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BackgroundNeuropathic pain (NPP) is a multifaceted pain syndrome that occurs as a consequence of physical injury or underlying diseases, with an incidence rate of 7%-10%, NPP poses a significant clinical challenge as current treatment options are ineffective. The accumulation of apoptotic cells and neuroinflammation play crucial roles in the pathological mechanisms of NPP. Here, we aim to investigate strategies for effectively clearing apoptotic cells and provide therapeutic interventions for NPP.MethodsCCI mice were treated with different concentrations of ozone (15μg, 30μg, 45μg) to investigate the effects on the accumulation of apoptotic cells and neuroinflammation. In vitro, the phagocytic function of BMDM towards apoptotic neutrophils after ozone treatment was examined.ResultsWe found ozone at a concentration of 30μg significantly alleviated mechanical hypersensitivity in CCI mice and ozone significantly upregulates the phagocytic activity of BMDM. Furthermore, we investigated the mechanisms and found ozone could activate AMPK, upregulate Gas6 (but not Protein S), activate MerTK (a key receptor involved in apoptosis), and enhance the phagocytic function of BMDM towards apoptotic neutrophils. It caused the promotion of SOCS3 expression and the suppression of inflammatory factors IL-1β, IL-6, and TNF-a. Interestingly, the effect of ozone in alleviating CCI-induced pain was abolished by the AMPK inhibitor CC and the MerTK receptor inhibitor UNC2541.ConclusionOzone facilitated macrophage clearance of apoptotic cells, decreased neuroinflammation by activation of p-AMPK/Gas6/MerTK/SOCS3 signaling pathway, which may become an effective therapeutic approach for neuropathic pain after further clinical validation.

Abstract Background Postoperative pain is a serious clinical problem with a poorly understood mechanism, and lacks effective treatment. Hydrogen (H2) can reduce neuroinflammation; therefore, we hypothesize that H2 may alleviate postoperative pain, and aimed to investigate the underlying mechanism. Methods Mice were used to establish a postoperative pain model using plantar incision surgery. Mechanical allodynia was measured using the von Frey test. Cell signaling was assayed using gelatin zymography, western blotting, immunohistochemistry, and immunofluorescence staining. Animals or BV-2 cells were received with/without ASK1 and Trx1 inhibitors to investigate the effects of H2 on microglia. Results Plantar incision surgery increased MMP-9 activity and ASK1 phosphorylation in the spinal cord of mice. MMP-9 knockout and the ASK1 inhibitor, NQDI-1, attenuated postoperative pain. H2 increased the expression of Trx1 in the spinal cord and in BV-2 cells. H2 treatment mimicked NQDI1 in decreasing the phosphorylation of ASK1, p38 and JNK. It also reduced MMP-9 activity, downregulated pro-IL-1β maturation and IBA-1 expression in the spinal cord of mice, and ameliorated postoperative pain. The protective effects of H2 were abolished by the Trx1 inhibitor, PX12. In vitro, in BV-2 cells, H2 also mimicked NQDI1 in inhibiting the phosphorylation of ASK1, p38, and JNK, and also reduced MMP-9 activity and decreased IBA-1 expression induced by LPS. The Trx1 inhibitor, PX12, abolished the protective effects of H2 in BV-2 cells. Conclusions For the first time, the results of our study confirm that H2 can be used as a therapeutic agent to alleviate postoperative pain through the Trx1/ASK1/MMP9 signaling pathway. MMP-9 and ASK1 may be the target molecules for relieving postoperative pain.

Abstract Background Emergence agitation after general anesthesia may cause several undesirable events in the clinic during patient anesthesia recovery, and acute alcohol intoxication, while rare in surgery, is one of the risk factors. Case presentation A 66-year-old male patient was found to have pancreatic tail neoplasm upon computed tomography (CT) examination. The surgeon planned to resect the pancreatic tail under general anesthesia. However, the surgeon found extensive tumor metastasis in the abdominal cavity, and thus performed a neurolytic celiac plexus block (NCPB) with 40 ml 95% ethyl alcohol and finished the surgery in approximately 1 h. Twenty minutes later, the patient was extubated and developed significant emergence agitation in the postoperative care unit, characterized by restlessness, uncontrollable movements, confusion and disorientation. The patient was flushed and febrile with an alcohol smell in his breath and was unable to follow commands. Patient symptoms were suspected to be due to acute alcohol intoxication. Thus, the patient was given 40 mg of propofol intravenously. Following treatment, the patient recovered with less confusion and disorientation after approximately 10 min. After treatment with propofol twice more, he regained consciousness, was calm and cooperative, had no pain, and could obey instructions approximately 1 h and 40 min following the last treatment. Following this treatment, the patient was transferred to the inpatient ward and felt well. Conclusions It is paramount to correctly identify the underlying cause of emergence agitation in order to successfully manage patient symptoms, since treatment plans vary between different etiological causes. Emergence agitation may be due to acute alcohol intoxication after intraoperative use of alcohol.

Context: Since December 2019, more than 80,000 patients have been diagnosed with coronavirus disease 2019 (COVID-19) in China. Social support status of COVID-19 patients, especially the impact of social support on their psychological status and quality of life, needs to be addressed with increasing concern.Objectives: In this study, we used social support rating scale (SSRS) to investigate the social support in COVID-19 patients and nurses.Methods: The present study included 186 COVID-19 patients at a Wuhan mobile cabin hospital and 234 nurses at a Wuhan COVID-19 control center. Responses to a mobile phone app-based questionnaire about social support, anxiety, depression, and quality of life were recorded and evaluated.Results: COVID-19 patients scored significantly lower than nurses did on the Social Support Rating Scale (SSRS). Among these patients, 33.9% had anxiety symptoms, while 23.7% had depression symptoms. Overall SSRS, subjective social support scores and objective support scores of patients with anxiety were lower than those of patients without anxiety. This result was also found in depression. In addition, all dimensions of social support were positively correlated with quality of life. Interestingly, in all dimensions of social support, subjective support was found to be an independent predictive factor for anxiety, depression, and quality of life, whereas objective support was a predictive factor for quality of life, but not for anxiety and depression via regression analysis.Conclusion: Medical staffs should pay attention to the subjective feelings of patients and make COVID-19 patients feel respected, supported, and understood from the perspective of subjective support, which may greatly benefit patients, alleviate their anxiety and depression, and improve their quality of life.

Abstract Background Management of neuropathic pain is a real clinical challenge. Despite intense investigation, the mechanisms of neuropathic pain remain substantially unidentified. Matrix metalloproteinase (MMP)-9 and MMP-2 have been reported to contribute to the development and maintenance of neuropathic pain. Therefore, inhibition of MMP-9/2 may provide a novel therapeutic approach for the treatment of neuropathic pain. In this study, we aim to investigate the effect of procyanidins (PC), clinically used health product, on MMP-9/2 in neuropathic pain. Methods The nociception was assessed by measuring the incidence of foot withdrawal in response to mechanical indentation in mice. Cell signaling was assayed using gelatin zymography, western blotting, and immunohistochemistry. The BV2 cells were cultured to investigate the effects of PC on microglia. Results Both in vitro and in vivo administration of PC significantly suppresses the activity of MMP-9/2. Oral administration of PC relieves neuropathic pain behaviors induced by chronic constriction sciatic nerve injury (CCI) in mice. Additionally, PC blocks the maturation of interleukin-1β, which is a critical substrate of MMPs, and markedly suppresses CCI-induced MAPK phosphorylation and neuronal and microglia activation, including the reduced phosphorylation of protein kinase C γ and NMDAR1. Furthermore, PC decreases the phosphorylation of p38 mitogen-activated protein kinase and inhibits the translocation of nuclear factor-κB (NF-κB) in microglia. Conclusions PC is an effective and safe approach to alleviate neuropathic pain via a powerful inhibition on the activation of MMP-9/2.

Background: Tolerance seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine. Methods: The microglial cell line BV-2 cells and mouse brain-derived endothelial cell line bEnd3 cells were used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signaling was assayed by western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using tail-flick tests. Results: We found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin. Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore, systemic administration of metformin significantly blocked morphine-induced microglial activation in the spinal cord and then attenuated the development of chronic morphine tolerance in mice. Conclusions: Metformin significantly attenuated morphine antinociceptive tolerance by suppressing morphine-induced microglial activation through increasing AMPK phosphorylation. [ABSTRACT FROM AUTHOR]