Pathogenic infections and tissue injuries trigger the assembly of inflammasomes, cytosolic protein complexes that activate caspase-1, leading to cleavage of pro-IL-1β and pro-IL-18 and to pyroptosis, ...a proinflammatory cell death program. Although microbial recognition by Toll-like receptors (TLRs) is known to induce the synthesis of the major caspase-1 substrate pro-IL-1β, the role of TLRs has been considered limited to up-regulation of the inflammasome components. During infection with a virulent microbe, TLRs and nucleotide-binding oligomerization domain-like receptors (NLRs) are likely activated simultaneously. To examine the requirements and outcomes of combined activation, we stimulated TLRs and a specific NLR, nucleotide binding and oligomerization, leucine-rich repeat, pyrin domain-containing 3 (NLRP3), simultaneously and discovered that such activation triggers rapid caspase-1 cleavage, leading to secretion of presynthesized inflammatory molecules and pyroptosis. This acute caspase-1 activation is independent of new protein synthesis and depends on the TLR-signaling molecule IL-1 receptor-associated kinase (IRAK-1) and its kinase activity. Importantly, Listeria monocytogene s induces NLRP3-dependent rapid caspase-1 activation and pyroptosis, both of which are compromised in IRAK-1–deficient macrophages. Our results reveal that simultaneous sensing of microbial ligands and virulence factors by TLRs and NLRP3, respectively, leads to a rapid TLR- and IRAK-1–dependent assembly of the NLRP3 inflammasome complex, and that such activation is important for release of alarmins, pyroptosis, and early IFN-γ production by memory CD8 T cells, all of which could be critical for early host defense.
To explore the prevalence of obesity among American Indian and Alaska Native (AIAN) adolescents aged 12-19 years in association with social determinants of health (SDOH), and mental health and ...substance use disorders.
Guided by the World Health Organization's Social Determinants of Health Framework, we examined data from the Indian Health Service (IHS) Improving Health Care Delivery Data Project from Fiscal Year 2013, supplemented by county-level data from the U.S. Census and USDA. Our sample included 26,226 AIAN adolescents ages 12-19 years. We described obesity prevalence in relationship to SDOH and adolescents' mental health and substance use disorder status. We then fit a multivariable logit generalized linear mixed model to estimate the relationships after adjusting for other individual and county level characteristics.
We observed a prevalence of 32.5% for obesity, 13.8% for mental health disorders, and 5.5% for substance use disorders. Females had lower odds of obesity than males (OR = 0.76, p < 0.001), which decreased with age. Having Medicaid coverage (OR = 1.09, p < 0.01), residing in a county with lower education attainment (OR = 1.17, p < 0.05), and residing in a county with higher rates of poverty (OR = 1.51, p < 0.001) were each associated with higher odds of obesity. Residing in a county with high access to a grocery store (OR = 0.73, p < 0.001) and residing in a county with a higher proportion of AIANs (OR = 0.83, p < 0.01) were each associated with lower odds of obesity. Those with mental health disorders had higher odds of obesity (OR = 1.26, p < 0.001); substance use disorders were associated with decreased odds of obesity (OR = 0.73, p < 0.001).
Our findings inform future obesity prevention and treatment programs among AIAN youth; in particular, the need to consider mental health, substance use, and SDOH.
Colonial historical trauma and ongoing structural racism have impacted Indigenous peoples for generations and explain the ongoing health disparities. However, Indigenous peoples have been engaging in ...multilevel, clinical trial interventions with Indigenous and allied research scientists resulting in promising success. In this paper, National Institutes of Health funded scientists in the field of Indigenous health have sought to describe the utility and need for multilevel interventions across Indigenous communities (Jernigan et al., 2020). We posit limitations to the existing socioecological, multilevel frameworks and propose a dynamic, interrelated heuristic framework, which focuses on the inter-relationships of the collective within the environment and de-centers the individual. We conclude with identified calls for action within multilevel clinical trial research.
The Diabetes Prevention Program (DPP) has been shown to prevent type 2 diabetes through lifestyle modification. The purpose of this study was to describe the literature on DPP translation, ...synthesizing studies using cultural adaptation and implementation research. A systematic search was conducted. Original studies evaluating DPP implementation and/or cultural adaptation were included. Data about cultural adaptation, implementation outcomes, and translation strategies was abstracted. A total of 44 were included, of which 15 reported cultural adaptations and 38 explored implementation. Many studies shortened the program length and reported a group format. The most commonly reported cultural adaptation (13 of 15) was with content. At the individual level, the most frequently assessed implementation outcome (
n
= 30) was adoption. Feasibility was most common (
n
= 32) at the organization level. The DPP is being tested in a variety of settings and populations, using numerous translational strategies and cultural adaptations. Implementation research that identifies, evaluates, and reports efforts to translate the DPP into practice is crucial.
Caveolae, lipid-rich microdomains of the sarcolemma, localize and enrich cardiac-protective signaling molecules. Caveolin-3 (Cav-3), the dominant isoform in cardiac myocytes, is a determinant of ...caveolar formation. We hypothesized that cardiac myocyte-specific overexpression of Cav-3 would enhance the formation of caveolae and augment cardiac protection in vivo.
Ischemic preconditioning in vivo increased the formation of caveolae. Adenovirus for Cav-3 increased caveolar formation and phosphorylation of survival kinases in cardiac myocytes. A transgenic mouse with cardiac myocyte-specific overexpression of Cav-3 (Cav-3 OE) showed enhanced formation of caveolae on the sarcolemma. Cav-3 OE mice subjected to ischemia/reperfusion injury had a significantly reduced infarct size relative to transgene-negative mice. Endogenous cardiac protection in Cav-3 OE mice was similar to wild-type mice undergoing ischemic preconditioning; no increased protection was observed in preconditioned Cav-3 OE mice. Cav-3 knockout mice did not show endogenous protection and showed no protection in response to ischemic preconditioning. Cav-3 OE mouse hearts had increased basal Akt and glycogen synthase kinase-3beta phosphorylation comparable to wild-type mice exposed to ischemic preconditioning. Wortmannin, a phosphoinositide 3-kinase inhibitor, attenuated basal phosphorylation of Akt and glycogen synthase kinase-3beta and blocked cardiac protection in Cav-3 OE mice. Cav-3 OE mice had improved functional recovery and reduced apoptosis at 24 hours of reperfusion.
Expression of caveolin-3 is both necessary and sufficient for cardiac protection, a conclusion that unites long-standing ultrastructural and molecular observations in the ischemic heart. The present results indicate that increased expression of caveolins, apparently via actions that depend on phosphoinositide 3-kinase, has the potential to protect hearts exposed to ischemia/reperfusion injury.
Indigenous food sovereignty and security are essential to Indigenous health and cultural perpetuity. Revitalization of traditional foodways can counteract the negative impacts of colonial food ...practices and policies on the health of Indigenous peoples. A mixed methods survey was conducted to describe the data needs of people working in Indigenous nutrition related fields. Results showed that nutrition education, academic scholarship, and community projects were the most frequently used data categories. With improved access, projects-in-progress and raw data would be utilized for reference and staying current. The most common barrier was not knowing where or how to access information. Raw research data, research, projects-in-progress, and tribal policy were the most difficult to access. The study concludes that an online Food Wisdom Repository can contribute to health equity by improving access to Indigenous knowledge and wise practices, cultivating culturally appropriate data sharing, and sustaining and extending current work in the field.
(1) Background: Settler colonialism has severely disrupted Indigenous ancestral ways of healing and being, contributing to an onslaught of health disparities. In particular, the United Houma Nation ...(UHN) has faced large land loss and trauma, dispossession, and marginalization. Given the paucity of research addressing health for Indigenous individuals living in Louisiana, this study sought to co-identify a United Houma Nation health framework, by co-developing a community land-based healing approach in order to inform future community-based health prevention programs. (2) Methods: This pilot tested, co-designed and implemented a land-based healing pilot study among Houma women utilizing a health promotion leadership approach and utilized semi-structured interviews among 20 UHN women to identify a UHN health framework to guide future results. (3) Results: The findings indicated that RTOR was a feasible pilot project. The initial themes were (1.) place, (2.) environmental/land trauma, (3.) ancestors, (4.) spirituality/mindfulness, (5.) cultural continuity, and (6.) environment and health. The reconnection to land was deemed feasible and seen as central to renewing relationships with ancestors (aihalia asanochi taha), others, and body. This mindful, re-engagement with the land contributed to subthemes of developing stronger tribal identities, recreating ceremonies, and increased cultural continuity, and transforming narratives of trauma into hope and resilience. Based on these findings a Houma Health (Uma Hochokma) Framework was developed and presented. (4) Conclusions: Overall, this study found that land can serve as a feasible therapeutic site for healing through reconnecting Houma tribal citizens to both ancestral knowledges and stories of resilience, as well as viewing self as part of a larger collective. These findings also imply that revisiting historically traumatic places encouraged renewed commitment to cultural continuity and health behaviors—particularly when these places are approached relationally, with ceremony, and traumatic events tied to these places, including climate change and environmental/land trauma, are acknowledged along with the love the ancestors held for future generations.
Abstract Volatile anesthetics protect the heart from ischemia/reperfusion injury but the mechanisms for this protection are poorly understood. Caveolae, sarcolemmal invaginations, and caveolins, ...scaffolding proteins in caveolae, localize molecules involved in cardiac protection. We tested the hypothesis that caveolae and caveolins are essential for volatile anesthetic-induced cardiac protection using cardiac myocytes (CMs) from adult rats and in vivo studies in caveolin-3 knockout mice (Cav-3−/− ). We incubated CM with methyl-β-cyclodextrin (MβCD) or colchicine to disrupt caveolae formation, and then exposed the myocytes to the volatile anesthetic isoflurane (30 min, 1.4%), followed by simulated ischemia/reperfusion (SI/R). Isoflurane protected CM from SI/R 23.2 ± 1.6% vs. 71.0 ± 5.8% cell death (assessed by trypan blue exclusion), P < 0.001 but this protection was abolished by MβCD or colchicine (84.9 ± 5.5% and 64.5 ± 6.1% cell death, P < 0.001). Membrane fractionation by sucrose density gradient centrifugation of CM treated with MβCD or colchicine revealed that buoyant (caveolae-enriched) fractions had decreased phosphocaveolin-1 and caveolin-3 compared to control CM. Cardiac protection in vivo was assessed by measurement of infarct size relative to the area at risk and cardiac troponin levels. Isoflurane-induced a reduction in infarct size and cardiac troponin relative to control (infarct size: 26.5% ± 2.6% vs. 45.3% ± 5.4%, P < 0.01; troponin: 27.7 ± 4.4 vs. 77.7 ± 11.8 ng/ml, P < 0.05). Isoflurane-induced cardiac protection was abolished in Cav-3−/− mice (infarct size: 53.4% ± 6.1% vs. 53.2% ± 3.5%, P < 0.01; troponin: 102.1 ± 22.3 vs. 105.9 ± 8.2 ng/ml, P < 0.01). Isoflurane-induced cardiac protection is thus dependent on the presence of caveolae and the expression of caveolin-3. We conclude that caveolae and caveolin-3 are critical for volatile anesthetic-induced protection of the heart from ischemia/reperfusion injury.
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