Nutrigenetic Interactions Might Modulate the Antioxidant and Anti-Inflammatory Status in Mastiha-Supplemented Patients With NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease with no therapeutic consensus. Oxidation and inflammation are hallmarks in the progression of this complex disease, which also involves interactions between the genetic background and the environment. Mastiha is a natural nutritional supplement known to possess antioxidant and anti-inflammatory properties. This study investigated how a 6-month Mastiha supplementation (2.1 g/day) could impact the antioxidant and inflammatory status of patients with NAFLD, and whether genetic variants significantly mediate these effects. We recruited 98 patients with obesity (BMI ≥ 30 kg/m2) and NAFLD and randomly allocated them to either the Mastiha or the placebo group for 6 months. The anti-oxidative and inflammatory status was assessed at baseline and post-treatment. Genome-wide genetic data was also obtained from all participants, to investigate gene-by-Mastiha interactions. NAFLD patients with severe obesity (BMI > 35kg/m2) taking the Mastiha had significantly higher total antioxidant status (TAS) compared to the corresponding placebo group (P value=0.008). We did not observe any other significant change in the investigated biomarkers as a result of Mastiha supplementation alone. We identified several novel gene-by-Mastiha interaction associations with levels of cytokines and antioxidant biomarkers. Some of the identified genetic loci are implicated in the pathological pathways of NAFLD, including the lanosterol synthase gene (LSS) associated with glutathione peroxidase activity (Gpx) levels, the mitochondrial pyruvate carrier-1 gene (MPC1) and the sphingolipid transporter-1 gene (SPNS1) associated with hemoglobin levels, the transforming growth factor-beta-induced gene (TGFBI) and the micro-RNA 129-1 (MIR129-1) associated with IL-6 and the granzyme B gene (GZMB) associated with IL-10 levels. Within the MAST4HEALTH randomized clinical trial (NCT03135873, www.clinicaltrials.gov) Mastiha supplementation improved the TAS levels among NAFLD patients with severe obesity. We identified several novel genome-wide significant nutrigenetic interactions, influencing the antioxidant and inflammatory status in NAFLD. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03135873.

Phytochemical characterization and effects on cell proliferation of Pinus nigra Arn. bark.

Pinus nigra Arn. bark extracts from Mokra gora (MG) and Tara mountains were analyzed with regard to their polyphenolic profile and antioxidative and antiproliferative activity. The ethanol extract from MG showed the highest phenolic, flavonoid, tannin, and proanthocyanidin content when compared with the acetone and methanol extracts from both sites. The same extract exhibited the highest ABTS (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt) and ferric reducing antioxidant power (FRAP) radical scavenging ability and total antioxidant activity (TAA). On the basis of high-performance liquid chromatography analysis, catechin, caffeic, syringic, p-coumaric, and ferulic acids were predominantly present in the MG extracts. The ethanol extract from MG was rich in syringic acid, epicatechin and its derivatives, and ferulic acid and its derivatives. The bark extracts also exerted a high cytotoxic bioactivity against all evaluated cell lines (HeLa, MCF7, HT-29, and MRC-5). The antiproliferative activity of P. nigra bark is probably related to the ferulic acid content and its synergistic activity to caffeic acid and taxifolin. The antioxidative role of the presented phenols was confirmed through the obtained significant linear correlation between the total phenolic content and DPPH (r = .934) as well as the FRAP% of the extracts (r = .948). Also, the TAA significantly depended on the proanthocyanidins (r = .902) and tannin contents (r = .914). The composition of the presented compounds could be related to promising antioxidant and antiproliferative efficacy of MG bark.

May Patients with Alcohol Liver Disease Benefit from Herbal Medicines?

Alcoholism is currently listed as the third leading cause of death. Chronic alcohol consumption brings serious medical complications like gastrointestinal, cardiovascular, musculoskeletal, respiratory system disorders. Liver can be seriously damage by alcohol misuse. Alcoholic Liver Disease (ALD) is the first important warning sign of alcohol abuse. Since effective therapies for ALD are still limited, natural products in the treatment of ALD become very important. In this regard, there have been done very few clinical trials with poor results. Silymarin, glycyrrhizin, garlic show some promising results in ALD patients while the in vivo and in vitro studies with green tee, quercetin and curcumin indicate positive effect on patients with ALD.

Phytotherapy and NAFLD--from goals and challenges to clinical practice.

Non-alcoholic fatty liver disease (NAFLD) is a global problem and one of the most common liver diseases in the world. Various pharmacological and non-pharmacological therapies seem to be non-effective and the patients are often advised not to expect a positive outcome. Hence, even in the modern Western society many patients reach for traditional herbal products. Silymarin, a lipophilic extract derived from milk thistle (Silybum marianum) has been used in liver and bile disorders for centuries. Strong antifibrotic, antioxidant, antiviral and anti-inflammatory activities of silymarin joined with its metabolic effect proven in vitro make it ideal as a drug candidate in the therapy of NAFLD. Several recent randomized clinical studies have demonstrated that silymarin versus placebo significantly contributes to amelioration of the liver condition affected by NAFLD since it reduces steatosis severity, liver ballooning and fibrosis, followed by lowered aminotransferase levels in both short and long lasting therapies. Silymarin is also as efficient as an insulin sensitizer in the NAFLD therapy, but with less adverse effects. Phase III clinical trials have confirmed silymarin to be currently the best medication for the NAFLD patients, but the problems associated with its standardization, formulation and dosage are yet to be solved. However, green tea (Camellia sinensis) and licorice (Glycyrrhiza glabra) root extracts have also been studied in the clinical trials in the therapy of NAFLD patients. Some other herbal products, which have been tested on animals and have the potential to be used in clinical trials, are briefly summarized in this paper.

Warfarin interactions with medicinal herbs.

Recognition of the adverse effects of medicinal herbs is not routine and the reports on such effects are even less frequent in clinical practice. Potential herb-drug interactions are of a major safety concern, especially for drugs with narrow therapeutic indices like warfarin, which can lead to severe adverse reactions that are sometimes life-threatening. The interactions between warfarin and medicinal herbs described in the literature have been summarized in this paper relying on Medline database (via PubMed) using the key words: warfarin, herbal supplements and interactions. The references on the analyzed literature have been investigated in order to collect the existing data. The case reports with severe adverse effects such as spontaneous postoperative bleeding, formation of hematomas, hematemesis, melena, thrombosis, subarachnoid hemorrhage and/or subdural hematomas after concomitant use of warfarin and the medicinal herbs: Panax ginseng, Hypericum perforatum, Salvia milthiorizza, Gingko biloba, Serenoa repens, Angelica sinensis, Vaccinium species, Allium sativum, Zingiber officinale, Tanacetum parthenium, Lucium barbarum, Matricaria chamomilla, Boswellia serrata and Camellia sinensis have been estimated. Some of the interactions between warfarin and medicinal herbs have been well assessed proving that they are closely-dependent. The interactions between warfarin and medicinal herbs, not generally reported in previous reviews, are presented in our review. The health professionals who are involved in treating the patients are expected to be fully informed about the interactions between warfarin and medicinal herbs in order to minimize the health risks of the patients.

New therapeutic potentials of milk thistle (Silybum marianum).

Silymarin is a bioflavonoid complex extract derived from dry seeds of Milk thistle [(Silybum marianum(L.) Gaemrnt. (Fam. Asteraceae/Compositaceae)] whose hepatoprotective effect has clinically been proved. Low toxicity, favorable pharmacokinetics, powerful antioxidant, detoxifying, preventive, protective and regenerative effects and side effects similar to placebo make silymarin extremely attractive and safe for therapeutic use. The medicinal properties of silymarin and its main component silibinin have been studied in the treatment of Alzheimer's disease, Parkinson's disease, sepsis, burns, osteoporosis, diabetes, cholestasis and hypercholesterolemia. Owing to its apoptotic effect, without cytotoxic effects, silymarin possesses potential applications in the treatment of various cancers. Silymarin is being examined as a neuro-, nephro- and cardio-protective in the damage of different etiologies due to its strong antioxidant potentials. Furthermore, it has fetoprotective (against the influence of alcohol) and prolactin effects and is safe to be used during pregnancy and lactation. Finally, the cosmetics industry is examining the antioxidant and UV-protective effects of silymarin. Further clinical studies and scientific evidence that silymarin and silibinin are effective in the therapy of various pathologies are indispensable in order to confirm their different flavonolignan pharmacological effects.

Development of axonal pathways in the human fetal fronto-limbic brain: histochemical characterization and diffusion tensor imaging.

The development of cortical axonal pathways in the human brain begins during the transition between the embryonic and fetal period, happens in a series of sequential events, and leads to the establishment of major long trajectories by the neonatal period. We have correlated histochemical markers (acetylcholinesterase (AChE) histochemistry, antibody against synaptic protein SNAP-25 (SNAP-25-immunoreactivity) and neurofilament 200) with the diffusion tensor imaging (DTI) database in order to make a reconstruction of the origin, growth pattern and termination of the pathways in the period between 8 and 34 postconceptual weeks (PCW). Histological sections revealed that the initial outgrowth and formation of joined trajectories of subcortico-frontal pathways (external capsule, cerebral stalk-internal capsule) and limbic bundles (fornix, stria terminalis, amygdaloid radiation) occur by 10 PCW. As early as 11 PCW, major afferent fibers invade the corticostriatal junction. At 13-14 PCW, axonal pathways from the thalamus and basal forebrain approach the deep moiety of the cortical plate, causing the first lamination. The period between 15 and 18 PCW is dominated by elaboration of the periventricular crossroads, sagittal strata and spread of fibers in the subplate and marginal zone. Tracing of fibers in the subplate with DTI is unsuccessful due to the isotropy of this zone. Penetration of the cortical plate occurs after 24-26 PCW. In conclusion, frontal axonal pathways form the periventricular crossroads, sagittal strata and 'waiting' compartments during the path-finding and penetration of the cortical plate. Histochemistry is advantageous in the demonstration of a growth pattern, whereas DTI is unique for demonstrating axonal trajectories. The complexity of fibers is the biological substrate of selective vulnerability of the fetal white matter.