Metabolomic Profiling and Biological Investigation of the Marine Sponge-Derived Fungus Aspergillus sp. SYPUF29 in Response to NO Condition.

Marine-derived fungi are assuming an increasingly central role in the search for natural leading compounds with unique chemical structures and diverse pharmacological properties. However, some gene clusters are not expressed under laboratory conditions. In this study, we have found that a marine-derived fungus Aspergillus sp. SYPUF29 would survive well by adding an exogenous nitric oxide donor (sodium nitroprusside, SNP) and nitric oxide synthetase inhibitor (L-NG-nitroarginine methyl ester, L-NAME) in culture conditions. Moreover, using the LC-MS/MS, we initially assessed and characterized the difference in metabolites of Aspergillus sp. SYPUF29 with or without an additional source of nitrogen. We have found that the metabolic pathway of Arginine and proline metabolism pathways was highly enriched, which was conducive to the accumulation of alkaloids and nitrogen-containing compounds after adding an additional source of nitrogen in the cultivated condition. Additionally, the in vitro anti-neuroinflammatory study showed that the extracts after SNP and L-NAME were administrated can potently inhibit LPS-induced NO-releasing of BV2 cells with lower IC50 value than without nitric oxide. Further Western blotting assays have demonstrated that the mechanism of these extracts was associated with the TLR4 signaling pathway. Additionally, the chemical investigation was conducted and led to nine compounds (SF1-SF9) from AS1; and six of them belonged to alkaloids and nitrogen-containing compounds (SF1-SF6), of which SF1, SF2, and SF8 exhibited stronger activities than the positive control, and showed potential to develop the inhibitors of neuroinflammation.

Fabrication of core-shell-like bimetallic SERS substrates with inter-coordination effect for catalysis of p-mercaptoaniline.

The present study discusses the core-shell structures of Au@Ag prepared by a seed-growth method. The morphology and composition of Au@Ag nanoparticles were analyzed, indicating that they were successfully prepared. By studying the surface-enhanced Raman scattering spectra (SERS) of p-mercaptoaniline (PATP) molecules adsorbed on Au@Ag substrates, it was found that PATP molecules could be oxidized to form p-mercaptoazobenzene (DMAB) on Au@Ag substrates, indicating that the gold-silver bimetallic nanomaterials could catalyze the PATP molecules with excellent enhancement effect and stability. In order to further study the enhancement effect of the Au@Ag substrate, the electric field strength of Au nanoparticles and Au@Ag nanoparticles was simulated by using the finite difference time domain (FDTD) method, which showed that the SERS enhancement effect of Au@Ag nanoparticles was more significant as well as consistent with the experimental results. This work provides a reference for further preparation of efficient and stable bimetallic SERS substrates.

HMGA2-mediated glutamine metabolism is required for Cd-induced cell growth and cell migration.

Cadmium (Cd) exposure significantly increases the risk of lung cancer. The demand for glutamine is increasing in cancers, including lung cancer. In this study, we investigated the role of glutamine metabolism in Cd-induced cell growth and migration. Firstly, we found that 2 µM Cd-treatment up-regulated the expression of ASCT2 (alanine, serine, cysteine-preferring transporter 2) and ASNS (asparagine synthetase) while downregulating mitochondrial glutaminase GLS1 in A549 cells. The same results were obtained in male BALB/c mice treated with 0.5 and 1 mg Cd/kg body weight. Subsequently, both glutamine deprivation and transfection with siASCT2 revealed that glutamine played a role in Cd-induced cell growth and migration. Furthermore, using 4-PBA (5 mM), an inhibitor of endoplasmic reticulum (ER) stress, Tm (0.1 µg/ml), an inducer of ER stress, siHMGA2, and over-expressing HMGA2 plasmids we demonstrated that ER stress/HMGA2 axis was involved in inducing ASCT2 and ASNS, while inhibiting GLS1. Additionally, the chromatin immunoprecipitation assay using an HMGA2 antibody revealed the direct binding of the HMGA2 to the promoter sequences of the ASCT2, ASNS, and GLS1 genes. Finally, dual luciferase reporter assay determined that HMGA2 increased the transcription of ASCT2 and ASNS while inhibiting the transcription of GLS1. Overall, we found that ER stress-induced HMGA2 controls glutamine metabolism by transcriptional regulation of ASCT2, ASNS and GLS1 to accelerate cell growth and migration during exposure to Cd at low concentrations. This study innovatively revealed the mechanism of Cd-induced cell growth which offers a fresh perspective on preventing Cd toxicity through glutamine metabolism.

ATF4-mediated different mode of interaction between autophagy and mTOR determines cell fate dependent on the level of ER stress induced by Cr(VI).

Hexavalent chromium [Cr(VI)] exists widely in occupational environments. The mechanistic target of rapamycin (mTOR) has been well-documented to regulate autophagy negatively. However, we found that low concentration of Cr(VI) (0.2 µM) elevated both mTOR and autophagy and promote cell survival. Conversely, high concentration of Cr(VI) (6 µM) caused cell death by inhibiting mTOR and subsequently inducing autophagy. Tunicamycin (Tm), as an Endoplasmic reticulum (ER) stress activator was used to induce mild ER stress at 0.1 µg/ml and it activated both autophagy and mTOR, which also caused cell migration in a similar manner to that observed with low concentration of Cr(VI). Severe ER stress caused by Tm (2 µg/ml) decreased mTOR, increased autophagy and then inhibited cell migration, which was the same as 6 µM Cr(VI) treatment, although Cr(VI) in high concentration inhibited ER stress. Activating transcription factor 4 (ATF4), a downstream target of ER stress, only increased under mild ER stress but decreased under severe ER stress and 6 µM Cr(VI) treatment. Chromatin immunoprecipitation (ChIP) experiment indicated that ATF4 could bind to the promoter of ATG4B and AKT1. To sum up, our data revealed that mild ER stress induced by low concentration of Cr(VI) could enhance transcriptional regulation of ATG4B and AKT1 by ATF4, which induced both autophagy and mTOR to promote cell viability.

Tamarixetin ameliorates cerebral ischemia-reperfusion injury via suppressing nicotinamide adenine dinucleotide phosphate oxidase 2/nucleotide-binding oligomerization domain like receptor family pyrin domain-containing 3 inflammasome activation.

Tamarixetin, a natural dietary flavone, exhibits remarkable potential for the treatment of ischemic stroke. The present article aimed to explore the impact of tamarixetin on ischemic stroke and elucidate the underlying mechanisms. Effects of tamarixetin on ischemic stroke were evaluated in rats using the middle cerebral artery occlusion and reperfusion (MCAO/R) model, by assessing the neurological deficit scores, brain water content, brain infraction, and neuronal damage. The levels of proinflammatory cytokines, NLRP3 inflammasome activation, reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression were measured in MCAO/R rats and lipopolysaccharide-stimulated cells. Tamarixetin administration improved the neurological dysfunction and neuronal loss in MCAO/R rats. In addition, tamarixetin reduced microglial hyperactivation and proinflammatory cytokines expression in vivo and in vitro. Tamarixetin attenuated NF-κB p65 phosphorylation and promoter activity, reduced NLRP3 expression and caspase-1 cleavage, and downregulated IL-1ß and IL-18 secretions to suppress NLRP3 inflammasome activation. The levels of superoxide anion, hydrogen peroxide, and ROS were also suppressed by tamarixetin. The downregulation of NADP+ and NADPH levels, and gp91phox expression indicated the ameliorative effects of tamarixetin on NADPH oxidase activation. In the gp91phox knockdown cells treated with lipopolysaccharide, the effects of tamarixetin on NADPH oxidase activation, ROS generation, and NLRP3 inflammasome activation were diminished. Moreover, tamarixetin protects neurons against microglial hyperactivation in vitro. Our findings support the potential of tamarixetin as a therapeutic agent for ischemic stroke, and its mechanism of action involves the inhibition of NADPH oxidase-NLRP3 inflammasome signaling.

Probe fusion all-optic OCT-PAM dual-mode imaging system for biomedical imaging.

We proposed a non-contact photoacoustic (PA) detection method using spectral domain optical coherence tomography (SDOCT). Two interference spectrums (A-lines) were acquired before and after the PA excitation with SDOCT. PA signal propagated within the sample causing the vibration. The vibration inner the sample introduced phase change between the acquired two A-lines. Thus, the PA signal can be detected by evaluating the difference in phase between the two A-lines. Based on the method, an OCT-PAM dual-mode imaging system was constructed. In the system, SDOCT served as the detection unit for PAM. Thus, the combination of the two imaging modalities was simplified. Another advantage of the system is that it realizes non-contact all-optic detection, which is attractive for biomedical imaging. Using the system, we imaged phantoms of carbon fibers, asparagus leaves and human hairs. Furthermore, the cortical vasculature of rat was imaged in vivo and the flow status was evaluated quantitatively.

Reynosin protects neuronal cells from microglial neuroinflammation by suppressing NLRP3 inflammasome activation mediated by NADPH oxidase.

Neuroinflammation, mediated by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing-3 (NLRP3) inflammasome, is a significant contributor to the pathogenesis of neurodegenerative diseases (NDDs). Reynosin, a natural sesquiterpene lactone (SL), exhibits a broad spectrum of pharmacological effects, suggesting its potential therapeutic value. However, the effects and mechanism of reynosin on neuroinflammation remain elusive. The current study explores the effects and mechanisms of reynosin on neuroinflammation using mice and BV-2 microglial cells treated with lipopolysaccharide (LPS). Our findings reveal that reynosin effectively reduces microglial inflammation in vitro, as demonstrated by decreased CD11b expression and lowered interleukin-1 beta (IL-1ß) and interleukin-18 (IL-18) mRNA and protein levels. Correspondingly, in vivo, results showed a reduction in the number of Iba-1 positive cells and alleviation of morphological alterations, alongside decreased expressions of IL-1ß and IL-18. Further analysis indicates that reynosin inhibits NLRP3 inflammasome activation, evidenced by reduced transcription of NLRP3 and caspase-1, diminished NLRP3 protein expression, inhibited apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization, and decreased caspase-1 self-cleavage. Additionally, reynosin curtailed the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, demonstrated by reduced NADP+ and NADPH levels, downregulation of gp91phox mRNA, protein expression, suppression of p47phox expression and translocation to the membrane. Moreover, reynosin exhibited a neuroprotective effect against microglial inflammation in vivo and in vitro. These collective findings underscore reynosin's capacity to mitigate microglial inflammation by inhibiting the NLRP3 inflammasome, thus highlighting its potential as a therapeutic agent for managing neuroinflammation.

Surface-enhanced Raman scattering spectroscopy monitoring and degradation of organic pollutants using a novel nanowire.

A multifunctional Ag/AlOOH nanowires (ANW) composite substrate was constructed, which not only accomplishes highly sensitive detection of organic dye molecules, but also has excellent performance in the degradation of pollutants. The ANW in the Ag/ANW substrate possesses a high aspect ratio, which extends the distribution area of Ag and enables a large number of hot spots on the active substrate. Additionally, due to the abundant OH groups on the ANW, there is an increased number of anchor sites for adsorbed metal ions in the Ag/ANW compound, thus contributing to the enhancement and degradation of molecules. Moreover, the constructed multifunctional Ag/ANW nanocomplexes also show great promise for practical applications, providing a reference for the detection and degradation of contaminants.

Americanin B inhibits pyroptosis in lipopolysaccharide-induced septic encephalopathy mice through targeting NLRP3 protein.

BACKGROUND: Sepsis is considered as a severe illness due to its high mortality. Sepsis can cause septic encephalopathy, thus leading to brain injury, behavioral and cognitive dysfunction. Pyroptosis is a type of regulated cell death (RCD) and takes a crucial part in occurrence and development of sepsis. Americanin B (AMEB) is a lignan compounds, which is extracted from Vernicia fordii. In our previous study, AMEB could inhibit microglial activation in inflammatory cell model. However, the function of AMEB in septic encephalopathy mice is uncertain. It would be worthwhile to ascertain the role and mechanism of AMEB in sepsis. PURPOSE: Current study designs to certify the relationship between pyroptosis and septic encephalopathy, and investigate whether AMEB can restrain NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation and restrict pyroptosis by targeting NLRP3 in septic mice model. STUDY DESIGN: C57BL/6 mice were utilized to perform sepsis model in vivo experiments. BV-2 cell lines were used for in vitro experiments. METHODS: In vivo sepsis model was established by lipopolysaccharide (LPS) intraperitoneal injection in male C57BL/6 J mice and in vitro model was exposed by LPS plus ATP in BV-2 cells. The survival rate was monitored on the corresponding days. NLRP3, apoptosis associated Speck-like protein (ASC), caspase-1, GasderminD (GSDMD), interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) level were detected by western blotting and immunofluorescence analysis. Molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) experiments, RNAi transfection and quantitative real-time PCR were applied to confirm the potential target of AMEB. RESULTS: The results suggested that AMEB could rise survival percentage and lighten brain injury in LPS-induced sepsis mice. In addition, AMEB could inhibit pyroptosis and the activiation of NLRP3 inflammasome. The inhibiting function of AMEB on the activiation of NLRP3 inflammasome is weakened following si-NLRP3 transfection. Moreover, AMEB exerted anti-pyroptosis effect via targeting NLRP3 protein. CONCLUSIONS: Our findings first indicate NLRP3 is an effective druggable target for septic encephalopathy related brain injury, and also provide a candidate-AMEB for the treatment of septic encephalopathy. These emerging findings on AMEB in models of sepsis suggest an innovative approach that may be beneficial in the prevention of septic encephalopathy.

High SERS performance of functionalized carbon dots in the detection of dye contaminants.

INTRODUCTION: The long-term overuse of malachite green (MG) has potential carcinogenic, teratogenic, and mutagenic effects. The functional nanocomposite is novel and challenging to construct and implement through surface enhanced Raman scattering (SERS) strategy to reveal the contributions in application. OBJECTIVES: The novel Ag-CDs (carbon dots)-PBA (phenyl boric acid) nanocomposite was constructed by a facile route to detect toxic MG molecule with high SERS sensitivity and good uniformity. METHODS: The enhanced substrate used for the detection of MG has been successfully constructed using PBA modulated Ag-CDs on a structured surface with rich binding sites. RESULTS: The fabricated Ag-CDs-PBA substrate can be used to analyze various probe molecules exhibiting high sensitivity, good signal reproducibility, and excellent stability. The mechanism between components has been proved by calculations originating from the plasmonic Ag and active electronic transmission among the bridging CDs and PBA via the close spatial π-π effect. In addition, the accelerated separation of electron-hole pairs was triggered to further improve the SERS activity of the hybrid via a bidirectional charge transfer (CT) process. Significantly, the Ag-CDs-PBA system shows distinctive selectivity, in which PBA can hinder the interference of other species without specific hydroxyl groups. CONCLUSION: Based on this deeper insight on plasmon-mediated mechanism, the SERS substrate was successfully practiced for quantitative determination in real water and fish samples. The strategy developed promises to be a new sensor technology and has great potential for environmental and food safety applications.

p53-dependent HIF-1α /autophagy mediated glycolysis to support Cr(VI)-induced cell growth and cell migration.

Cr(VI) is known to be seriously toxic and carcinogenic. Hypoxia-inducible factor-1α (HIF-1α) is a crucial regulator to promote tumor development. In this study, we found that Cr(VI) significantly increased the expression of HIF-1α in A549 cells and in lung of BALB/c mice but not in HELF cells. Treatment with Lificiguat (YC-1), HIF-1α inhibitor, or CoCl2, HIF-1α inducer, could alter Cr(VI)-induced autophagy, glycolysis, and cell growth in A549 cells but not in HELF cells, validating the involvement of HIF-1α in these effects of Cr(VI) in A549 cells. Co-treatments of pcATG4B with YC-1, or siATG4B with CoCl2 demonstrated the role of HIF-1α / autophagy axis in inducing glycolysis and cell growth in A549 cells. In HELF cells, however, only autophagy but not HIF-1α played a role in inducing glycolysis. The protein level of p53 was significantly lower in A549 cells than in HELF cells. RITA, a p53 inducer, attenuated Cr(VI)-induced HIF-1α and LC3-II in A549 cells, suggesting that p53 might be the mechanism underlying the different effects of Cr(VI) on HIF-1α in A549 and HELF cells. Thus, p53-dependent HIF-1α / autophagy-mediated glycolysis plays a role in facilitating Cr(VI)-induced carcinogenesis.

Effect of hot electron induced charge transfer generated by surface plasmon resonance on Ag@Au/ITO/PNTP systems.

The present study discusses the fabrication of a bimetallic material consisting of silver nanorods and gold nanospheres (designated Ag@Au), and its surface modification with 4-nitrothiophenol (PNTP) after deposition on an indium tin oxide (ITO) glass sheet, followed by laser irradiation at various wavelengths. The results indicate that the reduction of PNTP is more complete under irradiation at 532 nm due to the surface plasmon resonance (SPR) effects of the gold and silver nanomaterials. Moreover, the surface enhanced Raman scattering (SERS) of the PNTP adsorbed on the Ag@Au/ITO is found to be significantly stronger than that of PNTP adsorbed on Ag@Au alone, due to charge transfer (CT) at the interface. In addition, the SERS enhancement effect of the PNTP molecules on the Ag@Au/ITO substrate is optimal under 532 nm laser irradiation due to the hot electron-induced CT generated by the SPR effect. Thus, the system constructed herein combines the effects of SPR and CT, thereby assisting in a further understanding of the enhancement mechanism of SERS and, hence, the further development SERS research in metal-semiconductor-molecular systems.

De Novo Generation and Identification of Novel Compounds with Drug Efficacy Based on Machine Learning.

One of the main challenges in small molecule drug discovery is finding novel chemical compounds with desirable activity. Traditional drug development typically begins with target selection, but the correlation between targets and disease remains to be further investigated, and drugs designed based on targets may not always have the desired drug efficacy. The emergence of machine learning provides a powerful tool to overcome the challenge. Herein, a machine learning-based strategy is developed for de novo generation of novel compounds with drug efficacy termed DTLS (Deep Transfer Learning-based Strategy) by using dataset of disease-direct-related activity as input. DTLS is applied in two kinds of disease: colorectal cancer (CRC) and Alzheimer's disease (AD). In each case, novel compound is discovered and identified in in vitro and in vivo disease models. Their mechanism of actionis further explored. The experimental results reveal that DTLS can not only realize the generation and identification of novel compounds with drug efficacy but also has the advantage of identifying compounds by focusing on protein targets to facilitate the mechanism study. This work highlights the significant impact of machine learning on the design of novel compounds with drug efficacy, which provides a powerful new approach to drug discovery.

Melatonin Protects Injured Spinal Cord Neurons From Apoptosis by Inhibiting Mitochondrial Damage via the SIRT1/Drp1 Signaling Pathway.

Spinal cord injuries (SCIs) often result in limited prospects for recovery and a high incidence of disability. Melatonin (Mel), a hormone, is acknowledged for its neuroprotective attributes. Mel was examined in this study to discover if it alleviates SCIs via the sirtuin1/dynamin-related protein1 (SIRT1/Drp1) signaling pathway. SCIs were simulated in mice by inducing cord contusion at the T9-T10 vertebrae and causing inflammation in primary spinal neurons using lipopolysaccharide (LPS). The findings of our study demonstrated that Mel treatment effectively promoted neuromotor recovery through multiple mechanisms, including the reduction of neuronal death, suppression of astrocyte and microglia activation, and attenuation of neuroinflammation. Moreover, Mel therapy significantly upregulated the expression of SIRT1 in both spinal cord tissues and spinal neurons of mice. Additionally, Mel exhibited the potential to mitigate neuronal mitochondrial dysfunction by modulating the levels of Drp1 and TOMM20, thereby addressing the underlying factors contributing to this dysfunction. Furthermore, when SIRT1 was downregulated, it reversed the positive effects of Mel. Overall, our present study suggests that Mel has the capacity to modulate the SIRT1/Drp1 pathway, thereby ameliorating mitochondrial dysfunction, attenuating inflammation and apoptosis, and enhancing neural function subsequent to SCIs.

Crebanine ameliorates ischemia-reperfusion brain damage by inhibiting oxidative stress and neuroinflammation mediated by NADPH oxidase 2 in microglia.

BACKGROUND: The urgent challenge for ischemic stroke treatment is the lack of effective neuroprotectants that target multiple pathological processes. Crebanine, an isoquinoline-like alkaloid with superior pharmacological activities, presents itself as a promising candidate for neuroprotection. However, its effects and mechanisms on ischemic stroke remain unknown. METHODS: The effects of crebanine on brain damage following ischemic stroke were evaluated using the middle cerebral artery occlusion and reperfusion (MCAO/R) model. Mechanism of action was investigated using both MCAO/R rats and lipopolysaccharide (LPS)-activated BV-2 cells. RESULTS: We initially demonstrated that crebanine effectively ameliorated the neurological deficits in MCAO/R rats, while also reducing brain edema and infarction. Treatment with crebanine resulted in the up-regulation of NeuN+ fluorescence density and down-regulation of FJB+ cell count, and mitigated synaptic damage. Crebanine attenuated the hyperactivation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) by downregulating NADP+ and NADPH levels, suppressing gp91phox and p47phox expressions, and reducing p47phox membrane translocation in Iba-1+ cells. Additionally, crebanine reduced the quantity of Iba-1+ cells and protein expression. Correlation analysis has demonstrated that the inhibition of NOX2 activation in microglia is beneficial for mitigating I/R brain injuries. Moreover, crebanine exhibited significant antioxidant properties by down-regulating the expression of superoxide anion and intracellular reactive oxygen species in vivo and in vitro, and reducing lipid and DNA peroxidation. Crebanine exerted anti-inflammatory effect, as evidenced by the reduction in the expressions of nitric oxide, interleukin 1ß, tumor necrosis factor α, interleukin 6, and inducible nitric oxide synthase. The effect of crebanine was achieved through the suppression of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathway. This is supported by evidence showing reduced NF-κB p65 promoter activity and nucleus translocation, as well as suppressed IκBα phosphorylation and degradation. Additionally, it inhibited the phosphorylation of ERK, JNK, and p38 MAPKs. Importantly, the anti-oxidative stress and neuroinflammation effects of crebanine were further enhanced after silencing gp91phox and p47phox. CONCLUSION: Crebanine alleviated the brain damages of MCAO/R rats by inhibiting oxidative stress and neuroinflammation mediated by NOX2 in microglia, implying crebanine might be a potential natural drug for the treatment of cerebral ischemia.

Data-Knowledge-Driven Modeling and Operational Adjustment for the Pharmaceutical Tablet Manufacturing Process via Wet Granulation.

In the context of Pharma 4.0, pharmaceutical quality control (PQC) is beset by issues such as uncertainties from ever-changing critical material attributes and strong coupling between variables in the multi-unit pharmaceutical tablet manufacturing process (PTMP), and how to timely adjust the operational variables to deal with such challenges has become a key problem in PQC. In this study, we propose a novel data-knowledge-driven modeling and operational adjustment framework for PTMP by integrating Bayesian network (BN) and case-based reasoning (CBR). At the modeling level, first, a distributed concept is introduced, i.e., the BN model for each subunit of PTMP is established in accordance with the operation process sequence, and the transition variables are given by the BN model established first and retrieved as the new query for the next unit. Once the BN models of all subunits are built, they are integrated into a global BN model. At the operational adjustment level, by taking the expected critical quality attributes (CQAs) and related prior information as evidence, the operational adjustment is achieved through global BN reasoning. Finally, the case study in a sprayed fluidized-bed granulation-based PTMP demonstrates the feasibility and effectiveness in improving the terminal CQAs of the proposed method, which is also compared with other methods to showcase its efficacy and merits.

1H NMR-guided isolation of hasubanan alkaloids from the alkaloidal extract of Stephania longa.

1H NMR-guided fractionation led to the isolation of 16 alkaloids from the alkaloidal extract of Stephania longa, including 11 new hasubanan alkaloids (1-11) and five known alkaloids (12-16). Interestingly, compounds 2 and 11 are typically considered protonated tertiary amine compounds, whereas compounds 1 and 10 are regarded as oxidized versions of the corresponding compounds. Their gross structures were determined through an extensive analysis of spectroscopic data (NMR (nuclear magnetic resonance) and HRESIMS (high resolution electrospray ionization mass spectroscopy)), and their absolute configurations were established by comparing their experimental and calculated electronic circular dichroism (ECD) spectra. The new (3) and a known (12) compounds in all isolates displayed stronger antineuroinflammatory effects (IC50 values of 1.8 and 11.1 µM, respectively) than minocycline (IC50 value of 15.5 µM) against NO production on LPS-activated BV2 cells.

Cbl induced ubiquitination of HER2 mediate immune escape from HER2-targeted CAR-T.

Breast cancer (BC) with high HER2 expression has higher recurrence rate and worse prognosis, and its immunotherapy is promising. Based on the high expression of HER2, develop Chimeric Antigen Receptor T-cell (CAR-T) and PDL-1 immunotherapy, and study the molecular pathways of related immune cells and recurrence. HER2-CAR-T cells were constructed using retroviruses, and their specific recognition and immune effects on HER2+ BC cells were verified by in vivo and in vitro experiments. PDL-1 was used as adjuvant immunotherapy, knocking down PDL-1 in tumor cells or dendritic cells, or depleted macrophages to study immune pathways. The negative regulation of HER2 by cbl was determined by IP, ubiquitination experiments, and segmented plasmids, elucidating the molecular mechanism of HER2+ BC recurrence after immunotherapy. HER2-CAR-T specifically recognizes HER2-positive tumor cells and inhibits tumor growth in vivo and in vitro, and anti-PDL1 treatment enhances the therapeutic effect of HER2-CAR-T on tumors. HER2-CART therapy eradicated solid tumors after PDL1 knockdown in dendritic cells. Immunotherapy of relapsed tumors lost HER2 expression by upregulating cbl. HER2-CAR-T shows specific recognition of HER2+ cells and can mediate immune response therapy with the cooperation of PDL-1.

Isoamericanin A improves lipopolysaccharide-induced memory impairment in mice through suppression of the nicotinamide adenine dinucleotide phosphateoxidase-dependent nuclear factor kappa B signaling pathway.

Alzheimer's disease (AD) is the most frequent cause of dementia in the elderly. Isoamericanin A (ISOA) is a natural lignan possessing great potential for AD treatment. This study investigated the efficacy of ISOA on memory impairments in the mice intrahippocampal injected with lipopolysaccharide (LPS) and the underlying mechanism. Y-maze and Morris Water Maze data suggested that ISOA (5 and 10 mg/kg) ameliorated short- and long-term memory impairments, and attenuated neuronal loss and lactate dehydrogenase activity. ISOA exerted anti-inflammatory effect demonstrating by the reduction of ionized calcium-binding adapter molecule 1 positive cells and suppression of marker protein and pro-inflammation cytokines expressions induced by LPS. ISOA suppressed the nuclear factor kappa B (NF-κB) signaling pathway by inhibiting IκBα phosphorylation and NF-κB p65 phosphorylation and nuclear translocation. ISOA inhibited superoxide and intracellular reactive oxygen species accumulation by reducing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, demonstrating by suppressing NADP+ and NADPH contents, gp91phox expression, and p47phox expression and membrane translocation. These effects were enhanced in combination with NADPH oxidase inhibitor apocynin. The neuroprotective effect of ISOA was further proved in the in vitro models. Overall, our data revealed a novel pharmacological activity of ISOA: ameliorating memory impairment in AD via inhibiting neuroinflammation.

Complexation of a Nitrilotriacetate-Derived Triamide Ligand with Trivalent Lanthanides: A Thermodynamic and Crystallographic Study.

Non-heterocyclic N-donor nitrilotriacetate-derived triamide ligands are one of the most promising extractants for the selective extraction separation of trivalent actinides over lanthanides, but the thermodynamics and mechanism of the complexation of this kind of ligand with actinides and lanthanides are still not clear. In this work, the complexation behaviors of N,N,N',N',N″,N″-hexaethylnitrilotriacetamide (NTAamide(Et)) with four representative trivalent lanthanides (La3+, Nd3+, Eu3+, and Lu3+) were systematically investigated by using 1H nuclear magnetic resonance (1H NMR), ultraviolet-visible (UV-vis) and fluorescence spectrophotometry, microcalorimetry, and single-crystal X-ray diffractometry. 1H NMR spectroscopic titration of La3+ and Lu3+ indicates that two species of 1:2 and 1:1 metal-ligand complexes were formed in NO3- and ClO4- media. The stability constants of NTAamide(Et) with Nd3+ and Eu3+ obtained by UV-vis and fluorescence titration show that the complexing strength of NTAamide(Et) with Nd3+ is lower than that with Eu3+ in the same anionic medium, while that of the same lanthanide complex is higher in ClO4- medium than in NO3- medium. Meanwhile, the formation reactions for all metal-ligand complexes are driven by both enthalpy and entropy. The structures of lanthanide complexes in the single ClO4- and NO3- medium and the mixed one were determined to be [LnL2(MeOH)](ClO4)3 (Ln = La, Nd, Eu, and Lu), [LaL2(EtOH)2][La(NO3)6], and [LaL2(NO3)](ClO4)2, separately. The average bond lengths of lanthanide complexes decrease gradually with the decrease in ionic radii of Ln3+, indicating that heavier lanthanides form stronger complexes due to the lanthanide contraction effect, which coincides with the trend of the complexing strength obtained by spectroscopic titration. This work not only reveals the thermodynamics and mechanism of the complexation between NTAamide ligands and lanthanides but also obtains the periodic tendency of complexation between them, which may facilitate the separation of trivalent lanthanides from actinides.