A CRM1-dependent nuclear export signal in Autographa californica multiple nucleopolyhedrovirus Ac93 is important for the formation of intranuclear microvesicles.

Autographa californica multiple nucleopolyhedrovirus (AcMNPV) Ac93 is highly conserved in all sequenced baculovirus genomes, and it plays important roles in both the nuclear egress of nucleocapsids and the formation of intranuclear microvesicles. In this study, we characterized a cellular CRM1-dependent nuclear export signal (NES) of AcMNPV Ac93. Bioinformatic analysis revealed that AcMNPV Ac93 may contain an NES at amino acids 115-125. Green fluorescent protein (GFP) fused to the NES (GFP:NES) of AcMNPV Ac93 is localized to the cytoplasm of transfected cells. Multiple point mutation analysis demonstrated that NES is important for the nuclear export of GFP:NES. Bimolecular fluorescence complementation experiments and co-immunoprecipitation assays confirmed that Ac93 interacts with Spodoptera frugiperda CRM1 (SfCRM1). However, AcMNPV Ac34 inhibits cellular CRM1-dependent nuclear export of GFP:NES. To determine whether the NES in AcMNPV Ac93 is important for the formation of intranuclear microvesicles, an ac93-null AcMNPV bacmid was constructed; the wild-type and NES-mutated Ac93 were reinserted into the ac93-null AcMNPV bacmid. Immunofluorescence analysis showed that Ac93 and SfCRM1 were predominantly colocalized at intranuclear microvesicles in infected cells, while the construct containing point mutations at residues 123 and 125 of Ac93 resulted in a defect in budded virus production and the abolishment of intranuclear microvesicles. Together, these data demonstrate that Ac93 contains a functional NES, which is required for the production of progeny viruses and the formation of intranuclear microvesicles.IMPORTANCEAutographa californica multiple nucleopolyhedrovirus (AcMNPV) Ac93 is important for the formation of intranuclear microvesicles. However, how the baculovirus manipulates Ac93 for the formation of intranuclear microvesicles is unclear. In this study, we identified a nuclear export signal (NES) at amino acids 115-125 of AcMNPV Ac93. Our results showed that the NES is required for the interaction between Ac93 and Spodoptera frugiperda CRM1 (SfCRM1). However, AcMNPV Ac34 inhibits the nuclear export of green fluorescent protein fused to the NES. Our analysis revealed that Ac93 and SfCRM1 were predominantly colocalized at intranuclear microvesicles in AcMNPV-infected cells. Together, our results indicate that Ac93 participates in the formation of intranuclear microvesicles via the Ac93 NES-mediated CRM1 pathway.

Effect of Different Carbon Sources on Antioxidant Properties of Exopolysaccharides Produced by Scleroderma areolatum (Agaricomycetes).

Five kinds of exopolysaccharides (EPS) were obtained by fermentation of Scleroderma areolatum Ehrenb. with sucrose, glucose, maltose, lactose, and fructose as carbon sources. Antioxidant abilities of the obtained EPSs were evaluated by inhibiting AAPH, HO·, and glutathione (GS·) induced oxidation of DNA and quenching 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS· and galvinoxyl radicals. The effects of carbon sources on the antioxidant properties of EPSs could be examined. The results showed that five EPSs can effectively inhibit radicals induced oxidation of DNA, and the thiobarbituric acid reactive substances (TBARS) percentages were 44.7%-80.8%, 52.3%-77.5%, and 44.7%-73.3% in inhibiting AAPH, HO·, and GS· induced oxidation of DNA, respectively. All five EPSs could scavenge ABTS· and galvinoxyh, and exhibit superior activity in scavenging free radicals. Antioxidant abilities of EPS with fructose as carbon source were highest among five EPS.

Red flags alerting a posterior cranial fossa tumor from audiovestibular perspectives - a review.

BACKGROUND: There is no comprehensive and up-to-date overview of audiovestibular approach to the posterior fossa tumors in the literature. OBJECTIVE: This paper reviewed the literature relating to tumors at the posterior cranial fossa to find red flags alerting a posterior fossa lesion from audiovestibular perspectives. METHODS: This review was developed from articles published in those journals listed on the journal citation reports. Through the PubMed database, Embase, Google Scholar, and Cochrane library, 60 articles were finally obtained based on the PRISMA guidelines for reporting reviews. RESULTS: The presence of one red flag indicates a positive predictive value of 33% for detecting a posterior fossa lesion. Clinical features, namely, 1) mid-frequency sudden sensorineural hearing loss (SNHL), 2) bilateral sudden SNHL, and 3) rebound nystagmus may indicate a posterior fossa lesion, representing one, two, and three red flags, respectively. CONCLUSION: Those with 1) mid-frequency sudden SNHL, 2) bilateral sudden SNHL, and 3) rebound nystagmus trigger one, two, and three red flags, respectively, alerting clinicians the possibility of a posterior fossa lesion, which warrant MR imaging to exclude life-threatening or treatable conditions. SIGNIFICANCE: Patients with posterior fossa tumors may have potential life-threatening outcome.

Angular Position Sensor Based on Anisotropic Magnetoresistive and Anomalous Nernst Effect.

Magnetic position sensors have extensive applications in various industrial sectors and consumer products. However, measuring angles in the full range of 0-360° in a wide field range using a single magnetic sensor remains a challenge. Here, we propose a magnetic position sensor based on a single Wheatstone bridge structure made from a single ferromagnetic layer. By measuring the anisotropic magnetoresistance (AMR) signals from the bridge and two sets of anomalous Nernst effect (ANE) signals from the transverse ports on two perpendicular Wheatstone bridge arms concurrently, we show that it is possible to achieve 0-360° angle detection using a single bridge sensor. The combined use of AMR and ANE signals allows a mean angle error in the range of 0.51-1.05° within a field range of 100 Oe-10,000 Oe to be achieved.

Efficient Noncollinear Antiferromagnetic State Switching Induced by the Orbital Hall Effect in Chromium.

Recently, orbital Hall current has attracted attention as an alternative method to switch the magnetization of ferromagnets. Here we present our findings on electrical switching of the antiferromagnetic state in Mn3Sn/Cr, where despite the much smaller spin Hall angle of Cr, the switching current density is comparable to heavy metal-based heterostructures. However, the inverse process, i.e., spin-to-charge conversion in Cr-based heterostructures, is much less efficient than the Pt-based equivalents, as manifested in the 1 order of magnitude smaller terahertz emission intensity and spin current-induced magnetoresistance. These results in combination with the slow decay of terahertz emission against Cr thickness (diffusion length of ∼11 nm) suggest that the observed magnetic switching can be attributed to orbital current generation in Cr, followed by efficient conversion to spin current. Our work demonstrates the potential of light metals like Cr as efficient orbital/spin current sources for antiferromagnetic spintronics.

Incomplete Recovery from the Radiocontrast-Induced Dysregulated Cell Cycle, Adhesion, and Fibrogenesis in Renal Tubular Cells after Radiocontrast (Iohexol) Removal.

Contrast-induced nephropathy (CIN) is one of the most common causes of acute kidney injury (AKI). However, management is still limited, and the cellular response to radiocontrast removal for CIN remains unclear. This study aimed to explore the latent effects of iohexol in cultured renal tubular cells with or without the removal of iohexol by medium replacement. HK2 renal tubular cells were subcultured 24 h before use in CIN experiments. Three treatment groups were established: the control, a radiocontrast (iohexol)-only group at 75 mg I/mL (I-75), and iohexol exposure for 24 h with culture medium replacement (I-75/M). Cell cycle arrest, fibrogenic mediator assays, cell viability, cell function, and cell-cycle-related protein expression were compared between groups. Iohexol induced numerous changes in HK2 renal tubular cells, such as enlarged cell shape, cell cycle arrest, increased apoptosis, and polyploidy. Iohexol inhibited the expression of cyclins, CDKs, ZO-1, and E-cadherin but conversely enhanced the expression of p21 and fibrosis-related genes, including TGF-ß1, CTGF, collagen I, collagen III, and HIF-1α within 60 hr after the exposure. Except for the recovery from cell cycle arrest and cell cycle gene expression, notably, the removal of iohexol by medium replacement could not fully recover the renal tubular cells from the formation of polyploid cells, the adhesion or spreading, or the expression of fibrosis-related genes. The present study demonstrates, for the first time, that iohexol exerts latent cytotoxic effects on cultured renal tubular cells after its removal, suggesting that these irreversible cell changes may cause the insufficiency of radiocontrast reduction in CIN, which is worth investigating further.

Cervical cord compression with lower limb sensory disturbance: three case reports and a literature review.

Lower limb sensory disturbance can be a false localizing sign of cervical spondylotic myelopathy. It may lead to delayed or missed diagnosis, resulting in an inappropriate management plan, especially in the presence of concurrent lumbar lesions. Three Asian patients with lower limb sensory disturbance were ineffectively treated in the lumbar region. Magnetic resonance imaging showed cervical disc herniation and cervical spinal cord compression. The patients underwent anterior cervical discectomy and interbody fusion using a stand-alone cervical interbody fusion cage. Postoperative imaging showed that the spinal cord compression was relieved. On the first postoperative day, the lower limb sensory disturbance was also relieved. The patients showed good recovery at the 3-month postoperative follow-up. These three cases of cervical cord compression with lower limb sensory disturbance were easily misdiagnosed as lumbar spondylosis. Anterior cervical discectomy and fusion had a good therapeutic effect. Therefore, the presence of lower limb sensory disturbance in a non-radicular classic pattern should always raise suspicion of a possible cord compression at a higher level.

A NIR fluorescent probe for dual imaging of mitochondrial viscosity and FA in living cells and zebrafish.

Formaldehyde (FA) and viscosity play multiple roles in human health and diseases, and viscosity has great regional differences due to the diversity of subcellular organelles. However, it is challenging to achieve dual detection of viscosity and FA in subcellular organelles. Herein, we developed a near infrared (NIR) fluorescent probe FA-Cy, which can simultaneously monitor the viscosity and FA concentration of mitochondria in living cells. The probe could detect mitochondrial viscosity and exogenous and endogenous FA in living cells and zebrafish.

Distribution, Source Apportionment and Risk Assessment of Phthalate Esters in the Overlying Water of Baiyang Lake, China.

As a kind of endocrine disruptor compounds, the presence of phthalate esters (PAEs) has become a global concern. In this study, the pollution levels and spatial distribution of sixteen PAEs were investigated. Their potential sources and eco-environmental health risk were discussed in Baiyang Lake and its upstream rivers during different periods. PAEs were detected in all of samples, ranging from 1215 to 3014 ng·L-1 in October 2020 and 1384 to 3399 ng·L-1 in May 2021. Dibutyl phthalate (DBP) and di-isobutyl phthalate (DIBP) were the predominant monomers, with a detection rate of 100% and the highest concentrations in the overlying water. Restricted by multiple factors, the spatial distribution difference between Baiyang Lake and its upstream rivers in October was more significant than in May. The source apportionment revealed that agricultural cultivation and disorderly use and disposal of plastic products were the primary factors for the contamination. The human health risk assessment indicated that eight PAE congeners did not pose significant carcinogenic and non-carcinogenic harms to males, females and children. However, the ecological risks of DBP, DIBP and di (2-ethylhexyl) phthalate to algae, crustaceans and fish species were moderate or high-risk levels. This study provides an appropriate dataset for the assessment of the pollution of PEs to the water ecosystem affected by anthropogenic activities.

Risk Assessment of Phthalate Esters in Baiyangdian Lake and Typical Rivers in China.

Phthalate esters (PAEs) are frequently tracked in water environments worldwide. As a typical class of endocrine disruptor chemicals (EDCs), PAEs posed adverse effects on aquatic organisms at low concentration. Thus, they have attracted wide attention in recent years. In the present study, the concentrations of seven typical PAEs from 30 sampling sites in Baiyangdian Lake were measured, and the environmental exposure data of PAEs were gathered in typical rivers in China. Then, based on the aquatic life criteria (ALCs) derived from the reproductive toxicity data of aquatic organisms, two risk assessment methods, including hazard quotient (HQ) and probabilistic ecological risk assessment (PERA), were adopted to evaluate the ecological risks of PAEs in water. The sediment quality criteria (SQCs) of DEHP, DBP, BBP, DIBP and DEP were deduced based on the equilibrium partitioning method. Combined with the gathered environmental exposure data of seven PAEs in sediments from typical rivers in China, the ecological risk assessments of five PAEs in sediment were conducted only by the HQ method. The results of ecological risk assessment showed that in terms of water, DBP and DIBP posed low risk, while the risk of DEHP in Baiyangdian Lake cannot be ignored and should receive attention. In typical rivers in China, BBP and DEP posed no risk, while DIBP and DBP posed potential risk. Meanwhile, DEHP posed a high ecological risk. As far as sediment is concerned, DBP posed a high risk in some typical rivers in China, and the other rivers had medium risk. DEHP posed a high risk only in a few rivers and low to medium risk in others. This study provides an important reference for the protection of aquatic organisms and the risk management of PAEs in China.

VisImages: A Fine-Grained Expert-Annotated Visualization Dataset.

Images in visualization publications contain rich information, e.g., novel visualization designs and implicit design patterns of visualizations. A systematic collection of these images can contribute to the community in many aspects, such as literature analysis and automated tasks for visualization. In this paper, we build and make public a dataset, VisImages, which collects 12,267 images with captions from 1,397 papers in IEEE InfoVis and VAST. Built upon a comprehensive visualization taxonomy, the dataset includes 35,096 visualizations and their bounding boxes in the images. We demonstrate the usefulness of VisImages through three use cases: 1) investigating the use of visualizations in the publications with VisImages Explorer, 2) training and benchmarking models for visualization classification, and 3) localizing visualizations in the visual analytics systems automatically.

Remediation of copper and lead contaminated sediments using iron-based granule biochar: mechanisms and enzyme activity.

In recent years, there has been a growing concern about heavy metal contamination in sediments. In this study, iron-based granular biochar (MGB) is prepared to remediate Cu and Pb contaminated sediments. Characterizations via scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) show that the rough surface of MGB with abundant pore structures and a large number of oxygen-containing functional groups that facilitate stabilization of Cu and Pb in sediments. Potential mobility and bioavailability of Cu and Pb are investigated using BCR sequential extraction in the 35 day remediation experiment. The XPS results indicate that FeOOH and C-OH play a crucial part in stabilizing heavy metals. Large affinity of FeOOH for Pb allows it to occupy a proportion in F2 while C-OH is attractive to Cu. Changes of pH, organic matter (OM), and available phosphorus (AP) in sediments after adding MGB as well as the relationship between changes and the stable solidification of Cu and Pb are explored. The stable solidification of heavy metals effectively reduces the available phosphorus in sediments. Magnetic and particle properties of the material are used to reduce the impact of MGB aging on sediment environment and separate it from the remediated sediment. Finally, 3% of MGB significantly enhanced the sediment catalase activity in the biological enzyme activity experiment. All findings indicate that MGB is a green and environmentally friendly sediment remediation material with satisfactory potential in synergistically stabilizing heavy metals and phosphorus.Highlights The complexation of FeOOH with Pb on the surface of MGB fixes it to the reduced stateThe C-OH on the surface of MGB is more attractive to Cu than PbMGB effectively mitigates the release of bioavailable phosphorus from sediments to overlying water.

OBTracker: Visual Analytics of Off-ball Movements in Basketball.

In a basketball play, players who are not in possession of the ball (i.e., off-ball players) can still effectively contribute to the team's offense, such as making a sudden move to create scoring opportunities. Analyzing the movements of off-ball players can thus facilitate the development of effective strategies for coaches. However, common basketball statistics (e.g., points and assists) primarily focus on what happens around the ball and are mostly result-oriented, making it challenging to objectively assess and fully understand the contributions of off-ball movements. To address these challenges, we collaborate closely with domain experts and summarize the multi-level requirements for off-ball movement analysis in basketball. We first establish an assessment model to quantitatively evaluate the offensive contribution of an off-ball movement considering both the position of players and the team cooperation. Based on the model, we design and develop a visual analytics system called OBTracker to support the multifaceted analysis of off-ball movements. OBTracker enables users to identify the frequency and effectiveness of off-ball movement patterns and learn the performance of different off-ball players. A tailored visualization based on the Voronoi diagram is proposed to help users interpret the contribution of off-ball movements from a temporal perspective. We conduct two case studies based on the tracking data from NBA games and demonstrate the effectiveness and usability of OBTracker through expert feedback.

The association between mortality and use of Chinese herbal medicine among incident stage IV esophageal cancer patients: A retrospective cohort study with core herbs exploration.

Esophageal cancer (EC) remains a leading cause of death worldwide and in Taiwan. The prognosis of advanced-stage EC is notably poor, and the treatment options are limited. Chinese herbal medicine (CHM) has been widely used as a complementary treatment for cancer, yet the long-term effect of CHM in stage IV EC remains unclear. The multi-institutional cohort obtained from the Chang Gung research database (CGRD) was used to study the long-term outcome of CHM use among incident stage IV EC patients from 1 January 2002, to 31 December 2018. All patients were followed up to 5 years or the occurrence of death. The overall survival (OS) and disease-specific survival rates were conducted using Kaplan-Meier estimation. Overlap weighing and landmark analysis were used to eliminate confounding and immortal time biases. Furthermore, we demonstrated the core CHMs for stage IV EC by using the Chinese herbal medicine network (CMN) analysis on prescriptions. Nine hundred eighty-five stage IV EC patients were analyzed, including 74 CHM users and 911 non-CHM users. We found the use of CHM was associated with a higher 5-year overall survival rate than CHM nonusers (the cumulative probability: 19.52% versus 6.04%, log-rank test: p < 0.001, and the p < 0.001 with overlap weighting). In addition, the overall median survival time was about 7 months longer among CHM users. Moreover, the lower 1-, 3-, 5-year disease-specific survival rates were higher among CHM users. Additionally, the risk of all-cause mortality was lower among CHM users when considering accessible demographic covariates (adjusted hazard ratio: 0.59, 95%CI: 0.39, 0.89, p = 0.011). Furthermore, the CMN analysis revealed that CHMs improved health while relieving tumor burden. For example, Hedyotis diffusa Willd . was the core CHM with an anti-cancer effect, while Fritillaria thunbergii Miq and Sevilla maindronide Rochebrune were used together to relieve cancer-related gastrointestinal discomfort. The use of CHM seems safe and possibly beneficial among stage IV EC patients with a higher 5-year OS. Further clinical trials on CHM were guaranteed to explore the role of CHM in managing stage IV EC patients.

Gut Microbiota and Bile Acids Mediate the Clinical Benefits of YH1 in Male Patients with Type 2 Diabetes Mellitus: A Pilot Observational Study.

Our previous clinical trial showed that a novel concentrated herbal extract formula, YH1 (Rhizoma coptidis and Shen-Ling-Bai-Zhu-San), improved blood glucose and lipid control. This pilot observational study investigated whether YH1 affects microbiota, plasma, and fecal bile acid (BA) compositions in ten untreated male patients with type 2 diabetes (T2D), hyperlipidemia, and a body mass index ≥ 23 kg/m2. Stool and plasma samples were collected for microbiome, BA, and biochemical analyses before and after 4 weeks of YH1 therapy. As previous studies found, the glycated albumin, 2-h postprandial glucose, triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were significantly improved after YH1 treatment. Gut microbiota revealed an increased abundance of the short-chain fatty acid-producing bacteria Anaerostipes and Escherichia/Shigella. Furthermore, YH1 inhibited specific phylotypes of bile salt hydrolase-expressing bacteria, including Parabacteroides, Bifidobacterium, and Bacteroides caccae. Stool tauro-conjugated BA levels increased after YH1 treatment. Plasma total BAs and 7α-hydroxy-4-cholesten-3-one (C4), a BA synthesis indicator, were elevated. The reduced deconjugation of BAs and increased plasma conjugated BAs, especially tauro-conjugated BAs, led to a decreased glyco- to tauro-conjugated BA ratio and reduced unconjugated secondary BAs. These results suggest that YH1 ameliorates T2D and hyperlipidemia by modulating microbiota constituents that alter fecal and plasma BA compositions and promote liver cholesterol-to-BA conversion and glucose homeostasis.

Chidamide plus Tyrosine Kinase Inhibitor Remodel the Tumor Immune Microenvironment and Reduce Tumor Progression When Combined with Immune Checkpoint Inhibitor in Naïve and Anti-PD-1 Resistant CT26-Bearing Mice.

Combined inhibition of vascular endothelial growth factor receptor (VEGFR) and the programmed cell death protein 1 (PD-1) pathways has shown efficacy in multiple cancers; however, the clinical outcomes show limited benefits and the unmet clinical needs still remain and require improvement in efficacy. Using murine colon carcinoma (CT26) allograft models, we examined the efficacy and elucidated novel tumor microenvironment (TME) remodeling mechanisms underlying the combination of chidamide (a benzamide-based class l histone deacetylase inhibitor; brand name in Taiwan, Kepida®) with VEGF receptor tyrosine kinase inhibitor (TKIs; cabozantinib/regorafenib, etc.) and immune checkpoint inhibitors (ICIs; anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies). The TME was assessed using flow cytometry and RNA-sequencing to determine the novel mechanisms and their correlation with therapeutic effects in mice with significant treatment response. Compared with ICI alone or cabozantinib/regorafenib + ICI, combination of chidamide + cabozantinib/regorafenib + ICI increased the tumor response and survival benefits. In particular, treatment of CT26-bearing mice with chidamide + regorafenib + anti-PD-1 antibody showed a better objective response rate (ORR) and overall survival (OS). Similar results were observed in anti-PD-1 treatment-resistant mice. After treatment with this optimal combination, in the TME, RNA-sequencing revealed that downregulated mRNAs were correlated with leukocyte migration, cell chemotaxis, and macrophage gene sets, and flow cytometry analysis showed that the cell numbers of myeloid-derived polymorphonuclear suppressor cells and tumor-associated macrophages were decreased. Accordingly, chidamide + regorafenib + anti-PD-1 antibody combination therapy could trigger a novel TME remodeling mechanism by attenuating immunosuppressive cells, and restoring T-cell activation to enhance ORR and OS. Our studies also showed that the addition of Chidamide to the regorafenib + anti-PD-1 Ab combination could induce a durable tumor-specific response by attenuating immune suppression in the TME. In addition, this result suggests that TME remodeling, mediated by epigenetic immunomodulator combined with TKI and ICI, would be more advantageous for achieving a high objective response rate, when compared to TKI plus ICI or ICI alone, and maintaining long-lasting antitumor activity.

Magnetization switching in polycrystalline Mn3Sn thin film induced by self-generated spin-polarized current.

Electrical manipulation of spins is essential to design state-of-the-art spintronic devices and commonly relies on the spin current injected from a second heavy-metal material. The fact that chiral antiferromagnets produce spin current inspires us to explore the magnetization switching of chiral spins using self-generated spin torque. Here, we demonstrate the electric switching of noncollinear antiferromagnetic state in Mn3Sn by observing a crossover from conventional spin-orbit torque to the self-generated spin torque when increasing the MgO thickness in Ta/MgO/Mn3Sn polycrystalline films. The spin current injection from the Ta layer can be controlled and even blocked by varying the MgO thickness, but the switching sustains even at a large MgO thickness. Furthermore, the switching polarity reverses when the MgO thickness exceeds around 3 nm, which cannot be explained by the spin-orbit torque scenario due to spin current injection from the Ta layer. Evident current-induced switching is also observed in MgO/Mn3Sn and Ti/Mn3Sn bilayers, where external injection of spin Hall current to Mn3Sn is negligible. The inter-grain spin-transfer torque induced by spin-polarized current explains the experimental observations. Our findings provide an alternative pathway for electrical manipulation of non-collinear antiferromagnetic state without resorting to the conventional bilayer structure.

Research Advances of Injectable Functional Hydrogel Materials in the Treatment of Myocardial Infarction.

Myocardial infarction (MI) has become one of the serious diseases threatening human life and health. However, traditional treatment methods for MI have some limitations, such as irreversible myocardial necrosis and cardiac dysfunction. Fortunately, recent endeavors have shown that hydrogel materials can effectively prevent negative remodeling of the heart and improve the heart function and long-term prognosis of patients with MI due to their good biocompatibility, mechanical properties, and electrical conductivity. Therefore, this review aims to summarize the research progress of injectable hydrogel in the treatment of MI in recent years and to introduce the rational design of injectable hydrogels in myocardial repair. Finally, the potential challenges and perspectives of injectable hydrogel in this field will be discussed, in order to provide theoretical guidance for the development of new and effective treatment strategies for MI.

Carboplatin-Induced Thrombocytopenia through JAK2 Downregulation, S-Phase Cell Cycle Arrest and Apoptosis in Megakaryocytes.

Chemotherapy-induced thrombocytopenia (CIT) is a common complication when treating malignancies with cytotoxic agents wherein carboplatin is one of the most typical agents causing CIT. Janus kinase 2 (JAK2) is one of the critical enzymes to megakaryocyte proliferation and differentiation. However, the role of the JAK2 in CIT remains unclear. In this study, we used both carboplatin-induced CIT mice and MEG-01 cell line to examine the expression of JAK2 and signal transducer and activator of transcription 3 (STAT3) pathway. Under CIT, the expression of JAK2 was significantly reduced in vivo and in vitro. More surprisingly, the JAK2/STAT3 pathway remained inactivated even when thrombopoietin (TPO) was administered. On the other hand, carboplatin could cause prominent S phase cell cycle arrest and markedly increased apoptosis in MEG-01 cells. These results showed that the thrombopoiesis might be interfered through the downregulation of JAK2/STAT3 pathway by carboplatin in CIT, and the fact that exogenous TPO supplement cannot reactivate this pathway.

Berberine Suppresses Leukocyte Adherence by Downregulating CX3CL1 Expression and Shedding and ADAM10 in Lipopolysaccharide-Stimulated Vascular Endothelial Cells.

Berberine exerts therapeutic effects in inflammation-associated diseases. In a lipopolysaccharide (LPS)-induced endotoxemic acute lung injury (ALI) rat model, berberine alleviated lung injury through different anti-inflammatory mechanisms; however, treatment effects on CX3CL1 expression and shedding remain to be examined. As these processes play important roles in promoting the binding of leukocytes to the endothelium, the CX3CL1/CX3CR1 axis and its related pathways may serve as potential targets for the clinical treatment of ALI. The anti-inflammatory effects of berberine were investigated in LPS-stimulated rats, human umbilical cord vein endothelial cells (HUVECs), and THP-1 monocytic cells. Cx3cl1 expression in rat pulmonary tissues was examined using immunohistochemistry. CX3CL1, CX3CR1, RELA, STAT3, and ADAM10 levels were examined using Western blotting. CX3CL1 and ADAM10 mRNA levels were examined using quantitative real-time polymerase chain reaction. Soluble fractalkine levels in LPS-stimulated rats and HUVECs were examined using the enzyme-linked immunosorbent assay. Berberine significantly mitigated the LPS-induced upregulation of fractalkine and soluble fractalkine in rats and cultured HUVECs. Berberine mitigated the LPS-induced activation of the NF-κB and STAT3 signaling pathways. In THP-1 cells, berberine mitigated the LPS-induced upregulation of CX3CR1. Furthermore, the membrane expression of ADAM10 in LPS-stimulated HUVECs was suppressed by the berberine treatment. Berberine dose-dependently inhibited the LPS-induced activation of the CX3CL1/CX3CR1 axis and fractalkine shedding through ADAM10. These findings reveal a novel molecular mechanism underlying the inhibitory effect of berberine on monocyte adherence to the endothelium during inflammation.