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Mitochondria are central to myriad biochemical processes, and thus even their moderate impairment could have drastic cellular consequences if not rectified. Here, to explore cellular strategies for surmounting mitochondrial stress, we conducted a series of chemical and genetic perturbations to Saccharomyces cerevisiae and analysed the cellular responses using deep multiomic mass spectrometry profiling. We discovered that mobilization of lipid droplet triacylglycerol stores was necessary for strains to mount a successful recovery response. In particular, acyl chains from these stores were liberated by triacylglycerol lipases and used to fuel biosynthesis of the quintessential mitochondrial membrane lipid cardiolipin to support new mitochondrial biogenesis. We demonstrate that a comparable recovery pathway exists in mammalian cells, which fail to recover from doxycycline treatment when lacking the ATGL lipase. Collectively, our work reveals a key component of mitochondrial stress recovery and offers a rich resource for further exploration of the broad cellular responses to mitochondrial dysfunction., Competing Interests: Competing interests: J.J.C. is a consultant for Thermo Fisher Scientific, 908 Devices, and Seer. The remaining authors declare no competing interests., (© 2025. The Author(s).) more...

Background: The application of biologic agents has benefited patients with Behcet's uveitis (BU) who do not respond to conventional treatment regimens. However, there is currently no consensus on the optimal treatment regimen of interferon alpha-2a (IFN-α2a) for refractory BU., Objectives: To evaluate treatment outcomes and safety of IFN-α2a in a large series of refractory BU patients and to explore whether nonbiologic immunomodulatory agents (cyclosporin A) other than corticosteroids should be concomitantly used., Design: We conducted a retrospective cohort study, which included 153 BU patients who received IFN-α2a treatment between December 2012 and September 2023 with a minimum duration of 6 months., Methods: Best-corrected visual acuity (BCVA), the frequency of uveitis relapse, corticosteroid-sparing effect, and side effects were evaluated., Results: Of the 153 patients enrolled, 87 patients were treated with IFN-α2a plus corticosteroids (IC), and 66 patients were treated with IFN-α2a plus corticosteroids and cyclosporin A (ICC). Both IFN-α2a treatment regimens significantly improved BCVA as early as 2 months following treatment, and the improvement was maintained over at least a 2-year follow-up. At the final visit, 86.8% and 73.1% of the affected eyes in the ICC and IC groups achieved improved or stable vision, respectively. The ICC regimen was more effective at improving vision ( p  = 0.01). Overall, the frequency of uveitis relapse and the dose of oral prednisolone were significantly reduced in both groups after treatment (all p  < 0.0001). However, there were no statistically significant differences in these parameters between the two groups. None of the included patients experienced serious side effects that led to the discontinuation of IFN-α2a therapy., Conclusion: IFN-α2a treatment is a promising option for patients with refractory BU. Our results showed that cyclosporin A as an adjunct could enhance the therapeutic effect of IFN-α2a., (© The Author(s), 2024.) more...

The Alexandrine parakeet (Palaeornis eupatria), also known as the Alexandrine parrot, is a critically endangered species in the world and a national second class protected animal. Current knowledge on gut microbiome and metabolome of captive Alexandrine parrots is limited. In the current study, we characterized the effect of dietary change with pellet feeding on the gut microbiome and metaboliome in Alexandrine parrots using 16S gene sequencing and liquid chromatography with tandem mass spectrometry (LC-MS/MS). Total of 12 Alexandrine parrots were used in a cross-over study with each period for 10 days. The results showed that dietary change with pellet feeding did not affect alpha indices of gut microbiota. Cyanobacteria, Firmicutes and Proteobacteria were the predominant bacterial phyla in the gut of Alexandrine parrot with Cynobacteria being the highest. Change of diet significantly increased the relative abundance of Actinobacteria and decreased Spirochaetota. The relative abundance of Fusobacteriota tended to increase with pellet feeding. No treatment effects were observed between the control and pellet feeding groups at the genus level. Based on the annotation results from Clusters of Orthologous Genes (COG) database, dietary change with pellet feeding significantly increased the relative abundance of genes coding for extracellular structures and lipid transport and metabolism. Metabolomics analysis combined with enrichment analysis revealed that dietary change altered the concentrations of gut metabolites as well as the metabolic pattern, and significantly affected the concentrations of fecal metabolites involved in isoflavonoid biosynthesis, flavonoid biosynthesis, nucleotide metabolism etc. In summary, dietary changes with pellet feeding affected the gut microbial composition and metabolites to some extent. The relevance of current findings to Alexandrine parrots' health and potential zoonosis need further exploring., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...

Inherited forms of motor neuron disease (MND), including hereditary spastic paraplegias (HSP), are associated with the death or dysfunction of nerve cells that control skeletal muscle activity. However, in some cases, the impacts of genetic variants underlying MND act in a non-cell autonomous manner, instead affecting the function of other cell types necessary for neuronal maintenance. Pathological mutations in TFG, which have been implicated in HSP, lead to axonopathy within the corticospinal tract, but it remains unclear whether this problem arises due to perturbations within neurons or supporting neuroglia. To address this question, we leveraged a rat model harboring the recessive TFG p.R106C mutation (mRATBN7.2, g.11:43897639C>T, c.316C>T), which recapitulates multiple phenotypes associated with HSP in humans, including progressive motor deficits, leg spasticity, and indications of an inflammatory response within the motor cortex. In particular, we took advantage of cell type-specific gene therapies to demonstrate that the reintroduction of wild-type TFG into synapsin 1-positive neurons provides robust protection against MND, whereas its expression in GFAP-positive glial cells provides no significant improvement in quantitative measures of gait, despite a dramatic reduction in the presence of reactive astrocytes throughout the brain. These data strongly suggest that therapeutic approaches targeting neurons should be pursued in cases of TFG-HSP, with our animal model offering a unique platform for preclinical assessment., Competing Interests: Competing interests statement:The authors declare no competing interest. more...

Lifespan is influenced by complex interactions between genetic and environmental factors. Studying those factors in model organisms of a single genetic background limits their translational value for humans. Here, we mapped lifespan determinants in 85 C. elegans recombinant inbred advanced intercross lines (RIAILs). We assessed molecular profiles-transcriptome, proteome, and lipidome-and life-history traits, including lifespan, development, growth dynamics, and reproduction. RIAILs exhibited large variations in lifespan, which correlated positively with developmental time. We validated three longevity modulators, including rict-1, gfm-1, and mltn-1, among the top candidates obtained from multiomics data integration and quantitative trait locus (QTL) mapping. We translated their relevance to humans using UK Biobank data and showed that variants in GFM1 are associated with an elevated risk of age-related heart failure. We organized our dataset as a resource that allows interactive explorations for new longevity targets., Competing Interests: Declaration of interests J.J.C. is a consultant for Thermo Scientific, Seer, and 908 Devices. E.K., L.M., and M.C. are employees of and J.A. is a shareholder of Nagi Bioscience S.A., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.) more...

Hepatocellular cancer (HCC) remained a life-threatening carcinoma. Agents for HCC imaging and therapy were expected to possess different intratumoral retention time. To construct an agent with different intratumoral retention time when applied for tumor imaging or therapy remained great values. A lasialoglycoprotein receptor (ASGPR) targeted lactobionic acid derivative (LABO) was constructed for fluorescent imaging and photodynamic therapy of HCC. 18 F labeled LABO ( 18 F-LABO) was developed for PET imaging of HCC. LABO and 18 F-LABO showed similar molecular structure. LABO exhibited characteristic of viscosity and concentration-induced intratumoral in-situ self-assembly to expand the intratumoral retention. LABO was non-fluorescent at free stage, but emitted NIR fluorescence and generated irradiation-induced ROS after self-assembly for fluorescent imaging and photodynamic therapy. ASGPR specificity of LABO and 18 F-LABO was confirmed using HepG2 cell. Biodistribution and fluorescent imaging confirmed the different tumor retention time of LABO and 18 F-LABO when used for photodynamic therapy and PET imaging. PET imaging and photodynamic therapy were performed on HepG2 tumor bearing mice, which revealed that 18 F-LABO/LABO could specifically accumulated in the HepG2 tumor for tumor location/inhibition. LABO/ 18 F-LABO with excellent HCC specificity but different intratumoral behaviors showed great values for the PET/NIR imaging and photodynamic therapy for HCC., (© 2024. The Author(s).) more...

Objective: Diagnostic pitfalls often arise in the community because of potentially misleading similarities between juvenile idiopathic arthritis (JIA) and Blau syndrome, an immune-related disorder caused by NOD2 gene mutations. It remains unclear in which population and to what extent next-generation sequencing techniques can aid in diagnosis., Methods: We evaluated clinical usefulness of targeted next-generation sequencing in previously diagnosed JIA. Participants were required to have symptoms and signs suspected of Blau syndrome, including at least uveitis or cutaneous lesions in addition to arthritis. Targeted sequencing was conducted on NOD2 gene to detect diagnostic variants classified as pathogenic or likely pathogenic for Blau syndrome. We assessed the molecular diagnostic yield and clinical implications for patient care., Results: Between 1 May 2008 and 1 June 2021, sequencing data were accrued from 123 previously diagnosed JIA (median age: 5 years; female: 62.6%). Targeted NOD2 sequencing yielded a positive molecular diagnosis of Blau syndrome in 21.1% (95% CI: 14.9%, 29.2%), encompassing six heterozygous missense mutations classified as pathogenic variants. Among those receiving a molecular diagnosis, changes in clinical management and treatment were considered as having occurred in 38.5%. Nine predictors were identified as being associated with a higher diagnostic yield, providing clinical clues to suspect the possibility of Blau syndrome., Conclusion: Among some patients with paediatric-onset arthritis complicated with uveitis or cutaneous lesions, reassessment of the diagnosis of JIA may be warranted. Targeted NOD2 sequencing established the molecular diagnosis of Blau syndrome in nearly one-fifth of these cases and provided clinically relevant information for patient-care decisions., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.) more...

Radionuclide-drug conjugates (RDCs) designed from small molecule or nanoplatform shows complementary characteristics. We constructed a new RDC system with integrated merits of small molecule and nanoplatform-based RDCs. Erlotinib was labeled with 131 I to construct the bulk of RDC ( 131 I-ER). Floxuridine was mixed with 131 I-ER to develop a hydrogen bond-driving supermolecular RDC system ( 131 I-ER-Fu NPs). The carrier-free 131 I-ER-Fu NPs supermolecule not only demonstrated integrated merits of small molecule and nanoplatform-based RDC, including clear structure definition, stable quality control, prolonged circulation lifetime, enhanced tumor specificity and retention, and rapidly nontarget clearance, but also exhibited low biological toxicity and stronger antitumor effects. In vivo imaging also revealed its application for tumor localization of nonsmall cell lung cancer (NSCLC) and screening of patients suitable for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. We considered that 131 I-ER-Fu NPs showed potentials as an integrated platform for the radiotheranostics of NSCLC. more...

Enhancing radiotherapy sensitivity is crucial for improving treatment outcomes in triple-negative breast cancer (TNBC) patients. In this study, we investigated the potential of targeting Elongin B (ELOB) to enhance radiotherapy efficacy in TNBC. Analysis of TNBC patient cohorts revealed a significant association between high ELOB expression and poor prognosis in patients who received radiation therapy. Mechanistically, we found that ELOB plays a pivotal role in regulating mitochondrial function via modulating mitochondrial DNA expression and activities of respiratory chain complexes. Targeting ELOB effectively modulated mitochondrial function, leading to enhanced radiosensitivity in TNBC cells. Our findings highlight the importance of ELOB as a potential therapeutic target for improving radiotherapy outcomes in TNBC. Further exploration of ELOB's role in enhancing radiotherapy efficacy may provide valuable insights for developing novel treatment strategies for TNBC patients., (© 2024. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.) more...

Ethnopharmacological Relevance: As a traditional Chinese medicine, Artemisia argyi has been used medicinally and eaten for more than 2000 years in China. It is widely reported in treating inflammatory diseases such as eczema, dermatitis, arthritis, allergic asthma and colitis. Although several studies claim that its volatile oil and organic reagent extracts have certain anti-inflammatory effects, the water-soluble fractions and molecular mechanisms have not been studied., Aim of the Study: To evaluate the therapeutic effect of A. argyi water extract (AAWE) on lipopolysaccharide (LPS)-induced inflammatory responses and to identify the most effective water-soluble subfractions. Moreover, the relevant pharmacological and molecular mechanisms by which the active subfraction mitigates inflammation were further investigated., Materials and Methods: Firstly, RAW 264.7 cells stimulated with LPS were treated with AAWE (50, 100, and 200 μg/mL) or the water-soluble subfractions separated by D101 macroporous resin (AAWE1-AAWE4, 100 μg/mL), and NO production and mRNA levels of inflammatory genes were evaluated to determine the most effective water-soluble subfractions. Secondly, the chemical components of the active subfraction (AAWE4) were analyzed by UPLC-QTOF-MS. Thirdly, transcriptome and network pharmacology analysis, RT-qPCR and Western blotting assays were conducted to explore the underlying anti-inflammatory mechanism and active compounds of AAWE4. Subsequently, the binding ability of the potential active components in AAWE4 to the core targets was further determined by molecular docking. Eventually, the in vivo anti-inflammatory activity of AAWE4 (1.17, 2.34 and 4.68 g/kg, administered per day for 7 d) was evaluated in mice with LPS-induced systemic inflammation., Results: In this study, AAWE showed excellent anti-inflammatory effects, and its water-soluble subfraction AAWE4 exhibited the strongest inhibitory effect on NO concentration and inflammatory gene mRNA expression after LPS stimulation, indicating that it was the most effective subfraction. Thereafter, four main compounds in AAWE4 were confirmed or tentatively identified by UPLC-QTOF-MS, including three flavonoid glycosides and one phenolic acid. Furthermore, the transcriptome and network pharmacology analysis showed that AAWE4 inhibited inflammation via multiple pathways and multiple targets. Based on the RT-qPCR and Western blotting results, AAWE4 downregulated not only the p38, PI3K, CCL5, MMP9, AP-1, and BCL3 mRNA expression levels activated by LPS but also their upstream and downstream protein expression levels and protein phosphorylation (p-AKT/AKT, p-p38/p38, p-ERK/ERK, p-JNK/JNK). Moreover, four identified compounds (isochlorogenic acid A, vicenin-2, schaftoside and isoschaftoside) could significantly inhibit NO content and the overexpression of inflammatory factors TNF-α, IL-1β, iNOS and COX-2 mRNA induced by LPS, and the molecular docking confirmed the high binding activity of four active compounds with selected core targets (p38, AKT1, MMP9, and CCL5). In addition, the mRNA expression and immunohistochemical analysis showed that AAWE44 could inhibit lung inflammation via multiple pathways and multiple targets in vivo., Conclusions: The findings of this study suggest that the water-soluble subfraction AAWE4 from A. argyi ameliorated the inflammation caused by LPS through multiple pathways and multiple targets in vitro and in vivo, providing scientific support for the medicinal use of A. argyi. Importantly, it shows that the A. argyi subfraction AAWE4 can be developed as an anti-inflammatory drug., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.) more...

Lifespan is influenced by complex interactions between genetic and environmental factors. Studying those factors in model organisms of a single genetic background limits their translational value for humans. Here, we mapped lifespan determinants in 85 genetically diverse C. elegans recombinant intercross advanced inbred lines (RIAILs). We assessed molecular profiles - transcriptome, proteome, and lipidome - and life-history traits, including lifespan, development, growth dynamics, and reproduction. RIAILs exhibited large variations in lifespan, which positively correlated with developmental time. Among the top candidates obtained from multi-omics data integration and QTL mapping, we validated known and novel longevity modulators, including rict-1 , gfm-1 and mltn-1 . We translated their relevance to humans using UK Biobank data and showed that variants in RICTOR and GFM1 are associated with an elevated risk of age-related heart disease, dementia, diabetes, kidney, and liver diseases. We organized our dataset as a resource (https://lisp-lms.shinyapps.io/RIAILs/) that allows interactive explorations for new longevity targets., Competing Interests: Competing interests J.J.C. is a consultant for Thermo Scientific, Seer, and 908 Devices. E.K., L.M., and M.C. are employees of Nagi Bioscience S.A. Other authors do not declare a conflict related to this study. more...

Artemisia argyi (A. argyi), a plant with a longstanding history as a raw material for traditional medicine and functional diets in Asia, has been used traditionally to bathe and soak feet for its disinfectant and itch-relieving properties. Despite its widespread use, scientific evidence validating the antifungal efficacy of A. argyi water extract (AAWE) against dermatophytes, particularly Trichophyton rubrum, Trichophyton mentagrophytes, and Microsporum gypseum, remains limited. This study aimed to substantiate the scientific basis of the folkloric use of A. argyi by evaluating the antifungal effects and the underlying molecular mechanisms of its active subfraction against dermatophytes. The results indicated that AAWE exhibited excellent antifungal effects against the three aforementioned dermatophyte species. The subfraction AAWE6, isolated using D101 macroporous resin, emerged as the most potent subfraction. The minimum inhibitory concentrations (MICs) of AAWE6 against T. rubrum, M. gypseum, and T. mentagrophytes were 312.5, 312.5, and 625 μg·mL -1 , respectively. Transmission electron microscopy (TEM) results and assays of enzymes linked to cell wall integrity and cell membrane function indicated that AAWE6 could penetrate the external protective barrier of T. rubrum, creating breaches ("small holes"), and disrupt the internal mitochondrial structure ("granary"). Furthermore, transcriptome data, quantitative real-time PCR (RT-qPCR), and biochemical assays corroborated the severe disruption of mitochondrial function, evidenced by inhibited tricarboxylic acid (TCA) cycle and energy metabolism. Additionally, chemical characterization and molecular docking analyses identified flavonoids, primarily eupatilin (131.16 ± 4.52 mg·g -1 ) and jaceosidin (4.17 ± 0.18 mg·g -1 ), as the active components of AAWE6. In conclusion, the subfraction AAWE6 from A. argyi exerts antifungal effects against dermatophytes by disrupting mitochondrial morphology and function. This research validates the traditional use of A. argyi and provides scientific support for its anti-dermatophytic applications, as recognized in the Chinese patent (No. ZL202111161301.9)., (Copyright © 2024 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.) more...

Aims: To investigate the effect of succinic acid on the development of experimental autoimmune uveitis (EAU) and the underlying mechanism., Methods: Succinic acid was administrated intraperitoneally to evaluate its effects on immune response and EAU in mice. Intraocular inflammation was evaluated by histopathological scoring. Frequencies of Th1/Th17 cells were measured by flow cytometry. Concentrations of IFN-γ/IL-17A, neutrophil elastase (NE) and myeloperoxidase (MPO) were determined by enzyme-linked immunosorbent test. Infiltration of neutrophils and generation of neutrophil extracellular traps (NETs) within the eye were assessed by immumofluorescence. NETs formation in extracellular matrix was visualised by laser scanning confocal microscopy. Succinate receptor (SUCNR1) antagonist was used to investigate its effect on the generation of NETs., Results: Intraperitoneal injection of succinic acid exacerbated EAU severity as evidenced by severe histological changes in association with elevated frequencies of splenic Th1/Th17 cells, and upregulated levels of IFN-γ/IL-17A and NETs in plasma. In vitro experiments showed that succinic acid could promote the generation of NETs by neutrophils as shown by increased expression of NE and MPO.NETs could increase the frequencies of Th1/Th17 cells in CD4 + T cells and their expression of IFN-γ/IL-17A. In the experiment of receptor antagonism, the upregulatory effect of succinic acid on NETs could be significantly blocked by SUCNR1 antagonist., Conclusions: Succinic acid could worsen EAU induced by IRBP in mice. This effect was possibly mediated by its upregulation on NETs generation and frequencies of Th1/Th17 cells in affiliation with increased production of IFN-γ/IL-17A through succinic acid-SUCNR1 axis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Mass spectrometry-based large-scale multi-omics research has proven to be powerful in answering biological questions; nonetheless, it faces many challenges from sample preparation to downstream data integration. To efficiently extract biomolecules of different physicochemical properties, preparation of various sample type needs specific tailoring, especially of difficult ones, such as Caenorhabditis elegans . In this study, we sought to develop a multi-omics sample preparation method starting with a single set of C. elegans samples to save time, minimize variability, expand biomolecule coverage, and promote multi-omics integration. We investigated tissue disruption methods to effectively release biomolecules and optimized extraction strategies to achieve broader and more reproducible biomolecule coverage in proteomics, lipidomics, and metabolomics workflows. In our assessment, we also considered speediness and usability of the approaches. The developed method was validated through a study of 16 C. elegans samples designed to shine light on mitochondrial unfolded protein response (UPRmt), induced by three unique stressors─knocking down electron transfer chain element cco-1 , mitochondrial ribosome protein S5 mrps-5 , and antibiotic treatment Doxycycline. Our findings suggested that the method achieved great coverage of proteome, lipidome, and metabolome with high reproducibility and validated that all stressors triggered UPRmt in C. elegans , although generating unique molecular signatures. Innate immune response was activated, and triglycerides were decreased under all three stressor conditions. Additionally, Doxycycline treatment elicited more distinct proteomic, lipidomic, and metabolomic response than the other two treatments. This method has been successfully used to process Saccharomyces cerevisiae (data not shown) and can likely be applied to other organisms for multi-omics research. more...

Background: With the update of equipment, the hospital base of this study began to adopt craniospinal irradiation (CSI) intensity-modulated radiotherapy (IMRT) in May 2018 to replace the traditional CSI conventional radiotherapy (CRT) technology. The purpose of this study was designed to compare the differences in acute hematological adverse reactions induced by CSI-IMRT and CSI-CRT., Methods: The clinical data and hematological data of 102 patients with central nervous system malignant tumors who underwent CSI treatment at the 900th Hospital of Joint Logistics Support Force of PLA from January 2008 to August 2022 were analyzed retrospectively. The patients included 63 men and 39 women, aged 3 to 56 years old. On the basis of the radiotherapy technique used, the patients were divided into the CSI-IMRT group (38 cases) and CSI-CRT group (64 cases). Acute hematological adverse reactions during radiotherapy were compared between the two groups according to the Common Terminology Criteria for Adverse Events version 4.0. The Mann-Whitney U test was used to compare the measurement data, and the χ 2 test was used to compare the count data., Results: No significant difference was found between the CSI-IMRT group and the CSI-CRT group in terms of sex, histopathological type, tumor location, spinal cord invasion, surgery, and the Eastern Cooperative Oncology Group score (χ 2  = 0.004 to 6.213; all P  > .05). No significant difference was found in onset time of myelosuppression (11 days (interquartile range [IQR]: 7 to 14; minimum [min] to maximum [max]: 0 to 26) vs 8 days (IQR: 7 to 15; min to max: 3 to 29)) and nadir time of myelosuppression (21 days (IQR: 18 to 25; min to max: 12 to 35) vs 22 days (IQR: 15 to 25; min to max: 12 to 36)) between the CSI-IMRT group and the CSI-CRT group ( Z  = -0.856, -0.248; all P  > .05). There were no significant differences in the incidence of decreased white blood cell counts (WBC), platelet counts, and hemoglobin concentration between the CSI-IMRT group and the CSI-CRT group, 86.8% (33/38) vs 78.1% (50/64), 57.9% (22/38) vs 42.2% (27/64), 57.9% (22/38) vs 53.1% (34/64); χ 2  = 1.195, 2.357, 0.219; all P  > .05. There were no significant differences in the incidence of decreased WBC, platelet counts, and hemoglobin concentration (severe myelosuppression) in grades III and IV, 23.7% (9/38) vs 21.9% (14/64), 7.9% (3/38) vs 3.1% (2/64), 5.3% (2/38) vs 9.4% (6/64); χ 2  = 0.045, 1.164, 0.558; all P  > .05., Conclusions: There was no significant difference in the incidence of myelosuppression and severe myelosuppression (grade III or above) induced by CSI-IMRT and CSI-CRT. CSI-IMRT is worthy of further clinical application., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.) more...

Background: Familial hypercholesterolemia (FH) is an inherited disorder with markedly elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. Although many mutations have been reported in FH, only a few have been identified as pathogenic mutations. This study aimed to confirm the pathogenicity of the LDL receptor (LDLR) c.2160delC variant in FH., Methods: In this study, the proband and her family members were systematically investigated, and a pedigree map was drawn. High-throughput whole-exome sequencing was used to explore the variants in this family. Next, quantitative polymerase chain reaction (qPCR), western blot (WB) assays, and flow cytometry were conducted to detect the effect of the LDLR c.2160delC variant on its expression. The LDL uptake capacity and cell localization of LDLR variants were analyzed by confocal microscopy., Results: According to Dutch Lipid Clinic Network (DLCN) diagnostic criteria, three FH patients were identified with the LDLR c.2160delC variant in this family. An in-silico analysis suggested that the deletion mutation at the 2160 site of LDLR causes a termination mutation. The results of qPCR and WB verified that the LDLR c.2160delC variant led to early termination of LDLR gene transcription. Furthermore, the LDLR c.2160delC variant caused LDLR to accumulate in the endoplasmic reticulum, preventing it from reaching the cell surface and internalizing LDL., Conclusions: The LDLR c.2160delC variant is a terminating mutation that plays a pathogenic role in FH., (© 2023. The Author(s).) more...

Recombinant interferon-α2a (IFNα2a) has been widely used in the treatment of Behcet's uveitis (BU). However, the mechanism underlying its effects remains poorly understood. In this study, we investigated its effect on dendritic cells (DCs) and CD4 + T cells, which are essential for the development of BU. Our results showed that the expression of PDL1 and IRF1 was significantly decreased in DCs from active BU patients, and IFNα2a could significantly upregulate PDL1 expression in an IRF1-dependent manner. IFNα2a-treated DCs induced CD4 + T cells apoptosis and inhibited the Th1/Th17 immune response in association with reduced secretion of IFN-γ and IL-17. We also found that IFNα2a promoted Th1 cell differentiation and IL-10 secretion by CD4 + T cells. Finally, a comparison of patients before and after IFNα2a therapy revealed that the frequencies of Th1/Th17 cells significantly decreased in association with remission of uveitis after IFNα2a therapy. Collectively, these results show that IFNα2a could exert its effects by modulating the function of DCs and CD4 + T cells in BU., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.) more...

Background: Immune checkpoint inhibitors (ICIs) play an important role in the treatment of esophageal cancer (EC). However, their efficacy is variable, and there are still no effective and convenient biomarkers to identify and assess their efficacy. In recent years, programmed cell death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB) and other commonly used biomarkers still cannot meet clinical needs. PNI is easy to obtain and its predictive value for the prognosis of immunotherapy has been confirmed in many cancer species, but the relationship between PNI and the efficacy of immunotherapy for esophageal cancer is still unclear. Therefore, this study aims to explore the predictive value of PNI in advanced esophageal cancer treated with ICIs., Methods: The clinicopathological features of 78 patients with advanced EC who received immunotherapy in the 900th Hospital of the Joint Logistics Team from September 2018 to May 2022 were retrospectively analyzed. The laboratory test results within 10 days prior to the start of ICI treatment were recorded, including absolute lymphocyte count and albumin (ALB) level. Meanwhile, the effects of pre-treatment prognostic nutritional index (PNI) and body mass index (BMI) on the overall survival (OS) and progression-free survival (PFS) in patients with advanced EC were analyzed., Results: The median age of the enrolled patients was 58 years, and 38 patients (48.7%) received second-or-later-line therapy. The median progression-free survival (mPFS) and median overall survival (mOS) were 7.4 months and 13 months, respectively. The mPFS and mOS were 8.8 months and 15 months, respectively, in the high baseline PNI subgroup, which were significantly higher than those in the low baseline PNI subgroup (4.7 and 8.2 months, respectively; both P<0.05). Multivariate regression analysis showed that low baseline PNI was an independent predictor of poor PFS [hazard studio (HR) =0.35, 95% CI: 0.14-0.85, P=0.020) and poor OS (HR =0.41, 95% CI: 0.17-0.99, P=0.047) and treatment line was an independent predictor of PFS. Baseline BMI was not significantly associated with prognosis., Conclusions: PNI is a simple and effective biomarker for predicting the prognosis of immunotherapy in patients with advanced EC, although further prospective studies are warranted., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-48/coif). The authors have no conflicts of interest to declare., (2023 Journal of Gastrointestinal Oncology. All rights reserved.) more...

Multi-omics analysis is a powerful and increasingly utilized approach to gain insight into complex biological systems. One major hindrance with multi-omics, however, is the lengthy and wasteful sample preparation process. Preparing samples for mass spectrometry (MS)-based multi-omics involves extraction of metabolites and lipids with organic solvents, precipitation of proteins, and overnight digestion of proteins. These existing workflows are disparate and laborious. Here, we present a simple, efficient, and unified approach to prepare lipids, metabolites, and proteins for MS analysis. Our approach, termed the Bead-enabled Accelerated Monophasic Multi-omics (BAMM) method, combines an n -butanol-based monophasic extraction with unmodified magnetic beads and accelerated protein digestion. We demonstrate that the BAMM method affords comparable depth, quantitative reproducibility, and recovery of biomolecules as state-of-the-art multi-omics methods (e.g., Matyash extraction and overnight protein digestion). However, the BAMM method only requires about 3 h to perform, which saves 11 steps and 19 h on average compared to published multi-omics methods. Furthermore, we validate the BAMM method for multiple sample types and formats (biofluid, culture plate, and pellet) and show that in all cases, it produces high biomolecular coverage and data quality. more...

Purpose: To evaluate the intraocular pressure (IOP)-lowering effect of the combination of phacoemulsification with intraocular lens implantation (PEI), goniosynechialysis (GSL), and goniotomy (GT) in eyes of advanced primary angle-closure glaucoma (PACG) with cataract., Design: Multicenter observational study., Methods: We enrolled 83 eyes of 83 patients with advanced PACG who received combined PEI+GSL+GT at 8 ophthalmic institutes. Each patient was assessed before treatment and at 1, 7 days, 1, 3, 6, and 12 months postsurgery. The criteria for complete success were IOP within 6 to 18 mm Hg and at least 20% of reduction in IOP from baseline without ocular hypotensive medications or reoperation. The definition of qualified success was similar to that of complete success, except for the need for ocular hypotensive medications. The potential prognostic factors for surgical success were investigated using a multivariate logistic model., Results: All participants completed 1 year of follow-up. Complete and qualified success were achieved in 74 (89.1%) and 79 (95.2%) of 83 eyes, respectively. The mean preoperative and postsurgical IOPs were 27.4±7.3 and 14.2±2.6 mm Hg, respectively. Participants used an average of 2.0 and 0.3 types of ocular hypotensive medications before and after surgery, respectively. The chief complications included hyphema (n=9), IOP spike (n=9), and corneal edema (n=8). None of the eyes required reoperation or developed vision-threatening complications. Multivariate analysis showed that older age was associated with a higher probability of complete success (odds ratio=1.13; 95% CI: 1.02-1.25; P=0.020)., Conclusions: The 1-year results of combination of PEI+GSL+GT in treating advanced PACG cases with cataract appear to be safe and effective. Further large-scale multination and multicenter studies are warranted., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.) more...

The "real-world" data of programmed cell death protein 1 (PD-1) inhibitors in esophageal cancer (EPC) are still an unmet medical need, including the clinical efficacy and safety. Seventy-seven EPC data were studied retrospectively; the progression-free survival (PFS), risk factors (clinical stages larger than stage II, metastatic sites larger than 2, treatment lines larger than the first line, previous surgical treatment, combined positive score [CPS] expression, etc.), and the safety were analyzed. The median PFS for all patients was 7.2 months, clinical stage > stage II; the number of treatment lines > first line was significantly correlated with prognosis (all P < 0.05). Subgroup analysis showed that the median PFS of patients with clinical stage ≤ II was better; the results were the same for the patients with ≤2 metastatic sites, first-line PD-1 inhibitors, and not previously received radical surgery (all P < 0.05). Meanwhile, the incidence of adverse events (AEs) of varying degrees was 25.97% (20/77) in 20 patients and 6.49% (5/77) of grade 3/4 AEs. The highest AE was myelosuppression (15.58%), followed by liver function injury (7.79%). In addition, ≥2 lines of treatment and >2 metastatic sites predicted poor outcomes for patients with EPC who had failed first-line therapy or progressed with the combined immunotherapy and chemotherapy treatment strategy (all P < 0.05)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Cai, Wu, Li, Zhu, Lin, Yan, Mo, Luo and Fu.) more...

Purpose: The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology call for cautious interpretation of variants as causative of a monogenic disorder by stringent standards. We aimed to reclassify the pathogenicity of nucleotide binding oligomerization domain containing 2 (NOD2) variants according to the ACMG guidelines and to characterize clinical features in patients whose ocular disease might actually be explained by Blau syndrome., Design: Genetic analysis and descriptive study., Participants: A total of 1003 unrelated healthy individuals and 3921 sporadic patients who presented with uveitis., Methods: Whole-exome sequencing was performed on all healthy participants and 551 patients with uveitis, and targeted NOD2 resequencing was performed on the remaining 3370 patients with uveitis. Pathogenicity for Blau syndrome was classified for NOD2 variants identified by sequencing in study participants according to the ACMG guidelines. Clinical manifestations were compared among NOD2 variants of different levels of classification., Main Outcome Measures: Pathogenicity of variants., Results: Eight NOD2 gain-of-function mutations, p.R334W, p.R334Q, p.E383K, p.G481D, p.W490S, p.M513T, p.R587C, and p.N670K, were classified as pathogenic, and 66 patients (1.7%) with uveitis were diagnosed with Blau syndrome due to these mutations. Of 66 with Blau syndrome, anterior uveitis accounted for 39.4%, posterior uveitis for 9.1%, and panuveitis for 51.5%. A proportion of 21.2% of Blau syndrome presented as multifocal choroiditis, 48.5% had papillitis, and 74.2% showed retinal microvasculitis detected by fundus fluorescein angiography. Six NOD2 variants, p.P268S, p.R311W, p.R471C, p.A612T, p.R702W, and p.V955I, were considered nonpathogenic for Blau syndrome and were identified in 96 patients with uveitis. The incidence of bilateral uveitis (86.4%), secondary glaucoma (47.0%), epiretinal membrane (7.6%), choroidal neovascularization (4.6%), retinal atrophy (10.6%), arthritis (69.7%), joint deformity (51.5%), and skin rash (40.9%) was higher in Blau syndrome than in patients with uveitis carrying non-Blau-causing NOD2 variants. Patients with Blau syndrome permanently experienced overall poorer best-corrected visual acuity. Several rare NOD2 mutations, p.I722L (2 cases), p.T476P (1 case), p.T476del (1 case), and p.R439H (1 case), were newly identified., Conclusions: Pathogenic NOD2 variants for Blau syndrome were limited to those gain-of-function mutations and were associated with a high risk for arthritis, skin rash, permanent visual loss, and ocular complications in patients with uveitis., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.) more...

Allelopathy is considered an environmentally friendly and resource-conserving approach to weed control because allelochemicals degrade easily and cause less pollution than traditional chemical herbicides. In this study, the allelopathic active constituents of Artemisia argyi were elucidated by activity-guided isolation and ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). First, a crude extract prepared in water was fractionated using macroporous resin D101 to obtain three fractions (Fr.A-C). Combined with the allelopathic activity assay on Setaria viridis and Portulaca oleracea , Fr.C was determined to be the most active fraction. We identified 14 compounds in the active fraction (Fr.C) using UPLC-QTOF-MS, including 13 phenolic compounds. Accordingly, phenolic components have been suggested as the main allelochemicals in A. argyi . Thereafter, Fr.C was further isolated by octadecylsilyl (ODS) chromatography to obtain eight subfractions (Fr.C-1-Fr.C-8). Finally, isochlorogenic acid A (ICGAA) was purified from Fr.C-3 by semipreparative liquid chromatography, which was detected in the growth environment of A. argyi . Furthermore, we evaluated the allelopathic effects of ICGAA on six weeds from different families and genera for the first time. The results showed that ICGAA is a novel allelochemical with broad herbicidal activity. In addition, we analyzed the inhibitory effect and molecular mechanism of ICGAA on the growth of S. viridis seedlings. Optical microscopy and transmission electron microscopy (TEM) revealed the degradation of membrane structures and organelles after ICGAA treatment. Transcriptome and real-time polymerase chain reaction (RT-qPCR) analysis showed that ICGAA inhibited the growth of weeds mainly by inhibiting the diterpenoid biosynthesis pathway (especially gibberellins, GAs). The decrease of gibberellin (GA) contents after ICGAA treatment also confirmed these results. In brief, this study provides new material sources and theoretical support for developing biological herbicides for agroecosystems. more...

Artemisia argyi is widely distributed in Asia, and it often becomes the dominant population in the field because of its strong ecological niche competitiveness. Allelochemicals secreted by plants are generally considered an important reason for their dominance in ecological competition. In this study, the allelochemicals in A. argyi were screened by a series of experiments and their mechanisms were explored via transcriptomics. First, the inhibitory effects of A. argyi on Echinochloa crusgalli , Setaria viridis , Portulaca oleracea and Amaranthus retroflexus were evaluated. Then, we carried out a qualitative and quantitative analysis of the chemical composition of the aqueous extract of A. argyi to screen for potential allelochemicals that can inhibit weed growth. Four potential allelochemicals were quantified: neochlorogenic acid (5-CQA), chlorogenic acid (3-CQA), cryptochlorogenic acid (4-CQA), and caffeic acid (CA). Coincidentally, their allelopathic effects on weeds seemed to be identical to their content, in the order CA>4-CQA>5-CQA>3-CQA. These findings suggested that CA might be the main allelopathic compound in the aqueous extract of A. argyi . Subsequently, the allelopathic effect and molecular mechanism of CA on S. viridis leaves were investigated. The physiological results showed that CA significantly induced reactive oxygen species (ROS) production, led to malondialdehyde (MDA) accumulation, and disrupted enzyme activities (POD, SOD, CAT) in S. viridis leaves. Moreover, transcriptome results revealed that CA inhibited S. viridis growth by downregulating multiple genes involved in gibberellin (GA) and phytoalexin biosynthesis and Mitogen-activated protein kinase (MAPK) signaling pathways. In addition, differentially expressed genes (DEGs) related to the biosynthesis and signaling pathways of phytohormones were verified by Quantitative Real-Time PCR (RT-qPCR). Taken together, this study may be the first to identify allelochemicals and explore their molecular mechanism about A. argyi . Importantly, the ecological advantages of A. argyi could be applied to ecological regulation and the development of botanical herbicides., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Li, Zhu, Guo, Ji, Miao, Guo, Du and Liu.) more...

The mitochondrial unfolded protein response (UPRmt) is a promising pharmacological target for aging and age-related diseases. However, the integrative analysis of the impact of UPRmt activation on different signaling layers in animals with different genetic backgrounds is lacking. Here, we applied systems approaches to investigate the effect of UPRmt induced by doxycycline (Dox) on transcriptome, proteome, and lipidome in two genetically divergent worm strains, named N2 and CB4856. From the integrated omics datasets, we found that Dox prolongs lifespan of both worm strains through shared and strain-specific mechanisms. Specifically, Dox strongly impacts mitochondria, upregulates defense response, and lipid metabolism, while decreasing triglycerides. We further validated that lipid genes acs-2/20 and fat-7/6 were required for Dox-induced UPRmt and longevity in N2 and CB4856 worms, respectively. Our data have translational value as they indicate that the beneficial effects of Dox-induced UPRmt on lifespan are consistent across different genetic backgrounds through different regulators., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.) more...

Background: Peritoneal dialysis (PD) can be associated with abnormal cardiac structure and function and increased mortality risk. Therefore, in this study, we analyzed the cardiac structure and function dynamic changes using echocardiography during the first 2 years of PD therapy. We also assessed its associations with all-cause mortality risk after 2 years of follow-up., Methods: End-stage renal disease (ESRD) patients that have started PD from 2011 to 2017, and had echocardiography at baseline and years 1 and 2, were included in this study. Echocardiographic parameters were compared between baseline and year 2. Multivariable Cox models were used to estimate the association between echocardiographic parameters changes and all-cause mortality risk., Results: We finally enrolled 72 PD patients in this study. The mean right ventricular diameter (RVD) increased from baseline (18.31 mm) to year 1 (18.75 mm) and year 2 (19.65 mm). We also observed a significant decrease in cardiac output (CO) between baseline and year 2. Additionally, a slight decrease trend in ejection fraction (EF) was observed. Finally, every 1 % increase in RVD was associated with a 68.2 % higher mortality risk after dialysis (HR, 1.682; 95 % CI, 1.017-2.783)., Conclusions: Our results demonstrated a susceptibility for deteriorated right cardiac structure and function during the first 2 years of PD treatment. Also, higher all-cause mortality risk was observed after 2 years of PD. Altogether, these results highlighted the need for additional focus on regular echocardiographic examinations during long-term PD management., Trial Registration: The PD-CRISC cohort, registered with the Chinese Clinical Trial Registry ( ChiCTR1900023565 )., (© 2021. The Author(s).) more...

Chrysanthemum Flos is the prestigious traditional Chinese medicinal material and the popular health drink. This article comprehensively evaluated the chemical constituents, antioxidant activity, and hepatoprotective effects of 25 common chrysanthemum varieties in China. Firstly, we analyzed the chemical compositions of water extracts of chrysanthemum using UPLC/Q-TOF-MS, and identified 29 chemical components. The results displayed that chrysanthemum was rich in chemical constituents, but there were significant differences in the contents of four phenolic acids and five flavonoids among different varieties, and the coefficient of variation (CVs) ranged from 35.96 % to 114.62 %. Then, the antioxidant activities of different chrysanthemums were investigated, respectively via 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), and Ferric Reducing Antioxidant Power (FRAP) assays. The spectrum-effect relationships between nine main components and antioxidant activities were investigated to identify the antioxidant constitutes in chrysanthemums. Meanwhile, H 2 O 2 -induced hepatocyte injury testing showed wide variation in cultivar antioxidant capacity, with Tongchengju (TCJ) producing the best effect (90.32 %), followed by Chuju (CJ; 85.78 %). In addition, the hepatoprotective effects of 8 mainstream varieties were determined by the model of acute alcoholic liver injury. They protected liver from injury by affecting relevant liver function and antioxidant indexes. Huangshangongju (HSG) could decrease aspartate aminotransferase (AST) activity by 39.27 % in liver tissue; Hangju-Fubaiju (HJ-FBJ), Jinsihuangju (JSH), and Chuju (CJ) significantly decreased the malondialdehyde (MDA) content of liver tissue, which reduced by more than 40 %; Jinsihuangju (JSH) of used for tea could double the content of glutathione (GSH) and had the similar effect on superoxide dismutase (SOD) as the positive group, showing significant antioxidant capacity. Therefore, this study confirmed that chrysanthemums are potential resources as antioxidants, functional foods, and medicinal materials. Importantly, it may provide a scientific support for further development and utilization of chrysanthemum, and screen excellent varieties for different demands., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.) more...

We performed RNA-seq and high-resolution mass spectrometry on 128 blood samples from COVID-19-positive and COVID-19-negative patients with diverse disease severities and outcomes. Quantified transcripts, proteins, metabolites, and lipids were associated with clinical outcomes in a curated relational database, uniquely enabling systems analysis and cross-ome correlations to molecules and patient prognoses. We mapped 219 molecular features with high significance to COVID-19 status and severity, many of which were involved in complement activation, dysregulated lipid transport, and neutrophil activation. We identified sets of covarying molecules, e.g., protein gelsolin and metabolite citrate or plasmalogens and apolipoproteins, offering pathophysiological insights and therapeutic suggestions. The observed dysregulation of platelet function, blood coagulation, acute phase response, and endotheliopathy further illuminated the unique COVID-19 phenotype. We present a web-based tool (covid-omics.app) enabling interactive exploration of our compendium and illustrate its utility through a machine learning approach for prediction of COVID-19 severity., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Cyanobacteria blooms are crucial environmental issues by threatening both aquatic ecosystem and human health. A biomass by-product with antimicrobial activity, pyroligneous acid (PA) was tested for its suitability for removal of the cyanobacteria Microcystis aeruginosa (M. aeruginosa) in this work. Results show that the removal efficiency could reach up to 90% in the presence of 0.45% of PA and the inhibition to M. aeruginosa growth could extend to at least 40 days. The removal mechanism was studied. Both organic acids and phenols are functional content in M. aeruginosa removal and acetic acid is the most important one. Zeta potential analysis and morphology study show that the damage of cells dominates the flocculation and sedimentation of M. aeruginosa under low PA concentration (<0.7%), and increasing PA (≥0.7%) resulted in a trend of zeta potential to zero, thus removing any "shield" and triggering flocculation. Finally, study on the phenols residual after M. aeruginosa treatment shows that it could be close to 0 in 70 h. Therefore, this work proposes a possible method for world-wide treatment of cyanobacteria bloom and a new way for further utilization of PA., (Copyright © 2020 Elsevier Inc. All rights reserved.) more...

We performed RNA-Seq and high-resolution mass spectrometry on 128 blood samples from COVID-19 positive and negative patients with diverse disease severities. Over 17,000 transcripts, proteins, metabolites, and lipids were quantified and associated with clinical outcomes in a curated relational database, uniquely enabling systems analysis and cross-ome correlations to molecules and patient prognoses. We mapped 219 molecular features with high significance to COVID-19 status and severity, many involved in complement activation, dysregulated lipid transport, and neutrophil activation. We identified sets of covarying molecules, e.g., protein gelsolin and metabolite citrate or plasmalogens and apolipoproteins, offering pathophysiological insights and therapeutic suggestions. The observed dysregulation of platelet function, blood coagulation, acute phase response, and endotheliopathy further illuminated the unique COVID-19 phenotype. We present a web-based tool (covid-omics.app) enabling interactive exploration of our compendium and illustrate its utility through a comparative analysis with published data and a machine learning approach for prediction of COVID-19 severity. more...

Background: Sjögren syndrome (SS) is a rare disease in pediatrics, and little attention has been paid to the clinical feature in these patients. To date, there are few cases concern about neurological and nephrological disorders in childhood Sjögren syndrome. We describe a case of Sjögren syndrome in a 12-year-old girl who developed neurological disorders and interstitial nephritis and review the literature currently available on this topic., Case Presentation: A 12-year-old girl was admitted to our hospital for arthritis and glucosuria. She was required to do labial gland and renal biopsy, because the positive for anti-nuclear antibody and anti-Sjögren syndrome B (anti-SSB) antibody. Then the biopsy was performed revealing the lymphocytic infiltrate in the small area and renal tubular interstitial damage,thus the diagnosis of Sjögren syndrome with tubular interstitial damage was made. Three months later, she presented again with headache, fever, nausea, vomiting and was recovered without drug therapy. Based on the patient's medical history, laboratory and imaging examination, and treatment, we speculate that the disorders of the nervous system were caused by the Sjögren syndrome. The girl has stable renal function and no residual nervous system damage in the next 1.5 years, but she underwent low dose prednisone therapy because of persistent renal glucosuria., Conclusions: Nephrological disorders and neurological involvement are rare manifestations of Sjögren syndrome in children, and rarely presented as the initial symptoms. It should be suspected in children presenting with unexplained renal diseases, neurological abnormalities, or unexplained fever. Although there is no guidelines on the diagnosis and treatment of children Sjögren syndrome are currently available, early recognition and the appropriate treatment of renal damage and neurologic involvement would improve prognosis and prevent complications. more...

Currently, statins are the first-line therapies for dyslipidemia and atherosclerotic cardiovascular disease, however, their hypolipidemic effects have not been satisfactory. We performed a meta-analysis to compare lipid-lowering efficacy and safety of ezetimibe and statin combination therapy with double-dose statin monotherapy in patients with high cardiovascular risk. Fourteen studies involving 3105 participants were included in the final analysis; 1558 (50.18%) participants received ezetimibe and statin combination therapy and 1547 (49.82%) received double-dose statin monotherapy. Eight studies reported the percentages of changes in several lipid parameters from baseline to endpoint in both groups. Lipid parameters changed more significantly in patients coadministered with ezetimibe and statin (low-density lipoprotein cholesterol [LDL-C]: MD = -9.39, 95% CI -13.36 to -5.42; non-high-density lipoprotein cholesterol [non-HDL-C]: MD = -10.36, 95% CI -14.23 to -6.50; total cholesterol [TC]: MD = -8.11, 95% CI -10.95 to -5.26; and triglyceride [TG]: MD = -5.96, 95% CI -9.12 to -2.80), with moderate to high heterogeneity among the studies. Two out of fourteen studies investigated several different statins. Our subgroup analysis showed that, compared with double-dose atorvastatin monotherapy, ezetimibe and atorvastatin combination therapy significantly decreased LDL-C, non-HDL-C, TC, and TG levels by 14.16%, 14.01%, 11.06%, and 5.96%, respectively (p < 0.001). No significant difference was found in the incidence of laboratory-related adverse events (AEs) between statin combination therapy and monotherapy. Overall, ezetimibe and statin combination therapy significantly decreased LDL-C, non-HDL-C, and TC levels in patients with high cardiovascular risk, among which ezetimibe combined with atorvastatin had the best therapeutic effect. Compared with ezetimibe and statin combination therapy, double-dose statin monotherapy did not increase the risk of AEs. more...

Background: Simultaneous bilateral femoral neck fractures are extremely rare without obvious injury. Herein, we report the case of a patient on dialysis presenting with bilateral femoral neck fractures, which is a condition with high complication and mortality rates according to a review of the pertinent literature., Case Presentation: We report the case a 47-year-old female with a history of 8 years of haemodialysis due to polycystic kidney disease who presented with bilateral hip pain during walking. The clinical history and results of physical and radiographic examinations of this patient are shown. Single-stage bilateral hemiarthroplasty was performed after a multidisciplinary team consultation. Three days after the operation, she could ambulate with a walker. The woman gradually regained her previous ability to walk over 6 months after surgery., Conclusions: A multidisciplinary team consultation for perioperative management is necessary and effective in patients on dialysis. Early diagnosis with prompt surgical treatment could lead to favourable recovery. more...

Objective: The aetiology of Behçet's disease (BD), known as a systemic vasculitis, is not completely understood. Increasing evidence suggests that aberrant DNA methylation may contribute to the pathogenesis of BD. The aim of this epigenome-wide association study was to identify BD-associated methylation loci in Han Chinese., Methods: Genome-wide DNA methylation profiles were compared between 60 BD patients and 60 healthy controls using the Infinium Human Methylation 450 K Beadchip. BD-associated methylation loci were validated in 100 BD patients and 100 healthy controls by pyrosequencing. Gene expression and cytokine production was quantified by real-time PCR and ELISA., Results: A total of 4332 differentially methylated CpG sites were associated with BD. Five differentially methylated CpG sites (cg03546163, cg25114611, cg20228731, cg23261343 and cg14290576) revealed a significant hypomethylation status across four different genes (FKBP5, FLJ43663, RUNX2 and NFIL3) and were validated by pyrosequencing. Validation results showed that the most significant locus was located in the 5'UTR of FKBP5 (cg03546163, P = 3.81E-13). Four CpG sites with an aberrant methylation status, including cg03546163, cg25114611, cg23261343 and cg14290576, may serve as a diagnostic marker for BD (area under the receiver operating curve curve = 83.95%, 95% CI 78.20, 89.70%). A significantly inverse correlation was found between the degree of methylation at cg03546163 as well as cg25114611 and FKBP5 mRNA expression. Treatment with a demethylation agent, 5-Aza-2'-deoxycytidine resulted in an increase of FKBP5 mRNA expression and a stimulated IL-1β production., Conclusion: Our findings suggest that aberrant DNA methylation, independently of previously known genetic variants, plays a vital role in the pathogenesis of BD., Trial Registration: Chinese Clinical Trial Registry, chictr.org.cn, ChiCTR-CCC-12002184., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.) more...

The key transcription factors of T helper cell subpopulations, including T-bet, GATA3, ROR γ t, and Foxp3 are involved in various autoimmune diseases. Whether methylation of these master transcription factors is associated with the development of experimental autoimmune uveitis (EAU) and the possible epigenetic regulatory mechanisms involved has however not yet been addressed. In our study, significant methylation changes in both Tbx21 and Rorc were observed in one CpG site in the retinas of EAU mice. Two CpG sites of Tbx21 and one CpG site of Rorc showed significant dynamic methylation changes in the RPE-choroid complex during EAU. The mRNA expressions of Tbx21 and Rorc in both the retinas and RPE-choroid complexes correlated with the methylation changes at the various time points during EAU development. The methylation changes were associated with the production of the Th1/Th17 cells' signature cytokines, IFN- γ and IL-17. Dynamic changes in mRNA expression of DNA methyltransferases (DNMT1) were also noted, which may be related to the observed methylation changes of these genes. The present study provides evidence that DNA methylation of Tbx21 and Rorc may be associated with the development of EAU. DNMT1 activation may have an important effect on regulating DNA methylation dynamics. more...

Hepatitis B virus X protein (HBx) has been previously demonstrated to be associated with the regulation of cell proliferation; however, the exact mechanisms underlying this effect remain unclear. The present study aimed to investigate the regulatory mechanism of HBx on the cycle progression of primary renal tubular epithelial cells. Primary renal tubular epithelial cells of Sprague Dawley (SD) rats were separated and cultured. The morphology of cultured cells was characterized by immunohistochemical analysis and the results demonstrated that primary renal tubular epithelial cells with the expected morphology and distribution were successfully separated and cultured from SD rats. HBx gene pcDNA3.1/myc vector and empty vector were constructed and transfected into cells as HBx and empty groups, respectively. Following transfection, the mRNA and protein levels of HBx, cyclin A, cyclin D1 and cyclin E in cells were determined by reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively. The results demonstrated that following HBx gene transfection, the mRNA and protein levels of HBx, cyclin A, cyclin D1 and cyclin E in cells were significantly upregulated, compared with the empty control group (P<0.05). Furthermore, cell apoptosis and the cell cycle were evaluated by Annexin V‑fluorescein isothiocyanate/propidium iodide staining and flow cytometry. HBx gene transfection significantly inhibited the cell apoptosis (P<0.05), promoted cell cycle progression from the G1 to S phase and arrested the cell cycle in the S phase. Therefore, the results of the present study indicated that HBx gene transfection may regulate the apoptosis and cell cycle of primary renal tubular epithelial cells by affecting the expression of cyclins. The results of the present study may improve the understanding of pathogenesis associated with HBV‑associated glomerulonephritis, and may also provide insight and theoretical support for the future design and development of drugs for the treatment of hepatitis B virus. more...

Microorganisms in the rhizosphere of wetland plants can have a significant impact on phosphorus (P) interception. We investigated the seasonal pattern of microbial community structure and its relationship with different P forms in the rhizosphere of three plants Scirpus planiculmis, Zizania latifolia, and Phragmites australis from the Yeyahu Wetland, China. Chloroform fumigation-extraction was used to determine the soil microbial biomass P (SMBP) and phospholipid fatty acids (PLFA) were used to characterize microbial community composition. P fractions in rhizosphere soil samples were also observed using sequential chemical fractionation. Results showed that the average total PLFA (TPLFA) contents of rhizosphere soils ranged from 34.9 to 40.7nmol·g -1 and were highest in summer. Bacteria were predominant in the rhizospheres of all three plants, accounting for >63% of TPLFA. Aerobic bacteria, represented by 16:0 PLFA, were most abundant. Both organic P (OP) and inorganic P (IP) accumulated in the rhizosphere during the winter die-back phase. Furthermore, both TPLFA and bacterial PLFA decreased with increases in highly resistant OP (HR-OP), occluded P (Oc-P) and Calcium-bound P (Ca-P). This suggests that bacteria play an important role in P transformation and can make use of various P forms. We also found that SMBP was significantly negatively correlated with labile OP (L-OP), moderately labile OP (ML-OP) and HR-OP, reflecting a high degree of cross correlation between SMBP and the PLFA indices., (Copyright © 2018 Elsevier B.V. All rights reserved.) more...

Hydrogen sulfide is a highly toxic molecule to human health, but high-performance detection of it remains a challenge. Herein, we report an ultrasensitive photoelectrochemical (PEC) sensor for H bscript>2 S by modifying indium tin oxide (ITO) electrodes with Cd 2+ -doped amorphous TiO 2 hollow spheres, which are prepared by templating against colloidal silica particles followed by a cadmium-sodium cation exchange reaction. The amorphous TiO 2 hollow spheres act as both the probing cation carrier and the photoelectric beacon. Upon exposure to sulfide ions, the photocurrent of the functionalized photoanode proportionately decreases in response to the formation of CdS nanoparticles. The decreased photocurrent could be attributed to the mismatching bandgap between the amorphous TiO 2 and CdS nanoparticles: the photoexcited electrons and holes from amorphous TiO 2 are transferred to the conduction band and valence band of CdS, respectively, and then recombined. The decrease in photocurrent is linear with the concentration of sulfide ions in the range from 1 to 10 000 pmol L -1 with a detection limit of 0.36 pmol L -1 . Enabled by a unique sensitization mechanism, this PEC sensor features excellent performance in a wide linear range, high selectivity and sensitivity, high stability, and low fabrication cost. more...

The pathogenesis of Behcet's disease (BD) remains poorly understood. The purpose of this study was to investigate whether an aberrant DNA methylation of transcriptional and inflammatory factors, including TBX21, GATA3, RORγt, FOXP3, IFN-γ, IL-4, IL-17A and TGF-β , in CD4 + T confers risk to BD. We found that the promoter methylation level of GATA3, IL-4 and TGF-β was significantly up-regulated in active BD patients and negatively correlated with the corresponding mRNA expression. The mRNA expression of GATA3 and TGF-β was markedly down-regulated in active BD patients compared to healthy individuals. Treatment with corticosteroids and cyclosporine (CsA) resulted in a decrease of the methylation level of GATA3 and TGF-β in inactive BD patients. Our results suggest that an aberrant DNA methylation of GATA3 and TGF-β is associated with their mRNA expression and participates in the pathogenesis of BD., Competing Interests: CONFLICTS OF INTEREST The authors proclaim no financial interests in the present study. more...

Aberrant methylation change of IRF8 confers risk to various tumors, and abnormal expression of IRF8 is involved in many autoimmune diseases, including ocular Behcet's disease. However, whether the methylation change of IRF8 is associated with Vogt-Koyanagi-Harada (VKH) disease remains unknown. In the present study, we found a decreased IRF8 mRNA expression in association with a higher methylation level in monocyte-derived dendritic cells (DCs) from active VKH patients compared with the normal and inactive subjects. DCs incubated with cyclosporin a (CsA) or dexamethasone (DEX) showed a lower methylation and higher mRNA expression of IRF8 in active VKH patients. A demethylation reagent, 5-Aza-2'-deoxycytidine (DAC) showed a notable demethylation effect as evidenced by increasing the mRNA expression and reducing the methylation level of IRF8. It also suppressed the Th1 and Th17 responses through down-regulating the expression of co-stimulatory molecules (CD86, CD80, CD40), and reducing the production of pro-inflammatory cytokines (IL-6, IL-1β, IL-23, IL-12) produced by DCs. These findings shows that hypermethylation of IRF8 in DCs confers risk to VKH disease. Demethylation of IRF8 may offer a novel therapeutic strategy protect against VKH disease. more...

Aberrant methylation of interferon regulatory factor 8 (IRF8) has been noted in various tumors. IRF8 has also been reported to be involved in many autoimmune diseases, including Behcet's disease (BD). However, the methylation status of IRF8 in BD has not been reported. To address this issue, we investigated whether the degree of methylation of IRF8 in dendritic cells (DCs) plays a role in the development of BD. We found a lower mRNA expression and a higher methylation level of IRF8 in active ocular BD patients as compared to normal subjects and inactive patients. Treatment with a demethylation agent, 5-Aza-2'-deoxycytidine (DAC) resulted in an increase of mRNA expression and a reduction of the IRF8 methylation level. It also down-regulated the expression of the co-stimulatory molecules CD86, CD80, CD40, and reduced the production of IL-6, IL-1β, IL-23 and IL-12. An inhibition of Th1/Th17 responses was observed as evidenced by a decreased production of IFN-γ, IL-17, and a reduction of IFN-γ/IL-17- producing CD4 + T cells following treatment with DAC. This study shows that active ocular BD patients have an aberrant IRF8 methylation status. These findings suggest that epigenetic control of IRF8 expression may offer a future target in the treatment of ocular BD., Competing Interests: CONFLICTS OF INTEREST The authors declare no financial interests in the present study. more...

The goal of our study was to investigate the contribution of ABCB1 expression to the risk of clopidogrel resistance (CR). Platelets functions were measured using the Verify-Now P2Y12 assay. Applying Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP), the single-nucleotide polymorphisms (SNPs) was tested. Using bisulphite pyrosequencing assay, we investigated the association of the ABCB1 DNA methylation levels and CR. It was shown that female, hypertension, and lower albumin levels increased the risk of CR (P<0.05). If patients did not have hypoproteinaemia or had hypertension, the SNP in rs1045642 was associated with CR (CC vs. TT: albumin ≥35, P = 0.042; hypertension, P = 0.045; C vs. T: albumin ≥35, P = 0.033; hypertension, P = 0.040). Additionally, the platelet inhibition of the CT+TT genotype in rs1128503 was larger than that of the CC genotype (P = 0.021). Multivariate logistic regression analysis showed that male, higher albumin and hsCRP decreased the risk of CR, and the stent size maybe positively correlated with CR. The SNP in rs1045642 was related to all-cause mortality (P = 0.024). We did not find any relationship between the methylation levels of the ABCB1 promoter and CR. In conclusions, our study indicated that ABCB1 polymorphisms might be useful in further evaluating the pathogenesis of CR. more...

Purpose: We investigated the role of promoter methylation of transcriptional and inflammatory factors, including TBX21, GATA3, RORγt, FOXP3, IFN-γ, IL-4, IL-17A, and TGF-β in the development of Vogt-Koyanagi-Harada (VKH) disease., Methods: The promoter methylation levels were detected by the Sequenom MassARRAY system in CD4+ T cells that were separated from 20 healthy individuals and 32 VKH patients (20 in the active stage without medication, 12 in inactive stage with medication). The mRNA expression level of GATA3, IL-4, and TGF-β in CD4+ T cells was analyzed by real-time RT-PCR., Results: The promoter methylation levels of GATA3, IL-4, and TGF-β were significantly higher in active VKH patients than in healthy individuals (P < 0.05). A decreased mRNA expression of GATA3 and TGF-β was found in active VKH patients, which was correlated negatively with the DNA methylation of these factors. Treatment with systemic corticosteroid and cyclosporin A (CsA) decreased the methylation level of GATA3 and TGF-β in association with an increased mRNA expression of molecules and reduced disease activity., Conclusions: Our findings suggest that promoter hypermethylation of GATA3 and TGF-β in CD4+ T cells confers risk to VKH disease in Han Chinese. more...

Background: Although previous genome-wide association studies in various cohorts have identified several susceptibility loci underlying Behçet's disease (BD), this has not yet led to a breakthrough in the management of BD., Objective: This study aimed to further investigate the association of 26 candidate single nucleotide polymorphisms with previous genome-wide association studies-identified nearly positive P values (5.0 × 10 -8  < P < 1.0 × 10 -5 ) in Chinese Han patients with BD., Methods: A case-control association study was performed in 1206 patients with BD and 2475 healthy controls. Genotyping was performed using iPLEX Gold genotyping assay. Gene expression and cytokine production was quantified by real-time PCR and ELISA., Results: The results showed that significantly higher frequencies of the IL23R-IL12RB2/rs924080 TT genotype (P = 2.03 × 10 -8 ; odds ratio [OR] = 1.50), IL23R-IL12RB2/rs12141431 CC genotype (P = 2.18 × 10 -8 ; OR = 1.53), IL10/rs1800871 TT genotype (P = 5.88 × 10 -8 ; OR = 1.47), and IL10/rs3024490 TT genotype (P = 2.80 × 10 -5 ; OR = 1.34) were found in BD. Functional experiments showed an increased IL23R expression and IL-17 production in rs12141431/CC genotype carriers compared with GG genotype carriers. A decreased IL10 expression and IL-10 production was observed in rs3024490/TT genotype carriers as compared with GG genotype carriers., Conclusions: Our findings not only confirmed the association of IL10/rs1800871 and IL23R-IL12RB2/rs924080 with BD but also identified 2 susceptibility single nucleotide polymorphisms in IL10 and IL23R-IL12RB2 (rs3024490 and rs12141431) with BD in Han Chinese., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...

Background: A number of researches have evaluated the association between the ABCB1 polymorphism and the lipid-lowering response of statins, but the results have been inconclusive. To examine the lipid-lowering efficacy and safety associated with the ABCB1 C3435T polymorphism in hypercholesterolemic patients receiving statin, all available studies were included in this meta-analysis., Methods: A systematic search for eligible studies in the Cochrane library database, Scopus and PubMed was performed. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated by the meta-analysis., Results: The results indicated that the comparisons of CC+CT vs. TT were associated with a significant elevation of the serum HDL-C levels after statin treatment (CC+CT vs. TT: MD, 2.46; 95 % CI, 0.36 to 4.55; P = 0.02), and the ABCB1 C3435T variant in homozygotes was correlated with decreases in LDL-C (CC vs. TT: MD, 2.29; 95 % CI, 0.37 to 4.20; P = 0.02) as well as TC (CC vs. TT: MD, 3.05; 95 % CI, 0.58 to 5.53; P = 0.02) in patients treated with statin. However, we did not observe a significant association in the TG group or an association between other genetic models serum lipid parameters. In addition, statin treatment more than 5 months led to a higher risk of muscle toxicity., Conclusions: The evidence from the meta-analysis demonstrated that the ABCB1 C3435T polymorphism may represent a pharmacogenomic biomarker for predicting treatment outcomes in patients on statins and that statin treatment for more than 5 months can increase the risk of myopathy. more...

MDG-1, a water-soluble polysaccharide extracted from Ophiopogon japonicus, has potent hypoglycemic and weight control effects. We investigated the impact of MDG-1 on body weight, indirect calorimetry, body composition, plasma biochemical indices and obesity-related mitochondrial activity in diet-induced obese mice. Obese C57BL/6 mice induced by a high fat diet were given either vehicle or vehicle plus MDG-1 at 300 mg per body weight for 16-weeks. MDG-1 could evoked weight loss and reduce adipose tissue mass (by up to ∼ 50%) in the obese animals by increasing oxygen consumption and energy expenditure without inhibiting appetite or increasing physical activity. In addition, MDG-1 could ameliorate plasma lipid profiles, decrease leptin secretion, attenuate hepatic lipid accumulation and increased the expressions of genes related to lipid and energy metabolism in the liver. MDG-1 is a promising candidate drug to treat obesity-related metabolic diseases., (Copyright © 2014 Elsevier Ltd. All rights reserved.) more...

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder with systemic complications and has been a worldwide epidemic. Ophiopogon japonicus is a traditional Chinese medicine used to treat diabetes for thousands of years. From our previous work, we know that MDG-1, a water-soluble β-D-fructan polysaccharide from O. japonicas could treat T2DM experimentally. However, MDG-1 is poorly absorbed and its mechanism of action is still unknown. Therefore, a GC TOF/MS-based metabonomic approach in combination with multivariate statistical analysis was performed to investigate the mechanism of MDG-1 in a spontaneous diabetic model. Female diabetic KKay mice (21 weeks old) were randomly divided into a diabetic group (n = 6, gavaged with distilled water) and a MDG-1-Diabetic group (n = 7, gavaged with MDG-1, 300 mg kg(-1)) and female C57BL/6 mice (21 weeks old) were set as controls (n = 6, gavaged with distilled water). After 8-weeks of treatment, feces samples were collected for GC-TOF/MS analysis. Consequently, 12 potential biomarkers were identified, including monosugars (D-tagatose, D-lyxose, D-erythrose, xylo-hexos-5-ulose, 2-deoxy-galactose), butanedioic acid, amino acids (phenylalanine, L-lysine, L-methionine, L-aspartic acid) and purine derivatives (7H-purine, 2'-deoxyinosine). We assume the monosugars and butanedioic acid were the fermentation products of MDG-1 by intestinal microbes and MDG-1 actions against diabetes might be accomplished through the absorbable monosugars and butanedioic acid via suppressing intestinal glucose absorption, enhancing liver glycogenesis, inhibiting glycogenolysis and promoting GLP-1 secretion. Besides, MDG-1 might alleviate diabetes and diabetic nephropathy by reducing 7H-purine and 2'-deoxyinosine. Further omics-driven studies including genomics, proteomics and metabonomics were considered to be carried out to provide direct evidence of gut microbiome contribution to MDG-1 actions. more...

Purpose: Health literacy plays a key role in a patient's ability to use health information and services, and can affect health outcomes. This study aimed to explore radiation therapists' perspectives on how they support people with lower health literacy who are undergoing radiotherapy., Methods: Semi-structured interviews were conducted with 25 radiation therapists working in radiation oncology departments in New South Wales, Australia., Results: The four key themes were (1) the process of identifying a patient with low health literacy, (2) the perceived consequences of low health literacy, (3) managing and responding to the needs of different health literacy groups and (4) recommendations to address low health literacy in radiotherapy. Radiation therapists appeared to make an informal, intuitive judgment about a patient's health literacy, using a variety of verbal and non-verbal cues as well as impromptu conversations with the multi-disciplinary team. Patients perceived to have lower health literacy were described as having greater difficulties assimilating knowledge and engaging in self-care. Although participants reported communicating to patients at a basic level initially, they subsequently tailored their communication to match a patient's health literacy. Strategies reported to communicate to low health literacy groups ranged from using lay language with minimal medical terminology, using visual aids (photos), using analogies, reiterating information and asking family members with higher literacy to attend consultations., Conclusion: A more structured approach to supporting patients with low health literacy and integrating health literacy training in radiation oncology departments may help to minimise the adverse outcomes typically experienced by this population. more...

Obesity is becoming a health concern worldwide and metformin, a first line anti-diabetic drug, was associated with weight loss under different backgrounds. However, most researches focused on the anti-diabetic mechanism and less attention has been paid on the mechanism of weight loss of metformin. Therefore, we established a metabonomic method to evaluate metformin action in preventing obesity in a high fat diet-induced-obesity (DIO) mice model. 36 male C57BL/6 mice (8-week old) were randomly divided into control group (n=12, normal chow), model group (n=12, high fat chow) and metformin group (n=12, high fat chow and dosed with metformin) over 16 weeks. A urinary metabonomic study using UPLC-TOF/MS was performed in combination with multivariate statistical analysis. In addition, indices of body weight and food intake as well as fasting blood glucose, fed blood glucose, oral glucose tolerance test (OGTT) and plasma insulin were collected. Significant weight loss in metformin-treated mice was achieved and 21 potential biomarkers were identified. Decreased glucose, myristic acid, stearidonic acid, lysoPC (16:0), lysoPC (18:0), L-glutamic acid, L-methionine, L-threonine, L-phenylalanine, L-histidine, L-carnitine, L-malic acid and pantothenic acid in urine indicated that metformin may have exerted effects on energy metabolism. Further, based on the biomarkers, we cautiously propose that tricarboxylic acid cycle (TCA) may have been compromised by metformin and might contribute to the activation of adenosine monophosphate kinase (AMPK), then AMPK activation led to more β-oxidation of certain fatty acids and augmented lipolysis and thus induced weight loss. Related cellular and molecular studies are being considered to further investigate the underlying mechanism., (Copyright © 2013 Elsevier B.V. All rights reserved.) more...

Purpose: To investigate the efficacy of trabeculectomy, phacotrabeculectomy and phacoemulsification in the management of primary angle closure glaucoma (PACG)., Methods: A prospective observational study was performed in 88 chronic PACG patients (97 eyes) who were divided into three groups following defined indications to receive different surgical interventions. The indications and clinical outcomes were evaluated. The mean follow-up was (17.7 +/- 4.9) months., Results: Success rate in trabeculectomy, phacotrabeculectomy and phacoemulsification group was 81.08%, 78.57% per hundred and 81.25% per hundred, respectively. The anterior chamber depth was deeper and the angle was wider postoperatively vs. preoperatively both in phacotrabeculectomy and phacoemulsification group. No obvious changes were seen in trabeculectomy group. The coefficient of outflow facility of aqueous humor (C values) significantly increased in three groups postoperatively (P < 0.01). No severe intraoperative complications were found and the incidence of postoperative complications was low. Five eyes sustained hypotony 3 +/- 1.87 months in trabeculectomy group and 1 eye happened malignant glaucoma in phacotrabeculectomy group. The visual acuity in patients with phacotrabeculectomy plus intraocular lens implantation and those only with phacoemulsification plus intraocular lens implantation were improved 78.57% and 93.74%, respectively. No significant improvement was found in trabeculectomy group (chi2 = 47.10, P < 0.001)., Conclusion: Three surgical interventions were beneficial to manage PACG and with co-existing cataract. The indication choosing was suggested according to visual acuity, angle closure circumference, cataract, medication requirements and optic nerve damage. Phacotrabeculectomy was recommended for angle closed > or =180 degrees circumference while phacoemulsification for angle closed <180 degrees. more...