Natural products targeting the UPR signaling to tilt it towards pro-survival

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During 2019 January I thought a TDP-43 therapy was really missing and the next month I wrote a plea to develop a TDP-43 therapy. I am not sure it had any effect, but I sent emails to nearly 250 scientists the next months. A flurry of patents have been written which indicates it is now an active research topic. Now we are at a phase where there are even clinical trials targeting TDP-43.

Reducing the TDP-43 misfolded mislocated aggregates may stop ALS progression and it could help as well in other neurodegenerative diseases.

Now I think that a part of the set of drugs needed to really recover (in addition to TDP-43 therapies) is something targeting faulty UPR (Unfolded Protein Response). Here is a list of natural products targeting the UPR signaling to tilt it towards pro-survival. Some, it will not surprise you, have been discussed since a long time on Internet forums. (source doi: 10.1007/s11010-021-04223-0)

Name of compound / Mode of action / References

  • Ginkgolide / K(GK) Reduce ER by accentuating the IRE1/XBP1 activity. / [136]

  • Elatoside C / Inhibit ER stress induced genes like GRP78, CHOP, caspase-12 and JNK, reduce apoptosis. / [137]

  • Sulforaphane (SFN) /Inhibit GRP78,CHOP and caspase-12 by activating the SIRT1 pathway.SIRT1 decrease ER induced apoptosis by deacetylating eIF2α / [138]

  • Resveratrol / Reduce ER stress mediated apoptosis by downregulating the expression of GRP78, GRP94 and CHOP and upregulating the expression of Bcl-2 and Bax. Lowers the expression of GRP78 and CHOP in doxorubicin treated H9c2 cell. / [139–141]

  • Baicalin / Target the CHOP/eNOS/NO pathway by inhibiting CHOP and thus reducing apoptosis / [142]

  • Berberine / Decrease apoptosis by decreasing the phosphorylation rate of PERK and eIF2α and downregulating the expression of ATF4 and CHOP / [143]

  • Anisodamine / Downregulate the expression GRP78, CHOP, and cleaved caspase 3 and thus reduce cell death / [144, 145]

  • Rare ginsenoside-standardized extract (RGSE) / Inhibit the overexpression of GRP78, GRP94 and CHOP as well as decrease the phosphorylation level of PERK and IRE1α / [146]

  • Panax quinquefolium saponin (PQS) Improve ventricular remodeling by downregulating the expression of GRP78, CHOP, and Bax protein as well as increasing the expression of Bcl-2 protein, thus reducing apoptosis. Also inhibits apoptosis by targeting the PERK-eIF2α- ATF4- CHOP pathway / [147–149]

  • Notoginsenoside R1 (NGR1) Protect cells from acute ER stress by delaying the onset of ER stress by decreasing the expression of GRP78, p-PERK, ATF6, IREα. Inhibit the expression of CHOP, caspase-12, and p-JNK. Scavenges free radicals, thereby increasing the activity of antioxdidases / [150]

  • Paeonol / Relieve ER stress by activating AMPK/PPARδ pathway which in turn results in down regulation GRP78, eIF2α as well as lower ROS overproduction / [151]

  • Tournefolic acid B / Accentuate the phosphorylation of P13K and AKT as well as it downregulates the expression CHOP, caspase-12 thus inhibiting apoptosis during ER stress via PI3K/AKT pathways / [152]

  • Crocetin / Impair the function of nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase-1 signaling. Loss of Nrf2 activity was in turn shown to attenuate the expression of ER stress associated proteins / [153, 154]

  • Salvianolic acid B / Exert its cardioprotective role by improving cellular survival and reducing ER stress mediated apoptosis / [155, 156]

  • Flavonoids of astragalus (TFA) / Restores the mRNA and protein level of ER chaperone calumenin, rescues the interaction between SERCA2 and calumenin thus restoring ER homeostasis / [157]

  • Curcumin and masoprocol / Rescue Protein disulfde isomerase (PDI). Reduces the ROS generated ER stress by increasing the expression of GRP98 and inhibiting the activation of caspase-12 / [158]

  • SP600125 / Ameliorate the expression of CHOP in cardiomyocytes, reduce apoptosis [159] Panax Notoginseng Saponins (PNS) Protects cardiomyocytes against ER stress mediated mitochondrial injury by augmenting the autophagic response / [160]

  • Inonotus obliquus (IO) / Protects heart against Myocardial I/R injury by activating SIRT1 which in turn inhibits ER stress induced apoptosis - [161]

  • Fuziline Imparts its cardioprotective role by attenuating isoproterenol induced ER stress by targeting the PERK/eIF2α/ATF4/CHOP signaling axis / [162]

  • Protocatechualdehyde Imparts its anti-apoptotic role during oxygen–glucose deprivation/reoxygenation (OGD/R) mediated myocardial ischemic injury via targeting the PERK/ATF6α/IRE1α signaling molecules / [163]

  • Beta carotene / Exhibits its cardioprotective role in advanced glycation end products (AGEs)-induced cardiomyocyte apoptosis during diabetic cardiomyopathy by decreasing hyperactive ER stress molecules CHOP, ATF4 and GRP78 / [164]

  • Qishen granule (QSG) / Imparts its cardioprotective role during myocardial ischemia by augmenting the inositol requiring enzyme 1 (IRE-1)-αBcrystallin (CRYAB) signaling pathway thereby decreasing cardiac apoptosis / [165]

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

[136]. Wang S, Wang Z, Fan Q, Guo J, Galli G, Du G, Wang X, Xiao W (2016) Ginkgolide K protects the heart against endoplasmic reticulum stress injury by activating the inositol-requiring enzyme 1α/X box-binding protein-1 pathway. Br J Pharmacol 173(15):2402–2418.

[137]. Wang M, Meng XB, Yu YL, Sun GB, Xu XD, Zhang XP, Dong X, Ye JX, Xu HB, Sun YF, Sun XB (2014) Elatoside C protects against hypoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes through the reduction of endoplasmic reticulum stress partially depending on STAT3 activation. Apoptosis 19(12):1727–1735.

[138]. Li YP, Wang SL, Liu B, Tang L, Kuang RR, Wang XB, Zhao C, Song XD, Cao XM, Wu X, Yang PZ, Wang LZ, Chen AH (2016) Sulforaphane prevents rat cardiomyocytes from hypoxia/reoxygenation injury in vitro via activating SIRT1 and subsequently inhibiting ER stress. Acta Pharmacol Sin 37(3):344–353. https://

[139]. Lin Y, Zhu J, Zhang X, Wang J, Xiao W, Li B, Jin L, Lian J, Zhou L, Liu J (2016) Inhibition of cardiomyocytes hypertrophy by resveratrol is associated with amelioration of endoplasmic reticulum stress. Cell Physiol Biochem 39(2):780–789. https://

[140]. Hubbard BP, Sinclair DA (2014) Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 35:146–154. 12.004

[141]. Lou Y, Wang Z, Xu Y, Zhou P, Cao J, Li Y, Chen Y, Sun J, Fu L (2015) Resveratrol prevents doxorubicin-induced cardiotoxicity in H9c2 cells through the inhibition of endoplasmic reticulum stress and the activation of the Sirt1 pathway. Int J Mol Med 36(3):873–880.

[142]. Shen M, Wang L, Yang G, Gao L, Wang B, Guo X, Zeng C, Xu Y, Shen L, Cheng K, Xia Y, Li X, Wang H, Fan L, Wang X (2014) Baicalin protects the cardiomyocytes from ER stressinduced apoptosis: inhibition of CHOP through induction of endothelial nitric oxide synthase. PLoS ONE 9(2):e88389.

[143]. Zhao GL, Yu LM, Gao WL, Duan WX, Jiang B, Liu XD, Zhang B, Liu ZH, Zhai ME, Jin ZX, Yu SQ, Wang Y (2016) Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress. Acta Pharmacol Sin 37(3):354–367. 1038/aps.2015.136

[144]. Jia LJ, Chen W, Shen H, Ji D, Zhao XM, Liu XH (2008) Efects of anisodamine on microcirculation of the asystole rats during the cardiopulmonary resuscitation. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 20(12):737–739

[145]. Yin XL, Shen H, Zhang W, Yang Y (2011) Inhibition of endoplasm reticulum stress by anisodamine protects against myocardial injury after cardiac arrest and resuscitation in rats. Am J Chin Med 39(5):853–866. 1009251

[146]. Wang L-C, Zhang W-S, Liu Q, Li J, Alolga R, Liu K, Liu B-L, Li P, Qi L-W (2015) A standardized notoginseng extract exerts cardioprotection by attenuating apoptosis under endoplasmic reticulum stress conditions. J Funct Foods 16:20–27. https://doi. org/10.1016/j.jf.2015.04.018

[147]. Liu M, Wang XR, Wang C, Song DD, Liu XH, Shi DZ (2013) Panax quinquefolium saponin attenuates ventricular remodeling after acute myocardial infarction by inhibiting chop-mediated apoptosis. Shock 40(4):339–344. 0b013e3182a3f9e5

[148]. Liu M, Wang XR, Wang C, Song DD, Liu XH, Shi DZ (2012) Panax quinquefolium saponins reduce myocardial hypoxia-reoxygenation injury by inhibiting excessive endoplasmic reticulum stress. Shock 37(2):228–233. e3182a3f9e5

[149]. Liu M, Xue M, Wang XR, Tao TQ, Xu FF, Liu XH, Shi DZ (2015) Panax quinquefolium saponin attenuates cardiomyocyte apoptosis induced by thapsigargin through inhibition of endoplasmic reticulum stress. J Geriatr Cardiol 12(5):540–546

[150]. Yu Y, Sun G, Luo Y, Wang M, Chen R, Zhang J, Ai Q, Xing N, Sun X (2016) Cardioprotective efects of Notoginsenoside R1 against ischemia/reperfusion injuries by regulating oxidative stress- and endoplasmic reticulum stress- related signaling pathways. Sci Rep 6:21730.

[151]. Choy KW, Mustafa MR, Lau YS, Liu J, Murugan D, Lau CW, Wang L, Zhao L, Huang Y (2016) Paeonol protects against endoplasmic reticulum stress-induced endothelial dysfunction via AMPK/PPARdelta signaling pathway. Biochem Pharmacol 116:51–62.

[152]. Yu Y, Xing N, Xu X, Zhu Y, Wang S, Sun G, Sun X (2019) Tournefolic acid B, derived from Clinopodium chinense (Benth.) Kuntze, protects against myocardial ischemia/reperfusion injury by inhibiting endoplasmic reticulum stress-regulated apoptosis via PI3K/AKT pathways. Phytomedicine 52:178–186. https://

[153]. Yang M, Mao G, Ouyang L, Shi C, Hu P, Huang S (2020) Crocetin alleviates myocardial ischemia/reperfusion injury by regulating infammation and the unfolded protein response. Mol Med Rep 21(2):641–648.

[154]. Wang X, Yuan B, Cheng B, Liu Y, Zhang B, Wang X, Lin X, Yang B, Gong G (2019) Crocin alleviates myocardial ischemia/ reperfusion-induced endoplasmic reticulum stress via regulation of miR-34a/Sirt1/Nrf2 pathway. Shock 51:123–130. https://doi. org/10.1097/shk.0000000000001116

[155]. Xu L, Deng Y, Feng L, Li D, Chen X, Ma C, Liu X, Yin J, Yang M, Teng F, Wu W, Guan S, Jiang B, Guo D (2011) Cardioprotection of salvianolic acid B through inhibition of apoptosis network. PLoS ONE 6(9):e24036. al.pone.0024036

[156]. Chen R, Sun G, Yang L, Wang J, Sun X (2016) Salvianolic acid B protects against doxorubicin induced cardiac dysfunction via inhibition of ER stress mediated cardiomyocyte apoptosis. Toxicol Res (Camb) 5(5):1335–1345. 0111d

[157]. Zhou X, Xin Q, Wang Y, Zhao Y, Chai H, Huang X, Tao X, Zhao M (2016) Total favonoids of astragalus plays a cardioprotective role in viral myocarditis. Acta Cardiol Sin 32(1):81–88. https://

[158]. Pal R, Cristan EA, Schnittker K, Narayan M (2010) Rescue of ER oxidoreductase function through polyphenolic phytochemical intervention: implications for subcellular trafc and neurodegenerative disorders. Biochem Biophys Res Commun 392:567–571.

[159]. Cheng WP, Wang BW, Shyu KG (2009) Regulation of GADD153 induced by mechanical stress in cardiomyocytes. Eur J Clin Invest 39:960–971. 02193.x

[160]. Chen J, Li L, Bai X, Xiao L, Shangguan J, Zhang W, Zhang X, Wang S, Liu G (2021) Inhibition of autophagy prevents panax notoginseng saponins (PNS) protection on cardiac myocytes against endoplasmic reticulum (ER) stress-induced mitochondrial injury, Ca2+ homeostasis and associated apoptosis. Front Pharmacol 12:620812. 620812

[161]. Wu Y, Cui H, Zhang Y, Yu P, Li Y, Wu D, Xue Y, Fu W (2021) Inonotus obliquus extract alleviates myocardial ischemia/reperfusion injury by suppressing endoplasmic reticulum stress. Mol Med Rep 23(1):77.

[162]. Fan CL, Yao ZH, Ye MN, Fu LL, Zhu GN, Dai Y, Yao XS (2020) Fuziline alleviates isoproterenol-induced myocardial injury by inhibiting ROS-triggered endoplasmic reticulum stress via PERK/eIF2α/ATF4/Chop pathway. J Cell Mol Med 24(2):1332– 1344.

[163]. Wan YJ, Wang YH, Guo Q, Jiang Y, Tu PF, Zeng KW (2021) Protocatechualdehyde protects oxygen-glucose deprivation/ reoxygenation-induced myocardial injury via inhibiting PERK/ ATF6α/IRE1α pathway. Eur J Pharmacol 891:173723. https://

[164]. Zhao G, Zhang X, Wang H, Chen Z (2020) Beta carotene protects H9c2 cardiomyocytes from advanced glycation end productinduced endoplasmic reticulum stress, apoptosis, and autophagy via the PI3K/Akt/mTOR signaling pathway. Ann Transl Med 8(10):647

[165]. Zhang Q, Shi J, Guo D, Wang Q, Yang X, Lu W, Sun X, He H, Li N, Wang Y, Li C, Wang W (2020) Qishen Granule alleviates endoplasmic reticulum stress-induced myocardial apoptosis through IRE-1-CRYAB pathway in myocardial ischemia. J Ethnopharmacol 252:112573. 112573

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