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.FUNDINGThe following are funding sources NIH T32NS0007222, NIH R24DK082841, NIH R21NS102924, NIH R01DK115687, the Intramural Program of the NIDDK, the NeuroNetwork for Emerging Therapies, the Robert and Katherine Jacobs Environmental Health Initiative, the Robert E. Nederlander Sr. Program for Alzheimer’s Research, and the Sinai Medical Staff Foundation.TRIAL REGISTRATIONClinicalTrials.gov, NCT00340678.Despite the high morbidity and mortality among patients with extensive cutaneous burns in the intensive care unit due to the development of acute respiratory distress syndrome, effective therapeutics remain to be determined. This is primarily because the mechanisms leading to acute lung injury (ALI) in these patients remain unknown. We test the hypothesis that cutaneous chemical burns promote lung injury due to systemic activation of neutrophils, in particular, toxicity mediated by the deployment of neutrophil extracellular traps (NETs). We also demonstrate the potential benefit of a peptidyl arginine deiminase 4 (PAD4) inhibitor to prevent NETosis and to preserve microvascular endothelial barrier function, thus reducing the severity of ALI in mice. Our data demonstrated that phenylarsine oxide (PAO) treatment of neutrophils caused increased intracellular Ca2+-associated PAD4 activity. A dermal chemical burn by lewisite or PAO resulted in PAD4 activation, NETosis, and ALI. NETs disrupted the barrier function of endothelial cells in human lung microvascular endothelial cell spheroids. Citrullinated histone 3 alone caused ALI in mice. Pharmacologic or genetic abrogation of PAD4 inhibited lung injury following cutaneous chemical burns. Cutaneous burns by lewisite and PAO caused ALI by PAD4-mediated NETosis. PAD4 inhibitors may have potential as countermeasures to suppress detrimental lung injury after chemical burns.Excessive proliferation of vascular smooth muscle cells (SMCs) remains a significant cause of in-stent restenosis. Integrins, which are heterodimeric transmembrane receptors, play a crucial role in SMC biology by binding to the extracellular matrix protein with the actin cytoskeleton within the SMC. Integrin α9 plays an important role in cell motility and autoimmune diseases; however, its role in SMC biology and remodeling remains unclear. Herein, we demonstrate that stimulated human coronary SMCs upregulate α9 expression. Targeting α9 in stimulated human coronary SMCs, using anti-integrin α9 antibody, suppresses synthetic phenotype and inhibits SMC proliferation and migration. To provide definitive evidence, we generated an SMC-specific α9-deficient mouse strain. UBCS039 Genetic ablation of α9 in SMCs suppressed synthetic phenotype and reduced proliferation and migration in vitro. Mechanistically, suppressed synthetic phenotype and reduced proliferation were associated with decreased focal adhesion kinase/steroid receptor coactivator signaling and downstream targets, including phosphorylated ERK, p38 MAPK, glycogen synthase kinase 3β, and nuclear β-catenin, with reduced transcriptional activation of β-catenin target genes. Following vascular injury, SMC-specific α9-deficient mice or wild-type mice treated with murine anti-integrin α9 antibody exhibited reduced injury-induced neointimal hyperplasia at day 28 by limiting SMC migration and proliferation. Our findings suggest that integrin α9 regulates SMC biology, suggesting its potential therapeutic application in vascular remodeling.Individuals with heart failure (HF) frequently present with comorbidities, including obesity, insulin resistance, hypertension, and dyslipidemia. Many patients with HF experience cardiogenic dementia, yet the pathophysiology of this disease remains poorly understood. Using a swine model of cardiometabolic HF (Western diet+aortic banding; WD-AB), we tested the hypothesis that WD-AB would promote a multidementia phenotype involving cerebrovascular dysfunction alongside evidence of Alzheimer’s disease (AD) pathology. The results provide evidence of cerebrovascular insufficiency coupled with neuroinflammation and amyloidosis in swine with experimental cardiometabolic HF. Although cardiac ejection fraction was normal, indices of arterial compliance and cerebral blood flow were reduced, and cerebrovascular regulation was impaired in the WD-AB group. Cerebrovascular dysfunction occurred concomitantly with increased MAPK signaling and amyloidogenic processing (i.e., increased APP, BACE1, CTF, and Aβ40 in the prefrontal cortex and hippocampus) in the WD-AB group. Transcriptomic profiles of the stellate ganglia revealed the WD-AB group displayed an enrichment of gene networks associated with MAPK/ERK signaling, AD, frontotemporal dementia, and a number of behavioral phenotypes implicated in cognitive impairment. These provide potentially novel evidence from a swine model that cerebrovascular and neuronal pathologies likely both contribute to the dementia profile in a setting of cardiometabolic HF.

Kratom is a plant with partial opioid agonist effects, and its use has become popular to ameliorate symptoms of opioid withdrawal. However, use has been linked to thousands of poisonings, although most have involved use of other drugs. Little is known regarding prevalence and correlates of use in the general U.S.

Data were examined from the 2019 National Survey on Drug Use and Health, a nationally representative probability sample of non-institutionalized individuals aged ≥12 years in the U.S. (N=56,136). Prevalence and correlates of past-year kratom use were estimated. Data were analyzed in 2020.

An estimated 0.7% (95% CI=0.6, 0.8) of individuals in the U.S. have used kratom in the past year. Past-year proxy diagnosis of prescription opioid use disorder was associated with increased odds for kratom use (AOR=3.20, 95% CI=1.38, 7.41), with 10.4% (95% CI=6.7, 15.9) of those with use disorder reporting use. Opioid misuse not accompanied with use disorder was not associated with kratom use. Those reporting past-year cannabis use both with (AOR=4.33, 95% CI=2.61, 7.19) and without (AOR=4.57, 95% CI=3.29, 6.35) use disorder and those reporting past-year cocaine use (AOR=1.69, 95% CI=1.06, 2.69) and prescription stimulant misuse (AOR=2.10, 95% CI=1.44, 3.05) not accompanied with use disorder were at higher odds for kratom use.

Kratom use is particularly prevalent among those with prescription opioid use disorder, but it is also prevalent among people who use other drugs. Research is needed to determine reasons for use and potential dangers associated with adding kratom to drug repertoires.

Kratom use is particularly prevalent among those with prescription opioid use disorder, but it is also prevalent among people who use other drugs. Research is needed to determine reasons for use and potential dangers associated with adding kratom to drug repertoires.