Traditional Uses, Chemical Constituents and Pharmacological Activities of the Toona sinensis Plant

Toona sinensis (A. Juss.) Roem., which is widely distributed in China, is a homologous plant resource of medicine and food. The leaves, seeds, barks, buds and pericarps of T. sinensis can be used as medicine with traditional efficacy. Due to its extensive use in traditional medicine in the ancient world, the T. sinensis plant has significant development potential. In this review, 206 compounds, including triterpenoids (1–133), sesquiterpenoids (134–135), diterpenoids (136–142), sterols (143–147), phenols (148–167), flavonoids (168–186), phenylpropanoids (187–192) and others (193–206), are isolated from the T. sinensis plant. The mass spectrum cracking laws of representative compounds (64, 128, 129, 154–156, 175, 177, 179 and 183) are reviewed, which are conducive to the discovery of novel active substances. Modern pharmacological studies have shown that T. sinensis extracts and their compounds have antidiabetic, antidiabetic nephropathy, antioxidant, anti-inflammatory, antitumor, hepatoprotective, antiviral, antibacterial, immunopotentiation and other biological activities. The traditional uses, chemical constituents, compound cracking laws and pharmacological activities of different parts of T. sinensis are reviewed, laying the foundation for improving the development and utilization of its medicinal value.


Introduction
The Toona genus (Meliaceae) comprises about 15 species, which are distributed from Asia to Oceania.Approximately four species, including Toona sinensis (A.Juss.)Roem, Toona ciliata M. Roem., Toona microcarpa (C.DC.) Harms and Toona rubriflora C. J. Tseng, are found in China with distribution in the south, southwest and north [1].In addition to the characteristics of the species, T. sinensis seeds have membranous wings, which facilitate flying and spreading.More than 2000 years of cultivation history has resulted in the species' strong cold resistance.Of course, it already had this genetic advantage, which made it widely cultivated on the lands of China [2,3].T. sinensis has a long history of cultivation, wide distribution, strong adaptability and easy reproduction.It is a valuable multifunctional tree species that integrates food, medicine and materials, beautifies the environment and has significant potential for development and utilization [4,5].
T. sinensis was first published in Tang Materia Medica, describing its efficacy in transforming food and medicine, which were widely used in traditional medicine in the ancient world [6].The traditional efficacy of T. sinensis is closely associated with a variety of phytochemical constituents.Previous phytochemical investigations on this plant have revealed that the secondary metabolites include triterpenoids, sesquiterpenoids, diterpenoids, sterols, phenols, flavonoids and phenylpropanoids [7,8].Among the phytochemical constituents, triterpenoids are known to be the main constituents, such as limonoid, apo-tirucallane and tirucallane [9].It is important to quickly characterize the natural products in these complex plant extracts.Mass spectrometry is a powerful tool for analyzing chemical compositions.Understanding the cracking laws of compounds from T. sinensis is important for the discovery of active substances with novel structures [10].Modern studies have also reported that T. sinensis possesses various pharmacological activities, including antidiabetic, antidiabetic nephropathy, antioxidant, anti-inflammatory, antitumor, hepatoprotective, antiviral, antibacterial and other biological activities [11][12][13] (Figure 1).Together, these findings have provided many new insights and a strong scientific basis for supporting its practical use in medical situations.
constituents, triterpenoids are known to be the main constituents, such as limonoid, apotirucallane and tirucallane [9].It is important to quickly characterize the natural products in these complex plant extracts.Mass spectrometry is a powerful tool for analyzing chemical compositions.Understanding the cracking laws of compounds from T. sinensis is important for the discovery of active substances with novel structures [10].Modern studies have also reported that T. sinensis possesses various pharmacological activities, including antidiabetic, antidiabetic nephropathy, antioxidant, anti-inflammatory, antitumor, hepatoprotective, antiviral, antibacterial and other biological activities [11][12][13] (Figure 1).Together, these findings have provided many new insights and a strong scientific basis for supporting its practical use in medical situations.
In this review, we compile the progress on phytochemical studies over the past few decades, with all the elucidated compounds listed.The biological characterizations of the extracts and compounds isolated from T. sinensis plant are also discussed.Therefore, this review will provide a guide for the full utilization of these plants for new drug development and pharmaceutical applications through a comprehensive understanding of the development status of T. sinensis.

Traditional Uses
T. sinensis, a deciduous woody plant native to Eastern and Southeastern Asia, is used as a vegetable source in China and Malaysia and as animal fodder in India [14,15].The T. sinensis plant, a unique tree species in China, is popularly known as "Xiang Chun", In this review, we compile the progress on phytochemical studies over the past few decades, with all the elucidated compounds listed.The biological characterizations of the extracts and compounds isolated from T. sinensis plant are also discussed.Therefore, this review will provide a guide for the full utilization of these plants for new drug development and pharmaceutical applications through a comprehensive understanding of the development status of T. sinensis.
Triterpenoids are a class of terpenoids.The basic nucleus of a terpenoid is composed of 30 carbon atoms.Triterpenoids exist in plants in free form or as glycosides or esters combined with sugars.Triterpenoids are the main components of T. sinensis.A total of 133 triterpenoids have been isolated from various parts of T. sinensis, including dammarane, tirucallane, apo-tirucallane, limonoids, cycloartane and other triterpenoids.The most abundant tetracyclic triterpenoids in T. sinensis include dammarane, tirucallane, apo-tirucallane and limonoid triterpenoids [47].Their structural correlations are shown in Figure 2.

Tirucallane Triterpenoids
Tirucallane triterpenoids have a basic parent nucleus of cyclopentane, the A/B, B and C/D rings of which have a trans configuration.Tirucallane triterpenoids, in gener have five methyl groups and a side chain composed of eight carbon atoms on the C position of the parent nucleus.That is, the C-4 position has two methyl groups.The C and C-14 positions have one methyl group each (10β and 14β, respectively), and anoth methyl group is connected to the C-13 position (13α).The C-17 side chain is an α config ration.At present, nine tirucallane triterpenoids (12)(13)(14)(15)(16)(17)(18)(19)(20) have been isolated from the bar stem barks and seeds of T. sinensis.Three tirucallane triterpenoids (12, 16 and 17) ha been isolated from the barks of T. sinensis [24,26].Three tirucallane triterpenoids (13have been isolated from the seeds of T. sinensis [25].Three tirucallane triterpenoids (1 20) have been isolated from the stem barks of T. sinensis [23] (Figure 3).

Sesquiterpenoids and Diterpenoids
Sesquiterpenoids and diterpenoids are typically synthesized by polymerizing three to four molecules of isoprene.Sesquiterpenoids are natural terpenoids containing 15 carbon atoms.At present, two sesquiterpenoids (134 and 135) have been isolated from the pericarps of T. sinensis [1,27].Diterpenoids are terpenoids containing four isoprene units.They are natural products with complex and diverse structures and important biological activities.Seven diterpenoids (136-142) have been isolated from T. sinensis.Two diterpenoids (136 and 138) have been isolated from the barks of T. sinensis [26,37].Three diterpenoids (137,139 and 140) have been isolated from the leaves of T. sinensis [34].Two diterpenoids (141 and 142) have been isolated from the seeds of T. sinensis [25] (Figure 6).

Sterols
Sterols are derivatives of a hydrogenated benzene ring system.They are important active substances that are widely present in organisms.Five sterols (143-147) have been isolated from the pericarps of T. sinensis [1,27].Compound 143 has also been isolated from the barks and roots of T. sinensis [33,38] (Figure 6).

Sesquiterpenoids and Diterpenoids
Sesquiterpenoids and diterpenoids are typically synthesized by polymerizing three to four molecules of isoprene.Sesquiterpenoids are natural terpenoids containing 15 carbon atoms.At present, two sesquiterpenoids (134 and 135) have been isolated from the pericarps of T. sinensis [1,27].Diterpenoids are terpenoids containing four isoprene units.They are natural products with complex and diverse structures and important biological activities.Seven diterpenoids (136-142) have been isolated from T. sinensis.Two diterpenoids (136 and 138) have been isolated from the barks of T. sinensis [26,37].Three diterpenoids (137,139 and 140) have been isolated from the leaves of T. sinensis [34].Two diterpenoids (141 and 142) have been isolated from the seeds of T. sinensis [25] (Figure 6).

Sterols
Sterols are derivatives of a hydrogenated benzene ring system.They are important active substances that are widely present in organisms.Five sterols (143-147) have been isolated from the pericarps of T. sinensis [1,27].Compound 143 has also been isolated from the barks and roots of T. sinensis [33,38] (Figure 6).

Phenols
Phenols are naturally occurring metabolites found widely in plants.They have diverse pharmacological activities.Various phenolic compounds are distributed in different parts of T. sinensis.The contents of phenolic acid and its derivatives are relatively high.Twenty phenols (148-167) have been isolated from various parts of T. sinensis.Twelve compounds (148-156, 161-162 and 167) have been isolated from the pericarps of T. sinensis [1,27].Compounds 155 and 167 have also been isolated from the young leaves of T. sinensis [39].Four phenols (157-160) have been isolated from the roots of T. sinensis [33].Compound 163 has been isolated from the leaves of T. sinensis [12].Three compounds (164-166) have been isolated from leaves and shoots of T. sinensis [39] (Figure 7).

Phenols
Phenols are naturally occurring metabolites found widely in plants.They have diverse pharmacological activities.Various phenolic compounds are distributed in different parts of T. sinensis.The contents of phenolic acid and its derivatives are relatively high.Twenty phenols (148-167) have been isolated from various parts of T. sinensis.Twelve compounds (148-156, 161-162 and 167) have been isolated from the pericarps of T. sinensis [1,27].Compounds 155 and 167 have also been isolated from the young leaves of T. sinensis [39].Four phenols (157-160) have been isolated from the roots of T. sinensis [33].Compound 163 has been isolated from the leaves of T. sinensis [12].Three compounds (164-166) have been isolated from leaves and shoots of T. sinensis [39] (Figure 7).

Flavonoids
In general, a "flavonoid" refers to a compound formed by connecting two phenyl rings and a heterocyclic ring.That is, the general structure of flavonoids is a 15-carbon skeleton of C 6 -C 3 -C 6 .Flavonoids exist in almost all green plants (mainly in higher plants) and have a wide range of biological activities.The subclassification of flavonoids with different aglycones can be divided into flavan-3-ols, flavanones, flavones and flavonols, all of which have been isolated from T. sinensis.Nineteen flavonoids (168-186) have been isolated from various parts of T. sinensis.One flavan-3-ols (168) and two flavanones (172 and 173) have been isolated from the stems of T. sinensis [40].One flavan-3-ols (169) and one flavonol (186) have been isolated from the leaves of T. sinensis [12,40].Two flavan-3-ols (170 and 171) have been isolated from the leaves and wood of T. sinensis [42].One flavone (174) and two flavonols (184 and 185) have been isolated from the barks of T. sinensis [38].Five flavonols (175-177, 179 and 180) have been isolated from the young leaves of T. sinensis [39,41].Three flavonols (180-182) have been isolated from the pericarps of T. sinensis [1,25,39].One flavonol (183) has been isolated from the leaves and shoots of T. sinensis [39] (Figure 7).

Phenylpropanoids and Other Compounds
Phenylpropanoids are a group of naturally occurring organic compounds with one or several C 6 -C 3 units in the basic parent nucleus.They are present widely in higher plants.Six phenylpropanoid compounds (187-192) have been isolated from the leaves, root barks and pericarps of T. sinensis.Two phenylpropanoid compounds (187 and 189) have been isolated from the leaves of T. sinensis [44].Three phenylpropanoid compounds (188, 190 and 191) have been isolated from the root barks of T. sinensis [33].Two phenylpropanoid compounds (188 and 192) have been isolated from the pericarps of T. sinensis [1,27] (Figure 7).Two compounds (193 and 194) have been isolated from the leaves of T. sinensis [45].Twelve compounds (195-206) have been isolated from the root barks of T. sinensis [46] (Figure 7).
Based on literature findings, we summarized the chemical constituents isolated and purified from different parts of T. sinensis, which are helpful in identifying the active constituents of different medicinal parts and provide a reference for subsequent pharmacodynamics research.

Compound Cracking Laws
Molecules can undergo a variety of ionizations in ion sources, and the same molecule can produce a variety of ions.Many ion peaks can also be seen from the mass spectrum, and most of the ion peaks formed according to the self-cracking laws of the compounds.
Limonoid-type triterpenoids are the main chemical constituents of T. sinensis.Summarizing the cracking laws of these compounds by mass spectrometry (MS) for analyses of the chemical constituents of T. sinensis is important.The dissociation behaviors of limonoids upon high-resolution electrospray ionization-tandem mass spectrometry (HR-ESI-MS/MS) have been proposed [48].In this review article, the possible fragmentation pathways of gedunin (64) + and [M + H − C 18 H 26 O 5 ] + , respectively, were observed (Figure 8).Neutral losses of C 2 H 4 O 2 , H 2 O, CO and CO 2 were the main fragmentation patterns for limonoids in positive-ion mode.In addition, an identical characteristic ion at m/z 161.0594 (C 10 H 9 O 2 ) was found in the MS/MS spectra of the four limonoids, which played an important part in metabolite identification.Cycloartane-type triterpenoids are another type of triterpenoid from T. sinensis.The molecular weight of cycloeucalenol (128) and 24-methylenecycloartanol (129) was confirmed by their pseudo-molecular ions: the [M − H 2 O + H] + of cycloeucalenol (m/z 409) and 24-methylenecycloartanol (m/z 423), respectively.This confirmation was made using normal-phase liquid chromatography-mass spectrometry operating in atmospheric pressure chemical ionization mode.The protonated molecular ions [M + H] + of cycloeucalenol (m/z 427) and 24-methylenecycloartanol (m/z 441) were very abundant.The spectrum of cycloeucalenol (128) showed fragment ions at m/z 426 which were tentatively identified using gas chromatography-mass spectrometry.The fragment ions of 24-methylenecycloartanol (129) were at 440 Phenols and flavonoids are the main secondary metabolites of T. sinensis.[50].In brief, an identical characteristic ion at m/z 125.02 was found in the MS/MS spectrum, which played an important part in the metabolite identification of gallic acid and its derivatives.
In  [50].In summary, an identical characteristic ion at m/z 163 was found in the MS/MS spectrum, which might have an important role in the metabolite identification of flavonoids and their derivatives.

Pharmacological Activities
T. sinensis, a well-known medicinal herb, has been traditionally used for treating various diseases.Our review of the pharmacological activities of T. sinensis showed that the bioactive properties included antidiabetic, antidiabetic nephropathy, antioxidant, antiinflammatory, antitumor, hepatoprotective, antiviral and antibacterial, and immunopotentiation effects on the male reproductive system and other activities.Detailed information of T. sinensis is shown in Table 2.These properties of T. sinensis could help us to understand its pharmacological activities.They also encourage us to use it without hesitation as a treatment for related diseases.a ↑ upregulation; ↓ downregulation.

Antidiabetic Activity
Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia.In recent decades, the hypoglycemic effects of T. sinensis have attracted increasing attention.All parts of T. sinensis have different degrees of inhibition of DM.The non-polar extracts of T. sinensis leaves (TSLs) prepared using supercritical-CO 2 fluid have been shown to prevent the progression of DM and liver fibrosis, increase triglyceride levels and decrease adiponectin levels in low-dose streptozotocin (STZ)-induced mice with type-2 diabetes mellitus (T2DM) [52].Hence, TSL non-polar extracts might contain active ingredients to prevent T2DM [52].The effects of TSL water extracts on alloxan-induced diabetic Long-Evans rats have been studied.After administration of TSL extract or gallic acid (154), the mRNA and protein expression of glucose transporter 4 (GLUT4) increased significantly in rats suffering from DM.Therefore, TSLs have hypoglycemic effects, and the mechanism of action involves an increase in the insulin level mediating the action of GLUT4 in fat [53].Cellular glucose uptake with a combination of TSL water extracts and insulin has been found to be inhibited significantly by treatment of 3T3-L1 adipocytes with cycloheximide (inhibitor of protein synthesis) and calphostin C (inhibitor of protein kinase C) in normal-, medium-and high-glucose media [54].The anti-DM effects and mechanism of action of 95% ethanol (EtOH) extracts from TSLs have also been studied in vitro and in vivo.TSL EtOH extracts have been shown to stimulate glucose uptake via adenosine monophosphateactivated protein kinase (AMPK) activation in skeletal muscles, promote the expression of peroxisome proliferator-activated receptor-gamma and normalize adiponectin expression in adipose tissues, thereby ameliorating insulin resistance [55].
Rutin (183) from TSL water extracts can improve glucose uptake in C57BL/6 mice with insulin-resistant T2DM by increasing insulin-dependent receptor kinase (IRK) activity [56].Quercetin (179), a flavonoid isolated from TSL ethyl acetate (EtOAc) extracts, can reduce hyperglycemia induced by the consumption of a high-carbohydrate/high-fat diet (HFD) and alloxan in mice suffering from DM. Quercetin (179) significantly inhibits the activation of p65/nuclear factor-kappa B (NF-κB) and the extracellular signal-regulated kinase 1/2/mitogen-activated protein kinase (ERK1/2/MAPK) pathways, as well as the levels of caspase-9 and caspase-3 in the liver tissue of mice with DM [57].These actions can reduce the risk of DM and its secondary complications by lessening oxidative stress in the liver [57].

Antidiabetic Nephropathy Activity
The petroleum-ether extracts of T. sinensis seeds could reduce the blood glucose level, urinary albumin level, serum creatinine level and urea nitrogen level, as well as indices of renal function and oxidative stress.Renal abnormalities could be improved in rats suffering from diabetic nephropathy (DN).Protein expression of transforming growth factor-β1 (TGF-β1), collagen IV (Col IV) and connective tissue growth factor (CTGF) could be reduced using the petroleum-ether extracts of T. sinensis seeds, and the petroleum-ether extracts of T. sinensis seeds have been shown to have protective effects on rats DN by inhibiting oxidative stress and protein expression of TGF-β1, Col IV and CTGF [58].The n-butanol extracts of T. sinensis seeds (NBAE) could significantly reduce the blood glucose level, urinary albumin level, serum creatinine level and urea nitrogen level, as well as the indices of kidney function and oxidative stress.NBAE could increase the activities of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), and reduce the level of malondialdehyde (MDA) in the serum of rats with STZ-induced DN, showing significant antioxidant activity in vivo.NBAE have been found to inhibit the expression of TGF-β1, Col IV and CTGF protein in rats with STZ-induced DN, showing protective effects on the kidney in these animals [59].High glucose (HG) induces oxidative stress injury after stimulating glomerular mesangial cells (GMCs).This action leads to an increased reactive oxygen species (ROS) level, decreased nitric oxide (NO) level, increased expression of p47phox and decreased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream proteins NAD(P)H quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1).NBAE can significantly increase the expression of Nrf2, NQO1 and HO-1, thereby inhibiting HG-induced ROS elevation, inhibiting p47phox expression and stabilizing NO content [60].Compared with the DN group, in the DN+NBAE group, the blood glucose level was reduced significantly and injury was alleviated.Otherwise, levels of monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1) and phosphorylated-p65 were reduced.In vitro, NBAE decreased the expression of MCP-1 and ICAM-1 significantly, which was similar to the effect elicited by treatment with a blocker of NF-κB p65 [61] (Figure 9).

Antioxidant Activity
The α,α-diphenyl-β-pricryl-hydrazyl (DPPH) radical scavenging test showed that the DPPH free-radical scavenging activities of extracts of the leaves, roots and barks of T. sinensis were concentration-dependent, and the half-maximal inhibitory concentrations (IC50) were 2.09 × 10 −1 , 2.85 × 10 −1 and 2.77 × 10 −1 mg/mL, respectively.These extracts could also reduce the accumulation of amyloid β-protein, thiobarbituric acid-reactive substances (TBARS) and cognitive deterioration in mice and increase the activities of SOD, CAT and GSH-Px to promote the antioxidant defense system.The compounds of T. sinensis extracts could delay the aging process in mice, which merits further study [63].The antioxidant activities of TSL acetone extracts, including oxygen radical absorption capacity (ORAC), peroxyl radical scavenging capacity (PSC) and cellular antioxidant activity (CAA), were evaluated.Anti-proliferative activities against human liver cancer (HepG2) cells were assessed using the methylene-blue assay.TSL acetone extracts possessed significant antioxidant properties and anti-proliferative effects against HepG2 cells in vitro [64].TSL aqueous extracts and gallic acid (154) treatment significantly inhibited ROS generation and MDA formation in 2,2′-azo-bis (2-amidinopropane) hydrochloride (AAPH)-stimulated human umbilical vein endothelial cells.Furthermore, pretreatment with TSL aqueous extracts/gallic acid significantly augmented AAPH-depleted SOD/CAT activity in endothelial cells.However, AAPH-induced Bax/B-cell lymphoma-2 (Bcl-2) dysregulation was re- GMCs were cultured and induced by advanced glycosylation end products (AGEs) to simulate DN in vitro.The mechanism of action of kaempferitrin (178, KM) from T. sinensis seeds to protect GMCs from AGE-induced damage was investigated.KM could increase SOD activity, reduce the level of MDA, inhibit ROS production and protect against oxidative stress in AGE-induced GMCs.These findings suggest that KM might be a drug for treating DN in the future [43].KAE (175) significantly reduced levels of ROS, NADPH oxidase (NOX) and MDA and enhanced SOD activity in HG-induced GMCs.The production of TGF-β1, Col IV, NOX4 and p22phox was also inhibited by KAE treatment.In addition, KAE increased the expression of sestrin2 and AMPK in HG-induced GMCs [62].Three apotirucallane-type triterpenoids, toonasinensin B (39), 21β-O-methylmelianodiol (26) and 21α-O-methylmelianodiol (25), from the pericarps of T. sinensis, could increase SOD activity significantly and reduce the levels of MDA and ROS, thereby preventing DN by reducing oxidative stress in GMCs cultured under HG conditions [15].Additionally, in this model, the cytotoxicity and polyol pathway inhibitory activities of active constituents from the pericarps of T. sinensis were evaluated.Toonasinensin B (39), toonasinensin D (41), 21β-O-methylmelianodiol (26) and 21α-O-methylmelianodiol (25) had good inhibitory effects on GMCs.Moreover, it was shown that toonasinensin B (39), 21β-O-methylmelianodiol (26) and 21α-O-methylmelianodiol (25) inhibited the production of NADPH and sorbitol in HG-induced GMCs for the first time.These compounds could be developed for the treatment of DN [27].Two acyclic diterpenoids (141 and 142) were isolated from the seeds of T. sinensis.They could significantly upregulate Nrf2/HO-1 expression and reduce the expression of NF-κB, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), thereby improving oxidative stress in HG-induced GMCs [25] (Figure 9).

Antioxidant Activity
The α,α-diphenyl-β-pricryl-hydrazyl (DPPH) radical scavenging test showed that the DPPH free-radical scavenging activities of extracts of the leaves, roots and barks of T. sinensis were concentration-dependent, and the half-maximal inhibitory concentrations (IC 50 ) were 2.09 × 10 −1 , 2.85 × 10 −1 and 2.77 × 10 −1 mg/mL, respectively.These extracts could also reduce the accumulation of amyloid β-protein, thiobarbituric acid-reactive substances (TBARS) and cognitive deterioration in mice and increase the activities of SOD, CAT and GSH-Px to promote the antioxidant defense system.The compounds of T. sinensis extracts could delay the aging process in mice, which merits further study [63].The antioxidant activities of TSL acetone extracts, including oxygen radical absorption capacity (ORAC), peroxyl radical scavenging capacity (PSC) and cellular antioxidant activity (CAA), were evaluated.Anti-proliferative activities against human liver cancer (HepG2) cells were assessed using the methylene-blue assay.TSL acetone extracts possessed significant antioxidant properties and anti-proliferative effects against HepG2 cells in vitro [64].TSL aqueous extracts and gallic acid (154) treatment significantly inhibited ROS generation and MDA formation in 2,2 ′ -azo-bis (2-amidinopropane) hydrochloride (AAPH)-stimulated human umbilical vein endothelial cells.Furthermore, pretreatment with TSL aqueous extracts/gallic acid significantly augmented AAPH-depleted SOD/CAT activity in endothelial cells.However, AAPH-induced Bax/B-cell lymphoma-2 (Bcl-2) dysregulation was reversed significantly by pretreatment with TSL aqueous extracts/gallic acid.Therefore, T. sinensis might have antioxidant effects to protect endothelial cells from oxidative stress [65].TSL also showed that the aqueous extracts and gallic acid (154) had effective antioxidant activity against various oxidative systems in vitro, including the scavenging of free-radicals and superoxide anion radicals, total reducing power and metal chelation.Furthermore, AAPH-induced oxidative hemolysis, lipid peroxidation and a decline in SOD activity in human erythrocytes were prevented by TSL extracts and gallic acid (154).In conclusion, TSL aqueous extracts and gallic acid (154) have antioxidant properties [66].
Toonasinenine D (103) seemed to possess higher anti-radical activities on ABTS but lower scavenging activity on DPPH than other compounds [31].

Anti-Inflammatory Activity
TSL water extracts could upregulate the expression of HO-1 and downregulate the expression of TNF-α to inhibit the lipopolysaccharide (LPS)-induced inflammatory response from macrophages [69].TSL aqueous extracts increased the level of total GSH and the ratio of GSH/glutathione oxide (GSSG) in RAW264.7 cells treated with LPS but decreased the levels of GSSG, total NO, nitrate, nitrite, MDA and superoxide anion.TSL water extracts reversed the effects of LPS-induced cytokines, including IL-6 and IL-10, to modulate autophagy during inflammation [70].The adventitious shoot extracts of T. sinensis showed good anti-inflammatory activity on LPS-treated RAW 264.7 cells and Propionibacterium acnes-treated HaCaT cells.Hence, the adventitious shoot extracts of T. sinensis could be used as a drug for the treatment of inflammatory skin diseases.The effects were regulated by suppression of the MAPK pathway [71].TSL aqueous extracts possessed effective anti-inflammatory features, including the suppression of LPS-induced NO production, as well as TNF-α secretion and protein expression of inducible nitric oxide synthase (iNOS) in BV-2 microglial cells without cytotoxicity.The results indicated that TSL aqueous extracts could inhibit the inflammatory response of microglia in neurodegenerative diseases [72].Polyphenols extracted from T. sinensis seeds alleviated 6-hydroxydopamineinduced neuroinflammation by inhibiting the p38 MAPK signaling pathway in a rat model of Parkinson ′ s disease [73].
T. sinensis has important research value for hypoglycemia.It could be used as medicinal plant material with anti-DM and anti-DN activities.T. sinensis extracts and their chemical constituents exert antioxidant and anti-inflammatory effects, mainly by activating the Nrf2/HO-1 pathway and inhibiting the NF-κB pathway in cell and animal models.They have certain curative effects by preventing and relieving oxidative stress and inflammation in DM or DN.
T. sinensis has important research value for hypoglycemia.It could be used as medicinal plant material with anti-DM and anti-DN activities.T. sinensis extracts and their chemical constituents exert antioxidant and anti-inflammatory effects, mainly by activating the Nrf2/HO-1 pathway and inhibiting the NF-κB pathway in cell and animal models.They have certain curative effects by preventing and relieving oxidative stress and inflammation in DM or DN.

Antitumor Activity
It has been found that TSL aqueous extracts can inhibit the viability of osteosarcoma cell lines (MG-63, Saos-2 and U2OS) by increasing mRNA expression of pro-apoptotic factors.These data suggest that TSL extracts suppress the growth of osteosarcoma cells by inducing apoptosis and are promising anti-osteosarcoma plant extracts [78].TSL aqueous extracts exhibit anti-leukemia activity in murine mouse blood cells (WEHI-3).After treatment with TSL aqueous extracts, the activities of WEHI-3 cells were reduced significantly, protein expression of cytochrome-C, caspase-3 and Bax increased significantly and

Antitumor Activity
It has been found that TSL aqueous extracts can inhibit the viability of osteosarcoma cell lines (MG-63, Saos-2 and U2OS) by increasing mRNA expression of pro-apoptotic factors.These data suggest that TSL extracts suppress the growth of osteosarcoma cells by inducing apoptosis and are promising anti-osteosarcoma plant extracts [78].TSL aqueous extracts exhibit anti-leukemia activity in murine mouse blood cells (WEHI-3).After treatment with TSL aqueous extracts, the activities of WEHI-3 cells were reduced significantly, protein expression of cytochrome-C, caspase-3 and Bax increased significantly and protein expression of Bcl-2 decreased significantly.The potential therapeutic effects of TSL aqueous extracts on leukemia were confirmed [79].TSL aqueous extracts have anti-proliferative effects in human pre-myelocytic leukemia (HL-60) cells by apoptosis induction that is associated with cytochrome-C translocation, caspase-3 activation, poly (ADP-ribose) polymerase (PARP) degradation and dysregulation of Bcl-2 and Bax.Hence, TSL aqueous extracts may have potential as an agent of chemotherapeutic and cytostatic activity in human leukemia [80].TSL aqueous extracts effectively blocked cell-cycle progression by inhibiting the expression of cyclin D1 and E in lung cancer (A549) cells.In addition, the incubation of these extracts led to the activation of caspase-3-like proteases and apoptotic cell death.These results suggest that T. sinensis components have potent anti-cancer effects in vitro.The identification of the useful components in these extracts may lead to the development of a novel class of anti-cancer drugs [81].The activity of TSL aqueous extracts against small-cell lung cancer is mainly through inhibition of the expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4) in H441 cells (lung adenocarcinoma) and H661 cells (lung large cell carcinoma) (IC 50 of 0.20 and 0.12 mg/mL, respectively) and the blockade of the cell cycle in the G1 phase.TSL aqueous extracts have an anti-proliferative effect on nonsmall-cell lung cancer [82,83].Other studies have shown that treatment with TSL aqueous extracts arrested human renal carcinoma cells in the G0/G1 phase through at decrease in the expression of cyclin D1, CDK2 and CDK4, as well as an induction of the expression of p53 and FOXO3a protein.These results suggest that TSL aqueous extracts may be employed for cancer treatment [84].TSL aqueous extracts were more cytotoxic than other fractions and exhibited selectivity for ovarian cancer cell lines.TSL aqueous extracts arrested ovarian cancer (SKOV3) cells in the G2/M phase and induced their apoptosis.These results indicate that TSL could be developed into a promising anti-ovarian cancer drug [85].In addition, TSL aqueous extracts can inhibit the proliferation and induce the apoptosis of hamster cheek pouch squamous cell carcinoma induced by 7,12-dimethylbenz[a]anthracene (DMBA).Downregulation of the protein expression of survivin, X chromosome-linked inhibitor of apoptosis (XIAP), proliferating cell nuclear antigen (PCNA), iNOS and COX-2 and increased apoptotic activity suggested that TSL therapy might aid the prevention of oral cancer [86].
The phenolic in TSL extracts inhibited the proliferation of colon cancer cells, HepG2 cells and breast cancer (MCF-7) cells significantly, with EC 50 values of 4.00 ± 0.39, 153.16 ± 13.49 and 193.46 ± 14.68 µg/mL, respectively [87].Gallic acid (154) has been identified as the major anti-cancer compound in TSL extracts.It is cytotoxic to prostate cancer (DU145) cells (IC 50 15.6 ± 2.1 µg/mL) through ROS generation and mitochondria-mediated apoptosis.These results suggest that gallic acid (154) could be developed into a drug to counteract prostate cancer [88].In addition, gallic acid (154) extracted from TSL induced the death of human oral squamous cell carcinoma (HOSCC) cells by upregulating expression of the pro-apoptotic genes TNF-α, TP53BP2 and GADD45A and downregulating the expression of the anti-apoptotic genes survivin and cIAP1.There was no effect on normal oral epithelial cells [89].Betulinic acid (130) and 3-oxours-12-en-28-oic acid (133) extracted from T. sinensis roots inhibited the proliferation of human gastric cancer (MGC-803) cells and human prostate cancer (PC3) cells and led to apoptosis (IC 50 17.7 and 13.6 µM, 26.5 and 21.9 µM, respectively) [90].The limonin-type triterpenoids toonasinenine A (99), B (101), C (102), D (103) and toonafolin (100) from TSL extracts had significant effects on all tumor cell lines, except glioma cell lines.Toonasinenine I (114) and J (115) from TSL extracts showed high cytotoxic activity against glioma cell lines [31].T. sinensis extracts and compounds have a wide range of anti-cancer effects.TSL have been studied extensively and could be a source of antitumor drugs.The antitumor activities of T. sinensis extracts might be related to their high content of phenolic and limonin-type triterpenoids.

Hepatoprotective Activity
TSL water extracts showed anti-fibrotic effects on rats with liver injury treated with thioacetamide (TAA), including reduced collagen formation and inflammatory factors (TGF-β1).These data demonstrate the beneficial effects of TSL water extracts on human liver injury by increasing detoxification and metabolic pathways [90].Polysaccharides from TSL extracts reduced the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and MDA, increased the activities of SOD, GSH-Px, CAT and GSH, decreased the expression of TNF-α and IL-6 and improved the liver injury induced by CCl 4 in mice.Hence, the polysaccharides in TSL extracts may have a hepatoprotective effect [91].Polyphenols extracted from the barks and fruits of T. sinensis could be used to treat non-alcoholic fatty liver disease by reducing lipoprotein expression in HepG2 cells treated with free fatty acid (FFA), activating the AMPK pathway, promoting lipid metabolism and reducing lipid accumulation [92].In mice with HFD and alloxan-induced DM, quercetin (179) from TSL EtOH extracts alleviated oxidative stress and liver damage significantly according to the measurement of lipid peroxidation, NO content and iNOS activity [57].Quercitrin (180) alleviated APAP-induced liver injury by inhibiting Janus kinase (JNK) and p38 signaling pathways, activating defense genes and inhibiting pro-inflammatory genes in HepG2 cells and animal models [77].TSL extracts have good hepatoprotective activity and could be used as raw materials to protect against liver damage.

Antiviral and Antibacterial Activity
Extracts from the tender leaves of T. sinensis had an obvious inhibitory effect on severe acute respiratory syndrome coronavirus (SARS-CoV), and the selectivity index was 12-17.These leaves may be an important resource for the prevention and control of SARS-CoV [93].Aqueous extracts of the tender leaves of T. sinensis had a highly selective inhibitory effect on the formation of MDCK plaque by the influenza A (H1N1) virus on A549 cells.They inhibited viral attachment by significantly downregulating the expression of adhesion molecules and chemokines (VCAM-1, ICAM-1, E-selectin, IL-8 and fractalkine).These results suggest that aqueous extracts of the tender leaves of T. sinensis might be an alternative treatment or prevention for H1N1 virus infection [94].
The essential oil of T. sinensis leaves (TSL-EO) contains many sesquiterpenes.Standard broth-microdilution methods were used to evaluate the antibacterial activity of 20 strains of methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA).TSL-EO therapy revealed inhibitory activity against MSSA and MRSA, and the minimum inhibitory concentration (MIC) was 0.125 and 1 mg/mL, respectively.The biological activity of TSL-EO may be related to the high content of sesquiterpenes [95].EtOAc extracts of T. sinensis shoots contain many polyphenols, glycosides and terpenoids.Antibacterial activity was determined using the agar hole-diffusion method and microdilution method.TSL-EO showed high inhibitory activity against Staphylococcus aureus, Shigella dysentery and Escherichia coli with MIC values of 1.56, 0.78 and 0.39 mg/mL, respectively [50].In summary, T. sinensis has an inhibitory effect on various viruses and bacteria.The antiviral and antibacterial effects of TSL are the most extensive, and they can be used as a potential source of antiviral and antibacterial drugs.

Immunopotentiation
A type of fish (tilapia) that received TSL hot-water extracts (≤8 µg/g) exhibited significant stimulatory effects on non-specific immune mechanisms and disease resistance.TSL hot-water extracts could be used as an immunostimulant in tilapia, but continuous administration may be necessary to maintain the protective response [13].The immunomodulatory activities of T. sinensis seeds were evaluated using cyclophosphamide-induced immunodeficiency in mice.The polysaccharide TSP-3a had a significant immune-restoring activity and enhanced phagocytosis [17].Rutin (183) extracted from TSL methanol extracts could regulate various functions of crustaceans.The survival rate of the littoral shrimp was improved significantly after rutin injection, indicating that a certain dose of rutin could improve the immunity of littoral shrimp to alginolytic Vibrio infection [9].

Effects on the Male Reproductive System
TSL aqueous extracts repressed the ROS level, maintained the mitochondrial membrane potential (MMP) and restored sperm motility to improve sperm and testicular function under oxidative stress [96].Studies have shown that increased levels of oxidative stress may be one of the main causes of decreased semen quality.T. sinensis can improve the dynamic activity of human sperm.Primary Leydig cells from mice were purified and tested in vitro.TSL aqueous extracts significantly inhibited the production of testosterone stimulated by basal and human chorionic gonadotropin (HCG) in a dose-dependent manner [97].The protective effects of TSL EtOH extracts on oxidative stress were studied using H 2 O 2 -treated human sperm.Sperm motility, MMP, denosine triphosphate level and maintenance of chromatin structural integrity were investigated.Therapy with TSL EtOH extracts improved sperm function under oxidative stress by reducing ROS levels and cell death [98].In conclusion, T. sinensis extracts are good natural bioactive products that increase the dynamic activity of human sperm and have great potential for development.

Other Aspects
In addition to the pharmacological effects stated earlier, T. sinensis has effects against visceral pain and depression and has neuroprotective effects.The effects of TSL aqueous extracts on antinociceptive activity were studied in a mouse model of visceral pain.The extracts had the same anti-visceral pain properties as those of Rofecoxib and Diclofenac, which have research value in the treatment of refractory visceral pain in humans [99].Essential oil isolated from T. ciliata Roem.var.yunnanensis leaves could increase the contents of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT) and brainderived neurotrophic factor (BDNF) in the hippocampus of rats with chronic mild stress (CMS) and could have anti-depression effects [100].EtOH extracts of limonin compounds isolated from the young leaves and buds of T. sinensis showed significant neuroprotective effects on 6-hydroxydopamine-induced death of human neuroblastoma (SH-SY5Y) cells, with EC 50 values ranging from 0.27 ± 0.03 to 17.28 ± 0.16 µM in vitro [32].In summary, the pharmacological activities of different parts of T. sinensis are extensive, and it is a natural bioactive product with great potential for development.
Given the current situation of T. sinensis resources, the selection, propagation and large-scale cultivation of new varieties should be strengthened.We should also strive to increase the number of populations, improve the quality of varieties and seedlings, as well as perform large-scale and standardized production in suitable growth areas to ensure the sustainable use of resources [101].

Conclusions
T. sinensis is a unique and precious tree species and traditional woody vegetable.It is used widely in the international market and enjoys the reputation of "Chinese mahogany".It is a famous medicine and edible plant in China, whose leaves, stems, seeds, barks and pericarps can be used as medicines.The chemical constituents and biological activities of T. sinensis have been investigated widely.
In this review, 206 compounds were compiled from T. sinensis, including triterpenoids, sesquiterpenoids, diterpenoids, sterols, phenols, flavonoids and phenylpropanoids.Terpenoids are the main constituents isolated from plants of the Meliaceae family.With regard to the pharmacological activities described for T. sinensis, studies performed using different in vivo and in vitro experimental biological methods have supported most of their traditional medicinal uses.Its extracts and chemical constituents have excellent biological activities, such as anti-DM, anti-DN, antioxidant, anti-inflammatory, antitumor, hepatoprotective, antiviral/antibacterial and immunopotentiation effects.
In summary, the chemical constituents, compound cracking laws and pharmacological activities of different parts of T. sinensis were reviewed systematically.This information might highlight the importance of this plant and provide some directions for its future development.In addition, further studies of the biological activities of T. sinensis extracts and compounds are needed.

Figure 1 .
Figure 1.Different parts of the T. sinensis plant and its chemical constituents and pharmacological activities.

Figure 1 .
Figure 1.Different parts of the T. sinensis plant and its chemical constituents and pharmacological activities.

32 Figure 9 .
Figure 9. Antidiabetic and antidiabetic nephropathy activities of extracts or compounds from T sinensis.

Figure 9 .
Figure 9. Antidiabetic and antidiabetic nephropathy activities of extracts or compounds from T. sinensis.

Author Contributions:
Conceptualization, W.L. and H.S.; methodology, data curation, writing-original draft preparation, M.Z. and H.L.; investigation, M.Z., H.L., S.L., Y.W. and Y.Z.; writing-review and editing, R.W. and W.L.; project administration, W.L. and H.S.; funding acquisition, W.L., R.W. and Y.Z.All authors have read and agreed to the published version of the manuscript.Funding: This research was funded by the National Nature Science Foundation of China, grant number 82304700 and 81274049; the Natural Science Foundation of Shandong Province, grant numbers ZR2022QH093, ZR2021MH124 and ZR2021QE276; the Graduate Quality Education and Teaching Resource Project of Shandong Province, grant number SDYKC2022141; the Shandong Science and Technology Research Project of Traditional Chinese Medicine, grant numbers 2020Q057; the Government-Sponsored Visiting Scholar Research Program of Weifang Medical University, grant numbers 2022 7-16.

Table 1 .
Chemical compounds isolated from the T. sinensis plant.