Regulation of FSP1 myristoylation by NADPH: A novel mechanism for ferroptosis inhibition.

Excitotoxicity is a prevalent pathological event in neurodegenerative diseases. The involvement of ferroptosis in the pathogenesis of excitotoxicity remains elusive. Transcriptome analysis has revealed that cytoplasmic reduced nicotinamide adenine dinucleotide phosphate (NADPH) levels are associated with susceptibility to ferroptosis-inducing compounds. Here we show that exogenous NADPH, besides being reductant, interacts with N-myristoyltransferase 2 (NMT2) and upregulates the N-myristoylated ferroptosis suppressor protein 1 (FSP1). NADPH increases membrane-localized FSP1 and strengthens resistance to ferroptosis. Arg-291 of NMT2 is critical for the NADPH-NMT2-FSP1 axis-mediated suppression of ferroptosis. This study suggests that NMT2 plays a pivotal role by bridging NADPH levels and neuronal susceptibility to ferroptosis. We propose a mechanism by which the NADPH regulates N-myristoylation, which has important implications for ferroptosis and disease treatment.

Endoscopic submucosal tunnel dissection for early esophageal squamous cell carcinoma in patients with cirrhosis: A propensity score analysis.

BACKGROUND: Although early esophageal squamous cell carcinoma (EESCC) with cirrhosis is a relatively rare clinical phenomenon, the management of EESCC in cirrhotic patients continues to be a challenge. AIM: To evaluate the feasibility, safety, efficacy and long-term survival outcomes of endoscopic submucosal tunnel dissection (ESTD) for treating EESCC in patients with cirrhosis. METHODS: This was a single-center retrospective cohort study. We examined 590 EESCC patients who underwent ESTD between July 14, 2014, and May 26, 2021, from a large-scale tertiary hospital. After excluding 25 patients with unclear lesion areas or pathological results, the remaining 565 patients were matched at a ratio of 1:3 by using propensity score matching. A total of 25 EESCC patients with comorbid liver cirrhosis and 75 matched EESCC patients were ultimately included in the analysis. Parametric and nonparametric statistical methods were used to compare the differences between the two groups. The Kaplan-Meier method was used to create survival curves, and differences in survival curves were compared by the log-rank test. RESULTS: Among 25 patients with liver cirrhosis and 75 matched noncirrhotic patients, there were no significant differences in intraoperative bleeding (P = 0.234), 30-d post-ESTD bleeding (P = 0.099), disease-specific survival (P = 0.075), or recurrence-free survival (P = 0.8196). The mean hospitalization time and costs were significantly longer (P = 0.007) and higher (P = 0.023) in the cirrhosis group than in the noncirrhosis group. The overall survival rate was significantly lower in the cirrhosis group (P = 0.001). CONCLUSION: ESTD is technically feasible, safe, and effective for patients with EESCC and liver cirrhosis. EESCC patients with Child-Pugh A disease seem to be good candidates for ESTD.

RRx-001 Exerts Neuroprotection Against LPS-Induced Microglia Activation and Neuroinflammation Through Disturbing the TLR4 Pathway.

Neuroinflammation plays an important role in the pathogenesis of many central nervous system diseases. Here, we investigated the effect of an anti-cancer compound RRx-001 on neuroinflammation and its possible new applications. BV2 cells and primary microglia cells were used to evaluate the role of RRx-001 in LPS-induced microglial activation and inflammatory response in vitro. And, we found that the increase in the synthesis and release of cytokines and the up-regulation of pro-inflammatory factors in LPS-treated microglial cells were significantly reduced by RRx-001 pretreatment. As the most classical inflammatory pathways, NF-κB and MAPK signaling pathways were activated by LPS, but were inhibited by RRx-001. Transcription of NLRP3 was also reduced by RRx-001. In addition, LPS induced oxidative stress by increasing the expression of Nox mediated by transcription factors NF-κB and AP-1, while RRx-001 pretreatment ameliorated Nox-mediated oxidative stress. LPS-induced activation of TAK1, an upstream regulator of NF-κB and MAPK pathways, was significantly inhibited by RRx-001 pretreatment, whereas recruitment of MyD88 to TLR4 was not affected by RRx-001. LPS-primed BV2 condition medium induced injury of primary neurons, and this effect was inhibited by RRx-001. Furthermore, we established a neuroinflammatory mouse model by stereotactic injection of LPS into the substantia nigra pars compacta (SNpc), and RRx-001 dose-dependently reduced LPS-induced microglial activation and loss of TH + neurons in the midbrain. In conclusion, the current study found that RRx-001 suppressed microglia activation and neuroinflammation through targeting TAK1, and may be a candidate for the treatment of neuroinflammation-related brain diseases.

Long-term running exercise alleviates cognitive dysfunction in APP/PSEN1 transgenic mice via enhancing brain lysosomal function.

Amyloid-ß peptide (Aß) aggregation is the hallmark of Alzheimer's disease (AD). The imbalance between the production and clearance of Aß results in the accumulation and aggregation of Aß in the brain. Thus far, few drugs are available for AD treatment, but exercise has been recognized for its cognition-enhancing properties in AD patients. The underlying mechanisms remain unclear. Our recent study showed that long-term running exercise could activate the lysosomal function in the brains of mice. In this study, we investigated whether exercise could reduce Aß accumulation by activating lysosomal function in APP/PSEN1 transgenic mice. Started at the age of 5 months, the mice were trained with a running wheel at the speed of 18 r/min, 40 min/d, 6 d/week for 5 months, and were killed at the end of the 10th month, then brain tissue was collected for biochemical analyses. The cognitive ability was assessed in the 9th month. We showed that long-term exercise significantly mitigated cognitive dysfunction in AD mice, accompanied by the enhanced lysosomal function and the clearance of Aß in the brain. Exercise significantly promoted the nuclear translocation of transcription factor EB (TFEB), and increased the interaction between nuclear TFEB with AMPK-mediated acetyl-CoA synthetase 2, thus enhancing transcription of the genes associated with the biogenesis of lysosomes. Exercise also raised the levels of mature cathepsin D and cathepsin L, suggesting that more Aß peptides could be degraded in the activated lysosomes. This study demonstrates that exercise may improve the cognitive dysfunction of AD by enhancing lysosomal function.

[Establishment of a prostate cancer prognostic risk model based on the TCGA database and inflammation-related genes].

OBJECTIVE: To investigate the effect of inflammation-related genes on the prognosis of prostate cancer (PCa). METHODS: We downloaded PCa-related clinical data and mRNA sequencing data from the database Cancer Genome Atlas (TCGA) and inflammation-related pathway gene sets from MsigDB. Using univariate regression and LASSO regression analyses, we screened inflammation-related genes for the construction of a prognostic risk model and evaluated the performance of the model in predicting the prognosis of PCa by Kaplan-Meier and ROC analyses. Based on the nomogram, we calculated the risk scores of the patients, divided them into a high-risk and a low-risk group based on the median values of their risk scores, identified differentially expressed genes for enrichment analysis and verified the expression level of SPHK1 in the PCa tissue microarrays by immunohistochemical staining. RESULTS: Totally 19 inflammation-related genes were identified from 172 candidate genes for the construction of the prognostic risk model, including the risk genes CD14, PIK3R5, GABBR1, RELA, IRF7, SCARF1, MSR1, SPHK1, OSM and STAB1, and the protective genes AQP9, LPAR1, ATP2C1, NDP, CXCL6, P2RY2, DCBLD2, PCDH7, and IFNAR1. Kaplan-Meier analysis showed that the patients with high risk scores had a significantly lower recurrence-free survival and a worse prognosis than those with low risk scores. Differentially expressed genes were involved mainly in the activation of inflammatory response pathways. Immunohistochemical results indicated that the expression of SPHK1 was significantly higher in the tumorous than in the normal tissue and increased with the Gleason score. There was a correlation between the SPHK1 expression and envelope invasion. CONCLUSION: The prognostic risk model of inflammation-related genes constructed based on the TCGA database can effectively predict the prognosis of PCa.

NADPH is superior to NADH or edaravone in ameliorating metabolic disturbance and brain injury in ischemic stroke.

Our previous studies confirm that exogenous reduced nicotinamide adenine dinucleotide phosphate (NADPH) exerts a neuroprotective effect in animal models of ischemic stroke, and its primary mechanism is related to anti-oxidative stress and improved energy metabolism. However, it is unknown whether nicotinamide adenine dinucleotide (NADH) also plays a neuroprotective role and whether NADPH is superior to NADH against ischemic stroke? In this study we compared the efficacy of NADH, NADPH, and edaravone in ameliorating brain injury and metabolic stress in ischemic stroke. Transient middle cerebral artery occlusion/reperfusion (t-MCAO/R) mouse model and in vitro oxygen glucose deprivation/reoxygenation (OGD/R) model were established. The mice were intravenously administered the optimal dose of NADPH (7.5 mg/kg), NADH (22.5 mg/kg), or edaravone (3 mg/kg) immediately after reperfusion. We showed that the overall efficacy of NADPH in ameliorating ischemic injury was superior to NADH and edaravone. NADPH had a longer therapeutic time window (within 5 h) after reperfusion than NADH and edaravone (within 2 h) for ischemic stroke. In addition, NADPH and edaravone were better in alleviating the brain atrophy, while NADH and NADPH were better in increasing the long-term survival rate. NADPH showed stronger antioxidant effects than NADH and edaravone; but NADH was the best in terms of maintaining energy metabolism. Taken together, this study demonstrates that NADPH exerts better neuroprotective effects against ischemic stroke than NADH and edaravone.

TIGAR plays neuroprotective roles in KA-induced excitotoxicity through reducing neuroinflammation and improving mitochondrial function.

Excitotoxicity refers to the ability of excessive extracellular excitatory amino acids to damage neurons via receptor activation. It is a crucial pathogenetic process in neurodegenerative diseases. TP53 is confirmed to be involved in excitotoxicity. It is demonstrated that TP53 induced glycolysis and apoptotic regulator (TIGAR)-regulated metabolic pathway can protect against neuronal injury. However, the role of TIGAR in excitotoxicity and specific mechanisms is still unknown. In this study, an in vivo excitotoxicity model was constructed via stereotypical kainic acid (KA) injection into the striatum of mice. KA reduced TIGAR expression levels, neuroinflammatory responses and mitochondrial dysfunction. TIGAR overexpression could reverse KA-induced neuronal injury by reducing neuroinflammation and improving mitochondrial function, thereby exerting neuroprotective effects. Therefore, this study could provide a potential therapeutic target for neurodegenerative diseases.

NADPH and Mito-Apocynin Treatment Protects Against KA-Induced Excitotoxic Injury Through Autophagy Pathway.

AIM: Previous research recognizes that NADPH can produce reduced glutathione (GSH) as a coenzyme and produce ROS as a substrate of NADPH oxidase (NOX). Besides, excessive activation of glutamate receptors results in mitochondrial impairment. The study aims at spelling out the effects of NADPH and Mito-apocynin, a NOX inhibitor which specifically targets the mitochondria, on the excitotoxicity induced by Kainic acid (KA) and its mechanism. METHODS: The in vivo neuronal excitotoxicity model was constructed by stereotypically injecting KA into the unilateral striatum of mice. Administrated NADPH (i.v, intravenous) 30 min prior and Mito-apocynin (i.g, intragastric) 1 day prior, respectively, then kept administrating daily until mice were sacrificed 14 days later. Nissl staining measured the lesion of striatum and survival status of neurons. Cylinder test of forelimb asymmetry and the adhesive removal test reflected the behavioral deficit caused by neural dysfunction. Determined Total superoxide dismutase (T-SOD), malondialdehyde (MDA), and GSH indicated oxidative stress. Western blot presented the expression levels of LC3-II/LC3-I, SQSTM1/p62, TIGAR, and NOX4. Assessed oxygen consumption rate using High-Resolution Respirometry. In vitro, the MitoSOX Indicator reflected superoxide released by neuron mitochondria. JC-1 and ATP assay Kit were used to detect mitochondrial membrane potential (MMP) and energy metabolism, respectively. RESULTS: In this study, we have successfully established excitotoxic model by KA in vivo and in vitro. KA induced decreased SOD activity and increased MDA concentration. KA cause the change of LC3-II/LC3-I, SQSTM1/p62, and TIGAR expression, indicating the autophagy activation. NADPH plays a protective role in vivo and in vitro. It reversed the KA-mediated changes in LC3, SQSTM1/p62, TIGAR, and NOX4 protein expression. Mito-apocynin inhibited KA-induced increases in mitochondrial NOX4 expression and activity. Compared with NADPH, the combination showed more significant neuroprotective effects, presenting more neurons survive and better motor function recovery. The combination also better inhibited the over-activated autophagy. In vitro, combination of NADPH and Mito-apocynin performed better in restoring mitochondria membrane potential. CONCLUSION: In summary, combined administration of NADPH and NOX inhibitors offers better neuroprotection by reducing NADPH as a NOX substrate to generate ROS. The combined use of NADPH and Mito-apocynin can better restore neurons and mitochondrial function through autophagy pathway.

Neuroprotective effects of olanzapine against rotenone-induced toxicity in PC12 cells.

Olanzapine is an antipsychotic drug used to treat patients with schizophrenia due to its lower incidence of extrapyramidal symptoms. Previous studies have shown that olanzapine activates AMP-activated protein kinase (AMPK), and induce autophagy in SH-SY5Y cell line. In this study, we investigated whether olanzapine protected against rotenone-induced neurotoxicity in PC12 cells. We showed that treatment with olanzapine increased the phosphorylation of AMPK in both dose- and time-dependent manners in PC12 cells. In addition, olanzapine activated autophagy and increased autophagic vacuoles. Furthermore, olanzapine pretreatment could protect PC12 cells from rotenone-induced apoptosis. Besides, olanzapine pretreatment could suppress the rotenone-induced depolarization of mitochondrial potential and thus protect the cells. Moreover, pretreatment with specific AMPK inhibitor compound C or with autophagy inhibitor 3-methyladenine impaired the protective effect of olanzapine on rotenone-treated PC12 cells. In summary, our results show for the first time that olanzapine ameliorates rotenone-induced injury by activating autophagy through AMPK pathway.

NADPH protects against kainic acid-induced excitotoxicity via autophagy-lysosome pathway in rat striatum and primary cortical neurons.

PURPOSE: To investigate the effects and mechanisms of NADPH on Kainic acid (KA)-induced excitotoxicity. METHODS: KA, a non-N-methyl-d-aspartate glutamate receptor agonist, was exposed to adult SD rats via intrastriatal injection and rat primary cortical neurons to establish excitotoxic models in vivo and in vitro, respectively. To determine the effects of NADPH on KA-induced excitotoxicity, neuronal survival, neurologically behavioral score and oxidative stress were evaluated. To explore the mechanisms of neuroprotective effects of NADPH, the autophagy-lysosome pathway related proteins were detected. RESULTS: In vivo, NADPH (1 mg/kg or 2 mg/kg) diminished KA (2.5 nmol)-induced enlargement of lesion size in striatum, improved KA-induced dyskinesia and reversed KA-induced activation of glial cells. Nevertheless, the neuroprotective effect of NADPH was not significant under the condition of autophagy activation. NADPH (2 mg/kg) inhibited KA (2.5 nmol)-induced down-regulation of TP-53 induced glycolysis and apoptosis regulator (TIGAR) and p62, and up-regulation of the protein levels of LC3-II/LC3-I, Beclin-1 and Atg5. In vitro, the excitotoxic neuronal injury was induced after KA (50 µM, 100 µM or 200 µM) treatment as demonstrated by decreased cell viability. Moreover, KA (100 µM) increased the intracellular levels of calcium and reactive oxygen species (ROS) and declined the levels of the reduced form of glutathione (GSH). Pretreatment of NADPH (10 µM) effectively reversed these changes. Meanwhile NADPH (10 µM) inhibited KA (100 µM)-induced down-regulation of TIGAR and p62, and up-regulation of the ratio of LC3-II/LC3-I, Beclin-1, Atg5, active-cathepsin B and active-cathepsin D. CONCLUSIONS: Our data provide a possible mechanism that NADPH ameliorates KA-induced excitotoxicity by blocking the autophagy-lysosome pathway and up-regulating TIGAR along with its antioxidant properties.

Endoscopic Submucosal Single- or Multi-tunnel Dissection for Near-Circumferential and Circumferential Superficial Esophageal Neoplastic Lesions.

This study reports the outcomes of endoscopic submucosal single-tunnel dissection or endoscopic submucosal multi-tunnel dissection for the treatment of esophageal neoplastic lesions of at least three-quarters of the esophageal circumference, including circumferential superficial esophageal neoplastic lesions. From July 2014 to February 2018, a total of 124 lesions underwent endoscopic submucosal tunnel dissection at our hospital. One to four submucosal tunnels were created in the oral to anal direction. Of the 124 lesions, there were 83 noncomplete circumferential lesions and 41 circumferential lesions. Endoscopic submucosal single-tunnel dissection was performed in 54 patients, two-tunnel dissection in 43 patients, three-tunnel dissection in 19 patients, and four-tunnel dissection in 8 patients. The mean dissection speed was 22.8 ± 12.7 mm2/min. En bloc dissection was achieved in all lesions, and the R0 resection rate was 70.2 percent. No matter how large the lesion area was, there were no significant differences in the dissection speed and the R0 resection rate when lesions were at least three-quarters of the esophageal circumference. Esophageal stricture was observed in 54 patients and was relieved by placement of a retrievable metal stent or by endoscopic water balloon dilation. No recurrence was noted after 19.1 ± 12.4 months of follow-up. Our large sample size study showed that endoscopic submucosal tunnel dissection showed effectiveness and safety for the treatment of large superficial esophageal neoplastic lesions at least three-quarters of the esophageal circumference, including circumferential superficial esophageal neoplastic lesions.

Exercise activates lysosomal function in the brain through AMPK-SIRT1-TFEB pathway.

AIM: To study the effects of exercise on lysosomal functions. METHODS: Mouse exercise model was established and wheel running was scheduled as 18 rpm (14:00-17:00), 5 d/wk, for 8 weeks. Mice were injected EX527 to inhibit SIRT1 activity. The protein level was assayed with Western blot and immunofluorescence histochemistry. The transmission electron microscopic examination was used to show the structure of lysosome and mitochondria. RESULTS: Exercise promoted the nuclear translocation of TFEB in the cortex which upregulated the transcription of genes associated with autophagy and lysosome. Exercise directly activated autophagy/lysosome system via up-regulating of AMPK-SIRT1 signaling. The SIRT1 inhibitor EX527 decreased TFEB regulated gene transcription but had little effect on the nuclear translocation of TFEB. In addition, long-term exercise showed more significant effects on activation of lysosomes biogenesis compared with the short-term exercise and trehalose, a classical autophagy activator in the mTOR-independent pathway. CONCLUSION: Running exercise activates lysosomal function in the brain through AMPK-SIRT1-TFEB pathway.

NADPH ameliorates MPTP-induced dopaminergic neurodegeneration through inhibiting p38MAPK activation.

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). Although the pathogenic mechanism underlying PD remains largely unknown, decreased nigral glutathione (GSH) in postmortem brains of PD patients supports the presence of oxidative stress in PD. We found that Nicotinamide adenine dinucleotide phosphate (NADPH), which is important for maintaining the level of GSH, protected dopaminergic (DA) neurons from neurotoxicity of MPTP/MPP+. In the present study, NADPH prevented DA neurons from MPTP toxicity with increased GSH and decreased reactive oxygen species (ROS) levels in the ventral midbrain of mice, and improved motor activity. Our present results demonstrated that NADPH inhibited the phosphorylation of p38MAPK, decreased the level of TP53 protein, and inhibited TP53 nuclear translocation in DA neurons of SNpc and in MES23.5 cells. Furthermore, NADPH decreased the protein level of TP53 target gene, Bax, cleavage of PARP, and nuclei condensation. Taken together, NADPH abrogated MPTP-induced p38MAPK phosphorylation, TP53 nuclear translocation, and Bax induction, and finally, MPTP/MPP+-induced apoptosis of DA neurons. This study suggests that NADPH may be a novel therapeutic candidate for PD.

Esophagectomy after endoscopic submucosal dissection for esophageal carcinoma.

BACKGROUND: Endoscopic submucosal dissection (ESD) has been used to treat early stage esophageal cancer, but reports about additional esophagectomy after ESD and postoperative outcomes are lacking. Complete removal of cancer tissue together with lymph nodes was the advantage of esophagectomy; however, invasiveness, organ loss, postoperative complications, and worse postoperative quality of life were serious disadvantages. The purpose of this study was to find the clear indication of additional esophagectomy after ESD, and help the other patients avoid excessive surgery. METHODS: We reviewed the clinicopathologic data and outcomes consecutive patients who had esophageal cancer confirmed by endoscopic biopsy and who were treated with ESD and subsequent esophagectomy between October 2011 and December 2016 in our department. The esophagectomy necessity following ESD was defined and the groups with necessity (+) vs. (-) were compared retrospectively. The esophagectomy necessity outcomes were retrospectively analyzed to judge whether the surgery option was correct. RESULTS: Total 214 patients with esophageal and esophagogastric cancer have undergone ESD treatment in our center, of which 32 patients (23 men and 9 women; mean age, 60±8 years) ultimately required esophagectomy after ESD. All patients had complete resection (R0) from esophagectomy. Postoperative TNM staging included TisN0M0 (6 patients), T1aN0M0 (6 patients), T1bN0M0 (18 patients), T1bN1M0 (1 patient), and T2N3M0 (1 patient). Necessity of esophagectomy after ESD was associated with residual margin status. There was a significant difference in ESD specimen margin status between the esophagectomy necessity (+) vs. (-) groups (positive/negative margin: 8/3 vs. 2/9 patients; P=0.03). Esophagectomy should be delayed at least 30 days after ESD to enable resolution of esophageal edema (P=0.017) (206±68 vs. 163±56 mL, P=0.057). Median follow-up was 16.8 months (range, 11.2-54.5 months); 3 patients were lost to follow-up (9%) and 1 patient died of metastasis after esophagectomy. All other patients were alive with excellent postoperative disease-free survival. CONCLUSIONS: Indications for esophagectomy after ESD include ESD failure, cancer recurrence, esophageal rupture, esophageal stricture refractory to endoscopic dilation, and residual tumor at the ESD specimen margin. Stage T1b alone is not an indication for esophagectomy. According to our study, we recommend that esophagectomy should be delayed ≥30 dafter ESD unless urgent esophagectomy is indicated.

Diagnostic performance of magnifying endoscopy with narrow-band imaging in differentiating neoplastic colorectal polyps from non-neoplastic colorectal polyps: a meta-analysis.

Colorectal polyps are commonly seen in colonoscopy and the management of neoplastic polyps and non-neoplastic polyps are different. It is necessary to distinguish neoplastic polyps from non-neoplastic polyps in real-time. Therefore, we conducted a meta-analysis to assess the diagnostic accuracy of magnifying endoscopy with narrow-band imaging (ME-NBI) in diagnosing neoplastic colorectal polyps from non-neoplastic colorectal polyps. PubMed and EMBASE were searched for trials that used magnifying endoscopy with ME-NBI for diagnosing neoplastic colorectal polyps. Sixteen articles and 20 fourfold tables were obtained. Sensitivity (Sen), specificity (Spe), positive likelihood ratios (+ LRs), negative likelihood ratios (- LRs) and diagnostic odds ratios (DORs) were calculated. A summary receiver-operating characteristic (SROC) curve was constructed, and the area under the ROC curve (AUC) was calculated. We performed subgroup analyses based on polyp size and assessment criteria: (1) According to data extracted from 20 fourfold tables, the pooled Sen and Spe of ME-NBI for diagnosing neoplastic colorectal polyps < 10 mm were 0.94 (95% CI 0.92-0.95) and 0.76 (95% CI 0.72-0.80),respectively. The pooled Sen and Spe of ME-NBI for diagnosing all neoplastic polyps were 0.98 (95% CI 0.98-0.99) and 0.88 (95% CI 0.85-0.90), respectively. (2) Data pertaining to the following three assessment methods were analysed from 15 fourfold tables: surface pattern (SP), vessel pattern (VP) and the combination of SP and VP. The AUCs for these assessment criteria were 0.9533, 0.9518 and 0.9954, respectively. Conclusions were made that ME-NBI has high diagnostic accuracy in diagnosing neoplastic colorectal polyps based on the combination of SP with VP and is helpful in making real-time diagnoses.

[Diagnosis and Minimally Invasive Endoscopic Treatment of Early Esophageal Cancer and Precancerous Lesions].

Esophageal cancer is a common malignancy of digestive tract, and its prognosis is closely related to early diagnosis and treatment. In recent years, with the development of endoscopic diagnosis and treatment technology, especially the breakthrough progress of new endoscopic equipments, the detection rate of early esophageal cancer and precancerous lesions is significantly improved, and more and more patients with early esophageal cancer can be treated with minimally invasive endoscopic treatment. At present, endoscopic dissection has become the preferred treatment for early esophageal cancer and precancerous lesions. The advantages is not only less traumatic than traditional surgery, but also retain the physiological structure of esophagus, achieve accurate postoperative pathology and better postoperative quality of life of patients. However, endoscopic minimally invasive treatment in progress also face new problems to be solved, such as how to deal with multifocal esophageal lesions, how to estimate esophageal lesions infiltration depth and lymph node metastasis risk accurately, how to understand the discrepancy between biopsy and postoperative pathology, how to deal with the positive resection margins as well as intraoperative and postoperative complications, how to manage endoscopic treatment of the special subpopulation of the patients, whether and when additional radical surgery should be provided to the patients with non-curative endoscopic treatment, and so on. Aiming to the above problems and the purpose to improve the prognosis and the quality of life of esophageal cancer patients, this topic includes a series studies to explore standardized treatment scheme and management strategy for postoperative complications in the endoscopic treatment of early esophageal cancer and precancerious lesions.

[Accuracy of EUS and ME-NBI for Evaluating the Invasion Depth of Early Esophageal Cancer].

OBJECTIVE: To assess the accuracy of endoscopic ultrasound (EUS) and magnifying endoscopy with narrow-band imaging (ME-NBI) in evaluating the invasion depth of early esophageal carcinoma. METHODS: Patients who underwent endoscopic resection for early esophageal cancer from March 2013 to October 2017 were enrolled. The EUS and ME-NBI results were compared with the pathology results. RESULTS: A total of 392 lesions from 333 patients were assessed, including 83 mild and moderate dysplasia, 72 severe dysplasia, 235 squamous cell carcinoma, and 2 adenosquamous carcinoma. About 308 lesions were given EUS only, 7 had ME-NBI only, 77 underwent both EUS and ME-NBI. EUS resulted in a 43.9% accuracy for the 385 lesions, with poor consistency (Kappa=0.1) with the pathology results. But higher accuracy (68.2%) was found for lesions infiltrating into the submucosa of the lesions, compared with 40.5% for lesions contained within the mucosa (P=0.001). ME-NBI resulted in a 72.6% accuracy for the 84 lesions, with a medium consistency (Kappa=0.4). The accuracy for lesions contained within the mucosa was 91.0%, compared with 16.7% for lesions infilrtrating into the submucosa (P=0.001). EUS and ME-NBI for the 77 lesions demonstrated an accuracy of 42.9% for the EUS and 84.3% for the ME-NBI (P=0.001). CONCLUSIONS: ME-NBI has higher accuracy than EUS in evaluating the invasion depth of early esophageal carcinoma.

[Efficacy of Oral Corticosteroids in Preventing Esophageal Stenosis after Large Area Endoscopic Submucosal Tunnel Dissection].

OBJECTIVE: To evaluate the efficacy of oral corticosteroids in preventing esophageal stenosis after large area esophageal endoscopic submucosal tunnel dissection (ESTD). METHODS: The patients undertook esophageal ESTD were included from January 2014 to January 2018. The inclusion criteria was single lesion of esophageal early esophagus cancer with the extent more than 3/4 of circumferential degree. According to the inclusion time, the patients were divided into the trial group (ESTD + oral corticosteroids) and the control group (simple ESTD). The incidence of the total esophageal stenosis, intractable esophageal stenosis, the remission rate of dysphagia and the period from the dysphagia present were observed and compared in the two groups. RESULTS: A total of 101 cases of esophageal ESTD patients were included. There were 48 cases in the trial group, 28 cases of male and 20 cases of female, with an average age of (62.98±7.52) years; 53 cases in the control group, 28 cases of male and 25 cases of female, with an average age of (62.67±8.04) years. The rate of intractable esophageal stenosis in the trial group was lower than that in the control group (6.25% vs. 20.75%, P<0.05). The average endoscopic treatment times in the non-refractory stenosis patients in the trial group were significantly less than those in the control group 〔(1.85±0.27) times vs. (3.24±0.49) times, P<0.05〕, and the occurrence time of esophageal stenosis in the trial group was 51.06 d after ESTD, significantly later than that in the control group (29.12 d, P<0.05). CONCLUSIONS: Oral corticosteroids can effectively reduce the degree of esophageal stenosis after large area ESTD, as well as the incidence of intractable esophageal stenosis and the number of endoscopic treatment in non-refractory esophageal stenosis patients.

[Endoscopic Characteristics and Pathological Analysis of Esophageal Low-grade Intraepithelial Neoplasm].

OBJECTIVE: To explore endoscopic characteristics and pathological changes of esophageal low-grade intraepithelial neoplasm (LGIN) as well as its risk factors. METHODS: A total of 201 LGIN lesions from 169 cases were included from January 2009 to August 2017. The endoscopic characteristics and pathological changes were analysis. Logistic regression analysis was used to analyze the risk factors of LGIN. The endoscopic morphologic findings of esophageal mucosa lesions and the pathological findings of simple inflammatory lesions were enrolled as controls. RESULTS: LGIN occurred more common in elderly patients, the ratio of male to female was 2.5∶1. The maximum transverse and the maximum longitudinal diameter (MLD) were (0.9±0.8) cm,(1.4±1.3) cm, respectively. The most common location of lesion was in the middle segment of esophagus (52.2%). The morphological types of lesions were dominantly 0-Ⅱb (45.8%) and 0-Ⅱa (31.8%). There were 42 LGIN lesions with reflux esophagitis. Multiple dysplastic lesions accounted for 57.4%. After (10.3±12.1) months follow-up, 58.2% lesions were pathological reversal with 24.9% (50/201) of the lesion completely disappeared, and 28.9% lesions had no pathological changes, but 12.9% (26/201) lesions progressed to high-grade intraepithelial neoplasia and invasive cancer. Multivariate analysis indicated that age (compared to <45 years old) and longitudinal diameter of the lesion (compared to ≤0.5 cm) were independent risk factors for LGIN. The risk of esophageal LGIN in lesions with MLD > 0.5-1 cm was 1.96 times higher than that in lesions with MLD ≤ 0.5 cm. CONCLUSIONS: The MLD of esophageal mucosal lesions >0.5 cm and age >45 years old may increase the possibility of esophageal LGIN. Close follow-up is required for LGIN lesions with MLD>1 cm.

Combination of NAD+ and NADPH Offers Greater Neuroprotection in Ischemic Stroke Models by Relieving Metabolic Stress.

Both reduced nicotinamide adenine dinucleotide phosphate (NADPH) and ß-nicotinamide adenine dinucleotide hydrate (NAD+) have been reported to have potent neuroprotective effects against ischemic neuronal injury. Both NADPH and NAD+ are essential cofactors for anti-oxidation and cellular energy metabolism. We investigated if combined NADPH and NAD+ could offer better neuroprotective effects on cellular and animal models of ischemic stroke. In vitro studies with primary cultured neurons demonstrated that NAD+ was effective in protecting neurons against oxygen-glucose deprivation/reoxygenation (OGD/R) injury when given during the early time period of reoxygenation. In vivo studies in mice also suggested that NAD+ was effective for ameliorating ischemic brain damage when administered within 2 h after reperfusion. The combination of NADPH and NAD+ provided not only greater beneficial effects but also larger therapeutic window in both cellular and animal models of stroke. The combination of NADPH and NAD+ significantly increased the levels of adenosine triphosphate (ATP) and reduced the levels of reactive oxygen species (ROS) and oxidative damage of macromolecules. Furthermore, the combined medication significantly reduced long-term mortality, improved the functional recovery, and inhibited signaling pathways involved in apoptosis and necroptosis after ischemic stroke. The present study indicates that the combination of NAD+ and NADPH can produce greater therapeutic effects with smaller dose of NADPH; on the other hand, NADPH can significantly prolong the therapeutic window of NAD+. The current results suggest that the combination of NADPH and NAD+ may provide a novel effective therapy for ischemic stroke.