Phosphomannomutase 2 hyperinsulinemia: Recent advances of genetic pathogenesis, diagnosis, and management

Congenital hyperinsulinemia (CHI), is a clinically heterogeneous disorder that presents as a major cause of persistent and recurrent hypoglycemia during infancy and childhood. There are 16 subtypes of CHI-related genes. Phosphomannomutase 2 hyperinsulinemia (PMM2-HI) is an extremely rare subtype which is first reported in 2017, with only 18 families reported so far. This review provides a structured description of the genetic pathogenesis, and current diagnostic and therapeutic advances of PMM2-HI to increase clinicians’ awareness of PMM2-HI

Increased gene copy number of DEFA1/DEFA3 worsens sepsis by inducing endothelial pyroptosis.

Sepsis claims an estimated 30 million episodes and 6 million deaths per year, and treatment options are rather limited. Human neutrophil peptides 1-3 (HNP1-3) are the most abundant neutrophil granule proteins but their neutrophil content varies because of unusually extensive gene copy number polymorphism. A genetic association study found that increased copy number of the HNP-encoding gene DEFA1/DEFA3 is a risk factor for organ dysfunction during sepsis development. However, direct experimental evidence demonstrating that these risk alleles are pathogenic for sepsis is lacking because the genes are present only in some primates and humans. Here, we generate DEFA1/DEFA3 transgenic mice with neutrophil-specific expression of the peptides. We show that mice with high copy number of DEFA1/DEFA3 genes have more severe sepsis-related vital organ damage and mortality than mice with low copy number of DEFA1/DEFA3 or wild-type mice, resulting from more severe endothelial barrier dysfunction and endothelial cell pyroptosis after sepsis challenge. Mechanistically, HNP-1 induces endothelial cell pyroptosis via P2X7 receptor-mediating canonical caspase-1 activation in a NLRP3 inflammasome-dependent manner. Based on these findings, we engineered a monoclonal antibody against HNP-1 to block the interaction with P2X7 and found that the blocking antibody protected mice carrying high copy number of DEFA1/DEFA3 from lethal sepsis. We thus demonstrate that DEFA1/DEFA3 copy number variation strongly modulates sepsis development in vivo and explore a paradigm for the precision treatment of sepsis tailored by individual genetic information

Domain configurations in Co/Pd and L10-FePt nanowire arrays with perpendicular magnetic anisotropy

Perpendicular magnetic anisotropy [Co/Pd]15 and L10-FePt nanowire arrays of period 63 nm with linewidths 38 nm and 27 nm and film thickness 27 nm and 20 nm respectively were fabricated using a self-assembled PS-b-PDMS diblock copolymer film as a lithographic mask. The wires are predicted to support Neel walls in the Co/Pd and Bloch walls in the FePt. Magnetostatic interactions from nearest neighbor nanowires promote a ground state configuration consisting of alternating up and down magnetization in adjacent wires. This was observed over ~75% of the Co/Pd wires after ac-demagnetization but was less prevalent in the FePt because the ratio of interaction field to switching field was much smaller. Interactions also led to correlations in the domain wall positions in adjacent Co/Pd nanowires. The reversal process was characterized by nucleation of reverse domains, followed at higher fields by propagation of the domains along the nanowires. These narrow wires provide model system for exploring domain wall structure and dynamics in perpendicular anisotropy systems

Inhibition of COX2/PGD2-Related Autophagy Is Involved in the Mechanism of Brain Injury in T2DM Rat

The present study was designed to observe the effect of COX2/PGD2-related autophagy on brain injury in type 2 diabetes rats. The histopathology was detected by haematoxylin–eosin staining. The learning and memory functions were evaluated by Morris water maze. The levels of insulin and PGD2 were measured by enzyme-linked immunosorbent assay. The expressions of COX2, p-AKT(S473), p-AMPK(T172), Aβ, Beclin1, LC3BII, and p62 were measured by immunohistochemistry and Western blotting. In model rats, we found that the body weight was significantly decreased, the blood glucose levels were significantly increased, the plasma insulin content was significantly decreased, the learning and memory functions were impaired and the cortex and hippocampus neurons showed significant nuclear pyknosis. The levels of COX2, p-AKT(S473), PGD2, Aβ, Beclin1 and p62 were significantly increased, whereas the expression of p-AMPK(T172) and LC3BII was significantly decreased in the cortex and hippocampus of model rats. In meloxicam-treated rats, the body weight, blood glucose and the content of plasma insulin did not significantly change, the learning and memory functions were improved and nuclear pyknosis was improved in the cortex and hippocampus neurons. The expression of p-AMPK(T172), Beclin1 and LC3BII was significantly increased, and the levels of COX2, p-AKT(S473), PGD2, Aβ, and p62 were significantly decreased in the cortex and hippocampus of meloxicam-treated rats. Our results suggested that the inhibition of COX2/PGD2-related autophagy was involved in the mechanism of brain injury caused by type 2 diabetes in rats

Adapentpronitrile, a New Dipeptidyl Peptidase-IV Inhibitor, Ameliorates Diabetic Neuronal Injury Through Inhibiting Mitochondria-Related Oxidative Stress and Apoptosis

Our previous studies indicated that adapentpronitrile, a new adamantane-based dipeptidyl peptidase-IV (DPP-IV) inhibitor, has a hypoglycemic effect and ameliorates rat pancreatic β cell dysfunction in type 2 diabetes mellitus through inhibiting DPP-IV activity. However, the effect of adapentpronitrile on the neurodegenerative diseases has not been studied. In the present study, we first found that adapentpronitrile significantly ameliorated neuronal injury and decreased amyloid precursor protein (APP) and amyloid beta (Aβ) expression in the hippocampus and cortex in the high fat diet/STZ rat model of diabetes. Furthermore, adapentpronitrile significantly attenuated oxidative stress, downregulated expression of the pro-apoptotic proteins BAX, cytochrome c, caspase-9, and caspase-3, and upregulated expression of the anti-apoptotic protein Bcl-2, although there was no effect on GLP-1R expression. At 30 min post-injection of adapentpronitrile (50 mg/kg) via the tail vein, its concentration in normal rat brain was 0.2034 ± 0.0094 μg/g. Subsequently, we further confirmed the neuroprotective effects and mechanism of adapentpronitrile in HT22 cells treated with high glucose (HG) and aluminum maltolate [Al(mal)3] overload, respectively. Our results showed significant decreases in mitochondrial membrane potential (MTP) and Bcl-2 expression, accompanied by a significant increase in apoptosis, reactive oxygen species (ROS) generation, and the expression of pro-apoptotic proteins in HT22 cells exposed to these stimuli. Adapentpronitrile treatment protected against neuronal injury, suppressed ROS generation, and reduced MTP and mitochondrial apoptosis in HT22 cells; however, DPP-IV activity was not detected. Our results suggest that adapentpronitrile protects against diabetic neuronal injury, at least partially, by inhibiting mitochondrial oxidative stress and the apoptotic pathway in a DPP-IV-independent manner