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CO2 emissions are increasing with the expansion of export trade. Against the backdrop of the prominent trend of decarbonization in the global economy, the question of how to rise to the occasion to maintain the advantages of international trade, as well as achieving sustainable growth in export trade, has become an urgent issue for us to consider. This paper uses empirical analysis to propose and establish an econometric model of the symbiosis between carbon emissions and export trade dependence, economic structural changes and clean technology changes, based on the environmental Kuznets curve and using time series data for Guangdong Province from 2000 to 2021. The study found that there is a long-term, stable equilibrium relationship between the scale effect and technology effect on carbon emissions, and a positive relationship between the structural effect and carbon emissions. The study then constructed a symbiotic system of exports and carbon emissions from a symbiotic perspective. The Lotka–Volterra MCGP model was used to measure the evolution of the export and carbon emission symbiosis system from the optimization of three perspectives: the scale and structure of energy consumption under the dual constraints of export trade and carbon emissions, the scale of export trade under the carbon emission constraints, and the scale of carbon emissions under the export trade constraints. The results show that there is considerable room for improvement in the structure of energy consumption and carbon emissions in the current Guangdong export trade process. At the same time, this improvement can be achieved by adjusting the energy consumption structure and improving the efficiency of the system without changing the scale effect, technology effect or structural effect.

In response to infection or tissue damage, resident peritoneal macrophages (rpMACs) produce inflammatory lipid mediators from the polyunsaturated fatty acid (PUFA), arachidonic acid (AA). Long-chain acyl-CoA synthetase 4 (ACSL4) catalyzes the covalent addition of a CoA moiety to fatty acids, with a strong preference for AA and other PUFAs containing three or more double bonds. PUFA-CoA can be incorporated into phospholipids, which is the source of PUFA for lipid mediator synthesis. In this study, we demonstrated that deficiency of Acsl4 in mouse rpMACs resulted in a significant reduction of AA incorporated into all phospholipid classes and a reciprocal increase in incorporation of oleic acid and linoleic acid. After stimulation with opsonized zymosan (opZym), a diverse array of AA-derived lipid mediators, including leukotrienes, PGs, hydroxyeicosatetraenoic acids, and lipoxins, were produced and were significantly reduced in Acsl4-deficient rpMACs. The Acsl4-deficient rpMACs stimulated with opZym also demonstrated an acute reduction in mRNA expression of the inflammatory cytokines, Il6, Ccl2, Nos2, and Ccl5. When Acsl4-deficient rpMACs were incubated in vitro with the TLR4 agonist, LPS, the levels of leukotriene B4 and PGE2 were also significantly decreased. In LPS-induced peritonitis, mice with myeloid-specific Acsl4 deficiency had a significant reduction in leukotriene B4 and PGE2 levels in peritoneal exudates, which was coupled with reduced infiltration of neutrophils in the peritoneal cavity as compared with wild-type mice. Our data demonstrate that chronic deficiency of Acsl4 in rpMACs reduces the incorporation of AA into phospholipids, which reduces lipid mediator synthesis and inflammation.

APOE4 is a strong genetic risk factor for Alzheimer’s disease and Dementia with Lewy bodies; however, how its expression impacts pathogenic pathways in a human-relevant system is not clear. Here using human iPSC-derived cerebral organoid models, we find that APOE deletion increases α-synuclein (αSyn) accumulation accompanied with synaptic loss, reduction of GBA levels, lipid droplet accumulation and dysregulation of intracellular organelles. These phenotypes are partially rescued by exogenous apoE2 and apoE3, but not apoE4. Lipidomics analysis detects the increased fatty acid utilization and cholesterol ester accumulation in apoE-deficient cerebral organoids. Furthermore, APOE4 cerebral organoids have increased αSyn accumulation compared to those with APOE3. Carrying APOE4 also increases apoE association with Lewy bodies in postmortem brains from patients with Lewy body disease. Our findings reveal the predominant role of apoE in lipid metabolism and αSyn pathology in iPSC-derived cerebral organoids, providing mechanistic insights into how APOE4 drives the risk for synucleinopathies.

SummaryAutophagy is a homeostatic degradative process for cell components that enables stress resilience and can determine cellular fate and function. However, lipid sources for the rapid membrane expansions of autophagosomes, the workhorses of autophagy, are poorly understood. Here, we identify de novo lipogenesis (DNL) as a critical source of fatty acids (FA) to fuel autophagosome dynamics in adipocytes. Adipocyte fatty acid synthase (Fasn) deficiency markedly impairs autophagy, evident by autophagosome accumulation, and severely compromises degradation of the autophagic substrate p62. Autophagy dependence on FA produced by Fasn is not fully alleviated by exogenous FA in cultured adipocytes even though lipid droplet size is restored. Imaging studies reveal that Fasn colocalizes with nascent autophagosomes, while loss of Fasn decreases certain membrane phosphoinositides known to be required for autophagosome assembly. Together, our studies highlight a newly appreciated function for adipocyte DNL in autophagosome membrane formation and provide evidence that localized FA synthesis contributes to autophagosome dynamics.

Hepatic steatosis associated with high fat diets, obesity and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl-coenzyme A (AcCoA), a central metabolite and substrate for de novo lipogenesis (DNL), is produced from citrate by ATP-citrate lyase (ACLY) and from acetate through AcCoA synthase short chain family member 2 (ACSS2). However, the relative contributions of these two enzymes to hepatic AcCoA pools and DNL rates in response to high fat feeding is unknown. We report here that hepatocyte-selective depletion of either ACSS2 or ACLY caused similar 50% decreases in liver AcCoA levels in obese mice, showing that both pathways contribute to generation of this DNL substrate. Unexpectedly however, the hepatocyte ACLY depletion in obese mice paradoxically increased total DNL flux measured by D2O incorporation into palmitate, while in contrast ACSS2 depletion had no effect. The increase in liver DNL upon ACLY depletion was associated with increased expression of nuclear sterol regulatory element-binding protein 1c (SREBP1c) and of its target DNL enzymes. This upregulated DNL enzyme expression explains the increased rate of palmitate synthesis in ACLY depleted livers. Furthermore, this increased flux through DNL may also contribute to the observed depletion of AcCoA levels due to its increased conversion to Malonyl CoA (MalCoA) and palmitate. Together, these data indicate that in HFD fed obese mice, hepatic DNL is not limited by its immediate substrates AcCoA or MalCoA, but rather by activities of DNL enzymes.

The abundance of docosahexaenoic acid (DHA) in phospholipids in the brain and retina has generated interest to search for its role in mediating neurological functions. Besides the source of many oxylipins with pro-resolving properties, DHA also undergoes peroxidation, producing 4-hydroxyhexenal (4-HHE), although its function remains elusive. Despite wide dietary consumption, whether supplementation of DHA may alter the peroxidation products and their relationship to phospholipid species in brain and other body organs have not been explored sufficiently. In this study, adult mice were administered a control or DHA-enriched diet for three weeks, and phospholipid species and peroxidation products were examined in brain, heart and plasma. Results demonstrated that this dietary regimen increased (n-3) and decreased (n-6) species to different extent in all major phospholipid classes (PC, dPE, PE-pl, PI and PS) examined. Besides changes in phospholipid species, DHA-enriched diet also showed substantial increases in 4-HHE in brain, heart and plasma. Among different brain regions, the hippocampus responded to the DHA-enriched diet showing significant increase in 4-HHE. Considering the pro- and anti-inflammatory pathways mediated by the (n-6) and (n-3) polyunsaturated fatty acids, unveiling the ability for DHA-enriched diet to alter phospholipid species and lipid peroxidation products in the brain and in different body organs may be an important step forward towards understanding the mechanism(s) for this (n-3) fatty acid on health and diseases.

Mitochondrial dysfunction underlies many heritable diseases, acquired pathologies, and aging-related declines in health. Szeto–Schiller (SS) peptides comprise a class of amphipathic tetrapeptides that are efficacious toward a wide array of mitochondrial disorders and are believed to target mitochondrial membranes because they are enriched in the anionic phospholipid cardiolipin (CL). However, little is known regarding how SS peptides interact with or alter the physical properties of lipid bilayers. In this study, using biophysical and computational approaches, we have analyzed the interactions of the lead compound SS-31 (elamipretide) with model and mitochondrial membranes. Our results show that this polybasic peptide partitions into the membrane interfacial region with an affinity and a lipid binding density that are directly related to surface charge. We found that SS-31 binding does not destabilize lamellar bilayers even at the highest binding concentrations; however, it did cause saturable alterations in lipid packing. Most notably, SS-31 modulated the surface electrostatics of both model and mitochondrial membranes. We propose nonexclusive mechanisms by which the tuning of surface charge could underpin the mitoprotective properties of SS-31, including alteration of the distribution of ions and basic proteins at the interface, and/or modulation of bilayer physical properties. As a proof of concept, we show that SS-31 alters divalent cation (calcium) distribution within the interfacial region and reduces the energetic burden of calcium stress in mitochondria. The mechanistic details of SS-31 revealed in this study will help inform the development of future compound variants with enhanced efficacy and bioavailability.

Hepatic steatosis associated with high-fat diet, obesity, and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl CoA (AcCoA), a central metabolite and substrate for de novo lipogenesis (DNL), is produced from citrate by ATP-citrate lyase (ACLY) and from acetate through AcCoA synthase short chain family member 2 (ACSS2). However, the relative contributions of these two enzymes to hepatic AcCoA pools and DNL rates in response to high-fat feeding are unknown. We report here that hepatocyte-selective depletion of either ACSS2 or ACLY caused similar 50% decreases in liver AcCoA levels in obese mice, showing that both pathways contribute to the generation of this DNL substrate. Unexpectedly however, the hepatocyte ACLY depletion in obese mice paradoxically increased total DNL flux measured by D

Background The efficacy of therapy for cervical cancer is related to the alteration of multiple molecular events and signaling networks during treatment. The aim of this study was to evaluate gene expression alterations in advanced cervical cancers before- and after-trans-uterine arterial chemoembolization- (TUACE). Methods Gene expression patterns in three squamous cell cervical cancers before- and after-TUACE were determined using microarray technique. Changes in AKAP12 and CA9 genes following TUACE were validated by quantitative real-time PCR. Results Unsupervised cluster analysis revealed that the after-TUACE samples clustered together, which were separated from the before-TUACE samples. Using a 2-fold threshold, we identified 1131 differentially expressed genes that clearly discriminate after-TUACE tumors from before-TUACE tumors, including 209 up-regulated genes and 922 down-regulated genes. Pathway analysis suggests these genes represent diverse functional categories. Results from real-time PCR confirmed the expression changes detected by microarray. Conclusions Gene expression signature significantly changes during TUACE therapy of cervical cancer. Theses alterations provide useful information for the development of novel treatment strategies for cervical cancers on the molecular level.

Lipids are the critical components of cellular and plasma membrane, which constitute an impermeable barrier of cellular compartments, and play important roles on numerous cellular processes including cell growth, proliferation, differentiation, and signaling. Alterations in lipid metabolism have been implicated in the development and progression of cancers. However, unlike other biomolecules, the diversity in the structures and characteristics of lipid species results in the limited understanding of their metabolic alterations in cancers. Lipidomics is an emerging discipline that studies lipids in a large scale based on analytical chemistry principles and technological tools. Multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) uses direct infusion to avoid difficulties from alterations in concentration, chromatographic anomalies, and ion-pairing alterations to improve resolution and achieve rapid and accurate qualitative and quantitative analysis. In this chapter, lipids and lipid metabolism relevant to cancer research are introduced, followed by a brief description of MDMS-SL and other shotgun lipidomics techniques and some applications for cancer research.

Nonalcoholic steatohepatitis (NASH) is a severe liver disorder characterized by triglyceride accumulation, severe inflammation, and fibrosis. With the recent increase in prevalence, NASH is now the leading cause of liver transplant, with no approved therapeutics available. Although the exact molecular mechanism of NASH progression is not well understood, a widely held hypothesis is that fat accumulation is the primary driver of the disease. Therefore, diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in triglyceride synthesis, has been explored as a NASH target. RNAi-based therapeutics is revolutionizing the treatment of liver diseases, with recent chemical advances supporting long-term gene silencing with single subcutaneous administration. Here, we identified a hyper-functional, fully chemically stabilized GalNAc-conjugated small interfering RNA (siRNA) targeting DGAT2 (Dgat2-1473) that, upon injection, elicits up to 3 months of DGAT2 silencing (>80%–90%, p < 0.0001) in wild-type and NSG-PiZ “humanized” mice. Using an obesity-driven mouse model of NASH (ob/ob-GAN), Dgat2-1473 administration prevents and reverses triglyceride accumulation (>85%, p < 0.0001) without increased accumulation of diglycerides, resulting in significant improvement of the fatty liver phenotype. However, surprisingly, the reduction in liver fat did not translate into a similar impact on inflammation and fibrosis. Thus, while Dgat2-1473 is a practical, long-lasting silencing agent for potential therapeutic attenuation of liver steatosis, combinatorial targeting of a second pathway may be necessary for therapeutic efficacy against NASH.

Phospholipids play important roles in biological process even at a very low level. For example, bis(monoacylglycerol)phosphate (BMP) is involved in the pathogenesis of lysosomal storage diseases, and polyphosphoinositides (PPI) play critical roles in cellular signaling and functions. Phosphatidylglycerol (PG), a structural isomer of BMP, mediates lipid-protein and lipid-lipid interactions, and inhibits platelet activating factor and phosphatidylcholine transferring. However, due to their low abundance, the analysis of these phospholipids from biological samples is technically challenging. Therefore, the cellular function and metabolism of these phospholipids are still elusive. This chapter overviews a novel method of shotgun lipidomics after methylation with trimethylsilyl-diazomethane (TMS-D) for accurate and comprehensive analysis of these phospholipid species in biological samples. Firstly, a modified Bligh and Dyer procedure is performed to extract tissue lipids for PPI analysis, whereas modified methyl-tert-butylether (MTBE) extraction and modified Folch extraction methods are described to extract tissue lipids for PPI analysis. Secondly, TMS-D methylation is performed to derivatize PG/BMP and PPI, respectively. Then, we described the shotgun lipidomics strategies that can be used as cost-effective and relatively high-throughput methods to determine BMP, PG, and PPI species and isomers with different phosphate position(s) and fatty acyl chains. The described method of shotgun lipidomics after methylation achieves feasible and reliable quantitative analysis of low-abundance lipid classes. The application of this novel method should enable us to reveal the metabolism and functions of these phospholipids in healthy and disease states.

Lipid rafts are microdomains on plasma membrane that contain high levels of cholesterol and sphingolipids. Because of the detergent-resistant property of lipid rafts, lipid rafts isolated by methods that use detergents frequently yield different results. Artifacts can also be introduced through the use of detergents. These limitations could be overcome with a detergent-free method which eliminates possible artificial influences. Importantly, lipid rafts prepared with a detergent-free method is more compatible to mass spectrometric analysis since the ion suppression effect is largely reduced. This chapter describes a detergent-free two-step method for preparation of lipid rafts. Firstly, a purified plasma membrane fraction is prepared from cells by sedimentation of the post-nuclear supernatant (PNS) in a Percoll gradient. Secondly, the as-prepared plasma membranes are sonicated to release lipid rafts which are further isolated by flotation in a continuous gradient of Optiprep solution. Then, we introduce a typical shotgun lipidomics workflow that can be used as a cost-effective and relatively high throughput method to determine the lipidomes of lipid rafts. The method also makes an easy start for lipidomics studies.

Diabetes self-management is key to preventing diabetes complications disproportionately affecting Hispanics. Church appears a promising setting for delivering a diabetes self-management education support (DSMES) program. “Faith-placed” (FP) programing refers to health interventions implemented in the church setting; while “faith-based” (FB) signifies integrating spirituality with health interventions. The Building a Health Temple (BHT) DSMES program integrates spirituality with DSMES to improve diabetic outcomes. This cluster-randomized trial tests the effectiveness of BHT DSMES by adapting an existing DSMES program into faith-based context. A total of 360 participants will be recruited from 18 churches (~20 participants/church). Churches will be randomly assigned to either the FB or FP intervention arm. Intervention activities will be implemented over 14 consecutive weeks. Participants in the FB arm will participate in BHT DSMES including a Health Sermon, the Self-Management Resource Center (SMRC) Diabetes Self-Management Program (DSMP), and a 7-session Healthy Bible Study, delivered by two trained church lay health leaders. Participants in the FP arm will attend the same SMRC DSMP facilitated by outside health professional, followed by a 7-session community health and safety curriculum as a partial attention control intervention. The primary outcome will be a change in Hemoglobin A1c (HbA1c) level. Secondary outcomes include: changes in body mass index, waist circumference, diabetes distress score, diabetes self-care behaviors, eating behavior, and physical activity level. Data will be collected at baseline, 6, 9, and 12 months during the study period. The proposed study will lead to innovative DSMES program delivery through faith settings for Hispanic persons with diabetes.

Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of metabolism including glucose and lipid metabolism, with and without insulin. It is evident that central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms including restoration of dyslipidemia. However, the specific neurons that regulate these glucose-lowering and anti-dyslipidemia effects of leptin remain unidentified. Here we report that leptin receptors (LEPRs) in neurons expressing Cre recombinase driven by a short fragment of a promoter region ofIns2gene (RIP-Cre25Mgnneurons) are required for central leptin signaling to reverse hyperglycemia and dyslipidemia in insulin-deficient mice. Ablation of LEPRs in RIP-Cre25Mgnneurons completely blocks glucose-lowering effects of leptin in insulin-deficient mice. Further investigations reveal that insulin-deficient mice lacking LEPRs in RIP-Cre25Mgnneurons (RIP-CreΔLEPRmice) exhibit greater lipid levels in blood and liver compared to wild-type controls, and that leptin injection into the brain does not suppress dyslipidemia in insulin-deficient RIP-CreΔLEPRmice. Leptin administration into the brain combined with acipimox, which lowers blood lipids by suppressing triglyceride lipase activity, can restore normal glycemia in insulin-deficient RIP-CreΔLEPRmice, suggesting that excess circulating lipids are a driving-force of hyperglycemia in insulin-deficient RIP-CreΔLEPRmice. Collectively, our data demonstrate that LEPRs in RIP-Cre25Mgnneurons significantly contribute to glucose-lowering effects of leptin in an insulin-independent manner by suppression of dyslipidemia.

Mitochondrial dysfunction includes heritable diseases, acquired pathologies, and age-related declines in health. Szeto-Schiller (SS) peptides comprise a class of amphipathic tetrapeptides that have demonstrated efficacy in treating a wide array of mitochondrial disorders, and are believed to target mitochondrial membranes due to their enrichment in the anionic phospholipid cardiolipin (CL). However, little is known regarding how SS peptides interact with or alter the physical properties of lipid bilayers. In this study, we have analyzed the interactions of the lead compound SS-31 (Elamipretide) with model and mitochondrial membranes using biophysical and computational approaches. Our results show that this polybasic peptide partitions into the membrane interfacial region with affinity and binding density that are directly related to surface charge. SS-31 binding does not destabilize lamellar bilayers even at the highest binding concentrations; however, it does cause saturable alterations in lipid packing. Most notably, SS-31 modulates the surface electrostatic properties of model and mitochondrial membranes, which could play a significant role in the mitoprotective properties of this compound. As a proof of concept, we show that SS-31 alters ion distribution at the membrane interface with implications for maintaining mitochondrial membranes subject to divalent cation (calcium) stress. Taken together, these results support a mechanism of action in which SS peptides interact with lipid bilayers and alter the biophysical (primarily electrostatic) properties of mitochondrial membranes as their primary mechanism of action. Understanding this molecular mechanism is key to the development of future compound variants with enhanced efficacy.SignificanceSzeto-Schiller (SS) peptides are among the most promising therapeutic compounds for mitochondrial dysfunction. However, the molecular target(s) and the mechanism of action of SS peptides are poorly understood. In this study, we evaluate the interaction of the lead compound SS-31 (Elamipretide) with mitochondrial and synthetic model membranes using a host of biophysical techniques. Our results show that SS-31 membrane interaction is driven largely by the negative surface charge of mitochondrial membranes and that SS-31 alters lipid bilayer properties, most notably electrostatics at the membrane interface. This work supports a mechanism in which SS peptides act on a key physical property of mitochondrial membranes rather than with a specific protein complex, consistent with the exceptionally broad therapeutic efficacy of these compounds.

Background and Objective: Type 2 diabetes disproportionally affects Hispanics. Diabetes self-management is key to preventing its life threating complications. Most Hispanics affiliate with churches, presenting a promising venue for delivering diabetes self-management support (DSMS) program. “Faith-placed” (FP) programing refers to health intervention implemented in church setting; while "faith-based" (FB) signifies integrating spirituality with health interventions. Building a Healthy Temple DSMS Program integrates spirituality with DSMS to improve diabetic outcomes. Setting and Subjects: Predominantly Hispanic churches in Texas; Diabetic churchgoers. Methods: This 13-week cluster-RCT assigned 18 churches to: 1) FB Group receiving a Health Sermon, 6-session DSMS, and 6-session Healthy Bible Study delivered by trained church lay leaders; or 2) FP Group receiving 6-session DSMS accompanied by a 7-session partial attention control curriculum delivered by outside professionals. Key outcome measures included HbA1c, BMI, waist circumference (WC), DSM Self-efficacy and diabetes quality of life (DQL) using the Problem Areas in Diabetes Scale (PAID). Data are collected at baseline, 6, 9, and 12 months. Intervention effects were determined using Linear mixed-effect models, controlled for age, gender and baseline corresponding outcome measures. Preliminary Results: To date, 3 FP (n=48) and 3 FB churches (n=49) have delivered interventions and collected 9 month data. Post intervention, the FB Group appears to have a lower HbA1c than the FP Group (6.56 vs. 6.79; p=0.095). Single-group sub-analyses showed that only the FB Group sustained a 4% HbA1c reduction at 9 months (p Conclusions: Integrating spirituality with DSMS could lead to improved diabetes outcomes among Hispanic diabetic churchgoers. Disclosure S.R. Wilmoth: None. L. Carrillo: None. M. Pan: None. D. Chavarria: None. B. Wilhite: None. D. Parra-Medina: None. M. He: None. Funding American Diabetes Association (1-17-ICTS-029 to M.H.)

Glioblastoma (GBM), a mostly lethal brain tumor, acquires large amounts of free fatty acids (FAs) to promote cell growth. But how the cancer avoids lipotoxicity is unknown. Here, we identify that GBM upregulates diacylglycerol-acyltransferase 1 (DGAT1) to store excess FAs into triglycerides and lipid droplets. Inhibiting DGAT1 disrupted lipid homeostasis and resulted in excessive FAs moving into mitochondria for oxidation, leading to the generation of high levels of reactive oxygen species (ROS), mitochondrial damage, cytochrome c release, and apoptosis. Adding N-acetyl-cysteine or inhibiting FA shuttling into mitochondria decreased ROS and cell death induced by DGAT1 inhibition. We show in xenograft models that targeting DGAT1 blocked lipid droplet formation, induced tumor cell apoptosis, and markedly suppressed GBM growth. Together, our study demonstrates that DGAT1 upregulation protects GBM from oxidative damage and maintains lipid homeostasis by facilitating storage of excess FAs. Targeting DGAT1 could be a promising therapeutic approach for GBM.

Fatty acids are essential building blocks and energy substrates of lipids in cells. They constitute the major structural components of membrane lipids, i.e., glycerophospholipids and sphingolipids, and also serve as an important energy resource. Whereas excess fatty acids or dysregulation of fatty acid metabolism causes lipotoxicity, leading to severe cell damage. We previously identified that lipid metabolism is dramatically altered in glioblastoma (GBM), especially fatty acid synthesis, which is greatly elevated in various types of cancers. However, how tumor cells prevent excessive fatty acids accumulation from inducing lipotoxicity has rarely been studied. We recently identified that GBM greatly upregulates diacylglycerol-acyltransferase 1 (DGAT1) to direct excess fatty acids into triglycerides and lipid droplets to prevent oxidative stress. Inhibiting DGAT1 disrupts lipid homeostasis and shifts excessive fatty acids moving into mitochondria for oxidation, resulting in a high level of reactive oxygen species (ROS), mitochondrial damage, cytochrome c release and apoptosis. Inhibiting carnitine palmitoyltransferase to reduce fatty acids shuttling into mitochondria significantly decreases ROS and rescues cell death caused by DGAT1 inhibition. Xenograft models show that genetic or pharmacological inhibition of DGAT1 blocks lipid droplet formation, induces tumor cell apoptosis and markedly suppresses GBM tumor growth. Together, our study demonstrates that DGAT1 upregulation protects GBM from oxidative damage and maintains lipid homeostasis by facilitating excess fatty acids storage. Our data further show that targeting DGAT1 specifically induces lipotoxicity in tumor cells, while sparing normal brain, which is a very promising therapeutic strategy antagonizing GBM and has a high potential to shift current paradigm in treating GBM.

We retrospectively examined a large cohort of esophageal carcinoma patients who received early enteral nutrition (EEN) to clarify the validity of EEN compared with total parenteral nutrition (TPN). Included were a total of 665 consecutive patients with histologically confirmed carcinoma of the esophagus or esophagogastric junction; and all patients underwent esophagectomy. The patients were divided into two groups: TPN (n = 262) and EEN (n = 403). The TPN group consisted of patients who only received intravenous nutrition support after operation. The postoperative length of hospital stay (PLOS), anastomotic leakage, mortality after surgery, and hospital charges were reviewed and analyzed. Compared with the TPN group, the EEN group had significantly shorter mean PLOS (15.6 days vs. 22.5 days; P0.01). Multivariable linear regression analysis revealed EEN to be associated with shorter PLOS even after adjustment for tumor histology, tumor location, type of esophagectomy, and postoperative albumin infusion. Hospital charges were also significantly less for those in the EEN group than the TPN group. There was no significant difference between the two groups regarding the complication of anastomotic leakage and clinical outcome after surgery. These findings suggest that EEN reduces PLOS and hospital charges of Chinese esophageal cancer patients who had an esophagectomy.

The mechanical performance of fiber reinforced polymer (FRP) reinforced concrete structure is directly affected by the bond behavior between concrete and FRP bars, which is obviously different from steel bars. The bond characteristics of adhering sand and ribbed surface FRP bars (ASRSFBs) and plain FRP bars were investigated in pullout tests and compared to that of ribbed steel bars and plain steel bars, respectively. Results of the tests indicated that ASRSFBs showed good bond capacity with concrete and the bond strength and slip values of the profiled FRP bars were a little lower than that of ribbed steel bars, while the plain FRP bars were proved to be unable to serve as reinforcement owing to far lower bond strength than that of plain steel bars. Moreover, the specimens reinforced with ASRSFBs exhibited a pull-out failure mode, and the adhering sand on the surface of FRP bars were ground into powder-like. Shear slip was found between ribbed protrusion and core fiber of FRP bars, causing longitudinal shear-bond failure. It was concluded that the bond strength was controlled by the type of resin.

The protective effect of dietary carotenoid intake on the risk of breast cancer is inconclusive. Moreover, data on dietary carotenoids in relation to breast cancer in non-Western populations are scarce. The aim of the present study was to examine the association between dietary carotenoid intake and the risk of breast cancer among Chinese women. A total of 561 cases and 561 controls who were frequency matched by age (5-year interval) and residence were recruited in the present case–control study. Dietary intake information was collected by a face-to-face interview using a validated FFQ. The OR and 95 % CI were assessed by multivariate logistic regression after adjusting for various potential confounders. An inverse association was observed between the consumption of α-carotene, β-carotene, β-cryptoxanthin and lutein/zeaxanthin and the risk of breast cancer. The multivariate-adjusted OR for the highest quartile of intake compared with the lowest quartile of intake were 0·61 (95 % CI 0·43, 0·88) for α-carotene, 0·54 (95 % CI 0·38, 0·78) for β-carotene, 0·38 (95 % CI 0·26, 0·52) for β-cryptoxanthin and 0·49 (95 % CI 0·34, 0·71) for lutein/zeaxanthin. Lycopene intake was not found to be associated with the risk of breast cancer, with the adjusted OR of 0·89 (95 % CI 0·61, 1·30). These inverse associations were more evident among pre-menopausal women and women who were exposed to second-hand smoke. The protective effect of specific carotenoid intake was observed for all subtypes of hormone receptor status of breast cancer. The present study indicated that a greater intake of specific carotenoids was associated with a decreased risk of breast cancer among Chinese women residing in Guangdong.

Few epidemiological studies have evaluated the association of choline and betaine intake with breast cancer risk and the results remain inconsistent. This study aimed to assess the relationship between dietary intake of choline and betaine and the risk of breast cancer among Chinese women. A two‐stage case‐control study was conducted, with 807 cases and 807 age‐ (5‐year interval) and residence (rural/urban)‐matched controls. A validated food frequency questionnaire was used to assess dietary intake by face‐to‐face interview. An unconditional logistic regression model was used to calculate multivariate‐adjusted odds ratios (OR) and 95% confidence intervals (CI). A significant inverse association was found between dietary choline and betaine consumption and breast cancer risk. The adjusted OR for the highest quartile of intake compared with the lowest were 0.40 (95% CI = 0.28–0.57, P (trend)

To determine the effects of gonadal hormones on proliferation of the hippocampal neural cells, which are of importance in learning and memory function. 17β-Estradiol or testosterone was added to the culture at various concentrations. Their proliferation and protective effects on the neural cell were determined with BrdU, flow cytometry and MTT assay. Effects of the gonadal hormones on brain-derived neurotrophic factor (BDNF) expression were determined using ELISA and RT-PCR respectively. 17β-Estradiol and testosterone at 20 nM or higher concentrations significantly increased the neural cell proliferation and viability, and induced increasing in the S phase arrest which is essential for cell proliferation. Both estradiol and testosterone significantly increased the neural cell expression of cellular mature BDNF and BDNF mRNA. Effect of testosterone on hippocampal neural proliferation was blocked by Trk neurotrophin receptor inhibitor. 17β-Estradiol and testosterone promoted hippocampal neural proliferation and improved cell viability in vitro. The effect of testosterone on hippocampal neural cell proliferation required neurotrophin receptor activation.

Estrogen replacement therapy (ERT) reduces the risk of Alzheimer’s disease and symptoms in postmenopausal and elderly women. However, ERT is associated with increased risk of uterine and breast cancer. Dietary phytoestrogens have been suggested as a potential alternative to ERT, while little information is available regarding the effects and the underlying mechanisms of such treatment on central neuron function. The present study aimed to determine the effects of phytoestrogens including genistein and daidzein on the proliferation and survival of the hippocampus neural cells, which are of importance in learning and memory function. H19-7/IGF-IR neural cell line was cultured in DMEM absented of serum for 72 h, and treated with various concentrations of genistein, daidzein or 17β-estradiol. Neuronal cell viability and proliferation were determined by MTT and BrdU assay, respectively Cell cycle analysis was performed using flow cytometry. The effects of genistein and daidzein on brain-derived neurotrophic factor (BDNF) mRNA and protein expression were determined by RT-PCR and ELISA, respectively. The effect of Trk receptors inhibitor on genistein and daidzein — induced hippocampus neuronal cell proliferation was also examined. 17β-estradiol, genistein and daidzein ranged from 20 nM to 2000 nM significantly promoted hippocampus neuronal cell viability and proliferation. Similar to the effect of 17β-estradiol, genistein and daidzein induced an increase in the percentage of cells in S phase. Genistein and daidzein significantly increased the expression of BDNF mRNA and protein levels. The effect of genistien and daidzein on hippocampus neuronal proliferation was blocked by K252a, a selective Trk receptors inhibitor. This study concluded that genistein and daidzein improved hippocampus neuronal cell viability and proliferation in vitro. These neuroprotective effects might be mediated by BDNF-Trk pathway.

Nasopharyngeal carcinoma (NPC) is an endemic malignant disease of the head and neck region with unique features including striking ethnic and geographic variations as well as multifactorial etiology. Previous studies have demonstrated the anticancer properties of genistein, the major soy isoflavonoid, in several human cancer cells such as breast, prostate, colon, gastric, lung, and hepatoma. However, the action of genistein in NPC cells has not been determined. In this study, we investigated the inhibitory effects of genistein on NPC cells and its possible underlying mechanisms. We found that genistein dose-dependently inhibited the proliferation of human NPC cell line CNE2 cells. DNA flow cytometric analysis revealed that 30 to 120 microM genistein induced dramatic G2/M phase arrest in NPC cells. The mRNA expression levels, as shown by gene expression array and quantitative real-time polymerase chain reaction, and the protein expression levels of the cell cycle regulators p21(Cip1) and ATR (Ataxia telangiectasia and Rad3 related) were elevated following genistein treatment. Interestingly, we also observed concomitant induction of p15(Ink4b) in genistein induced inhibitory effects in NPC cells. Moreover, selective estrogen receptor modulators did not affect genistein induced growth inhibition. These findings provide new insights into the potential intervention of NPC with genistein.

Background Estrogen or phytoestrogens treatment has been suggested to improve cognitive function of the brain in postmenopausal women. However, there is lack of information on the mechanism of such treatment on the central nervous system. The present study aimed to determine the effects of estradiol and soy germ phytoestrogens on spatial memory performance in ovariectomized rats and to explore the underlying mechanisms affecting the central nervous system. Methods Ovariectomized Sprague-Dawley rats were fed a basic diet supplemented with soy germ phytoestrogens (0.4 g/kg or 1.6 g/kg) or 17β-estradiol (0.15 g/kg) for 12 weeks. At the end of the experiment, animals were evaluated for their spatial learning and memory performance by the Morris Water Maze task. The expressions of brain-derived neurotrophic factor (BDNF) and synaptic formation proteins in the hippocampal tissue were estimated using RT-PCR and ELISA. Results It was found that rats supplemented with soy germ phytoestrogens or estradiol performed significantly better in spatial memory acquisition and retention when compared to the rats fed on the control diet. Estradiol or the high dose of phytoestrogens treatment significantly increased BDNF concentration and the mRNA levels for BDNF and its TrkB receptors as well as the synaptic formation proteins, synaptophysin, spinophilin, synapsin 1 and PSD-95, in the hippocampal tissue of the experimental animals. It was also found that phytoestrogens, in contrast to estradiol, did not show any significant effect on the vaginal and uteri. Conclusion Soy germ phytoestrogens, which may be a substitute of estradiol, improved spatial memory performance in ovariectomized rats without significant side-effects on the vaginal and uteri. The memory enhancement effect may relate to the increase in BDNF and the synaptic formation proteins expression in the hippocampus of the brain.