[BI019] Molecular Cloning And Characterisation Of The 5 -Untranslated Region And Promoters In Human Peroxisome Proliferator-Activated Receptor Alpha (hPPARα).

The peroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptor gene superfamily of ligandactivated transcription factors [Issemann and Green, 1990]

Molecular cloning and characterisation of the 5’-untranslated region and promoters in human peroxisome proliferator-activated receptor alpha (hPPARα)

The peroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptor gene superfamily of ligandactivated transcription factors [Issemann and Green, 1990]

Rapamycin pre-treatment abrogates Tumour Necrosis Factor-\u3b1 down-regulatory effects on LXR-\u3b1 and PXR mRNA expression via inhibition of c-Jun N-terminal kinase 1 activation in HepG2 cells

The Liver X Receptor (LXR) and Pregnane X Receptor (PXR) are members of the nuclear receptor superfamily. Previously, they have been classified as important regulators of lipid homeostasis. However, recent studies have shown that they may be implicated in anti-inflammatory responses as well. This study shows that Tumour Necrosis Factor-\u3b1 (TNF-\u3b1) treatment reduces both LXR-\u3b1 and PXR mRNA expression. However, pre-treatment with rapamycin, an mTOR inhibitor, followed by TNF-\u3b1 stimulation, significantly induces LXR-\u3b1 and PXR mRNA expression to ~17- and ~2-fold, respectively. This suggests that mTORC1, a multi-molecular complex of which mTOR is a member, may act as a negative regulator that inhibits the induction of LXR-\u3b1 and PXR as anti-inflammatory genes. It is also shown here that inhibition of JNK1 via the mTOR/Akt pathway coincides with the up-regulation of LXR-\u3b1 and PXR mRNA, after TNF-\u3b1 treatment. Together, these observations suggest that JNK1 possibly act downstream of mTORC1 as an LXR-\u3b1 and PXR inhibitor. From the results gleaned in this study, rapamycin (and its analogues) may be used to reduce acute inflammation by promoting the induction of LXR-\u3b1 and PXR as anti-inflammatory genes

Coconut milk gavage enhanced fecal bile excretion by modulating hepatic Fxr expression but failed to improve fasting serum cholesterol profile in C57BL/6 mice

The consumption of coconut milk has long been regarded as detrimental to cardiovascular health due to its high saturated fatty acid content. Contradictorily, emerging evidences have highlighted that the fatty acids in coconut lipids, which comprise mostly of medium-chain fatty acids (MCFA), may be beneficial to the regulation of serum cholesterol. To identify the potential health effect of coconut milk on lipid metabolism, this current study employed an intragastric gavage method on C57BL/6 mice to investigate the physiological and molecular alteration in the mice subject after 8 weeks of gavage intervention. The supplementation of coconut milk did not affect the levels of serum triglyceride, but it induced the total serum cholesterol after 2 weeks of treatment. The serum cholesterol level subsequently plateaued, but an increase in bile acid excretion was observed, most likely through the modulation of bile regulating genes, i.e. farnesoid X receptor (Fxr) and Cyp7a1. Despite that, the total cholesterol to HDL cholesterol ratio of coconut milk group was comparable to that of the light cream group. In short, coconut milk supplementation promoted cholesterol excretion through the fecal bile route but did not significantly improve the serum cholesterol profile of C57BL/6 mice

Lauric acid abolishes interferon-gamma (IFN-γ)-induction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in human macrophages

Objective: To investigate the effect of different concentrations of lauric acid on Intercellular Adhesion Molecule-1 (ICAM-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1) expression in IFN-γ stimulated human monocytic THP-1 cell line. Methods: THP-1 cell were cultured using Roswell Park Memorial Institute medium supplemented with 10% fetal bovine serum. THP-1 monocytes were firstly differentiated into macrophages by using phorbol-12-myristate-13-acetate. IFN-γ response test was performed and total cellular RNA was extracted using TRI Reagent® LS before q-RT-PCR was carried out. Subsequently, IFN-γ treated THP-1 macrophages were stimulated with increasing doses of lauric acid for another 24 h, before q-RT-PCR. Results: The mRNA expression levels of ICAM-1 and VCAM-1 were normalized to β-actin and relatived to the untreated cells. The expressions of ICAM-1 and VCAM-1 were significantly induced in cells treated with 10 ng/mL of IFN-γ. This showed that IFN-γ could up-regulate inflammatory process and may cause atheroma formation. MTT assay was carried out to investigate the effect of lauric acid on undifferentiated and differentiated THP-1 cells. Although lauric acid did not have any significant impact on undifferentiated and differentiated THP-1 cell viability, the normalized fold expressions of ICAM-1 and VCAM-1 in IFN-γ-treated THP-1 macrophages were decreased significantly in a dose dependent manner with the presence of increasing doses of lauric acid. Conclusions: This study successfully proved that lauric acid was able to antagonize the up-regulatory effect of IFN-γ on ICAM-1 and VCAM-1 expressions in THP-1 macrophages. This indicates that lauric acid may be an anti-inflammatory therapeutic and prophylaxis agent for atherosclerosis

Rapamycin pre-treatment abrogates Tumour Necrosis Factor-α down-regulatory effects on LXR-α and PXR mRNA expression via inhibition of c-Jun N-terminal kinase 1 activation in HepG2 cells

The Liver X Receptor (LXR) and Pregnane X Receptor (PXR) are members of the nuclear receptor superfamily. Previously, they have been classified as important regulators of lipid homeostasis. However, recent studies have shown that they may be implicated in anti-inflammatory responses as well. This study shows that Tumour Necrosis Factor-α (TNF-α) treatment reduces both LXR-α and PXR mRNA expression. However, pre-treatment with rapamycin, an mTOR inhibitor, followed by TNF-α stimulation, significantly induces LXR-α and PXR mRNA expression to ~17- and ~2-fold, respectively. This suggests that mTORC1, a multi-molecular complex of which mTOR is a member, may act as a negative regulator that inhibits the induction of LXR-α and PXR as anti-inflammatory genes. It is also shown here that inhibition of JNK1 via the mTOR/Akt pathway coincides with the up-regulation of LXR-α and PXR mRNA, after TNF-α treatment. Together, these observations suggest that JNK1 possibly act downstream of mTORC1 as an LXR-α and PXR inhibitor. From the results gleaned in this study, rapamycin (and its analogues) may be used to reduce acute inflammation by promoting the induction of LXR-α and PXR as anti-inflammatory genes

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially