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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