Effectiveness of prehabilitation during neoadjuvant therapy for patients with esophageal or gastroesophageal junction cancer: a systematic review.

Progression of the physical weakness during neoadjuvant therapy (NAT) in patients with esophageal or gastroesophageal junction cancer is a serious problem; however, prehabilitation during NAT has the potential to overcome the unmet need. Nevertheless, systematic reviews on this topic have not been summarized. Therefore, this systematic review aimed to determine prehabilitation's effectiveness, acceptability, and safety during NAT for patients with esophageal or gastroesophageal junction cancer. An electronic search was performed in the MEDLINE, Web of Science, CENTRAL, CINAHL, and PEDro databases. A meta-analysis was conducted to assess the effectiveness of prehabilitation during NAT, along with a descriptive analysis of acceptance and safety. This study analyzed data from three randomized controlled trials (RCTs) and nine non-RCTs involving 664 patients. The meta-analysis of two RCTs demonstrated that prehabilitation during NAT may be more effective than usual care in enhancing tolerance to NAT and grip strength; moreover, one RCT and three non-RCTs revealed that prehabilitation may reduce the risk of postoperative complications. The adherence rates for exercise programs in two RCTs and seven non-RCTs were 55-76%. Additionally, two studies reported a 76% adherence rate for multimodal prehabilitation programs, including exercise, dietary, and psychological care. Six studies reported no serious prehabilitation-related adverse events during NAT. Prehabilitation during NAT may be a safe and beneficial intervention strategy for patients with esophageal or gastroesophageal junction cancer. However, the investigation of strategies to enhance adherence is essential. Furthermore, additional high-quality RCTs are needed to examine the effect of prehabilitation during NAT.

The implementation status of prehabilitation during neoadjuvant chemotherapy for patients with locally advanced esophageal cancer: a questionnaire survey to the board-certified facilities in Japan.

BACKGROUND: Prehabilitation during neoadjuvant therapy has the potential to improve clinical outcomes. However, information on its global dissemination status is limited. This Japanese nationwide survey investigated the implementation status of and barriers to prehabilitation during neoadjuvant chemotherapy (NAC) for patients with locally advanced esophageal cancer in hospitals. METHODS: This multicenter nationwide survey was conducted by post. The eligible facilities were 155 Japanese hospitals that had been certified within the last 10 years as authorized institutes for board-certified esophageal surgeons by the Japan Esophageal Society. We administered an original questionnaire to investigate the current status of prehabilitation during NAC. RESULTS: The response rate was 75% (117/155 facilities). Forty-six facilities (39%) provided prehabilitation during NAC. The most frequently selected reasons for not providing or providing insufficient prehabilitation were lack of human resources, issues with the reimbursement of medical fees, difficulty in providing continuous prehabilitation during repeated inpatient and outpatient care, the lack of established standard prehabilitation programs, challenges in providing multidisciplinary prehabilitation, and difficulty in managing physical symptoms. CONCLUSION: We observed that the implementation rate of prehabilitation during NAC was low. Critical reasons were not only the lack of medical resources but also the lack of evidence-based standard prehabilitation programs during NAC and the lack of evidence for how to continuously deliver prehabilitation during NAC to patients with physical symptoms.

Retrospective study on the trajectories of lower limb volume after outpatient-based complex decongestive therapy in post-operative gynecological cancer patients with lymphedema.

PURPOSE: To determine the effect of outpatient-based complex decongestive therapy in patients with secondary lower limb lymphedema (LLL) after gynecologic cancer surgery using group-based trajectory modeling (GBTM), and to examine factors predictive of the treatment course. METHODS: This retrospective study included participants who underwent surgery for gynecological cancer with pelvic lymph node dissection and subsequently visited the outpatient clinic for the treatment of stage II LLL according to the International Society of Lymphology. The improvement rate of edema at the initial visit and 3, 6, and 12 months later was assessed by calculating the volume of the lower extremity using the circumferential method. For evaluation of the patterns of treatment course, logistic regression analysis was performed after group estimation by the trend of the treatment course using GBTM. RESULTS: A total of 148 women (mean age 60.6 years (standard deviation: 13.4 years)) were analyzed. Three improvement trajectories were identified: (1) no response group, with worsening rather than improvement (n = 26); (2) moderate response group, with a slow improvement rate (n = 89); and (3) high response group, with a high improvement rate (n = 33). In addition, adherence to compression therapy at 3 months post-intervention was found to be a predictor in the no response group. CONCLUSIONS: GBTM estimated that there are three patterns of the treatment course in patients with LLL after gynecologic cancer surgery. Adherence to compression therapy at 3 months post-intervention is a predictor of the treatment effectiveness.

Priority of the basic and instrumental activities of daily living in older patients with cancer prescribed rehabilitation: a cross-sectional survey.

BACKGROUND: There is no information on whether vulnerable older patients with cancer consider basic activities of daily living (BADL) and instrumental activities of daily living (IADL) important outcomes. Our survey aimed to investigate the priority of BADL and IADL in outcomes among vulnerable older patients with cancer. METHODS: This was a single-center survey in a Japanese cancer center. Eligible patients were ≥ 65 years of age and were prescribed in-hospital rehabilitation while under cancer treatment. Using original self-administered ranking questionnaires, patients were asked to rank outcomes and subdomain of BADL and IADL. High-priority domains were defined as the highest, second-highest, and third-highest priority domains in individuals. RESULTS: A total of 169 patients were analyzed. The mean age was 74.0 years (standard deviation, 5.1 years) and the number of males was 107 (63%). The order of ranking of high-priority outcomes was BADL and IADL (n = 155), cognitive function (n = 91), mental function (n = 82), nutrition (n = 61), social function (n = 51), comorbidity (n = 39), and life span (n = 28). The top three high-priority independence subdomains of BADL and IADL were toilet use (n = 140), feeding (n = 134), and mobility (n = 69) among the BADL and shopping (n = 93), food preparation (n = 88), and ability to handle finances (n = 85) among the IADL. CONCLUSIONS: BADL and IADL can be considered the most important health outcomes in clinical trials and in practice among older patients with cancer and physical vulnerabilities.

Prognostic Impact of Postoperative Loss of Skeletal Muscle Mass in Patients Aged 70 Years or Older with Esophageal Cancer.

BACKGROUND: The number of patients with esophageal cancer aged ≥ 70 years with a poor prognosis is increasing. In general patients with esophageal cancer, postoperative loss of skeletal muscle mass (SMM) is a prognostic factor. This study was designed to investigate the prognostic impact of postoperative loss of SMM in patients aged ≥ 70 years with esophageal cancer. METHODS: This study was a single-center, retrospective cohort study. Patients with esophageal cancer who underwent R0 esophagectomy between 2016 and 2020 were included. The percentage postoperative loss of skeletal muscle mass index (SMI%) was calculated using computed tomography images before and at 4 ± 2 months after surgery. RESULTS: The number of subjects in the ≥ 70-year and < 70-year age groups was 166 and 218, respectively. The median SMI% was 5% in all patients; thus, 5% was defined as the cutoff point to define major loss of SMI. Major loss of SMI impacted 3-year overall survival (OS) in the ≥ 70-year age group, independent of age, sex, clinical stage, pathological T and N factors, Charlson comorbidity index, and length of hospital stay (adjusted hazard ratio [HR]: 4.400; 95% confidence interval: 1.202-16.105; P = 0.025). The adjusted HR of major loss of SMI in the ≥ 70-year age group was higher than in the < 70-year age group (adjusted HR: 4.400 vs. 2.388, respectively). CONCLUSIONS: Postoperative loss of SMI in patients with esophageal cancer aged ≥ 70 years more strongly impacted 3-year OS than in patients aged < 70 years.

Prognostic Impact of the Loss of Skeletal Muscle Mass During Neoadjuvant Chemotherapy on Older Patients with Esophageal Cancer.

BACKGROUND: In older adults, skeletal muscle mass is an important factor for health and prognosis. The loss of SMM during neoadjuvant therapy affects the prognosis of patients with locally advanced esophageal cancer. However, information is limited regarding this possibility in older patients. This study aimed to establish the prognostic impact of SMM loss during neoadjuvant chemotherapy on older patients with locally advanced esophageal cancer. METHODS: This was a single-center retrospective cohort study. Patients age 65 years or older had undergone R0 curative esophagectomy after NAC. The skeletal muscle mass index before and after NAC was calculated from computed tomography images. The percentage change in the SMI during NAC (SMI%) was calculated from the SMI before and after NAC. RESULTS: The study analyzed 150 patients with a mean age of 71.1 ± 3.7 years. The mean value of the SMI was 42.7 ± 7.2 cm2/m2 before NAC, and the SMI% was - 6.4% ± 5.9%. The cutoff of SMI% for overall survival was defined by the log-rank test as - 12%. The Cox proportional hazard model showed that major loss of the SMI (≥ 12%) significantly influenced OS (hazard ratio, 2.490; 95% confidence interval, 1.121-5.529; p = 0.025) independently of age, sex, pathologic T and N factors, or treatment regimen. CONCLUSIONS: Major SMI loss has an impact on OS after R0 curative esophagectomy for older patients with locally advanced esophageal cancer.

Association of sarcopenia with relative dose intensity of neoadjuvant chemotherapy in older patients with locally advanced esophageal cancer: A retrospective cohort study.

INTRODUCTION: Sarcopenia impacts the toxicity of chemotherapy in patients with cancer, but there is little information on the association of sarcopenia with the relative dose intensity (RDI) of chemotherapy. We investigated the association of sarcopenia with RDI of neoadjuvant chemotherapy (NAC) in older patients with locally advanced esophageal cancer (LAEC). MATERIALS AND METHODS: This was a single-center retrospective cohort study of patients aged ≥65 years who underwent curative esophagectomy after NAC for LAEC between 2016 and 2020. Skeletal muscle mass index (SMI) was calculated from computed tomography images at the L3 level. Sarcopenia was defined using the Youden index of SMI. Average RDI was calculated from delivered-dose intensity and standard-dose intensity of all drugs. The cutoff point of low average RDI was defined as <85%. The multivariate logistic regression model was used for the endpoint. RESULTS: We analyzed 188 patients with a mean age of 71.3 years. The cutoff points of sarcopenia for low average RDI were defined as 42.81 cm2/m2 in males and 37.48 cm2/m2 in females. Sarcopenia significantly affected low average RDI, adjusted for age, sex, body mass index, drug regimen, clinical stage, and creatinine clearance (adjusted odds ratio: 2.195, 95% confidence interval: 1.107-4.411, p = 0.024). Compared with the non-sarcopenia patients, the sarcopenia patients with low average RDI had a higher rate of dose reduction, delayed, or discontinuation after the first cycle because of neutropenia (45% vs. 38%), and decreased performance status (11% vs. 0%). DISCUSSION: Sarcopenia predicted low average RDI (<85%) of NAC in older patients with LAEC. In the future, the information about the mechanism of association of sarcopenia with RDI will progress the development of intervention strategy and novel supportive care.

Skeletal muscle mass recovery after oesophagectomy and neoadjuvant chemotherapy in oesophageal cancer: retrospective cohort study.

OBJECTIVE: Skeletal muscle mass (SMM) is an important biomarker for prognosis and health in older patients with cancer. Limited information is available on the recovery course of SMM after oesophagectomy following neoadjuvant chemotherapy (NAC) in older patients. This study was performed to investigate the recovery course of SMM after oesophagectomy following NAC and the preoperative predictors of delayed recovery in older patients with locally advanced oesophageal cancer (LAEC). METHODS: This single-centre retrospective cohort study involved older (≥65 years) and non-older (<65 years) patients with LAEC who underwent oesophagectomy following NAC. The SMM index (SMI) was calculated using CT images. One-way analysis of variance and multivariate logistic regression analysis were performed. RESULTS: In total, 110 older patients and 57 non-older patients were analysed. Loss of the SMI after NAC to 12 months postoperatively was significantly greater in older patients than in non-older patients (p<0.01). The significant preoperative predictor of delayed recovery of the SMI 12 months after surgery was loss of the SMI during NAC in older patients (per 1%: adjusted OR 1.249; 95% CI 1.131 to 1.403; p<0.001), but not in non-older patients (per 1%: OR 1.074; 95% CI 0.988 to 1.179; p=0.108). CONCLUSIONS: There is an especially large unmet need for preventing the long-term sequelae of SMM loss in older patients with LAEC after oesophagectomy following NAC. In older patients, loss of SMM during NAC is an especially useful biomarker for prescribing postoperative rehabilitation to prevent postoperative loss of SMM.

Impact of early postoperative factors on changes in skeletal muscle mass after esophagectomy in older patients with esophageal cancer.

BACKGROUND: Loss of skeletal muscle mass, measured by the skeletal muscle mass index (SMI), after esophagectomy negatively impacts prognosis. However, the information to develop novel supportive care options for preventing loss of skeletal muscle mass is limited. The purpose of this retrospective cohort study was to investigate the impact of early postoperative factors on change in SMI 4 months after curative esophagectomy in older patients with esophageal cancer. METHODS: This study included 113 subjects who underwent esophagectomy between 2015 and 2020. Preoperative and postoperative SMI (cm2/m2) were calculated from computed tomography images. The percentage change in SMI 4 months after surgery (SMI%) was calculated as follows: ([postoperative SMI - preoperative SMI] ÷ preoperative SMI) × 100. Potential factors affecting percentage change of SMI after surgery were analyzed by multiple regression. RESULTS: The mean SMI% was - 5.6%. The percentage change (per 1%) in quadriceps muscle strength in the first month after surgery (standardized ß = 0.190, p = 0.048) impacted the SMI%, which was independent of age, sex, preoperative SMI, comorbidity, pathological stage, and neoadjuvant chemotherapy. CONCLUSION: Quadriceps muscle weakness in the first month after esophagectomy impacted the SMI% in a dose-dependent relationship.

Efficacy of Group Cognitive Behavior Therapy Targeting Time Management for Adults with Attention Deficit/Hyperactivity Disorder in Japan: A Randomized Control Pilot Trial.

OBJECTIVE: Time-processing disorders in adults is a priority area for intervention. Time management program, which has been demonstrated to be effective in children with ADHD, has not been examined in adults. We anticipate the need for the development of specialized programs for adults. This is because it has been reported that time processing disorders have different patterns in childhood and adulthood. This study aimed to evaluate the therapeutic effect of a gCBT program focusing on time management for adults with ADHD. METHOD: Adults with ADHD were randomly assigned to gCBT (n = 24) or a treatment as usual group (n = 24). Outcome measures were masked clinically rated, self-reported, and family-reported ADHD symptoms. RESULTS: The gCBT group significantly reduced ADHD symptoms on all measures. CONCLUSION: Interventions focused on time management have been shown to be effective not only in children with ADHD but also in adult patients.

Eicosapentaenoic acid attenuates progression of hepatic fibrosis with inhibition of reactive oxygen species production in rats fed methionine- and choline-deficient diet.

BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is associated with fat accumulation in the liver, and develops to cirrhosis with the progression of hepatic fibrosis. Eicosapentaenoic acid (EPA) is used to treat hyperlipidemia, and suppresses hepatic fat accumulation. As the effect of EPA on NASH remains unclear, we assessed the therapeutic effect of EPA and its mechanisms in an animal model of NASH. METHODS: Wistar rats were fed a methionine- and choline-deficient (MCD) diet for 20 weeks, and given EPA ethyl ester (EPA-E, 1,000 mg/kg/day) or vehicle by gavage from week 12, at which hepatic fibrosis has already established. The liver was histologically analyzed for fibrosis and α-smooth muscle actin (αSMA) expression, and hepatic levels of transforming growth factor-ß1 (TGF-ß1), fibrogenic gene expression, reactive oxygen species (ROS), and triglyceride (TG) content were determined. Serum oxidative markers were also measured. RESULTS: EPA-E treatment significantly suppressed the MCD-induced increase in fibrotic area of liver sections, with repressed macronodule formation. EPA-E also suppressed increases in hepatic fibrogenic factors, αSMA expression, TGF-ß1 level, and messenger RNA (mRNA) levels of procollagens and connective tissue growth factor. EPA-E reduced MCD-induced increases in hepatic ROS level, serum oxidative markers, 8-isoprostane and ferritin, and hepatic TG content. Attenuation of hepatic fibrosis by EPA-E was significantly correlated with hepatic ROS level, but not TG content. CONCLUSIONS: EPA-E attenuates progression of hepatic fibrosis in developed steatohepatitis, and this effect is likely mediated by inhibition of ROS production. These actions may elicit the therapeutic effect of EPA-E against NASH.

Suppression of hepatic fat accumulation by highly purified eicosapentaenoic acid prevents the progression of d-galactosamine-induced hepatitis in mice fed with a high-fat/high-sucrose diet.

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains largely unknown. Here, we assessed the importance of hepatic fat accumulation on the progression of hepatitis. BALB/cA mice were fed with a standard diet (STD) or a high-fat and high-sucrose diet (HFHSD) for 14 days followed by intraperitoneal injection of d-galactosamine (DGalN) or vehicle. After 20-21 h, plasma and liver tissue were collected and analyzed. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in plasma were increased significantly in HFHSD-fed mice treated with DGalN compared to STD-fed mice treated with DGalN. This exacerbation by the HFHSD was also observed in the plasma soluble tumor necrosis factor receptor (sTNFR) levels, and hepatic levels of reactive oxygen species (ROS) and the fibrogenic gene expression, such as tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), connective tissue growth factor (CTGF) and osteopontin (OPN) in HFHSD-fed mice treated with DGalN. The triglyceride contents of the liver were significantly increased by the HFHSD. When eicosapentaenoic acid (EPA), a suppressor of sterol regulatory element binding protein 1 (SREBP-1), was administered to HFHSD-fed mice, the sensitivity of DGalN, as a result of plasma ALT and AST levels, was suppressed accompanied by reduced plasma sTNFR2 level and hepatic levels of triglyceride, ROS, and fibrogenic parameters, and by increased plasma adiponectin levels. These data suggest that the progression of steatotic liver injury closely depends on the accumulation of fat in the liver and is prevented by EPA through the suppression of the fatty liver change.

Highly purified eicosapentaenoic acid ethyl ester prevents development of steatosis and hepatic fibrosis in rats.

BACKGROUND AND AIMS: Pathogenesis of nonalcoholic steatohepatitis (NASH) is considered to be involved in fat accumulation, oxidative stress, inflammation, and fibrosis in liver, but no drug therapy has been established as yet. Eicosapentaenoic acid (EPA) is an agent used clinically to treat hypertriglyceridemia, and has been reported to suppress reactive oxygen species and inflammation. Here, we aimed to assess the effect of EPA on progression of hepatic fibrosis in an animal model of NASH. METHODS: Wistar rats were fed a methionine- and choline-deficient (MCD) diet and given EPA ethyl ester (EPA-E) (1,000 mg/kg/day) or vehicle by gavage for 8 or 20 weeks. RESULTS: The MCD diet caused development of hepatic fibrosis and nodule formation at 20 weeks. EPA-E treatment significantly suppressed MCD-induced increase in fibrosis and hepatic hydroxyproline, and inhibited nodule formation. EPA-E treatment also decreased hepatic transforming growth factor (TGF)-beta1, and messenger RNA (mRNA) levels of connective tissue growth factor. EPA-E suppressed MCD-induced elevation of serum levels of ferritin, 8-isoprostane, soluble tumor necrosis factor receptor 1 (sTNFR1), and sTNFR2 at 20 weeks, and hepatic triglyceride accumulation at 8 weeks. CONCLUSIONS: EPA-E prevents progression of hepatic fibrosis in an MCD-induced NASH model with reduction of oxidative stress, inflammation, and initial hepatic steatosis. Thus, EPA-E treatment may be a potential therapy to treat NASH.

Eicosapentaenoic acid inhibits interleukin-6 production in interleukin-1beta-stimulated C6 glioma cells through peroxisome proliferator-activated receptor-gamma.

Epidemiological studies suggest that intake of omega-3 polyunsaturated fatty acids improves neurological disorders such as Alzheimer's disease which exhibit inflammatory pathology. We therefore investigated the anti-inflammatory effects of eicosapentaenoic acid (EPA) on interleukin (IL)-1beta-stimulated C6 glioma cells. In the present study, EPA inhibited pro-inflammatory cytokine IL-6 production, a characteristic of certain neurodegenerative disorders, in IL-1beta-stimulated C6 glioma cells in dose-dependent fashion. EPA down-regulated the expression of IL-6 at mRNA level, indicating that the effect of EPA occurs at the transcriptional level. In addition, peroxisome proliferator-activated receptor (PPAR) gamma antagonists abolished the inhibitory effect of EPA on IL-1beta-induced IL-6 production, whereas PPARalpha antagonist did not block the inhibitory effect of EPA. EPA might thus contribute to the regulation of pro-inflammatory cytokine production in astrocytes through interaction with PPARgamma. Among the PPARgamma ligands tested in this study, ciglitazone, a synthetic agonist of PPARgamma, effectively inhibited IL-6 production, but while neither rosiglitazone nor 15-deoxy-Delta(12,14)-prostaglandin J2 did. These findings indicate that the coordination of PPAR gamma ligands is important in inhibiting the production of IL-6 in C6 glioma cells.

Establishment of an in vitro high-throughput screening assay for detecting phospholipidosis-inducing potential.

Excessive accumulation of phospholipids results in phospholipidosis (PL), which may interfere with cellular functions, leading to acute or chronic disease or even death. Electron-microscopic detection of cytoplasmic lamellar bodies is often used as a diagnostic criterion of PL, but a faster, more convenient procedure is required for high-throughput assay of the PL-inducing potential of candidate drugs. We have developed a 96-well microplate cell-culture method for detecting PL, using a phosphatidylcholine-conjugated dye (NBD-PC) and a fluoro-microplate reader. The fluorescence intensity due to NBD-PC was normalized to that of Hoechst33342, used as an indicator of cell number, to obtain the amount of NBD-PC taken up per living cell. To select a suitable cell type, we examined the PL-detection sensitivity of five cell lines, as well as human and rat primary hepatocyte cultures, with five cationic amphiphilic drugs (CAD) as PL inducers and a negative control compound. The cell lines CHO-K1 and CHL/IU gave the best results. The NBD-PC uptake per CHO-K1 cell showed a high correlation with the pathological score of PL for 24 compounds, including PL-positive and negative compounds. This high-throughput screening assay for PL-inducing potential (HTS-PL assay) offers high sensitivity and accuracy, and it allows simultaneous determination of cytotoxicity.

Characterization of structural and catalytic differences in rat intestinal alkaline phosphatase isozymes.

To understand the differences between the rat intestinal alkaline phosphatase isozymes rIAP-I and rIAP-II, we constructed structural models based on the previously determined crystal structure for human placental alkaline phosphatase (hPLAP). Our models of rIAP-I and rIAP-II displayed a typical alpha/beta topology, but the crown domain of rIAP-I contained an additional beta-sheet, while the embracing arm region of rIAP-II lacked the alpha-helix, when each model was compared to hPLAP. The representations of surface potential in the rIAPs were predominantly positive at the base of the active site. The coordinated metal at the active site was predicted to be a zinc triad in rIAP-I, whereas the typical combination of two zinc atoms and one magnesium atom was proposed for rIAP-II. Using metal-depleted extracts from rat duodenum or jejunum and hPLAP, we performed enzyme assays under restricted metal conditions. With the duodenal and jejunal extract, but not with hPLAP, enzyme activity was restored by the addition of zinc, whereas in nonchelated extracts, the addition of zinc inhibited duodenal IAP and hPLAP, but not jejunal IAP. Western blotting revealed that nearly all of the rIAP in the jejunum extracts was rIAP-I, whereas in duodenum the percentage of rIAP-I (55%) correlated with the degree of AP activation (60% relative to that seen with jejunal extracts). These data are consistent with the presence of a triad of zinc atoms at the active site of rIAP-I, but not rIAP-II or hPLAP. Although no differences in amino acid alignment in the vicinity of metal-binding site 3 were predicted between the rIAPs and hPLAP, the His153 residue of both rIAPs was closer to the metal position than that in hPLAP. Between the rIAPs, a difference was observed at amino acid position 317 that is indirectly related to the coordination of the metal at metal-binding site 3 and water molecules. These findings suggest that the side-chain position of His153, and the alignment of Q317, might be the major determinants for activation of the zinc triad in rIAP-I.

Alkaline phosphatases reduce toxicity of lipopolysaccharides in vivo and in vitro through dephosphorylation.

Intestinal alkaline phosphatase (AP), as a host defense factor, was first investigated in vivo using rats orally exposed to lipopolysaccharide (LPS). After the oral administration of LPS to rats, serum LPS content was increased within 2 hr and then decreased to 6 hr. In contrast, when L-phenylalanine (L-Phe), an inhibitor of intestinal-type AP isozymes, was simultaneously administered with LPS, serum LPS content significantly increased from 1 hr and the area under the concentration-time curve of serum LPS was augmented approximately 2-fold, suggesting that APs in the gastrointestinal tract reduced serum LPS content. In addition, LPS toxicity diminished by a treatment in vitro with intestinal APs, were recovered by the treatment in the co-presence of L-Phe. In the experiment using human aortic endothelial cells (HAECs), we observed that the cell viability decreased in a dose-dependent manner of LPS-exposure, and the LPS dose, exhibiting 50% viability of the cells, was 0.05 microg/ml. When the cells were exposed to LPS pretreated with 50 nIU/ml of intestinal AP at pH 10.0 and 8.0, the 50% viability was at 2.0 microg/ml of LPS. These results strongly suggest that the APs reduced the toxicity of LPS, as a host defense factor against LPS.