Hypoparathyroidism and late-onset hypogonadism in an adult male with familial 22q11.2 deletion syndrome: a case report with 3-year follow-up and review of the literature.

BACKGROUND: 22q11.2 deletion syndrome (DiGeorge syndrome) is associated with multiple organ dysfunctions such as cardiac defects, immunodeficiency, and hypoplasia of parathyroid glands. Moreover, the phenotype of 22q11.2 DS has clinical variability and heterogeneity. CASE PRESENTATION: In this report, we present the case of a 35-year-old patient with a past medical history that included recurrent infections, mild learning difficulties in childhood, pediatric obesity, and cataract. He was admitted to the endocrinology department for the management of hypogonadism and hypocalcemia. During the 3-year follow-up, the patient gradually developed primary hypoparathyroidism, hypogonadism, chronic renal failure, and heart failure, and his medical condition deteriorated. Meanwhile, in order to improve clinicians' awareness of the endocrine manifestations of adult 22q11.2 DS and reduce missed diagnoses, we reviewed 28 case reports of adult 22q11.2 DS to analyze the clinical characteristics. DISCUSSION: Here, we report the case of a young man diagnosed with 22q11.2 DS presented a rare combination of multiple endocrine disorders. This is the first time that a patient with 22q11.2DS had late-onset hypogonadism caused by primary testicular failure combined with decreased pituitary gonadotropin reserve in a patient with 22q11.2DS.

Characterization of a Parkinson's disease rat model using an upgraded paraquat exposure paradigm.

Animal models of human diseases are crucial experimental tools to investigate the mechanisms involved in disease pathogenesis and to develop new therapies. In spite of the numerous animal models currently available that reproduce several neuropathological features of Parkinson disease (PD), it is challenging to have one that consistently recapitulates human PD conditions in both motor behaviors and biochemical pathological outcomes. Given that, we have implemented a new paradigm to expose rats to a chronic low dose of paraquat (PQ), using osmotic minipumps and characterized the developed pathologic features over time. The PQ exposure paradigm used lead to a rodent model of PD depicting progressive nigrostriatal dopaminergic neurodegeneration, characterized by a 41% significant loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc), a significant decrease of 18% and 40% of dopamine levels in striatum at week 5 and 8, respectively, and a significant 1.5-fold decrease in motor performance. We observed a significant increase of microglia activation state, sustained levels of α-synucleinopathy and increased oxidative stress markers in the SNpc. In summary, this is an explorative study that allowed to characterize an improved PQ-based rat model that recapitulates cardinal features of PD and may represent an attractive tool to investigate several mechanisms underlying the various aspects of PD pathogenesis as well as for the validation of the efficacy of new therapeutic approaches that targets different mechanisms involved in PD neurodegeneration.

Liver extracellular volume fraction values obtained with magnetic resonance imaging can quantitatively stage liver fibrosis: a validation study in monkeys with nonalcoholic steatohepatitis.

OBJECTIVES: This study was to evaluate the diagnostic value of liver extracellular volume (LECV) for the staging of liver fibrosis in a cynomolgus monkey model of nonalcoholic steatohepatitis (NASH). METHODS: Forty-eight cynomolgus monkeys were enrolled in this prospective study. There are 17 healthy monkeys and 31 monkeys with NASH. Ten of these monkeys were used for repeatability assessment. The remaining 38 monkeys were used to compare LECV with other indicators including pathology fibrosis score, native T1, and serum chemical indexes by Spearman, Pearson correlation test, and ROC curves. The inter-reader variability was assessed by interclass correlation. The repeatability measurement of LECV was analyzed using Bland-Altman plots and the coefficient of variation. Partial correlation analysis was performed to assess the effects of fat content and inflammation scores on the correlation between LECV/T1 and liver fibrosis score. RESULTS: This study demonstrated a good intra-reader agreement (intraclass correlation = 0.79) of LECV in all monkeys and an excellent repeatability in 10 monkeys (coefficient of variation = 2.01%). The LECV has a strong correlation with the fibrosis score (r = 0.949; p < 0.0001), low-density lipoprotein (r = 0.72; p < 0.0001), and cholesterol (r = 0.70; p < 0.0001). LECV showed high diagnostic efficacy in the diagnosis of liver fibrosis (area under the curve of ROC, 0.945~1; p < 0.001). CONCLUSIONS: LECV may serve as a noninvasive valuable biomarker for the quantification and differentiating of the non-severe liver fibrosis (stage ≤ F3). However, circulating serum markers low-density lipoprotein and cholesterol (CHO) may not serve for this purpose. KEY POINTS: • This paper demonstrated the excellent repeatability (intraclass correlation coefficient = 0.79) of LECV in monkey animal model. • LECV-MRI has a strong correlation with histopathological fibrosis score stage (r = 0.949; p < 0.0001) and shows high diagnostic efficacy in the staging of non-severe liver fibrosis (the area under ROC curve ≥ 0.945). • The new fibrosis score maps appeared to provide a better imaging tool for the spatial assessment of liver fibrosis. It may eventually facilitate the diagnosis of liver fibrosis distribution.

Risk factors for severe acute kidney injury among patients with rhabdomyolysis.

BACKGROUND: Acute kidney injury (AKI) is a life-threatening complication of rhabdomyolysis (RM). The aim of the present study was to assess patients at high risk for the occurrence of severe AKI defined as stage II or III of KDIGO classification and in-hospital mortality of AKI following RM. METHODS: We performed a retrospective study of patients with creatine kinase levels > 1000 U/L, who were admitted to the West China Hospital of Sichuan University between January 2011 and March 2019. The sociodemographic, clinical and laboratory data of these patients were obtained from an electronic medical records database, and univariate and multivariate regression analyses were subsequently conducted. RESULTS: For the 329 patients included in our study, the incidence of AKI was 61.4% and the proportion of stage I, stage II, stage III were 18.8, 14.9 and 66.3%, respectively. The overall mortality rate was 19.8%; furthermore, patients with AKI tended to have higher mortality rates than those without AKI (24.8% vs. 11.8%; P < 0.01). The clinical conditions most frequently associated with RM were trauma (28.3%), sepsis (14.6%), bee sting (12.8%), thoracic and abdominal surgery (11.2%) and exercise (7.0%). Furthermore, patients with RM resulting from sepsis, bee sting and acute alcoholism were more susceptible to severe AKI. The risk factors for the occurrence of stage II-III AKI among RM patients included hypertension (OR = 2.702), high levels of white blood cell count (OR = 1.054), increased triglycerides (OR = 1.260), low level of high-density lipoprotein cholesterol (OR = 0.318), elevated serum phosphorus (OR = 5.727), 500010,000 U/L (OR = 8.093). Age ≥ 60 years (OR = 2.946), sepsis (OR = 3.206) and elevated prothrombin time (OR = 1.079) were independent risk factors for in-hospital mortality in RM patients with AKI. CONCLUSIONS: AKI is independently associated with mortality in patients with RM, and several risk factors were found to be associated with the occurrence of severe AKI and in-hospital mortality. These findings suggest that, to improve the quality of medical care, the early prevention of AKI should focus on high-risk patients and more effective management.

[Risk Factors for Sepsis Associated-Acute Kidney Injury in Intensive Care Unit Patients].

OBJECTIVE: To explore the risk factors of acute kidney injury (AKI) in patients with sepsis in intensive care unit (ICU). METHODS: The medical records of patients diagnosed with sepsis in ICU of West China Hospital of Sichuan University from March 2009 to June 2016 were retrospectively analyzed. Differences between AKI group and Non-AKI group in general data, background disease, ICU entry and exit dates, complications, laboratory data and other related data were analyzed through univariate and multivariate statistical methods. RESULTS: A total of 2331 patients with sepsis were included in the study, including 626 patients in the AKI group and 1695 patients in the Non-AKI group. The multivariate logistic regression analysis revealed that age >40 yr. (odds ratio (OR) =2.752), diabetes (OR=2.563), hypertension/coronary heart disease (OR=1.851), chronic kidney disease (OR=15.876), heart failure (OR=2.295), acute respiratory distress syndrome (OR=2.067), severe acute pancreatitis (OR=2.725), hypotension (OR=2.140), hypoproteinemia (OR=1.596), lactic acidosis (OR=2.164), organ failure>1 (OR=4.480), WBC>10×10 9L -1 (OR=4.166), serum creatinine (OR=4.401), PCT (OR=1.816), Cys-C (OR=7.046), mild anemia (OR=2.107), moderate anemia (OR=3.817), and severe anemia (OR=6.091) were all independent risk factors of SA-AKI. CONCLUSION: Several risk factors are related to the occurrence of SA-AKI in the ICU. Early identification and monitoring of risk factors for SA-AKI and early prevention of AKI can improve the prognosis of sepsis patients.

Simultaneous quantification of endogenous and exogenous plasma glucose by isotope dilution LC-MS/MS with indirect MRM of the derivative tag.

Quantification of endogenous and exogenous plasma glucose can help more comprehensively evaluate the glucose metabolic status. A ratio-based approach using isotope dilution liquid chromatography tandem mass spectrometry (ID LC-MS/MS) with indirect multiple reaction monitoring (MRM) of the derivative tag was developed to simultaneously quantify endo-/exogenous plasma glucose. Using diluted D-[13C6] glucose as tracer of exogenous glucose, 12C6/13C6 glucoses were first derivatized and then data were acquired in MRM mode. The metabolism of exogenous glucose can be tracked and the concentration ratio of endo/exo-genous glucose can be measured by calculating the endo-/exo-genous glucose concentrations from peak area ratio of specific daughter ions. Joint application of selective derivatization and MRM analysis not only improves the sensitivity but also minimizes the interference from the background of plasma, which warrants the accuracy and reproducibility. Good agreement between the theoretical and calculated concentration ratios was obtained with a linear correlation coefficient (R) of 0.9969 in the range of D-glucose from 0.5 to 20.0 mM, which covers the healthy and diabetic physiological scenarios. Satisfactory reproducibility was obtained by evaluation of the intra- and inter-day precisions with relative standard deviations (RSDs) less than 5.16%, and relative recoveries of 85.96 to 95.92% were obtained at low, medium, and high concentration, respectively. The method was successfully applied to simultaneous determination of the endo-/exogenous glucose concentration in plasma of non-diabetic and type II diabetic cynomolgus monkeys. Graphical Abstract The scheme of the proposed ratio-based approach using isotope dilution LC-MS/MS with indirect MRM of the derivative tag for simultaneous quantification of endogenous and exogenous plasma glucose.

In Vivo Confocal Microscopic Study of Hard Contact Lens-Induced Lipid Keratopathy Secondary to Corneal Neovascularization in a Rabbit Hypercholesterolemic Model.

OBJECTIVES: In vivo confocal microscopy was used to observe the morphological presentations and anatomical correlations between corneal neovascularization (NV) and intracorneal lipid deposition in a rabbit model of contact lens (CL)-induced lipid keratopathy secondary to corneal NV. METHODS: Rabbits were divided into 3 groups: (1) 8-week normal diet, (2) 8-week high-cholesterol diet, and (3) 4-week normal diet followed by 4-week high-cholesterol diet. Corneal NV was induced by closed-eye CL. The formation and maturation of corneal NV were shown by immunohistochemical staining against CD31 and high-molecular-weight melanoma-associated antigen. In vivo confocal microscopy identified corneal NV and lipid deposition. Acquired images for each eye were arranged and mapped into subconfluent montages. RESULTS: In group 1, corneal NV sprouting formed from the peripheral to the central cornea by the end of week 4. Pericytes around vessels were shown after 2 weeks of CL wear. In group 2, lipid deposition started from the peripheral cornea and progressively covered the whole cornea. In group 3, lipid deposition was found first in the central cornea after 2 weeks of high-cholesterol diet and progressed to cover the peripheral cornea. In vivo confocal microscopy demonstrated four different patterns of intracorneal lipid deposition: spindle shapes arranged randomly or in parallel, amorphous shapes, multiangular shapes, and mixed types. Intracorneal lipid deposition was distributed from basal corneal epithelium to deep stroma. CONCLUSIONS: Intracorneal lipids tend to accumulate around newly formed corneal NV but can extend to the area covered with mature NV. In vivo confocal microscopy can demonstrate various shapes and depths of intracorneal lipid deposition.

[Superior colliculus-pulvinar-amygdala subcortical visual pathway and its biological significance].

Superior colliculus-pulvinar-amygdala pathway is one of the subcortical visual pathways in mammalian brain. Some recent studies suggest that this pathway is involved in processing emotion-related visual information. This review discusses the possibility that this pathway is more related to visual alert rather than simply the early visual information processing. The biological significance of this pathway is also discussed. Instead of detecting "where" or "what" the visual target is, the task of this early visual stage is to send out a warning signal, i.e., "something appears", so that the brain can be set up in a state of alert, which is important for the survival of animals. Thus, in the early visual information process, detection of new object "emerging" or "disappearing" takes priority over the acquisition of its feature information of "texture" and "shape", etc. The subcortical pathway may provide the neural basis of early visual warning in topological perception, a biological significance critical for animal survival.

Distinct Nrf2 Signaling Mechanisms of Fumaric Acid Esters and Their Role in Neuroprotection against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Experimental Parkinson's-Like Disease.

UNLABELLED: A promising approach to neurotherapeutics involves activating the nuclear-factor-E2-related factor 2 (Nrf2)/antioxidant response element signaling, which regulates expression of antioxidant, anti-inflammatory, and cytoprotective genes. Tecfidera, a putative Nrf2 activator, is an oral formulation of dimethylfumarate (DMF) used to treat multiple sclerosis. We compared the effects of DMF and its bioactive metabolite monomethylfumarate (MMF) on Nrf2 signaling and their ability to block 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental Parkinson's disease (PD). We show that in vitro DMF and MMF activate the Nrf2 pathway via S-alkylation of the Nrf2 inhibitor Keap1 and by causing nuclear exit of the Nrf2 repressor Bach1. Nrf2 activation by DMF but not MMF was associated with depletion of glutathione, decreased cell viability, and inhibition of mitochondrial oxygen consumption and glycolysis rates in a dose-dependent manner, whereas MMF increased these activities in vitro However, both DMF and MMF upregulated mitochondrial biogenesis in vitro in an Nrf2-dependent manner. Despite the in vitro differences, both DMF and MMF exerted similar neuroprotective effects and blocked MPTP neurotoxicity in wild-type but not in Nrf2 null mice. Our data suggest that DMF and MMF exhibit neuroprotective effects against MPTP neurotoxicity because of their distinct Nrf2-mediated antioxidant, anti-inflammatory, and mitochondrial functional/biogenetic effects, but MMF does so without depleting glutathione and inhibiting mitochondrial and glycolytic functions. Given that oxidative damage, neuroinflammation, and mitochondrial dysfunction are all implicated in PD pathogenesis, our results provide preclinical evidence for the development of MMF rather than DMF as a novel PD therapeutic. SIGNIFICANCE STATEMENT: Almost two centuries since its first description by James Parkinson, Parkinson's disease (PD) remains an incurable disease with limited symptomatic treatment. The current study provides preclinical evidence that a Food and Drug Administration-approved drug, dimethylfumarate (DMF), and its metabolite monomethylfumarate (MMF) can block nigrostriatal dopaminergic neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of PD. We elucidated mechanisms by which DMF and its active metabolite MMF activates the redox-sensitive transcription factor nuclear-factor-E2-related factor 2 (Nrf2) to upregulate antioxidant, anti-inflammatory, mitochondrial biosynthetic and cytoprotective genes to render neuroprotection via distinct S-alkylating properties and depletion of glutathione. Our data suggest that targeting Nrf2-mediated gene transcription using MMF rather than DMF is a promising approach to block oxidative stress, neuroinflammation, and mitochondrial dysfunction for therapeutic intervention in PD while minimizing side effects.

Lack of exacerbation of neurodegeneration in a double transgenic mouse model of mutant LRRK2 and tau.

LRRK2 (leucine-rich repeat kinase) mutations constitute the most common cause of familial Parkinson's disease (PD). Microtubule-associated protein tau mutations cause a group of neurodegenerative diseases termed tauopathies. Genome-wide association studies show that, after α-synuclein, polymorphisms in the tau gene have the second strongest genetic association with PD. In a proportion of PD patients with LRRK2 mutations, and in several transgenic animal models of LRRK2, tau hyperphosphorylation and aggregation, rather than α-synuclein aggregation, are the most prominent neuropathologic findings. To further examine the relationship between LRRK2 and tau, we crossed LRRK2 R1441G BAC transgenic mice (Mus musculus) with tau P301S mutant transgenic mice and characterized their behavioral, neuropathological and biochemical phenotypes. We found that the combination of the two mutations does not increase tau hyperphosphorylation or aggregation nor does it exacerbate the behavioral and pathological deficits previously described in the tau P301S mice. The double-mutant mice had no shortening of lifespan and no worsening of motor or memory deficits. There was no increase in the aggregation of tau or α-synuclein. Dopaminergic neuron cell counts and striatal levels of dopamine and its metabolites were unaltered. There was no exacerbation of cell loss, microgliosis or astrogliosis in multiple brain regions. These results suggest that LRRK2 and tau do not interact to exacerbate behavioral, biochemical or pathological abnormalities in neurodegeneration and that LRRK2 and tau exert their pathogenic effects through independent mechanisms.

Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease.

Human pluripotent stem cells (PSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of PSCs into specialized cells such as spinal motoneurons or midbrain dopamine (DA) neurons has been achieved. However, the effective use of PSCs for cell therapy has lagged behind. Whereas mouse PSC-derived DA neurons have shown efficacy in models of Parkinson's disease, DA neurons from human PSCs generally show poor in vivo performance. There are also considerable safety concerns for PSCs related to their potential for teratoma formation or neural overgrowth. Here we present a novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells. Midbrain floor-plate precursors are derived from PSCs 11 days after exposure to small molecule activators of sonic hedgehog (SHH) and canonical WNT signalling. Engraftable midbrain DA neurons are obtained by day 25 and can be maintained in vitro for several months. Extensive molecular profiling, biochemical and electrophysiological data define developmental progression and confirm identity of PSC-derived midbrain DA neurons. In vivo survival and function is demonstrated in Parkinson's disease models using three host species. Long-term engraftment in 6-hydroxy-dopamine-lesioned mice and rats demonstrates robust survival of midbrain DA neurons derived from human embryonic stem (ES) cells, complete restoration of amphetamine-induced rotation behaviour and improvements in tests of forelimb use and akinesia. Finally, scalability is demonstrated by transplantation into parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell-based therapies in Parkinson's disease.

Predictive Factors Upon Discontinuation of Renal Replacement Therapy for Long-Term Chronic Dialysis and Death in Acute Kidney Injury Patients.

The specific timing for discontinuing renal replacement therapy (RRT) in acute kidney injury (AKI) patients is debatable. The predictive abilities of variables at the time of discontinuation of RRT for the long-term prognoses of patients have not been explored. This study aimed to explore the prognostic factors upon discontinuation of RRT for long-term chronic dialysis and death of patients with acute RRT-requiring AKI, thus improving decision making regarding the discontinuation of RRT and the follow-up of patients thereafter. A cohort of 302 AKI patients who required acute RRT and remained alive and free of dialysis for at least 30 days after discharge from January 2009 to December 2012 were followed up. The predictive abilities of general characteristics, RRT details, and variables upon discontinuation of RRT for long-term chronic dialysis and all-cause death were evaluated using Cox proportional hazards models. Kaplan-Meier analysis with a log-rank test was used to compare the survival curves between the strata of levels of good predictors upon discontinuation of RRT. After a median follow-up time of 4.1 years, 20 (6.6%) patients initiated chronic dialysis and 56 (18.5%) patients died. A higher CysC level upon discontinuation of RRT (HR 1.520, 95% CI 1.082-2.135; P = 0.016), comorbid chronic kidney disease, and a higher non-renal Charlson comorbidity index (CCI) were independently predictive for chronic dialysis. The hemoglobin level upon discontinuation of RRT was inversely predictive of death (HR 0.986, 95% CI 0.973-0.999; P = 0.035), and comorbid malignancy, the presence of multiple organ dysfunction syndrome, and a higher non-renal CCI also predicted death. Urine output upon discontinuation of RRT was marginally inversely predictive of death (HR 0.997, 95% CI 0.994-1.000; P = 0.056). Patients who discontinued RRT with CysC levels <2.97 mg/L, hemoglobin levels >85 g/L, and urine output >1130 mL/24 h showed significantly higher non-chronic dialysis and survival rates according to a log-rank test. Our study suggested that upon discontinuation of RRT, higher serum CysC levels had the most promising predictive value for long-term chronic dialysis, and lower hemoglobin levels predicted long-term death; lower urine output also marginally predicted long-term death. Based on the remission of the comprehensive condition, lower CysC levels and higher hemoglobin levels and urine output should be considered in the decision to stop RRT. Patients showing worse levels of these indices upon discontinuation of RRT should undergo stricter follow-up and treatment to improve long-term outcomes.

Coordinate regulation of mature dopaminergic axon morphology by macroautophagy and the PTEN signaling pathway.

Macroautophagy is a conserved mechanism for the bulk degradation of proteins and organelles. Pathological studies have implicated defective macroautophagy in neurodegeneration, but physiological functions of macroautophagy in adult neurons remain unclear. Here we show that Atg7, an essential macroautophagy component, regulates dopaminergic axon terminal morphology. Mature Atg7-deficient midbrain dopamine (DA) neurons harbored selectively enlarged axonal terminals. This contrasted with the phenotype of DA neurons deficient in Pten - a key negative regulator of the mTOR kinase signaling pathway and neuron size - that displayed enlarged soma but unaltered axon terminals. Surprisingly, concomitant deficiency of both Atg7 and Pten led to a dramatic enhancement of axon terminal enlargement relative to Atg7 deletion alone. Similar genetic interactions between Atg7 and Pten were observed in the context of DA turnover and DA-dependent locomotor behaviors. These data suggest a model for morphological regulation of mature dopaminergic axon terminals whereby the impact of mTOR pathway is suppressed by macroautophagy.

Novel risk score of contrast-induced nephropathy after percutaneous coronary intervention.

AIM: Contrast-induced nephropathy (CIN) post-percutaneous coronary intervention (PCI) is a major cause of acute kidney injury. In this study, we established a comprehensive risk score model to assess risk of CIN after PCI procedure, which could be easily used in a clinical environment. METHODS: A total of 805 PCI patients, divided into analysis cohort (70%) and validation cohort (30%), were enrolled retrospectively in this study. Risk factors for CIN were identified using univariate analysis and multivariate logistic regression in the analysis cohort. Risk score model was developed based on multiple regression coefficients. Sensitivity and specificity of the new risk score system was validated in the validation cohort. Comparisons between the new risk score model and previous reported models were applied. RESULTS: The incidence of post-PCI CIN in the analysis cohort (n = 565) was 12%. Considerably high CIN incidence (50%) was observed in patients with chronic kidney disease (CKD). Age >75, body mass index (BMI) >25, myoglobin level, cardiac function level, hypoalbuminaemia, history of chronic kidney disease (CKD), Intra-aortic balloon pump (IABP) and peripheral vascular disease (PVD) were identified as independent risk factors of post-PCI CIN. A novel risk score model was established using multivariate regression coefficients, which showed highest sensitivity and specificity (0.917, 95%CI 0.877-0.957) compared with previous models. CONCLUSION: A new post-PCI CIN risk score model was developed based on a retrospective study of 805 patients. Application of this model might be helpful to predict CIN in patients undergoing PCI procedure.

Inhibition to DRP1 translocation can mitigate p38 MAPK-signaling pathway activation in GMC induced by hyperglycemia.

Diabetic nephropathy (DN) is a serious complication of diabetes with a poorly defined etiology and limited treatment options. Early intervention is a key to preventing the progression of DN. Dynamin-related protein 1 (DRP1) regulates mitochondrial morphology by promoting its fission and is involved in the pathogenesis of numerous diseases. Furthermore, DRP1 is also closely associated with the development of diabetes, but its functional role in DN remains unknown. This study investigated the effect of DRP1 on early stage of DN. DRP1 expression has increased significantly in glomerular mesangial cell (GMC), which is cultivated in high glucose (HG). Ultra-microstructural changes of nephrons, expression of collagen IV and phosph-p38, ROS production, and mitochondrial function were evaluated and, at the same time, were compared with glomerular mesangial cell (GMC) cultured in normal-glucose (NG), mannitol, and a medium with mitochondrial division inhibitor 1 (Midivi-1). Endogenous DRP1 expression increased in DN. Compared to the control groups ofNG and mannitol, overexpression of DRP1 destroyed pathological changes typical of the GMC, like accumulation of extracellular matrix, and an increase in mitochondria division. In addition, Overexpression of DRP1 promoted the activation of p38, the accumulation of ROS, mitochondrial dysfunction, and the synthesis of collagen IV, and all these changes are suppressed by Midivi-1. This study demonstrates that DRP1 overexpression can accelerate pathological changes in the GMC cultured in HG. Further studies are needed to clarify the underlying mechanism of this destructive function.

Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington's disease.

There is substantial evidence that impairment of peroxisome proliferator-activated receptor (PPAR)-γ-coactivator 1α (PGC-1α) levels and activity play an important role in Huntington's disease (HD) pathogenesis. We tested whether pharmacologic treatment with the pan-PPAR agonist bezafibrate would correct a deficiency of PGC-1α and exert beneficial effects in a transgenic mouse model of HD. We found that administration of bezafibrate in the diet restored levels of PGC-1α, PPARs and downstream genes to levels which occur in wild-type mice. There were significant improvements in phenotype and survival. In the striatum, astrogliosis and neuronal atrophy were attenuated and numbers of mitochondria were increased. Bezafibrate treatment prevented conversion of type I oxidative to type II glycolytic muscle fibers and increased the numbers of muscle mitochondria. Finally, bezafibrate rescued lipid accumulation and apparent vacuolization of brown adipose tissue in the HD mice. These findings provide strong evidence that treatment with bezafibrate exerts neuroprotective effects which may be beneficial in the treatment of HD.

Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice.

Peroxisome proliferator-activated receptors (PPARs) are ligand-mediated transcription factors, which control both lipid and energy metabolism and inflammation pathways. PPARγ agonists are effective in the treatment of metabolic diseases and, more recently, neurodegenerative diseases, in which they show promising neuroprotective effects. We studied the effects of the pan-PPAR agonist bezafibrate on tau pathology, inflammation, lipid metabolism and behavior in transgenic mice with the P301S human tau mutation, which causes familial frontotemporal lobar degeneration. Bezafibrate treatment significantly decreased tau hyperphosphorylation using AT8 staining and the number of MC1-positive neurons. Bezafibrate treatment also diminished microglial activation and expression of both inducible nitric oxide synthase and cyclooxygenase 2. Additionally, the drug differentially affected the brain and brown fat lipidome of control and P301S mice, preventing lipid vacuoles in brown fat. These effects were associated with behavioral improvement, as evidenced by reduced hyperactivity and disinhibition in the P301S mice. Bezafibrate therefore exerts neuroprotective effects in a mouse model of tauopathy, as shown by decreased tau pathology and behavioral improvement. Since bezafibrate was given to the mice before tau pathology had developed, our data suggest that bezafibrate exerts a preventive effect on both tau pathology and its behavioral consequences. Bezafibrate is therefore a promising agent for the treatment of neurodegenerative diseases associated with tau pathology.

Involvement of inflammation-related miR-155 and miR-146a in diabetic nephropathy: implications for glomerular endothelial injury.

BACKGROUND: MicroRNAs have been demonstrated to play an important role in the pathogenesis of diabetic nephropathy (DN). In this study, we investigated both the repertoire of miRNAs in the kidneys of patients with DN and their potential regulatory role in inflammation-mediated glomerular endothelial injury. METHODS: The miRNA expression profiling of the renal biopsy samples was performed by a microarray analysis; then, in situ hybridization and real-time polymerase chain reaction (PCR) were used to determine the localization and expression of two of the miRNAs significantly up-regulated in human DN kidney samples, miR-155 and miR-146a, in the kidney tissues from type 1 and type 2 DN rat models. Human renal glomerular endothelial cells (HRGECs) cultured under high-glucose conditions were transfected with miR-155 and miR-146a mimics, and the transforming growth factor (TGF)-ß1, tumor necrosis factor (TNF)-α, and nuclear factor (NF)-κB expressions were examined by western blot, real-time PCR, and an electrophoresis mobility shift assay. RESULTS: The expression of both miR-155 and miR-146a was increased more than fivefold in the kidney samples of the DN patients compared with the controls, and the miR-155 expression was closely correlated with the serum creatinine levels (R = 0.95, P = 0.004). During the induction and progression of the disease in type 1 and type 2 DN rat models, miR-155 and miR-146a were demonstrated to increase gradually. In vitro, high glucose induced the over-expression of miR-155 and miR-146a in the HRGECs, which, in turn, increased the TNF-α, TGF-ß1, and NF-κB expression. CONCLUSIONS: Taken together, these findings indicate that the increased expression of miR-155 and miR-146a in the DN patients and in the experimental DN animal models was found to contribute to inflammation-mediated glomerular endothelial injury.

Astragalus membranaceus up-regulate Cosmc expression and reverse IgA dys-glycosylation in IgA nephropathy.

BACKGROUND: Decreased Core I ß3-Gal-T-specific molecular chaperone (Cosmc) expression induced IgA1 aberrant glycosylation is the main characteristic of IgA nephropathy (IgAN). This study tried to elucidate the effect of Astragalus membranaceus on Cosmc expression and IgA O-glycosylation of peripheral B lymphocytes in IgAN patients. METHODS: Peripheral B lymphocytes of 21 IgAN patients and 10 normal controls were isolated and cultured with or without lipopolysaccharide (LPS) and Astragalus membranaceus injection (AMI). Cosmc mRNA and protein expression levels were measured by real-time RT-PCR and Western blot. IgA1 and glycosylation level were determined by enzyme-linked immunosorbent assay (ELISA) and VV lectin-binding method. RESULTS: Cosmc mRNA expression and IgA1 O-glycosylation level in IgAN patients was significantly lower than normal controls at baseline. Treatment of LPS could obviously inhibit Cosmc expression and increase the IgA1 secretion in peripheral B lymphocytes of IgAN patients, which resulted in a significantly increase in IgA1 aberrant glycosylation level. Addition of AMI could remarkably up regulated Cosmc expression, decrease IgA1 secretion, and reverse glycosylation level in a dose related manner. CONCLUSION: AMI can up-regulate Cosmc expression of peripheral B lymphocytes and reverse IgA1 aberrant O-glycosylation level, which might be the underlying mechanism of AMI therapy in treating IgAN. TRIAL REGISTRATION: TCTR20140515001 (Registration Date: 2014-05-15).

Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes.

To direct human embryonic stem (HES) cells to a dopaminergic neuronal fate, we cocultured HES cells that were exposed to both sonic hedgehog and fibroblast growth factor 8 with telomerase-immortalized human fetal midbrain astrocytes. These astrocytes substantially potentiated dopaminergic neurogenesis by both WA09 and WA01 HES cells, biasing them to the A9 nigrostriatal phenotype. When transplanted into the neostriata of 6-hydroxydopamine-lesioned parkinsonian rats, the dopaminergic implants yielded a significant, substantial and long-lasting restitution of motor function. However, although rich in donor-derived tyrosine hydroxylase-expressing neurons, the grafts exhibited expanding cores of undifferentiated mitotic neuroepithelial cells, which can be tumorigenic. These results show the utility of recreating the cellular environment of the developing human midbrain while driving dopaminergic neurogenesis from HES cells, and they demonstrate the potential of the resultant cells to mediate substantial functional recovery in a model of Parkinson disease. Yet these data also mandate caution in the clinical application of HES cell-derived grafts, given their potential for phenotypic instability and undifferentiated expansion.