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Tanshinone IIA, a fat-soluble diterpenoid isolated from Salvia miltiorrhiza Bunge, has been shown to attenuate the cerebral ischemic injury. The aim of this study was to examine the effects on neuroprotection and microglia activation of Tanshinone IIA. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO). We found that Tanshinone IIA significantly reduced infarction volume, alleviated neuronal injuries, reduced the release of TNF-α, IL-1β, and IL-6, increased SOD activity, and decrease the content of MDA in MCAO rats. Hematoxylin and eosin staining, Nissl staining, TUNEL staining and immunofluorescence staining showed that Tanshinone IIA improved the distribution and morphology of neurons in brain tissues and reduced apoptosis. In addition, Co-immunofluorescence staining of rat brain tissues and the mRNA expression levels of CD11b, CD32, iNOS, and Arg-1, CD206, IL-10 in BV2 cells indicated that Tanshinone IIA can downregulate M1 microglia and upregulate M2 microglia in MCAO rats. Further, BV2 microglial cells were subjected to oxygen-glucose deprivation, the protein expression levels were detected by western blot. Tanshinone IIA inhibited the expression levels of NF-κB signaling pathway related proteins. Taken together, this study suggested that Tanshinone IIA modulated microglial M1/M2 polarization via the NF-κB signaling pathway to confer anti-neuroinflammatory effects.

China's coastal cities face increasingly severe compound flooding driven by rainfall and sea levels under climate change. However, the spatiotemporal variation patterns of compound inundation across China's coast remain insufficiently assessed. Here, we develop a statistical–hydrodynamic coupling framework to quantify historical (1979–2008) and future (2031–2060) compound inundation across 16 major coastal cities under historical, SSP2‐4.5 and SSP5‐8.5 scenarios. We pair design daily rainfall and design peak sea levels for each scenario and six return periods, convert them into 24 hr boundary forcing time series, and drive SFINCS to simulate compound inundation under combined, rainfall‐only, and sea level‐only conditions. We evaluate inundated area, mean and extreme inundation depth, and quantify dominance drivers and the compound effects. Results reveal strong spatiotemporal differences: the central coast tends to exhibit larger inundation extents, the southern coast deeper mean inundation depths, and the northern coast higher extreme inundation depths. Rainfall exerts stronger control on inundation extent, whereas sea level forcing governs inundation depth, with stronger rainfall dominance for inundated area in northern coast and stronger sea level dominance for mean depth in central coast. Compound effects can significantly increase extreme inundation depth, and their impact on inundated area is most pronounced in the central coast. The extreme inundation depth in Taizhou rises by 1.99 m, while 60% of Shanghai's inundated area will be affected under T = 100 years. This study provides a scientific basis for zonal prevention and control as well as differentiated adaptation strategies addressing compound flooding risk in coastal Chinese cities under climate change.

Immunotherapy is one of the key strategies for cancer treatment. The cGAS-cGAMP-STING-IRF3 pathway of cytosolic DNA sensing plays a pivotal role in antiviral defense. We report that the STING activator cGAMP possesses significant antitumor activity in mice by triggering the STING-dependent pathway directly. cGAMP enhances innate immune responses by inducing production of cytokines such as interferon-β, interferon-γ and stimulating dendritic cells activation, which induces the cross-priming of CD8 + T cells. The antitumor mechanism of cGAMP was verified by STING and IRF3, which were up-regulated upon cGAMP treatment. STING-deficiency dramatically reduced the antitumor effect of cGAMP. Furthermore, cGAMP improved the antitumor activity of 5-FU and clearly reduced the toxicity of 5-FU. These results demonstrated that cGAMP is a novel antitumor agent and has potential applications in cancer immunotherapy.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) protein that can be secreted and protects dopamine neurons and cardiomyocytes from ER stress and apoptosis. The mechanism of action of extracellular MANF has long been elusive. From a genetic screen for mutants with abnormal ER stress response, we identified the gene Y54G2A.23 as the evolutionarily conserved C. elegans MANF orthologue. We find that MANF binds to the lipid sulfatide, also known as 3- O -sulfogalactosylceramide present in serum and outer-cell membrane leaflets, directly in isolated forms and in reconstituted lipid micelles. Sulfatide binding promotes cellular MANF uptake and cytoprotection from hypoxia-induced cell death. Heightened ER stress responses of MANF-null C. elegans mutants and mammalian cells are alleviated by human MANF in a sulfatide-dependent manner. Our results demonstrate conserved roles of MANF in sulfatide binding and ER stress response, supporting sulfatide as a long-sought lipid mediator of MANF’s cytoprotection. MANF is a secreted ER stress-inducible protein that protects neurons, pancreatic β cells and cardiomyocytes from cell death under oxidative stress, hypoxic or ischemic conditions. Here the authors show that MANF confers cytoprotection through direct binding to sulfatide followed by cellular uptake in both C. elegans and mammalian cells.

We combined untargeted and targeted metabolomics to explore the mechanism of blood circulation and blood stasis activation in the traditional Chinese herb pair Panax notoginseng – Salvia miltiorrhiza (PS). In this study, the right hind limb of SD rats was struck by a 1 kg weight, causing traumatic blood stasis (TBS) model, then the rats were gavaged with PS (at ratios of 1:0, 0:1, 3:1, 1:1, and 1:3) for 5 consecutive days. At the end of treatment, blood samples were collected for blood rheology and metabolomics analysis, and muscle tissues of injured limbs were used for HE staining and q-PCR analysis. The results showed that different ratios of PS reduced swelling and improved stasis and blood viscosity in the injured limbs of rats, and intervened in metabolism by modulating 11, 11, 17, 15, and 13 differential metabolites, respectively. The PS (3:1) shows the best treatment effect and the most differential metabolites regression. Targeted metabolomics shows that PS (3:1) can increase the content of AA, and reduce the content of PGF 2 -α by down-regulating the expression of enzymes Ptgs1 and Cbrl12 and up-regulating the expression of enzyme Hpgd. These results suggested that the PS herb pair exerts its blood stasis activating effects by blocking the conversion of arachidonic acid to prostaglandins. Graphical abstract

Linear polyurethane was synthesized by Diels–Alder (DA) reaction between a polyurethane prepolymer end-capped with furan rings (MPF) and bismaleimide (BMI). The polymerization kinetics were studied following a preliminary kinetic study of the DA reaction between furfuryl alcohol (FA) and BMI compounds by attenuated total reflection infrared, ultraviolet–visible and in situ 1 H NMR spectroscopies, where in situ 1 H NMR spectroscopy was selected as the analytical method of choice to study the DA reaction between MPF and BMI. The results showed that the reaction followed second-order kinetics, and the most beneficial experimental conditions to maximize conversion were identified.

Monocyte locomotion inhibitory factor (MLIF) is a heat-stable pentapeptide from Entamoeba histolytica . Our previous study found that MLIF protects against ischemic stroke in rats and mice and exerts a neuroprotection effect in human neuroblastoma SH-SY5Y cells. Microglia/macrophage polarization has been proven to be vital in the pathology of ischemic stroke. Nevertheless, whether MLIF is able to modulate microglia/macrophage polarization remains unclear. We performed middle cerebral artery occlusion (MCAO) on C57BL/6J male mice and induced cultured BV2 microglia by oxygen-glucose deprivation (OGD), respectively. Immunfluorescence was utilized to detect the M1/2 markers, such as CD206 and CD16/32. qPCR and ELISA were used to detect the signature gene change of M1/2. The MAPK and NF-κB pathway associated proteins were measured by Western blot. To identify the protein target of MLIF, a pull-down assay was performed. We found that MLIF promoted microglia transferring from a “sick” M1 phenotype to a “healthy” M2 phenotype in vivo or in vitro . Furthermore, we proved that eukaryotic elongation factor 1A1 (eEF1A1) was involved in the modulation of microglia/macrophage polarization. Knocking down eEF1A1 by siRNA exhibited the M1 promotion effect and M2 inhibition effect. Taken together, our results demonstrated MLIF modulated microglia/macrophage polarization by targeting eEF1A1 in ischemic stroke.

Monocyte locomotion inhibitory factor (MLIF), a heat-stable pentapeptide, has been shown to exert potent anti-inflammatory effects in ischemic brain injury. In this study, we investigated the neuroprotective action of MLIF against oxygen-glucose deprivation (OGD)-induced injury in human neuroblastoma SH-SY5Y cells. MTT assay was used to assess cell viability, and flow cytometry assay and Hoechst staining were used to evaluate apoptosis. LDH assay was used to exam necrosis. The release of inflammatory cytokines was detected by ELISA. Levels of the apoptosis associated proteins were measured by western blot analysis. To identify the protein target of MLIF, pull-down assay and mass spectrometry were performed. We observed that MLIF enhanced cell survival and inhibited apoptosis and necrosis by inhibiting p-JNK, p53, c-caspase9 and c-caspase3 expression. In the microglia, OGD-induced secretion of inflammatory cytokines was markedly reduced in the presence of MLIF. Furthermore, we found that eukaryotic translation elongation factor 1A2 (eEF1A2) is a downstream target of MLIF. Knockdown eEF1A2 using short interfering RNA (siRNA) almost completely abrogated the anti-apoptotic effect of MLIF in SH-SY5Y cells subjected to OGD, with an associated decrease in cell survival and an increase in expression of p-JNK and p53. These results indicate that MLIF ameliorates OGD-induced SH-SY5Y neuroblastoma injury by inhibiting the p-JNK/p53 apoptotic signaling pathway via eEF1A2. Our findings suggest that eEF1A2 may be a new therapeutic target for ischemic brain injury.

Macrobrachium nipponense is one of the major economic species in freshwater aquaculture in China. As an important component of aquaculture ecosystem, microorganisms participate in key processes such as material cycling and water quality regulation, exerting significant impacts on the cultured organisms. In this study, high-throughput sequencing of the 16S rRNA, 18S rRNA, and ITS regions was employed to comparatively analyze the characteristics of microbial communities before and during the cultivation period, combined with correlation analysis of environmental factors. The results showed that the dominant microbial groups in the prawn pond water were Proteobacteria, Cyanobacteria, Ascomycota, Basidiomycota, Chlorophyta, and Arthropoda. The microbial community structure differed significantly between the pond water during the culture period and the pre-culture external river baseline: manifested as an increase in the relative abundances of Cyanobacteria, Chytridiomycota, and zooplankton, and a decrease in the abundances of Ascomycota, Basidiomycota, and Chlorophyta. Analysis of LEfSe revealed that the low-nitrogen pond was enriched with taxa such as Muribaculaceae; the high-nitrogen pond was enriched with taxa such as Cyanobium_PCC-6307; and the control pond was enriched with taxa such as CL500-29_marine_group. Functional prediction indicated that heterotrophic metabolism-related functions dominated the microbial communities. The abundance of fungal pathogens was significantly higher in the low-nitrogen group, while potential pathogenic bacteria were enriched in the high-nitrogen group. Ammonia nitrogen is a core environmental factor associated with differences in microbial community structure. The findings of this study can provide theoretical references and data support for water quality optimization and the construction of healthy aquaculture models in freshwater shrimp and crab farming waters.