Fish oil replacement with different vegetable oils in Onychostoma macrolepis: Effects on fatty acid metabolism based on whole-body fatty acid balance method and genes expression.

To evaluate the fatty acid (FA) metabolism status and possibility as a DHA source of farmed Onychostoma macrolepis, a total of 168 fish (2.03 ± 0.23 g) were fed four diets supplemented with fish oil (FO), linseed oil (LO), soybean oil (SO), and a mixture of LO and SO oil (MO), respectively, for 70 days. Body FA compositions were modified reflecting dietary FAs. Comparing liver and intestine fatty acids with fish fed four diets, the content of ARA in fish fed SO was significantly higher than others (P < 0.05), but showed no difference in muscle. The tissue FA profile showed that the FO-fed group successfully deposited DHA, while the LO-fed group converted ALA to DHA effectively, as well as the liver and intestine EPA was notably highest in the FO group, whereas no difference between the FO and LO group in the muscle. The FA results showed that the DHA contents in the muscle of Onychostoma macrolepis are at a medium-high level compared with several other fish species with the highest aquaculture yield. Correspondingly, in the fish fed diet with LO, SO, and MO, the genes of most FA biosynthesis, transportation, and transcriptional regulation factors were increased in the liver and muscle, but no significant difference was observed in the gene expression of Elovl4b, FATP1, and FABP10 in the muscle. In addition, the enzyme activity involved in PUFA metabolism was higher in fish fed vegetable oil-based diets, corroborating the results of the gene expression. Increased in vivo elongase and desaturase (Δ5, Δ6, and Δ9) activities were recorded in fish fed fish oil-devoid diets, which resulted in the appearance of products associated with elongase and desaturase activities in fish. Besides, as the specific n-3 PUFA synthesis substrate, the dietary supplementation of ALA not only retains most of the nutrition value but also ensures the muscular texture, such as fiber diameter and density. It is concluded that farmed O. macrolepis owns strong n-3 LC-PUFA biosynthetic capacity and high DHA contents so it can be a good DHA source for the population.

A novel synthesized Vanillin-Based Deep Eutectic Agent (V-DEA) mitigates postharvest fungal decay and improve shelf life and quality of cherry tomatoes.

Fusarium oxysporum and Botrytis cinerea are the main pathogens that cause fruit decay and reduce the postharvest shelf life of cherry tomatoes. Boosting the potency of natural products requires implementing structural modification to combat postharvest pathogens. Herein, we developed a novel Vanillin-Deep Eutectic Agent (V-DEA) from natural compounds and evaluated its effectiveness against tomato fruit rot pathogens. The results demonstrated that V-DEA suppressed mycelium growth and spore germination of F. oxysporum and B. cinerea by enhancing cell membrane permeability, increasing lipid peroxidation, and inhibiting enzyme activities. Importantly, using 8-mM V-DEA successfully prevented postharvest decay in cherry tomatoes, while 4-mM significantly extended their shelf life by reducing weight loss and shriveling, and enhancing key fruit qualities such as total soluble solids, ascorbic acid, tartaric acid, and lycopene. In conclusion, V-DEA exhibits dual properties as a potent pathogen inhibitor and antioxidant activity, thus prolonging the shelf life of cherry tomatoes.

Effects of glycerol monolaurate on estradiol and follicle-stimulating hormones, offspring quality, and mRNA expression of reproductive-related genes of zebrafish (Danio rerio) females.

This study aims to explore whether glycerol monolaurate (GML) can improve reproductive performance of female zebrafish (Danio rerio) and the survival percentage of their offspring. Three kinds of isonitrogenous and isolipid diets, including basal diet (control) and basal diet containing 0.75 g/kg GML (L_GML) and 1.5 g/kg GML (H_GML), were prepared for 4 weeks feeding trial. The results show that GML increased the GSI of female zebrafish. GML also enhanced reproductive performance of female zebrafish. Specifically, GML increased spawning number and hatching rate of female zebrafish. Moreover, GML significantly increased the levels of triglycerides (TG), lauric acid, and estradiol (E2) in the ovary (P < 0.05). Follicle-stimulating hormone (FSH) levels in the ovary and brain also significantly increased in the L_GML group (P < 0.05). Besides, dietary GML regulated the hypothalamus-pituitary-gonad (HPG) axis evidenced by the changed expression levels of HPG axis-related genes in the brain and ovary of the L_GML and H_GML groups compared with the control group. Furthermore, compared with the control group, the expression levels of HPG axis-related genes (kiss2, kiss1r, kiss2r, gnrh3, gnrhr1, gnrhr3, lhß, and esr2b) in the brain of the L_GML group were significantly increased (P < 0.05), and the expression levels of HPG axis-related genes (kiss1, kiss2, kiss2r, gnrh2, gnrh3, gnrhr4, fshß, lhß, esr1, esr2a, and esr2b) in the brain of the H_GML group were significantly increased (P < 0.05). These results suggest that GML may stimulate the expression of gnrh2 and gnrh3 by increasing the expression level of kiss1 and kiss2 genes in the hypothalamus, thus promoting the synthesis of FSH and E2. The expression levels of genes associated with gonadotropin receptors (fshr and lhr) and gonadal steroid hormone synthesis (cyp11a1, cyp17, and cyp19a) in the ovary were also significantly upregulated by dietary GML (P < 0.05). The increasing expression level of cyp19a also may promote the FSH synthesis. Particularly, GML enhanced the richness and diversity and regulated the species composition of intestinal microbiota in female zebrafish. Changes in certain intestinal microorganisms may be related to the expression of certain genes involved in the HPG axis. In addition, L_GML and H_GML both significantly decreased larvae mortality at 96 h post fertilization and their mortality during the first-feeding period (P < 0.05), revealing the enhanced the starvation tolerance of zebrafish larvae. In summary, dietary GML regulated genes related to HPG axis to promote the synthesis of E2 and FSH and altered gut microbiota in female zebrafish, and improved the survival percentage of their offspring.

Production, physico-chemical properties and antioxidant activity of melanin from Annulohypoxylon stygium (Lév.) Y.M. Ju, J.D. Rogers and H.M. Hsieh.

To obtain higher melanin production in liquid culture, culture conditions of Annulohypoxylon stygium (Lév.) Y.M. Ju, J.D. Rogers and H.M. Hsieh were optimised. The results showed that using single factor experiment and orthogonal test, the optimised production of melanin reached 2.20 g/L, which was 2.06 times higher than that of the control group. In addition, it was speculated that A. stygium melanin (AsM) was 3,4-dihydroxyphenylalanine (DOPA) melanin and showed an amorphous irregular structure. Moreover, it had good solubility in alkaline solution. AsM showed good antioxidant activity at a concentration of 500 mg/L, with DPPH, ABTS and OH radicals scavenging activities of 90.83%, 75.36% and 70.90%, respectively. AsM prevented alcohol-induced oxidative damage and oxidative stress in HepG2 cells by inhibiting the decrease of antioxidant key enzyme activity under alcohol stimulation. It was proved to have a great potential for application as a natural antioxidant and a substitute for synthetic pigments.

Combining detrended cross-correlation analysis with Riemannian geometry-based classification for improved brain-computer interface performance.

Riemannian geometry-based classification (RGBC) gained popularity in the field of brain-computer interfaces (BCIs) lately, due to its ability to deal with non-stationarities arising in electroencephalography (EEG) data. Domain adaptation, however, is most often performed on sample covariance matrices (SCMs) obtained from EEG data, and thus might not fully account for components affecting covariance estimation itself, such as regional trends. Detrended cross-correlation analysis (DCCA) can be utilized to estimate the covariance structure of such signals, yet it is computationally expensive in its original form. A recently proposed online implementation of DCCA, however, allows for its fast computation and thus makes it possible to employ DCCA in real-time applications. In this study we propose to replace the SCM with the DCCA matrix as input to RGBC and assess its effect on offline and online BCI performance. First we evaluated the proposed decoding pipeline offline on previously recorded EEG data from 18 individuals performing left and right hand motor imagery (MI), and benchmarked it against vanilla RGBC and popular MI-detection approaches. Subsequently, we recruited eight participants (with previous BCI experience) who operated an MI-based BCI (MI-BCI) online using the DCCA-enhanced Riemannian decoder. Finally, we tested the proposed method on a public, multi-class MI-BCI dataset. During offline evaluations the DCCA-based decoder consistently and significantly outperformed the other approaches. Online evaluation confirmed that the DCCA matrix could be computed in real-time even for 22-channel EEG, as well as subjects could control the MI-BCI with high command delivery (normalized Cohen's κ: 0.7409 ± 0.1515) and sample-wise MI detection (normalized Cohen's κ: 0.5200 ± 0.1610). Post-hoc analysis indicated characteristic connectivity patterns under both MI conditions, with stronger connectivity in the hemisphere contralateral to the MI task. Additionally, fractal scaling exponent of neural activity was found increased in the contralateral compared to the ipsilateral motor cortices (C4 and C3 for left and right MI, respectively) in both classes. Combining DCCA with Riemannian geometry-based decoding yields a robust and effective decoder, that not only improves upon the SCM-based approach but can also provide relevant information on the neurophysiological processes behind MI.

Polysaccharide from Pleurotus tuber-regium mycelium improves DSS-induced colitis in mice by regulating inflammatory cytokines, oxidative stress and gut microbiota.

Pleurotus tuber-regium (PTR) has been proved to have obvious pharmacological properties. In this study, a polysaccharide was extracted from the mycelium of PTR and administered to DSS-induced colitis mice to clarify the protective effect and mechanism of the PTR polysaccharide (PTRP) on colitis. The results showed that PTRP significantly improved the clinical symptoms and intestinal tissue damage caused by colitis and inhibited the secretion of pro-inflammatory cytokines and myeloperoxidase activity, while the levels of oxidative stress factors in mice decreased and the antioxidant capacity increased. The 16S rRNA sequencing of the mouse cecum content showed that PTRP changed the composition of gut microbiota, and the diversity and abundance of beneficial bacteria increased. In addition, PTRP also enhanced the production of short-chain fatty acids by regulating gut microbiota. In conclusion, our study shows that PTRP has the potential to relieve IBD symptoms and protect intestinal function by regulating inflammatory cytokines, oxidative stress and gut microbiota.

Hepatoprotective Effect of Annulohypoxylon stygium Melanin on Acute Alcoholic Liver Injury in Mice.

Annulohypoxylon stygium melanin (AsM) has various functional properties such as antioxidant and anti-radiation, but its biological activity in vivo has not been fully investigated. In this study, we researched the effects of AsM on the protection against acute liver injury in mice and its mechanism. The results showed that AsM had no significant effect on body weight in mice but reduced the liver index. It was able to significantly decrease the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), the contents of triglyceride (TG) and total cholesterol (TC) in mice. Simultaneously, it raised the levels of superoxide dismutase (SOD), peroxidase (CAT), and glutathione peroxidase (GSH-Px), which obviously exceeded those of the EtOH group. AsM could significantly lower the levels of inflammatory factors, with inhibition rates of 68.30%, 29.0%, and 19.50% for IL-1ß, IL-6, and TNF-α, respectively. H&E and Oil red O staining also showed that AsM ameliorated liver damage and lipid accumulation in mice. The protective mechanism of AsM may be associated to the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signaling pathway, which could activate the downstream antioxidant enzymes heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GCLM), and glutamate-cysteine ligase catalytic subunit (GCLC). These findings confirmed that AsM had an alleviating effect on alcoholic liver injury and provided new thoughts for the development of natural product.

An engineered Escherichia coli Nissle strain prevents lethal liver injury in a mouse model of tyrosinemia type 1.

BACKGROUND & AIMS: Hereditary tyrosinemia type 1 (HT1) results from the loss of fumarylacetoacetate hydrolase (FAH) activity and can lead to lethal liver injury. Therapeutic options for HT1 remain limited. In this study, we aimed to construct an engineered bacterium capable of reprogramming host metabolism and thereby provide a potential alternative approach for the treatment of HT1. METHODS: Escherichia coli Nissle 1917 (EcN) was engineered to express genes involved in tyrosine metabolism in the anoxic conditions that are characteristic of the intestine (EcN-HT). Bodyweight, survival rate, plasma (tyrosine/liver function), H&E staining and RNA sequencing were used to assess its ability to degrade tyrosine and protect against lethal liver injury in Fah-knockout (KO) mice, a well-accepted model of HT1. RESULTS: EcN-HT consumed tyrosine and produced L-DOPA (levodopa) in an in vitro system. Importantly, in Fah-KO mice, the oral administration of EcN-HT enhanced tyrosine degradation, reduced the accumulation of toxic metabolites, and protected against lethal liver injury. RNA sequencing analysis revealed that EcN-HT rescued the global gene expression pattern in the livers of Fah-KO mice, particularly of genes involved in metabolic signaling and liver homeostasis. Moreover, EcN-HT treatment was found to be safe and well-tolerated in the mouse intestine. CONCLUSIONS: This is the first report of an engineered live bacterium that can degrade tyrosine and alleviate lethal liver injury in mice with HT1. EcN-HT represents a novel engineered probiotic with the potential to treat this condition. IMPACT AND IMPLICATIONS: Patients with hereditary tyrosinemia type 1 (HT1) are characterized by an inability to metabolize tyrosine normally and suffer from liver failure, renal dysfunction, neurological impairments, and cancer. Given the overlap and complementarity between the host and microbial metabolic pathways, the gut microbiome provides a potential chance to regulate host metabolism through degradation of tyrosine and reduction of byproducts that might be toxic. Herein, we demonstrated that an engineered live bacterium, EcN-HT, could enhance tyrosine breakdown, reduce the accumulation of toxic tyrosine byproducts, and protect against lethal liver injury in Fah-knockout mice. These findings suggested that engineered live biotherapeutics that can degrade tyrosine in the gut may represent a viable and safe strategy for the prevention of lethal liver injury in HT1 as well as the mitigation of its associated pathologies.

Evaluation of the Clinical Efficacy of Heart Valve Surgery in Patients with a Cardiac Disorder and the Factors Contributing to Poor Patient Prognosis.

Objective: We aimed to investigate the clinical efficacy of heart valve surgery in patients with heart disease and the factors contributing to poor patient prognosis. Methods: This was a retrospective analysis of 172 patients with heart disease treated in Peking University International Hospital between January 2019 and December 2021, with surgical treatment in the study group (86 patients) and conservative treatment in the control group (86 patients), by comparing factors such as patient age, preoperative cardiac function status, type and degree of valve lesion, surgical method and time of aortic block and perioperative treatment in both groups with clinical cure rate. The risk factors for early postoperative death were analyzed by single-factor and multi-factor logistic regression methods. Results: Regression analysis showed that age, peripheral artery disease (PAD), diabetes mellitus (DM), hypertension (HTN), dietary habits and medical compliance were prognostic factors in patients after heart valve surgery. The incidence of complications was lower in the study group than in the control group (P < .05). The left anterior descending artery (LAD), left ventricular end-diastolic internal diameter (LVEDD), cardiothoracic ratio (CTR) and left ventricular end-systolic internal diameter (LVDS) was decreased in both groups, whereas the left ventricular ejection fraction (LVEF) and peak early diastolic flow rate/peak late diastolic flow rate (E/A) were increased. The changes were greater in the study group than in the control group (P < .05); life function scores and survival rates were higher in the study group than in the control group (P < .05). Conclusions: The analysis of relevant clinical risk factors identified some independent prognostic factors affecting early death after valve replacement. These can be used for preoperative risk assessment, identification of high-risk surgical patients and guiding daily clinical work. Rationalizing the indications for surgery, choosing the timing of surgery, myocardial protection and appropriate surgical approach can further reduce the rate of surgical morbidity and mortality and complications in this patient population.

A metabolite from commensal Candida albicans enhances the bactericidal activity of macrophages and protects against sepsis.

The gut microbiome is recognized as a key modulator of sepsis development. However, the contribution of the gut mycobiome to sepsis development is still not fully understood. Here, we demonstrated that the level of Candida albicans was markedly decreased in patients with bacterial sepsis, and the supernatant of Candida albicans culture significantly decreased the bacterial load and improved sepsis symptoms in both cecum ligation and puncture (CLP)-challenged mice and Escherichia coli-challenged pigs. Integrative metabolomics and the genetic engineering of fungi revealed that Candida albicans-derived phenylpyruvate (PPA) enhanced the bactericidal activity of macrophages and reduced organ damage during sepsis. Mechanistically, PPA directly binds to sirtuin 2 (SIRT2) and increases reactive oxygen species (ROS) production for eventual bacterial clearance. Importantly, PPA enhanced the bacterial clearance capacity of macrophages in sepsis patients and was inversely correlated with the severity of sepsis in patients. Our findings highlight the crucial contribution of commensal fungi to bacterial disease modulation and expand our understanding of the host-mycobiome interaction during sepsis development.

Preparation of Vanillin-Taurine Antioxidant Compound, Characterization, and Evaluation for Improving the Post-Harvest Quality of Litchi.

Litchi's post-harvest pericarp browning is one of the main constraints that drastically affect its visual attributes and market potential. Therefore, the vanillin-taurine Schiff base (VTSB) compound prepared from natural compounds of vanillin and taurine exhibited higher DPPH-radical-scavenging invitro antioxidant activity than vanillin. VTSB first-time report to mitigate the postharvest browning of litchi fruit. In this study, litchi fruits were dipped in 0.3 mM (based on pre-experiment) VTSB solution and stored at 25 ± 1 °C for six days to examine their effects on browning and postharvest quality. Fruit treated with VTSB had lower levels of browning degree (BD), browning index (BI), weight loss, soluble quinone (SQ), relative electrolyte leakage (REL), and malondialdehyde (MDA) than control fruit. Additionally, total anthocyanins and phenolic concentrations, Total soluble solids (TSS), and 2,2-diphenyl-1-picrylhydrazyl-free radical scavenging activity (DPPH-RSA) were preserved higher in VTSB-treated litchi fruit. The levels of Ascorbate peroxidase (APX), Superoxide dismutase (SOD), and Catalase (CAT) were higher in treated fruit, whereas polyphenol oxidase (PPO) and Peroxidase (POD) were decreased during the postharvest period. This study suggested that VTSB would be very useful for different post-harvest problems in the fruit and vegetable industry.

Gut microbial metabolite hyodeoxycholic acid targets the TLR4/MD2 complex to attenuate inflammation and protect against sepsis.

Sepsis, a critical condition resulting from the systemic inflammatory response to a severe microbial infection, represents a global public health challenge. However, effective treatment or intervention to prevent and combat sepsis is still lacking. Here, we report that hyodeoxycholic acid (HDCA) has excellent anti-inflammatory properties in sepsis. We discovered that the plasma concentration of HDCA was remarkably lower in patients with sepsis and negatively correlated with the severity of the disease. Similar changes in HDCA levels in plasma and cecal content samples were observed in a mouse model of sepsis, and these changes were associated with a reduced abundance of HDCA-producing strains. Interestingly, HDCA administration significantly decreased systemic inflammatory responses, prevented organ injury, and prolonged the survival of septic mice. We demonstrated that HDCA suppressed excessive activation of inflammatory macrophages by competitively blocking lipopolysaccharide binding to the Toll-like receptor 4 (TLR4) and myeloid differentiation factor 2 receptor complex, a unique mechanism that characterizes HDCA as an endogenous inhibitor of inflammatory signaling. Additionally, we verified these findings in TLR4 knockout mice. Our study highlights the potential value of HDCA as a therapeutic molecule for sepsis.

Synthesis of linear and star-shaped telechelic polyisobutylene by cationic polymerization.

Hydroxyl-terminated linear and star-shaped telechelic polyisobutylene have been successfully synthesized by living cationic polymerization using propylene oxide (PO)/Titanium tetrachloride (TiCl4) as the initiator system. A one-step method to prepare the terminal hydroxyl group was realized by selecting the cheap and beautiful epoxide as the functional initiator, which has the prospect of industrial application. The polymerization mechanism was proposed by the end structure analysis and Gaussian calculation results. At the same time, the living linear macromolecular chain was used as the starting point to react with divinyl compounds for synthesis of star-shaped hydroxyl-terminated polyisobutylene. The effects of initiator-crosslinking agent ratio, arm length, and reaction time on the coupling reaction were studied.

Melanin of fungi: from classification to application.

Melanin is a secondary metabolite composed of complex heterogeneous polymers. Fungal melanin is considered to be a sustainable and biodegradable natural pigment and has a variety of functional properties and biological activities. On one hand, due to its own specific properties it can play the role of antioxidant, anti-radiation, adsorption, and photoprotection. On the other hand, it has good biological activities such as hepatoprotective effect, hypolipidemic effect and anti-cancer. Therefore, it is widely used in various fields of daily life, including dyeing, food, biomedical and commercial industry. It is conducive to environmental protection and human health. However, the insolubility of fungal melanin in water, acids and organic solvents has been an obstacle to its commercial applications. Thus, the chemical modification methods of fungal melanin are summarized to increase its solubility and expand the application fields. Although fungal melanin has been used in many industries, as the structure and function of fungal melanin and modified melanin are further studied, more functional properties and bioactivities are expected to be discovered for a wide range of applications in the future.

A Diuretic Response is Associated with the Early Prognosis of Patients Undergoing Repeat Tricuspid Valve Surgery Due to Severe Tricuspid Regurgitation After Left-Sided Valvular Surgery.

OBJECTIVE: To analyze the factors affecting the early prognosis of patients undergoing repeat tricuspid valve surgery due to severe tricuspid regurgitation after left-sided valvular surgery. METHOD: We retrospectively analyzed 76 patients undergoing repeat tricuspid valve surgery due to severe tricuspid regurgitation after left-sided valvular surgery at Peking University International Hospital between October 2017 and February 2021. Patients were divided into two groups, according to preoperative weight control and whether the adjusted diuretic dose exceeded 40 mg of furosemide (or the equivalent dose). The factors affecting the early prognosis were analyzed through postoperative follow up. RESULTS: Thirty-five male patients (46.1%), aged 57±13 years, were enrolled in the study. For the patients who received a preoperative same dose of furosemide ≥40 mg/day and a same dose of furosemide <40 mg/day, the baseline data basically were the same. There were 76 patients (100%) who were followed up. Endpoint events during the follow up were as follows: Six patients (7.9%) died, two patients (2.6%) were admitted to the hospital or transferred to the intensive care unit due to cardiac insufficiency, and other conditions such as severe tricuspid regurgitation on repeat ultrasound, bilateral lower extremity edema, and inability to reduce or stop diuretics were found in five cases (6.6%). Compared with the group with the same dose of furosemide <40 mg/day group, the ≥40 mg/day group had a higher incidence of endpoints (12, 27.3% vs. 1, 3.1%, P = 0.006). CONCLUSION: In patients undergoing repeat tricuspid valve surgery due to severe tricuspid regurgitation after left-sided valvular surgery, a diuretic response was associated with surgical prognosis. Compared with the low-dose furosemide group, the high-dose group (≥40 mg/) had a significantly increased incidence of early events.

Characterization and mechanism study of aqueous cationic polymerization of p-methylstyrene.

Aqueous cationic polymerization has attracted considerable interest as a novel polymerization technique, because it conforms to the "green chemistry" trend and challenges the concept of traditional cationic polymerization. In this paper, a CumOH/B(C6F5)3/Et2O system was used to initiate the aqueous polymerization of p-methylstyrene through suspension and emulsion methods. Several types of surfactants were used, including the cationic surfactant CTAB, non-ionic surfactant NP-40, and anionic surfactant SDBS, and the influences of initiator concentration and temperature on polymerization were investigated. Consistent with previous literature, initiator activity was positively correlated with temperature unlike in traditional cationic polymerization. Gaussian 09W simulation software was used to calculate and optimize changes in the bond lengths and angles of B(C6F5)3 after ether was added to the system. The addition of ether increased the polarity of B(C6F5)3, rendering it soluble in water. 1H-NMR was used in identifying the main chain and terminal structures of the polymer, and the mechanism of p-methylstyrene aqueous phase cationic polymerization was proposed.

Glutaredoxin 1 regulates macrophage polarization through mediating glutathionylation of STAT1.

BACKGROUND: Macrophage polarization affects tumor growth, metabolism, and many other tumor processes. M1 macrophages can promote antitumor immunity response. Signal transducer and activator of transcription 1 (STAT1) is one of the critical transcription factors in this process, which promotes the expression of a series of inflammatory molecules. STAT1 has been reported as a potential target of reactive oxygen species (ROS)-induced glutathionylation, while the glutathionylation of STAT1 in macrophages and its underlying regulatory mechanism remains unclear. Glutaredoxin 1 (Grx1) functions as a deglutathionylation enzyme, which regulates the activities of many proteins through reversing glutathionylation. METHODS: GeneChip and RT-qPCR was first applied to test the mRNA level of Grx1 in M1 macrophages. Western blot was then used to evaluate the variations of the Grx1 protein expression in M1 macrophages. Next, immunoprecipitation was used to investigate the glutathionylated STAT1 in both wild-type and Grx1-/- mouse macrophages. Finally, the induced alterations of STAT1 activity and function by Grx1 in M1 macrophage were examined by western blot and RT-qPCR. RESULTS: In M1-type macrophages, the levels of Grx1 were elevated. Glutathionylation of STAT1 was negatively regulated by Grx1. Furthermore, depletion of Grx1 increased the activity of STAT1, and thereby promoted the mRNA level of C-X-C motif chemokine ligand 9 (CXCL9) during M1-type polarization of macrophages. CONCLUSIONS: Grx1 controlled deglutathionylation of STAT1, which in turn might regulate M1-type polarization of macrophages.

Structural Insight into the Mechanism of 4-Aminoquinolines Selectivity for the alpha2A-Adrenoceptor.

BACKGROUND: α2A-adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α2A-AR agonists are effective drugs for this condition. However, the lack of high selectivity for α2A-AR subtype of traditional drugs greatly limits their clinic usage. METHODS: A series of homobivalent 4-aminoquinolines conjugated by two 4-aminoquinoline moieties via varying alkane linker length (C2-C12) were characterized for their affinities for each α2-AR subtype. Subsequently, docking, molecular dynamics and mutagenesis were applied to uncover the molecular mechanism. RESULTS: Most 4-aminoquinolines (4-aminoquinoline monomer, C2-C6, C8-C10) were selective for α2A-AR over α2B- and α2C-ARs. Besides, the affinities are of similar linker length-dependence for each α2-AR subtype. Among all the compounds tested, C10 has the highest affinity for α2A-AR (pKi=-7.45±0.62), which is 12-fold and 60-fold selective over α2B-AR and α2C-AR, respectively. Docking and molecular dynamics suggest that C10 simultaneously interacts with orthosteric and "allosteric" sites of the α2A-AR. The mutation of F205 decreases the affinity by 2-fold. The potential allosteric residues include S90, N93, E94 and W99. CONCLUSION: The specificity of C10 for the α2A-AR and the potential orthosteric and allosteric binding sites proposed in this study provide valuable guidance for the development of novel α2A-AR subtype selective compounds.

Early Prognosis of Reduction Ascending Aortoplasty in Patients With Aortic Valve Disease: A Single Center's Experience.

BACKGROUND: Dilatation of the ascending aorta tends to develop in individuals with aortic valve disease. Reduction ascending aortoplasty (RAA) is an alternative procedure to ascending aortic replacement. This study was designed to identify the early prognosis of RAA for patients with aortic valve disease and dilatation of the ascending aorta. METHODS: From January 2010 to December 2013, 102 patients with aortic valve disease and ascending aortic dilatation who had undergone aortic valve replacement combined with RAA were enrolled. Fifty-seven patients with bicuspid aortic valve (BAV group) and 45 patients without BAV (non-BAV group) were analyzed. The study endpoints were postoperative death, reoperation, stroke, and aorta-related adverse events. RESULTS: Follow-up data were obtained from all patients. The mean follow-up time was 38.8 ± 13.0 months. More patients with mitral valve disease and tricuspid insufficiency were present in the non-BAV group. More patients with ascending aorta larger than 45 mm were present in the BAV group. Two patients died, and 1 patient experienced a stroke. There were no reoperations or aorta-related adverse events. The mean expansion degree and rate of ascending aorta were 0.39 ± 0.26 cm and 1.3 ± 0.8 mm/year, respectively, in patients with aortic redilatation. Redilatation was observed in the BAV group (37.0 ± 5.0 mm vs 35.5 ± 4.6 mm; p = 0.009), whereas the non-BAV group had no significant change. CONCLUSIONS: Reduction ascending aortoplasty shows good early results in patients with aortic valve disease and dilatation of the ascending aorta. Redilatation tends to happen in patients with BAV, and long-term follow-up is necessary.

[Low Intensity Anticoagulation Therapy for Chinese Population with Heart Valve Replacement--3 000 Cases Follow-up].

OBJECTIVE: To investigate the effect of low-intensity anticoagulation therapy for Chinese population with heart valve replacement. METHODS: From January 2011 to March 2012, 3 000 patients with heart valve replacement in Fuwai Hospital and West China Hospital were followed-up for 1 year, the method and intensity of postoperative anticoagulation, as well as the complications were studied and analyzed. RESULTS: The rate of follow-up was 88.57%, and the cumulative follow-up was 1 726.1 patient-years (Pty). The mean oral warfarin dosage was (2.68 ± 6.45) mg/d, and the mean INR values of the patients treated in Fuwai Hospital and West China Hospital were 2.01 ± 1.10 and 186 ± 0.69 respectively (total 54 379 samples). The total rates of anticoagulation complication and mortality were 5.79% Pty and 0.12% Pty respectively, among which the morbidity and mortality of hemorrhage were 3.59% Pty and 0.12% Pty respectively, while the morbidity and mortality of thromboembolism were 2.03% Pty and 0.00% Pty respectively. There are no significant differences of actual anticoagulation intensity (P = 0.28)and the complication rates between the two hospitals . CONCLUSION: The optimal intensity scope (INR) of 1.5-2.5 (mean 1.8-2.0) is safe and efficient for Chinese patients with prosthetic heart valves, and no significant regional difference in the intensity of anticoagulation therapy required.