Increased SERPINB2 potentiates 15LO1 expression via STAT6 signalling in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps.

BACKGROUND: SERPINB2, a biomarker of Type-2 (T2) inflammatory processes, has been described in the context of asthma. Chronic rhinosinusitis with nasal polyps (CRSwNP) is also correlated with T2 inflammation and elevated 15LO1 induced by IL-4/13 in nasal epithelial cells. The aim of this study was to evaluate the expression and location of SERPINB2 in nasal epithelial cells (NECs) and determine whether SERPINB2 regulates 15LO1 and downstream T2 markers in NECs via STAT6 signalling. METHODS: SERPINB2 gene expression in bulk and single-cell RNAseq database was analysed by bioinformatics analysis. SERPINB2, 15LO1 and other T2 markers were evaluated from CRSwNP and HCs NECs. The colocalization of SERPINB2 and 15LO1 was evaluated by immunofluorescence. Fresh NECs were cultured at an air-liquid interface with or without IL-13, SERPINB2 Dicer-substrate short interfering RNAs (DsiRNAs) transfection, exogenous SERPINB2, 15-HETE recombinant protein and pSTAT6 inhibitors. 15LO1, 15-HETE and downstream T2 markers were analysed by qRT-PCR, western blot and ELISA. RESULTS: SERPINB2 expression was increased in eosinophilic nasal polyps compared with that in noneosinophilic nasal polyps and control tissues and positively correlated with 15LO1 and other downstream T2 markers. SERPINB2 was predominantly expressed by epithelial cells in NP tissue and was colocalized with 15LO1. In primary NECs in vitro, SERPINB2 expression was induced by IL-13. Knockdown or overexpression SERPINB2 decreased or enhanced expression of 15LO1 and 15-HETE in NECs, respectively, in a STAT6-dependent manner. SERPINB2 siRNA also inhibited the expression of the 15LO1 downstream genes, such as CCL26, POSTN and NOS2. STAT6 inhibition similarly decreased SERPINB2-induced 15LO1. CONCLUSIONS: SERPINB2 is increased in NP epithelial cells of eosinophilic CRSwNP (eCRSwNP) and contributes to T2 inflammation via STAT6 signalling. SERPINB2 could be considered a novel therapeutic target for eCRSwNP.

Impact of tumor size on overall survival and cancer-specific survival of early-onset colon and rectal cancer: a retrospective cohort study.

PURPOSE: This study aimed to investigate the impact of tumor size on survival in early-onset colon and rectal cancer. METHODS: Early-onset colon and rectal cancer patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. Tumor size was analyzed as both continuous and categorical variables. Several statistical techniques, including restricted cubic spline (RCS), Cox proportional hazard model, subgroup analysis, propensity score matching (PSM), and Kaplan-Meier survival analysis, were employed to demonstrate the association between tumor size and overall survival (OS) and cancer-specific survival (CSS) of early-onset colon and rectal cancer. RESULTS: Seventeen thousand five hundred fifty-one (76.7%) early-onset colon and 5323 (23.3%) rectal cancer patients were included. RCS analysis confirmed a linear association between tumor size and survival. Patients with a tumor size > 5 cm had worse OS and CSS, compared to those with a tumor size ≤ 5 cm for both early-onset colon and rectal cancer. Notably, subgroup analysis showed that a smaller tumor size (≤ 50 mm) was associated with worse survival in stage II early-onset colon cancer, although not statistically significant. After PSM, Kaplan-Meier survival curves showed that the survival of patients with tumor size ≤ 50 mm was better than that of patients with tumor size > 50 mm. CONCLUSION: Patients with tumors larger than 5 cm were associated with worse survival in early-onset colon and rectal cancer. However, smaller tumor size may indicate a more biologically aggressive phenotype, correlating with poorer survival in stage II early-onset colon cancer.

Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment.

Epilepsy is a prevalent neurological disorder characterized by unprovoked seizures. γ-Aminobutyric acid (GABA) serves as the primary fast inhibitory neurotransmitter in the brain, and GABA binding to the GABAA receptor (GABAAR) regulates Cl- and bicarbonate (HCO3-) influx or efflux through the channel pore, leading to GABAergic inhibition or excitation, respectively. The neuron-specific K+-Cl- cotransporter 2 (KCC2) is essential for maintaining a low intracellular Cl- concentration, ensuring GABAAR-mediated inhibition. Impaired KCC2 function results in GABAergic excitation associated with epileptic activity. Loss-of-function mutations and altered expression of KCC2 lead to elevated [Cl-]i and compromised synaptic inhibition, contributing to epilepsy pathogenesis in human patients. KCC2 antagonism studies demonstrate the necessity of limiting neuronal hyperexcitability within the brain, as reduced KCC2 functioning leads to seizure activity. Strategies focusing on direct (enhancing KCC2 activation) and indirect KCC2 modulation (altering KCC2 phosphorylation and transcription) have proven effective in attenuating seizure severity and exhibiting anti-convulsant properties. These findings highlight KCC2 as a promising therapeutic target for treating epilepsy. Recent advances in understanding KCC2 regulatory mechanisms, particularly via signaling pathways such as WNK, PKC, BDNF, and its receptor TrkB, have led to the discovery of novel small molecules that modulate KCC2. Inhibiting WNK kinase or utilizing newly discovered KCC2 agonists has demonstrated KCC2 activation and seizure attenuation in animal models. This review discusses the role of KCC2 in epilepsy and evaluates its potential as a drug target for epilepsy treatment by exploring various strategies to regulate KCC2 activity.

Impact of varying dissolved organic carbon load on sediment phosphorus release and its periodic mechanisms.

Phosphorus (P) release from sediment poses a severe challenge for eutrophication management in the aquatic environment. The dissolved organic carbon (DOC) concentrations in riverine ecosystems have shown an increasing trend due to intensified climate change and anthropogenic activities, while their impact on sediment P cycling remains unclear. To investigate the effects of different DOC loads on sediment P release and the underlying mechanisms, we conducted a two-month experiment in 15 plexiglass tanks, with five gradient-increasing target DOC concentrations set according to reality: control (S0), 5 mg/L (S5), 10 mg/L (S10), 15 mg/L (S15), and 20 mg/L (S20). The results demonstrated that: i) DOC enrichment promoted the sediment P mobilization and release, with the underlying mechanisms exhibited periodic characteristics. ii) reduced dissolved oxygen (DO) concentration and stimulated alkaline phosphatase activity (APA) were likely the primary and sustained facilitating mechanisms. While after the termination of DOC load, elevated pH level was also considered a contributing factor when chlorophyll a (Chl a) ranged between 5.9 µg/L and 7.7 µg/L iii) ultimate concentration of total P (TP) in the overlying water depended on DOC load. After DOC addition was terminated, decreased TP concentrations were observed when DOC concentration was in the range of 5-15 mg/L, which may be attributed to the direct uptake of P by phytoplankton counteracting the minor promotion of P release induced by anoxic conditions. However, when DOC concentrations exceeded 15-20 mg/L, there were notable increments in TP concentrations. Our findings provide further insight into the response mechanisms of sediment P release to the increasing organic C load in natural ecosystems. The impact of broader C forms or C loads on sediment P cycling needs to be fully elucidated and even quantified in future studies, especially through large-scale field investigations to further clarify the coupled roles between C and P.

Increased CYR61 expression activates CCND1/c-Myc pathway to promote nasal epithelial cells proliferation in chronic rhinosinusitis with nasal polyps.

PURPOSE: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is a chronic sinonasal inflammatory disease characterized histologically by hyperplastic nasal epithelium and epithelial cells proliferation. Cysteine-rich angiogenic inducer 61 (CYR61) acts as a positive regulator of cell cycle process. Cyclin D1 (CCND1) and c-Myc play key roles in the processes of cell cycle and cell growth. The purpose of our research was to explore the expression and roles of CYR61, CCND1 and c-Myc in CRSwNP. METHODS: FeaturePlot and vlnPlot functions embedded in the seurat package (version 4.1.1) of R software (version 4.2.0) were applied to explore the cellular distribution of CYR61, CCND1 and c-Myc in the single-cell RNA sequencing (scRNA-seq) dataset of nasal tissue samples. CYR61, CCND1 and c-Myc immunolabeling and mRNA levels in nasal tissue samples were assessed by immunohistochemistry and real-time PCR. Co-localization of CYR61, CCND1 and c-Myc with basal epithelial cell marker P63 was assayed using double-label immunofluorescence staining. Furthermore, we collected and cultured human nasal epithelial cells (HNEC) to assess the regulation and role of CYR61 in vitro study. RESULTS: CYR61, CCND1 and c-Myc were primarily expressed by nasal epithelial cells. Significant upregulation of CYR61, CCND1 and c-Myc positive cells and increased levels of CYR61, CCND1 and c-Myc mRNA were found in nasal polyps in comparison to control samples. Of note, CYR61 mRNA and protein levels were altered by SEB, LPS, IFN-γ, IL-13, IL-17A and TGF-ß1 in HNEC. In addition, CYR61 intervention could increase CCND1 and c-Myc mRNA and protein levels to promote HNEC proliferation, and siRNA against ITGA2 (si-ITGA2) could reverse CYR61 induced upregulation of CCND1 and c-Myc mRNA and protein levels in HNEC and cell proliferation of HNEC. CONCLUSIONS: CYR61, CCND1 and c-Myc were primarily expressed by epithelial cells in nasal mucosa. CYR61, CCND1 and c-Myc expression levels were increased in CRSwNP compared with controls. CYR61 could interact with ITGA2 to enhance HNEC proliferation via upregulating CCND1 and c-Myc levels in the HNEC, leading to hyperplastic nasal epithelium in CRSwNP.

Escherichia coli infection mediates pyroptosis via activating p53-p21 pathway-regulated apoptosis and cell cycle arrest in bovine mammary epithelial cells.

Escherichia coli (E. coli) is a major environmental pathogen that causes mammary tissue damage and cell death, which results in substantial economic losses. Pyroptosis, a novel form of programmed cell death characterized by DNA fragmentation, chromatin condensation, cell swelling and leakage of cell contents, often occurs after inflammatory apoptotic pathways activation. Our objective was to investigate the intraction between E. coli infection and bovine mammary epithelial cells (bMECs) with pyroptosis and to explore the underlying regulatory mechanism. bMECs were infected with E. coli for 6 h. Lactic dehydrogenase activities, interleukin (IL)-10, IL-1ß, IL-18 and tumor necrosis factor-α concentrations, total apoptosis indexes, and protein expressions of P-cdc25c, P-CDK1, cleaved caspase 9, cleaved caspase 3, cleaved PARP, P-NF-κB, NLRP3, ASC, caspase 1, gasdermin D N-terminal, IL-1ß and IL-18 were significantly increased in E. coli infected bMECs. Whereas, cell membrane potential, protein levels of cdc25c, CDK1, cyclin B1, and Bcl-2/Bax level were markedly reduced. Furthermore, Ac-DEVD-CHO (specific inhibitor of apoptosis) dramatically suppressed pyroptosis in bMECs. Moreover, expressions of p53 and p21 promptly improved after E. coli infection, however, Pifithrin-α (specific inhibitor of p53) inhibited p53-p21 pathway, apoptosis, cell cycle arrest and pyroptosis. These results elaborated that E. coli infection of bMECs induced pyroptosis through activating the p53-p21 pathway-mediated apoptosis and cell cycle arrest. Taken together, inhibition of pyroptosis via suppressing of p53-p21 pathway may be an effective therapeutic approach for treating E. coli-induced mastitis, offering efficient theoretical support for the protection and treatment of bovine mastitis.

Changes in Resting-State Neural Activity and Nerve Fibres in Ischaemic Stroke Patients with Hemiplegia.

Many neuroimaging studies have reported that stroke induces abnormal brain activity. However, little is known about resting-state networks (RSNs) and the corresponding white matter changes in stroke patients with hemiplegia. Here, we utilized functional magnetic resonance imaging (fMRI) to measure neural activity and related fibre tracts in 14 ischaemic stroke patients with hemiplegia and 12 healthy controls. Fractional amplitude of low-frequency fluctuations (fALFF) calculation and correlation analyses were used to assess the relationship between regional neural activity and movement scores. Tractography was performed using diffusion tensor imaging (DTI) data to analyse the fibres passing through the regions of interest. Compared with controls, stroke patients showed abnormal functional connectivity (FC) between some brain regions in the RSNs. The fALFF was increased in the contralesional parietal lobe, with the regional fALFF being correlated with behavioural scores in stroke patients. Additionally, the passage of fibres across regions with reduced FC in the RSNs was increased in stroke patients. This study suggests that structural remodelling of functionally relevant white matter tracts is probably an adaptive response that compensates for injury to the brain.

Identification and validation of a pyroptosis-related prognostic model for colorectal cancer.

In this study, we explored the pyroptosis-related biomarkers and signatures of colorectal cancer (CRC). Gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA)-COADREAD and were analyzed for differentially expressed genes (DEGs). DEGs in CRC‒pyroptosis-related genes (CRC‒PRGs) were obtained by intersecting DEGs associated with CRC and PRGs. The CRC‒PRGs were verified; functional enrichment analysis was performed with Gene Ontology (GO) followed by cluster analysis. Cox analyses and LASSO regression were used in TCGA dataset to construct a prognostic model for patients with CRC. A prognostic risk assessment model was constructed and efficacy was evaluated. Decision curve analysis was utilized to assess the role of the Lasso-Cox regression prognostic model for clinical utility at 1, 3, and 5 years. Twelve CRC‒PRGs were identified as prognostic pyroptosis-related DEGs. CXCL8, IL13RA2, MELK, and POP1 were selected as prognostic genes to construct features with a good prognostic performance in GEO and TCGA. Functional enrichment indicated that the 4-gene signature might be involved in CRC tumorigenesis and development through various pathways by playing a prognostic role in CRC. Furthermore, the results of the immune landscape analysis showed that the expression of CXCL8 and IL13RA2 in TCGA-COADREAD dataset was positively correlated with significant differential enrichment of most immune cells. A novel prognostic model consisting of four key genes, CXCL8, IL13RA2, MELK, and POP1, can accurately predict the survival of patients with CRC. This finding may provide a new perspective for the treatment of pyroptosis-related CRC.

The Use of Exercise Challenge Testing and Fractional Exhaled Nitric Oxide in Diagnosis of Chest Tightness Variant Asthma in Children.

BACKGROUND: Chest tightness variant asthma (CTVA) in children presents with chest tightness as the sole manifestation. Diagnostic tests are needed given the lack of typical asthma symptoms. The present study aimed to investigate the diagnostic value of exercise challenge testing (ECT) and fractional exhaled nitric oxide (FeNO) in pediatric CTVA. METHODS: We included 98 children aged 6-13 years with chest tightness as the sole symptom for >4 weeks. All subjects underwent FeNO measurement, spirometry and ECT, and received 4-week budesonide/formoterol treatment. According to treatment responses, children were categorized into CTVA (n = 12) and non-CTVA (n = 86) groups. Differences in clinical characteristics and FeNO, spirometry, and ECT results were compared between the two groups. The FeNO and ECT diagnostic performances were determined using receiver operating characteristic (ROC) curve analysis. RESULTS: Children with CTVA exhibited significantly higher Mycoplasma pneumoniae IgG, total IgE, and FeNO values; greater post-ECT forced expiratory volume in 1 s (FEV1) fall; and more frequent sensitization to mites and pets than those without CTVA. Further logistic regression revealed that higher FEV1 fall (OR, 1.39; 95% CI: 1.11-1.74; p = 0.004) and higher FeNO values (OR, 1.04; 95% CI: 1.01-1.08; p = 0.014) were risk factors associated with CTVA. FEV1 fall and FeNO had similar areas under the ROC curve (AUCs) (0.79 vs. 0.78; p = 0.924), and their optimal CTVA-prediction cutoff values were 9.9% and 15.0 ppb, respectively. The AUC of FEV1 fall and FeNO combination was higher at 0.86 (95% CI: 0.78-0.93); however, no difference was observed using the single test (p > 0.05). Their combination exhibited a relatively higher sensitivity than that of FEV1 fall alone (0.75 vs. 0.67) and higher positive predictive value than that of FeNO alone (0.60 vs. 0.29). CONCLUSION: CTVA is a cause of unexplained recurrent chest tightness in children. FeNO ≥15.0 ppb and post-ECT FEV1 fall ≥9.9% are diagnostically valuable for CTVA in children, with their combination potentially contributing to greater diagnostic accuracy.

Study on the Baseline Factors and Platelet Indices That Predict Outcome of Acute Ischemic Stroke Patients after Thrombolytic Therapy.

BACKGROUND: The aim of the study was to investigate the baseline characters that influence 3-month clinical outcomes in patients with acute ischemic stroke (AIS) after thrombolytic therapy. METHODS: We consecutively enrolled 241 AIS patients who are treated with thrombolytic therapy with recombinant tissue plasminogen activator. Baseline characters were measured on admission including the National Institutes of Health Stroke Scale (NIHSS), Trial of Org 10172 in Acute Stroke Treatment (TOAST), risk factors, platelet indices, and lipid parameters. The subjects were divided into good or poor functional outcomes based on modified Rankin Scale at 3 months. The multivariate logistic regression was performed to explore the association between baseline factors and outcomes. Pearson correlation was used to investigate whether linear associations existed between platelet indices in different outcomes. RESULTS: Multivariate logistic regression analysis showed that the NIHSS, TOAST classification, diabetes, mean platelet volume (MPV) are important factors for predicting clinical outcomes after 3 months in AIS patients. We found a correlation between elevated MPV and worse outcome at 3 months, particularly in large-artery atherosclerosis stroke patients. MPV and platelet count are negative correlated (r = -0.375, p = 0.000). MPV and platelet-to-lymphocyte ratio (PLR) (r = 0.83, p = 0.000), MPV and platelet distribution width (PDW) (r = 0.820, p = 0.000) both have highly positive linear correlations in patients with good outcome. CONCLUSIONS: Overall, lower NIHSS and MPV levels on admission were predictors of good functional outcomes in patients with AIS after undergoing thrombolytic therapy. The correlations between MPV, PDW, and PLR may be helpful to evaluate prognosis in stroke patients and deserve further exploration.

Hops extract and xanthohumol ameliorate bone loss induced by iron overload via activating Akt/GSK3ß/Nrf2 pathway.

INTRODUCTION: Osteoporosis is closely related to iron metabolism. This study aimed to investigate whether hops extract (HLE) and its active component xanthohumol (XAN) could ameliorate bone loss caused by iron overload, and explored its potential mechanism. MATERIALS AND METHODS: Iron overload mice induced by iron dextran (ID) were used in vivo, and were treated with HLE and XAN for 3 months. Bone micro-structure and bone morphology parameters were determined by Micro-CT and TRAP staining. Bone metabolism markers and oxidation indexes in serum and bone tissue were evaluated. For in vitro experiment, bone formation indexes were determined. Moreover, the expression of key proteins in protein kinase B (Akt)/glycogen synthetase kinase 3ß (GSK3ß)/nuclear factor E2-related (Nrf2) pathway was evaluated by Western blotting. RESULTS: HLE and XAN effectively improved the bone micro-structure of the femur in mice, altered bone metabolism biomarkers, and regulated the expression of proteins related to bone metabolism. Additionally, they significantly promoted cell proliferation, runt-related gene 2 (Runx2) expression, and increased ALP activity in ID-induced osteoblasts. Moreover, HLE and XAN markedly inhibited the increase of oxidative stress caused by iron overload in vivo and in vitro. Further studies showed that they significantly up-regulated the expression of p-Akt, p-GSK3ß, nuclear-Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1) in ID-induced osteoblasts. CONCLUSION: These findings indicated hops and xanthohumol could ameliorate bone loss induced by iron overload via activating Akt/GSK3ß/Nrf2 pathway, which brought up a novel sight for senile osteoporosis therapy.

N200 and P300 component changes in Parkinson's disease: a meta-analysis.

BACKGROUND: Cognitive impairment can seriously affect the quality of life of Parkinson's disease (PD) patients. Although numerous studies showed that N200, P300 latency and amplitude are correlated with cognitive functions, there is a sufficient amount of controversial results. Therefore, it is necessary to conduct a meta-analysis of N200, P300 latency and amplitude data of event-related potential (ERP) in PD. METHODS: We systematically searched on PubMed and Web of Science for PD-related ERP studies published before December 2021. Standard mean difference (SMD) and 95% confidence interval (CI) estimates of N200 and P300 components were compared among PD patients, PD dementia (PDD) patients, PD non-dementia (PDND) patient, and healthy control (HC). RESULTS: Our meta-analysis showed prolonged N200 latency at the Fz, Cz electrode sites, prolonged P300 latency at the Fz sites in PD patients, compared to HC; prolonged N200 latency at the Cz, Pz electrode sites in PDND patients, compared to HC; prolonged P300 latency at the Cz site in PDD patients, compared to PDND patients; and reduced P300 amplitude at the Fz electrode site in PDND patients, compared to HC. CONCLUSIONS: N200 and P300 component may be potential electrophysiological biomarkers of early cognitive impairment in PD patients. Future studies are needed to confirm this conclusion. Estimates of N200 and P300 component can be a valuable support for clinicians in diagnosis of early cognitive impairment in PD patients due to the simplicity and non-invasiveness of the procedure.

Temporal heterogeneity of HER2 expression in metastatic gastric cancer: a case report.

Gastric cancer is a disease with high heterogeneity, and this heterogeneity may result in an uneven distribution of subclones with varied genetic properties at disease locations (spatial heterogeneity) or temporal changes in subclonal composition (temporal heterogeneity). We present the case of a 69-year-old woman with metastatic gastric cancer who presented for axillary lymph node enlargement and underwent axillary lymphadenectomy. Pathological evidence showed human epidermal growth factor receptor 2 (HER2)(3+). Abdominal computed tomography revealed a mass in the gastric body, gastroscopic biopsy showed HER2(3+). After tumor shrinkage by preoperative translational chemotherapy (oxaliplatin, calcium folate, fluorouracil) and targeted therapy (trastuzumab), she had laparoscopic-assisted total gastrectomy. However, HER2 immunohistochemistry was found to be diffusely negative in the surgically removed tissue, and there was no evidence of HER2 amplification in the whole exon sequencing either. After 10 months of trastuzumab treatment, her disease progressed. Although trastuzumab treatment was initially beneficial, the residual HER2-negative subclones may cause tumor recurrence and metastasis due to temporal heterogeneity, as shown in this case.

Sigma-1 Receptor in Retina: Neuroprotective Effects and Potential Mechanisms.

Retinal degenerative diseases are the major factors leading to severe visual impairment and even irreversible blindness worldwide. The therapeutic approach for retinal degenerative diseases is one extremely urgent and hot spot in science research. The sigma-1 receptor is a novel, multifunctional ligand-mediated molecular chaperone residing in endoplasmic reticulum (ER) membranes and the ER-associated mitochondrial membrane (ER-MAM); it is widely distributed in numerous organs and tissues of various species, providing protective effects on a variety of degenerative diseases. Over three decades, considerable research has manifested the neuroprotective function of sigma-1 receptor in the retina and has attempted to explore the molecular mechanism of action. In the present review, we will discuss neuroprotective effects of the sigma-1 receptor in retinal degenerative diseases, mainly in aspects of the following: the localization in different types of retinal neurons, the interactions of sigma-1 receptors with other molecules, the correlated signaling pathways, the influence of sigma-1 receptors to cellular functions, and the potential therapeutic effects on retinal degenerative diseases.

Quantitative evaluation of lipid layer thickness and blinking in children with allergic conjunctivitis.

PURPOSE: To quantitatively evaluate the lipid layer thickness (LLT) and blinking in children with or without allergic conjunctivitis (AC), and to compare those between the different types of AC. METHODS: For this case-control study, 81 children with symptomatic AC with an average age of 9.62 ± 2.67 years were enrolled and subdivided according to the subtypes of AC, including seasonal/perennial allergic conjunctivitis group and vernal keratoconjunctivitis (VKC)/atopic keratoconjunctivitis (AKC) group. Another 82 age-matched healthy children were enrolled as control group. All subjects underwent routine eye examination and measurements of LLT, the number of incomplete or total blinking, partial blinking rate by the LipiView interferometer over a 10-s period. Other ocular surface assessment included fluorescein tear breakup time (TBUT), lower tear meniscus height, meibomian gland loss (MGL), meibum expressibility and quality. RESULTS: Pediatric patients with AC had significant thinner LLT, shorter TBUT, decreased total blinking but increased partial blinking rate, especially in those with VKC/AKC (all P < 0.05). A significant deterioration of meibomian gland parameters was observed in AC group when compared with control subjects, demonstrated by severe upper and lower MGL, lid margin abnormalities, decreased meibum expressibility, and abnormal meibum quality, all of which were worse in the severe type of AC (all P < 0.05). Thinner LLT was significantly correlated with decreased TBUT (ß = 3.666, P < 0.001) and severity of upper MGL (ß = - 7.701, P = 0.002). CONCLUSION: Decreased LLT and blinking disorders in pediatric patients with AC may contribute to lipid layer deficiency in the long run, which should be considered and appropriately diagnosed for a more precise treatment.

Subconjunctival injection of tumor necrosis factor-α pre-stimulated bone marrow-derived mesenchymal stem cells enhances anti-inflammation and anti-fibrosis in ocular alkali burns.

PURPOSE: To investigate the therapeutic effect of subconjunctival injection of tumor necrosis factor-α (TNF-α) pre-stimulated bone marrow-derived mesenchymal stem cells (BMMSCs) on ocular alkali burns in a rat model. METHODS: After applying a 6 mm filter paper soaking in 1 N NaOH on the cornea of rats, the suspension of TNF-α pre-stimulated BMMSCs, BMMSCs and PBS were given subconjunctivally and respectively. Corneal epithelial defect, corneal opacity, inflammation as well as PTGS2 and TSG-6 expression on day 7 and fibrosis on day 14 were compared. RESULTS: TNF-α pre-stimulated BMMSCs group had a more predominate effect on promoting corneal epithelial repairing, decreasing corneal opacity, reducing inflammatory cells and CD68 + macrophages on day 7 and suppressing fibrosis on day 14 compared to BMMSCs group. Besides, it had significant increased expressions of PTGS2 and TSG-6 in vitro. Pre-treated with Indomethacin revealed a reverse effect on above-mentioned changes. CONCLUSION: Subconjunctival injection of TNF-α pre-stimulated BMMSCs enhanced anti-inflammatory and anti-fibrotic effect in ocular alkali burns, which was possibly though up regulation of PTGS2 and TSG-6 expression.

Green light exposure aggravates high-fat diet feeding-induced hepatic steatosis and pancreatic dysfunction in male mice.

The increased incidence of metabolic syndrome (MetS) has been demonstrated to be closely associated with external environments, such as unhealthy ambient light exposure. Of note, spectral distribution of the light functions as a critical determinant of light's pathophysiological effects. However, the effects of the lighting spectrum on metabolic homeostasis and the specific target organs remain elusive. To address this concern, we in this study high-fat diet (HFD)-fed obese mice with different spectra of the light, and divided them into white light (WL)-treated group, green light (GL)-treated group and blue light (BL)-treated group. We found that compared with BL- or WL-treated obese mice, animals exposed to GL showed worsened metabolic status, including increased body weight gain, impaired glucose tolerance/insulin sensitivity, increased levels of serum lipids, and decreased levels of serum insulin. At the organ level, GL exposure particularly exacerbated hepatic lipid accumulation and enlarged the islet volume. Taking advantages of metabolomics and transcriptomics analyses, we screened out taurocholic acid (TCA) and adenosine (AD) as two promising metabolites mediating the deleterious effects of GL on the liver and islets, respectively. In detail, GL aggravates HFD-induced lipid synthesis and gluconeogenesis in the liver via the reduction of TCA, while triggering inflammation and cellular dysfunction in islets via the induction of AD. Collectively, our findings confirmed that GL and the HFD have a synergistic effect in the induction of metabolic disorders. DATA AVAILABILITY: All data supported the paper are present in the paper and/or the Supplementary Materials. The original datasets are also available from the corresponding author upon request.

Natural Polyphenols in Metabolic Syndrome: Protective Mechanisms and Clinical Applications.

Metabolic syndrome (MetS) is a chronic disease, including abdominal obesity, dyslipidemia, hyperglycemia, and hypertension. It should be noted that the occurrence of MetS is closely related to oxidative stress-induced mitochondrial dysfunction, ectopic fat accumulation, and the impairment of the antioxidant system, which in turn further aggravates the intracellular oxidative imbalance and inflammatory response. As enriched anti-inflammatory and antioxidant components in plants, natural polyphenols exhibit beneficial effects, including improving liver fat accumulation and dyslipidemia, reducing blood pressure. Hence, they are expected to be useful in the prevention and management of MetS. At present, epidemiological studies indicate a negative correlation between polyphenol intake and MetS incidence. In this review, we summarized and discussed the most promising natural polyphenols (including flavonoid and non-flavonoid drugs) in the precaution and treatment of MetS, including their anti-inflammatory and antioxidant properties, as well as their regulatory functions involved in glycolipid homeostasis.

Endogenous circadian time genes expressions in the liver of mice under constant darkness.

BACKGROUND: The circadian rhythms regulate physiological functions and metabolism. Circadian Time (CT) is a unit to quantify the rhythm of endogenous circadian clock, independent of light influence. To understand the gene expression changes throughout CT, C57BL/6 J mice were maintained under constant darkness (DD) for 6 weeks, and the liver samples were collected starting at 9:00 AM (CT1), and every 4 h in a 24-h cycle (CT5, CT9, CT13, CT17 and CT21). Total RNA was extracted and subjected to RNA-Seq data (deposited as GSE 133342, L-DD). To compare gene oscillation pattern under normal light-dark condition (LD, GSE114400) and short time (2 days) dark-dark condition (S-DD, GSE70497), these data were retried from GEO database, and the trimmed mean of M-values normalization was used to normalize the three RNA-seq data followed by MetaCycle analysis. RESULTS: Approximate 12.1% of the genes under L-DD exhibited significant rhythmically expression. The top 5 biological processes enriched in L-DD oscillation genes were mRNA processing, aromatic compound catabolic process, mitochondrion organization, heterocycle catabolic process and cellular nitrogen compound mitotic catabolic process. The endogenous circadian rhythms of clock genes, P450 genes and lipid metabolism genes under L-DD were further compared with LD and S-DD. The oscillation patterns were similar but the period and amplitude of those oscillation genes were slightly altered. RT-qPCR confirmed the selected RNA sequence findings. CONCLUSIONS: This is the first study to profile oscillation gene expressions under L-DD. Our data indicate that clock genes, P450 genes and lipid metabolism genes expressed rhythmically under L-DD. Light was not the necessary factor for persisting circadian rhythm but influenced the period and amplitude of oscillation genes.

Chronic exposure to green light aggravates high-fat diet-induced obesity and metabolic disorders in male mice.

Light is involved in many critical physiological or biochemical processes of human beings, such as visual sensing and the production of vitamin D. Recent studies have showed that the lights of different wavelengths have a profound influence in life activities. For example, blue light promotes alertness, whereas green light (GL) induces sleep in mice. On the other hand, metabolic homeostasis is regulated by a variety of factors, including dietary habits and light exposure. Our study aims to study whether certain wavelength of light would affect metabolic status of mice. Mice were divided into normal diet-fed group and high-fat diet (HFD)-fed group, and then exposed to various colors of the light. Physiological parameters, such as body weight, food intake and water drinking were regularly measured. Glucose tolerance test and pyruvate tolerance test were simultaneously performed. After mice were humanely sacrificed, liver histology and serologic analysis were performed for detecting lipid levels. We found that GL group showed obvious glucose intolerance and increased levels of serum and liver lipid contents compared to white light group. Meanwhile, the expression levels of lipid metabolism-related genes were almost down-regulated in liver. Furthermore, melatonin receptor-1b and thyroid hormone receptor-ß expression levels were significantly lowered in liver of GL-treated obese mice, suggesting that these hormone pathways may mediate the changes of lipid metabolism. Our data indicate that GL has a detrimental effect on the energy metabolism and aggravates HFD-induced obesity in mice. In addition to malnutrition, the colors of the lights also have a profound influence in the metabolic homeostasis and should be taken into consideration in the therapy of metabolic disorders.