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C Miyaura

Publications and source records attributed to C Miyaura.

At least 55 records · Page 3Linked to original sources
PubMed1989

Spermidine-dependent proteins are involved in the fusion of mouse alveolar macrophages induced by 1 alpha,25-dihydroxyvitamin D3 and interleukin 4.

We have reported that 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] directly induces fusion of mouse alveolar macrophages by a mechanism involving protein synthesis (H. Tanaka et al., 1984, FEBS Lett. 174, 61). While examining further the mechanism of the fusion, we found that polyamines, most likely spermidine, are involved as an important intracellular mediator of the 1 alpha,25(OH)2D3 action in inducing protein synthesis, which in turn induces fusion of macrophages (T. Hayashi et al., 1986, J. Bone Miner. Res. 1, 235). In this study, spermidine-dependent proteins responsible for inducing fusion were examined by electrophoresis of [35S]methionine-labeled proteins. 1 alpha,25(OH)2D3 increased synthesis of 14 proteins at 24 h after the addition, before it initiated fusion at 36 h. When spermidine synthesis was inhibited by adding methylglyoxal bis(guanylhydrazone) (MGBG), the enhanced synthesis in 9 of the 14 proteins induced by 1 alpha,25(OH)2D3 was greatly diminished with a concomitant inhibition of fusion. Further addition of spermidine restored the synthesis of these 9 proteins and the fusion as well. The synthesis of 3 of the 9 proteins was similarly induced by interferon-gamma, retinoic acid, or lipopolysaccharides, which induced activation but not fusion of macrophages. The apparent molecular weights of the remaining 6 proteins were 142K, 98K, 78K, 60K, 50K, and 42K. Recombinant mouse interleukin 4 (IL-4) also induced fusion of alveolar macrophages by a spermidine-dependent mechanism, and it increased the synthesis of 5 proteins (172K, 98K, 78K, 53K, and 50K). These results suggest that 3 spermidine-dependent proteins (98K, 78K, and 50K) are involved in the fusion of mouse alveolar macrophages induced by 1 alpha,25(OH)2D3 and IL-4.

Animals↗
PubMed1989

A synthetic analogue of vitamin D3, 22-oxa-1 alpha,25-dihydroxyvitamin D3, is a potent modulator of in vivo immunoregulating activity without inducing hypercalcemia in mice.

The in vivo immunoregulating activity and the hypercalcemic action of 4 synthetic analogues of vitamin D3 with an oxygen atom in the side chain were compared with those of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] in mice. Oral administration of these vitamin D3 compounds augmented the primary immune response, induced by immunization with a suboptimal number of sheep erythrocytes, without inducing hypercalcemia. The order of the in vivo potency to induce the immune response was 22-oxa-1 alpha,25(OH)2D3 greater than 1 alpha,25(OH)2D3 not equal to 20-oxa-1 alpha,25(OH)2D3 not equal to 22-oxa-1 alpha(OH)D3 greater than 1 alpha(OH)D3 not equal to 20-oxa-1 alpha(OH)D3. 22-Oxa-1 alpha,25(OH)2D3 was about 50 times more potent than 1 alpha,25(OH)2D3 in inducing the in vivo primary immune response, but the former was only 1/100 as active as the latter in inducing hypercalcemia. These results suggest that the immunoregulating activity of vitamin D compounds can be separated structurally from their hypercalcemic action in vivo.

Animals↗
PubMed1989

Metabolism of vitamin D in human promyelocytic leukemia cells (HL-60) II. Does the differentiation of the cells alter the metabolism?

The metabolism of 25-hydroxyvitamin D3 (25-OH-D3) in human promyelocytic leukemia cells (HL-60) which had been exposed to 1 alpha, 25-dihydroxyvitamin D3 (1,25-(OH)2D3) was compared with that in untreated cells. 8 alpha, 25-Dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3-one (8,25-(OH)2-3-oxoneo-D3) was the only major metabolite in untreated HL-60 cells but exposure of the cells to 1,25-(OH)2D3 for 1 day significantly changed the metabolism: 24R,25-dihydroxyvitamin D3 (24R,25-(OH)2D3) was produced as the major metabolite together with 8,25-(OH)2-3-oxoneo-D3 whose production was also increased. The 1,25-(OH)2D3 treatment did not stimulate the production of 25-hydroxyvitamin D3 26,23-lactone by the HL-60 cells. The metabolism of 25-OH-D3 by HL-60 cells was also significantly affected by fetal bovine serum added to the incubation medium: production of 24R,25-(OH)2D3 was significantly reduced and formation of 8,25-(OH)2-3-oxoneo-D3 was completely abolished.

Calcifediol↗
PubMed1988

Recombinant human interleukin 6 (B-cell stimulatory factor 2) is a potent inducer of differentiation of mouse myeloid leukemia cells (M1).

Recombinant human interleukin 6 (IL-6), a lymphokine involved in the final differentiation of activated B-cells into antibody-forming cells, greatly suppressed proliferation and induced differentiation of murine myeloid leukemia cells (M1) into mature macrophage-like cells. When M1 cells were treated with IL-6, their growth was completely arrested as early as on day 2, and they were induced to differentiate morphologically into macrophage-like cells. Differentiation-associated properties such as phagocytic activity, adherence to the dish surface, Fc and C3 receptors, were also induced within 24 h by IL-6, and they reached their respective maximal levels on day 2 or 3. The potency of IL-6 in suppressing proliferation and inducing differentiation was much greater than that of 1 alpha,25-dihydroxyvitamin D3 one of the most potent inducers of M1 cells. The present report indicates that IL-6 is involved in the differentiation of not only B-cells but also myeloid leukemia cells.

Animals↗
PubMed1988

Calcium is essential in the fusion of mouse alveolar macrophages induced by 1 alpha,25-dihydroxyvitamin D3.

We have reported that the active form of vitamin D3, 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3], directly induces activation and fusion of mouse alveolar macrophages (Abe et al., 1983, 1984). The activated state appeared to be a prerequisite to the fusion of macrophages. Macrophages began to fuse 36 hr after adding 1 alpha,25(OH)2D3; the fusion rate attained a maximum of 70-80% at 72 hr. During the course of further investigating the mechanisms of fusion induced by the vitamin, we found that the calcium ion is closely involved in the fusion process of macrophages induced by 1 alpha,25(OH)2D3. When alveolar macrophages were cultured with 1 alpha,25(OH)2D3 in medium with graded concentrations (0.13-1.85 mM) of calcium, the fusion rate went down in parallel with the decrease of medium calcium. Neither calcium ionophore A23187 nor 12-O-tetradecanoylphorbol-13-acetate (TPA) induced fusion of freshly isolated macrophages, but the two compounds greatly promoted fusion of the macrophages pretreated for 18 hr with 1 alpha,25(OH)2D3. The vitamin effect for the first 18 hr was similar, irrespective of the medium calcium concentration. In contrast, millimolar amounts of calcium were essential in the subsequent period of incubation(18-72 hr) for inducing fusion. The activation of macrophages measured by the induction of cytotoxicity and the enhancement of glucose consumption by 1 alpha,25(OH)2D3 occurred similarly, irrespective of the medium calcium concentration. These results clearly indicate that the fusion process of alveolar macrophages induced by 1 alpha,25(OH)2D3 can be divided into two phases: 1) the calcium-independent priming phase (0-18 hr) and 2) the calcium-dependent progression phase (18-72 hr). 1 alpha,25(OH)2D3 is necessary only in the priming phase; A23187 and TPA can be substituted for 1 alpha,25(OH)2D3 in the progression phase.

Animals↗
PubMed1987

Synthetic analogues of vitamin D3 with an oxygen atom in the side chain skeleton. A trial of the development of vitamin D compounds which exhibit potent differentiation-inducing activity without inducing hypercalcemia.

Four analogues of vitamin D3 with an oxygen atom in the side chain skeleton were synthesized to determine whether their differentiation-inducing activity could be separated structurally from their activity to induce hypercalcemia. The order of the in vitro potency to reduce nitroblue tetrazolium in human myeloid leukemia cells (HL-60) was 22-oxa-1 alpha, 25-(OH)2D3 greater than 1 alpha, 25-(OH)2D3 greater than 20-oxa-1 alpha, 25-(OH)2D3 not equal to 22-oxa-1 alpha-(OH)D3 greater than 1 alpha-(OH)D3 greater than 20-oxa-1 alpha-(OH)D3. 22-Oxa-1 alpha, 25-(OH)2D3 was also about 10-times more potent than 1 alpha, 25-(OH)2D3 in suppressing proliferation and inducing differentiation of mouse myelomonocytic leukemia cells (WEHI-3), but the former was much weaker than the latter in inducing the release of 45Ca from prelabeled fetal mouse calvaria. These results suggest that the differentiation-inducing activity of vitamin D compounds can be separated structurally from their activity to induce hypercalcemia.

Animals↗
PubMed1987

Isolation, identification, and chemical synthesis of 8 alpha,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3-one. A new metabolite of 25-hydroxyvitamin D3 produced by mouse myeloid leukemia cells (M1).

It is known that phagocytic cells such as monocyte-macrophages and myeloid leukemia cells metabolize 25-hydroxyvitamin D3 to 10-oxo-19-nor-25-hydroxyvitamin D3. Now we have found that phagocytic cells metabolize 25-hydroxyvitamin D3 not only to 10-oxo-19-nor-25-hydroxyvitamin D3 but also to a new metabolite eluted just after 24R,25-dihydroxyvitamin D3 on straight phase high pressure liquid chromatography with a 2-propanol-hexane solvent system. The new metabolite, produced by murine myeloid leukemia cells (M1), was isolated in pure form and identified as 8,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3-one on the basis of mass, ultraviolet, infrared, and proton magnetic resonance spectra. The 8 alpha-hydroxy epimer of the putative metabolite was chemically synthesized in two steps starting from 25-hydroxyvitamin D3. The spectral data and chromatographic behavior of chemically synthesized 8 alpha,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3-one coincided exactly with those of the isolated metabolite, indicating that the stereochemistry of the hydroxyl group at the 8-position is alpha. On the basis of the structural characteristics of the two metabolites produced from 25-hydroxyvitamin D3 (the present metabolite and 10-oxo-19-nor-25-hydroxyvitamin D3), it is suggested that dioxygenases are involved in the production of these metabolites from 25-hydroxyvitamin D3 in phagocytic cells.

Animals↗
PubMed1987

Phagocytic cells metabolize 25-hydroxyvitamin D3 to 10-oxo-19-nor-25-hydroxyvitamin D3 and a new metabolite, 8 alpha,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3-one.

The metabolism of 25-hydroxyvitamin D3 [25(OH)D3] was examined in several phagocytic cells including alveolar macrophages and myeloid leukemia cells (M1, HL-60 and U937). Phagocytic cells converted 25(OH)D3 to 10-oxo-19-nor-25-hydroxyvitamin D3 and a new metabolite. The former metabolite was dominant in shorter incubation periods (1 h), whereas the latter dominated over longer incubation periods (24 h). The new metabolite was produced from 25(OH)D3 directly but not through 10-oxo-19-nor-25-hydroxyvitamin D3. The new metabolite was unequivocally identified as 8 alpha,25-dihydroxy-9-10-seco-4,6,10(19)-cholestatrien-3-one. These results suggest that phagocytic cells somehow promote oxidation of the triene part of vitamin D compounds.

Animals↗
PubMed1987

An ultrastructural study on the multinucleation process of mouse alveolar macrophages induced by 1 alpha,25-dihydroxyvitamin D3.

The multinucleation process of isolated alveolar macrophages induced by 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] was examined using a scanning electron microscope (SEM) and a transmission electron microscope (TEM). At the beginning of culture, most of the macrophages were spherical in shape. During incubation with 1.2 X 10(-8) M 1 alpha,25(OH)2D3, spreading macrophages appeared among the spherical macrophages, and they increased in number. Spreading macrophages extended many cytoplasmic processes toward adjacent macrophages, and interdigitations of these processes between those of neighboring cells were often seen. Two types of cell contact have been observed in the 1 alpha,25(OH)2D3-treated cells. In some, cytoplasmic processes were put into the cytoplasm of the adjacent cells, where clathrinlike structures were observed at the inner membrane of the concave portion. In others, spreading macrophages occasionally came in contact with adjacent cells by a peripheral rim of their cytoplasm with gap junctions. Cytoplasmic continuity was rarely observed at the boundaries between the closely associated cells. The two types of cell contact were also found, though not frequently, in the untreated cells. These results indicate that 1 alpha,25(OH)2D3 promotes multinucleation of alveolar macrophages through spreading forms with the formation of gap junctions and the coated membrane invagination.

Animals↗
PubMed1987

Fusion and activation of human alveolar macrophages induced by recombinant interferon-gamma and their suppression by dexamethasone.

Multinucleated giant cells appear in the inflamed tissues of granulomatous lung diseases. These giant cells are thought to be formed from macrophages by fusion, but its mechanism is not fully understood. Interferon-gamma (IFN-gamma) is a lymphokine that activates macrophages. In this report, we examined the in vitro effect of recombinant IFN-gamma on activation and fusion of human alveolar macrophages. Adding IFN-gamma to the culture promoted fusion of alveolar macrophages in a time- and dose-dependent manner, but untreated control macrophages remained mostly mononuclear. The fusion rate attained a maximum of about 20% on Day 5, and the number of nuclei per cell increased in parallel with the increase in IFN-gamma concentration. Adding IFN-gamma also activated some functions of the alveolar macrophages, as measured by increased glucose consumption and cytostatic activity against HeLa cells. Maximal cytostatic activity was obtained by adding 1,000 units/ml of IFN-gamma. The glucose consumption of alveolar macrophages from patients with cancer was relatively low, but IFN-gamma restored their glucose consumption approximately to the level in a healthy volunteer and in patients with pneumonia. Dexamethasone inhibited both the fusion and the activation of alveolar macrophages induced by IFN-gamma. These results suggest that IFN-gamma is involved in the pathogenesis of pulmonary granuloma formation by inducing activation and fusion of alveolar macrophages. The inhibitory effect of dexamethasone appears to reflect its therapeutic effects in treating patients with granulomatous lung diseases.

Bronchoalveolar Lavage Fluid↗
PubMed1987

Alteration of lipid metabolism associated with the activation of mouse alveolar macrophages induced by 1 alpha, 25-dihydroxyvitamin D3.

We have reported that 1 alpha, 25-dihydroxyvitamin D3 [1 alpha, 25-(OH)2D3] directly induces fusion and tumoricidal activity (activation) in murine alveolar macrophages. In this study we examined lipid metabolism associated with the fusion and activation of alveolar macrophages induced by 1 alpha, 25-(OH)2D3. Treatment of alveolar macrophages with 12 nM 1 alpha, 25-(OH)2D3 for 48 h caused a marked increase in incorporation of [14C]acetic acid and [14C]oleic acid into triacylglycerol. The macrophages treated with the vitamin began to fuse and show cytotoxicity at 48 h, whereas incorporation of the radioactive compounds into triacylglycerol started as early as 12 h after 1 alpha, 25-(OH)2D3 was added. The triacylglycerol synthesis induced by 1 alpha, 25-(OH)2D3 was greatly increased when 14C-labeled unsaturated fatty acids were used as tracers compared with 14C-labeled saturated fatty acids. The activity of diacylglycerol acyltransferase, which catalyzes the last step of the three acylations in triacylglycerol synthesis, was significantly higher in the macrophages treated with 1 alpha, 25-(OH)2D3 than in the control macrophages. Like 1 alpha, 25-(OH)2D3, retinoic acid and lypopolysaccharides also activated alveolar macrophages, but not induce any fusion. The activated macrophages cultured with retinoic acid or lypopolysaccharides also induced synthesis of triacylglycerol. These results indicate that 1 alpha, 25-(OH)2D3 induces the synthesis of triacylglycerol by preferentially incorporating unsaturated fatty acids into diacylglycerol, and that the alteration of lipid metabolism is related to the activation, rather than the fusion, of alveolar macrophages.

Acyltransferases↗
PubMed1987

The relationship between fusion and proliferation in mouse alveolar macrophages.

We have reported that protein factors separated from conditioned media of Concanavalin A-stimulated spleen cell cultures induce growth and fusion of mouse alveolar macrophages. A macrophages growth factor (MGF) was purified and, at the final step of purification on HPLC, eluted at the same position as a colony-stimulating factor (CSF), suggesting that MGF is identical with CSF. In the present study, we examined the relationship between proliferation and fusion of macrophages using purified CSF (MGF) and 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25-(OH)2D3]. The latter was used in place of a macrophage fusion factor which is supposed to be contained in the same conditioned medium, since a macrophage fusion factor has not yet been isolated. Adding less than 5% unfractionated conditioned medium from Concanavalin A-stimulated spleen cells markedly induced proliferation of alveolar macrophages without inducing fusion. In contrast, adding the same unfractionated conditioned medium at concentrations of 10% or more suppressed proliferation dose dependently, whereas it induced fusion reciprocally. Proliferation of macrophages was similarly enhanced by adding purified CSF or retinoic acid. Fusion of macrophages was induced by 1 alpha,25-(OH)2D3, but not by purified CSF or retinoic acid. Adding 1 alpha,25-(OH)2D3 together with purified CSF or retinoic acid completely suppressed the increase of proliferation induced by either growth factor, whereas that treatment rather potentiated the fusion induced by 1 alpha,25-(OH)2D3 alone. These results indicate that the fusion and proliferation of macrophages occur in a reciprocal fashion.

Animals↗
PubMed1986

Effects of retinoic acid on the activation and fusion of mouse alveolar macrophages induced by 1 alpha,25-dihydroxyvitamin D3.

1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] directly induces both fusion and cytotoxicity in murine alveolar macrophages. Unlike 1 alpha,25(OH)2D3, retinoic acid per se did not induce fusion of alveolar macrophages, but it greatly enhanced the 1 alpha,25(OH)2D3-induced fusion every time the macrophages were treated simultaneously with the two vitamins. The giant cells induced by the two vitamins were much larger than those induced by 1 alpha,25(OH)2D3 alone. The macrophages treated with 1 alpha,25(OH)2D3 started to fuse 36 h after the addition of the vitamin, whereas the macrophages pretreated with retinoic acid for 24 h began to fuse immediately after 1 alpha,25(OH)2D3 was added. 1 alpha,25(OH)2D3 and retinoic acid activated alveolar macrophages similarly, measured by the enhancement of glucose consumption and the induction of cytotoxicity against tumor cells, though 1 alpha,25(OH)2D3 was 100 times more potent than retinoic acid on a molar basis. Simultaneous treatment with physiological concentrations of 1 alpha,25(OH)2D3 (0.12 nM) and retinoic acid (10 nM) induced cytotoxicity additively. Morphological examinations revealed that the treated cells were enlarged and flattened with numerous filopodia. These results clearly indicate that both 1 alpha,25(OH)2D3 and retinoic acid similarly activate alveolar macrophages, and the activated state is prerequisite to the fusion of macrophages induced by 1 alpha,25(OH)2D3.

Animals↗
PubMed1986

Differentiation-inducing factor purified from conditioned medium of mitogen-treated spleen cell cultures stimulates bone resorption.

Spleen cells treated with mitogens produce a potent bone-resorbing factor called osteoclast-activating factor (OAF). To examine the relationship between the bone-resorbing factor and other protein factors produced by spleen cells, the colony-stimulating factor (CSF), the differentiation-inducing factor (DIF), the macrophage fusion factor (MFF), and the macrophage growth factor (MGF) were purified from 2.68 liters of conditioned medium of mouse spleen cell cultures treated with concanavalin A. Purification was performed successively by DEAE-cellulose, Blue Sepharose, and Sephadex G-150 column chromatography and high-pressure liquid chromatography (HPLC). The DIF was successfully separated from CSF and MGF on HPLC. CSF coincided with MGF on HPLC, but MFF disappeared before application to HPLC. Only the DIF exhibited bone-resorbing activity, whereas CSF and MGF did not. The DIFs purified from L929 cells and Ehrlich ascites tumors similarly exhibited bone-resorbing activity. The DIFs purified from spleen cells and Ehrlich ascites tumor cells exhibited neither interleukin 1 (IL-1) activity nor tumor necrosis factor (TNF) activity, though the unfractionated conditioned medium from spleen cells did exhibit them. In the light of recent reports that IL-1 beta and TNF also stimulate bone resorption, the term OAF should refer to a generic activity rather than a single factor.

Animals↗
PubMed1985

Syntheses and differentiating action of vitamin D endoperoxides. Singlet oxygen adducts of vitamin D derivatives in human myeloid leukemia cells (HL-60).

Singlet oxygen adducts of various vitamin D derivatives, 6,19-dihydro-6,19-epidioxyvitamin D (vitamin D endoperoxides, 2 and 2'), were chemically synthesized, and their biological activity in inducing differentiation of a human myeloid leukemia cell line (HL-60 cells) was examined. The potency of the endoperoxides derived from vitamin D derivatives possessing the 1 alpha-hydroxyl group such as 1 alpha, 25-dihydroxyvitamin D3 endoperoxides (2b and 2b') was markedly (10(-2)) diminished relative to the respective parent vitamin D compounds. In contrast, 25-hydroxyvitamin D3 endoperoxides [25-(OH)D3 endoperoxides, 2a and 2a'] and their analogues fluorinated at the 24- or 26- and 27-positions were 2.5-10 times more potent than 25-hydroxyvitamin D3 (1a) in spite of the absence of the conjugated triene structure typical of vitamin D compounds. The potency of these vitamin D endoperoxides (2 and 2'), especially those lacking the 1 alpha-hydroxyl group, in inducing differentiation of HL-60 cells was not correlated with their activity in binding to the cytosol receptor for 1 alpha, 25-dihydroxyvitamin D3 (1b). The binding efficiency to the receptor was relatively lower than the differentiating activity. To examine the action of vitamin D endoperoxides, carbon analogues of 25-(OH)D3 endoperoxides, two C-6 epimers of 25-hydroxy-6,19-dihydro-6,19-ethanovitamin D3 (6 and 6'), were synthesized. The carbon analogues (6 and 6') had no potential to induce differentiation of HL-60 cells. These results suggest that vitamin D endoperoxides (2 and 2') express their biological activity probably after being converted to some other compounds.

Binding, Competitive↗
PubMed1985

Mechanism of the differentiating action of 25-hydroxyvitamin D3 endoperoxides in human myeloid leukemia cells (HL-60).

The action of 25-hydroxy-6,19-dihydro-6,19-epidioxyvitamin D3 [25-(OH)D3 endoperoxides, 2a and 3a] in inducing differentiation of human myeloid leukemia cells (HL-60) was studied by using their radioactive derivatives (2a' and 3a'). When HL-60 cells were incubated with the labeled endoperoxides (2a' and 3a') in serum-free RPMI 1640 medium, no radioactivity was incorporated into either the cytosol or the chromatin fraction of the cells. When the radioactive endoperoxide (2a') was incubated in the culture medium for 3 days, with or without HL-60 cells, about 45% of the compound was similarly converted to 19,25-dihydroxy-6,19-dihydro-6,19-epoxyvitamin D3 (4a) and about 10% to 25-hydroxy-6,19-epoxyvitamin D3 (6a). These two new vitamin D derivatives were synthesized chemically and tested for their biological activities. Both compounds (4a and 6a) were about 2 times as active as 25-(OH)D3 endoperoxides (2a and 3a) and about 7 times as active as 25-hydroxyvitamin D3 (1a) in inducing differentiation of HL-60 cells. The differentiating activity of these compounds was well correlated with their activity in binding to the cytosol receptor for 1 alpha, 25-dihydroxyvitamin D3 in HL-60 cells. The in vitro bone-resorbing activity of 25-hydroxy-6,19-epoxyvitamin D3 (6a) and 25-(OH)D3 endoperoxide (2a) was higher than that of 25-hydroxyvitamin D3 (1a), indicating that the differentiating activity also paralleled the bone-resorbing activity in these vitamin D derivatives. These results suggest that 25-(OH)D3 endoperoxides (2a and 3a) induce differentiation of HL-60 cells and bone resorption after being converted to these two compounds.

Animals↗