Search

Low back pain (LBP) is a leading cause of labour loss and disability worldwide, and it also imposes a severe economic burden on patients and society. Among symptomatic LBP, approximately 40% is caused by intervertebral disc degeneration (IDD). IDD is the pathological basis of many spinal degenerative diseases such as disc herniation and spinal stenosis. Currently, the therapeutic approaches for IDD mainly include conservative treatment and surgical treatment, neither of which can solve the problem from the root by terminating the degenerative process of the intervertebral disc (IVD). Therefore, further exploring the pathogenic mechanisms of IDD and adopting targeted therapeutic strategies is one of the current research hotspots. Among the complex pathophysiological processes and pathogenic mechanisms of IDD, oxidative stress is considered as the main pathogenic factor. The delicate balance between reactive oxygen species (ROS) and antioxidants is essential for maintaining the normal function and survival of IVD cells. Excessive ROS levels can cause damage to macromolecules such as nucleic acids, lipids, and proteins of cells, affect normal cellular activities and functions, and ultimately lead to cell senescence or death. This review discusses the potential role of oxidative stress in IDD to further understand the pathophysiological processes and pathogenic mechanisms of IDD and provides potential therapeutic strategies for the treatment of IDD. [ABSTRACT FROM AUTHOR]

Brachytherapy is considered to be an unparalleled form of conformal radiation therapy, which involves the delivery of radiation directly to tumor lesions or the postoperative cavity. With the development of specific applicators, the exploitation of in situ drug-delivery platform introduces opportunities for the synchronous administration of radiosensitizers. In this study, an iodine-131 (I131)-labeled injectable thermosensitive methoxy poly(ethylene glycol)- b -poly(tyrosine) hydrogel (denoted as PETyr-I131) was developed via a facile method. The radioactive source of I131 was immobilized at the subcutaneous injection site and monitored via single-photon emission computed tomography in real time, and hematological and histopathological analyses revealed no obvious side effects. Additionally, the SmacN7 peptide conjugated with cell membrane-permeable oligosarginine (denoted as SmacN7-R9) was used to enhance the radiosensitivity of cancer cells, as confirmed by the results of reactive oxygen species detection, DNA damage assay, cell apoptosis assay, and clonogenic evaluation. Importantly, a synergistic brachytherapy treatment effect on tumor-bearing nude mice was achieved. The proposed thermosensitive supramolecular hydrogel platform, which conformally immobilizes radionuclides and delivers radiosensitizers by virtue of its proximity to the site of the primary tumor or the postoperative cavity, has great potential for achieving synergistic treatment outcomes with reduced radiation-related side effects. In this work, a kind of radioiodinated thermosensitive supramolecular hydrogel was developed, which was facilely used as the radioactive source for brachytherapy. Meanwhile, SmacN7-R9 peptide was combined as a model radiosensitizer to facilitate the activation of tumor cell apoptosis pathways and promotion of radiation-induced cytotoxicity. Synergistic brachytherapy outcomes were achieved from the in vitro and in vivo evaluations. Therefore, from the practical standpoint, this thermosensitive supramolecular hydrogel platform holds great potential for the 3D-conformally immobilizing radionuclide and delivering radiosensitizer by virtue of its proximity to the site of primary tumor lesions or postoperative cavity, resulting in synergetic treatment outcomes with reduced radiation associated side effects. Image, graphical abstract [ABSTRACT FROM AUTHOR]

P-type Ag-LaFeO 3 (AL) is a promising gas-sensing material owing to its large surface area, rich active oxygen lattice, good thermostability, controllable structure and strong reducibility. While the operating temperature of which is high. In this study, B, N, S and Cl doped graphene quantum dots (GQD) were prepared with a simple liquid-phase exfoliation method and with which decorated AL in order to low the operating temperature of AL. The sensors based on the doped GQD operated at room temperature and showed affinity toward different volatile organic compounds (VOCs). B-GQD revealed p-type semiconductor property and reduced the operating temperature of AL markedly form 90 °C to 55 °C when composite with it because of the synergy effect. Undoped GQD and N, S, Cl doped GQD showed n-type semiconductor property and oppositely increased the operating temperature of AL to different extent when composite with AL. That is, the more electrons in the outer layer of the doped element, the higher the temperature of GQD/AL composite rise. Thus the gas-sensing properties of B-GQD/AL composite was further researched, the results showed that the composite possessed high sensitivity, good selectivity, good stability and low operating temperature to low concentration of formaldehyde. [ABSTRACT FROM AUTHOR]

Peroxynitrite toxicity has been implicated in the pathogenesis of white matter injury. The mechanisms of peroxynitrite toxicity to oligodendrocytes (OLs), the major cell type of the white matter, are unknown. Using primary cultures of mature OLs that express myelin basic protein, we found that 3-morpholinosydnonimine, a peroxynitrite generator, caused toxicity to OLs. N,N,N′,N′-tetrakis (2-pyridylmethyl)ethylenediamine, a zinc chelator, completely blocked peroxynitrite-induced toxicity. Use of FluoZin-3, a specific fluorescence zinc indicator, demonstrated the liberation of zinc from intracellular stores by peroxynitrite. Peroxynitrite caused the sequential activation of extracellular signal-regulated kinase 42/44 (ERK42/44), 12-lipoxygenase, and generation of reactive oxygen species, which were all dependent upon the intracellular release of zinc. The same cell death pathway was also activated when exogenous zinc was used. These results suggest that in addition to preventing the formation of peroxynitrite, useful strategies in preventing disease progression in pathologies in which peroxynitrite toxicity plays a critical role might include maintaining intracellular zinc homeostasis, blocking phosphorylation of ERK42/44, inhibiting activation of 12-lipoxygenase, and eliminating the accumulation of reactive oxygen species. [ABSTRACT FROM AUTHOR]

Oxidative injury to premyelinating oligodendrocytes (preOLs) in developing white matter has been implicated in the pathogenesis of periventricular leukomalacia, the lesion underlying most cases of cerebral palsy in premature infants. In this study, we investigated the pathways of OL death induced by intracellular glutathione (GSH) depletion. We found that the lipoxygenase (LOX) inhibitors AA-861 and BMD-122 (N-benzyl-N-hydroxy-5-phenylpentamide; BHPP), but not the cyclooxygenase (COX) inhibitor indomethacin, fully protected the cells from GSH depletion caused by cystine deprivation. Arachidonic acid (AA), the substrate for 12-LOX, potentiated the toxicity of mild cystine deprivation and at higher concentration was itself toxic. This toxicity was also blocked by 12-LOX inhibitors. Consistent with a role for 12-LOX in the cell death pathway, 12-LOX activity increased following cystine deprivation in OLs. Blocking 12-LOX with AA-861 effectively inhibited the accumulation of reactive oxygen species (ROS) induced by cystine deprivation. These data suggest that, in OLs, intracellular GSH depletion leads to activation of 12-LOX, ROS accumulation and cell death. Mature OLs were more resistant than preOLs to cystine deprivation. The difference in sensitivity was not due to a difference in 12-LOX activity but rather appeared to be related to the presence of stronger antioxidant defense mechanisms in mature OLs. These results suggest that 12-LOX activation plays a key role in oxidative stress-induced OL death. [ABSTRACT FROM AUTHOR]

Abstract Pyrroloquinoline quinone (PQQ) is a redox active essential nutrient that can generate or scavenge superoxide depending on its microenvironment. PQQ has been shown previously to be neuroprotective in a rodent stroke model. Here we test whether PQQ interacts with reactive nitrogen species, known to be involved in the pathogenesis of stroke. Using rat forebrain neurons in culture, we determined that the toxicity of SIN-1 was mediated by peroxynitrite and that PQQ could block this toxic action. However, PQQ could not block the toxicity of peroxynitrite itself. Both SIN-1 and peroxynitrite caused ATP depletion, but only SIN-1 evoked ATP depletion was blocked by PQQ. In a cell-free system, PQQ blocked nitration of bovine serum albumin produced by SIN-1, but potentiated peroxynitrite-induced nitration. PQQ was unable to block ATP depletion and cell death induced by NO· donors (DEA/NO, DPT/NO and DETA/NO), indicating that it does not directly interact with nitric oxide, and suggesting that it acts as a superoxide scavenger. PQQ significantly potentiated cGMP accumulation evoked by SIN-1, similar to the effect of superoxide dismutase (SOD). However, unlike SOD, which potentiated neurotoxicity induced by SIN-1, PQQ blocked its toxicity, arguing against the possibility that PQQ functions simply as a SOD mimetic. Indeed, substantially less H2 O2 was produced by the incubation of SIN-1 with PQQ, when compared to SOD. These results suggest that PQQ scavenges superoxide without forming toxic levels of H2 O2 . Therefore, the protective effect of PQQ on stroke might be due, at least in part, to the suppression of peroxynitrite formation. [ABSTRACT FROM AUTHOR]

Skin injury caused by large doses of ionizing radiation is the common and severe side effect of radiotherapy. However, its therapeutic efficacy is always hindered by early reactive oxygen species generation, repetitive inflammatory microenvironment and bacterial infection risk. Herein, we report an anti-biofouling hydrogel with anti-inflammation and anti-oxidative properties for the treatment of irradiation-induced skin injury. The anti-biofouling hydrogel can be achieved by balancing oppositely charged alginate, hyaluronic acid (HA) and polylysine (PLL) at the optimal ratio, which effectively resist protein and bacterial adhesion, and evades immune response. Moreover, curcumin and epigallocatechin gallate (EGCG) can be facially encapsulated and substantially released from the hydrogel. Results showed that the resulting AHP-Cur/EGCG hydrogel can significantly weaken the development of skin injury and accelerate its healing process by alleviating inflammation, scavenging ROS and promoting angiogenesis. Therefore, the findings presented in this work provide an effective strategy for clinical management and treatment of ionizing radiation-induced skin injury. • Antifouling hydrogel achieved by balancing oppositely charged polyelectrolytes. • Hydrogel can resist protein, bacteria adhesion and induce negligible inflammation. • Hydrogel dressing can rapidly and effectively promote IR-induced injury healing. • Hydrogel dressing is promising for treatment of ionizing radiation-induced injury. [ABSTRACT FROM AUTHOR]

Heterogeneous catalytic ozonation (HCO) has been widely applied for the treatment of wastewater. In order to maintain the structural stability and surface catalytic activity of heterogeneous catalysts during the HCO treatment of electroless nickel plating effluent (ENPE), a MnFe 2 O 4 -C@Al 2 O 3 catalyst with a core-shell structure was synthesized. MnFe 2 O 4 -C@Al 2 O 3 was characterized and applied in the removal of total nickel (T Ni) and organic contaminants from actual ENPE, using a coupled system of HCO combined with a magnetic dithiocarbamate chelating resin (MnFe 2 O 4 -C@Al 2 O 3 /O 3 -MDCR). Results show that embedding Al 2 O 3 with C and MnFe 2 O 4 significantly increased the T Ni removal efficiency (99.3%), enhanced the O 3 -utilization efficiency and improved the generation of reactive oxygen species (ROS). The reaction rate (k = 0.7641 min−1) and O 3 -utilization efficiency established for T Ni removal (ΔT Ni /ΔO 3 =0.221) by the MnFe 2 O 4 -C@Al 2 O 3 /O 3 -MDCR system, were 220% and 140% higher than the Al 2 O 3 /O 3 -MDCR system, respectively. Catalytic mechanism analysis demonstrated that surface hydroxyl groups, oxygen vacancy, metals, the carbon surface and its functional groups, can all potentially serve as catalytic active sites, with 1O 2 and •OH considered to the predominant ROS. Overall, these findings verify that the synthesized MnFe 2 O 4 -C@Al 2 O 3 catalyst possesses excellent catalytic capabilities and outstanding structural stability, making it suitable for practical application in the treatment of wastewater effluent. [Display omitted] • Core-shell MnFe 2 O 4 -C@Al 2 O 3 was synthesized with superior mechanical stability. • MnFe 2 O 4 -C@Al 2 O 3 showed excellent catalytic performance and brilliant O 3 -utilization. • Abundant catalytic active sites were beneficial to the generation of various ROS. • High removal on T Ni , COD and TOC of ENPE by MnFe 2 O 4 -C@Al 2 O 3 /O 3 -MDCR system. • Novel FPE was constructed and firstly applied to assess the toxicity of ENPE. [ABSTRACT FROM AUTHOR]

Abstract: Cannabinoids have been consistently shown to suppress microglia activation and the release of cytotoxic factors including nitric oxide, superoxide and proinflammatory cytokines. However, the underlying molecular mechanisms and whether the action of cannabinoids is coupled to the activation of cannabinoid type 1 (CB1) and type 2 (CB2) receptors are still poorly defined. In this study we observed that the CB1 and CB2 receptor non-selective or selective agonists dramatically attenuate iNOS induction and ROS generation in LPS-activated microglia. These effects are due to their reduction of phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), cytosolic phospholipase A2 (cPLA2) and activation of NF-κB. Surprisingly, instead of reversing the effect of the respective CB1 and CB2 receptor agonists, the antagonists also suppress iNOS induction and ROS generation in activated microglia by similar mechanisms. Taken together, these results indicate that both cannabinoid receptor agonists and antagonists might suppress microglia activation by CB1 and CB2 receptor independent mechanisms, and provide a new insight into the mechanisms of microglia inhibition by cannabinoids. [Copyright &y& Elsevier]

Abstract: Peroxynitrite has been suggested to be the potent oxidant causing toxicity to neurons and oligodendrocytes (OLs). Our previous studies have illustrated that intracellular zinc liberation contributes to peroxynitrite toxicity to mature OLs. In this study, we further investigated the signaling pathways involved in this event and identified protein kinase C (PKC) as an important early signaling molecule. We found that a non-selective PKC inhibitor bisindolylmaleimide-1 blocked OL toxicity induced by a peroxynitrite generator SIN-1 and exogenous zinc. The protective effects were due to its inhibition on ERK1/2 phosphorylation and ROS generation. The same phenomenon was also observed in OLs following prolonged treatment with phorbol 12 myristate 13 acetate (PMA), which downregulates the conventional and the novel PKC isoforms (cPKCs and nPKCs). To determine the role of specific PKC isoforms, we found that a specific nPKC inhibitor rottlerin significantly reduced SIN-1- or zinc-induced toxicity, whereas Go6976, a cPKC inhibitor, reduced OL toxicity triggered by zinc, but not by SIN-1 at high concentrations. Rottlerin was more potent than Go6976 to attenuate ERK1/2 phosphorylation and ROS generation induced by SIN-1 or zinc. Surprisingly, zinc only induced phosphorylation of PKCθ, but not PKCδ. Knockdown of PKCθ using lentiviral shRNA attenuated SIN-1- or zinc-induced toxicity. These results suggest that PKCθ might be the major PKC isoform involved in peroxynitrite and zinc toxicity to mature OLs, and provide a rationale for development of specific inhibitors of PKCθ in the treatment of multiple sclerosis and other neurodegenerative diseases, in which peroxynitrite formation plays a pathogenic role. [Copyright &y& Elsevier]