Characterization of Leptin Receptor+ Stromal Cells in Lymph Node

Lymph node (LN)-resident stromal cells play an essential role in the proper functioning of LNs. The stromal compartment of the LN undergoes significant compensatory changes to produce a milieu amenable for regulation of the immune response. We have identified a distinct population of leptin receptor-expressing (LepR+) stromal cells, located in the vicinity of the high endothelial venules (HEVs) and lymphatics. These LepR+ stromal cells expressed markers for fibroblastic reticular cells (FRCs), but they lacked markers for follicular dendritic cells (FDCs) and marginal reticular cells (MRCs). Leptin signaling deficiency led to heightened inflammatory responses within the LNs of db/db mice, leakiness of HEVs, and lymphatic fragmentation. Leptin signaling through the JAK/STAT pathway supported LN stromal cell survival and promoted the anti-inflammatory properties of these cells. Conditional knockout of the LepR+ stromal cells in LNs resulted in HEV and extracellular matrix (ECM) abnormalities. Treatment of ob/ob mice with an agonist leptin fusion protein restored the microarchitecture of LNs, reduced intra-LN inflammatory responses, and corrected metabolic abnormalities. Future studies are needed to study the importance of LN stomal cell dysfunction to the pathogenesis of inflammatory responses in type 2 diabetes (T2D) in humans.

Prevention of Post-Transplant Diabetes Mellitus: Towards a Personalized Approach

Post-transplant diabetes is a frequent complication after transplantation. Moreover, patients suffering from post-transplant diabetes have increased cardiovascular morbidity and reduced survival. Pathogenesis mainly involves beta-cell dysfunction in presence of insulin resistance. Both pre- and post-transplant risk factors are well-described, and some of them may be corrected or prevented. However, the frequency of post-transplant diabetes has not decreased in recent years. We realized a critical appraisal of preventive measures to reduce post-transplant diabetes.

Circulating Blood-Based Biomarkers in Pulmonary Hypertension

Pulmonary hypertension (PH) is a serious hemodynamic condition, characterized by increased pulmonary vascular resistance (PVR), leading to right heart failure (HF) and death when not properly treated. The prognosis of PH depends on etiology, hemodynamic and biochemical parameters, as well as on response to specific treatment. Biomarkers appear to be useful noninvasive tools, providing information about the disease severity, treatment response, and prognosis. However, given the complexity of PH, it is impossible for a single biomarker to be adequate for the broad assessment of patients with different types of PH. The search for novel emerging biomarkers is still ongoing, resulting in a few potential biomarkers mirroring numerous pathophysiological courses. In this review, markers related to HF, myocardial remodeling, inflammation, hypoxia and tissue damage, and endothelial and pulmonary smooth muscle cell dysfunction are discussed in terms of diagnosis and prognosis. Extracellular vesicles and other markers with complex backgrounds are also reviewed. In conclusion, although many promising biomarkers have been identified and studied in recent years, there are still insufficient data on the application of multimarker strategies for monitoring and risk stratification in PH patients.

Emergence of Heartbeat Frailty in Advanced Age: Perspectives from Life-Long EKG Recordings in Mice

SAN failure, aka sick-sinus syndrome, which features sinus bradycardia, SAN impulse pauses, and irregularity of RR interval rhythms are manifestations of SAN cell dysfunction that increases exponentially with advanced age, i.e., SAN frailty. Abnormalities in intrinsic RR interval variability may be the earliest signatures of SAN cell dysfunction leading to SAN frailty in late life. We measured RR interval variability within EKG time-series prior to and during double autonomic blockade in long-lived C57/BL6 mice at 3 month intervals from 6 months of age until the end of life. Long-lived mice (those that achieved the median cohort lifespan of 24 months and beyond) displayed relatively minor changes in intrinsic RR interval variability prior to 21 months of age. Between 21 and 30 months of age, marked changes in intrinsic RR interval variability signatures in time, frequency, non-linear, and fragmentation domains result in a marked increase in the mean intrinsic RR interval. The effects of autonomic input partially compensated for the prolongation of the mean RR interval by impacting the age-associated deterioration in the RR interval variability signatures toward a youthful pattern. Cross-sectional analyses of other subsets of mice at ages at or beyond the median life span of our longitudinal cohort demonstrated increased non-cardiac, constitutional, whole body frailty, a decrease in energetic efficiency, and an increase in respiratory exchange ratio. In this context, we interpret the progressive increase in intrinsic RR interval variability beyond 21 months of age to be an indication of heartbeat frailty.

The circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis during obesity

The molecular link between obesity and β-cell decompensation that causes diabetes remains incompletely understood. Here we found that circGlis3, a circular RNA derived from Glis3, plays a critical role in islet β-cell compensation. circGlis3 was increased in islets of obese mouse models and moderately diabetic individuals with compensated β-cell function by Quaking (QKI)-mediated splicing. Overexpression of circGlis3 functions to restrain islet β-cell dysfunction and maintain β-cell mass in high-fat diet (HFD) fed mice and Leprdb/db mice. The cellular levels of circGlis3 modulate both insulin synthesis and secretion and lipotoxicity-induced apoptosis, resulting in profound changes in β-cell compensation. In an obesity model, circGlis3 promotes the synthesis and secretion of insulin by upregulating NeuroD1 and Creb1 through sponging miR-124-3p. In addition, we identified SCOTIN and fused in sarcoma (FUS) as interacting proteins using quantitative mass spectrometry. We demonstrated that the binding of SCOTIN to circGlis3 regulated the apoptosis of β-cell. And more, FUS binding to circGlis3 could decrease free circGlis3 in cytoplasm and block mechanism of circGlis3 via abnormal stable formation of stress granules (SGs) in hyperactive response to chronic stresses in obesity that is thought to contribute to the β-cell decompensation. These findings highlight a physiological role for circRNAs in compensation and indicate that modulation of circGlis3 expression may represent a potential strategy to protect against islet β-cell dysfunction and apoptosis during obesity.

Supportive treatment of vascular dysfunction in pediatric subjects with obesity: the OBELIX study

Introduction Overweight or obese children develop abnormal endothelial cell dysfunction and arterial intima–media thickening with increased vasomotor tone and inflammation. Curcumin, resveratrol, zinc, magnesium, selenium, and vitamin D have shown beneficial effects on endothelial function. We test, among overweight and obese pediatric subjects, the effects on the endothelium of a combination of curcumin, resveratrol, zinc, magnesium, selenium, and vitamin D. Methods Forty-eight subjects (6–17 years) were randomized into two groups (placebo vs treatment) attended three visits at 0, 3, and 6 months (±15 days). Endothelial function was assessed by means of a post-occlusive release hyperemic (PORH) test for estimation of delta flow (DF) and hyperemic AUC index, and a heat provocation test (HPT) to measure DF HPT (DFHPT). Results Significant DF difference was noted at 6 months in both groups (p < 0.001). Overall time trend was significantly different between baseline, 3 months, and 6 months both in placebo (p < 0.05) and treatment (p < 0.001) groups and their comparison (p < 0.001). No differences were noted in hyperemic AUC index (3 and 6 months), whilst there were significant differences in time trends of rreatment (p < 0.001) and placebo (p < 0.05) groups and their comparison (p < 0.001). DFHPT difference between groups was significant at 3 and 6 months (p < 0.05). The overall time trend was significant exclusively in Treatment group between 3 and 6 months (p < 0.05). Correlation with anthropometrics was found for DF and body mass index (r = 0.677 6 months, p < 0.05), as well as for hyperemic AUC index and males (r = 0.348, p < 0.05), while DFHPT showed no correlation. Conclusion Curcumin, resveratrol, zinc, magnesium, selenium, and vitamin D appear to be promising in enhancing endothelial function by improvement of both DF in the PORH test and DF in the HPT, lowering the risk of developing cardiovascular diseases in overweight and obese pediatric subjects.

Identification of Key Genes Associated with Endothelial Cell Dysfunction in Atherosclerosis Using Multiple Bioinformatics Tools

Atherosclerosis is the most notable cardiovascular disease, the latter being the main cause of death globally. Endothelial cell dysfunction plays a major role in the pathogenesis of atherosclerosis. However, it is currently unclear which genes are involved between endothelial cell dysfunction and atherosclerosis. This study was aimed at identifying these genes. Based on the GSE83500 dataset, the quantification of endothelial cell function was conducted using single-sample gene set enrichment analysis; the coexpression modules were conducted using weighted correlation network analysis. After building module-trait relationships, tan and yellow modules were regarded as hub modules. 10 hub genes from each hub module were identified by the protein-protein interaction network analysis. The key genes (RAB5A, CTTN, ITGB1, and MMP9) were obtained by comparing the expression differences of the hub gene between atherosclerotic and normal groups from the GSE28829 and GSE43292 datasets, respectively. ROC analysis showed the diagnostic value of key genes. Moreover, the differential expression of key genes in normal and atherosclerotic aortic walls was verified. In vitro, we establish a model of ox-LDL-injured endothelial cells and transfect RAB5A overexpression and shRNA plasmids. The results showed that overexpression of RAB5A ameliorates the proliferation and migration function of ox-LDL-injured endothelial cells, including the ability of tubule formation. It was speculated that the interferon response, Notch signaling pathways, etc. were involved in this function of RAB5A by using gene set variation analysis. With the multiple bioinformatics analysis methods, we detected that yellow and tan modules are related to the abnormal proliferation and migration of endothelial cells associated with atherosclerosis. RAB5A, CTTN, ITGB1, and MMP9 can be used as potential targets for therapy and diagnostic markers. In vitro, overexpression of RAB5A can ameliorate the proliferation and migration function of ox-LDL-injured endothelial cells, and the possible molecules involved in this process were speculated.

Molecular Mechanisms and Risk Factors for the Pathogenesis of Hydrocephalus

Hydrocephalus is a neurological condition due to the aberrant circulation and/or obstruction of cerebrospinal fluid (CSF) flow with consequent enlargement of cerebral ventricular cavities. However, it is noticed that a lot of patients may still go through symptomatic progression despite standard shunting procedures, suggesting that hydrocephalus is far more complicated than a simple CSF circulative/obstructive disorder. Growing evidence indicates that genetic factors play a fundamental role in the pathogenesis of some hydrocephalus. Although the genetic research of hydrocephalus in humans is limited, many genetic loci of hydrocephalus have been defined in animal models. In general, the molecular abnormalities involved in the pathogenesis of hydrocephalus include brain development and ependymal cell dysfunction, apoptosis, inflammation, free radical generation, blood flow, and cerebral metabolism. Moreover, recent studies have indicated that the molecular abnormalities relevant to aberrant cerebral glymphatic drainage turn into an attractive subject in the CSF circulation disorder. Furthermore, the prevalent risk factors could facilitate the development of hydrocephalus. In this review, we elicited some possible fundamental molecular mechanisms and facilitating risk factors involved in the pathogenesis of hydrocephalus, and aimed to widen the diagnosis and therapeutic strategies for hydrocephalus management. Such knowledge could be used to improve patient care in different ways, such as early precise diagnosis and effective therapeutic regimens.