Donor-acceptor-donor type AIEgens based on thieno[3.4-c]pyrrole-4,6-dione: Synthesis, electropolymerization, and electrochromism.

Photoelectric functional materials with electrochemical reversible activity and fluorescence intensities have attracted significant interest due to their wide range of applications in optoelectronic devices. In this work, a series of photoresponsive and electroactive monomers based on thieno[3.4-c]pyrrole-4,6-dione (TPD) are synthesized and characterized. They possess planar geometry with smaller dihedral angles owing to the existence of a noncovalent conformation lock coming from the S atoms and the O atoms. Crystallographic, spectroscopic, and computational results reveal that the introduction of the TPD unit can endow the monomers with aggregation-induced emission (AIE), reduced energy levels, and increased electrochemical activity. The monomers were successfully polymerized through the electrochemical method, and the corresponding polymers displayed reversible electrochemical activity and stability. Moreover, polymer films based on 3,3-dimethyl-3,4-dihydro-2H-thieno[3,4-b][1,4]dioxepine (ProE)-TPD have electrochromic properties in the near-infrared field with a high value of optical contrast ratio (∆T) of 27.1% at 1000 nm.

Cryo-electron tomography elucidates annular intraluminal configurations in Caenorhabditis elegans microtubules.

BACKGROUND INFORMATION: Microtubules serve as integral components in cellular operations such as cell division, intracellular trafficking, and cellular architecture. Composed of tubulin protein subunits, these hollow tubular structures have been increasingly elucidated through advanced cryo-electron microscopy (Cryo-EM), which has unveiled the presence of microtubule inner proteins (MIPs) within the microtubular lumen. RESULTS: In the present investigation, we employ a synergistic approach incorporating high-pressure freezing, cryo-focused ion beam milling, and Cryo-electron tomography (Cryo-ET) to interrogate the in situ architecture of microtubules in Caenorhabditis elegans larvae. Our Cryo-ET assessments across neuronal cilia and diverse tissue types consistently demonstrate the formation of annular configurations within the microtubular lumen. CONCLUSIONS: In concert with recently characterized MIPs, our in situ observations within a living organism corroborate the hypothesis that intricate luminal assemblages exist within microtubule scaffolds. These findings necessitate further exploration into the molecular constituents and functional ramifications of these internal microtubular configurations in both cellular physiology and pathophysiology.

Overview of Panax ginseng and its active ingredients protective mechanism on cardiovascular diseases.

ETHNIC PHARMACOLOGICAL RELEVANCE: Panax ginseng is a traditional Chinese herbal medicine used to treat cardiovascular diseases (CVDs), and it is still widely used to improve the clinical symptoms of various CVDs. However, there is currently a lack of summary and analysis on the mechanism of Panax ginseng exerts its cardiovascular protective effects. This article provides a review of in vivo and in vitro pharmacological studies on Panax ginseng and its active ingredients in reducing CVDs damage. AIM OF THIS REVIEW: This review summarized the latest literature on Panax ginseng and its active ingredients in CVDs research, aiming to have a comprehensive and in-depth understanding of the cardiovascular protection mechanism of Panax ginseng, and to provide new ideas for the treatment of CVDs, as well as to optimize the clinical application of Panax ginseng. METHODS: Enrichment of pathways and biological terms using the traditional Chinese medicine molecular mechanism bioinformatics analysis tool (BATMAN-TCM). The literature search is based on electronic databases such as PubMed, ScienceDirect, Scopus, CNKI, with a search period of 2002-2023. The search terms include Panax ginseng, Panax ginseng ingredients, ginsenosides, ginseng polysaccharides, ginseng glycoproteins, ginseng volatile oil, CVDs, heart, and cardiac. RESULTS: 132 articles were ultimately included in the review. The ingredients in Panax ginseng that manifested cardiovascular protective effects are mainly ginsenosides (especially ginsenoside Rb1). Ginsenosides protected against CVDs such as ischemic reperfusion injury, atherosclerosis and heart failure mainly through improving energy metabolism, inhibiting hyper-autophagy, antioxidant, anti-inflammatory and promoting secretion of exosomes. CONCLUSION: Panax ginseng and its active ingredients have a particularly prominent effect on improving myocardial energy metabolism remodeling in protecting against CVDs. The AMPK and PPAR signaling pathways are the key targets through which Panax ginseng produces multiple mechanisms of cardiovascular protection. Extracellular vesicles and nanoparticles as carriers are potential delivery ways for optimizing the bioavailability of Panax ginseng and its active ingredients.

Folate-PEG-PROTAC Micelles for Enhancing Tumor-Specific Targeting Proteolysis In Vivo.

Proteolysis targeting chimeras (PROTACs) technology is rapidly developed as a novel and selective medicinal strategy for the degradation of cellular proteins in cancer therapy. However, the applications of PROTACs as heterobifunctional molecules are largely limited by high molecular weight, low bioavailability, poor permeability, insufficient targeting, and low efficacy in vivo. Herein, self-assembling micelles of FA-PEG-PROTAC are designed for cancer cell selective targeting and reductive-response proteolysis in tumor-bearing mice. FA-PEG-PROTAC is prepared by conjugating folic acid (FA)-PEG with EGFR-targeting PROTAC via a disulfide bond. The FA-PEG-PROTAC micelles, formed by self-assembling, are demonstrated to significantly improve tumor targeting efficacy and exhibit excellent anti-tumor efficacy in the mouse xenograft model compared to the traditional PROTACs. The strategy of applying self-assembled FA-PEG-PROTAC micelles in tumor therapy can not only improve targeted proteolysis efficiency but also broaden applications in the development of PROTAC-based drugs.

The combined application of ear acupuncture in the treatment of allergic rhinitis: A meta-analysis.

Objective: Meta-analysis was used to evaluate the clinical efficacy of auricular acupressure in the treatment of allergic rhinitis. Methods: Randomised controlled trials (RCTS) on the treatment of allergic rhinitis with ear acupuncture were searched by computer in PubMed, Cochrane Library, Embase、Web of Science、China National Knowledge Infrastructure (CNKI), Wanfang Database (Wanfang), VIP database, and China Biomedical Literature Service System (CBM). The search time was from the establishment of the database to September 18, 2022. Meta-analysis was performed using RevMan 5.4 software. Results: A total of 15 papers with 1002 patients were included in the final study. ①Clinical efficiency: The clinical efficiency of ear acupuncture combined with control group was higher than that of control group, and the difference was statistically significant (P < 0.00001); ② Nasal symptom score: the effect of ear acupuncture combined with control group on allergic rhinitis on nasal symptoms was more obvious than that of control group, and the difference was statistically significant (P = 0.004); ③ Nasal itching symptom score: the efficacy of ear acupuncture combined with control group on allergic rhinitis on nasal itching symptom was significantly higher than that of control group, and the difference was statistically significant (P = 0.01). ④Sneeze symptom score: the effect of ear acupuncture combined with control group on allergic rhinitis on nasal itching symptom was more effective than that of control group, and the difference was statistically significant (P < 0.00001); ⑤Score of runny nose symptom: the effect of ear acupuncture combined with control group on allergic rhinitis on runny nose symptom was more obvious than that of control group, the difference was statistically significant (P = 0.004); ⑥Nasal congestion symptom scores: The effect of ear acupuncture combined with control group on allergic rhinitis on nasal congestion symptom was more obvious than that of control group, and the difference was statistically significant (P = 0.003). Conclusion: Ear acupuncture as an adjunctive therapy of allergic rhinitis can achieve better clinical efficacy.

Recent advances in understanding the regulatory mechanism of plasma membrane H+-ATPase through the brassinosteroid signaling pathway.

The polyhydroxylated steroid phytohormone brassinosteroids (BRs) control many aspects of plant growth, development and responses to environmental changes. Plasma membrane (PM) H+-ATPase, the well-known PM proton pump, is a central regulator in plant physiology, which mediates not only plant growth and development, but also adaptation to stresses. Recent studies highlight that PM H+-ATPase is at least partly regulated via the BR signaling. Firstly, the BR cell surface receptor BRASSINOSTEROID-INSENSITIVE 1 (BRI1) and multiple key components of BR signaling directly or indirectly influence PM H+-ATPase activity. Secondly, the SMALL AUXIN UP RNA (SAUR) gene family physically interacts with BRI1 to enhance organ development of Arabidopsis by activating PM H+-ATPase. Thirdly, RNA-sequencing (RNA-seq) assays showed that the expression of some SAUR genes is upregulated under the light or sucrose conditions, which is related to the phosphorylation state of the penultimate residue of PM H+-ATPase in a time-course manner. In this review, we describe the structural and functional features of PM H+-ATPase, and summarize recent progress toward understanding the regulatory mechanism of PM H+-ATPase by BRs, and briefly introduce how PM H+-ATPase activity is modulated by its own biterminal regions and the post-translational modifications.

HIF-1α regulates the cell viability in radioiodine-resistant papillary thyroid carcinoma cells induced by hypoxia through PKM2/NF-κB signaling pathway.

The curative treatment options for papillary thyroid cancer (PTC) encompass surgical intervention, radioactive iodine administration, and chemotherapy. However, the challenges of radioiodine (RAI) resistance, metastasis, and chemotherapy resistance remain inadequately addressed. The objective of this study was to investigate the protective role of hypoxia-inducible factor-1α (HIF-1α) in 131 I-resistant cells and a xenograft model under hypoxic conditions, as well as to explore potential mechanisms. The effects of HIF-1α on 131 I-resistant BCPAP and TPC-1 cells, as well as the xenograft model, were assessed in this study. Cell viability, migration, invasion, and apoptosis rates were measured using Cell Counting Kit-8, wound-healing, Transwell, and flow cytometry assays. Additionally, the expressions of Ki67, matrix metalloproteinase-9 (MMP-9), and pyruvate kinase M2 (PKM2) were examined using immunofluorescence or immunohistochemistry assays. Sodium iodide symporter and PKM2/NF-κBp65 relative protein levels were detected by western blot analysis. The findings of our study indicate that siHIF-1α effectively inhibits cell proliferation, cell migration, and invasion in 131 I-resistant cells under hypoxic conditions. Additionally, the treatment of siHIF-1α leads to alterations in the relative protein levels of Ki67, MMP-9, PKM2, and PKM2/NF-κBp65, both in vivo and in vitro. Notably, the effects of siHIF-1α are modified when DASA-58, an activator of PKM2, is administered. These results collectively demonstrate that siHIF-1α reduces cell viability in PTC cells and rat models, while also mediating the nuclear factor-κB (NF-κB)/PKM2 signaling pathway. Our findings provide a new rationale for further academic and clinical research on RAI-resistant PTC.

PHLDA1 is a P53 target gene involved in P53-mediated cell apoptosis.

Pleckstrin homeolike domain, family A, member 1 (PHLDA1) is a multifunctional protein that plays diverse roles in A variety of biological processes, including cell death, and hence its altered expression has been found in different types of cancer. Although studies have shown a regulatory relationship between p53 and PHLDA1, the molecular mechanism is still unclear. Especially, the role of PHLDA1 in the process of apoptosis is still controversial. In this study, we found that the expression of PHLDA1 in human cervical cancer cell lines was correlated with the up-expression of p53 after treatment with apoptosis-inducing factors. Subsequently, the binding site and the binding effect of p53 on the promoter region of PHLDA1 were verified by our bioinformatics data analysis and luciferase reporter assay. Indeed, we used CRISPR-Cas9 to knockout the p53 gene in HeLa cells and further confirmed that p53 can bind to the promoter region of PHLDA1 gene, and then directly regulate the expression of PHLDA1 by recruiting P300 and CBP to change the acetylation and methylation levels in the promoter region. Finally, a series of gain-of-function experiments further confirmed that p53 re-expression in HeLap53-/- cell can up-regulate the reduction of PHLDA1 caused by p53 knockout, and affect cell apoptosis and proliferation. Our study is the first to explore the regulatory mechanism of p53 on PHLDA1 by using the p53 gene knockout cell model, which further proves that PHLDA1 is a target-gene in p53-mediated apoptosis, and reveals the important role of PHLDA1 in cell fate determination.

Vimentin regulates nuclear segmentation in neutrophils.

Granulocytes are indispensable for various immune responses. Unlike other cell types in the body, the nuclei of granulocytes, particularly neutrophils, are heavily segmented into multiple lobes. Although this distinct morphological feature has long been observed, the underlying mechanism remains incompletely characterized. In this study, we utilize cryo-electron tomography to examine the nuclei of mouse neutrophils, revealing the cytoplasmic enrichment of intermediate filaments on the concave regions of the nuclear envelope. Aided by expression profiling and immuno-electron microscopy, we then elucidate that the intermediate-filament protein vimentin is responsible for such perinuclear structures. Of importance, exogenously expressed vimentin in nonimmune cells is sufficient to form cytoplasmic filaments wrapping on the concave nuclear surface. Moreover, genetic deletion of the protein causes a significant reduction of the number of nuclear lobes in neutrophils and eosinophils, mimicking the hematological condition of the Pelger-Huët anomaly. These results have uncovered a new component establishing the nuclear segmentation of granulocytes.