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Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive degenerative disease of skeletal muscle, characterized by intramuscular inflammation, muscle regeneration disorder and replacement of muscle with fibroadipose tissue. DMD is caused by the absence of normal dystrophy. Impaired self-renew ability and limited differentiation capacity of satellite cells are proved as main reasons for muscle regeneration failure. The deficiency of estrogen impedes the process of muscle regeneration. However, the role of estrogen receptor β (ERβ) in muscle regeneration is still unclear. This study aims to investigate the role and the pharmacological effect of ERβ activation on muscle regeneration in mdx mice. This study showed that mRNA levels of ERβ and myogenic-related genes both witnessed increasing trends in dystrophic context. Our results revealed that treatment with selective ERβ agonist (DPN, diarylpropionitrile) significantly increased myogenic differentiation 1 (MyoD-1) level and promoted muscle regeneration in mdx mice. Similarly, in mdx mice with muscle-specific estrogen receptor α (ERα) ablation, DPN treatment still promoted muscle regeneration. Moreover, we demonstrated that myoblasts differentiation was accompanied by raised nuclear accumulation of ERβ. DPN treatment augmented the nuclear accumulation of ERβ and, thus, contributed to myotubes formation. One important finding was that forkhead box O3A (FOXO3A), as a pivotal transcription factor in Myod-1 transcription, participated in the ERβ-promoted muscle regeneration. Overall, we offered an interesting explanation about the crucial role of ERβ during myogenesis.

Abstract Wounds are one of the most common health issues, and the cost of wound care and healing has continued to increase over the past decade. In recent years, there has been growing interest in developing innovative strategies to enhance the efficacy of wound healing. Tetrahedral framework nucleic acids (tFNAs) have emerged as a promising tool for wound healing applications due to their unique structural and functional properties. Therefore, it is of great significance to summarize the applications of tFNAs for wound healing. This review article provides a comprehensive overview of the potential of tFNAs as a novel therapeutic approach for wound healing. In this review, we discuss the possible mechanisms of tFNAs in wound healing and highlight the role of tFNAs in modulating key processes involved in wound healing, such as cell proliferation and migration, angiogenesis, and tissue regeneration. The targeted delivery and controlled release capabilities of tFNAs offer advantages in terms of localized and sustained delivery of therapeutic agents to the wound site. In addition, the latest research progress on tFNAs in wound healing is systematically introduced. We also discuss the biocompatibility and biosafety of tFNAs, along with their potential applications and future directions for research. Finally, the current challenges and prospects of tFNAs are briefly discussed to promote wider applications.

Background: Altered patterns of bile acids (BAs) are frequently present in liver fibrosis, and BAs function as signaling molecules to initiate inflammatory responses. Silybin meglumine (SLB-M) is widely used in treating various liver diseases including liver fibrosis. However, research on its effects on bile acid (BA) metabolism is limited. This study investigated the therapeutic effects of SLB-M on liver fibrosis and BA metabolism in a CCl4-induced murine model. Methods: A murine liver fibrosis model was induced by CCl4. Fibrosis was evaluated using HE, picrosirius red, and Masson’s trichrome staining. Liver function was assessed by serum and hepatic biochemical markers. Bile acid (BA) metabolism was analyzed using LC-MS/MS. Bioinformatics analyses, including PPI network, GO, and KEGG pathway analyses, were employed to explore molecular mechanisms. Gene expression alterations in liver tissue were examined via qRT-PCR. Results: SLB-M treatment resulted in significant histological improvements in liver tissue, reducing collagen deposition and restoring liver architecture. Biochemically, SLB-M not only normalized serum liver enzyme levels (ALT, AST, TBA, and GGT) but also mitigated disruptions in both systemic and hepatic BA metabolism by increased unconjugated BAs like cholic acid and chenodeoxycholic acid but decreased conjugated BAs including taurocholic acid and taurodeoxycholic acid, compared to that in CCl4-induced murine model. Notably, SLB-M efficiently improved the imbalance of BA homeostasis in liver caused by CCl4 via activating Farnesoid X receptor. Conclusions: These findings underscore SLB-M decreased inflammatory response, reconstructed BA homeostasis possibly by regulating key pathways, and gene expressions in BA metabolism.

Triptolide (TP) is the major bioactive component of traditional Chinese medicine Tripterygium wilfordii Hook. F., a traditional Chinese medicinal plant categorized within the Tripterygium genus of the Celastraceae family. It is recognized for its therapeutic potential in addressing a multitude of diseases. Nonetheless, TP is known to exhibit multi-organ toxicity, notably hepatotoxicity, which poses a significant concern for the well-being of patients undergoing treatment. The precise mechanisms responsible for TP-induced hepatotoxicity remain unresolved. In our previous investigation, it was determined that TP induces heightened hepatic responsiveness to exogenous lipopolysaccharide (LPS). Additionally, natural killer (NK) cells were identified as a crucial effector responsible for mediating hepatocellular damage in this context. However, associated activating receptors and the underlying mechanisms governing NK cell represented innate lymphoid cell (ILC) activation remained subjects of inquiry and were not yet investigated. Herein, activating receptor Killer cell lectin like receptor K1 (NKG2D) of group 1 ILCs was specifically upregulated in TP- and LPS-induced acute liver failure (ALF), and in vivo blockade of NKG2D significantly reduced group 1 ILC mediated cytotoxicity and mitigated TP- and LPS-induced ALF. NKG2D ligand UL16-binding protein-like transcript 1 (MULT-1) was found upregulated in liver resident macrophages (LRMs) after TP administration, and LRMs did exhibit NK cell activating effect. Furthermore, M1 polarization of LRMs cells was observed, along with an elevation in intracellular tumor necrosis factor (TNF)-α levels. In vivo neutralization of TNF-α significantly alleviated TP- and LPS-induced ALF. In conclusion, the collaborative role of group 1 ILCs and LRMs in mediating hepatotoxicity was confirmed in TP- and LPS-induced ALF. TP-induced MULT-1 expression in LRMs was the crucial mechanism in the activation of group 1 ILCs via MULT-1-NKG2D signal upon LPS stimulation, emphasizing the importance of infection control after TP administration.

Liquid biopsy is a technology that exhibits potential to detect cancer early, monitor therapies, and predict cancer prognosis due to its unique characteristics, including noninvasive sampling and real-time analysis. Circulating tumor cells (CTCs) and extracellular vesicles (EVs) are two important components of circulating targets, carrying substantial disease-related molecular information and playing a key role in liquid biopsy. Aptamers are single-stranded oligonucleotides with superior affinity and specificity, and they can bind to targets by folding into unique tertiary structures. Aptamer-based microfluidic platforms offer new ways to enhance the purity and capture efficiency of CTCs and EVs by combining the advantages of microfluidic chips as isolation platforms and aptamers as recognition tools. In this review, we first briefly introduce some new strategies for aptamer discovery based on traditional and aptamer-based microfluidic approaches. Then, we subsequently summarize the progress of aptamer-based microfluidics for CTC and EV detection. Finally, we offer an outlook on the future directional challenges of aptamer-based microfluidics for circulating targets in clinical applications.

Moonlighting enzymes are multifunctional proteins that perform multiple functions beyond their primary role as catalytic enzymes. Extensive research and clinical practice have demonstrated their pivotal roles in the development and progression of cancer, making them promising targets for drug development. This article delves into multiple notable moonlighting enzymes, including GSK-3, GAPDH, and ENO1, and with a particular emphasis on an enigmatic phosphatase, PTP4A3. We scrutinize their distinct roles in cancer and the mechanisms that dictate their ability to switch roles. Lastly, we discuss the potential of an innovative approach to develop drugs targeting these moonlighting enzymes: target protein degradation. This strategy holds promise for effectively tackling moonlighting enzymes in the context of cancer therapy.

Abstract Osteopontin (OPN) is a multifunctional cytokine that can impact cancer progression. Therefore, it is crucial to determine the key factors involved in the biological role of OPN for the development of treatment. Here, we investigated that OPN promoted hepatocellular carcinoma (HCC) cell proliferation and migration by increasing Reactive oxygen species (ROS) production and disclosed the underlying mechanism. Knockdown of OPN suppressed ROS production in vitro and in vivo, whereas treatment with human recombinant OPN produced the opposite effect. N-Acetyl-L-cysteine (NAC, ROS scavenger) partially blocked HCC cell proliferation and migration induced by OPN. Mechanistically, OPN induced ROS production in HCC cells by upregulating the expression of NADPH oxidase 1 (NOX1). NOX1 knockdown in HCC cells partially abrogated the cell proliferation and migration induced by OPN. Moreover, inhibition of JAK2/STAT3 phosphorylation effectively decreased the transcription of NOX1, upregulated by OPN. In addition, NOX1 overexpression increased JAK2 and STAT3 phosphorylation by increasing ROS production, creating a positive feedback loop for stimulating JAK2/STAT3 signaling induced by OPN. This study for the first time demonstrated that HCC cells utilized OPN to generate ROS for tumor progression, and disruption of OPN/NOX1 axis might be a promising therapeutic strategy for HCC.

Recently, there is a surge of research interest in configurable ferroelectric conductive domain walls which have been considered as possible fundamental building blocks for future electronic devices. In this work, by using piezoresponse force microscopy and conductive atomic force microscopy, we demonstrated the controlled manipulation of various conductive domain walls in epitaxial BiFeO3 thin films, e.g. neutral domain walls (NDW) and charged domain walls (CDWs). More interestingly, a specific type of nanoscale domains was also identified, which are surrounded by highly conductive circular CWDs. Similar nanoscale domains can also be controlled created and erasured by applying local field via conductive probe, which allow nondestructive current readout of different domain states with a large on/off resistance ratio up to 102. The results indicate the potential to design and develop high-density non-volatile ferroelectric memories by utilizing these programable conductive nanoscale domain walls.

Aims: Long non-coding RNAs (lncRNAs) contribute to the regulation of vital physiological processes and play a role in the pathogenesis of many diseases. Monocrotaline (MCT) can cause large-scale outbreaks of toxic liver disease in humans and animals in the form of hepatic sinusoidal obstruction syndrome (HSOS). Although many experiments have been carried out to explain the pathogenesis of Monocrotaline-induced hepatic sinusoidal obstruction syndrome and to develop treatments for it, no studies have examined the role of Long non-coding RNAs in this condition. This study aimed to investigate the Long non-coding RNAs–mRNA regulation network in Monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats.Main methods: We established a model for MCT-induced hepatic sinusoidal obstruction syndrome, and then carried out microarray for liver tissues of SD rats in a model of early hepatic sinusoidal obstruction syndrome (12 h Monocrotaline treatment vs. control group) to investigate the differentially expressed Long non-coding RNAs and mRNAs in early hepatotoxicity. This was followed by RT-PCR analysis of selected Long non-coding RNAs, which were markedly altered. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome analyses were also conducted.Key findings: 176 Long non-coding RNAs (63 downregulated and 113 upregulated) and 4,221 mRNAs (2,385 downregulated and 1836 upregulated) were differentially expressed in the Monocrotaline-treated group compared to the control group. The biological processes identified in GO enrichment analysis as playing a role in hepatotoxicity were positive regulation of guanosine triphosphate phosphohydrolase, liver development, and the oxidation-reduction process. Pathway analysis revealed that the metabolism pathways, gap junction, and ribosome biogenesis in eukaryotes were closely related to Monocrotaline-induced hepatotoxicity. According to these analyses, LOC102552718 might play an essential role in hepatotoxicity mechanisms by regulating the expression of inositol 1,4,5-trisphosphate receptor-1 (Itpr-1).Significance: This study provides a basis for further research on the molecular mechanisms underlying Monocrotaline-induced hepatotoxicity and its treatment, especially in the early stage, when successful treatment is critical before irreversible liver damage occurs.

Tripterygium wilfordii multiglycoside (GTW), extracted and purified from the peeled roots of T. wilfordii Hook.f. (TwHF), is a well-known traditional Chinese medicine and applied to various autoimmune diseases clinically. However, it has been reported to cause severe liver injury. At present, the mechanism underlying GTW-induced hepatotoxicity remain poorly defined. Here, we evaluated the effects of GTW on mouse liver and elucidated the associated mechanisms via label-free proteomics combined with bioinformatics analysis. Male C57BL/6J mice were randomly divided into normal group, a low-dose GTW (70 mg/kg) group and a high-dose GTW (140 mg/kg) group. After 1-week administration, GTW dose-dependently induced hepatotoxicity. Further analysis showed that GTW could act on the intestinal immune network for IgA production pathway, which plays an important role in maintaining intestinal homeostasis and influences the crosstalk between gut and liver. Western blots confirmed that GTW could decrease pIgR protein expression in the liver and ileum, and, as a result, the secretion of IgA into gut lumen was reduced. Further validation showed that intestinal barrier integrity was impaired in GTW-treated mice, promoting bacteria transferring to the liver and triggering proinflammatory response. Our study demonstrated that gut-liver axis may play a vital part in the progression of GTW-induced hepatotoxicity, which provides guidance for basic research and clinical application of GTW.

Cholestasis is a common, chronic liver disease that may cause fibrosis and cirrhosis. Tripterygium wilfordii Hook.f (TWHF) is a species in the Euonymus family that is commonly used as a source of medicine and food in Eastern and Southern China. Triptolide (TP) is an epoxy diterpene lactone of TWHF, as well as the main active ingredient in TWHF. Here, we used a mouse model of common bile duct ligation (BDL) cholestasis, along with cultured human intrahepatic biliary epithelial cells, to explore whether TP can relieve cholestasis. Compared with the control treatment, TP at a dose of 70 or 140 μg/kg reduced the serum levels of the liver enzymes alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in mice; hematoxylin and eosin staining also showed that TP reduced necrosis in tissues. Both in vitro and in vivo analyses revealed that TP inhibited cholangiocyte proliferation by reducing the expression of RelB. Immunohistochemical staining of CK19 and Ki67, as well as measurement of Ck19 mRNA levels in hepatic tissue, revealed that TP inhibited the BDL-induced ductular reaction. Masson 3 and Sirius Red staining for hepatic hydroxyproline showed that TP alleviated BDL-induced hepatic fibrosis. Additionally, TP substantially inhibited BDL-induced hepatic inflammation. In summary, TP inhibited the BDL-induced ductular reaction by reducing the expression of RelB in cholangiocytes, thereby alleviating liver injury, fibrosis, and inflammation.

The authors wish to make the following corrections to this paper [...]

Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke, but how to control the overactive neuroinflammation is still a long-standing challenge. Here, we designed a novel SIRT6 activator MDL-811 which remarkably inhibited inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and primary mouse microglia, which were abolished by silencing SIRT6. RNA-seq screening identified the forkhead box C1 (Foxc1) is a key gene evoked by MDL-811 stimulation and is required for the anti-inflammatory effects of MDL-811. We found MDL-811-activated SIRT6 directly interacted with enhancer of zeste homolog 2 (EZH2) and promoted deacetylation of EZH2 which could bind to the promoter of Foxc1 and upregulate its expression to modulate inflammation. Moreover, our data demonstrated that MDL-811 not only ameliorated sickness behaviors in neuroinflammatory mice induced by LPS, but also markedly reduced the brain injury in ischemic stroke mice in addition to promoting long-term functional recovery. Importantly, MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients, underlying an interesting translational perspective. Taken together, MDL-811 could be an alternative therapeutic candidate for ischemic stroke and other brain disorders associated with neuroinflammation.

Abstract Background Transforming growth factor‐β‐activated kinase 1 (TAK1) plays a key role in regulating fibroblast and myoblast proliferation and differentiation. However, the TAK1 changes associated with Duchenne muscular dystrophy (DMD) are poorly understood, and it remains unclear how TAK1 regulation could be exploited to aid the treatment of this disease. Methods Muscle biopsies were obtained from control donors or DMD patients for diagnosis (n = 6 per group, male, 2–3 years, respectively). Protein expression of phosphorylated TAK1 was measured by western blot and immunofluorescence analysis. In vivo overexpression of TAK1 was performed in skeletal muscle to assess whether TAK1 is sufficient to induce or aggravate atrophy and fibrosis. To explore whether TAK1 inhibition protects against muscle damage, mdx (loss of dystrophin) mice were treated with adeno‐associated virus (AAV)‐short hairpin TAK1 (shTAK1) or NG25 (a TAK1 inhibitor). Serum analysis, skeletal muscle performance and histology, muscle contractile function, and gene and protein expression were performed. Results We found that TAK1 was activated in the dystrophic muscles of DMD patients (n = 6, +72.2%, P

Ferroelectric topological defects show emerging exotic physical properties, which are important for future nanoelectronic devices. Here, the authors demonstrate conductive metallic conduction channels in two types of topological defects, namely vortex and center cores.

Hydrogen peroxide (H2O2) is the most significant reactive oxygen species in biological systems. Here, we reported an electrochemical sensor for the detection of H2O2 on the basis of bimetallic gold-platinum nanoparticles (Au3Pt7 NPs) supported by Co-based metal organic frameworks (Co-MOFs). First, Au3Pt7 NPs, with optimal electrocatalytic activity and accessible active surface, can be deposited on the surface of the Co-MOF–modified glassy carbon electrodes (Au3Pt7/Co-MOFs/GCE) by one-step electrodeposition method. Then, the electrochemical results demonstrated that the two-dimensional (2D) Co-MOF nanosheets as the supporting material displayed better electrocatalytic properties than the 3D Co-MOF crystals for reduction of H2O2. The fabricated Au3Pt7/2D Co-MOF exhibited high electrocatalytic activity, and the catalytic current was linear with H2O2 concentration from 0.1 μM to 5 mM, and 5–60 mM with a low detection limit of 0.02 μM (S/N = 3). The remarkable electroanalytical performance of Au3Pt7/2D Co-MOF can be attributed to the synergistic effect of the high dispersion of the Au3Pt7 NPs with the marvelous electrochemical properties and the 2D Co-MOF with high-specific surface areas. Furthermore, this sensor has been utilized to detect H2O2 concentrations released from the human Hela cells. This work provides a new method for improving the performance of electrochemical sensors by choosing the proper support materials from diverse crystal morphology materials.

Background Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the loss of dystrophin, which results in inflammation, fibrosis, and the inhibition of myoblast differentiation in skeletal muscle. Catalpol, an iridoid glycoside, improves skeletal muscle function by enhancing myogenesis; it has potential to treat DMD. We demonstrate the positive effects of catalpol in dystrophic skeletal muscle. Methods mdx (loss of dystrophin) mice (n = 18 per group) were treated with catalpol (200 mg/kg) for six consecutive weeks. Serum analysis, skeletal muscle performance and histology, muscle contractile function, and gene and protein expression were performed. Molecular docking and ligand–target interactions, RNA interference, immunofluorescence, and plasmids transfection were utilized to explore the protective mechanism in DMD by which catalpol binding with transforming growth factor‐β–activated kinase 1 (TAK1) in skeletal muscle. Results Six weeks of catalpol treatment improved whole‐body muscle health in mdx mice, which was characterized by reduced plasma creatine kinase (n = 18, −35.1%, P

Previously, we proposed a new perspective of triptolide (TP)-associated hepatotoxicity: liver hypersensitivity upon lipopolysaccharide (LPS) stimulation. However, the mechanisms for TP/LPS-induced hepatotoxicity remained elusive. The present study aimed to clarify the role of LPS in TP/LPS-induced hepatotoxicity and the mechanism by which TP induces liver hypersensitivity upon LPS stimulation. TNF-α inhibitor, etanercept, was injected intraperitoneally into mice to investigate whether induction of TNF-α by LPS participated in the liver injury induced by TP/LPS co-treatment. Mice and hepatocytes pretreated with TP were stimulated with recombinant TNF-α to assess the function of TNF-α in TP/LPS co-treatment. Additionally, time-dependent NF-κB activation and NF-κB-mediated pro-survival signals were measured in vivo and in vitro. Finally, overexpression of cellular FLICE-inhibitory protein (FLIP), the most potent NF-κB-mediated pro-survival protein, was measured in vivo and in vitro to assess its function in TP/LPS-induced hepatotoxicity. Etanercept counteracted the toxic reactions induced by TP/LPS. TP-treatment sensitized mice and hepatocytes to TNF-α, revealing the role of TNF-α in TP/LPS-induced hepatotoxicity. Mechanistic studies revealed that TP inhibited NF-κB dependent pro-survival signals, especially FLIP, induced by LPS/TNF-α. Moreover, overexpression of FLIP alleviated TP/LPS-induced hepatotoxicity in vivo and TP/TNF-α-induced apoptosis in vitro. Mice and hepatocytes treated with TP were sensitive to TNF-α, which was released from LPS-stimulated immune cells. These and other results show that the TP-induced inhibition of NF-κB-dependent transcriptional activity and FLIP production are responsible for liver hypersensitivity.

The extract of the medicinal plant, Tripterygium wilfordii Hook. f. (TW), has been used in the treatment of diverse autoimmune diseases, including rheumatoid arthritis. However, the high frequency of toxic side effects has limited its clinical use. In order to reduce toxicity without losing the therapeutic benefit, the pharmacological activity and toxicity of four compounds (T-96, triptolide, neotripterifordin, and tripterifordin) from TW were evaluated. The current study revealed that these compounds interfere with the IL-1β signaling pathway, which stimulates the secretion of pro-inflammatory cytokines (IL-6) in primary rheumatoid arthritis synovial fibroblasts (RASFs). These compounds inhibit IL-6 production, and among these, T-96 was the most effective. Moreover, T-96 blocks activation of NF-κB and p38 and ameliorates the joint destruction and the clinical signs of the disease in adjuvant-induced arthritic rats. These data suggest that among the four compounds of the TW, T-96 possesses highest anti-rheumatoid arthritis activity though inhibiting IL-1-mediated inflammatory signaling pathways.

The pharmacokinetics of Chinese materia medica (PCMM) has made a great contribution to investigations of the in vivo process of various components in Chinese materia medica (CMM), intending to provide useful information for clinical guidance related to CMM. However, some issues are worthy of further consideration, and current PCMM studies face a substantial challenge. First, high-dosage administration is prevalent in PCMM studies, and the obtained results might be meaningless and inappropriate for guiding the clinical application of CMM, as they deviate from clinical practice. Improvements in instrument sensitivity have not reduced the prevalence of high-dosage administration. In addition, the selection of components for detection in PCMM studies is usually uncertain, lacking sufficient scientific support, especially for components without clarified bioactivities. Therefore, the scientific value of current PCMM studies is limited. We believe that these abnormalities can be attributed to the poor recognition of the characteristics of CMM and the improper application of research approaches from Western medicines. Currently, the more pressing key scientific issues for CMM should be clinical effectiveness, quality control and bioactivity discovery, which are closely related to its own characteristics and are beneficial to its modern developments.

Inflammation, especially the release of pro-inflammatory mediators, contributes to hepatocyte injury during cholestasis. Alpha-naphthylisothiocyanate (ANIT) is widely used in rodents to mimic clinical cholestasis. Lymphocytes have been reported to exacerbate ANIT - induced hepatotoxicity. However, which cell and mechanism mediate hepatic inflammatory response and hepatocyte injury in cholestasis is still not clear. Invariant natural killer T (iNKT) cells are a unique subset of T lymphocytes which are supposed to exert immune-regulatory effect on cholestatic liver damage. In the present study, we hypothesized that iNKT cells played a role in the pathogenesis of ANIT-induced cholestatic hepatotoxicity. ANIT (50 mg/kg, intragastric gavage) was administered to male mice for 16, 48, or 72 h. We found that ANIT administration activated iNKT cells, releasing Th1 cytokine IFN-γ and Th2 cytokine IL-4. Administration of ANIT induced cholestatic liver injury, evidenced by the elevated serum ALT, AST, ALP, TBA, TG and TC levels, and significant hepatic histopathological changes. However, knockout of iNKT cell were resistant to the late development of ANIT - induced liver injury due to the reduced release of inflammatory cytokines CXCL10 and ICAM-1, as well as the down-regulation of nuclear receptor Egr1. We further revealed that the improvement of ALP in iNKT cell - deficient mice was partly associated with the up-regulation of transporter MRP2 and NTCP and bile acid metabolism enzyme CYP2B10. Collectively, these results suggested that iNKT cells aggravated ANIT-induced cholestatic liver injury by inducing inflammatory response which contributed to the understanding of the mechanisms of ANIT-induced cholestasis. More importantly, the iNKT cell regulation may promote effective measures that control cholestasis.

Abstract Creating a soil habitat is the first step to manage soil health for long‐term soil quality and output. This means using soil management methods that lessen the soil uproar. An experiment was established in 2016 and 2017 on a middle term (7 years) consistent tillage method in typical Latosolic red soil of Southern China to access the effects of four treatments: subsoiling (SS), two passes of rotary tillage (2RT), two passes of rotary tillage + subsoiling (2RTSS), and zero tillage (ZT), on soil organic carbon, soil total nitrogen, soil biological activities (bacteria, fungi, actinomycetes, urease, catalase, and phosphatase), and maize grain yield. The results showed that mean SOC, total N, biological activities, and maize grain yields were affected significantly (p

The performances of data transmissions in vehicular network are investigated. In the vehicular network, the data transmissions are realized by the proposed transmission strategies. Under a cognitive way, the specific strategy is adopted in the corresponding transmission duration. In this paper, the vehicle-to-pedestrian, vehicle-to-vehicle, and vehicle-to-infrastructure/network transmission modes are adopted to implement the data transmission. In the data transmission durations, the transmission modes transit among one another based on the strategies decisions. A state transition model is proposed to describe the communication and evaluate the performances. The concept of effective capacity is adopted, and the mathematical expression of effective capacity is derived. Besides, the effective capacity under the parameter constraints is also demonstrated. From the specific simulations, it is shown that the effective capacity is the most sensitive to quality-of-service exponent. The pedestrian density and vehicle density also impose significant impact on the transmission performances. Besides, short transmission range of the infrastructures and vehicles is necessary to improve the effective capacity.

Neuroinflammation is one of the important factors aggravating brain injury after ischemic stroke. We aimed to investigate the effects of cerebrolysin (CBL) on neuroinflammation in vivo and in vitro and the underlying mechanisms. The gene expressions of pro-inflammatory factors and anti-inflammatory factors were analyzed by real time PCR in rat transient middle cerebral artery occlusion (tMCAO) model, lipopolysaccharides-induced neuroinflammatory mice model and LPS-treated mouse primary microglia cells. The neuroprotective effects of CBL were evaluated by infarct size, Longa test and Rotarod test for long-term functional recovery in rats subjected to ischemia. The role of CREB/PGC-1α pathway in anti-neuroinflammatory effect of CBL was also determined by real time PCR and Western blotting. In the tMCAO model, administration of CBL at 3 h post-ischemia reduced infarct volume, promoted long-term functional recovery, decreased the gene expression of pro-inflammatory factors and increased the gene expression of anti-inflammatory factors. Correspondingly, in LPS-induced neuroinflammatory mice model, CBL treatment attenuated sickness behavior, decreased the gene expression of pro-inflammatory factors, and increased the gene expression of anti-inflammatory factors. In in vitro and in vivo experiments, CBL increased the protein expression levels of PGC-1α and phosphorylated CREB to play anti-inflammatory effect. Additionally, the application of the specific CREB inhibitor, 666-15 compound could effectively reverse the anti-inflammatory effect of CBL in primary mouse microglia cells and anti-ischemic brain injury of CBL in rats subjected to tMCAO. In conclusion, CBL ameliorated cerebral ischemia injury through reducing neuroinflammation partly via the activation of CREB/PGC-1α pathway and may play a therapeutic role as anti-neuroinflammatory agents in the brain disorders associated with neuroinflammation.

M2-type tumor-associated macrophages (TAMs) infiltration contributes to cancer malignant progression. However, the mechanisms for controlling recruitment and M2 polarization of macrophages by cancer cells are largely unclear. NADPH oxidase 4 (NOX4) is abundantly expressed in non-small cell lung cancer (NSCLC) and mediates cancer progression. NOXs are in close relation with cancer-related inflammation, nevertheless, whether tumoral NOXs influence microenvironmental macrophages remains undentified. This study found that there was a close association between NOX4 expression and macrophage chemotaxis in patients with NSCLC analyzed using TCGA RNA-sequencing data. NOX4 in NSCLC cells (A549 and Calu-1 cell lines) efficiently enhanced murine peritoneal macrophage migration and induces M2 polarization. Immunohistochemical analysis of clinical specimens confirmed the positive correlation of NOX4 and CD68 or CD206. The mechanical study revealed that tumoral NOX4-induced reactive oxygen species (ROS) stimulated various cytokine production, including CCL7, IL8, CSF-1 and VEGF-C, via PI3K/Akt signaling-dependent manner. Blockade of the function of these cytokines reversed NOX4 effect on macrophages. Specifically, the results showed that tumoral NOX4-educated M2 macrophages exhibited elevated JNK activity, expressed and released HB-EGF, thus facilitating NSCLC proliferation in vitro. Pretreatment of macrophages with JNK inhibitor blocked tumoral NOX4-induced HB-EGF production in M2 macrophages. Finally, in a xenograft mouse model, overexpression of NOX4 in A549 cells enhanced the tumor growth. Elimination of ROS by NAC or inhibition of NOX4 activity by GKT137831 suppressed tumor growth accompanied by reduction in macrophage infiltration and the percentage of M2 macrophages. In conclusion, our study indicates that tumoral NOX4 recruits M2 TAMs via ROS/PI3K signaling-dependent various cytokine production, thus contributing NSCLC cell growth. Keywords: NOX4, Macrophages, NSCLC, M2 polarization, Chemotaxis

Psoralen is a major component of the common traditional Chinese medicine Fructus Psoraleae (FP). In this study, we focused on psoralen to explore FP-induced hepatotoxicity and the underlying mechanisms. The acute oral median lethal dose of psoralen in ICR mice was determined to be 1,673 mg/kg. C57BL/6 mice were administered psoralen intragastrically at doses of 400 mg/kg or 800 mg/kg, and were sacrificed 24 h after treatment. Changes in various hepatotoxicity indicators demonstrated that psoralen can cause mild liver injury in mice. Psoralen inhibited the viability of normal human liver L02 cells in vitro by inducing S-phase arrest. In addition, psoralen in both the mouse livers and L02 cells upregulated cyclin E1 and p27 protein levels. The 2/3 partial hepatectomy mouse model was used to further explore the effects of psoralen on the liver regeneration and hepatocellular cycle arrest in vivo. The results showed that the decrease of liver regenerative and self-healing capabilities induced by hepatocellular cycle arrest may play an important role in the hepatotoxicity of psoralen. The further mechanism researches indicated that psoralen-induced hepatotoxicity was associated with inhibition of mTOR signalling pathway and mitochondrial injury; furthermore, MHY, an mTOR activator, partly alleviated the inhibition of mTOR and S-phase cycle arrest induced by psoralen in L02 cells. In conclusion, in this study we showed for the first time, that psoralen significantly induced liver injury in mice; the decrease of liver regenerative and compensatory capabilities induced by hepatocellular cycle arrest may play an important role in the progression of hepatotoxicity associated with the upregulation of cyclin E1 and p27, as well as the inhibition of mTOR signalling and mitochondrial injury. Our findings may contribute to the reduction of hepatotoxicity risk induced by Fructus Psoraleae.

Tuberculosis (TB) is one of the oldest infectious diseases that affected humankind and remains one of the world’s deadliest communicable diseases that could be considered as global emergency, but the discovery and development of isoniazid (INH) in the 1950s paved the way to an effective single and/or combined first-line anti-TB therapy. However, administration of INH induces severe hepatic toxicity in some patients. Previously, we establish a rat model of INH hepatotoxicity utilizing the inflammatory stress theory, in which bacterial lipopolysaccharide (LPS) potentially enhanced INH toxicity. These enhancing activities ranged between augmenting the inflammatory stress, oxidative stress, alteration of bile acid homeostasis, and CYP2E1 over-expression. Although pre-treatment with dexamethasone (DEX) helped overcome both inflammatory and oxidative stress which ended-up in alleviation of LPS augmenting effects, but still minor toxicities were being detected, alongside with CYP2E1 over expression. This finding positively indicated the corner-stone role played by CYP2E1 in the pathogenesis of INH/LPS-induced liver damage. Therefore, we examined whether INH/LPS co-treatment with CYP2E1 inhibitor diallyl sulfide (DAS) and DEX can protect against the INH/LPS-induced hepatotoxicity. Our results showed that pre-administration of both DAS and DEX caused significant reduction in serum TBA, TBil, and gamma-glutamyl transferase levels. Furthermore, the histopathological analysis showed that DAS and DEX could effectively reverse the liver lesions seen following INH/LPS treatment and protect against hepatic steatosis as indicated by absence of lipid accumulation. Pre-treatment with DAS alone could not completely block the CYP2E1 protein expression following INH/LPS treatment, as appeared in the immunoblotting and immunohistochemistry results. This is probably due to the fact that the combined enhancement activities of both INH and LPS on CYP2E1 protein expression levels might resist the blocking probabilities of DAS. In the meantime, addition of DEX to the DAS/INH/LPS combination caused a significant reduction in CYP2E1 protein expression as revealed by the immunoblotting and fading coloration in immunohistochemistry results. Thus, addition of DEX and DAS together caused strong protection against INH/LPS-induced hepatic damage. These findings reveal the potential therapeutic value of combining DAS and DEX with INH in TB management for reducing the potential risk and incidences of hepatotoxicity.

Based on the hypothesis that soil biochemical and maize yield components should be affected by different tillage methods, a field experiment was conducted to study the effects of subsoiling (SS), two passes of rotary tillage (2RT), two passes of rotary tillage + subsoiling (2RTSS), and zero tillage (ZT) on distribution of organic C, available NPK and soil enzyme, and its effects on maize yield in latosolic red soil of southern China in 2016 and 2017. ZT treatment had significantly higher organic C and available NPK than the other treatments, whereas the SS treatment had higher concentration of soil urease, catalase, and acid phosphatase. Also, maximum grain yield, dry matter, harvest index, and 1000-grain weight were recorded under SS treatment. Overall, although ZT facilitated more organic C and available NPK, soil with ZT had lower soil enzyme and maize yield components compared to SS treatment, and therefore SS treatment could be exploited as a strategy for soil health and productivity resulting in a sustainable agricultural system.

Triptolide (TP), a diterpenoid isolated from Tripterygium wilfordii Hook F, has an excellent pharmacological profile of immunosuppression and anti-tumor activities, but its clinical applications are severely restricted due to its severe and cumulative toxicities. The farnesoid X receptor (FXR) is the master bile acid nuclear receptor and plays an important role in maintaining hepatic metabolism homeostasis. Hepatic Sirtuin (Sirt1) is a key regulator of the FXR signaling pathway and hepatic metabolism homeostasis. The aims of this study were to determine whether Sirt1/FXR signaling pathway plays a critical role in TP-induced hepatotoxicity. Our study revealed that the intragastric administration of TP (400 μg/kg body weight) for 28 consecutive days increased bile acid accumulation, suppressed hepatic gluconeogenesis in rats. The expression of bile acid transporter BSEP was significantly reduced and cholesterol 7α-hydroxylase (CYP7A1) was markedly increased in the TP-treated group, whereas the genes responsible for hepatic gluconeogenesis were suppressed in the TP-treated group. TP also modulated the FXR and Sirt1 by decreasing its expression both in vitro and in vivo. The Sirt1 agonist SRT1720 and the FXR agonist obeticholic acid (OCA) were used both in vivo and in vitro. The remarkable liver damage induced by TP was attenuated by treatment with either SRT1720 or OCA, as reflected by decreased levels of serum total bile acids and alkaline phosphatase and increased glucose levels. Meanwhile, SRT1720 significantly alleviated TP-induced FXR suppression and FXR-targets involved in hepatic lipid and glucose metabolism. Based on these results, we conclude that Sirt1/FXR inactivation plays a critical role in TP-induced hepatotoxicity. Moreover, Sirt1/FXR axis represents a novel therapeutic target that could potentially ameliorate TP-induced hepatotoxicity.

Intrahepatic cholestasis is a kind of clinical syndrome along with hepatotoxicity which caused by intrahepatic and systemic accumulations of bile acid. There are several crucial generating factors of the pathogenesis of cholestasis, such as inflammation, dysregulation of bile acid transporters and oxidative stress. SIRT1 is regarded as a class III histone deacetylase (HDAC). According to a set of researches, SIRT1 is one of the most important factors which can regulate the hepatic bile acid metabolism. SRT1720 is a kind of activator of SIRT1 which is 1000 times more potent than resveratrol, and this paper is aimed to study its protective influence on hepatotoxicity and cholestasis induced by alpha-naphthylisothiocyanate (ANIT) in mice. The findings revealed that SRT1720 treatment increased FXR and Nrf2 gene expressions to shield against hepatotoxicity and cholestasis induced by ANIT. The mRNA levels of hepatic bile acid transporters were also altered by SRT1720. Furthermore, SRT1720 enhanced the antioxidative system by increasing Nrf2, SOD, GCLc, GCLm, Nqo1, and HO-1 gene expressions. In conclusion, a protective influence could be provided by SRT1720 to cure ANIT-induced hepatotoxicity and cholestasis, which was partly through FXR and Nrf2 activations. These results indicated that SIRT1 could be regarded as a therapeutic target to cure the cholestasis.

Acetaminophen (APAP) overdose-induced acute liver damage is mostly due to overwhelmingly increased oxidative stress. Nuclear factor-erythroid 2-related factor2 (Nrf2) plays an important role in alleviating APAP hepatic toxicity. Shikonin (SHK) enhances Nrf2 in multiple lines of normal cells. Nevertheless, whether SHK protects against APAP-induced liver toxicity remains undefined. This study found SHK defended APAP-induced liver toxicity, as well as reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, and reactive oxygen species (ROS), while it enhanced the liver glutathione (GSH) level in APAP-treated mice. SHK rescued the cell viability and GSH depletion, but neutralized oxidative stress in APAP-treated human normal liver L-02 cells. Mechanically, SHK increased Nrf2 expression in the exposure of APAP at the protein level but not at the mRNA level. Inhibition of Nrf2 blocked the SHK effect in APAP-treated hepatocytes. Furthermore, SHK improved Nrf2 stability through stimulating PI3K/Akt pathway, thus inhibiting GSK-3β. In vivo studies confirmed the close correlation of liver protection of SHK against APAP and Akt/GSK-3β/Nrf2 pathway. In conclusion, this study reveals that SHK prevents APAP hepatotoxicity by upregulation of Nrf2 via PI3K/Akt/GSK-3β pathway. Therefore, SHK may be a promising candidate against APAP-induced liver injury.

3,4-Dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol (HPN) is a synthetic analogue of 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(ethoxymethyl)benzyl)benzene-1,2-diol (BPN), which is isolated from marine red alga Rhodomela confervoides with potent protein tyrosine phosphatase 1B (PTP1B) inhibition (IC50 = 0.84 μmol/L). The in vitro assay showed that HPN exhibited enhanced inhibitory activity against PTP1B with IC50 0.63 μmol/L and high selectivity against other PTPs (T cell protein tyrosine phosphatase (TCPTP), leucocyte antigen-related tyrosine phosphatase (LAR), Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2). The results of antihyperglycemic activity using db/db mouse model demonstrated that HPN significantly decreased plasma glucose (P < 0.01) after eight weeks treatment period. HPN lowered serum triglycerides and total cholesterol concentration in a dose-dependent manner. Besides, both of the high and medium dose groups of HPN remarkably decreased HbA1c levels (P < 0.05). HPN in the high dose group markedly lowered the insulin level compared to the model group (P < 0.05), whereas the effects were less potent than the positive drug rosiglitazone. Western blotting results showed that HPN decreased PTP1B levels in pancreatic tissue. Last but not least, the results of an intraperitoneal glucose tolerance test in Sprague–Dawley rats indicate that HPN have a similar antihyperglycemic activity as rosiglitazone. HPN therefore have potential for development as treatments for Type 2 diabetes.

Pristimerin is a triterpenoid isolated from Celastrus and Maytenus spp. that has been shown to possess a variety of biological activities, including anti-cancer activity. However, little is known about pristimerin’s effects on tumor angiogenesis. In this study, we examined the function and the mechanism of this compound in tumor angiogenesis using multiple angiogenesis assays. We found that pristimerin significantly reduced both the volume and weight of solid tumors and decreased angiogenesis in a xenograft mouse tumor model in vivo. Pristimerin significantly inhibited the neovascularization of chicken chorioallantoic membrane (CAM) in vivo and abrogated vascular endothelial growth factor (VEGF)-induced microvessel sprouting in an ex vivo rat aortic ring assay. Furthermore, pristimerin inhibited the VEGF-induced proliferation, migration and capillary-like structure formation of human umbilical vascular endothelial cells (HUVECs) in a concentration-dependent manner. Mechanistic studies revealed that pristimerin suppressed the VEGF-induced phosphorylation of VEGF receptor 2 kinase (KDR/Flk-1) and the activity of AKT, ERK1/2, mTOR, and ribosomal protein S6 kinase. Taken together, our results provide evidence for the first time that pristimerin potently suppresses angiogenesis by targeting VEGFR2 activation. These results provide a novel mechanism of action for pristimerin which may be important in the treatment of cancer.

The main purpose of this study was to evaluate the intestinal absorption and the antineoplastic effect of the poorly water-soluble drug celastrol when liposomes were used as oral drug delivery system. Liposomes were prepared by the ethanol-injection method. An optimized liposome formulation composed of phospholipid, cholesterol and Tween-80 resulted in favorable encapsulation efficiency at 98.06 ± 0.94%. Homogeneous and stable particle size of 89.6 ± 7.3 nm and zeta potential of −(87.7 ± 5.8) mV were determined by laser particle size analyzer. Subsequently, the four-site perfusion rat intestinal model revealed that celastrol-loaded liposomes had improved effective permeability compared to the free drug in four intestinal segments (p < 0.05). Moreover, celastrol-loaded liposomes could also inhibit the tumor growth in C57BL/6 mice. These results suggest that liposomes could be a promising perioral carrier for celastrol.

BACKGROUND:Human head and neck squamous cell carcinoma (HNSCC) is the sixth most malignant cancer worldwide. Despite significant advances in the delivery of treatment and surgical reconstruction, there is no significant improvement of mortality rates for this disease in the past decades. Radiotherapy is the core component of the clinical combinational therapies for HNSCC. However, the tumor cells have a tendency to develop radiation resistance, which is a major barrier to effective treatment. HIV protease inhibitors (HIV PIs) have been reported with radiosensitizing activities in HNSCC cells, but the underlying cellular/molecular mechanisms remain unclear. Our previous study has shown that HIV PIs induce cell apoptosis via activation of endoplasmic reticulum (ER) stress. The aim of this study was to examine the role of ER stress in HIV PI-induced radiosensitivity in human HNSCC. METHODOLOGY AND PRINCIPAL FINDINGS:HNSCC cell lines, SQ20B and FaDu, and the most commonly used HIV PIs, lopinavir and ritonavir (L/R), were used in this study. Clonogenic assay was used to assess the radiosensitivity. Cell viability, apoptosis and cell cycle were analyzed using Cellometer Vision CBA. The mRNA and protein levels of ER stress-related genes (eIF2α, CHOP, ATF-4, and XBP-1), as well as cell cycle related protein, cyclin D1, were detected by real time RT-PCR and Western blot analysis, respectively. The results demonstrated that L/R dose-dependently sensitized HNSCC cells to irradiation and inhibited cell growth. L/R-induced activation of ER stress was correlated to down-regulation of cyclin D1 expression and cell cycle arrest under G0/G1 phase. CONCLUSION AND SIGNIFICANCE:HIV PIs sensitize HNSCC cells to radiotherapy by activation of ER stress and induction of cell cycle arrest. Our results provided evidence that HIV PIs can be potentially used in combination with radiation in the treatment of HNSCC.

HIV protease inhibitor (PI), the core component of highly active antiretroviral treatment (HAART) for HIV infection, has been implicated in HAART-associated cardiovascular complications. Our previous studies have demonstrated that activation of endoplasmic reticulum (ER) stress is linked to HIV PI-induced inflammation and foam cell formation in macrophages. Raltegravir is a first-in-its-class HIV integrase inhibitor, the newest class of anti-HIV agents. We have recently reported that raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of hepatic lipid metabolism by inhibiting ER stress. However, little information is available as to whether raltegravir would also prevent HIV PI-induced inflammatory response and foam cell formation in macrophages.In this study, we examined the effect of raltegravir on ER stress activation and lipid accumulation in cultured mouse macrophages (J774A.1), primary mouse macrophages, and human THP-1-derived macrophages, and further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed activation of inflammatory response and foam cell formation. The results indicated that raltegravir did not induce ER stress and inflammatory response in macrophages. Even more interestingly, HIV PI-induced ER stress, oxidative stress, inflammatory response and foam cell formation were significantly reduced by raltegravir. High performance liquid chromatography (HPLC) analysis further demonstrated that raltegravir did not affect the uptake of HIV PIs in macrophages.Raltegravir could prevent HIV PI-induced inflammatory response and foam cell formation by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the cardiovascular complications associated with current HAART.

This paper initiatively puts forward a novel synthesis design for generating UWB narrow pulse by using CI (Carrier Interference) subcarrier waveform synthesis and Bessel function expansion. Through adaptively adjusting the initial phases of multiple sub-carriers according to the location information, CI (Carrier Interference) sub-carrier waveform synthesis signal could achieve better performance. More specifically, when the carrier arrives at the receiver with a particular phase, the dynamic change of this signal amplitude can be significantly reduced by introducing sinusoidal frequency modulation signals. The method has significance for improving the overall performance of UWB communication system. This paper gives theoretical analysis and computer simulation results as well as the functional block diagram.

Background Picroside II (PII), an iridoid glycoside extracted from the rhizomes and stems of the genus Picroside, exhibits pronounced hepatoprotective properties. Pre-administration of PII protects against acute liver injury caused by D-galactosamine (D-Gal), carbon tetrachloride (CCl4), and acetaminophen (APAP). This study aimed to elucidate the ramifications of PII administration subsequent to the initiation of acute hepatic injury. Methods Exploring the role of PII treatment in APAP-treated cell and rat models and in D-Gal and CCl4-treated rat models. Results In rats, APAP treatment increased serum aspartate transaminase, alanine transaminase, and alkaline phosphatase levels and decreased glutathione activity and the fluidity of the liver mitochondrial membrane. In L-02 cells, APAP exposure resulted in a decrement in membrane potential, an augmentation in the liberation of reactive oxygen species, and an acceleration of apoptotic processes. Moreover, PII pre-administration protected against D-Gal-induced acute hepatic injury and CCl4-induced chronic hepatic injury in rodent models, whereas PII administration post-injury aggravated CCl4-induced chronic hepatic injury. Conclusions Our results suggest that the effects of PII depend on the hepatic physiological or pathological state at the time of intervention. While PII possesses the potential to avert drug-induced acute hepatic injury through the mitigation of oxidative stress, its administration post-injury may exacerbate the hepatic damage, underscoring the critical importance of timing in therapeutic interventions. [ABSTRACT FROM AUTHOR]