Acid-sensing ion channel 1a modulation of apoptosis in acidosis-related diseases: implications for therapeutic intervention.

Acid-sensing ion channel 1a (ASIC1a), a prominent member of the acid-sensing ion channel (ASIC) superfamily activated by extracellular protons, is ubiquitously expressed throughout the human body, including the nervous system and peripheral tissues. Excessive accumulation of Ca2+ ions via ASIC1a activation may occur in the acidified microenvironment of blood or local tissues. ASIC1a-mediated Ca2+­induced apoptosis has been implicated in numerous pathologies, including neurological disorders, cancer, and rheumatoid arthritis. This review summarizes the role of ASIC1a in the modulation of apoptosis via various signaling pathways across different disease states to provide insights for future studies on the underlying mechanisms and development of therapeutic strategies.

Cilengitide inhibits osteoclast adhesion through blocking the αvß3-mediated FAK/Src signaling pathway.

The remodeling of actin cytoskeleton of osteoclasts on the bone matrix is essential for osteoclastic resorption activity. A specific regulator of the osteoclast cytoskeleton, integrin αvß3, is known to provide a key role in the degradation of mineralized bone matrixes. Cilengitide is a potent inhibitor of integrins and is capable of affecting αvß3 receptors, and has anti-tumor and anti-angiogenic and apoptosis-inducing effects. However, its function on osteoclasts is not fully understood. Here, the cilengitide role on nuclear factor κB ligand-receptor activator (RANKL)-induced osteoclasts was explored. Cells were cultured with varying concentrations of cilengitide (0,0.002,0.2 and 20 µM) for 7 days, followed by detected via Cell Counting Kit-8, staining for tartrate resistant acid phosphatase (TRAP), F-actin ring formation, bone resorption assays, adhesion assays, immunoblotting assays, and real-time fluorescent quantitative PCR. Results demonstrated that cilengitide effectively restrained the functionality and formation of osteoclasts in a concentration-dependent manner, without causing any cytotoxic effects. Mechanistically, cilengitide inhibited osteoclast-relevant genes expression; meanwhile, cilengitide downregulated the expression of key signaling molecules associated with the osteoclast cytoskeleton, including focal adhesion kinase (FAK), integrin αvß3 and c-Src. Therefore, this results have confirmed that cilengitide regulates osteoclast activity by blocking the integrin αvß3 signal pathway resulting in diminished adhesion and bone resorption of osteoclasts.

Systematic analysis of the cuprotosis in tumor microenvironment and prognosis of gastric cancer.

Cuprotosis is a new programmed cell death related to cancer. However, the characteristics of cuprotosis in gastric cancer (GC) remain unknown. Ten cuprotosis molecules from 1544 GC patients were used to identify three GC molecular genotypes. Cluster A was characterized by the best clinical outcome and was significantly enriched in metabolic signaling pathways. Cluster B exhibited elevated immune activation, high immune stroma scores and was significantly enriched in tumor immune signaling pathways. Cluster C was characterized by severe immunosuppression and poor response to immunotherapy. Notably, the citrate cycle, cell cycle, and p53 signaling pathways were enriched in the differentially expressed genes among the three subtypes, which were critical signaling pathways for cell death. We also developed a cuprotosis signature risk score that could accurately predict the survival, immunity, and subtype of GC. This study presents a systematic analysis of cuprotosis molecules and provides new immunotherapeutic targets for GC patients.

An antigen processing and presentation signature for prognostic evaluation and immunotherapy selection in advanced gastric cancer.

Objective: The aim of the study was to propose a signature based on genes associated with antigen processing and presentation (APscore) to predict prognosis and response to immune checkpoint inhibitors (ICIs) in advanced gastric cancer (aGC). Background: How antigen presentation-related genes affected the immunotherapy response and whether they could predict the clinical outcomes of the immune checkpoint inhibitor (ICI) in aGC remain largely unknown. Methods: In this study, an aGC cohort (Kim cohort, RNAseq, N=45) treated by ICIs, and 467 aGC patients from seven cohorts were conducted to investigate the value of the APscore predicting the prognosis and response to ICIs. Subsequently, the associations of the APscore with the tumor microenvironment (TME), molecular characteristics, clinical features, and somatic mutation variants in aGC were assessed. The area under the receiver operating characteristic curve (AUROC) of the APscore was analyzed to estimate response to ICIs. Cox regression or Log-rank test was used to estimate the prognosis of aGC patients. Results: The APscore constructed by principal component analysis algorithms was an effective predictive biomarker of the response to ICIs in the Kim cohort and 467 aGC patients (Kim: AUC =0.85, 95% CI: 0.69-1.00; 467 aGC: AUC =0.69, 95% CI: 0.63-0.74). The APscore also was a prognostic biomarker in 467 aGC patients (HR=1.73, 95% CI: 1.21-2.46). Inhibitory immunity, decreased TMB and low stromal scores were observed in the high APscore group, while activation of immunity, increased TMB, and high stromal scores were observed in the low APscore group. Next, we evaluated the value of several central genes in predicting the prognosis and response to ICIs in aGC patients, and verified them using immunogenic, transcriptomic, genomic, and multi-omics methods. Lastly, a predictive model built successfully discriminated patients with vs. without immunotherapy response and predicted the survival of aGC patients. Conclusions: The APscore was a new biomarker for identifying high-risk aGC patients and patients with responses to ICIs. Exploration of the APscore and hub genes in multi-omics GC data may guide treatment decisions.

Insight into the role of DPP-4 in fibrotic wound healing.

Wound healing is a complex and long-term process consisting of hemostasis, inflammation, proliferation, and maturation/remodeling. These four stages overlap and influence each other; they affect wound healing in different ways, and if they do not function perfectly, they may cause scarring, proliferative scarring and keloid formation. A therapeutic target affecting wound healing in multiple ways will help the healing process proceed more effectively. DPP-4/CD26 is a multifunctional dimorphic glycoprotein widely distributed on the surface of a variety of cells, including fibroblasts and keratin-forming cells. It has been found to affect periwound inflammation, re-epithelialization, extracellular matrix secretion and skin fibrosis and is a potential target for promoting wound healing and inhibiting scar formation. After presenting a brief introduction of the wound healing process and DPP-4/CD26, this paper summarizes the effects of DPP-4/CD26 on cells involved in different stages of wound healing and discusses the feasibility of DPP-4/CD26 as a multifunctional target for the treatment of wound healing and inhibition of scar formation.

The ASIC3-M-CSF-M2 macrophage-positive feedback loop modulates fibroblast-to-myofibroblast differentiation in skin fibrosis pathogenesis.

Inflammation is one of the main pathological features leading to skin fibrosis and a key factor leading to the progression of skin fibrosis. Acidosis caused by a decrease in extracellular pH is a sign of the inflammatory process. Acid-sensing ion channels (ASICs) are ligand-gated ion channels on the cell membrane that sense the drop in extracellular pH. The molecular mechanisms by which skin fibroblasts are regulated by acid-sensing ion channel 3 (ASIC3) remain unknown. This study investigated whether ASIC3 is related to inflammation and skin fibrosis and explored the underlying mechanisms. We demonstrate that macrophage colony-stimulating factor (M-CSF) is a direct target of ASIC3, and ASIC3 activation promotes M-CSF transcriptional regulation of macrophages for M2 polarization. The polarization of M2 macrophages transduced by the ASIC3-M-CSF signal promotes the differentiation of fibroblasts into myofibroblasts through transforming growth factor ß1 (TGF-ß1), thereby producing an ASIC3-M-CSF-TGF-ß1 positive feedback loop. Targeting ASIC3 may be a new treatment strategy for skin fibrosis.

Insights into the role of adipose-derived stem cells: Wound healing and clinical regenerative potential.

The incidence of acute and chronic wound diseases is rising due to various reasons. With complicated pathogenesis, long course, difficult treatment and high disability, wound diseases have become a major burden for patients, their families, and society. Therefore, the focus of research is to identify new ideas and methods for treatment. Fat grafting has gained increased attention because of its effectiveness in wound treatment, and further analysis has uncovered that the stem cells derived from fat may be the main factor affecting wound healing. We summarize the function of adipose stem cells and analyze their possible mechanisms in tissue repair, helping to provide new ideas for the treatment of wound healing.

Targeted apoptosis of myofibroblasts by elesclomol inhibits hypertrophic scar formation.

BACKGROUND: Hypertrophic scar (HS) is characterized by the increased proliferation and decreased apoptosis of myofibroblasts. Myofibroblasts, the main effector cells for dermal fibrosis, develop from normal fibroblasts. Thus, the stimulation of myofibroblast apoptosis is a possible treatment for HS. We aimed to explore that whether over-activated myofibroblasts can be targeted for apoptosis by anticancer drug elesclomol. METHODS: 4',6-diamidino-2-phenylindole staining, flow cytometry, western blotting, collagen gel contraction and immunofluorescence assays were applied to demonstrate the proapoptotic effect of elesclomol in scar derived myofibroblasts and TGF-ß1 induced myofibroblasts. The therapeutic potential of elesclomol was investigated by establishing rabbit ear hypertrophic scar models. FINDINGS: Both 4',6-diamidino-2-phenylindole staining and flow cytometry indicated that elesclomol targets myofibroblasts in vitro. Collagen gel contraction assay showed that elesclomol inhibited myofibroblast contractility. Flow cytometry and western blot analysis revealed that elesclomol resulted in excessive intracellular levels of reactive oxygen species(ROS), and caspase-3 and cytochrome c proteins. Moreover, compared with the control group, the elesclomol group had a significantly lower scar elevation index in vivo. Immunofluorescence assays for TUNEL and α-smooth muscle actin indicated that elesclomol treatment increased the number of apoptotic myofibroblasts. INTERPRETATION: The above results indicate that elesclomol exerted a significant inhibitory effect on HS formation via targeted myofibroblast apoptosis associated with increased oxidative stress. Thus, elesclomol is a promising candidate drug for the treatment of myofibroblast-related diseases such as HS.

m6 A facilitates YTHDF-independent phase separation.

N6-methyladenosine (m6 A) is one of the most abundant messenger RNA (mRNA) modifications in eukaryotes and is involved in various key processes of RNA metabolism. In this issue of Nature, Ries et al (2019) described the fundamental features of m6A modification of mRNAs in regulating the composition of the phase-separated transcriptome on the basis of number and distribution, and provide strong evidence that m6A plays a role in regulating phase separation in cells.