Attenuated maladaptive emotion processing as a potential mediator of the relationship between dispositional mindfulness and mental health.

The emotion processing and regulation mechanisms by which dispositional (personality trait) mindfulness exerts its positive effects on mental health remain unclear. Here, we tested, using structural equation modeling, whether the relationship between higher dispositional mindfulness and better mental health is mediated by reduced maladaptive processing of emotional information (e.g., expressive suppression, impoverished emotional experiences, unprocessed emotions, avoidance, externalizing strategies) and associated lower negative affect, enhanced adaptive processing of emotional information (e.g., cognitive reappraisal) and associated higher positive affect, or a combination of these two emotion processing styles. Dispositional mindfulness, mental health, diverse emotional constructs with adaptive and maladaptive dimensions (including range and differentiation of emotional experiences, use of specific emotion regulation strategies, emotion processing deficits, negative affect repair strategies, negative mood regulation expectancies), and positive and negative affect were assessed using self-report measures in a non-clinical sample of 256 adults. The relationship between higher dispositional mindfulness and better mental health was found to be best explained by reduced maladaptive emotion processing styles and associated lower negative affect, rather than by enhanced adaptive emotion processing and higher positive affect. Further research should investigate whether the same mechanisms explain psychological benefits of cultivated mindfulness in people with low dispositional mindfulness and/or with mental health disorders following mindfulness skills training.

Is Future Mental Imagery Associated with Reduced Impact of the COVID-19 Pandemic on Negative Affect and Anhedonic Symptoms in Young People?

Background: Difficulties with prospective mental images are associated with adolescent depression. Current treatments mainly focus on verbal techniques to reduce negative affect (e.g. low mood) rather than enhancing positive affect, despite anhedonia being present in adolescents. We investigated the concurrent relationships between the vividness of negative and positive prospective mental imagery and negative affect and positive affect; and examined whether negative and positive prospective mental imagery moderated the impact of recent stress (COVID-19-linked stress) on negative and positive affect. Methods: 2602 young people (12-25 years) completed the Prospective Imagery Task and self-reported on symptoms of negative affect, anhedonia and COVID-19 linked stress. Results: Elevated vividness of negative future mental imagery and reduced vividness of positive future mental imagery were associated with increased negative affect, whereas only reduced vividness of positive future imagery was associated with increased symptoms of anhedonia. Elevated vividness of negative future images amplified the association between COVID-19 linked stress and negative affect, while elevated vividness of positive future images attenuated the association between COVID-19 linked stress and anhedonia. Conclusions: Future mental imagery may be differentially associated with negative and positive affect, but this needs to be replicated in clinical populations to support novel adolescent psychological treatments. Supplementary Information: The online version contains supplementary material available at 10.1007/s10608-023-10352-1.

Biogenesis of P-TEFb in CD4+ T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways.

The switch between HIV latency and productive transcription is regulated by an auto-feedback mechanism initiated by the viral trans-activator Tat, which functions to recruit the host transcription elongation factor P-TEFb to proviral HIV. A heterodimeric complex of CDK9 and one of three cyclin T subunits, P-TEFb is expressed at vanishingly low levels in resting memory CD4+ T cells and cellular mechanisms controlling its availability are central to regulation of the emergence of HIV from latency. Using a well-characterized primary T-cell model of HIV latency alongside healthy donor memory CD4+ T cells, we characterized specific T-cell receptor (TCR) signaling pathways that regulate the generation of transcriptionally active P-TEFb, defined as the coordinate expression of cyclin T1 and phospho-Ser175 CDK9. Protein kinase C (PKC) agonists, such as ingenol and prostratin, stimulated active P-TEFb expression and reactivated latent HIV with minimal cytotoxicity, even in the absence of intracellular calcium mobilization with an ionophore. Unexpectedly, inhibition-based experiments demonstrated that PKC agonists and TCR-mobilized diacylglycerol signal through MAP kinases ERK1/2 rather than through PKC to effect the reactivation of both P-TEFb and latent HIV. Single-cell and bulk RNA-seq analyses revealed that of the four known isoforms of the Ras guanine nucleotide exchange factor RasGRP, RasGRP1 is by far the predominantly expressed diacylglycerol-dependent isoform in CD4+ T cells. RasGRP1 should therefore mediate the activation of ERK1/2 via Ras-Raf signaling upon TCR co-stimulation or PKC agonist challenge. Combined inhibition of the PI3K-mTORC2-AKT-mTORC1 pathway and the ERK1/2 activator MEK prior to TCR co-stimulation abrogated active P-TEFb expression and substantially suppressed latent HIV reactivation. Therefore, contrary to prevailing models, the coordinate reactivation of P-TEFb and latent HIV in primary T cells following either TCR co-stimulation or PKC agonist challenge is independent of PKC but rather involves two complementary signaling arms of the TCR cascade, namely, RasGRP1-Ras-Raf-MEK-ERK1/2 and PI3K-mTORC2-AKT-mTORC1.

Consumption of hydrolyzable tannins-rich pomegranate extract suppresses inflammation and joint damage in rheumatoid arthritis.

OBJECTIVE: Although consumption of dietary supplements containing pomegranate extract (POMx) by patients with arthritis is on the rise, the efficacy of such preparations in suppressing joint inflammation and damage is not known. The present study was designed to evaluate a standardized preparation of POMx using collagen-induced arthritis (CIA) in mice, a widely used animal model of rheumatoid arthritis. METHODS: CIA-susceptible DBA/1 mice were fed POMx by gavage before and after immunization with chicken type II collagen. Severity of clinical arthritis was scored using a visual scoring system. Arthritic joints were analyzed by histopathology and graded. Lysates were generated from mouse joints and levels of anti-type II collagen immunoglobulin G and inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha were quantified by enzyme-linked immunosorbent assay. The effect of POMx on lipopolysaccharide-induced nitric oxide production was determined by Griess reaction and mitogen-activated protein kinase activation was studied by western immunoblotting in mouse macrophages. RESULTS: Consumption of POMx potently delayed the onset and reduced the incidence of CIA in mice. Severity of arthritis was also significantly lower in POMx-fed animals. Histopathology of the arthritic joints from POMx-fed mice demonstrated reduced joint infiltration by the inflammatory cells, and the destruction of bone and cartilage were alleviated. Levels of IL-6 were significantly decreased in the joints of POMx-fed mice with CIA. In mouse macrophages, POMx abrogated multiple signal transduction pathways and downstream mediators implicated in the pathogenesis of rheumatoid arthritis. CONCLUSION: Our studies suggest that inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular response by POMx or compounds derived from it may be a useful approach for the prevention of the onset and severity of inflammatory arthritis.

Chondroprotective effects of a proanthocyanidin rich Amazonian genonutrient reflects direct inhibition of matrix metalloproteinases and upregulation of IGF-1 production by human chondrocytes.

BACKGROUND: The Amazonian medicinal plant Sangre de grado (Croton palanostigma) has traditional applications for the treatment of wound healing and inflammation. We sought to characterize two extracts (progrado and zangrado) in terms of safety and oligomeric proanthocyanidin chain length. Additionally progrado was evaluated for antioxidant activity and possible chondroprotective actions. METHODS: Acute oral safety and toxicity was tested in rats according under OECD protocol number 420. The profile of proanthocyanidin oligomers was determined by HPLC and progrado's antioxidant activity quantified by the ORAC, NORAC and HORAC assays. Human cartilage explants, obtained from surgical specimens, were used to assess chondroproteciton with activity related to direct inhibitory effects on human matrix metalloproteinase (MMP, gelatinolytic) activity using synovial fluid and chondrocytes activated with IL-1beta (10 ng/ml). Additionally, progrado (2-10 mug/ml) was tested for its ability to maintain optimal IGF-1 transcription and translation in cartilage explants and cultured chondrocytes. RESULTS: Both progrado and zangrado at doses up to 2000 mg/kg (po) displayed no evidence of toxicity. Oligomeric proanthocyanidin content was high for both progrado (158 mg/kg) and zangrado (124 mg/kg), with zangrado almost entirely composed of short oligomers (<6 mer), whereas the majority of oligomers in progrado exceeded 10 mers. Progrado was a remarkably potent antioxidant in the standardized tests ORAC, NORAC and HORAC. Progrado was exceptionally effective in reducing both basal and IL-1beta induced glycosaminoglycan release from human cartilage explants at concentrations that also directly blocked the gelatinolytic activity of MMP-2 and MMP-9. Progrado prevented IL-1beta induced suppression of IGF-1 production from human cartilage explants as well as stimulating basal IGF-1 production (P < 0.05). Comparable changes in IGF-1 gene expression were noted in cultured human chondrocytes. CONCLUSION: Progrado has a promising safety profile, significant chondroprotective and antioxidant actions, directly inhibits MMP activity and promotes the production of the cartilage repair factor, IGF-1. This suggests that progrado may offer therapeutic benefits in joint health, wound healing and inflammation.