Benzyl Farnesyl Amine Mimetics are Potent Inhibitors of the Sterol Biosynthesis Pathway in Leishmania Amazonensis Leading to Oxidative Stress, Growth Arrest, and Ultrastructural Alterations

Leishmaniasis is a neglected disease caused by protozoan parasites of the Leishmania genus spread around the world. Benzyl farnesyl amine mimetics are known class of compounds selectively designed to inhibit the squalene synthase (SQS) enzyme that catalyzes the first committed reaction on the sterol biosynthesis pathway. Herein, we studied seven new benzyl farnesyl amine mimetics (SBC 37 - 43) against Leishmania amazonensis. After the first initial screening of cell viability, two inhibitors (SBC 39 and SBC 40) were selected for further studies. Against intracellular amastigotes, SBC 39 and SBC 40 presented selectivity indexes of 117.7 and 180, respectively, indicating that they are highly selective. Analyses of free sterol showed that SBC 39 and SBC 40 inhibit two enzymes, sterol Δ8 → Δ7 isomerase and SQS, resulting in depletion of endogenous 24-methyl sterols. Physiological analysis and electron microscopy revealed three main alterations: 1) in the mitochondrion ultrastructure and function; 2) the presence of lipid bodies and autophagosomes; and 3) the appearance of projections in the plasma membrane and extracellular vesicles inside the flagellar pocket. In conclusion, our results support the notion that benzyl farnesyl amine mimics have a potent effect against Leishmania amazonensis and should be an interesting novel pharmaceutical lead for the development of new chemotherapeutic alternatives to treat leishmaniasis.

The Stimulatory Effects of Intracellular α-Synuclein on Synaptic Transmission Are Attenuated by 2-Octahydroisoquinolin-2(1H)-ylethanamine

α-Synuclein (αSyn) species can be detected in synaptic boutons, where they play a crucial role in the pathogenesis of Parkinson’s Disease (PD). However, the effects of intracellular αSyn species on synaptic transmission have not been thoroughly studied. Here, using patch-clamp recordings in hippocampal neurons, we report that αSyn oligomers (αSynO), intracellularly delivered through the patch electrode, produced a fast and potent effect on synaptic transmission, causing a substantial increase in the frequency, amplitude and transferred charge of spontaneous synaptic currents. We also found an increase in the frequency of miniature synaptic currents, suggesting an effect located at the presynaptic site of the synapsis. Furthermore, our in silico approximation using docking analysis and molecular dynamics simulations showed an interaction between a previously described small anti-amyloid beta (Aβ) molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine), with a central hydrophobic region of αSyn. In line with this finding, our empirical data aimed to obtain oligomerization states with thioflavin T (ThT) and Western blot (WB) indicated that M30 interfered with αSyn aggregation and decreased the formation of higher-molecular-weight species. Furthermore, the effect of αSynO on synaptic physiology was also antagonized by M30, resulting in a decrease in the frequency, amplitude, and charge transferred of synaptic currents. Overall, the present results show an excitatory effect of intracellular αSyn low molecular-weight species, not previously described, that are able to affect synaptic transmission, and the potential of a small neuroactive molecule to interfere with the aggregation process and the synaptic effect of αSyn, suggesting that M30 could be a potential therapeutic strategy for synucleinopathies.

The Mangrove-Derived Diterpenoid Diaporthe B Inhibits the Stemness and Increases the Efficacy of Docetaxel in Prostate Cancer PC-3 Cells

The absolute configuration of diaporthe B, a pimarane diterpene isolated from the mangrove derived endophytic fungus Eutypella sp #3E, was determined by a single-crystal x-ray diffraction study. The present study aimed to investigate the effects of diaporthe B on docetaxel-resistant prostate cancer PC-3 cells. Results of our studies showed that docetaxel-resistant PC-3 cells had higher sphere-forming efficiency and an increase in adherence to collagen-coated culture plates. The protein levels of cancer stem cell (CSC)-related markers CD44, CD133, and ALDH1A1 were higher in the docetaxel-resistant PC-3 cells than in the parental cells. Treatment with diaporthe B dose-dependently inhibited the growth and induced apoptosis in the resistant cells. Moreover, diaporthe B treatment decreased the sphere-forming efficiency and the adherence to collagen-coated plates in docetaxel-resistant PC-3 cells. Diaporthe B also decreased the protein levels of CSC-related markers CD44, CD133, and ALDH1A1 in the resistant cells. In addition, a combination of diaporthe B and docetaxel had a more potent effect on growth inhibition and apoptosis in the resistant cells than either agent alone. Our studies suggest that diaporthe B inhibits the stemness of prostate cancer cells and may have therapeutic potential for enhancing the efficacy of docetaxel in docetaxel-resistant prostate cancer cells.

Conjunction of gallium doping and calcium silicate mediates osteoblastic and osteoclastic performances of tricalcium phosphate bioceramics

Gallium-containing biomaterials are considered promising for reconstructing osteoporotic bone defects, owing to the potent effect of gallium on restraining osteoclast activities. Nevertheless, the gallium-containing biomaterials were demonstrated to disturb the osteoblast activities. In this study, tricalcium phosphate (TCP) bioceramics were modified by gallium doping in conjunction with incorporation of calcium silicate (CS). The results indicated that the incorporation of CS promoted transition of β-TCP to α-TCP, and accelerated densification process, but did not improve the mechanical strength of bioceramics. The silicon released from the composite bioceramics diminished the inhibition effect of released gallium on osteoblast activities, and maintained its effect on restraining osteoclast activities. The TCP-based bioceramics doped with 2.5 mol% gallium and incorporated with 10 mol% CS are considered suitable for treating the bone defects in the osteoporotic environment.

Systematic investigation and comparison of US FDA-approved immunosuppressive drugs FK506, cyclosporine and rapamycin for neuromuscular regeneration following chronic nerve compression injury

Aim: To compare therapeutic benefits of different immunophilin ligands for treating nerve injuries. Materials & methods: Cyclosporine, FK506 and rapamycin, were evaluated first in vitro on a serum-free culture of embryonic dorsal root ganglia followed by a new in vivo model of chronic nerve compression. Results: Outcomes of the in vitro study have shown a potent effect of cyclosporine and FK506, on dorsal root ganglia axonal outgrowth, comparable to the effect of nerve growth factor. Rapamycin exhibited only a moderate effect. The in vivo study revealed the beneficial effects of cyclosporine, FK506 and rapamycin for neuromuscular regeneration. Cyclosporine showed the better maintenance of the tissues and function. Conclusion: Cyclosporine, FK506 and rapamycin drugs showed potential for treating peripheral nerve chronic compression injuries.

Preparation and characterization of branched micro/nano Se

Branched micro/nano Se was prepared by the redaction of L-Cys•HCl and H2SeO3 in hydrothermal method, as β-CD was used as soft template. The structures of products were characterized by SEM, TEM and XRD. Some important factors influencing the morphology of products were studied and discussed, including the amounts of soft template, the reaction temperature and the reaction time. The results showed that external causes had a potent effect on the morphology of micro/nano Se. The uniform branched micro/nano Se prepared under the optimal reaction condition was rhombohedral trigonal selenium t-Se0, but its crystallinity degree was low.

Major approaches to antiseptic management for endodontic treatment in the COVID-19 pandemic: a guideline

Introduction: In the COVID-19 pandemic scenario, in addition to the pathogenesis of SARS-CoV-2, microbial coinfection increases the difficulties of diagnosis, treatment, the prognosis of COVID-19, as well as it can worsen comorbidities and affect the risk of the life of patients. COVID-19 has had a profound impact on dentistry. In addition to endodontic treatment, a management protocol was suggested. Objective: To present the importance of effectively performing endodontic asepsis in the context of the COVID-19 pandemic, to elucidate that infection by the SARS-CoV-2 virus can lead to coinfection, worsening the conditions for endodontic treatment. Methods: The research was carried out from July 2021 to August 2021 and developed based on Scopus, PubMed, Science Direct, Scielo, and Google Scholar, following the Systematic Review-PRISMA rules. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results: A total of 70 articles were found involving the endodontic treatment and COVID-19. A total of 58 articles were evaluated in full and 39 were included and evaluated in the present study. It was found that ozone has high antimicrobial action. N-acetylcysteine (NAC) has a potent effect against endodontic biofilms. Calcium hydroxide is more effective as a root canal disinfectant in primary teeth than formocresol and camphorphenol. The association of 2% chlorhexidine followed by ozone gas for 24 seconds promoted the complete elimination of Candida albicans and Enterococcus faecalis. Low-intensity laser therapy has the property of oral sterilization, facilitating tissue healing and sterilization. Combining antimicrobial photodynamic therapy with antimicrobial irrigants may provide a synergistic effect. Conclusion: There are effective treatments for the sterilization of endodontic tissues, to avoid as much as possible the coinfection with SARS-CoV-2 and the consequent worsening of the infectious condition, highlighting calcium hydroxide, ozone therapy, and laser therapy.

Novel Nanocombinations of l-Tryptophan and l-Cysteine: Preparation, Characterization, and Their Applications for Antimicrobial and Anticancer Activities

Tungsten oxide WO3 nanoparticles (NPs) were prepared in a form of nanosheets with homogeneous size and dimensions in one step through acid precipitation using a cation exchange column. The resulting WO3nanosheet surface was decorated with one of the two amino acids (AAs) l-tryptophan (Trp) or l-cysteine (Cys) and evaluated for their dye removal, antimicrobial, and antitumor activities. A noticeable improvement in the biological activity of WO3 NPs was detected upon amino acid modification compared to the original WO3. The prepared WO3-Trp and WO3-Cys exhibited strong dye removal activity toward methylene blue and safranin dyes with complete dye removal (100%) after 6 h. WO3-Cys and WO3-Trp NPs revealed higher broad-spectrum antibacterial activity toward both Gram-negative and Gram-positive bacteria, with strong antifungal activity toward Candida albicans. Anticancer results of the modified WO3-Cys and WO3-Trp NPs against various kinds of cancer cells, including MCF-7, Caco-2, and HepG-2 cells, indicate that they have a potent effect in a dose-dependent manner with high selectivity to cancer cells and safety against normal cells. The expression levels of E2F2 and Bcl-2 genes were found to be suppressed after treatment with both WO3-Cys and WO3-Trp NPs more than 5-FU-treated cells. While expression level of the p53 gene in all tested cells was up-regulated after treatment 5–8 folds more as compared to untreated cells. The docking results confirmed the ability of both NPs to bind to the p53 gene with relevant potency in binding to other tested gens and participation of cysteine SH-functional group in such interaction.