Role of cyclooxygenase-2 in lipid metabolism in hepatic stellate cells

Hepatic stellate cells(HSCs) are a kind of adipocytes. In HSCs lipids mainly exist in the form of lipid droplets. They are abundantly found in the cytoplasm and their main constituents are triglycerides. Lipid metabolism in HSCs is closely related to its biological activity, however the mechanism of lipid droplets disappearance after HSC activation is not clearly established yet. Recent research shows that, cyclooxygenase-2 plays an important regulatory role in the lipid metabolism of HSCs. This paper seeks to review the subject based on studies that have been conducted so far to understand the role of cyclooxygenase-2 in the metabolism of lipids in HSCs.

Clinical study on the effect of jejunoileal side-to-side anastomosis on metabolic parameters in patients with type 2 diabetes

BACKGROUND At present,the existing internal medicine drug treatment can alleviate the high glucose toxicity of patients to a certain extent,to explore the efficacy of laparoscopic jejunoileal side to side anastomosis in the treatment of type 2 diabetes,the report is as follows.AIM To investigate the effect of jejunoileal side-to-side anastomosis on metabolic parameters in patients with type 2 diabetes mellitus(T2DM).METHODS We retrospectively analyzed the clinical data of 78 patients with T2DM who were treated via jejunoileal lateral anastomosis.Metabolic indicators were collected preoperatively,as well as at 3 and 6 months postoperative.The metabolic indicators analyzed included body mass index(BMI),systolic blood pressure(SBP),diastolic blood pressure(DBP),fasting blood glucose(FBG),2-hour blood glucose(PBG),glycated hemoglobin(HbA1c),fasting C-peptide,2-hour C-peptide(PCP),fasting insulin(Fins),2-hour insulin(Pins),insulin resistance index(HOMA-IR),βCellular function index(HOMA-β),alanine aminotransferase,aspartate aminotransferase,serum total cholesterol(TC),low-density lipoprotein cholesterol(L DL-C),triglycerides(TG),high-density lipoprotein,and uric acid(UA)levels.RESULTS SBP,DBP,PBG,HbA1c,LDL-C,and TG were all significantly lower 3 months postoperative vs preoperative values;body weight,BMI,SBP,DBP,FBG,PBG,HbA1c,TC,TG,UA,and HOMA-IR values were all significantly lower 6 months postoperative vs at 3 months;and PCP,Fins,Pins,and HOMA-βwere all significantly higher 6 months postoperative vs at 3 months(all P<0.05).CONCLUSION Side-to-side anastomosis of the jejunum and ileum can effectively treat T2DM and improve the metabolic index levels associated with it.

RARRES2's impact on lipid metabolism in triplenegative breast cancer:a pathway to brain metastasis

Breast cancer brain metastasis(BCBrM)is a crucial and hard area of research which guarantees an urgent need to understand the underlying molecular mechanisms.A recent study by Li et al.[1]published in Military Medical Research investigated the role of retinoic acid receptor responder 2(RARRES2)in regulating lipid metabolism in BCBrM,highlighting the clinical relevance of alterations in lipid metabolites,such as phosphatidylcholine(PC)and triacylglycerols(TAGs),by RARRES2 through the modulation of phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway.This commentary aims to elaborate on the key findings and their relevance to the field.

Asiaticoside ameliorates type 2 diabetes mellitus in rats by modulating carbohydrate metabolism and regulating insulin signaling

Objective:To evaluate the effect of asiaticoside on streptozotocin(STZ)and nicotinamide(NAD)-induced carbohydrate metabolism abnormalities and deregulated insulin signaling pathways in rats.Methods:Asiaticoside(50 and 100 mg/kg body weight)was administered to STZ-NAD-induced diabetic rats for 45 days,and its effects on hyperglycaemic,carbohydrate metabolic,and insulin signaling pathway markers were examined.Results:Asiaticoside increased insulin production,lowered blood glucose levels,and enhanced glycolysis by improving hexokinase activity and suppressing glucose-6-phosphatase and fructose-1,6-bisphosphatase activities.Abnormalities in glycogen metabolism were mitigated by increasing glycogen synthase activity and gluconeogenesis was decreased by decreasing glycogen phosphorylase activity.Furthermore,asiaticoside upregulated the mRNA expressions of IRS-1,IRS-2,and GLUT4 in STZ-NAD-induced diabetic rats and restored the beta cell morphology to normal.Conclusions:Asiaticoside has the potential to ameliorate type 2 diabetes by improving glycolysis,gluconeogenesis,and insulin signaling pathways.

Cyclooxygenase-2在急性胰腺炎大鼠肺微循环障碍中的作用

目的初步探讨急性胰腺炎大鼠肺组织Cyclooxygenase-2(Cox-2)的表达及其在急性胰腺炎肺微循环障碍中的作用。方法逆行胰胆管注射灭菌的4%牛磺胆酸钠诱导Sprague-Dawley大鼠急性出血坏死性胰腺炎(AHNP)模型。实验随机分为假手术组、AHNP组及Celecoxib预处理组,术后3、6、12和24h处死动物,取肺组织HE染色进行肺损伤的组织学评价,Mallory氏磷钨酸苏木精染色观察血管中的纤维素性血栓,免疫组化检测Cox-2蛋白表达。结果AHNP组肺组织Cox-2表达和病理学评分进行性增加,两者呈正相关(r=0.503,P=0.012)。在AHNP早期就可发现肺组织微血栓形成,其密度和损伤评分亦呈正相关(r=0.604,P=0.004);Celecoxib预处理在各时相点均减轻了肺损伤的程度、微血栓密度和Cox-2的表达水平(P<0.05);Celecoxib下调Cox-2表达程度与其改善肺组织病理损伤强度正相关,而与其降低微血栓形成的程度无明显相关性。结论肺微血栓形成所致的肺微循环障碍可能是诱导肺损伤发生的早期事件,并可能是始动因素;Cox-2过表达可能具有促凝血活性而在肺微血栓形成中扮演关键角色。

Influences of Na_2CO_3 Stress on Physiological Metabolisms of Different Alkali Tolerant Varieties of Stevia rebaudiana

[Objective] The research aimed to reveal physiological mechanisms of alkali tolerances of different Stevia rebaudiana varieties under alkali stress.[Method] By using matrix culture method,the influences of Na2CO3 on chlorophyll content,malondialdehyde（MDA）,superoxide dismutase（SOD）,peroxidase（POD） and Proline（Pro） content of leaves from different alkali tolerance varieties of S.rebaudiana [No.2 Shoutian（relative alkali tolerance variety） and No.4 Zhongshan（alkali sensitivity variety）] were studied.[Result] 1.2 g/L of Na2CO3 stress made that the chlorophyll contents of leaves from No.2 Shoutian and No.4 Zhongshan seedlings both decreased in different degrees.Moreover,MDA content of No.4 Zhongshan was higher than control during the whole stress period,and the largest increase amplitude was 43.2%.MDA content of No.2 Shoutian was lower than control in early and latter periods of stress,and increased the maximum on the 14th day of alkali stress,which was 24.4% higher than control.SOD activities of No.2 Shoutian and No.4 Zhongshan both showed a trend of first increasing and declining then in the alkali stress period,but the increasing extent of SOD activity in No.2 Shoutian was higher than that in No.4 Zhongshan.In latter period of Na2CO3 stress,SOD activity of No.2 Shoutian declined,but POD activity was higher than that of No.4 Zhongshan.It illustrated that POD had stronger scavenging capability of active oxygen.Pro contents of No.2 Shoutian and No.4 Zhongshan were higher than control in the stress period.It showed that the osmoregulation of Pro might not be key regulatory factor of alkali tolerance difference of the two S.rebaudiana varieties.[Conclusion] The research not only provided theoretical basis for further breeding new salt tolerance variety of S.rebaudiana,but also had important significance for improving utilized ratio of kaline soil and growing environment for mudflat in China.

Cyclooxygenase-2在口腔癌活检组织中的表达及预后意义

目的调查环氧化酶-2(COX-2)在口腔鳞状细胞癌(OSCC)中的表达及其预后意义。方法48例OSCC经外科手术治疗并分为两组:新辅助化疗24例及仅接受手术治疗24例。通过免疫组织化学技术评价了来自48例OSCC的经福尔马林固定、石蜡包埋预处理的活检组织内的COX-2表达水平。结果发现48例OSCC中有42例COX-2阳染,而在相邻正常口腔粘膜组织却未发现。COX-2表达与淋巴结转移之间没有显著性关系。但当分析预后意义时,低COX-2表达的仅接受手术治疗者具有更佳的生存率(P<0.01)。结论以上结果建议,活检组织内的COX-2表达可能是一个有用的患者预后生存因子,并且在确诊时可影响治疗方法的决定。

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies.Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully elucidated.Methods Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of TNBC.We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies.Key signaling pathway components were evaluated using multi-omics approaches.Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.Results We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming.Mechanistically,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.Conclusions Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM.RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

Hepatic angiotensin-converting enzyme 2 expression in metabolic dysfunction-associated steatotic liver disease and in patients with fatal COVID-19

BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD),characterised by hepatic lipid accumulation,causes inflammation and oxidative stress accompanied by cell damage and fibrosis.Liver injury(LI)is also frequently reported in patients hospitalised with coronavirus disease 2019(COVID-19),while preexisting MASLD increases the risk of LI and the development of COVID-19-associated cholangiopathy.Mechanisms of injury at the cellular level remain unclear,but it may be significant that severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)which causes COVID-19,uses angiotensin-converting expression enzyme 2(ACE2),a key regulator of the‘anti-inflammatory’arm of the renin-angiotensin system,for viral attachment and host cell invasion.AIM To determine if hepatic ACE2 levels are altered during progression of MASLD and in patients who died with severe COVID-19.METHODS ACE2 protein levels and localisation,and histological fibrosis and lipid droplet accumulation as markers of MASLD were determined in formalin-fixed liver tissue sections across the MASLD pathological spectrum(isolated hepatocellular steatosis,metabolic dysfunction-associated steatohepatitis(MASH)+/-fibrosis,end-stage cirrhosis)and in post-mortem tissues from patients who had died with severe COVID-19,using ACE2 immunohistochemistry and haematoxylin and eosin and picrosirius red staining of total collagen and lipid droplet areas,followed by quantification using machine learning-based image pixel classifiers.RESULTS ACE2 staining is primarily intracellular and concentrated in the cytoplasm of centrilobular hepatocytes and apical membranes of bile duct cholangiocytes.Strikingly,ACE2 protein levels are elevated in non-fibrotic MASH compared to healthy controls but not in the progression to MASH with fibrosis and in cirrhosis.ACE2 protein levels and histological fibrosis are not associated,but ACE2 and liver lipid droplet content are significantly correlated across the MASLD spectrum.Hepatic ACE2 levels are also increased in COVID-19 patients,especially those showing evidence of LI,but are not correlated with the presence of SARS-CoV-2 virus in the liver.However,there is a clear association between the hepatic lipid droplet content and the presence of the virus,suggesting a possible functional link.CONCLUSION Hepatic ACE2 levels were elevated in nonfibrotic MASH and COVID-19 patients with LI,while lipid accumulation may promote intra-hepatic SARS-CoV-2 replication,accelerating MASLD progression and COVID-19-mediated liver damage.

Indoleamine-2,3-dioxygenase 1/cyclooxygenase 2 expression prediction for adverse prognosis in colorectal cancer

AIM To evaluate indoleamine-2,3-dioxygenase 1/cyclooxygenase 2(IDO1/COX2) expression as an independent prognostic biomarker for colorectal cancer(CRC) patients.METHODS We retrospectively studied the medical records of 95 patients who received surgical resection from August 2008 to January 2010. All patients were randomly assigned to adjuvant treatment with or without celecoxib groups after surgery. We performed standard immunohistochemistry to assess the expression levels of IDO1/COX2 and evaluated the correlation of IDO1/COX2 with clinicopathological factors and overall survival(OS) outcomes.RESULTS The expression of nuclear IDO1 was significantly correlated with body mass index(P < 0.001), and IDO1 expression displayed no association with sex, age, tumor differentiation, T stage, N stage, carcinoembryonic antigen, cancer antigen 19-9, CD3+ and CD8+ tumor infiltrating lymphocytes, and COX2. In univariate analysis, we found that nuclear IDO1(P = 0.039), nuclear/cytoplasmic IDO1 [hazard ratio(HR) = 2.044, 95% confidence interval(CI): 0.871-4.798, P = 0.039], nuclear IDO1/COX2(HR = 3.048, 95%CI: 0.868-10.7, P = 0.0049) and cytoplasmic IDO1/COX2(HR = 2.109, 95%CI: 0.976-4.558, P = 0.022) all yielded significantly poor OS outcomes. Nuclear IDO1(P = 0.041), nuclear/cytoplasmic IDO1(HR = 3.023, 95%CI: 0.585-15.61, P = 0.041) and cytoplasmic IDO1/COX2(HR = 2.740, 95%CI: 0.764-9.831, P = 0.038) have significantly poor OS outcomes for the CRC celecoxib subgroup. In our multivariate Cox model, high coexpression of cytoplasmic IDO1/COX2 was found to be an independent predictor of poor outcome in CRC(HR = 2.218, 95%CI: 1.011-4.48, P = 0.047) and celecoxib subgroup patients(HR = 3.210, 95%CI: 1.074-9.590, P = 0.037).CONCLUSION Our results showed that cytoplasmic IDO1/COX2 coexpression could be used as an independent poor predictor for OS in CRC.

Effect of Propyl Gallate on Activity of Cyclooxygenase 1 and 2 in Mice's Peritoneal Macrophages*

Objective: To investigate the effect of Red Peony 801 (propyl gallate,PrG) on cyclooxygenase (COX) activity in murine peritoneal macrophages. Methods: A screening model for COX inhibitors in vitro based on murine peritoneal macrophages was used. COX-1 activity was reflected by the level of 6-ketoprostaglandin F1α(6-keto-PGF1α) in supernatants of cultured macrophages which were stimulated with calcium ionophore A23187 for a short-term, while COX-2 activity was reflected by the level of prostaglandin E2 (PGE2) in supernatants of cultured macrophages which were stimulated with lipopolysaccharide (LPS) for a long-term. Results: PrG did not affect A23187-induced, COX-1-derived 6-keto-PGF1α synthesis at the concentrations of 1×10-5, 5×10-6 mol/L (P>0.05), but enhanced 6-keto-PGF1α synthesis at the concentrations of 1×10-6, 5×10-7, 1×10-7 mol/L (P<0.01) in vitro, and showed a good dose-dependent manner. It inhibited LPS-induced, COX-2-derived PGE2 synthesis at the concentrations of 1×10-5,1×10-6 mol/L (P< 0. 05). Conclusion: Within the range of 1×10-5 to 1×10-7 mol/L, PrG activated COX-1 at lower concentrations and inhibited COX-2 at higher concentrations in murine peritoneal macrophages.

Cyclooxygenase 2 polymorphism and colorectal cancer:-765G>C variant modifies risk associated with smoking and body mass index

AIM： To explore whether cyclooxygenase 2 （COX-2） -765G〉C polymorphism is associated with susceptibility of colorectal cancer （CRC） and to evaluate the risk of colorectal cancer in relation to environmental exposures and polymorphism. METHODS： We conducted a case-control study of 137 patients with colorectal cancer and 199 cancerfree controls in northeast China. Multivariate logistic regression analysis was performed to calculate the adjusted odds ratio （OR） and 95% confidence interval （95% CI）. RESULTS： The -765G〉C polymorphism was not independently associated with CRC risk. However, risk associated with the polymorphism differed by smoking and body mass index （BMI）. Smoking and BMI associated risks were stronger among those with -765GG genotype, showing that smokers had a 2.682-fold greater risk of CRC than nonsmokers （51/43 vs 68/126, P = 0.006）. Compared to those with a normal body mass index （BMI 18.5-22.9）, those with overweight （BMI 23-24.9） had a 3.909-fold higher risk of CRC （OR = 3.909, 95% CI = 2.081-7.344; P 〈 0.001）, while those with obesity （BMI 〉 25） had a 2.031- fold higher risk of CRC （OR = 1.107, 95% CI = 1.107-3.726; P = 0.022）. is not associated with an increased risk of CRC, -765GG genotype appears to be related to an increased risk in the presence of smoking and higher BMI.

Relationship between expression and distribution of cyclooxygenase-2 and bcl-2 in human gastric adenocarcinoma

AIM: To explore expression and distribution features of COX-2 and bcl-2 in human gastric adenocarcinoma tissues and to study its biological significance.METHODS: Totally 36 human gastric carcinoma samples were enrolled in this study (cardiac adenocarcinoma 16 cases, distal gastric adenocarcinoma 20 cases). The expressions of COX-2 and bcl-2 in cancerous tissues and corresponding para-cancerous tissues were investigated by immunohistochemistry using COX-2 polyclonal antibody and bcl-2 monoclonal antibody. The normal gastric mucosa tissues were used as control.RESULTS: The expressions of COX-2 and bcl-2 in gastric carcinoma were significantly higher than that in the paracancerous tissues (77.8% vs 47.2%, P＜0.01, 80.56% vs 58.33%, P＜0.05). The expression of COX-2 in cardiac adenocarcinoma was remarkably higher than that in the distal gastric carcinoma (93.8% vs 65.0%, P＜0.01). The expression of COX-2 was mainly localized in the cytoplasm of tumor cells and partly in the nucleus. There is a transition of the COX-2 cytoplasmic positivity to nucleic in tumor cells with the increase of gastric carcinoma pathological grade. Interstitial macrophages, fibroblasts and vascular endothelial cells also expressed COX-2. The tissues with higher expression of COX-2 also expressed high level of bcl-2 protein.CONCLUSION: Abnormal expression pattern of COX-2within the tissues of human gastric cancer is correlated with tumor location and lymph node metastasis. COX-2may regulate expression of apoptosis suppressor gene (bcl-2) through interaction of tumor cells and stromal cells and play an important role in the generation and development of tumors, which will be of great help in developing new methods for antitumor therapy.

Comparative analysis of clinicopathological correlations of cyclooxygenase-2 expression in resectable pancreatic cancer

AIM:To perform a comparative analysis of clinicopathological correlations of cyclooxygenase2 (COX2) expression in pancreatic cancer, examined by monoclonal and polyclonal antibodies.METHODS: The COX2 expression in 85 resection specimens of pancreatic ductal adenocarcinoma was immunohistochemically examined using both monoclonal and polyclonal antibodies. The final immunoscores were obtained by multiplying the percentage of positive cells with the numeric score reflecting the staining intensity.COX2 expression levels were classified into three categories (0, 1+, and 2+) and the clinicopathological correlations were statistically evaluated and analyzed.RESULTS: The positive tumor expression rates of COX2 were 80.5% using monoclonal antibody and 69.4% using polyclonal antibody. In the KaplanMeier analysis, no significant correlations were found between levels of COX2 expression and overall survival (OS), but trends to longer OS were found in COX2 negative cases using monoclonal antibody. Significantly longer disease free survival was revealed in COX2 negative cases using monoclonal antibody (P = 0.019). No correlations between COX2 expression levels and grade (G), tumor (T) status and nodal (N) status were demonstrated. Low histological grade showed a strong association with a longer OS (P < 0.001). Correlation of survival and T status revealed a shorter OS in T3 tumors, but the results reached only marginal statistical significance (P = 0.070). In the multivariate Cox proportional hazards regression model, histological grade, T and N status remained valuable predictors of a worse survival with borderline significance for T [hazards ratio (HR) = 4.18 for G (if G = 3, P < 0.001); HR = 1.64 for T (if T = 3, P = 0.065); HR = 2.53 for N (if N = 1, P = 0.006)]. Higher grade, T or N status was associated with a worse OS. CONCLUSION: The immunohistochemically assessed level of COX2 expression does not seem to represent a valuable independent prognostic factor and is not superior to the conventional prognostic factors.

Correlation of brain cell glucose metabolism and patient's condition in children with epileptic encephalopathy An assessment using fluorine-18-fluoro-2-deoxy-D-glucose positron emission computed tomography

We examined a total of 16 children with epileptic encephalopathy using fluorine-18-fluoro-2-deoxy-D-glucose （18F-FDG） positron emission computed tomography （PET）, magnetic resonance imaging （MRI） and electroencephalography. Children with infantile spasms showed significant mental retardation, severely abnormal electroencephalogram recordings, and bilateral diffuse cerebral cortex hypometabolism with I^F-FDG PET imaging. MRI in these cases showed brain atrophy, multi-micropolygyria, macrogyria, and porencephalia. In cases with Lennox-Gastaut syndrome, 18F-FDG PET showed bilateral diffuse glucose hypometabolism, while MRI showed cortical atrophy, heterotopic gray matter and tuberous sclerosis. MRI in cases with myoclonic encephalopathy demonstrated bilateral frontal and temporal cortical and white matter atrophy and 18F-FDG PET imaging showed bilateral frontal lobe atrophy with reduced bilateral frontal cortex, occipital cortex, temporal cortex and cerebellar glucose uptake. In children who could not be clearly classified, MRI demonstrated cerebral cortical atrophy and ~aF-FDG PET exhibited multifocal glucose hypometabolism. Overall, this study demonstrated that the degree of brain metabolic abnormality was consistent with clinical seizure severity. In addition, ~SF-FDG PET imaging after treatment was consistent with clinical outcomes. These findings indicate that ~SF-FDG PET can be used to assess the severity of brain injury and prognosis in children with epileptic encephalopathy.

The roles of carboxylesterase and CYP isozymes on the in vitro metabolism of T-2 toxin

Background: T-2 toxin poses a great threat to human health because it has the highest toxicity of the currently known trichothecene mycotoxins. To understand the in vivo toxicity and transformation mechanism of T-2 toxin, we investigated the role of two principal phase Ⅰ drug-metabolizing enzymes(cytochrome P450 [CYP450] enzymes) on the metabolism of T-2 toxin, which are crucial to the metabolism of endogenous substances and xenobiotics. We also investigated carboxylesterase, which also plays an important role in the metabolism of toxic substances.Methods: A chemical inhibition method and a recombinant method were employed to investigate the metabolism of the T-2 toxin by the CYP450 enzymes, and a chemical inhibition method was used to study carboxylesterase metabolism. Samples incubated with human liver microsomes were analyzed by high performance liquid chromatography-triple quadrupole mass spectrometry(HPLC- Qq Q MS) after a simple pretreatment.Results: In the presence of a carboxylesterase inhibitor, only 20% T-2 toxin was metabolized. When CYP enzyme inhibitors and a carboxylesterase inhibitor were both present, only 3% of the T-2 toxin was metabolized. The contributions of the CYP450 enzyme family to T-2 toxin metabolism followed the descending order CYP3A4, CYP2E1, CYP1A2, CYP2B6 or CYP2D6 or CYP2C19.Conclusions: Carboxylesterase and CYP450 enzymes are of great importance in T-2 toxin metabolism, in which carboxylesterase is predominant and CYP450 has a subordinate role. CYP3A4 is the principal member of the CYP450 enzyme family responsible for T-2 toxin metabolism. The metabolite produced by carboxylesterase is HT-2, and the metabolite produced by CYP 3A4 is 3'-OH T-2. The different metabolites show different toxicities. Our results will provide useful data concerning the toxic mechanism, the safety evaluation, and the health risk assessment of T-2 toxin.

Role of cyclooxygenase-2 in gastric cancer development and progression

Although the incidence of gastric cancer has been declining in recent decades,it remains a major public health issue as the second leading cause of cancer death worldwide.In China,gastric cancer is still the main cause of death in patients with malignant tumors.Most patients are diagnosed at an advanced stage and mortality is high.Cyclooxygenase-2(COX-2)is a ratelimiting enzyme in prostanoid synthesis and plays an important role in the development and progression of gastric cancer.The expression of COX-2 in gastric cancer is upregulated and its molecular mechanisms have been investigated.Helicobacter pylori infection,tumor suppressor gene mutation and the activation of nuclear factor-kappa B may be responsible for the elevated expression of COX-2 in gastric cancer.The mechanisms of COX-2 in the development and progression of gastric cancer are probably through promoting the proliferation of gastric cancer cells,while inhibiting apoptosis,assisting angiogenesis and lymphatic metastasis,and participating in cancer invasion and immunosuppression.This review is intended to discuss,comment and summarize recent research progress on the role of COX-2 in gastric cancer development and progression,and elucidate the molecular mechanisms which might be involved in the carcinogenesis.

Helicobacter pylori infection, gastrin and cyclooxygenase-2 in gastric carcinogenesis

Gastric cancer is one of the most frequent neoplasms and a main cause of death worldwide, especially in China and Japan. Numerous epidemiological, animal and experimental studies support a positive association between chronic Helicobacter pylori(H. pylori) infection and the development of gastric cancer. However, the exact mechanism whereby H. pylori causes gastric carcinogenesis remains unclear. It has been demonstrated that expression of cyclooxygenase-2(COX-2) is elevated in gastric carcinomas and in their precursor lesions. In this review, we present the latest clinical and experimental evidence showing the role of gastrin and COX-2 in H. pylori-infected patients and their possible association with gastric cancer risk.

PKM2 promotes reductive glutamine metabolism

Objective:Pyruvate kinases M(PKM),including the PKM1 and PKM2 isoforms,are critical factors in glucose metabolism.PKM2promotes aerobic glycolysis,a phenomenon known as"the Warburg effect".The purpose of this study was to identify the roles of PKM2 in regulating cellular metabolism.Methods:The CRISPR/Cas9 system was used to generate the PKM-knockout cell model to evaluate the role of PKM in cellular metabolism.Lactate levels were measured by the Vitros LAC slide method on an autoanalyzer and glucose levels were measured by the autoanalyzer AU5800.The metabolism of ^(13)C_6-glucose or ^(13)C_5-glutamine was evaluated by liquid chromatography/mass spectrometry analyses.The effects of PKM on tumor growth were detected in vivo in a tumor-bearing mouse model.Results:We found that both PKM1 and PKM2 enabled aerobic glycolysis,but PKM2 converted glucose to lactate much more efficiently than PKM1.As a result,PKM2 reduced glucose levels reserved for intracellular utilization,particularly for the production of citrate,and thus increased theα-ketoglutarate/citrate ratio to promote the generation of glutamine-derived acetylcoenzyme A through the reductive pathway.Furthermore,reductive glutamine metabolism facilitated cell proliferation under hypoxia conditions,which supports in vivo tumor growth.In addition,PKM-deletion induced a reverse Warburg effect in tumorassociated stromal cells.Conclusions:PKM2 plays a critical role in promoting reductive glutamine metabolism and maintaining proton homeostasis.This study is helpful to increase the understanding of the physiological role of PKM2 in cancer cells.

Cyclooxygenase-2 plays a central role in the genesis of pancreatitis and associated lung injury

BACKGROUND: The exact mechanism by which cyclooxy- genase-2 (COX-2) promotes inflammation in pancreatitis in obscure. This study was undertaken to investigate the role of COX-2 inhibition in an animal model of pancreati- tis , a disease process characterized by a systemic inflamma- tory response and ensuing neutrophil-mediated lung injury. METHODS: Pancreatitis was induced in 24 Sprague-Daw- ley rats by intraperitoneal injection of 20% L-arginine (500 mg/100 g body weight). The animals were randomized into 3 groups (8 rats in each group); controls and rats with pancreatitis intravenously resuscitated with either normal saline (0.9% NaCl 3 ml/kg) at 24 and 48 hours or COX-2 inhibitor (parecoxib 1 mg/kg). Pancreatic and lung inju- ries were assessed histologically. Lung injury was assessed utilizing wet;dry ratio and myeloperoxidase activity to in- dicate pulmonary neutrophil infiltration. A Western blot was used to determine COX-2 protein expression in pancrea- tic tissue. RESULTS: The animals treated with COX-2 inhibitors dis- played significantly less pancreatic and lung injuries than their normal saline counterparts. Histological pancreatic and lung injury scores were significantly reduced (P <0.05) in the COX-2 treated group. Lung wet: dry ratios were sig- nificantly improved and pulmonary neutrophil infiltration was attenuated in the COX-2 group (P<0.05). Western blot analysis confirmed attenuated COX-2 protein expression. CONCLUSION: This study shows, for the first time in a rat model, that adjuvant COX-2 inhibition significandy attenu- ates the severity of both pancreatitis and its associated sys- temic inflammatory response and end-organ injury.