Following the publication of this paper, it was drawn to the Editor\'s attention by a concerned reader that the colony formation assay data shown in Fig. 4C on p. 6 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes, which had already been published. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 24: 685, 2021; DOI: 10.3892/mmr.2021.12325].

As a prevalent neurodegenerative disorder, Parkinson\'s disease is associated with oxidative stress. Our recent investigations revealed that reactive oxygen species (ROS) and PD-toxins like 6-hydroxydopamine (6-OHDA) can induce neuronal apoptosis through over-activation of Akt signaling. Chlorogenic acid (CGA), a natural acid phenol abundant in the human diet, is well-documented for its ability to mitigate intracellular ROS. In this study, we utilized CGA to treat experimental models of PD both in vitro and in vivo. Our study results demonstrated that SH-SY5Y and primary neurons exhibited cell apoptosis in response to 6-OHDA. Pretreatment with CGA significantly attenuated PD toxins-induced large amount of ROS, inhibiting Erk1/2 activation, preventing Akt inhibition, and hindering neuronal cell death. Combining the Erk1/2 inhibitor U0126 with CGA could reverse 6-OHDA-induced Akt inhibition, ROS, and apoptosis in the cells. Crucially, the Akt activator SC79 and ROS scavenger NAC both could eliminate excessive ROS via Akt and Erk1/2 signaling pathways, and CGA further potentiated these effects in PD models. Behavioral experiments revealed that CGA could alleviate gait abnormalities in PD model mice. The neuroprotective effects have been demonstrated in several endocrine regions and in the substantia nigra tissue, which shows the positive tyrosine hydroxylase (TH). Overall, our results suggest that CGA prevents the activation of Erk1/2 and inactivation of Akt by removing excess ROS in PD models. These findings propose a potential strategy for mitigating neuronal degeneration in Parkinson\'s disease by modulating the Akt/Erk1/2 signaling pathway through the administration of CGA and/or the use of antioxidants to alleviate oxidative stress.

The proliferation and differentiation of skeletal muscle satellite cells is a complex physiological process involving various transcription factors and small RNA molecules. This study aimed to understand the regulatory mechanisms underlying these processes, focusing on interferon-related development factor 2 (IFRD2) as a target gene of miRNA-2400 in bovine skeletal MuSCs (MuSCs). IFRD2 was identified as a target gene of miRNA-2400 involved in regulating the proliferation and differentiation of bovine skeletal MuSCs. Our results indicate that miR-2400 can target binding the 3\'UTR of IFRD2 and inhibit its translation. mRNA and protein expression levels of IFRD2 increased significantly with increasing days of differentiation. Moreover, overexpression of the IFRD2 gene inhibited proliferation and promoted differentiation of bovine MuSCs. Conversely, the knockdown of the gene had the opposite effect. Overexpression of IFRD2 resulted in the inhibition of ERK1/2 phosphorylation levels in bovine MuSCs, which in turn promoted differentiation. In summary, IFRD2, as a target gene of miR-2400, crucially affects bovine skeletal muscle proliferation and differentiation by precisely regulating ERK1/2 phosphorylation.

Berberrubine (BRB), a main metabolite of berberine, has stronger hypoglycemic and lipid-lowering activity than its parent form. We previously found that BRB could cause obvious nephrotoxicity, but the molecular mechanism involved remains unknown. In this study, we systematically integrated metabolomics and quantitative proteomics to reveal the potential mechanism of nephrotoxicity caused by BRB. Metabolomic analysis revealed that 103 significant- differentially metabolites were changed. Among the mentioned compounds, significantly upregulated metabolites were observed for phosphorylcholine, sn-glycerol-3-phosphoethanolamine, and phosphatidylcholine. The top three enriched KEGG pathways were the mTOR signaling pathway, central carbon metabolism in cancer, and choline metabolism in cancer. ERK1/2 plays key roles in all three metabolic pathways. To further confirm the main signaling pathways involved, a proteomic analysis was conducted to screen for key proteins (such as Mapk1, Mapk14, and Caspase), indicating the potential involvement of cellular growth and apoptosis. Moreover, combined metabolomics and proteomics analyses revealed the participation of ERK1/2 in multiple metabolic pathways. These findings indicated that ERK1/2 regulated the significant- differentially abundant metabolites determined via metabolomics analysis. Notably, through a cellular thermal shift assay (CETSA) and molecular docking, ERK1/2 were revealed to be the direct binding target involved in BRB-induced nephrotoxicity. To summarize, this study sheds light on the understanding of severe nephrotoxicity caused by BRB and provides scientific basis for its safe use and rational development.

The melanocortin-4 receptor (MC4R), a G protein-coupled receptor, is critically involved in regulating energy homeostasis as well as modulation of reproduction and sexual function. Two peptide antagonists (SHU9119 and MBP10) were derived from the endogenous agonist α-melanocyte stimulating hormone. But their pharmacology at human MC4R is not fully understood. Herein, we performed detailed pharmacological studies of SHU9119 and MBP10 on wild-type (WT) and six naturally occurring constitutively active MC4Rs. Both ligands had no or negligible agonist activity in Gαs-cAMP signaling on WT MC4R, but stimulated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation on WT and mutant MC4Rs. Mechanistic studies revealed that SHU9119 and MBP10 stimulated ERK1/2 signaling of MC4R by different mechanisms, with SHU9119-stimulated ERK1/2 signaling mediated by phosphatidylinositol 3-kinase (PI3K) and MBP10-initiated ERK1/2 activation through PI3K and β-arrestin. In summary, our studies demonstrated that SHU9119 and MBP10 were biased ligands for MC4R, preferentially activating ERK1/2 signaling through different mechanisms. SHU9119 acted as a biased ligand and MBP10 behaved as a biased allosteric modulator.

Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs that have been implicated in mediating granulosa cell (GC) proliferation and apoptosis. CircRAB11A was found to have a significantly higher expression in normal follicles compared to atrophic follicles. In this study, we determined that the knockdown of circRAB11A resulted in the inhibition of proliferation and promotion of apoptosis in GCs of chicken. Moreover, circRAB11A was found to act as a sponge for miR-24-5p, both member RAS oncogene family (RAB11A) and epidermal growth factor receptor (EGFR) were revealed to be targets of miR-24-5p through a dual-luciferase reporter assay. RAB11A or EGFR promoted proliferation and suppressed apoptosis in GCs through the phosphatidylinositol-kinase (PI3K)/AKT or extracellular signal-regulated kinase (ERK)1/2 pathway. These findings suggest that circRAB11A may function as a competing endogenous RNA (ceRNA) by targeting the miR-24-5p/RAB11A and miR-24-5p/EGFR axes and activating the ERK1/2 and PI3K/AKT pathways, offering a potential avenue for exploring the mechanism of follicle development.

In this study, we aimed to investigate cytoplasmic maturation and miRNA expression of mature oocytes cultured in porcine follicular fluid exosomes. We also examined the effect of miR-339-5p on oocyte maturation. Twenty eight differentially expressed miRNAs were detected using miRNA-seq. We then transfected cumulus oocyte complexes with miR-339-5p mimics and inhibitor during culture. The results showed that exosomes increased endoplasmic reticulum levels and the amount of lipid droplets, and decreased ROS levels, lipid droplet size, and percentage of oocytes with abnormal cortical granule distribution. Overexpressing miR-339-5p significantly decreased cumulus expansion genes, oocyte maturation-related genes, target gene proline/glutamine-rich splicing factor (SFPQ), ERK1/2 phosphorylation levels, oocyte maturation rate, blastocyst rate, and lipid droplet number, but increased lipid droplet size and the ratio of oocytes with abnormal cortical granule distribution. Inhibiting miR-339-5p reversed the decrease observed during overexpression. Mitochondrial membrane potential and ROS levels did not differ significantly between groups. In summary, exosomes promote oocyte cytoplasmic maturation and miR-339-5p regulating ERK1/2 activity through SFPQ expression, thereby elevating oocyte maturation and blastocyst formation rate in vitro.

Alzheimer\'s disease is characterized by abnormal β-amyloid and tau accumulation, mitochondrial dysfunction, oxidative stress, and synaptic dysfunction. Here, we aimed to assess the mechanisms and signalling pathways in the neuroprotective effect of gastrodin, a phenolic glycoside, on murine neuroblastoma N2a cells expressing human Swedish mutant APP (N2a/APP). We found that gastrodin increased the levels of presynaptic-SNAP, synaptophysin, and postsynaptic-PSD95 and reduced phospho-tau Ser396, APP and Aβ1-42 levels in N2a/APP cells. Gastrodin treatment reduced reactive oxygen species generation, lipid peroxidation, mitochondrial fragmentation and DNA oxidation; restored mitochondrial membrane potential and intracellular ATP production. Upregulated phospho-GSK-3β and reduced phospho-ERK and phospho-JNK were involved in the protective effect of gastrodin. In conclusion, we demonstrated the neuroprotective effect of gastrodin in the N2a/APP cell line by ameliorating the impairment on synaptic and mitochondrial function, reducing tau phosphorylation, Aβ1-42 levels as well as reactive oxygen species generation. These results provide new mechanistic insights into the potential effect of gastrodin in the treatment of Alzheimer\'s disease.

UNASSIGNED: To investigate the protective effects against abnormal uterine bleeding (AUB) and possible mechanisms of Xue Ping tablets (XPT) using a rat model.
UNASSIGNED: A total of 58 unmated female and 25 male SPF SD rats aged 8-9 weeks were selected. Eight unmated female rats were selected as the blank control group according to the complete random method. The other 50 rats were mated in a female/male ratio of 2:1. In the morning after mating, vaginal smears were collected. Presence of vaginal plug or sperm was regarded as the first day of pregnancy. All pregnant rats were given 8.3 mg/kg of mifepristone by gavage at 8:00 a.m. and 100 μg/kg misoprostol by gavage at 6:00 p.m. on the seventh day of pregnancy to induce incomplete abortion, thereby establishing a rat model of AUB. Forty rats were randomly divided into model, low- (220 mg/kg), medium- (441 mg/kg), high-dose (882 mg/kg) XPT, and positive control groups. The positive group was given 130 mg/kg Gong Xue Ning (GXN). The model group and the blank group were given an equal amount of distilled water.
UNASSIGNED: Compared with the model group, the volume of bleeding in the positive and middle- and high-dose XPT groups decreased (P < 0.05). Moreover, compared with the model group, the progesterone levels in the positive and XPT groups were significantly increased. Immunohistochemistry showed that XPT significantly decreased the expression levels of VEGF, p-ERK, NF-κB, SAA, MMP-2, MMP-9, TIMP-1, TIMP-2 and TIMP-3. WB results showed that XPT significantly decreased the expression levels of p-ERK, MMP-9, NF-κB, MMP-2 and VEGF. QRT-PCR results showed that XPT significantly decreased the expression levels of VEGF, NF-κB, SAA, MMP-2, TIMP-1, TIMP-2 and TIMP-3 (P < 0.05).
UNASSIGNED: XPT could reduce AUB by inhibiting the inflammatory factors involved in the VEGF-ERK1/2 pathway.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant tumor associated with Epstein-Barr virus (EBV) infection. Chemoradiotherapy is the mainstream treatment for locally advanced NPC, and chemotherapeutic drugs are an indispensable part of NPC treatment. However, the toxic side-effects of chemotherapy drugs limit their therapeutic value, and new chemotherapy drugs are urgently needed for NPC. Silvestrol, an emerging natural plant anticancer molecule, has shown promising antitumor activity in breast cancer, melanoma, liver cancer, and other tumor types by promoting apoptosis in cancer cells to a greater extent than in normal cells. However, the effects of silvestrol on NPC and its possible molecular mechanisms have yet to be fully explored.
METHODS: Cell counting kit-8 (CCK-8), cell scratch, flow cytometry, 5-ethynyl-2\'-deoxyuridine (EdU), and Western blot (WB) assays were used to evaluate the effects of silvestrol on the cell viability, cell cycle, apoptosis, and migration of NPC cells. RNA sequencing (RNA-Seq) was used to study the effect of extracellular signal-regulated kinase (ERK) inhibitors on the cell transcriptome, and immunohistochemistry (IHC) to assess protein expression levels in patient specimens.
RESULTS: Silvestrol inhibited cell migration and DNA replication of NPC cells, while promoting the expression of cleaved caspase-3, apoptosis, and cell cycle arrest. Furthermore, silvestrol altered the level of ERK phosphorylation. The ERK-targeted inhibitor LY3214996 attenuated silvestrol-mediated inhibition of NPC cell proliferation but not migration. Analysis of RNA-Seq data and WB were used to identify and validate the downstream regulatory targets of silvestrol. Expression of GADD45A, RAP1A, and hexokinase-II (HK2) proteins was inhibited by silvestrol and LY3214996. Finally, IHC revealed that GADD45A, RAP1A, and HK2 protein expression was more abundant in cancer tissues than in non-tumor tissues.
CONCLUSIONS: Silvestrol inhibits the proliferation of NPC cells by targeting ERK phosphorylation. However, the inhibition of NPC cell migration by silvestrol was independent of the Raf-MEK-ERK pathway. RAP1A, HK2, and GADD45A may be potential targets for the action of silvestrol.