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The aggregation of amyloid proteins has been suggested to be the main cause of multiple human disorders; for example, amyloid β aggregates in Alzheimer's disease and α‐synuclein aggregates in Parkinson's disease. In the search for therapeutic medicines, many molecules have been discovered and developed to modulate the aggregation of amyloid proteins. This century has witnessed the flourishing growth of supramolecular chemistry, and some biocompatible macrocycles have been proven to inhibit the aggregation of some amyloid proteins via host‐guest interactions and could thus be used for the prevention or treatment of related diseases. Here, we review the application of macrocycles in modulating the aggregation of amyloid proteins. Biocompatible macrocycles have been proven to modulate the aggregation of different amyloid proteins, making them potential candidates for treating multiple diseases.

α-Synuclein forms amyloid fibrils that are critical in the progression of Parkinson’s disease and serves as the pathological hallmark of this condition. Different posttranslational modifications have been identified at multiple sites of α-synuclein, influencing its conformation, aggregation and function. Here, we investigate how disease-related phosphorylation and O-GlcNAcylation at the same α-synuclein site (S87) affect fibril structure and neuropathology. Using semi-synthesis, we obtained homogenous α-synuclein monomer with site-specific phosphorylation (pS87) and O-GlcNAcylation (gS87) at S87, respectively. Cryo-EM revealed that pS87 and gS87 α-synuclein form two distinct fibril structures. The GlcNAc situated at S87 establishes interactions with K80 and E61, inducing a unique iron-like fold with the GlcNAc molecule on the iron handle. Phosphorylation at the same site prevents a lengthy C-terminal region including residues 73 to 140 from incorporating into the fibril core due to electrostatic repulsion. Instead, the N-terminal half of the fibril (1–72) takes on an arch-like fibril structure. We further show that both pS87 and gS87 α-synuclein fibrils display reduced neurotoxicity and propagation activity compared with unmodified α-synuclein fibrils. Our findings demonstrate that different posttranslational modifications at the same site can produce distinct fibril structures, which emphasizes link between posttranslational modifications and amyloid fibril formation and pathology. Here, the authors use cryo-EM to show that phosphorylating or O-GlcNAcylating α-synuclein on serine 87 leads to the formation of two distinct fibril structures. Both structures display reduced neurotoxicity and propagation activity.

Synucleinopathies are a group of neurodegenerative diseases associated with alpha-synuclein (α-Syn) aggregation. Recently, increasing evidence has demonstrated the existence of different structural characteristics or ‘strains’ of α-Syn, supporting the concept that synucleinopathies share several common features with prion diseases and possibly explaining how a single protein results in different clinical phenotypes within synucleinopathies. In earlier studies, the different strains were generated through the regulation of solution conditions, temperature, or repetitive seeded fibrillization in vitro . Here, we synthesize homogeneous α-Syn phosphorylated at serine 129 (pS129 α-Syn), which is highly associated with the pathological changes, and demonstrate that phosphorylation at Ser129 induces α-Syn to form a distinct strain with different structures, propagation properties, and higher cytotoxicity compared with the wild-type α-Syn. The results are the first demonstration that post-translational modification of α-Syn can induce different strain formation, offering a new mechanism for strain formation.

Background Formin, a highly conserved multi-domain protein, interacts with microfilaments and microtubules. Although specifically expressed formin genes in anthers are potentially significant in research on male sterility and hybrid wheat breeding, similar reports in wheat, especially in thermo-sensitive genic male sterile (TGMS) wheat, remain elusive. Results Herein, we systematically characterized the formin genes in TGMS wheat line BS366 named TaFormins ( TaFHs ) and predicted their functions in inducing stress response. In total, 25 TaFH genes were uncovered, majorly localized in 2A, 2B, and 2D chromosomes. According to the neighbor-joining (NJ) method, all TaFH proteins from wheat and other plants clustered in 6 sub-groups (A-F). The modeled 3D structures of TaFH1-A/B, TaFH2-A/B, TaFH3-A/B and TaFH3-B/D were validated. And different numbers of stress and hormone-responsive regulatory elements in their 1500 base pair promoter regions were contained in the TaFH genes copies. TaFHs had specific temporal and spatial expression characteristics, whereby TaFH1 , TaFH4 , and TaFH5 were expressed highly in the stamen of BS366. Besides, the accumulation of TaFHs was remarkably lower in a low-temperature sterile condition (Nanyang) than fertile condition (Beijing), particularly at the early stamen development stage. The pollen cytoskeleton of BS366 was abnormal in the three stages under sterile and fertile environments. Furthermore, under different stress levels, TaFHs expression could be induced by drought, salt, abscisic acid (ABA), salicylic acid (SA), methyl jasmonate (MeJA), indole-3-acetic acid (IAA), polyethylene glycol (PEG), and low temperature. Some miRNAs, including miR167, miR1120, and miR172, interacts with TaFH genes; thus, we constructed an interaction network between microRNAs, TaFHs, phytohormone responses, and distribution of cytoskeleton to reveal the regulatory association between upstream genes of TaFH family members and sterile. Conclusions Collectively, this comprehensive analysis provides novel insights into TaFHs and miRNA resources for wheat breeding. These findings are, therefore, valuable in understanding the mechanism of TGMS fertility conversion in wheat.

Background Two-line hybrid wheat technology system is one way to harness wheat heterosis both domestically and internationally. Seed vigor is a crucial parameter for assessing seed quality, as enhanced seed vigor can lead to yield increments of over 20% to a certain extent. MicroRNAs (miRNAs) were known to participate in the development and vigor of seed in plants, but its impact on seed vigor in two-line hybrid wheat remains poorly elucidated. Results The hybrid (BS1453/11GF5135) wheat exhibited superiority in seed vigor and anti-aging capacity, compared to its male parent (11GF5135, MP) and female parent (BS1453, FP). We identified four miRNAs associated with seed vigor, all of which are novel miRNAs. The majority of targets of miRNAs were related to ubiquitin ligases, kinases, sucrose synthases and hydrolases, involving in starch and sucrose metabolism, hydrolysis, catalysis, plant hormone signal transduction, and other pathways, which played crucial roles in seed development. Additionally, we also found miR531 was differentially expressed in both male parent and hybrid, and its target gene was a component of the E1 subunit of α-ketoate dehydrogenase complex, which interacted with dihydrolipoamide acetyltransferase (E2) and dihydrolipoyl dehydrogenase (E3). Finally, We established a presumptive interaction model to speculate the relationship of miR531 and seed vigor. Conclusions This study analyzed the seed vigor of two-line hybrid wheat, and screened seed vigor-related miRNAs. Meanwhile speculated the genetic relationship of hybrid and parents, in terms of miRNAs. Consequently, the present study provides new insights into the miRNA-mediated gene and protein interaction network that regulates seed vigor. These findings hold significance for enhancing the yield and quality of two-line hybrid wheat, facilitating its future applications.

Background Communication between cancer cells and tumor microenvironment (TME) plays a complicated role in cancer malignancy. Circular RNAs (circRNAs), known for their stability and conservation, contribute to TME remodeling in various cancers. This study aims to investigate the role of N6-methyladenosine (m6A)-modified circZNF548 in the proliferation and migration of non-small cell lung cancer (NSCLC) within the TME. Results circZNF548 expression is lower in NSCLC tissues than that in adjacent normal controls, and the higher circZNF548 levels correlate with the improved patient survival. circZNF548 overexpression suppresses NSCLC cell proliferation and migration, whereas siRNA-mediated downregulation promotes proliferation and migration. METTL14 overexpression decreases circZNF548 levels through m6A modification, whereas siRNA-mediated METTL14 downregulation increases them. circZNF548 interacts with and regulates the abundance of exosomal miR-7108-3p. CD8A and junction-mediating and regulating Y protein (JMY) are identified as downstream targets of miR-7108-3p. Exosomal miR-7108-3p suppresses the activation of CD3 + CD8 + T cells by decreasing CD107a levels and downregulating the production of IFN-γ, perforin 1, and granzyme B in TME. circZNF548 promotes CD3 + CD8 + T cell-mediated cytotoxicity and inhibits NSCLC cell proliferation by modulating exosomal miR-7108-3p and the JMY-p53 pathway. Conclusions m6A-modified circZNF548 suppresses NSCLC cell proliferation and migration by enhancing anti-tumor immunity via exosomal miR-7108-3p and the JMY-p53 pathway. These findings suggest new therapeutic targets for NSCLC. Highlights • circZNF548, affected by METTL14 through m6A, could suppress NSCLC cell proliferation by regulating the activation of CD3 + CD8 + T cells through exosomal miR-7108-3p and miR-7108-3p-JMY-p53 pathway. • Exosomal miR-7108-3p treatment suppressed the activation of CD3 + CD8 + T cells through decreasing CD107a levels and downregulating IFN-γ, perforin 1, and Granzyme B production. • CD8A was another downstream factor of miR-7108-3p, and CD8A-3ʹ-UTR recovery attenuated miR-7108-3p-promoting cell proliferation and cell migration.

The drug resistance and low response rates of immunotherapy limit its application. This study aimed to construct a new nanoparticle (CaCO -polydopamine-polyethylenimine, CPP) to effectively deliver interleukin-12 (IL-12) and suppress cancer progress through immunotherapy. The size distribution of CPP and its zeta potential were measured using a Malvern Zetasizer Nano-ZS90. The morphology and electrophoresis tentative delay of CPP were analyzed using a JEM-1400 transmission electron microscope and an ultraviolet spectrophotometer, respectively. Cell proliferation was analyzed by MTT assay. Proteins were analyzed by Western blot. IL-12 and HMGB1 levels were estimated by ELISA kits. Live/dead staining assay was performed using a Calcein-AM/PI kit. ATP production was detected using an ATP assay kit. The xenografts in vivo were estimated in C57BL/6 mice. The levels of CD80 /CD86 , CD3 /CD4 and CD3 /CD8 were analyzed by flow cytometry. CPP could effectively express EGFP or IL-12 and increase ROS levels. Laser treatment promoted CPP-IL-12 induced the number of dead or apoptotic cell. CPP-IL-12 and laser could further enhance CALR levels and extracellular HMGB1 levels and decrease intracellular HMGB1 and ATP levels, indicating that it may induce immunogenic cell death (ICD). The tumors and weights of xenografts in CPP-IL-12 or laser-treated mice were significantly reduced than in controls. The IL-12 expression, the CD80 /CD86 expression of DC from lymph glands, and the number of CD3 /CD8 T or CD3 /CD4 T cells from the spleen increased in CPP-IL-12-treated or laser-treated xenografts compared with controls. The levels of granzyme B, IFN-γ, and TNF-α in the serum of CPP-IL-12-treated mice increased. Interestingly, CPP-IL-12 treatment in local xenografts in the back of mice could effectively inhibit the growth of the distant untreated tumor. The novel CPP-IL-12 could overexpress IL-12 in melanoma cells and achieve immunotherapy to melanoma through inducing ICD, activating CD4 T cell, and enhancing the function of tumor-reactive CD8 T cells.

Amyloid proteins are closely related with amyloid diseases and do tremendous harm to human health. However, there is still a lack of effective strategies to treat these amyloid diseases, so it is important to develop novel methods. Accelerating the clearance of amyloid proteins is a favorable method for amyloid disease treatment. Recently, chemical methods for protein reduction have been developed and have attracted much attention. In this review, we focus on the latest progress of chemical methods that knock down amyloid proteins, including the proteolysis-targeting chimera (PROTAC) strategy, the “recognition-cleavage” strategy, the chaperone-mediated autophagy (CMA) strategy, the selectively light-activatable organic and inorganic molecules strategy and other chemical strategies.

This study aims to develop an innovative delivery system, (Q+M/MnOx)@Clip, to enhance the bioavailability and therapeutic efficacy of quercetin both in tumor treatment and pain alleviation. The (Q+M/MnOx)@Clip system was evaluated to enhance the release of quercetin, investigate its ability to target cancer cells, alleviate tumor hypoxia, and improve the efficacy of chemodynamic therapy (CDT). Tumor hypoxia markers and immune response activation were assessed, along with the impact on pain relief biomarkers. (Q+M/MnOx)@Clip successfully mitigated tumor hypoxia, facilitated controlled Q release, and enhanced CDT in vitro and in vivo. The system demonstrated a dual therapeutic effect: anti-tumor immunity and significant cancer pain relief by reducing HIF-1α and VEGF-A levels. The novel (Q+M/MnOx)@Clip system represents a promising advancement in nanomedicine, improving the bioavailability of quercetin and offering a more effective approach to cancer treatment by downregulation of HIF-1α and VEGF-A. This study demonstrates the potential for combining anti-tumor immunity with pain relief for triple-negative breast cancer therapy.

IntroductionDry eye (DE) is a multifactorial ocular surface disease causing considerable medical, social and financial implications. Currently, there is no recognised long-term, effective treatment to alleviate DE. Clinical evidence shows that electroacupuncture (EA) can improve DE symptoms, tear secretion and tear film stability, but it remains controversial whether it is just a placebo effect. We aim to provide solid clinical evidence for the EA treatment of DE.Methods and analysisThis is a multicentre, randomised, sham-controlled trial. A total of 168 patients with DE will be enrolled and randomly assigned to EA or sham EA groups to receive 4-week consecutive treatments and follow-up for 24 weeks. The primary outcome is the change in the non-invasive tear break-up time (NIBUT) from baseline to week 4. The secondary outcomes include tear meniscus height, the Schirmer I test, corneal and conjunctival sensation, the ocular surface disease index, corneal fluorescein staining, the numerical rating scale and the Chinese DE-related quality of life scale.Ethics and disseminationThe trial protocol and informed consent were approved by the Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine (identifier: 2021–119), Shanghai Eye Disease Prevention and Treatment Center (identifier: 2022SQ003) and Eye and ENT Hospital of Fudan University (identifier: 2022014).Trial registration numberNCT05552820.