BioFactors最新文献

{"title":"Nuclear receptor 4A1 (NR4A1) upregulated by n-butylidenephthalide via the mitogen-activated protein kinase (MAPK) pathway ameliorates drug-induced gingival enlargement","authors":"Tomoya Ueda,&nbsp;Shinji Matsuda,&nbsp;Yurika Ninomiya,&nbsp;Fuminori Nakashima,&nbsp;Keisuke Yasuda,&nbsp;Daisuke Furutama,&nbsp;Takumi Memida,&nbsp;Tetsuya Yoshimoto,&nbsp;Mikihito Kajiya,&nbsp;Kouji Ohta,&nbsp;Kazuhisa Ouhara,&nbsp;Noriyoshi Mizuno","doi":"10.1002/biof.2077","DOIUrl":"10.1002/biof.2077","url":null,"abstract":"<p>Drug-induced gingival enlargement (DIGE) is a side effect of ciclosporin, calcium channel blockers, and phenytoin. DIGE is a serious disease that leads to masticatory and esthetic disorders, severe caries, and periodontitis but currently has no standard treatment. We recently reported that nuclear receptor 4A1 (NR4A1) is a potential therapeutic target for DIGE. This study aimed to evaluate the therapeutic effects of <i>n</i>-butylidenephthalide (BP), which increases the expression of NR4A1, on DIGE. In this study, <i>NR4A1</i> mRNA expression was analyzed in the patients with periodontal disease (PD) and DIGE. We evaluated the effect of BP on NR4A1 expression in gingival fibroblasts and in a DIGE mouse model. RNA sequencing (RNA-seq) was conducted to identify the mechanisms by which BP increases NR4A1 expression. The results showed that <i>NR4A1</i> mRNA expression in the patients with DIGE was significantly lower than the patients with PD. BP suppressed the upregulation of <i>COL1A1</i> expression, which was upregulated by TGF-β. BP also ameliorated gingival overgrowth in DIGE mice and reduced <i>Col1a1</i> and <i>Pai1</i> expression. BP also decreased <i>Il1β</i> mRNA expression in gingival tissue in DIGE. RNA-seq results showed an increase in the expression of several genes related to mitogen-activated protein kinase including DUSP genes in gingival fibroblasts stimulated by BP. Treatment with ERK and JNK inhibitors suppressed the BP-induced increase in NR4A1 expression. In addition, BP promoted the phosphorylation of ERK in gingival fibroblasts. In conclusion, BP increases NR4A1 expression in gingival fibroblasts through ERK and JNK signaling, demonstrating its potential as a preventive and therapeutic agent against DIGE.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"50 6","pages":"1192-1207"},"PeriodicalIF":5.0,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11627475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholecystokinin neurotransmission in the central nervous system: Insights into its role in health and disease","authors":"Muhammad Asim,&nbsp;Huajie Wang,&nbsp;Abdul Waris,&nbsp;Gao Qianqian,&nbsp;Xi Chen","doi":"10.1002/biof.2081","DOIUrl":"10.1002/biof.2081","url":null,"abstract":"<p>Cholecystokinin (CCK) plays a key role in various brain functions, including both health and disease states. Despite the extensive research conducted on CCK, there remain several important questions regarding its specific role in the brain. As a result, the existing body of literature on the subject is complex and sometimes conflicting. The primary objective of this review article is to provide a comprehensive overview of recent advancements in understanding the central nervous system role of CCK, with a specific emphasis on elucidating CCK's mechanisms for neuroplasticity, exploring its interactions with other neurotransmitters, and discussing its significant involvement in neurological disorders. Studies demonstrate that CCK mediates both inhibitory long-term potentiation (iLTP) and excitatory long-term potentiation (eLTP) in the brain. Activation of the GPR173 receptor could facilitate iLTP, while the Cholecystokinin B receptor (CCKBR) facilitates eLTP. CCK receptors' expression on different neurons regulates activity, neurotransmitter release, and plasticity, emphasizing CCK's role in modulating brain function. Furthermore, CCK plays a pivotal role in modulating emotional states, Alzheimer's disease, addiction, schizophrenia, and epileptic conditions. Targeting CCK cell types and circuits holds promise as a therapeutic strategy for alleviating these brain disorders.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"50 6","pages":"1060-1075"},"PeriodicalIF":5.0,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11627476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiopoietin-like protein 4 induces growth hormone variant secretion and aggravates insulin resistance during pregnancy, linking obesity to gestational diabetes mellitus","authors":"Chun-Heng Kuo,&nbsp;Shu-Huei Wang,&nbsp;Hsien-Chia Juan,&nbsp;Szu-Chi Chen,&nbsp;Ching-Hua Kuo,&nbsp;Han-Chun Kuo,&nbsp;Shin-Yu Lin,&nbsp;Hung-Yuan Li","doi":"10.1002/biof.2076","DOIUrl":"10.1002/biof.2076","url":null,"abstract":"<p>Angiopoietin-like protein 4 (ANGPTL4) is a secretory glycoprotein involved in regulating glucose homeostasis in non-pregnant subjects. However, its role in glucose metabolism during pregnancy and the pathophysiology of gestational diabetes mellitus (GDM) remains elusive. Thus, this study aimed to clarify the relationship between ANGPTL4 and GDM and investigate the pathophysiology of placental ANGPTL4 in glucose metabolism. We investigated this issue using blood and placenta samples in 957 pregnant women, the human 3A-sub-E trophoblast cell line, and the L6 skeletal muscle cell line. We found that ANGPTL4 expression in the placenta was higher in obese pregnant women than in lean controls. Palmitic acid significantly induced ANGPTL4 expression in trophoblast cells in a dose–response manner. ANGPTL4 overexpression in trophoblast cells resulted in endoplasmic reticulum (ER) stress, which stimulated the expression and secretion of growth hormone-variant (GH2) but not human placental lactogen. In L6 skeletal muscle cells, soluble ANGPTL4 suppressed insulin-mediated glucose uptake through the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases 1/2 (ERK 1/2) pathways. In pregnant women, plasma ANGPTL4 concentrations in the first trimester predicted the incidence of GDM and were positively associated with BMI, plasma triglyceride, and plasma GH2 in the first trimester. However, they were negatively associated with insulin sensitivity index ISI_0,120 in the second trimester. Overall, placental ANGPTL4 is induced by obesity and is involved in the pathophysiology of GDM via the induction of ER stress and GH2 secretion. Soluble ANGPTL4 can lead to insulin resistance in skeletal muscle cells and is an early biomarker for predicting GDM.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"50 6","pages":"1176-1191"},"PeriodicalIF":5.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anticancer effect of minor phytocannabinoids in preclinical models of multiple myeloma","authors":"Cristina Aguzzi,&nbsp;Laura Zeppa,&nbsp;Maria Beatrice Morelli,&nbsp;Oliviero Marinelli,&nbsp;Martina Giangrossi,&nbsp;Consuelo Amantini,&nbsp;Giorgio Santoni,&nbsp;Hossain Sazzad,&nbsp;Massimo Nabissi","doi":"10.1002/biof.2078","DOIUrl":"10.1002/biof.2078","url":null,"abstract":"<p>Multiple myeloma (MM) is a blood cancer caused by uncontrolled growth of clonal plasmacells. Bone disease is responsible for the severe complications of MM and is caused by myeloma cells infiltrating the bone marrow and inducing osteoclast activation. To date, no treatment for MM is truly curative since patients relapse and become refractory to all drug classes. Cannabinoids are already used as palliative in cancer patients. Furthermore, their proper anticancer effect was demonstrated in many cancer models in vitro, in vivo, and in clinical trials. Anyway, few information was reported on the effect of cannabinoids on MM and no data has been provided on minor phytocannabinoids such as cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), and cannabidivarin (CBDV). Scientific literature also reported cannabinoids beneficial effect against bone disease. Here, we examined the cytotoxic activity of CBG, CBC, CBN, and CBDV in vitro in MM cell lines, their effect in modulating MM cells invasion toward bone cells and the bone resorption. Subsequently, according to the in vitro results, we selected CBN for in vivo study in a MM xenograft mice model. Results showed that the phytocannabinoids inhibited MM cell growth and induced necrotic cell death. Moreover, the phytocannabinoids reduced the invasion of MM cells toward osteoblast cells and bone resorption in vitro. Lastly, CBN reduced in vivo tumor mass. Together, our results suggest that CBG, CBC, CBN, and CBDV can be promising anticancer agents for MM.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"50 6","pages":"1208-1219"},"PeriodicalIF":5.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11627469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two peptides LLRLTDL and GYALPCDCL inhibit foam cell formation through activating PPAR-γ/LXR-α signaling pathway in oxLDL-treated RAW264.7 macrophages","authors":"Chathuri Kaushalya Marasinghe,&nbsp;Soon-Do Yoon,&nbsp;Jae-Young Je","doi":"10.1002/biof.2075","DOIUrl":"10.1002/biof.2075","url":null,"abstract":"<p>Foam cell formation plays a pivotal role in atherosclerosis-associated cardiovascular diseases. Bioactive peptides generated from marine sources have been found to provide multifunctional health advantages. In the present study, we investigated the anti-atherosclerotic effects of LLRLTDL (Bu1) and GYALPCDCL (Bu2) peptides, isolated from ark shell protein hydrolysates by assessing their inhibitory effect on oxidized LDL (oxLDL)-induced foam cell formation. The two peptides showed a promising anti-atherosclerotic effect by inhibiting foam cell formation, which was evidenced by inhibiting lipid accumulation in oxLDL-treated RAW264.7 macrophages and oxLDL-treated primary human aortic smooth muscle cells (HASMC). Two peptides effectively reduced total cholesterol, free cholesterol, cholesterol ester, and triglyceride levels by upregulating cholesterol efflux and downregulating cholesterol influx. Expression of cholesterol influx-related proteins such as SR-A1 and CD36 were reduced, whereas cholesterol efflux-related proteins such as ATP-binding cassette transporter ABCA-1 and ABCG-1 were highly expressed. In addition, Bu1 and Bu2 peptides increased PPAR-γ and LXR-α expression. However, PPAR-γ siRNA transfection reversed the foam cell formation inhibitory activity of Bu1 and Bu2 peptides. Furthermore, the synergistic effect of Bu1 and Bu2 peptides on foam cell formation inhibition was observed with PPAR-γ agonist thiazolidinediones, indicating that PPAR-γ signaling pathway plays a key role in foam cell formation of macrophages. Beyond their impact on foam cell formation, Bu1 and Bu2 peptides demonstrated anti-inflammatory potential by inhibiting the generation of pro-inflammatory cytokines and nitric oxide and NF-κB nuclear activation. Taken together, these results suggest that Bu1 and Bu2 peptides may be useful for atherosclerosis and associated anti-inflammatory therapies.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"50 6","pages":"1161-1175"},"PeriodicalIF":5.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vasoactive intestinal peptide exerts an osteoinductive effect in human mesenchymal stem cells","authors":"David Castro-Vázquez,&nbsp;Paula Arribas-Castaño,&nbsp;Iván García-López,&nbsp;Irene Gutiérrez-Cañas,&nbsp;Selene Pérez-García,&nbsp;Amalia Lamana,&nbsp;Raúl Villanueva-Romero,&nbsp;Alicia Cabrera-Martín,&nbsp;Karolina Tecza,&nbsp;Carmen Martínez,&nbsp;Yasmina Juarranz,&nbsp;Rosa P. Gomariz,&nbsp;Mar Carrión","doi":"10.1002/biof.2062","DOIUrl":"10.1002/biof.2062","url":null,"abstract":"<p>Several neuropeptides present in bone tissues, produced by nerve fibers and bone cells, have been reported to play a role in regulating the fine-tuning of osteoblast and osteoclast functions to maintain bone homeostasis. This study aims to characterize the influence of the neuropeptide vasoactive intestinal peptide (VIP) on the differentiation process of human mesenchymal stem cells (MSCs) into osteoblasts and on their anabolic function. We describe the mRNA and protein expression profile of VIP and its receptors in MSCs as they differentiate into osteoblasts, suggesting the presence of an autocrine signaling pathway in these cells. Our findings reveal that VIP enhances the expression of early osteoblast markers in MSCs under osteogenic differentiation and favors both bone matrix formation and proper cytoskeletal reorganization. Finally, our data suggest that VIP could be exerting a direct modulatory role on the osteoblast to osteoclast signaling by downregulating the receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio. These results highlight the potential of VIP as an osteoinductive differentiation factor, emerging as a key molecule in the maintenance of human bone homeostasis.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"50 6","pages":"1148-1160"},"PeriodicalIF":5.0,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11627472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140908119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deubiquitinase PSMD14 promotes tumorigenicity of glioblastoma by deubiquitinating and stabilizing β-catenin","authors":"Yang Wang,&nbsp;Yu Liu,&nbsp;Chongchen Ma,&nbsp;Cen Liu,&nbsp;Qikai Tang,&nbsp;Zhangjie Wang,&nbsp;Jiacheng Lu,&nbsp;Zhengxin Chen,&nbsp;Huibo Wang","doi":"10.1002/biof.2061","DOIUrl":"10.1002/biof.2061","url":null,"abstract":"<p>The deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14), a member of the JAB1/MPN/Mov34 metalloenzyme (JAMM) family, has been shown to function as an oncogene in various human cancers. However, the function of PSMD14 in glioma and the underlying mechanism remain unclear. In this study, our findings reveal a dramatic upregulation of PSMD14 in GBMs, which is associated with poor survival outcomes. Knocking down PSMD14 is associated with decreased proliferation and invasion of GBM cells in vitro and inhibited tumor growth in a xenograft mouse model. Mechanistically, PSMD14 directly interacts with β-catenin, leading to a decrease in the K48-linked ubiquitination of β-catenin and subsequent β-catenin stabilization. Increased β-catenin expression significantly reverses the inhibitory effects of PSMD14 knockdown on the migration, invasion, and tumor growth of GBM cells. Moreover, we observed a significant correlation between PSMD14 and β-catenin expression in human GBM samples. In summary, our results reveal that PSMD14 is a crucial deubiquitinase that is responsible for stabilizing the β-catenin protein, highlighting its potential for use as a therapeutic target for GBM.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"50 6","pages":"1134-1147"},"PeriodicalIF":5.0,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140830350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol transport and beyond: Illuminating the versatile functions of HDL apolipoproteins through structural insights and functional implications","authors":"Aishwarya Sudam Bhale,&nbsp;Olivier Meilhac,&nbsp;Christian Lefebvre d'Hellencourt,&nbsp;Mookambeswaran A. Vijayalakshmi,&nbsp;Krishnan Venkataraman","doi":"10.1002/biof.2057","DOIUrl":"10.1002/biof.2057","url":null,"abstract":"<p>High-density lipoproteins (HDLs) play a vital role in lipid metabolism and cardiovascular health, as they are intricately involved in cholesterol transport and inflammation modulation. The proteome of HDL particles is indeed complex and distinct from other components in the bloodstream. Proteomics studies have identified nearly 285 different proteins associated with HDL; however, this review focuses more on the 15 or so traditionally named “apo” lipoproteins. Important lipid metabolizing enzymes closely working with the apolipoproteins are also discussed. Apolipoproteins stand out for their integral role in HDL stability, structure, function, and metabolism. The unique structure and functions of each apolipoprotein influence important processes such as inflammation regulation and lipid metabolism. These interactions also shape the stability and performance of HDL particles. HDLs apolipoproteins have multifaceted roles beyond cardiovascular diseases (CVDs) and are involved in various physiological processes and disease states. Therefore, a detailed exploration of these apolipoproteins can offer valuable insights into potential diagnostic markers and therapeutic targets. This comprehensive review article aims to provide an in-depth understanding of HDL apolipoproteins, highlighting their distinct structures, functions, and contributions to various physiological processes. Exploiting this knowledge holds great potential for improving HDL function, enhancing cholesterol efflux, and modulating inflammatory processes, ultimately benefiting individuals by limiting the risks associated with CVDs and other inflammation-based pathologies. Understanding the nature of all 15 apolipoproteins expands our knowledge of HDL metabolism, sheds light on their pathological implications, and paves the way for advancements in the diagnosis, prevention, and treatment of lipid and inflammatory-related disorders.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"50 5","pages":"922-956"},"PeriodicalIF":5.0,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/biof.2057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140654637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BAG3 regulates cilia homeostasis of glioblastoma via its WW domain","authors":"Caterina Roth,&nbsp;Lara Paulini,&nbsp;Marina E. Hoffmann,&nbsp;Thorsten Mosler,&nbsp;Ivan Dikic,&nbsp;Andreas Brunschweiger,&nbsp;Hagen Körschgen,&nbsp;Christian Behl,&nbsp;Benedikt Linder,&nbsp;Donat Kögel","doi":"10.1002/biof.2060","DOIUrl":"10.1002/biof.2060","url":null,"abstract":"<p>The multidomain protein BAG3 exerts pleiotropic oncogenic functions in many tumor entities including glioblastoma (GBM). Here, we compared BAG3 protein–protein interactions in either adherently cultured or stem-like cultured U251 GBM cells. In line with BAG3's putative role in regulating stem-like properties, identified interactors in sphere-cultured cells included different stem cell markers (SOX2, OLIG2, and NES), while interactomes of adherent BAG3-proficient cells indicated a shift toward involvement of BAG3 in regulation of cilium assembly (ACTR3 and ARL3). Applying a set of BAG3 deletion constructs we could demonstrate that none of the domains except the WW domain are required for suppression of cilia formation by full-length BAG3 in U251 and U343 cells. In line with the established regulation of the Hippo pathway by this domain, we could show that the WW mutant fails to rescue YAP1 nuclear translocation. BAG3 depletion reduced activation of a YAP1/AURKA signaling pathway and induction of PLK1. Collectively, our findings point to a complex interaction network of BAG3 with several pathways regulating cilia homeostasis, involving processes related to ciliogenesis and cilium degradation.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"50 6","pages":"1113-1133"},"PeriodicalIF":5.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/biof.2060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140663663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel enzyme-resistant pancreatic polypeptide analogs evoke pancreatic beta-cell rest, enhance islet cell turnover, and inhibit food intake in mice","authors":"Wuyun Zhu,&nbsp;Neil Tanday,&nbsp;Ryan A. Lafferty,&nbsp;Peter R. Flatt,&nbsp;Nigel Irwin","doi":"10.1002/biof.2059","DOIUrl":"10.1002/biof.2059","url":null,"abstract":"<p>Pancreatic polypeptide (PP) is a postprandial hormone secreted from pancreatic islets that activates neuropeptide Y4 receptors (NPY4Rs). PP is known to induce satiety but effects at the level of the endocrine pancreas are less well characterized. In addition, rapid metabolism of PP by dipeptidyl peptidase-4 (DPP-4) limits the investigation of the effects of the native peptide. Therefore, in the present study, five novel amino acid substituted and/or fatty acid derivatized PP analogs were synthesized, namely [P³]PP, [K¹³Pal]PP, [P³,K¹³Pal]PP, [N-Pal]PP, and [N-Pal,P³]PP, and their impact on pancreatic beta-cell function, as well as appetite regulation and glucose homeostasis investigated. All PP analogs displayed increased resistance to DPP-4 degradation. In addition, all peptides inhibited alanine-induced insulin secretion from BRIN-BD11 beta cells. Native PP and related analogs (10⁻⁸ and 10⁻⁶ M), and especially [P³]PP and [K¹³Pal]PP, significantly protected against cytokine-induced beta-cell apoptosis and promoted cellular proliferation, with effects dependent on the NPY4R for all peptides barring [N-Pal,P³]PP. In mice, all peptides, except [N-Pal]PP and [N-Pal,P³]PP, evoked a dose-dependent (25, 75, and 200 nmol/kg) suppression of appetite, with native PP and [P³]PP further augmenting glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) induced reductions of food intake. The PP peptides had no obvious detrimental effect on glucose tolerance and they did not noticeably impair the glucose-regulatory actions of GLP-1 or CCK. In conclusion, Pro³ amino acid substitution of PP, either alone or together with mid-chain acylation, creates PP analogs with benefits on beta-cell rest, islet cell turnover, and energy regulation that may be applicable to the treatment of diabetes and obesity.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"50 6","pages":"1101-1112"},"PeriodicalIF":5.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/biof.2059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140626148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}