Antileishmanial High-Throughput Drug Screening Reveals Drug Candidates with New Scaffolds

Drugs currently available for leishmaniasis treatment often show parasite resistance, highly toxic side effects and prohibitive costs commonly incompatible with patients from the tropical endemic countries. In this sense, there is an urgent need for new drugs as a treatment solution for this neglected disease. Here we show the development and implementation of an automated high-throughput viability screening assay for the discovery of new drugs against Leishmania. Assay validation was done with Leishmania promastigote forms, including the screening of 4,000 compounds with known pharmacological properties. In an attempt to find new compounds with leishmanicidal properties, 26,500 structurally diverse chemical compounds were screened. A cut-off of 70% growth inhibition in the primary screening led to the identification of 567 active compounds. Cellular toxicity and selectivity were responsible for the exclusion of 78% of the pre-selected compounds. The activity of the remaining 124 compounds was confirmed against the intramacrophagic amastigote form of the parasite. In vitro microsomal stability and cytochrome P450 (CYP) inhibition of the two most active compounds from this screening effort were assessed to obtain preliminary information on their metabolism in the host. The HTS approach employed here resulted in the discovery of two new antileishmanial compounds, bringing promising candidates to the leishmaniasis drug discovery pipeline

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1, 2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis

What are the relative importance of smart car utilities from consumer perspective and who will lead them?

The long-standing signification of car is expected to accompany a big change, which results in the concept of smart car that can not only improve traffic safety by driving and controlling themselves like robots, but also entertain passengers and support their productive activities through connection to the Internet. Many related companies are seeking to enter the smart car market to take a leadership in the growing smart car market. While there are some researches regarding advanced technologies regarding smart car, there are relatively few efforts that focus on the standpoint of market demand. This study thus aims to understand customer value on upcoming smart car through evaluating the relative importance of idiosyncratic key services of smart car based on analytic hierarchy process analysis. In addition, this paper also evaluates firms and industries that are expected to perform well the preferred services through expert survey. The results show that the most important service is driving assistance, followed by infotainment, and IoT hub. Furthermore, Samsung Electronics ranked the highest, followed by Hyundai Motor, Naver, and SKT. In terms of industries, the rank is in the order of IT equipment manufacturers, platform providers, automobile manufacturers, and network providers. This analysis could help companies diagnose their capabilities and recognize their strengths and weaknesses

Regulation of C1-Ten protein tyrosine phosphatase by p62/SQSTM1-mediated sequestration and degradation

C1-Ten is a member of the tensin family of focal adhesion molecules but recent studies suggest it plays a more active role in many biological processes because of its potential association with diabetes and cancers. However, relatively little is known about the regulation of C1-Ten, such as changes in its protein level or cellular localization. The cellular localization of C1-Ten is unique because it is expressed in cytoplasmic puncta but nothing is known about these puncta. Here, we show that p62 sequestrates C1-Ten into puncta, making C1-Ten diffuse into the cytoplasm upon p62 depletion. More importantly, p62-mediated C1-Ten sequestration promoted C1-Ten ubiquitination and proteasomal degradation. p62-mediated protein reduction was specific to C1-Ten, and not other tensins such as tensin1 and tensin3. Thus, our results link cellular localization of C1-Ten to an off-switch site for C1-Ten. Additionally, p62 expression increased but C1-Ten protein decreased during muscle differentiation, supporting a role for p62 as a physiological regulator of C1-Ten.close0

Mitochondria-Targeting Peptoids

Mitochondria-specific delivery methods offer a valuable tool for studying mitochondria-related diseases and provide breakthroughs in therapeutic development. Although several small-molecule and peptide-based transporters have been developed, peptoids, proteolysis-resistant peptidomimetics, are a promising alternative to current approaches. We designed a series of amphipathic peptoids and evaluated their cellular uptake and mitochondrial localization. Two peptoids with cyclohexyl residues demonstrated highly efficient cell penetration and mitochondrial localization without significant adverse effects on the cells and mitochondria. These mitochondria-targeting peptoids could facilitate the selective and robust targeted delivery of bioactive compounds, such as drugs, antioxidants, and photosensitizers, with minimal off-target effects

Effectiveness of group cognitive behavioral therapy with mindfulness in end-stage renal disease hemodialysis patients

Background : Many patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD) experience depression. Depression influences patient quality of life (QOL), dialysis compliance, and medical comorbidity. We developed and applied a group cognitive behavioral therapy (CBT) program including mindfulness meditation for ESRD patients undergoing HD, and measured changes in QOL, mood, anxiety, perceived stress, and biochemical markers. Methods : We conducted group CBT over a 12-week period with seven ESRD patients undergoing HD and suffering from depression. QOL, mood, anxiety, and perceived stress were measured at baseline and at weeks 8 and 12 using the World Health Organization Quality of Life scale, abbreviated version (WHOQOL-BREF), the Beck Depression Inventory II (BDI-II), the Hamilton Rating Scale for Depression (HAM-D), the Beck Anxiety Inventory (BAI), and the Perceived Stress Scale (PSS). Biochemical markers were measured at baseline and after 12 weeks. The Temperament and Character Inventory was performed to assess patient characteristics before starting group CBT. Results : The seven patients showed significant improvement in QOL, mood, anxiety, and perceived stress after 12 weeks of group CBT. WHOQOL-BREF and the self-rating scales, BDI-II and BAI, showed continuous improvement across the 12-week period. HAM-D scores showed significant improvement by week 8; PSS showed significant improvement after week 8. Serum creatinine levels also improved significantly following the 12 week period. Conclusion : In this pilot study, a CBT program which included mindfulness meditation enhanced overall mental health and biochemical marker levels in ESRD patients undergoing HD

Inhibition of C1-Ten PTPase activity reduces insulin resistance through IRS-1 and AMPK pathways

Insulin resistance causes type 2 diabetes; therefore, increasing insulin sensitivity is a therapeutic approach against type 2 diabetes. Activating AMP-activated protein kinase (AMPK) is an effective approach for treating diabetes, and reduced insulin receptor substrate-1 (IRS-1) protein levels have been suggested as a molecular mechanism causing insulin resistance. Thus, dual targeting of AMPK and IRS-1 might provide an ideal way to treat diabetes. We found that 15,16-dihydrotanshinone I (DHTS), as a C1-Ten protein tyrosine phosphatase inhibitor, increased IRS-1 stability, improved glucose tolerance and reduced muscle atrophy. Identification of DHTS as a C1-Ten inhibitor revealed a new function of C1-Ten in AMPK inhibition, possibly through regulation of IRS-1. These findings suggest that C1-Ten inhibition by DHTS could provide a novel therapeutic strategy for insulin resistance-associated metabolic syndrome through dual targeting of IRS-1 and AMPK.111sciescopu

Inhibition of C1-Ten PTPase activity reduces insulin resistance through IRS-1 and AMPK pathways

Abstract Insulin resistance causes type 2 diabetes; therefore, increasing insulin sensitivity is a therapeutic approach against type 2 diabetes. Activating AMP-activated protein kinase (AMPK) is an effective approach for treating diabetes, and reduced insulin receptor substrate-1 (IRS-1) protein levels have been suggested as a molecular mechanism causing insulin resistance. Thus, dual targeting of AMPK and IRS-1 might provide an ideal way to treat diabetes. We found that 15,16-dihydrotanshinone I (DHTS), as a C1-Ten protein tyrosine phosphatase inhibitor, increased IRS-1 stability, improved glucose tolerance and reduced muscle atrophy. Identification of DHTS as a C1-Ten inhibitor revealed a new function of C1-Ten in AMPK inhibition, possibly through regulation of IRS-1. These findings suggest that C1-Ten inhibition by DHTS could provide a novel therapeutic strategy for insulin resistance-associated metabolic syndrome through dual targeting of IRS-1 and AMPK