Differences in the severity and mortality risk factors for patients hospitalized for COVID-19 pneumonia between the early wave and the very late stage of the pandemic.

Background: Since China's dynamic zero-COVID policy is cancelled on December 7, 2022, the rapidly growing number of patients has brought a major public health challenge. This study aimed to assess whether there were differences in the severity and mortality risk factors for patients hospitalized for COVID-19 pneumonia between the early wave and the very late stage of the pandemic. Methods: A retrospective cross-sectional study was carried out using data from 223 hospitalized patients diagnosed with COVID-19 pneumonia during the Omicron surge in Xi'an People's Hospital (Xi'an Fourth Hospital) from December 8, 2022, to January 31, 2023. Univariable and multivariable logistic regression analyses were used to identify potential risk factors associated with the severity and mortality of COVID-19 pneumonia during the first wave of the pandemic after the dynamic zero-COVID policy was retracted. Differences in the severity and mortality risk factors were assessed at different stages of the pandemic, mainly from demographic, clinical manifestation, laboratory tests and radiological findings of patients on admission. Results: The mean age of the 223 participants was 71.2 ± 17.4. Compared with the patients in the initial stage of the pandemic, the most common manifestation among patients in this study was cough (90.6%), rather than fever (79.4%). Different from the initial stage of the pandemic, older age, chest tightness, elevated neutrophil-to-lymphocyte ratio (NLR), decreased albumin (ALB) level and ground glass opacification (GGO) in radiological finding were identified as severity risk factors, instead of mortality risk factors for COVID-19 patients in the very late stage of the pandemic. Arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ≤300 mmHg, cardiovascular disease and laboratory findings including elevated levels of D-dimer, α-hydroxybutyrate dehydrogenase (α-HBDH), total bilirubin (TBIL), alanine aminotransferase (ALT), urea nitrogen (BUN), creatinine (CR), fasting blood glucose (FBG) and decreased platelet count (PLT) were still associated with mortality in the very late stage of the pandemic. Conclusion: Monitoring continuously differences in the severity and mortality risk factors for COVID-19 patients between different stages of the pandemic could provide evidence for exploring uncharted territory in the coming post-pandemic era.

A solid-state synthetic strategy toward nickel-based bimetallic interstitial compounds (MNi3Cx, M = Zn, In, Ga).

Bimetallic interstitial compounds with unique geometric properties have attracted increasing attention in energy-related fields and diverse chemical transformations. Current synthesis of these compounds generally involves at least one wet-chemistry step with the use of various solvents to prepare the bimetallic precursors, and no universal protocols for different compositions are yet available. Herein, a novel synthetic strategy toward a platform of nickel-based bimetallic interstitial compounds with the formula MNi3Cx, M = Zn, In, and Ga, was developed based on a straightforward solid-state transformation, i.e., simply annealing the hydroxides of the respective metals in the presence of different carbon precursors (cyanamide, dicyandiamide, melamine, and urea) in a hydrogen stream. The key process parameters influencing the compositions of the final products are studied and the formation mechanism is discussed based on advanced characterization techniques. Powder X-ray diffraction reveals MNi3Cx as a single phase and electron microscopy shows that the MNi3Cx particles are covered with N-doped carbon shells. Extrapolation to other bimetallic interstitial compounds failed when following the above protocol, and the successful examples are linked to the formation of the corresponding bimetallic alloys in the absence of carbon precursors. When evaluated for the selective hydrogenation of dimethyl oxalate, both InNi3C0.5 and ZnNi3C0.7 show comparable high activity. While ZnNi3C0.7 delivers the highest selectivity for methyl glycolate, tunable methyl glycolate and ethylene glycol are formed on InNi3C0.5. In general, this facile solvent-free strategy affords an interesting scaffold to fabricate more advanced multi-metallic interstitial compounds with broad applications.

Baseline white matter function predicts short-term treatment response in first-episode schizophrenia.

BACKGROUND AND PURPOSE: The detection and characterization of functional activities in the gray matter of schizophrenia (SZ) have been widely explored. However, the relationship between resting-state functional signals in the white matter of first-episode SZ and short-term treatment response remains unclear. METHODS: Thirty-six patients with first-episode SZ and 44 matched healthy controls were recruited in this study. Patients were classified as nonresponders and responders based on response to antipsychotic medication during a single hospitalization. The fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and functional connectivity (FC) of white matter were calculated. The relationships between functional changes and clinical features were analyzed. In addition, voxel-based morphometry was performed to analyze the white matter volume. RESULTS: One-way analysis of variance showed significant differences of fALFF and ReHo in the left posterior thalamic radiation and left cingulum (hippocampus) in the patient group, and the areas were regarded as seeds. The FC was calculated between seeds and other white matter networks. Compared with responders, nonresponders showed significantly increased FC between the left cingulum (hippocampus) and left posterior thalamic radiation, splenium of corpus callosum, and left tapetum, and were associated with the changes of clinical assessment. However, there was no difference in white matter volume between groups. CONCLUSION: Our work provides a novel insight that psycho-neuroimaging-based white matter function holds promise for influencing the clinical diagnosis and treatment of SZ.

Diabetes influences the fusion of autophagosomes with lysosomes in SH-SY5Y cells and induces Aß deposition and cognitive dysfunction in STZ-induced diabetic rats.

Diabetes has been regarded as an independent risk factor for Alzheimer's disease (AD). Our previous study found that diabetes activated autophagy, but lysosome function was impaired. Autophagy-lysosome dysfunction may be involved in Aß deposition in diabetic cognitive impairment. In the present study, we used STZ-induced diabetic rats and SH-SY5Y cells to investigate whether diabetes inhibits autophagosome fusion with lysosomes. We found that in the in vivo study, STZ-induced diabetic rats exhibited cognitive dysfunction, and the lysosome function-related factors CTSL, CTSD, and Rab7 were decreased (P < 0.05). In an in vitro study, the mRFP-GFP-LC3 assay showed that the fusion of autophagosomes with lysosomes was partly blocked in SH-SY5Y cells. High glucose treatment downregulated the number of autophagolysosomes, downregulated CTSD, CTSL, and Rab7 expression (P < 0.05), and then influenced the function of ACP2 to partly block the fusion of autophagosomes and lysosomes to inhibit Aß clearance. These findings indicate that high glucose treatment affected lysosome function, interfered with the fusion of autophagosomes with lysosomes, and partly blocked autophagic flux to influence Aß clearance.

Alternations of interhemispheric functional connectivity in patients with optic neuritis using voxel-mirrored homotopic connectivity: A resting state fMRI study.

BACKGROUND AND PURPOSE: We used the voxel-mirrored homotopic connectivity (VMHC) method to investigate brain interhemispheric functional connectivity changes in patients with optic neuritis (ON). METHODS: A total of 22 ON patients and 22 healthy controls (HCs) closely matched in age, sex, and weight were enrolled. All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI). Functional interaction between the hemispheres was assessed with the VMHC method. Correlation analysis was applied to explore the association between altered VMHC values in different brain areas and cognitive features. Receiver operating characteristic (ROC) curve analysis was applied to distinguish ON patients from HCs. RESULTS: Compared with HCs, ON patients had obviously reduced VMHC values in the right superior temporal gyrus, left margin superior gyrus, right superior motor cortex, and left middle cingulate gyrus. a negative relationship between best-corrected visual acuity and VMHC values in left margin superior gyrus was found, besides, the VMHC values within the right superior motor cortex and the right superior temporal gyrus were also anti-correlated with the Hamilton Depression Scales. The ROC curve displayed high diagnostic values in those altered regions. CONCLUSION: Abnormal VMHC values may reflect the underlying neuropathologic mechanism of ON.

Simultaneous Determination of RDX and HMX in Rat Plasma by LC-MS/MS and its Applications.

Background: 1,3,5-trinitroperhydro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) can cause serious toxicity problems in humans and animals, but direct analyses of RDX and HMX in biological samples are very limited. A rapid and efficient liquid chromatography-electrospray quadrupole linear ion trap mass spectrometry (LC-MS/MS) method suitable for the simultaneous determination of RDX and HMX in rat plasma after intravenous administration of two nitramine compound mixed solutions has been developed. Methods: Plasma samples were pretreated with one-step protein precipitation, the plasma consumption is as low as 100 µl. RDX, HMX, and internal standard mycophenolic acid were eluted for 8.0 min on a reversed-phase C18 analytical column with a water/acetonitrile mixture as the mobile phase. An electrospray ionization (ESI) source was applied and operated in negative ion mode. The optimized mass transition ion pairs (m/z) monitored for RDX, HMX, and internal standard mycophenolic acid were m/z 284.1→61.7, m/z 331.0→108.8, and m/z 319.2→191.1, respectively. Results: The detection ranges of both RDX and HMX in plasma were 5.00-200.00 ng⋅ml-1 with an LOD of 1.00 ng⋅ml-1. The extraction recoveries of RDX and HMX were 60.04 ± 4.18% and 79.57 ± 3.35%, respectively. The precision and accuracy met the requirements, and the method was stable under all tested conditions. Conclusion: The present method is miniaturized, effective, portable, rapid and can be easily used for simultaneous quantification of RDX and HMX in rat plasma.

Early Death and Survival of Patients With Acute Promyelocytic Leukemia in ATRA Plus Arsenic Era: A Population-Based Study.

Most randomized trials for acute promyelocytic leukemia (APL) have investigated highly selected patients under idealized conditions, and the findings need to be validated in the real world. We conducted a population-based study of all APL patients in Zhejiang Province, China, with a total population of 82 million people, to assess the generalization of all-trans retinoic acid (ATRA) and arsenic as front-line treatment. The outcomes of APL patients were also analyzed. Between January 2015 and December 2019, 1,233 eligible patients were included in the final analysis. The rate of ATRA and arsenic as front-line treatment increased steadily from 66.2% in 2015 to 83.3% in 2019, with no difference among the size of the center (≥5 or <5 patients per year, p = 0.12) or age (≥60 or <60 years, p = 0.35). The early death (ED) rate, defined as death within 30 days after diagnosis, was 8.2%, and the 3-year overall survival (OS) was 87.9% in the whole patient population. Age (≥60 years) and white blood cell count (>10 × 109/L) were independent risk factors for ED and OS in the multivariate analysis. This population-based study showed that ATRA and arsenic as front-line treatment are widely used under real-world conditions and yield a low ED rate and a high survival rate, which mimic the results from clinical trials, thereby supporting the wider application of APL guidelines in the future.

Resting-State Functional Magnetic Resonance Imaging and Functional Connectivity Density Mapping in Patients With Optic Neuritis.

Background: Using resting-state functional connectivity (rsFC), we investigated alternations in spontaneous brain activities reflected by functional connectivity density (FCD) in patients with optic neuritis (ON). Methods: We enrolled 28 patients with ON (18 males, 10 females) and 24 healthy controls (HCs; 16 males, 8 females). All subjects underwent functional magnetic resonance imaging (fMRI) in a quiet state to determine the values of rsFC, long-range FCD (longFCD), and short-range FCD (IFCD). Receiver operating characteristic (ROC) curves were generated to distinguish patients from HCs. Results: The ON group exhibited obviously lower longFCD values in the left inferior frontal gyrus triangle, the right precuneus and the right anterior cingulate, and paracingulate gyri/median cingulate and paracingulate gyri. The left median cingulate and paracingulate gyri and supplementary motor area (SMA) were also significantly lower. Obviously reduced IFCD values were observed in the left middle temporal gyrus/angular gyrus/SMA and right cuneus/SMA compared with HCs. Conclusion: Abnormal neural activities were found in specific brain regions in patients with ON. Specifically, they showed significant changes in rsFC, longFCD, and IFCD values. These may be useful to identify the specific mechanism of change in brain function in ON.

Pharmacokinetics, Bioavailability, Excretion and Metabolism Studies of Akebia Saponin D in Rats: Causes of the Ultra-Low Oral Bioavailability and Metabolic Pathway.

Background: Akebia saponin D (ASD) has a variety of biological activities and great medicinal potential, but its oral bioavailability is so low as to limit its development. Its pharmacokinetic profiles and excretion and metabolism in vivo have not been fully elucidated. This study was an attempt in this area. Methods: A simple LC-MS/MS method to simultaneously quantify ASD and its metabolites M1∼M5 in rat plasma, feces, urine and bile was established with a negative ESI model using dexketoprofen as the internal standard. Meanwhile, the UPLC-HR/MS system was used to screen all possible metabolites in the urine, feces and bile of rats, as compared with blank samples collected before administration. Absolute quantitative analysis was for M0, M3, M4, and M5, while semi-quantitative analysis was for M1, M2, and Orbitrap data. Results: The AUC0-t values after intravenous administration of 10 mg/kg and intragastrical administration of 100 mg/kg ASD were 19.05 ± 8.64 and 0.047 ± 0.030 h*µg/ml respectively. The oral bioavailability was determined to be extremely low (0.025%) in rats. The exposure of M4 and M5 in the oral group was higher than that of M0 in the terminal phase of the plasma concentration time profile, and ASD was stable in the liver microsome incubation system of rats, but metabolism was relatively rapid during anaerobic incubation of intestinal contents of rats, suggesting that the low bioavailability of ASD might have been attributed to the poor gastrointestinal permeability and extensive pre-absorption degradation rather than to the potent first pass metabolism. This assertion was further verified by a series of intervention studies, where improvement of lipid solubility and intestinal permeability as well as inhibition of intestinal flora increased the relative bioavailability to different extents without being changed by P-gp inhibition. After intravenous administration, the cumulative excretion rates of ASD in the urine and bile were 14.79 ± 1.87%, and 21.76 ± 17.61% respectively, but only 0.011% in feces, suggesting that the urine and bile were the main excretion pathways and that there was a large amount of biotransformation in the gastrointestinal tract. Fifteen possible metabolites were observed in the urine, feces and bile. The main metabolites were ASD deglycosylation, demethylation, dehydroxylation, decarbonylation, decarboxylation, hydroxylation, hydroxymethylation, hydroxyethylation and hydrolysis. Conclusion: The pharmacokinetics, bioavailability, metabolism and excretion of ASD in rats were systematically evaluated for the first time in this study. It has been confirmed that the ultra-low oral bioavailability is due to poor gastrointestinal permeability, extensive pre-absorption degradation and biotransformation. ASD after iv administration is not only excreted by the urine and bile, but possibly undergoes complex metabolic elimination.

Akebia saponin D ameliorates metabolic syndrome (MetS) via remodeling gut microbiota and attenuating intestinal barrier injury.

Metabolic syndrome (MetS) is a complex, multifactorial disease which lead to an increased risk of cardiovascular disease, type 2 diabetes, and stroke. However, selective, and potent drugs for the treatment of MetS are still lacking. Previous studies have found that Akebia saponin D (ASD) has beneficial effects on metabolic diseases such as obesity, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). Therefore, our study was designed to determine the effect and mechanism of action of ASD against MetS in a high-fat diet (HFD) induced mouse model. ASD significantly decreased plasma lipid and insulin resistance in these mice, and a targeted approach using metabolomic analyses of plasma and feces indicated that glucose and lipids in these mice crossed the damaged intestinal barrier into circulation. Furthermore, ASD was able to increase lipid excretion and inhibit intestinal epithelial lipid absorption. Results for gut microbiota composition showed that ASD significantly reduced HFD-associated Alistipes, Prevotella, and enhanced the proportions of Butyricimonas, Ruminococcus, and Bifidobacterium. After 14 weeks of ASD/fecal microbiota transplantation (FMT) interventions the developed gut barrier dysfunction was restored. Additionally, RNA-seq revealed that ASD reduced the lipid-induced tight junction (TJ) damage in intestinal epithelial cells via down-regulation of the PPAR-γ-FABP4 pathway in vitro and that use of the PPAR-γ inhibitor (T0070907) was able to partially block the effects of ASD, indicating that the PPAR-γ/FABP4 pathway is a critical mediator involved in the improvement of MetS. Our results demonstrated that ASD not only modifies the gut microbiome but also ameliorates the HFD-induced gut barrier disruption via down-regulation of the PPAR-γ-FABP4 pathway. These findings suggest a promising, and novel therapeutic strategy for gut protection against MetS.

HSD3B1 variant and androgen-deprivation therapy outcome in prostate cancer.

OBJECTIVE: Rate-limiting enzyme 3b-hydroxysteroid dehydrogenase type 1 (3ßHSD1) encoded by HSD3B1 catalyzes the transition of dehydroepiandrosterone (DHEA) to dihydrotestosterone (DHT). The HSD3B1 (1245C) variant renders 3bHSD1 of resistant to ubiquitination and degradation, leading to a large amount of protein accumulation in the cell. Multiple clinical studies have shown that this mutation was correlated with resistance to androgen-deprivation therapy in prostate cancer. However, the results were not consistent depending on different treatment strategy and in some researches, the number of observed cases was relatively small. METHODS: To determine the effects of HSD3B1 (1245C) variant on resistance to androgen-deprivation therapy in prostate cancer, we performed a meta-analysis of the available literature. Electronic database searches identified appropriately designed studies that detected HSD3B1 in prostate cancer. We conducted a systematic search of studies in the following databases: PubMed, and EMBASE published until August 10, 2020 using the following search terms: (HSD3B1 AND ((((prostate cancer) OR prostatic neoplasm) OR prostatic carcinoma) OR prostatic cancer). RESULTS: Eight researches were included in this research. The result validated that the HSD3B1 (1245C) variant allele was associated with a shorter PFS (HR, 1.97; 95% CI, 1.39-2.79; P = 0.0001) (homozygous wild-type group) in men with prostate cancer when treated with ADT, however, a higher PFS (HR, 0.68; 95% CI, 0.48-0.96; P = 0.03) when treated with ADT and CYP17A1 inhibitor. CONCLUSION: The HSD3B1 (1245C) variant is a predictor of ADT plus CYP17A1 inhibitor response in prostate cancer.

GLI1 activation is a key mechanism of erlotinib resistance in human non-small cell lung cancer.

Lung cancer is the leading cause of cancer-associated death worldwide. In recent years, the advancement of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeted therapies has provided clinical benefits for lung cancer patients with EGFR mutations. The response to EGFR-TKI varies in patients with lung cancer, and resistance typically develops during the course of the treatment. Therefore, understanding biomarkers which can predict resistance to EGFR-TKI is important. Overexpression of GLI causes activation of the Hedgehog (Hh) signaling pathway and plays a critical role in oncogenesis in numerous types of cancer. In the present study, the role of GLI1 in erlotinib resistance was investigated. GLI1 mRNA and protein expression levels were determined using reverse transcription-quantitative PCR and immunohistochemistry (IHC) in lung cancer cell lines and tumor specimens, respectively. GLI1 mRNA expression levels were found to be positively correlated with the IC50 of erlotinib in 15 non-small cell lung cancer (NSCLC) cell lines. The downregulation of GLI1 using siRNA sensitized lung cancer cells to the erlotinib treatment, whereas the overexpression of GLI1 increased the survival of lung cancer cells in the presence of erlotinib, indicating that Hh/GLI activation may play a critical role in the development of TKI resistance in lung cancer. Combined treatment with erlotinib and a GLI1 inhibitor reduced the cell viability synergistically. A retrospective study of patients with NSCLC treated with erlotinib revealed that those with a high IHC score for GLI1 protein expression had a poorer prognosis. These results indicated that GLI1 is a key regulator for TKI sensitivity, and patients with lung cancer may benefit from the combined treatment of TKI and GLI1 inhibitor.

Ceramide induces MMP-9 expression through JAK2/STAT3 pathway in airway epithelium.

BACKGROUND: Ceramide, a bioactive lipid, plays an essential role in the development of several pulmonary inflammatory diseases. Matrix metallopeptidase 9 (MMP-9) regulates the synthesis and degradation of extracellular matrix, and is associated with airway remodeling and tissue injury. This study was conducted to investigate the effects and underlying mechanisms of ceramide on MMP-9 expression in airway epithelium. METHODS: BEAS-2B cells, normal human bronchial epithelium cell lines, were pretreated with AG490, a selective janus tyrosine kinase 2 (JAK2) inhibitor, or Stattic, a selective signal transducer and activator of transcription 3 (STAT3) inhibitor. The cells were then stimulated with C6-ceramide. The levels of MMP-9 were determined by ELISA and real-time quantitative PCR (RT-qPCR). JAK2, phosphorylated JAK2 (p-JAK2), STAT3, and phosphorylated STAT3 (p-STAT3) expression was examined by Western blotting. BALB/c mice were pretreated with AG490 or Stattic before intratracheally instillated with C6-ceramide. Pathological changes in lung tissues were examined by Hematoxylin and Eosin staining, Periodic-acid Schiff staining, and Masson's trichrome staining. MMP-9, JAK2, p-JAK2, STAT3, and p-STAT3 expression in the lung tissues was examined by Western blotting. RESULTS: The expression of MMP-9, p-JAK2 and p-STAT3 in BEAS-2B cells was significantly increased after the treatment of C6-ceramide. Furthermore, the increased expression of MMP-9 induced by C6-ceramide was inhibited by AG490 and Stattic. Similar results were obtained in the lung tissues of C6-ceramide-exposed mice which were treated with AG490 or Stattic. CONCLUSIONS: Ceramide could up-regulate MMP-9 expression through the activation of the JAK2/STAT3 pathway in airway epithelium. Targeted modulation of the ceramide signaling pathway may offer a potential therapeutic approach for inhibiting MMP-9 expression. This study points to a potentially novel approach to alleviating airway remodeling in inflammatory airway diseases.

Cytomegalovirus Infection Is a Risk Factor in Gastrointestinal Cancer: A Cross-Sectional and Meta-Analysis Study.

BACKGROUND: This study was planned to investigate the association betweenhuman cytomegalovirus (HCMV) infection and gastrointestinal cancer (GIC) risk, by undertaking a meta-analysis and case-control cross-sectional study. SUMMARY: A cross-sectional study analysis of 160 GIC patients and 100 control subjects indicated significantly higher HCMV prevalence in GIC patients based on the HCMV IgM test. However, a similar analysis based on an IgG test revealed no significant relationship. Further meta-analysis of 11 studies, including 1,044 patients and 991 healthy subjects, displayed HCMV infection as an important risk factor for not only colorectal cancer occurrence and development based on a HCMV DNA test, but also for GIC based on a HCMV IgM test. However, the IgG test again displayed no significant relationship between HCMV infection and GIC occurrence. Key Message: Overall, our study revealed that HCMV infection is associated with an increased GIC risk. However, additional studies are warranted to elucidate the molecular mechanism underlying this association.

Targeted Metabolomics for Plasma Amino Acids and Carnitines in Patients with Metabolic Syndrome Using HPLC-MS/MS.

Metabolic syndrome (MetS) is a health disorder characterized by metabolic abnormalities that predict an increased risk to develop cardiovascular disease (CVD) and type 2 diabetes. Biomarkers can provide an insight into the novel mechanism for MetS and can be potentially used for personalized response to therapies. We exploited a targeted HPLC-MS/MS method to characterize plasma amino acids and carnitine metabolic profile in MetS patients. A training set (40 cases and 40 controls) and validation set (80 MetS patients and 80 healthy controls) were carried out to find the metabolic profiles. We discovered two carnitine metabolites including hydroxydecanoyl carnitine and methylglutarylcarnitine. Our results indicated that the decreased level of hydroxydecanoyl carnitine and methylglutarylcarnitine may be associated with the risk of MetS. These biomarkers may improve the risk prediction and provide a novel tool for monitoring of the progression of disease and response to treatment in MetS patients.

Curcumin inhibits the formation of atherosclerosis in ApoE-/- mice by suppressing cytomegalovirus activity in endothelial cells.

BACKGROUND: Curcumin (Cur) is a hydrophobic polyphenol compound derived from the rhizome of the herb Curcuma longa. Cur has a wide spectrum of biological and pharmacological activities. It has been shown that human cytomegalovirus (HCMV) infection was an important risk factor for atherosclerosis (AS) and Cur exhibited an outstanding anti-HCMV effect. However, anti-AS effects of Cur remain unclear when HCMV infected endothelial cells. AIMS: This study will investigate the anti-AS activities and mechanism of Cur,when HCMV infected in vivo and in vitro. MATERIALS AND METHODS: Cur (0.5, 1, and 2 µM) was used to explore the anti-AS activities and mechanism after HCMV infected endothelial cells in vitro. ApoE-/- mice were fed a high fat and cholesterol diet (HD) and given 4000,000 copies/mouse MCMV infection by intraperitoneal and treated with ganciclovir (5 mg/kg/d), Cur (25, 15 mg/kg/d) for 10 weeks in vivo. KEY FINDINGS: As our results showed that Cur inhibited CMV replication and proliferation, reduced the intracellular ROS overproduction, decreased the release of inflammatory cytokines, down-regulated the level of HMGB1-TLRS-NF-κB signaling pathway-related proteins in vitro experiments. Cur reduced the serum levels of LDL-C, TC and TG, significantly decreased the formation of atherosclerotic plaque in the aorta, reduced the lipid deposition in liver and inflammatory damage in heart, lung and kidney in vivo experiments. SIGNIFICANCE: This study showed that Cur prevent AS progression by inhibiting CMV activity and CMV-induced HMGB1-TLRS-NF-κB signaling pathway.

Vitamin D supplementation rescues simvastatin induced myopathy in mice via improving mitochondrial cristae shape.

Statin induced myopathy (SIM) is a main deleterious effect leading to the poor treatment compliance, while the preventive or therapeutic treatments are absent. Mounting evidences demonstrated that vitamin D plays a vital role in muscle as a direct modulator. The deficiency of vitamin D was considered as a cause of muscle dysfunction, whereas the supplementation resulted in a remission. However, there is no causal proof that vitamin D supplementation rescues SIM. Here, using the mice model of simvastatin-induced myopathy, we investigated the role of vitamin D supplementation and the mechanisms associated with mitochondria. Results indicated that simvastatin administration (80 mg/kg) impaired skeletal muscle with the increased serum creatine kinase (CK) level and the declined grip strength, which were alleviated by vitamin D supplementation. Moreover, vitamin D supplementation rescued the energy metabolism dysfunction in simvastatin-treated mice gastrocnemius by reducing the abnormal aggregation of muscular glycogen and lactic acid. Mitochondrial homeostasis plays a key role in the process of energy metabolism. Thus, the mitochondrial dysfunction is a mortal damage for the highly energy-requiring tissue. In our study, the mitochondrial cristae observed under transmission electron microscope (TEM) were lytic in simvastatin-treated gastrocnemius. Interestingly, vitamin D supplementation improved the mitochondrial cristae shape by regulating the expression of mitofusin-1/2 (MFN1/2), optic atrophy 1 (OPA1) and dynamin-related protein 1 (Drp1). As expected, the mitochondrial dysfunction and oxidative stress was mitigated by vitamin D supplementation. In conclusion, these findings suggested that moderate vitamin D supplementation rescued simvastatin induced myopathy via improving the mitochondrial cristae shape and function.

Dry eye induced by exposure to cigarette smoke pollution: An in vivo and in vitro study.

Exposure to cigarette smoke (CS) pollution has previously associated with dry eye symptoms but without detailed experimental data and elucidation of the mechanism. We aimed to evaluate the effects of CS on the ocular surfaces of mice and the extraction of DMSO lipid-soluble cigarette smoke particles (DCSP) on cultured human corneal epithelial cells (HCECs), and explore to elucidate the probable mechanism. C57BL mice were exposed to CS challenging. In vivo clinical evaluations, including corneal fluorescein staining, tear film break-up time, and confocal microscopic observations, were performed before exposure and post-exposure. At the end of the in vivo study, changes in corneal and conjunctival histology, corneal ultrastructure, and conjunctival goblet cell intensity were examined, expression of TUNLE and Ki67 in tissue were also detected. In vitro, cell confluence and caspase3/7 were assessed in DCSP treated HCECs. Production of TNF-α, IL-1ß and IL-6, activation of NF-κB and Ki67 were evaluated by means of ELISA and Western blot respectively in HCECs cultured with 0.6 µL/mL DCSP. We found that longer-term CS exposure induced dry eye symptoms in mice. Additionally, corneal and conjunctival epithelial damage occurred, the corneal ultrastructure changed, and the density of goblet cells decreased. Apoptosis and Ki67 increased in both the conjunctiva and the cornea of CS-exposed animals. Furthermore, although DCSP inhibited the proliferation of HCECs, expression of Ki67 increased and apoptosis was only induced significantly by 2.0 µL/mL DCSP. The release of IL-1ß and IL-6, activation of NF-κB were prompted by DCSP. The results indicated that CS is toxic to the ocular surface of mice and HCECs. Longer-term CS exposure in mice stimulates ocular surface changes that resemble those observed with dry eye. The mechanism may relate to inflammation and activation of NF-κB. In this study, we established a novel animal model to study dry eye, with the experimental data and elucidation of mechanism facilitating further research.

Chronic ghrelin administration suppresses IKK/NF-κB/BACE1 mediated Aß production in primary neurons and improves cognitive function via upregulation of PP1 in STZ-diabetic rats.

Diabetic rats display cognition impairments accompanied by activation of NF-κB signalling and increased Aß expression. Ghrelin has been suggested to improve cognition in diabetic rats. In this study, we investigated the role of ghrelin on cognition and NF-κB mediated Aß production in diabetic rats. A diabetic rat model was established with streptozotocin (STZ) injection, and diabetic rats were intracerebroventricularly administered with ghrelin or (D-lys3)-GHRP-6 (DG). Our results showed that diabetic rats had cognition impairment in the Morris water maze test, accompanied by the higher expression of Aß in the hippocampus. Western blot analysis showed that diabetic rats exhibited significantly decreased levels of GHSR-1a and protein phosphatase 1 (PP1) in the hippocampus and increased activation of the IKK/NF-κB/BACE1 pathway. Chronic ghrelin administration upregulated hippocampal PP1 expression, suppressed IKK/NF-κB/BACE1 mediated Aß production, and improved cognition in STZ-induced diabetic rats. These effects were reversed by DG. Then, primary rat hippocampal neurons were isolated and treated with high glucose, followed by Ghrelin and DG, PP1 or IKK. Similar to the in vivo results, high glucose suppressed the expression levels of GHSR-1a and PP1, activated the IKK/NF-κB/BACE1 pathway, increased Aß production. Ghrelin suppressed IKK/NF-κB/BACE1 induced Aß production. This improvement was reversed by DG and a PP1 antagonist and was enhanced by the IKK antagonist. Our findings indicated that chronic ghrelin administration can suppress IKK/NF-κB/BACE1 mediated Aß production in primary neurons with high glucose treatment and improve the cognition via PP1 upregulation in diabetic rats.

Discovery of metabolite profiles of metabolic syndrome using untargeted and targeted LC-MS based lipidomics approach.

Metabolic syndrome (MetS) is an important risk factor for type 2 diabetes, cardiovascular diseases and all-cause morbidity and mortality. Biomarkers can provide insight into the mechanism, facilitate early detection, and monitor progression of MetS and its response to therapeutic interventions. To identify potential biomarkers, we applied a non-targeted and targeted lipidomics method to characterize plasma metabolic profile in MetS patients. Metabolic profiling was performed on a non-target set (40 cases and 40 controls) on UHPLC-Q-TOF/MS and target set (80 MetS patients and 80 healthy controls) on UHPLC-Q-orbitrap MS. Using comprehensive screening and validation workflow, we identified a panel of three metabolites including PC(18:1/P-16:0), PC(o-22:3/22:3), PC(P-18:1/16:1). Our results indicated that the identified biomarkers may improve the risk prediction and provide a novel tool for monitoring of the progression of disease and response to treatment in MetS patients.