Cardiomyocyte electrical-mechanical synchronized model for high-content, dose-quantitative and time-dependent drug assessment

Cardiovascular diseases have emerged as a significant threat to human health. However, drug development is a time-consuming and costly process, and few drugs pass the preclinical assessment of safety and efficacy. The existing patch-clamp, Ca2+ imaging, and microelectrode array technologies in cardiomyocyte models for drug preclinical screening have suffered from issues of low throughput, limited long-term assessment, or inability to synchronously and correlatively analyze electrical and mechanical signals. Here, we develop a high-content, dose-quantitative and time-dependent drug assessment platform based on an electrical-mechanical synchronized (EMS) biosensing system. This microfabricated EMS can record both firing potential (FP) and mechanical beating (MB) signals from cardiomyocytes and extract a variety of characteristic parameters from these two signals (FP–MB) for further analysis. This system was applied to test typical ion channel drugs (lidocaine and isradipine), and the dynamic responses of cardiomyocytes to the tested drugs were recorded and analyzed. The high-throughput characteristics of the system can facilitate simultaneous experiments on a large number of samples. Furthermore, a database of various cardiac drugs can be established by heat map analysis for rapid and effective screening of drugs. The EMS biosensing system is highly promising as a powerful tool for the preclinical development of new medicines.

Critical NIH Resources to Advance Therapies for Pain: Preclinical Screening Program and Phase II Human Clinical Trial Network

Opioid-related death and overdose have now reached epidemic proportions. In response to this public health crisis, the National Institutes of Health (NIH) launched the Helping to End Addiction Long-term InitiativeSM, or NIH HEAL InitiativeSM, an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis. Herein, we describe two NIH HEAL Initiative programs to accelerate development of non-opioid, non-addictive pain treatments: The Preclinical Screening Platform for Pain (PSPP) and Early Phase Pain Investigation Clinical Network (EPPIC-Net). These resources are provided at no cost to investigators, whether in academia or industry and whether within the USA or internationally. Both programs consider small molecules, biologics, devices, and natural products for acute and chronic pain, including repurposed and combination drugs. Importantly, confidentiality and intellectual property are protected. The PSPP provides a rigorous platform to identify and profile non-opioid, non-addictive therapeutics for pain. Accepted assets are evaluated in in vitro functional assays to rule out opioid receptor activity and to assess abuse liability. In vivo pharmacokinetic studies measure plasma and brain exposure to guide the dose range and pretreatment times for the side effect profile, efficacy, and abuse liability. Studies are conducted in accordance with published rigor criteria. EPPIC-Net provides academic and industry investigators with expert infrastructure for phase II testing of pain therapeutics across populations and the lifespan. For assets accepted after a rigorous, objective scientific review process, EPPIC-Net provides clinical trial design, management, implementation, and analysis.

Animal Models of Adenomyosis

Adenomyosis is a nonmalignant uterine disorder in which endometrial tissue exists within and grows into the myometrium. Animal models have generated limited insight into the still-unclear pathogenesis of adenomyosis, provided a platform for preclinical screening of many drugs and compounds with potential as therapeutics, and elucidated mechanisms underlying the pain and fertility issues that occur in many women with the disease. Spontaneous adenomyosis has been studied in nonhuman primates, primarily in the form of case reports. Adenomyosis is routinely experimentally induced in mice through methods such as neonatal tamoxifen exposure, pituitary engraftment, and human tissue xenotransplantation. Several studies have also reported hormonal or environmental toxicant exposures that give rise to murine adenomyosis, and genetically engineered models have been created that recapitulate the human-like condition, most notably involving alteration of β-catenin expression. This review describes the animal models for adenomyosis and their contributions to our understanding of the factors underpinning the development of symptoms. Animal models represent a unique opportunity for understanding the molecular basis of adenomyosis and developing efficacious treatment options for affected women. Herein, we assess their different potentials and limitations with regard to identification of new therapeutic interventions and reflect on future directions for research and drug validation.

Effect of DNA methylation modulators on the production of osteoprotegerin by rheumatoid fibroblast-like synoviocytes in vitro: their migration and invasion

Objective. The purpose of the research was to study the effect of DNA methylation modulators on the production of proinflammatory cytokines by fibroblast-like synovial cells (FLC).Materials and methods. We used the cells derived from the synovial tissue of 6 patients with active rheumatoid arthritis (RA) after 3–7 in vitro culturing passages.Results. There was an IL-1β-induced up-regulation of osteoprotegerin (OPG) synthesis in the RA FLC cultures. The addition of methylating compounds S-Adenosyl methionine (SAMe) and genistein into the cultures resulted in a statistically significant decrease in the production of OPG, while the addition of the demethylating agent hydralazine did not change the synthesis of the cytokine. All three DNA methylation modulators used at different concentrations significantly reduced the percentage of spontaneous migration and invasion of FLC in the Boyden chamber.Conclusion. Enzymes and molecular complexes involved in DNA methylation could be potential therapeutic targets, and in vitro FLC cultures of RA patients can be used as a model for preclinical screening of new drug compounds.