Extracellular vesicles (EVs) are known as molecular carriers involved in cell communication and the regulation of (patho)physiological processes. miRNAs and growth factors are the main contents of ...EVs which make them a good candidate for the treatment of diseases caused by ischemia, but the low production of EVs by a cell producer and a significant variation of the molecular contents in EVs according to the cell source are the main limitations of their widespread use. Here, we show how to improve the therapeutic properties of mesenchymal stromal cell (MSC)-derived EVs (MSC-EVs) by modifying MSCs to enrich these EVs with specific angiomiRs (miR-135b or miR-210) using lentiviral vectors carrying miR-135b or miR-210. MSCs were obtained from the mouse bone marrow and transduced with a corresponding lentivector to overexpress miR-135b or miR-210. The EVs were then isolated by ultracentrifugation and characterized using a flow cytometer and a nanoparticle tracking analyzer. The levels of 20 genes in the MSCs and 12 microRNAs in both MSCs and EVs were assessed by RT‒qPCR. The proangiogenic activity of EVs was subsequently assessed in human umbilical vein endothelial cells (HUVECs). The results confirmed the overexpression of the respective microRNA in modified MSCs. Moreover, miR-135b overexpression upregulated miR-210-5p and follistatin, whereas the overexpression of miR-210 downregulated miR-221 and upregulated miR-296. The tube formation assay showed that EVs from MSCs overexpressing miR-210-5p (EVmiR210) significantly promoted tubular structure formation in HUVECs. A significant increase in angiogenic proteins (PGF, endothelin 1, and artemin) and genes (VEGF, activin A, and IGFBP1) in HUVECs treated with VEmiR210 justifies the better tubular structure formation of these cells compared with that of EVmiR135b-treated HUVECs, which showed upregulated expression of only artemin. Collectively, our results show that the EV cargo can be modified by lentiviral vectors to enrich specific miRNAs to achieve a specific angiogenic potential.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
1,8-Cineole is a naturally occurring compound found in essential oils of different plants and has well-known anti-inflammatory and antimicrobial activities. In the present work, we aimed to ...investigate its potential antimalarial effect, using the following experimental models: (1) the erythrocytic cycle of Plasmodium falciparum; (2) an adhesion assay using brain microvascular endothelial cells; and (3) an experimental cerebral malaria animal model induced by Plasmodium berghei ANKA infection in susceptible mice. Using the erythrocytic cycle of Plasmodium falciparum, we characterized the schizonticidal effect of 1,8-cineole. This compound decreased parasitemia in a dose-dependent manner with a half maximal inhibitory concentration of 1045.53 ± 63.30 μM. The inhibitory effect of 972 μM 1,8-cineole was irreversible and independent of parasitemia. Moreover, 1,8-cineole reduced the progression of intracellular development of the parasite over 2 cycles, inducing important morphological changes. Ultrastructure analysis revealed a massive loss of integrity of endomembranes and hemozoin crystals in infected erythrocytes treated with 1,8-cineole. The monoterpene reduced the adhesion index of infected erythrocytes to brain microvascular endothelial cells by 60%. Using the experimental cerebral malaria model, treatment of infected mice for 6 consecutive days with 100 mg/kg/day 1,8-cineole reduced cerebral edema with a 50% reduction in parasitemia. Our data suggest a potential antimalarial effect of 1,8-cineole with an impact on the parasite erythrocytic cycle and severe disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The U.S. is experiencing an alarming opioid epidemic, and although American Indians and Alaska Natives (AI/ANs) are especially hard hit, there is a paucity of opioid-related treatment research with ...these communities. AI/ANs are second only to Whites in the U.S. for overdose mortality. Thus, the National Institute on Drug Abuse convened a meeting of key stakeholders to elicit feedback on the acceptability and uptake of medication assisted treatment (MAT) for opioid use disorders (OUDs) among AI/ANs. Five themes from this one-day meeting emerged: 1) the mismatch between Western secular and reductionistic medicine and the AI/AN holistic healing tradition; 2) the need to integrate MAT into AI/AN traditional healing; 3) the conflict between standardized MAT delivery and the traditional AI/AN desire for healing to include being medicine free; 4) systemic barriers; and 5) the need to improve research with AI/ANs using culturally relevant methods. Discussion is organized around key implementation strategies informed by these themes and necessary for the successful adoption of MAT in AI/AN communities: 1) type of medication; 2) educational interventions; 3) coordination of care; and 4) adjunctive psychosocial counseling. Using a community-based participatory research approach is consistent with a “two eyed seeing” approach that integrates Western and Indigenous worldviews. Such an approach is needed to develop impactful research in collaboration with AI/AN communities to address OUD health disparities.
•AI/ANs exhibit alarming opioid use disorder (OUD) related health disparities.•MAT implementation with AI/ANs requires integrating MAT into traditional healing.•Some barriers to MAT implementation involve unique cultural considerations.•A “two-eyed seeing” approach uses both Western and indigenous worldviews.•Collaborative research is needed to address the AI/AN OUD health disparities.
IceCube-Gen2 is a future large-scale extension to the IceCube Neutrino Observatory, a cubic-kilometer-scale neutrino detector at the geographic South Pole. The IceCube data acquisition system ...architecture, while running stably with over 99% uptime, will be re-optimized for IceCube-Gen2 to solve design challenges with power consumption, communications bandwidth, and cable specifications. In particular, we describe how distribution of the photomultiplier tube signal digitization and pre-trigger storage can reduce power and bandwidth requirements. Additional changes to IceCube's custom communications protocol can also relax crosstalk requirements on the copper cabling. We report on the status of these optimizations in the prototype Gen2 digital optical module design for the upcoming IceCube Upgrade.
Vancomycin-resistant enterococci (VRE) cause many infections in the healthcare context. Knowledge regarding the epidemiology and burden of VRE infections, however, remains fragmented. We aimed to ...summarize recent studies on VRE epidemiology and outcomes in hospitals, long-term-care facilities (LTCFs) and nursing homes worldwide based on current epidemiological reports. We searched MEDLINE/PubMed, the Cochrane Library, and Web of Science for observational studies, which reported on VRE faecium and faecalis infections in in-patients published between January 2014 and December 2020. Outcomes were incidence, infection rate, mortality, length of stay (LOS), and healthcare costs. We conducted a meta-analysis on mortality (PROSPERO registration number: CRD42020146389). Of 681 identified publications, 57 studies were included in the analysis. Overall quality of evidence was moderate to low. VRE incidence was rarely and heterogeneously reported. VRE infection rate differed highly (1–55%). The meta-analysis showed a higher mortality for VRE faecium bloodstream infections (BSIs) compared with VSE faecium BSIs (risk ratio, RR 1.46; 95% confidence interval (CI) 1.17–1.82). No difference was observed when comparing VRE faecium vs VRE faecalis BSI (RR 1.00, 95% CI 0.52–1.93). LOS was higher in BSIs caused by E. faecium vs E. faecalis. Only three studies reported healthcare costs. In contrast to previous findings, our meta-analysis of included studies indicates that vancomycin resistance independent of VRE species may be associated with a higher mortality. We identified a lack of standardization in reporting outcomes, information regarding healthcare costs, and state-of-the-art microbiological species identification methodology, which may inform the set-up and reporting of future studies.
The genus Pouteria has been studied because it presents various activities, among which is its anti-inflammatory potential. The effects of Pouteria ramiflora Carbopol gel on the healing of skin ...wounds in diabetic rats were evaluated by microscopic imaging. Streptozotocin was administered intraperitoneally in animals that had fasted for 12 hours, a situation confirmed by the glycemic index (˃ 240 mg dL-1). An excision on the back of the animals was performed and three groups were formed: Control (Gel), Ethanolic extract (Ext) and Gel + extract 2% (Ext+gel); the histopathological evaluation occurred on the 7th, 14th, 21st and 30th days after the post-operative period. The results of the phytochemical prospecting of P. ramiflora extract demonstrated the major presence of phenolic compounds and flavonoids; the assessment of the inflammatory infiltrate on the 7th day was higher on group Ext and Ext+gel when compared to group Control; on the 14th day control and Ext (p<0.05). The quantification of fibroblasts was higher on the 7th day among the three treatments, control and Ext (p<0.05), on the 21st day. Angiogenesis showed a higher number of vessels in Ext+gel group (p<0.05) on the 7th day; in Control, Ext and Ext+gel (p<0.05) on the 14th day; and Control and Ext (p<0.05)on the 21st day. The histopathological results showed that the formulation Ext+gel was efficient in tissue reparation and decrease in inflammatory cells on the diabetic's animals.
School psychologists play important roles in working alongside Indigenous Peoples within Canada; however, a large gap exists between the discipline’s actions and the recommendations set forth by ...Indigenous Nations and governmental working groups. In this conceptual article, we seek to highlight the need for further Indigenous representation and engagement in the field of school psychology, as well as present key areas of relevance. We first briefly contextualize the relationship between Indigenous Peoples and school psychology, followed by the results of a brief survey concerning Indigenous representation and engagement across five school psychology doctoral programs in Canada. Next, we discuss nine key areas of consideration for school psychologists based on the Calls to Action of the Truth and Reconciliation Commission of Canada and the Calls for Justice of the National Inquiry into Missing and Murdered Indigenous Women and Girls. Each area of consideration provides school psychologists with a starting point for concrete actions when working with Indigenous students, families, and communities.
Acute kidney injury (AKI) caused by ischemia followed by reperfusion (I/R) is characterized by intense anion superoxide (O
) production and oxidative damage. We investigated whether extracellular ...vesicles secreted by adipose tissue mesenchymal cells (EVs) administered during reperfusion can suppress the exacerbated mitochondrial O
formation after I/R. We used Wistar rats subjected to bilateral renal arterial clamping (30 min) followed by 24 h of reperfusion. The animals received EVs (I/R + EVs group) or saline (I/R group) in the kidney subcapsular space. The third group consisted of false-operated rats (SHAM). Mitochondria were isolated from proximal tubule cells and used immediately. Amplex Red™ was used to measure mitochondrial O
formation and MitoTracker™ Orange to evaluate inner mitochondrial membrane potential (Δψ). In vitro studies were carried out on human renal proximal tubular cells (HK-2) co-cultured or not with EVs under hypoxic conditions. Administration of EVs restored O
formation to SHAM levels in all mitochondrial functional conditions. The gene expression of
and
remained unmodified; transcription of
(
) was upregulated. The co-cultures of HK-2 cells with EVs revealed an intense decrease in apoptosis. We conclude that the mechanisms by which EVs favor long-term recovery of renal structures and functions after I/R rely on a decrease of mitochondrial O
formation with the aid of the upregulated antioxidant HO-1/Nuclear factor erythroid 2-related factor 2 system, thus opening new vistas for the treatment of AKI.
Beginning in the mid-1990s, the construct of historical trauma was introduced into the clinical and health science literatures to contextualize, describe, and explain disproportionately high rates of ...psychological distress and health disparities among Indigenous populations. As a conceptual precursor to racial trauma, Indigenous historical trauma (IHT) is distinguished by its emphasis on ancestral adversity that is intergenerationally transmitted in ways that compromise descendent well-being. In this systematic review of the health impacts of IHT, 32 empirical articles were identified that statistically analyzed the relationship between a measure of IHT and a health outcome for Indigenous samples from the United States and Canada. These articles were categorized based on their specific method for operationalizing IHT, yielding 19 articles that were grouped as historical loss studies, 11 articles that were grouped as residential school ancestry studies, and three articles that were grouped as "other" studies. Articles in all three categories included diverse respondents, disparate designs, varied statistical techniques, and a range of health outcomes. Most reported statistically significant associations between higher indicators of IHT and adverse health outcomes. Analyses were so complex, and findings were so specific, that this groundbreaking literature has yet to cohere into a body of knowledge with clear implications for health policy or professional practice. At the conceptual level, it remains unclear whether IHT is best appreciated for its metaphorical or literal functions. Nevertheless, the enthusiasm surrounding IHT as an explanation for contemporary Indigenous health problems renders it imperative to refine the construct to enable more valid research.
The American Indian historical trauma (HT) concept is an important precursor to racial trauma (RT) theory that reflects the distinct interests of sovereign Indigenous nations but shares much of the ...same promise and challenge. Here, that promise and challenge is explored by tracing HT's theoretical development in terms of its anticolonial ambitions and organizing ideas. Three predominant modes of engaging HT were distilled form the literature (HT as a clinical condition, life stressor, and critical discourse), each informing a research program pursuing a different anticolonial ambition (healing trauma, promoting resilience, practicing survivance) organized by distinct ideas about colonization, wellness, and Indigeneity. Through critical reflection on these different ambitions and dialogue of their organizing ideas, conflict between research programs can be mitigated and a more productive anticolonialism realized in psychology and related health fields. Key recommendations emphasized clarifying clinical concepts (e.g., clinical syndrome vs. idiom of distress), disentangling clinical narratives of individual pathology (e.g., trauma) from social narratives of population adversity (e.g., survivance stories), attending to features of settler-colonialism not easily captured by heath indices (e.g., structural violence), and encouraging alignment of anticolonial efforts with constructive critiques establishing conceptual bridges to disciplines that can help to advance psychological understandings of colonization and Indigenous wellness (e.g., postcolonial studies). This conceptual framework was applied to the RT literature to elaborate similar recommendations for advancing RT theory and the interests of ethnic/racial minority populations through engagement with psychology and related health fields.
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