Impaired cardiovascular function during acute myocardial infarction (MI) is partly associated with recruitment of activated polymorphonuclear neutrophils. The protective role of arjunolic acid (AA; 2:3:23-Trihydroxy olean-12-en-28-oic acid) is studied in the modulation of neutrophil functions in vitro by measuring the reactive oxygen species (ROS) generation. Neutrophils were isolated from normal and acute MI mice to find out the efficacy of AA in reducing oxidative stress. Stimulation of neutrophils with phorbol-12-myristate-13-acetate (PMA) resulted in an oxidative burst of superoxide anion (O2•−) and enhanced release of lysosomal enzymes. The treatment of neutrophils with PMA induced phosphorylation of Ser345 on p47phox, a cytosolic component of NADPH oxidase. Furthermore, we observed activated ERK induced phosphorylation of Ser345 in MI neutrophils. Treatment with AA significantly inhibited the phosphorylation of P47phox and ERK in the stimulated controls and MI neutrophils. Oxidative phosphorylation activities in MI cells were lower than in control, while the glycolysis rates were elevated in MI cells compared to the control. In addition, we observed AA decreased intracellular oxidative stress and reduced the levels of O2•− in neutrophils. This study therefore identifies targets for AA in activated neutrophils mediated by the MAPK pathway on p47phox involved in ROS generation.

Spinal muscular atrophy (SMA) is a rare, autosomal recessive neuromuscular degenerative disease characterized by loss of spinal cord motor neurons leading to progressive muscle wasting. The most common pathology results from a homozygous disruption in the survival motor neuron 1 (SMN1) gene on chromosome 5q13 via deletion, conversion, or mutation. SMN2 is a near duplicate of SMN1 that can produce full-length SMN mRNA transcripts, but its overall production capability of these mRNA transcripts is lower than that seen in SMN1. This leads to lower levels of functional SMN protein within motor neurons. The FDA approved nusinersen in December 2016 to treat SMA associated with SMN1 gene mutation. It is administered directly to the central nervous system by intrathecal injection. An antisense oligonucleotide (ASO) drug, nusinersen, provides an upcoming and promising treatment option for SMA and represents a novel pharmacological approach with a mechanism of action relevant for other neurodegenerative disorders. Nusinersen begins with four initial loading doses that are followed by three maintenance doses per year. Three major studies (CHERISH, ENDEAR, and NURTURE) have shown to improve motor function in early and late-onset individuals and reduce the chances of ventilator requirements in pre-symptomatic infants. Studies investigating the timing of drug delivery in mouse models of SMA report the best outcomes when drugs are delivered early before any significant motor function is lost. Nusinersen is a novel therapeutic approach with consistent results in all three studies and is proof of the novel concept for treating SMA and other neurodegenerative disorders in the future.

No abstract

Background The COVID-19 pandemic revealed a substantial and unmet need for low-cost, easily accessible mechanical ventilation strategies for use in medical resource-challenged areas. Internationally, several groups developed non-conventional COVID-19 era emergency ventilator strategies as a stopgap measure when conventional ventilators were unavailable. Here, we compared our FALCON emergency ventilator in a rabbit model and compared its safety and functionality to conventional mechanical ventilation. Methods New Zealand white rabbits (n = 5) received mechanical ventilation from both the FALCON and a conventional mechanical ventilator (Engström Carestation™) for 1 h each. Airflow and pressure, blood O2 saturation, end tidal CO2, and arterial blood gas measurements were measured. Additionally, gross and histological lung samples were compared to spontaneously breathing rabbits (n = 3) to assess signs of ventilator induced lung injury. Results All rabbits were successfully ventilated with the FALCON. At identical ventilator settings, tidal volumes, pressures, and respiratory rates were similar between both ventilators, but the inspiratory to expiratory ratio was lower using the FALCON. End tidal CO2 was significantly higher on the FALCON, and arterial blood gas measurements demonstrated lower arterial partial pressure of O2 at 30 min and higher arterial partial pressure of CO2 at 30 and 60 min using the FALCON. However, when ventilated at higher respiratory rates, we observed a stepwise decrease in end tidal CO2. Poincaré plot analysis demonstrated small but significant increases in short-term and long-term variation of peak inspiratory pressure generation from the FALCON. Wet to dry lung weight and lung injury scoring between the mechanically ventilated and spontaneously breathing rabbits were similar. Conclusions Although conventional ventilators are always preferable outside of emergency use, the FALCON ventilator safely and effectively ventilated healthy rabbits without lung injury. Emergency ventilation using accessible and inexpensive strategies like the FALCON may be useful for communities with low access to medical resources and as a backup form of emergency ventilation.

Lysophosphatidic acid (LPA) is a naturally occurring glycerophospholipid and has been reported to increase heart rate and left ventricular pressure in the heart in vivo . The primary route of circulating LPA production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin (ATX). Lipid phosphate phosphatase-3 (LPP3) is a plasma membrane enzyme that regulates the availability of LPA by dephosphorylation. We made the novel discovery that tissue-specific deficiency of Ppap2b (gene that encodes LPP3) leads to embryonic lethality (endothelial LPP3), exaggerates vascular inflammation, increases heart rate, enhances endothelial permeability, and promotes the development of the neointima after vascular injury. Based on our earlier reports, we have generated mice that specifically lack LPP3 in cardiomyocytes. These mice showed early mortality ~8 months due to cardiac dysfunction. Whereas lack of LPP1 or LPP2 (global knockouts) didn’t had any obvious phenotypic effect. Lack of LPP3 accounts for less than 10 percent activity in cardiomyocytes purified from the Myh6-Ppap2b Δ , which augments our previous finding that the other two LPP isoforms have a lesser role in the cardiovascular system. Blood pressure was similar in Ppap2b fl/fl (96 ± 9 mmHg; n = 19) and Myh6-Ppap2b Δ mice (92 ± 7 mmHg; n = 19), although heart rates were significantly higher in Myh6-Ppap2b Δ 3-month old mice (642 ± 21 bpm, compared to Ppap2b fl/fl with 600± 17 bpm; P<0.001). Knockdown of LPP3 enhanced cardiomyocyte hypertrophy induced by LPA based on analysis of sarcomere organization, cell surface area, levels of fetal genes ANP and BNP, and ANF release from nuclei, which are hallmarks of cardiomyocyte hypertrophy, indicating that LPP3 negatively regulates cardiac dysfunction caused by LPA. We observed an increase in ATX levels accompanied by a decrease in LPP3 expression following infarction in the myocardium of Ppap2b fl/fl mice. Infarction induced expression of IL-6 and KC, were 3 ± 0.5-fold and 2 ± 0.6-fold higher, respectively, in Myh6-Ppap2b Δ mice. Analysis of plasma by cytokine antibody array confirmed the elevation in IL-6 and KC, whereas G-CSF and sICAM-1 appeared lower than in Ppap2b fl/fl .