Crocetin promotes clearance of amyloid-β by inducing autophagy via the STK11/LKB1-mediated AMPK pathway

Wani, Abubakar; Rihani, Sweilem B. Al; Sharma, Ankita; Weadick, Brenna; Govindarajan, Rajgopal; Khan, Sameer Ullah; Sharma, Parduman R.; Dogra, Ashish; Nandi, Utpal; Reddy, Chilakala N; Bharate, Sonali S.; Singh, Gurdarshan; Bharate, Sandip B.; Vishwakarma, Ram A.; Kaddoumi, Amal; Kumar, Ajay

doi:10.1080/15548627.2021.1872187

Cited by 108 publications

(60 citation statements)

References 64 publications

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“…All six compounds were detected at a first-time point (i.e., 10 min). The TCT reached C max at 6.83 ± 1.68 h in the plasma, which is higher than the previously reported maximum plasma concentration (C max ), i.e., 66.3 ± 9.2 min in rat plasma [42]. The five CS analytes T4C, T3C, C4C, T2C, and TCT, achieved C max at between 3 and 7 h, i.e., time to reach the maximum plasma concentration (T max ) except PIC, which attained C max at 0.67 h in the plasma.…”

Section: Pharmacokinetic Resultscontrasting

confidence: 75%

“…This KCS extract has upregulated synaptic proteins and reduced neuroinflammation associated with Aβ pathology in 5XFAD (AD model) mice brains. The treatment of active metabolite crocetin resulted in improved memory function by inducing autophagy mediated by AMPK pathway activation in mice in a separate study, which states the study requirement for in vivo therapeutics data [3,4,42].…”

Section: Introductionmentioning

confidence: 95%

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Bioanalytical Method Development and Validation Study of Neuroprotective Extract of Kashmiri Saffron Using Ultra-Fast Liquid Chromatography-Tandem Mass Spectrometry (UFLC-MS/MS): In Vivo Pharmacokinetics of Apocarotenoids and Carotenoids

et al. 2021

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Kashmir saffron (Crocus sativus L.), also known as Indian saffron, is an important Asian medicinal plant with protective therapeutic applications in brain health. The main bioactive in Kashmir or Indian Saffron (KCS) and its extract (CSE) are apocarotenoids picrocrocin (PIC) and safranal (SAF) with carotenoids, crocetin esters (crocins), and crocetins. The ultra-fast liquid chromatography(UFLC)- photodiode array standardization confirmed the presence of biomarkers PIC, trans-4-GG-crocin (T4C), trans-3-Gg-crocin (T3C), cis-4-GG-crocin (C4C), trans-2-gg-crocin (T2C), trans-crocetin (TCT), and SAF in CSE. This study’s objectives were to develop and validate a sensitive and rapid UFLC-tandem mass spectrometry method for PIC and SAF along T4C and TCT in rat plasma with internal standards (IS). The calibration curves were linear (R2 > 0.990), with the lower limit of quantification (LLOQ) as 10 ng/mL. The UFLC-MS/MS assay-based precision (RSD, <15%) and accuracy (RE, −11.03–9.96) on analytical quality control (QC) levels were well within the acceptance criteria with excellent recoveries (91.18–106.86%) in plasma samples. The method was applied to investigate the in vivo pharmacokinetic parameters after oral administration of 40 mg/kg CSE in the rats (n = 6). The active metabolite TCT and T4C, PIC, SAF were quantified for the first time with T3C, C4C, T2C by this validated bioanalytical method, which will be useful for preclinical/clinical trials of CSE as a potential neuroprotective dietary supplement.

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Section: Pharmacokinetic Resultscontrasting

confidence: 75%

Section: Introductionmentioning

confidence: 95%

Bioanalytical Method Development and Validation Study of Neuroprotective Extract of Kashmiri Saffron Using Ultra-Fast Liquid Chromatography-Tandem Mass Spectrometry (UFLC-MS/MS): In Vivo Pharmacokinetics of Apocarotenoids and Carotenoids

et al. 2021

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“…Autophagy is an evolutionary conserved mechanism by which cells recycle nutrients to maintain viability [ 17 – 22 ]. Proteins that cannot be renatured by chaperones are degraded via autophagy (along with the associated chaperone protein).…”

Section: Introductionmentioning

confidence: 99%

“…Hence ER stress signaling to restore homeostasis acts to both renature proteins and simultaneously to facilitate the break down excess protein load via autophagy. In AD the clearance of amyloid-β plaques can be mediated via autophagy, which correlates with improved in vivo mouse memory function [ 22 , 24 ]. Similar in vitro and in vivo findings to amyloid-β have been made for ALS aggregates and mutant Huntingtin aggregates [ 21 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43

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Booth

Roberts

et al. 2021

Aging

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Aberrant expression and denaturation of Tau, amyloid-beta and TDP-43 can lead to cell death and is a major component of pathologies such as Alzheimer’s Disease (AD). AD neurons exhibit a reduced ability to form autophagosomes and degrade proteins via autophagy. Using genetically manipulated colon cancer cells we determined whether drugs that directly inhibit the chaperone ATPase activity or cause chaperone degradation and endoplasmic reticulum stress signaling leading to macroautophagy could reduce the levels of these proteins. The antiviral chaperone ATPase inhibitor AR12 reduced the ATPase activities and total expression of GRP78, HSP90, and HSP70, and of Tau, Tau 301L, APP, APP692, APP715, SOD1 G93A and TDP-43. In parallel, it increased the phosphorylation of ATG13 S318 and eIF2A S51 and caused eIF2A-dependent autophagosome formation and autophagic flux. Knock down of Beclin1 or ATG5 prevented chaperone, APP and Tau degradation. Neratinib, used to treat HER2+ breast cancer, reduced chaperone levels and expression of Tau and APP via macroautophagy, and neratinib interacted with AR12 to cause further reductions in protein levels. The autophagy-regulatory protein ATG16L1 is expressed as two isoforms, T300 or A300: Africans trend to express T300 and Europeans A300. We observed higher basal expression of Tau in T300 cells when compared to isogenic A300 cells. ATG16L1 isoform expression did not alter basal levels of HSP90, HSP70 or HSP27, however, basal levels of GRP78 were reduced in A300 cells. The abilities of both AR12 and neratinib to stimulate ATG13 S318 and eIF2A S51 phosphorylation and autophagic flux was also reduced in A300 cells. Our data support further evaluation of AR12 and neratinib in neuronal cells as repurposed treatments for AD.

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“…There are several neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) where NLRP3 mediated chronic inflammation plays a crucial role in the pathological progression (Tan et al, 2013;Cho et al, 2014). Downregulation of autophagy has also been implicated in both AD and PD pathology, where it leads to reduced clearance of amyloid beta and alpha synuclein (Wani et al, 2019;Holbrook et al, 2021;Wani et al, 2021). Therefore, compounds like IIIM-941, which have the potential to target both inflammation and autophagy can raise new hope for the treatment of these diseases.…”

Section: Discussionmentioning

confidence: 99%

IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy

et al. 2021

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Aberrant activation of NLRP3 inflammasome has been implicated in several inflammatory diseases. Autophagy is one of the primary mechanisms that regulate NLRP3 inflammasome activity. In this study, we attempted to target NLRP3 inflammasome activity by a synthetic compound IIIM-941. We found that IIIM-941 inhibits ATP induced NLRP3 inflammasome by induction of autophagy through AMPK pathway in bone marrow derived macrophages (BMDMs) and J774A.1 cells. It was interesting to observe that IIIM-941 did not show any inhibitory activity against LPS induced pro-inflammatory cytokines TNF-α and IL-6. The anti-NLRP3 activity of IIIM-941 was significantly reversed when we attempted to block autophagy by using either pharmacological inhibitor bafilomycin A1or by using siRNA against AMPK. Further, we found that IIIM-941 downregulated the expression of NLRP3 and prevented the oligomerization of ASC to exert its anti-NLRP3 inflammasome effect in J774A.1 cells. We validated inhibitory activity of IIIM-941 against NLRP3 in three different mice models. The anti-inflammatory effect of IIIM-941 was highly significant in ATP induced peritoneal inflammation model. IIIM-941 was similarly effective in suppressing MSU induced IL-1β in the air pouch model of inflammation without affecting the levels of TNF-α and IL-6. Finally, oral efficacy of IIIM-941 was also proved in MSU indued foot paw edema model of inflammation in mice at 10 and 20 mg/kg (b.w.). The compounds like IIIM-941 can be explored further for the development of therapies against diseases such as Alzheimer’s disease and Parkinson’s disease, where hampered autophagy and NLRP3 activation play a crucial role in the pathological development.

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Crocetin promotes clearance of amyloid-β by inducing autophagy via the STK11/LKB1-mediated AMPK pathway

Cited by 108 publications

References 64 publications

Bioanalytical Method Development and Validation Study of Neuroprotective Extract of Kashmiri Saffron Using Ultra-Fast Liquid Chromatography-Tandem Mass Spectrometry (UFLC-MS/MS): In Vivo Pharmacokinetics of Apocarotenoids and Carotenoids

Bioanalytical Method Development and Validation Study of Neuroprotective Extract of Kashmiri Saffron Using Ultra-Fast Liquid Chromatography-Tandem Mass Spectrometry (UFLC-MS/MS): In Vivo Pharmacokinetics of Apocarotenoids and Carotenoids

Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43

IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy

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