Unraveling the molecular basis of cannabidiolic acid methyl Ester's anti-depressive effects in a rat model of treatment-resistant depression.

Major depressive disorder (MDD) stands as a significant cause of disability globally. Cannabidiolic Acid-Methyl Ester (CBDA-ME) (EPM-301, HU-580), a derivative of Cannabidiol, demonstrates immediate antidepressant-like effects, yet it has undergone only minimal evaluation in psychopharmacology. Our goal was to investigate the behavioral and potential molecular mechanisms associated with the chronic oral administration of this compound in the Wistar Kyoto (WKY) genetic model of treatment-resistant depression. Male WKY rats were subjected to behavioral assessments before and after receiving chronic (14-day) oral doses of CBDA-ME (0.5 mg/kg), 15 mg/kg of imipramine or vehicle. At the end of the study, plasma corticosterone levels and mRNA expression of various genes in the medial Prefrontal Cortex and Hippocampus were measured. Behavioral outcomes from CBDA-ME treatment indicated an antidepressant-like effect similar to imipramine, as oral ingestion reduced immobility and increased swimming duration in the Forced Swim Test. Neither treatment influenced locomotion in the Open Field Test nor preference in the Saccharin Preference Test. The behavioral impact in WKY rats coincided with reduced corticosterone serum levels, upregulated mRNA expression of Cannabinoid receptor 1, Fatty Acid Amide Hydrolase, and Corticotropin-Releasing Hormone Receptor 1, alongside downregulation of the Serotonin Transporter in the hippocampus. Additionally, there was an upregulation of CB1 mRNA expression and downregulation of Brain-Derived Neurotrophic Factor in the mPFC. These findings contribute to our limited understanding of the antidepressant effects of CBDA-ME and shed light on its potential psychopharmacological mechanisms. This discovery opens up possibilities for utilizing cannabinoids in the treatment of major depressive disorder and related conditions.

Karyotype variation in cultivars and spontaneous cocoa mutants (Theobroma cacao L.).

Four mutant cocoa accessions with morphological changes and a cultivar sample were karyomorphologically characterized. Slides were prepared by enzymatic digestion of the root meristem and squashed in 45% acetic acid, followed by 2% Giemsa staining. The chromosome number of 2n = 20 was seen in all accessions. The karyotype formula for Cacau Comum and Cacau Rui was 2n = 20m. Submetacentric chromosomes were observed in Cacau Pucala and Cacau Jaca, both with 2n = 18m + 2sm, but the karyotype formula for Cacau Sem Vidro was 2n = 16m + 4sm. Satellites were located on the long arm of the 1st and 2nd chromosome pairs of Cacau Comum, whereas Cacau Pucala had satellites on the 6th chromosome pair. Greater karyotypic variation in Cacau Sem Vidro was found, whose 1st and 2nd chromosome pairs had satellites on the long arm and 6th and 10th pairs had satellites on the short arm. Analysis revealed a lower average chromosome length in Cacau Comum (1.53 ± 0.026 µm) and a higher length in Cacau Sem Vidro (2.26 ± 0.038 µm). ANOVA revealed significant difference (P < 0.01) for the average chromosome length and the length of chromosome pairs within and between accessions. The average chromosome lengths of mutants of Cacau Rui and Cacau Jaca were not statistically different by the Tukey test at 5% probability. The karyotypic diversity observed in this study is not necessarily associated with the changing character of the accessions analyzed, but may reflect the genetic variation observed in Theobroma cacao.

A novel syndrome of abnormal striatum and congenital cataract: evidence for linkage to chromosomes 11.

We report a consanguineous family of three girls and one boy affected with a novel syndrome involving the lens and the basal ganglia. The phenotype is strikingly similar between affected siblings with cognitive impairment, attention deficit hyperactivity disorder (ADHD), microcephaly, growth retardation, congenital cataract, and dystonia. The magnetic resonance imaging showed unusual pattern of swelling of the caudate heads and thinning of the putamina with severe degree of hypometabolism on the [18F] deoxyglucose positron emission tomography. Furthermore, the clinical assessment provides the evidence that the neurological phenotype is very slowly progressive. We utilized the 10K single-nucleotide polymorphism (SNP) microarray genotyping for linkage analysis. Genome-wide scan indicated a 45.9-Mb region with a 4.2353 logarithm of the odds score on chromosome 11. Affymetrix genome-wide human SNP array 6.0 assay did not show any gross chromosomal abnormality. Targeted sequencing of two candidate genes within the linkage interval (PAX6 and B3GALTL) as well as mtDNA genome sequencing did not reveal any putative mutations.

Novel intragenic deletion in OPHN1 in a family causing XLMR with cerebellar hypoplasia and distinctive facial appearance.

X-linked mental retardation (XLMR) is notably a heterogeneous condition and often poses a diagnostic challenge. The oligophrenin 1 gene (OPHN1) is a protein with a Rho-GTPase-activating domain required in the regulation of the G-protein cycle. Mutations in the OPHN1 cause XLMR with cerebellar hypoplasia and distinctive facial appearance. We report a large Saudi family of four boys and one girl affected with XLMR. The boys had moderate MR, seizure disorder, facial dysmorphism, and cerebellar vermis hypoplasia. The girl had mild MR, seizures, and mild cerebellar hypoplasia. A novel deletion of at least exons 7-15 was identified by polymerase chain reaction analysis and multiple ligation probe amplification of the OPHN1 gene. The array comparative genomic hybridization further delineated approximately 68 kb deletion of the 7-15 exons and nearly half of intron 15. In addition, the X-inactivation confirmed random pattern in the girl. Although the affected boys have remarkably similar phenotype, there was some variability in the severity of the seizure disorder and the cerebellar hypoplasia. The report confirms the previous findings that carrier females may be symptomatic.

Clinical, biochemical and molecular characterization of peroxisomal diseases in Arabs.

Peroxisomes are single membrane-bound cellular organelles that carry out critical metabolic reactions perturbation of which leads to an array of clinical phenotypes known as peroxisomal disorders (PD). In this study, the largest of its kind in the Middle East, we sought to comprehensively characterize these rare disorders at the clinical, biochemical and molecular levels. Over a 2-year period, we have enrolled 17 patients representing 16 Arab families. Zellweger-spectrum phenotype was observed in 12 patients and the remaining 5 had the rhizomelic chondrodysplasia punctata phenotype. We show that homozygosity mapping is a cost-effective strategy that enabled the identification of the underlying genetic defect in 100% of the cases. The pathogenic nature of the mutations identified was confirmed by immunofluorescence and complementation assays. We confirm the genetic heterogeneity of PD in our population, expand the pool of pathogenic alleles and draw some phenotype/genotype correlations.

Single nucleotide polymorphisms from Theobroma cacao expressed sequence tags associated with witches' broom disease in cacao.

In order to increase the efficiency of cacao tree resistance to witches' broom disease, which is caused by Moniliophthora perniciosa (Tricholomataceae), we looked for molecular markers that could help in the selection of resistant cacao genotypes. Among the different markers useful for developing marker-assisted selection, single nucleotide polymorphisms (SNPs) constitute the most common type of sequence difference between alleles and can be easily detected by in silico analysis from expressed sequence tag libraries. We report the first detection and analysis of SNPs from cacao-M. perniciosa interaction expressed sequence tags, using bioinformatics. Selection based on analysis of these SNPs should be useful for developing cacao varieties resistant to this devastating disease.

Development of liver disease despite mannose treatment in two patients with CDG-Ib.

We report here the 6- and 2-year follow-up of two patients diagnosed at 2 months of age with CDG-Ib who were treated with mannose, with digestive symptoms, liver involvement and hyperinsulinemic hypoglycaemia. Both developed liver fibrosis while general condition improved and other symptoms disappeared.

Lipid clearing in premature infants during continuous heparin infusion: role of circulating lipases.

The nature of the lipases released into the circulation during low level continuous infusion of heparin (1 unit/ml total parenteral nutrition) and after bolus heparin injection (10 units/kg) was investigated in a group of 11 low birth weight infants (gestational age 27-34 wk, and postnatal age of 7-26 days) receiving total parenteral nutrition with Intralipid (0.5 g/kg). Hepatic lipase and extra-hepatic lipoprotein lipase were differentiated with the aid of an antibody specific for human hepatic lipase. The data show that continuous low level heparin infusion leads to a constant baseline postheparin lipolytic activity of 0.77 +/- 0.18 mumol free fatty acids released per milliliter serum per hour. Bolus heparin injection leads to peak lipolytic activity levels of 3.77 +/- 0.46 mumol free fatty acids per milliliter serum per hour, 10 min after injection. About two-thirds of the total postheparin lipolytic activity was of the hepatic type during low level continuous infusion or after bolus injection of heparin.

Effect of heparin on serum and tissue lipases in the developing rat.

The frequent inclusion of heparin in fluids used for total parenteral nutrition in infants, prompted an investigation of the ability of heparin to release lipoprotein lipase (LPL) and hepatic lipase (HL) from the endothelial surface into the circulation, and of the effect of heparin on tissue stores of lipase in the postnatal period. In rat pups, plasma postheparin lipolytic activity (PHLA) released by IP administration of heparin (0.5 unit/g body wt) was 15% of adult values at birth and increased rapidly to reach 60% on day 10. Repeated doses of heparin (in adult rats, given 0.1 unit/g IV) at 1 and 4 h after the initial dose did not affect the maximal response to heparin. In all age groups 80% of PHLA was inhibited by 0.5 M NaCl, suggesting a mostly nonhepatic origin for the released enzyme. Heart, lung, and liver lipase activities of rat pups were not significantly different from controls not given heparin. The pattern of change in tissue enzyme content was similar for heart and lung, but different from hepatic lipase. LPL activity in the former increased from 10 and 30% to 60 and 100% of adult values between birth and 10 days while in the latter enzyme activity exceeded adult levels at birth and decreased to 50% of adult values during the latter half of the suckling period (days 10-21). Our results demonstrate that heparin does not cause depletion of tissue lipases in the postnatal period. The parallel increases in LPL content of peripheral tissues and PHLA suggest that in all age groups heparin-induced release of LPL into the circulation is proportional to tissue lipolytic activity.