Membrane fluidity, permeability, and surface charges are controlled by phospholipid metabolism and transport. Despite the importance of phosphatidic acid (PA) as a bioactive molecule, the mechanical properties of PA translocation and subcellular accumulation are unknown. Here, we used a mobilizable, highly responsive genetically encoded fluorescent indicator, green fluorescent protein (GFP)-N160RbohD, to monitor PA dynamics in living cells. The majority of GFP-N160RbohD accumulated at the plasma membrane and sensitively responded to changes in PA levels. Cellular, pharmacological, and genetic analyses illustrated that both salinity and abscisic acid rapidly enhanced GFP-N160RbohD fluorescence at the plasma membrane, which mainly depended on hydrolysis of phospholipase D. By contrast, heat stress induced nuclear translocation of PA indicated by GFP-N160RbohD through a process that required diacylglycerol kinase activity, as well as secretory and endocytic trafficking. Strikingly, we showed that gravity triggers asymmetric PA distribution at the root apex, a response that is suppressed by PLDζ2 knockout. The broad utility of the PA sensor will expand our mechanistic understanding of numerous lipid-associated physiological and cell biological processes and facilitate screening for protein candidates that affect the synthesis, transport, and metabolism of PA.

Despite significant advances in interventional treatment, myocardial infarction (MI) and subsequent cardiac fibrosis remain major causes of high mortality worldwide. Liquiritin (LQ) is a flavonoid extract from licorice that possesses a variety of pharmacological properties. However, to our knowledge, the effects of LQ on myocardial fibrosis after MI have not been reported in detail. The aim of our research was to explore the potential role and mechanism of LQ in MI-induced myocardial damage.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease characterized by demyelination and neurodegeneration, for which traditional treatment offers limited relief. Microglial/macrophage modulation plays a critical role in the pathogenesis of MS. Oxygen free radical accumulation can induce axonal and nerve cell damage, and further promote MS development. We created a new recombinant protein based on flagellin from Legionella pneumophila named flagellin A with linked C- and N-terminal ends (FLaAN/C), which is an independent intellectual property of our team. We previously showed that FLaAN/C might mitigate radiation-induced damage by inhibiting inflammatory responses and oxidative stress. However, whether FLaAN/C protects against MS remains unknown. Here, we investigated the anti-inflammatory effects of FLaAN/C on mice with experimental autoimmune encephalomyelitis (EAE) induced by oligodendrocyte glycoprotein peptide 35-55 (MOG35-55). The mice were injected intraperitoneally with FLaAN/C after the onset of clinical symptoms, then clinical behavior scores and changes in body weight were recorded daily. The spinal lumbar spine in model mice was enlarged and accompanied by inflammatory cell infiltration and demyelination that were reversed by FLaAN/C. FLaAN/C also induced microglia/macrophages to generate less pro-inflammatory (CD86, iNOS, and TNF-α), and more anti-inflammatory (CD206, IL-10, and Arginase-1) cytokines. These findings suggesting that FLaAN/C promoted microglial/macrophages polarization from the inflammatory M1 to the anti-inflammatory M2 phenotype. Moreover, FLaAN/C inhibited release of the inflammatory cytokines, TNF-α, IL-8, IL-6, IL-17, and IFN-γ. These results indicated that the anti-inflammatory effect of FLaAN/C was associated with the inhibited generation of reactive oxygen species. FLaAN/C downregulated the expression of phosphorylated NF-κB-p65 and prevented downstream NLRP3 inflammasome-mediated pyroptosis. Collectively, these results indicated that FLaAN/C prevents pyroptosis by inhibiting the ROS/NF-κB/NLRP3 signaling pathway, and promotes the microglial/macrophage M1/M2 polarization that significantly alleviated inflammation in mouse models of EAE. Our findings suggested that FLaAN/C could be a promising candidate for MS therapy.

Adults aged 65 years and above account for over half of all cancer diagnoses in the United States, but little is known about trend of elderly cancer survival in the United States. We aimed to assess the survival trend for elderly cancer in the United States from 1995 to 2014.

The COVID-19 pandemic significantly changed society. We aimed to examine the systematic impact of the COVID-19 on injury burden in the United States.

Atopic dermatitis (AD), characterized by eczema as a chronic pruritic inflammatory skin disease, has become a serious health problem with recurrent clinical episodes. However, current clinical treatments have limited relief and are accompanied by adverse effects. Therefore, there is a necessity to develop new effective drugs for AD treatment. Angelica Yinzi (AYZ) is a classic ancient prescription for nourishing blood, moistening dryness, dispelling wind, and relieving itching. However, its mechanism for alleviating atopic dermatitis remains unknown. Therefore, this study aimed at determining the effects of AYZ and its potential mechanism in alleviating AD-like symptoms.

Crohn's disease (CD) is a chronic non-specific inflammatory bowel disease. Current CD therapeutics cannot fundamentally change the natural course of CD. Therefore, it is of great significance to find new treatment strategies for CD. Preclinical and clinical studies have shown that mesenchymal stromal cells (MSCs) are a promising therapeutic approach. However, the mechanism by which MSCs alleviate CD and how MSCs affect gut microbes are still unclear and need further elucidation.

Relatively little is known about the persistence of symptoms in patients with COVID-19 for more than 1 year after their acute illness.

The transformation of organic pollutants by stabilized nano-FeS in oxic conditions is far less understood than in anoxic states. Herein, carboxymethyl cellulose-stabilized FeS (CMC-FeS) nanofluids are prepared at a CMC-to-FeS mass ratio of 1/2 and their performance of tetracycline hydrochloride (TC) degradation under oxic conditions was investigated. Here, we showed that TC could be efficiently removed by oxygenation of CMC-FeS nanofluids at neutral initial pH. We found that CMC-FeS dosages as low as 15 mg/L can achieve the TC removal efficiency as high as 99.1% at an initial TC concentration of 50 mg/L. Oxidative degradation plays a predominated role in TC removal (accounting for 58.0%), adsorption has the second importance (accounting for 37.0%), and reduction has minor impact (accounting for 4.1%) toward TC removal. Electron spin resonance assays, fluorescent detection using coumarin as a probe, and radical scavenging experiments confirm that hydroxy radicals (•OH), both in free and surface-bound forms, contribute to oxidation of TC. Humic acids brought detrimental effects on TC removal and therefore should be biologically degraded in advance. This work offers a facile and cost-effective solution to decontaminate TC in natural and engineered water bodies.

The objective of this study was to investigate the protective effect of notoginsenoside R1 (NGR1) on cerebral ischemia-reperfusion injury (CIRI) in rats, and its molecular mechanism, to provide new insights into the diagnosis and treatment of CIRI. Sixty Sprague-Dawley rats were randomly divided into four groups including the sham-operation group (Sham), cerebral ischemia-reperfusion model group (CIR), NGR1 treatment group (NGR1), and nimodipine positive control group (NDC) with 15 rats each. Bilateral common carotid arteries occlusion was used to establish the rat CIRI model. The area of cerebral infarction at the end of reperfusion was calculated by triphenyl tetrazolium chloride staining. Apoptosis of hippocampal neurons in each group was detected by Annexin V/propidium iodide double staining. Hippocampal expression of brain-derived neurotrophic factor (BDNF) mRNA, and Bcl-2 and Bax protein at the end of reperfusion were measured by RT-qPCR and western blot analysis, respectively. Data were analyzed by SPSS software analysis to ensure statistical significance. At the end of reperfusion, the area of cerebral infarction in the NGR1 and NDC groups was significantly smaller than that of the CIR group. Apoptosis analysis showed that compared with the CIR group, the apoptosis rate of hippocampal neurons was significantly decreased in the NGR1 and NDC groups. RT-qPCR and western blot analysis showed that at the end of reperfusion, higher levels of BDNF mRNA and the anti-apoptotic factor, Bcl-2, and lower levels of the pro-apoptotic factor, Bax, in the hippocampus were found in the NGR1 and NDC groups compared with the CIR group. The protective effect of NGR1 on CIRI was significantly stronger than that of nimodipine. In conclusion, NGR1 can reduce the area of cerebral infarction, reduce apoptosis of hippocampal neurons, and protect rats from CIRI. Those effects were achieved by activating the expression of BDNF and Bcl-2, and by inhibiting the expression of Bax.

Hepatocellular carcinoma (HCC) remains one of the most lethal cancers. MicroRNA-155 (miR-155) and collagen triple helix repeat containing 1 (CTHRC1) were found to be involved in hepatocarcinogenesis, but their detailed functions in HCC are unclear. Here, we aimed to investigate the underlying role of miR-155-5p and CTHRC1 in HCC.

In view of the significant neuroprotective effect of Clausena lansium, we continued to separate the n-butanol and the water extracts from the stems of C. lansium in order to find the leading compounds with significant activity. Two new phenolic glycosides, Clausenolside A-B (1-2), one new pair of phenolic enantiomers (3a, 3b), and two new monoterpenoids, clausenapene A-B (4-5), together with twelve known analogues (6-17) were isolated from the stems of C. lansium. Compounds 1-17 were obtained from C. lansium for the first time. Compounds 3a, 3b, 4, 16, and 17 showed strong or moderate potential neuroprotective effects on inhibited PC12 cell injury induced by okadaic acid, and compound 9 exhibited strong potential hepatoprotective activities. Their structures were elucidated on the basis of spectroscopic analyses, including UV, IR, NMR experiments, and electronic circular dichroism (ECD) spectra.

The present study was designed to investigate the electrophysiological properties of strial pericytes and the effect of aspirin on pericyte K+ channels. Pericytes were identified by determining their morphological characteristics and using pericyte‑associated immunofluorescence techniques. The electrophysiological properties of strial pericytes were observed with a whole‑cell patch‑clamp technique. Alterations in the outward current of cochlear pericytes in the stria vascularis of guinea pigs were examined following the application of K+ channel retardants. The effects of aspirin on pericyte K+ channels were also evaluated with the whole‑cell patch‑clamp technique. The results demonstrated that pericytes were desmin positive, and their nuclei were large and surrounded by a small proportion of the cytoplasm. Cytoplasmic processes gradually declined in size as branches grew parallel to the capillary axis. Thus, capillaries were surrounded by tips. The electrophysiological properties of the cochlear pericytes in the stria vascularis of guinea pigs were also determined. The membrane capacitance of the pericytes was 5.9±0.3 pF, while the membrane resistance and resting potential were 2.2±0.3 GΩ and ‑30.9±1.2 mV, respectively. The current densities of the pericytes (pA/pF) were 3.2±0.7, 10.6±1.0, 15.7±0.9 and 21.3±1.2 at command voltages of 0, +20, +40, and +60 mV, respectively. The K+ channels were activated when the pericytes were within the range of ‑20 mV to +20 mV, particularly at 0 mV. The inhibition rates of the outward current of cochlear pericytes in the stria vascularis of the guinea pigs were determined by administering iberiotoxin (IBTX) and IBTX + 4‑aminopyridine. Once the background leakage current was removed, the following inhibition rates were obtained with 3, 10, 30, 300 and 1,000 µmol/l aspirin: 20.8±4.8, 34.1±6.9, 48.2±6.7, 63.6±7.1 and 65.7±8.1%, respectively. The outward current of the cochlear pericytes in the stria vascularis was inhibited by aspirin with a half maximal inhibitory concentration of 24.5±4.5 µmol/l. The membranes of the pericytes in the stria vascularis are characterized by high‑conductance calcium‑activated K+ (BKCa) and voltage‑dependent K+ (KV) channels. The outward current of the cochlear pericytes in the stria vascularis of guinea pigs was inhibited by aspirin in a concentration‑dependent manner. In addition, BKCa and KV channels were inhibited by aspirin.

Chronic lymphocytic leukemia (CLL) cells possess regulatory functions comparable to those of normal B10 cells, a regulatory B cell subset that suppresses effector T-cell function through STAT3-mediated IL-10 production. However, the mechanisms governing IL-10 production by CLL cells are not fully understood. Here, we show that the CXC chemokine ligand 12 (CXCL12)-CXCR4-STAT3 axis regulates IL-10 production by CLL cells and their ability to suppress T-cell effector function through an IL-10 mediated mechanism. Knockdown of STAT3 significantly impaired the ability of CLL cells to produce IL-10. Furthermore, experiments to assess the role of lenalidomide, an immunomodulatory agent with direct antitumor effect as well as pleiotropic activity on the immune system, showed that this agent prevents a CXCL12-induced increase in p-S727-STAT3 and the IL-10 response by CLL cells. Lenalidomide also suppressed IL-10-induced Y705-STAT3 phosphorylation in healthy T cells, thus reversing CLL-induced T-cell dysfunction. We conclude that the capacity of CLL cells to produce IL-10 is mediated by the CXCL12-CXCR4-STAT3 pathway and likely contributes to immunodeficiency in patients. Lenalidomide appears to be able to reverse CLL-induced immunosuppression through including abrogation of the CXCL12-CXCR4-S727-STAT3-mediated IL-10 response by CLL cells and prevention of IL-10-induced phosphorylation of Y705-STAT3 in T cells.

During the aging process, bone marrow mesenchymal stem cells (BMSCs) exhibit declined osteogenesis accompanied by excess adipogenesis, which will lead to osteoporosis. Here, we report that the H3 lysine 36 trimethylation (H3K36me3), catalyzed by histone methyltransferase SET-domain-containing 2 (SETD2), regulates lineage commitment of BMSCs. Deletion of Setd2 in mouse bone marrow mesenchymal stem cells (mBMSCs), through conditional Cre expression driven by Prx1 promoter, resulted in bone loss and marrow adiposity. Loss of Setd2 in BMSCs in vitro facilitated differentiation propensity to adipocytes rather than to osteoblasts. Through conjoint analysis of RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) data, we identified a SETD2 functional target gene, Lbp, on which H3K36me3 was enriched, and its expression was affected by Setd2 deficiency. Furthermore, overexpression of lipopolysaccharide-binding protein (LBP) could partially rescue the lack of osteogenesis and enhanced adipogenesis resulting from the absence of Setd2 in BMSCs. Further mechanistic studies demonstrated that the trimethylation level of H3K36 could regulate Lbp transcriptional initiation and elongation. These findings suggest that H3K36me3 mediated by SETD2 could regulate the cell fate of mesenchymal stem cells (MSCs) in vitro and in vivo, indicating that the regulation of H3K36me3 level by targeting SETD2 and/or the administration of downstream LBP may represent a potential therapeutic way for new treatment in metabolic bone diseases, such as osteoporosis.

This study aimed to examine the radioprotective effect of polydatin (PD) on crypt and endothelial cells of the small intestines of C57BL/6 mice that received abdominal irradiation (IR). Mice were treated with 6 MV X-ray (20 Gy) abdominal IR at a dose rate of 200 cGy/min. Thirty minutes before or after IR, mice were intraperitoneally injected with PD. The rate of survival of the mice at 30 days after IR was determined. The duodenum (upper small intestine), jejunum (middle small intestine), and ileum (lower small intestine) were collected and subjected to hematoxylin and eosin staining. Tissue sample sections were analyzed through light microscopy, and the lengths of at least 20 intestinal villi were measured in each group; the average number of crypts was obtained from 10 intestinal samples in each group. Microvessel density was assessed using CD31-positive (brown) vascular endothelial cells/cell clusters. FHs74Int cell proliferation was measured using the CCK-8 assay. PD administration (25 mg/kg) before IR was the most effective in prolonging the survival of C57BL/6 mice. PD reduced radiation-induced injury of intestinal villi, prevented loss of crypts, increased intestinal crypt growth, protected against IR-induced intestinal injury, and enhanced the proliferative potential and reduced the apoptosis of FHs74Int cells after IR. Moreover, PD increased small intestinal MVD and reduced the apoptosis of intestinal microvascular endothelial cells in mice after IR. Therefore, PD was found to be able to protect the two types of cells from radiation damage and to thus alleviate radiation-induced injury of small intestine.

Familial hypercholesterolemia (FH) is a common inherited cause of coronary heart disease (CHD) and premature death in an early age. Nevertheless, an ischemic heart failure (IHF) associated with FH seems to be rare, and an early diagnosis and therapy could influence the prognosis.

It remains unclear to what extent tumor heterogeneity impacts on protein biomarker discovery. Here, we quantified proteome intra-tissue heterogeneity (ITH) based on a multi-region analysis of prostate tissues using pressure cycling technology and SWATH mass spectrometry. We quantified 6,873 proteins and analyzed the ITH of 3,700 proteins. The level of ITH varied depending on proteins and tissue types. Benign tissues exhibited more complex ITH patterns than malignant tissues. Spatial variability of ten prostate biomarkers was validated by immunohistochemistry in an independent cohort (n=83) using tissue microarrays. PSA was preferentially variable in benign prostatic hyperplasia, while GDF15 substantially varied in prostate adenocarcinomas. Further, we found that DNA repair pathways exhibited a high degree of variability in tumorous tissues, which may contribute to the genetic heterogeneity of tumors. This study conceptually adds a new perspective to protein biomarker discovery: it suggests that recent technological progress should be exploited to quantify and account for spatial proteome variation to complement biomarker identification and utilization.

The aim of this study was to investigate the expression of FGF2 and FGFR2 in patients with idiopathic pulmonary fibrosis (IPF) and lung cancer (LC) as well as their clinical significance. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were used to detect FGF2 and FGFR2 expression in LC and adjacent normal tissues of LC patients and lavage fluid of idiopathic pulmonary fibers patients and normal controls (confirmed by bronchoalveolar lavage examination). The expression levels of FGF2 mRNA and protein in the non-small cell LC tissues were significantly higher than those in the adjacent normal tissues (P<0.001). The expression level of FGF2 protein in lavage fluid of patients with IPF was higher than that of the control group (P<0.001). The expression level of FGFR2 mRNA in the non-small cell LC tissues was significantly higher than that in the adjacent normal tissues (P<0.001). The expression level of FGFR2 protein in the non-small cell LC tissues was higher than that in the adjacent normal lung tissues (P<0.001). The expression levels of FGF2 mRNA and FGFR2 mRNA in cancer tissues were not significantly correlated with age, sex and history of smoking (P>0.05), but were significantly correlated with lymph node metastasis, tumor differentiation and TNM staging. FGF2 and FGFR2 proteins were highly expressed in cancer tissues of LC patients and lavage fluid of patients with IPF. The expression of FGF2 mRNA and FGFR2 mRNA was correlated with lymph node metastasis and TNM stage. The high expression levels of FGF2 mRNA and FGFR2 mRNA were associated with tumor metastasis and poor prognosis of LC patients.

We aimed to investigate T-cell receptor (TCR) repertoires in type 1 diabetes (T1D) patients receiving autologous hematopoietic stem cell transplantation (AHSCT) treatment.