• Childhood Kidney Diseases
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• 제28권2호
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• pp.51-58
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• 2024

Patients with chronic kidney disease (CKD) bear a significant financial burden and face numerous complications and higher mortality rates. The progression of CKD is associated with glomerular injury caused by glomerular hyperfiltration and oxidative stress. Factors such as uncontrolled hypertension, elevated urine protein levels, anemia, and underlying glomerular disease, contribute to CKD progression. In addition to conservative treatment, several medications are available to combat the progression of CKD to end-stage kidney disease. Renin-angiotensin-aldosterone system blockers could slow the progression of CKD by reducing glomerular hyperfiltration, lowering blood pressure, and decreasing inflammation. Mineralocorticoid receptor antagonists inhibit the mineralocorticoid receptor signaling pathway, thereby attenuating inflammation and fibrosis. Sodium-glucose cotransporter 2 inhibitors exhibit protective effects on the kidneys and against cardiovascular events. Tolvaptan, a selective vasopressin V2-receptor antagonist, decelerates the rate of increase in total kidney volume and deterioration of kidney function in patients with rapidly progressive autosomal dominant polycystic kidney disease. The protective effects of AST-120 remain controversial. Due to a lack of evidence regarding the efficacy and safety of these medications in children, it is imperative to weigh the benefits and adverse effects carefully. Further research is essential to establish the efficacy and safety profiles in pediatric populations.

• The Korean Journal of Physiology
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• 제30권2호
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• pp.279-288
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• 1996

Chronic exposure to cadmium impairs various renal tubular functions, including organic acid (anion) secretion. To investigate the mechanism of cadmium-induced alterations in the organic anion transport system, kinetics of p-aminohippurate (PAH) uptake was studied in renal cortical basolateral membrane vesicles (BLMV) isolated from cadmium-intoxicated rats (adult male Sprague-Dawley). Cadmium intoxication was induced by subcutaneous injections of $CdCl_{2}$ (2 mg Cd/kg per day) for 3 weeks. The renal plasma membrane vesicles were prepared by Percoll gradient centrifugation. The vesicular uptake of $^{14}C$-PAH was determined by rapid filtration technique using Millipore filter. Cadmium intoxication resulted in a marked attenuation of $Na^{+}$-dependent, ${\alpha}$-ketoglutarate (${\alpha}$KG)-driven PAH uptake with no changes in $Na^{+}$ and ${\alpha}$KG-independent transport component. Kinetic analysis indicated that Vmax, but not Km, of the $Na^{+}$-dependent, ${\alpha}$KG-driven component was reduced. A similar reduction of $Na^{+}$-dependent, ${\alpha}$KG-driven PAH uptake was observed in normal membrane vesicles directly exposed to inorganic cadmium in vitro, and this was accompanied by an inhibition of both $Na^{+}$-dependent ${\alpha}$KG uptake and ${\alpha}$KG-PAH exchange activity. These results indicate that during chronic exposure to cadmium, free cadmium ions liberated in the proximal tubular cytoplasm directly interact with the basolateral membrane and impair the active transport capacity for organic anions, most likely due to an inhibition of both $Na^{+}$-dicarboxylate cotransporter and dicarboxylate-organic anion antiporter activities.

• Molecules and Cells
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• 제38권6호
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• pp.548-561
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• 2015

By combining conventional single cell analysis with flow cytometry and public database searches with bioinformatics tools, we extended the expression profiling of thymic stromal cotransporter (TSCOT), Slc46A2/Ly110, that was shown to be expressed in bipotent precursor and cortical thymic epithelial cells. Genome scale analysis verified TSCOT expression in thymic tissue- and cell type- specific fashion and is also expressed in some other epithelial tissues including skin and lung. Coexpression profiling with genes, Foxn1 and Hoxa3, revealed the role of TSCOT during the organogenesis. TSCOT expression was detected in all thymic epithelial cells (TECs), but not in the $CD31^+$endothelial cell lineage in fetal thymus. In addition, ABC transporter-dependent side population and Sca-$1^+$ fetal TEC populations both contain TSCOT-expressing cells, indicating TEC stem cells express TSCOT. TSCOT expression was identified as early as in differentiating embryonic stem cells. TSCOT expression is not under the control of Foxn1 since TSCOT is present in the thymic rudiment of nude mice. By searching variations in the expression levels, TSCOT is positively associated with Grhl3 and Irf6. Cytokines such as IL1b, IL22 and IL24 are the potential regulators of the TSCOT expression. Surprisingly, we found TSCOT expression in the lung is diminished in lung cancers, suggesting TSCOT may be involved in the suppression of lung tumor development. Based on these results, a model for TEC differentiation from the stem cells was proposed in context of multiple epithelial organ formation.

• Asian-Australasian Journal of Animal Sciences
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• 제30권2호
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• pp.221-228
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• 2017

Objective: The objective of this experiment was to characterize the mRNA expression profile of type IIb sodium-inorganic phosphate cotransporter (NaPi-IIb) and the biochemical values of serum alkaline phosphatase (AKP), calcium, inorganic phosphorus, tibial ash and minerals of broiler chickens with aging. Methods: A total of 56 one-day-old Arbor Acres male broiler chickens were used. Broiler chickens were weighed and samples were collected weekly from day 1. Results: The result showed that before the growth inflection point, ash, calcium, and phosphorus content in the tibia of broiler chickens increased with growth (before 3 weeks of age), although there were no significant differences in chicks at different ages in the later period of the experiment and weight gain rate was relatively slow at this stage (4 to 6 weeks). NaPi-IIb gene expression in the small intestine in the early growth stage was higher than that in the later growth stage. Expression of calbindin and the vitamin D receptor protein in the intestinal mucosa increased with age in the duodenum and jejunum. Serum AKP activity first increased and subsequently decreased after peaking at 1 week of age, but there was no significant difference after 3 weeks of age. Conclusion: These results show that compared with the early growth stage, the weight-gain rate of broiler chickens in the late growth stage gradually decreased with gradual tibia maturation, along with weaker positive transport of phosphorus in the intestine and reinforced re-absorption of phosphorus in the kidney, which might be the reason that phosphorus requirement in the late growth stage was decreased.

• The Korean Journal of Physiology and Pharmacology
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• 제21권1호
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• pp.65-74
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• 2017

Here we investigated the central processing mechanisms of mechanical allodynia and found a direct excitatory link with low-threshold input to nociceptive neurons. Experiments were performed on male Sprague-Dawley rats weighing 230-280 g. Subcutaneous injection of interleukin 1 beta ($IL-1{\beta}$) ($1ng/10{\mu}L$) was used to produce mechanical allodynia and thermal hyperalgesia. Intracisternal administration of bicuculline, a gamma aminobutyric acid A ($GABA_A$) receptor antagonist, produced mechanical allodynia in the orofacial area under normal conditions. However, intracisternal administration of bicuculline (50 ng) produced a paradoxical anti-allodynic effect under inflammatory pain conditions. Pretreatment with resiniferatoxin (RTX), which depletes capsaicin receptor protein in primary afferent fibers, did not alter the paradoxical anti-allodynic effects produced by the intracisternal injection of bicuculline. Intracisternal injection of bumetanide, an Na-K-Cl cotransporter (NKCC 1) inhibitor, reversed the $IL-1{\beta}$-induced mechanical allodynia. In the control group, application of GABA ($100{\mu}M$) or muscimol ($3{\mu}M$) led to membrane hyperpolarization in gramicidin perforated current clamp mode. However, in some neurons, application of GABA or muscimol led to membrane depolarization in the $IL-1{\beta}$-treated rats. These results suggest that some large myelinated $A{\beta}$ fibers gain access to the nociceptive system and elicit pain sensation via $GABA_A$ receptors under inflammatory pain conditions.

• Reproductive and Developmental Biology
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• 제33권4호
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• pp.211-216
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• 2009

A cell frequently utilizes glucose as a fuel of energy and a major substrate of lipid and protein syntheses. A regulation of glucose movement into and out of the cells is precisely controlled by cooperative works of passive and sodium-dependent active processes. At least 13 glucose cotransporter (Slc2a, GLUT) isoforms involve in passive movement of glucose in cells. The efferent ductules (EDs) play in a number of important functions for maintenance of male fertility. In the present study, using real-time PCR analysis, we determined gene expression of five Slc2a isoforms in the EDs. In addition, we compared expression levels of these Slc2a isoforms according to postnatal development ages, 1 week, 2 weeks, 1 month, and 3 months. Results from the current study showed that expression of Slc2a1, Slc2a3, and Slc2a5 mRNAs reached the highest levels at 1 month of age, followed by a transient decrease at 3 months of age. In addition, the level of Slc2a4 mRNA reminded at steady until 1 month of age and was significantly reduced at 3 months of age, whereas the highest level of Slc2a 8 mRNA was detected at 2 weeks of age. Data from the present study indicate a differential expression of various Slc2a isoforms in the ED according to postnatal ages. Thus, it is believed that glucose movement through the epithelial cells in the ED would be regulated by the coordinated manner among Slc2a isoforms expressed at a given age.

• The Korean Journal of Physiology and Pharmacology
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• 제23권1호
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• pp.55-62
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• 2019

HM41322 is a novel oral sodium-glucose cotransporter (SGLT) 1/2 dual inhibitor. In this study, the in vitro and in vivo pharmacokinetic and pharmacologic profiles of HM41322 were compared to those of dapagliflozin. HM41322 showed a 10-fold selectivity for SGLT2 over SGLT1. HM41322 showed an inhibitory effect on SGLT2 similar to dapagliflozin, but showed a more potent inhibitory effect on SGLT1 than dapagliflozin. The maximum plasma HM41322 level after single oral doses at 0.1, 1, and 3 mg/kg were 142, 439, and 1830 ng/ml, respectively, and the $T_{1/2}$ was 3.1 h. HM41322 was rapidly absorbed and reached the circulation within 15 min. HM41322 maximized urinary glucose excretion by inhibiting both SGLT1 and SGLT2 in the kidney. HM41322 3 mg/kg caused the maximum urinary glucose excretion in normoglycemic mice ($19.32{\pm}1.16mg/g$) at 24 h. In normal and diabetic mice, HM41322 significantly reduced glucose excursion. Four-week administration of HM41322 in db/db mice reduced HbA1c in a dose dependent manner. Taken together, HM41322 showed a favorable preclinical profile of postprandial glucose control through dual inhibitory activities against SGLT1 and SGLT2.

• The Korean Journal of Physiology and Pharmacology
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• 제25권5호
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• pp.449-457
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• 2021

The sleep-wake cycle is regulated by the alternating activity of sleep- and wake-promoting neurons. The dorsal raphe nucleus (DRN) secretes 5-hydroxytryptamine (5-HT, serotonin), promoting wakefulness. Melatonin secreted from the pineal gland also promotes wakefulness in rats. Our laboratory recently demonstrated that daily changes in nitric oxide (NO) production regulates a signaling pathway involving with-no-lysine kinase (WNK), Ste20-related proline alanine rich kinase (SPAK)/oxidative stress response kinase 1 (OSR1), and cation-chloride co-transporters (CCC) in rat DRN serotonergic neurons. This study was designed to investigate the effect of melatonin on NO-regulated WNK-SPAK/OSR1-CCC signaling in wake-inducing DRN neurons to elucidate the mechanism underlying melatonin's wake-promoting actions in rats. Ex vivo treatment of DRN slices with melatonin suppressed neuronal nitric oxide synthase (nNOS) expression and increased WNK4 expression without altering WNK1, 2, or 3. Melatonin increased phosphorylation of OSR1 and the expression of sodium-potassium-chloride co-transporter 1 (NKCC1), while potassium-chloride co-transporter 2 (KCC2) remained unchanged. Melatonin increased the expression of tryptophan hydroxylase 2 (TPH2, serotonin-synthesizing enzyme). The present study suggests that melatonin may promote its wakefulness by modulating NO-regulated WNK-SPAK/OSR1-KNCC1 signaling in rat DRN serotonergic neurons.

• Journal of Veterinary Science
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• 제23권5호
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• pp.76.1-76.14
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• 2022

Background: Clinical dexamethasone (DEX) treatment or stress in bovines results in extensive physiological changes with prominent hyperglycemia and neutrophils dysfunction. Objectives: To elucidate the effects of DEX treatment in vivo on cellular energy status and the underlying mechanism in circulating neutrophils. Methods: We selected eight-month-old male bovines and injected DEX for 3 consecutive days (1 time/d). The levels of glucose, total protein (TP), total cholesterol (TC), and the proinflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α in blood were examined, and we then detected glycogen and adenosine triphosphate (ATP) content, phosphofructosekinase-1 (PFK1) and glucose-6-phosphate dehydrogenase (G6PDH) activity, glucose transporter (GLUT)1, GLUT4, sodium/glucose cotransporter (SGLT)1 and citrate synthase (CS) protein expression and autophagy levels in circulating neutrophils. Results: DEX injection markedly increased blood glucose, TP and TC levels, the Ca²⁺/P⁵⁺ ratio and the neutrophil/lymphocyte ratio and significantly decreased blood IL-1β, IL-6 and TNF-α levels. Particularly in neutrophils, DEX injection inhibited p65-NFκB activation and elevated glycogen and ATP contents and SGLT1, GLUT1 and GR expression while inhibiting PFK1 activity, enhancing G6PDH activity and CS expression and lowering cell autophagy levels. Conclusions: DEX induced neutrophils glucose uptake by enhancing SGLT1 and GLUT1 expression and the transformation of energy metabolism from glycolysis to pentose phosphate pathway (PPP)-tricarboxylic acid (TCA) cycle. This finding gives us a new perspective on deeper understanding of clinical anti-inflammatory effects of DEX on bovine.

• 한국발생생물학회지:발생과생식
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• 제12권1호
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• pp.19-30
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• 2008

수정란이 포배로 분화하는 것은 착상을 통하여 개체 발생이 성립되는 포유동물의 발생에 있어서 핵심적인 현상이다.. 초기 배아 발생 시기동안 배아는 생존을 위한 에너지원을 공급받아야 한다. 포유동물의 난자는 보통의 경우 난자 형성 동안 많은 양의 에니지원을 세포질에 비축하지 않기 때문에 발생 동안 수란관과 자궁으로부터 물질대사와 관련돼 여러 물질, 특히 에너지원을 획득해야 한다. 탄수화물은 착상전 배아의 주 에너지원으로 알려져 있다. 포도당, 젖산염, 피르브산염은 착상 전배아 배양액에서 없어서는 않될 성분으로, 초기 배아는 그 발생 단계에 따라 이들 물질에 대한 선호도를 각기 다르게 갖고 있다. 포도당수송체(glucose transporter)와 수소이온-단당류 동향수송체($H^+$-monocarboxylate cotransporter)는 탄수화물을 수송하는 주된 매개자로 이들의 발현 수준은 일차적으로 내인성 또는 인슐린이나 포도당과 같은 외인성 요인에 동시적으로 조절을 받는다. 비록 1960년대 이후 화학적으로 규명된 BWW와 같은 배양액을 이용하여 수정란이 성공적으로 포배로 발생되고 이식 후 정상적인 새끼가 태어났어도, 발생조절에 있어서 이들 탄수화물 물질대사 산물의 역할은 잘 알려져 있지 않다. 포도당은 밀착이 진행되는 상실배에서 물질대사 관련 효소와 수송체의 발현을 조절하고, 포배강 형성에 필요로 하는 에너지를 생산하는데 관련된 것으로 인식되고 있다. 다른 한편으로 cytokine은 배아에서 탄수화물의 대사율, 그리고 물질대사율 조절을 통하여 배아 발생을 조절할 수 있는 것으로 제안되어 왔다. 또한, 근래 들어 본인 등은 젖산염이 착상 전 배아의 발생을 조절할 수 있는 물질임을 밝히고 있다. 이러한 결과들은 탄수화물의 물질대사물이 초기 배아 시기에 에너지원으로서 뿐만이 아니라 생합성 경로 및 다른 조절경로에 참여하고 있음을 의미한다. 따라서 초기 배아 발생 동안 탄수화물 대사와 대사물질은 에너지원으로서 뿐만이 아니라 수정란이 착상할 수 있는 능력을 갖춘 포배로 발생하는 것을 조절하는 조절물질로 그 중요성이 있다.