Prenatal hormone stress triggers embryonic cardiac hypertrophy outcome by ubiquitin-dependent degradation of mitochondrial mitofusin 2.

Prenatal stress has been extensively documented as a contributing factor to adverse cardiac development and function in fetuses and infants. The release of glucocorticoids (GCs), identified as a significant stressor, may be a potential factor inducing cardiac hypertrophy. However, the underlying mechanism remains largely unknown. Herein, we discovered that corticosterone (CORT) overload induced cardiac hypertrophy in embryonic chicks and fetal mice in vivo, as well as enlarged cardiomyocytes in vitro. The impaired mitochondria dynamics were observed in CORT-exposed cardiomyocytes, accompanied by dysfunction in oxidative phosphorylation and ATP production. This phenomenon was found to be linked to decreased mitochondrial fusion protein mitofusin 2 (MFN2). Subsequently, we found that CORT facilitated the ubiquitin-proteasome-system-dependent degradation of MFN2 with an enhanced binding of appoptosin to MFN2, serving as the underlying cause. Collectively, our findings provide a comprehensive understanding of the mechanisms by which exposure to stress hormones induces cardiac hypertrophy in fetuses.

Phospholipid peroxidation inhibits autophagy via stimulating the delipidation of oxidized LC3-PE.

Phospholipid peroxidation of polyunsaturated fatty acids at the bis-allylic position drives ferroptosis. Here we identify a novel role for phospholipid peroxidation in the inhibition of autophagy. Using in vitro and in vivo models, we report that phospholipid peroxidation induced by glutathione peroxidase-4 inhibition and arachidonate 15-lipoxygenase overexpression leads to overload of peroxidized phospholipids and culminate in inhibition of autophagy. Functional and lipidomics analysis further demonstrated that inhibition of autophagy was associated with an increase of peroxidized phosphatidylethanolamine (PE) conjugated LC3. We further demonstrate that autophagy inhibition occurred due to preferential cleavage of peroxidized LC3-PE by ATG4B to yield delipidated LC3. Mouse models of phospholipid peroxidation and autophagy additionally supported a role for peroxidized PE in autophagy inhibition. Our results agree with the recognized role of endoplasmic reticulum as the primary source for autophagosomal membranes. In summary, our studies demonstrated that phospholipid peroxidation inhibited autophagy via stimulating the ATG4B-mediated delipidation of peroxidized LC3-PE.

Autophagic degradation of PML promotes susceptibility to HSV-1 by stress-induced corticosterone.

Rationale: Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that can cause a variety of clinical syndromes including mucocutaneous disease and HSV-1 encephalitis (HSE). Here, we characterize the molecular mechanisms underlying the susceptibility to HSV-1 under stressful conditions. Methods: Restraint stress and corticosterone (CORT, a primary stress hormone) were respectively used to establish HSV-1 susceptible model in vivo and in vitro. Viral titers were determined by plaque assay. Western blotting, immunofluorescence, transmission electron microscopy (TEM), qRT-PCR, H&E staining, IHC staining and flow cytometry were employed to evaluate virus-related protein expressions and detect the activation of autophagy. Loss- and gain-function assays, co-immunoprecipitation (co-IP) technique and autophagy agonist/antagonist treatments were applied in mechanistic experiments. Results: Restraint stress increased the susceptibility of mouse brain to HSV-1. Similarly, CORT treatment enhanced the susceptibility of neural cells to HSV-1. Furthermore, PML protein level in HSV-1 infected brain tissues and neural cells was remarkably decreased by stress treatment in vivo or CORT treatment in vitro, while its transcriptional level was not affected. Notably, a striking decline in protein expressions of ICP27 and gB was observed in PML-overexpressing cells, which was reversed by CORT treatment. By contrast, protein expression of gB was increased by knockdown with si-PML in virus-infected SH-SY5Y cells. We further discovered that CORT-driven PML degradation was dependent on the activation of autophagy in a ULK1-independent manner, rather than proteasome pathway. Bafilomycin A1 (BaF1) attenuated the augmentation effect of CORT on HSV-1 infection. The expressions of viral proteins were reduced in LC3-depleted cells, and the degradation of PML by CORT-induced autophagy was prevented in cells with LC3 knockdown by RNAi. Interestingly, PML was revealed to interact with the autophagic cargo receptor P62 and the autophagic effector protein LC3. Additionally, CORT failed to increase gB protein level when PML was silenced, providing direct evidence linking autophagic degradation of PML and CORT-induced virus susceptibility. Conclusion: Our results revealed that restraint stress/CORT increased HSV-1 susceptibility by delivering PML into autolysosomes for degradation. The results obtained from in vitro and in vivo models not only demonstrated the adverse effects of stress on HSV-1 infection, but also systematically investigated the underlying molecular mechanisms. These discoveries broaden our understanding of the interplay between host and viruses, and a comprehensive understanding of the role of autophagy in viral infection will provide information for future development of innovative drugs against viral infection.

Hookworm Infection: A Neglected Cause of Overt Obscure Gastrointestinal Bleeding

Hookworm infections are widely prevalent in tropical and subtropical areas, especially in low income regions. In the body, hookworms parasitize the proximal small intestine, leading to chronic intestinal hemorrhage and iron deficiency anemia. Occasionally, hookworms can cause overt gastrointestinal bleeding, but this is often ignored in heavily burdened individuals from endemic infectious areas. A total of 424 patients with overt obscure gastrointestinal bleeding were diagnosed by numerous blood tests or stool examinations as well as esophagogastroduodenoscopy, colonoscopy, capsule endoscopy or double-balloon enteroscopy. All of the patients lived in hookworm endemic areas and were not screened for hookworm infection using sensitive tests before the final diagnosis. The patients recovered after albendazole treatment, blood transfusion, and iron replacement, and none of the patients experienced recurrent bleeding in the follow-up. All the 31 patients were diagnosed with hookworm infections without other concomitant bleeding lesions, a rate of 7.3% (31/424). Seventeen out of 227 patients were diagnosed with hookworm infections in the capsule endoscopy (CE), and 14 out of 197 patients were diagnosed with hookworm infections in the double balloon enteroscopy (DBE). Hookworm infections can cause overt gastrointestinal bleeding and should be screened in patients with overt obscure gastrointestinal bleeding (OGIB) in endemic infectious areas with sensitive methods. Specifically, the examination of stool specimens is clinically warranted for most patients, and the proper examination for stool eggs relies on staff's communication.

CD64 Expression Is Increased in Patients with Severe Acute Pancreatitis: Clinical Significance

BACKGROUND/AIMS: Upregulated CD64 expression on neutrophils is the most useful marker for acute bacterial infections and systemic inflammation. However, it is unknown whether CD64 is involved in the pathogenesis of acute pancreatitis (AP). This study was designed to determine whether CD64 is implicated in severe acute pancreatitis (SAP), and thus, is a suitable marker for SAP. METHODS: SAP was induced in rats with an intraperitoneal injection of L-arginine. CD64 expression in the rat pancreas was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry. Additionally, the CD64 mRNA expression in peripheral blood leukocytes from 21 patients with mild acute pancreatitis (MAP) and 10 patients with SAP was investigated at the time of admission and during remission by qRT-PCR. RESULTS: CD64 mRNA and protein expression in the pancreas was significantly higher in rats with SAP, compared to the controls. The CD64 expression was higher in the patients with SAP than in the patients with MAP. During remission, CD64 mRNA decreased in both the MAP and SAP patients. The area under the curve of CD64 expression for the detection of SAP was superior to both the Ranson and the Acute Physiology and Chronic Health Evaluation II scores. CONCLUSIONS: The CD64 level was significantly increased in correlation with the disease severity in SAP and may act as a useful marker for predicting the development of SAP.