Microbial carbon use efficiency promotes global soil carbon storage.

Soils store more carbon than other terrestrial ecosystems1,2. How soil organic carbon (SOC) forms and persists remains uncertain1,3, which makes it challenging to understand how it will respond to climatic change3,4. It has been suggested that soil microorganisms play an important role in SOC formation, preservation and loss5-7. Although microorganisms affect the accumulation and loss of soil organic matter through many pathways4,6,8-11, microbial carbon use efficiency (CUE) is an integrative metric that can capture the balance of these processes12,13. Although CUE has the potential to act as a predictor of variation in SOC storage, the role of CUE in SOC persistence remains unresolved7,14,15. Here we examine the relationship between CUE and the preservation of SOC, and interactions with climate, vegetation and edaphic properties, using a combination of global-scale datasets, a microbial-process explicit model, data assimilation, deep learning and meta-analysis. We find that CUE is at least four times as important as other evaluated factors, such as carbon input, decomposition or vertical transport, in determining SOC storage and its spatial variation across the globe. In addition, CUE shows a positive correlation with SOC content. Our findings point to microbial CUE as a major determinant of global SOC storage. Understanding the microbial processes underlying CUE and their environmental dependence may help the prediction of SOC feedback to a changing climate.

Neofunctionalization of tandem duplicate genes encoding putative ß-L-arabinofuranosidases in Arabidopsis.

Tandem duplication, one of the major types of duplication, provides the raw material for the evolution of divergent functions. In this study, we identified 1 pair of tandem duplicate genes (AT5G12950 and AT5G12960) in Arabidopsis (Arabidopsis thaliana) that originated within the last 16 million years after the split of Arabidopsis from the Capsella-Boechera ancestor. We systematically used bioinformatic tools to redefine their putative biochemical function as ß-L-arabinofuranosidases that release L-Arabinose from the ß-L-Araf-containing molecules in Arabidopsis. Comprehensive transcriptomic and proteomic analyses using various datasets showed divergent expression patterns among tissues between the 2 duplicate genes. We further collected phenotypic data from 2 types of measurements to indicate that AT5G12950 and AT5G12960 have different roles resulting in divergent phenotypic effects. Overall, AT5G12950 and AT5G12960 represent putative ß-L-arabinofuranosidase encoding genes in Arabidopsis. After duplication, 1 duplicate copy developed diverged biological functions and contributed to a different phenotypic evolution in Arabidopsis.

Convergence in simulating global soil organic carbon by structurally different models after data assimilation.

Current biogeochemical models produce carbon-climate feedback projections with large uncertainties, often attributed to their structural differences when simulating soil organic carbon (SOC) dynamics worldwide. However, choices of model parameter values that quantify the strength and represent properties of different soil carbon cycle processes could also contribute to model simulation uncertainties. Here, we demonstrate the critical role of using common observational data in reducing model uncertainty in estimates of global SOC storage. Two structurally different models featuring distinctive carbon pools, decomposition kinetics, and carbon transfer pathways simulate opposite global SOC distributions with their customary parameter values yet converge to similar results after being informed by the same global SOC database using a data assimilation approach. The converged spatial SOC simulations result from similar simulations in key model components such as carbon transfer efficiency, baseline decomposition rate, and environmental effects on carbon fluxes by these two models after data assimilation. Moreover, data assimilation results suggest equally effective simulations of SOC using models following either first-order or Michaelis-Menten kinetics at the global scale. Nevertheless, a wider range of data with high-quality control and assurance are needed to further constrain SOC dynamics simulations and reduce unconstrained parameters. New sets of data, such as microbial genomics-function relationships, may also suggest novel structures to account for in future model development. Overall, our results highlight the importance of observational data in informing model development and constraining model predictions.

Across-model spread and shrinking in predicting peatland carbon dynamics under global change.

Large across-model spread in simulating land carbon (C) dynamics has been ubiquitously demonstrated in model intercomparison projects (MIPs), and became a major impediment in advancing climate change prediction. Thus, it is imperative to identify underlying sources of the spread. Here, we used a novel matrix approach to analytically pin down the sources of across-model spread in transient peatland C dynamics in response to a factorial combination of two atmospheric CO2 levels and five temperature levels. We developed a matrix-based MIP by converting the C cycle module of eight land models (i.e., TEM, CENTURY4, DALEC2, TECO, FBDC, CASA, CLM4.5 and ORCHIDEE) into eight matrix models. While the model average of ecosystem C storage was comparable to the measurement, the simulation differed largely among models, mainly due to inter-model difference in baseline C residence time. Models generally overestimated net ecosystem production (NEP), with a large spread that was mainly attributed to inter-model difference in environmental scalar. Based on the sources of spreads identified, we sequentially standardized model parameters to shrink simulated ecosystem C storage and NEP to almost none. Models generally captured the observed negative response of NEP to warming, but differed largely in the magnitude of response, due to differences in baseline C residence time and temperature sensitivity of decomposition. While there was a lack of response of NEP to elevated CO2 (eCO2 ) concentrations in the measurements, simulated NEP responded positively to eCO2 concentrations in most models, due to the positive responses of simulated net primary production. Our study used one case study in Minnesota peatland to demonstrate that the sources of across-model spreads in simulating transient C dynamics can be precisely traced to model structures and parameters, regardless of their complexity, given the protocol that all the matrix models were driven by the same gross primary production and environmental variables.

Cuproptosis-Associated lncRNA Gene Signature Establishes New Prognostic Profile and Predicts Immunotherapy Response in Endometrial Carcinoma.

Uterine corpus endometrial carcinoma (UCEC), a prevalent kind of cancerous tumor in female reproductive system that has a dismal prognosis in women worldwide. Given the very limited studies of cuproptosis-related lncRNAs (CRLs) in UCEC. Our purpose was to construct a prognostic profile based on CRLs and explore its assess prognostic value in UCEC victims and its correlation with the immunological microenvironment. METHODS: 554 UCEC tumor samples and 23 normal samples' RNA-seq statistics and clinical details were compiled from data in the TCGA database. CRLs were obtained using Pearson correlation analysis. Using LASSO Cox regression, multivariate Cox regression, and univariate Cox regression analysis, six CRLs are confirmed to develop a risk prediction model at last.We identified two main molecular subtypes and observed that multilayer CRLs modifications were related to patient clinicopathological features, prognosis, and tumor microenvironment (TME) cell infiltration characteristics, and then we verified the prognostic hallmark of UCEC and examined its immunological landscape.Finally, using qRT-PCR, model hub genes' expression patterns were confirmed. RESULTS: A unique CRL signature was established by the combination of six differently expressed CRLs that were highly linked with the prognosis of UCEC patients. According to their CRLs signatures, the patients were divided into two groups: the low-risk and the high-risk groups. Compared to individuals at high risk, patients at low risk had higher survival rates (p < 0.001). Additionally, Cox regression reveals that the profiles of lncRNAs linked to cuproptosis may independently predict prognosis in UCEC patients. The 1-, 3-, and 5-year risks' respective receiver operating characteristics (ROC) exhibited AUC values of 0.778, 0.810, and 0.854. Likewise, the signature could predict survival in different groups based on factors like stage, age, and grade, among others. Further investigation revealed differences between the different risk score groups in terms of drug sensitivity,immune cell infiltration,tumor mutation burden (TMB) score and microsatellite instability (MSI) score. Compared to the group of high risk, the low-risk group had greater rates of TMB and MSI. Results from qRT-PCR revealed that in UCEC vs normal tissues, AC026202.2, NRAV, AC079466.2, and AC090617.5 were upregulated,while LINC01545 and AL450384.1 were downregulated. CONCLUSIONS: Our research clarified the relationship between CRLs signature and the immunological profile and prognosis of UCEC.This signature will establish the framework for future investigations into the endometrial cancer CRLs mechanism as well as the exploitation of new diagnostic tools and new therapeutic.

Melamine Foam-Derived Carbon Scaffold for Dendrite-Free and Stable Zinc Metal Anode.

Aqueous Zn-ion batteries (AZIBs) are one of the most promising large-scale energy storage devices due to the excellent characteristics of zinc metal anode, including high theoretical capacity, high safety and low cost. Nevertheless, the large-scale applications of AZIBs are mainly limited by uncontrollable Zn deposition and notorious Zn dendritic growth, resulting in low plating/stripping coulombic efficiency and unsatisfactory cyclic stability. To address these issues, herein, a carbon foam (CF) was fabricated via melamine-foam carbonization as a scaffold for a dendrite-free and stable Zn anode. Results showed that the abundant zincophilicity functional groups and conductive three-dimensional network of this carbon foam could effectively regulate Zn deposition and alleviate the Zn anode's volume expansion during cycling. Consequently, the symmetric cell with CF@Zn electrode exhibited lower voltage hysteresis (32.4 mV) and longer cycling performance (750 h) than the pure Zn symmetric cell at 1 mA cm-2 and 1 mAh cm-2. Furthermore, the full battery coupling CF@Zn anode with MnO2 cathode can exhibit a higher initial capacity and better cyclic performance than the one with the bare Zn anode. This work brings a new idea for the design of three-dimensional (3D) current collectors for stable zinc metal anode toward high-performance AZIBs.

Identification of a 5-gene-risk score model for predicting luminal A-invasive lobular breast cancer survival.

Breast cancer is a devastating malignancy, among which the luminal A (LumA) breast cancer is the most common subtype. In the present study, we used a comprehensive bioinformatics approach in the hope of identifying novel prognostic biomarkers for LumA breast cancer patients. Transcriptomic profiling of 611 LumA breast cancer patients was downloaded from TCGA database. Differentially expressed genes (DEGs) between tumor samples and controls were first identified by differential expression analysis, before being used for the weighted gene co-expression network analysis. The subsequent univariate Cox regression and LASSO algorithm were used to uncover key prognostic genes for constructing multivariate Cox regression model. Patients were stratified into high-risk and low-risk groups according to the risk score, and subjected to multiple downstream analyses including survival analysis, gene set enrichment analysis (GSEA), inference on immune cell infiltration and analysis of mutation burden. Receiving operator curve analysis was also performed. A total of 7071 DEGs were first identified by edgeR package, pink module was found significantly associated with invasive lobular carcinoma (ILC). 105 prognostic genes and 9 predictors were identified, allowing the identification of a 5-key prognostic genes (LRRC77P, CA3, BAMBI, CABP1, ATP8A2) after intersection. These 5 genes, and the resulting Cox model, displayed good prognostic performance. Furthermore, distinct differences existed between two risk-score stratified groups at various levels. The identified 5-gene prognostic model will help deepen the understanding of the molecular and immunological mechanisms that affect the survival of LumA-ILC patients and guide and proper monitoring of these patients.

Fluorinated Hyaluronic Acid Encapsulated Perfluorocarbon Nanoparticles as Tumor-Targeted Oxygen Carriers to Enhance Radiotherapy.

The efficacy of radiotherapy is significantly constricted by tumor hypoxia. To overcome this obstacle, one promising approach is to use the perfluorocarbon-based O2 carriers combined with hyperoxic respiration to relieve tumor hypoxia. However, this passively transported oxygen carrier during hyperoxic respiration is prone to cause systemic oxidative stress and toxicity, which further limits its clinical application. Herein, we fabricate O2@PFC@FHA NPs for safe and specific oxygen delivery into tumors by using the fluorinated hyaluronic acid to encapsulate O2-saturated perfluorocarbon. Due to the interaction between HA and CD44 receptors, more FHA@PFC NPs accumulated in the tumor and the O2@PFC@FHA NPs significantly relieved tumor hypoxia. Notably, RT plus O2@PFC@FHA NPs resulted in almost threefold therapeutic improvement compared with RT without obvious systemic toxicity. Therefore, the O2@FHA@PFC NPs may have great potential to enhance the therapeutic efficacy of radiotherapy in the clinic.

Association between serum vitamin D levels and visceral adipose tissue among adolescents: a cross-sectional observational study in NHANES 2011-2015.

BACKGROUND: In recent years, obesity and vitamin D deficiency are more prevalent among adolescents. Improving our knowledge of the link between vitamin D and visceral adipose tissue (VAT) is essential for the health of adolescents. This study aimed to examine the connection between serum vitamin D levels and VAT mass among adolescents participating in the United States. METHODS: This is a cross-sectional study that used data from the 2011 to 2015 National Health and Nutrition Examination Survey (NHANES). The connection between serum vitamin D levels and VAT was investigated using weighted multiple linear regression models. Potential nonlinear relationships were explored using smooth curve fitting. RESULTS: The analysis included 3171 adolescents aged 12-19 years. Vitamin D levels were shown to be inversely linked with VAT in the full-adjusted model (ß = - 0.34, 95% CI: - 0.49 to - 0.19). When stratified analyses by gender, this negative relationship persisted in the girls' group (ß = - 0.39, 95% CI: - 0.60 to - 0.19), but not in the boys' group (ß = - 0.06, 95% CI: - 0.25 to 0.13). When stratified analysis by race, this negative relationship persisted in the Mexican American group (ß = - 0.61, 95% CI: - 1.03 to - 0.19), and the non-Hispanic White group (ß = - 0.27, 95% CI: - 0.54 to - 0.01), but not in the other groups. CONCLUSIONS: Our findings confirmed that serum vitamin D levels negatively correlated with VAT among adolescents in the United State, especially in girls, the Mexican American and non-Hispanic White. Further research is needed to determine whether increasing serum vitamin D levels decrease VAT among adolescents.

Clinical application of metagenomic next-generation sequencing technology in the diagnosis and treatment of pulmonary infection pathogens: A prospective single-center study of 138 patients.

INTRODUCTION: Rapid and accurate pathogen identification is essential for the treatment of pneumonia. Metagenomic next-generation sequencing (mNGS) is a newly developed technology to obtain microbial nucleic acid sequence information quickly, efficiently, and without bias. METHODS: We performed shotgun metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF) for pathogen identification in pneumonia in a prospective study with 138 patients from a single center. We compared the results of mNGS with standard methods including culture, staining, and targeted PCR and evaluated the clinical applicability of mNGS. RESULTS: Most of the patients (128/138, 92.75%) were cured or improved. One patient (1/138, 0.72%) died because of acute gastrointestinal bleeding, and 9 patients (9/138, 6.52%) showed no improvement. mNGS identified more bacteria (53 versus 27), fewer fungi (8 versus 31), and more viruses (16 versus 1) than standard methods. In total, treatment in 34 out of 138 cases (24.64%) was adjusted and optimized because of mNGS results. Positive mNGS results contributed to a definitive diagnosis in 23 cases (16.67%), which helped guide treatment decision by either adjusting the antibiotics without de-escalation or continuing the empirical treatment. mNGS also confirmed no active infection in 11 cases (7.97%) allowed for antibiotic de-escalation. CONCLUSION: This prospective clinical study evaluated the clinical utility of mNGS for the diagnosis of pneumonia and showed that mNGS of BALF provides valuable information for effective treatment.

Rare variation: the absence of both the celiac trunk artery and the common hepatic artery.

BACKGROUND: Knowledge of celiac trunk anatomy is important in gastrointestinal surgery, hepatopancreatobiliary surgery, transplantation and interventional radiology. Variations in the celiac trunk are common and should be predicted prior to these interventions. METHODS: A 58-year-old woman was admitted to our department for surgical treatment of gastric cancer (GC) confirmed by gastroduodenoscopy and gastric antrum biopsy. In the contrast-enhanced computed tomography (CT), we found an absence of both the celiac trunk artery (CA) and the common hepatic artery (CHA). Therefore, we used computerized three-dimensional (3D) vascular reconstruction technology to reconstruct the abdominal trunk and its branch vessels before operation. RESULTS: Computerized 3D vascular reconstruction confirmed an extremely rare vascular anomaly: the absence of both CA and CHA. The splenic artery (SA) and gastroduodenal artery (GDA) originated from the abdominal aorta (AA). The left gastric artery (LGA) originated from the AA directly above the junction of SA and the GDA. The left hepatic artery (LHA) originated from the left gastric artery (LGA). The right hepatic artery (RHA) originated from the superior mesenteric artery (SMA). Laparoscopic radical resection of GC was performed. This anomaly was also confirmed intraoperatively. This patient was discharged on the 10th day after surgery without any postoperative complication. There were no signs of tumor recurrence during the 6-month follow-up. CONCLUSION: Correct identification of abnormal abdominal large blood vessels and their relationship with tumors before surgery is of great significance to avoid intraoperative blood vessel damage, major postoperative complications and the missing of lymph node dissection.

CircRNA_0043691 sponges miR-873-3p to promote metastasis of gastric cancer.

Circular RNAs (circRNAs) are a class of novel RNAs, and aberrant expression of circRNAs has been implicated in human diseases, including gastric cancer (GC). This study aimed to identify the mechanism of circRNA_0043691 in regulating the progression of GC. GSE141977 was downloaded from Gene Expression Omibus ( http://www.ncbi.nlm.nih.gov/geo/ ). Differentially expressed circRNAs were obtained by R software. The expression levels of circRNA_0043691 in GC tissue and normal tissue were identified by quantitative real-time polymerase chain reaction (qRT-PCR). Knockdown of circRNA_0043691 was then constructed and verified by qRT-PCR. Cell viability, migration, and invasion capacity were determined by Cell Counting Kit-8 assay, Transwell migration, and invasion, respectively. Next, knockdown of miR-873-3p was constructed and co-cultured with circRNA_0043691 knockdown to identify whether knockdown of miR-873-3p could attenuate the circRNA_0043691 knockdown on GC cells proliferation, migration, and invasion. The relationship between miR-873-3p and circRNA_0043691 or GART was predicted by bioinformatics tools and verified by dual-luciferase reporter. A total of 211 circRNAs were significantly differentially expressed, including 143 remarkably downregulated circRNAs and 68 significantly upregulated circRNAs. CircRNA_0043691 was upregulated in GC tissue. Knockdown of circRNA_0043691 decreased cell viability, migration, and invasion in GC cells. CircRNA_0043691 has potential putative binding sites with miR-873-3p. Moreover, CircRNA_0043691 positively regulated GART expression by sponging miR-873-3p. Furthermore, knockdown of miR-591 could partially attenuate the si-circRNA_0043691 on the GART expression. GART was upregulated in GC tissue and knockdown of GART could inhibit GC cells proliferation and invasion. Knockdown of circRNA_0043691 delayed the progression of GC via modulating the miR-873-3p-GART axis.

A strangulated internal hernia beneath the left external iliac artery after radical hysterectomy with laparoscopic pelvic lymphadenectomy: a case report and literature review.

BACKGROUND: Ileum obstruction due to internal hernia beneath external iliac artery after pelvic lymph node dissection (PLND) is extremely rare. We reported a case of acute strangulated internal hernia between the left external iliac artery and psoas major as late complication of laparoscopic hysterectomy with pelvic lymphadenectomy. CASE PRESENTATION: A 46-year-old woman, who with histories of laparoscopic hysterectomy, bilateral salpingo-oophorectomy and PLND 9 years ago for the cervical malignant tumor, open appendectomy 18 years ago, visited our hospital complaining of aggravated left lower abdominal pain, bloating, nausea and vomiting from few hours ago. Left abdomen distention, tympanitic with rebound tenderness and muscular tension was detected during physical examinations. Accompanying with elevated inflammatory markers and mild intestinal dilatation showed in lab results and contrast-enhanced computed tomography (CT) respectively. After carefully reading the CT images, a small bowel was found between the left external iliac artery (EIA) and the psoas major, combined with the patient's surgical history, we suspected it might be internal hernia. Eventually, the emergency laparoscopic laparotomy confirmed our conjecture, the gap between the iliac vessels and the psoas major was closed with an absorbable suture, the patient was discharged on the fourth postoperative day. CONCLUSION: Primary closure of peritoneal fissue maybe an effective measure to potentially prevent internal hernia. The choice of surgical approach for pelvic tumors still needs further exploration but faster diagnosis and immediate laparotomy might promise a better prognosis.

Graph Based Multi-Layer K-Means++ (G-MLKM) for Sensory Pattern Analysis in Constrained Spaces.

In this paper, we focus on developing a novel unsupervised machine learning algorithm, named graph based multi-layer k-means++ (G-MLKM), to solve the data-target association problem when targets move on a constrained space and minimal information of the targets can be obtained by sensors. Instead of employing the traditional data-target association methods that are based on statistical probabilities, the G-MLKM solves the problem via data clustering. We first develop the multi-layer k-means++ (MLKM) method for data-target association at a local space given a simplified constrained space situation. Then a p-dual graph is proposed to represent the general constrained space when local spaces are interconnected. Based on the p-dual graph and graph theory, we then generalize MLKM to G-MLKM by first understanding local data-target association, extracting cross-local data-target association mathematically, and then analyzing the data association at intersections of that space. To exclude potential data-target association errors that disobey physical rules, we also develop error correction mechanisms to further improve the accuracy. Numerous simulation examples are conducted to demonstrate the performance of G-MLKM, which yields an average data-target association accuracy of 92.2%.

Driving GABAergic neurons optogenetically improves learning, reduces amyloid load and enhances autophagy in a mouse model of Alzheimer's disease.

The changes of local field potentials (LFP, mainly gamma rhythm and theta rhythm) in the brain are closely related to learning and memory formation. Reduced gamma rhythm (20-50 Hz) and theta rhythm (4-10 Hz) has been observed in the progression of Alzheimer's disease (AD), but it is not clear whether it is related to cognition in AD. Here, we investigated behaviorally driven gamma rhythm and theta rhythm in APP/PS1 mice, and optogenetically stimulated GABAergic neurons in the brain to better understand the relationship between the changes of LFP, cognition, and cellular pathologies. Optogenetically driving GABAergic neurons rescued memory formation in a water maze task and normalized theta and gamma rhythm in the EEG. Furthermore, the optogenetic stimulation alleviated neuroinflammation and levels of amyloid-ß (Aß)1-42 fragments, and induced autophagy. GABA blockers also reversed the normalization of theta and gamma rhythms in the brain by optogenetic stimulation. The results demonstrate that stimulation of GABAergic interneurons not only rescues LFP rhythms and memory formation, but furthermore activates autophagy and reduces neuroinflammation, which have beneficial additional effects such as clearing amyloid. This is a proof of concept for a novel therapeutic approach to AD treatment.

Resveratrol alleviates temporomandibular joint inflammatory pain by recovering disturbed gut microbiota.

Patients with temporomandibular disorders (TMDs) often experience persistent facial pain. However, the treatment of TMD pain is still inadequate. In recent years, the disturbance of gut microbiota has been shown to play an important role in the pathogenesis of different neurological diseases including chronic pain. In the present study, we investigated the involvement of gut microbiota in the development of temporomandibular joint (TMJ) inflammation. Intra-temporomandibular joint injection of complete Freund's adjuvant (CFA) was employed to induce TMJ inflammation. Resveratrol (RSV), a natural bioactive compound with anti-inflammatory property, was used to treat the CFA-induced TMJ inflammation. We observed that CFA injection not only induces persistent joint pain, but also causes the reduction of short-chain fatty acids (SCFAs, including acetic acid, propionic acid and butyric acid) in the gut as well as decreases relevant gut bacteria Bacteroidetes and Lachnospiraceae. Interestingly, systemic administration of RSV (i.p.) dose-dependently inhibits CFA-induced TMJ inflammation, reverses CFA-caused reduction of SCFAs and these gut bacteria. Moreover, CFA injection causes blood-brain barrier (BBB) leakage, activates microglia and enhances tumor necrosis factor alpha (TNFα) release in the spinal trigeminal nucleus caudalis (Sp5C). The RSV treatment restores the BBB integrity, inhibits microglial activation and decreases the release of TNFα in the Sp5C. Furthermore, fecal microbiota transplantation with feces from RSV-treated mice significantly diminishes the CFA-induced TMJ inflammation. Taken together, our results suggest that gut microbiome perturbation is critical for the development of TMJ inflammation and that recovering gut microbiome to normal levels could be a new therapeutic approach for treating such pain.

Anti-inflammatory effects of doxepin hydrochloride against LPS-induced C6-glioma cell inflammatory reaction by PI3K-mediated Akt signaling.

Recent studies have shown that tricyclic antidepressants (TCAs) may have anti-inflammatory and anticonvulsant effects in addition to its antidepressant effects. So far, the nonantidepressant effects of TCAs and their molecular pharmacological mechanisms remain completely unclear. Chronic inflammation in the brain parenchyma may be related to the pathogenesis and progression of various neurodegenerative diseases. As a common antidepressant and anti-insomnia drug, doxepin also may be a potential anti-inflammatory and anticonvulsant drug, so the study on the anti-inflammatory protective effect of doxepin and its molecular mechanism has become a very important issue in pharmacology and clinical medicine. Further elucidating the anti-inflammatory and neuroprotective effects of doxepin and its molecular mechanism may provide the important theoretical and clinical basis for the prevention and treatment of neurodegenerative disease. This study was designed to understand the glio-protective mechanism of doxepin against the inflammatory damage induced by lipopolysaccharide (LPS) exposure in C6-glioma cells. We found the treatment of C6-glioma cells with LPS results in deleterious effects, including the augmentation of inflammatory cytokine levels (tumor necrosis factor-α, interleukin-1ß), and suppresses the Akt phosphorylation. Furthermore, our outcomes demonstrated that doxepin was able to suppress these effects induced by LPS, through activation of the phosphatidylinositol-3-kinase-mediated protein kinase B (Akt) pathway. To sum up, these results highlight the potential role of doxepin against neuroinflammatory-related disease in the brain.

Therapeutic Effects of SRT2104 on Lung Injury in Rats with Emphysema via Reduction of Type II Alveolar Epithelial Cell Senescence.

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent and severe diseases worldwide with high societal and health care costs. The pathogenesis of COPD is very complicated, and no curative treatment is available. Cellular senescence promotes the development of COPD. Type II alveolar epithelial cells (AECII) play a momentous role in lung tissue repair and maintenance of alveolar homeostasis. Sirtuin 1 (SIRT1), an antiaging molecule involved in the response to chronic inflammation and oxidative stress, regulates many pathophysiological changes including stress resistance, apoptosis, inflammation, and cellular senescence. This study aimed to investigate whether the pharmacological SIRT1 activator SRT2104 protects against AECII senescence in rats with emphysema. Our findings confirmed that SRT2104 administration reduced the pathological characteristics of emphysema and improved lung function parameters, including pulmonary resistance, pulmonary dynamic compliance, and peak expiratory flow. Moreover, SRT2104 treatment upregulated the expression of surfactant proteins A and C, SIRT1, and forkhead box O 3a (FoxO3a), decreased senescence-associated-ß-galactosidase (SA-ß-gal) activity, increased SIRT1 deacetylase activity, and downregulated the levels of p53 and p21. Therefore, SRT2104 administration protected against AECII senescence in rats with emphysema via SIRT1/FoxO3a and SIRT1/p53 signaling pathways and may provide a novel potential therapeutic strategy for COPD.

A Pre-Existing Myogenic Temporomandibular Disorder Increases Trigeminal Calcitonin Gene-Related Peptide and Enhances Nitroglycerin-Induced Hypersensitivity in Mice.

Migraine is commonly reported among patients with temporomandibular disorders (TMDs), especially myogenic TMD. The pathophysiologic mechanisms related to the comorbidity of the two conditions remain elusive. In the present study, we combined masseter muscle tendon ligation (MMTL)-produced myogenic TMD with systemic injection of nitroglycerin (NTG)-induced migraine-like hypersensitivity in mice. Facial mechanical allodynia, functional allodynia, and light-aversive behavior were evaluated. Sumatriptan, an FDA-approved medication for migraine, was used to validate migraine-like hypersensitivity. Additionally, we examined the protein level of calcitonin gene-related peptide (CGRP) in the spinal trigeminal nucleus caudalis using immunohistochemistry. We observed that mice with MMTL pretreatment have a prolonged NTG-induced migraine-like hypersensitivity, and MMTL also enabled a non-sensitizing dose of NTG to trigger migraine-like hypersensitivity. Systemic injection of sumatriptan inhibited the MMTL-enhanced migraine-like hypersensitivity. MMTL pretreatment significantly upregulated the protein level of CGRP in the spinal trigeminal nucleus caudalis after NTG injection. Our results indicate that a pre-existing myogenic TMD can upregulate NTG-induced trigeminal CGRP and enhance migraine-like hypersensitivity.