B355252, A Novel Small Molecule, Confers Neuroprotection Against Cobalt Chloride Toxicity In Mouse Hippocampal Cells Through Altering Mitochondrial Dynamics And Limiting Autophagy Induction.

Cerebral hypoxia as often occurs in cases of stroke, hemorrhage, or other traumatic brain injuries, is one of the leading causes of death worldwide and a main driver of disabilities in the elderly. Using a chemical mimetic of hypoxia, cobalt chloride (CoCl2), we tested the ability of a novel small molecule, 4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-(piperazin-1-yl)phenoxy)thiophene-2-sulfonamide (B355252), to alleviate CoCl2-induced damage in mouse hippocampal HT22 cells. A dose-dependent decrease in cell viability was observed during CoCl2 treatment along with increases in mitochondrial membrane potential and generation of reactive oxygen species (ROS). B355252 conferred protection against these changes. We further found that mitochondrial dynamics, the balance between mitochondrial fusion and fission, were perturbed by CoCl2 treatment. Mitochondrial fusion, which was assessed by measuring the expression of proteins optic atrophy protein 1 (OPA1) and mitofusin 2 (Mfn2), declined due to CoCl2 exposure, but B355252 addition was able to elevate Mfn2 expression while OPA1 expression was unchanged. Mitochondrial fission, measured by phosphorylated dynamin-related protein 1 (p-DRP1) and fission protein 1 (FIS1) expression, also decreased following CoCl2 exposure, and was stabilized by B355252 addition. Finally, autophagy was assessed by measuring the conversion of cytosolic microtubule-associated protein 1A/1B-light chain three-I (LC3-I) to autophagosome-bound microtubule-associated protein 1A/1B-light chain three-II (LC3-II) and was found to be increased by CoCl2. B355252 addition significantly reduced autophagy induction. Taken together, our results indicate B355252 has therapeutic potential to reduce the damaging effects caused by CoCl2 and should be further evaluated for applications in cerebral ischemia therapy.

MicroRNA-483-5p Inhibits Hepatocellular Carcinoma Cell Proliferation, Cell Steatosis, and Fibrosis by Targeting PPARα and TIMP2.

MicroRNAs (miRNAs) are small non-coding RNA molecules that bind with the 3' untranslated regions (UTRs) of genes to regulate expression. Downregulation of miR-483-5p (miR-483) is associated with the progression of hepatocellular carcinoma (HCC). However, the significant roles of miR-483 in nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver diseases (AFLD), and HCC remain elusive. In the current study, we investigated the biological significance of miR-483 in NAFLD, AFLD, and HCC in vitro and in vivo. The downregulation of miR-483 expression in HCC patients' tumor samples was associated with Notch 3 upregulation. Overexpression of miR-483 in a human bipotent progenitor liver cell line HepaRG and HCC cells dysregulated Notch signaling, inhibited cell proliferation/migration, induced apoptosis, and increased sensitivity towards antineoplastic agents sorafenib/regorafenib. Interestingly, the inactivation of miR-483 upregulated cell steatosis and fibrosis signaling by modulation of lipogenic and fibrosis gene expression. Mechanistically, miR-483 targets PPARα and TIMP2 gene expression, which leads to the suppression of cell steatosis and fibrosis. The downregulation of miR-483 was observed in mice liver fed with a high-fat diet (HFD) or a standard Lieber-Decarli liquid diet containing 5% alcohol, leading to increased hepatic steatosis/fibrosis. Our data suggest that miR-483 inhibits cell steatosis and fibrogenic signaling and functions as a tumor suppressor in HCC. Therefore, miR-483 may be a novel therapeutic target for NAFLD/AFLD/HCC management in patients with fatty liver diseases and HCC.

TNFAIP8 regulates autophagy, cell steatosis, and promotes hepatocellular carcinoma cell proliferation.

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) expression has been linked to tumor progression in various cancer types, but the detailed mechanisms of TNFAIP8 are not fully elucidated. Here we define the role of TNFAIP8 in early events associated with development of hepatocellular carcinoma (HCC). Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins. TNFAIP8 also exhibited binding with fatty acids and modulated expression of lipid/fatty-acid metabolizing enzymes. Chronic feeding of mice with alcohol increased hepatic levels of TNFAIP8, autophagy, and steatosis but not in high-fat-fed obese mice. Similarly, higher TNFAIP8 expression was associated with steatotic livers of human patients with a history of alcohol use but not in steatotic patients with no history of alcohol use. Our data indicate a novel role of TNFAIP8 in modulation of drug resistance, autophagy, and hepatic steatosis, all key early events in HCC progression.

MicroRNA-214 targets PTK6 to inhibit tumorigenic potential and increase drug sensitivity of prostate cancer cells.

Prostate cancer is the most commonly diagnosed cancer in men with African American men disproportionally suffering from the burden of this disease. Biomarkers that could discriminate indolent from aggressive and drug resistance disease are lacking. MicroRNAs are small non-coding RNAs that affect numerous physiological and pathological processes, including cancer development and have been suggested as biomarkers and therapeutic targets. In the present study, we investigated the role of miR-214 on prostate cancer cell survival/migration/invasion, cell cycle regulation, and apoptosis. miR-214 was differentially expressed between Caucasian and African American prostate cancer cells. Importantly, miR-214 overexpression in prostate cancer cells induced apoptosis, inhibiting cell proliferation and colony forming ability. miR-214 expression in prostate cancer cells also inhibited cell migration and 3D spheroid invasion. Mechanistically, miR-214 inhibited prostate cancer cell proliferation by targeting protein tyrosine kinase 6 (PTK6). Restoration of PTK6 expression attenuated the inhibitory effect of miR-214 on cell proliferation. Moreover, simultaneous inhibition of PTK6 by ibrutinib and miR-214 significantly reduced cell proliferation/survival. Our data indicates that miR-214 could act as a tumor suppressor in prostate cancer and could potentially be utilized as a biomarker and therapeutic target.

Oncogenic Role of Tumor Necrosis Factor α-Induced Protein 8 (TNFAIP8).

Tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8) is a founding member of the TIPE family, which also includes TNFAIP8-like 1 (TIPE1), TNFAIP8-like 2 (TIPE2), and TNFAIP8-like 3 (TIPE3) proteins. Expression of TNFAIP8 is strongly associated with the development of various cancers including cancer of the prostate, liver, lung, breast, colon, esophagus, ovary, cervix, pancreas, and others. In human cancers, TNFAIP8 promotes cell proliferation, invasion, metastasis, drug resistance, autophagy, and tumorigenesis by inhibition of cell apoptosis. In order to better understand the molecular aspects, biological functions, and potential roles of TNFAIP8 in carcinogenesis, in this review, we focused on the expression, regulation, structural aspects, modifications/interactions, and oncogenic role of TNFAIP8 proteins in human cancers.