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A Treatise on the Role of Herpesvirus in Neurodegeneration
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Bernard W. Downs, Manashi Bagchi, Bruce S. Morrison, Jeffrey Galvin, Steve Kushner, Debasis Bagchi, Kenneth Blum
Moringa oleifera, Ventilago denticulata, Rheum tanguticum, and Stephania cerpharantha demonstrated anti-HSV-1 efficacy in both in-vitro and in-vivo models, while Astragalus root,lychee flower, Inulae radix, Curcuma longa, Ilex asperlla, Antrodia camphorata mycelia, Nelumbo nucifera, Tripterygium glaucum, almond skin, Ocimum basilicum, Houttuynia cordata,Yin Chen Hao Tang, Radix isatidis, Strobilanthes cusia, Panax notoginseng, Phyllanthus emblica, Origanum vulgare, Plantago major, Ranunculus sceleratus, and Inulae radix exhibited potent in-vitro efficacy again HSV-1. Euphorbia fischeriana exhibited potent in-vivo efficacy again HSV-1 [63]. It is very interesting to indicate that water and ethanol extract of lychee flower exhibited the beneficial effect via inhibition of mTOR and p706K phosphorylation [64], while the Nelumbo nucifera interrupts a-TIF/CI/Oct-1/GARAT multiproteins and DNA complex formation [65]. Methanolic extract of almond skin exhibited an inhibitory effect on viral absorption and blocked the production of viral particles [66]. Aqueous extract of Houttuynia cordata, enriched in flavonoids, exhibited inhibitory effect on NF-kb activation and blocked the viral binding/penetration and replication [67]. Quercetin was reported to induce inhibition of NF-κβ activation and viral entry, while isoquercetin exhibited potent inhibitory effect on NF-κβ activation [67]. Panax ginseng, enriched in notoginsenoside ST-4, a Dammarene-type saponin, exhibited its efficacy through HSV-1 penetration and viral protein (vp5) synthesis [68], while Euphorbia fisheriana demonstrated its efficacy mediated through STING/IRFs/ELF4 dependent pathway [69]. Astragalus polysaccharide demonstrated its efficacy mediated through TLR-3/NF-kb signaling pathway [70].
How can we turn the PI3K/AKT/mTOR pathway down? Insights into inhibition and treatment of cancer
Published in Expert Review of Anticancer Therapy, 2021
Said M. Afify, Aung Ko Ko Oo, Ghmkin Hassan, Akimasa Seno, Masaharu Seno
In case of negative regulation, AKT links to the mTOR signaling via TSC1/2 complex and the small GTPase Rheb. The TSC complex consists of TSC1, TSC2, and TBC1D7 [47], and inhibits the activity of the small GTPase Rheb [43,44,48–55]. AKT phosphorylates TSC2 at conserved consensus phosphorylation sequences resulting in Rheb activation [44]. Phosphorylation of the TSC complex allows the accumulation of GTP-bound Rheb relative to GDP-bound Rheb [44,54–56]. Since the GTPase activity of Rheb is slow compared to other Ras-related small G proteins [51,57], the GTP/GDP loading state of Rheb is highly regulated by the phosphorylation of TSC2, which is controlled by the activation of AKT. Activated Rheb binds to its effector mTOR, and thus, in turn mTOR is activated [58,59]. mTORC1 typically phosphorylates 4E-BP and S6K, activating the translation of the genes involved in cell proliferation, metabolism, and invasion. Phosphorylated 4E-BP1, binds elF4E to suppress the activity, and releases elF4E to initiate and increase mitochondria-related mRNA translation to enhance ATP production, supporting the abnormal energy metabolism in cancer. Also, without phosphorylation, the activity of elF4 is suppressed by 4E-BP, resulting in the suppression of protein synthesis related with cancer stemness and growth [60–63]. S6K signals via various pathways, sometimes related with cancer cell survival. For instance, S6 is the target of S6K, which is involved in mRNA translation [64]. Rapamycin has been demonstrated to enhance the degradation of HIF1-alpha so that mTOR activates HIF1-alpha in a hypoxia-independent manner, inducing angiogenesis [65]. After phosphorylation of AKT at T308 by PDK1, AKT phosphorylates SIN1 in mTORC2, activating mTORC2 to phosphorylate AKT at S473 as a positive feedback to enhance AKT activity [66] (Figure 2).