Role of serum eosinophil cationic protein in distinct endotypes of chronic rhinosinusitis.

BACKGROUND: Serum eosinophil cationic protein (ECP) levels affect the surgical outcome of chronic rhinosinusitis (CRS) with nasal polyps. Primary CRS can be classified into type 2 (T2) and non-T2. We aimed to differentiate the role of serum ECP levels in surgical outcomes between the distinct endotypes of primary CRS. METHODS: We prospectively enrolled patients with bilateral primary CRS who underwent surgical treatment with postoperative follow-up for at least 12 months. Endotyping and serum parameter measurements were completed within 1 week before surgery. RESULTS: In total, 113 patients were enrolled, including 65 with T2 CRS and 48 with non-T2 CRS. Patients in the T2 CRS group with uncontrolled CRS had significantly higher serum ECP levels than those in patients in the non-T2 CRS group. An optimal cut-off value was obtained at 17.0 λg/L using the receiver operating characteristic curve, attaining a sensitivity of 91.7% and specificity of 56.6%. Multivariate logistic regression analysis showed that a higher serum ECP level was an independent factor for postoperative uncontrolled disease. The hazard ratio was 11.3 for the T2 group, with serum ECP levels over 17.0 λg/L. In the non-T2 group, no parameters were significantly correlated with postoperative uncontrolled CRS. CONCLUSIONS: Serum ECP levels appear to be a feasible predictor of postoperative uncontrolled disease in patients with T2 CRS as preoperative serum ECP levels >17.0 λg/L in these patients have an approximately 16.7-fold increased risk of postoperative uncontrolled disease and should be closely monitored.

Tissue eosinophilia and computed tomography features in paediatric chronic rhinosinusitis with nasal polyps requiring revision surgery.

BACKGROUND: Endoscopic sinus surgery (ESS) is an effective and safe treatment modality for medically recalcitrant chronic rhinosinusitis (CRS) in the paediatric population, especially in older children or those with nasal polyposis (CRSwNP). We aimed to elucidate the inflammatory pattern and clinical characteristics of CRSwNP related to revision surgery after ESS in a paediatric population. METHODS: We retrospectively enrolled 146 patients with bilateral CRSwNP. Twenty-two patients had recurrent nasal polyps that required revision surgery. The clinical characteristics, computed tomography (CT) features, tissue eosinophil count, and immunoactivity of signature cytokines in the two groups were analysed. RESULTS: Tissue eosinophil infiltration and immunoreactivity of eosinophilic cationic protein and IL-5 in the sinus mucosa were higher in patients that required revision surgery. The revision surgery group was significantly younger and had positive aeroallergen test results, higher total Lund-Mackay scores, and ethmoid/maxillary sinus ratio on CT images than those without revision surgery. A nomogram was developed to predict the probability of the requirement of revision surgery according to the logistic regression analysis results. CONCLUSIONS: We developed a nomogram model using clinical characteristics, tissue eosinophilia, and CT features for the preoperative identification of patients vulnerable to revision surgery in paediatric CRSwNP. This could help clinicians predict the probability of recurrence and perform intensive postoperative adjunct therapy and follow-up.

Identifying a sphenoid sinus fungus ball using a nomogram model.

BACKGROUND: Sphenoid sinus fungus ball (SSFB) is a rare entity and usually presents with non-specific symptoms. SSFB could potentially lead to serious orbital and intracranial complications. Computed tomography (CT) scan is usually the first imaging test of the diagnostic workup in patients with specific clinical symptoms. This study aimed to compare the clinical characteristics and CT features between SSFB and unilateral (non-fungus ball) chronic sphenoid rhinosinusitis (USRS) and help differentiate between these two most common inflammatory diseases of the sphenoid sinus. METHODS: By retrospective database review, 66 patients with a histopathologic diagnosis of isolated SSFB were recruited for analysis. Fifty-four patients who underwent endoscopic sinus surgery with clinical and histopathological diagnoses of USRS were enrolled as the control group. Clinical characteristics and CT features were evaluated. RESULTS: Headache, rhinorrhoea, nasal obstruction, postnasal dripping, and hyposmia were the most common symptoms in both groups. In the univariate analysis, older age, lower white blood cell counts, irregular surface, bony dehiscence, lateral wall sclerosis, and intralesional hyperdensity (IH) were significant predictors for SSFB. Older age, irregular surface, and IH remained statistically significant in the multivariate analysis. Based on the results of the regression analysis, a nomogram for predicting the probability of SSFB was plotted. CONCLUSIONS: We developed a nomogram model as a novel preoperative diagnostic tool for identifying SSFB according to the predictors both in clinical characteristics and on CT features. This could help the clinicians in predicting the probability of SSFB, to reduce ineffective or delayed treatment and occurrence of complications.

Sleep impairment in patients with empty nose syndrome.

BACKGROUND: Empty nose syndrome (ENS) is characterized by paradoxical nasal obstruction that usually occurs after turbinate surgery. Patients with ENS may also experience significant psychiatric symptoms and sleep dysfunction, which negatively affect the quality of life of affected subjects. This study aimed to evaluate sleep impairment and sleepiness in patients with ENS. METHODS: Patients with ENS and control participants were recruited prospectively. The Sino-Nasal Outcome Test-25 (SNOT-25), Empty Nose Syndrome 6-item Questionnaire (ENS6Q), Epworth Sleepiness Scale (EpSS), and modified sleep quality index (MSQI) were used to evaluate the participants before and after nasal surgery. RESULTS: Forty-eight patients with ENS and forty-eight age- and sex-matched control subjects were enrolled. The SNOT-25, ENS6Q, EpSS, and MSQI scores in the ENS group were all significantly higher than those in the control group before and after surgery. After surgery, ENS patients all exhibited significant improvements in SNOT-25, ENS6Q, EpSS, and MSQI scores. Regression analysis revealed that SNOT-25 score was a significant predictor of EpSS and MSQI in preoperative evaluations. ENS patients experiencing daytime sleepiness suffered from significantly more "dryness of nose" and "suffocation" than those not experiencing daytime sleepiness. CONCLUSIONS: Patients with ENS experienced significantly impaired sleep quality and sleepiness. Nasal reconstruction surgery improved the sleep quality of ENS patients. The severity of sleep dysfunction is associated with the severity of ENS symptoms. Recognizing individuals with significant sleep impairment and sleepiness and providing appropriate management are critical issues for ENS patients.

Olfaction after endoscopic surgery for sellar and parasellar disease: an updated systematic review and meta-analysis.

BACKGROUND: Whether endoscopic surgery for sellar/parasellar disease causes significant deficits in olfactory function remains unclear. We aimed to systematically review the olfactory outcomes in such settings based on the evidence up to date. METHODS: PubMed, EMBASE, and CENTRAL were searched through February 1, 2021. Included studies were limited to endoscopic surgery for sellar/parasellar disease with follow-up olfactory function measured by standardized olfactory testing methods or subjective assessment. The primary outcome was the change in olfactory function after surgery assessed by standardized olfactory testing methods. The secondary outcome was the change in subjective olfactory function. Random-effects model was used in obtaining combine effects. Study quality was assessed using the Newcastleâ€"Ottawa scale. Sensitivity analysis was carried out using the leave-one-out approach, and publication bias was assessed using Egger's test. RESULTS: The results show no significant difference in olfaction assessed by standardized olfactory testing methods at 1-3 months post-surgery (880 patients in 16 studies) or at 6-12 months post-surgery (1320 patients in 16 studies) compared to pre-surgery, whereas a significantly lower subjective olfaction at 3 months was observed. In addition, the lack of significant change in olfaction as assessed by standardized olfactory testing methods was observed regardless of whether patients were treated with or without the nasoseptal flap (NSF) harvesting. Heterogeneity and publication bias were observed, whereas sensitivity analysis showed the meta-analysis results are robust. CONCLUSION: The findings of this updated systematic review and meta-analysis support the conclusion that endoscopic surgery for sellar and parasellar pathology may pose no greater risk of olfactory dysfunction. In addition, the current evidence does not support there is an increased risk of diminished olfaction among patients treated with NSF during surgery.

Bifidobacterium longum DS0956 and Lactobacillus rhamnosus DS0508 culture-supernatant ameliorate obesity by inducing thermogenesis in obese-mice.

Excessive body fat and the related dysmetabolic diseases affect both developed and developing countries. The aim of this study was to investigate the beneficial role of a bacterial culture supernatant (hereafter: BS) of Lactobacillus and Bifidobacterium and their potential mechanisms of action on white-fat browning and lipolysis. For selection of four candidates among 55 Lactic acid producing bacteria (LAB) from human infant faeces, we evaluated by Oil Red O staining and Ucp1 mRNA quantitation in 3T3-L1 preadipocytes. The expression of browning and lipolysis markers was examined along with in vitro assays. The possible mechanism was revealed by molecular and biological experiments including inhibitor and small interfering RNA (siRNA) assays. In a mouse model, physiological, histological, and biochemical parameters and expression of some thermogenesis-related genes were compared among six experimental groups fed a high-fat diet and one normal-diet control group. The results allow us to speculate that BS treatment promotes browning and lipolysis both in vitro and in vivo. Moreover, the BS may activate thermogenic programs via a mechanism involving PKA-CREB signaling in 3T3-L1 cells. According to our data, we can propose that two LAB strains, Bifidobacterium longum DS0956 and Lactobacillus rhamnosus DS0508, may be good candidates for a dietary supplement against obesity and metabolic diseases; however, further research is required for the development as dietary supplements or drugs.

Ex utero intrapartum treatment to extracorporeal membrane oxygenation: lifesaving management of a giant cervical teratoma.

BACKGROUND: Ex utero intrapartum treatment ('EXIT' procedure) is a well described method for maintaining maternal-fetal circulation in the setting of airway obstruction from compressive neck masses. When ex utero intrapartum treatment to airway is not feasible, ex utero intrapartum treatment to extracorporeal membrane oxygenation ('ECMO') has been described in fetal cardiopulmonary abnormalities. OBJECTIVE: This paper presents the case of a massively compressive midline neck teratoma managed with ex utero intrapartum treatment to extracorporeal membrane oxygenation, allowing for neonatal survival, with controlled airway management and subsequent resection. CASE REPORT: A 34-year-old-female presented with a fetal magnetic resonance imaging scan demonstrating a 15 cm compressive midline neck teratoma. Concern for failure of ex utero intrapartum treatment to airway was high. The addition of the ex utero intrapartum treatment to extracorporeal membrane oxygenation procedure provided time for the planned subsequent resection of the mass and tracheostomy. CONCLUSION: Ex utero intrapartum treatment procedures allow for securement of the difficult neonatal airway, while maintaining a supply of oxygenated blood to the newborn. Ex utero intrapartum treatment circulation lasts on average less than 30 minutes. The arrival of extracorporeal membrane oxygenation has enabled the survival of neonates with disease processes previously incompatible with life.

Zinc-depletion associates with tissue eosinophilia and collagen depletion in chronic rhinosinusitis.

BACKGROUND: Zinc plays an important role in many biological processes. Reduced zinc levels have been found in chronic rhinosinusitis (CRS) patients, however, its role in the pathophysiology of this disease remains unknown. This study examined zinc levels in the serum, mucus and tissue from CRS patients in relation to collagen content and eosinophil infiltration. The effect of zinc depletion on inflammatory cytokine production and collagen synthesis was assessed in vitro. METHODOLOGY: Zinc levels were determined in serum, mucus and tissue from controls, CRS with (CRSwNP) and without nasal polyps (CRSsNP) patients. Tissue zinc levels, collagen and inflammatory cell infiltration was examined using zinquin assays, immunofluorescence and histology on Tissue Micro Arrays. Cytokine expression and collagen synthesis was evaluated in zinc depleted primary human nasal epithelial cells (HNECs) and primary fibroblasts. RESULTS: CRSwNP patients showed reduced tissue zinc levels in correlation with a reduction in collagen content, and increased eosinophil numbers. Zinc depletion of HNECs and fibroblasts induced the production of pro-inflammatory cytokines and MUC5AC and reduced collagen secretion. CONCLUSIONS: These results suggest mucosal zinc depletion associates with tissue eosinophilia and collagen depletion in CRSwNP and induces pro-inflammatory cytokine expression and reduction of collagen synthesis in vitro.

What drives depression in empty nose syndrome? A Sinonasal Outcome Test-25 subdomain analysis.

BACKGROUND: Empty nose syndrome (ENS) is a debilitating disorder characterised by paradoxical nasal obstruction after excessive surgical excision of nasal tissues. ENS negatively impacts the quality of life (QOL) and psychological status of patients. This study aimed to determine the associations among disease-specific QOL impairments and the severity of anxiety and depression before and after surgery in ENS patients. METHODS: A total of 68 ENS patients were prospectively recruited and underwent submucosal Medpor implantation. QOL impairments and the severity of anxiety and depression were evaluated using the Sinonasal Outcome Test-25 (SNOT-25), Beck Depression Inventory-II (BDI-II), and Beck Anxiety Inventory (BAI) 1 day before and 6 months after surgery. RESULTS: The BDI-II and BAI scores were significantly associated with the total score and ear/facial symptoms, psychological dysfunction, sleep dysfunction, and empty nose symptoms domains of the SNOT-25. Surgery improved disease-specific and psychological symptoms. Post-operative changes in the BDI-II score were correlated with changes in the total score and sleep dysfunction and empty nose symptoms domains of the SNOT-25. A SNOT-25 total score of greater than 60, sleep dysfunction domain score of greater than 18, and empty nose symptoms domain score of greater than 14 were good predictors of moderate-to-severe depression. CONCLUSIONS: ENS symptoms are associated with psychological burden and could be good predictors of moderate-to-severe depression. Targeted symptom improvement could reduce the psychological burden.

A novel technique for unilateral supraglottoplasty.

OBJECTIVES: Traditional supraglottoplasty for pediatric laryngomalacia is most commonly conducted with either CO2 laser or cold steel instruments. While the procedure enjoys high success rates, serious complications such as excessive bleeding, supraglottic stenosis and aspiration can occur. Unilateral coblation supraglottoplasty may reduce this risk, but data on respiratory and swallowing outcomes are lacking. This study reports our experiences with unilateral coblation supraglottoplasty. METHODS: Pediatric patients with severe congenital laryngomalacia who underwent unilateral supraglottoplasty at a single institution from 2013 to 2016 were retrospectively reviewed. Bipolar radiofrequency ablation (Coblation) was utilized with partial arytenoidectomy, aryepiglottoplasty, and advancement of mucosal flaps. Outcome measures included apnea-hypopnea index (AHI), weight-by-age percentile, and decannulation rate. RESULTS: Twelve patients were included with an average age of 13.1 months (range 2-28 months). In patients without tracheostomy, 88% had complete resolution of respiratory symptoms, while the remainder had significant improvement. In patients without gastrostomy tubes, there was an average increase in weight-age percentile of 6.1, 7.8, and 15.3 points at 1, 3, and 6 months postoperatively, respectively. Three patients had complete polysomnography data with a mean preoperative AHI of 19.3 and postoperative AHI of 4.0. Three of four patients with tracheostomy have been decannulated at a mean follow-up of 1.5 years. There were no early or late postoperative complications and no revision supraglottoplasty. CONCLUSION: Unilateral supraglottoplasty with bipolar radiofrequency ablation can improve respiratory symptoms and decrease OSA severity in severe congenital laryngomalacia. This technique is safe and can lead to substantial improvement in AHI in patients with OSA.

LSD1 demethylates HIF1α to inhibit hydroxylation and ubiquitin-mediated degradation in tumor angiogenesis.

Lysine-specific demethylase 1 (LSD1), which has been considered as a potential therapeutic target in human cancer, has been known to regulate many biological functions through its non-histone substrates. Although LSD1-induced hypoxia-inducible factor alpha (HIF1α) demethylation has recently been proposed, the effect of LSD1 on the relationship between HIF1α post-translational modifications (PTMs) and HIF1α-induced tumor angiogenesis remains to be elucidated. Here, we identify a new methylation site of the HIF1α protein antagonized by LSD1 and the interplay between HIF1α protein methylation and other PTMs in regulating tumor angiogenesis. LSD1 demethylates HIF1α at lysine (K) 391, which protects HIF1α against ubiquitin-mediated protein degradation. LSD1 also directly suppresses PHD2-induced HIF1α hydroxylation, which has a mutually dependent interplay with Set9-mediated HIF1α methylation. Moreover, the HIF1α acetylation that occurs in a HIF1α methylation-dependent manner is inhibited by the LSD1/NuRD complex. HIF1α stabilized by LSD1 cooperates with CBP and MTA1 to enhance vascular endothelial growth factor (VEGF)-induced tumor angiogenesis. Thus, LSD1 is a key regulator of HIF1α/VEGF-mediated tumor angiogenesis by antagonizing the crosstalk between PTMs involving HIF1α protein degradation.

Lymphangioma Arising From the Ovary.

Primary lymphangioma arising from the ovary is a rare tumor, with only 24 cases reported to date. As it is often accompanied by ascites or recurrence, similar to a malignant tumor, an aggressive treatment approach is used for disease control. In this report, we describe a 75-year-old woman with a left ovarian lymphangioma that increased in size during the menopause period. Microscopic examination of the tumor showed thin-walled multilocular cystic spaces and immunoreactivity for D2-40, a specific marker for lymphatic endothelium, lining the cystic spaces. The patient has been doing well for 5 years postoperatively. Ovarian cystic lymphangioma should be included in the differential diagnosis of an ovarian cyst and long-term follow-up is recommended to exclude malignant behavior. We also summarize a total of 25 cases, including the case presented here.

An isolated intracranial mucocoele herniated from the frontal sinus.

Mucocoeles are chronic mucosa-lined retention cysts that occur due to sinus ostium obstruction and expand along the path of least resistance, most commonly involving the frontal sinus. A frontal mucocoele typically appears as a smooth and rounded expansile enlargement of a completely opacified frontal sinus, with or without thinning of the bony wall of the sinus. Here we report a rare case of isolated intracranial mucocoele that presented with posterior herniation to the anterior cranial fossa through a small bony defect on the posterior table of the frontal sinus. The findings upon imaging could easily be confused with intracranial abscess, potentially leading to craniotomy drainage. In the present case of mucocoele, the frontal intracranial lesion was completely resolved following endoscopic frontal sinusotomy.

MicroRNA-124 links p53 to the NF-κB pathway in B-cell lymphomas.

The contribution of microRNAs to lymphoma biology is not fully understood. In particular, it remains untested whether microRNA dysregulation could contribute to the emergence of the aggressive subset of B-cell lymphomas that coexpress MYC and BCL2. Here, we identify microRNA-124 (miR-124) as a negative regulator of MYC and BCL2 expression in B-cell lymphomas. Concordantly, stable or transient ectopic expression of miR-124 suppressed cell proliferation and survival, whereas genetic inhibition of this miRNA enhanced the fitness of these tumors. Mechanistically, the activities of miR-124 towards MYC and BCL2 intersect with both oncogenic and tumor-suppressive pathways. In respect to the former, we show that miR-124 directly targets nuclear factor-κB (NF-κB) p65, and using genetic approaches, we demonstrate that this interaction accounts for the miR-124-mediated suppression of MYC and BCL2. We also characterized miR-124 promoter region and identified a functional p53 binding site. In agreement with this finding, endogenous or ectopic expression of wild-type, but not mutant, p53 increased miR-124 levels and suppressed p65, MYC and BCL2. Our data unveil an miRNA-dependent regulatory circuitry that links p53 to the NF-κB pathway, which when disrupted in B-cell lymphoma may be associated with aberrant coexpression of MYC and BCL2 and poor prognosis.

P2 purinergic receptor activation of neuronal nitric oxide synthase and guanylyl cyclase in the dorsal facial area of the medulla increases blood flow in the common carotid arteries of cats.

In the dorsal facial area (DFA) of the medulla, an activation of either P2 purinergic receptor or nitric oxide synthase (NOS) results in the release of glutamate, leading to an increase in blood flow of the common carotid artery (CCA). It is not known whether activation of the P2 receptor by ATP may mediate activation of NOS/guanylyl cyclase to cause glutamate release and/or whether L-Arg (nitric oxide (NO) precursor) may also cause ATP release from any other neuron, to cause an increase in CCA flow. We demonstrated that microinjections of P2 receptor agonists (ATP, α,ß-methylene ATP) or NO precursor (L-arginine) into the DFA increased CCA blood flow. The P2-induced CCA blood flow increase was dose-dependently reduced by pretreatment with NG-nitro-arginine methyl ester (L-NAME, a non-specific NOS inhibitor), 7-nitroindazole (7-NI, a relatively selective neuronal NOS inhibitor) or methylene blue (MB, a guanylyl cyclase inhibitor) but not by that with D-NAME (an isomer of L-NAME) or N5-(1-iminoethyl)-L-ornithine (L-NIO, a potent endothelial NOS inhibitor). Involvement of glutamate release in these responses were substantiated by microdialysis studies, in which perfusions of ATP into the DFA increased the glutamate concentration in dialysates, but co-perfusion of ATP with L-NAME or 7-NI did not. Nevertheless, the arginine-induced CCA blood flow increase was abolished by combined pretreatment of L-NAME and MB, but not affected by pretreatment with a selective P2 receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). In conclusion, ATP activation of the P2 receptor in the DFA induced activation of neuronal NOS/guanylyl cyclase, which causes glutamate release leading to an increase in CCA blood flow. However, arginine activation of neuronal NOS/guanylyl cyclase, which also caused glutamate release and CCA blood flow increase, did not induce activation of P2 receptors. These findings provide important information for drug design and/or developing therapeutic strategies for the diseases associated with CCA blood flow that supplies intra- and extra-cranial tissues.

Screen-detected colorectal cancers are associated with an improved outcome compared with stage-matched interval cancers.

BACKGROUND: Colorectal cancers (CRCs) detected through the NHS Bowel Cancer Screening Programme (BCSP) have been shown to have a more favourable outcome compared to non-screen-detected cancers. The aim was to identify whether this was solely due to the earlier stage shift of these cancers, or whether other factors were involved. METHODS: A combination of a regional CRC registry (Northern Colorectal Cancer Audit Group) and the BCSP database were used to identify screen-detected and interval cancers (diagnosed after a negative faecal occult blood test, before the next screening round), diagnosed between April 2007 and March 2010, within the North East of England. For each Dukes' stage, patient demographics, tumour characteristics, and survival rates were compared between these two groups. RESULTS: Overall, 322 screen-detected cancers were compared against 192 interval cancers. Screen-detected Dukes' C and D CRCs had a superior survival rate compared with interval cancers (P=0.014 and P=0.04, respectively). Cox proportional hazards regression showed that Dukes' stage, tumour location, and diagnostic group (HR 0.45, 95% CI 0.29-0.69, P<0.001 for screen-detected CRCs) were all found to have a significant impact on the survival of patients. CONCLUSIONS: The improved survival of screen-detected over interval cancers for stages C and D suggest that there may be a biological difference in the cancers in each group. Although lead-time bias may have a role, this may be related to a tumour's propensity to bleed and therefore may reflect detection through current screening tests.

L-type calcium channels in sympathetic α3ß2-nAChR-mediated cerebral nitrergic neurogenic vasodilation.

AIM: Nicotine stimulation of α3ß2-nicotinic acetylcholine receptors (α3ß2-nAChRs) located on sympathetic nerves innervating basilar arteries causes calcium-dependent noradrenaline release, leading to activation of parasympathetic nitrergic nerves and dilation of basilar arteries. This study aimed to investigate the major subtype of calcium channels located on cerebral peri-vascular sympathetic nerves, which is involved in nicotine-induced α3ß2-nAChR-mediated nitrergic vasodilation in basilar arteries. METHODS: Nicotine- and transmural nerve stimulation (TNS)-induced dilation of isolated porcine basilar arteries was examined using in vitro tissue bath. Nicotine-induced calcium influx, nicotine-induced noradrenaline release and nicotine-induced inward currents were evaluated in rat superior cervical ganglion (SCG) neurones, peri-vascular sympathetic nerves of porcine basilar arteries and α3ß2-nAChRs-expressing oocytes respectively. mRNA and protein expression of Cav 1.2 and Cav 1.3 channels were detected by RT-PCR, Western blotting and immunohistochemistry. RESULTS: Nicotine-induced vasodilation was not affected by ω-agatoxin TK (selective P/Q-type calcium channel blocker) or ω-conotoxin GVIA (N-type calcium channel blocker). The vasodilation, however, was inhibited by nicardipine (L-type calcium channel blocker) in concentrations which did not affect TNS-induced vasodilation, suggesting the specific blockade. Nicardipine concentration-dependently inhibited nicotine-induced calcium influx in rat SCG neurones and reduced nicotine-induced noradrenaline release from peri-vascular sympathetic nerves of porcine basilar arteries. Nicardipine (10 µm), which significantly blocked nicotine-induced vasorelaxation by 70%, did not appreciably affect nicotine-induced inward currents in α3ß2-nAChRs-expressing oocytes. Furthermore, the mRNAs and proteins of Cav 1.2 and Cav 1.3 channels were expressed in porcine SCG and peri-vascular nerve terminals. CONCLUSION: The sympathetic neuronal calcium influx through L-type calcium channels is modulated by α3ß2-nAChRs. This calcium influx causes noradrenaline release, initiating sympathetic-parasympathetic (axo-axonal) interaction-induced nitrergic dilation of porcine basilar arteries.

ß-Lapachone induces programmed necrosis through the RIP1-PARP-AIF-dependent pathway in human hepatocellular carcinoma SK-Hep1 cells.

ß-Lapachone activates multiple cell death mechanisms including apoptosis, autophagy and necrotic cell death in cancer cells. In this study, we investigated ß-lapachone-induced cell death and the underlying mechanisms in human hepatocellular carcinoma SK-Hep1 cells. ß-Lapachone markedly induced cell death without caspase activation. ß-Lapachone increased PI uptake and HMGB-1 release to extracellular space, which are markers of necrotic cell death. Necrostatin-1 (a RIP1 kinase inhibitor) markedly inhibited ß-lapachone-induced cell death and HMGB-1 release. In addition, ß-lapachone activated poly (ADP-ribosyl) polymerase-1(PARP-1) and promoted AIF release, and DPQ (a PARP-1 specific inhibitor) or AIF siRNA blocked ß-lapachone-induced cell death. Furthermore, necrostatin-1 blocked PARP-1 activation and cytosolic AIF translocation. We also found that ß-lapachone-induced reactive oxygen species (ROS) production has an important role in the activation of the RIP1-PARP1-AIF pathway. Finally, ß-lapachone-induced cell death was inhibited by dicoumarol (a NQO-1 inhibitor), and NQO1 expression was correlated with sensitivity to ß-lapachone. Taken together, our results demonstrate that ß-lapachone induces programmed necrosis through the NQO1-dependent ROS-mediated RIP1-PARP1-AIF pathway.