Τετάρτη 11 Νοεμβρίου 2020

GBE attenuates arsenite‐induced hepatotoxicity by regulating E2F1‐autophagy‐E2F7a pathway and restoring lysosomal activity

Alexandros G.Sfakianakis shared this article with you from Inoreader
GBE attenuates arsenite‐induced hepatotoxicity by regulating E2F1‐autophagy‐E2F7a pathway and restoring lysosomal activity

Arsenite induced hepatotoxicity by promoting autophagosome and autophagolysosome accumulation. E2F1‐autophagy‐E2F7a pathway mediated arsenite‐induced autophagosome and autophagolysosome accumulation in liver cells. GBE attenuated arsenite‐induced hepatotoxicity partially by regulating E2F1‐autophagy‐E2F7a pathway.


Abstract

Arsenic is an environmental toxicant. Its overdose can cause liver damage. Autophagy has been reported to be involved in arsenite (iAs3+) cytotoxicity and plays a dual role in cell proliferation and cell death. However, the effect and molecular regulative mechanisms of iAs3+ on autophagy in hepatocytes remains largely unknown. Here, we found that iAs3+ exposure lead to hepatotoxicity by inducing autophagosome and autolysosome accumulation. On the one hand, iAs3+ promoted autophagosome synthesis by inhibiting E2F1/mTOR pathway in L‐02 human hepatocytes. On the other, iAs3+ blocked autophagosome degradation partially via suppressing the expression of INPP5E and Rab7 as well as impairing lysosomal activity. More importantly, autophagosome and autolysosome accumulation induced by iAs3+ increased the protein level of E2F7a, which could further inhibit cell viability and induce apoptosis of L‐02 cells. The t reatment of Ginkgo biloba extract (GBE) effectively reduced autophagosome and autolysosome accumulation and thus alleviated iAs3+‐induced hepatotoxicity. Moreover, GBE could also protect lysosomal activity, promote the phosphorylation level of E2F1 (Ser364 and Thr433) and Rb (Ser780) as well as suppress the protein level of E2F7a in iAs3+‐treated L‐02 cells. Taken together, our data suggested that autophagosome and autophagolysosome accumulation play a critical role for iAs3+‐induced hepatotoxicity, and GBE is a promising candidate for intervening iAs3+ induced liver damage by regulating E2F1‐autophagy‐E2F7a pathway and restoring lysosomal activity.

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GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells

Alexandros G.Sfakianakis shared this article with you from Inoreader
GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells

• GDF11 constrains aberrant lipid metabolism • GDF11 induces mitochondrial structural changes and function • Mitochondrial changes were related to a decrease in oxygen consumption rate.


Abstract

Growth differentiation factor 11 (GDF11) has been characterized as a key regulator of differentiation in cells that retain stemness features. Recently, it has been reported that GDF11 exerts tumor‐suppressive properties in hepatocellular carcinoma cells, decreasing clonogenicity, proliferation, spheroid formation, and cellular function, all associated with a decrement in stemness features, resulting in mesenchymal to epithelial transition and loss of aggressiveness. The aim of the present work was to investigate the mechanism associated with the tumor‐suppressive properties displayed by GDF11 in liver cancer cells. Hepatocellular carcinoma‐derived cell lines were exposed to GDF11 (50 ng/ml), RNA‐seq analysis in Huh7 cell line revealed that GDF11 exerted profound transcriptomic impact, which involved regulation of cholesterol metabolic process, steroid metabolic process as well as key signaling pathways, resembling endoplasmic reticulum‐related functions. Cholester ol and triglycerides determination in Huh7 and Hep3B cells treated with GDF11 exhibited a significant decrement in the content of these lipids. The mTOR signaling pathway was downregulated, and this was associated with a reduction in key proteins involved in the mevalonate pathway. In addition, real‐time metabolism assessed by Seahorse technology showed abridged glycolysis as well as glycolytic capacity, closely related to an impaired oxygen consumption rate and decrement in adenosine triphosphate production. Finally, transmission electron microscopy revealed mitochondrial abnormalities, such as cristae disarrangement, consistent with metabolic changes. Results provide evidence that GDF11 impairs cancer cell metabolism targeting lipid homeostasis, glycolysis, and mitochondria function and morphology.

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Insights into the regulatory role and clinical relevance of mediator subunit, MED12, in human diseases

Alexandros G.Sfakianakis shared this article with you from Inoreader
Insights into the regulatory role and clinical relevance of mediator subunit, MED12, in human diseases

This is a timely review that provides for the first time a wholesome view on the critical roles and pathways regulated by MED12, its interactions along with the implications of MED12 alterations/mutations in various cancers and nonneoplastic disorders.


Abstract

Transcriptional dysregulation is central to many diseases including cancer. Mutation or deregulated expression of proteins involved in transcriptional machinery leads to aberrant gene expression that disturbs intricate cellular processes of division and differentiation. The subunits of the mediator complex are master regulators of stimuli‐derived transcription and are essential for transcription by RNA polymerase II. MED12 is a part of the CDK8 kinase module of the mediator complex and is essential for kinase assembly and function. Other than its function in activation of the kinase activity of CDK8 mediator, it also brings about transcription repression or activation, in response to several signalling pathways, a function that is independent of its role as a part of kinase assembly. Accumulating evidence suggests that MED12 controls complex transcription programs that are defining in cell fate determination, differentiation, and carcinogenesis. Mutations or differential express ion of MED12 manifest in several human disorders and diseases. For instance, MED12 mutations are the gold standard for the diagnosis of several X‐linked intellectual disability syndromes. Further, certain MED12 mutations are categorised as driver mutations in carcinogenesis as well. This is a timely review that provides for the first time a wholesome view on the critical roles and pathways regulated by MED12, its interactions along with the implications of MED12 alterations/mutations in various cancers and nonneoplastic disorders. Based on the preclinical studies, MED12 indeed emerges as an attractive novel therapeutic target for various diseases and intellectual disorders.

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The potential use of theranostic bacteria in cancer

Alexandros G.Sfakianakis shared this article with you from Inoreader

Abstract

Conventional chemotherapy approaches have not been fully successful in the treatment of cancer, due to limitations imposed by the pathophysiology of solid tumors, leading to nonspecific drug uptake by healthy cells, poor bioavailability, and toxicity. Thus, novel therapeutic modalities for more efficient cancer treatment are urgently required. Living bacteria can be used as a theranostic approach for the simultaneous diagnosis and therapy of tumors. Herein, we summarize the currently available literature focused on the advantages and challenges for the use of theranostic bacteria in cancer therapy.

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Cancers, Vol. 12, Pages 3329: Current Advances and Hurdles in Chimeric Antigen Receptor Technology

Alexandros G.Sfakianakis shared this article with you from Inoreader
Μέσω Cancers

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Cancers, Vol. 12, Pages 3329: Current Advances and Hurdles in Chimeric Antigen Receptor Technology

Cancers doi: 10.3390/cancers12113329

Authors: Scott McComb Seung-Hwan Lee

Since tumor-specific T cells were first utilized to treat melanoma patients in 1986 [...]

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Cancers, Vol. 12, Pages 3330: Prognostic Factors Involved in the Epithelial–Mesenchymal Transition Process in Colorectal Cancer Have a Preponderant Role in Oxidative Stress: A Systematic Review and Meta-Analysis

Alexandros G.Sfakianakis shared this article with you from Inoreader
Μέσω Cancers

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Cancers, Vol. 12, Pages 3330: Prognostic Factors Involved in the Epithelial–Mesenchymal Transition Process in Colorectal Cancer Have a Preponderant Role in Oxidative Stress: A Systematic Review and Meta-Analysis

Cancers doi: 10.3390/cancers12113330

Authors: Eva Parisi Anabel Sorolla Robert Montal Rita González-Resina Anna Novell Antonieta Salud Maria Alba Sorolla

Epithelial-to-mesenchymal transition (EMT) is one of the most accepted mechanisms leading to metastasis, which is responsible for most of the cancer-related deaths. In order to identify EMT-related biomarkers able to predict clinical outcomes in colorectal cancer (CRC), a systematic review and meta-analysis of prognostic factors associated to overall survival (OS) and progression free survival (PFS) was conducted. The systematic literature search included studies from June 2014 to June 2019 available at PubMed and Scopus databases. Meta-analysis was performed for those markers appearing in minimum three works with a total number of 8656 participants. The rest were enlisted and subjected to functional enrichment. We identified nine clinical biomarkers and 73 EMT-related molecular biomarkers associated to OS and/or PFS in CRC. The significant enrichment of biomarkers found involved in cellular oxidoreductase activity suggests that ROS generation plays an active role in the EMT proc ess. Clinical practice needs new biomarkers with a reliable prognostic value able to predict clinical outcomes in CRC. Our integrative work supports the role of oxidative stress in tumorigenesis and EMT progress highlighting the importance of deciphering this specific mechanism to get a better understanding of metastasis.

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Cancers, Vol. 12, Pages 3331: Cancer Extracellular Matrix Proteins Regulate Tumour Immunity

Alexandros G.Sfakianakis shared this article with you from Inoreader
Μέσω Cancers

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Cancers, Vol. 12, Pages 3331: Cancer Extracellular Matrix Proteins Regulate Tumour Immunity

Cancers doi: 10.3390/cancers12113331

Authors: Gordon-Weeks Yuzhalin

The extracellular matrix (ECM) plays an increasingly recognised role in the development and progression of cancer. Whilst significant progress has been made in targeting aspects of the tumour microenvironment such as tumour immunity and angiogenesis, there are no therapies that address the cancer ECM. Importantly, immune function relies heavily on the structure, physics and composition of the ECM, indicating that cancer ECM and immunity are mechanistically inseparable. In this review we highlight mechanisms by which the ECM shapes tumour immunity, identifying potential therapeutic targets within the ECM. These data indicate that to fully realise the potential of cancer immunotherapy, the cancer ECM requires simultaneous consideration.

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Cancers, Vol. 12, Pages 3332: The Potential of Lonidamine in Combination with Chemotherapy and Physical Therapy in Cancer Treatment

Alexandros G.Sfakianakis shared this article with you from Inoreader
Μέσω Cancers

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Cancers, Vol. 12, Pages 3332: The Potential of Lonidamine in Combination with Chemotherapy and Physical Therapy in Cancer Treatment

Cancers doi: 10.3390/cancers12113332

Authors: Huang Sun Sun Li Zhao Zhong Peng

Lonidamine (LND) has the ability to resist spermatogenesis and was first used as an anti-spermatogenic agent. Later, it was found that LND has a degree of anticancer activity. Currently, LND is known to target energy metabolism, mainly involving the inhibition of monocarboxylate transporter (MCT), mitochondrial pyruvate carrier (MPC), respiratory chain complex I/II, mitochondrial permeability transition (PT) pore, and hexokinase II (HK-II). However, phase II clinical studies showed that LND alone had a weak therapeutic effect, and the effect was short and reversible. Interestingly, LND does not have the common side effects of traditional chemotherapeutic drugs, such as alopecia and myelosuppression. In addition, LND has selective activity toward various tumors, and its toxic and side effects do not overlap when combined with other chemotherapeutic drugs. Therefore, LND is commonly used as a chemosensitizer to enhance the antitumor effects of chemotherapeutic drugs based on its di sruption of energy metabolism relating to chemo- or radioresistance. In this review, we summarized the combination treatments of LND with several typical chemotherapeutic drugs and several common physical therapies, such as radiotherapy (RT), hyperthermia (HT), and photodynamic therapy (PDT), and discussed the underlying mechanisms of action. Meanwhile, the development of novel formulations of LND in recent years and the research progress of LND derivative adjudin (ADD) as an anticancer drug were also discussed.

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The p.Ser64Leu and p,Pro104Leu missense variants of PALB2 identified in familial pancreatic cancer patients compromise the DNA damage response

Alexandros G.Sfakianakis shared this article with you from Inoreader
Μέσω Human Mutation

ABSTRACT

PALB2 has been identified as a breast and pancreatic cancer susceptibility gene. Utilizing a targeted sequencing approach, we discovered two novel germline missense PALB2 variants c.191C>T and c.311C>T, encoding p.Ser64Leu and p.Pro104Leu, respectively, in individuals in a pancreatic cancer registry. No missense PALB2 variants from familial pancreatic cancer patients, and few PALB2 variants overall, have been functionally characterized. Given the known role of PALB2, we tested the impact of p.Ser64Leu and p.Pro104Leu variants on DNA damage responses. Neither p.Ser64Leu nor p.Pro104Leu had clear effects on interactions with BRCA1 and KEAP1, which are mediated by adjacent motifs in PALB2. However, both variants are associated with defective recruitment of PALB2, and the RAD51 recombinase downstream, to DNA damage foci. Further, p.Ser64Leu and p.Pro104Leu both largely compromise DNA double‐strand break‐initiated homologous recombination, and confer incr eased cellular sensitivity to ionizing radiation (IR) and the poly (ADP‐ribose) polymerase (PARP) inhibitor Olaparib. Taken together, our results represent the first demonstration of functionally deleterious PALB2 missense variants associated with familial pancreatic cancer and of deleterious variants in the N‐terminus outside of the coiled‐coil domain. Further, our results suggest the possibility of personalized treatments, using IR or PARP inhibitor, of pancreatic and other cancers that carry a deleterious PALB2 variant.

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Novel homozygous truncating variants in ZMYND15 causing severe oligozoospermia and their implications for male infertility

Alexandros G.Sfakianakis shared this article with you from Inoreader
Μέσω Human Mutation

ABSTRACT

Sequence variants of ZMYND15 cause azoospermia in humans, but they have not yet been reported in infertile men with severe oligozoospermia (SO).We performed whole‐exome and Sanger sequencing to identify suspected causative variants in 414 idiopathic participating infertile men with SO or azoospermia. Three novel homozygous truncating variants in ZMYND15 were identified in three of the 219 (1.37%) unrelated patients with SO,including c.1209T>A(p.Tyr403*), c.1650delC (p.Glu551Lysfs*75), and c.1622_1636delinsCCAC (p.Leu541Profs*39). In silico bioinformatic analyses as well as in vivo and in vitro experiments showed that the ZMYND15 variants carried by the affected subjects might be the underling cause for their infertility.One patient accepted intracytoplasmic sperm injection(ICSI) therapy using his ejaculated sperm and his wife successfully became pregnant. Our findings expand the disease phenotype spectrum by indicating that ZMYND15 variants cause SO and male infertility and suggest a possible correlation between the severity of male infertility caused by ZMYND15 variants and male age.

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A Novel Variant in COX16 Causes Cytochrome c Oxidase Deficiency, Severe Fatal Neonatal Lactic Acidosis, Encephalopathy, Cardiomyopathy and Liver Dysfunction

Alexandros G.Sfakianakis shared this article with you from Inoreader
Μέσω Human Mutation

ABSTRACT

COX16 is involved in the biogenesis of cytochrome‐c‐oxidase (complex IV), the terminal complex of the mitochondrial respiratory chain (RC). We present the first report of two unrelated patients with the homozygous nonsense variant c.244C>T(p.Arg82*) in COX16 with hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis and isolated complex IV deficiency. The absence of COX16 protein expression leads to a complete loss of the holo‐complex IV, as detected by western blot in patient fibroblasts. Lentiviral transduction of patient fibroblasts with wild‐type COX16 cDNA rescued complex IV biosynthesis. We hypothesize that COX16 could play a role in the copper delivery route of the COX2 module as part of the complex IV assembly. Our data provide clear evidence for the pathogenicity of the COX16 variant as a cause for the observed clinical features and the isolated complex IV deficiency in these two patients and that COX16 deficiency is a cause for mitochondrial disease.

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