Research Progress on Micro (Nano)Plastics Exposure-Induced miRNA-Mediated Biotoxicity.

Micro- and nano-plastics (MNPs) are ubiquitously distributed in the environment, infiltrate organisms through multiple pathways, and accumulate, thus posing potential threats to human health. MNP exposure elicits changes in microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), thereby precipitating immune, neurological, and other toxic effects. The investigation of MNP exposure and its effect on miRNA expression has garnered increasing attention. Following MNP exposure, circRNAs serve as miRNA sponges by modulating gene expression, while lncRNAs function as competing endogenous RNAs (ceRNAs) by fine-tuning target gene expression and consequently impacting protein translation and physiological processes in cells. Dysregulated miRNA expression mediates mitochondrial dysfunction, inflammation, and oxidative stress, thereby increasing the risk of neurodegenerative diseases, cardiovascular diseases, and cancer. This tract, blood, urine, feces, placenta, and review delves into the biotoxicity arising from dysregulated miRNA expression due to MNP exposure and addresses the challenges encountered in this field. This study provides novel insights into the connections between MNPs and disease risk.

Research Progress on Micro(nano)plastic-Induced Programmed Cell Death Associated with Disease Risks.

Due to their robust migration capabilities, slow degradation, and propensity for adsorbing environmental pollutants, micro(nano)plastics (MNPs) are pervasive across diverse ecosystems. They infiltrate various organisms within different food chains through multiple pathways including inhalation and dermal contact, and pose a significant environmental challenge in the 21st century. Research indicates that MNPs pose health threats to a broad range of organisms, including humans. Currently, extensive detection data and studies using experimental animals and in vitro cell culture indicate that MNPs can trigger various forms of programmed cell death (PCD) and can induce various diseases. This review provides a comprehensive and systematic analysis of different MNP-induced PCD processes, including pyroptosis, ferroptosis, autophagy, necroptosis, and apoptosis, based on recent research findings and focuses on elucidating the links between PCD and diseases. Additionally, targeted therapeutic interventions for these diseases are described. This review provides original insights into the opportunities and challenges posed by current research findings. This review evaluates ways to mitigate various diseases resulting from cell death patterns. Moreover, this paper enhances the understanding of the biohazards associated with MNPs by providing a systematic reference for subsequent toxicological research and health risk mitigation efforts.

Site-selective S-gem-difluoroallylation of unprotected peptides with 3,3-difluoroallyl sulfonium salts.

Bench-stable 3,3-difluoroallyl sulfonium salts (DFASs), featuring tunable activity and their editable C-ß and gem-difluoroallyl group, proved to be versatile fluoroalkylating reagents for site-selective S-gem-difluoroallylation of cysteine residues in unprotected peptides. The reaction proceeds with high efficiency under mild conditions (ambient temperature and aqueous and weak basic conditions). Various protected/unprotected peptides, especially bioactive peptides, are site-selectively S-gem-difluoroallylated. The newly added gem-difluoroallyl group and other functional groups derived from C-ß of DFASs are poised for ligation with bio-functional groups through click and radical chemistry. This stepwise "doubly orthogonal" modification of peptides enables the construction of bioconjugates with enhanced complexity and functionality. This proof of principle is successfully applied to construct a peptide-saccharide-biotin chimeric bioconjugate, indicating its great potential application in medicinal chemistry and chemical biology.

Benzimidazole-based structure optimization to discover novel anti-gastric cancer agents targeting ROS/MAPK pathway.

Given the malignancy of gastric cancer, developing highly effective and low-toxic targeted drugs is essential to prolong patient survival and improve patient outcomes. In this study, we conducted structural optimizations based on the benzimidazole scaffold. Notably, compound 8 f presented the most potent antiproliferative activity in MGC803 cells and induced cell cycle arrest at the G0/G1 phase. Further mechanistic studies demonstrated that compound 8 f caused the apoptosis of MGC803 cells by elevating intracellular reactive oxygen species (ROS) levels and activating the mitogen-activated protein kinase (MAPK) signaling pathway, accompanied by corresponding markers change. In vivo investigations additionally validated the inhibitory effect of compound 8 f on tumor growth in xenograft models bearing MGC803 cells without obvious toxicity. Our studies suggest that compound 8 f holds promise as a potential and safe lead compound for developing anti-gastric cancer agents.

Root-soil-microbiome interaction in the rhizosphere of Masson pine (Pinus massoniana) under different levels of heavy metal pollution.

Heavy metal pollution of the soil affects the environment and human health. Masson pine is a good candidate for phytoremediation of heavy metal in mining areas. Microorganisms in the rhizosphere can help with the accumulation of heavy metal in host plants. However, studies on its rhizosphere bacterial communities under heavy metal pollution are still limited. Therefore, in this study, the chemical and bacterial characteristics of Masson pine rhizosphere under four different levels of heavy metal pollution were investigated using 16 S rRNA gene sequencing, soil chemistry and analysis of plant enzyme activities. The results showed that soil heavy metal content, plant oxidative stress and microbial diversity damage were lower the farther they were from the mine dump. The co-occurrence network relationship of slightly polluted soils (C1 and C2) was more complicated than that of highly polluted soils (C3 and C4). Relative abundance analysis indicated Sphingomonas and Pseudolabrys were more abundant in slightly polluted soils (C1 and C2), while Gaiella and Haliangium were more abundant in highly polluted soils (C3 and C4). LEfSe analysis indicated Burkholderiaceae, Xanthobacteraceae, Gemmatimonadaceae, Gaiellaceae were significantly enriched in C1 to C4 site, respectively. Mantel analysis showed that available cadmium (Cd) contents of soil was the most important factor influencing the bacterial community assembly. Correlation analysis showed that eight bacterial genus were significantly positively associated with soil available Cd content. To the best of our knowledge, this is the first study to investigate the rhizospheric bacterial community of Masson pine trees under different degrees of heavy metal contamination, which lays the foundation for beneficial bacteria-based phytoremediation using Masson pines in the future.

Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold.

SHP2 plays a critical role in modulating tumor growth and PD-1-related signaling pathway, thereby serving as an attractive antitumor target. To date, no antitumor drugs targeting SHP2 have been approved, and hence, the search of SHP2 inhibitors with new chemical scaffolds is urgently needed. Herein, we developed a novel SHP2 allosteric inhibitor SDUY038 with a furanyl amide scaffold, demonstrating potent binding affinity (KD = 0.29 µM), enzymatic activity (IC50 = 1.2 µM) and similar binding interactions to SHP099. At the cellular level, SDUY038 exhibited pan-antitumor activity (IC50 = 7-24 µM) by suppressing pERK expression. Furthermore, SDUY038 significantly inhibited tumor growth in both xenograft and organoid models. Additionally, SDUY038 displayed acceptable bioavailability (F = 14%) and half-life time (t1/2 = 3.95 h). Conclusively, this study introduces the furanyl amide scaffold as a novel class of SHP2 allosteric inhibitors, offering promising lead compounds for further development of new antitumor therapies targeting SHP2.

STCS-Net: a medical image segmentation network that fully utilizes multi-scale information.

In recent years, significant progress has been made in the field of medical image segmentation through the application of deep learning and neural networks. Numerous studies have focused on optimizing encoders to extract more comprehensive key information. However, the importance of decoders in directly influencing the final output of images cannot be overstated. The ability of decoders to effectively leverage diverse information and further refine crucial details is of paramount importance. This paper proposes a medical image segmentation architecture named STCS-Net. The designed decoder in STCS-Net facilitates multi-scale filtering and correction of information from the encoder, thereby enhancing the accuracy of extracting vital features. Additionally, an information enhancement module is introduced in skip connections to highlight essential features and improve the inter-layer information interaction capabilities. Comprehensive evaluations on the ISIC2016, ISIC2018, and Lung datasets validate the superiority of STCS-Net across different scenarios. Experimental results demonstrate the outstanding performance of STCS-Net on all three datasets. Comparative experiments highlight the advantages of our proposed network in terms of accuracy and parameter efficiency. Ablation studies confirm the effectiveness of the introduced decoder and skip connection module. This research introduces a novel approach to the field of medical image segmentation, providing new perspectives and solutions for future developments in medical image processing and analysis.

Copper Difluorocarbene Enables Catalytic Difluoromethylation.

Despite the synthetic versatility of difluorocarbene, its high reactivity severely regulates widespread applications of difluorocarbene in organic synthesis. Here, we report a copper difluorocarbene-involved catalytic coupling, representing a new mode of the difluoromethylation reaction. This method allows difluoromethylation of a wide range of readily available allyl/propargyl electrophiles with NaBH3CN and low-cost difluorocarbene precursor BrCF2CO2K, featuring high cost-efficiency, high stereo- and regioselectivities, and high functional group tolerance, even with complex drug-like molecules. Applying the method led to the efficient synthesis of deuterated difluoromethylated compounds of medicinal interest. The resulting difluoromethylated allyl and allenyl products can serve as versatile synthons for diverse transformations, rendering the approach attractive for synthesizing complex fluorinated structures. Experimental mechanistic studies and computational calculations reveal that the formation of a difluoromethylcopper(I) intermediate through the nucleophilic attack of boron hydride on the copper(I) difluorocarbene is the key step in the reaction.

Enhancing Seed Germination of Cremastra appendiculata: Screening and Identification of Four New Symbiotic Fungi in the Psathyrellaceae Family.

Several coprinoid fungi have been identified as promotors of Cremastra appendiculata seed germination, while others appear ineffective. This study aimed to discern which genera within the Psathyrellaceae family exhibit this capability and to identify the most effective coprinoid fungi for the cultivation of C. appendiculata. We collected 21 coprinoid fungi from diverse sources and symbiotically cultured them with C. appendiculata seeds. 9 fungi were found to induce seed germination and support seed development, specifically within the genera Coprinellus, Tulosesus, and Candolleomyces. In contrast, fungi that failed to promote germination predominantly belonged to the genera Coprinopsis and Parasola. Notably, four fungi-Coprinellus xanthothrix, Coprinellus pseudodisseminatus, Psathyrella singeri, and Psathyrella candolleana-were documented for the first time as capable of enhancing C. appendiculata seed germination. Strain 218LXJ-10, identified as Coprinellus radians, demonstrated the most significant effect and has been implemented in large-scale production, underscoring its considerable practical value. These findings contribute vital scientific insights for the conservation and sustainable use of C. appendiculata resources.

Lycorine relieves the CCl4-induced liver fibrosis mainly via the JAK2/STAT3 and PI3K/AKT signaling pathways.

Liver fibrosis, a progressive process of fibrous scarring, results from the accumulation of extracellular matrix proteins (ECM). If left untreated, it often progresses to diseases such as cirrhosis and hepatocellular carcinoma. Lycorine, a natural alkaloid derived from medicinal plants, has shown diverse bioactivities by targeting JAK2/STAT3 signaling, but its pharmacological effects and potential molecular mechanisms in liver fibrosis remains largely unexplored. The purpose of this study is to elucidate the pharmacological activity and molecular mechanism of lycorine in anti-hepatic fibrosis. Findings indicate that lycorine significantly inhibited hepatic stellate cells (HSCs) activation by reducing the expression of α-SMA and collagen-1. In vivo, lycorine treatment alleviated carbon tetrachloride (CCl4) -induced mice liver fibrosis, improving liver function, decreasing ECM deposition, and inhibiting fibrosis-related markers' expression. Mechanistically, it was found that lycorine exerts protective activity through the JAK2/STAT3 and PI3K/AKT signaling pathways, as evidenced by transcriptome sequencing technology and small molecule inhibitors. These results underscore lycorine's potential as a therapeutic drug for liver fibrosis.

Understanding the links between micro/nanoplastics-induced gut microbes dysbiosis and potential diseases in fish: A review.

At present, the quantity of micro/nano plastics in the environment is steadily rising, and their pollution has emerged as a global environmental issue. The tendency of their bioaccumulation in aquatic organisms (especially fish) has intensified people's attention to their persistent ecotoxicology. This review critically studies the accumulation of fish in the intestines of fish through active or passive intake of micro/nano plastics, resulting in their accumulation in intestinal organs and subsequent disturbance of intestinal microflora. The key lies in the complex toxic effect on the host after the disturbance of fish intestinal microflora. In addition, this review pointed out the characteristics of micro/nano plastics and the effects of their combined toxicity with adsorbed pollutants on fish intestinal microorganisms, in order to fully understand the characteristics of micro/nano plastics and emphasize the complex interaction between MNPs and other pollutants. We have an in-depth understanding of MNPs-induced intestinal flora disorders and intestinal dysfunction, affecting the host's systemic system, including immune system, nervous system, and reproductive system. The review also underscores the imperative for future research to investigate the toxic effects of prolonged exposure to MNPs, which are crucial for evaluating the ecological risks posed by MNPs and devising strategies to safeguard aquatic organisms.

Demethylzeylasteral exerts potent efficacy against non-small-cell lung cancer via the P53 signaling pathway.

Lung cancer has one of the highest mortality rates worldwide, with non-small-cell lung cancer (NSCLC) constituting approximately 85% of all cases. Demethylzeylasteral (DEM), extracted from Tripterygium wilfordii Hook F, exhibits notable anti-tumor properties. In this study, we revealed that DEM could effectively induce NSCLC cell apoptosis. Specifically, DEM can dose-dependently suppress the viability and migration of human NSCLC cells. RNA-seq analysis revealed that DEM regulates the P53-signaling pathway, which was further validated by assessing crucial proteins involved in this pathway. Biacore analysis indicated that DEM has high affinity with the P53 protein. The CDX model demonstrated DEM's anti-tumor actions. This work provided evidence that DEM-P53 interaction stabilizes P53 protein and triggers downstream anti-tumor activities. These findings indicate that DEM treatment holds promise as a potential therapeutic approach for NSCLC, which warrants further clinical assessment in patients with NSCLC.

Repurposing diacerein to suppress colorectal cancer growth by inhibiting the DCLK1/STAT3 signaling pathway.

Double cortin-like kinase 1 (DCLK1) exhibits high expression levels across various cancers, notably in human colorectal cancer (CRC). Diacerein, a clinically approved interleukin (IL)-1ß inhibitor for osteoarthritis treatment, was evaluated for its impact on CRC proliferation and migration, alongside its underlying mechanisms, through both in vitro and in vivo analyses. The study employed MTT assay, colony formation, wound healing, transwell assays, flow cytometry, and Hoechst 33342 staining to assess cell proliferation, migration, and apoptosis. Additionally, proteome microarray assay and western blotting analyses were conducted to elucidate diacerein's specific mechanism of action. Our findings indicate that diacerein significantly inhibits DCLK1-dependent CRC growth in vitro and in vivo. Through high-throughput proteomics microarray and molecular docking studies, we identified that diacerein directly interacts with DCLK1. Mechanistically, the suppression of p-STAT3 expression following DCLK1 inhibition by diacerein or specific DCLK1 siRNA was observed. Furthermore, diacerein effectively disrupted the DCLK1/STAT3 signaling pathway and its downstream targets, including MCL-1, VEGF, and survivin, thereby inhibiting CRC progression in a mouse model, thereby inhibiting CRC progression in a mouse model.

Solamargine improves the therapeutic efficacy of anti-PD-L1 in lung adenocarcinoma by inhibiting STAT1 activation.

OBJECTIVE: The effect of solamargine on lung adenocarcinoma and its effect on STAT1 signaling pathway mediated immune escape were studied through network pharmacology and in vitro and in vivo experiments. METHODS: The solamargine targets were screened using the TCMSP and the LUAD targets were screened using the GeneCard, OMIM, PharmGkb, TTD and DrugBank databases. PPI network analysis and target prediction were performed using GO and KEGG. Colony formation assay, EDU staining, wound healing, transwell assay, Hoechst and flow cytometry were used to detect the effects of solamargine on the proliferation, migration and apoptosis of LUAD. Western blotting (WB) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect P-STAT1 and PD-L1 expression. And immunofluorescence was used to detect P-STAT1 expression. In vivo experiments, C57BL/6 mice were divided into control group, low concentration group, high concentration group, positive control group and combination group. Every other day, following seven consecutive doses, the size of the tumor was assessed. Finally, the expressions of P-STAT1, STAT1, PD-L1 and apoptosis index proteins were detected by WB. RESULTS: The anti-LUAD effect of solamargine was found by wound healing, colony formation assay, transwell assay, hoechst and EdU staining. The results of network pharmacological analysis showed that solamargine could suppress STAT1 expression level. Further enrichment assay of STAT1 showed that STAT1 was associated with immune-related pathways. In addition, molecular signal analysis by WB and RT-qPCR indicated that solamargine could reduce the expression levels of P-STAT1 and PD-L1 in a concentration-dependent manner. According to the results of in vivo assays, combination of solamargine and immune checkpoint inhibitors (ICIs) durvalumab could significantly inhibit the growth of Lewis transplanted tumors in C57BL/6 mice, and no toxic side effect was recoded. CONCLUSION: These results indicated that solamargine could inhibit the proliferation and promote the apoptosis of LUAD. It also could reduce the expression level of P-STAT1 protein and inhibit the expression level of PD-L1. At the same time, the combination with the ICIs can better block the expression of PD-L1 in cells, thereby inhibiting the immune escape pathway of tumor cells and achieving anti-tumor effects. This study proposed a novel combined therapeutic approach, involving the inhibition of STAT1 by solamargine in conjunction with ICIs.

Correlation between RNA N6-methyladenosine and ferroptosis in cancer: current status and prospects.

N6-methyladenosine (m6A) is the most abundant chemical modification in eukaryotic cells. It is a post-transcriptional modification of mRNA, a dynamic reversible process catalyzed by methyltransferase, demethylase, and binding proteins. Ferroptosis, a unique iron-dependent cell death, is regulated by various cell metabolic events, including many disease-related signaling pathways. And different ferroptosis inducers or inhibitors have been identified that can induce or inhibit the onset of ferroptosis through various targets and mechanisms. They have potential clinical value in the treatment of diverse diseases. Until now, it has been shown that in several cancer diseases m6A can be involved in the regulation of ferroptosis, which can impact subsequent treatment. This paper focuses on the concept, function, and biological role of m6A methylation modification and the interaction between m6A and ferroptosis, to provide new therapeutic strategies for treating malignant diseases and protecting the organism by targeting m6A to regulate ferroptosis.

Facile Preparation of ß-Cyclodextrin-Modified Polysulfone Membrane for Low-Density Lipoprotein Adsorption via Dopamine Self-Assembly and Schiff Base Reaction.

A facile method for the immobilization of ß-cyclodextrin on polysulfone membranes with the aim of selectively adsorbing low-density lipoprotein (LDL) was established, which is based on the self-assembly of dopamine on the membrane followed by the Schiff base reaction with mono-(6-ethanediamine-6-deoxy)-ß-cyclodextrin. The surface modification processes were validated using X-ray photoelectron spectroscopy and attenuated total reflectance Fourier-transform infrared spectroscopy. Surface wettability and surface charge of the membranes were investigated through the water contact angle and zeta potential analysis. The cyclodextrin-modified polysulfone membrane (PSF-CD) showed good resistance to protein solutions, as shown by the measurement of BSA adsorption. The assessment of BSA adsorption revealed that the cyclodextrin-modified polysulfone membrane (PSF-CD) exhibited excellent resistance to protein solutions. To investigate the adsorption and desorption behaviors of the membranes in single-protein or binary-protein solutions, an enzyme-linked immunosorbent assay was employed. The results revealed that the PSF-CD possessed remarkable adsorption capacity and higher affinity for LDL in both single-protein and binary-protein solutions, rendering it a suitable material for LDL apheresis.

Mining oomycete proteomes for phosphatome leads to the identification of specific expanded phosphatases in oomycetes.

Phosphatases are important regulators of protein phosphorylation and various cellular processes, and they serve as counterparts to kinases. In this study, our comprehensive analysis of oomycete complete proteomes unveiled the presence of approximately 3833 phosphatases, with most species estimated to have between 100 and 300 putative phosphatases. Further investigation of these phosphatases revealed a significant increase in protein serine/threonine phosphatases (PSP) within oomycetes. In particular, we extensively studied the metallo-dependent protein phosphatase (PPM) within the PSP family in the model oomycete Phytophthora sojae. Our results showed notable differences in the expression patterns of PPMs throughout 10 life stages of P. sojae, indicating their vital roles in various stages of oomycete pathogens. Moreover, we identified 29 PPMs in P. sojae, and eight of them possessed accessory domains in addition to phosphate domains. We investigated the biological function of one PPM protein with an extra PH domain (PPM1); this protein exhibited high expression levels in both asexual developmental and infectious stages. Our analysis confirmed that PPM1 is indeed an active protein phosphatase, and its accessory domain does not affect its phosphatase activity. To delve further into its function, we generated knockout mutants of PPM1 and validated its essential roles in mycelial growth, sporangia and oospore production, as well as infectious stages. To the best of our knowledge, this study provides the first comprehensive inventory of phosphatases in oomycetes and identifies an important phosphatase within the expanded serine/threonine phosphatase group in oomycetes.

Late-stage gem-difluoroallylation of phenol in bioactive molecules and peptides with 3,3-difluoroallyl sulfonium salts.

An efficient method for the late-stage selective O-fluoroalkylation of tyrosine residues with a stable yet highly reactive fluoroalkylating reagent, 3,3-difluoroallyl sulfonium salts (DFASs), has been developed. The reaction proceeds in a mild basic aqueous buffer (pH = 11.6) with high efficiency, high biocompatibility, and excellent regio- and chemoselectivity. Various oligopeptides and phenol-containing bioactive molecules, including carbohydrates and nucleosides, could be selectively O-fluoroalkylated. The added vinyl and other functional groups from DFASs can be valuable linkers for successive modification, significantly expanding the chemical space for further bioconjugation. The synthetic utility of this protocol has been demonstrated by the fluorescently labeled anti-cancer drug and the synthesis of O-link type 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid-tyrosine3-octreotate (DOTA-TATE), showing the prospect of the method in medicinal chemistry and chemical biology.

Research advances in microfluidic collection and detection of virus, bacterial, and fungal bioaerosols.

Bioaerosols are airborne suspensions of fine solid or liquid particles containing biological substances such as viruses, bacteria, cellular debris, fungal spores, mycelium, and byproducts of microbial metabolism. The global Coronavirus disease 2019 (COVID-19) pandemic and the previous emergence of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and influenza have increased the need for reliable and effective monitoring tools for bioaerosols. Bioaerosol collection and detection have aroused considerable attention. Current bioaerosol sampling and detection techniques suffer from long response time, low sensitivity, and high costs, and these drawbacks have forced the development of novel monitoring strategies. Microfluidic technique is considered a breakthrough for high performance analysis of bioaerosols. In recent years, several emerging methods based on microfluidics have been developed and reported for collection and detection of bioaerosols. The unique advantages of microfluidic technique have enabled the integration of bioaerosol collection and detection, which has a higher efficiency over conventional methods. This review focused on the research progress of bioaerosol collection and detection methods based on microfluidic techniques, with special attention on virus aerosols and bacterial aerosols. Different from the existing reviews, this work took a unique perspective of the targets to be collected and detected in bioaerosols, which would provide a direct index of bioaerosol categories readers may be interested in. We also discussed integrated microfluidic monitoring system for bioaerosols. Additionally, the application of bioaerosol detection in biomedicine was presented. Finally, the current challenges in the field of bioaerosol monitoring are presented and an outlook given of future developments.

CDK4/6 inhibitors in lung cancer: current practice and future directions.

Lung cancer is the leading cause of cancer-related deaths worldwide, and ∼85% of lung cancers are classified as nonsmall cell lung cancer (NSCLC). These malignancies can proliferate indefinitely, in part due to dysregulation of the cell cycle and the resulting abnormal cell growth. The specific activation of cyclin-dependent kinases 4 and 6 (CDK4/6) is closely linked to tumour proliferation. Approximately 80% of human tumours exhibit abnormalities in the cyclin D-CDK4/6-INK4-RB pathway. Specifically, CDK4/6 inhibitors either as monotherapy or combination therapy have been investigated in pre-clinical and clinical studies for the treatment of NSCLC, and promising results have been achieved. This review article focuses on research regarding the use of CDK4/6 inhibitors in NSCLC, including the characteristics and mechanisms of action of approved drugs and progress of pre-clinical and clinical research.