Development and Validation of Global Leadership Initiative on Malnutrition for Prognostic Prediction in Patients Who Underwent Cardiac Surgery

The Global Leadership Initiative on Malnutrition (GLIM) has achieved a consensus for the diagnosis of malnutrition in recent years. This study aims to determine the prognostic effect of the GLIM after cardiac surgery. A total of 603 patients in the training cohort and 258 patients in the validation cohort were enrolled in this study. Perioperative characteristics and follow-up data were collected. A nomogram based on independent prognostic predictors was developed for survival prediction. In total, 114 (18.9%) and 48 (18.6%) patients were defined as being malnourished according to the GLIM criteria in the two cohorts, respectively. Multivariate regression analysis showed that GLIM-defined malnutrition was an independent risk factor of total complication (OR 1.661, 95% CI: 1.063–2.594) and overall survival (HR 2.339, 95% CI: 1.504–3.637). The c-index was 0.72 (95% CI: 0.66–0.79) and AUC were 0.800, 0.798, and 0.780 for 1-, 2-, and 3-year survival prediction, respectively. The calibration curves of the nomogram fit well. In conclusion, GLIM criteria can efficiently identify malnutrition and has a prognostic effect on clinical outcomes after cardiac surgery. GLIM-based nomogram has favorable performance in survival prediction

Ginsenoside Rb1 Prevents Oxidative Stress-Induced Apoptosis and Mitochondrial Dysfunction in Muscle Stem Cells via NF-κB Pathway

Sarcopenia, featured by the progressive loss of skeletal muscle function and mass, is associated with the impaired function of muscle stem cells (MuSCs) caused by increasing oxidative stress in senescent skeletal muscle tissue during aging. Intact function of MuSCs maintains the regenerative potential as well as the homeostasis of skeletal muscle tissues during aging. Ginsenoside Rb1, a natural compound from ginseng, exhibited the effects of antioxidation and against apoptosis. However, its effects of restoring MuSC function during aging and improving age-related sarcopenia remained unknown. In this study, we investigated the role of Rb1 in improving MuSC function and inhibiting apoptosis by reducing oxidative stress levels. We found that Rb1 inhibited the accumulation of reactive oxygen species (ROS) and protected the cells from oxidative stress to attenuate the H2O2-induced cytotoxicity. Rb1 also blocked oxidative stress-induced apoptosis by inhibiting the activation of caspase-3/9, which antagonized the decrease in mitochondrial content and the increase in mitochondrial abnormalities caused by oxidative stress via promoting the protein expression of genes involved in mitochondrial biogenesis. Mechanistically, it was proven that Rb1 exerted its antioxidant effects and avoided the apoptosis of myoblasts by targeting the core regulator of the nuclear factor-kappa B (NF-κB) signal pathway. Therefore, these findings suggest that Rb1 may have a beneficial role in the prevention and treatment of MuSC exhaustion-related diseases like sarcopenia

Alpha-1 Antitrypsin Attenuates M1 Microglia-Mediated Neuroinflammation in Retinal Degeneration

Neurodegenerative diseases are a set of disorders characterized by progressive neuronal death and are associated with microglia-mediated neuroinflammation. Recently, neuroinflammation is proposed as a promising therapeutic target for many neurodegenerative diseases. Alpha-1 antitrypsin (AAT) is recognized as a novel immunomodulatory agent in autoimmune diseases and transplantation, however, its impact on neuroinflammation and neurodegeneration remains unknown. This study aims to explore the effects of AAT on microglia-mediated neuroinflammation and retinal degeneration in rd1 mouse model. We found reduced expression of AAT in rd1 retina, and AAT supplement exhibited certain protective effect on retinal degeneration, presenting with increased amount of photoreceptor nuclei, and amplified wave amplitudes in electroretinogram analysis. Of note, AAT shifted microglia phenotype from pro-inflammatory M1 (CD16/CD32+, iNOS+) to anti-inflammatory M2 (CD206+, Arg1+) both in vivo and in vitro, underscoring the concept of immunomodulation on microglia polarization by AAT during neurodegeneration. Furthermore, AAT suppressed the activation of STAT1, promoted the expression of IRF4 while inhibited IRF8 expression, indicating the involvement of these signaling pathways in AAT immunomodulation. Collectively, our data provided evidence for a novel protective role of AAT through immunomodulation on microglia polarization. Attenuating neuroinflammation by AAT may be beneficial to retard neurodegeneration in rd1 mice

IL-17 signaling induces iNOS+ microglia activation in retinal vascular diseases

Activation of microglia and inflammation-mediated vascular damages are suggested to play a decisive role in the pathogenesis of various retinopathies. The inducible nitric oxide synthase (iNOS) was required for activated microglia-mediated injuries. However, the induction mechanism of microglia activation during retinal vascular diseases is still elusive. Here we showed that IL-17 induced microglia activation with high expression of iNOS and promoted the development of retinal vascular diseases. IL-17-dependent activation of the STAT3-iNOS pathway was essentially required for microglia activation, which promoted endothelial cell growth and accelerated vascular leakage and leukostasis via IL-6 in vitro and in vivo. Taken together, our data provide novel mechanistic insights on microglia activation-mediated retinopathy, unveil the specific role of IL-17 on microglia, and define novel therapeutic targets for treating retinal vascular diseases

Imatinib Ameliorated Retinal Neovascularization by Suppressing PDGFR-α and PDGFR-β

Background/Aims: Platelet-derived growth factors (PDGFs) have emerged as pivotal in pathological angiogenesis, which is a hallmark of various tumors and retinal diseases. Here we evaluated the anti-angiogenic effect of imatinib, an inhibitor of PDGF receptors α and β (PDGFR-α and -β), in retinal neovascularization using an oxygen-induced retinopathy (OIR) model. Methods: The OIR model was established and given imatinib or vehicle treatments daily from P12 to P16. At the peak of angiogenesis at P17, the neovascularization area was quantified on retinal whole-mounts with isolectin B4 staining. Immunofluorescence staining and western blots were used to determine the effect of imatinib on different vascular cells and the pathway molecules involved. Results: Imatinib effectively suppressed pathological angiogenesis in OIR mice and reduced the number of all three types of vascular cells, including endothelial cells, pericytes, and smooth muscle cells. Moreover, the expression and activation of PDGFR-α and -β were inhibited by imatinib. The imatinib-treated OIR mice presented with reduced expression of other potent pro-angiogenic factors such as VEGF and FGF2. No obvious retinal or systemic side effects were observed in the imatinib treatment group. Conclusions: Imatinib appears to be safe and effective in suppressing retinal neovascularization. Targeting PDGFs/PDGFRs may also be important for anti-angiogenic treatment and offer a viable alternative treatment for retinal angiogenic diseases

miR-204-containing exosomes ameliorate GVHD-associated dry eye disease

Graft-versus-host disease (GVHD)-associated dry eye disease is characterized by extensive inflammatory destruction in the ocular surface and causes unbearable pain and visual impairment. Current treatments provide limited benefits. Here, we report that exosomes from mesenchymal stromal cells (MSC-exo) administered as eye drops notably alleviate GVHD-associated dry eye disease by suppressing inflammation and improving epithelial recovery in mice and humans. In a prospective clinical trial, 28 eyes with refractory GVHD-dry eye disease exhibited substantial relief after MSC-exo treatment, showing reduced fluorescein scores, longer tear-film breakup time, increased tear secretion, and lower OSDI scores. Mechanistically, MSC-exo reprogramed proinflammatory M1 macrophages toward the immunosuppressive M2 via miR-204-mediated targeting of the IL-6/IL-6R/Stat3 pathway. Blockade of miR-204 abolished the effects of MSC-exo, while overloading L929-exo with miR-204 markedly attenuated dry eye. Thus, this study suggests that MSC-exo are efficacious in treating GVHD-associated dry eye disease and highlights miR-204 as a potential therapeutic agent

A potent immunomodulatory role of exosomes derived from mesenchymal stromal cells in preventing cGVHD

Abstract Background Mesenchymal stromal cells (MSCs) are a promising therapy for preventing chronic Graft-Versus-Host Disease (cGVHD) due to their potent immunomodulatory properties. However, the safety concerns regarding the use of MSCs remain unsolved, and conflicting effects are observed due to the heterogeneity of MSCs. Recently, exosomes were shown to mediate the paracrine effects of MSCs, making it a potential candidate for cell-free therapies. The aim of this study is to investigate the efficacy and safety of MSCs-derived exosomes (MSCs-exo) in an established cGVHD mouse model. Methods Bone marrow (BM)-derived MSCs were cultured, and the supernatants of these cultures were collected to prepare exosomes using ultracentrifugation. Exosomes from human dermal fibroblasts (Fib-exo) were used as a negative control. The cGVHD model was established, and tail vein injections of MSCs-exo or Fib-exo were administered once per week for 6 weeks. The symptoms and signs of cGVHD were monitored, and histopathological changes were detected by hematoxylin and eosin and Masson staining. The effects of MSCs-exo on Th17, Th1, and Treg were evaluated by flow cytometry, qPCR, and Luminex. In addition, human peripheral blood mononuclear cells (PBMCs) were stimulated and treated with MSCs-exo in vitro. IL-17-expressing Th17 and IL-10-expressing Treg were evaluated by flow cytometry, qPCR, and ELISA. Results We found that MSCs-exo effectively prolonged the survival of cGVHD mice and diminished the clinical and pathological scores of cGVHD. Fibrosis in the skin, lung, and liver was significantly ameliorated by MSCs-exo application. In MSCs-exo treated mice, activation of CD4+ T cells and their infiltration into the lung were reduced. Of note, MSCs-exo exhibited potent immunomodulatory effects via the inhibition of IL-17-expressing pathogenic T cells and induction of IL-10-expressing regulatory cells during cGVHD. The expressions of Th17 cell-relevant transcription factors and pro-inflammatory cytokines was markedly reduced after MSCs-exo treatment. In vitro, MSCs-exo blocked Th17 differentiation and improved the Treg phenotype in PBMCs obtained from healthy donors and patients with active cGVHD, further indicating the regulatory effect of MSCs-exo on GVHD effector T cells. Conclusions Our data suggested that MSCs-exo could improve the survival and ameliorate the pathologic damage of cGVHD by suppressing Th17 cells and inducing Treg. This finding provides a novel alternative approach for the treatment of cGVHD

Image_1_Alpha-1 Antitrypsin Attenuates M1 Microglia-Mediated Neuroinflammation in Retinal Degeneration.tif

<p>Neurodegenerative diseases are a set of disorders characterized by progressive neuronal death and are associated with microglia-mediated neuroinflammation. Recently, neuroinflammation is proposed as a promising therapeutic target for many neurodegenerative diseases. Alpha-1 antitrypsin (AAT) is recognized as a novel immunomodulatory agent in autoimmune diseases and transplantation, however, its impact on neuroinflammation and neurodegeneration remains unknown. This study aims to explore the effects of AAT on microglia-mediated neuroinflammation and retinal degeneration in rd1 mouse model. We found reduced expression of AAT in rd1 retina, and AAT supplement exhibited certain protective effect on retinal degeneration, presenting with increased amount of photoreceptor nuclei, and amplified wave amplitudes in electroretinogram analysis. Of note, AAT shifted microglia phenotype from pro-inflammatory M1 (CD16/CD32⁺, iNOS⁺) to anti-inflammatory M2 (CD206⁺, Arg1⁺) both in vivo and in vitro, underscoring the concept of immunomodulation on microglia polarization by AAT during neurodegeneration. Furthermore, AAT suppressed the activation of STAT1, promoted the expression of IRF4 while inhibited IRF8 expression, indicating the involvement of these signaling pathways in AAT immunomodulation. Collectively, our data provided evidence for a novel protective role of AAT through immunomodulation on microglia polarization. Attenuating neuroinflammation by AAT may be beneficial to retard neurodegeneration in rd1 mice.</p