generates 1-aza-2-azoniaallenium cation intermediates (or azocarbenium ions), which are intercepted by nitriles via cascade polar [3+ + 2]-cycloaddition/rearrangement reactions to afford benzo[1,2,4]triazoloazepinium salts. These literature unprecedented fused tricycle compounds have been shown to exhibit antimicrobial activity against Gram-positive Staphylococcus aureus with in silico docking studies, suggesting that they may exhibit their antibiotic activity through inhibition of DNA gyrase. Additionally, when ethyl 2-(1-acetoxy-1,2,3,4-tetrahydronaphthalen-2-yl)diazene-1-carboxylate is employed, the reaction with BF3·Et2O produces 1,2-diaza-1,3-diene, which reacts with nitriles via a diaza-Diels-Alder reaction with inverse electron demand, leading to ethyl tetrahydronaphtho[1,2-e][1,2,4]triazine carboxylates. The DFT calculation has been performed to further prove the D-A reaction speculation.

circPTPN12/miR-21-5 p/∆Np63α pathway contributes to human endometrial fibrosis.

Emerging evidence demonstrates the important role of circular RNAs (circRNAs) in regulating pathological processes in various diseases including organ fibrosis. Endometrium fibrosis is the leading cause of uterine infertility, but the role of circRNAs in its pathogenesis is largely unknown. Here, we provide the evidence that upregulation of circPTPN12 in endometrial epithelial cells (EECs) of fibrotic endometrium functions as endogenous sponge of miR-21-5 p to inhibit miR-21-5 p expression and activity, which in turn results in upregulation of ΔNp63α to induce the epithelial mesenchymal transition (EMT) of EECs (EEC-EMT). In a mouse model of endometrium fibrosis, circPTPN12 appears to be a cofactor of driving EEC-EMT and administration of miR-21-5 p could reverse this process and improve endometrial fibrosis. Our findings revealed that the dysfunction of circPTPN12/miR-21-5 p/∆Np63α pathway contributed to the pathogenesis of endometrial fibrosis.

Structures and anti-melanoma activities of two polysaccharides from Angelica sinensis (Oliv.) Diels.

Polysaccharide is one of the necessary macromolecules in life activities, and it is also a very promising natural product for tumor prevention and treatment. In this study, two homogeneous polysaccharides (APS-4I and APS-4II) were isolated from Angelica sinensis (Oliv.) Diels. APS-4I was a linear glucan with molecular weight of 16.1 kDa, which was composed of 88.4% α-1,6-Glcp, 4.1% α-1,2-Glcp, 3.9% α-1,3-Glcp, and 2.8% α-T-Glcp. APS-4II was a novel polysaccharide with molecular weight of 11.1 kDa, which consisted of 55.4% α-1,6-Glcp, 10.4% α-1,3,5-Araf, 8.7% α-T-Araf, 9.2% α-1,5-Araf, 4.0% α-1,3-Araf, 3.6% α-1,4-Galp, and 9.1% ß-1,3-Galp. NMR results demonstrated that APS-4II has a backbone composed of →6)-α-Glcp-(1 → 6)-α-Glcp-(1 → 5)-α-Araf-. (1 → 5)-α-Araf-(1 → 3,5)-α-Araf-(1 → 3)-ß-Galp-(1 → 3)-ß-Galp-(1 → 4)-α-Galp-(1 → 3)-α-Araf-(1 → 3,5)-α-Araf-(1→. Both APS-4I and APS-4II inhibited the tumor growth of B16-bearing mice, and the suppressive effect of APS-4II reached 64.7 ± 7.3%. Meanwhile, there were higher lymphocyte numbers and the levels of IL-2, IFN-γ, and TNF-α in peripheral blood of APS-4II-treated mice than those in APS-4I-treated mice. Furthermore, APS-4II showed a higher inhibitory effect on the proliferation of B16 cells and stronger promoting effects on the proliferation of splenocytes, the phagocytosis of peritoneal macrophages, and the cytotoxicity of NK cells. These results demonstrated that APS-4II could be a promising therapeutic agent for melanoma.

Downregulation of CD151 induces oxidative stress and apoptosis in trophoblast cells via inhibiting ERK/Nrf2 signaling pathway in preeclampsia.

Preeclampsia (PE) is a pregnancy-related syndrome characterized by new-onset hypertension and proteinuria after gestational 20 weeks. Oxidative stress, resulting from the imbalance between the production of oxidants and antioxidants in placentas, is recognized as a key pathology of PE. To date, the molecules that regulate antioxidants production remain unclear. CD151, a member of tetraspanins, is an important regulator of many physiological functions. However, the function of CD151 in oxidative stress and its association with pregnancy-related complications are currently unknown. In the present study, we have demonstrated that CD151 was a key regulator of antioxidants in placentas. Compared with the placentas of the controls, the placentas of PE patients exhibited decreased CD151 expression accompanying with decreased antioxidant gene expression (HO-1, NQO-1, GCLC and SOD-1). In vitro, overexpression of CD151 in trophoblast cells could enhance HO-1, NQO-1, GCLC and SOD-1 expression but downregulation of CD151 decreased those antioxidant genes expression, which indicates CD151 is the upstream of antioxidants. Importantly, the phenotype of PE (hypertension and proteinuria) was mimicked in the downregulating CD151 induced mouse model. Moreover, the beneficial effect of CD151 in trophoblast cells was hindered when ERK and Nrf2 signaling were blocked. Overall, our results revealed CD151 might be a new target for PE treatment.

The antitumor role of a newly discovered α-d-glucan from Holotrichia diomphalia Bates as a selective blocker of aldolase A.

Aldolase A (ALDOA) facilitated aerobic glycolysis in cancer cells is a potential target in the treatment of hepatocellular carcinoma (HCC). However, only few effective inhibitors of ALDOA have been reported until now. In this research, we found a polysaccharide called HDPS-4II from Holotrichia diomphalia Bates, which can specifically bind to ALDOA with a dissociation constant of 2.86 µM. HDPS-4II with a molecular weight of 19 kDa was a linear triple-helix glucan composed of ɑ-d-1,4-Glcp and ɑ-d-1,6-Glcp in a ratio of 1.0:10.0. HDPS-4II significantly inhibited aldolase enzyme activity, glycolysis, and further inhibited the expression of phosphorylated AMPKα in HCC cells. Through analyzing ALDOA-overexpressing and -knockdown cells, it was confirmed that ALDOA mediated the viability and glycolysis inhibition of HDPS-4II. Moreover, HDPS-4II administration markedly inhibited tumor growth in mice xenografted with HCCs. These findings suggest that HDPS-4II, as an ALDOA antagonist, is a promising remedy in the treatment and prevention of HCC.