The externalizing and internalizing pathways to marijuana use initiation: Examining the synergistic effects of impulsiveness and sensation seeking.

Adolescent marijuana use has become increasingly more problematic compared with the past; thus, understanding developmental processes that increase the liability of marijuana use is essential. Two developmental pathways to adolescent substance use have been proposed: an externalizing pathway that emphasizes the expression of aggressive and delinquent behavior, and an internalizing pathway that emphasizes the role of depressive symptoms and negative affect. In this study, we aimed to examine the synergistic role of impulsiveness and sensation seeking in the two risk pathways to determine whether both high and low levels of the traits are risk factors for marijuana use. Our study included 343 adolescents (52% were girls, 78% identified as Hispanic) that oversampled high-risk youth (78% had a family history of substance use disorder), assessed biannually between the ages of 13-16 years old. Moderated mediation analyses revealed that high levels of sensation seeking indirectly predicted marijuana use through higher mean levels of externalizing behavior. The positive relationship between sensation seeking and externalizing behavior was only significant at high levels of impulsiveness. Conversely, low levels of sensation seeking indirectly predicted marijuana use through higher mean levels of internalizing behavior. The negative relationship between sensation seeking and internalizing behavior was only significant at low levels of impulsiveness. Collectively, these results demonstrate that high and low levels of both impulsiveness and sensation seeking confer increased risk of marijuana use, albeit through different mechanisms. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The Development of Externalizing and Internalizing Behaviors Among Youth With or Without a Family History of Substance Use Disorder: The Indirect Effects of Early-Life Stress and Impulsivity.

Youth with a family history of substance use disorder (FH+) are more prone to have externalizing and internalizing problems compared to youth without a family history of substance use disorder (FH-), increasing the likelihood of later maladjustment. However, mechanisms for this association remain understudied. In this longitudinal study, we examined if FH+ youth are more likely to experience early-life stressors (ELS), which in turn would increase impulsivity and the expression of externalizing and internalizing behaviors. Data were collected from youth and a parent (n = 386) during a baseline assessment (age 10-12 years) and every six months when the youth was 13-16 years old. In support of the primary hypothesis, FH+ youth reported higher levels of externalizing and internalizing behaviors through ELS to impulsivity providing a developmental pathway through which FH+ youth are more prone to externalizing and internalizing problems.

Induction of heme oxygenase-1 modulates the profibrotic effects of transforming growth factor-beta in human renal tubular epithelial cells.

Transforming growth factor-beta (TGF-beta) is implicated in a variety of kidney diseases where it promotes extracellular matrix (ECM) deposition and pro-inflammatory events, but it also stabilizes and attenuates tissue injury through the activation of cytoprotective proteins, including heme oxygenase-1 (HO-1). HO-1 catalyzes the conversion of heme into carbon monoxide (CO), iron, and biliverdin, which is subsequently converted to bilirubin. The beneficial effects of HO-1 induction include decreasing pro-oxidants (heme), increasing anti-oxidants (biliverdin and bilirubin), and producing a vasodilator with anti-apoptotic and anti-inflammatory properties (CO). The reaction products of HO-1 may also have antifibrogenic properties. The purpose of this study is to explore the effects of HO-1 expression and its reaction products on fibronectin, an ECM protein, in the kidney. The results demonstrate that kidneys of HO-1 knockout mice express significantly more fibronectin protein as compared to heterozygote mice. A potent inducer of HO-1, hemin, significantly decreases fibronectin protein with a concomitant increase in HO-1 protein. Cells expressing HO-1, via TGF-beta1 induction, have reduced fibronectin expression. Bilirubin, a product of the heme oxygenase reaction, attenuates TGF-beta1-mediated increases in fibronectin expression. These results indicate that HO-1 induction and activity may modulate the production of ECM components and suggest a potential role for TGF-beta-mediated HO-1 induction in attenuating renal fibrosis.

Mechanism of heme oxygenase-1 gene induction by curcumin in human renal proximal tubule cells.

Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme degradation, releasing iron, carbon monoxide, and biliverdin. Induction of HO-1 occurs as an adaptive and protective response to several inflammatory stimuli. The transcription factor activator protein-1 (AP-1) has been implicated in the activation of the HO-1 gene. To elucidate the molecular mechanism of HO-1 induction, we examined the effects of diferuloylmethane (curcumin), an inhibitor of the transcription factor AP-1. Surprisingly, curcumin by itself was a very potent inducer of HO-1. Curcumin has anti-inflammatory, antioxidant, and renoprotective effects. To evaluate the mechanism of curcumin-mediated induction of HO-1, confluent human renal proximal tubule cells were exposed to curcumin (1-8 microM). We observed a time- and dose-dependent induction of HO-1 mRNA that was associated with increased HO-1 protein. Coincubation of curcumin with actinomycin D completely blocked the upregulation of HO-1 mRNA. Blockade of nuclear factor-kappaB (NF-kappaB) with an IkappaBalpha phosphorylation inhibitor attenuated curcumin-mediated induction of HO-1 mRNA and protein. These data demonstrate that curcumin induces HO-1 mRNA and protein in renal proximal tubule cells. HO-1 induction by curcumin is mediated, at least in part, via transcriptional mechanisms and involves the NF-kappaB pathway.

Smad7-dependent regulation of heme oxygenase-1 by transforming growth factor-beta in human renal epithelial cells.

Heme oxygenase-1 (HO-1), a 32-kDa microsomal enzyme, is induced as a beneficial and adaptive response in cells/tissues exposed to oxidative stress. Transforming growth factor-beta1 (TGF-beta1) is a regulatory cytokine that has been implicated in a variety of renal diseases where it promotes extracellular matrix deposition and proinflammatory events. We hypothesize that the release of TGF-beta1 via autocrine and/or paracrine pathways may induce HO-1 and serve as a protective response in renal injury. To understand the molecular mechanism of HO-1 induction by TGF-beta1, we exposed confluent human renal proximal tubule cells to TGF-beta1 and observed a significant induction of HO-1 mRNA at 4 h with a maximal induction at 8 h. This induction was accompanied by increased expression of HO-1 protein. TGF-beta1 treatment in conjunction with actinomycin D or cycloheximide demonstrated that induction of HO-1 mRNA requires de novo transcription and, in part, protein synthesis. Exposure to TGF-beta1 resulted in marked induction of Smad7 mRNA with no effect on Smad6 expression. Overexpression of Smad7, but not Smad6, inhibited TGF-beta1-mediated induction of endogenous HO-1 gene expression. We speculate that the induction of HO-1 in the kidney is an adaptive response to the inflammatory effects of TGF-beta1 and manipulations of the Smad pathway to alter HO-1 expression may serve as a potential therapeutic target.

Angiotensin II-stimulated nitric oxide release from porcine pulmonary endothelium is mediated by angiotensin IV.

In this study, a nitric oxide (NO) sensor was used to examine the ability of angiotensin II (AngII), AngIV, and bradykinin (Bk) to stimulate NO release from porcine pulmonary artery (PPAE) and porcine aortic endothelial (PAE) cells and to explore the mechanism of the AngII-stimulated NO release. Physiologic concentrations of AngII, but not Bk, caused release of NO from PPAE cells. In contrast, Bk, but not AngII, stimulated NO release from PAE cells. AngIII-stimulated NO release from PPAE cells required extracellular L-arginine and was inhibited by L-nitro-arginine methyl ester. AT1 and AT2 receptor inhibition had no affect on AngII-mediated NO release or activation of NO synthase (NOS). AngIV, an AngII metabolite with binding sites that are pharmacologically distinct from the classic AngII receptors, stimulated considerably greater NO release and greater endothelial-type constitutive NOS activity than the same amount of AngII. The AngIV receptor antagonist, divalinal AngIV, blocked both AngII- and AngIV-mediated NO release as well as NOS activation. The results demonstrate that AngIV and the AngIV receptor are responsible, at least in part, for AngII-stimulated NO release and the associated endothelium-dependent vasorelaxation. Furthermore, these results suggest that differences exist in both AngII- and Bk-mediated NO release between PPAE and PAE cells, which may reflect important differences in response to these hormones between vascular beds.