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S Sugie

Publications and source records attributed to S Sugie.

At least 37 records · Page 2Linked to original sources
PubMed1999

Beta-catenin (Ctnnb1) gene mutations in diethylnitrosamine (DEN)-induced liver tumors in male F344 rats.

Alterations in multiple phosphorylation sites on exon 3 of the beta-catenin gene have recently been implicated in hepatocarcinogenesis in humans as well as mice. To identify genetic alterations which could be involved in the chemical-induced hepatocarcinogenesis of rats, we analyzed the status of the sites in the beta-catenin gene (Ctnnb1) of liver neoplasms induced by diethylnitrosamine (DEN) in male F344 rats, using the polymerase chain reaction-single strand conformation polymorphism method. In the present investigation, we examined 35 hepatocellular neoplasms (28 adenomas and 7 carcinomas) for the expression of mutations in the region of the beta-catenin gene. Point mutation at codon 32, 35, 37 or 41, which has been reported in human and mouse liver cell carcinomas and/or other cancers, was recognized in eleven (31%) out of 35 lesions (8 adenomas and 3 carcinomas). Our results indicate that Ctnnb1 mutations may contribute to hepatocarcinogenesis in rats. Our finding that Ctnnb1 mutation was present in adenomas as well as carcinomas also suggests that the mutation is a relatively early event in DEN-induced hepatocarcinogenesis in rats.

Adenoma↗
PubMed1998

Inhibitory effects of plumbagin and juglone on azoxymethane-induced intestinal carcinogenesis in rats.

The effects of two naphthoquinones, juglone and plumbagin, and an isocoumarin, hydrangenol, on intestinal carcinogenesis in rats were examined by dietary exposure during the initiation phase. Starting at 5 weeks of age, male F344 rats were fed the diets containing either of the test chemicals at a concentration of 200 ppm or the control diet without the compounds. At 6 weeks of age, all animals were treated with s.c. injections of azoxymethane (AOM) (15 mg/kg body weight, once weekly for 3 weeks) or saline alone. Animals fed experimental diets were changed to the control diet 1 week after the last carcinogen treatment. Animals given plumbagin together with the carcinogen had a lower incidence (41%) and smaller multiplicity (0.48 +/- 0.62) of tumors in the entire intestine compared with those exposed to carcinogen alone (68% and 1.04 +/- 0.62) (P < 0.05 and < 0.01, respectively). The incidence and multiplicity of tumors in the small intestine (7% and 0.07 +/- 0.25) and the multiplicity of tumors in the entire intestine (0.60 +/- 0.76) of animals treated with juglone and the carcinogen were significantly less than those of animals treated with carcinogen alone (P < 0.05 in each). Hydrangenol tended to decrease the incidence and the multiplicity of tumors in the entire intestine induced by AOM, but the effect was not statistically significant. The present data suggest that the naphthoquinones, juglone and plumbagin, could be promising chemopreventive agents for human intestinal neoplasia.

Animals↗
PubMed1998

Induction of apoptosis in colonic epithelium treated with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and its modulation by a P4501A2 inducer, beta-naphthoflavone, in male F344 rats.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is one of the mutagenic heterocyclic amines derived from cooked meat. In long-term experiments using rodents, carcinogenicity of PhIP in colon, mammary gland and prostate has been demonstrated. In this study, an experiment was designed to determine the apoptosis-inducing capacity of PhIP in colonic epithelium, a target organ for PhIP carcinogenicity, and possible modulating effects of beta-naphthoflavone (beta-NF), a P4501A2 inducer, on the apoptosis in rats. Out of eight groups of male F344 rats, four were given beta-NF in diet (1000 ppm) for a week beginning at 5 weeks of age. Four groups were given PhIP (100 mg/kg body weight) by gavage at 6 weeks of age. Twenty-four hours after the dosing of PhIP, cell death with typical morphology of apoptosis was apparent in the colon and the apoptotic index was significantly greater (P < 0.01) than of the control rats without exposure to PhIP. Prior administration of beta-NF caused significant acceleration of the induction of apoptosis by PhIP. Since PhIP requires metabolic activation by P4501A2 to exert genotoxic activities, the modulating effect of beta-NF on the PhIP-induced apoptosis will be through a P4501A2-dependent mechanism. Such assay of apoptotic indices in the colon may be useful not only for the evaluation of genotoxicity and/or the initiating capability of chemical agents with potentials for colorectal cancer, but also for the analysis of modifying agents on the carcinogenesis in the large bowel.

Animals↗
PubMed1998

Suppressive effect of irsogladine maleate on diethylnitrosamine-initiated and phenobarbital-promoted hepatocarcinogenesis in male F344 rats.

Modifying effects of irsogladine maleate (IRG) on diethylnitrosamine (DEN)-induced hepatocarcinogenesis were examined in male F344 rats. Six-week-old rats were divided into 8 groups. Groups 1 through 4 were given a single i.p. injection of DEN (200 mg/kg body weight) at the start of the experiment, whereas groups 5 through 8 received a single i.p. injection of saline as the vehicle treatment. Groups 1 and 8 were kept on the basal diet and distilled water throughout the experiment (36 weeks). Groups 2 and 7 were exposed to 500 ppm phenobarbital (PB) in the drinking water, starting one week after the carcinogen or vehicle treatment. Groups 3 and 5 were fed the diet mixed with 125 ppm IRG from one week after DEN or vehicle treatment. Groups 4 and 6 were given 125 ppm IRG-containing diet and drinking water with 500 ppm PB after the carcinogen or vehicle treatment. Liver neoplasms developed in groups 1 (1/15 rats, 7%) and 2 (14/14 rats, 100%). However, no liver tumors were found in rats of groups 3 through 8. Incidence and average number of liver neoplasms in group 4 (0/14 rats, 0%) were less than those in group 2 (P < 0.0001). The number of glutathione S-transferase placental form (GST-P)-positive liver cell foci in group 3 or 4 was significantly smaller than that in the appropriate control (P < 0.01, P < 0.001, respectively). The average and unit areas of these foci in group 4 were also significantly smaller than those in group 2 (P < 0.001, P < 0.05, respectively). These results suggest that IRG could be a chemopreventive agent for rat liver carcinogenesis.

Animals↗
PubMed1997

Suppressive effects of S-methyl methanethiosulfonate on promotion stage of diethylnitrosamine-initiated and phenobarbital-promoted hepatocarcinogenesis model.

Modifying effects of S-methyl methanethiosulfonate (MMTS) on diethylnitrosamine (DEN)-initiated and phenobarbital (PB)-promoted hepatocarcinogenesis were examined in rats. Five-week-old male F344 rats were divided into 8 groups. After a week, groups 1-5 were given DEN (100 mg/kg body weight, i.p.) once a week for 3 weeks, whereas groups 6-8 received vehicle treatment. Group 2 was given 100 ppm MMTS containing diet in the initiation phase. From 4 weeks after the start of experiment, groups 3 and 5 were fed MMTS, and groups 1-3 and 7 received drinking water containing 500 ppm PB. Group 6 was given MMTS diet alone throughout the experiment (24 weeks). The incidences of hepatocellular adenoma and total liver tumors were significantly smaller in group 3 than those of group 1. The average numbers of hepatocellular adenoma, carcinoma and total tumors in group 3 were significantly smaller than in group 1. Glutathione S-transferase placental form-positive foci were also significantly decreased by MMTS treatment in the promotion phase. MMTS treatment in the initiation or promotion phase reduced ornithine decarboxylase activity in the liver of rats given DEN. The antioxidant activity against lipid peroxidation of MMTS was confirmed in tests with rabbit erythrocyte membrane ghosts or rat hepatocytes. These results suggest that MMTS is a promising chemopreventive agent for liver neoplasia when concurrently administered with PB.

Animals↗
PubMed1997

Inhibitory effects of diallyl disulfide or aspirin on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced mammary carcinogenesis in rats.

Modifying effects of diallyl disulfide (DAD), aspirin or DL-alpha-difluoromethylornithine (DFMO) on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary carcinogenesis in SD rats were investigated. A total of 166 female rats, 6 weeks old, were divided into 8 groups. They were fed a high fat diet throughout the experiment. Starting at 7 weeks of age, groups 1-4 were given PhIP (85 mg/kg body weight in corn oil) by gavage 8 times in 10 days, and groups 5-8 were given corn oil alone. For the beginning 4 weeks, groups 2 and 5 were given DAD at 200 ppm in diet. Similarly groups 3 and 6, and groups 4 and 7 were given aspirin (400 ppm) and DFMO (400 ppm), respectively. Mammary carcinomas were only recognized in groups 1-4 at the termination (25 weeks after the start of experiment). Multiplicity (mean number/rat) of neoplasms in group 2 (PhIP+DAD, 0.90/rat) and group 3 (PhIP+aspirin, 1.37/rat) was significantly smaller than that in group 1 (PhIP alone, 2.45/ rat) (P < 0.005 and P < 0.05, respectively). These results indicate that dietary intake of DAD or aspirin during the time corresponding to initiation phase has chemopreventive potential on PhIP-induced mammary carcinogenesis in rats.

Administration, Oral↗
PubMed1997

Regressive effects of various chemopreventive agents on azoxymethane-induced aberrant crypt foci in the rat colon.

Regressive effects of four chemopreventive agents [5-hydroxy-4-(2-phenyl-(E)-ethenyl)-2(5H)-furanone (KYN-54), S-methyl methanethiosulfonate (MMTS), chlorogenic acid (CA), and piroxicam] on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in the colon of male F344 rats were examined by dietary exposure. At six weeks of age, 60 rats of groups 1 through 5 received subcutaneous injections of AOM (15 mg/kg body weight) once a weeks. Twelve weeks after the first carcinogen injection, when the occurrence of ACF was maximal, the rats in groups 2 through 5 were started on diet containing the test chemicals as follows: group 2, KYN-54 (0.02%); group 3, MMTS (0.01%); group 4, CA (0.025%); and group 5, piroxicam (0.0125%). Group 1 (20 rats) was kept on the basal diet alone, and group 6 (12 rats) served as an untreated control. Rats in each group were killed at 6, 12, 18, or 24 weeks after the start of the experiment, and the yield of ACF in the colon of each group at 18 or 24 weeks was compared with that at 12 weeks. The number of ACF per rat colon of each group at 18 or 24 weeks was smaller than that at 12 weeks. The reduction rates at 18 weeks were 7% in group 1 (AOM alone), 11% in group 2 (AOM + KYN-54), 10% in group 3 (AOM + MMTS), 51% in group 4 (AOM + CA) (P < 0.01), and 33% in group 5 (AOM + piroxicam) (P < 0.02), while at 24 weeks they were 12%, 26%, 51% (P < 0.002), 43% (P < 0.05), and 70% (P < 0.001), respectively. These results indicate that chemopreventive agents for large bowel carcinogenesis, i.e., KYN-54, MMTS, CA, and piroxicam, are not only able to prevent the development of ACF, but also can regress ACF, which are regarded as precursor lesions of colorectal cancer.

4-Butyrolactone↗
PubMed1997

Chemoprevention by naturally occurring and synthetic agents in oral, liver, and large bowel carcinogenesis.

A number of naturally occurring compounds and several related synthetic agents were confirmed to exert chemopreventive properties against carcinogenesis in the digestive organs. Phenolic compounds, widely distributed as plant constituents, possess chemopreventive activities in tongue, liver, and large bowel of rodents. Of them, a simple phenolic protocatechuic acid seems to be a promising compound. Organosulfur compounds contained in the cruciferous vegetables and known to activate detoxifying enzymes are regarded as a candidate group for cancer preventive agents. We proved a strong protective effect of S-methylmethanethiosulfonate, a constituent in these vegetables, on azoxymethane (AOM)-induced large bowel carcinogenesis. Some oxygenated carotenoids (xanthophylls) are reported to have antitumor effects. Naturally occurring xanthophylls astaxanthin and canthaxanthin have considerable preventive activities on 4-nitroquinoline-1-oxide (4-NQO)-induced tongue carcinogenesis and AOM-induced large bowel carcinogenesis. A novel synthesized retinoidal butenolide, KYN-54, which suppresses large bowel as well as tongue carcinogenesis could be a useful agent for prevention of digestive organ cancers. Some trace elements are known to have anticarcinogenic effects. Magnesium hydroxide, a protective agent in colorectal carcinogenesis, inhibits c-myc expression and ornithine decarboxylase activity in the mucosal epithelium of the intestine. Our results show that many agents with preventive effects in tongue, liver, and large bowel control carcinogen-induced hyperproliferation of cells in these organs. Carcinogens used to induce large bowel cancers also induce apoptosis in the target sites. Telomerase activity is increased in the tissues of preneoplastic as well as neoplastic lesions in experimental models such as dimethylbenz[a]anthracene-induced oral carcinogenesis in hamsters. These could be useful biomarkers in studies for cancer chemoprevention.

Animals↗
PubMed1996

Toxicity and tumorigenicity of purpurin, a natural hydroxanthraquinone in rats: induction of bladder neoplasms.

Chronic toxicity and tumorigenicity of purpurin, a natural hydroxyanthraquinone, was examined in two groups of male F344 rats. One group was given a basal diet mixed with purpurin at a concentration of 1% throughout the experiment (520 days). Another group was kept on the basal diet without purpurin during the experiment. Almost all animals given purpurin developed conspicuous changes of kidney resembling 'progressive chronic nephropathies', the severity and frequency of which were much stronger than in controls. In rats with purpurin treatment, marked hyperplasia of pelvic epithelium was frequently seen and several rats developed urinary bladder tumors (papilloma and carcinoma). Prominent crystallization in the renal pelvis and urinary bladder seems to be initially related to the toxic effects of this hydroxanthraquinone on the renal tubules and with the occurrence of epithelial hyperplasia and neoplasms.

Animals↗
PubMed1996

Chemopreventive effects of taurine on diethylnitrosamine and phenobarbital-induced hepatocarcinogenesis in male F344 rats.

Modifying effects of taurine, a naturally occurring organosulfur compound, on diethylnitrosamine (DEN) and phenobarbital (PB)-induced hepatocarcinogenesis were examined in rats. Male F344 rats, 5 weeks old, were divided into 8 groups. Rats of groups 1 through 5 were given i.p. injections of DEN (100 mg/kg body weight) once a week for 3 weeks from one week after the start of the experiment. Of them, animals of group 2 received taurine mixed in a basal diet at a concentration of 2000 ppm for the initial 4 weeks, and those of groups 3 and 5 were given the agent starting 4 weeks after the beginning of the experiment until the end (24 weeks). Rats in groups 1, 4, 7 and 8 were kept on the basal diet throughout the experiment (24 weeks). Group 6 was given taurine throughout the experiment and group 8 was treated as a vehicle control. Animals of groups 1,2, 3 and 7 received PB in drinking water at a dose of 500 ppm from one week after the end of carcinogen or vehicle treatment. Liver neoplasms were recognized only in DEN-treated groups. The incidence and average number of liver neoplasms of group 3 were significantly lower than those of group 1. The number of glutathione S-transferase placental form (GST-P)-positive foci of group 2 or 3 was significantly smaller than that of group 1 (P < 0.01 or P < 0.005). The average and unit areas of GST-P-positive foci in groups 2 and 3 were also significantly smaller than those in group 1 (P < 0.005 and P < 0.0001 and P < 0.0001, respectively). In this study, the level of ornithine decarboxylase activity in non-neoplastic liver tissue was reduced by taurine treatment in both the initiation and postinitiation phases. These results suggest that taurine could be a chemopreventive agent for liver neoplasia.

Animals↗
PubMed1996

Inhibitory effect of chlorophyllin on diethylnitrosamine and phenobarbital-induced hepatocarcinogenesis in male F344 rats.

Modifying effects of chlorophyllin (CHL) on the diethylnitrosamine (DEN)-phenobarbital (PB) hepatocarcinogenesis model were examined in rats. Five-week-old male F344 rats were divided into 8 groups. Groups 1 through 5 were given i.p. injections of DEN (100 mg/kg body weight) once a week for 3 weeks beginning one week after the start of the experiment, while groups 6 through 8 received vehicle treatment. Groups 1, 2, 3 and 7 received drinking water with 500 ppm PB from one week after the end of carcinogen or vehicle treatment. CHL-containing diet (2000 ppm) was given to group 2 during the initiation phase and to groups 3 and 5 during the promotion and the post-initiation phase, respectively. Group 6 was given the experimental diet alone throughout the experiment (24 weeks). Liver neoplasms were present in DEN-treated groups and PB treatment promoted liver tumorigenesis. The incidences of adenoma in groups 2 and 3 were significantly smaller than in group 1 (P<0.05 and P<0.02), although the reductions in the incidences of liver cell cancer were not significant. The average numbers of liver neoplasms/rat in group 2 were significantly smaller than in group 1 (P<0.05-P<0.005). Glutathione S-transferase placental form-positive foci were also significantly decreased by CHL treatment (P<0.05 and P<0.001). DEN and PB exposure increased liver ornithine decarboxylase activity and this increase was significantly inhibited by feeding of CHL during the initiation phase (P<0.001). These results suggest that CHL is a chemopreventive agent for liver neoplasia.

Animals↗
PubMed1996

Lack of inhibitory effect of benzyl isothiocyanate on 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)-induced mammary carcinogenesis in rats.

Modifying effects of benzyl isothiocyanate (BITC), a glucosinolate compound, were investigated on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary carcinogenesis in female SD rats. One hundred twenty five female rats were divided into 4 groups. Starting at 6 weeks of age, rats were fed high fat diet containing 23.5% corn oil (Groups 1 and 4) or the experimental diet (high fat diet with 400 ppm BITC) (Groups 2 and 3). At 7 weeks of age, Groups 1 and 2 were given PhIP (100 mg/kg body weight, 8 times for 16 days) by intragastric tube. One week after the final PhIP treatment, the experimental diet for Groups 2 and 3 switched to high fat diet. At the termination (31 weeks after the start of experiment), mammary adenocarcinomas were recognized in Group 1 (PhIP alone) and Group 2 (PhIP + BITC). The incidence of neoplasms was 74.2% in Group 1, and 62.5% in Group 2. The multiplicity of them was 1.71 +/- 1.70 in Group 1, and 1.91 +/- 2.94 in Group 2. Mean sizes of tumors were 9.9 +/- 7.1 mm in Group 1, and 10.8 +/- 6.8 mm in Group 2. But no significant differences for tumors were available between the two groups. These results imply that the glucosinolate compound does not have clear inhibitory effects on PhIP-induced mammary carcinogenesis in rats.

Animals↗
PubMed1995

Effect of fish oil on the development of AOM-induced glutathione S-transferase placental form positive hepatocellular foci in male F344 rats.

Omega-3 fatty acids, which are contained in fish oils and certain vegetable oils in contrast to corn oil or safflower oil rich in omega-6 fatty acids (linoteic acid), have been reported to reduce the carcinogenesis in several organs. In this study, the modifying effect of menhaden fish oil was investigated on the occurrence of azoxymethane (AOM)-induced glutathione S-transferase placental form (GST-P) positive hepatocellular foci, recognized preneoplastic lesions in the liver, in male F344 rats. Starting at five weeks of age, groups of animals were fed ad libitum a semipurified diet containing 5% corn oil (low fat). At seven weeks of age, all animals except the vehicle-treated groups were injected subcutaneously with AOM (15 mg/kg body wt, 1x/wk for 2 wks). Four days after the second injection, groups of animals were fed the diets containing 4% menhaden oil + 1% corn oil (low fish oil diet), 22.5% menhaden oil + 1% corn oil (high fish oil diet), and 5% corn oil. Thirty-four weeks after AOM injections, all animals were necropsied. Livers were sectioned and performed immunohistochemical staining of GST-P for quantitative analysis of enzyme altered foci of the liver. The results demonstrate that the density and the unit area of AOM-induced enzyme altered foci in the liver were significantly lower in the high fish oil group (0.60 +/- 0.08/cm2, 3.0 +/- 0.4 x 10(-4)) than in the 5% corn oil group (2.71 +/- 0.33/cm2, 16.6 +/- 2.6 x 10(-4)) and the low fish oil group (1.66 +/- 0.33/cm2, 11.1 +/- 1.9 x 10(-4)).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Alterations of nuclear pores in preneoplastic and neoplastic rat liver lesions induced by 2-acetylaminofluorene.

The nuclear pore density and area were measured on freeze-fractured nuclei of ACI/N rat liver altered foci, adenomas and carcinomas induced by 2-acetylaminofluorene, and compared with those of normal hepatocytes. The pore density of nuclei from these preneoplastic and neoplastic lesions was significantly higher than that of hepatocytes, but there was no difference between lesions. The area of nuclear pores of the focus cells did not differ from normal hepatocytes, whereas the areas of pores of adenoma and carcinoma cells were increased. Moreover, the nuclear pore area of carcinomas was significantly greater than that of adenomas. These results suggest that some changes may occur in nuclear pores in the progress of tumorigenesis.

2-Acetylaminofluorene↗
PubMed1994

Promoting and synergistic effects of chrysazin on 1,2-dimethylhydrazine-induced carcinogenesis in male ICR/CD-1 mice.

The modifying effects of chrysazin on 1,2-dimethylhydrazine (DMH)-induced colon and liver carcinogenesis were examined in male ICR/CD-1 mice. Starting at 6 weeks of age, mice were divided into four groups, two of which were treated with s.c. injections of DMH (20 mg/kg body wt) once a week for 12 weeks. A week after the final injection of DMH, one group was kept on the basal diet throughout the study (group I), and the other group was fed the diet containing chrysazin (mixed in basal diet at 0.2% concentration) alone for 42 weeks (group II). The other two groups were injected with normal saline and given the diet containing 0.2% chrysazin for 42 weeks (group III), or the basal diet during the experiment (group IV). The incidence and multiplicity of colon tumors of group II were significantly greater than those of group I (P < 0.05, P < 0.01). The incidence and multiplicity of the hepatocellular neoplasms of group II were larger than those of group I (P < 0.002, P < 0.02 respectively). In group III, colon tumors were not found, though a few liver neoplasms and severe inflammatory lesions of the colon were observed. The activity of ornithine decarboxylase of the colonic mucosa in mice exposed to chrysazin was stronger than that of animals without chrysazin. The results suggest that the promoting effect of chrysazin is probably related to an increase of cell proliferation in the target organ. A synergistic effect of DMH with chrysazin was also observed in liver tumorigenesis.

1,2-Dimethylhydrazine↗
PubMed1994

Inhibitory effects of benzyl thiocyanate and benzyl isothiocyanate on methylazoxymethanol acetate-induced intestinal carcinogenesis in rats.

The effects of two aromatic thiocyanates, benzyl thiocyanate (BTC) and benzyl isothiocyanate (BITC), on methylazoxymethanol (MAM) acetate-induced intestinal carcinogenesis were examined using female ACI/N rats. Starting at 5 weeks of age, animals were fed diets containing 100 or 400 p.p.m. BTC, 400 p.p.m. BITC or a control diet. At 6 weeks of age, all animals were treated with i.p. injections of MAM acetate (25 mg/kg body wt, once weekly for 3 weeks) or saline. Animals fed experimental diets were changed to the control diet from a week after the last carcinogen treatment. Three groups of animals fed the control diet were switched to 100 p.p.m. BTC, 400 p.p.m. BTC or 400 p.p.m. BITC diet from a week after carcinogen treatment. Animals given the high-dose BTC diet at the initiation and the post-initiation phase showed smaller incidence (5% and 17%) and multiplicity (0.05 +/- 0.21 and 0.17 +/- 0.37) of tumours in small intestine compared with those of rats exposed to the carcinogen alone (61% and 1.06 +/- 1.18). The incidence and multiplicity of tumors in small intestine (21% and 0.32 +/- 0.73) and the incidence of colon tumors of rats given BITC in the initiation phase (47%) were significantly lower than those of animals treated with carcinogen alone (61%, 1.06 +/- 1.18 and 83%). Bromodeoxyuridine labeling indices of the intestinal mucosal cells were measured. The labeling indices were reduced by BTC and BITC exposure at initiation phase in both small intestine and colon. The results of measurement of labeling indices correlated with the decreased tumor incidence and multiplicity in the intestine. These data suggest that BTC and BITC could be promising chemopreventive agents for human intestinal neoplasia.

Animals↗