{"title":"ROBO3 Drives Endometriosis Progression via Dual Wnt/β-Catenin Activation and M2 Macrophage Polarization.","authors":"Xinyue Zhou, Wei Zhou, Changhong Qu, Yisha Jiang, Wenzhu Liu, Lipeng Pei","doi":"10.1248/bpb.b25-00262","DOIUrl":"https://doi.org/10.1248/bpb.b25-00262","url":null,"abstract":"<p><p>Endometriosis, a prevalent gynecological disorder marked by ectopic growth of endometrial-like tissue, demonstrates malignant tumor-like properties including aggressive adhesion and invasiveness. Emerging evidence implicates roundabout guidance receptor 3 (ROBO3) in cellular pathophysiology, yet its role in endometriosis remains unexplored. In this study, we first found abnormally high ROBO3 expression in endometriosis by bioinformatics analysis. Next, functional assays revealed that ROBO3 is a key regulator promoting the invasion and migration of endometriotic stromal cells (ESCs) in vitro. Mechanistically, ROBO3 activates the Wnt/β-catenin signaling pathway, evidenced by increased phosphorylation of glycogen synthase kinase 3β, nuclear β-catenin accumulation, and upregulated c-myc expression. Pharmacological inhibition of Wnt/β-catenin with MSAB (5 μM) reversed ROBO3-mediated pro-invasive and pro-migratory effects. Furthermore, we discovered that ROBO3 enhances the secretion of chemokines CCL2 and CCL5 in ESCs, which subsequently promote macrophage polarization toward the M2 phenotype, as indicated through elevated expression of interleukin-10 and Arg-1. Collectively, our findings elucidate a dual mechanism whereby ROBO3 drives endometriosis progression through both intrinsic activation of Wnt/β-catenin signaling and extrinsic modulation of tumor-associated macrophages, underscoring ROBO3 as a promising therapeutic target for endometriosis.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 10","pages":"1503-1513"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Anti-atrial Fibrillatory Effects of the TRPC3 Channel Inhibitor Pyrazole-3 in Rats with Atrial Enlargement Induced by Chronic Volume Overload.","authors":"Megumi Aimoto, Yoshinobu Nagasawa, Taichi Kusakabe, Keisuke Kato, Akira Takahara","doi":"10.1248/bpb.b25-00415","DOIUrl":"https://doi.org/10.1248/bpb.b25-00415","url":null,"abstract":"<p><p>The effect of transient receptor potential canonical-3 (TRPC3) channel inhibitor pyrazole-3 (Pyr3) on the stability of atrial fibrillation (AF) was analyzed in a rat model of chronic volume overload. Male Wistar rats underwent aorto-venocaval shunt (AVS) surgery and received Pyr3 treatment intraperitoneally for 12 weeks. Morphological and electrophysiological assessments were performed at the end of the treatment period. Longer P-wave duration, atrial conduction time, and AF duration, in addition to greater atrial tissue weight, were detected in AVS rats compared with sham rats. Chronic Pyr3 administration prevented AVS-induced prolongation of P-wave duration and atrial conduction time, partially prevented atrial weight increase, and abbreviated AVS-induced prolongation of AF duration to similar levels as those in sham rats, without affecting the atrial effective refractory period. These results suggest that the TRPC3 inhibitor Pyr3 can ameliorate sustained AF associated with chronic volume overload by improving atrial conduction defects in AVS rats. Pharmacological inhibition of TRPC3 channels by Pyr3 thus represents a promising therapeutic strategy for preventing AF development related to structural modeling.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 10","pages":"1547-1554"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145298408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Preventive and Therapeutic Effects of Intracerebroventricular Administration of Maresin-1 on Lipopolysaccharide-Induced Depression-Like Behaviors in Mice.","authors":"Satoshi Deyama, Katsuyuki Kaneda, Masabumi Minami","doi":"10.1248/bpb.b24-00743","DOIUrl":"10.1248/bpb.b24-00743","url":null,"abstract":"<p><p>Enhanced inflammatory and immune responses have been observed in patients with major depressive disorder, pointing to anti-inflammatory substances as potential seeds for developing novel antidepressants. Omega-3 polyunsaturated fatty acid metabolites, such as resolvin D and E series, maresins, and protectins (collectively known as specialized pro-resolving mediators) demonstrate anti-inflammatory effects. This study examined the antidepressant-like effects of maresin-1 (MaR1) on lipopolysaccharide (LPS)-induced depression-like behaviors in mice. Using the tail suspension test (TST) and the forced swim test (FST), we assessed depression-like behaviors 26 and 28 h after intraperitoneal injection of LPS (0.8 mg/kg), respectively. An open field test (OFT) was also conducted to evaluate locomotor activity 24 h after LPS injection. Intracerebroventricular (i.c.v.) injection of MaR1 (10 ng/mouse) immediately after the LPS challenge mitigated the increased immobility time in the TST and FST, without affecting locomotor activity in the OFT, indicating the preventive effects of MaR1 on LPS-induced depression-like behaviors. Furthermore, i.c.v. injection of MaR1 23 h after the LPS challenge reduced the immobility time in both tests, underscoring its therapeutic potential. These findings suggest that MaR1 could be a promising seed for developing novel antidepressants.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 1","pages":"6-10"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Antipruritic Effects of Single Administration of Paroxetine on Acute and Chronic Itch.","authors":"Kosuke Matsuda, Hikaru Ishisaka, Masahito Sawahata, Toshiaki Kume, Daisuke Uta","doi":"10.1248/bpb.b24-00657","DOIUrl":"10.1248/bpb.b24-00657","url":null,"abstract":"<p><p>Itch is described as an unpleasant sensation, and chronic itch, such as that in atopic dermatitis (AD), often decreases a patient's QOL. There are few effective treatments for various chronic pruritic disorders that are not limited to inflammation. Selective serotonin reuptake inhibitors (SSRIs) are antidepressants used to treat some chronic pruritus disorders. However, there is little evidence from clinical and basic studies using animal models. In this study, we found that paroxetine suppressed acute and chronic itch in mouse models. Single administration of paroxetine (10 mg/kg) inhibited scratching behavior caused by histamine-dependent or histamine-independent itch. Moreover, paroxetine (10 mg/kg) inhibited spontaneous scratching behavior in AD model using NC/Nga mice without affecting locomotor function. These results suggest that paroxetine suppresses chronic itch caused by AD via histamine-dependent and -independent pathways. This study provides one of the few pieces of evidence that SSRIs suppress itch.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 2","pages":"184-187"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jisung Hwang, Deok Yong Sim, Chi-Hoon Ahn, Su-Yeon Park, Jin-Suk Koo, Bum-Sang Shim, Bonglee Kim, Sung-Hoon Kim
{"title":"Inhibition of LGR5/β-Catenin Axis and Activation of miR134 Are Critically Involved in Apoptotic Effect of Sanggenol L in Hepatocellular Carcinoma.","authors":"Jisung Hwang, Deok Yong Sim, Chi-Hoon Ahn, Su-Yeon Park, Jin-Suk Koo, Bum-Sang Shim, Bonglee Kim, Sung-Hoon Kim","doi":"10.1248/bpb.b24-00213","DOIUrl":"10.1248/bpb.b24-00213","url":null,"abstract":"<p><p>Although Sanggenol L (SL), derived from the root bark of Morus alba, has hepatoprotective, neuroprotective, and antitumor effects, the antitumor mechanism of SL remains unclear to date. Thus, in the current work, the apoptotic mechanisms of SL were investigated in HepG2 and Huh hepatocellular carcinoma (HCC) cells in relation to leucine-rich repeat containing G protein-coupled receptor 5 (LGR5)/β-catenin and miR134 signaling axis. Herein, SL significantly incremented cytotoxicity, sub-G1 population, and the number of terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) positive apoptotic bodies and also inhibited proliferation in HCCs. Consistently, SL activated pro-Caspase7 and pro-Caspase3 and induced the cleavage of Poly ADP-ribose polymerase (PARP) in HCCs. Of note, the pivotal role of LGR5/β-catenin signaling was verified in SL-induced apoptosis in LGR5 overexpressed AML-12 cells and LGR5 depleted HepG2 cells. Furthermore, SL upregulated miR134 expression levels in HepG2 cells, while miR134 inhibitors disturbed the capacity of SL to cleave PARP and pro-Caspase3 in HepG2 cells. Taken together, our findings highlight evidence that inhibition of the LGR5/β-catenin axis and upregulation of miR134 play critical roles in SL-induced apoptosis in HCCs.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 2","pages":"126-131"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Recent Antimicrobial Resistance Situation and Mechanisms of Resistance to Key Antimicrobials in Enterotoxigenic Escherichia coli.","authors":"Daichi Morita, Teruo Kuroda","doi":"10.1248/bpb.b24-00649","DOIUrl":"10.1248/bpb.b24-00649","url":null,"abstract":"<p><p>Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea in developing countries and is regularly imported into developed countries as a major cause of traveler's diarrhea. ETEC is usually self-limiting and not necessarily treated with antimicrobials, although antimicrobial treatment is recommended in malnourished children, severe cases, and traveler's diarrhea. However, resistant strains to representative therapeutic agents such as ciprofloxacin and azithromycin have been reported in recent years, and multidrug-resistant ETEC has also emerged. This review discusses the recent antimicrobial resistance surveillance in ETEC and the mechanisms of resistance to major antimicrobials.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 3","pages":"222-229"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Microfibril-Associated Protein 5 Contributes to the Elastic Fiber Abnormalities in Aged Skin.","authors":"Fumiaki Sato, Teruaki Oku, Yuka Nishigaki, Mana Suzuki, Hiroyasu Sakai, Hideyuki Takeshima, Yoshinori Kato","doi":"10.1248/bpb.b24-00828","DOIUrl":"https://doi.org/10.1248/bpb.b24-00828","url":null,"abstract":"<p><p>Elastic fibers, which contribute to the flexibility of tissues such as the skin, alveoli, and arteries, have a long half-life and are not regenerated once formed during the fetal stage. Consequently, the degradation of elastic fibers due to aging or inflammation can significantly impact tissue function. In the dermis, degeneration of elastic fibers is characterized by degradation in photoaging, driven by UV radiation, and structural abnormalities of elastic fibers in intrinsic aging. However, the mechanisms driving the abnormalities associated with intrinsic aging remain incomplete. This study aimed to identify the factors involved in the elastic fiber abnormalities associated with intrinsic aging of the dermis. Through a comprehensive analysis of gene expression, this study focused on microfibril-associated protein 5 (MFAP5) as a candidate gene responsible for the elastic fiber abnormalities associated with intrinsic aging. Immunofluorescence staining revealed that aged fibroblasts highly expressed MFAP5 and strongly localized it to aggregated elastic fibers. Furthermore, the elimination of MFAP5 expression suppressed elastic fiber aggregation. The exogenous addition of MFAP5 induced thickening and disorganization of elastic fibers, effects that were not observed with the overexpression of MFAP5 in young fibroblasts, which merely express MFAP5. Moreover, MFAP5 inhibited the interaction between latent transforming growth factor β binding protein 4 and fibulin-5, which are crucial for elastic fiber formation. These results suggest that excess MFAP5 expression associated with aging causes abnormalities in elastic fibers. Understanding the role of MFAP5 in elastic fiber abnormalities highlights its potential as a therapeutic target for mitigating intrinsic dermal aging and improving skin elasticity.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 4","pages":"450-456"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cry2 Alleviates Cisplatin-Induced Cytotoxicity in Mouse Renal Cortex Tubular Cell Lines.","authors":"Hiroki Yoshioka, Satoshi Yokota, Shintaro Torimoto, Hanane Horita, Yosuke Tsukiboshi, Tohru Maeda, Nobuhiko Miura","doi":"10.1248/bpb.b24-00811","DOIUrl":"https://doi.org/10.1248/bpb.b24-00811","url":null,"abstract":"<p><p>Cisplatin is a platinum-based drug that is widely used to treat various types of cancer. However, cisplatin is known to cause severe adverse effects, such as nephrotoxicity and ototoxicity. Clock genes, such as Bmal1 and Clock, regulate cisplatin-related homeostasis genes, such as Oct2 and Mate1. Although these clock genes may be involved in cisplatin-induced nephrotoxicity, their associations with other clock genes remain unclear. The aim of the present study was to investigate whether seven clock genes (Ciart, cryptochrome 1 (Cry1), Cry2, Npas2, Per1, Per2, and Per3) regulate cisplatin-induced renal toxicity in a renal cortex tubule cell line (MuRTE61). Cisplatin treatment decreases MuRTE61 cell viability in a dose-dependent manner. Cry2 expression levels increased after treatment with cisplatin for 24 h. Notably, Cry2 overexpression alleviated cisplatin-induced suppression of cell proliferation, apoptosis, and platinum content in MuRTE61 cells. Moreover, Cry2 overexpression upregulated the efflux-related transporters (Atp7a and Mrp2). These results suggest that Cry2 protects against cisplatin toxicity by reducing Pt accumulation and increasing the expression of Atp7a and Mrp2.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 4","pages":"390-398"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Syunki Yamada, Taiki Mihara, Tamaki Kurosawa, Aya Maruyama, Katsuyo Ohashi-Doi, Yuko Mitobe, Masatoshi Hori
{"title":"Delayed Upper Gastrointestinal Motility in Mice Treated with Oral Iron Tablets.","authors":"Syunki Yamada, Taiki Mihara, Tamaki Kurosawa, Aya Maruyama, Katsuyo Ohashi-Doi, Yuko Mitobe, Masatoshi Hori","doi":"10.1248/bpb.b24-00789","DOIUrl":"https://doi.org/10.1248/bpb.b24-00789","url":null,"abstract":"<p><p>Oral iron preparations for iron deficiency anemia have major side effects, such as nausea and vomiting, which are gastrointestinal symptoms widely known to occur with gastrointestinal motility disorders. However, it is unclear whether these symptoms are associated with gastrointestinal motility. This study aimed to explore the correlation between oral iron preparations that cause nausea and vomiting with gastrointestinal motility. Sodium ferrous citrate (SFC), a common ingredient in iron preparations, was used in this study. Gastrointestinal motility in mice was measured using the <sup>13</sup>C-octanoic acid breath test to determine gastric emptying and colonic transport capacities using the bead expulsion test. SFC significantly delayed gastric emptying. However, it did not affect the colonic transport capacity. Treatment with the antiemetic palonosetron, a 5-hydroxytryptamine 3 (5-HT<sub>3</sub>) receptor inhibitor, abolished the gastric evacuation retardation effect of SFC. However, the additive in the SFC formulation, palonosetron alone, did not affect the gastric emptying capacity. These results suggest that iron preparations cause vagal nausea and vomiting in the upper gastrointestinal tract due to chemical stimulation of the gastrointestinal blood with a concomitant reduction in gastric emptying capacity. Knowledge of the association of delayed gastric emptying with the onset of iron-induced nausea is useful for understanding iron-induced adverse effects.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 4","pages":"432-439"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Naoki Tamura, Kanzo Suzuki, Hirono Shiraki, Issei Waguri, Eri Segi-Nishida
{"title":"Production of Adeno-Associated Virus Vector Serotype rh.10 and Optimization of Its Purification via Chloroform Extraction.","authors":"Naoki Tamura, Kanzo Suzuki, Hirono Shiraki, Issei Waguri, Eri Segi-Nishida","doi":"10.1248/bpb.b24-00850","DOIUrl":"https://doi.org/10.1248/bpb.b24-00850","url":null,"abstract":"<p><p>Recombinant adeno-associated virus (AAV) vectors are widely used for manipulating gene expression. AAVrh.10 is a highly infectious AAV serotype for the central nervous system and various tissues. Owing to its potential use in research, we aimed to optimize the production strategy and develop a simple purification protocol for the AAVrh.10 vector. In this study, we explored a simple production and purification strategy for the AAVrh.10 vector via chloroform extraction and ultrafiltration. Initially, we evaluated the optimal conditions for AAVrh.10-CAG-GFP production using AAV-293 cells. AAVrh.10-CAG-GFP was successfully produced in a serum-free medium after plasmid transfection. Moreover, the culture medium contained a substantial amount of the virus. Therefore, both AAVrh.10-containing cell lysate and culture medium should be used to prepare the AAVrh.10 viral vector. To purify and concentrate AAVrh.10-CAG-GFP from the crude lysate and medium, we optimized the chloroform extraction and ultrafiltration strategies. Subsequently, purified AAVrh.10-CAG-GFP was used to infect HEK-293T cells. Overall, this study provides a simple and effective AAVrh.10 vector preparation strategy for basic and preclinical research.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 4","pages":"355-362"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}