GALNT14 genotype-guided chemoembolization plus sorafenib therapy in hepatocellular carcinoma: a randomized trial.

BACKGROUND: GALNT14-rs9679162 "TT" genotype is associated with favorable clinical outcomes in hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE). We investigated whether patients with GALNT14-rs9679162 "non-TT" unfavorable genotype benefited from chemoembolization plus sorafenib combination therapy. METHODS: Intermediate stage HCC patients were recruited for GALNT14-rs9679162 genotyping before TACE. Patients with "TT" genotype received only TACE, labeled as TT (TACE) group. Patients with "non-TT" genotype ("GG" or "GT") were randomized to receive either TACE alone, labeled as Non-TT (TACE) group, or TACE plus sorafenib, labeled as Non-TT (TACE + Sora) group. The latter group received sorafenib 400 mg daily plus TACE. RESULTS: From October 2015 to April 2019, 103 HCC patients scheduled to receive chemoembolization were screened. Of them, 84 met inclusion criteria and were assigned to TT (TACE) (n = 25), Non-TT (TACE) (n = 30) and Non-TT (TACE + Sora) (n = 29) groups according to their GALNT14 genotypes. Repeated TACE sessions were performed on-demand and patients were followed until November 2020. It was found that TT (TACE) and Non-TT (TACE + Sora) patients had shorter time-to-complete response compared with that in Non-TT (TACE) patients (p < 0.001 and 0.009, respectively). These two groups also had longer time-to-TACE progression (p < 0.001 and 0.006, respectively) and longer progression-free survival (p = 0.001 and 0.021, respectively). However, TT (TACE) patients harbored longer overall survival compared with those in non-TT (TACE + Sora) and non-TT (TACE) patients (p = 0.028, < 0.001, respectively). CONCLUSION: Combination of sorafenib and TACE for "non-TT" patients partially overcame the genetic disadvantage on treatment outcomes in terms of time-to-complete response, time-to-TACE progression and progression-free survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT02504983.

Apoptotic mechanisms of gastric cancer cells induced by isolated erinacine S through epigenetic histone H3 methylation of FasL and TRAIL.

Erinacine S, the new bioactive diterpenoid compound isolated from the ethanol extract of the mycelia of Hericium erinaceus, displays great health-promoting properties. However, the effects of erinacine S on inductive apoptosis in cancer cells such as gastric cancer and its molecular mechanisms remain unclear. Our results demonstrated that erinacine S treatment significantly induces cell apoptosis with increased ROS production in gastric cancer cells, but not in normal cells. Significantly, erinacine S also showed its inhibitory effects on tumor growth in an in vivo xenograft mouse model. Furthermore, immunohistochemical analyses revealed that erinacine S treatment significantly increases the FasL and TRAIL protein, whereas it decreases the levels of PCNA and cyclin D1 in the gastric cancer xenograft mice. Consistently, in AGS cells, erinacine S treatment not only triggers the activation of extrinsic apoptosis pathways (TRAIL, Fas-L and caspase-8, -9, -3), but it also suppresses the expression of the anti-apoptotic molecules Bcl-2 and Bcl-XL in a time-dependent manner. In addition, erinacine S also causes cell cycle G1 arrest by the inactivation of CDKs/cyclins. Moreover, our data revealed that activation of the ROS-derived and AKT/FAK/PAK1 pathways is involved in the erinacine S-mediated transcriptional activation of Fas-L and TRAIL through H3K4 trimethylation on their promoters. Together, this study sheds light on the anticancer effects of erinacine S on gastric cancer and its molecular mechanism in vitro and in vivo.

Post-Treatment with Erinacine A, a Derived Diterpenoid of H. erinaceus, Attenuates Neurotoxicity in MPTP Model of Parkinson's Disease.

Hericium erinaceus, a valuable pharmaceutical and edible mushroom, contains potent bioactive compounds such as H. erinaceus mycelium (HEM) and its derived ethanol extraction of erinacine A, which have been found to regulate physiological functions in our previous study. However, HEM or erinacine A with post-treatment regimens also shows effects on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, but its mechanisms remain unknown. By using annexin-V-fluorescein-isothiocyanate (FITC)/propidium iodide staining and a 2',7' -dichlorofluorescin diacetate (DCFDA) staining assay, the cell death, cell viability, and reactive oxygen species (ROS) of 1-methyl-4-phenylpyridinium (MMP+)-treated Neuro-2a (N2a) cells with or without erinacine A addition were measured, respectively. Furthermore, signaling molecules for regulating the p21/GADD45 cell death pathways and PAKalpha, p21 (RAC1) activated kinase 1 (PAK1) survival pathways were also detected in the cells treated with MPP+ and erinacine A by Western blots. In neurotoxic animal models of MPTP induction, the effects of HEM or erinacine A and its mechanism in vivo were determined by measuring the TH-positive cell numbers and the protein level of the substantia nigra through a brain histological examination. Our results demonstrated that post-treatment with erinacine A was capable of preventing the cytotoxicity of neuronal cells and the production of ROS in vitro and in vivo through the neuroprotective mechanism for erinacine A to rescue the neurotoxicity through the disruption of the IRE1α/TRAF2 interaction and the reduction of p21 and GADD45 expression. In addition, erinacine A treatment activated the conserved signaling pathways for neuronal survival via the phosphorylation of PAK1, AKT, LIM domain kinase 2 (LIMK2), extracellular signal-regulated kinases (ERK), and Cofilin. Similar changes in the signal molecules also were found in the substantia nigra of the MPTP, which caused TH+ neuron damage after being treated with erinacine A in the post-treatment regimens in a dose-dependent manner. Taken together, our data indicated a novel mechanism for post-treatment with erinacine A to protect from neurotoxicity through regulating neuronal survival and cell death pathways.

Hericium erinaceus mycelium and its isolated erinacine A protection from MPTP-induced neurotoxicity through the ER stress, triggering an apoptosis cascade.

BACKGROUND: Hericium erinaceus is an edible mushroom; its various pharmacological effects which have been investigated. This study aimed to demonstrate whether efficacy of oral administration of H. erinaceus mycelium (HEM) and its isolated diterpenoid derivative, erinacine A, can act as an anti-neuroinflammatory agent to bring about neuroprotection using an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease, which results in motor disturbances, in addition to elucidating the mechanisms involved. METHODS: Mice were treated with and without HEM or erinacine A, after MPTP injection for brain injuries by the degeneration of dopaminergic nigrostriatal neurons. The efficacy of oral administration of HEM improved MPTP-induced loss of tyrosine hydroxylase positive neurons and brain impairment in the substantia nigra pars compacta as measured by brain histological examination. RESULTS: Treatment with HEM reduced MPTP-induced dopaminergic cell loss, apoptotic cell death induced by oxidative stress, as well as the level of glutathione, nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE). Furthermore, HEM reversed MPTP-associated motor deficits, as revealed by the analysis of rotarod assessment. Our results demonstrated that erinacine A decreases the impairment of MPP-induced neuronal cell cytotoxicity and apoptosis, which were accompanied by ER stress-sustained activation of the IRE1α/TRAF2, JNK1/2 and p38 MAPK pathways, the expression of C/EBP homologous protein (CHOP), IKB-ß and NF-κB, as well as Fas and Bax. CONCLUSION: These physiological and brain histological changes provide HEM neuron-protective insights into the progression of Parkinson's disease, and this protective effect seems to exist both in vivo and in vitro.