PMID- 34715512
OWN - NLM
STAT- MEDLINE
DCOM- 20211122
LR  - 20211204
IS  - 1618-095X (Electronic)
IS  - 0944-7113 (Linking)
VI  - 93
DP  - 2021 Dec
TI  - Evaluation of therapeutic effect of Premna herbacea in diabetic rat and 
      isoverbascoside against insulin resistance in L6 muscle cells through 
      bioenergetics and stimulation of JNK and AKT/mTOR signaling cascade.
PG  - 153761
LID - S0944-7113(21)00304-4 [pii]
LID - 10.1016/j.phymed.2021.153761 [doi]
AB  - BACKGROUND: Premna herbacea Roxb., a perennial herb is well documented for its 
      therapeutic uses among the traditional health care-givers of Assam, India. 
      Scientific validation on the traditional use of the medicinal plant using modern 
      technology may promote further research in health care. PURPOSE: This study 
      evaluates the therapeutic potential of methanolic extract of P. herbacea (MEPH) 
      against type 2 diabetes mellitus (T2DM) and its phytochemical(s) in ameliorating 
      insulin resistance (IR), thereby endorsing the plant bioactives as effective 
      anti-hyperglycemic agents. METHODS: The anti-diabetic potential of the plant 
      extract was explored both in L6 muscle cells and high fructose high fat diet 
      (HF-HFD) fed male Sprague Dawley (SD) rats. Bioactivity guided fractionation and 
      isolation procedure yielded Verbascoside and Isoverbascoside (ISOVER) as 
      bioactive and major phytochemicals in P. herbacea. The bioenergetics profile of 
      bioactive ISOVER and its anti-hyperglycemic potential was validated in vitro by 
      XFe24 analyzer, glucose uptake assay and intracellular ROS generation by 
      flourometer, FACS and confocal microscopy. The potential of ISOVER was also 
      checked by screening various protein markers via immunoblotting. RESULTS: MEPH 
      enhanced glucose uptake in FFA-induced insulin resistant (IR) L6 muscle cells and 
      decreased elevated blood glucose levels in HF-HFD fed rats. Isoverbascoside 
      (ISOVER) was identified as most bioactive phytochemical for the first time from 
      the plant in the Premna genus. ISOVER activated the protein kinase 
      B/AMP-activated protein kinase signaling cascades and enhanced glucose uptake in 
      IR-L6 muscle cells. ISOVER decreased the phosphorylation of p38 mitogen-activated 
      protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) and increased that of 
      mammalian target of rapamycin (mTOR), thereby attenuating IR. However, molecular 
      docking revealed that ISOVER increases insulin sensitivity by targeting the JNK1 
      kinase as a competitive inhibitor rather than mTOR. These findings were further 
      supported by the bioenergetics profile of ISOVER. CONCLUSION: This study for the 
      first time depicts the functional properties of ISOVER, derived from Premna 
      herbacea, in ameliorating IR. The phytochemical significantly altered IR with 
      enhanced glucose uptake and inhibition of ROS through JNK-AKT/mTOR signaling 
      which may pave the way for further research in T2DM therapeutics.
CI  - Copyright (c) 2021 Elsevier GmbH. All rights reserved.
FAU - Kashyap, Bhaswati
AU  - Kashyap B
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India; Department of Molecular Biology and 
      Biotechnology, Cotton University, Panbazar, Guwahati-781001, Assam, India.
FAU - Barge, Sagar Ramrao
AU  - Barge SR
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India; Department of Molecular Biology and 
      Biotechnology, Cotton University, Panbazar, Guwahati-781001, Assam, India.
FAU - Bharadwaj, Simanta
AU  - Bharadwaj S
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India; Department of Molecular Biology and 
      Biotechnology, Cotton University, Panbazar, Guwahati-781001, Assam, India.
FAU - Deka, Barsha
AU  - Deka B
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India; Department of Molecular Biology and 
      Biotechnology, Cotton University, Panbazar, Guwahati-781001, Assam, India.
FAU - Rahman, Seydur
AU  - Rahman S
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India; Assam down town University, Sankar 
      Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India.
FAU - Ghosh, Aparajita
AU  - Ghosh A
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India.
FAU - Manna, Prasenjit
AU  - Manna P
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India; CSIR-North East Institute of Science and 
      Technology, Biological Science and Technology Division, Jorhat, Assam, 785006, 
      India.
FAU - Dutta, Partha Pratim
AU  - Dutta PP
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India; Assam down town University, Sankar 
      Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India.
FAU - Sheikh, Yunus
AU  - Sheikh Y
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India.
FAU - Kandimalla, Raghuram
AU  - Kandimalla R
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India.
FAU - Samanta, Suman Kumar
AU  - Samanta SK
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India.
FAU - Boruwa, Joshodeep
AU  - Boruwa J
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India.
FAU - Saikia, Shilpi
AU  - Saikia S
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India.
FAU - Swargiary, Deepsikha
AU  - Swargiary D
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India.
FAU - Kamboj, Parul
AU  - Kamboj P
AD  - Drug Discovery Research Centre, Translational Health Science and Technology 
      Institute (THSTI), Faridabad - 121001, Haryana, India.
FAU - Tuli, Deepika
AU  - Tuli D
AD  - Drug Discovery Research Centre, Translational Health Science and Technology 
      Institute (THSTI), Faridabad - 121001, Haryana, India.
FAU - Pal, Uttam
AU  - Pal U
AD  - S.N. Bose National Centre for Basic Sciences, JD Block, Sector III, Salt Lake 
      City, Kolkata 700106, West Bengal, India.
FAU - Borah, Jagat C
AU  - Borah JC
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India. Electronic address: borahjc@gmail.com.
FAU - Banerjee, Sanjay Kumar
AU  - Banerjee SK
AD  - Drug Discovery Research Centre, Translational Health Science and Technology 
      Institute (THSTI), Faridabad - 121001, Haryana, India. Electronic address: 
      skbanerjee@thsti.res.in.
FAU - Talukdar, Narayan Chandra
AU  - Talukdar NC
AD  - Biochemistry and Drug Discovery Lab - I, Life Science Division, Institute of 
      Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, 
      Garchuk- 781035, Guwahati, Assam, India; Assam down town University, Sankar 
      Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India.. Electronic 
      address: nctalukdar@yahoo.com.
LA  - eng
PT  - Journal Article
DEP - 20210922
PL  - Germany
TA  - Phytomedicine
JT  - Phytomedicine : international journal of phytotherapy and phytopharmacology
JID - 9438794
RN  - 0 (Glucosides)
RN  - 0 (Insulin)
RN  - 0 (Phenols)
RN  - 588LJK42AP (isoacteoside)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - *Diabetes Mellitus, Type 2/drug therapy
MH  - Energy Metabolism
MH  - Glucose
MH  - Glucosides
MH  - Insulin/metabolism
MH  - *Insulin Resistance
MH  - Male
MH  - Molecular Docking Simulation
MH  - Muscle Cells/metabolism
MH  - Phenols
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - TOR Serine-Threonine Kinases/metabolism
OTO - NOTNLM
OT  - Blood glucose
OT  - Insulin resistance
OT  - Isoverbascoside, Premna herbacea
OT  - ROS
OT  - T2DM
EDAT- 2021/10/30 06:00
MHDA- 2021/11/23 06:00
CRDT- 2021/10/29 20:24
PHST- 2021/03/28 00:00 [received]
PHST- 2021/09/06 00:00 [revised]
PHST- 2021/09/13 00:00 [accepted]
PHST- 2021/10/30 06:00 [pubmed]
PHST- 2021/11/23 06:00 [medline]
PHST- 2021/10/29 20:24 [entrez]
AID - S0944-7113(21)00304-4 [pii]
AID - 10.1016/j.phymed.2021.153761 [doi]
PST - ppublish
SO  - Phytomedicine. 2021 Dec;93:153761. doi: 10.1016/j.phymed.2021.153761. Epub 2021 
      Sep 22.