New perspectives on natural flavonoids on COVID-19-induced lung injuries.

The SARS-CoV-2 virus, responsible for COVID-19, spread rapidly worldwide and became a pandemic in 2020. In some patients, the virus remains in the respiratory tract, causing pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS), and sepsis, leading to death. Natural flavonoids (aglycone and glycosides) possess broad biological activities encompassing antiinflammatory, antiviral, antitumoral, antiallergic, antiplatelet, and antioxidant effects. While many studies have focused on the effects of natural flavonoids in experimental models, reports based on clinical trials are still insufficient. In this review, we highlight the effects of flavonoids in controlling pulmonary diseases, particularly the acute respiratory distress syndrome, a consequence of COVID-19, and their potential use in coronavirus-related diseases. Furthermore, we also focus on establishing a relationship between biological potential and chemical aspects of related flavonoids and discuss several possible mechanisms of action, pointing out some possible effects on COVID-19.

Interleukin-6 and the Gut Microbiota Influence Melanoma Progression in Obese Mice.

There is a strong correlation between obesity and cancer. Here, we investigated the influence of IL-6 and gut microbiota of obese mice in melanoma development. We first evaluated B16F10 melanoma growth in preclinical models for obesity: mice deficient for leptin (ob/ob) or adiponectin (AdpKO) and in wild-type mice (WT, C57BL/6J) fed a high-fat diet (HFD; 60% kcal from fat) for 12 weeks. The survival rates of ob/ob and HFD-fed mice were lower than those of their respective controls. AdpKO mice also died earlier than WT control mice. We then verified the involvement of IL-6 signaling in obese mice that were inoculated with melanoma cells. Both ob/ob and AdpKO mice had higher circulating IL-6 levels than wild-type mice. Melanoma tumor volumes in IL-6 KO mice fed an HFD were reduced compared to those of WT mice subjected to the same diet. Also evaluated the effect of microbiota in tumor development. Cohousing and fecal matter transfer experiments revealed that microbiota from ob/ob mice can stimulate tumor development in lean WT mice. Taken together, our data show that in some conditions IL-6 and the gut microbiota are key mediators that link obesity and melanoma.

Metformin exerts antitumor activity via induction of multiple death pathways in tumor cells and activation of a protective immune response.

The antitumor effect of metformin has been demonstrated in several types of cancer; however, the mechanisms involved are incompletely understood. In this study, we showed that metformin acts directly on melanoma cells as well as on the tumor microenvironment, particularly in the context of the immune response. In vitro, metformin induces a complex interplay between apoptosis and autophagy in melanoma cells. The anti-metastatic activity of metformin in vivo was assessed in several mouse models challenged with B16F10 cells. Metformin's activity was, in part, immune system-dependent, whereas its antitumor properties were abrogated in immunodeficient (NSG) mice. Metformin treatment increased the number of lung CD8-effector-memory T and CD4+Foxp3+IL-10+ T cells in B16F10-transplanted mice. It also decreased the levels of Gr-1+CD11b+ and RORγ+ IL17+CD4+ cells in B16F10-injected mice and the anti-metastatic effect was impaired in RAG-1-/- mice challenged with B16F10 cells, suggesting an important role for T cells in the protection induced by metformin. Finally, metformin in combination with the clinical metabolic agents rapamycin and sitagliptin showed a higher antitumor effect. The metformin/sitagliptin combination was effective in a BRAFV600E/PTEN tamoxifen-inducible murine melanoma model. Taken together, these results suggest that metformin has a pronounced effect on melanoma cells, including the induction of a strong protective immune response in the tumor microenvironment, leading to tumor growth control, and the combination with other metabolic agents may increase this effect.

Effect of rapid weight loss and glutamine supplementation on immunosuppression of combat athletes: a double-blind, placebo-controlled study.

The role of plasma glutamine concentration and glutamine supplementation on immunosuppression was investigated in combat athletes. Twenty-three male athletes were randomly assigned to receive glutamine (21 g/day, n=12) or placebo (ovalbumin, n=11) for 10 days. Six athletes who did not lose weight served as controls. Athletes were assessed 21 days before (-21d), 1 day before (-1d) and 5 days after (+5d) a competition. Weight reduction was similar between glutamine (-8.2%± 4.1%) and placebo (-8.5%±2.4%) and negligible in control (-0.6%±1.4%). In both weight-loss groups, the majority of athletes reported symptoms of upper respiratory symptoms, as assessed by the Wisconsin upper respiratory symptom survey questionnaire. Only two athletes reported symptoms in the control group. Immune cell function remained unchanged throughout the study except for an increase in neutrophil phagocytic activity (placebo: -21d=5,251±2,986; -1d=17,428±22,374; +5d=21,125±21,934; glutamine: -21d=6,096±3,549; -1d=11,029±17,113; +5d=28,186±21,032 FI) and a minor change in monocyte phagocytic activity (placebo: -21d=4,421±3,634; -1d=3,329±6,283; +5d=3,243± 2,553; glutamine: -21d=4,051±3,186; -1d=3,106±2,625; +5d=4,981± 4,598) in both glutamine and placebo after weight loss. Plasma glutamine and cortisol remained unchanged across the study. creatine kinase levels were increased in placebo (-21d=125.2±54.1; -1d=187.2± 73.5; +5d=111.3±59.1 U/L) but not in glutamine (-21d=136.2±58.2; -1d= 168.8±65.0; +5d=129.7±64.0 U/L). Rapid weight loss increased the frequency and severity of infection symptoms, but this was neither associated with plasma glutamine depletion nor counteracted by glutamine supplementation.

Immature Dental Pulp Stem Cells Showed Renotropic and Pericyte-Like Properties in Acute Renal Failure in Rats.

Acute renal failure (ARF) is a common renal disease that can lead to high mortality. Recovery from ARF occurs with the replacement of necrotic tubular cells by functional tubular epithelial cells and the normalization of microvascular endothelial cell function in the peritubular capillaries. Conventional therapeutic techniques are often ineffective against ARF. Hence, stem cell therapies, which act through multiple trophic and regenerative mechanisms, are encouraging. We investigated the homing of human immature dental pulp stem cells (IDPSCs) after endovenous (EV) or intraperitoneal (IP) injection, in immunocompetent Wistar rats with ARF induced by intramuscular injection of glycerol, without the use of immunosuppression. The cells, which had been cryopreserved for 6 years, were CD105(+), CD73(+), CD44(+), and partly, STRO-1(+) and CD146(+), and presented unaltered mesoderm differentiation potential. The presence of these cells in the tubular region of the kidney and in the peritubular capillaries was demonstrated. These cells accelerate tubular epithelial cell regeneration through significant increase of Ki-67-immunoreactive cells in damaged kidney. Flow cytometry analysis confirmed that IDPSCs home to the kidneys (EV 34.10% and IP 33.25%); a lower percentage of cells was found in the liver (EV 19.05% and IP 9.10%), in the muscles (EV 6.30% and IP 1.35%), and in the lungs (EV 2.0% and IP 1.85%). After infusion into rat, these cells express pericyte markers, such as CD146(+), STRO-1(+), and vascular endothelial growth factor (VEGF(+)). We found that IDPSCs demonstrate renotropic and pericyte-like properties and contributed to restore renal tubule structure in an experimental rat ARF model.

Lipidomic assessment of plasma and placenta of women with early-onset preeclampsia.

INTRODUCTION: Adipose tissue is responsible for triggering chronic systemic inflammatory response and these changes may be involved in the pathophysiology of preeclampsia. OBJECTIVE: To characterize the lipid profile in the placenta and plasma of patients with preeclampsia. METHODOLOGY: Samples were collected from placenta and plasma of 10 pregnant women with preeclampsia and 10 controls. Lipids were extracted using the Bligh-Dyer protocol and were analysed by MALDI TOF-TOF mass spectrometry. RESULTS: Approximately 200 lipid signals were quantified. The most prevalent lipid present in plasma of patients with preeclampsia was the main class Glycerophosphoserines-GP03 (PS) representing 52.30% of the total lipid composition, followed by the main classes Glycerophosphoethanolamines-GP02 (PEt), Glycerophosphocholines-GP01 (PC) and Flavanoids-PK12 (FLV), with 24.03%, 9.47% and 8.39% respectively. When compared to the control group, plasma samples of patients with preeclampsia showed an increase of PS (p<0.0001), PC (p<0.0001) and FLV (p<0.0001). Placental analysis of patients with preeclampsia, revealed the PS as the most prevalent lipid representing 56.28%, followed by the main class Macrolides/polyketides-PK04 with 32.77%, both with increased levels when compared with patients control group, PS (p<0.0001) and PK04 (p<0.0001). CONCLUSION: Lipids found in placenta and plasma from patients with preeclampsia differ from those of pregnant women in the control group. Further studies are needed to clarify if these changes are specific and a cause or consequence of preeclampsia.

Lipid fingerprinting in women with early-onset preeclampsia: a first look.

OBJECTIVES: The aim of this preliminary study was to characterize the plasma lipid profiling of women with preeclampsia. DESIGN AND METHODS: Plasma samples of 8 pregnant women with early-onset preeclampsia and 8 normal pregnant women were evaluated. Lipids were extracted from plasma using the Bligh-Dyer protocol. The extracts were subjected to MALDI-MS. Data matrix was exported for partial least squares discriminant analysis (PLS-DA) and a parameter VIP was employed to reflect the variable importance in the discriminant analysis. The major discriminant variables were selected and underwent to Mann-Whitney U test. RESULTS: A total of 1290 ions were initially identified and twelve m/z signals were highlighted as the most important lipids for the discrimination of patients with preeclampsia. The identification of these differential lipids was carried out through Lipid Database Search. CONCLUSIONS: The main classes identified were glycerophosphocholines [GP01], glycerophosphoserines [GP03], glycerophosphoglycerols [GP04], glycosyldiradylglycerols [GL05] and glycerophosphates [GP10].

sFlt-1 and IP-10 in women with early-onset preeclampsia.

Intense inflammatory response and an anti-angiogenic state have been implicated in the pathogenesis of preeclampsia. Here, we investigated this hypothesis evaluating the serum concentrations of CXCL10/IP-10, sFlt-1, and PlGF in women with early-onset preeclampsia. CXCL10/IP-10 was measured by Cytometric Bead Array. sFlt-1 and PlGF were measured by automated electrochemiluminescence immunoassay. The median serum concentration of CXCL10/IP-10 was 109.5pg/mL in preeclamptic women, as compared with 52.28pg/mL in the controls (P=0.0028). The mean serum level of sFlt-1 was 13,636pg/mL in preeclamptic women, as compared with 2020pg/mL in the controls (P<0.0001). PlGF levels were significantly lower in women with preeclampsia.

An open randomized study comparing immunosuppression therapy initiated before or after kidney transplantation in haploidentical living recipients.

BACKGROUND: Acute rejection is the most important risk factor for graft survival. Although many centers start immunosuppressive therapy days before the surgery in living donors, there is no systematic study concerning the possible advantages of this procedure. In this open randomized study, we compared the efficacy and safety of administration of cyclosporine (CSA; Neoral) and azathioprine before renal transplantation with the administration of the same schema after transplantation, in HLA haploidentical grafts. METHODS: Sixty renal transplant recipients of an HLA haploidentical allograft from living donors were randomized in two groups: (A) patients that started immunosuppression 3 d before transplantation (n = 30) and (B) those who started the drug schema on the first day after surgery (n = 30). We analyzed the incidence and severity of acute rejection, graft function and infection during the first 3 months after transplantation. RESULTS: The group of patients who started immunosuppression before had a mean trough level of CSA (299.70 +/- 154.03 ng/mL) in the expected range for an efficacious prevention of acute rejection at the surgery day. Thirteen patients (43.3%) in each group had acute rejection during the follow up (p = 1.00). Two grafts losses (3.3%) occurred, one in each group. Both groups had similar 3-month rejection-free graft survival (56.7 and 56.3%). The incidence of infection was also statistical comparable between groups A and B (56.7 vs. 46.7, p = 0.430). Graft function was similar in patients from both groups. CONCLUSIONS: Pre-transplant administration of immunosuppression did not reduce the incidence or severity of acute rejection episodes during the first 3 months of transplantation. Immunosuppressive drugs administered before engraftment did not increase the incidence of graft dysfunction or infection.