TGF-ß signaling pathway in spinal cord injury: Mechanisms and therapeutic potential.

Spinal cord injury (SCI) is a highly disabling central nervous system injury with a complex pathological process, resulting in severe sensory and motor dysfunction. The current treatment modalities only alleviate its symptoms and cannot effectively intervene or treat its pathological process. Many studies have reported that the transforming growth factor (TGF)-ß signaling pathway plays an important role in neuronal differentiation, growth, survival, and axonal regeneration after central nervous system injury. Furthermore, the TGF-ß signaling pathway has a vital regulatory role in SCI pathophysiology and neural regeneration. Following SCI, regulation of the TGF-ß signaling pathway can suppress inflammation, reduce apoptosis, prevent glial scar formation, and promote neural regeneration. Due to its role in SCI, the TGF-ß signaling pathway could be a potential therapeutic target. This article reported the pathophysiology of SCI, the characteristics of the TGF-ß signaling pathway, the role of the TGF-ß signaling pathway in SCI, and the latest evidence for targeting the TGF-ß signaling pathway for treating SCI. In addition, the limitations and difficulties in TGF-ß signaling pathway research in SCI are discussed, and solutions are provided to address these potential challenges. We hope this will provide a reference for the TGF-ß signaling pathway and SCI research, offering a theoretical basis for targeted therapy of SCI.

Mechanisms and functions of long noncoding RNAs in intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is a key pathological process underlying low back pain. Although, to date, specific molecular mechanisms have not been elucidated, at the cellular level, it is mainly due to pathological changes in the life process of nucleus pulposus (NP) cells in the intervertebral disc (IVD). These changes are closely related to cell proliferation, apoptosis, senescence, autophagy, inflammation, and extracellular matrix (ECM) remodeling. Long noncoding RNAs (lncRNAs) have gradually become a focus of scientific research because of their functional complexity and local tissue specific expression. Moreover, they mediate a series of cellular signaling pathways in NP cells by competing for microRNA (miRNA) or directly targeting gene expression by mRNA adsorption, thereby regulating cell life activities that play a vital role in the mechanism underlying IDD. In-depth studies on lncRNAs can help identify new therapeutic targets or aid in developing IDD treatment strategies at the gene level and those based on regenerative medicine, thus providing new ideas for researchers. This article reviews the classification, biological functions, mechanisms of action, and therapeutic potential of lncRNAs in IDD.

Ski Regulates the Inflammatory Response of Reactive Astrocytes Induced by Oxygen Glucose Deprivation/Reoxygenation (OGD/R) Through the NF-κB Pathway.

Spinal cord injury (SCI) is a common disease of the nervous system, including primary and secondary injuries. Neuronal inflammation after SCI is the most important pathological process of SCI and a chemical barrier to nerve function recovery after injury. Ski, an evolutionarily conserved functional transcriptional regulator protein, is upregulated in reactive astrocytes after SCI and regulates the biological characteristics of astrocytes. However, its role in the glial inflammatory response triggered by reactive astrocytes after spinal cord ischemia and its exact mechanism remains unclear. This study investigated the role and mechanism of Ski in the inflammatory response triggered by reactive astrocytes induced by oxygen and sugar deprivation/reoxygenation (OGD/R) model in vitro. In the ODG/R model, Ski expression was upregulated. In contrast, Ski upregulation was accompanied by increased levels of iNOS, IL-1ß, IL-6, TNF-α, and other inflammation-related factors. These results indicated that the inflammatory response triggered by astrocytes was significantly enhanced in OGD/R-stimulated astrocytes. Astrocytes were transfected with Ski specific siRNA to knock out Ski and subsequently attenuate OGD-induced astrocyte-triggered inflammation. Our results also suggest that Ski downregulation downregulates the expression of iNOS, IL-1ß, IL-6, and TNF-α in OGD/R-induced reactive astrocytes by inhibiting the activity of the NF-κB signaling pathway. In conclusion, downregulation of Ski can effectively inhibit glial inflammation in SCI by inhibiting the activity of the NF-κB pathway. These findings suggest that Ski is a promising therapeutic target for inflammatory responses after SCI.In conclusion, Ski downregulation can effectively inhibit glial inflammation in SCI by inhibiting the activity of the NF-κB pathway. These findings suggest that Ski might serve as a promising target for the treatment of inflammatory responses after SCI.

Ski regulates proliferation and migration of reactive astrocytes induced by lipopolysaccharide (LPS) through PI3K/Akt pathway.

Spinal cord injury (SCI) is a leading cause of disability and death worldwide. Reactive astrogliosis, a typical feature of SCI, undergoes various molecular and morphological changes and contributes to glial scar formation, which impedes axonal regeneration. Ski is a novel molecule that regulates the biological characteristics of astrocytes after spinal cord injury, but its function and the exact mechanism of its overexpression in reactive astrocyte proliferation and migration after SCI remain unclear. The purpose of this study was to elucidate the effect and mechanism of Ski on the proliferation and migration of reactive astrocytes, and to regulate the spatiotemporal formation of glial scars after SCI. In an in vitro lipopolysaccharide (LPS)-induced astrocyte injury model, the expression of Ski was upregulated in a time-dependent manner in LPS-induced astrocytes, and the upregulation of Ski was accompanied by that of PCNA, CDK4, CyclinD1, and other proliferation-related proteins. Our findings suggest that Ski promotes the proliferation and migration of reactive astrocytes. Next, astrocytes were transfected with a specific lentivirus to cause the overexpression of Ski, which significantly enhanced the proliferation and migration of reactive astrocytes and LPS-induced activation of the PI3K/Akt pathway. The PI3K/Akt pathway inhibitor LY294002 significantly inhibited the proliferation and migration of LPS-induced reactive astrocytes after Ski overexpression. In conclusion, Ski regulates LPS-induced astrocyte proliferation and migration through the PI3K/Akt pathway, making Ski a promising target for strategies to combat glial scarring after SCI.

The role of Wnt/mTOR signaling in spinal cord injury.

Spinal cord injury (SCI) is the most common disabling spinal injury, a complex pathologic process that can eventually lead to severe neurological dysfunction. The Wnt/mTOR signaling pathway is a pervasive signaling cascade that regulates a wide range of physiological processes during embryonic development, from stem cell pluripotency to cell fate. Numerous studies have reported that Wnt/mTOR signaling pathway plays an important role in neural development, synaptogenesis, neuron growth, differentiation and survival after the central nervous system (CNS) is damaged. Wnt/mTOR also plays an important role in regulating various pathophysiological processes after spinal cord injury (SCI). After SCI, Wnt/mTOR signal regulates the physiological and pathological processes of neural stem cell proliferation and differentiation, neuronal axon regeneration, neuroinflammation and pain through multiple pathways. Due to the characteristics of the Wnt signal in SCI make it a potential therapeutic target of SCI. In this paper, the characteristics of Wnt/mTOR signal, the role of Wnt/mTOR pathway on SCI and related mechanisms are reviewed, and some unsolved problems are discussed. It is hoped to provide reference value for the research field of the role of Wnt/mTOR pathway in SCI, and provide a theoretical basis for biological therapy of SCI.

Roles of MET in human cancer.

The MET proto-oncogene was first identified in osteosarcoma cells exposed to carcinogens. Although expressed in many normal cells, MET is overexpressed in many human cancers. MET is involved in the initiation and development of various human cancers and mediates proliferation, migration and invasion. Accordingly, MET has been successfully used as a biomarker for diagnosis and prognosis, survival, post-operative recurrence, risk assessment and pathologic grading, as well as a therapeutic target. In addition, recent work indicates that inhibition of MET expression and function has potential clinical benefit. This review summarizes the role, mechanism, and clinical significance of MET in the formation and development of human cancer.

Transcription Factor SP2 Regulates Ski-mediated Astrocyte Proliferation In Vitro.

Transcription factors bind specific sequences upstream of the 5' end of their target genes to ensure proper spatiotemporal expression of the target gene. This study aims to demonstrate that the transcription factor SP2 regulates expression of the Ski gene, which has specific binding sites for SP2, and thus enables Ski to regulate astrocyte proliferation. The upstream regulation mechanism of astrocyte proliferation was explored to further regulate the formation of glial scar in specific time and space after spinal cord injury. JASPAR and UCSC databases were used to predict transcription factor binding and the threshold was gradually reduced to screen transcription factors upstream of Ski, leading to the identification of SP2. Next, we analyzed the correlation between the expression of SP2 and Ski in normal astrocytes and reactive astrocytes, as well as the changes in astrocyte proliferation. To confirm that SP2 regulates Ski during astrocyte proliferation, astrocytes were transfected siRNA targeting SP2 and then astrocyte proliferation were analyzed. Finally, a dual luciferase reporter assay and Chromatin immunoprecipitation (ChIP) assay confirmed that the promoter region of Ski contained a specific SP2 binding site. This is the first that SP2 has been identified and confirmed to play an important role in astrocyte proliferation by regulating Ski expression. These results may help identify novel targets for the treatment of spinal cord injury.

MAPK /ERK signaling pathway: A potential target for the treatment of intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is a chronic skeletal muscle degenerative disease, which is considered the main cause of low back pain. It seriously affects the quality of life of patients and consequently brings a heavy economic burden to their families and the society. Although IDD is considered a natural process in degenerative lesions, it is mainly caused by aging, trauma, genetic susceptibility and other factors. It is closely related to changes in the tissue structure and function, including the progressive destruction of extracellular matrix, cell aging, cell death of the intervertebral disc (IVD), inflammation, and impairment of tissue biomechanical function. Currently, the treatment of IDD is aimed at alleviating symptoms rather than at targeting pathological changes in the IVD. Furthermore, the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway is closely related to various pathological processes in IDD, and the activation of the MAPK/ERK pathway promotes the degradation of the IVD extracellular matrix, cell aging, apoptosis, and inflammatory responses. It also induces autophagy and oxidative stress that accelerate the IVD process. In our current review, we summarize the latest developments in the negative regulation of IDD after activation of the MAPK/ERK signaling pathway and emphasize on its influence on IDD. Targeting this pathway may become an attractive treatment strategy for IDD in the near future.

The paradoxical role of matrix metalloproteinase-11 in cancer.

The microenvironment surrounding the tumor affects biological processes, such as cell proliferation, angiogenesis, apoptosis, and invasion. Therefore, the ability to change these environments is an important attribute for tumor cells to obtain specific functions necessary for growth and metastasis. Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic metalloenzymes that facilitate protease-dependent tumor progression by degrading extracellular matrix (ECM) proteins, releasing cytokines, growth factors, and other cell surface molecules. As one of the most widely studied MMPs, MMP-11 is an important protease that is expressed in cancer cells, stromal cells, and the adjacent microenvironment. MMP-11 has a dual effect on tumors. On one hand, MMP-11 promotes tumor development by inhibiting apoptosis and promoting the migration and invasion of cancer cells in the early stage. On the other hand, in animal models, MMP-11 has a protective effect on tumor growth and metastasis at an advanced stage. Based on current findings regarding the importance of MMP-11 in altering the tumor microenvironment, there is a need to further understand how stromal cells and the ECM regulate tumor progression, which may result in the re-examination of MMPs as drug targets for cancer and other diseases. In this review, we summarize the dual role of MMP-11 in cancer and its potential clinical significance.

Piezo-type mechanosensitive ion channel component 1 (Piezo1) in human cancer.

Piezo-type mechanosensitive ion channel component 1 (Piezo1) is a mechanosensitive ion channel protein that is evolutionarily conserved and multifunctional. It plays an important role as an oncogenic mediator in several malignant tumors. It mediates the proliferation, migration, and invasion of a variety of cancer cells through various mechanisms. Multiple studies have shown that the expression of Piezo1 is related to the clinical characteristics of senescence and cancer patients, making Piezo1 useful as a new biomarker for the diagnosis and prognosis of a variety of human cancers. Manipulating the expression or function of Piezo1 is a potential therapeutic strategy for different diseases. Piezo1 may be a promising tumor biomarker and therapeutic target. Here we review the biological function, mechanism of action, and potential clinical significance of Piezo1 in oncogenesis and progression.

CISD2 plays a role in age-related diseases and cancer.

CDGSH iron-sulfur domain 2 (Cisd2) is an evolutionarily conserved protein that plays an important regulatory role in aging-related diseases and cancers. Since its discovery, Cisd2 has been identified as a regulatory factor for the aging of the human body and the regulation of mammalian lifespan. Cisd2 is also an oncoprotein that regulates the occurrence and development of cancer. Cisd2 mediates the occurrence of diseases related to human aging and the proliferation, differentiation, metastasis, and invasion of various cancer cells through various mechanisms. Multiple studies have shown that Cisd2 expression is related to the clinical characteristics of aging-related diseases and patients with cancer, and its expression profile is a novel diagnostic and prognostic biomarker for a variety of human diseases. Modulating the expression or function of Cisd2 may be a potential treatment strategy for different diseases. In this review, we summarize the role of Cisd2 in human aging-related diseases and various cancers, as well as the biological functions, underlying mechanisms, and potential clinical significance.

Roles of matrix metalloproteinase-7 (MMP-7) in cancer.

Matrix metalloproteinase-7 (MMP-7) is a small proteolytic enzyme that secretes zinc and calcium endopeptidases. It can degrade a variety of extracellular matrix substrates and other substrates and plays important regulatory roles in many human pathophysiological processes. Since its discovery, MMP-7 has been recognized as a regulatory protein in wound healing, bone growth, and remodeling. Later, MMP-7 was reported to regulate the occurrence and development of cancers and mediate the proliferation, differentiation, metastasis, and invasion of several types of cancer cells via various mechanisms. Thus, matrix metalloproteinase-7 may be a promising tumor biomarker and therapeutic target. The expression of MMP-7 correlates with the clinical characteristics of cancer patients, and its expression profile is a new diagnostic and prognostic biomarker for a variety of human diseases. Hence, manipulating the expression or function of MMP-7 may be a potential treatment strategy for different diseases including cancers. This review summarizes the role played by MMP-7 in carcinogenesis of several human cancers, underlying mechanisms, and its clinical significance of the occurrence and development of cancers.

Biological Functions and Therapeutic Potential of Autophagy in Spinal Cord Injury.

Autophagy is an evolutionarily conserved lysosomal degradation pathway that maintains metabolism and homeostasis by eliminating protein aggregates and damaged organelles. Many studies have reported that autophagy plays an important role in spinal cord injury (SCI). However, the spatiotemporal patterns of autophagy activation after traumatic SCI are contradictory. Most studies show that the activation of autophagy and inhibition of apoptosis have neuroprotective effects on traumatic SCI. However, reports demonstrate that autophagy is strongly associated with distal neuronal death and the impaired functional recovery following traumatic SCI. This article introduces SCI pathophysiology, the physiology and mechanism of autophagy, and our current review on its role in traumatic SCI. We also discuss the interaction between autophagy and apoptosis and the therapeutic effect of activating or inhibiting autophagy in promoting functional recovery. Thus, we aim to provide a theoretical basis for the biological therapy of SCI.

Ski: Double roles in cancers.

The Ski (Sloan-Kettering Institute) is an evolutionarily conserved protein that plays a dual role as an oncoprotein and tumor suppressor gene in the development of human cancer. The Ski oncogene was first identified as a transforming protein of the avian Sloan-Kettering retrovirus in 1986. Since its discovery, Ski has been identified as a carcinogenic regulator in a variety of malignant tumors. Later, it was reported that Ski regulates the occurrence and development of some cancers by acting as an oncogene. Ski mediates the proliferation, differentiation, metastasis, and invasion of numerous cancer cells through various mechanisms. Several studies have shown that Ski expression is correlated with the clinical characteristics of cancer patients and is a promising biomarker and therapeutic target for cancer. In this review, we summarize the mechanisms and potential clinical implications of Ski in dimorphism, cancer occurrence, and progression in various types of cancer.