Phytochemical And Bioactivity Studies Of Strobilanthes Crispus L

Phytochemical investigation of the hexane, dichloromethane and methanol extracts of the leaves of Strobilanthes crispus has led to the isolation of nine compounds, comprising 1-heptacosanol (c-1), lignoceric acid (c-2) and stigmasterol (c-3) from the hexane extract, a mixture of four esters of β-amyrin (c-4), taraxerone (c-5), taraxerol (c-6) and a mixture of two esters of taraxerol (c-7) from the dichloromethane extract, as well as 4-acetyl-2,7-dihydroxy-1,4,8-triphenyloctane-3,5-dione (c-8) and stigmasterol 3-O-β-D-glucopyranoside (c-9) from the methanol extract. Structures of compounds c-1 to c-9 were elucidated with the aid of chromatographic and spectroscopic techniques

Chemical Constituents and Biological Activities of Strobilanthes crispus L.

Phytochemical investigation of Strobilanthes crispus has led to the isolation of 1-heptacosanol (1), tetracosanoic acid (2), stigmasterol (3) from the hexane extract, a mixture of four C20-C24 fatty acid esters of �- amyrin (4), taraxerol (5), taraxerone (6), a mixture of two C22 and C24 fatty acid esters of taraxerol (7) from the dichloromethane extract, 4-acetyl-2,7-dihydroxy-1,4,8-triphenyloctane-3,5-dione (8) and stigmasterol �-Dglucopyranoside (9) from the methanol extract. The dichloromethane and methanol crude extracts together with the isolated compounds (4-9) were tested for antibacterial activity using the determination of minimum inhibitory concentration assay and acetylcholinesterase inhibitory activity using the micro-plate assay. The majority of the samples tested indicated good activity against the Gram-positive bacteria (7.8�125.0 μg/mL), and moderate to weak activity against the Gram-negative bacteria (31.0�250.0 μg/mL) employed. Moderate to weak activity was observed against acetylcholinesterase. Compound (8) showed excellent antibacterial activity against Bacillus subtilis and Staphylococcus aureus, with MIC values of 15.6 and 7.8 μg/mL, respectively, and significant activity against Escherichia coli and Salmonella typhimurium, with MIC values of 62.5 and 31.0 μg/mL, respectively. Compound (8) also showed the highest acetylcholinesterase inhibitory activity, with an IC50 value of 31.0 μg/mL. This is the first report describing the antibacterial and acetylcholinesterase inhibitory activities of S. crispus on the basis of the isolated constituents. This research work has provided scientific proof of the traditional medicinal use of the leaves of S. crispus

Exposure to solar ultraviolet radiation establishes a novel immune suppressive lipidome in skin-draining lymph nodes

The ability of ultraviolet radiation to suppress the immune system is thought to be central to both its beneficial (protection from autoimmunity) and detrimental (carcinogenic) effects. Previous work revealed a key role for lipids particularly platelet-activating factor and sphingosine-1-phosphate in mediating UV-induced immune suppression. We therefore hypothesized that there may be other UV-induced lipids that have immune regulatory roles. To assess this, mice were exposed to an immune suppressive dose of solar-simulated UV (8 J/cm2). Lipidomic analysis identified 6 lipids (2 acylcarnitines, 2 neutral lipids, and 2 phospholipids) with significantly increased levels in the skin-draining lymph nodes of UV-irradiated mice. Imaging mass spectrometry of the lipids in combination with imaging mass cytometry identification of lymph node cell subsets indicated a preferential location of UV-induced lipids to T cell areas. In vitro co-culture of skin-draining lymph node lipids with lymphocytes showed that lipids derived from UV-exposed mice have no effect on T cell activation but significantly inhibited T cell proliferation, indicating that the lipids play an immune regulatory role. These studies are important first steps in identifying novel lipids that contribute to UV-mediated immune suppression

Intersection of diet and exercise with the gut microbiome and circulating metabolites in male bodybuilders : A pilot study

Diet, exercise and the gut microbiome are all factors recognised to be significant contributors to cardiometabolic health. However, diet and exercise interventions to modify the gut microbiota to improve health are limited by poor understanding of the interactions between them. In this pilot study, we explored diet–exercise–microbiome dynamics in bodybuilders as they represent a distinctive group that typically employ well-defined dietary strategies and exercise regimes to alter their body composition. We performed longitudinal characterisation of diet, exercise, the faecal microbial community composition and serum metabolites in five bodybuilders during competition preparation and post-competition. All participants reduced fat mass while conserving lean mass during competition preparation, corresponding with dietary energy intake and exercise load, respectively. There was individual variability in food choices that aligned to individualised gut microbial community compositions throughout the study. However, there was a common shift from a high protein, low carbohydrate diet during pre-competition to a more macronutrient-balanced diet post-competition, which was associated with similar changes in the gut microbial diversity across participants. The circulating metabolite profiles also reflected individuality, but a subset of metabolites relating to lipid metabolism distinguished between pre- and post-competition. Changes in the gut microbiome and circulating metabolome were distinct for each individual, but showed common patterns. We conclude that further longitudinal studies will have greater potential than cross-sectional studies in informing personalisation of diet and exercise regimes to enhance exercise outcomes and improve health

Cardiac Substrate Utilization and Relationship to Invasive Exercise Hemodynamic Parameters in HFpEF

We conducted transcardiac blood sampling in healthy subjects and subjects with heart failure with preserved ejection fraction (HFpEF) to compare cardiac metabolite and lipid substrate use. We demonstrate that fatty acids are less used by HFpEF hearts and that lipid extraction is influenced by hemodynamic factors including pulmonary pressures and cardiac index. The release of many products of protein catabolism is apparent in HFpEF compared to healthy myocardium. In subgroup analyses, differences in energy substrate use between female and male hearts were identified

TRAIL-Expressing Monocyte/Macrophages Are Critical for Reducing Inflammation and Atherosclerosis.

Circulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s) of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source. Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis. Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis. These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease

Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity

The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity

Impact of the Food Additive Titanium Dioxide (E171) on Gut Microbiota-Host Interaction

The interaction between gut microbiota and host plays a central role in health. Dysbiosis, detrimental changes in gut microbiota and inflammation have been reported in non-communicable diseases. While diet has a profound impact on gut microbiota composition and function, the role of food additives such as titanium dioxide (TiO2), prevalent in processed food, is less established. In this project, we investigated the impact of food grade TiO2 on gut microbiota of mice when orally administered via drinking water. While TiO2 had minimal impact on the composition of the microbiota in the small intestine and colon, we found that TiO2 treatment could alter the release of bacterial metabolites in vivo and affect the spatial distribution of commensal bacteria in vitro by promoting biofilm formation. We also found reduced expression of the colonic mucin 2 gene, a key component of the intestinal mucus layer, and increased expression of the beta defensin gene, indicating that TiO2 significantly impacts gut homeostasis. These changes were associated with colonic inflammation, as shown by decreased crypt length, infiltration of CD8+ T cells, increased macrophages as well as increased expression of inflammatory cytokines. These findings collectively show that TiO2 is not inert, but rather impairs gut homeostasis which may in turn prime the host for disease development

Design, synthesis and evaluation of C-terminal heat shock protein 90 (Hsp90) modulators as anticancer agents

This thesis describes C-terminal heat shock protein 90 (Hsp90) modulators aspotential anticancer agents. The McAlpine lab developed two molecules SM145 andSM122, which both bind between the N and middle domain of Hsp90 and allostericallymodulate the C-terminus. SM145 and SM122 disrupt Hsp90's protein folding function aswell as the interactions between co-chaperones and the C-terminus of Hsp90. Unlikecurrent Hsp90 inhibitors, these molecules also inhibit Hsp90 without inducing theproblematic cell rescue response.Chapter 2 describes the synthesis and structure-activity relationship (SAR) studiesof SM145. Two new Hsp90 inhibitors were identified during these studies: 12 and 23,where both of these compounds contained a single thiazolyl side chain. The authordesigned and synthesized these molecules, and they were made using a method that allowedthem to be produced in significantly improved yields over SM145. They also had muchgreater solubility, and approximately 2-fold greater potency than SM145. Mechanisticstudies of these derivatives have validated Hsp90 as a potential target. Both 12 and 23effectively suppressed Hsp90's function by disrupting the C-terminus chaperone functionwithout inducing the cell rescue response.Chapter 3 describes the synthesis of five derivatives where an N-methylation scanwas performed at a different position around the 23 backbone. Backbone N-methylationwas also undertaken on seven other derivatives that also incorporated two thiazolylmoieties, versus 23, which only has one thiazolyl moiety. N-methylation introduced aconformational impact on cyclic peptides, and impacted cytotoxicity.Chapter 4 describes the tumor selectivity between two classes of Hsp90 inhibitors,N-terminal inhibitor (AUY922) and C-terminal modulators (12 and 23) in cancer versusnormal cells. Comparison of both inhibitor classes revealed that 12 and 23 boundpreferentially to Hsp90 from tumor cells, selectively induce apoptosis and client proteindegradation that are associated with Hsp90 inhibition in cancer cells versus normal cells,while AUY922 failed to demonstrate differential selectivity for cancer over normal cells.Chapter 5 describes the synthesis and Hsp90 inhibitory effect of SM-based dimericinhibitors of Hsp90. The results revealed that the dimerized molecules are more effectivethan the monomeric inhibitor for inhibiting the binding interactions between Hsp90 and itsco-chaperones

Chemical Constituents and Biological Properties of the Marine Soft Coral Nephthea : A Review (Part 1)

The genus Nephthea is a member of the family Acyonaceae, subfamily Nephtheidae, and is distributed throughout the world mainly in the Indo-Pacific region. The genus Nephthea has been studied for its phytochemical constituents and these studies have resulted in the discovery of over a hundred compounds comprising amides, sesquiterpenes, diterpenes and steroids. Corresponding biological activities such as anti-inflammatory and cytotoxic activities have also been observed for some of the isolated constituents. Among the isolated constituents, steroids are the most abundant followed by diterpenes and sesqui biological activities reported for twelve species of the genus Nephthea, namely, Nephthea albida , Nephthea armata , Nephthea bayeri , Nephthea brassica , Nephthea capnelliformis , Nephthea crassica , Nephthea elongata , Nephthea erecta , Nephthea hainansis , Nephthea pacifica , Nephthea chabrolii and Nephthea sinulata . The purpose of the review is to draw greater attention to the potentials of soft corals as a source of new drugs and secondary metabolites