ZIPK collaborates with STAT5A in p53-mediated ROS accumulation in hyperglycemia-induced vascular injury.

In this study we investigate the role of Zipper-interacting protein kinase (ZIPK) in high glucose-induced vascular injury, focusing on its interaction with STAT5A and its effects on p53 and inducible nitric oxide synthase (NOS2) expression. Human umbilical vein endothelial cells (HUVECs) are cultured under normal (5 mM) and high (25 mM) glucose conditions. Protein and gene expression levels are assessed by western blot analysis and qPCR respectively, while ROS levels are measured via flow cytometry. ZIPK expression is manipulated using overexpression plasmids, siRNAs, and shRNAs. The effects of the ZIPK inhibitor TC-DAPK6 are evaluated in a diabetic rat model. Our results show that high glucose significantly upregulates ZIPK, STAT5A, p53, and NOS2 expressions in HUVECs, thus increasing oxidative stress. Silencing of STAT5A reduces p53 and NOS2 expressions and reactive oxygen species (ROS) accumulation. ZIPK is essential for high glucose-induced p53 expression and ROS accumulation, while silencing of ZIPK reverses these effects. Overexpression of ZIPK combined with STAT5A silencing attenuates glucose-induced alterations in p53 and NOS2 expression, thereby preventing cell damage. Coimmunoprecipitation reveals a direct interaction between ZIPK and STAT5A in the nucleus under high-glucose condition. In diabetic rats, TC-DAPK6 treatment significantly decreases ZIPK, p53, and NOS2 expressions. Our findings suggest that ZIPK plays a critical role in high glucose-induced vascular injury via STAT5A-mediated pathways, proposing that ZIPK is a potential therapeutic target for diabetic vascular complications.

Enhanced consolidation and removal of accumulated flocculants in dredged soil via leaching with vacuum preloading.

The vacuum preloading coupling flocculation treatment is a widely employed method for reinforcing soils with high water content in practical construction. However, uneven distribution and accumulation of flocculants pose significant damage to the soil environment and result in uneven soil consolidation, leading to severe issues in subsequent soil development and exploitation. To address these concerns, an evolved leaching with vacuum method is developed for facilitating soil consolidation while preventing the accumulation of flocculant in the soil. In this study, five model tests are conducted in which FeCl3 is chosen as the typical flocculant to promote soil consolidation, and deionized water is used for leaching. The final discharged water, settlement, water content and penetration resistance of soil are obtained to evaluate the soil reinforcement effect, while the flocculant removal effect is evaluated by the Fe3+ content in the filtrate and soil. The comprehensive reinforcement and flocculant removal effect show that this method is extremely effective compared to traditional vacuum preloading. The two leaching is clarified as the best choice, resulting in a 22% decrease in the soil water content and a 25% in soil penetration resistance, meanwhile a 12.8% removal rate of the flocculant. The test results demonstrate that leaching with vacuum preloading can contribute to promoting soil consolidation and reducing the accumulation of flocculant in the soil, ensuring the safe and eco-friendly use of the soil for future applications. The conclusions obtained are of significant theoretical value and technical support for practical construction and sustainable development.

A terpenoids database with the chemical content as a novel agronomic trait.

Natural products play a pivotal role in drug discovery, and the richness of natural products, albeit significantly influenced by various environmental factors, is predominantly determined by intrinsic genetics of a series of enzymatic reactions and produced as secondary metabolites of organisms. Heretofore, few natural product-related databases take the chemical content into consideration as a prominent property. To gain unique insights into the quantitative diversity of natural products, we have developed the first TerPenoids database embedded with Content information (TPCN) with features such as compound browsing, structural search, scaffold analysis, similarity analysis and data download. This database can be accessed through a web-based computational toolkit available at http://www.tpcn.pro/. By conducting meticulous manual searches and analyzing over 10 000 reference papers, the TPCN database has successfully integrated 6383 terpenoids obtained from 1254 distinct plant species. The database encompasses exhaustive details including isolation parts, comprehensive molecule structures, chemical abstracts service registry number (CAS number) and 7508 content descriptions. The TPCN database accentuates both the qualitative and quantitative dimensions as invaluable phenotypic characteristics of natural products that have undergone genetic evolution. By acting as an indispensable criterion, the TPCN database facilitates the discovery of drug alternatives with high content and the selection of high-yield medicinal plant species or phylogenetic alternatives, thereby fostering sustainable, cost-effective and environmentally friendly drug discovery in pharmaceutical farming. Database URL: http://www.tpcn.pro/.

Microbiological Mechanisms of Collaborative Remediation of Cadmium-Contaminated Soil with Bacillus cereus and Lawn Plants.

Severe cadmium contamination poses a serious threat to food security and human health. Plant-microbial combined remediation represents a potential technique for reducing heavy metals in soil. The main objective of this study is to explore the remediation mechanism of cadmium-contaminated soil using a combined approach of lawn plants and microbes. The target bacterium Bacillus cereus was selected from cadmium-contaminated soil in mining areas, and two lawn plants (Festuca arundinacea A'rid III' and Poa pratensis M'idnight II') were chosen as the target plants. We investigated the remediation effect of different concentrations of bacterial solution on cadmium-contaminated soil using two lawn plants through pot experiments, as well as the impact on the soil microbial community structure. The results demonstrate that Bacillus cereus promotes plant growth, and the combined action of lawn plants and Bacillus cereus improves soil quality, enhancing the bioavailability of cadmium in the soil. At a bacterial suspension concentration of 105 CFU/mL, the optimal remediation treatment was observed. The removal efficiency of cadmium in the soil under Festuca arundinacea and Poa pratensis treatments reached 33.69% and 33.33%, respectively. Additionally, the content of bioavailable cadmium in the rhizosphere soil increased by up to 13.43% and 26.54%, respectively. Bacillus cereus increased the bacterial diversity in the non-rhizosphere soil of both lawn plants but reduced it in the rhizosphere soil. Additionally, the relative abundance of Actinobacteriota and Firmicutes, which have potential for heavy metal remediation, increased after the application of the bacterial solution. This study demonstrates that Bacillus cereus can enhance the potential of lawn plants to remediate cadmium-contaminated soil and reshape the microbial communities in both rhizosphere and non-rhizosphere soils.

GDPD3 Deficiency Alleviates Neuropathic Pain and Reprograms Macrophagic Polarization Through PGE2 and PPARγ Pathway.

The complex mechanism of neuropathic pain involves various aspects of both central and peripheral pain conduction pathways. An effective cure for neuropathic pain therefore remains elusive. We found that deficiency of the gene Gdpd3, encoding a lysophospholipase D enzyme, alleviates the inflammatory responses in dorsal root ganglia (DRG) of mice under neuropathic pain and reduces PE (20:4) and PGE2 in DRG. Gdpd3 deficiency had a stronger analgesic effect on neuropathic pain than Celecoxib, a nonsteroidal anti-inflammatory drug. Gdpd3 deficiency also interferes with the polarization of macrophages, switching from M1 towards M2 phenotype. The PPARγ/ FABP4 pathway was screened by RNA sequencing as functional related with Gdpd3 deficient BMDMs stimulated with LPS. Both protein and mRNA levels of PPARγ in GDPD3 deficient BMDMs were higher than those of the litter control mice. However, GW9962 (inhibitor of PPARγ) could reverse the reprogramming polarization of macrophages caused by GDPD3 deficiency. Therefore, our study suggests that GDPD3 deficiency exerts a relieving effect on neuropathic pain and alleviates neuroinflammation in DRG by switching the phenotype of macrophages from M1 to M2, which was mediated through PGE2 and PPARγ/ FABP4 pathway.

Eu(III) functionalized ZnMOF based efficient dual-emission sensor integrated with self-calibrating logic gate for intelligent detection of epinephrine.

The rapid detection of epinephrine (EPI) in serum holds immense importance in the early disease diagnosis and regular monitoring. On the basis of the coordination post-synthetic modification (PSM) strategy, a Eu3+ functionalized ZnMOF (Eu3+@ZnMOF) was fabricated by anchoring the Eu3+ ions within the microchannels of ZnMOF as secondary luminescent centers. Benefiting from two independent luminescent centers, the prepared Eu3+@ZnMOF shows great potential as a multi-signal self-calibrating luminescent sensor in visually and efficiently detecting serum EPI levels, with high reliability, fast response time, excellentrecycleability, and low detection limits of 17.8 ng/mL. Additionally, an intelligent sensing system was designed in accurately and reliably detecting serum EPI levels, based on the designed self-calibrating logic gates. Furthermore, the possible sensing mechanisms were elucidated through theoretical calculations as well as spectral overlaps. This work provides an effective and promising strategy for developing MOFs-based self-calibrating intelligent sensing platforms to detect bioactive molecules in bodily fluids.

LGP2 Facilitates Bacterial Escape through Binding Peptidoglycan via EEK Motif and Suppressing NOD2-RIP2 Axis in Cyprinidae and Xenocyprididae Families.

RIG-I-like receptors and NOD-like receptors play pivotal roles in recognizing microbe-associated molecular patterns and initiating immune responses. The LGP2 and NOD2 proteins are important members of the RIG-I-like receptor and NOD-like receptor families, recognizing viral RNA and bacterial peptidoglycan (PGN), respectively. However, in some instances bacterial infections can induce LPG2 expression via a mechanism that remains largely unknown. In the current study, we found that LGP2 can compete with NOD2 for PGN binding and inhibit antibacterial immunity by suppressing the NOD2-RIP2 axis. Recombinant CiLGP2 (Ctenopharyngodon idella LGP2) produced using either prokaryotic or eukaryotic expression platform can bind PGN and bacteria in pull-down and ELISA assays. Comparative protein structure models and intermolecular interaction prediction calculations as well as pull-down and colocalization experiments indicated that CiLGP2 binds PGN via its EEK motif with species and structural specificity. EEK deletion abolished PGN binding of CiLGP2, but insertion of the CiLGP2 EEK motif into zebrafish and mouse LGP2 did not confer PGN binding activity. CiLGP2 also facilitates bacterial replication by interacting with CiNOD2 to suppress expression of NOD2-RIP2 pathway genes. Sequence analysis and experimental verification demonstrated that LGP2 having EEK motif that can negatively regulate antibacterial immune function is present in Cyprinidae and Xenocyprididae families. These results show that LGP2 containing EEK motif competes with NOD2 for PGN binding and suppresses antibacterial immunity by inhibiting the NOD2-RIP2 axis, indicating that LGP2 plays a crucial negative role in antibacterial response beyond its classical regulatory function in antiviral immunity.

Gibberellin-Mediated Sensitivity of Rice Roots to Aluminum Stress.

Aluminum toxicity poses a significant constraint on crop production in acidic soils. While phytohormones are recognized for their pivotal role in mediating plant responses to aluminum stress, the specific involvement of gibberellin (GA) in regulating aluminum tolerance remains unexplored. In this study, we demonstrate that external GA exacerbates the inhibitory impact of aluminum stress on root growth of rice seedlings, concurrently promoting reactive oxygen species (ROS) accumulation. Furthermore, rice plants overexpressing the GA synthesis gene SD1 exhibit enhanced sensitivity to aluminum stress. In contrast, the slr1 gain-of-function mutant, characterized by impeded GA signaling, displays enhanced tolerance to aluminum stress, suggesting the negative regulatory role of GA in rice resistance to aluminum-induced toxicity. We also reveal that GA application suppresses the expression of crucial aluminum tolerance genes in rice, including Al resistance transcription factor 1 (ART1), Nramp aluminum transporter 1 (OsNramp4), and Sensitive to Aluminum 1 (SAL1). Conversely, the slr1 mutant exhibits up-regulated expression of these genes compared to the wild type. In summary, our results shed light on the inhibitory effect of GA in rice resistance to aluminum stress, contributing to a theoretical foundation for unraveling the intricate mechanisms of plant hormones in regulating aluminum tolerance.

The evolution of preexisting primary immune thrombocytopenia after COVID-19 onset: A nationally representative, prospective, multicentre, observational study.

The symptoms in patients with primary immune thrombocytopenia (ITP) after COVID-19 onset remain largely unclear. The aim of this study was to describe the platelet count fluctuations in ITP patients following the diagnosis of COVID-19. A prospective multicentre observational study was conducted from December 15th, 2022, to January 31st, 2023 in 39 general hospitals across China. Patients with preexisting primary ITP who were newly diagnosed with COVID-19 were enrolled. A total of 1216 ITP patients with newly-diagnosed COVID-19 were enrolled. 375 (30.8%) patients experienced ITP exacerbation within eight weeks after the diagnosis of COVID-19, and most exacerbation (266/375, 70.9%) developed in the first two weeks. Immunosuppressive therapy for ITP and severe/critical COVID-19 infection were independent variables associated with ITP exacerbation. Overall the platelet count had a transient increasing trend, and the platelet peak value occurred at two weeks after COVID-19 infection. Then, the platelet count decreased to the baseline level in the following weeks. The platelet count had a transient increasing trend in ITP patients following the diagnosis of COVID-19. ITP exacerbation only occurred in less than one-third of ITP patients. Nonimmunosuppressive therapy may have an advantage to prevent ITP exacerbation during COVID-19.

Allosteric inhibitor of SHP2 enhances macrophage endocytosis and bacteria elimination by increasing caveolae activation and protects against bacterial sepsis.

The uncontrolled bacterial infection-induced cytokine storm and sequential immunosuppression are commonly observed in septic patients, which indicates that the activation of phagocytic cells and the efficient and timely elimination of bacteria are crucial for combating bacterial infections. However, the role of dysregulated immune cells and their disrupted function in sepsis remains unclear. Here, we found that macrophages exhibited the impaired endocytosis capabilities in sepsis by Single-cell RNA sequencing and bulk RNA sequencing. Caveolae protein Caveolin-1 (Cav-1) of macrophages was inactivated by SHP2 rapidly during Escherichia coli (E.coli) infection. Allosteric inhibitor of SHP2 effectively maintains Cav-1 phosphorylation to enhance macrophage to endocytose and eliminate bacteria. Additionally, TLR4 endocytosis of macrophage was also enhanced upon E.coli infection by SHP099, inducing an increased and rapidly resolved inflammatory response. In vivo, pretreatment or posttreatment with inhibitor of SHP2 significantly reduced the bacterial burden in organs and mortality of mice subjected E.coli infection or CLP-induced sepsis. The cotreatment of inhibitor of SHP2 with an antibiotic conferred complete protection against mortality in mice. Our findings suggest that Cav-1-mediated endocytosis and bacterial elimination may play a critical role in the pathogenesis of sepsis, highlighting inhibitor of SHP2 as a potential therapeutic agent for sepsis.

Role of autophagy and mitophagy of group 2 innate lymphoid cells in allergic and local allergic rhinitis.

Background: Roles of ILC2s in allergic rhinitis (AR) and local allergic rhinitis (LAR) are unclear. In this study, we are determined to find the levels of autophagy and mitophagy of ILC2s in allergic nasal inflammation. Methods: ELISA was used to detect type 2 inflammatory cytokines. Hematoxylin and eosin (H&E) staining were used to compare the eosinophil (EOS) infiltration of nasal tissue specimens. Flow cytometry was used to detect the levels of ILC2s and Th2 cells. Immunohistochemistry (IHC) and Western blot (WB) were used to detect the levels of Beclin1, LC3, p62, PINK1, Parkin, FUNDC1, and BNIP3 in nasal mucosa. The levels of autophagy related proteins and mitophagy related proteins of the ILC2s were detected by WB. The number of autophagosomes of ILC2s was observed by transmission electron microscopy. The co-localization levels of GFP-LC3 and Mito tracker in ILC2s were observed by confocal microscopy using immunofluorescence. Results: We found that the level of type 2 inflammation in AR and LAR mice was significantly increased. The levels of autophagy and mitophagy of AR and LAR mice in nasal mucosa and ILC2s were both increased. Conclusions: ILC2s may be associated with the occurrence and development of nasal allergic inflammation. The abnormal increase of autophagy and mitophagy levels in the nose may be associated with the incidence of AR and LAR. Abnormal autophagy and mitophagy levels of ILC2s cells may be one of the causes of allergic nasal inflammation.

USP10 promotes migration and cisplatin resistance in esophageal squamous cell carcinoma cells.

Cisplatin-based chemotherapy is the main treatment option for advanced or metastatic esophageal squamous cell carcinoma (ESCC). However, most ESCC patients develop drug resistance within 2 years after receiving cisplatin chemotherapy. Ubiquitin-specific protease 10 (USP10) is abnormally expressed in a variety of cancers, but the mechanistic roles of USP10 in ESCC are still obscure. Here, the effects of USP10 on the migration and cisplatin resistance of ESCC in vivo and in vitro and the underlying mechanisms have been investigated by bioinformatics analysis, RT-PCR, western blotting, immunoprecipitation, immunohistochemistry, cell migration and MTS cell proliferation assays, deubiquitination assay, and mouse tail vein injection model. USP10 was significantly up-regulated in ESCC tissues compared with adjacent normal tissues in both public databases and clinical samples and was closely associated with overall survival. Subsequent results revealed that USP10 contributed to the migration and cisplatin resistance of ESCC cells, while knocking down USP10 in cisplatin-resistant cells exhibited opposite effects in vitro and in vivo. Further Co-IP experiments showed that integrin ß1 and YAP might be targets for USP10 deubiquitination. Moreover, deficiency of USP10 significantly inhibited the migrative and chemo-resistant abilities of ESCC cells, which could be majorly reversed by integrin ß1 or YAP reconstitution. Altogether, USP10 was required for migration and cisplatin resistance in ESCC through deubiquinating and stabilizing integrin ß1/YAP, highlighting that inhibition of USP10 may be a potential therapeutic strategy for ESCC.