Pharmacokinetics and Pharmacodynamics of Ursodeoxycholic Acid in an Overweight Population With Abnormal Liver Function

Yoon S, Lee H, Ji SC, Yoon SH, Cho JY, Chung JY

Clin Pharmacol Drug Dev. 2020 Mar 19. doi: 10.1002/cpdd.790. [Epub ahead of print]

Abstract

Ursodeoxycholic acid (UDCA) is a secondary bile acid that is used to treat primary biliary cholangitis. Although UDCA has a hepatoprotective effect in some diseases, its benefit in nonalcoholic fatty liver disease (NAFLD) remains controversial. We aimed to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of UDCA in overweight subjects with elevated liver enzymes after multiple administrations of UDCA and compare these changes with vitamin E treatment. Overweight subjects (body mass index, 25-30 kg/m² ) with elevated alanine aminotransferase (ALT) level (40-200 IU/L) were enrolled. Subjects received one of the following three 8-week treatments: UDCA 300 mg twice daily UDCA 300 mg twice daily for 4 weeks followed by UDCA 300 mg twice daily and metformin 500 mg twice daily for 4 weeks, and vitamin E 400 IU twice daily. PK and PD (liver function, lipid profiles, insulin sensitivity, and miR-122) analyses were performed. Thirty subjects were enrolled; 1 subject withdrew his consent during the study. The PK characteristics were similar to those of healthy volunteers. The ALT and miR-122 levels decreased in the UDCA groups, whereas the ALT and aspartate aminotransferase levels decreased in the vitamin E group. The lipid profiles and insulin sensitivity did not show significant changes among the groups. There was no serious adverse event, and the safety profiles were similar among the treatment groups. The liver enzyme and miR-122 levels were decreased by UDCA. Considering UDCA and vitamin E have a hepatoprotective effect and different mechanisms of action, combination therapy could be an option for NAFLD.

Harandi VM, Oliveira BMS, Allamand V, Friberg A, Fontes-Oliveira CC, Durbeej M

Antioxidants (Basel). 2020 Mar 18;9(3). pii: E244. doi: 10.3390/antiox9030244.

Abstract

Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe neuromuscular disorder without a cure. Using transcriptome and proteome profiling as well as functional assays, we previously demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Reactive oxygen species (ROS) increase when oxygen homeostasis is not maintained and, here, we investigate whether oxidative stress indeed is involved in the pathogenesis of LAMA2-CMD. We also analyze the effects of two antioxidant molecules, N-acetyl-L-cysteine (NAC) and vitamin E, on disease progression in the dy^2J/dy^2J mouse model of LAMA2-CMD. We demonstrate increased ROS levels in LAMA2-CMD mouse and patient skeletal muscle. Furthermore, NAC treatment (150 mg/kg IP for 6 days/week for 3 weeks) led to muscle force loss prevention, reduced central nucleation and decreased the occurrence of apoptosis, inflammation, fibrosis and oxidative stress in LAMA2-CMD muscle. In addition, vitamin E (40 mg/kg oral gavage for 6 days/week for 2 weeks) improved morphological features and reduced inflammation and ROS levels in dy^2J/dy^2J skeletal muscle. We suggest that NAC and to some extent vitamin E might be potential future supportive treatments for LAMA2-CMD as they improve numerous pathological hallmarks of LAMA2-CMD.

Alberdi-Cedeño J, Ibargoitia ML, Guillén MD

Antioxidants (Basel). 2020 Mar 18;9(3). pii: E246. doi: 10.3390/antiox9030246.

Abstract

The aim of this study is the analysis of the in vitro digestion of corn oil, and of the effect of its enrichment with three levels of gamma– and alpha-tocopherol, by using, for the first time, ¹H nuclear magnetic resonance (¹H NMR) and a solid phase microextraction followed by gas chromatography/mass spectrometry (SPME-GC/MS). The attention is focused on the hydrolysis degree, the degradation of oil’s main components, the occurrence of oxidation reactions and main compounds formed, as well as on the bioaccessibility of oil’s main components, of compounds formed in the oxidation, and, of gamma– and alpha-tocopherol. The lipolysis levels reached are high and show a similar pattern in all cases. The oxidation of corn oil components during in vitro digestion is proven, as is the action of gamma-tocopherol as an antioxidant and alpha-tocopherol as a prooxidant. In the more alpha-tocopherol enriched samples, hydroperoxy-, hydroxy-, and keto-dienes, as well as keto-epoxy-monoenes and aldehydes, are generated. The bioaccessibility of the oil’s main components is high. The compounds formed in the oxidation process during in vitro digestion can also be considered bioaccessible. The bioaccessibility of alpha-tocopherol is smaller than that of gamma-tocopherol. The concentration of this latter compound remains unchanged during the in vitro digestion of the more alpha-tocopherol enriched oil samples.

Amarowicz R, Pegg RB

Curr Pharm Des. 2020 Mar 18. doi: 10.2174/1381612826666200318125620. [Epub ahead of print]

Abstract

Tree nuts and peanuts are healthful foods with a track record of helping to reduce the incidence of chronic diseases, most notably cardiovascular disease. At the point of consumption, all nuts contain low moisture and ≥ 50% lipid contents, but this is where similarities end. The levels of key nutrients and bioactives including vitamin C, vitamin E, L-arginine, minerals (such as selenium and zinc), and phenolics differ. Distinctions in the types and quantities of phenolic constituents for tree nut species as well as the impact of digestion will affect the nuts’ antioxidant potential in vivo. This chapter provides some insight into the different types of phenolics found in tree nuts and peanuts, the antioxidant potential of phenolic extracts using in vitro chemical assays, the effect of thermal processing on the stability of the nuts’ endogenous phenolics, and the impact on biomarkers of human health arising from randomized clinical trials. Key biomarkers include measures in the reduction of LDL oxidation as well as increases in the levels of vitamin E and selected phenolic compounds in blood plasma postprandially from those of baseline.

Zhang Z, Xiao W, Jia J, Chen Y, Zong C, Zhao L, Tian L

Oral Surg Oral Med Oral Pathol Oral Radiol. 2020 Mar;129(3):207-214. doi: 10.1016/j.oooo.2019.08.005. Epub 2019 Aug 29.

Abstract

OBJECTIVE:

The aim of this study was to evaluate the effect of combined application of pentoxifylline and vitamin E (PENTO) for the treatment of osteoradionecrosis of the jaws (ORNJ) by performing a meta-analysis.

STUDY DESIGN:

We searched for trials in 4 electronic databases (PubMed, Cochrane library, EMbase, and Web of Science) for studies that compared the effect of PENTO with those of other treatment methods. The range of exposed bone was chosen as the index to assess the effects of the different treatment methods. We performed the meta-analysis by using Review Manager 5.3.

RESULTS:

We identified 5 trials, which included 184 patients in the PENTO group and 180 patients in the “other treatment methods” (OTHER) group, and we performed a meta-analysis by using the random effect model. PENTO had a better effect compared with all the other treatment methods, and a statistically significant difference was noted (odds ratio [OR] = 4.54; 95% confidence interval [CI] 2.89-7.12; P < .01). PENTO was statistically different from antibiotics (OR = 7.02; 95% CI 1.33-37.01; P < .05) and hyperbaric oxygen therapy (OR = 20.06; 95% CI 1.74-230.78; P < .05) in terms of treatment effect. However, we could not confirm that PENTO was more effective than local surgery (OR = 6.50; 95% CI 0.80-53.09; P < .1).

CONCLUSIONS:

The results of this meta-analysis suggest that the application of PENTO for the treatment of ORNJ shows superior efficiency relative to the other treatment methods.

Mihajlovic M, Ivkovic B, Jancic-Stojanovic B, Zeljkovic A, Spasojevic-Kalimanovska V, Kotur-Stevuljevic J, Vujanovic D

Anticancer Drugs. 2020 Mar 16. doi: 10.1097/CAD.0000000000000924. [Epub ahead of print]

Abstract

Recent findings implied the significance of reactive oxygen species (ROS) as a part of tyrosine kinase inhibitors (TKIs) pharmacological activity. Evidences also suggested that toxic effects of TKIs were related to ROS production. The results regarding benefits of vitamin E usage alongside with prescribed TKIs therapy are ambiguous. We aimed to examine oxidative stress and antioxidative defense in human serum treated with four different TKIs and their possible interactions with hydrosoluble vitamin E analog (Trolox). An in-vitro experiment with serum pool as a substitute model was performed. Different parameters of oxidative stress and antioxidative defense were measured in serum pool with and without addition of TKIs (axitinib, crizotinib, nilotinib, and imatinib), before and after addition of Trolox. Z score statistic was used for calculation of Prooxidative and Antioxidative scores. The highest oxidative potential was recorded for samples incubated with imatinib and nilotinib, while the lowest damaging scores were observed for crizotinib and axitinib (nilotinib vs. imatinib, P < 0.05; axitinib vs. imatinib, P < 0.01; crizotinib vs. imatinib, P < 0.001). The best capability for antioxidative protection was seen in samples with nilotinib, then with imatinib, while the lowest level was obtained in samples with crizotinib and axitinib (imatinib and axitinib vs. nilotinib, P < 0.05 for both; crizotinib vs. nilotinib, P < 0.01; axitinib vs. imatinib, P < 0.05, crizotinib vs. imatinib, P < 0.01). Our results demonstrated the opposite effects of Trolox in combination with imatinib and nilotinib. Usage of antioxidant in combination with TKIs should be carefully evaluated in each specific case.

Tadokoro K, Ohta Y, Inufusa H, Loon AFN, Abe K

Int J Mol Sci. 2020 Mar 13;21(6). pii: E1974. doi: 10.3390/ijms21061974.

Abstract

Oxidative stress plays a crucial role in Alzheimer’s disease (AD) from its prodromal stage of mild cognitive impairment. There is an interplay between oxidative stress and the amyloid β (Aβ) cascade via various mechanisms including mitochondrial dysfunction, lipid peroxidation, protein oxidation, glycoxidation, deoxyribonucleotide acid damage, altered antioxidant defense, impaired amyloid clearance, inflammation and chronic cerebral hypoperfusion. Based on findings that indicate that oxidative stress plays a major role in AD, oxidative stress has been considered as a therapeutic target of AD. In spite of favorable preclinical study outcomes, previous antioxidative components, including a single antioxidative supplement such as vitamin C, vitamin E or their mixtures, did not clearly show any therapeutic effect on cognitive decline in AD. However, novel antioxidative supplements can be beneficial for AD patients. In this review, we summarize the interplay between oxidative stress and the Aβ cascade, and introduce novel antioxidative supplements expected to prevent cognitive decline in AD.

Bagheri Hosseinabadi M, Khanjani N, Atashi A, Norouzi P, Mirbadie SR, Mirzaii M

Mutat Res. 2020 Feb - Mar;850-851:503150. doi: 10.1016/j.mrgentox.2020.503150. Epub 2020 Feb 4.

Abstract

Extremely low frequency electromagnetic fields have been classified as a possible human carcinogen by the International Agency for Research on Cancer and this has raised some concern about its health effects on employees extensively exposed to these fields at thermal power plants. In this study, the effect of using vitamin E and C supplements have been examined on employees working at a thermal power plant. In this randomized controlled, double-blind clinical trial, 81 employees from different parts of the thermal power plant were enrolled between July and November 2017, and divided into four groups: Group 1 received vitamin E (400 units/day), Group 2: vitamin C (1000 mg/day), Group 3: vitamin E + C and Group 4: no intervention. DNA damage was measured in peripheral blood lymphocytes using comet assay and apoptosis, using flow cytometry. Based on the results, tail intensity and tail length in the vitamin E group, and all comet assay indices in the vitamin E + C and vitamin C groups (except DNA damage index) significantly decreased after the intervention, while the comet assay indices did not change significantly in the control group. None of the flow cytometry indices including early apoptosis, late apoptosis and necrosis changed after intervention in either group. The use of antioxidant vitamins such as E and C, can increase the activity of the non-enzymatic antioxidant defense system, and protect DNA from damage caused by exposure to extremely low frequency magnetic fields. But, taking these vitamins has no effect on apoptosis. It seems that consumption of vitamin E affected all investigated comet assay indices and can be probably considered as the best intervention.

Kumari K, Rai MP, Bansal N, Prashat GR, Kumari S, Srivathsa R, Dahuja A, Sachdev A, Praveen S, Vinutha T

3 Biotech. 2020 Mar;10(3):110. doi: 10.1007/s13205-020-2086-9. Epub 2020 Feb 11.

Abstract

Gamma-tocopherol methyltransferase (γ-TMT) converts γ-toc to α-toc-the rate limiting step in toc biosynthesis. Sequencing results revealed that the coding regions of γ-TMT1 and γ-TMT3 were strongly similar to each other (93% at amino acid level). Based on the differences in the N-terminal amino acids, Glycine max–γ-TMT proteins are categorized into three isoforms: γ-TMT1, 2 and 3. In silico structural analysis revealed the presence of chloroplast transit peptide (cTP) in γ-TMT1 and γ-TMT3 protein. However, other properties of transit peptide like presence of hydrophobic amino acids at the first three positions of N-terminal end and lower level of acidic amino acids were revealed only in γ-TMT3 protein. Subcellular localization of GFP fused γ-TMT1 and γ-TMT3 under 35S promoter was studied in Nicotiana benthamiana using confocal microscopy. Results showed that γ-TMT1 was found in the cytosol and γ-TMT3 was found to be localized both in cytosol and chloroplast. Further the presence γ-TMT3 in chloroplast was validated by quantifying α-tocopherol through UPLC. Thus the present study of cytosolic localization of the both γ-TMT1 and γ-TMT3 proteins and chloroplastic localization of γ-TMT3 will help to reveal the importance of γ-TMT encoded α-toc in protecting both chloroplastic and cell membrane from plant oxidative stress.

Medvedev VL, Mihailov IV, Rozenkranc AM, Efremov ME, Muratov KU, Budanov AA

Urologiia. 2020 Mar;(1):32-38.

Abstract

AIM:

to evaluate the efficiency of dietary supplements Renotinex for the complex treatment of patients with urinary stone disease who undergone to extracorporeal shock wave lithotripsy (ESWL).

MATERIALS AND METHODS:

a total of 60 patients with uncomplicated form of the urinary stone disease with the first stone episode (of size up to 1 cm) were evaluated. Patients were divided into two groups of 30 people and treated by ESWL. In the first group, patients additionally received Renotinex. In the second group, standard complex therapy (antispasmodics, analgesics, non-steroidal anti-inflammatory drugs) was prescribed. The urinary level of 2-microglobulin and serum level of tocopherol were considered as markers of damage and inflammation. Pain intensity was assessed using visual analogue scale. Follow-up studies were carried out on the 1st, 7th and 14th day of therapy. Duration of treatment and follow-up was 1 month. The average number of ESWL sessions was 2.6 in both groups.

RESULTS:

according to the study, it was established that components of Renotinex had antiseptic, antispasmodic, anti-inflammatory effects on the genitourinary system, enhancing renal blood flow and decreasing the permeability of the kidney capillaries. In addition, Renotinex has diuretic effect and nephroprotective effect, and improves renal function, alleviating aggressive therapeutic influence of ESWL. Antioxidant and nephroprotective effect are among the main mechanisms of action of Renotinex.

CONCLUSION:

In patients who received Renotinex as dietary supplements fragments after ESWL pass twice as fast, while in patients who did not receive Renotinex, there was more pronounced damage to the kidney parenchyma diagnosed by urine level of 2-microglobulin. The serum concentration of vitamin E increases, while taking Renotinex, which may prevent the peroxidation of polyunsaturated lipids in cell membranes and enhances the nephroprotective effect of Renotinex.