Re-watering solution facilitates seed germination and seedling growth of Carex schmidtii: Implication for species re-introduction in degraded semi-arid wetlands.

Water deficiency threatens the health and function of wetlands in semi-arid areas. Optimum re-watering is an effective method for close-to-natural restoration to mitigate wetland degradation. Although the ecological importance of optimal re-watering as a nature-based solution for promoting wetland plant growth has been widely recognized, the response mechanisms of seed germination and seedling growth to re-watering are still poorly understood despite their decisive impact on plant life history. To fill this gap, this study compared the characteristics of seed germination and seedling growth in Carex schmidtii under initial water content with three levels (30%, 50%, and 70%) and five re-watering treatments (maintained at constant water content and re-watering to 100% on 7th, 14th, 21st, and 28th day). Moreover, the degree of reserve mobilization during four germination stages (seed suckering, sprouting, 20% germination, and seedling growth) was investigated. The results showed that water deficiency and re-watering treatments significantly affected C. schmidtii seed germination, seedling growth, and reserve mobilization. Compared with the other treatments, 50% moisture content and re-watering to 100% on the 14th day (50%-RT3) treatment significantly improved germination traits (germination rate, daily germination rate, germination index, and vigor index) and seedling growth characteristics (shoot length, root length, shoot biomass, root biomass, and total biomass). Furthermore, the degree of mobilization of starch, soluble protein, fat, and soluble sugar accumulation in C. schmidtii seeds under 50%-RT3 was higher than that in the other treatments. The structural equation model showed that the characteristics of seed germination and seedling growth of C. schmidtii were directly related to water deficiency and re-watering treatments, whereas reserve mobilization indirectly affected seed germination and seedling growth. These findings demonstrated that water deficiency and re-watering treatments have a crucial regulatory effect on seed germination and seedling growth of wetland plant species through a dual mechanism. This study provides information for the formulation of an optimum re-watering strategy for wetland vegetation restoration in semi-arid areas of the world.

Optimal concentration of Lugol's solution for detecting early esophageal carcinoma: A randomized controlled trial.

BACKGROUND AND AIM: Lugol chromoendoscopy is the standard technique to detect an esophageal squamous cell carcinoma (ESCC). However, a high concentration of Lugol's solution can induce mucosal injury and adverse events. We aimed to investigate the optimal concentration of Lugol's solution to reduce mucosal injury and adverse events without degrading image quality. METHODS: This was a two-phase double-blind randomized controlled trial. In phase I, 200 eligible patients underwent esophagogastroduodenoscopy and then were randomly (1:1:1:1:1) sprayed with 1.2%, 1.0%, 0.8%, 0.6%, or 0.4% Lugol's solution. Image quality, gastric mucosal injury, adverse events, and operation satisfaction were compared to investigate the minimal effective concentration. In phase II, 42 cases of endoscopic mucosectomy for early ESCC were included. The patients were randomly assigned (1:1) to the minimal effective (0.6%) or conventional (1.2%) concentration of Lugol's solution for further comparison of the effectiveness. RESULTS: In phase I, the gastric mucosal injury was significantly reduced in 0.6% group (P < 0.05). Furthermore, there was no statistical significance in image quality between 0.6% and higher concentrations of Lugol's solution (P > 0.05, respectively). It also showed that the operation satisfaction decreased in 1.2% group compared with the lower concentration groups (P < 0.05). In phase II, the complete resection rate was 100% in both groups, while 0.6% Lugol's solution showed higher operation satisfaction (W = 554.500, P = 0.005). CONCLUSIONS: The study indicates that 0.6% might be the optimal concentration of Lugol's solution for early detection and delineation of ESCC, considering minimal mucosal injury and satisfied image. The registry of clinical trials: ClinicalTrials.gov (NCT03180944).

New ε-N-thioglutaryl-lysine derivatives as SIRT5 inhibitors: Chemical synthesis, kinetic and crystallographic studies.

SIRT5 has been implicated in various physiological processes and human diseases, including cancer. Development of new highly potent, selective SIRT5 inhibitors is still needed to investigate disease-related mechanisms and therapeutic potentials. We here report new ε-N-thioglutaryllysine derivatives, which were designed according to SIRT5-catalysed deacylation reactions. These ε-N-thioglutaryllysine derivatives displayed potent SIRT5 inhibition, of which the potential photo-crosslinking derivative 8 manifested most potent inhibition with an IC50 value of 120 nM to SIRT5, and low inhibition to SIRT1-3 and SIRT6. The enzyme kinetic assays revealed that the ε-N-thioglutaryllysine derivatives inhibit SIRT5 by lysine-substrate competitive manner. Co-crystallographic analyses demonstrated that 8 binds to occupy the lysine-substate binding site by making hydrogen-bonding and electrostatic interactions with SIRT5-specific residues, and is likely positioned to react with NAD+ and form stable thio-intermediates. Compound 8 was observed to have low photo-crosslinking probability to SIRT5, possibly due to inappropriate position of the diazirine group as observed in SIRT5:8 crystal structure. This study provides useful information for developing drug-like inhibitors and cross-linking chemical probes for SIRT5-related studies.

Discovery of toxoflavin, a potent IRE1α inhibitor acting through structure-dependent oxidative inhibition.

Inositol-requiring enzyme 1α (IRE1α) is the most conserved endoplasmic reticulum (ER) stress sensor with two catalytic domains, kinase and RNase, in its cytosolic portion. IRE1α inhibitors have been used to improve existing clinical treatments against various cancers. In this study we identified toxoflavin (TXF) as a new-type potent small molecule IRE1α inhibitor. We used luciferase reporter systems to screen compounds that inhibited the IRE1α-XBP1s signaling pathway. As a result, TXF was found to be the most potent IRE1α RNase inhibitor with an IC50 value of 0.226 µM. Its inhibitory potencies on IRE1α kinase and RNase were confirmed in a series of cellular and in vitro biochemical assays. Kinetic analysis showed that TXF caused time- and reducing reagent-dependent irreversible inhibition on IRE1α, implying that ROS might participate in the inhibition process. ROS scavengers decreased the inhibition of IRE1α by TXF, confirming that ROS mediated the inhibition process. Mass spectrometry analysis revealed that the thiol groups of four conserved cysteine residues (CYS-605, CYS-630, CYS-715 and CYS-951) in IRE1α were oxidized to sulfonic groups by ROS. In molecular docking experiments we affirmed the binding of TXF with IRE1α, and predicted its binding site, suggesting that the structure of TXF itself participates in the inhibition of IRE1α. Interestingly, CYS-951 was just near the docked site. In addition, the RNase IC50 and ROS production in vitro induced by TXF and its derivatives were negative correlated (r = -0.872). In conclusion, this study discovers a new type of IRE1α inhibitor that targets a predicted new alternative site located in the junction between RNase domain and kinase domain, and oxidizes conserved cysteine residues of IRE1α active sites to inhibit IRE1α. TXF could be used as a small molecule tool to study IRE1α's role in ER stress.

Detection performance of PCR for Legionella pneumophila in environmental samples: a systematic review and meta-analysis.

BACKGROUND: Legionellosis remains a public health problem. The most common diagnostic method to detect Legionella pneumophila (L. pneumophila) is culture. Polymerase chain reaction (PCR) is a fast and accurate method for this detection in environmental samples. METHODS: Four databases were searched for studies that evaluated the detection efficiency of PCR in L. pneumophila. The quality evaluation was conducted using Review Manager 5.3. We used Meta-DiSc 1.4 software and the Stata 15.0 software to create forest plots, a meta-regression, a bivariate boxplot and a Deeks' funnel plot. RESULTS: A total of 18 four-fold tables from 16 studies were analysed. The overall pooled sensitivity and specificity of PCR was 94% and 72%, respectively. The positive likelihood ratio (RLR) and negative likelihood ratio (NLR) was 2.73 and 0.12, respectively. The result of the diagnostic odds ratio (DOR) was 22.85 and the area under the curve (AUC) was 0.7884. CONCLUSION: Establishing a laboratory diagnostic tool for L. pneumophila detection is important for epidemiological studies. In this work, PCR demonstrated a promising diagnostic accuracy for L. pneumophila.

Diagnostic value of Lipoarabinomannan antigen for detecting Mycobacterium tuberculosis in adults and children with or without HIV infection.

OBJECTIVES: Even today, tuberculosis (TB) remains a leading public health problem; yet, the current diagnostic methods still have a few shortcomings. Lipoarabinomannan (LAM) provides an opportunity for TB diagnosis, and urine LAM detection seems to have a promising and widely applicable prospect. DESIGN OR METHODS: Four databases were systematically searched for eligible studies, and the quality of the studies was evaluated using the quality assessment of diagnostic accuracy studies-2 (QUADAS-2). Graphs and tables were created to show sensitivity, specificity, likelihood ratios, diagnostic odds ratio (DOR), the area under the curve (AUC), and so on. RESULTS: Based on the included 67 studies, the pooled sensitivity of urine LAM was 48% and specificity was 89%. In the subgroup analyses, the FujiLAM test had higher sensitivity (69%) and specificity (92%). Furthermore, among patients infected with human immunodeficiency virus (HIV), 50% of TB patients were diagnosed using a urine LAM test. Besides, the CD4+ cell count was inversely proportional to the sensitivity. CONCLUSIONS: Urine LAM is a promising diagnostic test for TB, particularly using the FujiLAM in HIV-infected adults whose CD4+ cell count is ≤100 per µl. Besides, the urine LAM test shows various sensitivities and specificities in different subgroups in terms of age, HIV infection status, CD4+ cell count, and testing method.

Impact of the COVID-19 pandemic on congenital diaphragmatic hernia patients: a single-center retrospective study.

PURPOSE: To investigate the impact of COVID-19 on the treatment of children with congenital diaphragmatic hernia (CDH). METHODS: We retrospectively collected and compared the data of patients with CDH admitted between January 1, 2020 and December 31, 2021(study group) with the CDH patients admitted before the pandemic between January 1, 2018 and December 31, 2019 (control group). RESULTS: During the pandemic, 41 patients with CDH diagnosed prenatally were transferred to our hospital, and 40 underwent surgical repair. The number of patients treated in our hospital increased by 24.2% compared with the 33 patients before the pandemic. During the pandemic, the overall survival rate, postoperative survival rate and recurrence rate were 85.4%, 87.5% and 7.3%, respectively, and there were no significant differences compared with the control group (75.8%, 83.3% and 9.1%, respectively). The average length of hospital stay in patients admitted during the pandemic was longer than that in the control group (31 days vs. 16 days, P < 0.001), and the incidence of nosocomial infection was higher than that in the control group (19.5% vs. 3%, P = 0.037). CONCLUSIONS: CDH patients confirmed to be SARS-CoV-2 infection-free can receive routine treatment. Our data indicate that the implementation of protective measures during the COVID-19 pandemic, along with appropriate screening and case evaluation, do not have a negative impact on the prognosis of children.

Heme protects intestinal mucosal barrier in DSS-induced colitis through regulating macrophage polarization in both HO-1-dependent and HO-1-independent way.

Hemoglobin-derived heme was reported to play protective roles in hemorrhagic diseases by modulating the macrophages toward recovery. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases (IBD). However, whether heme provides anti-inflammatory profiles in macrophages, thus contributing to the intestinal mucosal barrier protection, is unclear. In the current study, we investigated the beneficial effects of heme on DSS-induced colitis mice and explored the underlying mechanisms. In vivo, systemic heme supplementation by hemin injection relieved intestinal inflammation and remedied intestinal mucosal barrier damage by correcting abnormal intestinal macrophage polarization. In vitro, we confirmed the reciprocally regulating effects of hemin on M1/M2 macrophage polarization in BMDM. Intriguingly, with knockdown of HO-1, the inhibiting effects of hemin on M1 polarization were maintained, while the promoting effects on M2 polarization were reversed. Further research proved that hemin repressed the inflammatory profiles in macrophages through inhibiting the translocation of NF-κB p65 by disrupting IRF5-NF-κB p65 complex formation in Spi-C-dependent way. In conclusion, these results showed that the modification of colon tissue microenvironment with heme supplementation plays a protective role in DSS-induced colitis mice through regulating the macrophage polarization in both HO-1-dependent and HO-1-independent way, indicating a new choice to therapeutically modulate the macrophage function and prevent IBD.

Triptolide analog LLDT-8 ameliorates psoriasis-like dermatitis in BALB/c mice via suppressing the IL-36α signaling pathway.

Triptolide has shown a good immunosuppressive effect on autoimmune diseases. However, the toxicity limited its widely clinical practice. In this study, we investigated the effects and underlying mechanisms of (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, on a murine psoriasis-like dermatitis model and related cell lines. Here, we showed that LLDT-8 significantly attenuated symptoms of psoriasis-like dermatitis induced by imiquimod (IMQ, a TLR7 agonist) by reducing the psoriasis area and severity index (PASI) score and inflammatory parameters. The action of LLDT-8 was involved in down-regulated interleukin (IL)-36α expression and blocked IL-36α pathway by LC-MS-based label-free quantitative (LFQ) proteomic approach and further experiments. Meanwhile, we observed that LLDT-8 significantly inhibited the expression of IL-36α in R837-treated bone marrow-derived dendritic cells (BMDCs). In conclusion, LLDT-8 notably alleviated IMQ-induced psoriasis-like skin inflammation via suppressing the IL-36α signaling pathway, suggesting LLDT-8 might be a potential drug for the treatment of psoriasis.

[Prediction of Prenatal Ultrasound Screening Staff's Situation in Beijing Based on ARIMA Model].

Objective To understand the current situation and predict the trends in number and composition of prenatal ultrasound screening staff in Beijing. Methods We analyzed the region,age,professional title and other characteristics of prenatal ultrasound screening personnel in Beijing during 2007-2015.We then built an ARIMA model basing on the current situation to predict the number and composition of the staff in 2016-2020. Results The number of prenatal ultrasound screening staff showed an upward trend in 2007-2020 and was predicted to reach 1269 in 2020.During this period,the educational achievement and professional title of the staff showed a downward trend,and the working years became shorter,mainly below 5 years.The proportion of resident doctors remained at 26.6%,and that of the staff receiving further education would reach 43.2% by the end of 2020. Conclusion The prediction under ARIMA model suggests that efforts should be made to strengthen the training of young doctors and provide them opportunities for further study.

Algibacter marinivivus sp. nov., isolated from the surface of a marine red alga.

A Gram-stain-negative, non-flagellated bacterium, designated ZY111T, was isolated from the surface of a marine red alga, which was collected from the coast in Weihai, Shandong Province, PR China. Strain ZY111T exhibited growth at 4-37 °C (optimum, 25-28 °C) in the presence of 0-8.0 % (w/v) NaCl (optimum, 2.0-4.0% NaCl) and at pH 6.5-9.5 (optimum, pH 7.0-8.0). The 16S rRNA gene sequence analysis revealed that strain ZY111T belonged to the genus Algibacter, with Algibacter amylolyticus DSM 29199T as its closest relative (97.7 % similarity). The averagenucleotide identity value of strain ZY111T with A. amylolyticus DSM 29199T was 79.03 %. The digitalDNA-DNA hybridization value of strain ZY111T with A. amylolyticus DSM 29199T was 22.40 %. The dominant fatty acids were iso-C15 : 0, iso-C15 : 1 G, iso-C15 : 0 3-OH and iso-C17 : 0 3-OH. The sole respiratory quinone was determined to be menaquinone-6. The polar lipid profile of strain ZY111T consisted of phosphatidylethanolamine, two unidentified aminolipids and three unidentified lipids. The G+C content was 31.9 mol%. The phenotypic, chemotaxonomic and phylogenetic data clearly showed that strain ZY111T represents a novel species of the genus Algibacter, for which the name Algibacter marinivivus sp. nov. is proposed. The type strain is ZY111T (=KCTC 62373T=MCCC 1H00295T).

Heat stress-induced expression of Px-pdrg and Px-aspp2 in insecticide-resistant and -susceptible Plutella xylostella.

p53, DNA damage regulated gene (PDRG) and apoptosis-stimulating p53 protein 2 (ASPP2) are p53-related genes which can promote apoptosis. The full-length cDNA sequence of the Px-pdrg and Px-aspp2 genes were characterized and their mRNA expression dynamics under heat stress were studied in diamondback moth (DBM) Plutella xylostella collected from Fuzhou, China. The full-length cDNA of Px-pdrg and Px-aspp2 spans 721 and 4201 bp, containing 395 and 3216 bp of the open reading frame, which encode a putative protein comprising 130 and 1072 amino acids with a calculated molecular weight of 14.58 and 118.91 kDa, respectively. As compared to 25°C, both Px-pdrg and Px-aspp2 were upregulated in chlorpyrifos-resistant (Rc) and -susceptible (Sm) strains of DBM adults and pupae under heat stress. In addition, Rc DBM showed a significantly higher expression level of Px-pdrg and Px-aspp2 in contrast to Sm DBM. The results indicate that high temperature can significantly promote apoptosis process, especially in Rc-DBM. Significant fitness cost in Rc-DBM might be associated with drastically higher transcript abundance of Px-pdrg and Px-aspp2 under the heat stress.

Screening of the potentially active compounds from Polygonatum sibiricum using RAW264.7 cellular membranes coated magnetic beads fishing followed by HPLC analysis.

Target biomolecule-immobilized magnetic beads could be used as a powerful tool for screening active compounds present in natural products. Low damage rates of the target proteins, associated with the availability of diverse automated online approaches for analysis, make it a valuable tool for affinity studies. RAW264.7 cells (a kind of murine macrophage cell line) were used in this study. These cellular membranes were immobilized onto the surface of MBs and were used for screening the active compounds of Polygonatum sibiricum. Combining this technique with HPLC led to the identification of an active compound and its biological activity was confirmed. This is the first report establishing the use of RAW264.7 cellular membrane-coated magnetic bead fishing followed by HPLC analysis for screening active compounds from natural products.

Cross-linkage urease nanoparticles: a high-efficiency signal-generation tag for portable pH meter-based electrochemical immunoassay of lipocalin-2 protein diagnostics.

An innovative signal-transduction tag based on cross-linked urease nanoparticles (CLENP) was designed for the development of a pH meter-based immunoassay of lipocalin-2 (LCN2). The CLENP was synthesized with a typical desolvation method using ethanol as desolvation agent, followed by functionalization with polyaspartic acid. The carboxylated CLENP were used as the signal-generation tags for the labelling of secondary antibodies via the carbodiimide coupling. Upon target LCN2 introduction, a sandwich-type immune reaction was performed between capture antibody-coated plate and the labeled secondary antibody on the CLENP. The conjugated CLENP in the microplate hydrolyzed urea into ammonia (NH4+) and carbonate (CO32-), resulting in the pH change of solution, which was determined with a handheld pH meter. The pH variation was proportional to target concentration in the sample. By monitoring the pH variation of the urea solution, the level of LCN2 at a concentration as low as 5.2 pg mL-1 was evaluated. The pH meter-based electrochemical immunoassay can be utilized for mass production of miniaturized lab-on-a-chip devices with handheld pH meter, thereby opening new opportunities for protein diagnostics and biosecurity. Graphical abstract An innovative signal-transduction tag based on cross-linked urease nanoparticles was designed for high-efficiency immunoassay of lipocalin-2 with pH meter readout.

Identifying Psychological Strains in Suicide Notes.

The Strain Theory of Suicide and mental disorders proposes that psychological strains precede suicidal behaviors and psychiatric disorders. This study was designed to test the theory with a large sample of suicide notes collected from Tasmania, Australia. The content of 261 suicide notes was analyzed for the presence of four psychological strains. It was found that 39.6% of the 261 suicide notes had at least one of the four psychological strains, with aspiration and coping strains being the most prevalent. We then compared the ratings of psychological strains with ratings of thwarted belonging and perceived burdensomeness and found that the presence of aspiration strain and coping strain was associated with thwarted belonging, while aspiration and deprivation strains were associated with perceived burdensomeness.

Inhibitory effects of ursolic acid from Bushen Yijing Formula on TGF-ß1-induced human umbilical vein endothelial cell fibrosis via AKT/mTOR signaling and Snail gene.

The present study aimed to investigate the functional components from Bushen Yijing Formula and their inhibition of endothelial-mesenchymal transition (EndMT) and fibrosis in human umbilical vascular endothelial cells (HUVECs). HUVEC fibrosis was induced by treatment of transforming growth factor ß (TGF-ß) as the cellular model. Expression of EndMT biomarker gene and cofactors were determined by quantitative real-time-PCR, western blotting, and immunofluorescence. Angiogenesis capacity of vein endothelial cells was evaluated using tube formation assay. Ursolic acid and drug-contained serum ameliorated EndMT biomarker gene expression changes and angiogenesis capacity suppression induced by TGF-ß treatment. Slug, Snail, and Twist gene expression and phosphorylation of mammalian target of rapamycin (mTOR) and AKT altered by TGF-ß in HUVECs were suppressed by ursolic acid and drug-contained serum. Treatment with the mTOR signaling pathway inhibitor, rapamycin, inhibited the phosphorylation of mTOR and AKT, decreased Snail and Vimentin protein levels, and increased VE-cad protein levels. Overexpression of Snail gene promoted expression of EndMT-related genes and suppressed angiogenesis in HUVECs, which were attenuated by application of ursolic acid and drug-contained serum. Ursolic acid from Bushen Yijing Formula inhibits human umbilical vein endothelial cell EndMT and fibrosis, mediated by AKT/mTOR signaling and Snail gene expression.

Steroidal saponins from the rhizome of Polygonatum sibiricum.

Four new steroidal saponins, 3-O-ß-D-glucopyranosyl(1→4)-ß-D-fucopyranosyl -(25R)-spirost-5-en-3ß,17α-diol (1), 3-O-ß-D-glucopyranosyl(1→4)-ß-D- fucopyranosyl-(25S)-spirost-5-en-3ß,17α-diol (2), 3-O-ß-D-glucopyranosyl(1→2) -ß-D-glucopyranosyl(1→4)-ß-D-fucopyranosyl-(25R)-spirost-5-en-3ß,17α-diol (3), 3-O-ß-D-glucopyranosyl(1→4)-ß-D-fucopyranosyl-(25R/S)-spirost-5-en-3ß,12ß-diol (4), together with five known steroidal saponins were isolated from the ethanolic extract of the rhizome of Polygonatum sibiricum. Chemical structures of these compounds were elucidated by spectroscopic techniques. Anti-inflammatory activities of these new compounds were evaluated.

[Application of active components from traditional Chinese medicine in treatment of inflammatory bowel disease].

Inflammatory bowel disease(IBD) is a non-specific and chronic recurrent autoimmune disease that involves the gastrointestinal tract. Clinical symptoms of intestinal bleeding, diarrhea, and weight loss threat to human health and induce colorectal cancer. The pathogenesis included living environment, genetic factors, immune cell infiltration and immune stress, weakened mucosal barrier defense and intestinal flora imbalance. At present, clinical treatment drugs mainly include aminosalicylic acid, corticosteroids, immunosuppressants, biological agents, etc., in view of the disadvantages of poor therapeutic effect and expensive price. The active ingredients of traditional Chinese medicine(TCM) in the treatment IBD have various biological activities and multiple targets such as anti-inflammatory, antibacterial, anti-tumor and immune regulation. This article summarized the application and the research progress in protecting intestinal epithelial barrier, maintaining intestinal microbial homeostasis, inhibiting causative factors, and regulating Th1/Th17/Treg balance about TCM in the treatment of IBD. The review provided new ideas for further development of the new drugs on the mechanism based on active ingredients of TCM in IBD treatment.

Membrane-Bound CD40L Promotes Senescence and Initiates Senescence-Associated Secretory Phenotype via NF-κB Activation in Lung Adenocarcinoma.

BACKGROUND/AIMS: Cellular senescence acts as a barrier against tumorigenesis. The CD40L transgene, expressed in some tumor cells, not only becomes visible to antigen-presenting cells but also actively catalyzes its own termination. Here, we evaluated the effect of a membrane-bound mutant form of human CD40L (CD40L-M) on senescence and the senescence-associated secretory phenotype (SASP) in non-small cell lung cancer (NSCLC). METHODS: CD40 expression levels in the NSCLC cell lines A549/TR, A549/DDP and H460 were examined by flow cytometry. Senescent cells and tissues were identified via SA-ß-gal activity. Cell proliferation was visualized by EdU labeling. qRT-PCR, Western blotting, and immunofluorescence staining were conducted to assess mRNA and protein expression levels of CD40L, γ-H2A.X, p65, p-p65, IκBα, p53, p21 and p16. Cytokines secreted from transfected cells were tested by ELISA and cell migration assay. Capsid tyrosine-modified rAAV5-CD40L-M was packaged and carried out in vivo. RESULTS: Overexpression of CD40L-M promoted senescence, inhibited proliferation, increased DNA damage-associated γ-H2A.X, and initiated the SASP in CD40-positive NSCLC cells. NF-κB signaling was activated by CD40L-M overexpression in these cells. Knockdown of NF-κB partially overcame senescence and failed to induce SASP. Furthermore, increased p53 and p21 protein levels induced by CD40L-M were also reduced following NF-κB suppression. CONCLUSIONS: These data showed that the membrane-bound CD40L mutant may promote cellular senescence and initiate the SASP of NSCLC cells in an NF-κB-dependent manner. Therefore, CD40L-M-induced senescence may be a potential approach to protect against lung adenocarcinoma.

Topical administration of reversible SAHH inhibitor ameliorates imiquimod-induced psoriasis-like skin lesions in mice via suppression of TNF-α/IFN-γ-induced inflammatory response in keratinocytes and T cell-derived IL-17.

DZ2002, a reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor with immunosuppressive properties and potent therapeutic activity against various autoimmune diseases in mice. The present study was designed to characterize the potential therapeutic effects of DZ2002 on murine model of psoriasis and reveal the correlated mechanisms. In this report, we demonstrated that in vitro, DZ2002 significantly decreased the expression of pro-inflammatory cytokines and adhesion molecule including IL-1α, IL-1ß, IL-6, IL-8, TNF-α and ICAM-1 by inhibiting the phosphorylation of p38 MAPK, ERK and JNK in TNF-α/IFN-γ-stimulated HaCaT human keratinocytes. Topical administration of DZ2002 alleviated the imiquimod (IMQ)-induced psoriasis-like skin lesions and inflammation in mice, the therapeutic effect was comparable with the Calcipotriol. Moreover, the inflammatory skin disorder was restored by DZ2002 treatment characterized by reducing both of the CD3+ T cell accumulation and the psoriasis-specific cytokines expression. Further, we found that DZ2002 improved IMQ-induced splenomegaly and decreased the frequency of splenic IL-17-producing T cells. Our finding offered the convincing evidence that SAHH inhibitor DZ2002 might attenuate psoriasis by simultaneously interfering the abnormal activation and differentiation of keratinocytes and accumulation of IL-17-producing T cells in skin lesions.