Research topic: Dedicated to the 90 th Anniversary of the Founding of Shenyang Pharmaceutical University
Professor LI Ning, is the associate dean of Chinese Materia Medica of Shenyang Pharmaceutical University, the "Youth talent" of LiaoNing Revitalization Talents Program, the "Talent of Hundred level" of Liaoning BaiQianWan Talents Program, the "Leading talent" of both Shenyang High-Level Talent Program and Xinjiang Uygur Autonomous Region. She has focused on the research of chemoprevention of critical diseases, especially the neurodegenerative disease and cancer, through post-transcriptional mechanism on the perspective view of ‘preventive treatment strategy’ of the Traditional Chinese theory. She has hosted seven projects of National Natural Science Foundation of China, and published more than 120 SCI papers on famous academic journals, born several prizes like the "First Prize of Provincial Science and technology progress award", and obtained the authorization of 20 invention patents.
Title：Recent progress on betulinic acid and its derivatives as antitumor agents: a mini review
[Abstract] Natural products are one of the important sources for the discovery of new drugs. Betulinic acid (BA), a pentacyclic triterpenoid widely distributed in the plant kingdom, exhibits powerful biological effects, including antitumor activity against various types of cancer cells. A considerable number of BA derivatives have been designed and prepared to remove their disadvantages, such as poor water solubility and low bioavailability. This review summarizes the current studies of the structural diversity of antitumor BA derivatives within the last five years, which provides prospects for further research on the structural modification of betulinic acid.
Title：Research progress on naturally-occurring and semi-synthetic ocotillol-type ginsenosides in the genus Panax L. (Araliaceae)
[Abstract] Ocotillol (OT)-type ginsenosides, one subtype of ginsenosides, consist of a dammarane skeleton and a tetrahydrofuran ring. Most naturally-occurring OT-type ginsenosides exist in Panax species, particularly in Panax quinquefolius, which may be attributed to the warm and humid climate of its native areas. Till now, merely 28 types of naturally-occurring OT-type ginsenosides have been isolated. In contrast, semi-synthesized OT-type ginsenosides are attracted considerable attentions. These ginsenosides can be obtained through oxidation and cyclization of side chains of dammarane-type ginsenosides, and other methods, which may change their physical and chemical properties and further improve their bioavailabilities. It is also notable that the pharmacological activities of ginsenosides are closely related to the stereoisomers caused by the configuration at C-20. Semi-synthesis of OT-type ginsenosides can facilitate our understanding of the biosynthesis, transformation and metabolism of OT-type ginsenosides in the body. This review will systematically summarize the research progress on naturally-occurring and semi-synthetic OT-type ginsenosides, which provides a theoretical basis for their bioactivity-guided research.
Title：Probing the new strategy for the oral formulations of taxanes: changing the method with the situation
[Abstract] The first-generation taxanes (including paclitaxel and docetaxel) are widely used for the treatment of various cancers in clinical settings. In the past decade, a series of new-generation taxanes have been developed which are effective in the inhibition of tumor resistance. However, intravenous (i.v.) infusion is still the only route of administration, and may result in serious adverse reactions with respect to the utilization of Cremophor EL or Tween-80 as solvent. Besides, the dosing schedule is also limited. Therefore, oral administration of taxanes is urgently needed to avoid the adverse reactionss and increase dosing frequency. In this review, we first outlined the discovery and development of taxane-based anticancer agents. Furthermore, we summarized the research progress on the oral formulations of taxanes and proposed some thoughts on the future development of oral taxane formulations.
Title：A review: biosynthesis of plant-derived labdane-related diterpenoids
[Abstract] Plant-derived labdane-related diterpenoids (LRDs) represent a large group of terpenoids. LRDs possess either a labdane-type bicyclic core structure or more complex ring systems derived from labdane-type skeletons, such as abietane, pimarane, kaurane, etc. Due to their various pharmaceutical activities and unique properties, many of LRDs have been widely used in pharmaceutical, food and perfume industries. Biosynthesis of various LRDs has been extensively studied, leading to characterization of a large number of new biosynthetic enzymes. The biosynthetic pathways of important LRDs and the relevant enzymes (especially diterpene synthases and cytochrome P450 enzymes) were summarized in this review.
Title：Lignans with (N, N-diethyl)methyl amino group from Buxus rugulosa
[Abstract] Buxrugulosides A–E, four lignan glycosides ( 1–4 ) and a protocatechuate derivative ( 5 ) featuring a rare (N, N-diethyl)methyl amino group at aromatic rings, were obtained from the aerial parts of Buxus rugulosa, which is famous for treating coronary heart disease. Their structures including absolute configurations were elucidated by HRMS, 1D and 2D NMR, and by comparing their CD data with previous reports. Compound 1 was a rare sesquilignan, and all of these compounds were the first example of lignans with (N, N-diethyl)methyl amino group.
Title：Discovery of alkaloids from the leaves of Isatis indigotica Fortune with neuroprotective activity
[Abstract] Seven alkaloids including five undescribed ones ( 1a / 1b , 2 , 3 and 5 ) were obtained from the leaves of Isatis indigotica Fortune. Their structures were established by extensive spectroscopic analyses. The absolute configurations of compounds 1a , 1b , 3 and 5 were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Subsequently, the neuroprotective effects of all the isolates against H2O2-induced injury in SH-SY5Y cells were evaluated in vitro by MTT assay. Moreover, Annexin V-FITC/PI double staining was performed, while the activities of antioxidant enzymes (SOD, CAT and GSH-Px) for compounds 1a and 1b were measured.
Title：New tirucallane-type triterpenoids from the resin of Boswellia carterii and their NO inhibitory activities
[Abstract] Six new tirucallane-type triterpenoids ( 1 − 6 ), along with ten known triterpenoids, were isolated from methylene chloride extract of the resin of Boswellia carterii Birdw. By the application of the comprehensive spectroscopic data, the structures of the compounds were clarified. The experimental electronic circular dichroism spectra were compared with those calculated, which allowed to assign the absolute configurations. Compounds 5 and 6 possesed a 2, 3-seco tirucallane-type triterpenoid skeleton, which were first reported. Their inhibitory activity against NO formation in LPS-activated BV-2 cells were evaluated. Compound 9 showed appreciable inhibitory effect, with an IC50 value of 7.58 ± 0.87 μmol·L−1.
Title：Sesquiterpenes and polyphenols with glucose-uptake stimulatory and antioxidant activities from the medicinal mushroom Sanghuangporus sanghuang
[Abstract] A chemical investigation on the fermentation products of Sanghuangporus sanghuang led to the isolation and identification of fourteen secondary metabolites ( 1 − 14 ) including eight sesquiterpenoids ( 1 − 8 ) and six polyphenols ( 9 − 14 ). Compounds 1 − 3 were sesquiterpenes with new structures which were elucidated based on NMR spectroscopy, high resolution mass spectrometry (HRMS) and electronic circular dichroism (ECD) data. All the isolates were tested for their stimulation effects on glucose uptake in insulin-resistant HepG2 cells, and cellular antioxidant activity. Compounds 9 − 12 were subjected to molecular docking experiment to primarily evaluate their anti-coronavirus (SARS-CoV-2) activity. As a result, compounds 9 − 12 were found to increase the glucose uptake of insulin-resistant HepG2 cells by 18.1%, 62.7%, 33.7% and 21.4% at the dose of 50 μmol·L−1, respectively. Compounds 9 − 12 also showed good cellular antioxidant activities with CAA50 values of 12.23, 23.11, 5.31 and 16.04 μmol·L−1, respectively. Molecular docking between COVID-19 Mpro and compounds 9 − 12 indicated potential SARS-CoV-2 inhibitory activity of these four compounds. This work provides new insights for the potential role of the medicinal mushroom S. sanghuang as drugs and functional foods.
Title：Biotransformation of α-asarone by Alternaria longipes CGMCC 3.2875
[Abstract] Biotransformation of α-asarone by Alternaria longipes CGMCC 3.2875 yielded two pairs of new neolignans, (+) (7S, 8S, 7′S, 8′R) iso-magnosalicin ( 1a )/(−) (7R, 8R, 7'R, 8′S) iso-magnosalicin ( 1b ) and (+) (7R, 8R, 7′S, 8'R) magnosalicin ( 2a )/(−) (7S, 8S, 7′R, 8'S) magnosalicin ( 2b ), and four known metabolites, (±) acoraminol A ( 3 ), (±) acoraminol B ( 4 ), asaraldehyde ( 5 ), and 2, 4, 5-trimethoxybenzoic acid ( 6 ). Their structures, including absolute configurations, were determined by extensive analysis of NMR spectra, X-ray crystallography, and quantum chemical ECD calculations. The cytotoxic activity and Aβ42 aggregation inhibitory activity of all the compounds were evaluated. Compound 2 displayed significant anti-Aβ42 aggregation activity with an inhibitory rate of 60.81% (the positive control EGCG: 69.17%). In addition, the biotransformation pathway of α-asarone by Alternaria longipes CGMCC 3.2875 was proposed.
Title：Sulfite as the substrate of C-sulfonate metabolism of α, β-unsaturated carbonyl containing andrographolide: analysis of sulfite in rats’ intestinal tract and the reaction kinetics of andrographolide with sulfite
[Abstract] One-sixth of the currently known natural products contain α, β-unsaturated carbonyl groups. Our previous studies reported a rare C-sulfonate metabolic pathway. Sulfonate groups were linked to the β-carbon of α, β-unsaturated carbonyl-based natural compounds through this pathway. However, the mechanism of this type of metabolism is still not fully understood, especially whether it is formed through enzyme-mediated biotransformation or direct sulfite addition. In this work, the enzyme-mediated and non-enzymatic pathways were studied. First, the sulfite content in rat intestine was determined by LC-MS/MS. The results showed that the amount of sulfite in rat intestinal contents was from 41.5 to 383 μg∙g−1, whereas the amount of sulfite in rat feed was lower than the lower limit of quantitation (20 μg∙g−1). Second, the reaction kinetics of sulfite-andrographolide reactions in phosphate buffer solutions (pH 6−8) was studied. The half-lives of andrographolide ranged from minutes to hours. This was suggested that the C-sulfonate reaction of andrographolide was very fast. Third, the C-sulfonate metabolites of andrographolide were both detected when andrographolide and L-cysteine-S-conjugate andrographolide were incubated with the rat small intestine contents or sulfite, indicating that the sulfite amount in rat intestine contents was high enough to react with andrographolide, which assisted a significant portion of andrographolide metabolism. Finally, the comparison of andrographolide metabolite profiles among liver homogenate (with NADPH), liver S9 (with NADPH), small intestine contents homogenate (with no NADPH), and sulfite solution incubations showed that the C-sulfonate metabolites were predominantly generated in the intestinal tract by non-enzymatic pathway. In summary, sulfite can serve as a substrate for C-sulfonate metabolism, and these results identified non-enzymatically nucleophilic addition as the potential mechanism for C-sulfonate metabolism of compounds containing α, β-unsaturated carbonyl moiety.
Title：Comparison of Murraya exotica and Murraya paniculata by fingerprint analysis coupled with chemometrics and network pharmacology methods
[Abstract] There are two source plants for the traditional Chinese medicine Murrayae Folium et Cacumen (MFC) in Chinese Pharmacopoeia, i.e. Murraya exotica L. and M. paniculata (L.) Jack. Herein, a chemical comparison of M. exotica and M. paniculata by high performance liquid chromatography (HPLC) fingerprint analysis coupled with chemometrics and network pharmacology was performed. The main peaks in the fingerprints were identified by liquid chromatography coupled with ion trap/time-of-flight mass spectrometry (LC-IT-TOF-MS) and authenticated by references. The chemometrics results showed that the HPLC fingerprints of these two species were clearly divided into two categories using hierarchical cluster analysis (HCA) and principal component analysis (PCA), and a total of 13 significantly differentiated markers were screened out by orthogonal partial least squares-discriminant analysis (OPLS-DA). However, the following network pharmacology analysis showed that these discriminated markers were found to act via many common targets and metabolic pathways, indicating the possibly similar pharmacological effects and mechanisms for M. exotica and M. paniculata. The above results provide valuable evidence for the equivalent use of these two plants in clinical settings. Moreover, the chromatographic fingerprint analysis coupled with chemometrics and network pharmacology supplies an efficient approach for the comparative analysis of multi-source TCMs like MFC.
Title：Recent progress on betulinic acid and its derivatives as antitumor agents: a mini review
[Abstract] Natural products are one of the important sources for the discovery of new drugs. Betulinic acid (BA), a pentacyclic triterpenoid widely distributed in the plant kingdom, exhibits powerful biological effects, including antitumor activity against various types of cancer cells. A considerable number of BA derivatives have been designed and prepared to remove their disadvantages, such as poor water solubility and low bioavailability. This review summarizes the current studies of the structural diversity of antitumor BA derivatives within the last five years, which provides prospects for further research on the structural modification of betulinic acid.
Title：Research progress on naturally-occurring and semi-synthetic ocotillol-type ginsenosides in the genus Panax L. (Araliaceae)
[Abstract] Ocotillol (OT)-type ginsenosides, one subtype of ginsenosides, consist of a dammarane skeleton and a tetrahydrofuran ring. Most naturally-occurring OT-type ginsenosides exist in Panax species, particularly in Panax quinquefolius, which may be attributed to the warm and humid climate of its native areas. Till now, merely 28 types of naturally-occurring OT-type ginsenosides have been isolated. In contrast, semi-synthesized OT-type ginsenosides are attracted considerable attentions. These ginsenosides can be obtained through oxidation and cyclization of side chains of dammarane-type ginsenosides, and other methods, which may change their physical and chemical properties and further improve their bioavailabilities. It is also notable that the pharmacological activities of ginsenosides are closely related to the stereoisomers caused by the configuration at C-20. Semi-synthesis of OT-type ginsenosides can facilitate our understanding of the biosynthesis, transformation and metabolism of OT-type ginsenosides in the body. This review will systematically summarize the research progress on naturally-occurring and semi-synthetic OT-type ginsenosides, which provides a theoretical basis for their bioactivity-guided research.
Title：Probing the new strategy for the oral formulations of taxanes: changing the method with the situation
[Abstract] The first-generation taxanes (including paclitaxel and docetaxel) are widely used for the treatment of various cancers in clinical settings. In the past decade, a series of new-generation taxanes have been developed which are effective in the inhibition of tumor resistance. However, intravenous (i.v.) infusion is still the only route of administration, and may result in serious adverse reactions with respect to the utilization of Cremophor EL or Tween-80 as solvent. Besides, the dosing schedule is also limited. Therefore, oral administration of taxanes is urgently needed to avoid the adverse reactionss and increase dosing frequency. In this review, we first outlined the discovery and development of taxane-based anticancer agents. Furthermore, we summarized the research progress on the oral formulations of taxanes and proposed some thoughts on the future development of oral taxane formulations.
Title：A review: biosynthesis of plant-derived labdane-related diterpenoids
[Abstract] Plant-derived labdane-related diterpenoids (LRDs) represent a large group of terpenoids. LRDs possess either a labdane-type bicyclic core structure or more complex ring systems derived from labdane-type skeletons, such as abietane, pimarane, kaurane, etc. Due to their various pharmaceutical activities and unique properties, many of LRDs have been widely used in pharmaceutical, food and perfume industries. Biosynthesis of various LRDs has been extensively studied, leading to characterization of a large number of new biosynthetic enzymes. The biosynthetic pathways of important LRDs and the relevant enzymes (especially diterpene synthases and cytochrome P450 enzymes) were summarized in this review.
Title：Lignans with (N, N-diethyl)methyl amino group from Buxus rugulosa
[Abstract] Buxrugulosides A–E, four lignan glycosides ( 1–4 ) and a protocatechuate derivative ( 5 ) featuring a rare (N, N-diethyl)methyl amino group at aromatic rings, were obtained from the aerial parts of Buxus rugulosa, which is famous for treating coronary heart disease. Their structures including absolute configurations were elucidated by HRMS, 1D and 2D NMR, and by comparing their CD data with previous reports. Compound 1 was a rare sesquilignan, and all of these compounds were the first example of lignans with (N, N-diethyl)methyl amino group.
Title：Discovery of alkaloids from the leaves of Isatis indigotica Fortune with neuroprotective activity
[Abstract] Seven alkaloids including five undescribed ones ( 1a / 1b , 2 , 3 and 5 ) were obtained from the leaves of Isatis indigotica Fortune. Their structures were established by extensive spectroscopic analyses. The absolute configurations of compounds 1a , 1b , 3 and 5 were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Subsequently, the neuroprotective effects of all the isolates against H2O2-induced injury in SH-SY5Y cells were evaluated in vitro by MTT assay. Moreover, Annexin V-FITC/PI double staining was performed, while the activities of antioxidant enzymes (SOD, CAT and GSH-Px) for compounds 1a and 1b were measured.
Title：New tirucallane-type triterpenoids from the resin of Boswellia carterii and their NO inhibitory activities
[Abstract] Six new tirucallane-type triterpenoids ( 1 − 6 ), along with ten known triterpenoids, were isolated from methylene chloride extract of the resin of Boswellia carterii Birdw. By the application of the comprehensive spectroscopic data, the structures of the compounds were clarified. The experimental electronic circular dichroism spectra were compared with those calculated, which allowed to assign the absolute configurations. Compounds 5 and 6 possesed a 2, 3-seco tirucallane-type triterpenoid skeleton, which were first reported. Their inhibitory activity against NO formation in LPS-activated BV-2 cells were evaluated. Compound 9 showed appreciable inhibitory effect, with an IC50 value of 7.58 ± 0.87 μmol·L−1.
Title：Sesquiterpenes and polyphenols with glucose-uptake stimulatory and antioxidant activities from the medicinal mushroom Sanghuangporus sanghuang
[Abstract] A chemical investigation on the fermentation products of Sanghuangporus sanghuang led to the isolation and identification of fourteen secondary metabolites ( 1 − 14 ) including eight sesquiterpenoids ( 1 − 8 ) and six polyphenols ( 9 − 14 ). Compounds 1 − 3 were sesquiterpenes with new structures which were elucidated based on NMR spectroscopy, high resolution mass spectrometry (HRMS) and electronic circular dichroism (ECD) data. All the isolates were tested for their stimulation effects on glucose uptake in insulin-resistant HepG2 cells, and cellular antioxidant activity. Compounds 9 − 12 were subjected to molecular docking experiment to primarily evaluate their anti-coronavirus (SARS-CoV-2) activity. As a result, compounds 9 − 12 were found to increase the glucose uptake of insulin-resistant HepG2 cells by 18.1%, 62.7%, 33.7% and 21.4% at the dose of 50 μmol·L−1, respectively. Compounds 9 − 12 also showed good cellular antioxidant activities with CAA50 values of 12.23, 23.11, 5.31 and 16.04 μmol·L−1, respectively. Molecular docking between COVID-19 Mpro and compounds 9 − 12 indicated potential SARS-CoV-2 inhibitory activity of these four compounds. This work provides new insights for the potential role of the medicinal mushroom S. sanghuang as drugs and functional foods.
Title：Biotransformation of α-asarone by Alternaria longipes CGMCC 3.2875
[Abstract] Biotransformation of α-asarone by Alternaria longipes CGMCC 3.2875 yielded two pairs of new neolignans, (+) (7S, 8S, 7′S, 8′R) iso-magnosalicin ( 1a )/(−) (7R, 8R, 7'R, 8′S) iso-magnosalicin ( 1b ) and (+) (7R, 8R, 7′S, 8'R) magnosalicin ( 2a )/(−) (7S, 8S, 7′R, 8'S) magnosalicin ( 2b ), and four known metabolites, (±) acoraminol A ( 3 ), (±) acoraminol B ( 4 ), asaraldehyde ( 5 ), and 2, 4, 5-trimethoxybenzoic acid ( 6 ). Their structures, including absolute configurations, were determined by extensive analysis of NMR spectra, X-ray crystallography, and quantum chemical ECD calculations. The cytotoxic activity and Aβ42 aggregation inhibitory activity of all the compounds were evaluated. Compound 2 displayed significant anti-Aβ42 aggregation activity with an inhibitory rate of 60.81% (the positive control EGCG: 69.17%). In addition, the biotransformation pathway of α-asarone by Alternaria longipes CGMCC 3.2875 was proposed.
Title：Sulfite as the substrate of C-sulfonate metabolism of α, β-unsaturated carbonyl containing andrographolide: analysis of sulfite in rats’ intestinal tract and the reaction kinetics of andrographolide with sulfite
[Abstract] One-sixth of the currently known natural products contain α, β-unsaturated carbonyl groups. Our previous studies reported a rare C-sulfonate metabolic pathway. Sulfonate groups were linked to the β-carbon of α, β-unsaturated carbonyl-based natural compounds through this pathway. However, the mechanism of this type of metabolism is still not fully understood, especially whether it is formed through enzyme-mediated biotransformation or direct sulfite addition. In this work, the enzyme-mediated and non-enzymatic pathways were studied. First, the sulfite content in rat intestine was determined by LC-MS/MS. The results showed that the amount of sulfite in rat intestinal contents was from 41.5 to 383 μg∙g−1, whereas the amount of sulfite in rat feed was lower than the lower limit of quantitation (20 μg∙g−1). Second, the reaction kinetics of sulfite-andrographolide reactions in phosphate buffer solutions (pH 6−8) was studied. The half-lives of andrographolide ranged from minutes to hours. This was suggested that the C-sulfonate reaction of andrographolide was very fast. Third, the C-sulfonate metabolites of andrographolide were both detected when andrographolide and L-cysteine-S-conjugate andrographolide were incubated with the rat small intestine contents or sulfite, indicating that the sulfite amount in rat intestine contents was high enough to react with andrographolide, which assisted a significant portion of andrographolide metabolism. Finally, the comparison of andrographolide metabolite profiles among liver homogenate (with NADPH), liver S9 (with NADPH), small intestine contents homogenate (with no NADPH), and sulfite solution incubations showed that the C-sulfonate metabolites were predominantly generated in the intestinal tract by non-enzymatic pathway. In summary, sulfite can serve as a substrate for C-sulfonate metabolism, and these results identified non-enzymatically nucleophilic addition as the potential mechanism for C-sulfonate metabolism of compounds containing α, β-unsaturated carbonyl moiety.
Title：Comparison of Murraya exotica and Murraya paniculata by fingerprint analysis coupled with chemometrics and network pharmacology methods
[Abstract] There are two source plants for the traditional Chinese medicine Murrayae Folium et Cacumen (MFC) in Chinese Pharmacopoeia, i.e. Murraya exotica L. and M. paniculata (L.) Jack. Herein, a chemical comparison of M. exotica and M. paniculata by high performance liquid chromatography (HPLC) fingerprint analysis coupled with chemometrics and network pharmacology was performed. The main peaks in the fingerprints were identified by liquid chromatography coupled with ion trap/time-of-flight mass spectrometry (LC-IT-TOF-MS) and authenticated by references. The chemometrics results showed that the HPLC fingerprints of these two species were clearly divided into two categories using hierarchical cluster analysis (HCA) and principal component analysis (PCA), and a total of 13 significantly differentiated markers were screened out by orthogonal partial least squares-discriminant analysis (OPLS-DA). However, the following network pharmacology analysis showed that these discriminated markers were found to act via many common targets and metabolic pathways, indicating the possibly similar pharmacological effects and mechanisms for M. exotica and M. paniculata. The above results provide valuable evidence for the equivalent use of these two plants in clinical settings. Moreover, the chromatographic fingerprint analysis coupled with chemometrics and network pharmacology supplies an efficient approach for the comparative analysis of multi-source TCMs like MFC.
