Toll-like receptor 4 signaling pathway in sensory neurons mediates remifentanil-induced postoperative hyperalgesia via transient receptor potential ankyrin 1.

Background: Remifentanil-induced postoperative hyperalgesia (RIH) refers to a state of hyperalgesia or aggravated pre-existing pain after remifentanil exposure. There has been considerable interest in understanding and preventing RIH. However, the mechanisms responsible for RIH are still not completely understood. Toll-like receptor 4 (TLR4), a classic innate immune receptor, has been detected in sensory neurons and participates in various nociceptive conditions, whereas its role in RIH remains unclear. Transient receptor potential ankyrin 1 (TRPA1) always serves as a nociceptive channel, whereas its role in RIH has not yet been investigated. This study aimed to determine whether the TLR4 signaling pathway in sensory neurons engaged in the development of RIH and the possible involvement of TRPA1 during this process. Methods: A rat model of remifentanil-induced postoperative hyperalgesia (RIH) was established, which presented decreased paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). The mRNA and protein expression levels of TLR4, phosphorylated NF-κB, and TRPA1 in the dorsal root ganglion (DRG) from RIH model were analyzed by real-time PCR, western blot, and immunofluorescence. The TLR4 antagonist TAK-242 and the TRPA1 antagonist HC-030031 were applied to determine the role of sensory neuron TLR4 signaling and TRPA1 in RIH. Results: Compared with control, PWMT and PWTL were significantly decreased in RIH model. Moreover, the mRNA and protein expression of TLR4 and TRPA1 in DRG were upregulated after remifentanil exposure together with increased NF-κB phosphorylation. TLR4 antagonist TAK-242 mitigated mechanical pain in RIH together with downregulated expression of TLR4, phosphorylated NF-κB, and TRPA1 in DRG neurons. In addition, TRPA1 antagonist HC-030031 also alleviated mechanical pain and decreased TRPA1 expression in RIH without affecting TLR4 signaling in DRG. Conclusions: Taken together, these results suggested that activation of TLR4 signaling pathway engaged in the development of RIH by regulating TRPA1 in DRG neurons. Blocking TLR4 and TRPA1 might serve as a promising therapeutic strategy for RIH.

Epidemiology of suspected life-threatening perioperative anaphylaxis: a cross-sectional multicentre study in China.

BACKGROUND: Perioperative anaphylaxis is relatively rare but can be life-threatening. The incidence in China is unknown and may differ from other global geographic regions. This study was therefore designed to understand the incidence of perioperative anaphylaxis in China. METHODS: We enrolled 112 tertiary care hospitals from seven distinct geographic areas in mainland China. We collected information about Ring and Messmer III and IV reactions from September 2018 to August 2019. A collaborative educational learning network was used to reduce diagnostic errors. Information about patient characteristics, clinical features, treatment, and clinical outcomes were recorded and analysed. RESULTS: A total of 447 cases of 5 078 118 surgical procedures met inclusion criteria. The incidence of suspected perioperative anaphylaxis throughout China was one in 11 360 anaesthetics (95% confidence interval [CI], with a range of 1:12 521 to 1:10 397). The incidence in South China was higher (one in 6050; 95% CI, from 1:8013 to 1:4859) than in Northeast China (one in 19 262; 95% CI, from 1:33 088 to 1:13 585) (P<0.01) with an increasing trend from the north to the south. The most common clinical manifestations were hypotension (91.1%) and tachycardia (65.3%). The majority of patients (83.4%) were given epinephrine. A total of 27 patients (6.0%) required cardiopulmonary resuscitation. Ultimately, nine patients died (2.0%). CONCLUSIONS: This nationwide survey showed an incidence of perioperative anaphylaxis of one in 11 360, but this varied significantly by region. The underlying reason for this pattern remains unknown and could be attributable to environmental or genetic influences, which requires further investigation. CLINICAL REGISTRY NUMBER: ChiCTR1900025956.

A monomer purified from Paris polyphylla (PP-22) triggers S and G2/M phase arrest and apoptosis in human tongue squamous cell carcinoma SCC-15 by activating the p38/cdc25/cdc2 and caspase 8/caspase 3 pathways.

Recent studies have shown that the aqueous, ethanolic extracts and a monomer compound of Paris polyphylla exhibit anticancer activity toward several types of cancer cell lines, but the anticancer activity of (3ß,17α,25R)-spirost-5-ene-3,17-diol 3-O-α-L-rhamnopyranosyl-(1 â†’ 2)-ß-D-glucopyranoside, a monomer isolated from P. polyphylla (PP), named PP-22, has not been reported previously. In this study, we investigated the effect of PP-22 on human tongue squamous cell carcinoma SCC-15 cells in vitro. MTT assays showed that PP-22 inhibited the growth of SCC-15 cells and had no obvious inhibitory effects on human liver L02 cells. Flow cytometry assays showed that the percentages of apoptotic cells were increased. In addition, cleaved caspase-8, cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) could be detected by Western blotting. Flow cytometry also showed that PP-22 triggered S and G2/M phases arrest in SCC-15 cells, and on the other hand, the expression of cyclin A, cyclin E2, cyclin B1, phospho-cell division cycle2 (p-cdc2)(Tyr15), p-Wee1, Myt1, and p53 was upregulated. Moreover, p-p38 levels increased, p-extracellular signal-regulated kinase (ERK) levels decreased, and cdc25B expression was inhibited. Furthermore, the p38/mitogen-activated protein kinase (MAPK) inhibitor SB203580 reversed the increase of the expression level of p38, p-cdc2 (Tyr15), cleaved caspase 3, cleaved PARP, p-p53, and p53 and reversed the decrease in cdc25B expression. In conclusion, these results demonstrated that PP-22 activated p38, inhibited cdc25B, increased p-cdc2 (Tyr15), and triggered S and G2/M phase arrest, as well as activated p53 through the p38-p53 pathway, inhibited the MAPK/ERK pathway, activated the caspase 8/caspase 3 pathway, and triggered the extrinsic apoptotic pathway in SCC-15 cells.

Bioinformatics analysis revealed underlying molecular mechanisms associated with asthma severity and identified GABAergic related pathway as a potential therapy for Th2-high endotype asthma.

Background: Asthma, a principally T helper 2 (Th2) cell mediated immunological disease, is categorized into Th2-high and Th2-low endotypes. The influence of these endotypes on clinical characteristics and treatment responsiveness in asthma is yet to be completely understood. This study delves into the underlying molecular mechanisms of Th2 endotypes on asthma. Methods: Transcriptomics data of airway epithelial and corresponding clinical information were sourced from the GEO. The co-expression modules were established by WGCNA. Cytoscape was applied to construct PPI networks, and hub genes were determined via the Cytohubba plugin. Additionally, a functional enrichment analysis was conducted on the co-expressed genes from the relevant modules. The relative abundances levels of 22 different types of immune cells in asthma patients were evaluated by CIBERSORT algorithm. Results: There were 471 genes in the pink module significantly correlated with Th2 endotype. Overall, 151 DEGs were identified in the various Th2 endotypes, and 66 were obtained through intersection with the pink module. In the PPI network, the ten most important genes that regulate Th2 endotypes were selected as hub genes. In Th2-high endotype asthma, the hub genes were significantly related to γ-aminobutyric acid (GABA) pathways, indicating that hub genes can mainly regulate Th2-high endotype asthma through GABAergic system. Conclusions: The severity of asthma is influenced by different Th2 endotypes. GABAergic related hub genes may provide innovative insights for the treatment of Th2-high asthma.

Electroacupuncture-induced activation of GABAergic system alleviates airway inflammation in asthma model by suppressing TLR4/MyD88/NF-κB signaling pathway.

BACKGROUND: Electroacupuncture (EA) has been shown to attenuate airway inflammation in asthmatic mice; however, the underlying mechanism is not fully understood. Studies have shown that EA can significantly increase the inhibitory neurotransmitter γ-aminobutyric acid (GABA) content in mice, and can also increase the expression level of GABA type A receptor (GABAAR). Furthermore, activating GABAAR may relieve inflammation in asthma by suppressing toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) signaling pathway. Therefore, this study aimed to investigate the role of GABAergic system and TLR4/MyD88/NF-κB signaling pathway in asthmatic mice treated with EA. METHODS: A mouse model of asthma was established, and a series of methods including Western blot and histological staining assessment were employed to detect the level of GABA, and expressions of GABAAR and TLR4/MyD88/NF-κB in lung tissue. In addition, GABAAR antagonist was used to further validate the role and mechanism of GABAergic system in mediating the therapeutic effect of EA in asthma. RESULTS: The mouse model of asthma was established successfully, and EA was verified to alleviate airway inflammation in asthmatic mice. The release of GABA and the expression of GABAAR were significantly increased in asthmatic mice treated with EA compared with untreated asthmatic mice ( P  < 0.01), and the TLR4/MyD88/NF-κB signaling pathway was down-regulated. Moreover, inhibition of GABAAR attenuated the beneficial effects of EA in asthma, including the regulation of airway resistance and inflammation, as well as the inhibitory effects on TLR4/MyD88/NF-κB signaling pathway. CONCLUSION: Our findings suggest that GABAergic system may be involved in mediating the therapeutic effect of EA in asthma, possibly by suppressing the TLR4/MyD88/NF-κB signaling pathway.

Clinical characteristics and allergen detection of perioperative anaphylaxis: a 12-year retrospective analysis from an anesthesia clinic in China.

BACKGROUND: Anaphylaxis during anesthesia is a rare but often a potentially life-threatening event for patients. Identifying culprit agents responsible for anaphylaxis is of great important for avoiding potential re-exposure to allergens, but it poses great challenge for anesthetists. This retrospective study aimed to analyze the culprits of patients with a history of perioperative anaphylaxis referred to an anesthesia allergy clinic in China, and to evaluate the role of allergy diagnostic tests in clinical practice. METHODS: A total of 145 patients (102 female/43 male) who attended the Anesthesia Allergy Clinic for allergen detection between 1 January 2009 and 31 December 2020 were reviewed retrospectively. Clinical characteristics, results of allergy diagnostic tests including skin, and/or basophil activation tests, and the incidence of repeat anaphylaxis after use of recommended alternative anesthetics were obtained. RESULTS: Of these 145 patients, 109 patients (75.2%, 74 females/35 males) were determined to experience perioperative anaphylaxis. The most common presenting clinical feature was cardiovascular manifestations (n = 63, 57.8%). According to diagnostic work up, the most common causative agents for perioperative anaphylaxis were neuromuscular blocking agents (n = 35, 32.1%). After diagnostic work up, 52 patients underwent repeat anesthesia. None of these patients experienced recurrent anaphylaxis. CONCLUSIONS: This study suggests that neuromuscular blocking agents are the main cause of perioperative anaphylaxis. For patients with perioperative anaphylaxis, allergy diagnostic tests are essential to identify causative agents, and to find suitable alternative drugs for the future planning of subsequent anesthetics.

Effects of colloid preload on the incidence of hypotension in spinal anesthesia for cesarean section: a systematic review and meta-analysis.

BACKGROUND: Hypotension is a common complication caused by spinal anesthesia (SA), which may have adverse impacts on the condition of the parturient and fetus. Liquid infusion was found to be relatively effective for reducing the incidence of hypotension. However, the question of whether colloid preload can optimize hemodynamic variables in the cesarean section remains controversial. This study aims to determine the effects of colloid preload on the incidence of hypotension induced by SA in elective cesarean section. METHODS: Related keywords were searched on PubMed, EMBASE, and Cochrane Library from inception dates to May 2020. Studies included were evaluated for eligibility and quality. The primary outcome was the intra-operative incidence of hypotension and severe hypotension. The secondary outcomes included the lowest intra-operative systolic blood pressure, the maximal intra-operative heart rate, the intra-operative needs of ephedrine and phenylephrine, the incidence of maternal nausea and/or vomiting, and neonatal outcomes (umbilical artery pH and Apgar scores). Apart from the above, RevMan 5.3 was used for the data analysis. RESULTS: Altogether nine randomized controlled trials were included in the meta-analysis. There were no significant differences in the incidence of intra-operative hypotension, severe hypotension, or neonatal outcomes between the colloid preload group and control group, except for the umbilical artery pH. CONCLUSION: This meta-analysis suggests that colloid preload does not significantly reduce the incidence of hypotension associated with SA in elective cesarean section.

Risk of True Allergy to Local Anesthetics: 10-Year Experience from an Anesthesia Allergy Clinic in China.

BACKGROUND: Local anesthetics (LAs) have been widely used throughout the healthcare settings, especially in local anesthesia and pain management. The incidence of allergic reactions to LAs remains uncertain. The danger of allergic reactions to the use of LAs in every day of clinical practice is a matter of great concern. Therefore, it is necessary to investigate the risk of true allergy to LAs. METHODS: This study retrospectively evaluated the medical records of patients who were referred to an anesthesia allergy clinic in China and underwent allergy tests with LAs over a 10-year period from 2009 to 2019. The following information was collected from medical records: demographics of the patients, reasons for referral, clinical features of drug hypersensitivity reaction (DHR), and test results with LAs. Skin tests combined with an in vitro method, basophil activation test (BAT), were used to investigate allergic reactions to LAs. RESULTS: A group of 109 patients were included in the analysis. The main reason for referral was the presence of a suspected DHR after procedures with LAs (n=68, 62%), the second most common reason for referral was a history of DHR to other drugs and the need to use LAs for upcoming procedures (n=41, 38%). Of the 68 patients with a suspected DHR to LAs, only six cases presented true allergy and showed positive results in skin tests and/or BAT. And all 41 patients who had a history of DHR to other drugs presented negative in all tests. CONCLUSION: Risk of true allergy to LAs may be very low. However, patients with a suspected history of DHR to LAs should be considered for allergy tests. Skin tests and BAT may be useful in the investigation and diagnosis of true allergy to LAs in clinical practice.