Targeted Literature Review of the Burden of Respiratory Syncytial Infection among High-Risk and Elderly Patients in Asia Pacific Region.

INTRODUCTION: The burden of respiratory syncytial virus (RSV), which causes acute respiratory illness, is well recognized among the pediatric population but also imposes a significant risk to the elderly (age ≥ 60) and those with underlying comorbidities. The study aimed to review the most recent data on epidemiology and burden (clinical and economic) of RSV in the elderly/high-risk populations in China, Japan, South Korea, Taiwan, and Australia. METHODS: A targeted review was conducted of English, Japanese, Korean, and Chinese language articles published from 1 January 2010 to 7 October 2020 relevant for the purpose. RESULTS: A total of 881 studies were identified, and 41 were included. The median proportion of elderly patients with RSV in all adult patients with acute respiratory infection (ARI) or community acquired pneumonia was 79.78% (71.43-88.12%) in Japan, 48.00% (3.64-80.00%) in China, 41.67% (33.33-50.00%) in Taiwan, 38.61% in Australia, and 28.57% (22.76-33.33%) in South Korea. RSV was associated with a high clinical burden on those patients with comorbidities such as asthma and chronic obstructive pulmonary disease. In China, inpatients with ARI showed a significantly higher rate of RSV-related hospitalization than outpatients (13.22% versus 4.08%, p < 0.01). The median length of hospital stay among elderly patients with RSV was longest in Japan (30 days) and shortest in China (7 days). Mortality data varied by region with some studies reporting rates as high as 12.00% (9/75) in hospitalized elderly patients. Finally, data on the economic burden was only available for South Korea, with the median cost of a medical admission for an elderly patient with RSV being US dollar (USD) 2933. CONCLUSION: RSV infection is a major source of disease burden among elderly patients, especially in regions with aging populations. It also complicates the management of those with underlying diseases. Appropriate prevention strategies are required to reduce the burden among the adult, especially the elderly, population. Data gaps regarding economic burden of RSV infection in the Asia Pacific region indicates the need for further research to increase our understanding on the burden of this disease in this region.

An Australian Real-World Study of Treatment Persistence of Ustekinumab in Crohn's Disease.

INTRODUCTION: Real-world treatment persistence to ustekinumab for Crohn's disease (CD) was studied using Australian Pharmaceutical Benefits Scheme (PBS) data. Demographic and treatment pattern characteristics were also investigated. METHODS: Our retrospective cohort analysis included PBS 10% sample data for ustekinumab from September 2017 to March 2020, and for other biologics from October 2007 to capture earlier line(s) of therapy. Included patients received ustekinumab for CD prescribed by a gastroenterologist. Treatment persistence overall and by prior biologic experience, mono- or combination therapy, sex and age were estimated using Kaplan-Meier methods. A Cox proportional hazards regression analysis was performed to assess the effect of age, sex and line of therapy on persistence. RESULTS: Data were available for 301 patients. Of these, 58.8% were female and 76.7% were aged 26-65 years. Median follow-up from first ustekinumab dispense was 16 months. Median persistence to ustekinumab had not been reached. Twelve-month persistence to ustekinumab was 82.6% (95% CI 78.1-87.5%). Patients receiving ustekinumab as their first biologic therapy had 12-month persistence of 88.0% (80.8-95.9%) compared to 80.6% (75.0-86.6%) for patients who had previously received other biologic therapies (p=0.059). The adjusted analysis showed a trend to longer persistence for patients receiving ustekinumab as their first biologic therapy compared to biologic experienced patients (HR 1.86 (95% CI 0.95-3.63), p=0.070). Males had higher persistence to ustekinumab than females (HR 0.36 (0.20-0.66), p<0.001). Receiving ustekinumab as a monotherapy or in combination with azathioprine, mercaptopurine, 5ASAs, methotrexate, or corticosteroids had no effect on persistence (p=0.22). CONCLUSION: In an Australian real-world setting, persistence to ustekinumab was demonstrated to be over 80% at 12 months. Use as monotherapy or in combination with other therapy for CD did not affect persistence. Differences in treatment persistence by gender and previous biologic use warrant further investigation as further long-term data becomes available.

In vivo morphologic comparison of saphenous vein grafts and native coronary arteries following non-ST elevation myocardial infarction.

OBJECTIVE: This study aimed to assess the pathophysiological differences between saphenous vein grafts (SVG) and native coronary arteries (NCA) following presentation with non-ST elevated myocardial infarction (NSTEMI). BACKGROUND: There is accelerated pathogenesis of de novo coronary disease in harvested SVG following coronary artery bypass (CABG) surgery, which contributes to both early and late graft failure, and is also causal in adverse outcomes following vein graft PCI. However in vivo assessment, with OCT imaging, comparing the differences between vein grafts and NCAs has not previously been performed. METHODS: We performed a retrospective, observational, analysis in patients who underwent PCI with adjunctive OCT imaging following presentation with NSTEMI, where the infarct-related artery (IRA) was either in an SVG or NCA. RESULTS: A total of 1550 OCT segments was analysed from thirty patients with a mean age of 66.3 (±9.0) years were included. The mean graft age of 13.9 (±5.6) years in the SVG group. OCT imaging showed that the SVG group had evidence of increased lipid pool burden (lipid pool quadrants, 2.1 vs 2.7; p = 0.021), with a reduced fibro-atheroma cap-thickness in the SVG group (45.0 µm vs 38.5 µm; p = 0.05) and increased burden of calcification (calcified lesion length = 0.4 mm vs 1.8 mm; p = 0.007; calcified quadrants = 0.2 vs 0.9; p = 0.001; arc of superficial calcium deposits = 11.6° vs 50.9°; p = 0.007) when compared to NCA. CONCLUSION: This OCT study has demonstrated that vein grafts have a uniquely atherogenic environment which leads to the development of calcified, lipogenic, thin-capped fibro-atheroma's, which may be pivotal in the increased, acute and chronic graft failure rate, and may underpin the increased adverse outcomes following vein graft PCI.

Management of cardiorenal metabolic syndrome in diabetes mellitus: a phytotherapeutic perspective.

Cardiorenal syndrome (CRS) is a complex disease in which the heart and kidney are simultaneously affected and their deleterious declining functions are reinforced in a feedback cycle, with an accelerated progression. Although the coexistence of kidney and heart failure in the same individual carries an extremely bad prognosis, the exact cause of deterioration and the pathophysiological mechanisms underlying the initiation and maintenance of the interaction are complex, multifactorial in nature, and poorly understood. Current therapy includes diuretics, natriuretic hormones, aquaretics (arginine vasopressin antagonists), vasodilators, and inotropes. However, large numbers of patients still develop intractable disease. Moreover, the development of resistance to many standard therapies, such as diuretics and inotropes, has led to an increasing movement toward utilization and development of novel therapies. Herbal and traditional natural medicines may complement or provide an alternative to prevent or delay the progression of CRS. This review provides an analysis of the possible mechanisms and the therapeutic potential of phytotherapeutic medicines for the amelioration of the progression of CRS.

Healing the diabetic heart: modulation of cardiometabolic syndrome through peroxisome proliferator activated receptors (PPARs).

Cardiometabolic syndrome is a mixture of interrelated risk factors predisposing individuals to elevated risk of atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Nuclear receptors, specifically peroxisome proliferator-activated receptors (PPARs), were identified to play a pivotal role in the regulation of metabolic homeostasis. However, with rosiglitazone currently under intense scrutiny great concerns have arisen regarding the safety of the thiazolidinedione PPAR-γ agonist family as a whole. This review discusses the current concern with PPAR-γ agonists by exploring if PPARs can still be considered worth pursuing as a viable target for cardiovascular diseases. We examine current research focusing on identifying ligands that are dual and pan-PPAR agonists, selective PPAR-γ modulators, PPAR-ß/δ agonists and that are of natural origin.

The role of herbal PPAR modulators in the treatment of cardiometabolic syndrome.

For thousands of years, natural medicines have played an important role in treating and preventing human diseases worldwide. Natural products offer large structural diversity, and modern techniques for separation, structure elucidation, screening and combinatorial synthesis have led to revitalization of plant products as sources of new drugs. The number of people with cardiometabolic syndrome is increasing worldwide. This is expected to increase the prevalence of potentially harmful distortions of lipid distribution and thus intensify the need for appropriate intervention. With increasing evidence of the pathophysiological importance of the dyslipidaemia associated with type 2 diabetes mellitus, hypertension and insulin resistance, a more aggressive approach to lipid management is required. Nuclear receptors are an attractive and promising target for drug development. Functioning as transcription factors and thereby controlling cellular processes at the level of gene expression, modulation of nuclear receptor activity produces selective alterations in downstream gene expression. These characteristics, combined with their involvement in significant diseases, make nuclear receptors a key target for the development of disease-specific therapy. This review examines natural product libraries as a rich source of ligands for nuclear receptors and their potential as promising therapeutic agents for clinical practice. Continual evolution in drug discovery from plants remains an important source of new pharmaceuticals. Furthermore, by uncovering the regulatory mechanisms and transcriptional targets of the PPARs and other related receptors, it will be possible to provide a comprehensive insight into the pathogenesis of metabolic disease and, at the same time, offer valuable information for rational drug design, ultimately leading to a reduction in the chronic microvascular complications of cardiometabolic syndrome.

Increased renal collagen cross-linking and lipid accumulation in nephropathy of Zucker diabetic fatty rats.

BACKGROUND: Zucker diabetic fatty (ZDF) rat is a genetic model of type 2 diabetes and obesity. The mechanism underlying nephropathy in ZDF rats, however, remains unclear. METHODS: ZDF rats were compared to age-matched Zucker lean (ZL) rats. Physiological and blood biochemical parameters, renal glomerular cross-sectional area (hematoxylin-eosin staining), fibrosis (van Giesen staining), collagen composition (Sircol Collagen Assay), lipids (enzymatic method) and mRNA expression (RT-PCR) were determined. RESULTS: ZDF rats showed an increase in renal-insoluble collagen content and the ratio of renal-insoluble to salt-soluble collagen (2- and 1.5-fold of the control animals). There were increases in renal glomerulosclerosis and interstitial fibrosis in ZDF rats (increased to 2-fold) in the glomerular mesangium and tubulointerstitium, and increased glomerular area. Renal triglyceride accumulated to greater than 2-fold of those levels in ZL rats. These changes were accompanied by hypoalbuminemia, and elevated plasma blood urea nitrogen and uric acid levels. Gene profiling showed increased expression of transcripts encoding the glomerulosclerotic mediator collagens I and IV, plasminogen activator inhibitor-1, transforming growth factor-beta1, and angiotensin II type 1 receptor in ZDF rat kidney. Moreover, renal expression of mRNAs encoding sterol regulatory element-binding protein-1, a nuclear transcription factor that activates genes involved in fatty acid synthesis, and acetyl-CoA carboxylase, a key enzyme that mediates fatty acid synthesis, was increased in ZDF rats. CONCLUSIONS: Our findings suggest that dysregulated gene expression may result in increased renal collagen cross-linking and lipid accumulation, that may be associated with development of nephropathy in the animal model of type 2 diabetes and obesity.

Salacia root, a unique Ayurvedic medicine, meets multiple targets in diabetes and obesity.

In many traditional schools of medicine it is claimed that a balanced modulation of several targets can provide a superior therapeutic effect and decrease in side effect profile compared to a single action from a single selective ligand, especially in the treatment of certain chronic and complex diseases, such as diabetes and obesity. Diabetes and obesity have a multi-factorial basis involving both genetic and environmental risk factors. A wide array of medicinal plants and their active constituents play a role in the prevention and treatment of diabetes. Salacia roots have been used in Ayurvedic medicine for diabetes and obesity since antiquity, and have been extensively consumed in Japan, the United States and other countries as a food supplement for the prevention of obesity and diabetes. Recent pharmacological studies have demonstrated that Salacia roots modulate multiple targets: peroxisome proliferator-activated receptor-alpha-mediated lipogenic gene transcription, angiotensin II/angiotensin II type 1 receptor, alpha-glucosidase, aldose reductase and pancreatic lipase. These multi-target actions may mainly contribute to Salacia root-induced improvement of type 2 diabetes and obesity-associated hyperglycemia, dyslipidemia and related cardiovascular complications seen in humans and rodents. The results of bioassay-guided identification indicate that mangiferin, salacinol, kotalanol and kotalagenin 16-acetate are at least in part responsible for these multi-target regulatory activities of Salacia roots. The evidence suggests that this unique traditional medicine fulfills a multiple-target strategy in the prevention and treatment of diabetes and obesity. Although toxicological studies have suggested minimal adverse effects of the herbal medicine in rodents, a clinical trial is crucial to further confirm the safety of Salacia roots. In addition, further mechanistic studies are necessary in order to allow a better understanding of how use of Salacia root may interact with other therapeutic interventions.

Gypenoside XLIX, a naturally occurring PPAR-alpha activator, inhibits cytokine-induced vascular cell adhesion molecule-1 expression and activity in human endothelial cells.

Vascular cell adhesion molecule-1 (VCAM-1) is involved in several diseases, including chronic inflammation and atherosclerosis. Inhibition of the expression of this adhesion molecule is one of the key targets of anti-inflammatory, anti-cancer and anti-atherosclerotic drugs. Gynostemma pentaphyllum is a traditional medicine widely used in the treatment of respiratory inflammation, hyperlipidemia and atherosclerosis. However, its molecular mechanisms of action are still largely unknown. Gypenoside XLIX, a dammarane-type glycoside, is a prominent component of G. pentaphyllum. We have recently demonstrated Gypenoside XLIX to be a selective peroxisome proliferator-activated receptor (PPAR)-alpha activator. Here we demonstrate that Gypenoside XLIX concentration-dependently (0-300 microM) inhibited VCAM-1 promoter activity after induction by cytokine tumor necrosis factor (TNF)-alpha in human umbilical vein endothelial cells (HUVECs) transfected with promoter-reporter construct pVCAM-1-LUC. Furthermore, Gypenoside XLIX inhibited TNF-alpha-induced VCAM-1 mRNA and protein overexpression in HUVECs. The result of the enzyme immunoassay demonstrated that Gypenoside XLIX inhibited TNF-alpha-induced increase in cell surface VCAM-1 protein levels in HUVECs. In the present study we show that activities of Gypenoside XLIX are similar to those of Wy-14643, a potent synthetic PPAR-alpha activator. Furthermore, Gypenoside XLIX-induced inhibition on TNF-alpha-stimulated VCAM-1 promoter hyperactivity was completely abolished by a selective blocker of PPAR-alpha, MK-886. Thus, our findings suggest that Gypenoside XLIX inhibits cytokine-induced VCAM-1 overexpression and hyperactivity in human endothelial cells via a PPAR-alpha-dependent pathway. These data provide new insight into the rational basis of the use of the traditional Chinese herbal medicine G. pentaphyllum in the treatment of inflammatory and cardiovascular diseases, including atherosclerosis.

Gypenoside XLIX, a naturally occurring gynosaponin, PPAR-alpha dependently inhibits LPS-induced tissue factor expression and activity in human THP-1 monocytic cells.

Tissue factor (TF) is involved not only in the progression of atherosclerosis and other cardiovascular diseases, but is also associated with tumor growth, metastasis, and angiogenesis and hence may be an attractive target for directed cancer therapeutics. Gynostemma pentaphyllum (GP) is widely used in the treatment of various cardiovascular diseases including atherosclerosis, as well as cancers. Gypenoside (Gyp) XLIX, a dammarane-type glycoside, is one of the prominent components in GP. We have recently reported Gyp XLIX to be a potent peroxisome proliferator-activated receptor (PPAR)-alpha activator. Here we demonstrate that Gyp XLIX (0-300 microM) concentration dependently inhibited TF promoter activity after induction by the inflammatory stimulus lipopolysaccharide (LPS) in human monocytic THP-1 cells transfected with promoter reporter constructs pTF-LUC. Furthermore, Gyp XLIX inhibited LPS-induced TF mRNA and protein overexpression in THP-1 monocyte cells. Its inhibition of LPS-induced TF hyperactivity was further confirmed by chromogenic enzyme activity assay. The activities of Gyp XLIX reported in this study were similar to those of Wy-14643, a potent synthetic PPAR-alpha activator. Furthermore, the Gyp XLIX-induced inhibitory effect on TF luciferase activity was completely abolished in the presence of the PPAR-alpha selective antagonist MK-886. The present findings suggest that Gyp XLIX inhibits LPS-induced TF overexpression and enhancement of its activity in human THP-1 monocytic cells via PPAR-alpha-dependent pathways. The data provide new insights into the basis of the use of the traditional Chinese herbal medicine G. pentaphyllum for the treatment of cardiovascular and inflammatory diseases, as well as cancers.

Gypenoside XLIX isolated from Gynostemma pentaphyllum inhibits nuclear factor-kappaB activation via a PPAR-alpha-dependent pathway.

Nuclear factor (NF)-kappaB is important in the generation of inflammation. Besides regulating lipid metabolism, peroxisome proliferator-activated receptor (PPAR)-alpha activators also reduce NF-kappaB activation to terminate activation of inflammatory pathways. Gynostemma pentaphyllum (GP) has been used to treat various inflammatory diseases and hyperlipidemia. Here, we demonstrate that GP extract and one of its main components, Gypenoside XLIX (Gyp-XLIX) inhibited LPS-induced NF-kappaB activation in murine macrophages. Furthermore, Gyp-XLIX restored the LPS- and TNF-alpha-induced decrease in cytosolic I-kappaBalpha protein expression and inhibited the translocation of NF-kappaB(p65) to the nucleus in THP-1 monocyte and HUVEC cells. The inhibition of LPS- and TNF-alpha-induced NF-kappaB luciferase activity in macrophages was abolished by MK-886, a selective PPAR-alpha antagonist. GP extract and Gyp-XLIX (EC(50): 10.1 microM) enhanced PPAR-alpha luciferase activity in HEK293 cells transfected with the tK-PPREx3-Luc reporter plasmid and expression vectors for PPAR-alpha. Additionally, Gyp-XLIX specifically enhanced PPAR-alpha mRNA and protein expression in THP-1-derived macrophage cells. The selectivity of Gyp-XLIX for PPAR-alpha was demonstrated by the activation of only PPAR-alpha in HEK293 cells transfected with expression vectors for PPAR-alpha, PPAR-beta/delta or PPAR-gamma1 plasmids and in THP-1-derived macrophage naturally expressing all three PPAR isoforms. The present study demonstrates that Gyp-XLIX, a naturally occurring gynosaponin, inhibits NF-kappaB activation via a PPAR-alpha-dependent pathway.

Salacia oblonga root improves cardiac lipid metabolism in Zucker diabetic fatty rats: modulation of cardiac PPAR-alpha-mediated transcription of fatty acid metabolic genes.

Excess cardiac triglyceride accumulation in diabetes and obesity induces lipotoxicity, which predisposes the myocytes to death. On the other hand, increased cardiac fatty acid (FA) oxidation plays a role in the development of myocardial dysfunction in diabetes. PPAR-alpha plays an important role in maintaining homeostasis of lipid metabolism. We have previously demonstrated that the extract from Salacia oblonga root (SOE), an Ayurvedic anti-diabetic and anti-obesity medicine, improves hyperlipidemia in Zucker diabetic fatty (ZDF) rats (a genetic model of type 2 diabetes and obesity) and possesses PPAR-alpha activating properties. Here we demonstrate that chronic oral administration of SOE reduces cardiac triglyceride and FA contents and decreases the Oil red O-stained area in the myocardium of ZDF rats, which parallels the effects on plasma triglyceride and FA levels. Furthermore, the treatment suppressed cardiac overexpression of both FA transporter protein-1 mRNA and protein in ZDF rats, suggesting inhibition of increased cardiac FA uptake as the basis for decreased cardiac FA levels. Additionally, the treatment also inhibited overexpression in ZDF rat heart of PPAR-alpha mRNA and protein and carnitine palmitoyltransferase-1, acyl-CoA oxidase and 5'-AMP-activated protein kinase mRNAs and restored the downregulated acetyl-CoA carboxylase mRNA. These results suggest that SOE inhibits cardiac FA oxidation in ZDF rats. Thus, our findings suggest that improvement by SOE of excess cardiac lipid accumulation and increased cardiac FA oxidation in diabetes and obesity occurs by reduction of cardiac FA uptake, thereby modulating cardiac PPAR-alpha-mediated FA metabolic gene transcription.

Salacia oblonga root improves postprandial hyperlipidemia and hepatic steatosis in Zucker diabetic fatty rats: activation of PPAR-alpha.

Salacia oblonga (SO) root is an Ayurvedic medicine with anti-diabetic and anti-obese properties. Peroxisome proliferator-activated receptor (PPAR)-alpha, a nuclear receptor, plays an important role in maintaining the homeostasis of lipid metabolism. Here, we demonstrate that chronic oral administration of the water extract from the root of SO to Zucker diabetic fatty (ZDF) rats, a genetic model of type 2 diabetes and obesity, lowered plasma triglyceride and total cholesterol (TC) levels, increased plasma high-density lipoprotein levels and reduced the liver contents of triglyceride, non-esterified fatty acids (NEFA) and the ratio of fatty droplets to total tissue. By contrast, the extract had no effect on plasma triglyceride and TC levels in fasted ZDF rats. After olive oil administration to ZDF the extract also inhibited the increase in plasma triglyceride levels. These results suggest that SO extract improves postprandial hyperlipidemia and hepatic steatosis in ZDF rats. Additionally, SO treatment enhanced hepatic expression of PPAR-alpha mRNA and protein, and carnitine palmitoyltransferase-1 and acyl-CoA oxidase mRNAs in ZDF rats. In vitro, SO extract and its main component mangiferin activated PPAR-alpha luciferase activity in human embryonic kidney 293 cells and lipoprotein lipase mRNA expression and enzyme activity in THP-1 differentiated macrophages; these effects were completely suppressed by a selective PPAR-alpha antagonist MK-886. The findings from both in vivo and in vitro suggest that SO extract functions as a PPAR-alpha activator, providing a potential mechanism for improvement of postprandial hyperlipidemia and hepatic steatosis in diabetes and obesity.

Harpagoside suppresses lipopolysaccharide-induced iNOS and COX-2 expression through inhibition of NF-kappa B activation.

Preparations of Harpagophytum procumbens, known as devil's claw, are used as an adjunctive therapy for the treatment of pain and osteoarthritis. Pharmacological evaluations have proven the effectiveness of this herbal drug as an anti-inflammatory and analgesic agent. The present study has investigated the mechanism of action of harpagoside, one of the major components of Harpagophytum procumbens, using human HepG2 hepatocarcinoma and RAW 264.7 macrophage cell lines. Harpagoside inhibited lipopolysaccharide-induced mRNA levels and protein expression of cyclooxygenase-2 and inducible nitric oxide in HepG2 cells. These inhibitions appeared to correlate with the suppression of NF-kappaB activation by harpagoside, as pre-treating cells with harpagoside blocked the translocation of NF-kappaB into the nuclear compartments and degradation of the inhibitory subunit IkappaB-alpha. Furthermore, harpagoside dose-dependently inhibited LPS-stimulated NF-kappaB promoter activity in a gene reporter assay in RAW 264.7 cells, indicating that harpagoside interfered with the activation of gene transcription. These results suggest that the inhibition of the expression of cyclooxygenase-2 and inducible nitric oxide by harpagoside involves suppression of NF-kappaB activation, thereby inhibiting downstream inflammation and subsequent pain events.

The pathophysiological function of peroxisome proliferator-activated receptor-gamma in lung-related diseases.

Research into respiratory diseases has reached a critical stage and the introduction of novel therapies is essential in combating these debilitating conditions. With the discovery of the peroxisome proliferator-activated receptor and its involvement in inflammatory responses of cardiovascular disease and diabetes, attention has turned to lung diseases and whether knowledge of this receptor can be applied to therapy of the human airways. In this article, we explore the prospect of peroxisome proliferator-activated receptor-gamma as a marker and treatment focal point of lung diseases such as asthma, chronic obstructive pulmonary disorder, lung cancer and cystic fibrosis. It is anticipated that peroxisome proliferator-activated receptor-gamma ligands will provide not only useful mechanistic pathway information but also a possible new wave of therapies for sufferers of chronic respiratory diseases.

A novel LXR-alpha activator identified from the natural product Gynostemma pentaphyllum.

Liver X receptors (LXR) play an important role in cholesterol homeostasis by serving as regulatory sensors of cholesterol levels in tissues. The present study reports a novel LXR-alpha activator, (20S)-2alpha, 3beta, 12beta, 24(S)-pentahydroxydammar-25-ene 20-O-beta-d-glucopyranoside (TR1), a dammarane-type gynosaponin, isolated from the herbal medicine, Gynostemma pentaphyllum. Gynosaponin TR1 demonstrated greater selectivity toward activation of the LXR-alpha isoform than LXR-beta in HEK293 cells. TR1 selectively enhanced LXR-mediated transcriptional activation and protein expression of ABCA1 and apoE gene expression and secretion in THP-1-derived macrophages. The selectivity of TR1 for LXR-alpha was consistent with ligand docking studies, which showed favourable interaction of TR1 in the LXR-alpha-binding domain, whereas the presence of the sugar substituent interfered with binding to the LXR-beta site. Findings from the present study may provide insight into the development of pharmaceutical agents for treating atherosclerosis.

Pomegranate flower improves cardiac lipid metabolism in a diabetic rat model: role of lowering circulating lipids.

Excess triglyceride (TG) accumulation and increased fatty acid (FA) oxidation in the diabetic heart contribute to cardiac dysfunction. Punica granatum flower (PGF) is a traditional antidiabetic medicine. Here, we investigated the effects and mechanisms of action of PGF extract on abnormal cardiac lipid metabolism both in vivo and in vitro. Long-term oral administration of PGF extract (500 mg kg(-1)) reduced cardiac TG content, accompanied by a decrease in plasma levels of TG and total cholesterol in Zucker diabetic fatty (ZDF) rats, indicating improvement by PGF extract of abnormal cardiac TG accumulation and hyperlipidemia in this diabetic model. Treatment of ZDF rats with PGF extract lowered plasma FA levels. Furthermore, the treatment suppressed cardiac overexpression of mRNAs encoding for FA transport protein, peroxisome proliferator-activated receptor (PPAR)-alpha, carnitine palmitoyltransferase-1, acyl-CoA oxidase and 5'-AMP-activated protein kinase alpha2, and restored downregulated cardiac acetyl-CoA carboxylase mRNA expression in ZDF rats, whereas it showed little effect in Zucker lean rats. The results suggest that PGF extract inhibits increased cardiac FA uptake and oxidation in the diabetic condition. PGF extract and its component oleanolic acid enhanced PPAR-alpha luciferase reporter gene activity in human embryonic kidney 293 cells, and this effect was completely suppressed by a selective PPAR-alpha antagonist MK-886, consistent with the presence of PPAR-alpha activator activity in the extract and this component. Our findings suggest that PGF extract improves abnormal cardiac lipid metabolism in ZDF rats by activating PPAR-alpha and thereby lowering circulating lipid and inhibiting its cardiac uptake.

Herbal or natural medicines as modulators of peroxisome proliferator-activated receptors and related nuclear receptors for therapy of metabolic syndrome.

The use of herbal or natural medicines for the treatment of various disorders has a long and extensive history. Many of these herbal medicines are finding their way onto the world market as alternatives to prescribed drugs currently available to treat various disorders/ailments. In particular, hyperlipidaemia is a major risk factor for atherosclerotic coronary vascular disease, which can culminate in mortality in diabetes mellitus. There is overwhelming evidence that patients with type 2 diabetes mellitus often have metabolic syndrome and require a multifactorial intervention including aggressive treatment of arterial hypertension and dyslipidaemia to prevent cardiovascular complications. One of the most active areas of metabolic research into potential treatments is in the role of nuclear receptors as therapeutic targets for both glucose and lipid metabolism. The purpose of this review is to highlight the recent advances made by pharmaceutical and research organizations in identifying biologically active compounds from natural plant products capable of modulating nuclear receptors such as peroxisome proliferator-activated receptors and, to a lesser extent, liver X receptor and farnesoid X receptor. The specific features presented by these receptors provide an in-depth insight into the pathogenesis of metabolic disease and thus, a means of establishing potential mechanisms of action with traditional medicine. In hindsight, the review offers valuable information for rational drug design using known active compounds of plant origin. Further research may ultimately lead to a reduction in both the chronic microvascular complications of type 2 diabetes mellitus and the risk of cardiovascular disease and metabolic syndrome with the use of traditional medicine.

An overview on biological mechanisms of PPARs.

Peroxisome proliferator activated receptors (PPARs) are transcriptional factors belonging to the ligand-activated nuclear receptor superfamily. They are ubiquitously expressed throughout the body. On activation by endogenously secreted prostaglandins and fatty acids, they initiate transcription of an array of genes that are involved in energy homeostasis. So far, three major types have been identified, namely PPAR-alpha, PPAR-beta/delta and PPAR-gamma. PPAR-alpha and PPAR-gamma are crucial for lipid and glucose metabolism, respectively. Although limited information is available on PPAR-beta biological functions, recent studies have shown that PPAR-beta also regulates glucose metabolism and fatty acid oxidation. The discovery of PPAR-alpha agonists such as fibrates and PPAR-gamma agonists such as thiozolidinediones enables recognition of the mechanisms involved in ameliorating the adverse effects of chronic disorders such as atherosclerosis and diabetes. In addition, PPARs are also involved in the regulation of various types of tumours, inflammation, cardiovascular diseases and infertility. The importance of these transcription factors in physiology and pathophysiology has instigated much research in this field. In this article, structural features of PPARs, their gene transcription mechanisms and recent developments in the discovery of their biological functions are reviewed.

Salacia oblonga improves cardiac fibrosis and inhibits postprandial hyperglycemia in obese Zucker rats.

Diabetes has a markedly greater incidence of cardiovascular disease than the non-diabetic population. The heart shows a slowly developing increase in fibrosis in diabetes. Extended cardiac fibrosis results in increased myocardial stiffness, causing ventricular dysfunction and, ultimately, heart failure. Reversal of fibrosis may improve organ function survival. Postprandial hyperglycemia plays an important role in the development of type 2 diabetes and cardiovascular complications, and has been proposed as an independent risk factor for cardiovascular diseases. Salacia oblonga (S.O.) is traditionally used in the prevention and treatment of diabetes. We investigated the effects of its water extract on cardiac fibrosis and hyperglycemia in a genetic model of type 2 diabetes, the obese Zucker rat (OZR). Chronic administration of the extract markedly improved interstitial and perivascular fibrosis in the hearts of the OZR. It also reduced plasma glucose levels in non-fasted OZR, whereas it had little effect in the fasted animals, suggesting inhibition of postprandial hyperglycemia in type 2 diabetic animals, which might play a role in improvement of the cardiac complications of OZR. Furthermore, S.O. markedly suppressed the overexpression of mRNAs encoding transforming growth factor betas 1 and 3 in the OZR heart, which may be an important part of the overall molecular mechanisms. S.O. dose-dependently inhibited the increase of plasma glucose in sucrose-, but not in glucose-loaded mice. S.O. demonstrated a strong inhibition of alpha-glucosidase activity in vitro, which is suggested to contribute to the improvement of postprandial hyperglycemia.