PMID- 38117448
OWN - NLM
STAT- MEDLINE
DCOM- 20240229
LR  - 20240302
IS  - 1573-6903 (Electronic)
IS  - 0364-3190 (Print)
IS  - 0364-3190 (Linking)
VI  - 49
IP  - 4
DP  - 2024 Apr
TI  - Neuroprotective and Anti-inflammatory Effects of Rubiscolin-6 Analogs with 
      Proline Surrogates in Position 2.
PG  - 895-918
LID - 10.1007/s11064-023-04070-z [doi]
AB  - Naturally occurring peptides, such as rubiscolins derived from spinach leaves, 
      have been shown to possess some interesting activities. They exerted central 
      effects, such as antinociception, memory consolidation and anxiolytic-like 
      activity. The fact that rubiscolins are potent even when given orally makes them 
      very promising drug candidates. The present work tested whether rubiscolin-6 
      (R-6, Tyr-Pro-Leu-Asp-Leu-Phe) analogs have neuroprotective and anti-inflammatory 
      effects. These hypotheses were tested in the 6-hydroxydopamine (6-OHDA) injury 
      model of human neuroblastoma SH-SY5Y and lipopolysaccharide (LPS)-stimulated RAW 
      264.7 macrophages. The determination of reactive oxygen species (ROS), 
      mitochondrial membrane potential (MMP), Caspase-3 activity, lipid peroxidation 
      and nitric oxide (NO) production allowed us to determine the effects of peptides 
      on hallmarks related to Parkinson's Disease (PD) and inflammation. Additionally, 
      we investigated the impact of R-6 analogs on serine-threonine kinase (also known 
      as protein kinase B, AKT) and mammalian target of rapamycin (mTOR) activation. 
      The treatment with analogs 3 (Tyr-Inp-Leu-Asp-Leu-Phe-OH), 5 
      (Dmt-Inp-Leu-Asp-Leu-Phe-OH) and 7 (Tyr-Inp-Leu-Asp-Leu-Phe-NH(2)) most 
      effectively prevented neuronal death via attenuation of ROS, mitochondrial 
      dysfunction and Caspase-3 activity. Peptides 5 and 7 significantly increased the 
      protein expression of the phosphorylated-AKT (p-AKT) and phosphorylated-mTOR 
      (p-mTOR). Additionally, selected analogs could also ameliorate LPS-mediated 
      inflammation in macrophages via inhibition of intracellular generation of ROS and 
      NO production. Our findings suggest that R-6 analogs exert protective effects, 
      possibly related to an anti-oxidation mechanism in in vitro model of PD. The data 
      shows that the most potent peptides can inhibit 6-OHDA injury by activating the 
      PI3-K/AKT/mTOR pathway, thus playing a neuroprotective role and may provide a 
      rational and robust approach in the design of new therapeutics or even functional 
      foods.
CI  - (c) 2023. The Author(s).
FAU - Perlikowska, Renata
AU  - Perlikowska R
AD  - Department of Biomolecular Chemistry, Faculty of Medicine, Medical University, 
      Mazowiecka 6/8, 92-215, Lodz, Poland. renata.perlikowska@umed.lodz.pl.
FAU - Silva, Joana
AU  - Silva J
AD  - MARE-Marine and Environmental Sciences Centre, ARNET - Aquatic Research Network, 
      Politecnico de Leiria, 2520-630, Peniche, Portugal.
FAU - Alves, Celso
AU  - Alves C
AD  - MARE-Marine and Environmental Sciences Centre, ARNET - Aquatic Research Network, 
      ESTM, Politecnico de Leiria, 2520-614, Peniche, Portugal.
FAU - Susano, Patricia
AU  - Susano P
AD  - MARE-Marine and Environmental Sciences Centre, ARNET - Aquatic Research Network, 
      Politecnico de Leiria, 2520-630, Peniche, Portugal.
FAU - Zaklos-Szyda, Malgorzata
AU  - Zaklos-Szyda M
AD  - Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and 
      Food Sciences, Lodz University of Technology, Stefanowskiego 2/22, 90-537, Lodz, 
      Poland.
FAU - Skibska, Agnieszka
AU  - Skibska A
AD  - Department of Biomolecular Chemistry, Faculty of Medicine, Medical University, 
      Mazowiecka 6/8, 92-215, Lodz, Poland.
FAU - Adamska-Bartlomiejczyk, Anna
AU  - Adamska-Bartlomiejczyk A
AD  - Department of Biomolecular Chemistry, Faculty of Medicine, Medical University, 
      Mazowiecka 6/8, 92-215, Lodz, Poland.
FAU - Wtorek, Karol
AU  - Wtorek K
AD  - Department of Biomolecular Chemistry, Faculty of Medicine, Medical University, 
      Mazowiecka 6/8, 92-215, Lodz, Poland.
FAU - do Rego, Jean-Claude
AU  - do Rego JC
AD  - Platform of Behavioural Analysis (SCAC), Inserm US51 - CNRS UAR2026 HeRaCLes, 
      Institute For Research and Innovation in Biomedicine (IRIB), University of Rouen 
      Normandy, Rouen, France.
FAU - do Rego, Jean-Luc
AU  - do Rego JL
AD  - Platform of Behavioural Analysis (SCAC), Inserm US51 - CNRS UAR2026 HeRaCLes, 
      Institute For Research and Innovation in Biomedicine (IRIB), University of Rouen 
      Normandy, Rouen, France.
FAU - Kluczyk, Alicja
AU  - Kluczyk A
AD  - Faculty of Chemistry, University of Wroclaw, 50-383, Wroclaw, Poland.
FAU - Pedrosa, Rui
AU  - Pedrosa R
AD  - MARE-Marine and Environmental Sciences Centre, ARNET - Aquatic Research Network, 
      ESTM, Politecnico de Leiria, 2520-614, Peniche, Portugal.
LA  - eng
GR  - No DEC-2021/05/X/ST5/00294/the National Science Center/
GR  - BPN/BPT/2021/1/00053/Polish National Agency for Academic Exchange/
GR  - FCT/DRI/PNAAE 2021.09608.CBM/Programme for Cooperation in Science between 
      Portugal and Poland through project NEURONS/
GR  - UIDP/04292/2020 and UIDB/04292/2020/The Portuguese Foundation for Science and 
      Technology (FCT)/
GR  - LA/P/0069/2020/Associate Laboratory ARNET/
GR  - PTDC/BIA-OUT/29250/2017/CROSS-ATLANTIC/
PT  - Journal Article
DEP - 20231220
PL  - United States
TA  - Neurochem Res
JT  - Neurochemical research
JID - 7613461
RN  - 0 (rubiscolin 6)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - 0 (Reactive Oxygen Species)
RN  - 8HW4YBZ748 (Oxidopamine)
RN  - EC 3.4.22.- (Caspase 3)
RN  - 0 (Lipopolysaccharides)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (Peptides)
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Peptide Fragments)
RN  - EC 4.1.1.39 (Ribulose-Bisphosphate Carboxylase)
SB  - IM
MH  - Humans
MH  - Apoptosis
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Oxidopamine/toxicity
MH  - Caspase 3/metabolism
MH  - Lipopolysaccharides/pharmacology
MH  - Cell Line, Tumor
MH  - *Neuroblastoma/metabolism
MH  - *Parkinson Disease/drug therapy
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Peptides/therapeutic use
MH  - Anti-Inflammatory Agents/pharmacology/therapeutic use
MH  - Inflammation/drug therapy
MH  - *Neuroprotective Agents/pharmacology/therapeutic use
MH  - *Peptide Fragments
MH  - *Ribulose-Bisphosphate Carboxylase
PMC - PMC10901950
OTO - NOTNLM
OT  - 6-hydroxydopamine
OT  - Antioxidant activity
OT  - Apoptosis
OT  - Inflammation
OT  - Natural compounds
OT  - Neuroprotection
OT  - Oxidative stress
OT  - Peptides
COIS- The authors declare that there are no conflicts of interest.
EDAT- 2023/12/20 12:42
MHDA- 2024/02/29 06:42
PMCR- 2023/12/20
CRDT- 2023/12/20 11:13
PHST- 2023/06/06 00:00 [received]
PHST- 2023/11/16 00:00 [accepted]
PHST- 2023/09/27 00:00 [revised]
PHST- 2024/02/29 06:42 [medline]
PHST- 2023/12/20 12:42 [pubmed]
PHST- 2023/12/20 11:13 [entrez]
PHST- 2023/12/20 00:00 [pmc-release]
AID - 10.1007/s11064-023-04070-z [pii]
AID - 4070 [pii]
AID - 10.1007/s11064-023-04070-z [doi]
PST - ppublish
SO  - Neurochem Res. 2024 Apr;49(4):895-918. doi: 10.1007/s11064-023-04070-z. Epub 2023 
      Dec 20.