Efficient construction of the hexacyclic ring core of palau'amine : the pKa concept for proceeding with unfavorable equilibrium reactions

Palau'amine has received a great deal of attention as an attractive synthetic target due to its intriguing molecular architecture and significant immunosuppressive activity, and we achieved its total synthesis in 2015. However, the synthesized palau'amine has not been readily applicable to the mechanistic study of immunosuppressive activity, because it requires 45 longest linear steps from a commercially available compound. Here, we report the short-step construction of the ABCDEF hexacyclic ring core of palau'amine. The construction of the CDE tricyclic ring core in a single step is achieved by our pKa concept for proceeding with unfavorable equilibrium reactions, and a palau'amine analog without the aminomethyl and chloride groups is synthesized in 20 longest linear steps from the same starting material. The palau'amine analog is confirmed to retain the immunosuppressive activity. The present synthetic approach for a palau'amine analog has the potential for use in the development of palau'amine probes for mechanistic elucidation

Liposome co-incubation with cancer cells secreted exosomes (extracellular vesicles) with different proteins expressions and different uptake pathways

We recently showed that in vitro incubation of cells with liposomes of varying compositions can increase exosome secretion and increase the yield of harvested exosomes (extracellular vesicles, EVs). This might foster their potential therapeutic implementations. In the current study, we investigated the surface proteins and the uptake of the harvested exosomes (EVs) to see if the incubation of cells with liposomes would change the biological properties of these exosomes (EVs). Interestingly, exosomes (EVs) induced by solid cationic liposomes lacked some major exosome marker proteins such as CD9, flotillin-1, annexin-A2 and EGF, and subsequently had lower levels of cellular uptake upon re-incubation with donor cancer cells. However, exosomes (EVs) induced under normal condition and by fluid cationic liposomes, displayed the entire spectrum of proteins, and exhibited higher uptake by the donor cancer cells. Although endocytosis was the major uptake pathway of exosomes (EVs) by tumor cells, endocytosis could occur via more than one mechanism. Higher exosome uptake was observed in donor B16BL6 cells than in allogeneic C26 cells, indicating that donor cells might interact specifically with their exosomes (EVs) and avidly internalize them. Taken together, these results suggest a technique for controlling the characteristics of secreted exosomes (EVs) by incubating donor cancer cells with liposomes of varying physiochemical properties

Modulation of steroidogenesis by Actaea racemosa and vitamin C combination, in letrozole induced polycystic ovarian syndrome rat model : promising activity without the risk of hepatic adverse effect

Background: Complementary remedies such as the Chinese herb 'Sheng Ma' (Black cohosh; Actaea racemosa 'AR') are being sought to overcome the shortcomings of conventional hormonal and surgical therapies developed for the treatment of polycystic ovary syndrome (PCOS). However, AR-induced hepatotoxicity necessitates a cautionary warning to be labeled on its products as recommended by the United States Pharmacopeia, where four out of seven hepatotoxic cases in Sweden were possibly associated with black cohosh products. Methods: We investigated the effects, safety, and molecular targets of black cohosh ethanolic extract and/or vitamin C on ovarian functionality and oxidative response in hyperandrogenism-induced PCOS rats. A well-established rat model using oral letrozole, daily, for 21 days was employed. The rats then received the AR extract with and without vitamin C for 28 days. The hormonal evaluation, antioxidant status, histopathological examination, immunohistochemical analysis, cell proliferation, and the expression ratio of the aromatase (Cyp19α1) gene were evaluated. Additionally, holistic profiling of the AR arsenal of secondary metabolites was performed using ultra-high-performance liquid chromatography (UHPLC) coupled with quadrupole high-resolution time of flight mass spectrometry (QTOF-MS). Results: Beneficial effects were exerted by AR in PCOS rats as antioxidant status, hormonal profile, lipid profile, glucose level, liver functions, and the induced Ki-67 expression in the granulosa, theca cell layers and interstitial stromal cells were all improved. Notably, the combination of AR with vitamin C was not only more effective in reversing the dysregulated levels of testosterone, luteinizing hormone, and mRNA level of Cyp19α1 gene in the PCOS rat, but also safer. The combination regulated both ovarian and hepatic malondialdehyde (MDA) and glutathione (GSH) levels with histological improvement observed in the liver and ovaries. In addition, the untargeted metabolomic profiling enabled the identification of 61 metabolites allocated in five major chemical classes. Conclusion: This study demonstrated the benefit of the combinatorial effects of AR and vitamin C in mitigating the reproductive and metabolic disorders associated with PCOS with the elimination of AR hepatotoxic risk

Entwicklung nachhaltiger Pflanzenschutzstrategien zur Bek_mpfung von Schadschmetterlingen im olivenanbau

Current olive growing practices range from the traditional Mediterranean olive grove to intensively managed olive plantations. Insecticides against major olive pests, like the olive moth (Prays oleae, Lep.: Yponomeutidae) and the jasmine moth, (Palpita unionalis, Lep.: Pyralidae) are still applied frequently. The European Union-funded international research project TRIPHELIO is aimed at the development of economically feasible and sustainable insecticide-free control methods for key Lepidopterous pests of olive. Main research activities focus on (1) the use of pheromones for mating disruption and improved monitoring of target pests, (2) habitat management strategies to enhance the activity of natural enemies in the olive grove, and (3) the use of inundative releases of mass-reared egg parasitoids of the genus Trichogramma. Moreover, tools for successful integration of the methods developed into an integrated pest management (IPM) strategy for olive pests were explored by optimising techniques for surveillance as well as considering potential side-effects of common pesticides on beneficial organisms. An intense exchange of scientific information and technology between European and North African countries was undertaken to create solutions for a wide range of olive growing regions. Key results and recommendations for further essential steps towards practical implementation are presented in this publication.Zusammenfassung Traditionelle, extensiv bearbeitete Olivenhaine, aber auch moderne Intensiv-Plantagen mit k_nstlicher Bew_sserung und hohem Einsatz von D_ngern bzw. chemischen Pflanzenschutzmitteln kennzeichnen die derzeitigen verschiedenen Anbauformen der Olive im Mittelmeerraum. Schadlepidopteren wie die Olivenmotte (Prays oleae, Lep.: Yponomeutidae) und die Jasminmotte (Palpita unionalis, Lep.: Pyralidae) werden durch regelm_ssigen Insektizideinsatz bek_mpft. Das von der EU gef_rderte internationale Forschungsprojekt TRIPHELIO zielte auf die Entwicklung insektizidfreier Alternativmethoden durch (1) die Optimierung der pheromongest _tzten _berwachung und Verwirrtechnik, (2) der Anwendung von Habitatmanagement-Strategien zur F_rderung nat_rlicher Gegenspieler, und (3) dem Einsatz von Trichogramma-Schlupfwespen. Zus_tzlich wurden Module f_r eine optimale Anwendung biotechnischer und biologischer Methoden bez_glich der Ph_nologie der Schadinsekten und m_glicher Nebenwirkungen von Pestiziden erarbeitet. Die intensive Kooperation zwischen Wissenschaftlern und Praktikern aus mehreren L_ndern Europas und Nordafrikas erlaubte den Entwurf m_glicher L_sungsans_tze f_r verschiedene Anbaubedingungen und klimatische Regionen des Mittelmeerraumes. Die wichtigsten Ergebnisse und Ausblicke f_r eine zuk_nftige praktische Umsetzung werden in dieser Ver_ffentlichung beschrieben

Electrospun Nanofibers Revisited: An Update on the Emerging Applications in Nanomedicine

Electrospinning (ES) has become a straightforward and customizable drug delivery technique for fabricating drug-loaded nanofibers (NFs) using various biodegradable and non-biodegradable polymers. One of NF’s pros is to provide a controlled drug release through managing the NF structure by changing the spinneret type and nature of the used polymer. Electrospun NFs are employed as implants in several applications including, cancer therapy, microbial infections, and regenerative medicine. These implants facilitate a unique local delivery of chemotherapy because of their high loading capability, wide surface area, and cost-effectiveness. Multi-drug combination, magnetic, thermal, and gene therapies are promising strategies for improving chemotherapeutic efficiency. In addition, implants are recognized as an effective antimicrobial drug delivery system overriding drawbacks of traditional antibiotic administration routes such as their bioavailability and dosage levels. Recently, a sophisticated strategy has emerged for wound healing by producing biomimetic nanofibrous materials with clinically relevant properties and desirable loading capability with regenerative agents. Electrospun NFs have proposed unique solutions, including pelvic organ prolapse treatment, viable alternatives to surgical operations, and dental tissue regeneration. Conventional ES setups include difficult-assembled mega-sized equipment producing bulky matrices with inadequate stability and storage. Lately, there has become an increasing need for portable ES devices using completely available off-shelf materials to yield highly-efficient NFs for dressing wounds and rapid hemostasis. This review covers recent updates on electrospun NFs in nanomedicine applications. ES of biopolymers and drugs is discussed regarding their current scope and future outlook