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PubMed1998

Chemopreventive effect of squalene on colon cancer.

Epidemiologic and laboratory studies suggest a cancer protective effect and/or lack of a tumor promoting effect by dietary olive oil as compared with other types of non-marine oils. Squalene, a constituent of olive oil, and a key intermediate in cholesterol synthesis may be regarded as partially responsible for the beneficial effects of olive oil, which include decreased mortality rates among populations with high olive oil consumption. Thus, in this study we have assessed the chemopreventive efficacy of squalene on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF). In addition, we measured the effect of squalene on serum cholesterol levels in the rats. Male F34 rats (5 weeks old) were fed the control diet (modified AIN-76A) or experimental diets containing 1% squalene or 320 p.p.m. sulindac. Two weeks later, all animals except those in vehicle (normal saline)-treated groups were s.c. injected with AOM (15 mg/kg body wt, once weekly for 2 weeks). At 16 weeks of age, all rats were killed, colons were evaluated for ACF and serum was assayed for the cholesterol levels. As expected, dietary administration of sulindac suppressed ACF development and reduced crypt multiplicity, i.e. number of aberrant crypts/focus. Administration of dietary squalene inhibited total ACF induction and crypt multiplicity by approximately >46% (P < 0.001). Further, squalene at a level of 1% did not show any significant effect on serum cholesterol levels. Our finding that squalene significantly suppresses colonic ACF formation and crypt multiplicity strengthens the hypothesis that squalene possesses chemopreventive activity against colon carcinogenesis.

Animals↗
PubMed1981

Squalene and sterol synthesis in isolated small-intestinal cells of the rat.

To compare the synthesis rate of cholesterol in different cells of the small intestine, isolated villous and crypt cells were incubated with a mixture of 14C-acetate and 3H-mevalonate in the presence of unlabeled carriers. The synthesis rate of squalene (includes the portion converted to sterols) from acetate was tenfold higher in the crypt than villous cells. The synthesis rate of squalene from mevalonate and the cyclization rate of squalene (the portion found in sterols) were about twofold higher in crypt than in villous cells. The conversion of acetate to squalene was correlated with that to fatty acids in the crypt cells only (r = 0.823), and the ratio of the two synthesis rates (squalene/fatty acids) was threefold higher in crypt than in villous cells. Despite the significant differences in the synthesis rates of squalene and sterols the concentrations of squalene and methyl sterols were similar in the two cell types. THe cholesterol content was, however, consistently higher in villous than in crypt cells, but the concentration was not correlated with the synthesis of squalene in the two cell types. The appearance of labeled squalene was clearly lower than that of labeled sterols in the lipoprotein-free incubation medium, but no differences were found between villous and crypt cells.

Acetates↗
PubMed1990

Regulation of squalene epoxidase in HepG2 cells.

Regulation of squalene epoxidase in the cholesterol biosynthetic pathway was studied in a human hepatoma cell line, HepG2 cells. Since the squalene epoxidase activity in cell homogenates was found to be stimulated by the addition of Triton X-100, enzyme activity was determined in the presence of this detergent. Incubation of HepG2 cells for 18 h with L-654,969, a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, increased squalene epoxidase activity dose-dependently. On the other hand, low density lipoprotein (LDL) and 25-hydroxy-cholesterol decreased the enzyme activity. These results demonstrate that squalene epoxidase is regulated by the concentrations of endogenous and exogenous sterols. The affinity of the enzyme for squalene was not changed by treatment with L-654,969. Cytosolic (S105) fractions, prepared from HepG2 cells treated with or without L-654,969, had no effect on microsomal squalene epoxidase activity of HepG2 cells, in contrast to the stimulating effect of S105 fractions from rat liver homogenate. Mevalonate, LDL, and oxysterol treatment abolished the effect of L-654,969. Simultaneous addition of cycloheximide and actinomycin D also prevented enzyme induction in HepG2 cells. From these results, the change in squalene epoxidase activity is thought to be caused by the change in the amount of enzyme protein. It is further suggested that squalene epoxidase activity is suppressed only by sterols, not by nonsterol derivative(s) of mevalonate, in contrast to the regulation of HMG-CoA reductase.

Binding, Competitive↗
PubMed1982

Diurnal variation of cholesterol precursors squalene and methyl sterols in human plasma lipoproteins.

Animal cholesterol synthesis shows a marked diurnal variation, a phenomenon, at the moment, not known to occur in man. Since cholesterol precursors in serum reflect overall cholesterol synthesis in many conditions, a 24-hr profile of squalene and methyl sterols was studied in plasma lipoproteins in order to demonstrate whether these cholesterol precursors could exhibit a diurnal cycling in healthy human subjects. During the 24-hr period, lipoproteins of density < 1.006 g/ml transported 30-50% of the plasma squalene. Free methyl sterols were found mainly in low density lipoproteins (LDL) and esterified methyl sterols in LDL and high density lipoproteins (HDL). Postprandial hyperlipidemia at noon was associated with an inconsistent increase of the squalene and free methyl sterol concentrations in the lipoproteins of density < 1.006 g/ml. In terms of micro g per mg of cholesterol, the precursor contents were, however, low in each lipoprotein during the daytime. During the night and early morning, the values were several times higher. Thus the peak plasma squalene and methyl sterol contents occurred at midnight and 4 am. The highest variation was found for squalene in the density class < 1.006 g/ml and for lanosterol and diunsaturated dimethyl sterol in LDL and HDL. For different methyl sterols, the mean diurnal variation was 3.5- to 6.9-fold in LDL, 2.0- to 4.5-fold in HDL, and 2.6- to 3.6-fold in the density class < 1.006 g/ml. The respective values for squalene were 2.2, 1.4, and 2.9. Esterified methyl sterols varied slightly in the density class < 1.006 g/ml only, and the percentage esterification exhibited a diurnal fluctuation that was the reciprocal of that of free methyl sterol levels. The rapid and marked diurnal fluctuation of squalene and free methyl sterols in plasma lipoproteins suggests that these precursors are metabolized on and off lipoproteins. The variation is most likely caused by changes in cholesterol synthesis, inferring that circadian rhythm also regulates human cholesterol production.-Miettinen, T. A. Diurnal variation of cholesterol precursors squalene and methyl sterols in human plasma lipoproteins.

Adolescent↗
PubMed1976

Effect of a supernatant protein on microsomal squalene epoxidase and 2,3-oxidosqualene-lanosterol cyclase.

Squalene epoxidation catalyzed by rat liver microsomes requires oxygen NADPH, and the 105,000 x g supernatant (S105). The supernatant can be replaced by a partially purified S105 protein (SPF) and phospholipids (Tai, H., and Bloch, K. (1972) J. Biol. Chem. 247, 3767). When washed microsomes are preincubated anaerobically with [14C]squalene and S105 without NADPH, followed by centrifugation and washing to remove the unbound squalene and S105, epoxidation in the presence of O2 and NADPH occurs subsequently at the same rate as in direct assays containing all required components from the start. Partially purified SPF (65-fold) shows the same effect. Washed microsomes preincubated anaerobically with squalene alone, or with bovine serum albumin instead of S105, also take up large amounts of squalene, but the squalene so incorporated is only poorly converted to epoxide. The epoxidation of endogenous squalene formed in liver homogenates from [14C]mevalonate is also stimulated by S105. The incorporation of squalene into microsomes is temperature dependent. 2,3-Oxidosqualene-lanosterol cyclase (cyclase) also requires S105 for optimal activity. It is suggested that the S105 protein acts internally within the microsomal membrane system facilitating the access of substrate to specific enzyme sites.

Animals↗
PubMed1999

Squalene and its potential clinical uses.

Squalene, an isoprenoid compound structurally similar to beta-carotene, is an intermediate metabolite in the synthesis of cholesterol. In humans, about 60 percent of dietary squalene is absorbed. It is transported in serum generally in association with very low density lipoproteins and is distributed ubiquitously in human tissues, with the greatest concentration in the skin, where it is one of the major components of skin surface lipids. Squalene is not very susceptible to peroxidation and appears to function in the skin as a quencher of singlet oxygen, protecting human skin surface from lipid peroxidation due to exposure to UV and other sources of ionizing radiation. Supplementation of squalene to mice has resulted in marked increases in cellular and non-specific immune functions in a dose-dependent manner. Squalene may also act as a "sink" for highly lipophilic xenobiotics. Since it is a nonpolar substance, it has a higher affinity for un-ionized drugs. In animals, supplementation of the diet with squalene can reduce cholesterol and triglyceride levels. In humans, squalene might be a useful addition to potentiate the effects of some cholesterol-lowering drugs. The primary therapeutic use of squalene currently is as an adjunctive therapy in a variety of cancers. Although epidemiological, experimental and animal evidence suggests anti-cancer properties, to date no human trials have been conducted to verify the role this nutrient might have in cancer therapy regimens.

Animals↗
PubMed1979

Squalene synthetase activity in human fibroblasts: regulation via the low density lipoprotein receptor.

Squalene synthetase (farnesyltransferase; farnesyl diphosphate:farnesyl-diphosphate farnesyltransferase, EC 2.5.1.21), the enzyme in the cholesterol biosynthetic pathway that converts farnesyl pyrophosphate into squalene, is subject to regulation in cultured human fibroblasts. When cholesterol-carrying low density lipoprotein (LDL) was removed from the serum of the culture medium, squalene synthetase activity increased 8-fold over 24 hr. When LDL was added back to the medium, squalene synthetase was slowly suppressed, 50% and 90% reduction occurring in 15 and 48 hr, respectively. Suppression of squalene synthetase required uptake of LDL via the LDL receptor; hence, it did not occur in mutant fibroblasts from a patient with homozygous familial hypercholesterolemia that lack receptors. The addition of a mixture of 25-hydroxycholesterol and cholesterol suppressed squalene synthetase equally well in normal and mutant fibroblasts. Coupled with previous data, the current findings indicate that cholesterol derived from LDL regulates at least two enzymes in the cholesterol synthetic pathway in fibroblasts: (i) its primary action is to rapidly suppress 3-hydroxy-3-methylglutaryl coenzyme A reductase [mevalonate:NADP(+), oxidoreductase (CoA-acylating), EC 1.1.1.34], which reduces mevalonate production by 95% within 8 hr, and (ii) its secondary action is to slowly suppress squalene synthetase. The LDL-mediated suppression of squalene synthetase does not regulate de novo cholesterol synthesis; it occurs after 3-hydroxy-3-methylglutaryl coenzyme A reductase is already suppressed. Rather, we hypothesize that it may function to allow the pool size of farnesyl pyrophosphate to be maintained in the presence of LDL so that low levels of mevalonate can be shunted preferentially into nonsterol products, such as ubiquinone-10 and dolichol. This mechanism may explain the earlier observation that the synthesis of ubiquinone-10 in fibroblasts proceeds at a normal rate in the presence of LDL despite a 95% decrease in mevalonate production.

Cells, Cultured↗
PubMed1997

Endotoxin, tumor necrosis factor, and interleukin-1 decrease hepatic squalene synthase activity, protein, and mRNA levels in Syrian hamsters.

Recent studies have shown that endotoxin (LPS) administration to Syrian hamsters markedly increased hepatic HMG-CoA reductase activity, protein mass, and mRNA levels, but only produced a modest increase in hepatic cholesterol synthesis, suggesting that LPS may also influence other key enzymes involved in the regulation of cholesterol metabolism. In the present study, we have examined the effect of LPS and cytokines on the activity, protein mass, and mRNA level of squalene synthase, which is the first committed enzyme in cholesterol biosynthesis and is located at a branch point in the mevalonate pathway. Our results demonstrate that LPS administration produces a marked decrease in the mRNA levels of squalene synthase. This decrease in squalene synthase mRNA occurred very rapidly (90 min after LPS) and required relatively small doses of LPS (1 microg/100 gm body weight). LPS also significantly decreased squalene synthase activity and protein mass. Finally, LPS produced a marked decrease in squalene synthase mRNA, activity, and protein levels when the basal levels of squalene synthase expression were increased 4-fold by prior treatment with bile acid binding resin, colestipol. Tumor necrosis factor and interleukin-1, which mediate many of the metabolic effects of LPS, also decreased hepatic squalene synthase activity and mRNA levels. Taken together, our results suggest that the discordant regulation of HMG-CoA reductase and squalene synthase during the host response to infection and inflammation may have substantial effects on the regulation of substrate flux into the non-sterol pathways of mevalonate metabolism.

Animals↗
PubMed1988

Regulation of squalene epoxidase activity by membrane fatty acid composition in yeast.

Depriving Saccharomyces cerevisiae strain GL7 of exogenous unsaturated fatty acid supplements causes this sterol biosynthetic mutant to accumulate squalene at the expense of squalene epoxide and squalene diepoxide. To further characterize the apparent relationship between squalene epoxidase activity and membrane fatty acid composition, a variety of unsaturated fatty acids differing in their chain lengths and in the positions and orientation (cis or trans) of their double bonds were tested for their ability to promote turnover of endogenous squalene in cells previously deprived of olefinic supplements. All of the unsaturated fatty acids tested were found to restore squalene epoxidase activity but there were marked differences in their efficacies that best were correlated with the extent to which they reduced the medium chain (C-10 + C-12) saturated fatty acid content of cellular phospholipids. Additional studies demonstrated that de novo protein synthesis was required for the restoration of squalene epoxidase activity in unsaturated fatty acid-deprived cells.

Cell Membrane↗
PubMed2000

Antibodies to squalene in Gulf War syndrome.

Gulf War Syndrome (GWS) is a multisystemic illness afflicting many Gulf War-era veterans. The molecular pathological basis for GWS has not been established. We sought to determine whether the presence of antibodies to squalene correlates with the presence of signs and symptoms of GWS. Participants in this blinded cohort study were individuals immunized for service in Desert Shield/Desert Storm during 1990-1991. They included 144 Gulf War-era veterans or military employees (58 in the blinded study), 48 blood donors, 40 systemic lupus erythematosus patients, 34 silicone breast implant recipients, and 30 chronic fatigue syndrome patients. Serum antibodies to squalene were measured. In our small cohort, the substantial majority (95%) of overtly ill deployed GWS patients had antibodies to squalene. All (100%) GWS patients immunized for service in Desert Shield/Desert Storm who did not deploy, but had the same signs and symptoms as those who did deploy, had antibodies to squalene. In contrast, none (0%) of the deployed Persian Gulf veterans not showing signs and symptoms of GWS have antibodies to squalene. Neither patients with idiopathic autoimmune disease nor healthy controls had detectable serum antibodies to squalene. The majority of symptomatic GWS patients had serum antibodies to squalene.

Autoantibodies↗
PubMed1992

Development of a radiometric spot-wash assay for squalene synthase.

The principle of selective elution from a solid phase has been exploited to develop an assay for the determination of squalene biosynthesis in rat liver homogenates. Using either [1-14C]isopentenyl diphosphate as a precursor for squalene or [2-14C]farnesyl diphosphate as a direct substrate of squalene synthase, the production of radiolabeled squalene is determined after adsorption of assay mixtures onto silica gel thin-layer chromatography sheets and selective elution of the diphosphate precursors into a solution of sodium dodecyl sulfate at alkaline pH. The use of [2-14C]farnesyl diphosphate, and of an endogenous oxygen consumption system (ascorbate/ascorbate oxidase) to prevent further metabolism of squalene, allows the method to be applied as a dedicated assay for squalene synthase activity. The assay has been developed in microtiter plate format and may be deployed either in a quantitative, low-throughout mode or in a qualitative, high-through-put mode. The latter is suitable for screening to aid in the discovery of new inhibitors of squalene synthase.

Animals↗
PubMed2003

Preparative separation and purification of squalene from the microalga Thraustochytrium ATCC 26185 by high-speed counter-current chromatography.

High-speed counter-current chromatography (HSCCC) was successfully applied to the preparative separation and purification of squalene from microalgae. Crude squalene was obtained from the microalga Thraustochytrium ATCC 26185 by extraction with organic solvents. The crude squalene was further separated using a waterless two-phase solvent system composed of n-hexane-methanol (2:1, v/v). The upper phase as the mobile phase was pumped into the column at a flow-rate of 2.0 ml min(-1) in the tail-to-head elution mode. The fractions purified and collected were analyzed by high-performance liquid chromatography. The method yielded 0.2 mg squalene at 96% purity from 150 mg of the crude squalene (0.14% squalene) with 95% recovery. The separation of squalene by HSCCC was completed in 90 min.

Countercurrent Distribution↗
PubMed2000

Squalene synthase: steady-state, pre-steady-state, and isotope-trapping studies.

Squalene synthase catalyzes two consecutive reactions in sterol biosynthesis-the condensation of two molecules of farnesyl diphosphate (FPP) to form the cyclopropylcarbinyl intermediate presqualene diphosphate (PSPP) and the subsequent rearrangement and reduction of PSPP to form squalene. Steady-state and pre-steady-state kinetic studies, in combination with isotope-trapping experiments of enzyme.substrate complexes, indicate that two molecules of FPP add to the enzyme before NADPH and that PSPP is converted directly to squalene without dissociating from the enzyme under normal catalytic conditions. In addition, formation of PSPP or a prior conformational change in squalene synthase is the rate-limiting step for synthesis of squalene from FPP via PSPP in the presence of NADPH and for synthesis of PSPP in the absence of NADPH. Squalene synthase is inhibited at high concentrations of FPP. Inhibition is specific for the formation of squalene, but not PSPP, and is competitive with respect to NADPH. In addition, the binding of either NADPH or a third, nonreacting molecule of FPP stimulates the rate of PSPP formation. A kinetic mechanism is proposed to account for these observations.

Binding, Competitive↗
PubMed2002

The arthritogenic adjuvant squalene does not accumulate in joints, but gives rise to pathogenic cells in both draining and non-draining lymph nodes.

A single intradermal injection of the adjuvant-oil squalene induces T cell-mediated arthritis in DA rats. The chain of events leading from non-specific provocation of the immune system to arthritis, with clinical similarities to rheumatoid arthritis, is largely undetermined. Here, we combined in vivo tracking of tritium-labelled squalene with lymph node (LN) cell transfer experiments to determine where critical activation events may take place. The majority of squalene remained at the injection site (79%). The amounts recovered in peripheral joints (<1%) were equal to that recovered in other organs that can be targets in autoimmune diseases. This argues that arthritis does not develop as a consequence of adjuvant accumulation in joints. In contrast, substantial amounts of squalene were recovered in hyperplastic LN draining the injection site (1-13%). The adjuvant was deposited to a larger extent in cells than in extracellular matrix. The draining LN cells could transfer arthritis to naïve irradiated DA rats following in vitro stimulation with conA. Interestingly, non-draining LN were also hyperplastic and harboured arthritogenic cells, although they contained low amounts of squalene (<1%). Consequently, the amount of arthritogenic adjuvant in a particular LN is not closely linked to the development of pathogenic cells. The distribution pattern of squalene was similar in MHC-identical but arthritis-resistant PVG.1AV1 and LEW.1AV1 rats, and it was unaffected by T cell depletion with a monoclonal antibody (R73). Thus, T cells and non-MHC genes do not regulate dissemination of squalene, but rather determine arthritis development at the level of adjuvant response.

Adjuvants, Immunologic↗
PubMed1995

Tellurite specifically affects squalene epoxidase: investigations examining the mechanism of tellurium-induced neuropathy.

A peripheral neuropathy characterized by a transient demyelinating/remyelinating sequence results when young rats are fed a tellurium-containing diet. The neuropathy occurs secondary to a systemic block in cholesterol synthesis. Squalene accumulation suggested the lesion was at the level of squalene expoxidase, a microsomal monooxygenase that uses NADPH cytochrome P450 reductase to receive its necessary reducing equivalents from NADPH. We have now demonstrated directly specificity for squalene epoxidase; our in vitro studies show that squalene epoxidase is inhibited 50% in the presence of 5 microM tellurite, the presumptive in vivo active metabolite. Under these conditions, the activities of other monooxygenases, aniline hydroxylase and benzo(a)pyrene hydroxylase, were inhibited less than 5%. We also present data suggesting that tellurite inhibits squalene epoxidation by interacting with highly susceptible -SH groups present on this monooxygenase. In vivo studies of specificity were based on the compensatory response to feeding of tellurium. Following tellurium intoxication, there was up-regulation of squalene epoxidase activity both in liver (11-fold) and sciatic nerve (fivefold). This induction was a specific response, as demonstrated in liver by the lack of up-regulation following exposure to the nonspecific microsomal enzyme inducer, phenobarbital. As a control, we also measured the microsomal monooxygenase activities of aniline hydroxylase and benzo(a)pyrene hydroxylase. Although they were induced following phenobarbital exposure, activities of these monooxygenases were not affected following tellurium intoxication, providing further evidence of specificity of tellurium intoxication for squalene epoxidase.

Aniline Hydroxylase↗
PubMed1998

Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis by dietary olive oil and squalene.

Epidemiological studies have suggested that frequent olive oil consumption may be a protective factor against lung cancer formation. Squalene, a characteristic compound in olive oil, is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and has been proposed to inhibit the farnesylation of ras oncoproteins. The present study investigated the effect of dietary olive oil and squalene in a mouse lung tumorigenesis model. Female A/J mice were fed AIN-76A diets containing 5% corn oil (control), 19.6% olive oil, or 2% squalene starting at 3 weeks before a single dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (103 mg/kg, i.p.). Animals were maintained on their respective diets throughout the study. At 16 weeks after NNK administration, 100% of the mice in the control group had lung tumors with a tumor multiplicity of 16 tumors per mouse. The olive oil and squalene diets significantly (P < 0.05) decreased the lung tumor multiplicity by 46 and 58%, respectively. The squalene diet significantly (P < 0.05) decreased lung hyperplasia by 70%. In mice fed a diet containing 2% squalene for 3 weeks, the activation of NNK was increased by 1.4- and 2.0-fold in lung and liver microsomes, respectively, but its relationship to the inhibition of carcinogenesis is not clear. These results demonstrate that dietary olive oil and squalene can effectively inhibit NNK-induced lung tumorigenesis.

Animals↗
PubMed1992

Terbinafine: mode of action and properties of the squalene epoxidase inhibition.

Terbinafine (Lamisil) has primarily fungicidal action against many fungi as a result of its specific mechanism of squalene epoxidase inhibition. Treated fungi accumulate squalene while becoming deficient in ergosterol, an essential component of fungal cell membranes. The cidal action is closely associated with the development of high intracellular squalene concentrations, which are believed to interfere with fungal membrane function and cell wall synthesis. In the case of Candida albicans, growth inhibition with terbinafine appears to result from the ergosterol deficiency. The filamentous form of this fungus is more susceptible than the yeast form. Measurement of ergosterol biosynthesis by incorporation of radiolabelled precursors indicates a correlation between inhibition of growth and ergosterol biosynthesis in a range of pathogenic fungi. Terbinafine is a potent non-competitive inhibitor of squalene epoxidase from Candida (Ki = 30 nM). In contrast, inhibition of rat liver squalene epoxidase only occurs at higher drug concentrations (Ki = 77 microM), and is competitive with squalene. Thus, terbinafine has no effect on cholesterol biosynthesis in vivo. Squalene epoxidase is not an enzyme of the cytochrome P-450 type, thereby avoiding potential inhibition of this class of enzymes.

Antifungal Agents↗
PubMed1979

Effects of weight reduction on squalene, methyl sterols and cholesterol and on their synthesis in human adipose tissue.

Quantitation of cholesterol and its precursors from human adipose tissue biopsies revealed very high squalene and moderately high methyl sterol concentrations. The squalene and cholesterol values were correlated with each other. Weight reduction in obese subjects following a jejuno-ileal bypass resulted in a significant but transient increase in adipose tissue cholesterol. The squalene concentration was also increased postoperatively, the maximum being reached about 6 months later than that of cholesterol as if the mobilization of squalene from shrunken adipocytes had been slow. Weight reduction with a 2--14 day total fast significantly reduced the adipocyte size but had no consistent effect on adipose tissue squalene, methyl sterol and cholesterol concentrations or on their adipocyte contents. Incubation of adipose tissue with labelled acetate and mevalonate revealed that the bulk of the labels in non-saponifiable lipids stayed in the large intermediate pools of methyl sterols and squalene in particular, fairly little being found in the cholesterol fraction itself. The total fast inhibited the incorporation of both 14C-acetate and 3H-mevalonate to squalene, methyl sterols and cholesterol, suggesting that cholesterol synthesis was inhibited before and after the mevalonate step.

Adipose Tissue↗