Explore the vast range of titles available.

Enzymes play key roles in different cellular processes, for example, in signal transduction, cell differentiation and proliferation, metabolic processes, DNA damage repair, apoptosis, and response to stress. A deregulation of enzymes has been considered one of the first causes of several diseases, including cancers. In the last several years, enzyme inhibitors, being good candidates as drugs in the pathogenic processes, have received an increasing amount of attention for their potential application in pharmacology. The marine environment is considered a challenging source of enzyme inhibitors for pharmacological applications. In this review, we report on secondary metabolites with enzyme inhibitory activity, focusing our attention on marine sponges and bacteria as promising sources. In the case of sponges, we only reported the kinase inhibitors, because this class was the most representative isolated so far from these marine organisms.

Background Fragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy. Design CONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS. Methods Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist–Community Edition FXS (ABC-C FXS ) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the FMR1 methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely. Results A total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the FMR1 promoter and full mutation of FMR1 . Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of FMR1 (nominal P  = 0.020). This group also achieved statistically significant improvements in Caregiver Global Impression‐Change in SA and isolation, irritable and disruptive behaviors, and social interactions (nominal P -values: P  = 0.038, P  = 0.028, and P  = 0.002). Similar results were seen in patients with 100% methylation of FMR1 . ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%). Conclusions In CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe. Trial registration The CONNECT-FX trial is registered on Clinicaltrials.gov (NCT03614663).

Multiple lines of evidence suggest a central role for the endocannabinoid system (ECS) in the neuronal development and cognitive function and in the pathogenesis of fragile X syndrome (FXS). This review describes the ECS, its role in the central nervous system, how it is dysregulated in FXS, and the potential role of cannabidiol as a treatment for FXS. FXS is caused by deficiency or absence of the fragile X messenger ribonucleoprotein 1 ( FMR1 ) protein, FMRP, typically due to the presence of >200 cytosine, guanine, guanine sequence repeats leading to methylation of the FMR1 gene promoter. The absence of FMRP, following FMR1 gene-silencing, disrupts ECS signaling, which has been implicated in FXS pathogenesis. The ECS facilitates synaptic homeostasis and plasticity through the cannabinoid receptor 1, CB 1 , on presynaptic terminals, resulting in feedback inhibition of neuronal signaling. ECS-mediated feedback inhibition and synaptic plasticity are thought to be disrupted in FXS, leading to overstimulation, desensitization, and internalization of presynaptic CB 1 receptors. Cannabidiol may help restore synaptic homeostasis by acting as a negative allosteric modulator of CB 1 , thereby attenuating the receptor overstimulation, desensitization, and internalization. Moreover, cannabidiol affects DNA methylation, serotonin 5HT 1A signal transduction, gamma-aminobutyric acid receptor signaling, and dopamine D 2 and D 3 receptor signaling, which may contribute to beneficial effects in patients with FXS. Consistent with these proposed mechanisms of action of cannabidiol in FXS, in the CONNECT-FX trial the transdermal cannabidiol gel, ZYN002, was associated with improvements in measures of social avoidance, irritability, and social interaction, particularly in patients who are most affected, showing ≥90% methylation of the FMR1 gene.

Morgana is a ubiquitous HSP90 co-chaperone protein coded by the CHORDC1 gene. Morgana heterozygous mice develop with age a myeloid malignancy resembling human atypical myeloid leukemia (aCML), now renamed MDS/MPN with neutrophilia. Patients affected by this pathology exhibit low Morgana levels in the bone marrow (BM), suggesting that Morgana downregulation plays a causative role in the human malignancy. A decrease in Morgana expression levels is also evident in the BM of a subgroup of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients showing resistance or an incomplete response to imatinib. Despite the relevance of these data, the mechanism through which Morgana expression is downregulated in patients’ bone marrow remains unclear. In this study, we investigated the possibility that Morgana expression is regulated by miRNAs and we demonstrated that Morgana is under the control of four miRNAs (miR-15a/b and miR-26a/b) and that miR-15a may account for Morgana downregulation in CML patients.

Objective: The aim of our study was to assess the effect of a short-term treatment with low-moderate corticosteroid (CS) doses by both a quantitative and qualitative assessment of chest HRCT of COVID-19 pneumonia. Methods: CORTICOVID is a single-center, cross-sectional, retrospective study involving severe/critical COVID-19 patients with mild/moderate ARDS. Lung total severity score was obtained according to Chung and colleagues. Moreover, the relative percentages of lung total severity score by ground glass opacities, consolidations, crazy paving, and linear bands were computed. Chest HRCT scores, P/F ratio, and laboratory parameters were evaluated before (pre-CS) and 7–10 days after (post-CS) methylprednisolone of 0.5–0.8 mg/kg/day. Findings: A total of 34 severe/critical COVID-19 patients were included in the study, of which 17 received Standard of Care (SoC) and 17 CS therapy in add-on. CS treatment disclosed a significant decrease in HRCT total severity score [median = 6 (IQR: 5–7.5) versus 10 (IQR: 9–13) in SoC, p < 0.001], as well in single consolidations [median = 0.33 (IQR: 0–0.92) versus 6.73 (IQR: 2.49–8.03) in SoC, p < 0.001] and crazy paving scores [mean = 0.19 (SD = 0.53) versus 1.79 (SD = 2.71) in SoC, p = 0.010], along with a significant increase in linear bands [mean = 2.56 (SD = 1.65) versus 0.97 (SD = 1.30) in SoC, p = 0.006]. GGO score instead did not significantly differ at the end of treatment between the two groups. Most post-CS GGO, however, derived from previous consolidations and crazy paving [median = 1.5 (0.35–3.81) versus 2 (1.25–3.8) pre-CS; p = 0.579], while pre-CS GGO significantly decreased after methylprednisolone therapy [median = 0.66 (0.05–1.33) versus 1.5 (0.35–3.81) pre-CS; p = 0.004]. CS therapy further determined a significant improvement in P/F levels [median P/F = 310 (IQR: 235.5–370) versus 136 (IQR: 98.5–211.75) in SoC; p < 0.001], and a significant increase in white blood cells, lymphocytes, and neutrophils absolute values. Conclusion: The improvement of all chest HRCT findings further supports the role of CS adjunctive therapy in severe/critical COVID-19 pneumonia.

Maternal mRNAs are synthesized during oogenesis to initiate the development of future generations. Some maternal mRNAs are determinants of somatic or germline fate and must be translationally repressed until embryogenesis. However, the translational repressors themselves are also temporally regulated. We use polar granule component (pgc), a Drosophila maternal mRNA, as a model system to ask how maternal mRNAs are repressed while the regulatory landscape is continually shifting. pgc, a potent transcriptional silencer and germline determinant, is translationally regulated throughout oogenesis. We find the 3 UTR of pgc mRNA contains a conserved ten-nucleotide sequence that is bound by different conserved RNA binding proteins (RBPs) at different stages of oogenesis to continuously repress translation except for a brief expression in the stem cell daughter. Pumilio (Pum) binds to this sequence in undifferentiated and early differentiating oocytes and recruits other temporally restricted translational regulators to block pgc translation. After differentiation, Pum levels diminish and Bruno (Bru) levels increase, allowing Bru to bind the same 3 UTR sequence and take over translational repression of pgc mRNA. We have identified a class of maternal mRNAs regulated during oogenesis by both Pum and Bru, including Zelda, activator of the zygotic genome, that contain this core 10-nt regulatory sequence. Our data suggests that this hand off mechanism is more generally utilized to inhibit translation of maternal mRNAs during oogenesis.

Maternal mRNAs are synthesized during oogenesis to initiate the development of future generations. Some maternal mRNAs are determinants of somatic or germline fate and must be translationally repressed until embryogenesis. However, the translational repressors themselves are also temporally regulated. We use polar granule component (pgc), a Drosophila maternal mRNA, as a model system to ask how maternal mRNAs are repressed while the regulatory landscape is continually shifting. pgc, a potent transcriptional silencer and germline determinant, is translationally regulated throughout oogenesis. We find that the 3’UTR of pgc mRNA contains a conserved ten-nucleotide sequence that is bound by different conserved RNA binding proteins (RBPs) at different stages of oogenesis to continuously repress translation except for a brief expression in the stem cell daughter. Pumilio (Pum) binds to this sequence in undifferentiated and early differentiating oocytes and recruits other temporally restricted translational regulators to block pgc translation. After differentiation, Pum levels diminish and Bruno (Bru) levels increase, allowing Bru to bind the same 3’UTR sequence and take over translational repression of pgc mRNA. We have identified a class of maternal mRNAs regulated during oogenesis by both Pum and Bru, including Zelda, activator of the zygotic genome, which contain this core 10-nt regulatory sequence. Our data suggests that this hand off mechanism is more generally utilized to inhibit translation of maternal mRNAs during oogenesis.