Deep Eutectic Solvent-Assisted Corrosion Boosting Bulk FeCoNiCrMo High-Entropy Alloys as Highly Efficient Oxygen Evolution Reaction Catalyst.

The key to enhancing water electrolysis efficiency lies in selecting highly efficient catalysts. Currently, high-entropy alloys (HEAs) are utilized in electrocatalysis applications owing to their diverse elemental composition, disordered elemental distribution, and the high solubility of each element, endowing them with excellent catalytic performance. The experiments were conducted using isoatomic FeNiCrMo HEA as a precursor, with a high-activity three-dimensional nanoporous structure rapidly synthesized via electrochemical one-step dealloying in a choline chloride-thiourea (ChCl-TU) deep eutectic solvent (DES). The results indicate that the dealloyed Fe20Co20Ni20Cr20Mo20 HEA mainly consists of two phases: face-centered cubic and σ phases. The imbalance in the distribution of elements in these two phases leads to quite different corrosion speeds with the FCC phase being preferentially corroded. Furthermore, synergistic electron coupling between surface atoms in the three-dimensional nanoporous structure strengthens the behavior of the oxygen evolution reaction (OER). At a current density of 40 mA cm-2, the overpotential after dealloying decreased to 370 mV, demonstrating excellent stability. The technique demonstrated in this work provides a novel approach to improve the catalytic activity of OER.

The short- and long-term outcomes of laparoscopic D2 lymphadenectomy plus complete mesogastrium excision for lymph node-negative gastric cancer.

BACKGROUND: Patients with T1-3N0M0 gastric cancer (GC) who undergo radical gastrectomy maintain a high recurrence rate. The free cancer cells in the mesogastric adipose connective tissue (Metastasis V) maybe the reason for recurrence in these individuals. We aimed to evaluate whether D2 lymphadenectomy plus complete mesogastrium excision (D2 + CME) was superior to D2 lymphadenectomy with regard to safety and oncological efficacy for T1-3N0M0 GC. METHODS: Patients with T1-3N0M0 GC who underwent radical resection from January 2014 to July 2018 were retrospectively analyzed; there were 323 patients, of whom 185 were in the D2 + CME group and 138 in the D2 group. The primary endpoint was 5-year disease-free survival (DFS). Secondary endpoints include the 5-year overall survival (OS), recurrence pattern, morbidity, mortality, and surgical outcomes. RESULTS: D2 + CME was associated with less intraoperative bleeding loss, a greater number of lymph nodes harvested, and less time to first postoperative flatus, but the postoperative morbidity was similar. The 5-year DFS was 95.6% (95% CI 92.7-98.5%) and 90.4% (95% CI 85.5-95.3%) in the D2 + CME group and the D2 group, respectively, with a hazard ratio (HR) of 0.455 (95% CI 0.188-1.097; p = 0.071). In terms of recurrence patterns, local recurrence was more prone to occur in the D2 group (p = 0.031). Subgroup analysis indicated that for patients with T1b-3N0M0 GC, the 5-year DFS in the D2 + CME group was considerably greater than that in the D2 group (95.3% [95% CI 91.6-99.0%] vs. 87.6% [95% CI 80.7-94.5%], HR 0.369, 95% CI 0.138-0.983; log-rank p = 0.043). CONCLUSION: Laparoscopic D2 + CME for T1-3N0M0 GC is safe and feasible. Furthermore, it not only reduces the local recurrence rate but also improves the 5-year DFS in cases of T1b-3N0M0 GC.

Construction of a nomogram based on clinicopathologic features to predict the likelihood of No. 253 lymph node metastasis in rectal cancer patients.

PURPOSE: To explore the high-risk factors for rectal cancer No.253 lymph node metastasis (LNM) and to construct a risk nomogram for the individualized prediction of No.253 LNM. METHODS: This was a retrospective analysis of 425 patients with rectal cancer who underwent laparoscopic-assisted radical surgery. Independent risk factors for rectal cancer No.253 LNM was identified using multivariate logistic regression analysis, and a risk prediction nomogram was constructed based on the independent risk factors. In addition, the performance of the model was evaluated by discrimination, calibration, and clinical benefit. RESULTS: Multivariate logistic regression analysis showed that No.253 lymphadenectasis on CT (OR 10.697, P < 0.001), preoperative T4-stage (OR 4.431, P = 0.001), undifferentiation (OR 3.753, P = 0.004), and preoperative Ca199 level > 27 U/ml (OR 2.628, P = 0.037) were independent risk factors for No.253 LNM. A nomogram was constructed based on the above four factors. The calibration curve of the nomogram was closer to the ideal diagonal, indicating that the nomogram had a better fitting ability. The area under the ROC curve (AUC) was 0.865, which indicated that the nomogram had high discriminative ability. In addition, decision curve analysis (DCA) showed that the model could show better clinical benefit when the threshold probability was between 1% and 50%. CONCLUSION: Preoperative No.253 lymphadenectasis on CT, preoperative T4-stage, undifferentiation, and elevated preoperative Ca199 level were found to be independent risk factors for the No.253 LNM. A predictive model based on these risk factors can help surgeons make rational clinical decisions.

Effect of phenylephrine rescue injection on hypotension after spinal anaesthesia for caesarean delivery when guided by both heart rate and SBP during an early warning window: A randomised controlled trial.

BACKGROUND: Spinal anaesthesia is now the most common technique for caesarean delivery. However, because of the intermittent nature of noninvasive blood pressure (NIBP) measurements, maternal blood pressure may become hypotensive between the measurements. There is thus an inbuilt delay before the anaesthesiologist can intervene to counteract the hypotension. Based on the principle that changes in blood pressure can induce compensatory changes in the heart rate (HR), combining the NIBP with real-time HR, we designed two warning windows to predict hypotension and hypertension. OBJECTIVE: To evaluate whether phenylephrine administration guided by these warning windows would help maintain haemodynamic stability. SETTING: A teaching hospital. DESIGN: A randomised controlled trial. PATIENTS: One hundred and ten pregnant women scheduled for elective caesarean delivery were enrolled, from which, after exclusions, 86 were eligible for the study. INTERVENTIONS: All eligible patients received a continuous intravenous infusion of phenylephrine as soon as spinal anaesthesia was initiated. Thereafter, patients were randomly assigned to two groups. In the test group (Win-Group): rescue phenylephrine administration was triggered by an early warning window of HR above 100 beats per minute (bpm) and SBP 90 to 110 mmHg; pausing the infusion phenylephrine was triggered by a HR lower than 60 bpm and SBP greater than 90 mmHg. In the control group, phenylephrine was guided by BP only when it appeared on the monitor: SBP less than 90 mmHg was the trigger for administering rescue phenylephrine; SBP greater than 110 mmHg was the trigger for pausing the phenylephrine infusion. MAIN OUTCOME MEASURES: The primary outcome was incidence of hypotension. Secondary outcomes were the incidence of hypertension and other adverse haemodynamic events. RESULTS: The incidence of hypotension was significantly lower in the Win-Group than in the BP-Group (27.8 vs. 66.7%, P  = 0.001). The minimum SBP was significantly higher in Win-Group than in BP-Group (93.9 ±â€Š9.49 vs. 86.7 ±â€Š11.16 mmHg, P   =  0.004). There was no significant difference in the incidence of hypertension between groups. CONCLUSION: After spinal anaesthesia for caesarean delivery, when phenylephrine infusion is guided by HR along with BP from a warning window it effectively reduces the incidence of hypotension without any significant effect on incidence of hypertension. TRIAL REGISTRATION: Chictr.org.cn; Identifier: ChiCTR 2100041812.

The novel norcantharidin derivative DCZ5417 suppresses multiple myeloma progression by targeting the TRIP13-MAPK-YWHAE signaling pathway.

BACKGROUND: Multiple myeloma (MM), an incurable disease owing to drug resistance, requires safe and effective therapies. Norcantharidin (NCTD), an active ingredient in traditional Chinese medicines, possesses activity against different cancers. However, its toxicity and narrow treatment window limit its clinical application. In this study, we synthesized a series of derivatives of NCTD to address this. Among these compounds, DCZ5417 demonstrated the greatest anti-MM effect and fewest side effects. Its anti-myeloma effects and  the mechanism were further tested. METHODS: Molecular docking, pull-down, surface plasmon resonance-binding, cellular thermal shift, and ATPase assays were used to study the targets of DCZ5417. Bioinformatic, genetic, and pharmacological approaches were used to elucidate the mechanisms associated with DCZ5417 activity. RESULTS: We confirmed a highly potent interaction between DCZ5417 and TRIP13. DCZ5417 inhibited the ATPase activity of TRIP13, and its anti-MM activity was found to depend on TRIP13. A mechanistic study verified that DCZ5417 suppressed cell proliferation by targeting TRIP13, disturbing the TRIP13/YWHAE complex and inhibiting the ERK/MAPK signaling axis. DCZ5417 also showed a combined lethal effect with traditional anti-MM drugs. Furthermore, the tumor growth-inhibitory effect of DCZ5417 was demonstrated using in vivo tumor xenograft models. CONCLUSIONS: DCZ5417 suppresses MM progression in vitro, in vivo, and in primary cells from drug-resistant patients, affecting cell proliferation by targeting TRIP13, destroying the TRIP13/YWHAE complex, and inhibiting ERK/MAPK signaling. These results imply a new and effective therapeutic strategy for MM treatment.

The short- and long-term effect of membrane anatomy-guided laparoscopic D2 lymphadenectomy plus regional complete mesogastrium excision for locally advanced gastric cancer.

OBJECTIVE: Retrospectively analyzed the short- and long-term efficacy between laparoscopic D2 lymphadenectomy plus regional complete mesogastrium excision (D2 + rCME) and traditional laparoscopic D2 in the treatment of patients with locally advanced gastric cancer (LAGC), in order to obtain more evidence for D2 + rCME gastrectomy. METHODS: A total of 599 LAGC patients who underwent laparoscopy-assisted radical gastrectomy from January 2014 to December 2019, including 367 cases in the D2 + rCME group and 232 cases in the D2 group. Intraoperative and postoperative clinicopathological parameters, postoperative complications and long-term survival in the two groups were statistically analyzed. RESULTS: No significant differences in the positive rate of mesogastric tumor deposits, the number of positive lymph nodes and postoperative length of stay were found between the two groups (P > 0.05). In the D2 + rCME group, intraoperative blood loss was significantly reduced (84.20 ± 57.64 ml vs. 148.47 ± 76.97 ml, P < 0.001), the time to first postoperative flatus and first liquid diet intake were significantly shortened (3[2-3] days vs. 3[3-3] days, P < 0.001; 7[7-8] days vs. 8[7-8] days, P < 0.001), and the number of lymph nodes dissected was greater (43.57 ± 16.52 pieces vs. 36.72 ± 13.83 pieces, P < 0.001). The incidence of complications did not significantly differ between the D2 + rCME group (20.7%) and D2 group (19.4%) (P > 0.05). Although there was no statistically difference in 3-year OS and DFS between the two groups. However, the trend was better in D2 + rCME group. In subgroup analysis, patients with positive tumor deposits (TDs) in the D2 + rCME group had significantly better 3-year DFS compared With D2 group (P < 0.05). CONCLUSION: Laparoscopic D2 + rCME is safe and feasible for the treatment of LAGC and is characterized by less bleeding, greater lymph node dissection and rapid recovery, without increasing postoperative complications. D2 + rCME group showed a better trend of long-term efficacy, especially significant beneficial for LAGC patients who with positive TDs.

Preventing Spinal Hypotension During Cesarean Birth With Two Initial Boluses of Norepinephrine in Chinese Parturients: A Randomized, Double-Blind, Controlled Trial.

BACKGROUND: Norepinephrine is effective in preventing spinal hypotension during cesarean birth; however, an optimal regimen has not been determined. We hypothesized that an initial bolus of norepinephrine improves efficacy of spinal hypotension prophylaxis beyond continuous norepinephrine alone. METHODS: In this double-blind, controlled study, 120 patients scheduled for cesarean birth under spinal anesthesia were randomly allocated to receive a norepinephrine bolus at 0.05 or 0.10 µg/kg, followed by norepinephrine infusion at a rate of 0.05 µg·kg -1 ·min -1 . The primary outcome was the frequency of spinal hypotension during cesarean birth. The doses of the rescue drug (phenylephrine), frequency of nausea or vomiting, duration of hypotension, frequency of intraoperative hypertension, frequency of bradycardia, and fetal outcomes were also compared. RESULTS: One-hundred-fifteen patients were included in the analysis. Compared with the 0.05 µg/kg group, the frequency of spinal hypotension was lower in the 0.10 µg/kg group (20.7% vs 45.6%; odds ratio [OR], 0.31; 95% confidence interval (CI), 0.14-0.71; P = .004). Fewer rescue doses of phenylephrine (0 [0,0] vs 0 [0,80]; 95% CI for the difference, 0 (0-0); P = .006) were required, and the frequency of nausea or vomiting was lower (5.2% vs 17.5%; OR, 0.26; 95% CI, 0.07-0.99; P = .04) in the 0.10 µg/kg group. The duration of hypotension was shorter in the 0.10 µg/kg group than that in the 0.05 µg/kg group (0 [0,0] vs 0 [0,2]; 95% CI for the difference, 0 [0-0]; P = .006). The incidence of intraoperative hypertension, frequency of bradycardia, and fetal outcomes were comparable between the 2 groups. CONCLUSIONS: With a fixed-rate norepinephrine infusion of 0.05 µg·kg -1 ·min -1 , the 0.10 µg/kg initial bolus was more effective in reducing the incidence of spinal hypotension compared with the 0.05 µg/kg initial bolus.

A prediction nomogram for postoperative gastroparesis syndrome in right colon cancer: a retrospective study.

PURPOSE: To investigate the high-risk factors for postoperative gastroparesis syndrome (PGS) in right colon cancer and to build a prediction nomogram for personalized prediction of PGS. METHODS: Our study retrospectively analyzed 361 patients with right colon cancer who underwent right hemicolectomy at The First Hospital of Putian City in Fujian Province, China and who were hospitalized between January 2012 and July 2022. Multivariate logistic regression was used to determine the independent risk factors for PGS and to establish a nomogram model. Furthermore, discrimination, calibration, and clinical benefits were used to evaluate the model. RESULTS: The multivariate logistic regression revealed that dissection of the subpyloric lymph nodes (No. 206 lymph node) (OR 5.242, P = 0.005), preoperative fasting blood glucose level (OR 3.708, P = 0.024), preoperative albumin level (OR 3.503, P = 0.020), and total operative time (OR 4.648, P = 0.014) were independent risk factors for PGS. Based on the above four factors, the area under the ROC curve (AUC) and C-index of the nomogram were 0.831. The prediction nomogram's calibration curve was closer to the ideal diagonal, and the Hosmer‒Lemeshow test indicated that the nomogram fit well (P = 0.399). Moreover, the decision curve analysis revealed that the model can present better clinical benefits when the threshold probability was between 1 and 28%, and the internal validation verified the dependability of the model (C-index = 0.948). CONCLUSIONS: A risk prediction nomogram based on perioperative factors provided the physician with a simple, visual, and efficient tool for the prediction and management of PGS in right colon cancer.

Position-Wise Gated Res2Net-Based Convolutional Network with Selective Fusing for Sentiment Analysis.

Sentiment analysis (SA) is an important task in natural language processing in which convolutional neural networks (CNNs) have been successfully applied. However, most existing CNNs can only extract predefined, fixed-scale sentiment features and cannot synthesize flexible, multi-scale sentiment features. Moreover, these models' convolutional and pooling layers gradually lose local detailed information. In this study, a new CNN model based on residual network technology and attention mechanisms is proposed. This model exploits more abundant multi-scale sentiment features and addresses the loss of locally detailed information to enhance the accuracy of sentiment classification. It is primarily composed of a position-wise gated Res2Net (PG-Res2Net) module and a selective fusing module. The PG-Res2Net module can adaptively learn multi-scale sentiment features over a large range using multi-way convolution, residual-like connections, and position-wise gates. The selective fusing module is developed to fully reuse and selectively fuse these features for prediction. The proposed model was evaluated using five baseline datasets. The experimental results demonstrate that the proposed model surpassed the other models in performance. In the best case, the model outperforms the other models by up to 1.2%. Ablation studies and visualizations further revealed the model's ability to extract and fuse multi-scale sentiment features.

Supramolecular Core-Shell Nanoassemblies with Tumor Microenvironment-Triggered Size and Structure Switch for Improved Photothermal Therapy.

Photothermal therapy (PTT) is demonstrated to be an effective methodology for cancer treatment. However, the relatively low photothermal conversion efficiency, limited tumor accumulation, and penetration still remain to be challenging issues that hinder the clinical application of PTT. Herein, the core-shell hierarchical nanostructures induced by host-guest interaction between water-soluble pillar[5]arene (WP5) and polyethylene glycol-modified aniline tetramer (TAPEG) are constructed. The pH-responsive performance endows the core-shell nanostructures with size switchable property, with an average diameter of 200 nm in the neutral pH and 60 nm in the acidic microenvironment, which facilitates not only tumor accumulation but also tumor penetration. Moreover, the structure switch of WP5⊃TAPEG under acidic microenvironment and the dual mechanism regulated extending of п conjugate, inclusion in the hydrophobic cavity of WP5 and the dense distribution in the core-shell structured assemblies, dramatically enhance the absorption in the near-infrared-II region and, further, the photothermal conversion efficiency (60.2%). The as-designed intelligent nanoplatform is demonstrated for improved antitumor efficacy via PTT.

History of the COVID-19 pandemic: Origin, explosion, worldwide spreading.

The SARS-CoV-2 virus of the COVID-19 pandemic, that is presently devastating the entire world, had been active well before January of this year, when its pathogenic potential exploded full force in Wuhan. It had caused the onset of small disease outbreaks in China, and probably elsewhere as well, which failed to reach epidemic potential. The distant general origin of its zoonosis can be traced back to the ecosystem changes that have decreased biodiversity, greatly facilitating the contacts between humans and the animal reservoirs that carry pathogens, including SARS-CoV-2. These reservoirs are the bats. The transition between the limited outbreaks that had occurred through 2019 and the epidemic explosion of December-January was made possible by the great amplification of the general negative conditions that had caused the preceding small outbreaks. In the light of what we have now learned, the explosion was predictable, and could have happened wherever the conditions that had allowed it, could be duplicated. What could not have been predicted was the second transition, from epidemic to pandemic. Research has now revealed that the globalization of the infection appears to have been caused by a mutation in the spike protein of the SARS-CoV-2, that has dramatically increased its transmissibility.

Biodiversity loss and COVID-19 pandemic: The role of bats in the origin and the spreading of the disease.

The loss of biodiversity in the ecosystems has created the general conditions that have favored and, in fact, made possible, the insurgence of the COVID-19 pandemic. A lot of factors have contributed to it: deforestation, changes in forest habitats, poorly regulated agricultural surfaces, mismanaged urban growth. They have altered the composition of wildlife communities, greatly increased the contacts of humans with wildlife, and altered niches that harbor pathogens, increasing their chances to come in contact with humans. Among the wildlife, bats have adapted easily to anthropized environments such as houses, barns, cultivated fields, orchards, where they found the suitable ecosystem to prosper. Bats are major hosts for αCoV and ßCoV: evolution has shaped their peculiar physiology and their immune system in a way that makes them resistant to viral pathogens that would instead successfully attack other species, including humans. In time, the coronaviruses that bats host as reservoirs have undergone recombination and other modifications that have increased their ability for inter-species transmission: one modification of particular importance has been the development of the ability to use ACE2 as a receptor in host cells. This particular development in CoVs has been responsible for the serious outbreaks in the last two decades, and for the present COVID-19 pandemic.

SS-31 ameliorates hepatic injury in rats subjected to severe burns plus delayed resuscitation via inhibiting the mtDNA/STING pathway in Kupffer cells.

Hepatic injury is common in patients who suffer from severe burns plus delayed resuscitation (B + DR). Stimulator of interferon genes (STING) is primarily expressed in Kupffer cells (KCs). We demonstrated that B + DR caused hepatic injury and oxidative stress. Reactive oxygen species (ROS) damage mitochondrial membranes in hepatocytes, leading to the release of mitochondrial DNA (mtDNA) into the hepatocyte cytosol and the circulation. The damaged hepatocytes then activate the mtDNA/STING pathway in KCs and trigger KCs polarization towards pro-inflammatory phenotype. SS-31 is a strong antioxidant that specifically concentrates in the inner mitochondrial membrane. SS-31 prevented hepatic injury by neutralizing ROS, inhibiting the release of mtDNA, protecting hepatocyte mitochondria, suppressing the activation of the mtDNA/STING pathway and inhibiting KCs polarization into pro-inflammatory phenotype.

Deficiency of ß-Arrestin 2 in Dendritic Cells Contributes to Autoimmune Diseases.

Altered migration and immune responses of dendritic cells (DCs) lead to inflammatory and autoimmune diseases. Our studies demonstrated that ß-arrestin 2 deficiency promoted migration and cytokine production of mouse bone marrow-derived DCs. We further found that ß-arrestin 2 directly interacted with Zbtb46, a DC-specific transcription factor. What's more, our results suggested that the interaction between ß-arrestin 2 and Zbtb46 might negatively regulate DC migration. Using RNA sequencing, we indicated that genes CD74, NR4A1, and ZFP36 might be the target genes regulated by the interaction between ß-arrestin 2 and Zbtb46. Mice with selective deficiency of ß-arrestin 2 in DCs developed severer experimental autoimmune encephalomyelitis with more DC infiltration in the CNS and increased IL-6 in serum. In the systemic lupus erythematosus mice model, Arrb2fl/fl Itgax-cre+ mice were prone to exacerbation of lupus nephritis with a higher level of IL-6 and DC accumulation. Taken together, our study identified ß-arrestin 2 as a new regulator of DC migration and immune properties, providing new insights into the mechanisms underlying the development of autoimmune disease.

Bifunctional Peptide-Conjugated Gold Nanoparticles for Precise and Efficient Nucleus-Targeting Bioimaging in Live Cells.

Real-time in situ imaging of organelles is increasingly important in modern biomedical analysis and diseases diagnosis. To realize this goal, organelle-targeting nanoparticles as one of the most commonly used technologies in subcellular sensing and imaging has attracted a lot of interest. The biocompatibility, specificity, and binding efficiency are especially critical for efficient organelle-targeting bioimaging. Gold nanoparticles (AuNPs) fabricated with bifunctional peptides constructed with both Au-binding affinity and nucleus-targeting ability were designed and examined for efficient nucleus-targeting bioimaging. Such a design is expected to achieve an oriented assembling of peptides by the medium of the Au-binding peptides specifically assembled on the surface of AuNPs, with the nucleus-targeting end open for accessibility. The bifunctional peptides showed strong binding affinity toward AuNPs and led to a binding capability ∼1.5 times higher than that of the bare nucleus-targeting peptides, ensuring good surface coverage of the nanoparticles for enhanced nucleus-targeting ability. Such fabricated AuNPs demonstrated over 90% cell viability after incubation for 24 h with HepG2 cells, which were highly biocompatible. Precise and efficient bioimaging of the nucleus was achieved for HepG2 cells by using the fabricated AuNPs as observed with a confocal laser scanning microscope, a dark-field/fluorescence microscope, and a transmission electron microscope. The high surface coverage and oriented binding pattern appeared to be a promising strategy for construction of organelle-targeting agencies.

Betaine Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Dendritic Cell-Derived IL-6 Production and Th17 Differentiation.

IL-17-secreting T cells (Th17 cells) play a pathogenic role in multiple autoimmune diseases, including multiple sclerosis (MS), and dendritic cell (DC)-derived cytokines play pivotal roles in promoting the differentiation of naive CD4+ T cells into Th cell subsets (Th1 and Th17). Therefore, small molecules blocking the key cytokines produced by DCs will be beneficial in MS. In this article, we report that betaine treatment ameliorates MS pathogenesis by inhibiting DC-derived IL-6 production and Th17 differentiation. Using experimental autoimmune encephalomyelitis, a widely used mouse model of MS, we found that, compared with the vehicle-treated group, betaine-treated mice exhibited less severe experimental autoimmune encephalomyelitis symptoms, including lower clinical scores, reduced leukocyte infiltration, and less extensive demyelination in the CNS. Moreover, a significantly lower percentage of Th17 cells, one of the major pathogenic effector cells in MS progression, was observed in the peripheral immune system and in the CNS. Interestingly, in the in vitro Th17-differentiation assay, no significant change in Th17 cells was observed between the vehicle- and betaine-treated groups, whereas in the in vitro DC culture experiment, betaine treatment significantly decreased DC-derived IL-6 production. In the DC-T cell coculture experiment, a significantly decreased Th17 differentiation was observed upon betaine treatment. All of these data demonstrated that betaine inhibited Th17 differentiation indirectly by reducing IL-6 production by DCs. In brief, our findings demonstrated the pivotal roles of betaine in modulating MS pathogenesis and suggested that it may serve as a potential novel drug candidate for the treatment of MS.

Novel cyclophosphamide of natural products osalmide and pterostilbene induces cytotoxicity and cell cycle arrest in diffuse large B-cell lymphoma cells.

Diffuse large B-cell lymphoma (DLBCL) is the most common category and disease entity of non-Hodgkin lymphoma. Osalmide and pterostilbene are natural products with anticancer activities via different mechanism. In this study, using a new synthetic strategy for the two natural products, we obtained the compound DCZ0801, which was previously found to have anti-multiple myeloma activity. We performed both in vitro and in vivo assays to investigate its bioactivity and explore its underlying mechanism against DLBCL cells. The results showed that DCZ0801 treatment gave rise to a dose- and time-dependent inhibition of cell viability as determined by CCK-8 assay and flow cytometry assay. Western blot analysis results showed that the expression of caspase-3, caspase-8, caspase-9 and Bax was increased, while BCL-2 and BCL-XL levels were decreased, which suggested that DCZ0801 inhibited cell proliferation and promoted intrinsic apoptosis. In addition, DCZ0801 induced G0/G1 phase arrest by downregulating the protein expression levels of CDK4, CDK6 and cyclin D1. Furthermore, DCZ0801 exerted an anti-tumor effect by down-regulating the expressions of p-PI3K and p-AKT. There also existed a trend that the expression of p-JNK and p-P38 was restrained. Intraperitoneal injection of DCZ0801 suppressed tumor development in xenograft mouse models. The preliminary metabolic study showed that DCZ0801 displayed a rapid metabolism within 30 min. These results demonstrated that DCZ0801 may be a new potential anti-DLBCL agent in DLBCL therapy.

Transcriptional regulation of O-GlcNAc homeostasis is disrupted in pancreatic cancer.

Many intracellular proteins are reversibly modified by O-linked GlcNAc (O-GlcNAc), a post-translational modification that dynamically regulates fundamental cellular processes in response to diverse environmental cues. Accumulating evidence indicates that both excess and deficiency of protein O-GlcNAcylation can have deleterious effects on the cell, suggesting that maintenance of O-GlcNAc homeostasis is essential for proper cellular function. However, the mechanisms through which O-GlcNAc homeostasis is maintained in the physiologic state and altered in the disease state have not yet been investigated. Here, we demonstrate the existence of a homeostatic mechanism involving mutual regulation of the O-GlcNAc-cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) at the transcriptional level. Specifically, we found that OGA promotes Ogt transcription through cooperation with the histone acetyltransferase p300 and transcription factor CCAAT/enhancer-binding protein ß (C/EBPß). To examine the role of mutual regulation of OGT and OGA in the disease state, we analyzed gene expression data from human cancer data sets, which revealed that OGT and OGA expression levels are highly correlated in numerous human cancers, particularly in pancreatic adenocarcinoma. Using a KrasG12D -driven primary mouse pancreatic ductal adenocarcinoma (PDAC) cell line, we found that inhibition of extracellular signal-regulated kinase (ERK) signaling decreases OGA glycosidase activity and reduces OGT mRNA and protein levels, suggesting that ERK signaling may alter O-GlcNAc homeostasis in PDAC by modulating OGA-mediated Ogt transcription. Our study elucidates a transcriptional mechanism that regulates cellular O-GlcNAc homeostasis, which may lay a foundation for exploring O-GlcNAc signaling as a therapeutic target for human disease.

Critical Role of P2Y12 Receptor in Regulation of Th17 Differentiation and Experimental Autoimmune Encephalomyelitis Pathogenesis.

Adenosine 5'-diphosphate is a key endogenous cell-signaling molecule that can activate P2 purinergic receptor family members. ADP-P2Y signaling is reported to be associated with inflammation, but its function in T cell differentiation and autoimmune diseases pathogenesis is unclear. In this study, we found that the P2Y12 receptor was upregulated in the peripheral immune tissues of experimental autoimmune encephalomyelitis (EAE) mice. Deficiency of P2Y12 led to a reduced peak severity and cumulative disease score in EAE mice, followed by a dramatic reduction of leukocyte infiltration and less extensive demyelination. The percentage of Th17, one of the main pathogenic T cells in EAE, was sharply decreased in P2Y12 knockout mice, accompanied by decreased IL-17A production and a low mRNA level of Th17-related genes. In vitro culture assay further verified that P2Y12 directly regulated Th17 differentiation. More interestingly, clopidogrel and ticagrelor, two P2Y12-specific antagonists, effectively alleviated the disease severity of EAE and inhibited Th17 differentiation both in vivo and in vitro. Further study demonstrated that blocking the P2Y12 receptor also ameliorated the symptoms of 2,4,6-trinitrobenzenesulfonic acid-induced colitis and multiple low-dose streptozocin-induced type 1 diabetes. Our findings not only revealed the critical role of P2Y12 in Th17 differentiation and EAE pathogenesis, but also suggested the promising potential of P2Y12 antagonists in the treatment of autoimmune diseases.