New recognition of the heart-brain axis and its implication in the pathogenesis and treatment of PTSD.

Post-traumatic stress disorder (PTSD) is a complex psychological disorder provoked by distressing experiences, and it remains without highly effective intervention strategies. The exploration of PTSD's underlying mechanisms is crucial for advancing diagnostic and therapeutic approaches. Current studies primarily explore PTSD through the lens of the central nervous system, investigating concrete molecular alterations in the cerebral area and neural circuit irregularities. However, the body's response to external stressors, particularly the changes in cardiovascular function, is often pronounced, evidenced by notable cardiac dysfunction. Consequently, examining PTSD with a focus on cardiac function is vital for the early prevention and targeted management of the disorder. This review undertakes a comprehensive literature analysis to detail the alterations in brain and heart structures and functions associated with PTSD. It also synthesizes potential mechanisms of heart-brain axis interactions relevant to the development of PTSD. Ultimately, by considering cardiac function, this review proposes novel perspectives for PTSD's prophylaxis and therapy.

ZMIZ1 Regulates Proliferation, Autophagy and Apoptosis of Colon Cancer Cells by Mediating Ubiquitin-Proteasome Degradation of SIRT1.

There are nearly 1.15 million new cases of colon cancer, as well as 586,858 deaths from colon cancer worldwide in 2020. The aim of this study is to reveal whether ZMIZ1 can control the fate of colon cancer cells and the mechanism by which it functions. Specific shRNA transfection was used to knock down the expression of ZMIZ1 in colon cancer cell lines (HCT116 and HT29), and cell proliferation was detected using EdU and CCK-8 reagents, apoptosis by flow cytometry, and autophagy by western blot. The interaction of ZMIZ1 and SIRT1 was analyzed. Knockdown of ZMIZ1 significantly inhibited autophagy and proliferation, and induced apoptosis of HCT116 and HT29 cells. The mRNA level of SIRT1 was not affected by ZMIZ1 knockdown, but the protein level of SIRT1 was significantly decreased and the protein level of the SIRT1-specific substrate, acetylated FOXO3a, was reduced. Immunoprecipitation assays identified the interaction between SIRT1 and ZMIZ1 in HCT116 and HT29 cells. ZMIZ1 increased intracellular ubiquitination of SIRT1. Knockdown or pharmacological inhibition of SIRT1 neutralized the effects of ZMIZ knockdown on proliferation, autophagy and apoptosis in HCT116 and HT29 cells. ZMIZ1 may control the fate of colon cancer cells through the SIRT1/FOXO3a axis. Targeting ZMIZ1 would be beneficial for the treatment of colon cancer.

Protective effect of soluble dietary fiber from Rosa roxburghii Tratt residue on dextran sulfate sodium-induced ulcerative colitis by regulating serum metabolism and NF-κB pathway in mice.

BACKGROUND: Ulcerative colitis (UC) refers to an idiopathic chronic inflammatory bowel disease that starts with inflammation of the intestinal mucosa. Dietary fiber plays a crucial role in maintaining the normal architecture of the intestinal mucosa. In this study, the protective effect and potential mechanism of soluble dietary fiber from Rosa roxburghii Tratt residue (SDFR) on dextran sulfate sodium (DSS)-induced UC mice were explored. RESULTS: The results revealed that SDFR could ameliorate body weight loss and pathological injury, improve the structure and crypt destruction in colon in DSS-induced mice. Moreover, the levels of NO, IL-1ß, TNF-α, MPO and protein expression of iNOS and COX-2 were decreased after administration of SDFR. Notably, nontargeted metabolomics analysis indicated that there were significant differences in 51 potential metabolites in serum between the DSS and control groups. SDFR intervention could regulate aberrant alterations of these metabolites and mitigate UC via regulating metabolic pathways, including arachidonic acid and glycerophospholipid metabolism. CONCLUSION: This study provides novel evidence that SDFR could be used as a potential modulator to relieve UC. Also, the results provide a theoretical basis for the utilization of byproducts in Rosa roxburghii Tratt fruit processing. © 2024 Society of Chemical Industry.

Curculigoside rescues hippocampal synaptic deficits elicited by PTSD through activating cAMP-PKA signaling.

Chronic traumatic stress results in various psychiatric disorders, especially posttraumatic stress disorder (PTSD). Previous study demonstrated that curculigoside (CUR) a component of Rhizoma Curculiginis prevented fear extinction and stress-induced depression-like behaviors. However, its effects on PTSD and the mechanisms are still not completely clear. In this study, we observed typical PTSD-like phenotypes, synaptic deficit, and reduction of BDNF/TrkB signaling pathway in mice receiving modified single prolonged stress and electrical stimulation (SPS&S). By contrast, systemic administration of CUR blocked PTSD-like phenotypes and synaptic deficits, including reduction of BDNF/TrkB signaling pathway, GluA1 and Arc expression. Importantly, CUR reversed the impairment of PKA signaling pathway elicited by PTSD. We further confirmed that the effects of CUR on synaptic function were through PKA signaling pathway, as H-89, an inhibitor of PKA blocked the effect of CUR on behavioral changes and BDNF/TrkB signaling pathway. Thereafter, we verified that CUR on synaptic function were through PKA pathway using direct intracerebral injection of CUR and H-89. Direct intracerebral injection of CUR activated PKA/CREB/BDNF/TrkB, which was blocked by H-89. Additionally, the docking results showed high binding energies of CUR with A2AR, AC, PRKACA, and PRKAR1A, which might indicate that CUR functions through regulating PKA signaling pathway. In conclusion, CUR prevented the behavioral changes and hippocampal synaptic deficits elicited by PTSD through activating cAMP-PKA signaling.

Transcriptomic comparison sheds new light on regulatory networks for dimorphic flower development in response to photoperiod in Viola prionantha.

BACKGROUND: Chasmogamous (CH)-cleistogamous (CL) dimorphic flowers are developed in Viola prionantha. However, the environmental and genetic factors necessary for the CH-CL transition are unknown. RESULTS: In the present work, short-day (SD) conditions induced CH flowers, whereas long days (LDs) triggered CL flowers in V. prionantha. Compared to fully developed CH flowers, CL flowers had less mature stamens, no nectar glands, and immature petals. Comparative transcriptomics revealed differentially expressed genes (DEGs) during CL and CH development. Core genes in the photoperiod pathway, such as V. prionantha orthologs of GIGANTEA (GI), CONSTANS (CO), and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1), which promote floral induction, were highly expressed in CL flowers, whereas UNUSUAL FLORAL ORGANS (UFO) and B-class MADS-box genes for floral organ identity and development showed an opposite alteration. Moreover, genes in the glycolytic process, sucrose metabolic process, and fatty acid biosynthetic process were all highly expressed in CH flowers. Interestingly, V. prionantha orthologs of the B-class MADS-box genes APETALA3 (AP3) and PISTILLATA (PI) might relate to these sugar-fatty acid processes and were co-expressed with GAIP-B-like and YABBY5 (YAB5), which regulate the development of the petal, stamen, and nectary. Compared to CH flowers, DEGs and hub genes in the most significantly correlated modules of the gene co-expression network, which are involved in abiotic and biotic responses, were upregulated in CL flowers. CONCLUSIONS: We proposed an integrative model for transcription regulation of genes in the photoperiod pathway, floral organ development, stress response, and sugar-fatty acid processes to determine CH-CL flower development in V. prionantha. Particularly, under LDs, activated GI may induce genes involved in the stress-response pathways, and then downregulated AP3 and PI or UFO to inhibit the sugar-fatty acid metabolic processes, together forming CL flowers. In contrast, CH flowers were produced under SDs. This work provides novel insights into the developmental evolution of dimorphic flowers in Viola.

Astrocytic Kir4.1 regulates NMDAR/calpain signaling axis in lipopolysaccharide-induced depression-like behaviors in mice.

The activation of Nod-like receptor protein 3 (NLRP3) inflammasome propagates pro-inflammatory signaling cascades linking to depression-like behaviors. However, the signaling pathway contributing to NLRP3 inflammasome activation and depression-like behaviors is still not clear. In this study, we evidenced that lipopolysaccharide (LPS) injection (i.p.) triggered depression-like behaviors, promoted the expression of Kir4.1, p-GluN2B and calpain-1, and activated NLRP3 inflammasome. The blockage of N-methyl-d-aspartate receptors (NMDAR) by memantine reduced LPS-induced depression-like behaviors, NLRP3 inflammasome and astrocyte activation, and calpain-1 expression. Additionally, memantine also inhibited LPS-induced reduction of postsynaptic density protein 95 (PSD-95) and Arc expression. Specific reduction of Kir4.1 in astrocytes attenuated LPS-induced expression of NLRP3 and calpain-1, and phosphorylation of GluN2B. Interestingly, LPS-induced expression of calpain-1 largely co-localized with GFAP, indicating the specific function of calpain-1 in astrocytes. Together, these data indicate that astrocytic Kir4.1 could regulate NMDAR/calpain-1 signaling axis, contributing to depression-like behaviors, likely through regulating NLRP3 inflammasome activation.

Significance of KDM6A mutation in bladder cancer immune escape.

BACKGROUND: Bladder cancer (BC) is the fourth most prevalent neoplasm in men and is associated with high tumour recurrence rates, leading to major treatment challenges. Lysine-specific demethylase 6A (KDM6A) is frequently mutated in several cancer types; however, its effects on tumour progression and clinical outcome in BC remain unclear. Here, we explored the potential role of KDM6A in regulating the antitumor immune response. METHODS: We mined The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases for somatic mutation and clinical data in patients with BC. RESULTS: We found frequent mutations in 12 genes in both cohorts, including TP53, KDM6A, CSMD3, MUC16, STAG2, PIK3CA, ARID1A, RB1, EP300, ERBB2, ERBB3, and FGFR3. The frequency o KDM6A mutations in the TCGA and ICGC datasets was 25.97 and 24.27%, respectively. In addition, KDM6A mutation was associated with a lower number of tumour-infiltrating immune cells (TIICs) and indicated a state of immune tolerance. KDM6A mutation was associated with lower KDM6A mRNA level compared with that in samples carrying the wild-type gene. Further, survival analysis showed that the prognosis of patients with low KDM6A expression was worse than that with high KDM6A expression. Using the CIBERSORT algorithm, Tumor Immune Estimation Resource site, and Gene Set Enrichment Analysis, we found that KDM6A mutation downregulated nine signalling pathways that participate in the immune system and attenuated the tumour immune response. CONCLUSION: Overall, we conclude that KDM6A mutation is frequent in BC and promotes tumour immune escape, which may serve as a novel biomarker to predict the immune response.

Sex differences in circulating neuregulin1-ß1 and ß-secretase 1 expression in childhood-onset schizophrenia.

OBJECTIVE: Early-onset schizophrenia is a severe and rare form of schizophrenia that is clinically and neurobiologically continuous with the adult form of schizophrenia. Neuregulin1 (NRG1)-mediated signaling is crucial for early neurodevelopment, which exerts its function by limited ß-secretase 1 (BACE1) proteolysis processing. However, circulating neuregulin1-ß1 (NRG1-ß1), an isoform of NRG1, and its cleavage enzyme BACE1 have not been studied in early-onset patients with schizophrenia. METHODS: In this study, we collected plasma and clinical information from 71 young patients (7 ≤ age years ≤20) with schizophrenia and 53 age- and sex-matched healthy controls. Immunoassay was used to test levels of circulating NRG1-ß1 and BACE1 expression. We further analyzed the relationship of disease-onset age and gender with NRG1-ß1 and BACE1 levels. RESULTS: We found that circulating plasma levels of NRG1-ß1 were significantly decreased in young patients with early-onset schizophrenia. In males with childhood onset schizophrenia (COS), NRG1-ß1 was reduced and was inversely correlated with positive symptom of PANSS; moreover, these male patients with higher plasma BACE1 levels showed more severe general symptoms of PANSS and defective social functioning; whereas, no aforementioned results were found in adolescent-onset schizophrenia (AOS). Notably, young female patients with COS and AOS had no significant change in NRG1-ß1 and BACE1, which demonstrated a sex-dependent effect in early-onset schizophrenia. CONCLUSION: Our results suggest that decreased levels of NRG1-ß1 and its cleavage enzyme BACE1 contribute to increased risk of etiology of schizophrenia. Synthetic biomarkers may have clinical applications for the early diagnosis of male COS.

Comparison of the Rhizosphere Soil Microbial Community Structure and Diversity Between Powdery Mildew-Infected and Noninfected Strawberry Plants in a Greenhouse by High-Throughput Sequencing Technology.

The aim of this study was to compare the microbial community structure and diversity in powdery mildew-infected and noninfected strawberry plant rhizosphere soils in the greenhouse based on variations in the 16S rRNA gene V3-V4 and fungal ITS2 regions by Illumina amplicon sequencing. Powdery mildew infection reduced the number of operational taxonomic units (OTUs) and prokaryotic and fungal community richness/diversity indexes in the rhizosphere soils compared with those in healthy plant soils. Furthermore, 3543 prokaryotic and 581 fungal OTUs were obtained at the 97% similarity level. Proteobacteria, Actinobacteria, Bacteroidetes, Acidobacteria, and Chloroflexi were the dominant bacterial phyla; Woesearchaeota_DHVEG-6, Bathyarchaeota, and Thaumarchaeota were the dominant archaea; and Ascomycota, Basidiomycota, unclassified_fungi, and Zygomycota were the dominant fungal phyla. Their proportions differed significantly among samples. Wolbachia, Devosia, Pseudolabrys, Streptomyces, and Rhizomicrobium were the most abundant bacterial genera; their proportions differed significantly among samples. Most Pseudomonas, Streptomyces, and 'norank' group members might be potential antagonistic microorganisms of powdery mildew pathogens, and Wolbachia and Rickettsia might be pathogen-transmitting vectors. Microascus, Clitopilus, and Ciliophora were the dominant fungi, and their community structures and abundances significantly differed among samples. Microascus, Talaromyces, Zopfiella, and Cryptococcus were relatively more abundant in the powdery mildew-infected strawberry plant rhizosphere soils. Fusarium, Trichoderma, Clitopilus, and 'unclassified' group members may be potential antagonistic populations. The results suggested that powdery mildew-infected strawberry fruits and plants cannot be consumed. This report is the first study to illustrate differences in the rhizosphere soil prokaryotic and fungal communities between powdery mildew-infected and noninfected strawberry plants in a greenhouse.

Facile construction of a molecularly imprinted polymer-based electrochemical sensor for the detection of milk amyloid A.

A molecularly imprinted electrochemical sensor for the detection of serum amyloid A (MAA) in milk was established for early diagnosis of subclinical mastitis in dairy cows. The electrochemical sensor was initially constructed using a nanocomposite material (reduced graphene oxide/gold nanoparticles, AuNPs@rGO) to modify the working electrode. The template protein, MAA, was then immobilized using pyrrole as the functional monomer to carry out the electropolymerization. Finally, the template protein was removed to form a molecular imprint film with the capability to qualitatively and quantitatively signaling of MAA. Cyclic voltammetry (CV), differential pulse voltammetry (DPV), and scanning electron microscopy (SEM) were used to characterize the modification process of the molecularly imprinted electrochemical sensors. Under optimized conditions, the sensor shows two well-behaved linear relationships in the MAA concentration range 0.01 to 200 ng/mL. A lower detection limit was estimated to be 5 pg/mL (S/N = 3). Other parameters including the selectivity, reproducibility (RSD 3.2%), and recovery rate (96.1-103%) are all satisfactory. Compared with the traditional methods, detection of MAA to determine the subclinical mastitis of dairy cows can efficiently be diagnosed and hence prevent an outbreak of dairy cow mastitis. The electrochemical sensor can detect MAA more rapidly, sensitively, and inexpensively than the ELISA-based MAA detection. These advantages indicate that the method is promising for early diagnosis of dairy cows.

Curculigoside facilitates fear extinction and prevents depression-like behaviors in a mouse learned helplessness model through increasing hippocampal BDNF.

Curculigoside (CUR) is the main active component of traditional Chinese medicine Curculigoorchioides Gaertn (Xianmao in Chinese), which exhibits a variety of pharmacological activities. In this study we investigated the effects of CUR on fear extinction and related depression-like behaviors in mice. In fear conditioning task, we found that administration of CUR (1.6, 8, 40 mg·kg-1·d-1, ip, for 7 days) did not affect memory consolidation, but CUR at higher doses (8, 40 mg·kg-1·d-1) significantly facilitated fear extinction, especially on D3 and D4. Moreover, CUR administration significantly ameliorated the fear conditioning-induced depression-like behaviors, likely through promoting fear extinction. We showed that CUR increased the expression of brain-derived neurotrophic factor (BDNF) and phosphorylation of tropomyosin receptor kinase B (TrkB) in the hippocampus, and activated protein kinase B (Akt)-mammalian target of the rapamycin (mTOR) signaling pathway. Administration of the selective TrkB agonist 7,8-dihydroxyflavone (7,8-DHF, 5 mg·kg-1·d-1, ip) also facilitated fear extinction, ameliorated depression-like behaviors. We established a mouse learned helplessness (LH) model to evaluate the antidepressant activity of CUR. The spatial memory was assessed in Morris water maze. We showed that LH-induced depression-like behaviors, including prolonged immobility times in forced swim and tail suspension tests as well as spatial memory impairments; LH also downregulated BDNF expression and the Akt-mTOR signaling pathway in the hippocampus. Administration of CUR (1.6, 8, 40 mg·kg-1·d-1, ip, for 14 days) or 7,8-DHF (5 mg·kg-1·d-1, ip, for 3 days) prevented LH-induced depression-like behaviors and promoted BDNF expression and the Akt-mTOR signaling pathway. In conclusion, CUR can accelerate the fear memory extinction and ameliorate depression-like behaviors in mice via promoting BDNF expression and activating the Akt-mTOR signaling pathway in the hippocampus.

Cholesterol inhibits entotic cell-in-cell formation and actomyosin contraction.

Cell-in-cell structure is prevalent in human cancer, and associated with several specific pathophysiological phenomena. Although cell membrane adhesion molecules were found critical for cell-in-cell formation, the roles of other membrane components, such as lipids, remain to be explored. In this study, we attempted to investigate the effects of cholesterol and phospholipids on the formation of cell-in-cell structures by utilizing liposome as a vector. We found that Lipofectamine-2000, the reagent commonly used for routine transfection, could significantly reduce entotic cell-in-cell formation in a cell-specific manner, which is correlated with suppressed actomyosin contraction as indicated by reduced ß-actin expression and myosin light chain phosphorylation. The influence on cell-in-cell formation was likely dictated by specific liposome components as some liposomes affected cell-in-cell formation while some others didn't. Screening on a limited number of lipids, the major components of liposome, identified phosphatidylethanolamine (PE), stearamide (SA), lysophosphatidic acid (LPA) and cholesterol (CHOL) as the inhibitors of cell-in-cell formation. Importantly, cholesterol treatment significantly inhibited myosin light chain phosphorylation, which resembles the effect of Lipofectamine-2000, suggesting cholesterol might be partially responsible for liposomes' effects on cell-in-cell formation. Together, our findings supporting a role of membrane lipids and cholesterol in cell-in-cell formation probably via regulating actomyosin contraction.

Microdialysis sampling combined with ultra-high-performance liquid chromatography/tandem mass spectrometry for the determination of geniposide in dialysate of joint cavities in adjuvant arthritis rats.

RATIONALE: Microdialysis has been used to detect the concentrations of drugs in tissues. Geniposide (GE), an iridoid glycoside compound, is the main bioactive component of Gardenia jasminoides Ellis fruit. We previously demonstrated that GE could control the activity of cytokines and reduce levels of inflammation in adjuvant arthritis (AA) rats, but the topic of concentration changes over time in the joint synovia of AA has rarely been studied. METHODS: In this study, a microdialysis technique combined with ultra-high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (UHPLC/ESI-MS/MS) was set up and confirmed to assay GE in the dialysate of the joint cavity in AA rats. Mass detection was conducted in multiple reaction monitoring (MRM) mode with negative ESI, and paeoniflorin (Pae) was used as an internal standard (IS). RESULTS: A lower limit of quantitation (LLOQ) of 5 ng/mL was found using this method and with good linearity in the range of 5-4000 ng/mL. All the validation data including accuracy, precision, intra and inter-day repeatability and stability meet the requirements. The relative recoveries of GE were determined at approximately 40.01%. CONCLUSIONS: The measurements based on microdialysis combined with UHPLC/ESI-MS/MS provide a method for sampling and rapid sensitive analysis of GE in the dialysate of the joint cavity in AA rats. This method should be considered for future pharmacokinetics studies.

A Microdialysis in Adjuvant Arthritic Rats for Pharmacokinetics⁻Pharmacodynamics Modeling Study of Geniposide with Determination of Drug Concentration and Efficacy Levels in Dialysate.

Microdialysis, a sampling method for pharmacokinetics⁻pharmacodynamics (PK⁻PD) modeling in preclinical and clinical studies, is a convenient in vivo sampling technique. Geniposide (GE), an iridoid glycoside compound, is the major active ingredient of Gardenia jasminoides Ellis fruit which has an anti-inflammatory effect. In this study, an articular cavity microdialysis sampling system for adjuvant arthritic (AA) rats was established to study the effect of GE on the release of prostaglandin E2 (PGE2) in AA rats induced by Freund's complete adjuvant (FCA). An UHPLC-MS/MS method was developed to determine the concentrations of GE and PGE2 in the dialysate. Through the determination of drug concentrations and PGE2 efficacy levels in the dialysate, the developed methods were successfully applied to set up concentration⁻time and effect⁻time profiles followed by PK⁻PD modeling of GE's effect on decreasing PGE2 release after oral administration of GE. The effect was well described by the developed PK⁻PD modeling, indicating that GE may play an anti-inflammatory role via decreasing AA-induced elevated PGE2 levels. In the selection of suitable endogenous small molecules as effect markers, the establishment of AA rat joint-cavity microdialysis is an attractive technique for rational PK⁻PD studies.

Immunosuppressive Effect of Geniposide on Mitogen-Activated Protein Kinase Signalling Pathway and Their Cross-Talk in Fibroblast-Like Synoviocytes of Adjuvant Arthritis Rats.

Geniposide (GE), an iridoid glycoside compound derived from Gardenia jasminoides Ellis fruit, is known to have anti-inflammatory and immunoregulatory activities. The aim of this study was to investigate the protective mechanism of GE in the regulation of the mitogen-activated protein kinase (MAPK) signalling pathway and the cross-talk among the MAPK signalling pathway in fibroblast-like synoviocytes (FLS) of adjuvant arthritis (AA) rats. AA was induced by injecting with Freund's complete adjuvant. Male SD rats and FLS were subjected to treatment with GE (30, 60 and 120 mg/kg) in vivo from day 14 to 21 after immunization and GE (25, 50 and 100 µg/mL) in vitro, respectively. The proliferation of FLS was assessed by MTT. IL-4, IL-17, IFN-γ, and TGF-ß1 were determined by ELISA. Key proteins in the MAPK signalling pathway were detected by Western blot. GE significantly reduced the proliferation of FLS, along with decreased IFN-γ and IL-17 and increased IL-4 and TGF-ß1. In addition, GE decreased the expression of p-JNK, p-ERK1/2 and p-p38 in FLS of AA rats. Furthermore, disrupting one MAPK pathway inhibited the activation of other MAPK pathways, suggesting cross-talk among MAPK signalling. In vivo study, it was also observed that GE attenuated histopathologic changes in the synovial tissue of AA rats. Collectively, the mechanisms by which GE exerts anti-inflammatory and immunoregulatory effects may be related to the synergistic effect of JNK, ERK1/2 and p38. Targeting MAPK signalling may be a new therapeutic strategy in inflammatory/autoimmune diseases.

Antiinflammation Effects and Mechanisms Study of Geniposide on Rats with Collagen-Induced Arthritis.

Geniposide (GE), an iridoid glycoside compound purified from Gardenia jasminoides Ellis, has antiinflammatory and other pharmacological effects, but its mechanism of actions on rheumatoid arthritis (RA) have not been clarified. The purpose of this article was to investigate the pharmacological effects of GE on collagen-induced arthritis (CIA) rats and its feasible mechanisms. Collagen-induced arthritis was induced by injection of chicken type II collagen emulsion. The rats were orally administered with GE (33, 66, and 132 mg/kg) from days 14 to 30 after immunization. The histological examination showed that GE could attenuate histopathologic changes of mesenteric lymph node (MLN) in CIA rats. Geniposide inhibited the production of Interleukin 6 (IL-6) and IL-17, while promoting the production of IL-4 and transforming growth factor-beta 1 in MLN lymphocytes (MLNLs). Moreover, the proliferation capability of MLNLs was increased after the administration of GE. In addition, the treatment with GE in vivo decreased the expressions of P-Raf, P-MEK, and P-Erk1/2 in MLNLs. These results may highlight the antiinflammatory effects and possible mechanisms of GE in MLNLs of RA. Copyright © 2017 John Wiley & Sons, Ltd.

Immune Tolerance Effect in Mesenteric Lymph Node Lymphocytes of Geniposide on Adjuvant Arthritis Rats.

Rheumatoid arthritis (RA) is a systemic, Th1 cytokine-predominant autoimmune disease result in a chronic and inflammatory disorder. Geniposide (GE), an iridoid glycoside compound that is purified from Gardenia jasminoides Ellis, has antiinflammatory and other immunoregulatory effects, but its exact mechanism of actions on RA is unknown. The aim of this study was to elucidate antiinflammation effects of GE on adjuvant arthritis (AA) rats and its possible immune tolerance mechanisms. Male Sprague-Dawley rats were administered with GE (30, 60, and 120 mg/kg) orally from day 17 to 24 after immunization. Lymphocyte proliferation was assessed by MTT. Levels of interleukin-2 (IL-2), IL-4, and transforming growth factor-ß1 were tested by ELISA. The expression of ß2-AR, GRK2, and ß-arrestin-1 and ß-arrestin-2 was detected by western blot. Geniposide was found to relieve the secondary hind paw swelling and arthritis scores, along with attenuating histopathologic changes and decreasing IL-2 and increasing IL-4, transforming growth factor-ß1 in mesenteric lymph node (MLN) lymphocytes of AA rats. In addition, GE in vivo increased the expression of ß2-AR and decreased the expression of GRK2, ß-arrestin-1 and ß-arrestin-2, and level of cyclic adenosine monophosphate of MLN lymphocytes in AA rats. From these results, we can infer that GE on immune tolerance effects, ß2-AR desensitization, and ß2-AR-AC-cyclic adenosine monophosphate transmembrane signal transduction of MLN lymphocytes plays crucial roles in antiinflammatory and immunoregulatory pathogeneses of RA. Copyright © 2017 John Wiley & Sons, Ltd.

Acute kidney injury in China: a cross-sectional survey.

BACKGROUND: Acute kidney injury (AKI) has become a worldwide public health problem, but little information is available about the disease burden in China. We aimed to evaluate the burden of AKI and assess the availability of diagnosis and treatment in China. METHODS: We launched a nationwide, cross-sectional survey of adult patients who were admitted to hospital in 2013 in academic or local hospitals from 22 provinces in mainland China. Patients with suspected AKI were screened out on the basis of changes in serum creatinine by the Laboratory Information System, and we reviewed medical records for 2 months (January and July) to confirm diagnoses. We assessed rates of AKI according to two identification criteria: the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) AKI definition and an increase or decrease in serum creatinine by 50% during hospital stay (expanded criteria). We estimated national rates with data from the 2013 report by the Chinese National Health and Family Planning Commission and National Bureau of Statistics. FINDINGS: Of 2,223,230 patients admitted to the 44 hospitals screened in 2013, 154,950 (7·0%) were suspected of having AKI by electronic screening, of whom 26,086 patients (from 374,286 total admissions) were reviewed with medical records to confirm the diagnosis of AKI. The detection rate of AKI was 0·99% (3687 of 374,286) by KDIGO criteria and 2·03% (7604 of 374,286) by expanded criteria, from which we estimate that 1·4-2·9 million people with AKI were admitted to hospital in China in 2013. The non-recognition rate of AKI was 74·2% (5608 of 7555 with available data). Renal referral was done in 21·4% (1625 of 7604) of the AKI cases, and renal replacement therapy was done in 59·3% (531 of 896) of those who had the indications. Delayed AKI recognition was an independent risk factor for in-hospital mortality, and renal referral was an independent protective factor for AKI under-recognition and mortality INTERPRETATION: AKI has become a huge medical burden in China, with substantial underdiagnosis and undertreatment. Nephrologists should take the responsibility for leading the battle against AKI. FUNDING: National 985 Project of China, National Natural Science Foundation of China, Beijing Training Program for Talents, International Society of Nephrology Research Committee, and Bethune Fund Management Committee.

Design, synthesis and preliminary evaluation of the anti-inflammatory of the specific selective targeting druggable enzymome cyclooxygenase-2 (COX-2) small molecule.

CONTEXT: Development of a reliable and selective anti-inflammatory agent of cyclooxygenase-2 (COX-2), induced or up-regulated by inflammatory/injury stimulus such as IL-1ß, TNF-α and LPS in the various types of organs, tissues and cells, with low side effects is a long-standing medicinal chemistry problem with significant social implications. OBJECTIVE: To target druggable enzymome COX-2 by exploiting NSAIDs and genipin (GEP) in anti-inflammatory infection. MATERIALS AND METHODS: The compound aspirin GEP ester (AGE) was designed by computer-assisted screening, synthesized in the esterification of the acylate derivative and the methylate derivative with Et3N, and evaluated with 20, 40 and 60 mg/kg from days 18 to 24 after immunization in collagen-induced arthritis (CIA) rats by the sequential enzymatic experiments, western-blot analysis and pathological observation methods. RESULTS: AGE exhibited higher binding affinity with COX-1 and displayed the lowest estimated free energy with COX-2 than other ligands built by hanging NSAIDs with GEP, and was characterized by 1H NMR, 13C NMR and HRMS. AGE was competed against COX-2 with molecule-dependent potencies and selectivity (IC50: 0.36 mM; selectivity index: 275) in the sequential enzymatic experiments and decreased the expression of COX-2 in peripheral blood lymphocytes of CIA rats. AGE (40 and 60 mg/kg) could significantly relieve the secondary hind paw swelling and arthritis index, along with observing AGE attenuated histopathological changes of fibroblast like synovial tissue (FLST) and mesenteric lymph node lymphocytes (MLNL) in CIA rats. DISCUSSION AND CONCLUSION: AGE pharmacophore reported herein may be an effective strategy to develop a novel anti-inflammatory agent and potential inhibitor of COX-2.

Genome-wide characterization and analysis of F-box protein-encoding genes in the Malus domestica genome.

The F-box protein family is a large family that is characterized by conserved F-box domains of approximately 40-50 amino acids in the N-terminus. F-box proteins participate in diverse cellular processes, such as development of floral organs, signal transduction and response to stress, primarily as a component of the Skp1-cullin-F-box (SCF) complex. In this study, using a global search of the apple genome, 517 F-box protein-encoding genes (F-box genes for short) were identified and further subdivided into 12 groups according to the characterization of known functional domains, which suggests the different potential functions or processes that they were involved in. Among these domains, the galactose oxidase domain was analyzed for the first time in plants, and this domain was present with or without the Kelch domain. The F-box genes were distributed in all 17 apple chromosomes with various densities and tended to form gene clusters. Spatial expression profile analysis revealed that F-box genes have organ-specific expression and are widely expressed in all organs. Proteins that contained the galactose oxidase domain were highly expressed in leaves, flowers and seeds. From a fruit ripening expression profile, 166 F-box genes were identified. The expressions of most of these genes changed little during maturation, but five of them increased significantly. Using qRT-PCR to examine the expression of F-box genes encoding proteins with domains related to stress, the results revealed that F-box proteins were up- or down-regulated, which suggests that F-box genes were involved in abiotic stress. The results of this study helped to elucidate the functions of F-box proteins, especially in Rosaceae plants.