Virgin coconut oil abrogates depression-associated cognitive deficits by modulating hippocampal antioxidant balance, GABAergic and glutamatergic receptors in mice

Objectives GABA and glutamate neurotransmission play critical roles in both the neurobiology of depression and cognition; and Virgin coconut oil (VCO) is reported to support brain health. The present study investigated the effect of VCO on depression-associated cognitive deficits in mice. Methods Thirty male mice divided into five groups were either exposed to chronic unpredicted mild stress (CUMS) protocol for 28 days or pre-treated with 3 mL/kg b. wt. of VCO for 21 days or post-treated with 3 mL/kg b. wt. of VCO for 21 days following 28 days of CUMS exposure. Mice were subjected to behavioural assessments for depressive-like behaviours and short-term memory, and thereafter euthanised. Hippocampal tissue was dissected from the harvested whole brain for biochemical and immunohistochemical evaluations. Results Our results showed that CUMS exposure produced depressive-like behaviours, cognitive deficits and altered hippocampal redox balance. However, treatment with VCO abrogated depression-associated cognitive impairment, and enhanced hippocampal antioxidant concentration. Furthermore, immunohistochemical evaluation revealed significant improvement in GABAA and mGluR1a immunoreactivity following treatment with VCO in the depressed mice. Conclusions Therefore, findings from this study support the dietary application of VCO to enhance neural resilience in patients with depression and related disorders.

Cnestis ferruginea Vahl ex DC (Connaraceae) downregulates expression of immediate early genes in kainic acid-induced temporal lobe epilepsy in mice

Objectives This study investigates the influence of Cnestis ferruginea (CF) on kainic acid (KA)-induced immediate early genes (IEGs) associated with hippocampal sclerosis in temporal lobe epilepsy (TLE) in mice. Methods Animals were randomly divided into preventive treatment; vehicle (10 mL/kg, p.o.) or CF (400 mg/kg, p.o.) for three consecutive days before KA (5 mg/kg, i.p.) on days 4 and 5. In the reversal model, KA (5 mg/kg, i.p.) was administered on days 1 and 2 before CF (400 mg/kg) administration on days 3–5. Animals were euthanized on day 5, 6 h after KA exposure in preventive model and 1 h after CF administration in reversal model to estimate markers of IEGs. Results KA upregulated the expression of c-Fos protein by 3.32-, 9.45-, 8.13-, and 8.66-fold in the hippocampal CA1, CA2, CA3, and DG regions, respectively. Also, KA elevated inducible nitric oxide synthase protein expression by 10.9-, 10.6-, 9.78-, and 9.51-fold. Besides, mRNA expression of brain-derived neurotrophic factors and heat shock protein was increased by 2.38- and 1.39-fold, respectively, after exposure to KA which were attenuated by CF. Conclusions CF attenuated KA-induced IEGs and could be used as an adjunct in TLE.

Prevalence of ABCB1 3435C>T polymorphism in the Cuban population

Objectives ABCB1 gene polymorphisms can modify P-glycoprotein function with clinical consequences. Methods The 3435C>T polymorphism prevalence was analyzed using oligonucleotide probes and next-generation sequencing in 421 unrelated healthy individuals living in Cuba. Data were stratified by gender, ethnic background and residence. The genotype and allelic frequencies were determined. Results The genotype distribution met the Hardy–Weinberg equilibrium assumption. The allelic frequency was 63.5% for the 3435C variant. The genotype frequencies were 41.1% for CC, 44.9% for CT and 14.0% for TT. The allele and genotype distributions differed between individuals living in La Habana and Santiago de Cuba (p<0.05) when ethnic background was analyzed. The allelic distribution was similar among Admixed and Black subjects, and they differed from Caucasians. The CC genotype was equally distributed among Admixed and Black subjects, and they differed from Caucasians. The TT genotype frequency differed between Caucasians and Admixed. The CT genotype was distributed differently among the three groups. Similar distribution was obtained in Brazilians, whereas some similarities were observed in African, Spanish and Chinese populations, consistent with the mixed Cuban ethnic origin. Conclusions This is the first report on allele and genotype frequencies of the 3435C>T polymorphism in Cuba, which may support personalized medicine programs.

Modifying effects of TNF-α, IL-6 and VDR genes on the development risk and the course of COVID-19. Pilot study

Objectives COVID-19 continues to range around the world and set morbidity and mortality antirecords. Determining the role of genetic factors in the development of COVID-19 may contribute to the understanding of the pathogenetic mechanisms that lead to the development of complications and fatalities in this disease. The aim of our study was to analyze the effect of TNF-α (rs1800629), IL-6 (rs1800795) and VDR (rs731236 and rs1544410) genes variants on the development risk and the course of COVID-19 in intensive care patients. Methods The study group included 31 patients with diagnosis “viral COVID-19 pneumonia”. All patients underwent standard daily repeated clinical, instrumental and laboratory examinations. Determination of IL-6, TNF-α, and VDR genes variants was performed using the PCR-RFLP method. Results It was found a significant increase in the rate of the CC genotype and C allele (38.7 vs. 12.0% and 0.6 vs. 0.4%, respectively) of the IL-6 gene in all patients of the study in comparison with population frequencies. There was a significantly higher rate of heterozygous genotypes TC and GA of the VDR gene in group of died patients. The rs1800629 variant of the TNF-α gene is associated with the need for respiratory support and its longer duration in patients with COVID-19. Conclusions The obtained results support a hypothesis about the influence of variants of IL-6, TNF-α and VDR genes on severity of COVID-19. However, in order to draw definite conclusions, further multifaceted research in this area are need.

Predicting drug–drug interactions by electrochemically driven cytochrome P450 3A4 reactions

Objectives Human cytochrome P450 3A4 is the most abundant hepatic and intestinal Phase I enzyme that metabolizes approximately 60% marketed drugs. Simultaneous administration of several drugs may result in appearance of drug–drug interaction. Due to the great interest in the combination therapy, the exploration of the role of drug as “perpetrator” or “victim” is important task in pharmacology. In this work the model systems based on electrochemically driven cytochrome P450 3A4 for the analysis of drug combinations was used. We have shown that the analysis of electrochemical parameters of cytochrome P450 3A4 and especially, potential of the start of catalysis, Eonset, possess predictive properties in the determination of the leading (“perpetrator”) properties of drug. Based on these experimental data, we concluded, that the more positive potential of the start of catalysis, Eonset, the more pronounced the role of drug as leading medication. Methods Electrochemically driven cytochrome P450 3A4 was used as probe and measuring tool for the estimation of the role of interacting drugs. Results It is shown that the electrochemical non-invasive model systems for monitoring the catalytic activity of cytochrome P450 3A4 can be used as prognostic devise in assessment of drug/drug interacting medications. Conclusions Cytochrome P450 3A4 activity was studied in electrochemically driven system. Method was implemented to monitor drug/drug interactions. Based on the obtained experimental data, we can conclude that electrochemical parameter such as potential of onset of catalysis, Eonset, has predictive efficiency in assessment of drug/drug interacting medications in the case of the co-administration.

Comparison of different autoanalyzers for the determination of lymphocyte and neutrophil counts in mouse blood

Objectives Autoanalyzers are used in clinical haematology for analysis of blood samples in clinical as well as in nonclinical studies. The results from these analyzers vary from machine to machine. In this study, we compared the lymphocyte and neutrophil count of mouse blood between ADVIA 2120i, Horiba Yumizen H2500 and CellaVision analyzers against manual counting as gold standard. Methods Blood samples from 28 female BALB/c mice were collected and analyzed. Agreement between different autoanalyzers and manual counting were determined by Bland–Altman method. Results A high level of agreement was found between CellaVision and manual technique for lymphocyte (Bias=4.75, 95% limits of agreement −14 to 24) and neutrophil count (Bias=0.68 (−17 to 19)). Agreement in lymphocyte count was also observed between ADVIA and manual counting, but to a lesser extent compared to CellaVision (Bias=13.9 (−10.45 to 38.27)). However, no agreement was observed for ADVIA (Neutrophils), Horiba (lymphocytes and neutrophils) with manual counting. Conclusions Our data suggests that CellaVision could be used for the differential counting of neutrophil and lymphocytes in mouse blood sample.

Influence of GSTM1, GSTT1, and GSTP1 genetic polymorphisms on disorders in transplant patients: a systematic review

The glutathione-S-transferase (GST) enzymes are phase II isoenzymes responsible for protection against free radicals and xenobiotics. Since these proteins are described as polymorphic, polymorphisms in genes that encode them may alter enzymatic function and contribute to oxidative stress. In this context, such polymorphisms were already associated with several diseases and multiple therapeutic outcomes. A systematic review was performed to evaluate studies regarding the association between polymorphisms in three genes encoding enzymes of the GST family – GSTM1, GSTT1, and GSTP1 – and disorders in transplant patients. A total of 125 articles on which inclusion and exclusion criteria were applied were identified at PubMed database. Thirty-two studies met the target criteria and were included in the review. The mechanisms by which GST genotypes influence the development of disorders in transplant patients differ by disorder: they may participate in it by decreasing metabolism of drugs administered to patients undergoing transplantation, then exposing them to greater toxicity; by decreasing the repair ability against oxidative stress; or by encoding proteins that may be recognized as foreign, setting of an alloimmune reaction. Although some results are better established – such as GSTM1 null genotype’s role in the development of toxicity events in transplant patients – others require further evidences, as GST influence on the development of pulmonary decline and posttransplant diabetes mellitus (PTDM). The importance of investigating these associations lies in a personalized medicine, in which the high-risk genotype patient has its treatment individualized and its care for prophylaxis and surveillance increased, potentially reducing this population’s morbimortality.

Genotype-based chemotherapy for patients with gastrointestinal tumors: focus on oxaliplatin, irinotecan, and fluoropyrimidines

This review aimed to summarize the pharmacogenetic studies of the most commonly used drugs in the chemotherapy of gastrointestinal (GI) tumors: oxaliplatin, irinotecan, and fluoropyrimidines. So far, it has not been possible to develop an effective genotype-based approach for oxaliplatin. More and more evidence is emerging in favor of the fact that the choice of a dose of fluorouracil based on pharmacogenetic testing according to DPYD*2A, can be not only effective but also cost-effective. Additional, well-planned trials of the UGT1A1 genotype-based approach to irinotecan therapy are predicted to reduce adverse drug events in people with the UGT1A1*28/*28 genotypes and improve treatment efficacy in the rest of the patients, which might be cost-effective.

The association of cytochrome 7A1 and ATP-binding cassette G8 genotypes with type 2 diabetes among Jordanian patients

Objectives Increased cholesterol levels were found to be associated with diabetes mellitus type II (DM2). The cholesterol is metabolized by cytochrome 7A1 (CYP7A1) and transported in the intestine by ATP-binding cassette G8 (ABCG8). Genetic variants in CYP7A1 and ABCG8 genes can affect the cholesterol levels. The aim of this study is to compare the frequency of CYP7A1 rs3808607 and ABCG8 rs11887534 and rs4148217 genotypes between healthy and DM2 subjects from Jordanian population. Methods A total of 117 DM2 patients and 100 healthy controls, of Jordanian Arabic origin, were genotyped for CYP7A1 rs3808607 and ABCG8 rs11887534 and rs4148217 genetic variants using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism technique. Results The study showed that homozygosity of rs3808607 (A-204C) genotype in CYP7A1 was significantly higher in DM2 patients (ANOVA, p<0.05) with an odd ratio of 2.66, but rs11887534 (G55C) and rs4148217 (C1199A) genetic polymorphisms in ABCG8 were found in comparable frequencies in both healthy and DM2 subjects. Conclusions The results of this study indicate that CYP7A1 rs3808607 genetic polymorphism is associated with DM2. Further clinical studies are required to confirm this finding among DM2 patients of Jordanian origin.

Study of the pharmacokinetics of various drugs under conditions of antiorthostatic hypokinesia and the pharmacokinetics of acetaminophen under long-term spaceflight conditions

Objectives To study the pharmacokinetics and relative bioavailability of drugs of different chemical structure and pharmacological action under conditions simulating the effects of some factors of spaceflight, as well as the peculiarities of the pharmacokinetics of acetaminophen under long-term spaceflight conditions. Methods The pharmacokinetics of verapamil (n=8), propranolol (n=8), etacizine (n=9), furosemide (n=6), and acetaminophen (n=7) in healthy volunteers after a single oral administration under normal conditions (background) and under antiorthostatic hypokinesia (ANOH), the pharmacokinetics of acetaminophen in spaceflight members under normal ground conditions (background) (n=8) and under prolonged spaceflight conditions (SF) (n=5) were studied. Results The stay of volunteers under antiorthostatic hypokinesia had different effects on the pharmacokinetics and bioavailability of drugs: Compared to background, there was a decreasing trend in Vz for verapamil (−54 Δ%), furosemide (−20 Δ%), propranolol (−8 Δ%), and acetaminophen (−9 Δ%), but a statistically significant increase in Vz was found for etacizine (+39 Δ%); there was an increasing trend in Clt for propranolol (+13 Δ%) and acetaminophen (+16 Δ%), and a decreasing trend in Clt for etacizine, verapamil, and furosemide (−22, −23 and −9 Δ% respectively) in ANOH. The relative bioavailability of etacizine, verapamil, and furosemide in ANOH increased compared to background (+40, +23 and +13 Δ%, respectively), propranolol and acetaminophen decreased (−5 and −12 Δ% accordingly). The relative rate of absorption of etacizine and furosemide in ANOH decreased (−19 and −20 Δ%, respectively) while that of verapamil, propranolol, and acetaminophen increased (+42, +58 and +26 Δ%, respectively). A statistically significant decrease in AUC0-∞ (−57 Δ%), Cmax (−53 Δ%), relative bioavailability of acetaminophen (−52 Δ%) and a sharp increase in Clt (+147 Δ%), Tmax (+131 Δ%) as well as a trend towards a significant decrease in T1/2 (−53 Δ%), MRT (−36 Δ%) and a moderate increase in Vz (+24 Δ%) were found under control compared to background. Unidirectional changes in AUC0-∞, Clt, T1/2, MRT and relative bioavailability of acetaminophen, which are more pronounced in SF and opposite dynamics for Cmax, Tmax, Vz were found in ANOH and SP compared to background studies. Conclusions The data obtained allow recommending the studied drugs for rational pharmacotherapy in the possible development of cardiovascular disease in manned spaceflight.