PMID- 33472276
OWN - NLM
STAT- MEDLINE
DCOM- 20210708
LR  - 20210708
IS  - 1099-0844 (Electronic)
IS  - 0263-6484 (Linking)
VI  - 39
IP  - 4
DP  - 2021 Jun
TI  - The diterpene Manool extracted from Salvia tingitana lowers free radical 
      production in retinal rod outer segments by inhibiting the extramitochondrial 
      F(1) F(o) ATP synthase.
PG  - 528-535
LID - 10.1002/cbf.3618 [doi]
AB  - Uncontrolled oxidative stress production, especially in the outer retina is one 
      of the causes of retinal degenerations. Mitochondria are considered the principal 
      source of oxidative stress. However, a Reactive Oxygen Intermediates (ROI) 
      production in the retinal photoreceptor layer seems to depend also on the 
      expression of an extramitochondrial oxidative phosphorylation (OxPhos) machinery 
      in the rod outer segments (OS). In fact, OS conduct aerobic metabolism, producing 
      ATP through oxygen consumption, although it is devoid of mitochondria. As 
      diterpenes display an antioxidant effect, we have evaluated the effect Manool, 
      extracted from Salvia tingitana, on the extramitochondrial OxPhos and the ROI 
      production in the retinal rod OS. Results confirm that the OxPhos machinery is 
      ectopically expressed in the OS and that F(1) F(o) -ATP synthase is a target of 
      Manool, which inhibited the OS ATP synthesis, binding the F(1) moiety with high 
      affinity, as analysed by molecular docking. Moreover, the overall slowdown of 
      OxPhos metabolism reduced the ROI production elicited in the OS by light 
      exposure, in vitro. In conclusion, data are consistent with the antioxidant 
      properties of Salvia spp., suggesting its ability to lower oxidative stress 
      production, a primary risk factor for degenerative retinal diseases. SIGNIFICANCE 
      OF THE STUDY: Here we show that Manool, a diterpene extracted from Salvia 
      tingitana has the potential to lower the free radical production by light-exposed 
      rod outer segments in vitro, by specifically targeting the rod OS F(1) F(o) -ATP 
      synthase belonging to the extramitochondrial OxPhos expressed on the disk 
      membrane. The chosen experimental model allowed to show that the rod OS is a 
      primary producer of oxidative stress linked to the pathogenesis of degenerative 
      retinal diseases. Data are also consistent with the antioxidant and 
      anti-inflammatory action of Salvia spp., suggesting a beneficial effect also in 
      vivo.
CI  - (c) 2021 John Wiley & Sons Ltd.
FAU - Ravera, Silvia
AU  - Ravera S
AD  - Dipartimento di Medicina Sperimentale, Universita di Genova, Genova, Italy.
FAU - Esposito, Alfonso
AU  - Esposito A
AD  - Centro di Biologia Integrata (CIBIO), Universita di Trento, Trento, Italy.
FAU - Degan, Paolo
AU  - Degan P
AD  - UOC Mutagenesi, IRCCS Policlinico San Martino -IST (Istituto Nazionale per la 
      Ricerca sul Cancro), Genova, Italy.
FAU - Caicci, Federico
AU  - Caicci F
AD  - Dipartimento di Biologia, Universita di Padova, Padova, Italy.
FAU - Manni, Lucia
AU  - Manni L
AD  - Dipartimento di Biologia, Universita di Padova, Padova, Italy.
FAU - Liguori, Anna
AU  - Liguori A
AD  - Dipartimento di Farmacia (DIFAR), Universita di Genova, Genova, Italy.
FAU - Bisio, Angela
AU  - Bisio A
AD  - Dipartimento di Farmacia (DIFAR), Universita di Genova, Genova, Italy.
FAU - Iobbi, Valeria
AU  - Iobbi V
AD  - Dipartimento di Farmacia (DIFAR), Universita di Genova, Genova, Italy.
FAU - Schito, Anna
AU  - Schito A
AD  - Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate (DISC), Sezione di 
      Microbiologia, Universita di Genova, Genova, Italy.
FAU - Traverso, Carlo Enrico
AU  - Traverso CE
AD  - Clinica Oculistica, (DINOGMI) Universita di Genova, Genova, Italy.
FAU - Panfoli, Isabella
AU  - Panfoli I
AUID- ORCID: 0000-0002-6261-1128
AD  - Dipartimento di Farmacia (DIFAR), Universita di Genova, Genova, Italy.
LA  - eng
GR  - Project N.11039 "ANTEA"/INTERREG ALCOTRA/
PT  - Journal Article
DEP - 20210120
PL  - England
TA  - Cell Biochem Funct
JT  - Cell biochemistry and function
JID - 8305874
RN  - 0 (Antioxidants)
RN  - 0 (Diterpenes)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Free Radicals)
RN  - AT5PJ0PV00 (manool)
RN  - EC 3.6.3.14 (Proton-Translocating ATPases)
SB  - IM
MH  - Animals
MH  - Antioxidants/chemistry/isolation & purification/*pharmacology
MH  - Cattle
MH  - Diterpenes/chemistry/isolation & purification/*pharmacology
MH  - Enzyme Inhibitors/chemistry/isolation & purification/*pharmacology
MH  - Free Radicals/antagonists & inhibitors/metabolism
MH  - Models, Molecular
MH  - Oxidative Stress/drug effects
MH  - Proton-Translocating ATPases/*antagonists & inhibitors/genetics/metabolism
MH  - Retinal Photoreceptor Cell Outer Segment/*drug effects/metabolism
MH  - Salvia/*chemistry
OTO - NOTNLM
OT  - ATP synthase
OT  - Manool
OT  - Salvia tingitana
OT  - oxidative phosphorylation
OT  - rod outer segments
EDAT- 2021/01/21 06:00
MHDA- 2021/07/09 06:00
CRDT- 2021/01/20 20:08
PHST- 2020/11/17 00:00 [revised]
PHST- 2020/08/24 00:00 [received]
PHST- 2020/12/28 00:00 [accepted]
PHST- 2021/01/21 06:00 [pubmed]
PHST- 2021/07/09 06:00 [medline]
PHST- 2021/01/20 20:08 [entrez]
AID - 10.1002/cbf.3618 [doi]
PST - ppublish
SO  - Cell Biochem Funct. 2021 Jun;39(4):528-535. doi: 10.1002/cbf.3618. Epub 2021 Jan 
      20.