Spinal cord injury (SCI) often leads to serious motor and sensory dysfunction of the limbs below the injured segment. SCI not only results in physical and psychological harm to patients but can also ...cause a huge economic burden on their families and society. As there is no effective treatment method, the prevention, treatment, and rehabilitation of patients with SCI have become urgent problems to be solved. In recent years, mesenchymal stem cells (MSCs) have attracted more attention in the treatment of SCI. Although MSC therapy can reduce injured volume and promote axonal regeneration, its application is limited by tumorigenicity, a low survival rate, and immune rejection. Accumulating literature shows that exosomes have great potential in the treatment of SCI. In this review, we summarize the existing MSC-derived exosome studies on SCI and discuss the advantages and challenges of treating SCI based on exosomes derived from MSCs.
Intervertebral disc degeneration (IDD) is a common clinical degenerative disease of the spine. A series of factors, such as inflammation, oxidative stress and mechanical stress, promote degradation ...of the extracellular matrix (ECM) of the intervertebral discs (IVD), leading to dysfunction and structural destruction of the IVD. Nuclear factor‐κB (NF‐κB) transcription factor has long been regarded as a pathogenic factor of IDD. Therefore, NF‐κB may be an ideal therapeutic target for IDD. As NF‐κB is a multifunctional functional transcription factor with roles in a variety of biological processes, a comprehensive understanding of the function and regulatory mechanism of NF‐κB in IDD pathology will be useful for the development of targeted therapeutic strategies for IDD, which can prevent the progression of IDD and reduce potential risks. This review discusses the role of the NF‐κB signalling pathway in the nucleus pulposus (NP) in the process of IDD to understand pathological NP degeneration further and provide potential therapeutic targets that may interfere with NF‐κB signalling for IDD therapy.
Intervertebral disc degeneration (IDD) is a common clinical degenerative disease of the spine. A series of factors, such as inflammation, oxidative stress, and mechanical stress, promote degradation of the extracellular matrix (ECM) of the intervertebral discs (IVD), leading to dysfunction and structural destruction of the IVD. Nuclear factor‐κB (NF‐κB) transcription factor has long been regarded as the pathogenic factor of IDD. Therefore, NF‐κB may be an ideal therapeutic target for IDD. As NF‐κB is a multifunctional functional transcription factor with roles in a variety of biological processes, a comprehensive understanding of the function and regulatory mechanism of NF‐κB in IDD pathology will be useful for the development of targeted therapeutic strategies for IDD, which can prevent the progression of IDD and reduce potential risks. This review discusses the role of the NF‐κB signalling pathway in the nucleus pulposus (NP) in the process of IDD to understand pathological NP degeneration further and provide potential therapeutic targets that may interfere with NF‐κB signalling for IDD therapy.
Exosomes are extracellular vesicles with a diameter ranging from 30 to 150 nm, which are an important medium for intercellular communication and are closely related to the progression of certain ...diseases. Therefore, exosomes are considered promising biomarkers for the diagnosis of specific diseases, and thereby, treatments based on exosomes are being widely examined. For exosome-related research, a rapid, simple, high-purity, and recovery isolation method is the primary prerequisite for exosomal large-scale application in medical practice. Although there are no standardized methods for exosome separation and analysis, various techniques have been established to explore their biochemical and physicochemical properties. In this review, we analyzed the progress in exosomal isolation strategies and proposed our views on the development prospects of various exosomal isolation techniques.
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•Inflammation, oxidative stress and mitochondrial dysfunction were closely related to IDD.•Among sirtuin family members, SIRT1, SIRT2, SIRT3 and SIRT6 were closely related to IDD.•Some sirtuin ...activating compounds exerted anti-senescence effects of IVD.
Intervertebral disc degeneration (IDD) is one of the main causes of low back pain, which seriously reduces the quality of life of patients and places a heavy economic burden on their families. Cellular senescence is considered to be an important factor leading to IDD, and inflammatory response, oxidative stress, and mitochondrial dysfunction are closely related to intervertebral disc (IVD) senescence. Therefore, inhibition of the inflammatory response and oxidative stress, along with maintaining mitochondrial function, may be useful in treating IDD. The sirtuins are a family of evolutionarily conserved nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, which are the major molecules mediating life extension or delay of aging-related diseases. The sirtuin protein family consist of seven members (SIRT1 – 7), which are mainly involved in various aging-related diseases by regulating inflammation, oxidative stress, and mitochondrial function. Among them, SIRT1, SIRT2, SIRT3, and SIRT6 are closely related to IDD. In addition, some activators of sirtuin proteins, such as resveratrol, melatonin, magnolol, 1,4-dihydropyridine (DHP), SRT1720, and nicotinamide mononucleotide (NMN), have been evaluated in preclinical studies for their effects in preventing IDD. This review described the biological functions of sirtuins and the important roles of SIRT1, SIRT2, SIRT3, and SIRT6 in IDD by regulating oxidative stress, inflammatory response, and mitochondrial function. In addition, we introduce the status of some sirtuin activators in IDD preclinical studies. This review will provide a background for further clarification of the molecular mechanism underlying IDD and the development of potential therapeutic drugs.
Efficient biosynthesis of microbial bioactive natural products (NPs) is beneficial for the survival of producers, while self‐protection is necessary to avoid self‐harm resulting from ...over‐accumulation of NPs. The underlying mechanisms for the effective but tolerable production of bioactive NPs are not well understood. Herein, in the biosynthesis of two fungal polyketide mycotoxins aurovertin E (1) and asteltoxin, we show that the cyclases in the gene clusters promote the release of the polyketide backbone, and reveal that a signal peptide is crucial for their subcellular localization and full activity. Meanwhile, the fungus adopts enzymatic acetylation as the major detoxification pathway of 1. If intermediates are over‐produced, the non‐enzymatic shunt pathways work as salvage pathways to avoid excessive accumulation of the toxic metabolites for self‐protection. These findings provided new insight into the interplay of efficient backbone release and multiple detoxification strategies for the production of fungal bioactive NPs.
The biosynthesis of aurovertins involves a coordinated strategy for the tolerable production of fungal mycotoxins. A cyclase promotes the release of the polyketide backbone, while enzymatic acetylation functions as the major detoxification pathway, and non‐enzymatic shunt pathways function as salvage routes to avoid excessive accumulation of the toxic metabolites.
β-sitosterol (BS), a major bioactive constituent present in plants, has shown potent anti-cancer activity against many human cancer cells, but its activity in pancreatic cancer (PC) cells has rarely ...been reported. Gemcitabine (GEM) is one of the first-line drugs for PC therapy, however, the treatment effect is not sustained due to prolonged drug resistance. In this study, we firstly studied the anti-PC activity and the mechanism of BS alone and in combination with GEM
and
. BS effectively inhibited the growth of PC cell lines by inhibiting proliferation, inducing G0/G1 phase arrest and apoptosis, suppressed the NF- kB activity, and increased expression of the protein Bax but decreased expression of the protein Bcl-2. Moreover, BS inhibited migration and invasion and downregulated epithelial-mesenchymal transition (EMT) markers and AKT/GSK-3β signaling pathways. Furthermore, the combination of BS and GEM exhibited a significant synergistic effect in MIAPaCa-2 and BXPC-3 cells. More importantly, the combined treatment with BS and GEM lead to significant growth inhibition of PC xenografts. Overall, our data revealed a promising treatment option for PC by the combination therapy of BS and GEM.
Soluble epoxide hydrolase (sEH) is an α/β hydrolase fold protein and widely distributed in numerous organs including the liver, kidney, and brain. The inhibition of sEH can effectively maintain ...endogenous epoxyeicosatrienoic acids (EETs) levels and reduce dihydroxyeicosatrienoic acids (DHETs) levels, resulting in therapeutic potentials for cardiovascular, central nervous system, and metabolic diseases. Therefore, since the beginning of this century, the development of sEH inhibitors is a hot research topic. A variety of potent sEH inhibitors have been developed by chemical synthesis or isolated from natural sources. In this review, we mainly summarized the interconnected aspects of sEH with cardiovascular, central nervous system, and metabolic diseases and then focus on representative inhibitors, which would provide some useful guidance for the future development of potential sEH inhibitors.
Background: Cardiovascular disease is one of the major threats to human life and health, and vascular aging is an important cause of its occurrence. Antisense non-coding RNA in the INK4 locus (ANRIL) ...is a kind of long non-coding RNA (lncRNA) that plays important roles in cell senescence. However, the role and mechanism of ANRIL in senescence of vascular smooth muscle cells (VSMCs) are unclear. Methods: Cell viability and cell cycle were evaluated using an MTT assay and flow cytometry analysis, respectively. Senescence-associated (SA)-β-galactosidase (gal) staining was used to determine cell senescence. Dual luciferase reporter assays were conducted to confirm the binding of ANRIL and miR-181a, as well as miR-181a and Sirt1. The expression of ANRIL, miR-181a, and Sirt1 was determined using qRT-PCR and protein levels of SA-β-gal and p53–p21 pathway-related proteins were evaluated by Western blotting. Results: ANRIL and Sirt1 were down-regulated, whereas miR-181a was up-regulated in aging VSMCs. In young and aging VSMCs, over-expression of ANRIL could down-regulate miR-181a and up-regulate Sirt1. MTT and SA-β-gal staining assays showed that over-expression of ANRIL and inhibition of miR-181a promoted cell viability and inhibited VSMC senescence. The dual-luciferase reporter assay determined that miR-181a directly targets ANRIL and the 3′-UTR of Sirt1. Furthermore, over-expression of ANRIL inhibited cell cycle arrest and the p53–p21 pathway. Conclusion: ANRIL promotes cell viability and inhibits senescence in VSMCs, possibly by regulating miR-181a/Sirt1, and alleviating cell cycle arrest by inhibiting the p53–p21 pathway. This study provides novel insights for the role of ANRIL in the development of cell senescence.
AIM To explore the mechanism by which micro RNA-155(miR-155) regulates the pathogenesis of experimental colitis.METHODS A luciferase assay was performed to confirm the binding of miR-155 to the ...SHIP-1 3’-UTR. MiR-155 mimics, negative controls and SHIP-1 expression/knockdown vectors were established and then utilized in gain-and loss-of-function studies performed in raw264.7 cells and primary bone marrow-derived macrophages (BMDMs). Thereafter, dextran sulfate sodium(DSS)-induced colitis mouse model with or without antagomiR-155 treatment was established, and the levels of miR-155 and SHIP-1, as well as the pro-inflammatory capabilities, were measured by western blot, quantitative polymerase chain reaction, and immunohistochemistry.RESULTS MiR-155 directly bound to the 3’-UTR of SHIP-1 mRNA and induced a significant decrease in SHIP-1 expression in both raw264.7 cells and primary BMDMs. MiR-155 markedly promoted cell proliferation and proinflammatory secretions including IL-6, TNF-α, IL-1β, and IFN-γ, whereas these effects could be reversed by the restoration of SHIP-1 expression. In vivo studies showed that antagomiR-155 administration could alleviate DSS-induced intestinal inflammation in Balb/c mice. Moreover, significantly increased SHIP-1 expression, as well as decreased Akt activation and inflammatory response, were observed in the antagomiR-155-treated mice.CONCLUSION MiR-155 promotes experimental colitis by repressing SHIP-1 expression. Thus, the inhibition of miR-155 might be a promising strategy for therapy.
Spinal cord injury (SCI) is a highly disabling disorder for which few effective treatments are available. Grape seed proanthocyanidins (GSPs) are polyphenolic compounds with various biological ...activities. In our preliminary experiment, GSP promoted functional recovery in rats with SCI, but the mechanism remains unclear. Therefore, we explored the protective effects of GSP on SCI and its possible underlying mechanisms. We found that GSP promoted locomotor recovery, reduced neuronal apoptosis, increased neuronal preservation, and regulated microglial polarisation in vivo. We also performed in vitro studies to verify the effects of GSP on neuronal protection and microglial polarisation and their potential mechanisms. We found that GSP regulated microglial polarisation and inhibited apoptosis in PC12 cells induced by M1-BV2 cells through the Toll-like receptor 4- (TLR4-) mediated nuclear factor kappa B (NF-κB) and phosphatidylinositol 3-kinase/serine threonine kinase (PI3K/AKT) signaling pathways. This suggests that GSP regulates microglial polarisation and prevents neuronal apoptosis, possibly by the TLR4-mediated NF-κB and PI3K/AKT signaling pathways.
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