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.


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