Systemic effects of gut microbiota and its relationship with disease and modulation

published_or_final_versio

HIV-1 Tat dysregulation of KSHV induced immune response through the production of IL-8

Poster PresentationHuman immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS) and is a major health issue around the world. HIV is known to induce a number of pathological problems in AIDS patients via the transactivator (Tat) protein that is expressed and released by infected cells. One of the most important function of Tat is the dysregulation of the immune response. IL-8 is a chemokine known to be highly expressed in AIDS patients and Tat plays a major role in its production. IL-8 increases the HIV transmission and replication rate; and plays a role in Kaposi's sarcoma associated herpesvirus (KSHV) infection, which is a major opportunistic pathogen that AIDS patients are at risk to. KSHV is also known to induce the expression of IL-8 in patients, and IL-8 is known to assist tumour development by increasing angiogenesis. In our study, we investigated the role that Tat may have in manipulating the expression of IL-8 induced by KSHV in primary blood monocyte derived macrophages (PBMac). The results showed that pretreatment of PBMac with Tat inhibited the expression of IL-8 induced by KSHV by approximately 40%. We also found that Tat was able to inhibit the phosphorylation of STAT-1 induced by KSHV, and the inhibition of STAT-1 phosporylation was related to the expression of IL-8 induced by KSHV. In conclusion, we found that Tat was able to manipulate the expression of IL-8 induced by KSHV in macrophages, and this inhibition of IL-8 expression was regulated through the STAT-1 related pathways.published_or_final_versio

Investigating the role of interleukin-17A on cytokines production by macrophages in response to bacterial infections

Poster PresentationInterleukin-17A (IL-17A) has been shown to associate with a variety of infection diseases. In this study, we investigate whether IL-17A affects cytokines production of human peripheral blood-derived macrophages during Mycobacteriun bovis BCG or Klebsiella pneumoniae infection. We observed that IL-17A-treated macrophages exhibited suppressed productions of TNF-α and IL-6 in response to BCG infection. The reduction of cytokines production was not associated with cell death. On the other hand, IL-17A promoted TNF-α and IL-6 production by macrophages during K. pneumoniae infection. Furthermore, IL-17A did not affect TNF-α production induced by LPS and Pam3 Cys, which are TLR4 and TLR2 agonists, respectively. The data suggest that the differential regulation of cytokines production by IL-17A requires whole bacterium infection.published_or_final_versio

Medication beliefs, adherence, and outcomes in people with asthma: The importance of treatment beliefs in understanding inhaled corticosteroid nonadherence—a retrospective analysis of a real-world data set

BACKGROUND: Poor adherence to inhaled corticosteroids (ICSs) increases asthma morbidity and mortality and is influenced by patients’ treatment beliefs. This study maps patients’ beliefs about ICSs across 6 countries examining variations in beliefs, and their relationship with adherence and outcomes. OBJECTIVE: We sought to explore the relationship between patient treatment beliefs, and adherence and outcomes in asthma across 6 countries. METHODS: Patients 18 years or older with asthma, receiving ICS alone or in combination with a long-acting β2-agonist, were included from a point-in-time paper survey of patients with asthma in Europe and the United States. Clinical characteristics, such as adherence and asthma control, were collected by self- and physician-report. Patients completed the Beliefs about Medicines Questionnaire, adapted for ICSs. Relationships between patient treatment beliefs, adherence, and outcomes were examined using regression analyses. RESULTS: Data from 1312 patients were analyzed. Patients were from Germany (24%), the United States (21%), France (21%), Spain (16%), Italy (10%), and the United Kingdom (9%). Most had physician-reported mild-intermittent asthma (87%), and mean age was 40 ± 15.5 years. There was considerable variation in necessity beliefs between countries, with respondents in Italy having more doubts about treatment necessity and respondents in Spain showing higher concerns. Patients with doubts about ICS necessity and high concerns had lower self-reported (necessity: χ2(2) = 34.31, P < .001; concerns: χ2(2) = 20.98, P < .001) and physician-reported adherence (necessity: χ2(2) = 11.70, P = .003; concerns: χ2(2) = 34.45, P < .001). Patients with high necessity beliefs (F(2, 483) = 3.33; P = .037) and high concerns (F(2,483) = 23.46; P < .001) reported poorer control. Physician estimates of adherence did not correlate well with patient self-report (ρ = 0.178, P < .001). CONCLUSIONS: ICS necessity beliefs and concerns were associated with adherence and asthma control. This has implications for the design of adherence interventions

Genetically modified "obligate" anaerobic Salmonella typhimurium as a therapeutic strategy for neuroblastoma

published_or_final_versio

Pharmacist-led adherence support in general practice: a qualitative interview study of adults with asthma.

OBJECTIVES: The National Health Service (NHS) in England recently introduced general practice pharmacists (GPPs) to provide medication-focused support to both patients and the general practice team. This healthcare model may benefit people with asthma, who currently receive suboptimal care and demonstrate low medication adherence. This study aimed to explore the perspectives of adults with asthma on the potential for pharmacist-led adherence support delivered in general practice, with a focus on how these perspectives are formed. DESIGN AND SETTING: The study was conducted in the United Kingdom (UK) utilising a qualitative interview methodology. Participants were invited to partake in a telephone-based semistructured interview, followed by an online questionnaire for demographic details and asthma history. Qualitative data were analysed using thematic analysis. PARTICIPANTS: Participants (n=17) were adults with asthma in the UK with a prescription for an inhaled corticosteroid. Participants did not have previous experience with GPPs and were asked to provide their views on a proposed GPP-led service. RESULTS: Participant perspectives of GPPs were determined by trust in pharmacists, perceived gaps in asthma care and the perceived strain on the NHS. Trust was based on pharmacists' perceived clinical competency, established over time, and gauged through a 'benchmarking' process. GPP's fit in current asthma care was assessed based on potential role overlap with other healthcare professionals, continuity of care and medication-related support needs. Participants navigated the NHS based on a perceived hierarchy of healthcare professionals (general practitioners on top, nurses, then pharmacists), and this influenced their perspectives of GPPs. CONCLUSION: While the GPP scheme shows promise based on the perspectives of people with asthma, the identified barriers to optimal patient engagement and service implementation will need to be addressed for the service to be effective.The research was funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care North Thames at Barts Health NHS Trust

An Internet-Based Intervention to Promote Alcohol-Related Attitudinal and Behavioral Change Among Adolescents: Protocol of a Cluster Randomized Controlled Trial

published_or_final_versio

The C-ETS2-TFEB Axis Promotes Neuron Survival under Oxidative Stress by Regulating Lysosome Activity

Excessive reactive oxygen species/reactive nitrogen species (ROS/RNS) produced as a result of ageing causes damage to macromolecules and organelles or leads to interference of cell signalling pathways, which in turn results in oxidative stress. Oxidative stress occurs in many neurodegenerative diseases (e.g., Parkinson’s disease) and contributes to progressive neuronal loss. In this study, we show that cell apoptosis is induced by oxidative stress and that lysosomes play an important role in cell survival under oxidative stress. As a compensatory response to this stress, lysosomal genes were upregulated via induction of transcription factor EB (TFEB). In addition, localization of TFEB to the nucleus was increased by oxidative stress. We also confirmed that TFEB protects cells from oxidative stress both in vitro and in vivo. Finally, we found that C-ETS2 senses oxidative stress, activates TFEB transcription, and mediates the upregulation of lysosomal genes. Our results demonstrate a mechanistic pathway for inducing lysosomal activity during ageing and neurodegeneration.published_or_final_versio

Phosphorylation of MITF by AKT affects its downstream targets and causes TP53-dependent cell senescence

Microphthalmia-associated transcription factor (MITF) plays a crucial role in the melanogenesis and proliferation of melanocytes that is dependent on its abundance and modification. Here, we report that epidermal growth factor (EGF) induces senescence and cyclin-dependent kinase inhibitor 1A (CDKN1A) expression that is related to MITF. We found that MITF could bind TP53 to regulate CDKN1A. Furthermore, the interaction between MITF and TP53 is dependent on AKT activity. We found that AKT phosphorylates MITF at S510. Phosphorylated MITF S510 enhances its affinity to TP53 and promotes CDKN1A expression. Meanwhile, the unphosphorylative MITF promotes TYR expression. The levels of p-MITF-S510 are low in 90% human melanoma samples. Thus the level of p-MITF-S510 could be a possible diagnostic marker for melanoma. Our findings reveal a mechanism for regulating MITF functions in response to EGF stimulation and suggest a possible implementation for preventing the over proliferation of melanoma cells.published_or_final_versio

Effectiveness of a Technology-Based Injury Prevention Program for Enhancing Mothers’ Knowledge of Child Safety: Protocol for a Randomized Controlled Trial

Protocolpublished_or_final_versio