Michal Heger

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

This review addresses the oncopharmacological properties of curcumin at the molecular level. First, the interactions between curcumin and its molecular targets are addressed on the basis of curcumin’s distinct chemical properties, which include H-bond donating and accepting capacity of the β-dicarbonyl moiety and the phenylic hydroxyl groups, H-bond accepting capacity of the methoxy ethers, multivalent metal and nonmetal cation binding properties, high partition coefficient, rotamerization around multiple C–C bonds, and the ability to act as a Michael acceptor. Next, the in vitro chemical stability of curcumin is elaborated in the context of its susceptibility to photochemical and chemical modification and degradation (e.g., alkaline hydrolysis). Specific modification and degradatory pathways are provided, which mainly entail radical-based intermediates, and the in vitro catabolites are identified. The implications of curcumin’s (photo)chemical instability are addressed in light of pharmaceutical curcumin preparations, the use of curcumin analogues, and implementation of nanoparticulate drug delivery systems. Furthermore, the pharmacokinetics of curcumin and its most important degradation products are detailed in light of curcumin’s poor bioavailability. Particular emphasis is placed on xenobiotic phase I and II metabolism as well as excretion of curcumin in the intestines (first pass), the liver (second pass), and other organs in addition to the pharmacokinetics of curcumin metabolites and their systemic clearance. Lastly, a summary is provided of the clinical pharmacodynamics of curcumin followed by a detailed account of curcumin’s direct molecular targets, whereby the phenotypical/biological changes induced in cancer cells upon completion of the curcumin-triggered signaling cascade(s) are addressed in the framework of the hallmarks of cancer. The direct molecular targets include the ErbB family of receptors, protein kinase C, enzymes involved in prostaglandin synthesis, vitamin D receptor, and DNA.

Physiological and biochemical basis of clinical liver function tests: a review

Objective:To review the literature on the most clinically relevant and novel liver function tests used for the assessment of hepatic function before liver surgery. Background:Postoperative liver failure is the major cause of mortality and morbidity after partial liver resection and develops as a result of insufficient remnant liver function. Therefore, accurate preoperative assessment of the future remnant liver function is mandatory in the selection of candidates for safe partial liver resection. Methods:A MEDLINE search was performed using the key words “liver function tests,” “functional studies in the liver,” “compromised liver,” “physiological basis,” and “mechanistic background,” with and without Boolean operators. Results:Passive liver function tests, including biochemical parameters and clinical grading systems, are not accurate enough in predicting outcome after liver surgery. Dynamic quantitative liver function tests, such as the indocyanine green test and galactose elimination capacity, are more accurate as they measure the elimination process of a substance that is cleared and/or metabolized almost exclusively by the liver. However, these tests only measure global liver function. Nuclear imaging techniques (99mTc-galactosyl serum albumin scintigraphy and 99mTc-mebrofenin hepatobiliary scintigraphy) can measure both total and future remnant liver function and potentially identify patients at risk for postresectional liver failure. Conclusions:Because of the complexity of liver function, one single test does not represent overall liver function. In addition to computed tomography volumetry, quantitative liver function tests should be used to determine whether a safe resection can be performed. Presently, 99mTc-mebrofenin hepatobiliary scintigraphy seems to be the most valuable quantitative liver function test, as it can measure multiple aspects of liver function in, specifically, the future remnant liver.

Transporters involved in the hepatic uptake of 99mTc-mebrofenin and indocyanine green

BACKGROUND & AIMS (99m)Tc-mebrofenin hepatobiliary scintigraphy (HBS) and the indocyanine green (ICG) clearance test are used for the assessment of hepatic function before and after liver surgery. The hepatic uptake of (99m)Tc-mebrofenin and ICG is considered similar to the uptake of organic anions such as bilirubin and bile acids. Little is known about hepatic uptake mechanisms of both compounds and recent evidence suggests that the hepatic transporters for ICG and (99m)Tc-mebrofenin are distinct. The aim of this study was to identify the specific human hepatic transporters of (99m)Tc-mebrofenin and ICG. METHODS The uptake of (99m)Tc-mebrofenin was investigated in cRNA-injected Xenopus laevis oocytes expressing human OATP1B1, OATP1B3, OATP2B1, or NTCP. Chinese hamster ovary (CHO) cells stably expressing OATP1B1, OATP1B3, OATP2B1, or NTCP were used as a mammalian expression system. ICG transport into CHO cells was additionally imaged with confocal microscopy. RESULTS We demonstrated that OATP1B1 and OATP1B3 are involved in the transport of (99m)Tc-mebrofenin. OATP1B1 showed an approximately 1.5-fold higher affinity for (99m)Tc-mebrofenin compared to OATP1B3. ICG is transported by OATP1B3 and NTCP. CONCLUSIONS The transporter specificity of (99m)Tc-mebrofenin and ICG partially overlaps as both compounds are transported by OATP1B3. (99m)Tc-mebrofenin is also taken up by OATP1B1, whereas ICG is additionally transported by NTCP.

Mechanistic overview of reactive species-induced degradation of the endothelial glycocalyx during hepatic ischemia/reperfusion injury.

Endothelial cells are covered by a delicate meshwork of glycoproteins known as the glycocalyx. Under normophysiological conditions the glycocalyx plays an active role in maintaining vascular homeostasis by deterring primary and secondary hemostasis and leukocyte adhesion and by regulating vascular permeability and tone. During (micro)vascular oxidative and nitrosative stress, which prevails in numerous metabolic (diabetes), vascular (atherosclerosis, hypertension), and surgical (ischemia/reperfusion injury, trauma) disease states, the glycocalyx is oxidatively and nitrosatively modified and degraded, which culminates in an exacerbation of the underlying pathology. Consequently, glycocalyx degradation due to oxidative/nitrosative stress has far-reaching clinical implications. In this review the molecular mechanisms of reactive oxygen and nitrogen species-induced destruction of the endothelial glycocalyx are addressed in the context of hepatic ischemia/reperfusion injury as a model disease state. Specifically, the review focuses on (i) the mechanisms of glycocalyx degradation during hepatic ischemia/reperfusion, (ii) the molecular and cellular players involved in the degradation process, and (iii) its implications for hepatic pathophysiology. These topics are projected against a background of liver anatomy, glycocalyx function and structure, and the biology/biochemistry and the sources/targets of reactive oxygen and nitrogen species. The majority of the glycocalyx-related mechanisms elucidated for hepatic ischemia/reperfusion are extrapolatable to the other aforementioned disease states.

The sterile immune response during hepatic ischemia/reperfusion

Hepatic ischemia and reperfusion elicits an immune response that lacks a microbial constituent yet poses a potentially lethal threat to the host. In this sterile setting, the immune system is alarmed by endogenous danger signals that are release by stressed and dying liver cells. The detection of these immunogenic messengers by sentinel leukocyte populations constitutes the proximal trigger for a self-perpetuating cycle of inflammation, in which consecutive waves of cytokines and chemokines orchestrate the influx of various leukocyte subsets that ultimately confer tissue destruction. This review focuses on the temporal organization of sterile hepatic inflammation, using surgery-induced trauma as a template disease state.

An overview of clinical and experimental treatment modalities for port wine stains

Port wine stains (PWS) are the most common vascular malformation of the skin, occurring in 0.3% to 0.5% of the population. Noninvasive laser irradiation with flashlamp-pumped pulsed dye lasers (selective photothermolysis) currently comprises the gold standard treatment of PWS; however, the majority of PWS fail to clear completely after selective photothermolysis. In this review, the clinically used PWS treatment modalities (pulsed dye lasers, alexandrite lasers, neodymium:yttrium-aluminum-garnet lasers, and intense pulsed light) and techniques (combination approaches, multiple passes, and epidermal cooling) are discussed. Retrospective analysis of clinical studies published between 1990 and 2011 was performed to determine therapeutic efficacies for each clinically used modality/technique. In addition, factors that have resulted in the high degree of therapeutic recalcitrance are identified, and emerging experimental treatment strategies are addressed, including the use of photodynamic therapy, immunomodulators, angiogenesis inhibitors, hypobaric pressure, and site-specific pharmaco-laser therapy.

Controversies in the Use of Portal Vein Embolization

Background/Aims: Portal vein embolization (PVE) has reached worldwide acceptance to increase future remnant liver (FRL) volume before undertaking major liver resection. The aim of this overview is to point out and discuss current controversies in the application of PVE. Methods: Review of literature pertaining to techniques of PVE, complications, tumor proliferation, timing of resection, and hypertrophy response after PVE. Results: Procedure-related complications after PVE include hematoma, hemobilia, overflow of embolization material, and thrombosis of portal vein branch(es) of the non-embolized lobe. Persistence of the embolized, atrophic lobe is usually not harmful. Embolization of the portal branches to segment 4 in addition to embolization of the right portal trunk is controversial and is advised only in selected cases. It remains undecided whether embolization of the portal venous system is more effective in inducing hypertrophy of the FRL than ligation of the portal vein. Accelerated tumor growth after PVE is a major concern and requires consideration of post-PVE chemotherapy. A waiting time of 3 weeks between PVE and liver resection is advised. Post-hepatectomy regeneration is not hampered after preoperative PVE. Conclusion: PVE is a useful preoperative intervention to increase volume and function of the FRL. Further progress awaits clarification of the mechanisms of the hypertrophy response induced by PVE in conjunction with new embolization materials and protective chemotherapy.

Assessment of tissue oxygen saturation during a vascular occlusion test using near-infrared spectroscopy: the role of probe spacing and measurement site studied in healthy volunteers

IntroductionTo assess potential metabolic and microcirculatory alterations in critically ill patients, near-infrared spectroscopy (NIRS) has been used, in combination with a vascular occlusion test (VOT), for the non-invasive measurement of tissue oxygen saturation (StO2), oxygen consumption, and microvascular reperfusion and reactivity. The methodologies for assessing StO2 during a VOT, however, are very inconsistent in the literature and, consequently, results vary from study to study, making data comparison difficult and potentially inadequate. Two major aspects concerning the inconsistent methodology are measurement site and probe spacing. To address these issues, we investigated the effects of probe spacing and measurement site using 15 mm and 25 mm probe spacings on the thenar and the forearm in healthy volunteers and quantified baseline, ischemic, reperfusion, and hyperemic VOT-derived StO2 variables.MethodsStO2 was non-invasively measured in the forearm and thenar in eight healthy volunteers during 3-minute VOTs using two InSpectra tissue spectrometers equipped with a 15 mm probe or a 25 mm probe. VOT-derived StO2 traces were analyzed for base-line, ischemic, reperfusion, and hyperemic parameters. Data were categorized into four groups: 15 mm probe on the forearm (F15 mm), 25 mm probe on the forearm (F25 mm), 15 mm probe on the thenar (T15 mm), and 25 mm probe on the thenar (T25 mm).ResultsAlthough not apparent at baseline, probe spacing and measurement site significantly influenced VOT-derived StO2 variables. For F15 mm, F25 mm, T15 mm, and T25 mm, StO2 ownslope was -6.4 ± 1.7%/minute, -10.0 ± 3.2%/minute, -12.5 ± 3.0%/minute, and -36.7 ± 4.6%/minute, respectively. StO2 upslope was 105 ± 34%/minute, 158 ± 55%/minute, 226 ± 41%/minute, and 713 ± 101%/minute, and the area under the hyperemic curve was 7.4 ± 3.8%·minute, 10.1 ± 4.9%·minute, 12.6 ± 4.4%·minute, and 21.2 ± 2.7%·minute in these groups, respectively. Furthermore, the StO2 parameters of the hyperemic phase of the VOT, such as the area under the curve, significantly correlated to the minimum StO2 during ischemia.ConclusionsNIRS measurements in combination with a VOT are measurement site-dependent and probe-dependent. Whether this dependence is anatomy-, physiology-, or perhaps technology-related remains to be elucidated. Our study also indicated that reactive hyperemia depends on the extent of ischemic insult.

Sterile inflammation in hepatic ischemia/reperfusion injury: Present concepts and potential therapeutics

Ischemia and reperfusion (I/R) injury is an often unavoidable consequence of major liver surgery and is characterized by a sterile inflammatory response that jeopardizes the viability of the organ. The inflammatory response results from acute oxidative and nitrosative stress and consequent hepatocellular death during the early reperfusion phase, which causes the release of endogenous self‐antigens known as damage‐associated molecular patterns (DAMPs). DAMPs, in turn, are indirectly responsible for a second wave of reactive oxygen and nitrogen species (ROS and RNS) production by driving the chemoattraction of various leukocyte subsets that exacerbate oxidative liver damage during the later stages of reperfusion. In this review, the molecular mechanisms underlying hepatic I/R injury are outlined, with emphasis on the interplay between ROS/RNS, DAMPs, and the cell types that either produce ROS/RNS and DAMPs or respond to them. This theoretical background is subsequently used to explain why current interventions for hepatic I/R injury have not been very successful. Moreover, novel therapeutic modalities are addressed, including MitoSNO and nilotinib, and metalloporphyrins on the basis of the updated paradigm of hepatic I/R injury.

Reversal of hepatic steatosis by omega-3 fatty acids measured non-invasively by (1) H-magnetic resonance spectroscopy in a rat model

Background and Aim:  Living donors with marked (> 33%) macrovesicular steatosis (MaS) are excluded from living donor liver transplantation procedures. Experimental studies have shown that the development of steatosis can be prevented by supplementation with omega‐3 fatty acids (FA), but no studies have investigated the reduction of steatosis using omega‐3 FA. The aim of the present study was to investigate whether administration of omega‐3 FA is effective in reducing steatosis.