(S)-5-Methylmellein Isolated from an Endogenous Lichen Fungus Rosellinia corticium as a Potent Inhibitor of Human Monoamine Oxidase A

In this study, the inhibitory activities against human monoamine oxidases (hMAOs) were evaluated using a library of 195 endogenous lichen fungi from Ukraine. Among them, the extract ELF68 of the endogenous fungus Rosellinia corticium from the lichen Pseudevernia furfuracea (L.) Zopf. exhibited the strongest inhibitory activity against hMAO-A. Using the activity-guided method, (S)-5-methylmellein (5MM) was isolated from the extract and had an IC50 value of 5.31 µM for hMAO-A with a lower potency for hMAO-B (IC50 = 9.15 µM). Compound 5MM also moderately inhibited acetylcholinesterase (IC50 = 27.07 µM) but very weakly inhibited butyrylcholinesterase and β-secretase. Compound 5MM had a Ki value of 2.45 μM and was a reversible competitive inhibitor of hMAO-A. A molecular docking study predicted that (S)-5MM showed higher binding affinity for hMAO-A (−6.8 kcal/mol) than hMAO-B (−6.4 kcal/mol). Its isomer, (R)-5MM, exhibited lower binding affinities for hMAO-A (−6.6 kcal/mol) and hMAO-B (−5.2 kcal/mol), compared to (S)-5MM. The S-form interacted with hMAO-A through hydrogen bonding with the Phe208 residue (distance: 1.972 Å), while the R-form interacted with the Asn181 residue (2.375 Å). The results of an in silico pharmacokinetic analysis indicated that 5MM did not violate Lipinski’s five rules and showed high gastrointestinal absorption and blood–brain barrier permeability. These results suggest that 5MM can be considered a candidate in the treatment of neuropsychiatric disorders, such as depression and cardiovascular disease.

Long-term effectiveness and safety of endoxifen in the treatment of bipolar mania: a case report

Bipolar disorder (BD) displays abnormalities in protein kinase C (PKC) signaling, and evidence suggests that inhibiting PKC may help treat mania. Endoxifen a potent inhibitor of the PKC signaling pathway, is effective in controlling acute bipolar mania, at doses of 8 mg OD, for a period of 3-weeks. Here we present the case of a patient with severe mania, increased alcohol consumption administered endoxifen 8 mg BID for a period of 3-months, to achieve a better response. High-dose, long-term treatment with endoxifen was efficacious in controlling manic symptoms, with no adverse effects. Additionally, the patient didn’t consume alcohol during the course of treatment. This case showed the long-term effectiveness and safety of high-dose endoxifen to control mania in a patient with BD.

Biological Role of Vitamin K—With Particular Emphasis on Cardiovascular and Renal Aspects

Vitamin K (VK) plays many important functions in the body. The most important of them include the contribution in calcium homeostasis and anticoagulation. Vascular calcification (VC) is one of the most important mechanisms of renal pathology. The most potent inhibitor of this process—matrix Gla protein (MGP) is VK-dependent. Chronic kidney disease (CKD) patients, both non-dialysed and hemodialysed, often have VK deficiency. Elevated uncarboxylated matrix Gla protein (ucMGP) levels indirectly reflected VK deficiency and are associated with a higher risk of cardiovascular events in these patients. It has been suggested that VK intake may reduce the VC and related cardiovascular risk. Vitamin K intake has been suggested to reduce VC and the associated cardiovascular risk. The role and possibility of VK supplementation as well as the impact of anticoagulation therapy on VK deficiency in CKD patients is discussed.

Lactoferrin-Functionalized Noble Metal Nanoparticles as New Antivirals for HSV-2 Infection

(1) Background: Lactoferrin has been recognized as a potent inhibitor of human herpetic viruses, such as herpes simplex type 1 (HSV-1) and 2 (HSV-2). In this work, we tested if silver and gold nanoparticles modified with lactoferrin (LF-Ag/AuNPs) can become novel microbicides with additional adjuvant properties to treat genital herpes infection. (2) Methods: The antiviral and cytotoxic activities of LF-Ag/AuNPs were tested in human skin HaCaT and vaginal VK-2-E6/E7 keratinocytes. Viral titers and immune responses after treatment with LF-Ag/AuNPs were tested in murine vaginal HSV-2 infection. (3) Results: LF-Ag/AuNPs inhibited attachment and entry of HSV-2 in human keratinocytes much better than lactoferrin. Furthermore, pretreatment with LF-AgNPs led to protection from infection. Infected mice treated intravaginally with LF-Ag/AuNPs showed lower virus titers in the vaginal tissues and spinal cords in comparison to treatment with lactoferrin. Following treatment, vaginal tissues showed a significant increase in CD8+/granzyme B + T cells, NK cells and dendritic cells in comparison to NaCl-treated group. LF-Ag/AuNPs-treated animals also showed significantly better expression of IFN-γ, CXCL9, CXCL10, and IL-1β in the vaginal tissues. (4) Conclusions: Our findings show that LF-Ag/AuNPs could become effective novel antiviral microbicides with immune-stimulant properties to be applied upon the mucosal tissues.

TM2D genes regulate Notch signaling and neuronal function in Drosophila

TM2 domain containing (TM2D) proteins are conserved in metazoans and encoded by three separate genes in each model organism species that has been sequenced. Rare variants in TM2D3 are associated with Alzheimer’s disease (AD) and its fly ortholog almondex is required for embryonic Notch signaling. However, the functions of this gene family remain elusive. We knocked-out all three TM2D genes (almondex, CG11103/amaretto, CG10795/biscotti) in Drosophila and found that they share the same maternal-effect neurogenic defect. Triple null animals are not phenotypically worse than single nulls, suggesting these genes function together. Overexpression of the most conserved region of the TM2D proteins acts as a potent inhibitor of Notch signaling at the γ-secretase cleavage step. Lastly, Almondex is detected in the brain and its loss causes shortened lifespan accompanied by progressive motor and electrophysiological defects. The functional links between all three TM2D genes are likely to be evolutionarily conserved, suggesting that this entire gene family may be involved in AD.

CRCM5484: A BET- BDII Selective Compound With Differential Anti-Leukemic Drug Potentiation

Differentially screening the Fr-PPIChem chemical library on the BET BRD4-BDII versus -BDI bromodomains led to the discovery of a BDII selective tetrahydropyridothienopyrimidinone (THPTP)-based compound. Structure-activity relationship (SAR) and hit-to-lead approaches allowed us to develop CRCM5484, a highly potent inhibitor of BET proteins with a preferential and 475-fold selectivity for the second bromodomain of the BRD3 protein (BRD3-BDII) over its first bromodomain (BRD3-BDI). Its very low activity was demonstrated in various cell-based assays, corresponding with recent data describing other selective BDII compounds. However, screening on a drug sensitivity and resistance-profiling platform revealed its ability to potentiate the antileukemic activity in combination with various FDA-approved and/or in-development drugs in a cell- and context-dependent differential manner. Altogether, the results confirm the originality of the THPTP molecular mode of action in the BD cavity and its potential as chemical platform for the development of potent and selective bromodomain inhibitors.

Chemical and thermal profile of Plectranthus amboinicus essential oil for its application as a bioherbicide

The species Plectranthus amboinicus is an aromatic herb with great application in popular medicine due to the diversity of biological properties. Chemically, its essential oil (EO) is characterized by two chemotypes, thymol and carvacrol, which vary depending on factors such as seasonality. Despite being an extensively exploited species, studies of the bioherbicidal potential of this species are insufficient. In this context, the EO of P. amboinicus leaves, extracted in two different seasonal periods, were characterized regarding chemical profile (by gas chromatography mass spectrometry - GC-MS) and thermal profile (DTG) and was subjected to bioherbicide tests (germination test and seedling development) against Eragrostis plana, commonly known as capim annoni, an invader of pastures in the Pampas region. P. amboinicus EO was a potent inhibitor of E. plana germination, reducing accumulated germination by over 70% when exposed to 0.1% EO, and a complete inhibition of germination was observed when exposed to 0.5%. Following the effects observed in germination, the initial growth of E. plana was significantly affected by concentrations above 0.05%. The major constituent identified via GC-MS was carvacrol, representing 87.5% of the volatile composition of P. amboinicus leaves. In addition, P. amboinicus EO presented high thermal stability up to 100 °C, which is an interesting result regarding its use as a bioproduct.

Effects of Organophosphorus and Pyrethroid Pesticides on Antioxidant Enzymes and Reactivation Effects of Pralidoxime: In vitro Studies

The present study was aimed to assess the inhibition effects of organophosphate pesticides, malathionR, dichlorvosR; pyrethroid pesticides, deltamethrinR, λ-cyhalothrinR on antioxidantenzymes and reactivation ability of pralidoxime against pesticide inhibited-antioxidant enzymes. Oximes were reported by reactivation ability against organophosphate inhibited- acetylcholinesterase and we focused to investigate the reactivation effect of pralidoxime against organophosphate inhibited–antioxidant enzymes. IC50 values were determined by means of activity percentage diagrams. The concentrations of deltamethrinR, malathionR,dichlorvosR, λ-cyhalothrinR that inhibited 50% of catalase were 5.2 μM, 158 μM, 133 μM,320 μM, respectively, inhibited 50% of superoxide dismutase were 62 μM, 240 μM, 328 μM, 2320 μM, respectively and inhibited 50% of glutathione peroxidase were 0.7 μM, 1198 μM, 1638 μM, 98 μM, respectively. All pesticide doses showed inhibition effect on antioxidant enzymes. DeltamethrinR was found to be a more potent inhibitor for the antioxidant enzymesfollowed by the rest of pesticides used in this study. Reactivation effect of pralidoxime was determined for organophosphate inhibited-enzymes. Reactivation results showed that only catalase is reactivated by pralidoxime against dichlorvosR and malathionR. Under the exposureof 50-800 μM malathionR concentrations, catalase activity % was calculated as 72-11%,respectively. After inhibited catalase by malathionR incubated with 1 mM and 10 mMpralidoxime, catalase activity % was calculated as 92-31% and 98-39%, respectively. Under the exposure of 100-1500 μM dichlorvosR concentrations, catalase activity % was calculatedas 50-6%, respectively. After inhibited catalase by dichlorvosR incubated with 1 mM and 10mM pralidoxime, catalase activity % was calculated as 95-30% and 93-28%, respectively. When the results are examined, it is seen that increasing the pralidoxime concentration does not significantly affect the reactivation percentage of the catalase enzyme.