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Diet-induced metabolic changes of the human gut microbiome: importance of short-chain fatty acids, methylamines and indoles.
Abdul Rahim, MBH, Chilloux, J, Martinez-Gili, L, Neves, AL, Myridakis, A, Gooderham, N, Dumas, ME
Acta diabetologica. 2019;(5):493-500
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Abstract
The human gut is a home for more than 100 trillion bacteria, far more than all other microbial populations resident on the body's surface. The human gut microbiome is considered as a microbial organ symbiotically operating within the host. It is a collection of different cell lineages that are capable of communicating with each other and the host and has an ability to undergo self-replication for its repair and maintenance. As the gut microbiota is involved in many host processes including growth and development, an imbalance in its ecological composition may lead to disease and dysfunction in the human. Gut microbial degradation of nutrients produces bioactive metabolites that bind target receptors, activating signalling cascades, and modulating host metabolism. This review covers current findings on the nutritional and pharmacological roles of selective gut microbial metabolites, short-chain fatty acids, methylamines and indoles, as well as discussing nutritional interventions to modulate the microbiome.
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Fluvastatin for lowering lipids.
Adams, SP, Sekhon, SS, Tsang, M, Wright, JM
The Cochrane database of systematic reviews. 2018;(3):CD012282
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Abstract
BACKGROUND Fluvastatin is thought to be the least potent statin on the market, however, the dose-related magnitude of effect of fluvastatin on blood lipids is not known. OBJECTIVES Primary objectiveTo quantify the effects of various doses of fluvastatin on blood total cholesterol, low-density lipoprotein (LDL cholesterol), high-density lipoprotein (HDL cholesterol), and triglycerides in participants with and without evidence of cardiovascular disease.Secondary objectivesTo quantify the variability of the effect of various doses of fluvastatin.To quantify withdrawals due to adverse effects (WDAEs) in randomised placebo-controlled trials. SEARCH METHODS The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to February 2017: the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 1), MEDLINE (1946 to February Week 2 2017), MEDLINE In-Process, MEDLINE Epub Ahead of Print, Embase (1974 to February Week 2 2017), the World Health Organization International Clinical Trials Registry Platform, CDSR, DARE, Epistemonikos and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. No language restrictions were applied. SELECTION CRITERIA Randomised placebo-controlled and uncontrolled before and after trials evaluating the dose response of different fixed doses of fluvastatin on blood lipids over a duration of three to 12 weeks in participants of any age with and without evidence of cardiovascular disease. DATA COLLECTION AND ANALYSIS Two review authors independently assessed eligibility criteria for studies to be included, and extracted data. We entered data from placebo-controlled and uncontrolled before and after trials into Review Manager 5 as continuous and generic inverse variance data, respectively. WDAEs information was collected from the placebo-controlled trials. We assessed all trials using the 'Risk of bias' tool under the categories of sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential biases. MAIN RESULTS One-hundred and forty-five trials (36 placebo controlled and 109 before and after) evaluated the dose-related efficacy of fluvastatin in 18,846 participants. The participants were of any age with and without evidence of cardiovascular disease, and fluvastatin effects were studied within a treatment period of three to 12 weeks. Log dose-response data over doses of 2.5 mg to 80 mg revealed strong linear dose-related effects on blood total cholesterol and LDL cholesterol and a weak linear dose-related effect on blood triglycerides. There was no dose-related effect of fluvastatin on blood HDL cholesterol. Fluvastatin 10 mg/day to 80 mg/day reduced LDL cholesterol by 15% to 33%, total cholesterol by 11% to 25% and triglycerides by 3% to 17.5%. For every two-fold dose increase there was a 6.0% (95% CI 5.4 to 6.6) decrease in blood LDL cholesterol, a 4.2% (95% CI 3.7 to 4.8) decrease in blood total cholesterol and a 4.2% (95% CI 2.0 to 6.3) decrease in blood triglycerides. The quality of evidence for these effects was judged to be high. When compared to atorvastatin and rosuvastatin, fluvastatin was about 12-fold less potent than atorvastatin and 46-fold less potent than rosuvastatin at reducing LDL cholesterol. Very low quality of evidence showed no difference in WDAEs between fluvastatin and placebo in 16 of 36 of these short-term trials (risk ratio 1.52 (95% CI 0.94 to 2.45). AUTHORS' CONCLUSIONS Fluvastatin lowers blood total cholesterol, LDL cholesterol and triglyceride in a dose-dependent linear fashion. Based on the effect on LDL cholesterol, fluvastatin is 12-fold less potent than atorvastatin and 46-fold less potent than rosuvastatin. This review did not provide a good estimate of the incidence of harms associated with fluvastatin because of the short duration of the trials and the lack of reporting of adverse effects in 56% of the placebo-controlled trials.
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Efficacy of sequential therapies with sorafenib-sunitinib versus sunitinib-sorafenib in metastatic renal cell carcinoma: A systematic review and meta-analysis.
Wen, T, Xiao, H, Luo, C, Huang, L, Xiong, M
Oncotarget. 2017;(12):20441-20451
Abstract
The most efficient sequence of targeted agents for metastatic renal cell carcinoma patients has yet to be identified. Whether the sequence of sorafenib and sunitinib really matters is controversial and not answered clearly until now. This meta-analysis aims to estimate the efficacy of receptor tyrosine kinase inhibitors sorafenib-sunitinib and sunitinib-sorafenib for metastatic renal cell carcinoma, on the outcome of first-line progression-free survival, second-line progression-free survival, total progression-free survival and overall survival.We searched PubMed, Embase, Cochrane Library and ClinicalTrails.gov for eligible studies. Data were analyzed using random or fixed effects model depending on the heterogeneity of the eligible studies. Heterogeneity across studies were analyzed using Q and I2 statistics.Of 902 identified studies, ten were qualified in our analysis (N = 1732 patients). Sorafenib-sunitinib yielded no statistically significant benefit in first-line progression-free survival (fixed effects; HR = 0.95; 95%CI 0.75-1.21; p = 0.702), total progression-free survival (random effects; HR = 0.92; 95%CI 0.71-1.19; p = 0.531) and overall survival (fixed effects; HR = 0.89; 95%CI 0.72-1.09; p = 0.257), compared with sunitinib-sorafenib. Second-line progression-free survival was longer for sorafenib-sunitinib than sunitinib-sorafenib (fixed effects; HR = 0.55; 95%CI 0.44-0.68; p = 0.000).Sequential therapies with sorafenib and sunitinib is well tolerated and efficient in mRCC. However, there are no evidence supported that sorafenib-sunitinib has the superiority to sunitinib-sorafenib in sequence. The ideal sequence of targeted agents requires further elucidation.
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[Total synthesis of biologically active alkaloids using bio-inspired indole oxidation].
Ishikawa, H
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2015;(3):383-90
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Abstract
Many tryptophan-based dimeric diketopiperazine (DKP) alkaloids including WIN 64821 and ditryptophenaline, which exhibit fascinating biological activities, have been isolated from fungi. These alkaloids possess a unique architecture; therefore several total syntheses of these compounds have been accomplished via bio-inspired reactions. Despite these elegant strategies, we were convinced that a more direct bio-inspired solution for the preparation of tryptophan-based DKP alkaloids was possible because in a true biosynthesis, direct dimerization of tryptophan occurs in aqueous media without incorporation of a protecting group on the substrates. Thus we developed direct bio-inspired dimerization reactions in aqueous, acidic media, along with a novel biomimetic pathway, to provide C2-symmetric and non-symmetric dimeric compounds from commercially available amine-free tryptophan derivatives using Mn(OAc)3, VOF3, and V2O5 as one-electron oxidants. In addition, concise two-pot or three-step syntheses of the naturally occurring dimeric DKP alkaloids (+)-WIN 64821, (-)-ditryptophenaline, and (+)-naseseazine B were accomplished with total yields of 20%, 13%, and 20%, respectively. The present synthesis has several noteworthy features: 1) the tryptophan-based C2-symmetric and non-symmetric dimeric key intermediates can be prepared on a multigram scale in one step; 2) the developed oxidation reaction was carried out in aqueous, acidic solution without deactivation of the metal oxidants; 3) protection of the primary amine can be avoided by salt formation in aqueous acid; 4) for the total two-pot operation, the reaction media are environmentally friendly water and ethanol; 5) satisfactory total yields are obtained compared with previously reported syntheses.
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Risk of gastrointestinal events with sorafenib, sunitinib and pazopanib in patients with solid tumors: a systematic review and meta-analysis of clinical trials.
Santoni, M, Conti, A, De Giorgi, U, Iacovelli, R, Pantano, F, Burattini, L, Muzzonigro, G, Berardi, R, Santini, D, Cascinu, S
International journal of cancer. 2014;(4):763-73
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Abstract
Gastrointestinal (GI) events have been described with sorafenib, sunitinib and pazopanib in cancer patients. We performed an up-to-date meta-analysis to determine the incidence and relative risk (RR) in patients with cancer treated with these agents. PubMed databases were searched for articles published till May 2013. Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% CIs were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. A total of 6,447 patients were available for the meta-analysis; 2,260 had renal cell carcinoma (RCC) and 4,187, 1,691 non-small cell lung cancers, 599 hepatocellular cancers, 1,066 breast cancers, 165 neuroendocrine tumors, 304 gastrointestinal stromal tumors and 362 soft tissue sarcomas. Diarrhea was the most common GI event. When stratified by tumor type (RCC vs. non-RCC), the difference among the incidences of GI events was significant for diarrhea (p < 0.001) and vomiting (p = 0.006), that resulted higher in RCC patients. In RCC patients, sorafenib registered the lower incidence and RR of all grades GI events. The difference was statistically significant for sorafenib versus sunitinib-related all and high-grade events (p < 0.001) and for sorafenib versus pazopanib all grades GI events (p < 0.001) and high-grade anorexia (p < 0.001). Treatment with VEGFR TKIs sorafenib, sunitinib and pazopanib is associated with a significant increase in the risk of GI events in patients with cancer, and frequent clinical monitoring should be emphasized when managing these three and newer VEGFR TKIs.
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Molecular marker for predicting treatment response in advanced renal cell carcinoma: does the promise fulfill clinical need?
Garcia-Roig, M, Ortiz, N, Lokeshwar, V
Current urology reports. 2014;(1):375
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Abstract
Renal cell carcinoma (RCC) is largely diagnosed incidentally on imaging taken for unrelated reasons. The management of localized lesions is primarily extirpative with excellent results. Treatment of advanced RCC has evolved over recent years with the use of targeted therapies such as tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and antibody-mediated therapies. The treatment response to these targeted therapies is highly variable, with no clear clinical method of identifying patients who will benefit from or not tolerate therapy. The field of molecular markers has evolved significantly in the last decade, with a multitude of markers identified that predict treatment response and drug toxicity. The following review critically evaluates those molecular markers that have been assessed for their utility in predicting treatment response in patients with advanced/metastatic renal cell carcinoma (mRCC). Identifying the ideal treatment for these patients will improve responses to therapy, minimize morbidity, and save significant healthcare dollars.
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Influence of the tryptophan-indole-IFNγ axis on human genital Chlamydia trachomatis infection: role of vaginal co-infections.
Aiyar, A, Quayle, AJ, Buckner, LR, Sherchand, SP, Chang, TL, Zea, AH, Martin, DH, Belland, RJ
Frontiers in cellular and infection microbiology. 2014;:72
Abstract
The natural history of genital Chlamydia trachomatis infections can vary widely; infections can spontaneously resolve but can also last from months to years, potentially progressing to cause significant pathology. The host and bacterial factors underlying this wide variation are not completely understood, but emphasize the bacterium's capacity to evade/adapt to the genital immune response, and/or exploit local environmental conditions to survive this immune response. IFNγ is considered to be a primary host protective cytokine against endocervical C. trachomatis infections. IFNγ acts by inducing the host enzyme indoleamine 2,3-dioxgenase, which catabolizes tryptophan, thereby depriving the bacterium of this essential amino acid. In vitro studies have revealed that tryptophan deprivation causes Chlamydia to enter a viable but non-infectious growth pattern that is termed a persistent growth form, characterized by a unique morphology and gene expression pattern. Provision of tryptophan can reactivate the bacterium to the normal developmental cycle. There is a significant difference in the capacity of ocular and genital C. trachomatis serovars to counter tryptophan deprivation. The latter uniquely encode a functional tryptophan synthase to synthesize tryptophan via indole salvage, should indole be available in the infection microenvironment. In vitro studies have confirmed the capacity of indole to mitigate the effects of IFNγ; it has been suggested that a perturbed vaginal microbiome may provide a source of indole in vivo. Consistent with this hypothesis, the microbiome associated with bacterial vaginosis includes species that encode a tryptophanase to produce indole. In this review, we discuss the natural history of genital chlamydial infections, morphological and molecular changes imposed by IFNγ on Chlamydia, and finally, the microenvironmental conditions associated with vaginal co-infections that can ameliorate the effects of IFNγ on C. trachomatis.
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Specific binding of anionic porphyrin and phthalocyanine to the G-quadruplex with a variety of in vitro and in vivo applications.
Yaku, H, Murashima, T, Miyoshi, D, Sugimoto, N
Molecules (Basel, Switzerland). 2012;(9):10586-613
Abstract
The G-quadruplex, a four-stranded DNA structure with stacked guanine tetrads (G-quartets), has recently been attracting attention because of its critical roles in vitro and in vivo. In particular, the G-quadruplex functions as ligands for metal ions and aptamers for various molecules. Interestingly, the G-quadruplex can show peroxidase-like activity with an anionic porphyrin, iron (III) protoporphyrin IX (hemin). Importantly, hemin binds to G-quadruplexes with high selectivity over single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), which is attributable to an electrostatic repulsion of phosphate groups in ssDNA and dsDNA. The G-quadruplex and hemin-G-quadruplex complex allow development of sensing techniques to detect DNA, metal ions and proteins. In addition to hemin, anionic phthalocyanines also bind to the G-quadruplex formed by human telomere DNA, specifically over ssDNA and dsDNA. Since the binding of anionic phthalocyanines to the G-quadruplex causes an inhibition of telomerase activity, which plays a role in the immortal growth of cancer cells, anionic phthalocyanines are promising as novel anticancer drug candidates. This review focuses on the specific binding of hemin and anionic phthalocyanines to G-quadruplexes and the applications in vitro and in vivo of this binding property.
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The resurgence of niacin: from nicotinic acid to niaspan/laropiprant.
Markel, A
The Israel Medical Association journal : IMAJ. 2011;(6):368-74
Abstract
Hypercholesterolemia is one of the main factors in the development of atherosclerotic cardiovascular disease. The advent of statins led to huge progress in the treatment of hypercholesterolemia, yet the proportion of patients with prohibitive lipid values and the high incidence of cardiovascular events despite treatment are still very high. Niacin, one of the older drugs used to treat hyperlipidemia, was shown to reduce low-density lipoprotein-cholesterol (LDL-C) and triglycerides and to markedly increase high-density lipoprotein-cholesterol (HDL-C) levels. This drug came into disuse owing to frequent side effects, mainly flushing, but in recent years a reemergence of its application has occurred, and multiple clinical trials have shown its effectiveness in the treatment of hyperlipidemia and in the reduction of cardiovascular events. New formulations such as extended-release niacin (ERN) have been developed with the purpose of reducing side effects. Lately, a new compound, laropiprant, which selectively antagonizes the prostaglandin 2 (PGD2) receptor responsible for flushing, has been developed. Laropiprant, when combined with ERN, significantly reduces the incidence of flushing. New and ongoing trials will definitively prove in the long term whether this drug combination significantly reduces the severity of flushing and the incidence of cardiovascular events.
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[Current aspects of second-line and sequence therapy of metastatic renal cell carcinoma].
Gschwend, JE
Onkologie. 2010;:10-1
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Abstract
The treatment objective in the metastatic situation is to delay progression while maintaining the best possible quality of life. Since several targeted therapies with different modes of action already exist, sequence therapy is increasingly being considered. Current data regarding sequential treatment is still insufficient and several approaches are being tested in ongoing clinical studies. Based on current data, guidelines, and the therapeutic algorithms supported by national and international professional associations, the German Cancer Society's interdisciplinary task force on renal cell carcinoma (RCC) recommends the following approach: since the efficacy of cytokines is very limited after a previous cytokine-based therapy has failed, Sorafenib or Sunitinib are the treatment of choice. Treatment with other targeted substances is recommended after first-line therapy has failed as a number of retrospective studies have documented relevant activity. Everolimus currently is the treatment of first choice when VEGF-directed therapy has failed. Based on the results of phase II studies, other tyrosine kinase inhibitors can alternatively be applied.