Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
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Displaying 1-15 of 15 articles from this issue
Regular Articles
  • Xingkui Tao, Xingtao Zhang, Fan Feng
    2022 Volume 45 Issue 5 Pages 553-560
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: March 18, 2022
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    Supplementary material

    Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer-related mortality, and it has a high risk of early recurrence and distant metastasis. The prerequisite for the deterioration of NSCLC is the malignant proliferation and migration of cancer cells, and in this study Astragalus membranaceus polysaccharides (APS) was firstly showed that it could decrease the cell proliferation of A549 and NCI-H1299. Through bioinformatics analysis, the up-regulation of miR-195-5p was positively correlated with the survival rate of lung cancer patients. Real-time PCR indicated APS could increase the expression level of miR-195-5p, and the miR-195-5p inhibitor was used to verify that it could reverse the inhibitory effect of Astragalus polysaccharide on lung cancer cell migration and invasion. Therefore, we believe that APS could inhibit the proliferation and migration of NSCLC cells by regulating miR-195-5p, which laid the foundation for further research on the functional mechanism of miR-195-5p in NSCLC.

  • Yinglei Liu, Yang Cao, Haili Kai, Yuwen Han, Menghui Huang, Liusijie G ...
    2022 Volume 45 Issue 5 Pages 561-568
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: February 19, 2022
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    Ovarian cancer has long been considered the second-highest cancer threat to women’s reproductive system with high mortality. This is ascribed to the absence of highly efficient therapy and cancer metastasis. Accordingly, there is an urgent need for the development of new agents. Recently, Traditional Chinese medicine has gained extensive interest because of its safe use, validity, and distinct pharmacological effects. Polyphyllin E (PPE), as a major constituent in Rhizoma Paridis, is a promising cancer-fighting agent. However, the effect of PPE on ovarian cancers as well as associated latent mechanisms is still not completely understood. In this study, PPE was found to prohibit the proliferation of SK-OV-3 and OVCAR-3 ovarian cancer cells, causing marked cell death. Additionally, low-dose PPE could also inhibit motility and invasion of ovarian cancer cells. The mechanistic assessment revealed PPE-mediated matrix metalloproteinases, i.e., MMP2 and MMP9, inhibition via the AKT–nuclear factor kappa B (AKT/NF-κB) signaling pathway. Rescue experiments with transfection of AKT lentiviral particles remarkably reversed PPE inhibitory effects against ovarian cancer cells. In conclusion, PPE could inhibit proliferation of ovarian cancer cell migration and invasion by down-regulating the AKT/NF-κB pathway. Moreover, it has the potential to act as a novel agent for ovarian cancer treatment.

  • Songjie Xu, Qichao Wu, Wenkai Zhang, Tao Liu, Yanjun Zhang, Wenxiu Zha ...
    2022 Volume 45 Issue 5 Pages 569-575
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Spinal cord injury (SCI) is a disastrous event that often leads to permanent neurological deficits involving motor, sensory, and autonomic dysfunctions in patients. Accumulating research has demonstrated that riluzole may play crucial roles in the process of spinal tissue repair, but the underlying mechanisms remain elusive. This study verified the effectiveness of riluzole and speculated that a riluzole-afforded protection mechanism may be associated with the glycogen synthase kinase-3 beta (GSK-3β)/collapsin response mediator protein-2 (CRMP-2) pathway in rats after spinal cord injury. Here, a modified Allen’s weight dropping model was generated and riluzole at 4 mg/kg was injected intraperitoneally after surgery and twice a day for 7 consecutive days. At 6 weeks after SCI, we found that riluzole treatment reduced the central cavity size of the spinal cord and improved neurological functions. Meanwhile, riluzole-treated rats exhibited shorter latency and larger amplitude in motor evoked potentials and somatosensory evoked potentials, compared with vehicle-treated rats. Furthermore, Western blotting and immunofluorescence data revealed that the expression levels of GSK-3β and phosphorylated-GSK-3β were lower in riluzole-treated SCI rats compared with vehicle-treated rats. We next detected the expression CRMP-2 and phosphorylated CRMP-2 and found that the expression of CRMP-2 showed no difference between the riluzole-treated and vehicle-treated groups; however, administration of riluzole downregulated phosphorylated CRMP-2 expression. The current findings suggest that after SCI, administration of riluzole promotes neurological functional restoration, which may be associated, in part, with its activation of the GSK-3β/CRMP-2 signaling pathway.

  • Miwa Goto, Yusei Kobira, Shinichiro Kaneko, Hidetoshi Arima, Akihiro M ...
    2022 Volume 45 Issue 5 Pages 576-582
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    The aim of this study was to investigate the beneficial effects of sacran, a sulfated polysaccharide, on renal damage and intestinal microflora, in 5/6 nephrectomy rats as a model for chronic kidney disease (CKD). 5/6 Nephrectomy rats were divided into sacran treated and non-treated groups and examined for lethality after 4 weeks. The 5/6 nephrectomy rats were also divided into three groups: sacran treated, non-treated and AST-120 treated groups, and treated orally in a concentration-dependent manner for 4 weeks. Renal function was estimated by biochemical and histopathological analyses. Metagenomic analysis of feces from each group after 4 weeks was also performed and changes in intestinal microflora were compared. The administration of sacran to CKD rats at ≥19 mg/d increased their survival. In addition, the sacran-treated group improved CKD-related parameters in a concentration-dependent manner, and the inhibitory effect of 40 mg/d of sacran was comparable to that of AST-120. The changes in the intestinal microflora of the sacran treated group were positively correlated with an increase in the number of Lactobacillus species, which are known to be rich in beneficial bacteria, and the increment of this beneficial bacteria was negatively correlated with the concentration of indoxyl sulfate, a uremic toxin, in plasma. These results strongly suggest that the oral administration of sacran could contribute to the stabilization of intestinal microflora in CKD rats and to the reduction of oxidative stress as well as the inhibition of progression of CKD.

    Editor's pick

    Sacran, a type of new sulfated polysaccharide, is a biomaterial with excellent water solubility and safety, and is expected to be used in pharmaceuticals of the future. In the present study, sacran suppressed oxidative stress and inhibited the progression of chronic kidney disease (CKD). Sacran also had a multifaceted effect on the progression of CKD by altering the mix of intestinal microflora as a prebiotic in addition to the above effects. Thus, sacran is expected to have an effective nephroprotective effect especially when oxidative stress initially appears at the early stage of renal failure.

  • Naho Minegaki, Tetsuo Koshizuka, Kouki Hatasa, Hiroki Kondo, Hiroki Ka ...
    2022 Volume 45 Issue 5 Pages 583-589
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Supplementary material

    Royal jelly (RJ) has been used as a functional foodstuff and in cosmetics for many years. RJ contains various molecules, including major royal jelly proteins (MRJPs), and affords a number of health benefits such as anti-inflammatory activity. As MRJP3 has been reported to possess anti-inflammatory properties by the in vitro analysis, we investigated the anti-inflammatory effects of MRJP3 and its derived peptides both in vitro and in vivo. Expression of both tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) mRNAs in lipopolysaccharides (LPS)-stimulated THP-1 cells was reduced by the addition of MRJP3 or its C-terminal tandem penta-peptide repeats (TPRs) sequence. In the herpes simplex virus type 1 (HSV-1)-induced herpes stromal keratitis (HSK) model mice, the instillation of TPRs reduced the disease scores and the expression levels of TNF-α and IL-6 in HSV-1-infected eyes. In addition, synthetic penta-peptides derived from TPRs reduced the expression of TNF-α and IL-6 both in the THP-1 cell cultures and in the HSK model mice. Our results indicated that MRJP3 TPRs would be useful in controlling inflammation.

  • Yoko Kunimitsu, Kayoko Morio, Sachi Hirata, Kazuhiro Yamamoto, Tomohir ...
    2022 Volume 45 Issue 5 Pages 590-595
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    The gut microbiome influences tumor response to immune checkpoint inhibitors (ICIs). The proton pump inhibitors (PPI) significantly impair diversity of the gut microbiota and can affect the efficacy of ICIs. Therefore, the present study aimed to evaluate the influence of PPI on survival in patients with metastatic or unresectable urothelial carcinoma receiving pembrolizumab. We conducted a retrospective cohort study of patients with metastatic or unresectable urothelial carcinoma receiving pembrolizumab. The use of PPI was defined as any administration for ≥30 d within 60 d prior and/or 30 d after treatment initiation. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method, and Cox proportional hazards regression analysis was performed to investigate prognostic factors based on patient characteristics. Seventy-nine patients were included in the analysis, and 34 patients (43.0%) received PPI. There were no significant differences in OS and PFS between PPI users and nonusers (median OS: 8.2 months vs. 11.2 months, hazard ratio (HR): 1.36, 95% confidence interval (CI): 0.75–2.42, p = 0.296; median PFS: 3.5 months vs. 5.1 months, HR: 1.63, 95% CI: 0.95–2.80, p = 0.069). In the multivariable analysis, PPI use was not associated with OS (HR 0.80, 95% CI 0.40–1.56, p = 0.526) or PFS (HR 1.44, 95% CI 0.79–2.60, p = 0.233). In conclusion, the estimated effect size of PPI use on survival in Japanese patients with metastatic or unresectable urothelial carcinoma treated with pembrolizumab was not reproducible.

  • Ling Cheng, Tingting Wang, Zhiling Gao, Wenkai Wu, Yezhi Cao, Linghu W ...
    2022 Volume 45 Issue 5 Pages 596-604
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Drug-induced liver injury (DILI) occurs frequently worldwide. Acetaminophen (APAP) is a common drug causing DILI. Current treatment methods are difficult to achieve satisfactory results. Therefore, there is an urgent need to provide safe and effective treatment for patients. Schizandrin B (Sch B), the main component of Schisandra, has a protective effect on liver. However, the potential mechanism of Sch B in the treatment of APAP induced liver injury has not been elucidated to date. In our research, we studied the effect of Sch B on protecting damaged liver cells and explored the potential mechanism underlying its ability to reduce APAP liver injury. We found that Sch B could reduce hepatocyte apoptosis, oxidative stress injury and inflammatory response. These effects were positively correlated with the dose of Sch B. Sch B regulated glucose 6-phosphate dehydrogenase expression by upregulating the expression of p21-activated kinase 4 and polo-like kinase 1. Sch B could inhibit the mitogen-activated protein kinase (MAPK)–c-Jun N-terminal kinase (JNK)–extracellular signal-regulated kinase (ERK) signaling pathway and regulate the expression of apoptosis-related proteins to reduce the incidence of cell apoptosis. In addition, Sch B reduced the expression levels of reactive oxygen species and inflammatory cytokines in hepatocyte. Consequently, we described for the first time that Sch B could not only activate the pentose phosphate pathway but also inhibit the MAPK–JNK–ERK signaling pathway, thereby achieving antioxidative and anti-inflammatory effects and inhibiting hepatocyte apoptosis. These findings indicated the potential use of Sch B in curing liver damage induced by APAP.

  • Zhe Wang, Yating Cheng, Ye Lu, Guoqiang Sun, Lin Pei
    2022 Volume 45 Issue 5 Pages 605-613
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: March 15, 2022
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    Supplementary material

    Accumulating studies suggest that hippocampal neurogenesis plays a crucial role in the pathological mechanism of depression. As a classic antidepressant, lithium chloride can play an antidepressant role by inhibiting glycogen synthase kinase 3β (GSK3β) and promoting neurogenesis. Correspondingly, baicalin is a compound extracted from natural plants, which shows potential antidepressant effect, however, whether baicalin exerts antidepressant effects by promoting neurogenesis still needs further investigation. In the current study, we established an in vitro depression model through corticosterone induced PC-12 cells, and explored the potential mechanism of baicalin’s antidepressant effect by comparing it with lithium chloride alone and the coadministration with lithium chloride. We used Cell Counting Kit-8 (CCK-8) assay, 5-ethynil-2′-deoxyuridine (EdU) staining and cell cycle analysis to evaluate the state of cell survival and cell proliferation. The protein expression levels of neurodevelopmental related factors Doublecortin (DCX), brain-derived neurotrophic factor (BDNF), and the GSK3β pathway-related proteins and mRNA were detected by Western blot and Real-time PCR. The results showed that baicalin could decrease the expression level of GSK3β, while upregulate the expression level of DCX, BDNF, Cyclin D1-cyclin dependent kinase 4/6 (CDK4/6), thus promoted cell proliferation and survival in corticosterone (CORT) induced PC-12 cells. Moreover, this effect was enhanced when baicalin and lithium chloride were coadministration. Taking the above results together, we conclude that baicalin can promote the proliferation and development of PC-12 cells by regulating GSK3β pathway, so as to reverse the depressive-like pathological changes induced by corticosterone.

  • Yan Luo, Liwei Liu, Jihua Zhao, Yue Jiao, Meiyu Zhang, Guangli Xu, Yum ...
    2022 Volume 45 Issue 5 Pages 614-624
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Hepatocellular carcinoma (HCC) is one of the most frequent cancers. Sinomenine (SIN) is a compound derived from Sinomenium acutum. Our previous investigations have found that SIN inhibited protein kinase B (AKT) signaling to induce autophagic death of tumor cells. However, whether inhibition of this pathway by SIN could impact the proliferation of HCC cells is unknown. Thus, we applied SIN to SK-Hep-1 cells and used cell counting kit 8 (CCK8), lactate dehydrogenase (LDH), colony formation and 5-ethynyl-20-deoxyuridine (EdU) incorporation experiments to detect cell viability. Then, staining with annexin V/propidium iodide (PI) coupled with terminal deoxynucleotidyl transferase-mediated biotinylated uridine 5′-triphosphate (UTP) nick end labeling (TUNEL) staining were utilized to monitor apoptosis. Changes in cell mitochondrial membrane capacity were explored via 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining, whilst Western blot or immunohistochemistry was applied to evaluate the expression levels of key proteins, consisting of Cleaved Caspase 3, AKT1, B-cell leukemia/lymphoma 2 (BCL-2), phosphatidylinositol 3-kinase (PI3K) p85α, and Cleaved Caspase 9 etc. The Balb/c nude mice were utilized to establish HCC xenograft tumor model, administered by SIN. After treatments, the tumor volume along with weight were measured. The results illustrated that SIN suppressed SK-Hep-1 HCC cells’ proliferation, enhanced the collapse of potential of the mitochondrial membrane, triggered cell apoptosis, down-regulated PI3K p85α, AKT1, BCL-2, Pro-Caspase 9, Pro-Caspase 3 expressions, and up-regulated Cleaved Caspase 9 and Cleaved Caspase 3 expressions in vitro and in vivo. Meanwhile, SIN reduced the tumor volume along with weight of mice. In addition, insulin-like growth factor-1 (IGF-1), a powerful activator of the PI3K/AKT pathway, could reverse the high apoptosis of SK-Hep-1 HCC cells induced by SIN. Overall, inhibition of PI3K/AKT1 signaling cascade by SIN induced HCC cells apoptosis.

    Editor's pick

    Hepatocellular carcinoma is one of the most frequent cancers. Sinomenine (SIN) is a compound derived from Sinomenium acutum. Authors’ investigations have found that SIN suppressed SK-Hep-1 cells’ proliferation, enhanced the collapse of potential of the mitochondrial membrane, triggered cell apoptosis, down-regulated PI3K p85α, AKT1, BCL-2, Pro-Caspase 9, Pro-Caspase 3 expressions, and up-regulated Cleaved Caspase 9 and Cleaved Caspase 3 expressions. In addition, insulin-like growth factor-1 could reverse the high apoptosis of SK-Hep-1 cells induced by SIN. Therefore, authors revealed that inhibition of PI3K/AKT1 signaling cascade by SIN induced hepatocellular carcinoma cells apoptosis.

  • Hajime Moteki, Masahiko Ogihara, Mitsutoshi Kimura
    2022 Volume 45 Issue 5 Pages 625-634
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    The mechanism of insulin-like growth factor type-I (IGF-I) secretion stimulated by S-allyl-L-cysteine (SAC) was investigated as part of a study of SAC-induced DNA synthesis and cell proliferation in primary cultures of adult rat hepatocytes. When 10−6 M SAC was added to the culture, the amount of IGF-I in the medium was significantly increased at 10 min. The peak IGF-I level (140 pg/mL) was observed 20 min after SAC stimulation. The SAC-induced IGF-I secretion was completely suppressed by a selective Janus kinase 2 (JAK2) inhibitor (TG101209), a selective phospholipase C (PLC) inhibitor (U-73122), an intracellular Ca2+ chelating agent (BAPTA-AM), and a granule secretion inhibitor (somatostatin). On the other hand, 10−6 M SAC-stimulated hepatocytes showed increased intracellular Ca2+ concentration in a time-dependent manner from 0 to 10 min. Phosphorylation of SAC-induced JAK2 and IGF-I receptor tyrosine kinase (RTK) was completely suppressed by TG101209. In addition, U-73122, BAPTA-AM, and somatostatin did not suppress SAC-induced JAK2 phosphorylation, but significantly suppressed SAC-induced IGF-I RTK phosphorylation. Furthermore, binding of the monoclonal antibody against growth hormone (GH) to GH receptor was dose-dependently suppressed by SAC on immunofluorescence. These results showed that SAC promotes cell proliferation by stimulating GH receptor/JAK2/phospholipase C pathways and promoting autocrine secretion of IGF-I in primary cultures of adult rat hepatocytes.

  • Megumi Aimoto, Keita Yagi, Aya Ezawa, Yayoi Tsuneoka, Kohei Kumada, Ta ...
    2022 Volume 45 Issue 5 Pages 635-642
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Supplementary material

    Atrial enlargement is thought to provide arrhythmogenic substrates, leading to the induction of atrial fibrillation (AF). In this study, we investigated the anatomical, molecular biological, and electrophysiological characteristics of remodeled atria in an animal model with chronic volume overload. We used rats that underwent abdominal aorto-venocaval shunt (AVS) surgery. In the in vivo studies, marked changes in electrocardiogram parameters, such as the P-wave duration, PR interval, and QRS width, as well as prolongation of the atrial effective refractory period were observed 12 weeks after the creation of AVS (AVS-12W), which were undetected at 8 weeks postoperative (AVS-8W) despite obvious atrial and ventricular enlargement. Moreover, the duration of AF induced by burst pacing in the AVS-12W rats was significantly longer than that in the Sham and AVS-8W rats. In the isolated atria, a longer action potential duration at 90% repolarization was detected in the AVS-12W rats compared with that in the Sham group. The mRNA levels of the Kv and Kir channels in the right atrium were mostly upregulated in the AVS-8W rats but were downregulated in the AVS-12W rats. These results show that chronic volume overload caused by abdominal AVS provides arrhythmogenic substrates in the rat atrium. The difference in gene expression in the right atrium between the AVS-8W and AVS-12W rats may partly explain the acquisition of arrhythmogenicity.

    Editor's pick

    Atrial enlargement often provides arrhythmogenic substrates, leading to the induction of atrial fibrillation. The authors examined the anatomical, molecular biological, and electrophysiological characteristics of remodeled atria in rats with 8- and 12-week of aorto-venocaval shunt (AVS). It is noteworthy that marked electrophysiological changes were detected only in the AVS-12W rat despite obvious increments in atrial and ventricular tissue weights and altered gene expression in the AVS-8W rat, which suggests that the electrical remodeling observed in the atrium is preceded by structural remodeling after AVS surgery. These findings provide important information on experimental evidence regarding the timing of generation of arrhythmogenic substrate in the atria.

  • Natsuki Yamagiwa, Haruka Kobayashi, Haruka Okabayashi, Miki Yasuda, Ke ...
    2022 Volume 45 Issue 5 Pages 643-648
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: March 02, 2022
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    Plasmalogens are a group of glycerophospholipids containing a vinyl-ether bond at the sn-1 position in the glycerol backbone. Cellular membrane plasmalogens are considered to have important roles in homeostasis as endogenous antioxidants, differentiation, and intracellular signal transduction pathways including neural transmission. Therefore, reduced levels of plasmalogens have been suggested to be associated with neurodegenerative diseases such as Alzheimer’s disease. Interestingly, although arachidonic acid is considered to be involved in learning and memory, it could be liberated and excessively activate neuronal activity to the excitotoxic levels seen in Alzheimer’s disease patients. Here, we examined the protective effects of several kinds of plasmalogens against cellular toxicity caused by arachidonic acid in human neuroblastoma SH-SY5Y cells. As a result, only phosphatidylcholine-plasmalogen-oleic acid (PC-PLS-18) showed protective effects against arachidonic acid-induced cytotoxicity based on the results of lactate dehydrogenase release and ATP depletion assays, as well as cellular morphological changes in SH-SY5Y cells. These results indicate that PC-PLS-18 protects against arachidonic acid-induced cytotoxicity, possibly via improving the stability of the cellular membrane in SH-SY5Y cells.

  • Naoya Hirata, Shigeru Yamada, Shota Yanagida, Atsushi Ono, Yukuto Yasu ...
    2022 Volume 45 Issue 5 Pages 649-658
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Growing evidence suggests that cancer originates from cancer stem cells (CSCs), which can be identified by aldehyde dehydrogenase (ALDH) activity-based flow cytometry. However, the regulation of CSC growth is not fully understood. In the present study, we investigated the effects of Transforming Growth Factor-β (TGFβ) in breast CSC expansion. Stimulation with TGFβ increased the ALDH-positive breast CSC population via the phosphorylation of sphingosine kinase 1 (SphK1), a sphingosine-1-phosphate (S1P)-producing enzyme, and subsequent S1P-mediated S1P receptor 3 (S1PR3) activation. These data suggest that TGFβ promotes breast CSC expansion via the ALK5/SphK1/S1P/S1PR3 signaling pathway. Our findings provide new insights into the role of TGFβ in the regulation of CSCs.

    Editor's pick

    Breast cancer are originated from cancer stem cells (CSCs), which contribute to drug resistance and recurrence. The authors examined the effects of transforming growth factor beta (TGFβ) signaling on proliferation of breast CSCs. TGFβ induced the proliferation of CSCs via phosphorylation of sphingosine kinase 1 (SphK1) via a Smad-independent manner and subsequent production of sphingosine-1-phosphate (S1P). Moreover, Notch pathway was involved in the S1P response via S1P receptor 3. These results suggest that TGFβ-SphK1-S1P-Notch signaling pathway is a novel therapeutic target in breast cancer.

Notes
  • Aozora Nagaoka, Makoto Sakurai, Katsuyoshi Kamiie, Atsuko Masumi
    2022 Volume 45 Issue 5 Pages 659-663
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Previously we showed that the water-soluble fraction of sorghum extract (SE) improves adipogenesis in 3-isobutyl-1-methylxanthine (IBMX)/dexamethasone/insulin (MDI)/thiazolidinedione (TZD)-induced 3T3-L1 preadipocytes but downregulates genes related to peroxisome proliferator-activated receptor γ (PPARγ) and adipogenesis in both MDI- and MDI/TZD-induced 3T3-L1 adipocytes. In this study, we showed that SE treatment altered the accumulation of stained lipids in 3T3-L1 adipocytes induced by MDI/troglitazone (Tro). Immunoblot analyses indicated that SE treatment reduced adipocyte protein 2 (aP2) expression and induced peroxisome proliferator-activated receptor α (PPARα) protein expression in the presence of Tro in 3T3-L1 adipocytes. MDI/Tro treatment, but not MDI treatment, of 3T3-L1 cells induced PPARγ phosphorylation at Ser273. SE downregulated PPARγ expression in MDI-induced 3T3-L1 adipocytes and did not affect its phosphorylation at Ser273 in MDI- and MDI/Tro-induced 3T3-L1 adipocytes. Therefore, SE likely promotes adipogenesis and lipid metabolism in 3T3-L1 preadipocytes by cooperating with Tro independent of PPARγ Ser273 phosphorylation.

  • Rubii Kondo, Naoki Kawata, Yoshiaki Suzuki, Hisao Yamamura
    2022 Volume 45 Issue 5 Pages 664-667
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Hepatic stellate cells (HSCs) play a significant role in the development of chronic liver diseases. Hepatic damage activates HSCs and results in hepatic fibrosis. The functions of activated HSCs require an increase in the cytosolic Ca2+ concentration ([Ca2+]cyt). However, the regulatory mechanisms underlying Ca2+ signaling in activated HSCs remain largely unknown. In the present study, functional analyses of Ca2+-sensing receptors (CaSRs) were performed using activated human HSCs, LX-2. Expression analyses revealed that CaSR proteins were expressed in α-smooth muscle actin-positive LX-2 cells. Extracellular Ca2+ restoration (from 0 to 2.2 mM) increased [Ca2+]cyt in these cells. The extracellular Ca2+-induced increase in [Ca2+]cyt was reduced by the CaSR antagonists, NPS2143 and Calhex 231. Furthermore, the growth of LX-2 cells was blocked by NPS2143 and Calhex 231 in concentration-dependent manners (IC50 = 6.0 and 9.5 μM, respectively). LX-2 cell proliferation was also attenuated by NPS2143 and Calhex 231. In conclusion, CaSRs are functionally expressed in activated HSCs and regulate Ca2+ signaling and cell proliferation. The present results provide insights into the molecular mechanisms underlying hepatic fibrosis and will contribute to the development of potential therapeutic targets.

    Editor's pick

    Hepatic stellate cells (HSCs) are a key player in the pathogenesis of hepatic fibrosis including cirrhosis. The development of hepatic fibrosis is associated with enhanced calcium signaling in HSCs. However, the regulatory mechanism of calcium signaling in HSCs is largely unknown. In addition, there is no specific therapeutic drug for hepatic fibrosis currently. This report reveals that calcium-sensing receptors are expressed in human HSCs and function in the regulation of calcium signaling and cell proliferation. These findings help to elucidate the molecular mechanism of hepatic fibrosis and develop a potential therapeutic target for hepatic fibrosis.

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