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Î²-Sitosterol treatment attenuates cognitive deficits and prevents amyloid plaque deposition in amyloid protein precursor/presenilin 1 mice

Jian Ya YE ; Li LI ; Qing Mao HAO ; Yong QIN ; Chang Sheng MA

The Korean Journal of Physiology and Pharmacology.2020;24(1):39-46. doi:10.4196/kjpp.2020.24.1.39

Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia worldwide, and is mainly characterized by aggregated Î²-amyloid (AÎ²). Increasing evidence has shown that plant extracts have the potential to delay AD development. The plant sterol Î²-Sitosterol has a potential role in inhibiting the production of platelet AÎ², suggesting that it may be useful for AD prevention. In the present study, we aimed to investigate the effect and mechanism of Î²-Sitosterol on deficits in learning and memory in amyloid protein precursor/presenilin 1 (APP/PS1) double transgenic mice. APP/PS1 mice were treated with Î²-Sitosterol for four weeks, from the age of seven months. Brain AÎ² metabolism was evaluated using ELISA and Western blotting. We found that Î²-Sitosterol treatment can improve spatial learning and recognition memory ability, and reduce plaque load in APP/PS1 mice. Î²-Sitosterol treatment helped reverse dendritic spine loss in APP/PS1 mice and reversed the decreased hippocampal neuron miniature excitatory postsynaptic current frequency. Our research helps to explain and support the neuroprotective effect of Î²-Sitosterol, which may offer a novel pharmaceutical agent for the treatment of AD. Taken together, these findings suggest that Î²-Sitosterol ameliorates memory and learning impairment in APP/PS1 mice and possibly decreases AÎ² deposition.

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Gardenia jasminoides extract and its constituent, genipin, inhibit activation of CD3/CD28 co-stimulated CD4+ T cells via ORAI1 channel

Hyun Jong KIM ; Yu Ran NAM ; JooHan WOO ; Woo Kyung KIM ; Joo Hyun NAM

The Korean Journal of Physiology and Pharmacology.2020;24(4):363-372. doi:10.4196/kjpp.2020.24.4.363

Gardenia jasminoides (GJ) is a widely used herbal medicine with antiinflammatory properties, but its effects on the ORAI1 channel, which is important in generating intracellular calcium signaling for T cell activation, remain unknown. In this study, we investigated whether 70% ethanolic GJ extract (GJEtOH) and its subsequent fractions inhibit ORAI1 and determined which constituents contributed to this effect. Whole-cell patch clamp analysis revealed that GJEtOH (64.7% ± 3.83% inhibition at 0.1 mg/ml) and all its fractions showed inhibitory effects on the ORAI1 channel. Among the GJ fractions, the hexane fraction (GJHEX, 66.8% ± 9.95% at 0.1 mg/ml) had the most potent inhibitory effects in hORAI1-hSTIM1 co-transfected HEK293T cells. Chemical constituent analysis revealed that the strong ORAI1 inhibitory effect of GJHEX was due to linoleic acid, and in other fractions, we found that genipin inhibited ORAI1. Genipin significantly inhibited IORAI1 and interleukin-2 production in CD3/ CD28-stimulated Jurkat T lymphocytes by 35.9% ± 3.02% and 54.7% ± 1.32% at 30 μM, respectively. Furthermore, the same genipin concentration inhibited the proliferation of human primary CD4+ T lymphocytes stimulated with CD3/CD28 antibodies by 54.9% ± 8.22%, as evaluated by carboxyfluorescein succinimidyl ester assay. Our findings suggest that genipin may be one of the active components of GJ responsible for T cell suppression, which is partially mediated by activation of the ORAI1 channel. This study helps us understand the mechanisms of GJ in the treatment of inflammatory diseases.

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Analysis of temperature-dependent abnormal bursting patterns of neurons in Aplysia

Nam Gyu HYUN ; Kwangho HYUN ; Saecheol OH ; Kyungmin LEE

The Korean Journal of Physiology and Pharmacology.2020;24(4):349-362. doi:10.4196/kjpp.2020.24.4.349

Temperature affects the firing pattern and electrical activity of neurons in animals, eliciting diverse responses depending on neuronal cell type. However, the mechanisms underlying such diverse responses are not well understood. In the present study, we performed in vitro recording of abdominal ganglia cells of Aplysia juliana , and analyzed their burst firing patterns. We identified atypical bursting patterns dependent on temperature that were totally different from classical bursting patterns observed in R15 neurons of A. juliana . We classified these abnormal bursting patterns into type 1 and type 2; type 1 abnormal single bursts are composed of two kinds of spikes with a long interspike interval (ISI) followed by short ISI regular firing, while type 2 abnormal single bursts are composed of complex multiplets. To investigate the mechanism underlying the temperature dependence of abnormal bursting, we employed simulations using a modified Plant model and determined that the temperature dependence of type 2 abnormal bursting is related to temperaturedependent scaling factors and activation or inactivation of potassium or sodium channels.

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Comparative study of acute in vitro and short-term in vivo triiodothyronine treatments on the contractile activity of isolated rat thoracic aortas

Ruth Mery LÓPEZ ; Jorge Skiold LÓPEZ ; Jair LOZANO ; Héctor FLORES ; Rosa Angelica CARRANZA ; Antonio FRANCO ; Enrique Fernando CASTILLO

The Korean Journal of Physiology and Pharmacology.2020;24(4):339-348. doi:10.4196/kjpp.2020.24.4.339

We aimed to characterize the participation of rapid non-genomic and delayed non-genomic/genomic or genomic mechanisms in vasoactive effects to triiodothyronine (T3), emphasizing functional analysis of the involvement of these mechanisms in the genesis of nitric oxide (NO) of endothelial or muscular origin. Influences of in vitro and in vivo T3 treatments on contractile and relaxant responsiveness of isolated rat aortas were studied. In vivo T3-treatment was 500 μg·kg–1·d–1, subcutaneous injection, for 1 (T31d) and 3 (T33d) days. In experiments with endothelium- intact aortic rings contracted with phenylephrine, increasing concentrations of T3 did not alter contractility. Likewise, in vitro T3 did not modify relaxant responses induced by acetylcholine or sodium nitroprusside (SNP) nor contractile responses elicited by phenylephrine or angiotensin II in endothelium-intact aortas. Concentration- response curves (CRCs) to acetylcholine and SNP in endothelium-intact aortic rings from T31d and T33d rats were unmodified. T33d, but not T31d, treatment diminished CRCs to phenylephrine in endothelium-intact aortic rings. CRCs to phenylephrine remained significantly depressed in both endothelium-denuded and endothelium- intact, nitric oxide synthase inhibitor-treated, aortas of T33d rats. In endotheliumdenuded aortas of T33d rats, CRCs to angiotensin II, and high K+ contractures, were decreased. Thus, in vitro T3 neither modified phenylephrine-induced active tonus nor CRCs to relaxant and contractile agonists in endothelium-intact aortas, discarding rapid non-genomic actions of this hormone in smooth muscle and endothelial cells. Otherwise, T33d-treatment inhibited aortic smooth muscle capacity to contract, but not to relax, in an endothelium- and NO-independent manner. This effect may be mediated by delayed non-genomic/genomic or genomic mechanisms.

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Luteolin reduces fluid hypersecretion by inhibiting TMEM16A in interleukin-4 treated Calu-3 airway epithelial cells

Hyun Jong KIM ; JooHan WOO ; Yu-Ran NAM ; Yohan SEO ; Wan NAMKUNG ; Joo Hyun NAM ; Woo Kyung KIM

The Korean Journal of Physiology and Pharmacology.2020;24(4):329-338. doi:10.4196/kjpp.2020.24.4.329

Rhinorrhea in allergic rhinitis (AR) is characterized by the secretion of electrolytes in the nasal discharge. The secretion of Cl– and HCO3 – is mainly regulated by cystic fibrosis transmembrane conductance regulator (CFTR) or via the calciumactivated Cl– channel anoctamin-1 (ANO1) in nasal gland serous cells. Interleukin-4 (IL-4), which is crucial in the development of allergic inflammation, increases the expression and activity of ANO1 by stimulating histamine receptors. In this study, we investigated ANO1 as a potential therapeutic target for rhinorrhea in AR using an ANO1 inhibitor derived from a natural herb. Ethanolic extracts (30%) of Spirodela polyrhiza (SPEtOH) and its five major flavonoids constituents were prepared. To elucidate whether the activity of human ANO1 (hANO1) was modulated by SPEtOH and its chemical constituents, a patch clamp experiment was performed in hANO1-HEK293T cells. Luteolin, one of the major chemical constituents in SPEtOH, significantly inhibited hANO1 activity in hANO1-HEK293T cells. Further, SPEtOH and luteolin specifically inhibited the calcium-activated chloride current, but not CFTR current in human airway epithelial Calu-3 cells. Calu-3 cells were cultured to confluency on transwell inserts in the presence of IL-4 to measure the electrolyte transport by Ussing chamber. Luteolin also significantly inhibited the ATP-induced increase in electrolyte transport, which was increased in IL-4 sensitized Calu-3 cells. Our findings indicate that SPEtOH and luteolin may be suitable candidates for the prevention and treatment of allergic rhinitis. SPEtOH- and luteolin-mediated ANO1 regulation provides a basis for the development of novel approaches for the treatment of allergic rhinitis-induced rhinorrhea.

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Activation of the renin-angiotensin system in high fructose-induced metabolic syndrome

Mina KIM ; Ga Young DO ; Inkyeom KIM

The Korean Journal of Physiology and Pharmacology.2020;24(4):319-328. doi:10.4196/kjpp.2020.24.4.319

High fructose intake induces hyperglycemia and hypertension. However, the mechanism by which fructose induces metabolic syndrome is largely unknown. We hypothesized that high fructose intake induces activation of the renin-angiotensin system (RAS), resulting in hypertension and metabolic syndrome. We provided 11-week-old Sprague–Dawley rats with drinking water, with or without 20% fructose, for two weeks. We measured serum renin, angiotensin II (Ang II), and aldosterone (Aldo) using ELISA kits. The expression of RAS genes was determined by quantitative reverse transcription polymerase chain reaction. High fructose intake increased body weight and water retention, regardless of food intake or urine volume. After two weeks, fructose intake induced glucose intolerance and hypertension. High fructose intake increased serum renin, Ang II, triglyceride, and cholesterol levels, but not Aldo levels. High fructose intake increased the expression of angiotensinogen in the liver; angiotensin-converting enzyme in the lungs; and renin, angiotensin II type 1a receptor (AT1aR), and angiotensin II type 1b receptor (AT1bR) in the kidneys. However, expression of AT1aR and AT1bR in the adrenal glands did not increase in rats given fructose. Taken together, these results indicate that high fructose intake induces activation of RAS, resulting in hypertension and metabolic syndrome.

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Exploring the beneficial role of telmisartan in sepsis-induced myocardial injury through inhibition of high-mobility group box 1 and glycogen synthase kinase-3βuclear factor-κB pathway

Yan JIN ; Hong WANG ; Jing LI ; Minyan DANG ; Wenzhi ZHANG ; Yan LEI ; Hao ZHAO

The Korean Journal of Physiology and Pharmacology.2020;24(4):311-317. doi:10.4196/kjpp.2020.24.4.311

In the present experimental study, cecal ligation and puncture significantly increased the myocardial injury assessed in terms of excess release of creative kinase-MB (CK-MB), cardiac troponin I (cTnI), interleukin (IL)-6 and decrease of IL-10 in the blood following 12 h of laparotomy procedure as compared to normal control. Also, a significant increase in protein expression levels of high-mobility group box 1 (HMGB1) and decreased phosphorylation of glycogen synthase kinase-3β (GSK-3β) was observed in the myocardial tissue as compared to normal control. A single independent administration of telmisartan (2 and 4 mg/kg) and AR-A014418 (1 and 2 mg/kg) substantially reduced sepsis-induced myocardial injury in terms of decrease levels of CK-MB, cTnI and IL-6, HMGB1, GSK-3β and increase in IL-10 and p-GSK-3β in the blood in sepsis- subjected rats. The effects of telmisartan at dose 4 mg/kg and AR-A014418 at a dose of 2 mg/kg were significantly higher than the telmisartan at a dose of 2 mg/kg and AR-A014418 1 mg/kg respectively. Further, no significant effects on different parameters were observed in the sham control group in comparison to normal. Therefore it is plausible to suggest that sepsis may increase the levels of angiotensin II to trigger GSK-3β-dependent signaling to activate the HMGB1/receptors for advanced glycation end products, which may promote inflammation and myocardial injury in sepsis-subjected rats.

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Combination therapy with cilostazol, aripiprazole, and donepezil protects neuronal cells from β-amyloid neurotoxicity through synergistically enhanced SIRT1 expression

Hye Jin HEO ; So Youn PARK ; Yi Sle LEE ; Hwa Kyoung SHIN ; Ki Whan HONG ; Chi Dae KIM

The Korean Journal of Physiology and Pharmacology.2020;24(4):299-310. doi:10.4196/kjpp.2020.24.4.299

Alzheimer’s disease (AD) is a multi-faceted neurodegenerative disease. Thus, current therapeutic strategies require multitarget-drug combinations to treat or prevent the disease. At the present time, single drugs have proven to be inadequate in terms of addressing the multifactorial pathology of AD, and multitarget-directed drug design has not been successful. Based on these points of views, it is judged that combinatorial drug therapies that target several pathogenic factors may offer more attractive therapeutic options. Thus, we explored that the combination therapy with lower doses of cilostazol and aripiprazole with add-on donepezil (CAD) might have potential in the pathogenesis of AD. In the present study, we found the superior efficacies of donepezil add-on with combinatorial mixture of cilostazol plus aripiprazole in modulation of expression of AD-relevant genes: Aβ accumulation, GSK-3β, P300, acetylated tau, phosphorylated-tau levels, and activation of α-secretase/ADAM 10 through SIRT1 activation in the N2a Swe cells expressing human APP Swedish mutation (N2a Swe cells). We also assessed that CAD synergistically raised acetylcholine release and choline acetyltransferase (CHAT) expression that were declined by increased β-amyloid level in the activated N2a Swe cells. Consequently, CAD treatment synergistically increased neurite elongation and improved cell viability through activations of PI3K, BDNF, β-catenin and a7-nicotinic cholinergic receptors in neuronal cells in the presence of Aβ1-42. This work endorses the possibility for efficient treatment of AD by supporting the synergistic therapeutic potential of donepezil add-on therapy in combination with lower doses of cilostazol and aripiprazole.

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Endothelial Ca2+ signaling-dependent vasodilation through transient receptor potential channels

Kwang-Seok HONG ; Man-Gyoon LEE

The Korean Journal of Physiology and Pharmacology.2020;24(4):287-298. doi:10.4196/kjpp.2020.24.4.287

Ca2+ signaling of endothelial cells plays a critical role in controlling blood flow and pressure in small arteries and arterioles. As the impairment of endothelial function is closely associated with cardiovascular diseases (e.g., atherosclerosis, stroke, and hypertension), endothelial Ca2+ signaling mechanisms have received substantial attention. Increases in endothelial intracellular Ca2+ concentrations promote the synthesis and release of endothelial-derived hyperpolarizing factors (EDHFs, e.g., nitric oxide, prostacyclin, or K+ efflux) or directly result in endothelial-dependent hyperpolarization (EDH). These physiological alterations modulate vascular contractility and cause marked vasodilation in resistance arteries. Transient receptor potential (TRP) channels are nonselective cation channels that are present in the endothelium, vascular smooth muscle cells, or perivascular/sensory nerves. TRP channels are activated by diverse stimuli and are considered key biological apparatuses for the Ca2+ influx-dependent regulation of vasomotor reactivity in resistance arteries. Ca2+- permeable TRP channels, which are primarily found at spatially restricted microdomains in endothelial cells (e.g., myoendothelial projections), have a large unitary or binary conductance and contribute to EDHFs or EDH-induced vasodilation in concert with the activation of intermediate/small conductance Ca2+-sensitive K+ channels. It is likely that endothelial TRP channel dysfunction is related to the dysregulation of endothelial Ca2+ signaling and in turn gives rise to vascular-related diseases such as hypertension. Thus, investigations on the role of Ca2+ dynamics via TRP channels in endothelial cells are required to further comprehend how vascular tone or perfusion pressure are regulated in normal and pathophysiological conditions.

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Association between interstitial cells of Cajal and anti-vinculin antibody in human stomach

Ji Hyun KIM ; Seung Joo NAM ; Sung Chul PARK ; Sang Hoon LEE ; Tae Suk KIM ; Minjong LEE ; Jin Myung PARK ; Dae Hee CHOI ; Chang Don KANG ; Sung Joon LEE ; Young Joon RYU ; Kyungyul LEE ; So Young PARK

The Korean Journal of Physiology and Pharmacology.2020;24(2):185-191. doi:10.4196/kjpp.2020.24.2.185

Interstitial cells of Cajal (ICC) are known as the pacemaker cells of gastrointestinal tract, and it has been reported that acute gastroenteritis induces intestinal dysmotility through antibody to vinculin, a cytoskeletal protein in gut, resulting in small intestinal bacterial overgrowth, so that anti-vinculin antibody can be used as a biomarker for irritable bowel syndrome. This study aimed to determine correlation between serum anti-vinculin antibody and ICC density in human stomach. Gastric specimens from 45 patients with gastric cancer who received gastric surgery at Kangwon National University Hospital from 2013 to 2017 were used. ICC in inner circular muscle, and myenteric plexus were counted. Corresponding patient's blood samples were used to determine the amount of anti-vinculin antibody by enzyme-linked immunosorbent assay. Analysis was done to determine correlation between anti-vinculin antibody and ICC numbers. Patients with elevated anti-vinculin antibody titer (above median value) had significantly lower number of ICC in inner circular muscle (71.0 vs. 240.5, p = 0.047), and myenteric plexus (12.0 vs. 68.5, p < 0.01) compared to patients with lower anti-vinculin antibody titer. Level of serum anti-vinculin antibody correlated significantly with density of ICC in myenteric plexus (r = âˆ’0.379, p = 0.01; Spearman correlation). Increased level of circulating anti-vinculin antibody was significantly correlated with decreased density of ICC in myenteric plexus of human stomach.

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