Emodin inhibits HDAC6 mediated NLRP3 signaling and relieves chronic inflammatory pain in mice.

Chronic pain reduces the quality of life and ability to function of individuals suffering from it, making it a common public health problem. Neuroinflammation which is mediated by the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in the spinal cord participates and modulates chronic pain. A chronic inflammatory pain mouse model was created in the current study by intraplantar injection of complete Freund's adjuvant (CFA) into C57BL/6J left foot of mice. Following CFA injection, the mice had enhanced pain sensitivities, decreased motor function, increased spinal inflammation and activated spinal astrocytes. Emodin (10 mg/kg) was administered intraperitoneally into the mice for 3 days. As a result, there were fewer spontaneous flinches, higher mechanical threshold values and greater latency to fall. Additionally, in the spinal cord, emodin administration reduced leukocyte infiltration level, downregulated protein level of IL-1ß, lowered histone deacetylase (HDAC)6 and NLRP3 inflammasome activity and suppressed astrocytic activation. Emodin also binds to HDAC6 via four electrovalent bonds. In summary, emodin treatment blocked the HDAC6/NLRP3 inflammasome signaling, suppresses spinal inflammation and alleviates chronic inflammatory pain.

GSK-3ß inhibition alleviates arthritis pain via reducing spinal mitochondrial reactive oxygen species level and inflammation.

Pain is the main symptom of osteoarthritis, which severely reduces the patients' quality of life. Stimulated neuroinflammation and elevated mitochondrial oxidative stress are associated arthritis pain. In the present study, arthritis model was established by intra-articular injection of complete Freund's adjuvant (CFA) on mice. Knee swelling, pain hypersensitivity and motor disability were observed in CFA-induced mice. In spinal cord, neuroinflammation was triggered and presented as severe infiltration of inflammatory cells and up-regulated expressions of glial fibrillary acidic protein (GFAP), nuclear factor-kappaB (NF-κB), PYD domains-containing protein 3 (NLRP3), cysteinyl aspartate specific proteinase (caspase-1) and interleukin-1 beta (IL-1ß). Mitochondrial function was disrupted and characterized as elevated expressions of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), dihydroorotate dehydrogenase (DHODH) and cytochrome C (Cyto C), and reduced expressions of Bcl-2 and Mn-superoxide dismutase (Mn-SOD) activity. Meanwhile, as a potential target for pain management, glycogen synthase kinase-3 beta (GSK-3ß) activity was up-regulated in CFA induced mice. To explore potential therapeutic options for arthritis pain, GSK-3ß inhibitor TDZD-8 was intraperitoneally injected for three days on CFA mice. Animal behavioral tests found that TDZD-8 treatment elevated mechanical pain sensitivity, suppressed spontaneous pain and recovered motor coordination. Morphological and protein expression analysis indicated that TDZD-8 treatment decreased spinal inflammation score and inflammatory related protein levels, recovered mitochondrial related protein levels, and increased Mn-SOD activity. In summary, TDZD-8 treatment inhibits GSK-3ß activity, reduces mitochondrial mediated oxidative stress, suppresses spinal inflammasome response, and alleviates arthritis pain.

Ultrasound-guided paravertebral nerve block anesthesia on the stress response and hemodynamics among lung cancer patients.

BACKGROUND: Thoracic surgery for radical resection of lung tumor requires deep anesthesia which can lead to an adverse inflammatory response, loss of hemodynamic stability, and decreased immune function. Herein, we evaluated the feasibility and benefits of ultrasound-guided paravertebral nerve block anesthesia, in combination with general anesthesia, for thoracic surgery for lung cancer. The block was performed by diffusion of anesthetic drugs along the paravertebral space to achieve unilateral multi-segment intercostal nerve and dorsal branch nerve block. AIM: To evaluate the application of ultrasound-guided paravertebral nerve block anesthesia for lung cancer surgery to inform practice. METHODS: The analysis was based on 140 patients who underwent thoracic surgery for lung cancer at our hospital between January 2018 and May 2020. Patients were randomly allocated to the peripheral + general anesthesia (observation) group (n = 74) or to the general anesthesia (control) group (n = 66). Patients in the observation group received ultrasound-guided paravertebral nerve block anesthesia combined with general anesthesia, with those in the control group receiving an epidural block combined with general anesthesia. Measured outcomes included the operative and anesthesia times, as well as the mean arterial pressure (MAP), heart rate (HR), and blood oxygen saturation (SpO2) measured before surgery, 15 min after anesthesia (T1), after intubation, 5 min after skin incision, and before extubation (T4). RESULTS: The dose of intra-operative use of remifentanil and propofol and the postoperative use of sufentanil was lower in the observation group (1.48 ± 0.43 mg, 760.50 ± 92.28 mg, and 72.50 ± 16.62 mg, respectively) than control group (P < 0.05). At the four time points of measurement (T1 through T4), MAP and HR values were higher in the observation than control group (MAP, 90.20 ± 9.15 mmHg, 85.50 ± 7.22 mmHg, 88.59 ± 8.15 mmHg, and 90.02 ± 10.02 mmHg, respectively; and HR, 72.39 ± 8.22 beats/min, 69.03 ± 9.03 beats/min, 70.12 ± 8.11 beats/min, and 71.24 ± 9.01 beats/min, respectively; P < 0.05). There was no difference in SpO2 between the two groups (P > 0.05). Postoperative levels of epinephrine, norepinephrine, and dopamine used were significantly lower in the observation than control group (210.20 ± 40.41 pg/mL, 230.30 ± 65.58 pg/mL, and 54.49 ± 13.32 pg/mL, respectively; P < 0.05). Similarly, the postoperative tumor necrosis factor-α and interleukin-6 levels were lower in the observation (2.43 ± 0.44 pg/mL and 170.03 ± 35.54 pg/mL, respectively) than control group (P < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P > 0.05). CONCLUSION: Ultrasound-guided paravertebral nerve block anesthesia improved the stress and hemodynamic response in patients undergoing thoracic surgery for lung cancer, with no increase in the rate of adverse events.