A positive feedback loop between PLD1 and NF-κB signaling promotes tumorigenesis of nasopharyngeal carcinoma.

Phospholipase D (PLD) lipid-signaling enzyme superfamily has been widely implicated in various human malignancies, but its role and underlying mechanism remain unclear in nasopharyngeal carcinoma (NPC). Here, we analyze the expressions of 6 PLD family members between 87 NPC and 10 control samples through transcriptome analysis. Our findings reveal a notable upregulation of PLD1 in both NPC tumors and cell lines, correlating with worse disease-free and overall survival in NPC patients. Functional assays further elucidate PLD1's oncogenic role, demonstrating its pivotal promotion of critical tumorigenic processes such as cell proliferation and migration in vitro, as well as tumor growth in vivo. Notably, our study uncovers a positive feedback loop between PLD1 and the NF-κB signaling pathway to render NPC progression. Specifically, PLD1 enhances NF-κB activity by facilitating the phosphorylation and nuclear translocation of RELA (p65), which in turn binds to the promoter of PLD1, augmenting its expression. Moreover, RELA overexpression significantly rescues the inhibitory effects in PLD1-depleted NPC cells. Importantly, the application of the PLD1 inhibitor, VU0155069, significantly inhibits NPC tumorigenesis in a patient-derived xenograft model. Together, our findings identify PLD1/NF-κB signaling as a positive feedback loop with promising therapeutic and prognostic potential in NPC.

Clinical, histopathological characteristics and malignant transformation of proliferative verrucous leukoplakia with 36 patients: a retrospective longitudinal study.

BACKGROUND: Proliferative verrucous leukoplakia (PVL), distinguished by its malignant transformation rate of 43.87% to 65.8%, stands as the oral potentially malignant disorder with the highest propensity for malignancy. PVL is marked by distinctive heterogeneity regarding the clinical or histopathological characteristics as well as prognostic factors pertinent to this condition. The purpose of this study is to compile and assess the clinicopathological features, malignant transformation, and associated risk factors in patients diagnosed with PVL. METHODS: This study is a hospital-based retrospective longitudinal study of 36 patients diagnosed with PVL from 2013 to 2023. We conducted complete clinical and histopathological evaluations of the patients. RESULTS: The cohort comprised 16 males and 20 females, yielding a male-to-female ratio of 1:1.25. The follow-up period ranged from 8 to 125 months, with an average of 47.50 months. The most common clinical type of lesion was the verrucous form (58.33%), and the gingiva was the most common site (44.44%). Each patient had between 2 to 7 lesions, averaging 3.36 per patient. During the follow-up period, twelve patients (33.3%) developed oral cancer, with an average time to malignant transformation of 35.75 months. Kaplan-Meier survival analysis indicated that patients with complaints of pain, roughness, or a rough sensation, with diabetes, and the presence of cytologic atypia histologically showed a higher risk of malignant transformation (p < 0.05). In this study, the rate of malignant transformation in the treatment group (5/23) was lower than that in the untreated group (7/13), however, no statistically significant difference (p = 0.05). CONCLUSION: The main complaints of pain, roughness, or foreign body sensation, coupled with cytologic atypia histologically are indicative of an increased risk of malignant transformation in PVL. Further research is needed to elucidate the influence of these clinicopathological parameters on the malignant progression of PVL.

TAAR1 in dentate gyrus is involved in chronic stress-induced impairments in hippocampal plasticity and cognitive function.

Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating major depressive disorder (MDD). The role of TAAR1 in the regulation of adult neurogenesis is recently supported by transcriptomic data. However, it remains unknown whether TAAR1 in dentate gyrus (DG) mediate chronic stress-induced negative effects on hippocampal plasticity and related behavior in mice. The present study consisted of a series of experiments using RNAscope, genetic approaches, behavioral tests, immunohistochemical staining, Golgi-Cox technique to unravel the effects of TAAR1 on alterations of dentate neuronal plasticity and cognitive function in the chronic social defeat stress model. The mice subjected to chronic defeat stress exhibited a noteworthy decrease in the mRNA level of TAAR1 in DG. Additionally, they exhibited compromised social memory and spatial object recognition memory, as well as impaired proliferation and maturation of adult-born dentate granule cells. Moreover, the selective knockout TAAR1 in DG mostly mimicked the cognitive function deficits and neurogenesis impairment induced by chronic stress. Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD.

Randomized Controlled Trial Investigating the Impact of High-Flow Nasal Cannula Oxygen Therapy on Patients Undergoing Robotic-Assisted Laparoscopic Rectal Cancer Surgery, with a Post-Extubation Atelectasis as a Complication.

Background: Utilizing high-flow nasal cannula (HFNC) oxygen therapy may prevent the collapse of alveoli and improve overall alveolar ventilation. In this study, we aimed to investigate the impact of HFNC on postoperative atelectasis in individuals undergoing robotic-assisted laparoscopic surgery. Methods: Patients undergoing robotic-assisted laparoscopic surgery for rectal cancer were randomly assigned to the control or HFNC groups. After the surgical procedure was complete and the trachea was extubated, both groups underwent an initial lung ultrasound (LUS) scan. In the post-anesthesia care unit (PACU), the control group received conventional nasal cannula oxygen therapy, while the HFNC group received high-flow nasal cannula oxygen therapy. A second LUS scan was conducted before the patient was transferred to the ward. The primary outcome measured was the total LUS score at the time of PACU discharge. Results: In the HFNC group (n = 39), the LUS score and the incidence of atelectasis at PACU discharge were significantly lower compared to the control group (n = 39) [(5 vs 10, P < 0.001), (48.72% vs 82.05%, P = 0.002)]. None of the patients in the HFNC group experienced hypoxemia in the PACU, whereas six patients in the control group did (P = 0.03). Additionally, the minimum SpO2 value in the PACU was notably higher in the HFNC group compared to the control group [99 vs 97, P < 0.001]. Conclusion: Based on the results, HFNC improves the extent of postoperative atelectasis and decreases the occurrence of atelectasis in individuals undergoing robotic-assisted laparoscopic surgery for rectal cancer.

Branched-chain amino acids promote occurrence and development of cardiovascular disease dependent on triglyceride metabolism via activation of the mTOR/SREBP-1/betatrophin pathway.

Branched-chain amino acid (BCAA) metabolism is associated with triglyceride (TG) metabolism and the development of cardiovascular disease (CVD). However, the underlying mechanism remains uncertain. This study included 1302 subjects and followed for 4-5 years. A hyperbranched-chain aminoacidemia rat model was induced by high fructose diet (HFTD). The relationship between BCAAs and TG level and its regulatory mechanism was investigated in vitro. As results, as baseline BCAA percentile increased, subjects had higher prevalence and incidence of T2DM, NAFLD, and CVD risk (P < 0.05). In animal model, the accumulation of BCAAs and TG and betatrophin expression were significantly elevated in the HFTD group when comparing with those in the SD group(P < 0.05). Immunofluorescence and Masson's trichrome staining revealed that the area of interstitial fibrosis was significantly increased in the HFTD group compared with control group. Met treatment significantly decreased TG levels and betatrophin expression and reversed myocardial fibrosis (P < 0.05). In vitro, LO2 cells, stimulated with 0.1-5 mM BCAAs, displayed a significant dose-dependent increase in betatrophin expression (P < 0.05). And 5 mM BCAAs stimulation significantly increased the p-mTOR and SREBP-1 expression (P < 0.05). However, this effect could be reversed by using the corresponding inhibitor or siRNAs. In conclusions, BCAAs promote occurrence and development of cardiovascular disease dependent on TG metabolism via activation of the mTOR/SREBP-1/betatrophin pathway. The study provides a new theory for the pathogenesis of CVD caused by amino acid metabolism disorders.

NRAMP6c plays a key role in plant cadmium accumulation and resistance in tobacco (Nicotiana tabacum L.).

Tobacco plants (Nicotiana tabacum L.) exhibit considerable potential for phytoremediation of soil cadmium (Cd) pollutants, owing to their substantial biomass and efficient metal accumulation capabilities. The reduction of Cd accumulation in tobacco holds promise for minimizing Cd intake in individuals exposed to cigar smoking. NRAMP transporters are pivotal in the processes of Cd accumulation and resistance in plants; however, limited research has explored the functions of NRAMPs in tobacco plants. In this investigation, we focused on NtNRAMP6c, one of the three homologs of NRAMP6 in tobacco. We observed a robust induction of NtNRAMP6c expression in response to both Cd toxicity and iron (Fe) deficiency, with the highest expression levels detected in the roots. Subsequent subcellular localization and heterologous expression analyses disclosed that NtNRAMP6c functions as a plasma membrane-localized Cd transporter. Moreover, its overexpression significantly heightened the sensitivity of yeast cells to Cd toxicity. Through CRISPR-Cas9-mediated knockout of NtNRAMP6c, we achieved a reduction in Cd accumulation and an enhancement in Cd resistance in tobacco plants. Comparative transcriptomic analysis unveiled substantial alterations in the transcriptional profiles of genes associated with metal ion transport, photosynthesis, and macromolecule catabolism upon NtNRAMP6c knockout. Furthermore, our study employed plant metabolomics and rhizosphere metagenomics to demonstrate that NtNRAMP6c knockout led to changes in phytohormone homeostasis, as well as shifts in the composition and abundance of microbial communities. These findings bear significant biological implications for the utilization of tobacco in phytoremediation strategies targeting Cd pollutants in contaminated soils, and concurrently, in mitigating Cd accumulation in tobacco production destined for cigar consumption.

Single-Cell Analysis Reveals Malignant Cells Reshape the Cellular Landscape and Foster an Immunosuppressive Microenvironment of Extranodal NK/T-Cell Lymphoma.

Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive type of lymphoma associated with Epstein-Barr virus (EBV) and characterized by heterogeneous tumor behaviors. To better understand the origins of the heterogeneity, this study utilizes single-cell RNA sequencing (scRNA-seq) analysis to profile the tumor microenvironment (TME) of NKTCL at the single-cell level. Together with in vitro and in vivo models, the study identifies a subset of LMP1+ malignant NK cells contributing to the tumorigenesis and development of heterogeneous malignant cells in NKTCL. Furthermore, malignant NK cells interact with various immunocytes via chemokines and their receptors, secrete substantial DPP4 that impairs the chemotaxis of immunocytes and regulates their infiltration. They also exhibit an immunosuppressive effect on T cells, which is further boosted by LMP1. Moreover, high transcription of EBV-encoded genes and low infiltration of tumor-associated macrophages (TAMs) are favorable prognostic indicators for NKTCL in multiple patient cohorts. This study for the first time deciphers the heterogeneous composition of NKTCL TME at single-cell resolution, highlighting the crucial role of malignant NK cells with EBV-encoded LMP1 in reshaping the cellular landscape and fostering an immunosuppressive microenvironment. These findings provide insights into understanding the pathogenic mechanisms of NKTCL and developing novel therapeutic strategies against NKTCL.

Efficacy and safety of clopidogrel versus aspirin monotherapy for secondary prevention in patients with coronary artery disease: a meta-analysis.

Background: The benefits and risks of aspirin verse clopidogrel monotherapy in patients with coronary artery disease (CAD) remain controversial. This meta-analysis evaluated the efficacy and safety of aspirin verse clopidogrel monotherapy for long-term treatment in patients with CAD. Methods: Literature was searched in the Pubmed, the Cochrane Library, and the Embase databases until March 2023. The Cochrane Risk of Bias Tool was used to assess the risk of bias in included studies. Data were extracted from the included studies, heterogeneity analysis, and pooled analysis conducted by RevMan 5.3 software. Results: A total of five trials were included, involving 11, 766 patients with CAD. Compared with the aspirin group, the clopidogrel group was associated with reduced risk of major adverse cardiac and cerebrovascular events (MACCE) [risk ratio (RR) = 0.68, P = 0.0007], myocardial infarction (MI, RR = 0.66, P = 0.01), stroke (RR = 0.58, P = 0.003), and BARC major bleeding (RR = 0.63, P = 0.02). There were no significant differences in death from any cause (RR = 1.06, P = 0.59) and vascular death (RR = 0.92, P = 0.62) between the two groups. Conclusions: Patients with CAD use clopidogrel could further reduce the risk of MACCE, MI, stroke, and BARC major bleeding, compared with the use of aspirin. This finding supported the use of clopidogrel rather than aspirin in patients with CAD who required long-term antiplatelet monotherapy for preventing ischemic events.

Potential correlation of oral flora with pemphigus vulgaris - A case control study.

Background/purpose: Oral flora is related to various immune-related diseases. Herein we explored the characteristics of oral flora in patients with pemphigus vulgaris (PV) and analyzed the correlation between oral flora and PV. Materials and methods: Twenty-two untreated patients with PV and 12 healthy controls (HC) were included in this case-control study. The characteristics of salivary microbiome were assessed by high-throughput sequencing using the 16S rRNA Illumina MiSeq approach, and differences between the PV and HC groups were determined. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database was applied to screen key metabolic pathways and preliminarily explore potential mechanisms underlying PV occurrence and development. Results: The abundance of oral flora in the PV group was significantly lower than that in the HC group, and there were characteristic changes. The relative abundance of Prevotella and Agrobacterium in the PV group was significantly higher than that in the HC group (P < 0.05) and that of Neisseria, Lautropia, and Fusobacterium was significantly lower (P < 0.05). There was a linear correlation between Prevotella and serum Dsg3 level in PV. KEGG pathway analyses indicated significant differences in nine metabolic pathways between the PV and HC groups (P < 0.05), namely carbohydrate metabolism, digestive system, neurodegenerative disease, glycan biosynthesis and metabolism, drug resistance: antimicrobial, infectious disease: viral, circulatory system, excretory system, and nervous system. Conclusion: The oral flora of patients with PV presented characteristic changes, and several metabolic pathways were affected, including N-glycan biosynthesis and metabolism. Prevotella spp. appear to require the most attention in PV. We believe that oral flora dysbacteriosis contributes to PV occurrence and development.

SHED-exos promote saliva secretion by suppressing p-ERK1/2-mediated apoptosis in glandular cells.

OBJECTIVES: Confirm that stem cells from human exfoliated deciduous teeth-derived exosomes (SHED-exos) can limit inflammation-triggered epithelial cell apoptosis and explore the molecular mechanism. METHODS: SHED-exos were injected into the submandibular glands (SMGs) of non-obese diabetic (NOD) mice, an animal model of Sjögren's syndrome (SS). Cell death was evaluated by western blotting and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling staining. RESULTS: SHED-exos treatment promoted the saliva flow rates of NOD mice, accompanied by decreased cleaved caspase-3 levels and apoptotic cell numbers in SMGs. SHED-exos inhibited autophagy, pyroptosis, NETosis, ferroptosis, necroptosis and oxeiptosis marker expression in SS-damaged glands. Mechanistically, Kyoto Encyclopedia of Genes and Genomes analysis of exosomal miRNAs suggested that the rat sarcoma virus (RAS)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway might play an important role. In vivo, the expression of Kirsten RAS, Harvey RAS, MEK1/2 and p-ERK1/2 was upregulated in SMGs, and this change was blocked by SHED-exos treatment. In vitro, SHED-exos suppressed p-ERK1/2 activation and increased cleaved caspase-3 and apoptotic cell numbers, which were induced by IFN-γ. CONCLUSION: SHED-exos suppress epithelial cell death, which is responsible for promoting salivary secretion. SHED-exos inhibited inflammation-triggered epithelial cell apoptosis by suppressing p-ERK1/2 activation, which is involved in these effects.

SRSF3/AMOTL1 splicing axis promotes the tumorigenesis of nasopharyngeal carcinoma through regulating the nucleus translocation of YAP1.

Dysregulation of serine/arginine splicing factors (SRSFs) and abnormal alternative splicing (AS) have been widely implicated in various cancers but scarcely investigated in nasopharyngeal carcinoma (NPC). Here we examine the expression of 12 classical SRSFs between 87 NPC and 10 control samples, revealing a significant upregulation of SRSF3 and its association with worse prognosis in NPC. Functional assays demonstrate that SRSF3 exerts an oncogenic function in NPC progression. Transcriptome analysis reveals 1,934 SRSF3-regulated AS events in genes related to cell cycle and mRNA metabolism. Among these events, we verify the generation of a long isoform of AMOTL1 (AMOTL1-L) through a direct bond of the SRSF3 RRM domain with the exon 12 of AMOTL1 to promote exon inclusion. Functional studies also reveal that AMOTL1-L promotes the proliferation and migration of NPC cells, while AMOTL1-S does not. Furthermore, overexpression of AMOTL1-L, but not -S, significantly rescues the inhibitory effects of SRSF3 knockdown. Additionally, compared with AMOTL1-S, AMOTL1-L has a localization preference in the intracellular than the cell membrane, leading to a more robust interaction with YAP1 to promote nucleus translocation. Our findings identify SRSF3/AMOTL1 as a novel alternative splicing axis with pivotal roles in NPC development, which could serve as promising prognostic biomarkers and therapeutic targets for NPC.

A metabolomics-based analysis of the metabolic pathways associated with the regulation of branched-chain amino acids in rats fed a high-fructose diet.

Previous studies have shown that the elevated levels of circulating branched-chain amino acids (BCAAs) are associated with the development of insulin resistance and its complications, including obesity, type 2 diabetes, cardiovascular disease and some cancers. However, animal models that can mimic the metabolic state of chronically elevated BCAAs in humans are rare. Therefore, the aim of this study was to establish the above animal model and analyse the metabolic changes associated with high BCAA levels. Sixteen 8-week-old Sprague-Dawley (SD) rats were randomly divided into two groups and given either a high fructose diet or a normal diet. BCAA levels as well as blood glucose and lipid levels were measured at different time points of feeding. The mRNA expression levels of two key enzymes of BCAA catabolism, ACAD (acyl-CoA dehydrogenase) and BCKDH (branched-chain α-keto acid dehydrogenase), were measured by qPCR, and the protein expression levels of these two enzymes were analysed by immunohistochemistry. Finally, the metabolite expression differences between the two groups were analysed by Q300 metabolomics technology. Our study confirms that defects in the catabolic pathways of BCAAs lead to increased levels of circulating BCAAs, resulting in disorders of glucose and lipid metabolism characterized by insulin resistance by affecting metabolic pathways associated with amino acids and bile acids.

Safety of prone emergence from general endotracheal anesthesia in patients undergoing ERCP: a randomized controlled trial.

BACKGROUND: Conventional supine emergence and prone extubation from general endotracheal anesthesia (GEA) are associated with extubation-related adverse events (ERAEs). Given the minimally invasive nature of endoscopic retrograde cholangiopancreatography (ERCP) as well as the improved ventilation/perfusion matching and easier airway opening in the prone position, we aimed to assess the safety of prone emergence and extubation in patients undergoing ERCP under GEA. METHODS: Totally, 242 eligible patients were recruited and randomized into the supine extubation group (n = 121; supine group) and the prone extubation group (n = 121; prone group). The primary endpoint was the incidence of ERAEs during emergence, including hemodynamic fluctuations, coughing, stridor, and hypoxemia requiring airway maneuvers. The secondary endpoints included the incidence of monitoring disconnections, extubation time, recovery time, room exit time, and post-procedure sore throat. RESULTS: The incidence of ERAEs was significantly lower in the prone group compared with the supine group (8.3% vs 34.7%, OR = 0.17, 95% CI 0.18-0.56; P < 0.001). Moreover, the prone group demonstrated no monitoring disconnections, shorter extubation time and room exit time, faster recovery, and, lower frequency and milder sore throat after the procedure. CONCLUSIONS: For patients undergoing ERCP under GEA, compared with supine, prone emergence, and extubation had remarkably lower rates of EAREs and better recovery, and can maintain continuous monitoring and improve efficiency.

Efficacy and safety of electrical acupoint stimulation for postoperative nausea and vomiting: A systematic review and meta-analysis.

BACKGROUND: Postoperative nausea and vomiting are typical postsurgical complications. Drug therapy is only partially effective. The goal of our meta-analysis is to systematically evaluate the efficacy and safety of electrical acupoint stimulation for postoperative nausea and vomiting and to score the quality of evidence supporting this concept. METHODS: PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched from inception to March 19, 2020. RESULTS: Twenty-six studies (2064 patients) were included. Compared with control treatment, electrical acupoint stimulation reduced the incidence of postoperative nausea and vomiting (RR 0.49, 95% CI 0.41 to 0.57, P < 0.001), postoperative nausea (RR 0.55, 95% CI 0.47 to 0.64, P < 0.001) and postoperative vomiting (RR 0.56, 95% CI 0.45 to 0.70, P < 0.001). Electrical acupoint stimulation also reduced the number of patients requiring antiemetic rescue (RR 0.60, 95% CI 0.43 to 0.85, P = 0.004). No differences in adverse events were observed. Subgroup analysis showed that both electroacupuncture (RR 0.58, 95% CI 0.46 to 0.74, P < 0.001) and transcutaneous electrical acupoint stimulation (RR 0.44, 95% CI 0.34 to 0.58, P < 0.001) had significant effects. Electrical acupoint stimulation was effective whether administered preoperatively (RR 0.40, 95% CI 0.27 to 0.60, P < 0.001), postoperatively (RR 0.59, 95% CI 0.46 to 0.76, P < 0.001), or perioperatively (RR 0.50, 95% CI 0.37 to 0.67, P < 0.001). The quality of evidence was moderate to low. CONCLUSIONS: Electrical acupoint stimulation probably reduce the incidence of postoperative nausea and vomiting, postoperative nausea, postoperative vomiting, and reduce the number of patients requiring antiemetic rescue, with few adverse events.

Metabolic engineering of a 1,8-cineole synthase enhances aphid repellence and increases trichome density in transgenic tobacco (Nicotiana tabacum L.).

BACKGROUND: The green peach aphid (Myzus persicae Sulzer) is a harmful agricultural pest that causes severe crop damage by directly feeding or indirectly vectoring viruses. 1,8-cineole synthase (CINS) is a multiproduct enzyme that synthesizes monoterpenes, with 1,8-cineole dominating the volatile organic compound profile. However, the relationship between aphid preference and CINS remains elusive. RESULTS: Here, we present evidence that SoCINS, a protein from garden sage (Salvia officinalis), enhanced aphid repellence and increased trichome density in transgenic tobacco. Our results demonstrated that overexpression of SoCINS (SoCINS-OE) led to the emission of 1,8-cineole at a level of up to 181.5 ng per g fresh leaf. Subcellular localization assay showed that SoCINS localized to chloroplasts. A Y-tube olfactometer assay and free-choice assays revealed that SoCINS-OE plants had a repellent effect on aphids, without incurring developmental or fecundity-related penalties. Intriguingly, the SoCINS-OE plants displayed an altered trichome morphology, showing increases in trichome density and in the relative proportion of glandular trichomes, as well as enlarged glandular cells. We also found that SoCINS-OE plants had significantly higher jasmonic acid (JA) levels than wild-type plants. Furthermore, application of 1,8-cineole elicited increased JA content and trichome density. CONCLUSION: Our results demonstrate that SoCINS-OE plants have a repellent effect on aphids, and suggest an apparent link between 1,8-cineole, JA and trichome density. This study presents a viable and sustainable approach for aphid management by engineering the expression of 1,8-cineole synthase gene in plants, and underscores the potential usefulness of monoterpene synthase for pest control. © 2023 Society of Chemical Industry.

SHED-derived exosomes ameliorate hyposalivation caused by Sjögren's syndrome via Akt/GSK-3ß/Slug-mediated ZO-1 expression.

BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disorder characterized by sicca syndrome and/or systemic manifestations. The treatment is still challenging. This study aimed to explore the therapeutic role and mechanism of exosomes obtained from the supernatant of stem cells derived from human exfoliated deciduous teeth (SHED-exos) in sialadenitis caused by SS. METHODS: SHED-exos were administered to the submandibular glands (SMGs) of 14-week-old non-obese diabetic (NOD) mice, an animal model of the clinical phase of SS, by local injection or intraductal infusion. The saliva flow rate was measured after pilocarpine intraperitoneal injection in 21-week-old NOD mice. Protein expression was examined by western blot analysis. Exosomal microRNA (miRNAs) were identified by microarray analysis. Paracellular permeability was evaluated by transepithelial electrical resistance measurement. RESULTS: SHED-exos were injected into the SMG of NOD mice and increased saliva secretion. The injected SHED-exos were taken up by glandular epithelial cells, and further increased paracellular permeability mediated by zonula occluden-1 (ZO-1). A total of 180 exosomal miRNAs were identified from SHED-exos, and Kyoto Encyclopedia of Genes and Genomes analysis suggested that the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway might play an important role. SHED-exos treatment down-regulated phospho-Akt (p-Akt)/Akt, phospho-glycogen synthase kinase 3ß (p-GSK-3ß)/GSK-3ß, and Slug expressions and up-regulated ZO-1 expression in SMGs and SMG-C6 cells. Both the increased ZO-1 expression and paracellular permeability induced by SHED-exos were abolished by insulin-like growth factor 1, a PI3K agonist. Slug bound to the ZO-1 promoter and suppressed its expression. For safer and more effective clinical application, SHED-exos were intraductally infused into the SMGs of NOD mice, and saliva secretion was increased and accompanied by decreased levels of p-Akt/Akt, p-GSK-3ß/GSK-3ß, and Slug and increased ZO-1 expression. CONCLUSION: Local application of SHED-exos in SMGs can ameliorate Sjögren syndrome-induced hyposalivation by increasing the paracellular permeability of glandular epithelial cells through Akt/GSK-3ß/Slug pathway-mediated ZO-1 expression.

Effect of the annealing treatment on structural and transport properties of thermoelectric Smy(FexNi1-x)4Sb12thin films.

The crystallographic and transport properties of thin films fabricated by pulsed laser deposition and belonging to the Smy(FexNi1-x)4Sb12filled skutterudite system were studied with the aim to unveil the effect exerted by temperature and duration of thermal treatments on structural and thermoelectric features. The importance of annealing treatments in Ar atmosphere up to 523 K was recognized, and the thermal treatment performed at 473 K for 3 h was selected as the most effective in improving the material properties. With respect to the corresponding bulk compositions, a significant enhancement in phase purity, as well as an increase in electrical conductivity and a drop in room temperature thermal conductivity, were observed in annealed films. The low thermal conductivity, in particular, can be deemed as deriving from the reduced dimensionality and the consequent substrate/film interfacial stress, coupled with the nanometric grain size.

Isoflurane impairs GluN2B-containing NMDA receptors trafficking and cognition via decreasing histone acetylation and EphB2 expression in aged hippocampal neurons.

Perioperative neurocognitive disorders (PND) is a common complication that occurs among elderly patients in the perioperative course. Current clinical evidence has shown that isoflurane exposure could cause cognitive decline, but the exact molecular mechanisms remain unclear. As both NMDARs-dependent synaptic plasticity and histone acetylation play vital roles in processing learning and memory, we postulated that these alternations might occur in the isoflurane-associated PND. Here, we found that isoflurane impaired fear memory in aged mice, decreased GluN2B-containing NMDA receptors phosphorylation and trafficking, as well as the expression of EphB2, a key regulator of synaptic localization of NMDA receptors. We also identified that isoflurane could increase the expression of HDAC2, which was significantly enriched at the ephb2 gene promoter and regulated the transcription of ephb2. Furthermore, we showed that suberoylanilide hydroxamic acid (SAHA), a nonselective HDAC inhibitor or knocking-down HDAC2 rescued the cognitive dysfunction in isoflurane-treated aged mice via increasing acetylation of H3Ac, expression of EphB2 and promoting NMDA receptor trafficking. Collectively, our study highlighted the crucial role of histone posttranslational modifications for EphB2-GluN2B signals in isoflurane-associated PND, and modulating HDAC2 might be a new therapeutic strategy for isoflurane-associated PND.

Identification of Six microRNAs as Potential Biomarkers for Pemphigus Vulgaris: From Diagnosis to Pathogenesis.

BACKGROUND: Pemphigus vulgaris (PV) is a potentially fatal autoimmune bullous disease. The role of microRNA (miRNA, miR) in the diagnosis and pathogenesis of PV remains unknown. This study aims to provide potential miRNA biomarkers for PV diagnosis and therapy options. METHODS: Serum samples were obtained from 22 PV patients, 15 mucous membrane pemphigoid (MMP) patients, and 10 normal controls (NC). Total RNA was extracted from the serum samples, and 12 selected miRNAs were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatic analyses including target gene prediction and enrichment analysis were performed. RESULTS: Twelve miRNAs were increased in the serum of the PV group compared with the NC group, in which six miRNAs had good efficacy to diagnose PV from MMP with the area under the receiver operator characteristic curves of 0.970 to 0.988. A series test for the combination of miR-584-5p and miR-155-5p reached the sensitivity and specificity of 95.5% and 100%. Bioinformatic analysis revealed target gene enrichment in the cell adhesion pathways, immune-relating pathways, and P38 mitogen-activated protein kinases signaling pathway. CONCLUSION: The study provides new insights and targets of miRNAs for the precise diagnosis and the exploration of pathogenesis for PV, which may serve as a reference for further research into autoimmune bullous diseases.