Magnesium Isoglycyrrhizinate Reduces the Target-Binding Amount of Cisplatin to Mitochondrial DNA and Renal Injury through SIRT3

Nephrotoxicity is the dose-limiting factor of cisplatin treatment. Magnesium isoglycyrrhizinate (MgIG) has been reported to ameliorate renal ischemia–reperfusion injury. This study aimed to investigate the protective effect and possible mechanisms of MgIG against cisplatin-induced nephrotoxicity from the perspective of cellular pharmacokinetics. We found that cisplatin predominantly accumulated in mitochondria of renal tubular epithelial cells, and the amount of binding with mitochondrial DNA (mtDNA) was more than twice that with nuclear DNA (nDNA). MgIG significantly lowered the accumulation of cisplatin in mitochondria and, in particular, the degree of target-binding to mtDNA. MgIG notably ameliorated cisplatin-induced changes in mitochondrial membrane potential, morphology, function, and cell viability, while the magnesium donor drugs failed to work. In a mouse model, MgIG significantly alleviated cisplatin-caused renal dysfunction, pathological changes of renal tubules, mitochondrial ultrastructure variations, and disturbed energy metabolism. Both in vitro and in vivo data showed that MgIG recovered the reduction of NAD⁺-related substances and NAD⁺-dependent deacetylase sirtuin-3 (SIRT3) level caused by cisplatin. Furthermore, SIRT3 knockdown weakened the protective effect of MgIG on mitochondria, while SIRT3 agonist protected HK-2 cells from cisplatin and specifically reduced platinum-binding activity with mtDNA. In conclusion, MgIG reduces the target-binding amount of platinum to mtDNA and exerts a protective effect on cisplatin-induced renal injury through SIRT3, which may provide a new strategy for the treatment of cisplatin-induced nephrotoxicity.     

Self-Amplifying RNA Approach for Protein Replacement Therapy

Messenger RNA (mRNA) technology has already been successfully tested preclinically and there are ongoing clinical trials for protein replacement purposes; however, more effort has been put into the development of prevention strategies against infectious diseases. Apparently, mRNA vaccine approval against coronavirus disease 2019 (COVID-19) is a landmark for opening new opportunities for managing diverse health disorders based on this approach. Indeed, apart from infectious diseases, it has also been widely tested in numerous directions including cancer prevention and the treatment of inherited disorders. Interestingly, self-amplifying RNA (saRNA)-based technology is believed to display more developed RNA therapy compared with conventional mRNA technique in terms of its lower dosage requirements, relatively fewer side effects, and possessing long-lasting effects. Nevertheless, some challenges still exist that need to be overcome in order to achieve saRNA-based drug approval in clinics. Hence, the current review discusses the feasibility of saRNA utility for protein replacement therapy on various health disorders including rare hereditary diseases and also provides a detailed overview of saRNA advantages, its molecular structure, mechanism of action, and relevant delivery platforms.     

Serum SELENBP1 and VCL Are Effective Biomarkers for Clinical and Forensic Diagnosis of Coronary Artery Spasm

Coronary artery spasm (CAS) plays an important role in the pathogenesis of many ischemic heart entities; however, there are no established diagnostic biomarkers for CAS in clinical and forensic settings. This present study aimed to identify such serum biomarkers by establishing a rabbit CAS provocation model and integrating quantitative serum proteomics, parallel reaction monitoring/mass spectrometry-based targeted proteomics, and partial least-squares discriminant analysis (PLS-DA). Our results suggested that SELENBP1 and VCL were potential candidate biomarkers for CAS. In independent clinical samples, SELENBP1 and VCL were validated to be significantly lower in serum but not blood cells from CAS patients, with the reasons for this possibly due to the decreased secretion from cardiomyocytes. The areas under the curve of the receiver operating characteristics (ROC) analysis were 0.9384 for SELENBP1 and 0.9180 for VCL when diagnosing CAS. The CAS risk decreased by 32.3% and 53.6% for every 10 unit increases in the serum SELENBP1 and VCL, respectively. In forensic samples, serum SELENBP1 alone diagnosed CAS-induced deaths at a sensitivity of 100.0% and specificity of 72.73%, and its combination with VCL yielded a diagnostic specificity of 100.0%, which was superior to the traditional biomarkers of cTnI and CK-MB. Therefore, serum SELENBP1 and VCL could be effective biomarkers for both the clinical and forensic diagnosis of CAS.     

From 2D to 3D Co-Culture Systems: A Review of Co-Culture Models to Study the Neural Cells Interaction

The central nervous system (CNS) controls and regulates the functional activities of the organ systems and maintains the unity between the body and the external environment. The advent of co-culture systems has made it possible to elucidate the interactions between neural cells in vitro and to reproduce complex neural circuits. Here, we classified the co-culture system as a two-dimensional (2D) co-culture system, a cell-based three-dimensional (3D) co-culture system, a tissue slice-based 3D co-culture system, an organoid-based 3D co-culture system, and a microfluidic platform-based 3D co-culture system. We provide an overview of these different co-culture models and their applications in the study of neural cell interaction. The application of co-culture systems in virus-infected CNS disease models is also discussed here. Finally, the direction of the co-culture system in future research is prospected.     

MicroRNA-381 Regulates Proliferation and Differentiation of Caprine Skeletal Muscle Satellite Cells by Targeting PTEN and JAG2

In our previous study, microRNA (miR)-381 was found to be the most down-regulated miRNA in skeletal muscle of Liaoning cashmere goats with higher skeletal muscle mass, but the molecular mechanism involved remains unclear. In this study, primary caprine skeletal muscle satellite cells (SMSCs) were isolated and identified. We investigated the effect of miR-381 on the viability, proliferation and differentiation of caprine SMSCs, and the target relationships of miR-381 with jagged canonical Notch ligand 2 (JAG2) and phosphatase and tensin homolog (PTEN). Cells isolated were positive for SMSC-specific marker protein Pax7. This suggests that purified SMSCs were obtained. The expression level of miR-381 achieved a peak value on day 4 after SMSC differentiation, and miR-381 also significantly increased the expression levels of myogenic differentiation marker genes: myosin heavy chain (MyHC), myogenin (MyoG) and myocyte enhancer factor 2C (MEF2C) in differentiated SMSCs, the area of MyHC-positive myotubes and the myogenic index. These findings suggest that miR-381 promoted myogenic differentiation of caprine SMSCs. The CCK8 assay and EDU staining analysis showed that miR-381 mimic both inhibited the viability of SMSCs and decreased the percentage of EDU-labeled positive SMSCs. In contrast, miR-381 inhibitor had the opposite effect with miR-381 mimic. A dual luciferase reporter assay verified that miR-381 can target JAG2 and PTEN by binding to the 3′-untranslated regions (3′-UTR) of the genes. The transfection of miR-381 mimic into caprine SMSCs resulted in decreases in expression levels of JAG2 and PTEN, while miR-381 inhibitor increased the two target genes in expression. This is the first study to reveal the biological mechanisms by which miR-381 regulates caprine SMSC activities.     

Trifuhalol A Suppresses Allergic Inflammation through Dual Inhibition of TAK1 and MK2 Mediated by IgE and IL-33

The activation and degranulation of immune cells play a pivotal role in allergic inflammation, a pathological condition that includes anaphylaxis, pruritus, and allergic march-related diseases. In this study, trifuhalol A, a phlorotannin isolated from Agarum cribrosum, inhibited the degranulation of immune cells and the biosynthesis of IL-33 and IgE in differentiated B cells and keratinocytes, respectively. Additionally, trifuhalol A suppressed the IL-33 and IgE-mediated activation of RBL-2H3 cells through the regulation of the TAK1 and MK2 pathways. Hence, the effect of trifuhalol A on allergic inflammation was evaluated using a Compound 48/80-induced systemic anaphylaxis mouse model and a house dust mite (HDM)-induced atopic dermatitis (AD) mouse model. Trifuhalol A alleviated anaphylactic death and pruritus, which appeared as an early-phase reaction to allergic inflammation in the Compound 48/80-induced systemic anaphylaxis model. In addition, trifuhalol A improved symptoms such as itching, edema, erythema, and hyperkeratinization in HDM-induced AD mice as a late-phase reaction. Moreover, the expression of IL-33 and thymic stromal lymphopoietin, inflammatory cytokines secreted from activated keratinocytes, was significantly reduced by trifuhalol A administration, resulting in the reduced infiltration of immune cells into the skin and a reduction in the blood levels of IgE and IL-4. In summarizing the above results, these results confirm that trifuhalol A is a potential therapeutic candidate for the regulation of allergic inflammation.