“…17,18) Moreover, EA has been shown to have several positive effects such as anti-inflammation, antiviral, anticancer, and cardioprotection. [19][20][21][22] These results suggest that EA can penetrate blood brain barrier and can do positive effects to the brain function. However, the effect of EA on neurite outgrowth and aged brain function has not been studied.…”
Aging leads to functional changes in the brain and decreases ability of learning and memory. Neurite outgrowth is important in learning and memory, therefore regulation of neurite outgrowth might be a candidate for treating aged brain. Echinocystic acid (EA), a pentacyclic triterpene, has shown to exert various neurological effects. However, the effect of EA on neurite outgrowth has not been studied. In this study, we examined if EA is effective on neurite outgrowth and memory in aged mice. The effect of EA on neurite outgrowth was observed by examining neurite processes of Neuro2a cells treated with EA. Western blot analysis was conducted to examine possible mechanisms. Morris water maze test was used to examine the effect of EA on learning and memory in aged mice. Immunohistochemistry was conducted to observe the effect of EA on neurite outgrowth in the hippocampus. EA was shown to induce neurite outgrowth in a concentration dependent manner without affecting cell viability. Moreover, EA treatment increased phosphorylation of c-jun N-terminal kinase (JNK) and JNK inhibitor, SP600125, blocked the effect of EA on neurite outgrowth. These results demonstrated that EA treatment promotes neurite outgrowth through the JNK signaling pathway. In in vivo experiments, EA treatment increased neurite outgrowth in aged mouse hippocampus. Moreover, EA treatment enhanced spatial learning and memory in aged mice. These results suggest that EA can be developed as a new, naturally occurring drug to treat ageing-related neurological diseases.Key words echinocystic acid; neurite outgrowth; aging; spatial memory The ability to remember certain types of information declines with aging.
“…17,18) Moreover, EA has been shown to have several positive effects such as anti-inflammation, antiviral, anticancer, and cardioprotection. [19][20][21][22] These results suggest that EA can penetrate blood brain barrier and can do positive effects to the brain function. However, the effect of EA on neurite outgrowth and aged brain function has not been studied.…”
Aging leads to functional changes in the brain and decreases ability of learning and memory. Neurite outgrowth is important in learning and memory, therefore regulation of neurite outgrowth might be a candidate for treating aged brain. Echinocystic acid (EA), a pentacyclic triterpene, has shown to exert various neurological effects. However, the effect of EA on neurite outgrowth has not been studied. In this study, we examined if EA is effective on neurite outgrowth and memory in aged mice. The effect of EA on neurite outgrowth was observed by examining neurite processes of Neuro2a cells treated with EA. Western blot analysis was conducted to examine possible mechanisms. Morris water maze test was used to examine the effect of EA on learning and memory in aged mice. Immunohistochemistry was conducted to observe the effect of EA on neurite outgrowth in the hippocampus. EA was shown to induce neurite outgrowth in a concentration dependent manner without affecting cell viability. Moreover, EA treatment increased phosphorylation of c-jun N-terminal kinase (JNK) and JNK inhibitor, SP600125, blocked the effect of EA on neurite outgrowth. These results demonstrated that EA treatment promotes neurite outgrowth through the JNK signaling pathway. In in vivo experiments, EA treatment increased neurite outgrowth in aged mouse hippocampus. Moreover, EA treatment enhanced spatial learning and memory in aged mice. These results suggest that EA can be developed as a new, naturally occurring drug to treat ageing-related neurological diseases.Key words echinocystic acid; neurite outgrowth; aging; spatial memory The ability to remember certain types of information declines with aging.
“…Treatment of compound 27 with hydroxylamine hydrochloride provided isoxazole 29 in good yield [ 27 ]. Exposure of compound 22 to Baeyer–Villiger conditions delivered ring expansion product 30 [ 28 , 29 ], which was further transformed into ring A opening derivatives 31 and 32 by hydrolysis or reduction of ester [ 30 ]. Scheme 2 Reagents and conditions: ( a ) HCOOEt, Na, Et 2 O, reflux, 76%; b NaBH 4 , MeOH, r.t., 69%; c NH 2 OH•HCl, EtOH-H 2 O (10:1), reflux, 56%; d m -CPBA, NaHCO 3 , DCM, r.t., 71%; e 10% NaOH aqueous, MeOH, reflux, 82%; f LiAlH 4 , dry THF, r.t.−50 °C, 50% …”
The dammarane triterpenoid (20
S
,24
R
)-epoxy-dammarane-3
β
,12
β
,25-triol obtained from
Cyclocarya paliurus
in our previous study showed inhibitory activity on
α
-glucosidase in vitro with an inhibitory ratio of 32.2% at the concentration of 200 μM. In order to reveal the structure-activity relationships (SARs) and get more active compounds, 42 derivatives of (20
S
,24
R
)-epoxy-dammarane-3
β
,12
β
,25-triol were synthesized by chemical modification on the hydroxyls (C-3 and C-12), rings A and E, and assayed for their
α
-glucosidase and PTP1B inhibitory activities. Two compounds (
8
,
26
) increased activity against
α
-glucosidase, and four compounds (
8
,
15
,
26
,
42
) significantly inhibited PTP1B. It was noted that compounds
8
and
26
could inhibit both
α
-glucosidase and PTP1B as dual-target inhibitors with IC
50
values of 489.8, 467.7 μM (
α
-glucosidase) and 319.7, 269.1 μM (PTP1B). Compound
26
was revealed to be a mix-type inhibitor on
α
-glucosidase and a noncompetitive-type inhibitor on PTP1B based on enzyme kinetic study. Furthermore, compound
42
could selectively inhibited PTP1B as a mix-type inhibitor with IC
50
value of 134.9 μM, which was 2.5-fold higher than the positive control, suramin sodium (IC
50
339.0 μM), but not inhibit
α
-glucosidase.
“…In the case of the echinocystic acid derivatives, we followed a different approach involving initial preparation of a suitably protected triterpene having an oxidized C3-OH position as a ketone functionality via appropriate protecting group manipulation and oxidation reactions (Scheme 1). Briefly, commercially available echinocystic acid was selectively benzylated (benzyl bromide, sodium carbonate) and its C3and C16-hydroxyl groups were orthogonally protected as a trifluoroacetate (trifluoroacetic anhydride, triethylamine) and a silyl ether (triethylsilyl trifluoromethanesulfonate (TESOTf), 2,6lutidine), respectively, giving intermediate 7 (37). Selective deprotection of the C3-OH and subsequent oxidation with pyridinium chlorochromate (PCC), followed by removal of the benzyl ester afforded the desired C3-keto echinocystic acid scaffold (kEA, 8).…”
Section: Synthesis Of Saponin Triterpene Variantsmentioning
Vaccine adjuvants are key for optimal vaccine efficacy, increasing the immunogenicity of the antigen and potentiating the immune response. Saponin adjuvants such as the carbohydrate-based QS-21 natural product are among the most promising candidates in vaccine formulations, but suffer from inherent drawbacks that have hampered their use and approval as stand-alone adjuvants. Despite the recent development of synthetic derivatives with improved properties, their full potential has not yet been reached, allowing the prospect of discovering further optimized saponin variants with higher potency. Herein, we have designed, chemically synthesized, and immunologically evaluated novel oxime-derivatized saponin adjuvants with targeted structural modifications at key triterpene functionalities. The resulting analogues have revealed important findings into saponin structure-activity relationships, including adjuvant mechanistic insights, and have shown superior adjuvant activity in terms of significantly increased antibody response augmentation compared to our previous saponin leads. These newly identified saponin oximes emerge as highly promising synthetic adjuvants for further preclinical development towards potential next generation immunotherapeutics for future vaccine applications.
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