The Effects of Overnight Fasting Duration on Glucose and Lipid Metabolism in a Sprague-Dawley Rat Model of Nonalcoholic Steatohepatitis with Advanced Fibrosis.

Nonalcoholic steatohepatitis (NASH) can progress to hepatic fibrosis, and is associated with cardiovascular and liver-related mortality. To understand the pathogenesis of NASH, reliable animal models of the disease are useful. In animal studies, the animals are usually fasted overnight before biospecimens are taken, but little is known about the effects of fasting. Here, we investigated the impact of overnight fasting for approximately 9 to 17 h on glucose and lipid metabolism in a Sprague-Dawley (SD) rat model of diet-induced moderate and advanced NASH in comparison to normal SD rats. Our results revealed that in the moderate NASH model rats, the fasting duration did not affect glucose and lipid metabolism, the histopathological findings, or the hepatic mRNA expression levels of genes related to lipid metabolism, cholesterol metabolism, inflammation, fibrosis, and oxidative stress. In contrast, in the normal rats, significant fasting time-dependent reductions were observed in the epididymal fat pad weight and the hepatic mRNA expression levels of adipose differentiation-related protein and heme oxygenase-1. Moreover, in the advanced NASH model rats, a significant fasting time-dependent reduction and increase were observed in the serum insulin level and mRNA expression level of alpha-smooth muscle actin, respectively. Our present results suggest that the influence of the overnight fasting duration differs among the healthy condition, moderate NASH, and advanced NASH statuses. Further studies are needed in humans to determine the appropriate overnight fasting duration for the accurate evaluation of glucose and lipid metabolism in NASH patients.

Effective approach for improving a gummy smile : Upward movement of the maxillary occlusal plane using midpalatal miniscrews and a modified transpalatal arch.

PURPOSE: Correction of a gummy smile by orthodontic treatment alone has recently become feasible with the use of miniscrews. However, the optimal treatment mechanics remain unclear. Here we cephalometrically evaluated jaw and tooth displacement in cases where a gummy smile was improved using a level anchorage system (LAS). METHODS: Sixteen patients underwent orthodontic treatment using an LAS consisting of a modified transpalatal arch and midpalatal miniscrews. Cephalometric pretreatment and posttreatment measurements were compared using the paired t­test to determine significant skeletal and dental changes. The Mann-Whitney U test was used for nonparametric data. Spearman's rank correlation coefficient was used to evaluate correlations between different variables and the vertical change in prosthion position which was used to indicate the amount of gingival exposure. RESULTS: The changes noted after treatment were intrusion of the maxillary first molars (P < 0.001) combined with only minor extrusion of the mandibular first molars. Suppressed extrusion of the mandibular first molars was significantly correlated with greater upward movement of the prosthion (r = 0.676, P < 0.01). Upward movement of the prosthion was also significantly correlated with intrusion of the maxillary and mandibular incisors, anterior upward movement of the maxillary occlusal plane, and an increase of the SNP angle. CONCLUSIONS: Treatment involving the combined use of miniscrews and a modified transpalatal arch resulted in intrusion of the maxillary first molars and maxillary incisors and consequently elevated the maxillary occlusal plane. The results of this study suggest that intruding the maxillary occlusal plane and minimizing mandibular molar extrusion were effective to induce autorotation of the mandible and to improve a gummy smile.

GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans.

Chronically elevated intraocular pressure (IOP) is the major risk factor of primary open-angle glaucoma, a leading cause of blindness. Dysfunction of the trabecular meshwork (TM), which controls the outflow of aqueous humor (AqH) from the anterior chamber, is the major cause of elevated IOP. Here, we demonstrate that mice deficient in the Krüppel-like zinc finger transcriptional factor GLI-similar-1 (GLIS1) develop chronically elevated IOP. Magnetic resonance imaging and histopathological analysis reveal that deficiency in GLIS1 expression induces progressive degeneration of the TM, leading to inefficient AqH drainage from the anterior chamber and elevated IOP. Transcriptome and cistrome analyses identified several glaucoma- and extracellular matrix-associated genes as direct transcriptional targets of GLIS1. We also identified a significant association between GLIS1 variant rs941125 and glaucoma in humans (P = 4.73 × 10-6), further supporting a role for GLIS1 into glaucoma etiology. Our study identifies GLIS1 as a critical regulator of TM function and maintenance, AqH dynamics, and IOP.

Genetic influence of cytokine polymorphisms on the clinical outcome of Japanese gastrointestinal cancer patients in palliative care.

Gastrointestinal cancer is one of the most common causes of mortality globally. The present study examined the influence of cytokine genetic polymorphisms [interleukin (IL)-1B C-31T, IL-1RN VNTR, IL-6 C-634G, IL-8 T-251A, IL-10 T-819C and IL-10 A-1082G] on clinical outcomes in patients with gastrointestinal cancer in palliative care. A total of 59 patients with gastrointestinal cancer who were admitted to Iga City General Hospital were analyzed. Genotyping was conducted using a polymerase chain reaction with confronting two-pair primers. Patients with at least one IL-1RN 2 allele demonstrated a significantly better survival (P=0.0275) while those with IL-6-634 G/G demonstrated a worse survival (P=0.0024). Multivariate analyses using the Cox proportional hazard model revealed that those with at least one IL-1RN 2 allele, IL-6-634 G/G or IL-10-1082 A/G had a significantly elevated adjusted hazard ratio of 9.20 (P=0.014), 41.01 (P=0.001) or 6.49 (P=0.046), respectively, compared with those with each homozygous wild-type polymorphism. In addition, the evaluation of weight loss by genotype revealed the potential influence of IL-10 T-819C genotype (P=0.072). IL-1RN, IL-6 and IL-10 polymorphisms were associated with the survival of patients with gastrointestinal cancer, suggesting the clinical feasibility of genetic testing in patients with gastrointestinal cancer in palliative care.

Polymorphisms in folic acid metabolism genes do not associate with cancer cachexia in Japanese gastrointestinal patients.

We used clinical data from Iga General Hospital to examine the association between polymorphisms in MTR (methionine synthase) A2756G (rs1805087), MTRR (methionine synthase reductase) His595Tyr (rs10380), MTHFR (methylenetetrahydrofolate reductase) C677T (rs1801133), MTHFR A1298C (rs1801131) and SHMT (serine hydroxymethyltransferase) C1420T (rs1979277), which are genes involved in folate metabolism, and the risk of weight loss in patients with gastrointestinal cancers, with the aim of establishing personalized palliative care for each patient based on genetic information. The data from 59 patients (37 males and 22 females) with gastrointestinal cancers who visited the outpatient clinic for cancer chemotherapy and palliative care at Iga General Hospital from December 2011 to August 2015 were analyzed. There was no significant association between the single nucleotide polymorphisms (SNPs) in the folate metabolizing genes examined and weight loss defined as weight loss of more than 5 percent or more than 10 percent during the first 6 months after initiation of chemotherapy. We did not detect any significant association between any of the SNPs examined and overall survival of patients. The present study indicated that these SNPs have relatively limited or no roles in the genesis of cachexia in patients with gastrointestinal cancers; however, further investigations into the roles of these folate metabolizing genes in the context of cancer palliative care, from clinical, biological and epidemiological viewpoints are warranted.

Fish oil-enriched nutrition combined with systemic chemotherapy for gastrointestinal cancer patients with cancer cachexia.

Despite recent advances in chemotherapy for gastrointestinal cancer, a crucial factor related to poor prognosis is reduced tolerance to chemotherapy induced by cancer cachexia. Fish oil (FO)-derived eicosapentaenoic acid (EPA) modulates inflammation in patients with various malignancies; however, the impact of FO-enriched nutrition as a combined modality therapy on clinical outcomes remains controversial. We systemically analysed chronological changes in biochemical and physiological status using bioelectrical impedance analysis in 128 gastrointestinal cancer patients provided with or without FO-enriched nutrition during chemotherapy. Furthermore, we evaluated the clinical significance of FO-enriched nutrition and clarified appropriate patient groups that receive prognostic benefits from FO-enriched nutrition during treatment of gastrointestinal cancer. The control group showed significant up-regulation of serum CRP) levels and no significant difference in both skeletal muscle mass and lean body mass. In contrast, the FO-enriched nutrition group showed no changes in serum CRP concentration and significantly increased skeletal muscle mass and lean body mass over time. Furthermore, high CRP levels significantly correlated with reduced tolerance to chemotherapy, and FO-enriched nutrition improved chemotherapy tolerance and prognosis, particularly in gastrointestinal cancer patients with a modified Glasgow prognostic score (mGPS) of 1 or 2. We conclude that FO-enriched nutrition may improve the prognosis of patients with cancer cachexia and systemic inflammation (i.e., those with a mGPS of 1 or 2).

Rapid downregulation of cyclin D1 induced by geranylgeranoic acid in human hepatoma cells.

Geranylgeranoic acid (GGA) and its derivatives are currently under development as chemopreventive agents against second primary hepatoma in Japan. We aimed to evaluate chemoprevention targets of GGA and a surrogate marker of chemopreventive response to clarify the molecular mechanism of hepatoma chemoprevention with GGA. Human hepatoma-derived cell lines such as HuH-7, PLC/PRF/5, and HepG-2, were treated with GGA and its derivatives. Cellular dynamics of several cell-cycle-related proteins were assessed by either immunoblotting or immunofluorescence method. The cellular expression of cyclin D1 protein was suppressed immediately after GGA treatment. This reduction was partially blocked by pretreatment with 26S proteasome inhibitor MG-132, indicating that proteasomal degradation was involved in GGA-induced disappearance of cyclin D1. A phosphorylation of retinoblastoma protein (RB) at serine 780, a target site of cyclin D1-dependent kinase 4, was rapidly decreased in GGA-treated HuH-7 cells. Furthermore, subcellular fractionation, Western blotting, and immunofluorescence revealed GGA-induced nuclear accumulation of RB. These results strongly suggest that cyclin D1 may be a target of chemopreventive GGA in human hepatoma cells. GGA-induced rapid repression of cyclin D1, and a consequent dephosphorylation and nuclear translocation of RB, may influence cell cycle progression and may be relevant to GGA-induced cell death mechanisms.

Polished rice as natural sources of cancer-preventing geranylgeranoic acid.

Geranylgeranoic acid, a 20-carbon polyprenoic acid (all-trans 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecatetraenoic acid) and its derivatives were previously developed as synthetic "acyclic retinoids" for cancer chemoprevention. Recently, we demonstrated the natural occurrence of geranylgeranoic acid in various medicinal herbs (Shidoji and Ogawa, 2004). In this present study, we present several lines of evidence to demonstrate that geranylgeranyl diphosphate taken in foods could be metabolized to GGA through geranylgeraniol and geranylgeranyl aldehyde via the following steps: 1) The conversion from geranylgeranyl diphosphate to geranylgeraniol was demonstrated to occur by the action of bovine intestinal alkaline phosphatase, with a K(m) of 46.1 µM. 2) Geranylgeraniol oxidase-mediated conversion of geranylgeraniol to geranylgeranyl aldehyde was revealed in rat liver homogenates, which activity was mainly localized in the mitochondrial fraction. The mitochondrial enzyme showed a K(m) of 92.9 µM. 3) The conversion of geranylgeranyl aldehyde to geranylgeranoic acid by geranylgeranyl aldehyde dehydrogenase in rat liver homogenates was absolutely dependent on exogenously added NAD(+) or NADP(+). The K(m) of the mitochondrial geranylgeranyl aldehyde dehydrogenase was 27.5 µM for geranylgeranyl aldehyde. Taken together, our data suggest that cancer preventive geranylgeranoic acid could be a physiological metabolite from commonly consumed foods.

Induction of an incomplete autophagic response by cancer-preventive geranylgeranoic acid (GGA) in a human hepatoma-derived cell line.

GGA (geranylgeranoic acid) is a natural polyprenoic acid, derivatives of which has been shown to prevent second primary hepatoma. GGA induces mitochondria-mediated PCD (programmed cell death), which may be relevant to cancer prevention. To gain further insights into GGA-induced PCD, autophagy processes were examined in human hepatoma-derived HuH-7 cells. Treatment of HuH-7/GFP (green fluorescent protein)-LC3 cells with GGA induced green fluorescent puncta in the cytoplasm within 30 min and their massive accumulation at 24 h. After 15 min of GGA treatment, a burst of mitochondrial superoxide production occurred and LC3ß-I was appreciably converted into LC3ß-II. GGA-induced early stages of autophagy were unequivocally confirmed by electron-microscopic observation of early/initial autophagic vacuoles. On the other hand, LC3ß-II as well as p62/SQSTM1 (sequestosome 1) continuously accumulated and co-localized in the cytoplasmic puncta after GGA treatment. Furthermore, GGA treatment of HuH-7/mRFP (monomeric red fluorescent protein)-GFP-LC3 cells showed yellow fluorescent puncta, whereas glucose deprivation of the cells gave red fluorescent puncta. These results strongly suggest that GGA induces the initial phase of autophagy, but blocks the maturation process of autolysosomes or late stages of autophagy, insomuch that GGA provides substantial accumulation of autophagosomes under serum-starvation conditions in human hepatoma cells.

Isolation and tyrosinase inhibitory effects of polyphenols from the leaves of persimmon, Diospyros kaki.

The main polyphenols were isolated from the leaves of six selected persimmon cultivars. Seven compounds were obtained by reverse-phase HPLC, and their structures were elucidated by multiple NMR measurements. These compounds are hyperoside, isoquercitrin, trifolin, astragalin, chrysontemin, quercetin-3-O-(2''-O-galloyl-ß-D-glucopyranoside) (QOG), and kaempferol-3-O-(2''-O-galloyl-ß-D-glucopyranoside) (KOG). Their inhibitory activity was tested against tyrosinase for the oxidation of L-DOPA, and only chrysontemin showed inhibitory activity. To investigate the differences of their inhibitory effects, the tyrosinase inhibitory activities of their aglycons, cyanidin, quercetin, and kaempferol, were also tested. As a result, it was confirmed that the most influential moiety for tyrosinase inhibition was the 3',4'-dihydroxy groups of the catechol moiety. Moreover, the tyrosinase inhibitory activity of chrysontemin, which was identified in persimmon leaves for the first time, is supported by a simulated model of chrysontemin docking into mushroom tyrosinase.

Transcriptional profiling reveals a role for RORalpha in regulating gene expression in obesity-associated inflammation and hepatic steatosis.

Retinoid-related orphan receptor (ROR)α4 is the major RORα isoform expressed in adipose tissues and liver. In this study we demonstrate that RORα-deficient staggerer mice (RORα(sg/sg)) fed with a high-fat diet (HFD) exhibited reduced adiposity and hepatic triglyceride levels compared with wild-type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of RORα(sg/sg) mice. In contrast, overexpression of RORα in mouse hepatoma Hepa1-6 cells significantly increased the expression of genes that were repressed in RORα(sg/sg) liver, including Sult1b1, Adfp, Cidea, and ApoA4. ChIP and promoter analysis suggested that several of these genes were regulated directly by RORα. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of RORα(sg/sg) mice fed with an HFD. The infiltration of macrophages and the expression of many immune response and proinflammatory genes, including those encoding various chemo/cytokines, Toll-like receptors, and TNF signaling proteins, were significantly reduced in RORα(sg/sg) WAT. Moreover, RORα(sg/sg) mice fed with an HFD were protected from the development of insulin resistance. RORα(sg/sg) mice consumed more oxygen and produced more carbon dioxide, suggesting increased energy expenditure in this genotype. Our study indicates that RORα plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, RORα may provide a novel therapeutic target in the management of obesity and associated metabolic diseases.

Capitalizing on the demographic transition: tackling noncommunicable diseases in South Asia

It provides information to encourage countries to develop, adopt, and implement effective and timely country and regional responses that reduce both population-level risk factors and the noncommunicable diseases burden.

A case of a fibroadenoma coexisting with an invasive lobular carcinoma in the breast.

A case of a fibroadenoma coexisting with an invasive lobular carcinoma of the breast in a 60-year-old female is presented, and its pathological features are correlated with high-resolution magnetic resonance imaging (HR-MRI) and other imaging findings. The patient presented with the chief complaint of having a palpable mass in her right breast for 3 months. Mammography revealed a lobular mass with a micro-lobulated margin, which suggested a malignant nature; however, it included coarse calcifications. Sonographic imaging and HR-MRI findings were compatible with malignant tumor. Cytology was performed, and the results indicated an invasive carcinoma. Breast-conserving surgery was performed as a curative operation. The pathological features revealed a fibroadenoma coexisting with an invasive lobular carcinoma. This case suggests that radiologists should always pay attention to the associated malignant imaging characteristics, such as the shape and border of the mass, whenever a mass demonstrates benign-like calcifications.

Nuclear orphan receptor TAK1/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance.

OBJECTIVE: The nuclear receptor TAK1/TR4/NR2C2 is expressed in several tissues that are important in the control of energy homeostasis. In this study, we investigate whether TAK1 functions as a regulator of lipid and energy homeostasis and has a role in metabolic syndrome. RESEARCH DESIGN AND METHODS: We generated TAK1-deficient (TAK1⁻(/)⁻) mice to study the function of TAK1 in the development of metabolic syndrome in aged mice and mice fed a high-fat diet (HFD). (Immuno)histochemical, biochemical, and gene expression profile analyses were performed to determine the effect of the loss of TAK1 expression on lipid homeostasis in liver and adipose tissues. In addition, insulin sensitivity, energy expenditure, and adipose-associated inflammation were compared in wild-type (WT) and TAK1⁻(/)⁻ mice fed a HFD. RESULTS: TAK1-deficient (TAK1⁻(/)⁻) mice are resistant to the development of age- and HFD-induced metabolic syndrome. Histo- and biochemical analyses showed significantly lower hepatic triglyceride levels and reduced lipid accumulation in adipose tissue in TAK1⁻(/)⁻ mice compared with WT mice. Gene expression profiling analysis revealed that the expression of several genes encoding proteins involved in lipid uptake and triglyceride synthesis and storage, including Cidea, Cidec, Mogat1, and CD36, was greatly decreased in the liver and primary hepatocytes of TAK1⁻(/)⁻ mice. Restoration of TAK1 expression in TAK1⁻(/)⁻ hepatocytes induced expression of several lipogenic genes. Moreover, TAK1⁻(/)⁻ mice exhibited reduced infiltration of inflammatory cells and expression of inflammatory genes in white adipose tissue, and were resistant to the development of glucose intolerance and insulin resistance. TAK1⁻(/)⁻ mice consume more oxygen and produce more carbon dioxide than WT mice, suggesting increased energy expenditure. CONCLUSIONS: Our data reveal that TAK1 plays a critical role in the regulation of energy and lipid homeostasis, and promotes the development of metabolic syndrome. TAK1 may provide a new therapeutic target in the management of obesity, diabetes, and liver steatosis.

Downregulation of trefoil factor 3 gene expression in the colon of the senescence-accelerated mouse (SAM)-P6 revealed by oligonucleotide microarray analysis.

Global comparison of the colonic gene expression profiles between 14-month-old senescenceaccelerated mouse (SAM)-P6 mice and SAM-R1 mice, a wild-type control, was conducted with an oligonucleotide microarray containing more than 5,000 mouse genes. Eight genes were upregulated more than two-fold and 94 genes were downregulated more than two-fold in SAM-P6 mice. The three cell defense genes intelectin1 (Itln1), trefoil factor 3 (intestinal) (Tff3) and "deleted in malignant brain tumors 1" (Dmbt1) were among those extensively downregulated. Quantitative RT-PCR analysis confirmed that Itln1 mRNA was almost undetectable in SAM-P6 colon, whereas it was readily detected in SAM-R1 colon. Colonic expression of both Tff3 and Dmbt1 mRNA was also substantially decreased, to one third and two thirds of the levels in SAM-R1 mice, respectively. A 14 kDa Tff3 dimer was detected by Western blotting in the colon of all three SAM-R1 mice, but was not present in three SAM-P6 mice. No upregulation of 3 cell defense genes was detected in 3-month-old SAM-R1 as well as SAM-P6 mice. These results suggest that a diminution of the intestinal trefoil factor system may be involved in the acceleration of aging in SAM-P6 mice.

Clinical application of a new indwelling catheter with a side-hole and spirally arranged shape-memory alloy for hepatic arterial infusion chemotherapy.

A new indwelling catheter, G-spiral (GSP), was developed for hepatic arterial infusion chemotherapy (HAIC) by way of an implanted catheter-port system (CPS). Here we evaluated its physical properties and the outcomes of its clinical use. The GSP vessel-fixing power and its ability to follow a guidewire were determined with a vascular in vitro model, and Student t test was used to determine statistical significance (P < 0.05). A retrospective analysis was performed to evaluate the technical success rate and to identify the clinical complications associated with radiologic CPS implantation with GSP in 65 patients with unresectable hepatic tumors. The mean vessel-fixing power of the GSP (14.4 g) significantly differed from that of a GSP with a cut shape-memory alloy (3.3 g). The mean resistance to following the guidewire displayed by the GSP (88.5 g) was significantly less than that for a 5F W-spiral (106.3 g) or 4F Cobra-type angiographic catheter (117.8 g). The CPS was placed successfully in 64 of 65 cases (98.5%). Hepatic artery occlusion was observed in one case. Occlusion, cracking, and infection of CPS were observed in one, two, and one case, respectively. The GSP is a highly useful indwelling catheter that can be used for HAIC.

Radiologic-pathological correlation of punctate hyperechoic foci by ultrasound in stereotactic vacuum-assisted breast biopsy samples.

PURPOSE: To correlate punctate hyperechoic foci (PHF) on ultrasound (US) with microcalcifications detected by mammography (MMG) and at histopathology. MATERIALS AND METHODS: Forty-eight subjects who underwent stereotactic vacuum-assisted breast biopsy (SVABB) for evaluation of breast microcalcifications between April and December 2008 were evaluated for 191 lesions obtained after SVABB. The concordance between PHF on US with microcalcifications detected on MMG and histopathology was therefore evaluated for 191 lesions. Values for sensitivity and specificity were determined against histopathology as the reference standard. RESULTS: In 154 of 191 samples (80.6%), the PHF on US corresponded with microcalcifications on MMG and histopathology. The overall sensitivity and specificity were 85.3% and 80.0%, respectively, for US, and 89.7% and 90.7%, respectively, for MMG. There were no significant differences between values for US and MMG. At US, 12 PHF did not correlate with any microcalcifications at MMG or histopathology. Histopathology revealed collagen fibers in fatty tissue in 5 of 12 lesions and collagenization in 2 of 12 lesions. CONCLUSION: There was a general concordance between PHF on US and microcalcifications detected at MMG. However, in addition to microcalcifications, collagen fibers in fatty tissue and collagenization may account for some PHF. This possibility should be considered when interpreting US findings.

Enhanced Glucose Requirement in Human Hepatoma-derived HuH-7 Cells by Forced Expression of the bcl-2 Gene.

To explore the metabolic effects of Bcl-2 in tumor cells, a stable clone of HuH-7/bcl-2 and its control HuH-7/neo were established. Mitochondrial localization of ectopic Bcl-2 was demonstrated both by western blotting and immunofluorescence. HuH-7/bcl-2 cells consumed glucose at a higher rate, exhausted the available cellular ATP and died on day 9, while HuH-7/neo cells were still alive for 10 days under the same condition where cells were cultured without replenishment of the medium. The expression of the hexokinase II gene was up-regulated in HuH-7/bcl-2 at its protein level. Taken together, we suggest that the forced expression of Bcl-2 in human hepatoma may cause the cells to become more glucose-dependent for survival.

Desmoid tumor of the breast: the role of proton magnetic resonance spectroscopy for a benign breast lesion mimicking a malignancy.

Desmoid tumor of the breast is an extremely rare condition. It is difficult to provide a correct preoperative diagnosis of desmoid tumor of the breast because of its tendency to mimic breast carcinoma on physical examination and conventional imaging such as mammography and sonography. We present a case of desmoid tumor of the breast that mimicked breast carcinoma, in which proton magnetic resonance spectroscopy assisted the result of biopsy, thus enabling a correct preoperative diagnosis.

Formation of lipid droplets induced by 2,3-dihydrogeranylgeranoic acid distinct from geranylgeranoic acid.

Geranylgeranoic acid (GGA) and 2,3-dihydrogeranylgeranoic acid (2,3-diGGA) are geranylgeraniol-derived metabolites (Kodaira et al. (2002) J Biochem 132: 327-334). In the present study, we examined the effects of these acids on HL-60 cells. The cells were differentiated into neutrophils by GGA stimulation like retinoic acid stimulation. In the case of cells stimulated with 2,3-diGGA, neutrophils were not detected, but the formation of lipid droplets was induced. On the other hand, when the cells were cultured in the presence of 0.1% FBS instead of 10% FBS, apoptotic cells were induced not only by GGA stimulation but also with 2,3-diGGA. In the latter case, when the cells were cultured in the co-presence of a caspase-3 inhibitor (Ac-DMQD-CHO), the lipid droplets formation was observed in the cells. These results suggest that GGA and 2,3-diGGA are extremely different from each other with respect to their effects on HL-60 cells.