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At least 991 records · Page 55Linked to original sources
PubMed2003

Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus.

OBJECTIVES: This study evaluated myocardial function in relation to high-energy phosphate (HEP) metabolism in asymptomatic patients with uncomplicated type 2 diabetes mellitus using magnetic resonance (MR) techniques. BACKGROUND: Myocardial dysfunction may occur in patients with type 2 diabetes mellitus in the absence of coronary artery disease or left ventricular (LV) hypertrophy. The mechanisms underlying this diabetic cardiomyopathy are largely unknown, but may involve altered myocardial energy metabolism. METHODS: We assessed myocardial systolic and diastolic function and HEP metabolism in 12 asymptomatic normotensive male patients with recently diagnosed, well-controlled type 2 diabetes and 12 controls, using MR imaging and phosphorus-31-nuclear MR spectroscopy (31P-MRS) on a 1.5 T clinical scanner; 31P-MR spectra were quantified, and myocardial HEP metabolism was expressed as phosphocreatine to adenosine-triphosphate (PCr/ATP) ratio. RESULTS: No differences were found in LV mass and systolic function between patients and controls. However, early (E) acceleration peak, deceleration peak, peak filling rate, and transmitral early-to-late diastolic peak flow (E/A) ratio, all indexes of diastolic function, were significantly decreased in patients compared with controls (p < 0.02). In addition, myocardial PCr/ATP in patients was significantly lower than in controls (1.47 vs. 1.88, p < 0.01). Inverse associations were found between myocardial PCr/ATP and E acceleration peak, E deceleration peak, and E peak filling rate (all, p < 0.05). CONCLUSIONS: These results indicate that altered myocardial energy metabolism may contribute to LV diastolic functional changes in patients with recently diagnosed, well-controlled and uncomplicated type 2 diabetes.

Adenosine Triphosphate↗
PubMed1992

[PI metabolism and Ca mobilization in patients with platelet dysfunction].

The effect of STA2, thrombin and NaF on PI metabolism and Ca mobilization was investigated in patients with three kinds of platelet dysfunction, one each with platelet cyclo-oxygenase deficiency (A), defective aggregation to A23187 (B) and defective aggregation to STA2 (C). These responses were normal in patient (A), suggesting cyclooxygenase activity did not affect PI metabolism and Ca mobilization. PI metabolism was also normal in (B), although Ca mobilization in response to A23187 was delayed and that in response to thrombin was defective in the presence of extracellular Ca2+. This suggests that the patient's platelets have a defective IP3-induced Ca mobilization pathway. STA2 selectively failed to induce IP3 formation and Ca mobilization in (C), although 3H-labelled thromboxane ligand (3H-U46619) bound to the patient's platelets normally. It was suggested that the patient's platelets have a defect in postreceptor signal transduction, especially thromboxane receptor-mediated PLC activation pathway.

Blood Coagulation Disorders↗
PubMed2026

Proteins as Regulators of Metabolic Changes in Sepsis: Alterations in Body Fluids, Immune Cells, and Organs through the Eyes of Proteomics.

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and profound metabolic alterations that contribute to immune dysfunction and organ failure. This Review synthesizes proteomic evidence on sepsis-associated alterations in proteins involved in metabolic pathways across circulating biofluids, immune cells, and organs. Across plasma and urine, proteomic studies identify disturbances in lipoprotein-associated pathways, redox homeostasis, mitochondrial function, and substrate metabolism, indicating that protein signatures of metabolic dysregulation are systemic and detectable across biofluids. In immune cells, monocytes and neutrophils, proteomic analyses reveal a shift toward glycolysis with concurrent impairment of mitochondrial pathways alongside phenotype-dependent differences in lipid and redox-related programs. Organ-level studies further show that metabolic responses are heterogeneous, with distinct trajectories in the kidney, heart, liver, lung, skeletal muscle, and brain. These observations support the concept that sepsis involves compartment-specific remodeling of metabolism-associated protein networks rather than a single convergent metabolic state. Proteomics also highlights potential translational opportunities by identifying metabolism-associated proteins linked to disease severity, clinical phenotypes, and biologically distinct patient subgroups, although the current evidence remains largely exploratory and context-dependent. Overall, proteomics provides a complementary framework for understanding the molecular regulation of sepsis-associated metabolic dysfunction and may refine biological stratification and therapeutic targeting, particularly when integrated with longitudinal sampling and multiomic data.

Humans↗
PubMed1996

Increased preproenkephalin mRNA and preprotachykinin mRNA in the striatum of Rolling mouse Nagoya.

Although Rolling mouse Nagoya (RMN) has been considered to demonstrate cerebellar dysfunction, our previous metabolic and electrophysiological studies also revealed a dysfunction of the basal ganglia, with the presumable primary site of dysfunction being the striatum. In the present study, we investigated the neurochemical functions of the striatum. In RMN, both preproenkephalin mRNA and preprotachykinin mRNA increased significantly in the striatum, with unaltered GAD mRNA, [(3)H]spiperone binding, [(3)H]QNB binding and preprosomatostatin mRNA, thus indicating the dysfunction of striatal projection neurons. These findings support the hypothesis that the site of primary dysfunction in the basal ganglia is in the striatum of RMN.

Animals↗
PubMed2002

Glucose transport and metabolism in chondrocytes: a key to understanding chondrogenesis, skeletal development and cartilage degradation in osteoarthritis.

Despite the recognition that degenerative cartilage disorders like osteoarthritis (OA) and osteochondritis dissecans (OCD) may have nutritional abnormalities at the root of their pathogenesis, balanced dietary supplementation programs have played a secondary role in their management. This review emphasizes the importance and role of nutritional factors such as glucose and glucose-derived sugars (i.e. glucosamine sulfate and vitamin C) in the development, maintenance, repair, and remodeling of cartilage. Chondrocytes, the cells of cartilage, consume glucose as a primary substrate for ATP production in glycolysis and utilize glucosamine sulfate and other sulfated sugars as structural components for extracellular matrix synthesis and are dependent on hexose uptake and delivery to metabolic and biosynthetic pools. Data from several laboratories suggests that chondrocytes express multiple isoforms of the GLUT/SLC2A family of glucose/polyol transporters. These facilitative glucose transporter proteins are expressed in a tissue and cell-specific manner, exhibit distinct kinetic properties, and are developmentally regulated. They may also be regulated by endocrine factors like insulin and insulin-like growth factor I (IGF-I) and cytokines such as interleukin 1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF-alpha). Recent studies suggest that degeneration of cartilage may be triggered by metabolic disorders of glucose balance and that OA occurs coincident with metabolic disease, endocrine dysfunction and diabetes mellitus. Based on these metabolic, endocrine and developmental considerations we present a novel hypothesis regarding the role of glucose transport and metabolism in cartilage physiology and pathophysiology and speculate that supplementation with sugar-derived vitamins and nutraceuticals may benefit patients with degenerative joint disorders.

Animals↗
PubMed1998

Analysis of abnormalities in purine metabolism leading to gout and to neurological dysfunctions in man.

A modelling approach is used to analyse diseases associated with purine metabolism in man. The specific focus is on deficiencies in two enzymes, hypoxanthine:guanine phosphoribosyltransferase and adenylosuccinate lyase. These deficiencies can lead to a number of symptoms, including neurological dysfunctions and mental retardation. Although the biochemical mechanisms of dysfunctions associated with adenylosuccinate lyase deficiency are not completely understood, there is at least general agreement in the literature about possible causes. Simulations with our model confirm that accumulation of the two substrates of the enzyme can lead to significant biochemical imbalance. In hypoxanthine:guanine phosphoribosyltransferase deficiency the biochemical mechanisms associated with neurological dysfunctions are less clear. Model analyses support some old hypotheses but also suggest new indicators for possible causes of neurological dysfunctions associated with this deficiency. Hypoxanthine:guanine phosphoribosyltransferase deficiency is known to cause hyperuricaemia and gout. We compare the relative importance of this deficiency with other known causes of gout in humans. The analysis suggests that defects in the excretion of uric acid are more consequential than defects in uric acid synthesis such as hypoxanthine:guanine phosphoribosyltransferase deficiency.

AMP Deaminase↗
PubMed1996

[Death due to cold of a 63-year-old male associated with hepatocellular carcinoma--bibliographic consideration on alcohol metabolism of the patients with liver dysfunction].

In the early morning of late December, a 63-year-old man was found dead in front of his apartment house. At medico-legal autopsy, subcutaneous hemorrhages of the occipital region and linear fractures of the occipital bone was observed, but there was no cerebral contusion leading him to death. Many white tumors, ranging from 0.5 to 2.0 cm in diameter, were observed in the liver. On sections of the liver, hepatic parenchyma was found entirely occupied by the tumors, which were histopathologically diagnosed as moderately- or well-differentiated hepatocellular carcinoma. Alcohol concentrations of the mixed intracardiac blood and the urine were determined to be 1.9 and 3.6 mg/ml, respectively. Through the police investigation, it became clarified that the male had been sleeping in front of his apartment house about at 10:30 p.m. on the day before he was found dead. The cause of his death was, therefore, considered due to cold, and the authors gave a bibliographic consideration on blood and urine alcohol concentrations and alcohol metabolism of a patient with liver dysfunction due to hepatocellular carcinoma.

Alcohol Drinking↗
PubMed2000

Effects of propofol containing EDTA on mineral metabolism in medical ICU patients with pulmonary dysfunction.

OBJECTIVE: To determine whether the addition of disodium edetate (EDTA) to propofol significantly alters mineral metabolism, adverse events, and outcome in critically ill medical patients with acute pulmonary dysfunction. DESIGN: Multicentre, double-randomised, double-blind, comparative trial. SETTING: Medical intensive care units of 5 health centres. PATIENTS: A total of 85 haemodynamically stable men and women aged 18-81 years who had pulmonary dysfunction or adult respiratory distress syndrome as a primary diagnosis or complication and who were expected to require at least 48 hours of sedation and mechanical ventilation. INTERVENTIONS: Patients were randomised to receive propofol with or without EDTA and then to 1 of 2 sedation levels: light (Modified Ramsay Sedation Scale [MRSS] score of 2 to 3) or deep (MRSS score of 4 to 5). Propofol was administered by continuous infusion at an initial rate of 5 microg/kg per min and titrated as needed. MEASUREMENTS AND RESULTS: Approximately 63 % of patients had a high severity of illness as indicated by an Acute Physiology and Chronic Health Evaluation II score > or = 19. As expected, these patients had a higher mortality rate but did not require a higher dose of propofol or propofol with EDTA. Extensive evaluation of cation homeostasis showed that ionised calcium and magnesium concentrations remained remarkably stable during treatment. Total calcium concentration was low as a result of hypoalbuminemia. Parathyroid hormone (PTH) concentration was elevated in both study groups at baseline, on day 4, and at the end of sedation. There were no significant differences in electrolyte levels and no progression to renal dysfunction. There were also no significant differences in haemodynamic or adverse-event profiles. Treatment-related adverse events occurred in 5 patients in each group; 4 of these (in 3 patients receiving propofol and 1 patient receiving propofol with EDTA) were considered serious. Because a large percentage of patients experienced a change in sedation level, no analyses were performed using sedation level. CONCLUSIONS: The addition of EDTA to propofol does not alter calcium and magnesium homeostasis in critically ill patients with acute pulmonary dysfunction. The reason for the elevation in PTH concentrations in such patients is not known.

Adult↗
PubMed2005

Myocardial and vascular dysfunction and exercise capacity in the metabolic syndrome.

The metabolic syndrome (MS) is associated with cardiovascular risk exceeding that expected from atherosclerotic risk factors, but the mechanism of this association is unclear. We sought to determine the effects of the MS on myocardial and vascular function and cardiorespiratory fitness in 393 subjects with significant risk factors but no cardiovascular disease and negative stress echocardiographic findings. Myocardial function was assessed by global strain rate, strain, and regional systolic velocity (s(m)) and diastolic velocity (e(m)) using tissue Doppler imaging. Arterial compliance was assessed using the pulse pressure method, involving simultaneous radial applanation tonometry and echocardiographic measurement of stroke volume. Exercise capacity was measured by expired gas analysis. Significant and incremental variations in left ventricular systolic (s(m), global strain, and strain rate) and diastolic (e(m)) function were found according to the number of components of MS (p <0.001). MS contributed to reduced systolic and diastolic function even in those without left ventricular hypertrophy (p <0.01). A similar dose-response association was present between the number of components of the MS and exercise capacity (p <0.001) and arterial compliance. The global strain rate and e(m) were independent predictors of exercise capacity. In conclusion, subclinical left ventricular dysfunction corresponded to the degree of metabolic burden, and these myocardial changes were associated with reduced cardiorespiratory fitness. Subjects with MS who also have subclinical myocardial abnormalities and reduced cardiorespiratory fitness may have a higher risk of cardiovascular disease events and heart failure.

Blood Pressure↗
PubMed2000

Lipid metabolism in peroxisomes: enzymology, functions and dysfunctions of the fatty acid alpha- and beta-oxidation systems in humans.

Peroxisomes are subcellular organelles present in virtually all eukaryotic cells catalysing a number of indispensable functions in cellular metabolism. The importance of peroxisomes in man is stressed by the existence of an expanding group of genetic diseases in which there is an impairment in one or more peroxisomal functions. One of the major functions of peroxisomes concerns their role in lipid metabolism, which includes: (i) fatty acid betaoxidation; (ii) ether phospholipid synthesis; (iii) fatty acid alpha-oxidation; and (iv) isoprenoid biosynthesis. In this paper, we review the current state of knowledge concerning the peroxisomal fatty acid alpha- and beta-oxidation systems with particular emphasis on the enzymes involved and the various disorders of fatty acid oxidation in peroxisomes. We also pay attention to the fact that some of the metabolites that accumulate as the result of a defect in peroxisomal alpha- and/or beta-oxidation are activators of members of the family of nuclear receptors, including peroxisome-proliferator-activated receptor alpha.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2007

Disturbed glucose metabolism is associated with left ventricular dysfunction using tissue Doppler imaging in patients with myocardial infarction.

AIMS: To investigate the association between glucose abnormalities and left ventricular (LV) function assessed by tissue Doppler imaging (TDI) in patients with previous history of myocardial infarction and without known diabetes mellitus. PATIENTS AND METHODS: In a cross-sectional study, 123 patients, aged 31-80 years, with a history of previous myocardial infarction and without known diabetes mellitus were examined with TDI echocardiography. A standard oral glucose test (OGTT) with 75 g of glucose was performed. RESULTS: Two-hour plasma glucose were significantly and negatively associated with TDI parameters such as LV ejection time; early diastolic filling velocity (E'-v); ratio of the early to late diastolic filling velocity (E'/A') and positively associated with regional myocardial performance index (MPI) (P<0.05). Left ventricular ejection time and MPI were significantly higher; E'/A' and E'-v were significantly lower in patients with disturbed glucose metabolism compared with patients with normal glucose tolerance (P<0.01). These differences remain significant also when the patients with DM were excluded. CONCLUSIONS: The present study demonstrates that disturbed glucose metabolism is associated with more pronounced LV dysfunction using TDI in patients with myocardial infarction. These abnormalities in LV function were more common not only in subjects with diabetes, but also in patients with prediabetic condition, impaired glucose intolerance.

Adult↗
PubMed2001

Oxidative stress could precede endothelial dysfunction and insulin resistance in Indian Mauritians with impaired glucose metabolism.

AIMS/HYPOTHESIS: To measure oxidative stress, endothelial dysfunction and insulin resistance in Indian Mauritians at different stages of development of Type II (non-insulin-dependent) diabetes mellitus. METHODS: Plasma total 8-epi-PGF2alpha, an indicator of oxidative stress, was determined in age-matched subjects with normal glucose metabolism (n = 39), impaired glucose tolerance (n = 14), newly diagnosed diabetes (n = 8) and established diabetes (n = 14). Plasma glucose and insulin were measured at baseline and 2 h following an oral glucose tolerance test. Endothelial function was assessed by non-invasive digital pulse wave photoplethysmography. RESULTS: Plasma 8-epi-PGF2alpha increased in subjects with impaired glucose tolerance (p < 0.05) compared with control subjects, and was even higher in newly diagnosed diabetic patients (p < 0.01) and established (p < 0.01) diabetic patients. A tendency towards reduced endothelial function in subjects with impaired glucose tolerance became significant in patients with newly diagnosed and established diabetes (p < 0.01), and was correlated with 8-epi-PGF2alpha (r = 0.36, p < 0.01). Insulin resistance (homeostasis model assessment) did not change in subjects with impaired glucose tolerance compared with control subjects, but increased in newly diagnosed (p < 0.01) and established (p < 0.001) diabetic subjects. The 8-epi-PGF2alpha was correlated with fasting glucose (r = 0.50, p < 0.001), triglycerides (r = 0.40, p < 0.001) and insulin resistance (r = 0.35, p < 0.001). CONCLUSION/INTERPRETATION: Oxidant stress is an early event in the evolution of Type II diabetes and could precede the development of endothelial dysfunction and insulin resistance.

Blood Glucose↗
PubMed2006

Reciprocal relationships between insulin resistance and endothelial dysfunction: insights from therapeutic interventions.

Endothelial dysfunction contributes to cardiovascular diseases that are also characterized by insulin resistance. Insulin resistance is a hallmark of metabolic disorders including Type 2 diabetes, obesity, and the metabolic syndrome that are also characterized by endothelial dysfunction. Metabolic actions of insulin to promote glucose disposal are augmented by vascular actions of insulin in endothelium to stimulate production of the vasodilator nitric oxide (NO). Indeed, NO-dependent increases in blood flow to skeletal muscle account for 25% to 40% of the increase in glucose uptake in response to insulin stimulation. PI 3-kinase-dependent insulin signaling pathways in endothelium related to production of NO share striking similarities with metabolic pathways in skeletal muscle that promote glucose uptake. Other distinct non-metabolic branches of insulin signaling pathways regulate secretion of the vasoconstrictor endothelin-1 (ET-1) in endothelium. Metabolic insulin resistance is characterized by pathway-specific impairment in PI 3-kinase-dependent signaling that in endothelium may cause imbalance between production of NO and secretion of ET-1 leading to decreased blood flow that worsens insulin resistance. Therapeutic interventions in both animal models and human studies demonstrate that improving endothelial function ameliorates insulin resistance while improving insulin sensitivity ameliorates endothelial dysfunction. Taken together, cellular, physiological, clinical, and epidemiological studies strongly support a reciprocal relationship between endothelial dysfunction and insulin resistance that helps to link cardiovascular and metabolic diseases. In this review, pathophysiological mechanisms that couple endothelial dysfunction with insulin resistance will be discussed with an emphasis on important therapeutic implications for the metabolic syndrome.

Animals↗
PubMed2026

Integrative subtyping by bile acid metabolism identifies CLCA1/UGT2A3/ZG16 as markers of immune dysfunction and poor prognosis in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the primary driver of cancer-related death and illness across the world. Despite the full-scale shift of the treatment approach for some colorectal cancer patients due to the use of immune checkpoint inhibitors (ICIs), primary resistance still poses a huge challenge to clinicians. Bile acid metabolism is involved in the pathogenesis of CRC. However, its particular function in shaping the tumor immune microenvironment (TIME) and its effect on prognosis and immune treatment response remain unclear. METHODS: Based on the transcriptome and clinical data from The Cancer Genome Atlas-Colon Adenocarcinoma (TCGA-COAD) cohort, we performed unsupervised consensus clustering and classified patients into different molecular subtypes according to bile acid metabolism. We subsequently compared overall survival (OS), immune cell infiltration levels, and differentially expressed genes among the subtypes. In addition, protein-protein interaction (PPI) network and Cox proportional hazards regression were used to identify key hub genes. Finally, the expression of these crucial hub genes was validated in the Gene Expression Omnibus (GEO) cohort and independent clinical patients. RESULTS: The bile-low group showed a significant reduction in OS time (p = 0.0049). The infiltration levels of CD8+ T cells (p < 0.05) and M1 macrophages (p < 0.01) were significantly higher in the bile-low group than in the bile-high group. We identified three key genes-CLCA1, UGT2A3, and ZG16-and found that they all were downregulated in tumor tissues across the TCGA-COAD and GEO datasets, as well as in independent clinical samples. Survival analysis showed that high CLCA1 expression was significantly associated with favorable overall survival (p < 0.001), whereas UGT2A3 (p = 0.23) and ZG16 (p = 0.17) did not reach statistical significance. The three hub genes were negatively correlated with the (TIDE) score (CLCA1: R = - 0.24, p < 0.001; UGT2A3: R = - 0.15, p = 0.0022; ZG16: R = - 0.14, p = 0.0039). CONCLUSION: Our findings suggest that bile acid metabolism could shape the TIME via key genes CLCA1, UGT2A3, and ZG16, and subsequently modify CRC prognosis and immunotherapy responses. These genes may serve as potential prognostic indicators and mechanistic mediators linking bile acid metabolism to T-cell dysfunction, offering insights for future combination strategies targeting the metabolism-barrier-immunity axis.

CLCA1↗
PubMed2003

The hepatic and intestinal metabolic activities of P450 in rats with surgery- and drug-induced renal dysfunction.

PURPOSE: The hepatic and intestinal metabolic activities of P450 were evaluated in rats with surgery- and drug-induced renal dysfunction. METHODS: Renal failure was induced by five-sixths nephrectomy (NR), bilateral ureter ligation (BUL), the intramuscular injection of glycerol (GL), and the intraperitoneal injection of cisplatin (CDDP). Phenytoin 4-hydroxylation, debrisoquine 4-hydroxylation, and testosterone 6beta-hydroxylation were estimated to evaluate the metabolic activities of cytochrome P450 (CYP) 2C, 2D, and 3A, respectively. RESULTS: The hepatic CYP3A metabolic activities were decreased by 65.9% and 60.2% in NR and GL rats, respectively. The hepatic CYP2C metabolic activity was decreased by 48.8% in CDDP rats. No alteration in hepatic drug-metabolizing activities was observed in BUL rats. On the other hand, the intestinal CYP3A metabolic activity was weakly increased in GL rats but not significantly altered in NR, CDDP, and BUL rats. CONCLUSIONS: This study suggested (a) that only selected P450 metabolic activity in the liver is decreased in renal failure, (b) that extent of the decrease in hepatic metabolic activities of P450 is dependent on the etiology of renal failure, and (c) that alteration of CYP3A metabolic activity in the intestine is not always correlated with that in the liver.

Animals↗
PubMed1998

Day and night dysfunction in intraretinal melatonin and related indoleamines metabolism, correlated with the development of glaucoma-like disorder in an avian model.

As previous studies have suggested that melatonin and serotonin may be involved in the regulation of intraocular pressure, retinal concentrations of melatonin, 5-HT, and related indoleamines measured at day and at night were studied during the development of a glaucoma-like disorder with increased intraocular pressure in the al mutant quail. Indoleamine levels were determined by HPLC with electrochemical detection in 1-month-, 3-month-, and 7-month-old al mutant and control quails. Morphology and numbers of melatonin-synthesizing and 5-HT-containing cells, labelled immunohistochemically with an anti-hydroxyindol-0-methyltransferase (HIOMT) antibody and an anti-5-HT antibody, respectively, were studied. Major findings were that: (1) no significant changes in morphology of melatonin-synthesizing cells or in the morphology and density of 5-HT-containing amacrine cells were observed during the development of glaucoma: (2) 5-HT metabolism was modified during the night at 1 month of age and during the day after 3 months; and (3) melatonin metabolism was modified during the night at 7 months and during the day after 3 months. These results demonstrate a relationship between the temporal evolution of this avian glaucoma and a dysfunction in indoleamine retinal metabolism.

Acetylserotonin O-Methyltransferase↗
PubMed2006

[Bone metabolic abnormality in diabetes: especially about osteoblast dysfunction].

As for the factor in the diabetes in which it takes part in a bone abnormal metabolism, this is given the insulin lack state, a high blood glucose state, and the complications accompanying diabetes, such as arteriosclerosis, neuropathy, and a renal dysfunction. The absolute, and/or relative insulin lack state deteriorate the function and reduce the number of osteoblast, in addition, the osteoblast dysfunction is also caused by the sorbitol accumulation brought in the osteoblast as the result of the continuation of high blood glucose state. It also prompts the osteoclastic bone absorption, and suppresses the expression of transcription factor gene that regulates the osteoblast differentiation, and resultantly, the apoptosis of the osteoblast is promoted. By these mechanisms intertwining, the differentiation and the maturity of the osteoblast is thought to be decrease and the bone formation process is obstructed.

Animals↗