Current Molecular Medicine - Current Issue

Polypyrimidine tract binding protein is a 57-Kda protein located in the perinucleolar compartment where it binds RNA and regulates several biological functions through the regulation of RNA splicing. Numerous research articles have been published that address the cellular network and functions of PTB and its isoforms in various disease states.

Through an extensive PubMed search, we attempt to summarize the relevant research into this biomolecule.

Besides its roles in embryonic development, neuronal cell growth, RNA metabolism, apoptosis, and hematopoiesis, PTB can affect cancer growth via several metabolic, proliferative, and structural mechanisms. PTB overexpression has been documented in several cancers where it plays a role as a novel prognostic factor.

The diverse carcinogenic effect opens an argument into its potential role in inhibitory targeted therapy.

The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Adenosine monophosphate-activated protein kinase (AMPK) activation is beneficial for NAFLD treatment. Recent studies show the excessive fission of mitochondria during NAFLD progression, so targeting mitochondria dynamics may be a possible target for NAFLD. Still, little is known about whether AMPK regulates mitochondrial dynamics in hepar.

This study investigated whether AMPK activation alleviates hepatic steatosis by regulating mitochondrial dynamics mediated by GTPase dynamin-related protein 1 (Drp1).

Human hepatocyte line L-02 cells were cultured and subjected to palmitic acid (PA) treatment for 24 h to establish a hepatic steatosis model in vitro, which was pre-treated with different tool drugs. Hepatocyte function, hepatocyte lipid content, mitochondrial reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) were examined. The expression levels of genes and proteins associated with mitochondrial dynamics were assessed using reverse transcription-quantitative PCR and western blotting.

The results indicated that 5-Aminoimidazole-4-carboxamide 1-β-D-ribofura-noside (AICAR), an AMPK activator, improved hepatocyte function, as demonstrated by decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity (P<0.05 or P<0.01). In addition, AICAR decreased total cholesterol (TC) and triglyceride (TG) content and lipid deposition in hepatocytes (P<0.01); decreased ROS production; improved MMP (P<0.01); reduced fission-1 (Fis1) and mitochondrial fission factor (Mff) mRNA expression; and downregulated p-Drp1 (Ser 616) protein expression. In contrast, AICAR increased mitochondrial fusion factor mitofusin-1 (Mfn1) and mitofusin-2 (Mfn2) mRNA expression and upregulated p-Drp1 (Ser 637) protein expression. Mdivi-1, a Drp-1 inhibitor, was used to confirm whether mitochondrial dynamics regulated by Drp1-mediated the role of AICAR. Similar to AICAR, Mdivi-1 improved hepatocyte function and MMP significantly, decreased ROS production and lipid deposition, downregulated Fis1 and Mff mRNA expression, downregulated p-Drp1 (Ser 616) protein expression, and enhanced Mfn1 and Mfn2 mRNA and p-Drp1 (Ser 637) protein expression. However, Compound C, an AMPK-specific inhibitor, had less impact on the protective effect of Mdivi-1.

The results demonstrated that AMPK activation has a protective effect on hepatic steatosis in vitro, largely dependent on the inhibition of Drp1-mediated mitochondrial fission.

The degeneration of dopaminergic (DA) neurons has emerged as a crucial pathological characteristic in Parkinson’s disease (PD). To enrich the related knowledge, we aimed to explore the impact of the METTL14-TRAF6-cGAS-STING axis in mitochondrial dysfunction and ferroptosis underlying DA neuron degeneration.

1-methyl-4-phenylpyridinium ion (MPP⁺) was used to treat DA neuron MN9D to develop the PD cell models. Afterward, a cell counting kit, flow cytometer, DCFH-DA fluorescent probe, and Dipyrromethene Boron Difluoride staining were utilized to measure the cell viability, iron concentration, ROS level, and lipid peroxidation, respectively. Meanwhile, the mitochondrial ultrastructure, the activity of mitochondrial respiratory chain complexes, and levels of malondialdehyde and glutathione were monitored. In addition, reverse transcription-quantitative polymerase chain reaction and western blot assays were adopted to measure the expression of related genes. cGAS ubiquitylation and TRAF6 messenger RNA (mRNA) N6-methyladenosine (m6A) levels, the linkages among METTL14, TRAF6, and the cGAS-STING pathway were also evaluated.

METTL14 expression was low, and TRAF6 expression was high after MPP⁺ treatment. In MPP⁺-treated MN9D cells, METTL14 overexpression reduced ferroptosis, ROS generation, mitochondrial injury, and oxidative stress (OS) and enhanced mitochondrial membrane potentials. TRAF6 overexpression had promoting impacts on mitochondrial dysfunction and ferroptosis in MPP⁺-treated MN9D cells, which was reversed by further overexpression of METTL14. Mechanistically, METTL14 facilitated the m6A methylation of TRAF6 mRNA to down-regulate TRAF6 expression, thus inactivating the cGAS-STING pathway.

METTL14 down-regulated TRAF6 expression through TRAF6 m6A methylation to inactivate the cGAS-STING pathway, thereby relieving mitochondrial dysfunction and ferroptosis in DA neurons.

As a complex of natural plant compounds, tanshinone is renowned for its remarkable antioxidant properties. However, the potential impact of tanshinone on melanocyte pigmentation regulation has yet to be elucidated. This study aimed to explore the protective effects of tanshinone I (T-I) and dihydrotanshinone (DHT) on melanogenesis by modulating nuclear factor E2-related factor 2 (Nrf2) signaling and antioxidant defenses in human epidermal melanocyte (HEM) cells.

HEM cells and Nrf2 knockdown HEM cells were subjected to ultraviolet A (UVA) and treated with T-I and/or DHT. Then, the anti-melanogenic properties of T-I and DHT were examined by assessing tyrosinase activity, melanogenesis-related proteins, and melanin content in UVA-irradiated HEM cells. Furthermore, the antioxidant activities of T-I and DHT were evaluated by assessing oxidant formation and modulation of Nrf2-related antioxidant defenses, including reactive oxygen species (ROS), glutathione (GSH) content, and the activity and expression of antioxidant enzymes, such as catalase (CAT), heme oxygenase-1 (HO-1), and superoxide dismutase (SOD).

Our findings revealed that T-I and DHT diminished melanogenesis in UVA-irradiated HEM cells, activated Nrf2-antioxidant response element signaling, and enhanced antioxidant defenses in the irradiated cells. Furthermore, Nrf2 knockdown by shRNA abolished the anti-melanogenesis effects of T-I and DHT on HEM cells against oxidative damage.

These results suggest that T-I and DHT inhibit UVA-induced melanogenesis in HEM cells, possibly through redox mechanisms involving Nrf2 signaling activation and increased antioxidant defenses. This indicates that T-I and DHT have potential as whitening agents in cosmetics and medical treatments for hyperpigmentation disorders.

To explore a new approach for the treatment of renal interstitial fibrosis (RIF), we detected the expression of matrix metalloproteinase-9 (MMP9) and vascular endothelial growth factor (VEGF).

Twenty-four male Sprague Dawley (SD) rats were randomly divided into 2-week normal control (2NC) group, 4-week NC (4NC) group, 2-week unilateral ureteral obstruction (2UUO) group, and 4-week UUO (4UUO) group. We performed left ureteral ligation on UUO groups. Then, we sacrificed the rats of the 2NC group and 2UUO group at 2 weeks and the other groups at 4 weeks after the surgery. Immunohistochemistry and western blot were applied to detect the expression of MMP9, VEGF, fibronectin (FN), type IV collagen (Col-IV), and transforming growth factor-β1 (TGF-β1). MMP9 levels reduced after UUO surgery. Its expression was less in the 4UUO group than in the 2UUO group (P<0.05). The expression of VEGF, TGF-β1, FN, and Col-IV was higher in UUO groups than in NC groups (P<0.05). The expression of these indicators was higher in the 4UUO group than in the 2UUO group (P<0.05).

In the correlation analysis, MMP9 levels in UUO groups had a negative correlation with the expression of TGF-β1, VEGF, Col-IV, FN, and RIF index (all P<0.05). In UUO groups, VEGF levels had a positive correlation with the expression of TGF-β1, Col-IV, FN, and RIF index (all P<0.05).

In conclusion, with the aggravation of RIF lesions, MMP9 levels decreased, and VEGF levels increased. Whether there is a mutual inhibition relationship between them remains to be confirmed by further experiments.

3-Amino-4-(2,4,5-trifluorophenyl) butyric acid has potential pharmacological effects in promoting insulin secretion. Menthol promotes drug transdermal absorption and hypoglycemic effects.

The objective of the study was to combine the 3-amino-4-(2,4,5-trifluorophenyl) butyric acid and menthol to develop a new candidate drug molecule that can be used as a hypoglycemic drug in type II diabetes.

In this study, the molecular structure of 3-amino-4-(2,4,5-trifluorophenyl) butyric acid in sitagliptin was modified by replacing pyrazine imidazole with menthol. The structure of the target compound was characterized by nuclear magnetic resonance (NMR). The anti-diabetic activity of BHF in N000180 BKS.Cg-Dock7m+/ +Leprdb/Nju mice with spontaneous diabetes was preliminarily studied.

A potential multi-target drug molecule, 3-amino-4-(2,4,5-trifluorophenyl) butyrate (BHF), was synthesized by combining 3-amino-4-(2,4,5-trifluorophenyl) butyric acid and menthol. BHF is suitable for hyperglycemic mice and has a significant hypoglycemic effect; the low dose of 10 mg/kg-1 started to be effective, and the high dose of 40 mg/kg-1 was more effective than the positive drug metformin.

In this study, BHF has been synthesized and presented significant antidiabetic activities.