PMID- 37866705
OWN - NLM
STAT- MEDLINE
DCOM- 20231121
LR  - 20231121
IS  - 1096-1186 (Electronic)
IS  - 1043-6618 (Linking)
VI  - 197
DP  - 2023 Nov
TI  - Penicopeptide A (PPA) from the deep-sea-derived fungus promotes 
      osteoblast-mediated bone formation and alleviates ovariectomy-induced bone loss 
      by activating the AKT/GSK-3beta/beta-catenin signaling pathway.
PG  - 106968
LID - S1043-6618(23)00324-9 [pii]
LID - 10.1016/j.phrs.2023.106968 [doi]
AB  - The potential of marine natural products as effective drugs for osteoporosis 
      treatment is an understudied area. In this study, we investigated the ability of 
      lead compounds from deep-sea-derived Penicillium solitum MCCC 3A00215 to promote 
      bone formation in vitro and in vivo. We found that penicopeptide A (PPA) promoted 
      osteoblast mineralization among bone marrow mesenchymal stem cells (BMSCs) in a 
      concentration-dependent manner, and thus, we selected this natural peptide for 
      further testing. Our further experiments showed that PPA significantly promoted 
      the osteogenic differentiation of BMSCs while inhibiting their adipogenic 
      differentiation and not affecting their chondrogenic differentiation. Mechanistic 
      studies showed that PPA binds directly to the AKT and GSK-3beta and activates 
      phosphorylation of AKT and GSK-3beta, resulting in the accumulation of beta-catenin. We 
      also evaluated the therapeutic potential of PPA in a female mouse model of 
      ovariectomy-induced systemic bone loss. In this model, PPA treatment prevented 
      decreases in bone volume and trabecular thickness. In conclusion, our in vitro 
      and in vivo results demonstrated that PPA could promote osteoblast-related bone 
      formation via the AKT, GSK-3beta, and beta-catenin signaling pathways, indicating the 
      clinical potential of PPA as a candidate compound for osteoporosis prevention.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Xie, Chun-Lan
AU  - Xie CL
AD  - Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of 
      Medicine, Xiamen University, Xiamen 361102, China; Key Laboratory of Marine 
      Genetic Resources, Third Institute of Oceanography, Ministry of Natural 
      Resources, Xiamen 361005, China.
FAU - Yue, Yu-Ting
AU  - Yue YT
AD  - Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of 
      Medicine, Xiamen University, Xiamen 361102, China; Department of Orthopedics 
      Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen 
      University, 361102, Xiamen,China.
FAU - Xu, Jing-Ping
AU  - Xu JP
AD  - Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of 
      Medicine, Xiamen University, Xiamen 361102, China.
FAU - Li, Na
AU  - Li N
AD  - Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of 
      Medicine, Xiamen University, Xiamen 361102, China.
FAU - Lin, Ting
AU  - Lin T
AD  - Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of 
      Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
FAU - Ji, Guang-Rong
AU  - Ji GR
AD  - Department of Orthopedics Surgery, Xiang'an Hospital of Xiamen University, School 
      of Medicine, Xiamen University, 361102, Xiamen,China. Electronic address: 
      jiguangrong@sina.cn.
FAU - Yang, Xian-Wen
AU  - Yang XW
AD  - Key Laboratory of Marine Genetic Resources, Third Institute of Oceanography, 
      Ministry of Natural Resources, Xiamen 361005, China. Electronic address: 
      yangxianwen@tio.org.cn.
FAU - Xu, Ren
AU  - Xu R
AD  - Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of 
      Medicine, Xiamen University, Xiamen 361102, China; The First Affiliated Hospital 
      of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cells, State 
      Key Laboratory of Cellular Stress Biology, Faculty of Medicine and Life Sciences, 
      Xiamen University, Xiamen 361102, China. Electronic address: xuren526@xmu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20231020
PL  - Netherlands
TA  - Pharmacol Res
JT  - Pharmacological research
JID - 8907422
RN  - 0 (beta Catenin)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Female
MH  - Animals
MH  - Mice
MH  - Humans
MH  - beta Catenin
MH  - Glycogen Synthase Kinase 3 beta
MH  - Osteogenesis
MH  - Proto-Oncogene Proteins c-akt
MH  - *Bone Diseases, Metabolic
MH  - Fungi
MH  - Osteoblasts
MH  - Ovariectomy/adverse effects
MH  - Signal Transduction
MH  - *Osteoporosis/drug therapy/etiology
OTO - NOTNLM
OT  - (R)-Mevalonolactone (PubChem CID:6419891)
OT  - (-)-Cyclopenol (PubChem CID: 16681741)
OT  - (-)-Solitumidines D (PubChem CID: 155552764)
OT  - 3'-diol orsellinate (PubChem CID: 71501072)
OT  - AKT/GSK-3beta/beta-catenin
OT  - Hydroxypropan-2'
OT  - Indole-3-acetic acid methyl ester (PubChem CID: 74706)
OT  - Marine natural product
OT  - Osteoblasts
OT  - Osteoporosis
OT  - Penicopeptide A
OT  - Solitumidine A (PubChem CID: 155529073)
OT  - Solitumine A (PubChem CID: 155537754)
OT  - Viridicatin (PubChem CID: 67206)
OT  - Viridicatol (PubChem CID: 115033)
OT  - mL-236A (PubChem CID: 173651)
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/10/23 00:43
MHDA- 2023/11/21 06:42
CRDT- 2023/10/22 19:33
PHST- 2023/07/11 00:00 [received]
PHST- 2023/10/19 00:00 [revised]
PHST- 2023/10/19 00:00 [accepted]
PHST- 2023/11/21 06:42 [medline]
PHST- 2023/10/23 00:43 [pubmed]
PHST- 2023/10/22 19:33 [entrez]
AID - S1043-6618(23)00324-9 [pii]
AID - 10.1016/j.phrs.2023.106968 [doi]
PST - ppublish
SO  - Pharmacol Res. 2023 Nov;197:106968. doi: 10.1016/j.phrs.2023.106968. Epub 2023 
      Oct 20.