Green by Design: Convergent Synthesis, Computational Analyses, and Activity Evaluation of New FXa Inhibitors Bearing Peptide Triazole Linking Units

Green chemistry implementation has led to promising results in waste reduction in the pharmaceutical industry. However, the early sustainable development of pharmaceutically active compounds and ingredients remains a considerable challenge. Herein, we wish to report a green synthesis of new pharmaceutically active peptide triazoles as potent factor Xa inhibitors, an important drug target associated with the treatment of diverse cardiovascular diseases. The new inhibitors were synthesized in three steps, featuring cycloaddition reactions (high atom economy), microwave-assisted organic synthesis (energy efficiency), and copper nanoparticle catalysis, thus featuring Earth-abundant metals. The molecules obtained showed FXa inhibition, with IC50-values as low as 17.2 μM and no associated cytotoxicity in HEK293 and HeLa cells. These results showcase the environmental potential and chemical implications of the applied methodologies for the development of new molecules with pharmacological potential.

Curcumin May Prevent Basement Membrane Disassembly by Matrix Metalloproteinases and Progression of the Bladder Cancer

Authors present a review of crucial mechanisms contributing to the invasion of the basement membrane (BM) of the urothelium by cancer cells and to the progression of bladder cancer (BC). The breeching of the urothelial BM, facilitated by an aberrant activation of matrix metalloproteinases (MMP) is particularly perilous. Inhibition of activation of these proteinases constitutes a logic opportunity to restrain progression. Because of limited efficacy of current therapeutic methods, the search for the development of alternative approaches constitutes “the hot spot” of modern oncology. Recent studies revealed significant anticancer potential of natural phytochemicals. Especially, curcumin has emerged as a one of the most promising phytochemicals and showed its efficacy in several human malignancies. Therefore, this article addresses experimental and clinical data indicating multi-directional inhibitory effect of curcumin on the growth of bladder cancer. We particularly concentrate on the mechanisms, by which curcumin inhibits the MMP’s activities, thereby securing BM integrity and alleviating the eventual cancer invasion into the bladder muscles. Authors review the recently accumulating data, that curcumin constitutes a potent factor contributing to the more effective treatment of the bladder cancer.

The Mind of the Artist

Because artists make something out of nothing, the process can seem like magic, divinely inspired and inexplicable. It’s not. A single, potent factor lies at the heart of most everything creative: the mysterious, multifaceted trait of “openness.” This book describes the role of the openness dimension in the typical artist mind: how it loosens thinking, how it widens feelings, how it motivates behavior, and how it foments a useful inner chaos encouraging artistic invention. For creatives, openness is a unifying glue. It binds together states and processes at the core of the art-making impulse. A related key variable is trauma, according to scientific findings: the raw material with which so many artists work. In novels, poems, stories, and photographs, trauma gets symbolically repeated, shaped in the direction of a torturous beauty. Scientifically astute, conceptually subtle, and packed with richly detailed artist examples—from David Bowie to Frida Kahlo, from John Coltrane to Francesca Woodman, from Diane Arbus to Kurt Cobain—The Mind of the Artist demystifies artistic genius. It is a new, true portrait of artistic vision.

LANTANA CAMARA: A POTENT INFLUENTIAL FACTOR IN IMPROVING THE GASTRIC MUCOSA OF WISTAR RATS RAVAGED BY ULCER

Over the years, traditional medicine has been used to treat various degrees and forms of ailment with significant positive therapeutic outcomes. We designed this research to ascertain the use of Lantana camara as a potent factor in improving gastric ulcer caused by the administration of aspirin in Wistar rats. 250mg/kg of the extract was used to evaluate the anti-ulcer capacity of the plant extract. The omeprazole was used as a standard drug (20mg/kg). It was found that the Gastric mucosa was significantly improved after the administration of 250mg/kg of the extract after aspirin-induced ulcer. The present study justifies the traditional usage of this plant to treat the gastric ulcer.

Locus coeruleus activity improves cochlear implant performance

Cochlear implants are neuroprosthetic devices that can provide hearing to deaf patients1. Despite significant benefits offered by cochlear implants, there are highly variable outcomes in how quickly hearing is restored and perceptual accuracy after months or years of use2,3. Cochlear implant use is believed to require neuroplasticity within the central auditory system, and differential engagement of neuroplastic mechanisms might contribute to outcome variability4-7. Despite extensive studies on how cochlear implants activate the auditory system4,8-12, our understanding of cochlear implant-related neuroplasticity remains limited. One potent factor enabling plasticity is the neuromodulator norepinephrine from the brainstem locus coeruleus. Here we examined behavioral responses and neural activity in locus coeruleus and auditory cortex of deafened rats fitted with multi-channel cochlear implants. Animals were trained on a reward-based auditory task, with considerable individual differences of learning rates and maximum performance. Photometry from locus coeruleus predicted when implanted subjects would begin responding to sounds and longer-term perceptual accuracy, which were augmented by optogenetic locus coeruleus stimulation. Auditory cortical responses to cochlear implant stimulation reflected behavioral performance, with enhanced responses to rewarded stimuli and decreased distinction between unrewarded stimuli. Adequate engagement of central neuromodulatory systems is thus a potential clinically-relevant target for optimizing neuroprosthetic device use.

Locus coeruleus activity improves cochlear implant performance

Cochlear implants are neuroprosthetic devices that can provide hearing to deaf patients1. Despite significant benefits offered by cochlear implants, there are highly variable outcomes in how quickly hearing is restored and perceptual accuracy after months or years of use2,3. Cochlear implant use is believed to require neuroplasticity within the central auditory system, and differential engagement of neuroplastic mechanisms might contribute to outcome variability4-7. Despite extensive studies on how cochlear implants activate the auditory system4,8-12, our understanding of cochlear implant-related neuroplasticity remains limited. One potent factor enabling plasticity is the neuromodulator norepinephrine from the brainstem locus coeruleus. Here we examined behavioral responses and neural activity in locus coeruleus and auditory cortex of deafened rats fitted with multi-channel cochlear implants. Animals were trained on a reward-based auditory task, with considerable individual differences of learning rates and maximum performance. Photometry from locus coeruleus predicted when implanted subjects would begin responding to sounds and longer-term perceptual accuracy, which were augmented by optogenetic locus coeruleus stimulation. Auditory cortical responses to cochlear implant stimulation reflected behavioral performance, with enhanced responses to rewarded stimuli and decreased distinction between unrewarded stimuli. Adequate engagement of central neuromodulatory systems is thus a potential clinically-relevant target for optimizing neuroprosthetic device use.

THE BENEFIT EFFECT OF GINGER SUPPLEMENTATION AGAINST NICKEL-INDUCED HEPATOTOXICITY IN ALBINO WISTAR RATS

Objective: This study was performed to study the potential capacity effect of ginger on the modulation effects of nickel-induced hepatotoxicity. Methods: Thirty-two female albino Wistar rats were divided into four groups of eight each. One served as a control group, the second group (Gi) received ginger 20 g/kg diet, while the third group (Ni) was given nickel 800 mg/L in their drinking water as NiSO46H2O and the fourth group (Ni+Gi) was treated daily with both nickel and ginger. The experiment was lasted for 21 days. Results: The exposure to nickel led to a significant decrease in body weight and food intake with an increase of liver weight. Nickel treatment also produced oxidative liver injury characterized by an increase of glucose, cholesterol, triglyceride, total lipids, bilirubin, malondialdehyde (MDA) concentrations and glutamate-pyruvate transaminase, glutamic oxaloacetic transaminase, and alkaline phosphatase activities. Meanwhile, serum total proteins and liver reduced glutathione (GSH) levels, catalase, GSH peroxidase, and GSH superoxide dismutase activities were decreased. These results are substantiated with marked changes in the histopathology, whereas the supplementation of ginger resulted in a restoration of the previous parameters. Conclusion: It seems that ginger supplementation is a potent factor for reducing the oxidative severity of nickel hepatotoxicity through its antioxidant action.

Jonatan Meir, Kabbalistic Circles in Jerusalem (1896–1948), trans. Avi Aronsky. Leiden: Brill, 2016. 269 pp.

This chapter reviews the book Kabbalistic Circles in Jerusalem (1896–1948) (2016), by Jonatan Meir, translated by Avi Aronsky. In Kabbalistic Circles in Jerusalem, Meir focuses on the proliferation of Sharabian yeshivot and shows that it represented a critical move toward exotericism within what was previously one of the most esoteric branches of modern Kabbalah. He highlights the institutional, economic, and cultural factors underlying this phenomenon—the last pertaining to the competing claims of ethnic groups such as the Baghdadis, Bukharins, and immigrants from Aleppo (Halabis). Meir explores these changes in the context of the literary and political life of pre-state Jerusalem to demonstrate how the Sharabian seminaries became a potent factor in the life of the city.

Fragment-Based Lead Generation of 5-Phenyl-1H-pyrazole-3-carboxamide Derivatives as Leads for Potent Factor Xia Inhibitors

FXIa is suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. In this paper, we defined 5-phenyl-1H-pyrazole-3-carboxylic acid derivatives as privileged fragments for FXIa inhibitors’ lead discovery. After replacing the (E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamide moiety in compound 3 with 5-(3-chlorophenyl)-1H-pyrazole-3-carboxamide, we traveled from FXIa inhibitor3 to a scaffold that fused the privileged fragments into a pharmacophore for FXIa inhibitors. Subsequently, we synthesized and assessed the FXIa inhibitory potency of a series of 5-phenyl-1H-pyrazole-3-carboxamide derivatives with different P1, P1′ and P2′moiety. Finally, the SAR of them was systematically investigated to afford the lead compound 7za (FXIa Ki = 90.37 nM, 1.5× aPTT in rabbit plasma = 43.33μM) which exhibited good in vitro inhibitory potency against FXIa and excellent in vitro coagulation activities. Furthermore, the binding mode of 7za with FXIa was studied and the results suggest that the 2-methylcyclopropanecarboxamide group of 7za makes 2 direct hydrogen bonds with Tyr58B and Thr35 in the FXIa backbone, making 7za binds to FXIa in a highly efficient manner.