With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage.

Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintain protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensure cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, with a concentration on cardioprotection, neuroprotection, cancer, and autoimmune diseases. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.

Greater Loss of Central Adiposity from Low-Carbohydrate versus Low-Fat Diet in Middle-Aged Adults with Overweight and Obesity.

The objective of this study is to determine whether middle-aged adults prescribed a low carbohydrate-high fat (LCHF) or low fat (LF) diet would have greater loss of central fat and to determine whether the insulin resistance (IR) affects intervention response. A total of 50 participants (52.3 ± 10.7 years old; 36.6 ± 7.4 kg/m2 BMI; 82% female) were prescribed either a LCHF diet (n = 32, carbohydrate: protein: fat of 5%:30%:65% without calorie restriction), or LF diet (n = 18, 63%:13-23%: 10-25% with calorie restriction of total energy expenditure-500 kcal) for 15 weeks. Central and regional body composition changes from dual-x-ray absorptiometry and serum measures were compared using paired t-tests and ANCOVA with paired contrasts. IR was defined as homeostatic model assessment (HOMA-IR) > 2.6. Compared to the LF group, the LCHF group lost more android (15.6 ± 11.2% vs. 8.3 ± 8.1%, p < 0.01) and visceral fat (18.5 ± 22.2% vs. 5.1 ± 15.8%, p < 0.05). Those with IR lost more android and visceral fat on the LCHF verses LF group (p < 0.05). Therefore, the clinical prescription to a LCHF diet may be an optimal strategy to reduce disease risk in middle-aged adults, particularly those with IR.

Rapid Throughput Concentration-Response Analysis of Human Taste Discrimination.

Human taste threshold measurements often are used to infer tastant receptor functionality. However, taste thresholds can be influenced by receptor-independent variables. Examination of the full range of taste-active concentrations by taste discrimination has been hampered by logistics of testing multiple concentrations in replicate with human subjects. We developed an automated rapid throughput operant methodology for taste discrimination and applied it to concentration-response analysis of human taste. Tastant solutions (200 µl) drawn from a 96-well plate and self-administered to the tongue served as discriminative stimuli for money-reinforced responses on a touch-sensitive display. Robust concentration-response functions for "basic taste" stimuli were established, with particular focus on agonists of the taste 1 receptor member 2-taste 1 receptor member 3 heterodimer receptor (TAS1R2/R3). With a training cue of 100 mM sucrose, EC50 values of 56, 79, and 310 µM and 40 mM were obtained for rebaudioside A, sucralose, acesulfame potassium, and sucrose, respectively. Changing the sucrose training cue to 300 mM had no impact, but changing to 30 mM resulted in slight leftward shifts in potencies. A signal detection method also was used to determine values of d', a probabilistic value for discriminability, which indicated that 5 mM was near the limits of detection for sucrose. With repeated testing, both EC50 values and 5 mM sucrose d' values were established for each individual subject. The results showed little correspondence between threshold sensitivities and EC50 values for sucrose. We conclude that concentration-response analysis of taste discrimination provides a more reliable means of inferring receptor function than measurement of discriminability at the lowest detectable tastant concentrations. SIGNIFICANCE STATEMENT: Many inferences about human tastant receptor functionality have been made from taste threshold measurements, which can be influenced by variables unrelated to receptors. We herein report a new methodology that enables rigorous concentration-response analysis of human taste discrimination and its use toward quantitative characterization of tastant agonist activity. Our data suggest that taste discrimination concentration-response functions are a more reliable reflection of underlying receptor activity than threshold measures obtained at the lowest detectable tastant concentrations.

Effects of weight loss during a very low carbohydrate diet on specific adipose tissue depots and insulin sensitivity in older adults with obesity: a randomized clinical trial.

BACKGROUND: Insulin resistance and accumulation of visceral adipose tissue (VAT) and intermuscular adipose tissue (IMAT) place aging adults with obesity at high risk of cardio-metabolic disease. A very low carbohydrate diet (VLCD) may be a means of promoting fat loss from the visceral cavity and skeletal muscle, without compromising lean mass, and improve insulin sensitivity in aging adults with obesity. OBJECTIVE: To determine if a VLCD promotes a greater loss of fat (total, visceral and intermuscular), preserves lean mass, and improves insulin sensitivity compared to a standard CHO-based/low-fat diet (LFD) in older adults with obesity. DESIGN: Thirty-four men and women aged 60-75 years with obesity (body mass index [BMI] 30-40 kg/m2) were randomized to a diet prescription of either a VLCD (< 10:25:> 65% energy from CHO:protein:fat) or LFD diet (55:25:20) for 8 weeks. Body composition by dual-energy X-ray absorptiometry (DXA), fat distribution by magnetic resonance imaging (MRI), insulin sensitivity by euglycemic hyperinsulinemic clamp, and lipids by a fasting blood draw were assessed at baseline and after the intervention. RESULTS: Participants lost an average of 9.7 and 2.0% in total fat following the VLCD and LFD, respectively (p < 0.01). The VLCD group experienced ~ 3-fold greater loss in VAT compared to the LFD group (- 22.8% vs - 1.0%, p < 0.001) and a greater decrease in thigh-IMAT (- 24.4% vs - 1.0%, p < 0.01). The VLCD group also had significantly greater thigh skeletal muscle (SM) at 8 weeks following adjustment for change in total fat mass. Finally, the VLCD had greater increases in insulin sensitivity and HDL-C and decreases in fasting insulin and triglycerides compared to the LFD group. CONCLUSIONS: Weight loss resulting from consumption of a diet lower in CHO and higher in fat may be beneficial for older adults with obesity by depleting adipose tissue depots most strongly implicated in poor metabolic and functional outcomes and by improving insulin sensitivity and the lipid profile. TRIAL REGISTRATION: NCT02760641. Registered 03 May 2016 - Retrospectively registered.

Drug antagonism and single-agent dominance result from differences in death kinetics.

Cancer treatment generally involves drugs used in combinations. Most previous work has focused on identifying and understanding synergistic drug-drug interactions; however, understanding antagonistic interactions remains an important and understudied issue. To enrich for antagonism and reveal common features of these combinations, we screened all pairwise combinations of drugs characterized as activators of regulated cell death. This network is strongly enriched for antagonism, particularly a form of antagonism that we call 'single-agent dominance'. Single-agent dominance refers to antagonisms in which a two-drug combination phenocopies one of the two agents. Dominance results from differences in cell death onset time, with dominant drugs acting earlier than their suppressed counterparts. We explored mechanisms by which parthanatotic agents dominate apoptotic agents, finding that dominance in this scenario is caused by mutually exclusive and conflicting use of Poly(ADP-ribose) polymerase 1 (PARP1). Taken together, our study reveals death kinetics as a predictive feature of antagonism, due to inhibitory crosstalk between cell death pathways.