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Background Surgeon and anesthetist share the airway in a simpler way in the resection and reconstruction phase of tracheal surgery in tubeless spontaneous-ventilation video-assisted thoracoscopic surgery (SV-VATS). Tubeless SV-VATS means stable spontaneous ventilation in the resection and reconstruction phase to anesthesiologist, and unobstructed surgical field to surgeon. What’s the ideal airway management strategy during “Visual Field tubeless” SV-VATS for tracheal surgery is still an open question in the field. Methods We retrospectively reviewed 33 patients without sleeve and carina resections during the study period (2018–2020) in our hospital. The initial management strategy for these patients was spontaneous ventilation for intrathoracic tracheal resection and reconstruction. We obtained and reviewed medical records from our institution’s clinical medical records system to evaluate the airway management strategy and device failure rate for tracheal resection in Tubeless SV-VATS. Results Between 2018 and 2020, SV-VATS was first attempted in the 33 patients who had intrathoracic tracheal surgery but without sleeve and carina resections. All patients underwent bronchoscopy (33/33) and 8 patients (8/33) received partial resection before surgery. During the surgery, the airway device comprised either a ProSeal laryngeal mask airway (ProSeal LMA) (n = 27) or single lumen endotracheal tube (n = 6). During the resection and reconstruction phase, Visual Field tubeless SV-VATS failed in 9 patients, and breathing support switched to plan B which is traditional ventilation of a single lumen endotracheal tube for cross field intubation (n = 4) and ProSeal LMA alongside a high-frequency catheter (high-frequency jet ventilation, HFJV) (n = 5) into the distal trachea ventilation. Preoperative respiratory failure or other ventilation-related complications were not observed in this cohort. Conclusion Base on current analysis either ProSeal LMA or endotracheal tube is an effective airway management strategy for tubeless SV-VATS with appropriate patient selection. It also provides breathing support conversion option when there’s inadequate ventilation.

Microglial activation-induced neuroinflammation is critical in the pathogenesis of neurodegenerative diseases. Activated microglia are regulated mainly by innate pattern recognition receptors (PRRs) on their surface, of which macrophage receptor with collagenous structure (Marco) is a well-characterized scavenger receptor constitutively expressed on specific subsets of macrophages, including microglia. Increasing evidence has shown that Marco is involved in the pathogenesis of a range of inflammatory processes. However, research on the role of Marco in regulating neuroinflammation has reported conflicting results. In the present study, we examined the role Marco played in triggering neuroinflammation and its underlying mechanisms. The results demonstrated that silencing the Marco gene resulted in a significantly reduced neuroinflammatory response and vice versa. α-Syn stimulation in Marco overexpressing cells induced a pronounced inflammatory response, suggesting that Marco alone could trigger an inflammatory response. We also found that TLR2 significantly promoted Marco-mediated neuroinflammation, indicating TLR2 was an important co-receptor of Marco. Knocking down the TLR2 gene in microglia and mouse substantia nigra resulted in decreased expression of Marco. Subsequent mechanistic studies showed that deleting the SRCR domain of Marco resulted in disruption of the inflammatory response and the interaction between TLR2 and Marco. This suggested that TLR2 binds directly to the SRCR domain of Marco and regulates Marco-mediated neuroinflammation. In summary, this investigation revealed that TLR2 could potentiate Marco-mediated neuroinflammation by interacting with the SRCR domain of Marco, providing a new target for inhibiting neuroinflammation in neurodegenerative diseases.

Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are co-located at blood–brain barrier (BBB) cells, preventing their substrates from entering brain. Accumulating evidence demonstrates that liver failure impairs P-gp and BCRP expression and function in the brain. In the current study, we investigated how liver failure influenced the expression and function of brain BCRP and P-gp in rats subjected to bile duct ligation (BDL). The function of BCRP, P-gp and BBB integrity was assessed using distribution of prazosin, rhodamine 123 and fluorescein, respectively. We showed that BDL significantly decreased BCRP function, but increased P-gp function without affecting BBB integrity. Furthermore, we found that BDL significantly downregulated the expression of membrane BCRP and upregulated the expression of membrane P-gp protein in the cortex and hippocampus. In human cerebral microvascular endothelial cells, NH(4)Cl plus unconjugated bilirubin significantly decreased BCRP function and expression of membrane BCRP protein, but upregulated P-gp function and expression of membrane P-gp protein. The decreased expression of membrane BCRP protein was linked to the decreased expression of membrane radixin protein, while the increased expression of membrane P-gp protein was related to the increased location of membrane ezrin protein. Silencing ezrin impaired membrane location of P-gp, whereas silencing radixin impaired membrane location of BCRP protein. BDL rats showed the increased expression of membrane ezrin protein and decreased expression of membrane radixin protein in the brain. We conclude that BDL causes opposite effects on the expression and function of brain BCRP and P-gp, attributing to the altered expression of membrane radixin and ezrin protein, respectively, due to hyperbilirubinemia and hyperammonemia.

Breast cancer resistance protein (BCRP) is one of ATP-binding cassette (ABC) transporters in brain microvessel endothelial cells that transport their substrates from brain to blood, thus limiting substrates to crossing into brain through blood–brain barrier. Our previous works show that bile duct ligation (BDL) impairs expression and function of brain BCRP in rats. Since zidovudine (AZT) is BCRP substrate, we investigated whether impaired expression and function of BCRP increased brain distribution and toxicity of AZT in BDL-D7 rats. After administration of AZT (10 mg/kg, i.v.), BDL markedly increased brain AZT concentrations, compared with sham-operated (SO) rats. The ratio of AZT brain-to-plasma area under concentration curve (AUC) in BDL rats was increased to 1.6-folds of SO rats. After treatment with AZT (100 mg/kg every day, i.v.) for 7 days, BDL significantly impaired cognitive functions compared with SO rats, evidenced by the significantly decreased percentage of alternation in Y-maze test and prolonged escaped latency in two-way passive avoidance trial. Furthermore, AZT treatment caused significant decrease in copies of mitochondrial DNA and mitochondrial membrane potential in hippocampus of BDL rats. Moreover, AZT treatment caused a significant decrease of cortex microtubule-associated protein 2 and hippocampus synaptophysin levels in BDL rats. AZT-induced CNS adverse alterations in BDL rats were not observed in SO rats treated with AZT. In conclusion, BDL decreases the function and expression of brain BCRP in rats, leading to increased brain distribution of AZT, which in turn enhances AZT CNS toxicity, leading to mitochondrial dysfunction, neuronal damage, and ultimately cognitive dysfunction.

Neuroinflammation has been implicated as an important factor in the neurodegenerative diseases, and multiple candidates with anti-inflammatory effects have been shown to be beneficial for the treatment of neurodegenerative diseases. Our previous study demonstrated that a novel synthetic phloroglucinol derivative from Lysidice rhodostegia roots (code name: Compound 21) exerted neuroprotective effect through suppressing neuroinflammation. The aim of this study was to reveal the underlying molecular mechanism. The results indicated that the anti-inflammatory effects of Compound 21 were mediated through suppression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the production of reactive oxygen species (ROS). Further study showed that this suppression on NADPH oxidase was mediated by inhibiting the translocation and activity of its subunit Rac1. It is well established that Rac1 activation is regulated by a variety of guanine nucleotide exchange factors (GEFs), so we tried to find out whether GEFs were involved in the anti-inflammatory effects of Compound 21. The results showed that Compound 21 treatment down-regulated the expression and activity of GEF Kalirin, thus modulating the activity of Rac1 GTPase. Altogether, our data suggested that Compound 21 exerted the anti-neuroinflammatory effect through suppressing Kalirin signaling pathways, decreasing Rac1-NADPH oxidase activation and the subsequent pro-inflammatory cytokine production. The present study provided solid evidence to support Compound 21 as a potential candidate of neuroinflammatory inhibitor. Moreover, our findings have shed new light on the role of Rac1 and GEF Kalirin in neuroinflammation, which provides potential targets for neuroinflammation-related diseases, such as neurodegenerative diseases.

Sorafenib resistance is one of the main obstacles to the treatment of advanced/recurrent hepatocellular carcinoma (HCC). Here, sorafenib-resistant HCC cells and xenografts in nude mice were used as experimental models. A cohort of patients with advanced recurrent HCC who were receiving sorafenib therapy was used to assess the clinical significance of this therapy. Our data showed that 14-3-3η maintained sorafenib resistance in HCC. An analysis of the underlying molecular mechanisms revealed that 14-3-3η stabilizes hypoxia-inducible factor 1α (HIF-1α) through the inhibition of ubiquitin-dependent proteasome protein degradation, which leads to the maintenance of cancer stem cell (CSC) properties. We further found that microRNA-16 (miR-16) is a competent miRNA that reverses sorafenib resistance by targeting the 3′-UTR of 14-3-3η and thereby inhibits 14-3-3η/HIF-1α/CSC properties. In HCC patients, significant negative correlations were found between the expression of miR-16 and 14-3-3η, HIF-1α, or CSC properties. Further analysis showed that low miR-16 expression but high 14-3-3η expression can prognosticate sorafenib resistance and poor survival. Collectively, our present study indicated that miR-16/14-3-3η is involved in sorafenib resistance in HCC and that these two factors could be potential therapeutic targets and biomarkers for predicting the response to sorafenib treatment.