LUẬN án TIẾN sĩ dược học FULL (dược cổ TRUYỀN) nghiên cứu thành phần hóa học và tác dụng dược lý của sâm VN chế biến

BỘ GIÁO DỤC VÀ ĐÀO TẠO ĐẠI HỌC Y DƯỢC THÀNH PHỐ HỒ CHÍ MINH NGHIÊN CỨU THÀNH PHẦN HỐ HỌC VÀ TÁC DỤNG DƯỢC LÝ CỦA SÂM VIỆT NAM CHẾ BIẾN LUẬN ÁN TIẾN SĨ DƯỢC HỌC Thành phố Hồ Chí Minh - Năm 2018 NGHIÊN CỨU THÀNH PHẦN HOÁ HỌC VÀ TÁC DỤNG DƯỢC LÝ CỦA SÂM VIỆT NAM CHẾ BIẾN Chuyên ngành: Dược liệu - Dược học cổ truyền Mã số: 9720206 LUẬN ÁN TIẾN SĨ DƯỢC HỌC Người hướng dẫn khoa học: Thành phố Hồ Chí Minh - Năm 2018 LỜI CAM ĐOAN Tôi xin cam đoan cơng trình nghiên cứu riêng tơi Các số liệu, kết trình bày luận án trung thực chưa công bố cơng trình khác Tác giả MỤC LỤC Trang Trang phụ bìa Lời cam đoan DANH MỤC CÁC KÝ HIỆU, CHỮ VIẾT TẮT, BẢNG ĐỐI CHIẾU THUẬT NGỮ ANH VIỆT i DANH MỤC CÁC HỢP CHẤT PHÂN LẬP .iv DANH MỤC HÌNH v DANH MỤC BIỂU ĐỒ vii DANH MỤC BẢNG viii MỞ ĐẦU Chương 1.TỔNG QUAN TÀI LIỆU 1.1 THỰC VẬT HỌC CÁC LOÀI THUỘC CHI PANAX 1.2 THÀNH PHẦN HĨA HỌC CỦA CÁC LỒI THUỘC CHI PANAX .8 1.3 THÀNH PHẦN HÓA HỌC VÀ TÁC DỤNG SINH HỌC TỪ CÁC DẠNG CHẾ BIẾN K HÁC NHAU CỦA CÁC LOÀI THUỘC CHI PANAX .13 1.4 PHÂN TÍCH SAPONIN TRONG CÁC LOÀI THUỘC CHI PANAX .24 1.5 SÂM VIỆT NAM 30 Chương 2.NGUYÊN VẬT LIỆU VÀ PHƯƠNG PHÁP NGHIÊN CỨU 42 2.1 NGUYÊN VẬT LIỆU 42 2.2 NƠI THỰC HIỆN ĐỀ TÀI .45 2.3 PHƯƠNG PHÁP NGHIÊN CỨU 45 Chương 3.KẾT QUẢ 64 3.1 KIỂM NGHIỆM NGUYÊN LIỆU 64 3.2 PHÂN TÍCH THÀNH PHẦN SAPONIN TRONG CÁC BỘ PHẬN CỦA SÂM VN 64 3.3 THÀNH PHẦN SAPONIN CỦA SÂM VN CHẾ BIẾN 74 3.4 NGHIÊN CỨU SỰ THAY ĐỔI THÀNH PHẦN HĨA HỌC SAPONIN TRONG Q TRÌNH CHẾ BIẾN SÂM VN 107 3.5 SỰ THAY ĐỔI TÁC DỤNG SINH HỌC CỦA SÂM VN QUA QUÁ TRÌNH CHẾ BIẾN 113 Chương 4.BÀN LUẬN 121 4.1 PHÂN TÍCH THÀNH PHẦN SAPONIN TRONG SÂM VN .121 4.2 THÀNH PHẦN SAPONIN CỦA SÂM VN CHẾ BIẾN 125 4.3 SỰ THAY ĐỔI TÁC DỤNG SINH HỌC DO QUÁ TRÌNH CHẾ BIẾN SÂM VN 133 KẾT LUẬN 137 KIẾN NGHỊ 139 DANH MỤC CÁC CÔNG TRÌNH NGHIÊN CỨU LIÊN QUAN 140 TÀI LIỆU THAM KHẢO i DANH MỤC CÁC KÝ HIỆU, CHỮ VIẾT TẮT, BẢNG ĐỐI CHIẾU THUẬT NGỮ ANH VIỆT Chữ viết tắt ACN Chữ nguyên Acetonitrile Nghĩa tiếng Việt Acetonitril ADP Adenosine Diphosphate Adenosin Diphosphat AF Arginine-Fructose Arginin-Fructose AFG Arginine-Fructose-Glucose Arginin-Fructose-Glucose ALT Alanine Aminotransferase APCI Atmospheric Pressure Chemical Ionization Ion hóa hóa học áp suất khí Ara α-L-arabinopyranosyl α-L-arabinopyranosyl AST Aspartate Aminotransferase Bcl-2 B-cell lymphoma COSY Correlation Spectroscopy Phổ tương quan COX Cyclooxygenase Cyclooxygenase CTPT Công thức phân tử DBMA 7,12-Dimethylbenz[a]anthracene DCF-DA 2′,7′-Dichlorodihydrofluorescein diacetate DHPPD Dihydro Protopanaxadiol Dihydro Protopanaxadiol DHPPT Dihydro Protopanaxatriol Dihydro Protopanaxatriol DPPH 1,1-diphenyl-2-picrylhydrazyl 1,1-diphenyl-2-picrylhydrazyl EA Ethyl acetate ELISA Enzyme-linked immunosorbent assay Xét nghiệm hấp thụ miễn dịch liên kết với enzym ELSD Evaporative light scattering detector Đầu dò tán xạ ánh sáng bay EP European Pharmacopeia Dược điển Châu Âu ESI Electrospray Ionization Ion hóa phun điện tử FBS Fetal bovine serum G- Ginsenoside Ginsenosid Glc β-D-glucospyranosyl β-D-glucospyranosyl HMBC Heteronuclear Multiple Bond Coherence Kết nối dị hạt nhân nhiều nối ii Chữ viết tắt HPLC Chữ nguyên High Performance Liquid Chromatography Nghĩa tiếng Việt Sắc ký lỏng hiệu cao HPMAE High Pressure Microwave Assisted Extraction Chiết xuất hỗ trợ vi sóng áp suất cao HR-ESI-MS High Resolution ElectroSpray Ionisation Mass Spectrometry Phổ khối phân giải cao ion hóa HSQC Heteronuclear Single Quantum Correlation Phổ tương quan dị hạt nhân IBα Nuclear Factor of Kappa Light Polypeptide Gene Enhancer in B-Cells Inhibitor alpha IC50 Inhibition Concentration 50% IL Interleukin iNOS Inducible NO Synthase Enzyme cảm ứng tổng hợp nitric oxit IRAK1 IL-1 Receptor Associated Kinase Kinase kết hợp với thụ thể IL-1 IT-TOF-MS Iontrap-Time of Flight-Mass Spectroscopy Khối phổ bẫy ion thời gian bay J Coupling constant Hằng số ghép KLTP Khối lượng phân tử KP Korean Pharmacopeia Dược điển Hàn Quốc LC/MS Liquid Chromatography-Mass Spectroscopy Sắc ký lỏng ghép khối phổ LPS Lipopolysaccharides Lipopolysaccharid MAE Microwave assisted extraction Chiết xuất hỗ trợ sóng siêu âm MDA Malondialdehyde Malondialdehyd MeOH Methanol MG Malonyl ginsenoside miRNA Micro RNA M-R2 Majonoside-R2 Majonosid-R2 NF-B Nuclear Factor Kappa Beta Yếu tố nhân kappa B NMR Nuclear Magnetic Resonance Cộng hưởng từ hạt nhân N-R1 Notoginsenoside R1 Notoginsenosid R1 Nồng độ ức chế 50% Malonyl ginsenosid Chữ viết tắt Chữ nguyên Nghĩa tiếng Việt OA Oleanolic acid Acid oleanolic OCT Ocotillol Ocotillol p53 Protein p53 PDA Photodiod array PG Prostaglandin PLE Pressurized liquid extraction Chiết lỏng áp suất cao PPD Protopanaxadiol Protopanaxadiol ppm Parts per million Phần triệu PPT Protopanaxatriol Protopanaxatriol Prep-HPLC Preparative High Performance Liquid Chromatography P-RT4 Pseudoginsenoside RT4 Q-TOF-MS Quadrupole-Time of flight-Mass Spectroscopy RID Refractive Index Detector Đầu dò số khúc xạ ROESY Rotating Frame Nuclear Overhauser Effect Spectroscopy Hiệu ứng hạt nhân Overhauser ROS Reactive Oxygen Species Gốc tự oxy hóa RP-18 Reversed Phase C-18 Pha đảo C-18 Rt Retention Time Thời gian lưu Sâm VN Sâm Việt Nam SKC Sắc ký cột SKĐ Sắc ký đồ SKLM Sắc ký lớp mỏng TAK1 Tumor Growth Factor-β-Activated Kinase TNF Tumor Necrosis Factor TPA 12-O-Tetradecanoylphorbol-13-acetate USP United State Pharmacopeia Dược điển Mỹ UV Ultraviolet Tử ngoại Xyl β-D-xylopyranosyl β-D-xylospyranosyl Đầu dò dãy diod quang Sắc ký lỏng hiệu cao điều chế Pseudoginsenosid RT4 Khối phổ Tứ cực - Thời gian bay Enzyme Kinase hoạt hóa yếu tố sinh trưởng β khối u Yếu tổ hoại tử khối u DANH MỤC CÁC HỢP CHẤT PHÂN LẬP STT Tên gọi 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 20(R) Ginsenosid Rg3 20(R) Ginsenosid Rh1 20(S) Ginsenosid Rg3 20(S) Ginsenosid Rh1 20(S) Protopanaxatriol oxid II (OCT) 3-O-β-D-Xylopyranosyl-(1→2)-β-Dglucopyranosyl(1→2)-β-D-glucopyranosyl20(S)-protopanaxadiol 20-O-β-Dxylopyranosyl (1→3)- β -D-xylopyranosyl (1→6)-β-D-glucopyranosid Daucosterol Ginsenosid Ra1 Ginsenosid Rb1 Ginsenosid Rb2 Ginsenosid Rd Ginsenosid Re Ginsenosid Rg1 Ginsenosid Rg3 Ginsenosid Rg5 Ginsenosid Rh1 Ginsenosid Rh4 Ginsenosid Rk1 Ginsenosid Rk3 Majonosid R1 Majonosid R2 Notoginsenosid D Notoginsenosid R1 Notoginsenosid R2 Notoginsenosid R4 Panaxynol Pseudo-ginsenosid RT4 Stigmasterol & sitosterol Vina-ginsenosid R11 Vina-ginsenosid R2 Ký hiệu 20(R) G-Rg3 20(R) G-Rh1 20(S) G-Rg3 20(R) G-Rh1 OCT G-Ra1 G-Rb1 G-Rb2 G-Rd G-Re G-Rg1 G-Rg3 G-Rg5 G-Rh1 G-Rh4 G-Rk1 G-Rk3 M-R1 M-R2 N-D N-R1 N-R2 N-R4 P-RT4 V-R11 V-R2 Hợp chất đánh số 1a 3b 1b 3a 26 22 20 19 18 17 16 14 10 11 12 23 15 21 24 25 13 DANH MỤC HÌNH Trang Hình 1.1 Cấu trúc gen trnK “Nguồn: Zhu, 2003” Hình 1.2 Cây phát sinh loài dựa kết hợp liệu gen trnK trình tự gen 18S rRNA .6 Hình 1.3 Khung saponin phần đường phổ biến saponin thuộc chi Panax .9 Hình 1.4 Sự hình thành ginsenosid trình chế biến (hấp) .15 Hình 1.5 Nhận diện truyền tín hiệu lipopolysacharid (LPS) đại thực bào 23 Hình 1.6 Phần mặt đất (a) phần mặt đất (b) Sâm VN .32 Hình 1.7 Các hợp chất polyacetylen phân lập từ phần mặt đất Sâm VN 34 Hình 1.8 Cấu trúc saponin phân lập từ Sâm VN 35 Hình 3.9 Bộ phận mặt đất Sâm VN 64 Hình 3.10 SKĐ SKLM phận khác Sâm VN 64 Hình 3.11 SKĐ ELSD (a) LC/MS (b) rễ Sâm VN 66 Hình 3.12 SKĐ HPLC/ELSD đại diện cho phận khác Sâm VN 68 Hình 3.13 Hình ảnh đại diện Sâm VN tươi (A), sấy khơ (B) sau chế biến (C) .74 Hình 3.14 SKĐ đại diện HPLC/ELSD phân tích mẫu Sâm VN chưa chế biến (A) Sâm VN chế biến (B) 75 Hình 3.15 Sơ đồ quy trình chiết cao từ dược liệu Sâm VN chế biến 76 Hình 3.16 Sơ đồ phân lập thành phần từ cao EA 78 Hình 3.17 SKĐ HPLC/ELSD phân tích mẫu rễ (a) phân đoạn Bu1.25 (b) .80 Hình 3.18 Sơ đồ phân lập thành phần từ cao Bu1 80 Hình 3.19 Quy trình phân lập hợp chất từ cao chiết Bu2 .82 Hình 3.20 Cấu trúc phần đường gắn vào vị trí C-20 hợp chất 22 (a) notoginsenosid Q (b) 101 Hình 3.21 Cấu trúc hợp chất 22 102 Hình 3.22 Cấu trúc notoginsenosid D (hợp chất 23) 105 Hình 3.23 SKĐ HPLC/ELSD đại diện Sâm VN chế biến 105 ℃ 109 Hình 3.24 SKĐ HPLC/ELSD đại diện Sâm VN chế biến 120 ℃ 110 DANH MỤC CÁC CƠNG TRÌNH NGHIÊN CỨU LIÊN QUAN TẠP CHÍ TRONG NƯỚC Isolation of Ginsenoside Isomers from Processed Vietnamese Ginseng by Preparative HPLC Journal of Medicinal Materials (2015) Ginsenoside-Rk1 and ginsenoside-Rg5 isolated from processed Vietnamese ginseng Journal of Medicinal Materials (2015) Phân lập thiết lập chất chuẩn majonosid–R2 từ sâm Việt Nam (Panax vietnamensis Ha et Grushv.), Tạp chí Dược học, Số 53, tập 8, tr 14-20, Tạp chí Dược học (2014) Ginsenoside-Rk3 and ginsenoside-Rh4 isolated from processed Vietnamese ginseng (Panax vietnamensis Ha et Grushv.) Journal of Medicinal Materials (2013) TẠP CHÍ QUỐC TẾ Ginseng Saponins in Different Parts of Panax vietnamensis Chemical & pharmaceutical bulletin 01/2015; 63(11):950-954 Anti-inflammatory effects of vina-ginsenoside R2 and majonoside R2 isolated from Panax vietnamensis and their metabolites in lipopolysaccharidestimulated macrophages International Immunopharmacology 09/2015; 28(1):700-706 Effects of steaming on saponin compositions and antiproliferative activity of Vietnamese ginseng Journal of ginseng research 07/2015; 39(3) Processed Vietnamese ginseng: Preliminary results in Chemistry and Biological activity, Journal of Ginseng Research, 2014, 38(2) TÀI LIỆU THAM KHẢO TIẾNG VIỆT Nguyễn Như Chính, Nguyễn Hữu Đồng, Đặng Ngọc Phái, Nguyễn Minh Đức, Nguyễn Minh Cang, Nguyễn Đức Hạnh, et al (2009), "Đánh giá chất lượng Sâm Việt nam di thực", Tạp chí Y học TP Hồ Chí Minh, 13 (1), tr 96-102 Nguyễn Thượng Dong, Trần Công Luận, Nguyễn Thị Thu Hương (2007), Sâm Việt Nam số thuốc thuộc họ 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VN chế biến cần thiết Với lý trên, đề tài ? ?Nghiên cứu thành phần hóa học tác dụng dược lý Sâm VN chế biến? ?? thực với mục tiêu sau: Phân tích, phân lập xác định thành phần hóa học saponin Sâm VN