Targeting autophagy to counteract neuroinflammation: A novel antidepressant strategy.

Depression is a common disease that affects physical and mental health and imposes a considerable burden on afflicted individuals and their families worldwide. Depression is associated with a high rate of disability and suicide. It causes a severe decline in productivity and quality of life. Unfortunately, the pathophysiological mechanisms underlying depression have not been fully elucidated, and the risk of its treatment is still presented. Studies have shown that the expression of autophagic markers in the brain and peripheral inflammatory mediators are dysregulated in depression. Autophagy-related genes regulate the level of autophagy and change the inflammatory response in depression. Depression is related to several aspects of immunity. The regulation of the immune system and inflammation by autophagy may lead to the development or deterioration of mental disorders. This review highlights the role of autophagy and neuroinflammation in the pathophysiology of depression, sumaries the autophagy-targeting small moleculars, and discusses a novel therapeutic strategy based on anti-inflammatory mechanisms that target autophagy to treat the disease.

Predicting Osteoporotic Fracture in Patients With Early-Stage Diabetic Kidney Disease Using a Radiomic Model: A Longitudinal Cohort Study.

OBJECTIVE: There is an urgent need for effective predictive strategies to accurately evaluate the risk of fragility fractures in elderly patients in the early stages of diabetic kidney disease (DKD). METHODS: This longitudinal cohort study included 715 older patients in the early stages of DKD diagnosed between January 2015 and August 2019. Patients were randomly allocated to a training cohort (n = 499) and a validation cohort (n = 216). The least absolute shrinkage and selection operator method was used to select key features for dual-energy x-ray absorptiometry-based radiomic analysis. A radiomic model was constructed using Cox proportional hazards regression. The performance of the radiomic model was compared with that of traditional fracture assessment tools through a receiver operating characteristic curve, calibration curve, and decision curve analysis. RESULTS: Over a mean follow-up period of 4.72 ± 1.60 years, 65 participants (9.09%) experienced incident fragility fractures. Seventeen features were ultimately selected to create the radiomic model. The calibration plots of this model demonstrated satisfactory agreement between the observed and predicted outcomes. Moreover, the radiomic model outperformed traditional fracture assessment tools in both the training and validation cohorts according to the area under the receiver operating characteristic curve and decision curve analysis. CONCLUSIONS: The novel radiomic model has demonstrated a more effective prediction of fragility fracture in elderly patients in the early stages of DKDcompared to traditional fracture assessment tools.

Increased expression of the P2Y12 receptor is involved in the failure of autogenous arteriovenous fistula caused by stenosis.

OBJECTIVE: This study investigated the role of the P2Y12 receptor in autogenous arteriovenous fistula (AVF) failure resulting from stenosis. METHODS: Stenotic venous tissues and blood samples were obtained from patients with end-stage renal disease (ESRD) together with AVF stenosis, while venous tissues and blood samples were collected from patients with ESRD undergoing initial AVF surgery as controls. Immunohistochemistry and/or immunofluorescence techniques were utilized to assess the expression of P2Y12, transforming growth factor-ß1 (TGF-ß1), monocyte chemotactic protein 1 (MCP-1), and CD68 in the venous tissues. The expression levels of P2Y12, TGFß1, and MCP-1 were quantified using quantitative reverse transcription-polymerase chain reaction and western blot analyses. Double and triple immunofluorescence staining was performed to precisely localize the cellular localization of P2Y12 expression. RESULTS: Expression levels of P2Y12, TGFß1, MCP-1, and CD68 were significantly higher in stenotic AVF venous tissues than in the control group tissues. Double and triple immunofluorescence staining of stenotic AVF venous tissues indicated that P2Y12 was predominantly expressed in α-SMA-positive vascular smooth muscle cells (VSMCs) and, to a lesser extent, in CD68-positive macrophages, with limited expression in CD31-positive endothelial cells. Moreover, a subset of macrophage-like VSMCs expressing P2Y12 were observed in both stenotic AVF venous tissues and control venous tissues. Additionally, a higher number of P2Y12+/TGF-ß1+ double-positive cells were identified in stenotic AVF venous tissues than in the control group tissues. CONCLUSION: Increased expression of P2Y12 in stenotic AVF venous tissues of patients with ESRD suggests its potential involvement in the pathogenesis of venous stenosis within AVFs.

Clinical outcome of percutaneous angioplasty and covered stent placement for treatment of left brachiocephalic vein obstruction in hemodialysis patients.

BACKGROUND: Left brachiocephalic vein (LBV) obstruction is a common complication in patients undergoing hemodialysis. This study aimed to compare the clinical characteristics and outcomes of patients with LBV obstruction who underwent percutaneous angioplasty or stenting. METHODS: We performed a retrospective study of 67 hemodialysis patients with LBV stenosis or occlusion who underwent percutaneous transluminal angioplasty (PTA; n = 25) or percutaneous transluminal stenting (PTS; n = 42). We compared the clinical characteristics, lesion features, and patency between the two groups of patients. RESULTS: The average age, sex, smoking history, body mass index, obstruction period, comorbidities, and clinical manifestations were comparable between the PTA and PTS groups. Prior ipsilateral catheterization was less common in the PTS group than in the PTA group (14.3% vs 36.0%, p < 0.05). Smaller sized balloons were used in the PTS group than in the PTA group (p < 0.05). The overall primary patency rates were similar between the two groups, whereas the secondary patency rate in the PTS group was higher than that in the PTA group (p < 0.05). The average age, sex, smoking history, body mass index, obstruction period, prior ipsilateral catheterization, comorbidities, and types of lesions were comparable between patients with or without restenosis, while patients with restenosis had a higher percentage of high venous pressure than those without restenosis (87.5% vs 60.5%, p < 0.05). CONCLUSION: The primary patency rates were similar in the angioplasty and the stenting groups. Stenting has a significantly higher secondary patency rate than angioplasty alone for treating LBV obstruction and is required more commonly in patients without prior ipsilateral catheterization.

Activation of the Nrf2/ARE signaling pathway ameliorates hyperlipidemia-induced renal tubular epithelial cell injury by inhibiting mtROS-mediated NLRP3 inflammasome activation.

Dyslipidemia is the most prevalent independent risk factor for patients with chronic kidney disease (CKD). Lipid-induced NLRP3 inflammasome activation in kidney-resident cells exacerbates renal injury by causing sterile inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that modulates the cellular redox balance; however, the exact role of Nrf2 signaling and its regulation of the NLRP3 inflammasome in hyperlipidemia-induced kidney injury are poorly understood. In this study, we demonstrated that activation of the mtROS-NLRP3 inflammasome pathway is a critical contributor to renal tubular epithelial cell (RTEC) apoptosis under hyperlipidemia. In addition, the Nrf2/ARE signaling pathway is activated in renal tubular epithelial cells under hyperlipidemia conditions both in vivo and in vitro, and Nrf2 silencing accelerated palmitic acid (PA)-induced mtROS production, mitochondrial injury, and NLRP3 inflammasome activation. However, the activation of Nrf2 with tBHQ ameliorated mtROS production, mitochondrial injury, NLRP3 inflammasome activation, and cell apoptosis in PA-induced HK-2 cells and in the kidneys of HFD-induced obese rats. Furthermore, mechanistic studies showed that the potential mechanism of Nrf2-induced NLRP3 inflammasome inhibition involved reducing mtROS generation. Taken together, our results demonstrate that the Nrf2/ARE signaling pathway attenuates hyperlipidemia-induced renal injury through its antioxidative and anti-inflammatory effects through the downregulation of mtROS-mediated NLRP3 inflammasome activation.

Hidden in the mediastinum: a case of extramedullary hematopoiesis unveiled through thoracoscopy.

Extramedullary hematopoiesis (EMH) is a rare condition characterized by proliferation of hematopoietic stem cells outside the bone marrow, usually as a compensatory response to hematological disease. Although EMH primarily occurs in the liver and spleen, it can manifest in atypical locations, such as the mediastinum. We herein describe an asymptomatic 66-year-old man with incidentally discovered posterior mediastinal EMH. A 28- × 32-mm mass was detected during a routine examination. Laboratory findings were within normal limits. Computed tomography revealed a well-defined enhancing mass with a density of 60 Hounsfield units, suggestive of a neurogenic tumor. Surgical resection confirmed EMH, characterized by megakaryocytes and hematopoietic precursors. The patient recovered smoothly and was discharged 5 days postoperatively. Accurate preoperative diagnosis of EMH is challenging, as illustrated by this case. Although typically associated with anemia or hematological abnormalities, EMH can present without such signs. Surgical resection and histopathological examination are essential for diagnosis. This case emphasizes the diagnostic complexity of posterior mediastinal EMH, even in patients without overt hematological disorders. Posterior mediastinal EMH is exceedingly rare and diagnostically demanding. A high index of suspicion and histological tissue analysis are crucial for optimal management. Video-assisted thoracoscopic surgery enables both diagnosis and treatment through mass excision.

CT-determined low skeletal muscle index predicts poor prognosis in patients with colorectal cancer.

BACKGROUND: Sarcopenia is highly prevalent among patients with colorectal cancer (CRC). Computed tomography (CT)-based assessment of low skeletal muscle index (SMI) is widely used for diagnosing sarcopenia. However, there are conflicting findings on the association between low SMI and overall survival (OS) in CRC patients. The objective of this study was to investigate whether CT-determined low SMI can serve as a valuable prognostic factor in CRC. METHODS: We collected data from patients with CRC who underwent radical surgery at our institution between June 2020 and November 2021. The SMI at the third lumbar vertebra was calculated using CT scans, and the cutoff values for defining low SMI were determined using receiver operating characteristic curves. Univariate and multivariate analyses were performed to assess the associations between clinical characteristics and postoperative major complications. RESULTS: A total of 464 patients were included in the study, 229 patients (46.7%) were classified as having low SMI. Patients with low SMI were older and had a lower body mass index (BMI), a higher neutrophil to lymphocyte ratio (NLR), and higher nutritional risk screening 2002 (NRS2002) scores compared to those with normal SMI. Furthermore, patients with sarcopenia had a higher rate of major complications (10.9% vs. 1.3%; p < 0.001) and longer length of stay (9.09 ± 4.86 days vs. 8.25 ± 3.12 days; p = 0.03). Low SMI and coronary heart disease were identified as independent risk factors for postoperative major complications. Moreover, CRC patients with low SMI had significantly worse OS. Furthermore, the combination of low SMI with older age or TNM stage II + III resulted in the worst OS in each subgroup analysis. CONCLUSIONS: CT-determined low SMI is associated with poor prognosis in patients with CRC, especially when combined with older age or advanced TNM stage.

Gut dysbiosis induces the development of depression-like behavior through abnormal synapse pruning in microglia-mediated by complement C3.

BACKGROUND: Remodeling eubiosis of the gut microenvironment may contribute to preventing the occurrence and development of depression. Mounting experimental evidence has shown that complement C3 signaling is associated with the pathogenesis of depression, and disruption of the gut microbiota may be an underlying cause of complement system activation. However, the mechanism by which complement C3 participates in gut-brain crosstalk in the pathogenesis of depression remains unknown. RESULTS: In the present study, we found that chronic unpredictable mild stress (CUMS)-induced mice exhibited obvious depression-like behavior as well as cognitive impairment, which was associated with significant gut dysbiosis, especially enrichment of Proteobacteria and elevation of microbiota-derived lipopolysaccharides (LPS). In addition, peripheral and central complement C3 activation and central C3/CR3-mediated aberrant synaptic pruning in microglia have also been observed. Transplantation of gut microbiota from CUMS-induced depression model mice into specific pathogen-free and germ-free mice induced depression-like behavior and concomitant cognitive impairment in the recipient mice, accompanied by increased activation of the complement C3/CR3 pathway in the prefrontal cortex and abnormalities in microglia-mediated synaptic pruning. Conversely, antidepressants and fecal microbiota transplantation from antidepressant-treated donors improved depression-like behaviors and restored gut microbiome disturbances in depressed mice. Concurrently, inhibition of the complement C3/CR3 pathway, amelioration of abnormal microglia-mediated synaptic pruning, and increased expression of the synapsin and postsynaptic density protein 95 were observed. Collectively, our results revealed that gut dysbiosis induces the development of depression-like behaviors through abnormal synapse pruning in microglia-mediated by complement C3, and the inhibition of abnormal synaptic pruning is the key to targeting microbes to treat depression. CONCLUSIONS: Our findings provide novel insights into the involvement of complement C3/CR3 signaling and aberrant synaptic pruning of chemotactic microglia in gut-brain crosstalk in the pathogenesis of depression. Video Abstract.

Forkhead Box Protein K1 Promotes Chronic Kidney Disease by Driving Glycolysis in Tubular Epithelial Cells.

Renal tubular epithelial cells (TECs) undergo an energy-related metabolic shift from fatty acid oxidation to glycolysis during chronic kidney disease (CKD) progression. However, the mechanisms underlying this burst of glycolysis remain unclear. Herein, a new critical glycolysis regulator, the transcription factor forkhead box protein K1 (FOXK1) that is expressed in TECs during renal fibrosis and exhibits fibrogenic and metabolism-rewiring capacities is reported. Genetic modification of the Foxk1 locus in TECs alters glycolytic metabolism and fibrotic lesions. A surge in the expression of a set of glycolysis-related genes following FOXK1 protein activation contributes to the energy-related metabolic shift. Nuclear-translocated FOXK1 forms condensate through liquid-liquid phase separation (LLPS) to drive the transcription of target genes. Core intrinsically disordered regions within FOXK1 protein are mapped and validated. A therapeutic strategy is explored by targeting the Foxk1 locus in a murine model of CKD by the renal subcapsular injection of a recombinant adeno-associated virus 9 vector encoding Foxk1-short hairpin RNA. In summary, the mechanism of a FOXK1-mediated glycolytic burst in TECs, which involves the LLPS to enhance FOXK1 transcriptional activity is elucidated.

Nanoscale coordination polymer Fe-DMY downregulating Poldip2-Nox4-H2O2 pathway and alleviating diabetic retinopathy.

Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes and the leading cause of blindness and severe visual impairment in adults. The high levels of glucose trigger multiple intracellular oxidative stress pathways, such as POLDIP2, resulting in excessive reactive oxygen species (ROS) production and increased expression of vascular cell adhesion molecule-1 (VCAM-1), hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF), causing microvascular dysfunction. Dihydromyricetin (DMY) is a natural flavonoid small molecule antioxidant. However, it exhibits poor solubility in physiological environments, has a short half-life in vivo, and has low oral bioavailability. In this study, we present, for the first time, the synthesis of ultra-small Fe-DMY nano-coordinated polymer particles (Fe-DMY NCPs), formed by combining DMY with low-toxicity iron ions. In vitro and in vivo experiments confirm that Fe-DMY NCPs alleviate oxidative stress-induced damage to vascular endothelial cells by high glucose, scavenge excess ROS, and improve pathological features of DR, such as retinal vascular leakage and neovascularization. Mechanistic validation indicates that Fe-DMY NCPs can inhibit the activation of the Poldip2-Nox4-H2O2 signaling pathway and downregulate vital vascular function indicators such as VCAM-1, HIF-1α, and VEGF. These findings suggest that Fe-DMY NCPs could serve as a safe and effective antioxidant and microangio-protective agent, with the potential as a novel multimeric drug for DR therapy.

Maternal hypothyroidism during pregnancy alters the function of the retinol-binding protein 4-mediated mitochondrial permeability conversion pore in the kidneys of offspring rats

OBJECTIVES To determine the role of the RBP4/PiC/SIRT3 signaling pathway in the opening of the mitochondria permeability transition pore (mPTP) in offspring rats with hypothyroidism during pregnancy. METHODS Sixty Sprague-Dawley (SD) rats were employed in this study. Pregnancy was deemed successful when a sperm was found in the uterus. After one week of pregnancy, offspring rats were divided into the following groups: overall hypothyroidism group (OH group), subclinical hypothyroidism group (SCH group), and normal control group (CON group). The establishment of the hypothyroidism model was confirmed when the serum thyroid stimulating hormone (TSH) levels were higher than normal value and TT4 level was within the normal range. The renal mitochondria of offspring rats were extracted on the 14th postnatal day (P14) and 35th postnatal day (P35). RESULTS At P14, no significant differences in the degree of mPTP opening and expression of phosphoric acid carrier vector (PiC) were detected between the rats in the OH group and the SCH group. However, the expression level of silent mating-type information regulation 3 homolog (SIRT3) was markedly reduced. Retinol-binding protein 4 (RBP4) expression increased in the rats from the OH group, relative to that in those from the SCH group. At P35, the degree of mPTP opening and the expression levels of PiC and RBP4 in the OH group were higher than those in the SCH group. However, SIRT3 expression in the OH group was lower than that observed in the SCH group. CONCLUSION RBP4 plays an important role in early renal mitochondrial damage and renal impairment in rats suffering from hypothyroidism during pregnancy. The RBP4/PiC/SIRT3 pathway is thus involved in the opening of the renal mPTP in offspring rats with hyperthyroidism.