A Pilot, Virtual Exercise Intervention Improves Health and Fitness during the COVID-19 Pandemic

International Journal of Exercise Science 15(7): 1395-1417, 2022. Physical activity levels are low in individuals with chronic disease (e.g., obesity) and have worsened during the COVID-19 pandemic. Purpose: Our pilot study tested a virtual exercise intervention for rural-dwelling adults with chronic disease from January-April 2021 for changes in mental health, physical fitness, and physical activity and for intervention fidelity. Methods: Participants (n = 8 [7 female]; age = 57.5 ± 13.8 years, body mass index = 38.2 ± 8.0 kg/m2) completed an exercise intervention led virtually by collegiate health science majors. Participants attended two 60-minute sessions/week for 12 weeks, completing individually-tailored and progressed aerobic and muscle-strengthening training. A non-randomized control group matched on gender and age continued normal activity during the 12 weeks. Changes in mental health, physical fitness, and physical activity measures were evaluated using a 2x2 (group x time) analysis of covariance. Results: Both groups improved mental health, but only intervention participants lost weight (3.1 ± 1.0 kg; no change in controls). Step test, arm curls, and chair stands improved by 16.1-20.6% in the intervention and 7.8-12.1% in the control groups. Intervention participants did not increase overall physical activity during or after the intervention. Intervention fidelity was high; participants attended ~73% of sessions and rated the sessions 4.7 ± 0.6 (out of 5). Researcher observations rated exercise sessions as meeting 12.7 ± 0.6 of 16 goals. Conclusions: Our virtual exercise program was associated with positive mental health and physical fitness changes. Such programs may provide a method, even beyond the pandemic, to improve fitness in adults with chronic disease

Matrix Product Eigenstates for One-Dimensional Stochastic Models and Quantum Spin Chains

We show that all zero energy eigenstates of an arbitrary $m$--state quantum spin chain Hamiltonian with nearest neighbor interaction in the bulk and single site boundary terms, which can also describe the dynamics of stochastic models, can be written as matrix product states. This means that the weights in these states can be expressed as expectation values in a Fock representation of an algebra generated by $2m$ operators fulfilling $m^2$ quadratic relations which are defined by the Hamiltonian.Comment: 11 pages, Late

Implementation of Epigenetic Variation in Sorghum Selection and Implications for Crop Resilience Breeding

Crop resilience and yield stability are complex traits essential for food security. Sorghum bicolor is an important grain crop that shows promise for its natural resilience to drought and potential for marginal land production. We have developed sorghum lines in the Tx430 genetic background suppressed for MSH1 expression as a means of inducing de novo epigenetic variation, and have used these materials to evaluate changes in plant growth vigor. Plant crossing and selection in two distinct environments revealed features of phenotypic plasticity derived from MSH1 manipulation. Introduction of an epigenetic variation to an isogenic sorghum population, in the absence of selection, resulted in 10% yield increase under ideal field conditions and 20% increase under extreme low nitrogen conditions. However, incorporation of early-stage selection amplified these outcomes to 36% yield increase under ideal conditions and 64% increase under marginal field conditions. Interestingly, the best outcomes were derived by selecting mid-range performance early-generation lines rather than highest performing. Data also suggested that phenotypic plasticity derived from the epigenetic variation was nonuniform in its response to environmental variability but served to reduce genotype x environment interaction. The MSH1-derived growth vigor appeared to be associated with enhanced seedling root growth and altered expression of auxin response pathways, and plants showed evidence of cold tolerance, features consistent with observations made previously in Arabidopsis. These data imply that the MSH1 system is conserved across plant species, pointing to the value of parallel model plant studies to help devise effective plant selection strategies for epigenetic breeding in multiple crops

Inhibiting heat-shock protein 90 reverses sensory hypoalgesia in diabetic mice

Increasing the expression of Hsp70 (heat-shock protein 70) can inhibit sensory neuron degeneration after axotomy. Since the onset of DPN (diabetic peripheral neuropathy) is associated with the gradual decline of sensory neuron function, we evaluated whether increasing Hsp70 was sufficient to improve several indices of neuronal function. Hsp90 is the master regulator of the heat-shock response and its inhibition can up-regulate Hsp70. KU-32 (N-{7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy]-8-methyl-2-oxo-2H-chromen-3-yl}acetamide) was developed as a novel, novobiocin-based, C-terminal inhibitor of Hsp90 whose ability to increase Hsp70 expression is linked to the presence of an acetamide substitution of the prenylated benzamide moiety of novobiocin. KU-32 protected against glucose-induced death of embryonic DRG (dorsal root ganglia) neurons cultured for 3 days in vitro. Similarly, KU-32 significantly decreased neuregulin 1-induced degeneration of myelinated Schwann cell DRG neuron co-cultures prepared from WT (wild-type) mice. This protection was lost if the co-cultures were prepared from Hsp70.1 and Hsp70.3 KO (knockout) mice. KU-32 is readily bioavailable and was administered once a week for 6 weeks at a dose of 20 mg/kg to WT and Hsp70 KO mice that had been rendered diabetic with streptozotocin for 12 weeks. After 12 weeks of diabetes, both WT and Hsp70 KO mice developed deficits in NCV (nerve conduction velocity) and a sensory hypoalgesia. Although KU-32 did not improve glucose levels, HbA1c (glycated haemoglobin) or insulin levels, it reversed the NCV and sensory deficits in WT but not Hsp70 KO mice. These studies provide the first evidence that targeting molecular chaperones reverses the sensory hypoalgesia associated with DPN.This work was supported by grants from the Juvenile Diabetes Research Foundation and the National Institutes of Health [NS054847 and DK073594] (to R.T.D.) and [CA120458 and CA109265] (to B.S.J.B.)

Engineering an Antibiotic to Fight Cancer: Optimization of the Novobiocin Scaffold to Produce Anti-Proliferative Agents

Development of the DNA gyrase inhibitor, novobiocin, into a selective Hsp90 inhibitor was accomplished through structural modifications to the amide side chain, coumarin ring, and sugar moiety. These species exhibit ~700-fold improved anti-proliferative activity versus the natural product as evaluated by cellular efficacies against breast, colon, prostate, lung, and other cancer cell lines. Utilization of structure–activity relationships established for three novobiocin synthons produced optimized scaffolds, which manifest mid-nanomolar activity against a panel of cancer cell lines and serve as lead compounds that manifest their activities through Hsp90 inhibition

Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells

Background: The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance resulting from induction of the heat shock response (HSR) has led to both scheduling and administration concerns. Therefore, Hsp90 inhibitors that do not induce the heat shock response represent a promising new direction for the treatment of prostate cancer. Herein, the development of a C-terminal Hsp90 inhibitor, KU174, is described, which demonstrates anti-cancer activity in prostate cancer cells in the absence of a HSR and describe a novel approach to characterize Hsp90 inhibition in cancer cells. Methods: PC3-MM2 and LNCaP-LN3 cells were used in both direct and indirect in vitro Hsp90 inhibition assays (DARTS, Surface Plasmon Resonance, co-immunoprecipitation, luciferase, Western blot, anti-proliferative, cytotoxicity and size exclusion chromatography) to characterize the effects of KU174 in prostate cancer cells. Pilot in vivo efficacy studies were also conducted with KU174 in PC3-MM2 xenograft studies. Results: KU174 exhibits robust anti-proliferative and cytotoxic activity along with client protein degradation and disruption of Hsp90 native complexes without induction of a HSR. Furthermore, KU174 demonstrates direct binding to the Hsp90 protein and Hsp90 complexes in cancer cells. In addition, in pilot in-vivo proof-of-concept studies KU174 demonstrates efficacy at 75 mg/kg in a PC3-MM2 rat tumor model. Conclusions: Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for the treatment of prostate cancer

A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice

This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on 2015 February 13; 347(6223): 779–784, DOI: 10.1126/science.aaa0314.Acute myeloid leukemia (AML) is the most common form of adult leukemia. The transcription factor fusion CBFβ-SMMHC (core binding factor β and the smooth-muscle myosin heavy chain), expressed in AML with the chromosome inversion inv(16)(p13q22), outcompetes wild-type CBFβ for binding to the transcription factor RUNX1, deregulates RUNX1 activity in hematopoiesis, and induces AML. Current inv(16) AML treatment with nonselective cytotoxic chemotherapy results in a good initial response but limited long-term survival. Here, we report the development of a protein-protein interaction inhibitor, AI-10-49, that selectively binds to CBFβ-SMMHC and disrupts its binding to RUNX1. AI-10-49 restores RUNX1 transcriptional activity, displays favorable pharmacokinetics, and delays leukemia progression in mice. Treatment of primary inv(16) AML patient blasts with AI-10-49 triggers selective cell death. These data suggest that direct inhibition of the oncogenic CBFβ-SMMHC fusion protein may be an effective therapeutic approach for inv(16) AML, and they provide support for transcription factor targeted therapy in other cancers

A Second Generation 2-Methoxyestradiol Prodrug Is Effective Against Barrett's Adenocarcinoma in a Mouse Xenograft Model

This is the author's accepted manuscript. The original is available at http://mct.aacrjournals.org/content/12/3/2552-Methoxyestradiol (2-ME2) is an endogenous metabolite of estradiol. In preclinical models, 2-ME2 is effective against different types of tumors. Unfortunately, only low systemic concentrations of 2-ME2 can be achieved following oral administration, even after very high doses are administered to patients. In an effort to solve this problem we have now synthesized and tested a new prodrug of 2-ME2 that is water soluble due to a bio-reversible hydrophilic group added at the 3-position and more effectively resists metabolic inactivation due to an ester moiety added to mask the 17-position alcohol. We are reporting here for the first time that this double prodrug of 2-ME2 is effective as an antiproliferative and anti-cancer agent for both in vitro and in vivo studies against Barrett's esophageal adenocarcinoma (BEAC), and provided greater potency than 2-ME2 in inhibiting the growth of BEAC xenografts. Finally, studies indicate that, like 2-ME2, the 2-ME2-PD1 exhibits anticancer effect through possible disruption of microtubule-network

Inhibiting heat-shock protein 90 reverses sensory hypoalgesia in diabetic mice

Increasing the expression of Hsp70 (heat-shock protein 70) can inhibit sensory neuron degeneration after axotomy. Since the onset of DPN (diabetic peripheral neuropathy) is associated with the gradual decline of sensory neuron function, we evaluated whether increasing Hsp70 was sufficient to improve several indices of neuronal function. Hsp90 is the master regulator of the heat-shock response and its inhibition can up-regulate Hsp70. KU-32 (N-{7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy]-8-methyl-2-oxo-2H-chromen-3-yl}acetamide) was developed as a novel, novobiocin-based, C-terminal inhibitor of Hsp90 whose ability to increase Hsp70 expression is linked to the presence of an acetamide substitution of the prenylated benzamide moiety of novobiocin. KU-32 protected against glucose-induced death of embryonic DRG (dorsal root ganglia) neurons cultured for 3 days in vitro. Similarly, KU-32 significantly decreased neuregulin 1-induced degeneration of myelinated Schwann cell DRG neuron co-cultures prepared from WT (wild-type) mice. This protection was lost if the co-cultures were prepared from Hsp70.1 and Hsp70.3 KO (knockout) mice. KU-32 is readily bioavailable and was administered once a week for 6 weeks at a dose of 20 mg/kg to WT and Hsp70 KO mice that had been rendered diabetic with streptozotocin for 12 weeks. After 12 weeks of diabetes, both WT and Hsp70 KO mice developed deficits in NCV (nerve conduction velocity) and a sensory hypoalgesia. Although KU-32 did not improve glucose levels, HbA1c (glycated haemoglobin) or insulin levels, it reversed the NCV and sensory deficits in WT but not Hsp70 KO mice. These studies provide the first evidence that targeting molecular chaperones reverses the sensory hypoalgesia associated with DPN