Explore the vast range of titles available.

Wound healing is impaired in diabetes mellitus, but the mechanisms involved in this process are virtually unknown. Proteins belonging to the insulin signaling pathway respond to insulin in the skin of rats. The purpose of this study was to investigate the regulation of the insulin signaling pathway in wound healing and skin repair of normal and diabetic rats, and, in parallel, the effect of a topical insulin cream on wound healing and on the activation of this pathway. We investigated insulin signaling by immunoblotting during wound healing of control and diabetic animals with or without topical insulin. Diabetic patients with ulcers were randomized to receive topical insulin or placebo in a prospective, double-blind and placebo-controlled, randomized clinical trial (NCT 01295177) of wound healing. Expression of IR, IRS-1, IRS-2, SHC, ERK, and AKT are increased in the tissue of healing wounds compared to intact skin, suggesting that the insulin signaling pathway may have an important role in this process. These pathways were attenuated in the wounded skin of diabetic rats, in parallel with an increase in the time of complete wound healing. Upon topical application of insulin cream, the wound healing time of diabetic animals was normalized, followed by a reversal of defective insulin signal transduction. In addition, the treatment also increased expression of other proteins, such as eNOS (also in bone marrow), VEGF, and SDF-1α in wounded skin. In diabetic patients, topical insulin cream markedly improved wound healing, representing an attractive and cost-free method for treating this devastating complication of diabetes. ClinicalTrials.gov NCT01295177.

Impaired wound healing has been widely reported in diabetes. Linoleic acid (LA) accelerates the skin wound healing process in non-diabetic rats. However, LA has not been tested in diabetic animals. We investigated whether oral administration of pure LA improves wound healing in streptozotocin-induced diabetic rats. Dorsal wounds were induced in streptozotocin-induced type-1 diabetic rats treated or not with LA (0.22 g/kg b.w.) for 10 days. Wound closure was daily assessed for two weeks. Wound tissues were collected at specific time-points and used to measure fatty acid composition, and contents of cytokines, growth factors and eicosanoids. Histological and qPCR analyses were employed to examine the dynamics of cell migration during the healing process. LA reduced the wound area 14 days after wound induction. LA also increased the concentrations of cytokine-induced neutrophil chemotaxis (CINC-2αβ), tumor necrosis factor-α (TNF-α) and leukotriene B4 (LTB4), and reduced the expression of macrophage chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1). These results together with the histological analysis, which showed accumulation of leukocytes in the wound early in the healing process, indicate that LA brought forward the inflammatory phase and improved wound healing in diabetic rats. Angiogenesis was induced by LA through elevation in tissue content of key mediators of this process: vascular-endothelial growth factor (VEGF) and angiopoietin-2 (ANGPT-2). Oral administration of LA hastened wound closure in diabetic rats by improving the inflammatory phase and angiogenesis.

The effects of oral ingestion of oleic (OLA) and linoleic (LNA) acids on wound healing in rats were investigated. LNA increased the influx of inflammatory cells, the concentration of hydrogen peroxide (H2O2) and cytokine-induced neutrophil chemoattractant-2αβ (CINC-2αβ), and the activation of the transcription factor activator protein-1 (AP-1) in the wound at 1hour post wounding. LNA decreased the number of inflammatory cells and IL-1, IL-6, and macrophage inflammatory protein-3 (MIP-3) concentrations, as well as NF-κB activation in the wound at 24hours post wounding. LNA accelerated wound closure over a period of 7 days. OLA increased TNF-α concentration and NF-κB activation at 1hour post wounding. A reduction of IL-1, IL-6, and MIP-3α concentrations, as well as NF-κB activation, was observed 24hours post wounding in the OLA group. These data suggest that OLA and LNA accelerate the inflammatory phase of wound healing, but that they achieve this through different mechanisms.

[This corrects the article DOI: 10.1371/journal.pone.0165115.].

Background Cachexia is a multifactorial and multiorgan syndrome associated with cancer and other chronic diseases and characterized by severe involuntary body weight loss, disrupted metabolism, inflammation, anorexia, fatigue, and diminished quality of life. This syndrome affects around 50% of patients with colon cancer and is directly responsible for the death of at least 20% of all cancer patients. Systemic inflammation has been recently proposed to underline most of cachexia‐related symptoms. Nevertheless, the exact mechanisms leading to the initiation of systemic inflammation have not yet been unveiled, as patients bearing the same tumour and disease stage may or may not present cachexia. We hypothesize a role for gut barrier disruption, which may elicit persistent immune activation in the host. To address this hypothesis, we analysed the healthy colon tissue, adjacent to the tumour. Methods Blood and rectosigmoid colon samples (20 cm distal to tumour margin) obtained during surgery, from cachectic (CC = 25) or weight stable (WSC = 20) colon cancer patients, who signed the informed consent form, were submitted to morphological (light microscopy), immunological (immunohistochemistry and flow cytometry), and molecular (quantification of inflammatory factors by Luminex® xMAP) analyses. Results There was no statistical difference in gender and age between groups. The content of plasma interleukin 6 (IL‐6) and IL‐8 was augmented in cachectic patients relative to those with stable weight (P = 0.047 and P = 0.009, respectively). The number of lymphocytic aggregates/field in the gut mucosa was higher in CC than in WSC (P = 0.019), in addition to those of the lamina propria (LP) eosinophils (P < 0.001) and fibroblasts (P < 0.001). The area occupied by goblet cells in the colon mucosa was decreased in CC (P = 0.016). The M1M2 macrophages percentage was increased in the colon of CC, in relation to WSC (P = 0.042). Protein expression of IL‐7, IL‐13, and transforming growth factor beta 3 in the colon was significantly increased in CC, compared with WSC (P = 0.02, P = 0.048, and P = 0.048, respectively), and a trend towards a higher content of granulocyte‐colony stimulating factor in CC was also observed (P = 0.061). The results suggest an increased recruitment of immune cells to the colonic mucosa in CC, as compared with WSC, in a fashion that resembles repair response following injury, with higher tissue content of IL‐13 and transforming growth factor beta 3. Conclusions The changes in the intestinal mucosa cellularity, along with modified cytokine expression in cachexia, indicate that gut barrier alterations are associated with the syndrome.

ObjectiveThe aim of the present study was to associate phase angle (PhA) with sarcopenia and its components in physically active older women.MethodsA cross-sectional study was performed with 94 physically active older women. PhA and muscle mass were assessed by bioelectrical impedance. Muscle strength was measured by handgrip strength (HGS) and functional capacity was evaluated by 4-meter walk test. Sarcopenia was diagnosed according to the European Consensus on Definition and Diagnosis of Sarcopenia (2010). Participants were evaluated according to the PhA tercile. The individuals were divided into two groups: 1st vs. 2nd and 3rd terciles. The individuals in the first tercile were considered having low PhA (< 5.7º).ResultsLow PhA was not associated with sarcopenia (OR = 1.50 (0.520–4.319)), low muscle mass index (OR = 1.50 (0.520–4.319)), low HGS (OR = 3.15 (0.954–10.401)) and low walk speed (OR = 1.46 (0.384–5.534)). In addition, PhA had a weak correlation with walk speed (r = 0.24, p = 0.023) and walk speed was able to predict the PhA variations by 3.9%.ConclusionPhA was not associated with sarcopenia and its components in physically active older women. Although PhA was correlated with walk speed, the biological meaning of this association is questionable, since the power of the prediction was low.

The epigenetic changes associated with melanoma progression to advanced and metastatic stages are still poorly understood. To shed light on the CpG methylation dynamics during melanoma development, we analyzed the methylome profiles of a four-stage cell line model of melanoma progression: non-tumorigenic melanocytes (melan-a), premalignant melanocytes (4C), non-metastatic melanoma cells (4C11−), and metastatic melanoma cells (4C11+). We identified 540 hypo- and 37 hypermethylated gene promoters that together characterized a malignancy signature, and 646 hypo- and 520 hypermethylated promoters that distinguished a metastasis signature. Differentially methylated genes from these signatures were correlated with overall survival using TCGA-SKCM methylation data. Moreover, multivariate Cox analyses with LASSO regularization identified panels of 33 and 31 CpGs, respectively, from the malignancy and metastasis signatures that predicted poor survival. We found a concordant relationship between DNA methylation and transcriptional levels for genes from the malignancy ( Pyroxd2 and Ptgfrn ) and metastasis ( Arnt2 , Igfbp4 and Ptprf ) signatures, which were both also correlated with melanoma prognosis. Altogether, this study reveals novel CpGs methylation markers associated with malignancy and metastasis that collectively could improve the survival prediction of melanoma patients.

IntroductionInfluenza A is a virus from the Orthomixoviridae family responsible for high lethality rates and morbidity, despite clinically proven vaccination strategies and some anti-viral therapies. The eicosanoid Lipoxin A4 (LXA4) promotes the resolution of inflammation by decreasing cell recruitment and pro-inflammatory cytokines release, but also for inducing activation of apoptosis, efferocytosis, and macrophage reprogramming.ObjectiveHere, we evaluated whether a synthetic lipoxin mimetic, designated AT-01-KG, would improve the course of influenza A infection in a murine model.MethodMice were infected with influenza A/H1N1 and treated with AT-01-KG (1.7 μg/kg/day, i.p.) at day 3 post-infection.ResultsAT-01-KG attenuated mortality, reducing leukocyte infiltration and lung damage at day 5 and day 7 post-infection. AT-01-KG is a Formyl Peptide Receptor 2 (designated FPR2/3 in mice) agonist, and the protective responses were not observed in fpr2/3 −/− animals. In mice treated with LXA4 (50 μg/kg/day, i.p., days 3–6 post-infection), at day 7, macrophage reprogramming was observed, as seen by a decrease in classically activated macrophages and an increase in alternatively activated macrophages in the lungs. Furthermore, the number of apoptotic cells and cells undergoing efferocytosis was increased in the lavage of treated mice. Treatment also modulated the adaptive immune response, increasing the number of T helper 2 cells (Th2) and regulatory T (Tregs) cells in the lungs of the treated mice.ConclusionTherefore, treatment with a lipoxin A4 analog was beneficial in a model of influenza A infection in mice. The drug decreased inflammation and promoted resolution and beneficial immune responses, suggesting it may be useful in patients with severe influenza.

Cachexia is a paraneoplastic syndrome that accompanies and compromises cancer treatment, especially in advanced stages, affecting the metabolism and function of several organs. The adipose tissue is the first to respond to the presence of the tumor, contributing to the secretion of factors which drive the systemic inflammation, a hallmark of the syndrome. While inflammation is a defensive innate response, the control mechanisms have been reported to be disrupted in cachexia. On the other hand, little is known about the role of NLRP3 inflammasome in this scenario, a multiprotein complex involved in caspase-1 activation and the processing of the cytokines IL-1β and IL-18. based on the evidence from our previous study with a rodent model of cachexia, we examined the activation of the NLRP3 inflammasome pathway in two adipose tissue depots obtained from patients with colorectal cancer and compared with that another inflammatory pathway, NF-κB. For CC we found opposite modulation in ScAT and PtAT for the gene expression of TLR4, Caspase-1 (cachectic group) and for NF-κB p50, NF-κB p65, IL-1β. CD36, expression was decreased in both depots while that of NLRP3 and IL-18 was higher in both tissues, as compared with controls and weight stable patients (WSC). Caspase-1 basal protein levels in the ScAT culture supernatant were higher in WSC and (weight stable patients) CC, when compared to controls. Basal ScAT explant culture medium IL-1β and IL-18 protein content in ScAT supernatant was decreased in the WSC and CC as compared to CTL explants. The results demonstrate heterogeneous responses in the activation of genes of the NLRP3 inflammasome pathway in the adipose tissue of patients with cancer cachexia, rendering this pathway a potential target for therapy aiming at decreasing chronic inflammation in cancer.

Central nervous system (CNS) malignant neoplasms may lead to venous thromboembolism (VTE) and bleeding, which result in rehospitalization, morbidity and mortality. We aimed to assess the incidence of VTE and bleeding in this population. Methods: This systematic review and meta-analysis (PROSPERO CRD42023423949) were based on a standardized search of PubMed, Virtual Health Library and Cochrane (n = 1653) in July 2023. After duplicate removal, data screening and collection were conducted by independent reviewers. The combined rates and 95% confidence intervals for the incidence of VTE and bleeding were calculated using the random effects model with double arcsine transformation. Subgroup analyses were performed based on sex, age, income, and type of tumor. Heterogeneity was calculated using Cochran’s Q test and I 2 statistics. Egger’s test and funnel graphs were used to assess publication bias. Results: Only 36 studies were included, mainly retrospective cohorts (n = 30, 83.3%) from North America (n = 20). Most studies included were published in high-income countries. The sample size of studies varied between 34 and 21,384 adult patients, mostly based on gliomas (n = 30,045). For overall malignant primary CNS neoplasm, the pooled incidence was 13.68% (95%CI 9.79; 18.79) and 11.60% (95%CI 6.16; 18.41) for VTE and bleeding, respectively. The subgroup with elderly people aged 60 or over had the highest incidence of VTE (32.27% - 95%CI 14.40;53.31). The studies presented few biases, being mostly high quality. Despite some variability among the studies, we observed consistent results by performing sensitivity analysis, which highlight the robustness of our findings. Conclusions: Our study showed variability in the pooled incidence for both overall events and subgroup analyses. It was highlighted that individuals over 60 years old or diagnosed with GBM had a higher pooled incidence of VTE among those with overall CNS malignancies. It is important to note that the results of this meta-analysis refer mainly to studies carried out in high-income countries. This highlights the need for additional research in Latin America, and low- and middle-income countries.