Understanding Alcohol-Induced Hepatotoxicity
The formation of megamitochondria—oversize and misshapen mitochondria—in the livers of patients is a hallmark of alcoholic liver diseases. To identify the underlying mechanisms, Palma et al (Am J Pathol 2019, 189:580–589) studied the mitochondrial and cellular responses to alcohol. In hepatoma cells, alcohol treatment inhibited cell growth and promoted megamitochondria formation, which was mediated by dynamin-1-like protein (Drp1). Genetically inactivating Drp1 induced development of megamitochondria but did not promote ethanol-induced cellular growth. Liver-specific inactivation of Drp1 in mice resulted in megamitochondria, which increased upon ethanol administration. However, ethanol-induced toxicity was reduced in these mice. Drp1-mediated megamitochondria formation may be protective against ethanol toxicity.
NF-κB Signaling Mediates Necrotizing Enterocolitis
Necrotizing enterocolitis (NEC) is characterized by intestinal inflammation and necrosis in premature infants. Using a NEC mouse model, Managlia et al (Am J Pathol 2019, 189: 604–618) studied the role of the previously implicated transcription factor, nuclear factor-κB (NF-κB), in myeloid cells during NEC. The catalytic sub-unit, IKKβ, of the IKK complex was conditionally deleted in specific cell types to inhibit NF-κB signaling and the impacted cells traced. NF-κB was critical for NEC-induced activation and recruitment of monocytes in intestines of newborns, as well as their differentiation to macrophages. Impairing NF-κB signaling improved mouse survival and decreased incidence of severe NEC, independent of changes in intestinal barrier. Inhibiting early monocyte recruitment to the infant intestine may ameliorate symptoms of NEC.
Understanding Bone Healing
Clinical administration of bone morphogenetic protein-2 (BMP2) for bone regeneration may result in abnormal bone formation due to imbalance between adipogenesis and osteogenesis. Since BMP-2 activates an adipogenesis master regulator gene, peroxisome proliferator activated receptor γ (PPARG), Wang et al (Am J Pathol 2019, 189:648–664) explored this relationship. Knock-down of PPARγ with concurrent administration of BMP2 in a mouse model reduced adipogenesis and impaired BMP2-induced osteogenesis, leading to bone non-union. BMP2-induced adipogenesis was inhibited; cell proliferation, migration, invasion, and osteogenesis decreased; and cell apoptosis increased when PPARγ was knocked down in vitro. The clinical use of PPARγ inhibitors in bone healing should be carefully considered.
Exploring Prion Protein Localization
Alterations in the composition of gangliosides—sialic acid–containing glycosphingolipids—may alter localization of proteins associated with lipid rafts. Kobayashi et al (Am J Pathol 2019, 189:677–686) studied the role of gangliosides in the pathogenesis of prion diseases. Two different mouse-adapted prion strains were intracerebrally transmitted in three independent ganglioside synthase knock-out mouse models (GD2/GM2 synthase, GD3 synthase, and GM3 synthase). Administration of Chandler prion strain in GD2/GM2 synthase knock-out mice resulted in significantly shorter disease incubation time, decreased prion protein deposition in the brain, reduced glial reaction, and decreased localization of prion proteins to lipid rafts. Gangliosides may be critical for the localization of prion proteins in lipid rafts.
Managing Human Testicular Seminoma
The role of the cancer biomarker leptin and its receptor in the growth and progression of human testicular seminoma remains unknown. Panza et al (Am J Pathol 2019, 189:687–698) therefore studied this link. The expression of leptin and its receptor was significantly increased in human testicular seminoma compared to normal adult testis. TCam-2 human seminoma cells also expressed both molecules and exhibited increased activation of their downstream effectors. Leptin stimulation in vitro significantly increased proliferation and migration of TCam-2 cells. Treatment with leptin receptor antagonist fully reversed these effects in vitro. In vivo treatment with leptin receptor antagonist decreased seminoma tumor growth in xenografted tumors. Leptin receptor may be targeted in testicular seminoma.
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Published online: January 16, 2019
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- PreviewThe Food and Drug Administration–approved clinical dose (1.5 mg/mL) of bone morphogenetic protein-2 (BMP2) has been reported to induce significant adverse effects, including cyst-like adipose-infiltrated abnormal bone formation. These undesirable complications occur because of increased adipogenesis, at the expense of osteogenesis, through BMP2-mediated increases in the master regulatory gene for adipogenesis, peroxisome proliferator-activated receptor-γ (PPARγ). Inhibiting PPARγ during osteogenesis has been suggested to drive the differentiation of bone marrow stromal/stem cells toward an osteogenic, rather than an adipogenic, lineage.
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- Ganglioside Synthase Knockout Reduces Prion Disease Incubation Time in Mouse ModelsThe American Journal of PathologyVol. 189Issue 3
- PreviewLocalization of the abnormal and normal isoforms of prion proteins to detergent-resistant membrane microdomains, lipid rafts, is important for the conformational conversion. Lipid rafts are enriched in sialic acid–containing glycosphingolipids (namely, gangliosides). Alteration in the ganglioside composition of lipid rafts can affect the localization of lipid raft–associated proteins. To investigate the role of gangliosides in the pathogenesis of prion diseases, we performed intracerebral transmission study of a scrapie prion strain Chandler and a Gerstmann-Sträussler-Scheinker syndrome prion strain Fukuoka-1 using various knockout mouse strains ablated with ganglioside synthase gene (ie, GD2/GM2 synthase, GD3 synthase, or GM3 synthase).
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