bims-meglyc 2023-01-01 papers

Front Genet. 2022 ;13 1019283

Perinatal manifestations of congenital disorders of glycosylation-A clue to early diagnosis.

Milena Greczan, Dariusz Rokicki, Dorota Wesół-Kucharska, Magdalena Kaczor, Agata Rawiak, Aleksandra Jezela-Stanek.

N-glycosylation defects-isolated or mixed with other glycosylation defects-are the most frequent congenital disorders of glycosylation and present mostly in childhood, with a specific combination of non-specific phenotypic features. The diagnosis, however, is often delayed. The aim of this study is to describe the perinatal phenotype of congenital disorders of N-glycosylation. We present an analysis of perinatal symptoms in a group of 24 one-center Polish patients with N-glycosylation defects-isolated or mixed. The paper expands the perinatal phenotype of CDGs and shows that some distinctive combinations of symptoms present in the perinatal period should raise a suspicion of CDGs in a differential diagnosis.

Keywords: CDG (congenital disorders of glycosylation); dysmorphia; effusion; glycosylation; hydrops fetalis; thrombocytopenia

DOI: https://doi.org/10.3389/fgene.2022.1019283

Mol Cells. 2022 Dec 28.

Golgi Stress Response: New Insights into the Pathogenesis and Therapeutic Targets of Human Diseases.

Won Kyu Kim, Wooseon Choi, Barsha Deshar, Shinwon Kang, Jiyoon Kim.

The Golgi apparatus modifies and transports secretory and membrane proteins. In some instances, the production of secretory and membrane proteins exceeds the capacity of the Golgi apparatus, including vesicle trafficking and the post-translational modification of macromolecules. These proteins are not modified or delivered appropriately due to insufficiency in the Golgi function. These conditions disturb Golgi homeostasis and induce a cellular condition known as Golgi stress, causing cells to activate the 'Golgi stress response,' which is a homeostatic process to increase the capacity of the Golgi based on cellular requirements. Since the Golgi functions are diverse, several response pathways involving TFE3, HSP47, CREB3, proteoglycan, mucin, MAPK/ETS, and PERK regulate the capacity of each Golgi function separately. Understanding the Golgi stress response is crucial for revealing the mechanisms underlying Golgi dynamics and its effect on human health because many signaling molecules are related to diseases, ranging from viral infections to fatal neurodegenerative diseases. Therefore, it is valuable to summarize and investigate the mechanisms underlying Golgi stress response in disease pathogenesis, as they may contribute to developing novel therapeutic strategies. In this review, we investigate the perturbations and stress signaling of the Golgi, as well as the therapeutic potentials of new strategies for treating Golgi stress-associated diseases.

Keywords: Golgi stress; Golgi stress response; human disease; pathogenesis; therapeutic target

DOI: https://doi.org/10.14348/molcells.2023.2152

Rev Neurol (Paris). 2022 Dec 22. pii: S0035-3787(22)00846-3. [Epub ahead of print]

Strategy for genetic analysis in hereditary neuropathy.

M Masingue, G Fernández-Eulate, R Debs, C Tard, C Labeyrie, S Leonard-Louis, M A Masson, P Latour, T Stojkovic.

Inherited neuropathies are a heterogeneous group of slowly progressive disorders affecting either motor, sensory, and/or autonomic nerves. Peripheral neuropathy may be the major component of a disease such as Charcot-Marie-Tooth disease or a feature of a more complex multisystemic disease involving the central nervous system and other organs. The goal of this review is to provide the clinical clues orientating the genetic diagnosis in a patient with inherited peripheral neuropathy. This review focuses on primary inherited neuropathies, amyloidosis, inherited metabolic diseases, while detailing clinical, neurophysiological and potential treatment of these diseases.

Keywords: Amyloidosis; Charcot-Marie-Tooth disease; Genome; Inborn error of metabolism; Inherited neuropathy

DOI: https://doi.org/10.1016/j.neurol.2022.11.007

Heliyon. 2022 Dec;8(12): e12294

Excessive gluconeogenesis causes the hepatic insulin resistance paradox and its sequelae.

Arnold N Onyango.

Background: Hepatic insulin signaling suppresses gluconeogenesis but promotes de novo lipid synthesis. Paradoxically, hepatic insulin resistance (HIR) enhances both gluconeogenesis and de novo lipid synthesis. Elucidation of the etiology of this paradox, which participates in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, the metabolic syndrome and hepatocellular carcinoma, has not been fully achieved.
Scope of review: This article briefly outlines the previously proposed hypotheses on the etiology of the HIR paradox. It then discusses literature consistent with an alternative hypothesis that excessive gluconeogenesis, the direct effect of HIR, is responsible for the aberrant lipogenesis. The mechanisms involved therein are explained, involving de novo synthesis of fructose and uric acid, promotion of glutamine anaplerosis, and induction of glucagon resistance. Thus, gluconeogenesis via lipogenesis promotes hepatic steatosis, a component of NAFLD, and dyslipidemia. Gluconeogenesis-centred mechanisms for the progression of NAFLD from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis are suggested. That NAFLD often precedes and predicts type 2 diabetes is explained by the ability of lipogenesis to cushion against blood glucose dysregulation in the earlier stages of NAFLD.
Major conclusions: HIR-induced excessive gluconeogenesis is a major cause of the HIR paradox and its sequelae. Such involvement of gluconeogenesis in lipid synthesis rationalizes the fact that several types of antidiabetic drugs ameliorate NAFLD. Thus, dietary, lifestyle and pharmacological targeting of HIR and hepatic gluconeogenesis may be a most viable approach for the prevention and management of the HIR-associated network of diseases.

Keywords: Endoplasmic reticulum stress; Hexosamine biosynthetic pathway; Polyol pathway; Reactive oxygen species; Reductive carboxylation; Reductive stress

DOI: https://doi.org/10.1016/j.heliyon.2022.e12294

Front Pharmacol. 2022 ;13 1061842

Antisense oligonucleotide is a promising intervention for liver diseases.

Kailing Lu, Qijing Fan, Xiaoju Zou.

As the body's critical metabolic organ, the liver plays an essential role in maintaining proper body homeostasis. However, as people's living standards have improved and the number of unhealthy lifestyles has increased, the liver has become overburdened. These have made liver disease one of the leading causes of death worldwide. Under the influence of adverse factors, liver disease progresses from simple steatosis to hepatitis, to liver fibrosis, and finally to cirrhosis and cancer, followed by increased mortality. Until now, there has been a lack of accepted effective treatments for liver disease. Based on current research, antisense oligonucleotide (ASO), as an alternative intervention for liver diseases, is expected to be an effective treatment due to its high efficiency, low toxicity, low dosage, strong specificity, and additional positive characteristics. In this review, we will first introduce the design, modification, delivery, and the mechanisms of ASO, and then summarize the application of ASO in liver disease treatment, including in non-alcoholic fatty liver disease (NAFLD), hepatitis, liver fibrosis, and liver cancer. Finally, we discuss challenges and perspectives on the transfer of ASO drugs into clinical use. This review provides a current and comprehensive understanding of the integrative and systematic functions of ASO for its use in liver disease.

Keywords: NAFLD; antisense oligonucleotide (ASO); hepatitis; liver cancer; liver fibrosis

DOI: https://doi.org/10.3389/fphar.2022.1061842