Alnustone promotes megakaryocyte differentiation and platelet production via the interleukin-17A/interleukin-17A receptor/Src/RAC1/MEK/ERK signaling pathway.

OBJECTIVES: Thrombocytopenia is a disease in which the number of platelets in the peripheral blood decreases. It can be caused by multiple genetic factors, and numerous challenges are associated with its treatment. In this study, the effects of alnustone on megakaryocytes and platelets were investigated, with the aim of developing a new therapeutic approach for thrombocytopenia. METHODS: Random forest algorithm was used to establish a drug screening model, and alnustone was identified as a natural active compound that could promote megakaryocyte differentiation. The effect of alnustone on megakaryocyte activity was determined using cell counting kit-8. The effect of alnustone on megakaryocyte differentiation was determined using flow cytometry, Giemsa staining, and phalloidin staining. A mouse model of thrombocytopenia was established by exposing mice to X-rays at 4 Gy and was used to test the bioactivity of alnustone in vivo. The effect of alnustone on platelet production was determined using zebrafish. Network pharmacology was used to predict targets and signaling pathways. Western blotting and immunofluorescence staining determined the expression levels of proteins. RESULTS: Alnustone promoted the differentiation and maturation of megakaryocytes in vitro and restored platelet production in thrombocytopenic mice and zebrafish. Network pharmacology and western blotting showed that alnustone promoted the expression of interleukin-17A and enhanced its interaction with its receptor, and thereby regulated downstream MEK/ERK signaling and promoted megakaryocyte differentiation. CONCLUSIONS: Alnustone can promote megakaryocyte differentiation and platelet production via the interleukin-17A/interleukin-17A receptor/Src/RAC1/MEK/ERK signaling pathway and thus provides a new therapeutic strategy for the treatment of thrombocytopenia.

Study on Plastic Constitutive Relation and Ductile Fracture Criterion of AM60B Magnesium Alloy.

It is currently a challenge to accurately predict the deformation and fracture behavior of metal parts in automobile crashes. Many studies have shown that the deformation and fracture behavior of materials are significantly affected by the stress state during automobile crashes with complex stress state characteristics. In order to further promote the application of die-cast magnesium alloys in automobiles, it is particularly important to study the material deformation and fracture behavior of die-cast magnesium alloys. In this paper, the mechanical properties of the AM60B die-cast magnesium alloy sheet under four stress states (shear, tension, R10 notch tension, and cupping) were designed and tested. Based on the von Mises isotropic constitutive model and Swift weighted Hockett-Sherby hardening model, the plastic constitutive model of die-cast magnesium alloy was established. Based on the plastic model and the fracture model (JC, MMC, and DIEM) considering the influence of three stress states, the deformation and fracture behavior of the AM60B die-cast magnesium alloy front-end members in three-point bending were predicted by experiments and finite element simulation. The experimental results show that the deformation mode and loading-displacement curve trend of the AM60B die-cast magnesium alloy front members are the same, the crack initiation point and crack initiation time are the same, and the crack shape is similar. The results show that the complex stress state constitutive model parameters and the DIEM fracture model obtained in this paper can accurately predict the deformation and fracture failure behavior of the AM60B die-cast magnesium alloy sheet.

Protective Role of Dioscin against Doxorubicin-Induced Chronic Cardiotoxicity: Insights from Nrf2-GPX4 Axis-Mediated Cardiac Ferroptosis.

Recent evidence suggests that ferroptosis, an iron-facilitated cell death with excessive lipid peroxidation, is a critical mechanism underlying doxorubicin (DOX)-induced cardiotoxicity (DIC). Although dioscin has been reported to improve acute DIC, direct evidence is lacking to clarify the role of dioscin in chronic DIC and its potential mechanism in cardiac ferroptosis. In this study, we used chronic DIC rat models and H9c2 cells to investigate the potential of dioscin to mitigate DIC by inhibiting ferroptosis. Our results suggest that dioscin significantly improves chronic DIC-induced cardiac dysfunction. Meanwhile, it significantly inhibited DOX-induced ferroptosis by reducing Fe2+ and lipid peroxidation accumulation, maintaining mitochondrial integrity, increasing glutathione peroxidase 4 (GPX4) expression, and decreasing acyl-CoA synthetase long-chain family 4 (ACSL4) expression. Through transcriptomic analysis and subsequent validation, we found that the anti-ferroptotic effects of dioscin are achieved by regulating the nuclear factor-erythroid 2-related factor 2 (Nrf2)/GPX4 axis and Nrf2 downstream iron metabolism genes. Dioscin further downregulates nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and upregulates expression of frataxin (FXN) and ATP-binding cassette B8 (ABCB8) to limit mitochondrial Fe2+ and lipid peroxide accumulation. However, Nrf2 inhibition diminishes the anti-ferroptotic effects of dioscin, leading to decreased GPX4 expression and increased lipid peroxidation. This study is a compelling demonstration that dioscin can effectively reduce DIC by inhibiting ferroptosis, which is dependent on the Nrf2/GPX4 pathway modulation.

An Innovative Inducer of Platelet Production, Isochlorogenic Acid A, Is Uncovered through the Application of Deep Neural Networks.

(1) Background: Radiation-induced thrombocytopenia (RIT) often occurs in cancer patients undergoing radiation therapy, which can result in morbidity and even death. However, a notable deficiency exists in the availability of specific drugs designed for the treatment of RIT. (2) Methods: In our pursuit of new drugs for RIT treatment, we employed three deep learning (DL) algorithms: convolutional neural network (CNN), deep neural network (DNN), and a hybrid neural network that combines the computational characteristics of the two. These algorithms construct computational models that can screen compounds for drug activity by utilizing the distinct physicochemical properties of the molecules. The best model underwent testing using a set of 10 drugs endorsed by the US Food and Drug Administration (FDA) specifically for the treatment of thrombocytopenia. (3) Results: The Hybrid CNN+DNN (HCD) model demonstrated the most effective predictive performance on the test dataset, achieving an accuracy of 98.3% and a precision of 97.0%. Both metrics surpassed the performance of the other models, and the model predicted that seven FDA drugs would exhibit activity. Isochlorogenic acid A, identified through screening the Chinese Pharmacopoeia Natural Product Library, was subsequently subjected to experimental verification. The results indicated a substantial enhancement in the differentiation and maturation of megakaryocytes (MKs), along with a notable increase in platelet production. (4) Conclusions: This underscores the potential therapeutic efficacy of isochlorogenic acid A in addressing RIT.

Comparison of 18 F-AlF-NOTA-PRGD2 and 18 F-FDG PET/CT Imaging in a Case of Primary Uveal Melanoma.

ABSTRACT: Uveal melanoma is the most common intraocular malignancy in adults with a high rate of metastasis and mortality. This study presented the PET/CT imaging of 18 F-AlF-NOTA-PRGD2 and 18 F-FDG in a patient with primary uveal melanoma. In addition to fundus photograph and ophthalmic ultrasonography, both 18 F-AlF-NOTA-PRGD2 and 18 F-FDG PET/CT imaging showed increased radioactive uptake in the lesions within the scan area. The tumoral lesions presented significantly higher uptake of 18 F-AlF-NOTA-PRGD2 compared with that of 18 F-FDG.

Herbal medicines provide regulation against iron overload in cardiovascular diseases: Informing future applications.

ETHNOPHARMACOLOGICAL RELEVANCE: Iron is an essential micronutrient for maintaining physiological activities, especially for highly active cardiomyocytes. Inappropriate iron overload or deficiency has a significant impact on the incidence and severity of cardiovascular diseases (CVD). Iron overload exerts potentially deleterious effects on doxorubicin (DOX) cardiomyopathy, atherosclerosis, and myocardial ischemia-reperfusion injury (MI/RI) by participating in lipid peroxides production. Notably, iron overload-associated cell death has been defined as a possible mechanism for ferroptosis. At present, some traditional herbal medicines and extracts have been included in the study of regulating iron overload and the subsequent therapeutic effect on CVD. AIM OF THE STUDY: To give an outline of iron metabolism and ferroptosis in cardiomyocytes and to focus on herbal medicines and extracts to prevent iron overload in CVD. MATERIALS AND METHODS: Literature information was systematically collected from ScienceDirect, PubMed, Google Scholar, Web of Science, China National Knowledge Infrastructure, WanFang data, as well as classic books and clinical reports. RESULTS: After understanding the mechanism of iron overload on CVD, this paper reviews the therapeutic function of various herbal medicines in eliminating iron overload in CVD. These include Chinese herbal compound prescriptions (Salvia miltiorrhiza injection, Gegen Qinlian decoction, Tongxinluo, Banxia-Houpu decoction), plant extracts, phenylpropanoids, flavonoids, terpenoids, and polyphenols. Among them, flavonoids are considered to be the most promising compounds because of their prominent iron chelation. Mechanically, these herbal medicines act on the Nrf2 signaling pathway, AMPK signaling pathway, and KAT5/GPX4 signaling pathway, thereby attenuating iron overload and lipid peroxidation in CVD. CONCLUSION: Our review provides up-to-date information on herbal medicines that exert cardiovascular protective effects by modulating iron overload and ferroptosis. These herbal medicines hold promise as a template for preventing iron overload in CVD.

Interleukins in Platelet Biology: Unraveling the Complex Regulatory Network.

Interleukins, a diverse family of cytokines produced by various cells, play crucial roles in immune responses, immunoregulation, and a wide range of physiological and pathological processes. In the context of megakaryopoiesis, thrombopoiesis, and platelet function, interleukins have emerged as key regulators, exerting significant influence on the development, maturation, and activity of megakaryocytes (MKs) and platelets. While the therapeutic potential of interleukins in platelet-related diseases has been recognized for decades, their clinical application has been hindered by limitations in basic research and challenges in drug development. Recent advancements in understanding the molecular mechanisms of interleukins and their interactions with MKs and platelets, coupled with breakthroughs in cytokine engineering, have revitalized the field of interleukin-based therapeutics. These breakthroughs have paved the way for the development of more effective and specific interleukin-based therapies for the treatment of platelet disorders. This review provides a comprehensive overview of the effects of interleukins on megakaryopoiesis, thrombopoiesis, and platelet function. It highlights the potential clinical applications of interleukins in regulating megakaryopoiesis and platelet function and discusses the latest bioengineering technologies that could improve the pharmacokinetic properties of interleukins. By synthesizing the current knowledge in this field, this review aims to provide valuable insights for future research into the clinical application of interleukins in platelet-related diseases.

Liuweiwuling Tablet relieves the inflammatory transformation of hepatocellular carcinoma by inhibiting the PI3K/AKT/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Liuweiwuling Tablet (LWWL) is a patented Chinese medicine approved by the Chinese National Medical Products Administration (NMPA). Clinically, it is used to treat a range of liver diseases that precede hepatocellular carcinoma (HCC), including hepatitis, liver fibrosis and cirrhosis. LWWL is hypothesized to inhibit the inflammatory transformation of HCC, which may have a positive impact on the prevention and treatment of HCC. However, its exact mechanism of action remains unknown. AIM OF THE STUDY: To investigate how LWWL is effective in the treatment of HCC and to validate the pathways involved in this process. MATERIALS AND METHODS: An in vivo model of HCC induced by diethylnitrosamine (DEN) was established to study the effect of LWWL on the development of HCC. The rat serum was analyzed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (γ-GT). The rat liver tissues were stained with hematoxylin and eosin (HE) and Masson's trichrome for pathological analysis. Rat liver tissue was subjected to transcriptome sequencing. Expression of inflammatory and liver fibrosis-related factors in bone marrow-derived macrophages (BMDMs) and LX-2 cells was detected by QRT-PCR, ELISA and Western blot (WB). The expression of apoptosis and stemness genes in HepG2 and Huh7 cells was assessed through flow cytometry and QRT-PCR. Transcriptomics, network pharmacology, WB, and QRT-PCR were employed to validate the mechanisms associated with the amelioration of HCC development by LWWL. RESULTS: LWWL significantly reduced the severity of hepatitis and liver fibrosis, the expression of tumor stemness genes, and the incidence of HCC. In addition, LWWL inhibited the release of inflammatory substances and nuclear accumulation of P65 protein in BMDMs as well as the conversion of LX-2 cells to fibroblasts. LWWL inhibited the proliferation of HepG2 and Huh7 cells, including the initiation of apoptosis and the reduction of stemness gene expression. Importantly, LWWL regulates the PI3K/AKT/NF-κB pathway, which affects hepatic inflammation and cancer progression. CONCLUSION: LWWL inhibited the occurrence and development of HCC by modulating the severity of hepatitis and liver fibrosis, indicating the potential clinical relevance of LWWL in preventing and treating HCC.

Corrigendum: Different immunological mechanisms between AQP4 antibody-positive and MOG antibody-positive optic neuritis based on RNA sequencing analysis of whole blood.

[This corrects the article DOI: 10.3389/fimmu.2023.1095966.].

Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC.

BACKGROUND: Abnormal activation of NLRP3 inflammasome is related to a series of inflammatory diseases, including type 2 diabetes, gouty arthritis, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders. Therefore, targeting NLRP3 inflammasome is regarded as a potential therapeutic strategy for many inflammatory diseases. A growing number of studies have identified tanshinone I (Tan I) as a potential anti-inflammatory agent because of its good anti-inflammatory activity. However, its specific anti-inflammatory mechanism and direct target are unclear and need further study. METHODS: IL-1ß and caspase-1 were detected by immunoblotting and ELISA, and mtROS levels were measured by flow cytometry. Immunoprecipitation was used to explore the interaction between NLRP3, NEK7 and ASC. In a mouse model of LPS-induced septic shock, IL-1ß levels in peritoneal lavage fluid and serum were measured by ELISA. Liver inflammation and fibrosis in the NASH model were analyzed by HE staining and immunohistochemistry. RESULTS: Tan I inhibited the activation of NLRP3 inflammasome in macrophages, but had no effect on the activation of AIM2 or NLRC4 inflammasome. Mechanistically, Tan I inhibited NLRP3 inflammasome assembly and activation by targeting NLRP3-ASC interaction. Furthermore, Tan I exhibited protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including septic shock and NASH. CONCLUSIONS: Tan I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC, and exhibits protective effects in mouse models of LPS-induced septic shock and NASH. These findings suggest that Tan I is a specific NLRP3 inhibitor and may be a promising candidate for treating NLRP3 inflammasome-related diseases.

An Energy-Efficient Small-Area Configurable Analog Front-End Interface for Diverse Biosignals Recording.

We introduce a fully integrated configurable analog front-end (CAFE) sensor intended to accommodate various types of bio-potential signals in this article. The proposed CAFE is composed of an AC-coupled chopper-stabilized amplifier to effectively reduce 1/f noise and an energy- and area-efficient tunable filter to tune this interface to the bandwidth of various specific signals of interest. A tunable active-pseudo-resistor is integrated into the amplifier's feedback to realize a reconfigurable high-pass cutoff frequency and enhance its linearity, while the filter is designed using a subthreshold-source-follower-based pseudo-RC (SSF-PRC) topology to attain the required super-low cutoff frequency without the need for extremely low biasing current sources. Implemented in TSMC 40 nm technology, the chip occupies an active area of 0.048 [Formula: see text] while consuming 2.47 µW DC power from a 1.2-V supply voltage. Measurement results indicate that the proposed design achieved a mid-band gain of 37 dB, with an integrated input-referred noise ( VIRN) of 1.7 µVrms within 1-260 Hz. The total harmonic distortion (THD) of the CAFE is below 1 % with a 2.4 m Vpp input signal. With a wide-range bandwidth adjustment capability, the proposed CAFE can be used in both wearable and implantable recording devices to acquire different bio-potential signals.

A Rapid and Sensitive UHPLC-MS/MS Method for Determination of Chlorogenic Acid and Its Application to Distribution and Neuroprotection in Rat Brain.

Chlorogenic acid (5-CQA) is a phenolic natural product that has been reported to improve neurobehavioral disorders and brain injury. However, its pharmacokinetics and distribution in the rat brain remain unclear. In this study, we established a rapid and sensitive UHPLC-MS/MS method for the determination of 5-CQA in rat plasma, cerebrospinal fluid (CSF), and brain tissue to investigate whether it could pass through the blood-brain barrier (BBB) and its distribution in the rat brain, and a Caenorhabditis elegans (C. elegans) strain paralysis assay was used to investigate the neuroprotective effect of 5-CQA in different brain tissues. Chromatographic separation of 5-CQA and glycyrrhetinic acid (GA, used as internal standard) was completed in 0.5 min, and the full run time was maintained at 4.0 min. Methodological validation results presented a high accuracy (95.69-106.81%) and precision (RSD ≤ 8%), with a lower limit of quantification of 1.0 ng/mL. Pharmacokinetic results revealed that 5-CQA can pass through the BBB into the CSF, but the permeability of BBB to 5-CQA (ratio of mean AUC0-∞ of CSF to plasma) was only approximately 0.29%. In addition, 5-CQA can penetrate into the rat brain extensively and is distributed with different intensities in different nuclei. A C. elegans strain paralysis assay indicated that the neuroprotective effect of 5-CQA is positively correlated with its content in different brain tissues. In conclusion, our study for the first time explored the BBB pass rate and brain tissue distribution of 5-CQA administered via the tail vein by the UHPLC-MS/MS method and investigated the potential main target area of 5-CQA for neuroprotection, which could provide a certain basis for the treatment of nervous system-related diseases of 5-CQA.

Xanthotoxin, a novel inducer of platelet formation, promotes thrombocytopoiesis via IL-1R1 and MEK/ERK signaling.

BACKGROUND: Thrombocytopenia is a common hematological disease caused by many factors. It usually complicates critical diseases and increases morbidity and mortality. The treatment of thrombocytopenia remains a great challenge in clinical practice, however, its treatment options are limited. In this study, the active monomer xanthotoxin (XAT) was screened out to explore its medicinal value and provide novel therapeutic strategies for the clinical treatment of thrombocytopenia. METHODS: The effects of XAT on megakaryocyte differentiation and maturation were detected by flow cytometry, Giemsa and phalloidin staining. RNA-seq identified differentially expressed genes and enriched pathways. The signaling pathway and transcription factors were verified through WB and immunofluorescence staining. Tg (cd41: eGFP) transgenic zebrafish and mice with thrombocytopenia were used to evaluate the biological activity of XAT on platelet formation and the related hematopoietic organ index in vivo. RESULTS: XAT promoted the differentiation and maturation of Meg-01 cells in vitro. Meanwhile, XAT could stimulate platelet formation in transgenic zebrafish and recover platelet production and function in irradiation-induced thrombocytopenia mice. Further RNA-seq prediction and WB verification revealed that XAT activates the IL-1R1 target and MEK/ERK signaling pathway, and upregulates the expression of transcription factors related to the hematopoietic lineage to promote megakaryocyte differentiation and platelet formation. CONCLUSION: XAT accelerates megakaryocyte differentiation and maturation to promote platelet production and recovery through triggering IL-1R1 and activating the MEK/ERK signaling pathway, providing a new pharmacotherapy strategy for thrombocytopenia.

APP in the Neuromuscular Junction for the Development of Sarcopenia and Alzheimer's Disease.

Sarcopenia, an illness condition usually characterized by a loss of skeletal muscle mass and muscle strength or function, is often associated with neurodegenerative diseases, such as Alzheimer's disease (AD), a common type of dementia, leading to memory loss and other cognitive impairment. However, the underlying mechanisms for their associations and relationships are less well understood. The App, a Mendelian gene for early-onset AD, encodes amyloid precursor protein (APP), a transmembrane protein enriched at both the neuromuscular junction (NMJ) and synapses in the central nervous system (CNS). Here, in this review, we highlight APP and its family members' physiological functions and Swedish mutant APP (APPswe)'s pathological roles in muscles and NMJ. Understanding APP's pathophysiological functions in muscles and NMJ is likely to uncover insights not only into neuromuscular diseases but also AD. We summarize key findings from the burgeoning literature, which may open new avenues to investigate the link between muscle cells and brain cells in the development and progression of AD and sarcopenia.

Study on the Preparation and Performance of Silicone-Modified Phenolic Resin Binder for Rail Grinding Wheels.

A scheme for manufacturing heavy-duty rail grinding wheels with silicone-modified phenolic resin (SMPR) as a binder in the field of rail grinding is presented to improve the performance of grinding wheels. To optimize the heat resistance and mechanical performance of rail grinding wheels, an SMPR for industrial production of rail grinding wheels was prepared in a two-step reaction using methyl-trimethoxy-silane (MTMS) as the organosilicon modifier by guiding the occurrence of the transesterification and addition polymerization reactions. The effect of MTMS concentration on the performance of silicone-modified phenolic resin for application in rail grinding wheels was investigated. The molecular structure, thermal stability, bending strength, and impact strength values of the SMPR were characterized by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and mechanical property testing, and the effect of MTMS content on the resin properties was investigated. The results indicated that MTMS successfully improved the performance of the phenolic resin. The thermogravimetric weight loss temperature of the SMPR modified by MTMS with 40% phenol mass at 30% weight loss is 66% higher than that of common phenolic resin (UMPR), exhibiting the best thermal stability; in addition, its bending strength and impact strength were enhanced by approximately 14% and 6%, respectively, compared with those of common UMPR. This study utilized an innovative Bronsted acid as a catalyst and simplified several intermediate reactions in the conventional silicone-modified phenolic resin technology. This new investigation of the synthesis process decreases the manufacturing cost of the SMPR, liberates it from the restrictions of grinding applications, and enables the SMPR to maximize its performance in the rail grinding industry. This study serves as a reference for future work on resin binders for grinding wheels and the development of rail grinding wheel manufacturing technology.

Anomalous intense coherent secondary photoemission from a perovskite oxide.

Photocathodes-materials that convert photons into electrons through a phenomenon known as the photoelectric effect-are important for many modern technologies that rely on light detection or electron-beam generation1-3. However, current photocathodes are based on conventional metals and semiconductors that were mostly discovered six decades ago with sound theoretical underpinnings4,5. Progress in this field has been limited to refinements in photocathode performance based on sophisticated materials engineering1,6. Here we report unusual photoemission properties of the reconstructed surface of single crystals of the perovskite oxide SrTiO3(100), which were prepared by simple vacuum annealing. These properties are different from the existing theoretical descriptions4,7-10. In contrast to other photocathodes with a positive electron affinity, our SrTiO3 surface produces, at room temperature, discrete secondary photoemission spectra, which are characteristic of efficient photocathode materials with a negative electron affinity11,12. At low temperatures, the photoemission peak intensity is enhanced substantially and the electron beam obtained from non-threshold excitations shows longitudinal and transverse coherence that differs from previous results by at least an order of magnitude6,13,14. The observed emergence of coherence in secondary photoemission points to the development of a previously undescribed underlying process in addition to those of the current theoretical photoemission framework. SrTiO3 is an example of a fundamentally new class of photocathode quantum materials that could be used for applications that require intense coherent electron beams, without the need for monochromatic excitations.

Different immunological mechanisms between AQP4 antibody-positive and MOG antibody-positive optic neuritis based on RNA sequencing analysis of whole blood.

Purpose: To compare the different immunological mechanisms between aquaporin 4 antibody-associated optic neuritis (AQP4-ON) and myelin oligodendrocyte glycoprotein antibody-associated optic neuritis (MOG-ON) based on RNA sequencing (RNA-seq) of whole blood. Methods: Whole blood was collected from seven healthy volunteers, 6 patients with AQP4-ON and 8 patients with MOG-ON, and used for RNA-seq analysis. An examination of immune cell infiltration was performed using the CIBERSORTx algorithm to identify infiltrated immune cells. Results: RNA-seq analysis showed that the inflammatory signaling was mainly activated by TLR2, TLR5, TLR8 and TLR10 in AQP4-ON patients, while which was mainly activated by TLR1, TLR2, TLR4, TLR5 and TLR8 in MOG-ON patients. Biological function identification of differentially expressed genes (DEGs) based on Gene Ontology (GO) term and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis, as well as Disease Ontology (DO) analysis, showed that the inflammation in AQP4-ON was likely mediated by damage-associated molecular pattern (DAMP), while which in MOG-ON was likely mediated by pathogen-associated molecular pattern (PAMP). Analysis of immune cell infiltration showed that the proportion of immune cell infiltration was related to patients' vision. The infiltration ratios of monocytes (rs=0.69, P=0.006) and M0 macrophages (rs=0.66, P=0.01) were positively correlated with the BCVA (LogMAR), and the infiltration ratio of neutrophils was negatively correlated with the BCVA (LogMAR) (rs=0.65, P=0.01). Conclusion: This study reveals different immunological mechanisms between AQP4-ON and MOG-ON based on transcriptomics analysis of patients' whole blood, which may expand the current knowledge regarding optic neuritis.

Effects of Atorvastatin on Bile Acid Metabolism in High-fat Diet-fed ApoE -/- Mice.

ABSTRACT: Statins are considered as the cornerstone of the prevention and treatment of atherosclerotic cardiovascular disease, where pleiotropic effects are thought to contribute greatly in addition to the lipid-lowering effect. Bile acid metabolism has been gradually reported to be involved in the antihyperlipidemic and antiatherosclerotic effects of statins, but with inconsistent results and few studies carried out on animal models of atherosclerosis. The study aimed to examine the possible role of bile acid metabolism in the lipid-lowering and antiatherosclerotic effects of atorvastatin (ATO) in high-fat diet-fed ApoE -/- mice. The results showed that the levels of liver and faecal TC as well as ileal and faecal TBA were significantly increased in mice of the model group after 20 weeks of high-fat diet feeding compared with the control group, with significantly downregulated mRNA expression of liver LXR-α, CYP7A1, BSEP, and NTCP. ATO treatment further increased the levels of ileal and faecal TBA and faecal TC, but no obvious effect was observed on serum and liver TBA. In addition, ATO significantly reversed the mRNA levels of liver CYP7A1 and NTCP, and no obvious changes were observed in the expression of LXR-α and BSEP. Our study suggested that statins may enhance the synthesis of bile acids and facilitate the reabsorption of bile acids from the ileum via portal into the liver, possibly through the upregulation of the expression of CYP7A1 and NTCP. The results are helpful in enriching the theoretical basis for the clinical use of statins and have good translational value.

Schisandrin C enhances cGAS-STING pathway activation and inhibits HBV replication.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra Chinensis (Turcz.) Baill. is a long-term used traditional Chinese medicine with the functions of tonifying the kidney and calming the heart, tonifying qi and engendering fluid. It can be used to treat insomnia and dreaminess, spermatorrhea, coughs, as well as liver and kidney deficiency of Yin or Yang Syndrome. Modern pharmacological studies have shown that Schisandra Chinensis regulates host immunity and exhibits anti-cancer, antiviral and liver-protecting effects. However, the specific mechanism by which Schisandra Chinensis modulates antiviral immunity is unknown. AIM OF THE STUDY: We sought to explore the therapeutic effect of the active components of Schisandra Chinensis on anti-viral immunity and further investigate the underlying mechanism. MATERIALS AND METHODS: Immunoblotting, quantitative real-time PCR, enzyme-linked immunosorbent assay, immunofluorescence, and immunoprecipitation were used to investigate the effect of schisandrin C (SC), one of the most abundant and biologically active components of Schisandra Chinensis, on the activation of cGAS-STING signaling pathway and the underlying mechanism. In addition, CMA-mediated STING activation and hydrodynamic injection-mediated HBV-replicating mouse model were used to investigate the effect of SC on the activation of STING signaling pathway and its antiviral effect in vivo. RESULTS: SC promoted cGAS-STING pathway activation, accompanied by increased production of interferon ß (IFN ß) and downstream gene expression. Moreover, SC also exerted anti-HBV effects, reducing HBeAg, HBcAg, HBsAg, and HBV DNA levels in hydrodynamic injection-mediated HBV-replicating mouse model and elevating the production of IFN ß and expression of interferon-stimulated genes (IFIT1, ISG15, and CXCL10). Mechanistically, SC could facilitate the interaction between TANK-binding kinase 1 (TBK1) and STING, which is important for IRF3 phosphorylation and production of IFN ß. CONCLUSIONS: Our study confirmed that SC enhances cGAS-STING pathway activation and inhibits HBV replication, as well as provides clues for chronic hepatitis B and other infectious diseases treated by SC.

Fabrication, Optimization, and Evaluation of Paclitaxel and Curcumin Coloaded PLGA Nanoparticles for Improved Antitumor Activity.

Codelivery of chemotherapeutic drugs in nanoparticles can enhance the therapeutic effects against tumors. However, their anticancer properties and physiochemical characteristics can be severely influenced by many formulation parameters during the preparation process. It is a complicated development phase to select the optimal parameters for preparation of nanoparticles based on the commonly used one single parameter method, which consumes a lot of money, time, and effort, and sometimes even fails. Therefore, the statistical analysis based on Box-Behnken design (BBD) has attracted much attention in bioengineering fields because it can illustrate the influence of parameters, build mathematical models, and predict the optimal combinational factors in a decreased number of experiments. In this study, we used a three-factor three-level BBD design to optimize the preparation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles coloaded with two anticancer drugs curcumin and paclitaxel (PLGA-CUR-PTX nanoparticles). The surfactant concentration, polymer concentration, and oil-water ratio were selected as independent variables. An optimized model of the formulation for PLGA-CUR-PTX nanoparticles was validated. The optimal nanoparticles possessed a uniform spherical shape, with an average size of 99.94 nm, and the drug encapsulation efficiencies of CUR and PTX were 63.53 and 80.64%, respectively. The drug release from nanoparticles showed a biphasic release behavior, with a release mechanism via diffusion and fundamentally quasi-Fickian diffusion. The optimized nanoparticles demonstrated an enhanced cytotoxicity effect with lower IC50 values to 4T1 and MCF-7 breast cancer cell lines compared to free drugs. In summary, BBD optimization of CUR and PTX coloaded nanoparticles yielded a favorable drug carrier that holds potential as an alternative treatment for anticancer therapy.