bims-glecem 2023-01-08 papers

Issue of 2023–01–08
five papers selected by
Dipsikha Biswas, Københavns Universitet

Medicine (Baltimore). 2022 Dec 30. 101(52): e32510

Recurrent pancreatitis and sepsis in glycogen storage disease type Ia caused by complex heterozygous mutations in 2 sisters: Case report.

Qin Liu, Fang Yu, Huilin Lu, Jian Luo, Ting Sun, Lu Yu, Shenglian Gan.

RATIONALE: Glycogen storage disease (GSD) is a glycogen metabolism disorder caused by congenital enzyme defects, with type I being the most common. Owing to the rarity of glycogen storage disease type Ia (GSD Ia) and the involvement of diverse systems, patients are prone to delayed diagnosis and inappropriate treatment. Additional studies are required to standardize the diagnosis and treatment of GSD Ia.
PATIENT CONCERNS: We report 2 cases of GSD Ia that occurred in 2 sisters. The elder sister also had recurrent pancreatitis, and the pancreatic pseudocyst rupture resulted in sepsis, portal hypertension, and splenic infarction. The younger sister had the same mutation site, but the clinical phenotypes were not identical.
DIAGNOSIS: Abdominal computed tomography and laboratory examinations revealed regional portal hypertension, splenic infarction, and sepsis in the elder sister; diagnosis was confirmed by whole exome sequencing. Sanger sequencing was used to confirm that the younger sister and their parents also had the mutation site.
INTERVENTIONS: The elder sister was treated with corn starch therapy, and medication for antiinfection and reducing hypertriglyceridemia, inhibiting trypsin activity, relieving hyperuricemia. The younger sister was treated with raw cornstarch-based nutritional therapy and sodium bicarbonate.
OUTCOMES: The elder sister's infection was controlled and she gradually returned to a normal diet. After discharge, hyperlipidemia was not controlled satisfactorily, but hypoglycemia, hyperuricemia, hyperlactatemia, and anemia improved.
LESSONS: GSD should be considered in childhood patients with hypoglycemia, hypertriglyceridemia, hyperuricemia, and hyperlactatemia. Gene sequencing can enable quick identification of GSD subtypes. This case report highlights the common clinical manifestations can be linked to rare diseases. Clinical work requires careful observation of the correlations between patient history, physical examinations, and laboratory examinations.

DOI: https://doi.org/10.1097/MD.0000000000032510

Anim Cells Syst (Seoul). 2022 ;26(6): 300-309

Yap signalling regulates ductular reactions in mice with CRISPR/Cas9-induced glycogen storage disease type Ia.

Yixia Xie, Baowei Hu, Yue Gao, Yaxin Tang, Guohe Chen, Jiayuan Shen, Zhikai Jiang, He Jiang, Jiwei Han, Junyan Yan, Lifang Jin.

Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in the glucose-6-phosphatase (G6Pase, G6pc) enzyme, which catalyses the final step of gluconeogenesis and glycogenolysis. Accumulation of G6pc can lead to an increase in glycogen and development of fatty liver. Ductular reactions refer to the proliferation of cholangiocytes and hepatic progenitors, which worsen fatty liver progress. To date, however, ductular reactions in GSD-Ia remain poorly understood. Here, we studied the development and potential underlying mechanism of ductular reactions in GSD-Ia in mice. We first generated GSD-Ia mice using CRISPR/Cas9 to target the exon 3 region of the G6pc gene. The typical GSD-Ia phenotype in G6pc -/- mice was then analysed using biochemical and histological assays. Ductular reactions in G6pc -/- mice were tested based on the expression of cholangiocytic markers cytokeratin 19 (CK19) and epithelial cell adhesion molecule (EpCAM). Yes-associated protein 1 (Yap) signalling activity was measured using western blot (WB) analysis and quantitative real-time polymerase chain reaction (qRT-PCR). Verteporfin was administered to the G6pc -/- mice to inhibit Yap signalling. The CRISPR/Cas9 system efficiently generated G6pc -/- mice, which exhibited typical GSD-Ia characteristics, including retarded growth, hypoglycaemia, and fatty liver disease. In addition, CK19- and EpCAM-positive cells as well as Yap signalling activity were increased in the livers of G6pc -/- mice. However, verteporfin treatment ameliorated ductular reactions and decreased Yap signalling activity. This study not only improves our understanding of GSD-Ia pathophysiology, but also highlights the potential of novel therapeutic approaches for GSD-Ia such as drug targeting of ductular reactions.

Keywords: CRISPR-Cas9; G6pc; GSD-Ia; ductular reactions; yap

DOI: https://doi.org/10.1080/19768354.2022.2139755

J Immunother Cancer. 2022 Dec;pii: e005655. [Epub ahead of print]10(12):

Macrophage GSK3β-deficiency inhibits the progression of hepatocellular carcinoma and enhances the sensitivity of anti-PD1 immunotherapy.

Guangshun Sun, Hanyuan Liu, Jie Zhao, Jinyu Zhang, Tian Huang, Guoqiang Sun, Siqi Zhao, Zihao Zhang, Hengsong Cao, Dawei Rong, Xiangyi Kong, Qinghua Ji, Li Liu, Xuehao Wang, Weiwei Tang, Yongxiang Xia.

BACKGROUND: Glycogen synthase kinase 3β (GSK3β) was originally discovered to regulate glycogen synthesis and show a relationship to tumors. However, the biological functions of GSK3β in tumor-associated macrophages (TAMs) in cancers including hepatocellular carcinoma (HCC) remain unclear.
METHODS: The enrichment of GSK3β in tumor tissues was assessed by Gene Expression Omnibus (GEO) database. The in vitro and in vivo assays assisted in evaluating how GSK3β in TAMs affected HCC in terms of proliferation, invasion and migration. Immunofluorescence was used to assess GSK3β expression in TAMs in the anti-PD1 therapy non-responsive HCC group and the responsive group. Western blot and coimmunoprecipitation were performed to demonstrate the interaction between GSK3β and PD-L1. We carried out in vivo experiments in a C57BL/6 mouse model of HCC established through subcutaneous injection.
RESULTS: GEO single-cell RNA sequencing data suggested that GSK3β was highly enriched in TAMs of HCC. According to in vitro and in vivo experiments, reducing GSK3β in TAMs inhibits the cancer cell proliferation, invasion, and migration. The immunofluorescence and immunohistochemistry results confirmed that the GSK3β is significantly upregulated in TAMs of the anti-PD1 therapy non-responsive group in comparison with the responsive group. In vitro and in vivo experiments confirmed that reduced GSK3β in TAMs are capable of enhancing the sensitivity of anti-PD1 immunotherapy for HCC by decreasing PD-L1 ubiquitination. Mass spectrometry results suggested that high expression of CD14+GSK3β+ in the peripheral blood mononuclear cell (PBMC) can predict non-responsive to anti-PD1 treatment. Moreover, escitalopram is confirmed to act as GSK3β inhibitor that can increase the sensitivity of anti-PD1 immunotherapy for HCC.
CONCLUSIONS: This study revealed that macrophage GSK3β deficiency can inhibit the development of HCC by inhibiting the M2 phenotype and enhance the sensitivity of anti-PD1 immunotherapy for HCC by decreasing PD-L1 ubiquitination. The expression of CD14+GSK3β+ in PBMC can noninvasively predict anti-PD1 sensitivity in HCC patients, which provides novel strategies to predict anti-PD1 sensitivity, increase anti-PD1 therapeutic effect, and bring new hope for HCC patients.

Keywords: immunotherapy; liver neoplasms; macrophages; programmed cell death 1 receptor; tumor microenvironment

DOI: https://doi.org/10.1136/jitc-2022-005655

Cell Cycle. 2023 Jan 02. 1-17

Natural compounds regulate the PI3K/Akt/GSK3β pathway in myocardial ischemia-reperfusion injury.

Amir Hossein Ajzashokouhi, Ramin Rezaee, Navid Omidkhoda, Gholamreza Karimi.

The PI3K/Akt/GSK3β pathway is crucial in regulating cardiomyocyte growth and survival. It has been shown that activation of this pathway alleviates the negative impact of ischemia-reperfusion. Glycogen synthase kinase-3 (GSK3β) induces apoptosis through stimulation of transcription factors, and its phosphorylation has been suggested as a new therapeutic target for myocardial ischemia-reperfusion injury (MIRI). GSK3β regulatory role is mediated by the reperfusion injury salvage kinase (RISK) pathway, and its inhibition by Akt activation blocks mitochondrial permeability transition pore (mPTP) opening and enhances myocardial survival. The present article discusses the involvement of the PI3K/Akt/GSK3β pathway in cardioprotective effects of natural products against MIRI.

Keywords: PI3K/Akt/GSK3β pathway; apoptosis; cardiomyocyte; injury; ischemia-reperfusion; natural compounds

DOI: https://doi.org/10.1080/15384101.2022.2161959