Mechanisms underlying the cytotoxicity of a novel quinazolinedione‐based redox modulator, QD 232, in pancreatic cancer cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109817/1/bph12855.pd

Preclinical Evaluation of Novel Triphenylphosphonium Salts with Broad-Spectrum Activity

BACKGROUND: Recently, there has been a surge of interest in developing compounds selectively targeting mitochondria for the treatment of neoplasms. The critical role of mitochondria in cellular metabolism and respiration supports this therapeutic rationale. Dysfunction in the processes of energy production and metabolism contributes to attenuation of response to pro-apoptotic stimuli and increased ROS production both of which are implicated in the initiation and progression of most human cancers. METHODOLOGY/PRINCIPAL FINDINGS: A high-throughput MTT-based screen of over 10,000 drug-like small molecules for anti-proliferative activity identified the phosphonium salts TP187, 197 and 421 as having IC₅₀ concentrations in the submicromolar range. TP treatment induced cell cycle arrest independent of p53 status, as determined by analysis of DNA content in propidium iodide stained cells. In a mouse model of human breast cancer, TP-treated mice showed significantly decreased tumor growth compared to vehicle or paclitaxel treated mice. No toxicities or organ damage were observed following TP treatment. Immunohistochemical staining of tissue sections from TP187-treated tumors demonstrated a decrease in cellular proliferation and increased caspase-3 cleavage. The fluorescent properties of analog TP421 were exploited to assess subcellular uptake of TP compounds, demonstrating mitochondrial localization. Following mitochondrial uptake cells exhibited decreased oxygen consumption and concomittant increase in mitochondrial superoxide production. Proteomics analysis of results from a 600 target antibody microarray demonstrated that TP compounds significantly affected signaling pathways relevant to growth and proliferation. CONCLUSIONS/SIGNIFICANCE: Through our continued interest in designing compounds targeting cancer-cell metabolism, the Warburg effect, and mitochondria we recently discovered a series of novel, small-molecule compounds containing a triphenylphosphine moiety that show remarkable activity in a panel of cancer cell lines as well as in a mouse model of human breast cancer. The mechanism of action includes mitochondrial localization causing decreased oxygen consumption, increased superoxide production and attenuated growth factor signaling

Efficacy of mHealth aided 12-week meditation and breath intervention on change in burnout and professional quality of life among health care providers of a tertiary care hospital in north India: a randomized waitlist-controlled trial

IntroductionBurnout is “Chronic workplace stress that has not been successfully managed.” Professional quality of life (PQL) includes work related experiences of compassion satisfaction and compassion fatigue. Healthcare providers (HCPs) are highly susceptible to burnout and compassion fatigue due to their demanding work, which lowers PQL. Burnout leads to poor care, medical errors, and patient safety across healthcare disciplines. Yoga has been shown to improve resilience, reduce stress, and increase self-compassion and psycho-physiological coherence. This study compared HCPs in a mHealth-aided 12-week yoga-based meditation and breath intervention to waitlist controls for HCP burnout and PQL at a north Indian tertiary care hospital.MethodsThis was randomized waitlist-controlled trial. Total 98 HCPs (62 males and 36 females) with an average age of 28.26 ± 3.547 years were enrolled consecutively from March 2021 to November 2022. Randomization was done with opaque sealed envelopes numbered in a computer-generated sequence. The experimental group (n = 49) received 12 online weekly yoga sessions and performed daily home practice (6 days a week). The waitlisted control group (n = 49) continued their daily routine. Maslach’s burnout inventory (MBI), professional quality of life (PQL) and anthropometric measurements were assessed at baseline and after 12 weeks.ResultsAfter 12 weeks, the MBI outcomes of emotional exhaustion, depersonalization, and personal accomplishment showed a highly significant difference between the two groups (p < 0.001). PQL outcomes of compassion satisfaction, burnout, and secondary trauma also differed significantly (p < 0.001). Within group analysis showed that MBI and PQL outcomes improved significantly (p < 0.001) for the experimental group after 12 weeks.ConclusionThe current study contributes to the existing evidence on the effectiveness of Yoga in managing stress and developing resilience among doctors, nurses, and other medical professionals. Integrating yoga into healthcare settings is crucial for addressing the detrimental impact of burnout on decision-making and promoting positive patient outcomes. mHealth technologies have the potential to enhance the user-friendliness of yoga-based interventions by personalizing the practice space and time. Yoga-based interventions and mHealth technologies can effectively address physician burnout, in a simple and implementable manner

Πλοηγούμαι πλέκοντας αποσπάσματα : τέσσερα παιχνίδια που θέλουν να βγουν από το σπίτι

<p>Results of TP421 proteomics screen for proteins whose total abundances were decreased in response to TP421 treatment.</p

Two atypical presentations of lepra reactions

Leprosy or Hansen's disease is a chronic infectious granulomatous disease with varied presentation, especially in the setting of lepra reactions. We report two such atypical presentations each of Type I and Type II Lepra reactions; the first being an elderly male presenting with fever, while the second case being of a young boy being evaluated for cervical lymphadenitis

Design and discovery of novel quinazolinedione-based redox modulators as therapies for pancreatic cancer

Background: Altered cellular bioenergetics and oxidative stress are emerging hallmarks of most cancers including pancreatic cancer. Elevated levels of intrinsic reactive oxygen species (ROS) in tumors make them more susceptible to exogenously induced oxidative stress. Excessive oxidative insults overwhelm their adaptive antioxidant capacity and trigger ROS-mediated cell death. Recently, we have discovered a novel class of quinazolinediones that exert their cytotoxic effects by modulating ROS-mediated signaling. Methods: Cytotoxic potential was determined by colorimetric and colony formation assays. An XF24 Extracellular Flux Analyzer, and colorimetric and fluorescent techniques were used to assess the bioenergetics and oxidative stress effects, respectively. Mechanism was determined by Western blots. Results: Compound 3a (6-[(2-acetylphenyl)amino]quinazoline-5,8-dione) was identified through a medium throughput screen of ~ 1000 highly diverse in-house compounds and chemotherapeutic agents for their ability to alter cellular bioenergetics. Further structural optimizations led to the discovery of a more potent analog, 3b (6-[(3-acetylphenyl)amino]quinazoline-5,8-dione) that displayed anti-proliferative activities in low micromolar range in both drug-sensitive and drug-resistant cancer cells. Treatment with 3b causes Akt activation resulting in increased cellular oxygen consumption and oxidative stress in pancreatic cancer cells. Moreover, oxidative stress induced by 3b promoted activation of stress kinases (p38/JNK) resulting in cancer cell death. Treatment with antioxidants was able to reduce cell death confirming ROS-mediated cytotoxicity. Conclusion: In conclusion, our novel quinazolinediones are promising lead compounds that selectively induce ROS-mediated cell death in cancer cells and warrant further preclinical studies.</br

Sparsity-Based Pixel Super Resolution for Lens-Free Digital In-line Holography

Lens-free digital in-line holography (LDIH) is a promising technology for portable, wide field-of-view imaging. Its resolution, however, is limited by the inherent pixel size of an imaging device. Here we present a new computational approach to achieve sub-pixel resolution for LDIH. The developed method is a sparsity-based reconstruction with the capability to handle the non-linear nature of LDIH. We systematically characterized the algorithm through simulation and LDIH imaging studies. The method achieved the spatial resolution down to one-third of the pixel size, while requiring only single-frame imaging without any hardware modifications. This new approach can be used as a general framework to enhance the resolution in nonlinear holographic systems

Top ranked HGF signaling pathway.

<p>Molecules in green are down-regulated in our microarray results while those in red are up-regulated. Proteins whose phosphorylation level was affected by TP421 treatment are denoted by *.</p