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Biomedical subjects

K Noguchi

Publications and source records attributed to K Noguchi.

At least 91 records · Page 5Linked to original sources
PubMed2000

The relationship between persistent secretion of RANTES and residual infiltration of eosinophils and memory T lymphocytes after Helicobacter pylori eradication.

Helicobacter pylori (HP)-infected gastric mucosa displays a conspicuous infiltration of mononuclear cells as well as neutrophils. RANTES is a potent chemoattractant peptide for memory T lymphocytes and eosinophils. RANTES protein concentration and the numbers of RANTES-, CD45RO-, and major basic protein (MBP)-positive cells were therefore evaluated in the gastric mucosa from 51 patients with HP-positive chronic gastritis before and after HP eradication and from 22 HP-negative healthy volunteers. RANTES protein concentration was significantly elevated in HP-positive cases and remained high after HP eradication. The numbers of RANTES-, CD45RO-, and MBP-positive cells were significantly increased in HP-positive cases and were well correlated with RANTES protein levels. All tended to decrease after HP eradication, but did not reach the level of HP-negative cases, even at 24 months after HP eradication. It was concluded that persistent expression and secretion of RANTES were closely related to residual infiltration of memory T lymphocytes and eosinophils, for a prolonged period after HP eradication. This seems to be an important mechanism of prolonged gastric mucosal immune response against HP infection, even after HP eradication, and of persistent mucosal damage and atrophy.

Adult↗
PubMed2000

Determination of YM992, a novel selective serotonin reuptake inhibitor, in rat and dog plasma by high-performance liquid chromatography with fluorescence detection.

A high-performance liquid chromatographic method with fluorescence detection was developed for the determination of (S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride (YM992) in plasma. Plasma samples were extracted with n-hexane under alkali condition. After the organic solvent was evaporated to dryness, the residue was treated with 4-fluoro-7-nitrobezofurazan (NBD-F) in borate buffer (pH 7.5) at room temperature for 20 min. The reaction was terminated with hydrochloric acid and the resultant solution was injected onto HPLC without further purification. No interfering peak was observed at the retention time of YM992 or the internal standard. The calibration curve was linear with the concentration of YM992 up to 200 ng/ml. The limit of quantitation was 1 ng/ml. The intra- and inter-day relative standard deviation was less than 5.6% and 4.1%, respectively, and the intra- and inter-day relative error ranged from -3.0% to 17.2% and 2.8% to 7.5%, respectively. Using the assay, the plasma concentration of YM992 could be determined up to 8 and 10 h after the oral administration of YM992 to rats and dogs, respectively.

4-Chloro-7-nitrobenzofurazan↗
PubMed2000

Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury.

Activating transcription factor 3 (ATF3), a member of ATF/CREB family of transcription factors, is induced in a variety of stressed tissue. ATF3 regulates transcription by binding to DNA sites as a homodimer or heterodimer with Jun proteins. The purpose of this study was to examine the expression and regulation of ATF3 after axonal injury in neurons in dorsal root ganglia (DRG) and spinal cord. In naive rats, ATF3 was not expressed in the DRG and spinal cord. Following the cut of peripheral nerve, ATF3 was immediately induced in virtually all DRG neurons and motoneurons that were axotomized, and the time course of induction was dependent on the distance between the injury site and the cell body. Double labeling using immunohistochemistry revealed that the population of DRG neurons expressing ATF3 included those expressing c-jun, and in motoneurons ATF3 and c-jun were concurrently expressed after axotomy. In contrast to c-jun, ATF3 was not induced transsynaptically in spinal dorsal horn neurons. We conclude that ATF3 is specifically induced in sensory and motoneurons in the spinal cord following nerve injury and should be regarded as an unique neuronal marker of nerve injury in the nervous system.

Activating Transcription Factor 3↗
PubMed2000

Detecting meningeal carcinomatosis from breast cancer with thallium-201 SPECT.

Thallium-201 (201Tl) scintigraphy is one of the imaging methods used in the detection of various tumors including brain metastasis. We evaluated a patient with meningeal carcinomatosis from breast cancer by using 201Tl single-photon emission computed tomography (SPECT). Meningeal spread of a tumor was noted on enhanced CT. SPECT revealed tumor localization in meningeal carcinomatosis. These results suggest that SPECT with 201Tl may be useful in detecting meningeal carcinomatosis from breast cancer.

Breast Neoplasms↗
PubMed2000

Gliosarcoma with thallium-201 SPECT.

Thallium-201 (201Tl) chloride scintigraphy is the imaging method use for the detection of various tumors including glioblastoma, but only limited information on 201Tl uptake in gliosarcoma is available. We investigated a patient with gliosarcoma by means of 201Tl single-photon emission computed tomography (SPECT) and MRI. SPECT imaging revealed high 201Tl uptake in the tumor, which was closely correlated with contrast-enhancement on MRI. These results suggest that SPECT with 201Tl may be useful for detecting gliosarcoma and provide physiological information on this tumor.

Adult↗
PubMed2000

Suppression of neuropeptides' mRNA expression by herbal medicines in a rat model of peripheral inflammation.

The traditional Chinese medicines have been used clinically for a long time in some Asian countries, however, very few studies have been done to demonstrate the working mechanisms of these medicines using recently developed biochemical methodologies. In this study, we examined the anti-inflammatory effect of Huang-Lian-Jie-Du-Tang (HLJDT), a combination of herbs used in traditional Chinese medicine, on paw edema, thermal hyperalgesia and the mRNA increase of neuropeptides in spinal dorsal horn and hypothalamic neurons using a rat model of peripheral inflammation and hyperalgesia. The rats that received HLJDT from 3 days before the injection of complete Freund's adjuvant (CFA) into the plantar had significantly less edema and reduced thermal hyperalgesia compared to control rats that received CFA injection. The up-regulation of preprodynorphin mRNA in L4-5 dorsal horn neurons 8 hours after CFA injection that was observed in control rats, was also decreased in the HLJDT-treated rats. Moreover, there was a significant decrease in mRNA level of corticotropin-releasing factor in the paraventricular hypothalamic nucleus in the HLJDT-treated rats. These data demonstrate that HLJDT is anti-inflammatory, and produces changes in mRNA expression in dorsal horn and hypothalamic neurons. This is the first demonstrated that a traditional Chinese medicine can affect the excitability of neurons through an anti-inflammatory action.

Animals↗
PubMed2000

Dorsal column-thalamic pathway is involved in thalamic hyperexcitability following peripheral nerve injury: a lesion study in rats with experimental mononeuropathy.

A total of 68 neurons were recorded from the ventro-postero-lateral nucleus of thalamus (VPL) in rats with a unilateral chronic constriction injury (CCI) of the sciatic nerve (n=20), sham operation (n=24) and naive rats (n=24), and effects of the lesion of dorsal column (DC) pathway [DC lesion or DC+gracile nucleus lesions] on VPL nucleus neuronal activities were studied. In the VPL nucleus contralateral to the CCI (receiving input from the injured nerve), response latencies of low threshold mechanoreceptive (LTM) and wide dynamic range (WDR) neurons to electrical stimulation of the sciatic nerve were significantly longer than that in the contralateral VPL nucleus receiving input from the sham-operated side (P<0.05). In contrast, response latencies of LTM and WDR neurons to DC stimulation were not different between the sham operated and CCI sides (0.05). Background activity of WDR neurons was significantly higher in the VPL nucleus contralateral to the CCI side when compared to neurons in the VPL nucleus contralateral to the sham operated side and in naive animals. Responses of LTM and WDR neurons to innocuous mechanical stimulation of the receptive fields were significantly decreased after DC and DC+gracile nucleus lesions in all animals. However, the responses of WDR neurons to noxious stimuli were selectively reduced only in rats with CCI by DC and DC+gracile nucleus lesions (P<0.05). The decrease in noxious stimulus-evoked responses of WDR neurons in the VPL nucleus contralateral to the CCI side after DC and DC+gracile nucleus lesions was greater than that in the VPL nucleus contralateral to the sham operated side and naive animals. These results indicated that DC and DC+gracile nucleus lesions produced selective and stronger effect on noxious responses of VPL nucleus WDR neurons receiving input from the site of nerve injury. The findings suggest that the gracile nucleus-thalamic pathway conveys, or modulates, nociceptive information to the VPL nucleus following peripheral nerve injury, resulting in an increase in VPL nucleus response to noxious stimuli that contributes to the development of mechanical hyperalgesia.

Animals↗
PubMed2000

Discovery of a muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors among 2-[(1S,3S)-3-sulfonylaminocyclopentyl]phenylacetamide derivatives.

In the course of developing a metabolically stable M3 receptor antagonist from the prototype antagonist, J-104129 (1), introduction of certain substituents into the cyclopentane ring of 1 was found to be effective not only in improving metabolic stability but also in greatly enhancing the subtype selectivity. Among the cyclopentane analogues, sulfonamide derivatives (10f) and (10g) displayed 160- and 310-fold selectivity for M3 over M2 receptors, and both were significantly more selective than the prototype antagonist (120-fold). Subsequent derivatization of the sulfonamide series led to the highly selective M3 receptor antagonists (10h, 10i and 10j) with >490-fold selectivity for M3 over M2 receptors. Among them, p-nitrophenylsulfonamide (J-107320, 10h) exhibited 1100-fold selectivity for M3 receptors (Ki = 2.5 nM) over M2 receptors (Ki = 2800 nM) in the human muscarinic receptor binding assay using [3H]-NMS as a radio ligand.

Alkenes↗
PubMed2000

Isolation and characterisation of adenoid squamous carcinoma cells highly producing SCC antigen and CEA from carcinoma of the maxillary sinus.

A serially transplantable adenoid squamous carcinoma tumour line (SCCMM) derived from carcinoma of the maxillary sinus of a 56-year-old male with high serum levels of SCC antigen (SCC-Ag) and carcinoembryonic antigen (CEA) was established in athymic nude mice. Nude mouse tumours produced by transplantation of operated material showed similar histological features to those of the original tumour and expression of SCC-Ag and CEA immunohistochemically. In addition, SCC-Ag and CEA in sera of tumour-bearing nude mice were detected at high levels in proportion to the relative tumour weight. The primary cultured tumour cells demonstrated the expression of SCC-Ag and CEA and the production of these antigens into culture medium. The serum levels of these tumour antigens were decreased concomitant with tumour regression by antitumour drug administration. Therefore, this tumour line and its cultured cells could provide a useful model for investigation of the relationship between tumour growth and expression of these tumour antigens.

Animals↗
PubMed2000

Prostaglandins E2 and I2 downregulate tumor necrosis factor alpha-induced intercellular adhesion molecule-1 expression in human oral gingival epithelial cells.

In the present study, we examined whether prostaglandin (PG) E2 and PGI2 regulated intercellular adhesion molecule-1 (ICAM-1) expression in human oral gingival epithelial cells stimulated with tumor necrosis factor alpha (TNF alpha). TNF alpha potently induced ICAM-1 expression in a dose- and time-dependent fashion. PGE2 and carbacyclin (a stable analogue of PGI2) significantly decreased ICAM-1 expression in TNF alpha-challenged oral gingival epithelial cells. Next, of the four subtypes of PGE2 receptors (EP1, EP2, EP3 and EP4), we examined which subtype(s) mediated inhibition of TNF alpha-induced ICAM-1 expression by PGE2. 11-deoxy-PGE2, an EP2/EP4 agonist, significantly suppressed TNF alpha-induced ICAM-1 expression, whereas butaprost, an EP2 agonist, sulprostone, an EP1/EP3 agonist, and ONO-AP-324, an EP3 agonist, caused no effect on it. By reverse transcriptase-polymerase chain reaction, expression of EP4 mRNA was detected in oral gingival epithelial cells. Dibutyryl cAMP, a cAMP analogue, and forskolin, a direct activator of adenylate cyclase, significantly inhibited TNF alpha-induced ICAM-1 expression in oral gingival epithelial cells. From these results, we suggest that PGE2 and PGI2 inhibit TNF alpha-elicited ICAM-1 expression by cAMP-dependent pathways via EP4 receptors and IP receptors, respectively.

Acetates↗
PubMed2000

Comparison of contractile responses relative to protein between isolated diabetic and non-diabetic rat aortae to KCl and alpha-adrenoceptor agonists in different extracellular calcium concentrations.

The influence of extracellular Ca2+ concentration on contractile responses of aortae isolated from diabetic rats to KCl and alpha-adrenoceptor agonists was compared with that of non-diabetic rat aortae. Diabetic rats 6 weeks after administration of streptozotocin showed significantly lower body weight and higher plasma glucose concentration, but the protein content per each aortic ring preparation was not significantly different from that of non-diabetic preparation. Both diabetic and non-diabetic aortae showed concentration-dependent contractile responses to norepinephrine, which were concentration-dependently inhibited by prazosin. On the other hand, clonidine induced small contractions in both aortae, which tended to be more inhibited by prazosin than yohimbine. In non-diabetic aortae, the contractile responses to KCl, norepinephrine, methoxamine and clonidine were significantly greater with 2.5 mmol/l of extracellular Ca2+ than 1.25 mmol/l. In diabetic aortae, however, the contractile responses were not significantly influenced by changes in extracellular Ca2+ concentration. Additionally, the contractile responses to each agonist were markedly greater in non-diabetic aortae than diabetic ones. The present results indicate that the contractions of diabetic vasculature do not respond to changes in extracellular Ca2+ concentration, suggesting that there may be some impairment of Ca2+ related mechanisms.

Adrenergic alpha-Agonists↗
PubMed2000

Identification of cytochrome P450 isoform involved in the metabolism of YM992, a novel selective serotonin re-uptake inhibitor, in human liver microsomes.

1. In vitro studies were conducted to identify the hepatic cytochrome P450 isoform involved in the metabolism of YM992, ((S)-2-[[(fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride), a novel serotonin re-uptake inhibitor, in human liver microsomes. 2. Microsomes prepared from yeast expressing CYP1A1, CYP1A2 and CYP2D6 effectively metabolized YM992. A significant correlation was observed between the rate of YM992 metabolism and 7-ethoxyresorufin O-deethylation, CYP1A1/2 specific activity, in liver microsomes from 16 individual donors (r2 = 0.628, p < 0.001). Alpha-naphtoflavone and isosafrole, CYP1A1/2 inhibitors, suppressed the metabolism of YM992 in human liver microsomes in a concentration-dependent manner. 3. The metabolism of YM992 in human liver microsomes was inhibited by approximately 95% by antibodies which recognize both CYP1A1 and CYP1A2 whereas antibodies specific for CYP1A1 did not show inhibitory effects. 4. The same major metabolites, M6 and M7, were generated from YM992 after incubation with human liver microsomes and recombinant human CYP1A2. 5. These results suggest that the metabolism of YM992 in human liver microsomes is mainly catalysed by CYP1A2, and that YM992 might increase plasma concentration of concomitant drugs metabolized by CYP1A2 due to competitive inhibition.

Benzoflavones↗
PubMed2000

Functional evaluation of hydronephrosis by diffusion-weighted MR imaging. Relationship between apparent diffusion coefficient and split glomerular filtration rate.

PURPOSE: To determine the relationship between apparent diffusion coefficient (ADC) values measured by diffusion-weighted MR imaging and split renal function determined by renal scintigraphy in patients with hydronephrosis. MATERIAL AND METHODS: Diffusion-weighted imaging on a 1.5 T MR unit and renal scintigraphy were performed in 36 patients with hydronephrosis (45 hydronephrotic kidneys, 21 non-hydronephrotic kidneys). ADC values of the individual kidneys were measured by diffusion-weighted MR imaging. Split renal function (glomerular filtration rate (GFR)) was determined by renal scintigraphy using 99mTc-DTPA. The relationship between ADC values and split GFR was examined in 66 kidneys. The hydronephrotic kidneys were further classified into three groups (severe renal dysfunction, GFR <10 ml/min, n=7; moderate renal dysfunction, GFR 10-25 ml/min, n= 10; normal renal function, GFR >25 ml/ min, n=28), and mean values for ADCs were calculated. RESULTS: In hydronephrotic kidneys, there was a moderate positive correlation between ADC values and split GFR (R2=0.56). On the other hand, in nonhydronephrotic kidneys, poor correlation between ADC values and split GFR was observed (R2=0.08). The mean values for ADCs of the dysfunctioning hydronephrotic kidneys (severe renal dysfunction, 1.32 x 10(-3) +/- 0.18 x 10(-3) mm2/s; moderate renal dysfunction, 1.38 x 10(-3) +/- 0.10 x 10(-3) mm2/s) were significantly lower than that of the normal functioning hydronephrotic kidneys (1.63 x 10(-3) +/- 0.12 +/- 10(-3) mm2/s). CONCLUSION: These results indicated that measurement of ADC values by diffusion-weighted MR imaging has a potential value in the evaluation of the functional status of hydronephrotic kidneys.

Adult↗
PubMed2000

Cyclooxygenase-2-dependent prostaglandin E2 down-regulates intercellular adhesion molecule-1 expression via EP2/EP4 receptors in interleukin-1beta-stimulated human gingival fibroblasts.

Prostaglandin E2 (PGE2), which exerts its actions via EP receptors (EP1, EP2, EP3, and EP4), is a bioactive metabolite of arachidonic acid produced by cyclooxygenase (COX)-1 and/or COX-2. We have previously demonstrated that PGE2 down-regulates intercellular adhesion molecule-1 (ICAM-1) expression in interleukin-1beta (IL-1beta)-stimulated human gingival fibroblasts (HGF). In the present study, we investigated which COX was involved in down-regulation of ICAM-1 expression by PGE2 in IL-1beta-stimulated HGF and which subtypes of EP receptors modulated the ICAM-1 expression. NS-398, a specific COX-2 inhibitor, completely inhibited PGE2 production by IL-1beta-stimulated HGF, as did indomethacin, a COX-1/COX-2 inhibitor. Northern blot analysis and immunocytochemical staining showed that mRNA and protein of COX-2 were expressed in IL-1beta-challenged HGF, but not in unstimulated HGF, and that the expression of mRNA and protein of COX-1 was similar both in unstimulated and in stimulated cells. NS-398 and indomethacin enhanced ICAM-1 expression in IL-1beta-challenged HGF. EP1, EP2, and EP4 receptor mRNA was expressed in HGF according to reverse-transcription/polymerase chain-reaction. PGE2, 11-deoxy-PGE1 (a selective EP2/EP4 agonist), and Butaprost (a selective EP2 agonist) attenuated IL-1beta-elicited ICAM-1 expression, although Butaprost was less potent than PGE2 and 11-deoxy-PGE1. AH-23848B, an EP4 antagonist, antagonized the inhibitory effect of IL-1beta-elicited ICAM-1 expression by PGE2. Sulprostone, an EP1/EP3 agonist, had no effect on IL-1beta-elicited ICAM-1 expression. Analysis of these data suggests that COX-2-derived PGE2 down-regulates ICAM-1 expression via EP2/EP4 receptors in IL-1beta-stimulated HGF.

Analysis of Variance↗
PubMed2000

Effect of chronic treatment with perindopril on endothelium-dependent relaxation of aorta and carotid artery in SHRSP.

Endothelium-dependent relaxation of aorta and carotid artery from stroke-prone spontaneously hypertensive rats (SHRSP) and the effect of chronic treatment of SHRSP with perindopril, an angiotensin converting enzyme inhibitor, on endothelium-dependent relaxation were studied. Endothelium-dependent relaxation was induced by acetylcholine (ACh) in preparations of SHRSP and normotensive Wistar Kyoto rats (WKY) precontracted with noradrenaline. The ACh-induced relaxation in both preparations was abolished by L-nitroarginine. The ACh-induced relaxation was impaired in preparations from SHRSP and contraction was observed at high concentrations of ACh. In the presence of indomethacin, impairment of endothelium-dependent relaxation in SHRSP was minimized and the contraction was inhibited. The relaxation with sodium nitroprusside did not differ between the preparations from WKY and SHRSP. Treatment of SHRSP with perindopril (2 mg/kg/day) for 6 weeks decreased systolic blood pressure and improved the ACh-induced relaxation of aorta and carotid artery. The treatment inhibited the contraction by higher concentrations of ACh in the presence of L-nitroarginine. These results indicate that the impairment of endothelium-dependent relaxation in aorta and carotid artery of SHRSP may be caused by the reduced availability of nitric oxide. The perindopril-treatment may prevent these changes in SHRSP.

Acetylcholine↗
PubMed2000

Cyclooxygenase-2-dependent prostaglandin production by peripheral blood monocytes stimulated with lipopolysaccharides isolated from periodontopathogenic bacteria.

BACKGROUND: Prostaglandin E2 (PGE2) plays important roles in the pathogenesis of periodontal disease. Recent studies have revealed the existence of 2 isozymes of cyclooxygenase (COX), called COX-1 and COX-2. The purpose of the present study was to investigate the contribution of COX-1 and COX-2 to PGE2 production by human peripheral blood monocytes that are stimulated with lipopolysaccharides (LPS) from periodontopathogenic bacteria. METHODS: LPS were isolated from Actinobacillus actinomycetemcomitans (A. actinomycetemcomitans) and Porphyromonas gingivalis (P. gingivalis) by the phenol-water method. Peripheral blood monocytes were stimulated with LPS for the indicated periods, and the levels of PGE2 or interleukin (IL)-1 beta in the culture media were measured by enzyme-linked immunosorbent assay. Expression of COX-1 and -2 proteins was studied by immunocytochemical staining, and COX-2 mRNA expression was examined by Northern blot analysis. RESULTS: Peripheral blood monocytes stimulated with A. actinomycetemcomitans- or P. gingivalis-LPS produced PGE2 in a time- and dose-dependent manner. Indomethacin, a non-selective COX-1/COX-2 inhibitor, and NS-398, a specific COX-2 inhibitor, completely inhibited PGE2 production. Immunocytochemical staining of COX-1 and COX-2 proteins showed that expression of COX-2 protein was increased in monocytes that were stimulated with A. actinomycetemcomitans- or P. gingivalis-LPS, compared with that in unstimulated monocytes, whereas expression of COX-1 protein was not altered. Northern blot analysis showed that monocytes stimulated with A. actinomycetemcomitans- or P. gingivalis-LPS expressed COX-2 mRNA, while COX-2 mRNA was not detectable in unstimulated cells. Treatment of A. actinomycetemcomitans-LPS-stimulated monocytes with NS-398 induced a significant increase of IL-1 beta production to the same extent as treatment with indomethacin. CONCLUSIONS: These results suggest that COX-2 is induced in monocytes stimulated with LPS derived from A. actinomycetemcomitans and P. gingivalis and that the COX-2 is primarily responsible for PGE2 production. COX-2 may be pivotal in PGE2 production in periodontal lesions and may be involved in inflammatory responses.

Aggregatibacter actinomycetemcomitans↗
PubMed2000

Clinicopathologic study on hepatocellular carcinoma negative for hepatitis B surface antigen and antibody to hepatitis C virus.

Among 326 consecutively resected cases of hepatocellular carcinoma (HCC), we studied clinicopathologic features of 13 cases (NBNC-HCC) negative for hepatitis B surface antigen (HBsAg), antibody to HBsAg (HBsAb), antibody to hepatitis B core antigen (HBcAb), hepatitis B envelope antigen (HBeAg), antibody to HBeAg (HBeAb), and antibody to hepatitis C virus (HCVAb). Forty-four HCC cases positive only for HBsAg (B-HCC) and 232 cases positive only for HCVAb (C-HCC) were studied as controls. Clinically, NBNC-HCC cases showed good liver function reserve. None of NBNC-HCC cases had periodic medical check ups and HCC was detected in 12 cases (92.3%) incidentally. Pathologically, the mean tumor diameter was significantly larger and the histologic grade was less differentiated in NBNC-HCC cases than in B-HCC and C-HCC cases. In the background liver, liver cirrhosis was associated in 15.4% of NBNC-HCC cases, 50.0% of B-HCC and 38.2% of C-HCC cases. The degree of inflammation and fibrosis was less in NBNC-HCC cases, and two cases (15.4%) had almost normal liver histology. In NBNC-HCC cases, synchronous and metachronous multicentric occurrence was not observed. In B-HCC cases, synchronous multicentric occurrence was found in 1 case (20.0%), but no metachronous multicentric occurrence. In C-HCC cases, synchronous and metachronous multicentric occurrence was found in 13 (43.3%) and 8 (30.8%) cases, respectively. However, the cumulative recurrence-free rate was not significantly different among the three groups. Accordingly, it was suggested that better prognosis could be expected in NBNC-HCC cases compared with B- and C-HCC cases, if the cancer could be detected in the early stage.

Aged↗