Non­coding RNAs: Role of miRNAs and lncRNAs in the regulation of autophagy in hepatocellular carcinoma (Review).

The term autophagy describes a process that supports nutrient cycling and metabolic adaptation that is accomplished via multistep lysosomal degradation. These activities modulate cell, tissue and internal environment stability, and can also affect the occurrence and development of cancer. Previous studies have mostly described autophagy as having dual effects in cancer, serving to limit tumorigenesis in the early stages of cancer, but promoting tumor progression in certain types of cancer. There have been indications in recent years that microRNAs (miRNAs/miRs) and long non­coding RNAs (lncRNAs), as types of non­coding RNAs, play major roles in the occurrence, invasion, development and drug resistance of hepatocellular carcinoma (HCC) and in the migration of HCC cells by governing HCC cell autophagy. Therefore, understanding which miRNAs and lncRNAs play such roles and the relevant molecular mechanisms is critical. The present review highlights the significant functions of miRNAs and lncRNAs in the regulation of autophagy in HCC and the relevant mechanisms, aiming to provide novel insight into HCC therapeutics.

Construction of lipid raft-coupled agarose gels as bioaffinity chromatography materials and validation with tropomyosin-related kinase A-targeted drugs.

In order to improve the separation process of affinity chromatography that has silica as the main carrier material, we sought to construct Lipid Rafts@CNBr-Sepharose 4B affinity chromatography model. We extracted the lipid rafts from U251 cells with a descaler method and sucrose density gradient centrifugation. Afterwards, it was discovered via immunofluorescence that the lipid rafts contain a large amount of tropomyosin-related kinase A (TrkA) protein. Also, agarose powder in the lyophilised state was pretreated, before the lipid rafts were coupled to the agarose gel in a coupling buffer of alkaline pH. CNBr-Sepharose 4B affinity gel packing was characterised using UV spectrophotometric, immunofluorescence and scanning electron microscopic techniques, wherein and the results showed that the lipid rafts were successfully coupled to the agarose gels. Three compounds were used to verify the specific sorption of Sepharose 4B and CNBr-Sepharose 4B, which showed no specific sorption on the materials. Of note, the prepared Lipid Rafts@CNBr-Sepharose 4B agarose gels packed with TrkA-rich target proteins could be successfully validated for the active drug gefitinib with high affinity sorption efficiency and eluted with good recovery and reproducibility. This study broadens the range of affinity chromatography carrier materials and provides a reference for research in active drug screening.

Mechanisms of Action of Mesenchymal Stem Cells in Metabolic-Associated Fatty Liver Disease.

Metabolic-associated fatty liver disease (MAFLD) is currently the most common chronic liver disease worldwide. However, its pathophysiological mechanism is complicated, and currently, it has no FDA-approved pharmacological therapies. In recent years, mesenchymal stem cell (MSC) therapy has attracted increasing attention in the treatment of hepatic diseases. MSCs are multipotent stromal cells that originated from mesoderm mesenchyme, which have self-renewal and multipotent differentiation capability. Recent experiments and studies have found that MSCs have the latent capacity to be used for MAFLD treatment. MSCs have the potential to differentiate into hepatocytes, which could be induced into hepatocyte-like cells (HLCs) with liver-specific morphology and function under appropriate conditions to promote liver tissue regeneration. They can also reduce liver tissue injury and reverse the development of MAFLD by regulating immune response, antifibrotic activities, and lipid metabolism. Moreover, several advantages are attributed to MSC-derived exosomes (MSC-exosomes), such as targeted delivery, reliable reparability, and poor immunogenicity. After entering the target cells, MSC-exosomes help regulate cell function and signal transduction; thus, it is expected to become an emerging treatment for MAFLD. In this review, we comprehensively discussed the roles of MSCs in MAFLD, main signaling pathways of MSCs that affect MAFLD, and mechanisms of MSC-exosomes on MAFLD.

Regulation of inflammation and apoptosis by GPR43 via JNK/ELK1 in acute lung injury.

Acute lung injury (ALI) is mostly relevant to acute and severe lung inflammation. We first utilized lipopolysaccharide (LPS) to induce mice for establishing a mouse model of ALI and detected decreased expression of GPR43 in the lung tissue in mice with ALI. Mice expressing increased GPR43 showed improvement in lung injury compared to LPS-treated mice. Additionally, ALI mice transfected with lenti-GPR43 significantly decreased the mRNA levels of TNF-α, IL-1ß, IL-6, MPO, COX2 and iNOS, and apoptosis levels in the lungs, as well as the phosphorylation levels of JNK and ELK1 compared to LPS-treated mice with lenti-vector infection. Subsequently, we employed LPS to induce alveolar type ii epithelial cells and observed that Ov-GPR43 infection markedly reduced the expression levels of inflammatory factors and apoptosis levels, while exposure of cells to anisomycin was also effective in blunting the effects of Ov-GPR43 on these processes. Taken together, these results demonstrate a role of GPR43 in mediating lung injury through JNK/ELK1 and imply the therapeutic potential of targeting GPR43 against ALI.

JTE-013 Alleviates Inflammatory Injury and Endothelial Dysfunction Induced by Sepsis In Vivo and In Vitro.

BACKGROUND: Nowadays, there is no approved targeted agent for lung injury induced by sepsis. S1PR2 is confirmed to be a promising diagnosis and treatment target. JTE-013 as S1PR2 antagonists may be an agent of great potential. In this research, we sought to determine the functional role of JTE-013 in lung injury induced by sepsis. MATERIALS AND METHODS: Seventy-two rats were assigned into normal group, sepsis model group and JTE-013 group. The animal model of lung injury induced by sepsis was constructed by cecal ligation and puncture. The human pulmonary microvascular endothelial cells (HPMECs) were divided into control, LPS and LPS + JTE-013 group. HPMECs induced by LPS served as the cell model of lung injury induced by sepsis. HE staining assay was performed for assessment of the pathological condition and Evans blue was applied for assessment of pulmonary tissue permeability. Wet/dry ratio was measured as indicators of pulmonary edema degree and neutrophil count was measured as indicators of infection status. The levels of inflammatory factors were detected by corresponding kits, cell survival by CCK-8 assay and protein expression level by western blot. RESULTS: S1PR2 was highly expressed in vivo model of lung injury induced by sepsis. It was observed that JTE-013 as antagonist of S1PR2 alleviated the lung tissue injury, endothelial dysfunction and pulmonary edema induced by sepsis. In addition, JTE-013 reduced neutrophil count and levels of inflammatory factors. Moreover, results confirmed that JTE-013 enhanced cell viability and mitigated inflammatory response in cell model of sepsis. CONCLUSIONS: Overall, JTE-013 as an antagonist of S1PR2 could relieve inflammatory injury and endothelial dysfunction induced by sepsis in vivo and vitro, resulting in attenuation of lung injury. These findings elucidated that JTE-013 may be a promising targeted agent for lung injury induced by sepsis.