Identification of clinical candidates against West Nile virus by activity screening in vitro and effect evaluation in vivo.

The West Nile virus (WNV) is a member of the flavivirus and is known to cause encephalitis. There is currently no specific treatment for WNV infection. Repurposing of clinically approved drugs appeared promising for rapidly identifying effective, safe, and readily available candidates for antiviral drugs. Here, we screened the small-molecule compounds with anti-WNV activity from 978 Food Drug Administration-approved drugs. Four compounds, including cilnidipine, mycophenolate mofetil, nitazoxanide, and teriflunomide, were found to efficiently abrogate WNV infection in Vero cells and human neuroblastoma SH-SY5Y cells. The four compounds also exert broad-spectrum antiviral activity against the Zika virus, Japanese encephalitis virus, yellow fever virus, tick-borne encephalitis virus, and chikungunya virus. Furthermore, nitazoxanide (a synthetic benzamide) and teriflunomide (an inhibitor of dihydroorotate dehydrogenase, DHODH) protected 20% and 40% of mice from lethal WNV challenge, respectively. Both drugs, which are orally bioavailable and have been approved clinically for many years, may be promising therapeutics for WNV infection. Moreover, the other two DHODH inhibitors, ML390 and vidofludimus, also displayed potent activity against WNV infection in vitro and in vivo.

Antiviral efficacy of selective estrogen receptor modulators against SARS-CoV-2 infection in vitro and in vivo reveals bazedoxifene acetate as an entry inhibitor.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the seventh member of the coronavirus family that can infect humans. Recently, more contagious and pathogenic variants of SARS-CoV-2 have been continuously emerging. Clinical candidates with high efficacy and ready availability are still in urgent need. To identify potent anti-SARS-CoV-2 repurposing drugs, we evaluated the antiviral efficacy of 18 selective estrogen receptor modulators (SERMs) against SARS-CoV-2 infection. Six SERMs exhibited excellent anti-SARS-CoV-2 effects in Vero E6 cells and three human cell lines. Clomifene citrate, tamoxifen, toremifene citrate, and bazedoxifene acetate reduced the weight loss of hamsters challenged with SARS-CoV-2, and reduced hamster pulmonary viral load and interleukin-6 expression when assayed at 4 days postinfection. In particular, bazedoxifene acetate was identified to act on the penetration stage of the postattachment step via altering cholesterol distribution and endosome acidification. And, bazedoxifene acetate inhibited pseudoviruses infection of original SARS-CoV-2, Delta variant, Omicron variant, and SARS-CoV. These results offer critical information supporting bazedoxifene acetate as a promising agent against coronaviruses.

Layered double hydroxide nanoparticles as an adjuvant for inactivated foot-and-mouth disease vaccine in pigs.

BACKGROUND: Foot-and-mouth disease (FMD) is a highly transmissible disease that leads to vast economic losses in many countries. Prevention using inactivated vaccines is one effective measure used to control FMD. Unfortunately, inactivated FMD vaccines provide only short-term protection and require a cold-chain system. In recent years, many studies have shown that layered double metal hydroxides (LDHs) carrying antigens can be used to strongly induce immune responses. In this study, LDH nanoparticles (NPs) were prepared by hydrothermal synthesis. LDH particle size, electric potential, and morphology were measured and observed. The adsorption capacity of LDH NPs to FMDV was tested. The effects of LDH as an adjuvant on inactivated FMDV vaccines were further evaluated and compared with commercial FMDV Montanide ISA-206 in BALB/C female mice and Yorkshire pigs. RESULTS: LDH NPs were successfully prepared with a uniform particle size of ~ 87.21 nm, regular edges, a loose hexagonal shape and positive zeta charge of 32 mV. The maximum absorption concentration was 0.16-0.31 µg FMDV/µg LDH. In the mouse experiment, antibody levels in group LDH + FMDV were significantly higher compared to group saline + FMDV (P < 0.01) from days 42-98 and were significantly higher to group ISA-206 + FMDV on day 56 post-immunization (P < 0.05). After day 14 post-immunization, IFN-γ content was significantly increased (P < 0.05). In the pig experiment, antibody levels in both the ISA-206 + FMDV and LDH + FMDV were positive and were significantly higher compared with the PBS group on day 7 (P < 0.005). Antibody levels in 90% pigs were positive on day 56 in the LDH group. The neutralizing antibody levels in the LDH and ISA-206 groups were significantly higher from days 7-28 compared to the PBS control group (P < 0.05). Thus, LDH NPs were effective at inducing an immune response against FMDV. CONCLUSIONS: LDHs with a loose hexagonal shape and a positive charge were prepared and evaluated as adjuvant for FMD vaccine. It was demonstrated that LDHs can induce immune responses in mice and pigs. In addition, the LDHs produced antibodies continuously which may indicate a slow-release effect. The study shows that LDHs may act as a potentially useful FMDV adjuvant.

Aptamer based fluorometric sulfamethazine assay based on the use of graphene oxide quantum dots.

The authors have developed a homogeneous "off-on" fluorometric method for the determination of the antibiotic sulfamethazine (SMZ). Aptamer against SMZ was labeled with graphene oxide quantum dots upon which the Graphene oxide quenched the blue fluorescence of the GOQDs. On addition of SMZ, the aptamers will bind SMZ and this will cause the release of GOQDs. As a result, fluorescence will be regenerated. Fluorescence, best measured at excitation/emission wavelengths of 365/455 nm, increases linearly in the 8 pg·mL-1 to 60 ng·mL-1 SMZ concentration range, with a 5 pg·mL-1 detection limit. The method is reliable and was successfully applied to the determination of SMZ in spiked milk samples, with recoveries ranging from 89 to 96% depending on analyte concentration. Graphical abstract Graphene oxide quantum dots (GOQDs) were covalently bound to the aptamer (apt) against sulfamethazine (SMZ) and adsorbed on the surface of graphene oxide (GO). This results in quenching of the fluorescence of GOQDs. On addition of SMZ, fluorescence is restored due to the release of GOQD@apt from GO.

Novel all-hydrocarbon stapled p110α[E545K] peptides as blockers of the oncogenic p110α[E545K]-IRS1 interaction.

To follow up on our recent discovery of the 18-amino acid all-hydrocarbon [i, i + 4]-stapled p110α[E545K] peptide 1 that was shown to potently block the intracellular p110α[E545K]-IRS1 interaction (a protein-protein interaction uniquely present in cancer cells expressing p110α[E545K]) and the growth of the xenograft tumors formed by cancers harboring this mutation, in the current study we prepared and examined six derivatives of 1, i.e. stapled peptides 2-A, 2-B, 3-A, 3-B, 4-A, 4-B. We found that 2-A, 2-B, 4-A, and 4-B had higher % α-helicity than 1; moreover, the enhanced % α-helicity also led to an enhanced proteolytic stability. When compared with 1, the structurally simplified 14-amino acid 4-A and 4-B were found to more potently deactivate the AKT phosphorylation at Ser473 in the p110α[E545K]-expressing colon cancer cells, whose activation was previously demonstrated by us to be specifically derived from the p110α[E545K]-IRS1 interaction. The preliminary findings from the current study have laid a foundation for future more extensive studies on the stapled p110α[E545K] peptides newly identified in the current study.

The efficacy of Guolin-Qigong on the body-mind health of Chinese women with breast cancer: a randomized controlled trial.

PURPOSE: This study was to evaluate the efficacy of a complementary Chinese treatment modality Guolin-Qigong (GLQG) for patients with breast cancer on the body-mind health. METHODS: A randomized controlled clinical trial was conducted among 158 women with breast cancer. Subjects were randomized to receive GLQG (test group) versus a physical stretching program (control group) following conventional treatment for breast cancer. GLQG and stretching interventions were performed twice a week over 24 weeks. The primary outcome was the change in quality of life (QoL). Secondary outcome measures included anxiety, depression, and clinical indicators. All participants were assessed at four time-points, at the beginning of the study (T1), after 12 weeks of the intervention (T2), immediately after 24-week intervention (T3), and at 48-week follow-up visit (T4). RESULTS: Improvements in QoL were evident in both groups but the test group fared better than the control group at the 12th week (P < 0.01) and particularly in emotional well-being (P < 0.01) and breast cancer-specific well-being (P < 0.001). The test group showed an improvement in anxiety levels (P < 0.01), whereas the control group showed improvements in depression (P < 0.05) but there was no significant difference between groups (P > 0.05). Both groups showed improvements in immunological function and the test group fared better than the control in TNF-α levels (P < 0.05). The results in subjects who practiced more than 4 times and 6 h per week were similar to that of all subjects; however, the improvement in anxiety in the GLQG group was more obvious. There are positive correlations between QoL and anxiety and depression. CONCLUSIONS: Both GLQG and physical stretching are beneficial during recovery following breast cancer. GLQC was more effective in terms of Qol improvements than physical stretching. Both programs brought improvements in anxiety or depression but had were comparable. GLQC group had a greater effect on immunological function than physical exercise.

HDAC2 is required by the physiological concentration of glucocorticoid to inhibit inflammation in cardiac fibroblasts.

We previously suggested that endogenous glucocorticoids (GCs) may inhibit myocardial inflammation induced by lipopolysaccharide (LPS) in vivo. However, the possible cellular and molecular mechanisms were poorly understood. In this study, we investigated the role of physiological concentration of GCs in inflammation induced by LPS in cardiac fibroblasts and explored the possible mechanisms. The results showed that hydrocortisone at the dose of 127 ng/mL (equivalent to endogenous basal level of GCs) inhibited LPS (100 ng/mL)-induced productions of TNF-α and IL-1ß in cardiac fibroblasts. Xanthine oxidase/xanthine (XO/X) system impaired the anti-inflammatory action of GCs through downregulating HDAC2 activity and expression. Knockdown of HDAC2 restrained the anti-inflammatory effects of physiological level of hydrocortisone, and blunted the ability of XO/X system to downregulate the inhibitory action of physiological level of hydrocortisone on cytokines. These results suggested that HDAC2 was required by the physiological concentration of GC to inhibit inflammatory response. The dysfunction of HDAC2 induced by oxidative stress might be account for GC resistance and chronic inflammatory disorders during the cardiac diseases.

The chemical biology of sirtuins.

The sirtuin family of enzymes are able to catalyze the N(ε)-acyl-lysine deacylation reaction on histone and non-histone protein substrates. Over the past years since the discovery of its founding member (i.e. the yeast silent information regulator 2 (sir2) protein) in 2000, the sirtuin-catalyzed deacylation reaction has been demonstrated to play an important regulatory role in multiple crucial cellular processes such as transcription, DNA damage repair, and metabolism. This reaction has also been regarded as a current therapeutic target for human diseases such as cancer, and metabolic and neurodegenerative diseases. The unique ß-nicotinamide adenine dinucleotide (ß-NAD(+) or NAD(+))-dependent nature of the sirtuin-catalyzed deacylation reaction has also engendered extensive mechanistic studies, resulting in a mechanistic view of the enzyme chemistry supported by several lines of experimental evidence. On the journey toward these knowledge advances, chemical biological means have constituted an important functional arsenal; technically, a variety of chemical probes and modulators (inhibitors and activators) have been developed and some of them have been employed toward an enhanced mechanistic and functional (pharmacological) understanding of the sirtuin-catalyzed deacylation reaction. On the other hand, an enhanced mechanistic understanding has also facilitated the development of a variety of chemical probes and modulators. This article will review the tremendous accomplishments achieved during the past few years in the field of sirtuin chemical biology. It is hoped that this would also help to set a stage for how outstanding mechanistic and functional questions for the sirtuin-catalyzed deacylation reaction could be addressed in the future from the chemical biology perspective.

AMP-activated protein kinase-dependent autophagy mediated the protective effect of sonic hedgehog pathway on oxygen glucose deprivation-induced injury of cardiomyocytes.

Sonic hedgehog (Shh) pathway has been reported to protect cardiomyocytes in myocardial infarction (MI), but the underlying mechanism is not clear. Here, we provide evidence that Shh pathway induces cardiomyocytes survival through AMP-activated protein kinase-dependent autophagy. Shh pathway agonist SAG increased the expression of LC3-II, and induced the formation of autophagosomes in cultured H9c2 cardiomyocytes under oxygen glucose deprivation (OGD) 1 h and 4 h. Moreover, SAG induced a profound AMP-activated protein kinase (AMPK) activation, and then directly phosphorylated and activated the downstream autophagy initiator Ulk1, independent of the autophagy suppressor mammalian target of rapamycin (mTOR) complex 1. Taken together, our results have shown that Shh activates AMPK-dependent autophagy in cardiomyocytes under OGD, suggesting a role of autophagy in Shh-induced cellular protection.

Novel sirtuin inhibitory warheads derived from the N(ε)-acetyl-lysine analog L-2-amino-7-carboxamidoheptanoic acid.

Built upon the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead L-2-amino-7-carboxamidoheptanoic acid (L-ACAH, a close structural analog of N(ε)-acetyl-lysine) that our laboratory discovered recently, in the current study, its carboxamide NH2-ethylated analog was found to be a ∼2.4-6.6-fold stronger SIRT1/2/3 inhibitory warhead than L-ACAH. Carboxamide NH2-dodecylated and carboxymethylated analogs of L-ACAH were also identified as potent SIRT6 and SIRT5 inhibitory warheads, respectively.

Characteristics of TCM constitutions of adult Chinese women in Hong Kong and identification of related influencing factors: a cross-sectional survey.

BACKGROUND: Traditional Chinese Medicine Constitution (TCMC) refers to an integrated, metastable and natural specialty of individual in morphosis, physiological functions and psychological conditions. It is formed on the basis of innate and acquired endowments in the human life process, which can be divided into normal constitution and unbalanced ones. The aim of this study was to investigate the distribution of TCMCs of Chinese women in Hong Kong and its acquired influencing factors. METHODS: Local Chinese women between 30 to 65 years old, were recruited from 18 districts of Hong Kong (n=944), and were assessed using the Traditional Chinese Medicine Physical Constitution Scale for their TCMC types. Social-demographic, reproductive, lifestyle, systemic health and emotional status information were collected through structured questionnaire. The associations between different independent factors and each TCMC type, as well as the complex unbalanced TCMC types were tested individually. Significant factors related to unbalanced TCMC types were identified in final models using multiple factor analysis. RESULTS: A total of 764 (80.9%) participants were diagnosed with unbalanced TCMCs. The most common TCMC type was Qi-deficiency constitution (53.9%), followed by Phlegm-wetness (38.9%), Yang-deficiency (38.2%), Yin-deficiency (35.5), Blood-stasis (35.4) and Qi-depressed (31%) constitution. Six hundred and eleven participants (64.7%) had at least two types of combined and unbalanced constitutions. Stepwise logistic analysis indicated that poor systemic health condition (OR, 1.76-2.89), negative emotions (OR=1.39), overweight (OR=1.58), high educational level (OR=1.18) and mental work (OR=1.44) were significantly positively correlated with certain unbalanced TCMCs. Meanwhile, aging (OR, 0.59-0.73), exercise habit (OR, 0.61-0.79) and reproductive history (OR=0.72) showed inverse associations with unbalanced constitutions. In addition, systemic health condition and emotional status, exercise habit and age were significantly associated with the combined unbalanced TCMC types. CONCLUSION: The majority of middle-aged Chinese women in Hong Kong had unbalanced and complex TCMCs. Qi-deficiency, Phlegm-wetness and Yang-deficiency constitutions are the most common constitutions. Poor systemic health condition, less-than-satisfactory emotional life, overweight and mental work are associated with and may be contributors for the formation of unbalanced TCMCs, while regular physical exercise was found to be a potential protective factor for unbalanced TCMCs.

Research note: effects of hyperpigmentation of the visceral peritoneum on body weight and selection method in Chinese yellow-feathered broilers.

We previously identified a dark blue appearance through the skin of abdomen, especially the colored chicken breeds, called hyperpigmentation of the visceral peritoneum (HVP) which characterized by intense pigmentation of connective tissue in the visceral peritoneum. The HVP has recently garnered increasing attention due to its negative impact on carcass appearance, and been an important concern in the poultry industry, especially for the Chinese yellow-feathered broilers. In this study, we measured the in vivo HVP at different time points, and analyzed the correlation between the HVP in vivo and postmortem. Then, established an accurate and reliable HVP phenotypic measuring method in vivo for early selection in chickens and analyzed the association of phenotypic variations with the in vivo HVP traits with growth traits. The results showed that the in vivo HVP at 21 d of age in chickens have a high heritability (h2 = 0.452) through estimating genetic parameters, and in vivo HVP levels at 21 and 42 d were both significantly associated with those postmortem in chickens, suggesting that directional selection on reducing HVP can be implemented as early as at 21 d in the breeding and production of chickens. Although, we found HVP had no effect on the body weight at 1 d, it could significantly reduce the body weight at 21, 42, 70 d and 91 d in chickens. This suggests HVP not only has a negative effect on carcass traits, but also significantly reduces the production in the poultry industry.

Nifuroxazide Prevents Chikungunya Virus Infection Both In Vitro and In Vivo via Suppressing Viral Replication.

Chikungunya virus (CHIKV) is a reemerging arbovirus causing disease on a global scale, and the potential for its epidemics remains high. CHIKV has caused millions of cases and heavy economic burdens around the world, while there are no available approved antiviral therapies to date. In this study, nifuroxazide, an FDA-approved antibiotic for acute diarrhea or colitis, was found to significantly inhibit a variety of arboviruses, although its antiviral activity varied among different target cell types. Nifuroxazide exhibited relatively high inhibitory efficiency in yellow fever virus (YFV) infection of the hepatoma cell line Huh7, tick-borne encephalitis virus (TBEV) and west nile virus (WNV) infection of the vascular endothelial cell line HUVEC, and CHIKV infection of both Huh7 cells and HUVECs, while it barely affected the viral invasion of neurons. Further systematic studies on the action stage of nifuroxazide showed that nifuroxazide mainly inhibited in the viral replication stage. In vivo, nifuroxazide significantly reduced the viral load in muscles and protected mice from CHIKV-induced footpad swelling, an inflammation injury within the arthrosis of infected mice. These results suggest that nifuroxazide has a potential clinical application as an antiviral drug, such as in the treatment of CHIKV infection.

PRL1 and PRL3 promote macropinocytosis via its lipid phosphatase activity.

PRL1 and PRL3, members of the protein tyrosine phosphatase family, have been associated with cancer metastasis and poor prognosis. Despite extensive research on their protein phosphatase activity, their potential role as lipid phosphatases remains elusive. Methods: We conducted comprehensive investigations to elucidate the lipid phosphatase activity of PRL1 and PRL3 using a combination of cellular assays, biochemical analyses, and protein interactome profiling. Functional studies were performed to delineate the impact of PRL1/3 on macropinocytosis and its implications in cancer biology. Results: Our study has identified PRL1 and PRL3 as lipid phosphatases that interact with phosphoinositide (PIP) lipids, converting PI(3,4)P2 and PI(3,5)P2 into PI(3)P on the cellular membranes. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis, facilitating nutrient extraction, cell migration, and invasion, thereby contributing to tumor development. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis. Additionally, we found a correlation between PRL1/3 expression and glioma development, suggesting their involvement in glioma progression. Conclusions: Combining with the knowledge that PRLs have been identified to be involved in mTOR, EGFR and autophagy, here we concluded the physiological role of PRL1/3 in orchestrating the nutrient sensing, absorbing and recycling via regulating macropinocytosis through its lipid phosphatase activity. This mechanism could be exploited by tumor cells facing a nutrient-depleted microenvironment, highlighting the potential therapeutic significance of targeting PRL1/3-mediated macropinocytosis in cancer treatment.

Identification of tyrphostin AG879 and A9 inhibiting replication of chikungunya virus by screening of a kinase inhibitor library.

Chikungunya virus (CHIKV) is a globally public health threat. There are currently no medications available to treat CHIKV infection. High-throughput screening of 419 kinase inhibitors was performed based on the cytopathic effect method, and six kinase inhibitors with reduced cytopathic effects, including tyrphostin AG879 (AG879), tyrphostin 9 (A9), sorafenib, sorafenib tosylate, regorafenib, and TAK-632, were identified. The anti-CHIKV activities of two receptor tyrosine kinase inhibitors, AG879 and A9, that have not been previously reported, were selected for further evaluation. The results indicated that 50% cytotoxic concentration (CC50) of AG879 and A9 in Vero cells were greater than 30 µM and 6.50 µM, respectively and 50% effective concentration (EC50) were 0.84 µM and 0.36 µM, respectively. The time-of-addition and time-of-removal assays illustrated that both AG879 and A9 function in the middle stage of CHIKV life cycle. Further, AG879 and A9 do not affect viral attachment; however, they inhibit viral RNA replication, and exhibit antiviral activity against CHIKV Eastern/Central/South African and Asian strains, Ross River virus and Sindbis virus in vitro.

Long-term divergent selection for residual feed intake in Chinese broiler chickens.

This study aimed to assess the effect of inbreeding on production traits using a long-term closed-line population recorded for residual feed intake (RFI). The study first used data from a previously reported population to determine the appropriate period of divergent selection for RFI. The results showed that RFI had similar moderate heritability estimates (0.28-0.34) during the fast-growing period (7-12 wk), and RFI at 7 to 10 wk had the highest heritability (0.34). Therefore, divergent selection was performed in a Chinese broiler population for RFI at 7 to 10 wk; the total sample size from generations zero (G0) to 13 was 9050. The divergence between the 2 lines increased steadily throughout generations, resulting in G13 with average RFI values of 304.55 in high RFI (HRFI) males, -160.31 in low RFI (LRFI) males, 296.30 in HRFI females and -157.55 in LRFI females. The feed intake (FI) and feed conversion ratio were almost higher in HRFI broilers than in LRFI broilers, and the magnitude of the difference in FI increased from approximately 4% for both sexes in G1 to approximately 33% in G13. Body weight gain was irregular from G1 to G13 and higher in LRFI broilers than in HRFI broilers after G10. Indeed, the HRFI broilers consumed more food, but they were lighter than LRFI broilers. In G13, LRFI males had heavier slaughter weight, longer cecum length, more white blood cells (WBC), red blood cells (RBC) and hemoglobin (HGB), but triglycerides, lower dressed percentage, percentage of half eviscerated yield, and eviscerated yield than HRFI males. LRFI females had a higher percentage of breast muscle and gizzard yield, longer cecum length, and more WBCs, RBCs and HGB but less abdominal fat and serum total cholesterol than HRFI females. This study was the first to verify that long-term divergent selection for RFI in Chinese broiler chickens is positive and beneficial.

Using association rules mining to explore pattern of Chinese medicinal formulae (prescription) in treating and preventing breast cancer recurrence and metastasis.

BACKGROUND: Chinese herbal medicine is increasingly widely used as a complementary approach for control of breast cancer recurrence and metastasis. In this paper, we examined the implicit prescription patterns behind the Chinese medicinal formulae, so as to explore the Chinese medicinal compatibility patterns or rules in the treatment or control of breast cancer recurrence and metastasis. METHODS: This study was based on the herbs recorded in Pharmacopoeia of the People's Republic of China, and the literature sources from Chinese Journal Net and China Master Dissertations Full-text Database (1990 - 2010) to analyze the compatibility rule of the prescription. Each Chinese herb was listed according to the selected medicinal formulae and the added information was organized to establish a database. The frequency and the association rules of the prescription patterns were analyzed using the SPSS Clenmentine Data Mining System. An initial statistical analysis was carried out to categorize the herbs according to their medicinal types and dosage, natures, flavors, channel tropism, and functions. Based on the categorization, the frequencies of occurrence were computed. RESULTS: The main prescriptive features from the selected formulae of the mining data are: (1) warm or cold herbs in the Five Properties category; sweet or bitter herbs in the Five Flavors category and with affinity to the liver meridian are the most frequently prescribed in the 96 medicinal formulae; (2) herbs with tonifying and replenishing, blood-activating and stasis-resolving, spleen-strengthening and dampness-resolving or heat-clearing and detoxicating functions that are frequently prescribed; (3) herbs with blood-tonifying, yin-tonifying, spleen-strengthening and dampness-resolving, heat-clearing and detoxicating, and blood-activating with stasis-resolving functions that are interrelated and prescribed in combination with qi-tonifying herbs. CONCLUSIONS: The results indicate that there is a close relationship between recurrence and metastasis of breast cancer with liver dysfunctions. These prescriptions focus on the herbs for nourishing the yin-blood, and emolliating and regulating the liver which seems to be the key element in the treatment process. Meanwhile, the use of qi-tonifying and spleen-strengthening herbs also forms the basis of prescription patterns.

Endogenous glucocorticoids inhibit myocardial inflammation induced by lipopolysaccharide: involvement of regulation of histone deacetylation.

Emerging evidence indicates that myocardial inflammation plays a key role in the pathogenesis of cardiac diseases. But the exact mechanisms for this chronic inflammatory disorder have not been elucidated. Glucocorticoids (GCs) are the most effective anti-inflammatory treatments available for many inflammatory diseases. However, it is unknown whether endogenous GCs are able to exert anti-inflammatory effect on myocardial inflammation. In this study, the potential role of endogenous GCs in the regulation of myocardial inflammation was investigated. We showed that the reduction of endogenous GC level by adrenalectomy promoted the production of basal and lipopolysaccharide (LPS)-induced proinflammatory cytokines, which could be partly reversed by supplementing with exogenous physiological level of hydrocortisone. Inhibition of GC receptor (GR) signaling pathway with GR antagonist mifepristone (RU486) or histone deacetylase inhibitor trichostatin A (TSA) also increased the levels of basal and LPS-induced proinflammatory cytokines. Moreover, blockade of GC-GR signaling pathway by adrenalectomy, RU486 or TSA enhanced LPS-induced myocardial nuclear factor-κB activation and histone acetylation but inhibited myocardial histone deacetylase expression and activity. Cardiac function studies demonstrated that blockade of the GC-GR signaling pathway aggravated inflammation-induced cardiac dysfunction. These findings indicate that endogenous GCs are able to inhibit myocardial inflammation induced by LPS. Endogenous GCs represent an important endogenous anti-inflammatory mechanism for myocardium in rats and such mechanism injury may be an important factor for pathogenesis of cardiac diseases.

School EFL Teachers' Research Identity Construction in the Chinese University-School Community.

Despite a relatively large number of studies on teachers' identity development in the University-School community, few studies have explicitly focused on school EFL teachers' research identity construction. This study adopts the Activity Theory and examines three English as a foreign language (EFL) teachers from three middle schools in a University-School community in China. It investigates how three teachers constructed their research identity and what factors influenced the construction of their identities within the University-School activity system from the dual perspectives of the school and university teachers. Data are collected through semi-structured narrative interviews, triangulated by documents such as meeting minutes, and then analyzed by NVivo 12. The findings of this study show that (1) the University-School collaborative program helps form a University-School community of both teaching and research; (2) in this community, school EFL teachers continuously construct their identities in a spiral process of "practitioner" and "researcher"; (3) it highlights the internal factors containing the research experience and the stage of career and the external factors including the curriculum reform context and the communication in the community. The findings carry important implications for school EFL teachers' research identity construction and professional development in the University-School cooperation.