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The physiological and pharmacological roles of prostaglandins in hair growth

The Korean Journal of Physiology and Pharmacology.2022;26(6):405-413. doi:10.4196/kjpp.2022.26.6.405

Hair loss is a common status found among people of all ages. Since the role of hair is much more related to culture and individual identity, hair loss can have a great influence on well-being and quality of life. It is a disorder that is observed in only scalp patients with androgenetic alopecia (AGA) or alopecia areata caused by stress or immune response abnormalities. Food and Drug Administration (FDA)-approved therapeutic medicines such as finasteride, and minoxidil improve hair loss temporarily, but when they stop, they have a limitation in that hair loss occurs again. As an alternative strategy for improving hair growth, many studies reported that there is a relationship between the expression levels of prostaglandins (PGs) and hair growth. Four major PGs such as prostaglandin D2 (PGD2 ), prostaglandin I2 (PGI2 ), prostaglandin E2 (PGE2 ), and prostaglandin F2 alpha (PGF2α ) are spatiotemporally expressed in hair follicles and are implicated in hair loss. This review investigated the physiological roles and pharmacological interventions of the PGs in the pathogenesis of hair loss and provided these novel insights for clinical therapeutics for patients suffering from alopecia.

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Corrigendum to: Chronic cerebral hypoperfusion and plasticity of the posterior cerebral artery following permanent bilateral common carotid artery occlusion

Kyung-Ok CHO ; Seul-Ki KIM ; Seong Yun KIM

The Korean Journal of Physiology and Pharmacology.2022;26(6):557-557. doi:10.4196/kjpp.2022.26.6.557

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Gaseous signal molecule SO2 regulates autophagy through PI3K/ AKT pathway inhibits cardiomyocyte apoptosis and improves myocardial fibrosis in rats with type II diabetes

Junxiong ZHAO ; Qian WU ; Ting YANG ; Liangui NIE ; Shengquan LIU ; Jia ZHOU ; Jian CHEN ; Zhentao JIANG ; Ting XIAO ; Jun YANG ; Chun CHU

The Korean Journal of Physiology and Pharmacology.2022;26(6):541-556. doi:10.4196/kjpp.2022.26.6.541

Myocardial fibrosis is a key link in the occurrence and development of diabetic cardiomyopathy. Its etiology is complex, and the effect of drugs is not good.Cardiomyocyte apoptosis is an important cause of myocardial fibrosis. The purpose of this study was to investigate the effect of gaseous signal molecule sulfur dioxide (SO2 ) on diabetic myocardial fibrosis and its internal regulatory mechanism. Masson and TUNEL staining, Western-blot, transmission electron microscopy, RT-qPCR, immunofluorescence staining, and flow cytometry were used in the study, and the interstitial collagen deposition, autophagy, apoptosis, and changes in phosphatidylinositol 3-kinase (PI3K)/AKT pathways were evaluated from in vivo and in vitro experiments. The results showed that diabetic myocardial fibrosis was accompanied by cardiomyocyte apoptosis and down-regulation of endogenous SO2 -producing enzyme aspartate aminotransferase (AAT)1/2 . However, exogenous SO2 donors could up-regulate AAT1/2 , reduce apoptosis of cardiomyocytes induced by diabetic rats or high glucose, inhibit phosphorylation of PI3K/AKT protein, up-regulate autophagy, and reduce interstitial collagen deposition. In conclusion, the results of this study suggest that the gaseous signal molecule SO2 can inhibit the PI3K/AKT pathway to promote cytoprotective autophagy and inhibit cardiomyocyte apoptosis to improve myocardial fibrosis in diabetic rats. The results of this study are expected to provide new targets and intervention strategies for the prevention and treatment of diabetic cardiomyopathy.

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Group 1 metabotropic glutamate receptor 5 is involved in synaptically-induced Ca2+ -spikes and cell death in cultured rat hippocampal neurons

Ji Seon YANG ; Sujeong JEON ; Hyun-Jong JANG ; Shin Hee YOON

The Korean Journal of Physiology and Pharmacology.2022;26(6):531-540. doi:10.4196/kjpp.2022.26.6.531

Group 1 metabotropic glutamate receptors (mGluRs) can positively affect postsynaptic neuronal excitability and epileptogenesis. The objective of the present study was to determine whether group 1 mGluRs might be involved in synapticallyinduced intracellular free Ca2+ concentration ([Ca2+ ] i ) spikes and neuronal cell death induced by 0.1 mM Mg2+ and 10 µM glycine in cultured rat hippocampal neurons from embryonic day 17 fetal Sprague–Dawley rats using imaging methods for Ca2+and 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays for cell survival. Reduction of extracellular Mg2+ concentration ([Mg2+ ] o ) to 0.1 mM induced repetitive [Ca2+ ] i spikes within 30 sec at day 11.5. The mGluR5 antagonist 6-Methyl-2-(phenylethynyl) pyridine (MPEP) almost completely inhibited the [Ca2+ ] i spikes, but the mGluR1 antagonist LY367385 did not. The group 1 mGluRs agonist, 3,5-dihydroxyphenylglycine (DHPG), significantly increased the [Ca2+ ] i spikes. The phospholipase C inhibitor U73122 significantly inhibited the [Ca2+ ] i spikes in the absence or presence of DHPG. The IP3 receptor antagonist 2-aminoethoxydiphenyl borate or the ryanodine receptor antagonist 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate also significantly inhibited the [Ca2+ ] i spikes in the absence or presence of DHPG. The TRPC channel inhibitors SKF96365 and flufenamic acid significantly inhibited the [Ca2+ ] i spikes in the absence or presence of DHPG. The mGluR5 antagonist MPEP significantly increased the neuronal cell survival, but mGluR1 antagonist LY367385 did not. These results suggest a possibility that mGluR5 is involved in synapticallyinduced [Ca2+ ] i spikes and neuronal cell death in cultured rat hippocampal neurons by releasing Ca2+ from IP3 and ryanodine-sensitive intracellular stores and activating TRPC channels.

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Lactate promotes vascular smooth muscle cell switch to a synthetic phenotype by inhibiting miR-23b expression

Yanchao HU ; Chunyan ZHANG ; Yajie FAN ; Yan ZHANG ; Yiwen WANG ; Congxia WANG

The Korean Journal of Physiology and Pharmacology.2022;26(6):519-530. doi:10.4196/kjpp.2022.26.6.519

Recent research indicates that lactate promotes the switching of vascular smooth muscle cells (VSMCs) to a synthetic phenotype, which has been implicated in various vascular diseases. This study aimed to investigate the effects of lactate on the VSMC phenotype switch and the underlying mechanism. The CCK-8 method was used to assess cell viability. The microRNAs and mRNAs levels were evaluated using quantitative PCR. Targets of microRNA were predicted using online tools and confirmed using a luciferase reporter assay. We found that lactate promoted the switch of VSMCs to a synthetic phenotype, as evidenced by an increase in VSMC proliferation, mitochondrial activity, migration, and synthesis but a decrease in VSMC apoptosis. Lactate inhibited miR-23b expression in VSMCs, and miR-23b inhibited VSMC's switch to the synthetic phenotype. Lactate modulated the VSMC phenotype through downregulation of miR-23b expression, suggesting that overexpression of miR-23b using a miR-23b mimic attenuated the effects of lactate on VSMC phenotype modulation. Moreover, we discovered that SMAD family member 3 (SMAD3) was the target of miR-23b in regulating VSMC phenotype. Further findings suggested that lactate promotes VSMC switch to synthetic phenotype by targeting SMAD3 and downregulating miR-23b. These findings suggest that correcting the dysregulation of miR-23b/ SMAD3 or lactate metabolism is a potential treatment for vascular diseases.

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Neogambogic acid relieves myocardial injury induced by sepsis via p38 MAPK/NF-κB pathway

Wei FU ; Xiaowei FANG ; Lidong WU ; Weijuan HU ; Tao YANG

The Korean Journal of Physiology and Pharmacology.2022;26(6):511-518. doi:10.4196/kjpp.2022.26.6.511

Sepsis-associated myocardial injury, an invertible myocardial depression, is a common complication of sepsis. Neogambogic acid is an active compound in garcinia and exerts anthelmintic, anti-inflammatory, and detoxification properties.The role of neogambogic acid in sepsis-associated myocardial injury was assessed.Firstly, mice were pretreated with neogambogic acid and then subjected to lipopolysaccharide treatment to induce sepsis. Results showed that lipopolysaccharide treatment induced up-regulation of biomarkers involved in cardiac injury, including lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and troponin I (cTnI).However, pretreatment with neogambogic acid reduced levels of LDH, CK-MB, and cTnI, and ameliorated histopathological changes in the heart tissues of septic mice.Secondly, neogambogic acid also improved cardiac function in septic mice through reduction in left ventricular end-diastolic pressure, and enhancement of ejection fraction, fractional shortening, and left ventricular systolic mean pressure. Moreover, neogambogic acid suppressed cardiac apoptosis and inflammation in septic mice and reduced cardiac fibrosis. Lastly, protein expression of p-p38, p-JNK, and p-NFκB in septic mice was decreased by neogambogic acid. In conclusion, neogambogic acid exerted anti-apoptotic, anti-fibrotic, and anti-inflammatory effects in septic mice through the inactivation of MAPK/NF-κB pathway.

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Thermotherapy as an alternative to exercise for metabolic health in obese postmenopausal women: focus on circulating irisin level

Seung-Jea LEE ; Tae-Wook KIM ; Tae-Hwan PARK ; In-Ho LEE ; Eun-Chul JANG ; Soon-Chan KWON ; Hye-Jin LEE ; Jeong-Hwan CHOI ; Jeong-Beom LEE

The Korean Journal of Physiology and Pharmacology.2022;26(6):501-509. doi:10.4196/kjpp.2022.26.6.501

Irisin is a myokine caused by exercise that improves insulin resistance and weight loss. However, under unfavorable conditions such as air pollution, and during the pandemic, outdoor activities are uncomfortable. Therefore, in this study, the effect of heat therapy (half bath 42 ± 0.5°C for 30 min) on irisin circulation levels as an exercise alternative for middle-aged obese women after menopause was investigated. Subjects were 33 women aged 49.54 ± 6.04 years, with parameters of height, 160.12 ± 4.33 cm, weight, 69.71 ± 7.52 kg, body surface area 1.73 ± 0.13 m2 , body mass index, 27.19 ± 3.40 kg/m2 . The results suggest that circulating irisin levels showed a significant increase after one-time thermotherapy (TH-1). However, the increase in circulating irisin levels after 15 treatments (TH-15, 5 days/week, 3 weeks) was significantly varied. The level of adiponectin, which increases fatty oxidation to reduce fatty deposition, increased significantly at TH-1, but further increased at TH-15, which was significantly different from the level of TH-1. In addition, the basic serum free fatty acid (FFA) level was significantly increased at TH-15 compared to TH-1. Significant differences were also found in the lipid profile (body mass index, waist circumference, and % body fat). Thermotherapy can significantly increase the tympanic temperature and induce changes in circulating irisin and adiponectin levels. Thus, it resulted in positive changes in FFA and lipid profiles. Therefore, repeated thermotherapy is effective in increasing circulating irisin levels in postmenopausal obese women.

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Cell-cell contacts via N-cadherin induce a regulatory renin secretory phenotype in As4.1 cells

Jai Won CHANG ; Soohyun KIM ; Eun Young LEE ; Chae Hun LEEM ; Suhn Hee KIM ; Chun Sik PARK

The Korean Journal of Physiology and Pharmacology.2022;26(6):479-499. doi:10.4196/kjpp.2022.26.6.479

The lack of a clonal renin-secreting cell line has greatly hindered the investigation of the regulatory mechanisms of renin secretion at the cellular, biochemical, and molecular levels. In the present study, we investigated whether it was possible to induce phenotypic switching of the renin-expressing clonal cell line As4.1 from constitutive inactive renin secretion to regulated active renin secretion. When grown to postconfluence for at least two days in media containing fetal bovine serum or insulin-like growth factor-1, the formation of cell-cell contacts via N-cadherin triggered downstream cellular signaling cascades and activated smooth muscle-specific genes, culminating in phenotypic switching to a regulated active renin secretion phenotype, including responding to the key stimuli of active renin secretion. With the use of phenotype-switched As4.1 cells, we provide the first evidence that active renin secretion via exocytosis is regulated by phosphorylation/dephosphorylation of the 20 kDa myosin light chain. The molecular mechanism of phenotypic switching in As4.1 cells described here could serve as a working model for full phenotypic modulation of other secretory cell lines with incomplete phenotypes.

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The WNT/Ca2+ pathway promotes atrial natriuretic peptide secretion by activating protein kinase C/transforming growth factor-β activated kinase 1/activating transcription factor 2signaling in isolated beating rat atria

Zhi-yu LI ; Ying LIU ; Zhuo-na HAN ; Xiang LI ; Yue-ying WANG ; Xun CUI ; Ying ZHANG

The Korean Journal of Physiology and Pharmacology.2022;26(6):469-478. doi:10.4196/kjpp.2022.26.6.469

WNT signaling plays an important role in cardiac development, but abnormal activity is often associated with cardiac hypertrophy, myocardial infarction, remodeling, and heart failure. The effect of WNT signaling on regulation of atrial natriuretic peptide (ANP) secretion is unclear. Therefore, the purpose of this study was to investigate the effect of Wnt agonist 1 (Wnta1) on ANP secretion and mechanical dynamics in beating rat atria. Wnta1 treatment significantly increased atrial ANP secretion and pulse pressure; these effects were blocked by U73122, an antagonist of phospholipase C. U73122 also abolished the effects of Wnta1-mediated upregulation of protein kinase C (PKC) β and γ expression, and the PKC antagonist Go 6983 eliminated Wnta1-induced secretion of ANP. In addition, Wnta1 upregulated levels of phospho-transforming growth factor-β activated kinase 1 (p-TAK1), TAK1 banding 1 (TAB1) and phospho-activating transcription factor 2 (p-ATF2); these effects were blocked by both U73122 and Go 6983. Wnta1-induced ATF2 was abrogated by inhibition of TAK1. Furthermore, Wnta1 upregulated the expression of T cell factor (TCF) 3, TCF4, and lymphoid enhancer factor 1 (LEF1), and these effects were blocked by U73122 and Go 6983. Tak1 inhibition abolished the Wnta1-induced expression of TCF3, TCF4, and LEF1 and Wnta1-mediated ANP secretion and changes in mechanical dynamics. These results suggest that Wnta1 increased the secretion of ANP and mechanical dynamics in beating rat atria by activation of PKC–TAK1–ATF2–TCF3/LEF1 and TCF4/LEF1 signaling mainly via the WNT/Ca2+ pathway. It is also suggested that WNT–ANP signaling is implicated in cardiac physiology and pathophysiology.

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Involvement of adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 in diallyl trisulfide-induced cytotoxicity in hepatocellular carcinoma cells

Feng GUAN ; Youming DING ; Yikang HE ; Lu LI ; Xinyu YANG ; Changhua WANG ; Mingbai HU

The Korean Journal of Physiology and Pharmacology.2022;26(6):457-468. doi:10.4196/kjpp.2022.26.6.457

It has been demonstrated that APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) is involved in the regulation of several growth-related signaling pathways and thus closely associated with the development and progression of some cancers. Diallyl trisulfide (DAT), a garlic-derived bioactive compound, exerts selective cytotoxicity to various human cancer cells through interfering with pro-survival signaling pathways. However, whether and how DAT affects survival of human hepatocellular carcinoma (HCC) cells remain unclear. Herein, we tested the hypothesis of the involvement of APPL1 in DAT-induced cytotoxicity in HCC HepG2 cells. We found that Lys 63 (K63)-linked polyubiquitination of APPL1 was significantly decreased whereas phosphorylation of APPL1 at serine residues remained unchanged in DAT-treated HepG2 cells. Compared with wild-type APPL1, overexpression of APPL1 K63R mutant dramatically increased cell apoptosis and mitigated cell survival, along with a reduction of phosphorylation of STAT3, Akt, and Erk1/2. In addition, DAT administration markedly reduced protein levels of intracellular TNF receptor-associated factor 6 (TRAF6). Genetic inhibition of TRAF6 decreased K63-linked polyubiquitination of APPL1. Moreover, the cytotoxicity impacts of DAT on HepG2 cells were greatly attenuated by overexpression of wild-type APPL1. Taken together, these results suggest that APPL1 polyubiquitination probably mediates the inhibitory effects of DAT on survival of HepG2 cells by modulating STAT3, Akt, and Erk1/2 pathways.

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