A botulinum neurotoxin-like function of Potentilla chinensis extract that inhibits neuronal SNARE complex formation, membrane fusion, neuroexocytosis, and muscle contraction.

CONTEXT: Botulinum neurotoxins (BoNTs) are popularly used to treat various diseases and for cosmetic purposes. They act by blocking neurotransmission through specific cleavage of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Recently, several polyphenols were shown to interfere with SNARE complex formation by wedging into the hydrophobic core interface, thereby leading to reduced neuroexocytosis. OBJECTIVE: In order to find industrially-viable plant extract that functions like BoNT, 71 methanol extracts of flowers were screened and BoNT-like activity of selected extract was evaluated. MATERIALS AND METHODS: After evaluating the inhibitory effect of 71 flower methanol extracts on SNARE complex formation, seven candidates were selected and they were subjected to SNARE-driven membrane fusion assay. Neurotransmitter release from neuronal PC12 cells and SNARE complex formation inside the cell was also evaluated. Finally, the effect of one selected extract on muscle contraction and digit abduction score was determined. RESULTS: The extract of Potentilla chinensis Ser. (Rosaceae)(Chinese cinquefoil) flower inhibited neurotransmitter release from neuronal PC12 cells by approximately 90% at a concentration of 10 µg/mL. The extract inhibited neuroexocytosis by interfering with SNARE complex formation inside cells. It reduced muscle contraction of phrenic nerve-hemidiaphragm by approximately 70% in 60 min, which is comparable to the action of the Ca²âº-channel blocker verapamil and BoNT type A. DISCUSSION AND CONCLUSION: While BoNT blocks neuroexocytosis by cleaving SNARE proteins, the Potentilla chinensis extract exhibited the same activity by inhibiting SNARE complex formation. The extract paralyzed muscle as efficiently as BoNT, suggesting the potential versatility in cosmetics and therapeutics.

SNARE-wedging polyphenols as small molecular botox.

Most cosmetic and therapeutic applications of Clostridium botulinum neurotoxin (BoNT) are related to muscle paralysis caused by the blocking of neurotransmitter release at the neuromuscular junction. BoNT specifically cleaves SNARE proteins at the nerve terminal and impairs neuroexocytosis. Recently, we have shown that several polyphenols inhibit neurotransmitter release from neuronal PC12 cells by interfering with SNARE complex formation. Based on our previous result, we report here that myricetin, delphinidin, and cyanidin indeed paralyze muscle by inhibiting acetylcholine release at the neuromuscular junction. While the effect of myricetin on muscle paralysis was modest compared to BoNT/A, myricetin exhibited a shorter response time than BoNT/A. Intraperitoneally-injected myricetin at an extreme dose of 1000 mg/kg did not induce death of mice, alleviating the safety issue. Thus, these polyphenols might be useful in treating various human hypersecretion diseases for which BoNT/A has been the only option of choice.

A double-blind randomized controlled comparison of APDDR-0901, a novel cosmeceutical formulation, and 0.1% adapalene gel in the treatment of mild-to-moderate acne vulgaris.

Topical retinoids have been widely used in the treatment of acne. They comprise several products used as prescription drugs as well as cosmeceuticals. Of these products, retinol has better tolerability compared with prescription retinoids such as tretinoin, but it is only used in cosmeceuticals due to its low biologic activity. A combination formulation could be an effective alternative to address the problem of decreased therapeutic activity. Recently, hexamidine diisethionate is known to have antibacterial activity, and rose extract has been shown to possess anti-inflammatory activity. In this study, we compared the efficacy and safety of the combination product APDDR-0901 (0.03% retinol, 0.7% rose extract, and 0.05% hexamidine diisethionate) vs 0.1% adapalene gel for the treatment of mild-to-moderate acne. This 12-week, multicenter, double-blinded study included 97 patients with mild-to-moderate acne. Efficacy was evaluated using 4 discrete variables: lesion count, acne grade, physician-assessed global improvement, and patient self-assessment. We also assessed safety profiles, including cutaneous irritation. Both APDDR-0901 and adapalene showed significant improvements without significant differences. Otherwise, the APDDR-0901 group showed better safety profiles, particularly in the first 2 weeks. In conclusion, APDDR-0901 could be an effective and safe alternative in the treatment of mild-to-moderate acne.

In vitro structure-activity relationship and in vivo studies for a novel class of cyclooxygenase-2 inhibitors: 5-aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives.

5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives were studied as a novel class of selective cyclooxygenase-2 inhibitors with regard to synthesis, in vitro SAR, antiinflammatory activities, pharmacokinetic considerations, and gastric safety. 1f, a representative compound for methyl sulfone derivatives, showed a COX-2 IC(50) comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED(50) of 0.1 mg kg(-1) day(-1) was observed against adjuvant-induced arthritis by a preventive model, positioning 20b as one of the most potent COX-2 inhibitors ever reported. Furthermore, 20b showed strong analgesic activity as indicated by its ED(50) of 0.25 mg/kg against carrageenan-induced thermal hyperalgesia in the Sprague-Dawley rat. 3(2H)Furanone derivatives showed due gastric safety profiles as selective COX-2 inhibitors upon 7-day repeat dosing. A highly potent COX-2 inhibitor of the 3(2H)furanone scaffold could be considered suitable for a future generation COX-2 selective arthritis medication with improved safety profiles.