Intestinal Accumulation Research Articles

Role of fluoro-2-deoxyglucose positron emission tomography for the detection of gastrointestinal tract lesions in patients with lung cancer.

The purpose of this study was to clarify the clinical characteristics of lung cancer patients with abnormal accumulation of fluoro-2-deoxyglucose (FDG) in the gastrointestinal tract imaged by positron emission tomography (PET). Of 1071 consecutive patients with primary lung cancer who underwent PET from October 2005 through to March 2010, 25 patients (2.3%) showed localized abnormal FDG accumulation in the gastrointestinal tract. We retrospectively compared the location of abnormal accumulation in the gastrointestinal tract, the maximum standardized uptake value in 1 hour, and final clinical diagnosis. Of the 25 cases, 12 (48%) were true PET-positive cases (esophageal cancer in one case, gastric cancer in one, colorectal cancer in seven, gastrointestinal stromal tumor in one, and lung cancer metastasis to the stomach and small intestine in one patient each). The 13 cases with false PET-positives were gastric polyp in one, gastritis in four, colon polyp in two, diverticulitis in one, and normal physiological accumulation in five. There was also a significant difference between malignancy and benign intestinal accumulation excluding the stomach (P = 0.002). PET was useful for screening the gastrointestinal tract (except the stomach) for malignancy in lung cancer patients.

Targeting Acyl-CoA:Diacylglycerol Acyltransferase 1 (DGAT1) with Small Molecule Inhibitors for the Treatment of Metabolic Diseases

Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final step in triglyceride synthesis. Findings from genetically modified mice as well as pharmacological studies suggest that inhibition of DGAT1 is a promising strategy for the treatment of obesity and type 2 diabetes. Here we characterize a tool DGAT1 inhibitor compound, T863. We found that T863 is a potent inhibitor for both human and mouse DGAT1 in vitro, which acts on the acyl-CoA binding site of DGAT1 and inhibits DGAT1-mediated triacylglycerol formation in cells. In an acute lipid challenge model, oral administration of T863 significantly delayed fat absorption and resulted in lipid accumulation in the distal small intestine of mice, mimicking the effects of genetic ablation of DGAT1. In diet-induced obese mice, oral administration of T863 for 2 weeks caused weight loss, reduction in serum and liver triglycerides, and improved insulin sensitivity. In addition to the expected triglyceride-lowering activity, T863 also lowered serum cholesterol. Hepatic IRS2 protein was dramatically up-regulated in mice treated with T863, possibly contributing to improved insulin sensitivity. In differentiated 3T3-L1 adipocytes, T863 enhanced insulin-stimulated glucose uptake, suggesting a possible role for adipocytes to improve insulin sensitivity upon DGAT1 inhibition. These results reveal novel mechanistic insights into the insulin-sensitizing effects of DGAT1 inhibition in mouse models. Taken together, our study provides a comprehensive evaluation of a small molecule inhibitor for DGAT1 and suggests that pharmacological inhibition of DGAT1 holds promise in treating diverse metabolic disorders.

Campylobacter jejuni Induces Colitis Through Activation of Mammalian Target of Rapamycin Signaling

Campylobacter jejuni is the worldwide leading cause of bacterial-induced enteritis. The molecular and cellular events that lead to campylobacteriosis are poorly understood. We identify mammalian target of rapamycin (mTOR) as a signaling pathway that leads to C jejuni-induced intestinal inflammation. Germ-free (control) or conventionally derived Il10(-/-) mice that express enhanced green fluorescent protein (EGFP) under the control of nuclear factor κB (Il10(-/-); NF-κB(EGFP) mice) were infected with C jejuni (10(9) colony-forming units/mouse) for 12 days; their responses were determined using histologic, semiquantitative reverse-transcription polymerase chain reaction, fluorescence in situ hybridization, transmission electron microscopy, and tissue culture analyses. mTOR signaling was blocked by daily intraperitoneal injections of the pharmacologic inhibitor rapamycin (1.5 mg/kg). CD4(+) T cells were depleted by intraperitoneal injections of antibodies against CD4 (0.5 mg/mouse every 3 days). Bacterial survival in splenocytes was measured using a gentamycin killing assay. C jejuni induced intestinal inflammation, which correlated with activation of mTOR signaling and neutrophil infiltration. The inflamed intestines of these mice had increased levels of interleukin-1β, Cxcl2, interleukin-17a, and EGFP; C jejuni localized to colons and extraintestinal tissues of infected Il10(-/-); NF-κB(EGFP) mice compared with controls. Rapamycin, administered before or after introduction of C jejuni, blocked C jejuni-induced intestinal inflammation and bacterial accumulation. LC3II processing and killing of C jejuni were increased in splenocytes incubated with rapamycin compared with controls. mTOR signaling mediates C jejuni-induced colitis in Il10(-/-) mice, independently of T-cell activation. Factors involved in mTOR signaling might be therapeutic targets for campylobacteriosis.

ChemInform Abstract: Distribution and Accumulation of Antibiotics in Cells and Tissues and Toxicity Studies by Immunocytochemistry

AbstractReview: 85 refs.

Differential expression of human riboflavin transporters -1, -2, and -3 in polarized epithelia: A key role for hRFT-2 in intestinal riboflavin uptake

Transport of riboflavin (RF) across both the brush border membrane (BBM) and basolateral membrane (BLM) of the polarized enterocyte occurs via specific carrier-mediated mechanisms. Although, three human riboflavin transporters (hRFTs), i.e., hRFT-1, hRFT-2 and hRFT-3 are expressed in the intestine, little is known about the cell surface domain(s) at which these specific hRFTs are expressed. Here, we used live cell confocal imaging of intestinal epithelial Caco-2 and renal MDCK cells to show that the hRFT-1 is mainly expressed at the BLM, hRFT-2 is exclusively expressed at the apical membrane, while hRFT-3 is mostly localized inside intracellular vesicular structures (with some expression at the BLM). Further the level of hRFT-2 mRNA expression in Caco-2 cells and in native human intestine is significantly higher than that of hRFT-1 and -3; hRFT-2 was also more efficient in transporting 3H-RF than hRFT-1 and -3. These findings implied an important role for hRFT-2 in intestinal RF uptake, a conclusion that was further supported by findings of hRFT-2 gene-specific siRNA knockdown investigation. These results show that members of the hRFT family are differentially expressed in polarized epithelia, and that the apically expressed hRFT-2 plays a key role in intestinal RF accumulation.

Close association of intestinal autofluorescence with the formation of severe oxidative damage in intestine of nematodes chronically exposed to Al 2O 3-nanoparticle

In nematodes, acute exposure (24-h) to 8.1–30.6 mg/L Al 2O 3-nanoparticles (NPs) or Al 2O 3 did not influence intestinal autofluorescence, whereas chronic exposure (10-d) to Al 2O 3-NPs at concentrations of 8.1–30.6 mg/L or Al 2O 3 at concentrations of 23.1–30.6 mg/L induced significant increases of intestinal lipofuscin accumulation, and formation of severe stress response and oxidative damage in intestines. Moreover, significant differences of intestinal autofluorescence, stress response and oxidative damage in intestines of Al 2O 3-NPs exposed nematodes from those in Al 2O 3 exposed nematodes were detected at examined concentrations. Oxidative damage in intestine was significantly correlated with intestinal autofluorescence in exposed nematodes, and oxidative damage in intestine was more closely associated with intestinal autofluorescence in nematodes exposed to Al 2O 3-NPs than exposed to Al 2O 3. Thus, chronic exposure to Al 2O 3-NPs may cause adverse effects on intestinal lipofuscin accumulation by inducing the formation of more severe oxidative stress in intestines than exposure to Al 2O 3 in nematodes.

Distribution and Accumulation of Antibiotics in Cells and Tissues and Toxicity Studies by Immunocytochemistry

No true immunocytochemistry (ICC) for drugs nor its application to pharmacokinetic studies is available. Recently, our studies have shown that ICC for drugs is extremely useful for such studies by utilizing easy and safe techniques, and gives direct evidence of drug localization. We have therefore developed antibodies and a series of pretreatment conditions for the immunodetection of drugs and have localized sites of drug uptake or accumulation in several tissues of rats following the administration of drugs. This review describes preparation of anti-drug antibody, specificity of antibody, fixation of drug in situ in rat tissues and cells, treatment of paraffin section specimens prior to immunoreaction, precision, and their application to a variety of types of antibiotics anti-cancer anthracyclines daunorubicin, doxorubicin, and epirubicin, bleomycin analog peplomycin, antimicrobial agents gentamicin, and amoxicillin. ICC for the anti-cancer anthracyclines demonstrated that the drug accumulates in a characteristic pattern in the heart, liver, kidney, gastrointestinal tract, and hair follicles, which represent the sites targeted by the drug toxicity. Some, but not all, of these drug accumulations are associated with the induction of apoptosis. It was also noted that there are striking differences in accumulation among the anthracyclines in rat tissues, maybe contributing the mechanisms of the differences in anti-tumor activities of the anthracyclines. Both ICCs for gentamicin and peplomycin identified characteristic necrotic-like cells in the specific sites of the kidney, suggesting the sites are readily affected by some chemotherapeutic agents. ICC for amoxicillin demonstrated that the sites of the drug accumulation in small intestine, liver and kidney are closely correlated with the specific sites in which certain transporter systems for penicillin occur. Thus, an ICC method is a potential new tool for pharmacokinetic studies of wide variety types of drugs containing a primary amino group(s) in their molecules.

Distorted copper homeostasis with decreased sensitivity to cisplatin upon chaperone Atox1 deletion in Drosophila

Copper is an integral part of a number of proteins and thus an essential trace metal. However, free copper ions can be highly toxic and every organism has to carefully control its bioavailability. Eukaryotes contain three copper chaperones; Atx1p/Atox1 which delivers copper to ATP7 transporters located in the trans-Golgi network, Cox17 which provides copper to the mitochondrial cytochrome c oxidase, and CCS which is a copper chaperone for superoxide dismutase 1. Here we describe the knockout phenotype of the Drosophila homolog of mammalian Atox1 (ATX1 in yeast). Atox1-/- flies develop normally, though at reduced numbers, and the eclosing flies are fertile. However, the mutants are unable to develop on low-copper food. Furthermore, the intestinal copper importer Ctr1B, which is regulated by copper demand, fails to be induced upon copper starvation in Atox1-/- larvae. At the same time, intestinal metallothionein is upregulated. This phenotype, which resembles the one of the ATP7 mutant, is best explained by intestinal copper accumulation, combined with insufficient delivery to the rest of the body. In addition, compared to controls, Drosophila Atox1 mutants are relatively insensitive to the anticancer drug cisplatin, a compound which is also imported via Ctr1 copper transporters and was recently found to bind mammalian Atox1.

Scientific Opinion on the substantiation of health claims related to activated charcoal and reduction of excessive intestinal gas accumulation (ID 1938) and reduction of bloating (ID 1938) pursuant to Article 13(1) of Regulation (EC) No 1924/2006

Scientific Opinion on the substantiation of health claims related to activated charcoal and reduction of excessive intestinal gas accumulation (ID 1938) and reduction of bloating (ID 1938) pursuant to Article 13(1) of Regulation (EC) No 1924/2006

Dissecting the impact of protein versus energy host nutrition on the expression of immunity to gastrointestinal parasites during lactation

Many mammals exhibit a periparturient relaxation of previously established immune responses (PPRI) to gastrointestinal nematodes culminating in increased worm burdens. It has been suggested that the extent of PPRI may have a nutritional basis as it is considerably augmented when protein supply is scarce. Subsequent studies have shown that increased dietary protein intake can ameliorate this phenomenon. However, this effect is often confounded with increased food intake and thus increased energy levels. Herein, we aimed to dissect the effects of protein and energy nutrition on the immune status and resistance to re-infection with gastrointestinal nematodes in the periparturient host. The lactating, Nippostrongylus brasiliensis re-infected rat was utilised as an established model for mammalian PPRI. Experimental animals were assigned to restricted feeding regimens designed to achieve four pre-determined levels of crude protein (CP) at one of two levels of metabolisable energy (ME) and parasitological and immunological measurements taken at either day 6 or day 9 post re-infection. We clearly show that increased supply of dietary CP, but not increased dietary ME, significantly reduced worm burdens. The increased magnitude of worm expulsion with increased dietary CP supply strongly correlated with mucosal mast cell accumulation in the small intestine. In addition, increased CP and not ME supply increased mucosal eosinophil numbers. Furthermore, increased CP led to higher levels of total IgG at high ME only and there were interactive effects of CP and ME on serum levels of IgG1 and IgG2a. Perhaps surprisingly, CP nutrition did not affect expression of either Th1 (IFN-γ) or Th2 (IL-4, IL-13) cytokines in the mesenteric lymph nodes. These data emphasise the role of immunonutrition, and particularly dietary protein, in combating infectious disease such as gastrointestinal parasitism.

Immunopathogenesis of Ascaridia galli infection in layer chicken

Gastro-intestinal nematode infections in mammals are associated with local T lymphocyte infiltrations, Th2 cytokine induction, and alterations in epithelial cell secretion and absorption. This study demonstrates that Ascaridia (A.) galli infection in chicken also elicits local gut-associated immune reactions and changes in the intestinal electrogenic nutrient transport. In A. galli-infected birds we observed infiltrations of different T cell populations in the intestinal lamina propria and accumulation of CD4+ lymphocytes in the epithelium. The Th2 cytokines IL-4 and IL-13 dominated the intestinal immune reactions following A. galli infection. A. galli-specific systemic IgY antibodies were detected after two weeks post infection, and did only poorly correlate with detected worm numbers. Electrogenic transport of alanin and glucose was impaired in A. galli-infected chicken. Our data provide circumstantial evidence that local immune responses and electro-physiological intestinal functions may be connected and contribute to the elimination of worm infection.

Interleukin-23 Drives Intestinal Inflammation through Direct Activity on T Cells

(Immunity 33, 279–288; August 27, 2010) In this paper, there was an error in Figure 1F . The histology panel on the left is incorrect; it is the same as the image on the right taken in a different frame. Thus, both images depict the liver of a Rag1−/− host transferred with Il23r−/− T cells. The correct image of a representative liver section of a Rag1−/− host transferred with WT T cells is published here, along with the rest of the figure. The authors regret any inconvenience this error has caused. Interleukin-23 Drives Intestinal Inflammation through Direct Activity on T CellsAhern et al.ImmunityAugust 27, 2010In BriefMutations in the IL23R gene are linked to inflammatory bowel disease susceptibility. Experimental models have shown that interleukin-23 (IL-23) orchestrates innate and T cell-dependent colitis; however, the cell populations it acts on to induce intestinal immune pathology are unknown. Here, using Il23r−/− T cells, we demonstrated that T cell reactivity to IL-23 was critical for development of intestinal pathology, but not for systemic inflammation. Through direct signaling into T cells, IL-23 drove intestinal T cell proliferation, promoted intestinal Th17 cell accumulation, and enhanced the emergence of an IL-17A+IFN-γ+ population of T cells. Full-Text PDF Open Access

Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration

It is of urgent need to identify the exact physico-chemical characteristics which allow maximum uptake and accumulation in secondary target organs of nanoparticulate drug delivery systems after oral ingestion. We administered radiolabelled gold nanoparticles in different sizes (1.4–200 nm) with negative surface charge and 2.8 nm nanoparticles with opposite surface charges by intra-oesophageal instillation into healthy adult female rats. The quantitative amount of the particles in organs, tissues and excrements was measured after 24 h by gamma-spectroscopy. The highest accumulation in secondary organs was mostly found for 1.4 nm particles; the negatively charged particles were accumulated mostly more than positively charged particles. Importantly, 18 nm particles show a higher accumulation in brain and heart compared to other sized particles. No general rule accumulation can be made so far. Therefore, specialized drug delivery systems via the oral route have to be individually designed, depending on the respective target organ.

Development and Evaluation of Endothelin-A Receptor (Radio)Ligands for Positron Emission Tomography

The expression and function of endothelin (ET) receptors are abnormal in cardiovascular diseases, tumor progression, and tumor metastasis. A previously reported promising radioligand for positron emission tomography (PET) based on the non-peptide ET(A) receptor antagonist PD 156707 showed specific binding to target receptors in the myocardium but high accumulation in bile and intestine, probably because of its high lipophilicity. In this study we describe the synthesis of a series of fluorinated derivatives with hydrophilic building blocks. All compounds were evaluated as high affinity ET(A) receptor ligands (16, 17, 23-26, K(i) = 1.4-7.9 nM) with high subtype selectivity over the ET(B) receptor. [(18)F]3-Benzo[1,3]dioxol-5-yl-4-{3-[1-(2-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}ethyl)-1H-[1,2,3]triazol-4-ylmethoxy]-4,5-dimethoxybenzyl}-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one ([(18)F]17) was synthesized as one of the radioligands of this series that possesses a higher hydrophilicity and an excellent stability in human serum. Improved clearance properties and specific uptake in target organs have been confirmed by biodistribution studies and small animal PET imaging.

Modulated pharmacokinetics and increased small intestinal toxicity of methotrexate in bilirubin-treated rats

The effect of bilirubin treatment on the pharmacokinetics and small intestinal toxicity of methotrexate was evaluated in rats, since bilirubin and its glucuronide conjugates can suppress multidrug resistance-associated protein-mediated transport. Rats were treated intravenously with bilirubin and the various clearances and tissue distribution of methotrexate were estimated under a steady-state plasma concentration. Intestinal toxicity induced by methotrexate was also evaluated by measuring the leakage of alkaline phosphatase (ALP) activity. Probenecid, an inhibitor for multidrug resistance-associated protein and organic anion transporters, was used for comparison. The treatment with bilirubin increased the steady-state plasma concentration and reduced biliary excretion clearance, urinary excretion clearance and intestinal exsorption clearance of methotrexate, as did treatment with probenecid. The intestinal absorption and jejunum distribution of methotrexate also significantly increased in bilirubin- and probenecid-treated rats. A greater leakage of ALP activity to the luminal fluid, with a lower ALP activity in the intestinal mucosal membrane after intestinal perfusion of methotrexate, was observed in bilirubin- and probenecid-treated rats. Hyperbilirubinemia, which is involved under various disease states, may increase the small intestinal accumulation and toxicities of methotrexate, since high plasma concentrations of conjugated bilirubin can suppress the function of multidrug resistance-associated proteins, which facilitate the efflux of methotrexate out of cells.

The WSX-1 pathway restrains intestinal T-cell immunity

Mechanisms regulating intestinal T-cell accumulation during inflammation have considerable therapeutic value. In this study, LPS increased Staphylococcus aureus enterotoxin A-specific T cells in the gut through induction of IL-12 family members. Mice deficient in IL-12 (p35(-/-)) favored T(h)17 differentiation in lamina propria, whereas mice lacking both IL-12 and IL-23 (p40(-/-)) produced significantly fewer T(h)17 cells. However, serum analysis revealed that IL-27p28 was much higher and sustained following LPS injection than other IL-12 family cytokines. Strikingly, WSX-1 (IL-27Rα) deficiency resulted in log-fold increases in lamina propria T(h)17 cells without affecting T(h)1 numbers. These results may be explained by increased expression of α4β7 on WSX-1-deficient T cells after immunization. WSX-1-deficient regulatory T cells (Tregs) were also perturbed, producing more IL-17 and less IL-10 than wild-type Tregs. Thus, IL-27 blockade may provide a new pathway to improve mucosal vaccination.

Determination of differential heavy metal and trace element accumulation in liver, gills, intestine and muscle of sterlet (Acipenser ruthenus) from the Danube River in Serbia by ICP-OES

The accumulation of heavy metals in fish has been extensively studied and well documented. However, the research has been mainly focused on the muscle tissue, while the distribution patterns among other tissues, such as liver and gills, have been mostly neglected. Within the present study, the concentrations of Ag, Al, As, B, Ba, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb, Se, Sr, Zn and Li in the muscle, gills, liver and intestine of the sterlet (Acipenser ruthenus) from the Danube River have been assessed by using the inductively-coupled plasma optical spectrometry. The analysis has revealed a high degree of differential accumulation of the studied heavy metals and trace elements in the tissues of the Danube sterlet. Liver appeared to be the main heavy metal storage tissue, while the lowest levels of analyzed metals were found in muscles. Heavy metal concentrations in the muscle were at acceptable levels for human consumption, except partly for cadmium. We conclude that, in order to enable a more efficient control of contaminants in fish products, there is an apparent need to resolve the problem of lack of legal limits for many metals in European legislation.

Impact of Medication Discontinuation on Increased Intestinal FDG Accumulation in Diabetic Patients Treated With Metformin

We evaluated the impact of stopping medication for 2 days on reductions in the high intestinal FDG uptake induced by metformin. One hundred thirty-eight diabetic patients were divided into two groups: one in which the antihyperglycemic drug regimen included metformin (group A; n = 107) and one in which the regimen did not include metformin (group B; n = 31). Fifty-two patients without diabetes mellitus served as the control group (group C). Group A was divided into two subgroups: 77 patients (group A1) were taking metformin at the time of FDG PET/CT scans, whereas the remaining 30 patients (group A2) were asked to stop taking metformin for 2 days before PET/CT scans. In addition, 10 diabetic patients underwent two consecutive PET/CT scans before and after the discontinuation of metformin. The intestinal FDG uptake and blood glucose levels were compared among the four groups, as well as before and after the discontinuation of metformin. The high intestinal FDG uptake in group A1 was significantly reduced after the discontinuation of metformin (p < 0.001 vs group A2); thus, there were no significant differences among group A2, group B, and group C (p = 0.581-0.872). There were also no statistically significant differences in the blood glucose levels among the three groups of diabetic patients (p > 0.9). In 10 patients who underwent serial PET/CT scans, mean intestinal FDG uptake decreased by 64% without significant changes in the blood glucose level. Hidden colorectal malignancies were revealed in two patients after the discontinuation of medication. The discontinuation of metformin for 2 days is feasible for reducing the high intestinal FDG uptake induced by metformin.

Role of Organic Cation Transporter 1, OCT1 in the Pharmacokinetics and Toxicity of cis-Diammine(pyridine)chloroplatinum(II) and Oxaliplatin in Mice

PurposeThe goal of this study was to test the hypothesis that by controlling intracellular uptake, organic cation transporter 1, Oct1 is a key determinant of the disposition and toxicity of cis-diammine(pyridine)chloroplatinum(II)(CDPCP) and oxaliplatin.MethodsPharmacokinetics, tissue accumulation and toxicity of CDPCP and oxaliplatin were compared between Oct1-/- and wild-type mice.ResultsAfter intravenous administration, hepatic and intestinal accumulation of CDPCP was 2.7-fold and 3.9-fold greater in Oct1 wild-type mice (p < 0.001). Deletion of Oct1 resulted in a significantly decreased clearance (0.444 ± 0.0391 ml/min*kg versus 0.649 ± 0.0807 ml/min*kg in wild-type mice, p < 0.05) and volume distribution (1.90 ± 0.161 L/kg versus 3.37 ± 0.196 L/kg in wild-type mice, p < 0.001). Moreover, Oct1 deletion resulted in more severe off-target toxicities in CDPCP-treated mice. Histologic examination of the liver and measurements of liver function indicated that the level of hepatic toxicity was mild and reversible, but was more apparent in the wild-type mice. In contrast, the effect of Oct1 on the pharmacokinetics and toxicity of oxaliplatin in the mice was minimal.ConclusionsOur study suggests that Oct1 plays an important role in the pharmacokinetics, tissue distribution and toxicity of CDPCP, but not oxaliplatin.

Aluminum nanoparticle exposure in L1 larvae results in more severe lethality toxicity than in L4 larvae or young adults by strengthening the formation of stress response and intestinal lipofuscin accumulation in nematodes

Toxicity of Al 2O 3-NPs, as compared to that of Al 2O 3, to L1-larval, L4-larval or young adult nematodes was evaluated. When exposure was performed at L1-larval stage, the significant increases of lethality, stress response, and intestinal lipofuscin autofluorescence were observed in 6.3–203.9 mg/L of Al 2O 3-NPs exposed nematodes. In contrast, when exposure was performed at L4-larval or young adult stage, the significant increases of lethality and intestinal lipofuscin autofluorescence were observed in 12.7–203.9 mg/L of Al 2O 3-NPs exposed nematodes, and the significant inductions of stress response were detected in 25.5–203.9 mg/L of Al 2O 3-NPs exposed nematodes. Moreover, the lethality was significantly correlated with the stress response and the intestinal lipofuscin autofluorescence in Al 2O 3-NPs exposed nematodes. These data imply that Al 2O 3-NPs exposure in L1 larvae causes more severe lethality toxicity than in L4 larvae or young adults by strengthening the formation of stress response and intestinal lipofuscin accumulation in nematodes.