Supporting the Bereaved in the COVID-19 Era: A Scoping Review of Interventions.

People whose family member(s) friend(s) have died from COVID-19 or other causes have been deeply affected by the physical and social restrictions imposed during the pandemic. These limitations have affected end-of-life care and support for the bereaved. The purpose of this review is to identify: the published studies of evaluated programs about interventions for people who have experienced bereavement during the COVID-19 pandemic, and to develop recommendations for researchers and policy makers. Using scoping review methodology, a literature review was undertaken for articles published from January 1, 2020 through February 28, 2023 to identify interventions shown to be beneficial to people who have experienced the death of loved ones during the COVID-19 pandemic. The search yielded 1588 articles of which three studies met the criteria of utilizing a pre and post-test design with only one of these, a randomized controlled trial. The interventions included in this review demonstrate preliminary efficacy.

Temporal Dynamics of Acute Stress-Induced Dendritic Remodeling in Medial Prefrontal Cortex and the Protective Effect of Desipramine.

Stressful events are associated with increased risk of mood disorders. Volumetric reductions have been reported in brain areas critical for the stress response, such as medial prefrontal cortex (mPFC), and dendritic remodeling has been proposed as an underlying factor. Here, we investigated the time-dependent effects of acute stress on dendritic remodeling within the prelimbic (PL) region of the PFC, and whether treatment with the antidepressant desipramine (DMI) may interfere. Rodents were subjected to foot-shock stress: dendritic length and spine density were analyzed 1 day, 7 days, and 14 days after stress. Acute stress produced increased spine density and decreased cofilin phosphorylation at 1 day, paralleled with dendritic retraction. An overall shift in spine population was observed at 1 day, resulting in a stress-induced increase in small spines. Significant atrophy of apical dendrites was observed at 1 day, which was prevented by chronic DMI, and at 14 days after stress exposure. Chronic DMI resulted in dendritic elaboration at 7 days but did not prevent the effects of FS-stress. Collectively, these data demonstrate that 1) acute stressors may induce rapid and sustained changes of PL neurons; and 2) chronic DMI may protect neurons from rapid stress-induced synaptic changes.

Over-expression of PRAS40 enhances insulin sensitivity in skeletal muscle.

CONTEXT: Silencing proline-rich Akt substrate of 40-kDa (PRAS40) impairs insulin signalling in skeletal muscle. OBJECTIVE: This study assessed the effects of over-expressing wild type or mutant AAA-PRAS40, in which the major phosphorylation sites and mTORC1-binding site were mutated, on insulin signalling in skeletal muscle. RESULTS: Over-expression of WT-PRAS40, but not AAA-PRAS40, impaired the insulin-mediated activation of the mTORC1-pathway in human skeletal muscle cells (hSkMC). However, insulin-mediated Akt-phosphorylation was increased upon over-expression of WT-PRAS40 both in hSkMC and mouse skeletal muscle. Also over-expression of AAA-PRAS40 had an insulin-sensitizing effect, although to a lesser extent as WT-PRAS40. The insulin-sensitizing effect associated with increased IRS1 protein abundance and inhibition of proteasome activity. Finally, over-expression of WT-PRAS40 reversed hyperinsulinemia-induced insulin resistance. CONCLUSION: This study identifies PRAS40 as a regulator of insulin sensitivity in hSkMC. In contrast to the mTORC1-pathway, the insulin-sensitizing action of PRAS40 occurs independent of binding of PRAS40 to the mTORC1-complex.

Adipocyte-derived factors impair insulin signaling in differentiated human vascular smooth muscle cells via the upregulation of miR-143.

Cardiovascular complications are common in patients with type 2 diabetes. Adipokines have been implicated in the induction of proliferative and pro-atherogenic alterations in human vascular smooth muscle cells (hVSMC). Other reports demonstrated the importance of the miRNA cluster miR-143/145 in the regulation of VSMC homeostasis and insulin sensitivity. Here we investigated whether the detrimental effects of adipokines on hVSMC function could be ascribed to alterations in miR-143/145 expression. The exposure of hVSMC to conditioned media (CM) from primary human subcutaneous adipocytes increased the expression of smooth muscle α-actin (SMA), and the miR-143/145 cluster, but markedly impaired the insulin-mediated phosphorylation of Akt and its substrate endothelial nitric oxide synthase (eNOS). Furthermore, CM promoted the phosphorylation of SMAD2 and p38, which have both been linked to miR-143/145 induction. Accordingly, the induction of miR-143/145 as well as the inhibition of insulin-mediated Akt- and eNOS-phosphorylation was prevented when hVSMC were treated with pharmacological inhibitors for Alk-4/5/7 and p38 before the addition of CM. The transfection of hVSMC with precursor miR-143, but not with precursor miR-145, resulted in impaired insulin-mediated phosphorylation of Akt and eNOS. This inhibition of insulin signaling by CM and miR-143 is associated with a reduction in the expression of the oxysterol-binding protein-related protein 8 (ORP8). Finally, the knock-down of ORP8 resulted in impaired insulin-mediated phosphorylation of Akt in hVSMC. Thus, the detrimental effects of adipocyte-derived conditioned media on insulin action in primary hVSMC can be ascribed to the Alk- and p38-dependent induction of miR-143 and subsequent downregulation of ORP8.

Activin A impairs insulin action in cardiomyocytes via up-regulation of miR-143.

AIMS: Enhanced activin A release from epicardial adipose tissue (EAT) has been linked to the development of cardiac dysfunction in type 2 diabetes (T2D). This study examined whether the inhibition of insulin action induced by epicardial adipokines in cardiomyocytes can be ascribed to alterations in miRNA expression. METHODS AND RESULTS: Expression levels of miRNAs were assessed by real-time PCR in primary adult rat cardiomyocytes (ARC) exposed to conditioned media generated from EAT biopsies (CM-EAT) from patients with and without T2D. CM-EAT-T2D altered the expression of eight miRNAs in ARC vs. CM-EAT from patients without T2D. Of these, only expression of the miR-143/145 cluster was affected by activin A in the same direction as CM-EAT-T2D. Accordingly, activin A neutralizing antibodies prevented the induction of the miR-143/145 cluster by CM-EAT-T2D. Subsequently, the impact of the miR-143/145 cluster on insulin action was investigated. Transfection of HL-1 cells with precursor-miR-143 (pre-miR-143), but not pre-miR-145, blunted the insulin-mediated phosphorylation of Akt and its substrate proline-rich Akt substrate of 40 kDa (PRAS40), and reduced insulin-stimulated glucose uptake. Also lentivirus-mediated expression of pre-miR-143 in ARC reduced insulin-induced Akt phosphorylation. These effects were ascribed to down-regulation of the miR-143 target and regulator of insulin action, the oxysterol-binding protein-related protein 8 (ORP8) in both ARC and HL-1 cells. Finally, LNA-anti-miR-143 protected against the detrimental effects of CM-EAT-T2D on insulin action in ARC. CONCLUSION: Activin A released from EAT-T2D inhibits insulin action via the induction of miR-143 in cardiomyocytes. This miRNA inhibits the Akt pathway through down-regulation of the novel regulator of insulin action, ORP8.

Cardioprotective properties of omentin-1 in type 2 diabetes: evidence from clinical and in vitro studies.

CONTEXT: Adipokines are linked to the development of cardiovascular dysfunction in type 2 diabetes (DM2). In DM2-patients, circulating levels of omentin-1, an adipokine preferentially expressed in epicardial adipose tissue, are decreased. This study investigated whether omentin-1 has a cardioprotective function. METHODS: Omentin-1 levels in plasma and cardiac fat depots were determined in DM2-patients versus controls. Moreover, the relation between omentin-1 levels and cardiac function was examined in men with uncomplicated DM2. Finally, we determined whether omentin-1 could reverse the induction of cardiomyocyte dysfunction by conditioned media derived from epicardial adipose tissue from patients with DM2. RESULTS: Omentin-1 was highly expressed and secreted by epicardial adipose tissue, and reduced in DM2. Circulating omentin-1 levels were lower in DM2 versus controls, and positively correlated with the diastolic parameters early peak filling rate, early deceleration peak and early deceleration mean (all P<0.05). The improved diastolic function following pioglitazone treatment associated with increases in omentin-1 levels (P<0.05). In vitro, exposure of cardiomyocytes to conditioned media derived from epicardial adipose tissue from patients with DM2 induced contractile dysfunction and insulin resistance, which was prevented by the addition of recombinant omentin. CONCLUSION: These data identify omentin-1 as a cardioprotective adipokine, and indicate that decreases in omentin-1 levels could contribute to the induction of cardiovascular dysfunction in DM2.

Secretory products from epicardial adipose tissue of patients with type 2 diabetes mellitus induce cardiomyocyte dysfunction.

BACKGROUND: Secreted factors from epicardial adipose tissue (EAT) have been implicated in the development of cardiomyocyte dysfunction. This study aimed to assess whether alterations in the secretory profile of EAT in patients with type 2 diabetes mellitus (DM2) affect contractile function and insulin action in cardiomyocytes. METHODS AND RESULTS: Contractile function and insulin action were analyzed in primary adult rat cardiomyocytes incubated with conditioned media (CM) generated from explants of EAT biopsies obtained from patients without and with DM2. CM from subcutaneous and pericardial adipose tissue biopsies from the same patients served as the control. Cardiomyocytes treated with CM (EAT) from DM2 patients showed reductions in sarcomere shortening, cytosolic Ca(2+) fluxes, expression of sarcoplasmic endoplasmic reticulum ATPase 2a, and decreased insulin-mediated Akt-Ser473-phosphorylation as compared with CM from the other groups. Profiling of the CM showed that activin A, angiopoietin-2, and CD14 selectively accumulated in CM-EAT-DM2 versus CM-EAT in patients without DM2 and CM from the other fat depots. Accordingly, EAT biopsies from DM2 patients were characterized by clusters of CD14-positive monocytes. Furthermore, SMAD2-phosphorylation, a downstream target of activin A signaling, was elevated in cardiomyocytes treated with CM (EAT) from DM2 patients, and the detrimental effects of CM (EAT) from DM2 patients were partially abolished in cardiomyocytes pretreated with a neutralizing antibody against activin A. Finally, both recombinant activin A and angiopoietin-2 reduced cardiomyocyte contractile function, but only activin A reduced the expression of sarcoplasmic endoplasmic reticulum ATPase 2a. CONCLUSIONS: Collectively, our data implicate DM2-related alterations in the secretory profile of EAT in the pathogenesis of diabetes mellitus-related heart disease.

Secretory products of guinea pig epicardial fat induce insulin resistance and impair primary adult rat cardiomyocyte function.

Epicardial adipose tissue (EAT) has been implicated in the development of heart disease. Nonetheless, the crosstalk between factors secreted from EAT and cardiomyocytes has not been studied. Here, we examined the effect of factors secreted from EAT on contractile function and insulin signalling in primary rat cardiomocytes. EAT and subcutaneous adipose tissue (SAT) were isolated from guinea pigs fed a high-fat (HFD) or standard diet. HFD feeding for 6 months induced glucose intolerance, and decreased fractional shortening and ejection fraction (all P < 0.05). Conditioned media (CM) generated from EAT and SAT explants were subjected to cytokine profiling using antibody arrays, or incubated with cardiomyocytes to assess the effects on insulin action and contractile function. Eleven factors were differentially secreted by EAT when compared to SAT. Furthermore, secretion of 30 factors by EAT was affected by HFD feeding. Most prominently, activin A-immunoreactivity was 6.4-fold higher in CM from HFD versus standard diet-fed animals and, 2-fold higher in EAT versus SAT. In cardiomyocytes, CM from EAT of HFD-fed animals increased SMAD2-phosphorylation, a marker for activin A-signalling, decreased sarcoplasmic-endoplasmic reticulum calcium ATPase 2a expression, and reduced insulin-mediated phosphorylation of Akt-Ser473 versus CM from SAT and standard diet-fed animals. Finally, CM from EAT of HFD-fed animals as compared to CM from the other groups markedly reduced sarcomere shortening and cytosolic Ca(2+) fluxes in cardiomyocytes. These data provide evidence for an interaction between factors secreted from EAT and cardiomyocyte function.