AMPK and SIRT1 activation contribute to inhibition of neuroinflammation by thymoquinone in BV2 microglia

Thymoquinone is a known inhibitor of neuroinflammation. However, the mechanism(s) involved in its action remain largely unknown. In this study, we investigated the roles of cellular reactive oxygen species (ROS), 5′ AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) in the anti-neuroinflammatory activity of thymoquinone. We investigated effects of the compound on ROS generation in LPS-activated microglia using the fluorescent 2′,7′-dichlorofluorescin diacetate (DCFDA)-cellular ROS detection. Immunoblotting was used to detect protein levels of p40phox, gp91phox, AMPK, LKB1 and SIRT1. Additionally, ELISA and immunofluorescence were used to detect nuclear accumulation of SIRT1. NAD+/NADH assay was also performed. The roles of AMPK and SIRT1 in anti-inflammatory activity of thymoquinone were investigated using RNAi and pharmacological inhibition. Our results show that thymoquinone reduced cellular ROS generation, possibly through inhibition of p40phox and gp91phox protein. Treatment of BV2 microglia with thymoquinone also resulted in elevation in the levels of LKB1 and phospho-AMPK proteins. We further observed that thymoquinone reduced cytoplasmic levels and increased nuclear accumulation of SIRT1 protein and increased levels of NAD+. Results also show that the anti-inflammatory activity of thymoquinone was abolished when the expressions of AMPK and SIRT1 were suppressed by RNAi or pharmacological antagonists. Pharmacological antagonism of AMPK reversed thymoquinone-induced increase in SIRT1. Taken together, we propose that thymoquinone inhibits cellular ROS generation in LPS-activated BV2 microglia. It is also suggested that activation of both AMPK and NAD+/SIRT1 may contribute to the anti-inflammatory, but not antioxidant activity of the compound in BV2 microglia

Libyan National Health Services The Need to Move to Management-by-Objectives

In the last four decades, there has been a substantial horizontal expansion of health services in Libya. This resulted in improvement in morbidity and mortality, in particularly those related to infectious disease. However, measures such as the national performance gap indicator reveal an underperforming health system. In this article, we discuss aspects related to the Libyan health system and its current status including areas of weakness. Overcoming current failures and further improvement are unlikely to occur spontaneously without proper planning. Defining community health problems, identifying unmet needs, surveying resources to meet them, establishing SMART (specific, measurable, achievable, and realistic and time specific) objectives, and projecting administrative action to accomplish the proposed programs, are a must. The health system should rely on newer approaches such as management-by-objectives and risk-management rather than the prevailing crisis-management attitude

Inhibition of neuroinflammation by thymoquinone requires activation of Nrf2/ARE signalling

Thymoquinone is an antioxidant phytochemical that has been shown to inhibit neuroinflammation. However, little is known about the potential roles of intracellular antioxidant signalling pathways in its anti-inflammatory activity. The objective of this study was to elucidate the roles played by activation of the Nrf2/ARE antioxidant mechanisms in the anti-inflammatory activity of this compound. Thymoquinone inhibited lipopolysaccharide (LPS)-induced neuroinflammation through interference with NF-B signalling in BV2 microglia. Thymoquinone also activated Nrf2/ARE signalling by increasing nuclear localisation, DNA binding and transcriptional activity of Nrf2, as well as increasing protein levels of HO-1 and NQO1. Suppression of Nrf2 activity through siRNA or with the use of trigonelline resulted in the loss of anti-inflammatory activity by thymoquinone. Taken together, our studies show that thymoquinone inhibits NF-kappaB-dependent neuroinflammation in BV2 microglia, by targeting antioxidant pathway involving activation of both Nrf2/ARE. We propose that activation of Nrf2/ARE signalling pathway by thymoquinone probably results in inhibition of NF-kappaB-mediated neuroinflammation

Health Policy and Systems Research in Twelve Eastern Mediterranean Countries: a stocktaking of production and gaps (2000-2008)

<p>Abstract</p> <p>Background</p> <p>The objectives of this study are to: (1) profile the production of Health Policy and Systems Research (HPSR) published between 2000 and 2008 in 12 countries in the Eastern Mediterranean Region (EMR): Bahrain, Egypt, Jordan, Lebanon, Libya, Morocco, Oman, Palestine, Sudan, Syria, Tunisia, and Yemen; (2) identify gaps; and (3) assess the extent to which existing HPSR produced in the region addresses regional priorities pertaining to Health Financing, Human Resources for Health and the Role of the Non-State Sector. This is the first stocktaking paper of HPSR production and gaps in the EMR.</p> <p>Methods</p> <p>Articles indexed on Medline between years 2000 and 2008 for the 12 study countries were selected. A MeSH term based search was conducted using country names. Articles were assessed using a coding sheet adapted for the region which included themes on: Governance Arrangements, Financial Arrangements, Delivery Arrangements, and Implementation Strategies. Identified articles were matched against regional research priorities to assess the extent to which research production aligns with priorities.</p> <p>Results</p> <p>A total of 1,487 articles (11.94%) fit the criteria in the coding sheet. Results showed an increase in HPSR production which peaked after 2005. Most identified articles focused on Delivery Arrangements (68.1%), and Implementation Strategies (24.4%). Most HPSR addressed priorities in Human Resources for Health (39%<b>)</b>, and some articles focused on Health Financing (12%) and Role of the Non-State Sector (6.1%).</p> <p>Conclusions</p> <p>Despite global calls for producing and translating HPSR into policy, there are still significant gaps in the EMR. More efforts are needed to produce HPSR and align production and translation with the demand for evidence by policymakers. Findings can help inform and direct future plans and activities for the Evidence Informed Policy Network- EMR, World Health Organization- EMR, and the Middle East and North Africa Health Policy Forum, in addition to being useful for countries that host or are planning to host KT platforms in the region.</p

Inhibition of neuroinflammation in BV2 microglia by the biflavonoid kolaviron is dependent on the Nrf2/ARE antioxidant protective mechanism

Kolaviron is a mixture of bioflavonoids found in the nut of the West African edible seed Garcinia kola, and it has been reported to exhibit a wide range of pharmacological activities. In this study, we investigated the effects of kolaviron in neuroinflammation. The effects of kolaviron on the expression of nitric oxide/inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2)/cyclooxygenase-2, cellular reactive oxygen species (ROS) and the pro-inflammatory cytokines were examined in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Molecular mechanisms of the effects of kolaviron on NF-B and Nrf2/ARE signalling pathways were analysed by immunoblotting, binding assay, and reporter assay. RNA interference was used to investigate the role of Nrf2 in the anti-inflammatory effect of kolaviron. Neuroprotective effect of kolaviron was assessed in a BV2 microglia/HT22 hippocampal neuron co-culture. Kolaviron inhibited the protein levels of NO/iNOS, PGE2/COX-2, cellular ROS and the proinflammatory cytokines (TNFα and IL-6) in LPS-stimulated microglia. Further mechanistic studies showed that kolaviron inhibited neuroinflammation by inhibiting IB/NF-B signalling pathway in LPS-activated BV2 microglia. Kolaviron produced antioxidant effect in BV2 microglia by increasing HO-1 via the Nrf2/ antioxidant response element (ARE) pathway. RNAi experiments revealed that Nrf2 is need for the anti-inflammatory effect of kolaviron. Kolaviron protected HT22 neurons from neuroinflammation-induced toxicity. Kolaviron inhibits neuroinflammation through Nrf2-dependent mechanisms. This compound may therefore be beneficial in neuroinflammation-related neurodegenerative disorders

The epidemiology of chronic pain in Libya: a cross-sectional telephone survey.

BACKGROUND: Chronic pain is a public health problem although there is a paucity of prevalence data from countries in the Middle East and North Africa. The aim of this study was to estimate the prevalence of chronic pain and neuropathic pain in a sample of the general adult population in Libya. METHODS: A cross-sectional telephone survey was conducted before the onset of the Libyan Civil War (February 2011) on a sample of self-declared Libyans who had a landline telephone and were at least 18 years of age. Random sampling of household telephone number dialling was undertaken in three major cities and interviews conducted using an Arabic version of the Structured Telephone Interviews Questionnaire on Chronic Pain previously used to collect data in Europe. In addition, an Arabic version of S-LANSS was used. 1212 individuals were interviewed (response rate = 95.1 %, mean age = 37.8 ± 13.9 years, female = 54.6 %). RESULTS: The prevalence of chronic pain ≥ 3 months was 19.6 % (95 % CI 14.6 % to 24.6 %) with a mean ± SD duration of pain of 6 · 5 ± 5 · 7 years and a higher prevalence for women. The prevalence of neuropathic pain in the respondents reporting chronic pain was 19 · 7 % (95 % CI 14 · 6-24 · 7), equivalent to 3 · 9 % (95 % CI 2 · 8 to 5 · 0 %) of the general adult population. Only, 71 (29 · 8 %) of respondents reported that their pain was being adequately controlled. CONCLUSIONS: The prevalence of chronic pain in the general adult population of Libya was approximately 20 % and comparable with Europe and North America. This suggests that chronic pain is a public health problem in Libya. Risk factors are being a woman, advanced age and unemployment. There is a need for improved health policies in Libya to ensure that patients with chronic pain receive effective management

Antimalarial drug artemether inhibits neuroinflammation in BV2 microglia through Nrf2-dependent mechanisms

Artemether, a lipid-soluble derivative of artemisinin has been reported to possess anti-inflammatory properties. In this study, we have investigated the molecular mechanisms involved in the inhibition of neuroinflammation by the drug. The effects of artemether on neuroinflammation-mediated HT22 neuronal toxicity were also investigated in a BV2 microglia/HT22 neuron co-culture. To investigate effects on neuroinflammation, we used LPS-stimulated BV2 microglia treated with artemether (5-40µM) for 24 hours. ELISAs and western blotting were used to detect pro inflammatory cytokines, nitric oxide, PGE2, iNOS, COX-2 and mPGES-1. BACE-1 activity and Aβ levels were measured with ELISA kits. Protein levels of targets in NF-kappaB and p38 MAPK signalling, as well as HO-1, NQO1 and Nrf2 were also measured with western blot. NF-kappaB binding to the DNA was investigated using EMSA. MTT, DNA fragmentation and ROS assays in BV2-HT22 neuronal co-culture were used to evaluate the effects of artemether on neuroinflammation-induced neuronal death. The role of Nrf2 in the anti-inflammatory activity of artemether was investigated in BV2 cells transfected with Nrf2 siRNA. Artemether significantly suppressed pro-inflammatory mediators (NO/iNOS, PGE2/COX-2/mPGES-1, TNFα, and IL-6), Aβ and BACE-1 in BV2 cells following LPS stimulation. These effects of artemether were shown to be mediated through inhibition of NF-kappaB and p38MAPK signalling. Artemether produced increased levels of HO-1, NQO1 and GSH in BV2 microglia. The drug activated Nrf2 activity by increasing nuclear translocation of Nrf2 and its binding to antioxidant response elements in BV2 cells. Transfection of BV2 microglia with Nrf2 siRNA resulted in the loss of both anti-inflammatory and neuroprotective activities of artemether. We conclude that artemether induces Nrf2 expression and suggest that Nrf2 mediates the anti-inflammatory effect of artemether in BV2 microglia. Our results suggest that this drug has a therapeutic potential in neurodegenerative disorders

Libyan National Health Services: The Need to Move to Management-by-Objectives

In the last four decades, there has been a substantial horizontal expansion of health services in Libya. This resulted in improvement in morbidity and mortality, in particularly those related to infectious disease. However, measures such as the national performance gap indicator reveal an underperforming health system. In this article, we discuss aspects related to the Libyan health system and its current status including areas of weakness. Overcoming current failures and further improvement are unlikely to occur spontaneously without proper planning. Defining community health problems, identifying unmet needs, surveying resources to meet them, establishing SMART (specific, measurable, achievable, and realistic and time specific) objectives, and projecting administrative action to accomplish the proposed programs, are a must. The health system should rely on newer approaches such as management-by-objectives and risk-management rather than the prevailing crisis-management attitude