bims-glecem 2022-12-11 papers

Issue of 2022–12–11
three papers selected by
Dipsikha Biswas, Københavns Universitet

Cytokine. 2022 Nov 30. pii: S1043-4666(22)00297-6. [Epub ahead of print]162 156088

Cytokine profiling in patients with hepatic glycogen storage disease: Are there clues for unsolved aspects?

Karina Colonetti, Filippo Pinto E Vairo, Marina Siebert, Tatiéle Nalin, Soraia Poloni, Luiz Fernando Wurdig Roesch, Carolina Fischinger Moura de Souza, Franciele Cabral Pinheiro, Ida Vanessa Doederlein Schwartz.

INTRODUCTION: Hepatic Glycogen Storage Diseases (GSD) are rare genetic disorders in which the gluconeogenesis pathway is impaired. Cytokines control virtually every aspect of physiology and may help to elucidate some unsolved questions about phenotypes presented by GSD patients.
METHODS: This was an exploratory study in which 27 GSD patients on treatment (Ia = 16, Ib = 06, III = 02, IXα = 03) and 24 healthy age- and sex-matched subjects had plasma samples tested for a panel of 20 cytokines (G-CSF,GM-CSF, IL-1α,IL-1β, IL-4, IL-6, IL-8, IL-10, IL-13, IL-17A, GRO, IP-10/CXCL10, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, MDC/CCL22, IFN-γ, TNF-α, TNF-β, VEGF) through a multiplex kit and analyzed in comparison to controls and among patients, regarding to clinical features as anemia, hepatic adenocarcinoma and triglyceride levels.
RESULTS: Patients (GSD-Ia/III/IX) presented reduced levels of IL-4 (p = 0.040), MIP-1α/CCL3 (p = 0.003), MDC/CCL22 (p < 0.001), TNF-β (p = 0.045) and VEGF (p = 0.043) compared to controls. When different types of GSD were compared, G-CSF was higher in GSD-Ib than -Ia (p < 0.001) and than -III/IX (p = 0.033) patients; IL-10 was higher in GSD-Ib than in GSD-Ia patients (p = 0.019); and GSD-III/IX patients had increased levels of IP-10/CXCL10 than GSD-Ib patients (p = 0.019). When GSD-I patients were gathered into the same group and compared with GSD-III/IX patients, IP10/CXCL10 and MCP-1 were higher in the latter group (p = 0.005 and p = 0.013, respectively). GSD-I patients with anemia presented higher levels of IL-4 and MIP-1α in comparison with patients who had not. Triglyceride level was correlated with neutrophil count and MDC levels on GSD-Ia patients without HCA.
CONCLUSION: Altogether, altered levels of cytokines in GSD-I patients reflect an imbalance in immunoregulation process. This study also indicates that neutrophils and some cytokines are affected by triglyceride levels, and future studies on the theme should consider this variable.

Keywords: Chemokines; Cytokines; Glycogen storage disease

DOI: https://doi.org/10.1016/j.cyto.2022.156088

Discov Med. 2022 Mar-Apr;33(169):33(169): 55-67

Ethiadin Induces Apoptosis and Suppresses Growth of MCF-7 Breast Cancer Cells by Regulating the Phosphorylation of Glycogen Synthase Kinase 3 Beta (GSK3beta).

Yazhe Ren, Guangsen Bao, Hengbin Yang, Zhangjun Cao, Zhiyu Shao, Yunlong Zhang.

Glycogen synthase kinase 3 beta (GSK3β) has emerged as a therapeutic target for breast cancer. As inhibitors of GSK-3β, 1,2,4-thiadiazole-3,5-dione (TDZD) family members have been reported as potential candidates for cancer treatment. In this study, the anticancer effects of ethiadin (ETD-174), one of the chemical synthesis compounds of TDZD, were investigated in MCF-7 human breast cancer cells. MCF-7 cells incubated with different doses of ETD-174 for different time periods. CCK-8 assays were carried out to test the effect of ETD-174 on the proliferation of MCF-7 cells. The occurrence of apoptosis was detected by Hoechst 33258 staining and flow cytometry. ETD-174 on cell migration and colony formation were examined by wound healing experiments and soft agar assays. Relative protein expressions were conducted with immunoblot assay. ETD-174 demonstrated a higher degree of cytotoxicity in MCF-7 cells. Topical morphological changes of apoptotic body formation after ETD-174 treatment were observed. Meanwhile, apoptosis was elicited by ETD-174. Also, ETD-174 could inhibit the migration and clonality of MCF-7 cells. After the treatment with ETD-174, the level of phosphorylation of GSK3βSer9 in MCF-7 cells increased significantly, and the enzymatic activity of GSK3β decreased. ETD-174 is likely to have an effective suppressor role in breast cancer, suggesting that pharmacological inhibition of GSK3β as a novel treatment modality for breast cancer should warrant further investigation.

J Biochem. 2022 Dec 07. pii: mvac094. [Epub ahead of print]

Phosphorylation of PBX2, a novel downstream target of mTORC1, is determined by GSK3 and PP1.

Reona Wada, Shun Fujinuma, Hirokazu Nakatsumi, Masaki Matsumoto, Keiichi I Nakayama.

Mechanistic target of rapamycin complex 1 (mTORC1) is a serine-threonine kinase that is activated by extracellular signals such as nutrients and growth factors. It plays a key role in the control of various biological processes such as protein synthesis and energy metabolism by mediating or regulating the phosphorylation of multiple target molecules, some of which remain to be identified. We have here reanalyzed a large-scale phosphoproteomics data set for mTORC1 target molecules and identified pre-B cell leukemia transcription factor 2 (PBX2) as such a novel target that is dephosphorylated downstream of mTORC1. We confirmed that PBX2, but not other members of the PBX family, is dephosphorylated in an mTORC1 activity-dependent manner. Furthermore, pharmacological and gene knockdown experiments revealed that glycogen synthase kinase 3 (GSK3) and protein phosphatase 1 (PP1) are responsible for the phosphorylation and dephosphorylation of PBX2, respectively. Our results thus suggest that the balance between the antagonistic actions of GSK3 and PP1 determines the phosphorylation status of PBX2 and its regulation by mTORC1.

Keywords: glycogen synthase kinase 3 (GSK3); mechanistic target of rapamycin complex 1 (mTORC1); phosphorylation; pre–B cell leukemia transcription factor 2 (PBX2); protein phosphatase 1 (PP1)

DOI: https://doi.org/10.1093/jb/mvac094