Defibrotide inhibits donor leucocyte-endothelial interactions and protects against acute graft-versus-host disease.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an effective therapy for the treatment of high-risk haematological malignant disorders and other life-threatening haematological and genetic diseases. Acute graft-versus-host disease (aGvHD) remains the most frequent cause of non-relapse mortality following allo-HCT and limits its extensive clinical application. Current pharmacologic agents used for prophylaxis and treatment of aGvHD are not uniformly successful and have serious secondary side effects. Therefore, more effective and safe prophylaxis and therapy for aGvHD are an unmet clinical need. Defibrotide is a multi-target drug successfully employed for prophylaxis and treatment of veno-occlusive disease/sinusoidal obstruction syndrome. Recent preliminary clinical data have suggested some efficacy of defibrotide in the prevention of aGvHD after allo-HCT. Using a fully MHC-mismatched murine model of allo-HCT, we report here that defibrotide, either in prophylaxis or treatment, is effective in preventing T cell and neutrophil infiltration and aGvHD-associated tissue injury, thus reducing aGvHD incidence and severity, with significantly improved survival after allo-HCT. Moreover, we performed in vitro mechanistic studies using human cells revealing that defibrotide inhibits leucocyte-endothelial interactions by down-regulating expression of key endothelial adhesion molecules involved in leucocyte trafficking. Together, these findings provide evidence that defibrotide may represent an effective and safe clinical alternative for both prophylaxis and treatment of aGvHD after allo-HCT, paving the way for new therapeutic approaches.

Dietary Supplementation with an Extract of Aloysia citrodora (Lemon verbena) Improves Sleep Quality in Healthy Subjects: A Randomized Double-Blind Controlled Study.

Seventy-one healthy subjects with sleep disturbances participated in a randomized, double-blind controlled trial in which dietary supplementation with an extract of Aloysia citrodora (lemon verbena) (n = 33) or placebo (n = 38) was administered for 90 days. There were between-group differences in favor of the experimental group in the visual analogue scale (VAS) for sleep quality (6.5 ± 1.6 vs. 5.5 ± 2.1, p = 0.021) as well as in the overall score (5.8 ± 2.4, p = 0.008) and scores for sleep latency (1.6 ± 1.0 vs. 1.9 ± 0.7, p = 0.027) and sleep efficiency (84.5 ± 12.8 vs. 79.8 ± 13.6, p = 0.023) in the Pittsburgh Sleep Quality Index (PSQI). Sleep-related variables (latency, efficiency, wakefulness after sleep onset, awakenings) assessed by actigraphy also showed better scores in the experimental group (p = 0.001). Plasma nocturnal melatonin levels also increased significantly in the experimental group (199.7 ± 135.3 vs. 174.7 ± 115.4 pg/mL, p = 0.048). Changes in anthropometric parameters and physical activity levels were not found. In summary, a dietary supplement of lemon verbena administered for 3 months was associated with a significant improvement in sleep quality as compared with placebo in a population of healthy subjects with sleep problems.

Effect of the Combination of Hibiscus sabdariffa in Combination with Other Plant Extracts in the Prevention of Metabolic Syndrome: A Systematic Review and Meta-Analysis.

Metabolic syndrome is a complex and multifactorial disorder associated with increased risk of cardiovascular disease and type 2 diabetes, exacerbated by a sedentary lifestyle and situations such as the COVID-19 pandemic. Recent studies have shown that consumption of fruits and vegetables high in polyphenols has a protective effect, reducing cardiovascular risk. Hibiscus sabdariffa (HS) in combination with other plant extracts has recently attracted scientists' attention due to its potential use in the treatment of metabolic syndrome. This systematic review and meta-analysis examines the effects of HS in combination with other plant extracts on the prevention of metabolic syndrome, exploring their synergistic effects and potential as therapeutic agents. For this purpose, a systematic search of randomized clinical trials (RCTs) was conducted in four different databases and the data obtained were then used for a meta-analysis. Initially, the titles and abstracts of 1368 studies were read. From these, 16 studies were examined closely for their eligibility, and finally, seven RCTs with 332 participants were included in both the meta-analysis and the qualitative analysis. Our results show that HS in combination with other plant extracts improved anthropometric parameters, blood pressure, and lipid profile (low density lipoprotein cholesterol and total cholesterol) compared to a placebo control group. It is important to note that although this meta-analysis suggests that HS in combination with other plant extracts may have a beneficial effect on cardiovascular parameters, further research is needed to determine the optimal dose and intake duration.

Efficacy of Boswellia serrata Extract and/or an Omega-3-Based Product for Improving Pain and Function in People Older Than 40 Years with Persistent Knee Pain: A Randomized Double-Blind Controlled Clinical Trial.

A single-center, randomized, double-blind, controlled clinical trial with four arms was conducted in healthy subjects with persistent knee discomfort (pain intensity on 1-10 cm visual analog scale (VAS) > 3) aged 40 years and older treated with a dietary supplement for 8 weeks. The study groups were Boswellia serrata extract (n = 29), an omega-3-based product (AvailOm® 50 High EPA) (n = 31), Boswellia + AvailOm® (n = 30), and placebo (n = 30). The intake of Boswellia + AvailOm® improved the quality of life (QoL) (WOMAC index) and some variables of muscle strength. Statistically significant differences between the AvailOm® and the placebo groups in the decrease of pain intensity were found. Weekly VAS scores showed a significant decrease in pain perception when comparing the AvailOm® product to the placebo, with the lowest VAS scores at week 8. Consumption of Boswellia improved sleep latency. The time to perform the Up and Go test decreased after the intake of AvailOm®. There was an increase in the omega-3 fatty acids, with the greatest increase in the Boswellia + AvailOm® group. AvailOm® was safe and effective in reducing pain and improving the QoL and functionality of subjects over 40 years with persistent knee pain.

Enforced mesenchymal stem cell tissue colonization counteracts immunopathology.

Mesenchymal stem/stromal cells (MSCs) are distributed within all tissues of the body. Though best known for generating connective tissue and bone, these cells also display immunoregulatory properties. A greater understanding of MSC cell biology is urgently needed because culture-expanded MSCs are increasingly being used in treatment of inflammatory conditions, especially life-threatening immune diseases. While studies in vitro provide abundant evidence of their immunomodulatory capacity, it is unknown whether tissue colonization of MSCs is critical to their ability to dampen/counteract evolving immunopathology in vivo. To address this question, we employed a murine model of fulminant immune-mediated inflammation, acute graft-versus-host disease (aGvHD), provoked by donor splenocyte-enriched full MHC-mismatched hematopoietic stem cell transplant. aGvHD induced the expression of E-selectin within lesional endothelial beds, and tissue-specific recruitment of systemically administered host-derived MSCs was achieved by enforced expression of HCELL, a CD44 glycoform that is a potent E-selectin ligand. Compared to mice receiving HCELL- MSCs, recipients of HCELL+ MSCs had increased MSC intercalation within aGvHD-affected site(s), decreased leukocyte infiltrates, lower systemic inflammatory cytokine levels, superior tissue preservation, and markedly improved survival. Mechanistic studies reveal that ligation of HCELL/CD44 on the MSC surface markedly potentiates MSC immunomodulatory activity by inducing MSC secretion of a variety of potent immunoregulatory molecules, including IL-10. These findings indicate that MSCs counteract immunopathology in situ, and highlight a role for CD44 engagement in unleashing MSC immunobiologic properties that maintain/establish tissue immunohomeostasis.

Exofucosylation of Adipose Mesenchymal Stromal Cells Alters Their Secretome Profile.

Mesenchymal stromal cells (MSCs) constitute the cell type more frequently used in many regenerative medicine approaches due to their exclusive immunomodulatory properties, and they have been reported to mediate profound immunomodulatory effects in vivo. Nevertheless, MSCs do not express essential adhesion molecules actively involved in cell migration, a phenotypic feature that hampers their ability to home inflamed tissues following intravenous administration. In this study, we investigated whether modification by fucosylation of murine AdMSCs (mAdMSCs) creates Hematopoietic Cell E-/L-selectin Ligand, the E-selectin-binding CD44 glycoform. This cell surface glycan modification of CD44 has previously shown in preclinical studies to favor trafficking of mAdMSCs to inflamed or injured peripheral tissues. We analyzed the impact that exofucosylation could have in other innate phenotypic and functional properties of MSCs. Compared to unmodified counterparts, fucosylated mAdMSCs demonstrated higher in vitro migration, an altered secretome pattern, including increased expression and secretion of anti-inflammatory molecules, and a higher capacity to inhibit mitogen-stimulated splenocyte proliferation under standard culture conditions. Together, these findings indicate that exofucosylation could represent a suitable cell engineering strategy, not only to facilitate the in vivo MSC colonization of damaged tissues after systemic administration, but also to convert MSCs in a more potent immunomodulatory/anti-inflammatory cell therapy-based product for the treatment of a variety of autoimmune, inflammatory, and degenerative diseases.

Flavonoids in Kidney Health and Disease.

This review summarizes the latest advances in knowledge on the effects of flavonoids on renal function in health and disease. Flavonoids have antihypertensive, antidiabetic, and antiinflammatory effects, among other therapeutic activities. Many of them also exert renoprotective actions that may be of interest in diseases such as glomerulonephritis, diabetic nephropathy, and chemically-induced kidney insufficiency. They affect several renal factors that promote diuresis and natriuresis, which may contribute to their well-known antihypertensive effect. Flavonoids prevent or attenuate the renal injury associated with arterial hypertension, both by decreasing blood pressure and by acting directly on the renal parenchyma. These outcomes derive from their interference with multiple signaling pathways known to produce renal injury and are independent of their blood pressure-lowering effects. Oral administration of flavonoids prevents or ameliorates adverse effects on the kidney of elevated fructose consumption, high fat diet, and types I and 2 diabetes. These compounds attenuate the hyperglycemia-disrupted renal endothelial barrier function, urinary microalbumin excretion, and glomerular hyperfiltration that results from a reduction of podocyte injury, a determinant factor for albuminuria in diabetic nephropathy. Several flavonoids have shown renal protective effects against many nephrotoxic agents that frequently cause acute kidney injury (AKI) or chronic kidney disease (CKD), such as LPS, gentamycin, alcohol, nicotine, lead or cadmium. Flavonoids also improve cisplatin- or methotrexate-induced renal damage, demonstrating important actions in chemotherapy, anticancer and renoprotective effects. A beneficial prophylactic effect of flavonoids has been also observed against AKI induced by surgical procedures such as ischemia/reperfusion (I/R) or cardiopulmonary bypass. In several murine models of CKD, impaired kidney function was significantly improved by the administration of flavonoids from different sources, alone or in combination with stem cells. In humans, cocoa flavanols were found to have vasculoprotective effects in patients on hemodialysis. Moreover, flavonoids develop antitumor activity against renal carcinoma cells with no toxic effects on normal cells, suggesting a potential therapeutic role in patients with renal carcinoma.