Impact of acute heat treatment on autophagy and insulin signaling in C2C12 myotubes

A major risk factor for the development of type 2 diabetes is reduced skeletal muscle insulin sensitivity. It is known that exercise and caloric restriction can improve skeletal muscle insulin resistance, but the mechanism by which this occurs is not completely elucidated. The AMP-activated protein kinase (AMPK), is thought to be a major contributor to the metabolic benefits observed after exercise training and caloric restriction. Activation of AMPK in skeletal muscle can have a wide range of effects, one of which is the initiation of macroautophagy (herein referred to as autophagy). Autophagy is the bulk degradation system of the cell and is essential for the maintenance of cellular homeostasis. Another intervention that has been shown to have insulin sensitizing effects and activation of AMPK, is heat treatment. Heat treatment consists of acute bouts of low heat loads. Although high heat loads have been shown to regulate autophagy, whether low heat loads given with heat treatment can regulate autophagy has yet to be investigated. Additionally, the role that autophagy plays in the heat-induced insulin sensitization of skeletal muscle has not been investigated. Thus, the aims for the following studies were to investigate autophagy regulation with heat treatment and to identify what role autophagy may have in the insulin sensitizing effects of heat treatment in insulin resistant skeletal muscle cells. Here we show that heat treatment activates protein signaling involved in the initiation of autophagy and autophagosome formation in skeletal muscle cells. Additionally, when autophagy was inhibited, heat treatment was able to decrease autophagosomal accumulation. This suggests that heat can increase basal autophagy, and potentially rescue autophagic flux when inhibited. When myotubes were treated with palmitate, insulin signaling decreased, autophagy initiation was blunted, autophagosomal accumulation occurred, and cell stress markers were elevated. Heat treatment was able to reduce some markers of insulin resistance, reduce cell stress markers, and partially drive autophagosomal degradation. When autophagy was inhibited, the mild attenuation of insulin resistance was removed. This suggests that autophagy plays a role in insulin sensitization, and that heat treatment may attenuate insulin resistance, at least partially through the induction of autophagy, but further investigation is necessary to understand the extent or magnitude of this role

Targeting the HSP60/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness

Trypanosoma brucei are protozoan parasites that cause African sleeping sickness in humans (also known as Human African Trypanosomiasis—HAT). Without treatment, T. brucei infections are fatal. There is an urgent need for new therapeutic strategies as current drugs are toxic, have complex treatment regimens, and are becoming less effective owing to rising antibiotic resistance in parasites. We hypothesize that targeting the HSP60/10 chaperonin systems in T. brucei is a viable anti-trypanosomal strategy as parasites rely on these stress response elements for their development and survival. We recently discovered several hundred inhibitors of the prototypical HSP60/10 chaperonin system from Escherichia coli, termed GroEL/ES. One of the most potent GroEL/ES inhibitors we discovered was compound 1. While examining the PubChem database, we found that a related analog, 2e-p, exhibited cytotoxicity to Leishmania major promastigotes, which are trypanosomatids highly related to Trypanosoma brucei. Through initial counter-screening, we found that compounds 1 and 2e-p were also cytotoxic to Trypanosoma brucei parasites (EC50 = 7.9 and 3.1 μM, respectively). These encouraging initial results prompted us to develop a library of inhibitor analogs and examine their anti-parasitic potential in vitro. Of the 49 new chaperonin inhibitors developed, 39% exhibit greater cytotoxicity to T. brucei parasites than parent compound 1. While many analogs exhibit moderate cytotoxicity to human liver and kidney cells, we identified molecular substructures to pursue for further medicinal chemistry optimization to increase the therapeutic windows of this novel class of chaperonin-targeting anti-parasitic candidates. An intriguing finding from this study is that suramin, the first-line drug for treating early stage T. brucei infections, is also a potent inhibitor of GroEL/ES and HSP60/10 chaperonin systems

Revolutionary women: notable Revolutionary era women deserving of a commemorative postage stamp

Revolution is a term globally recognized. Throughout Earth’s history, there have been countless social endeavors classified as revolutions. Some revolutions result in social justice, some result in the birth of a nation; on the eve of the 19th century in North America, a revolution of the latter took place. The American Revolution gave way to the formation of a new nation and a history of the United States of America began. In American and much of world history, many of the details are dominated with male driven successes, stories of male heroes, and a presidential history of all male leaders. The revolutionary war and its history has been studied and taught for over two hundred years and during these two hundred plus years, the narrative has narrowed in on men, The Founding Fathers. However, any narrowing of information is damaging to the character of the entire era. It is for this reason, one should ask were all the founders fathers; or were some of those that made an impact on the revolution mothers and daughters too? Although abundantly studied in academics, a public involvement in the study and commemoration of female revolutionaries is a pioneer endeavor. One of the most commemorative actions the nation can take is putting remarkable women on postage stamp that can be seen and used across the United States. The Citizens Stamp Advisory Committee (CSAC) was formed with the expectation impactful people, places, and things may be commemorated as the nation should see fit. Through evidence and ideas, it is evident that a stamp set about revolutionary era women is a serious contender for become the next major collectable commemorative set. (Author abstract)Summers, C.E. (2017). Revolutionary women: notable Revolutionary era women deserving of a commemorative postage stamp. Retrieved from http://academicarchive.snhu.eduMaster ArtsHistoryCollege of Online and Continuing Educatio

Preparation of anti-vicinal amino alcohols: asymmetric synthesis of D-erythro-Sphinganine, (+)-spisulosine and D-ribo-phytosphingosine

Two variations of the Overman rearrangement have been developed for the highly selective synthesis of anti-vicinal amino alcohol natural products. A MOM-ether directed palladium(II)-catalyzed rearrangement of an allylic trichloroacetimidate was used as the key step for the preparation of the protein kinase C inhibitor D-erythro-sphinganine and the antitumor agent (+)-spisulosine, while the Overman rearrangement of chiral allylic trichloroacetimidates generated by asymmetric reduction of an alpha,beta-unsaturated methyl ketone allowed rapid access to both D-ribo-phytosphingosine and L-arabino-phytosphingosine

Principles of Periodontology

Periodontal diseases are among the most common diseases affecting humans. Dental biofilm is a contributor to the etiology of most periodontal diseases. It is also widely accepted that immunological and inflammatory responses to biofilm components are manifested by signs and symptoms of periodontal disease. The outcome of such interaction is modulated by risk factors (modifiers), either inherent (genetic) or acquired (environmental), significantly affecting the initiation and progression of different periodontal disease phenotypes. While definitive genetic determinants responsible for either susceptibility or resistance to periodontal disease have yet to be identified, many factors affecting the pathogenesis have been described, including smoking, diabetes, obesity, medications, and nutrition. Currently, periodontal diseases are classified based upon clinical disease traits using radiographs and clinical examination. Advances in genomics, molecular biology, and personalized medicine may result in new guidelines for unambiguous disease definition and diagnosis in the future. Recent studies have implied relationships between periodontal diseases and systemic conditions. Answering critical questions regarding host‐parasite interactions in periodontal diseases may provide new insight in the pathogenesis of other biomedical disorders. Therapeutic efforts have focused on the microbial nature of the infection, as active treatment centers on biofilm disruption by non‐surgical mechanical debridement with antimicrobial and sometimes anti‐inflammatory adjuncts. The surgical treatment aims at gaining access to periodontal lesions and correcting unfavorable gingival/osseous contours to achieve a periodontal architecture that will provide for more effective oral hygiene and periodontal maintenance. In addition, advances in tissue engineering have provided innovative means to regenerate/repair periodontal defects, based upon principles of guided tissue regeneration and utilization of growth factors/biologic mediators. To maintain periodontal stability, these treatments need to be supplemented with long‐term maintenance (supportive periodontal therapy) programs

Potent acyl-CoA synthetase 10 inhibitors kill <i>Plasmodium falciparum</i> by disrupting triglyceride formation

Identifying how small molecules act to kill malaria parasites can lead to new chemically validated targets. By pressuring Plasmodium falciparum asexual blood stage parasites with three novel structurally-unrelated antimalarial compounds (MMV665924, MMV019719 and MMV897615), and performing whole-genome sequence analysis on resistant parasite lines, we identify multiple mutations in the P. falciparum acyl-CoA synthetase (ACS) genes PfACS10 (PF3D7_0525100, M300I, A268D/V, F427L) and PfACS11 (PF3D7_1238800, F387V, D648Y, and E668K). Allelic replacement and thermal proteome profiling validates PfACS10 as a target of these compounds. We demonstrate that this protein is essential for parasite growth by conditional knockdown and observe increased compound susceptibility upon reduced expression. Inhibition of PfACS10 leads to a reduction in triacylglycerols and a buildup of its lipid precursors, providing key insights into its function. Analysis of the PfACS11 gene and its mutations point to a role in mediating resistance via decreased protein&nbsp;stability

MalDA, Accelerating Malaria Drug Discovery

© 2021 The Authors The Malaria Drug Accelerator (MalDA) is a consortium of 15 leading scientific laboratories. The aim of MalDA is to improve and accelerate the early antimalarial drug discovery process by identifying new, essential, druggable targets. In addition, it seeks to produce early lead inhibitors that may be advanced into drug candidates suitable for preclinical development and subsequent clinical testing in humans. By sharing resources, including expertise, knowledge, materials, and reagents, the consortium strives to eliminate the structural barriers often encountered in the drug discovery process. Here we discuss the mission of the consortium and its scientific achievements, including the identification of new chemically and biologically validated targets, as well as future scientific directions