Structural Characters and Pharmacological Activity of Protopanaxadiol-Type Saponins and Protopanaxatriol-Type Saponins from Ginseng

Ginseng has a long history of drug application in China, which can treat various diseases and achieve significant efficacy. Ginsenosides have always been deemed important ingredients for pharmacological activities. Based on the structural characteristics of steroidal saponins, ginsenosides are mainly divided into protopanaxadiol-type saponins (PDS, mainly including Rb1, Rb2, Rd, Rc, Rh2, CK, and PPD) and protopanaxatriol-type saponins (PTS, mainly including Re, R1, Rg1, Rh1, Rf, and PPT). The structure differences between PDS and PTS result in the differences of pharmacological activities. This paper provides an overview of PDS and PTS, mainly focusing on their chemical profile, pharmacokinetics, hydrolytic metabolism, and pharmacological activities including antioxidant, antifatigue, antiaging, immunodulation, antitumor, cardiovascular protection, neuroprotection, and antidiabetes. It is intended to contribute to an in-depth study of the relationship between PDS and PTS.


Introduction
Over the centuries, traditional Chinese medicines have been widely used to treat numerous diseases for their perceived efectiveness, fewer side efects, and relatively low cost, which are currently attracting the most attention from researchers worldwide as alternative and supplemental medicines [1].Ginseng is a traditional Chinese medicine, also known as the God of grass, the king of herbs, that is the dried root or rhizome of the Araliaceae plant ginseng (Panax ginseng C.A. Meyer).Panax is derived from the word "panacea," which means a cure for all diseases and a source of longevity as well as physical strength and resistance [2].
Ginseng includes diverse chemical constituents, such as ginsenosides, fatty acids, polysaccharides, and polyacetylenes.Te extensive pharmacological activities can be attributed primarily to the triterpene saponins [3].Saponins include four-ring triterpene saponins (protopanaxadiol-type saponin (PDS) and protopanaxatriol-type saponin (PTS)) and fve-ring triterpene saponins (oleanane-type saponin).PDS and PTS are major efective components of ginseng.Modern pharmacological studies have proved that PDS and PTS have various efects such as antifatigue, antishock, antitumor, blood sugar regulation, immunoregulation, and the protection of liver, kidney, heart, spleen, thymus, and so on.However, PDS and PTS are poorly intestinal absorption and have low oral bioavailability because of their unfavorable physicochemical traits, such as large molecular mass (>500 Da), high hydrogen-bonding capacity (>12), high molecular fexibility (>10), and biliary excretion [4].Several ginsenosides such as Rb1, Rb2, Rc, and Rd are absorbed into the bile and show remarkably long elimination half-life (20∼40 h in mice) [5].Some ginsenosides with large molecular mass (Ra1, Re, Rb1, Rb2, etc.) are hydrolyzed by intestinal bacteria to produce secondary saponins including rare ginsenosides compound K (CK), Rh1, Rh2, Rg3, and Rg5, the later exert the better bioactivity and higher bioavailability.Te protopanaxadiol (PPD)-type ginsenoside Rb1 is hydrolyzed into Rd ⟶ F2 ⟶ CK ⟶ 20(S)-PPD [6]; the protopanaxatriol (PPT)-type ginsenoside Rg1 is hydrolyzed into Rh1 ⟶ 20(S)-PPT [7].Te human study showed that CK and Rh1 might reach the systemic circulation [8], and the plasma proteinbinding ratio of Rd and CK was 80∼95% and 99% in rats, respectively [4].Te diversities of PDS and PTS in the structural forms show a close relationship between biological and pharmacological actions.Terefore, the studies on the structure and transformation of PDS and PTS are important in understanding their biological efects and the possible health benefts of ginsenosides in humans.

Chemical Structure Characteristics of PDS and PTS
Ginsenosides comprise a hydrophobic four-ring steroidal system and a diverse range of sugar, such as glucose (glc), rhamnose (rha), xylose (xyl), and arabinose (ara) attached to the C-3, C-6, and C-20 positions.Most ginsenosides belong to the dammarane type, which divide into four types, i.e., PDS contains a hydrogen atom at C-6 (Rb1, Rb2, Rb3, Rc, Rd, Rg3, Rh2, etc.), the PTS group contains a C-6 sugar sidechain (Re, Rf, Rg1, Rg2, etc.), the oleanane type (Ro), and the ocotillol group (F11).Figure 1 shows the chemical structures of the two basic ginseng saponin types, and Table 1 summarizes the chemical structure characteristics of the saponin side chain in diferent ginsenosides.Te main ginsenosides include the PPD-type ginsenoside Rb1, Rb2, Rc, Rd, and PPT-type ginsenoside Re and Rg1 in the ginseng, which account for more than 90% of the total ginsenoside content.

Pharmacokinetics of PDS and PTS
Te chemical structures of PDS and PTS are tetracyclic triterpene saponins consisting of diferent positions and numbers of hydroxyl groups; therefore, the absorption, distribution, elimination metabolism, and bioavailability of PDS and PTS are obvious diferences in the body.At a given dose, the T max of oral PPD and PPT was 1.82 h and 0.58 h, respectively, and the absorption of PPT was faster than that of PPD.Meanwhile, PPT was eliminated rapidly from the body with an average T 1/2 for 0.80 h and Cl for 4.27 L/h/kg after i.v.administration; however, PPD was eliminated relatively slowly with a T 1/2 for 6.25 h and Cl for 0.98 L/h/kg.Te C max was 0.13 μg/mL and 1.04 μg/mL for PPT and PPD.Te bioavailability of PPT and PPD was 3.69% and 48.12%, respectively.Te absorption and bioavailability of PPD were higher than those of PPT, and the elimination rate of PPD was slower than that of PPT [16].Te T max of oral Rb1, Rb2, and Rb3 was 2 h, 4.8 h, and 1.5 h, respectively; the AUC 0-36h of Rb1 (63.5 mg/L•h) was about 10 times larger than that of Rb2 (6.4 mg/L•h) and was 1.7 times larger than that of Rb3 (37.4 mg/L•h).T max showed that the absorption of Rb3 was relatively fast, and Rb1 was relatively slow; AUC 0-36h showed that the absorption of Rb1 was more than Rb2 and Rb3.Te T 1/2 of Rb1, Rb2 and Rb3 was 12.5 h, 15.4 h, and 24.9 h through the tail vein, respectively; they were slowly eliminated in vivo, the elimination of Rb1 was the fastest, while Rb3 was the slowest among Rb1, Rb2, and Rb3.Te bioavailability of Rb1, Rb2, and Rb3 was 0.78%, 0.08, and 0.52%, respectively; they were poor oral absorption [17].T 1/2 of Re, Rg2, Rg1, Rh1, and PPT were 0.2 h, 0.1 h, 0.1 h, 0.4-0.7 h, and 1.9 h, respectively [20].Te Cl of Rb1, Rd, Re, and Rg1 was 0.08 L/h/kg, 0.01 L/h/kg, 1.8 L/h/kg, and 1.1 L/h/kg, respectively [19].Although the ginsenosides were poorly absorbed orally, the absorption of PDS was signifcantly higher than PTS in vivo.Te T 1/2 of PDS was higher than that of PTS, and the Cl of PDS was slower than that of PTS.PDS is trihydroxy substituted at C-3, C-12, and C-20, while PTS is at C-3, C-6, C-12, and C-20, such an elimination rate of PTS was faster than that of PDS because of the extra C-6 hydroxyl group [21].Meanwhile, the T max was increased with a reduction in the number of glycosides in the PDS.After absorbing, ginsenosides are widely distributed in various organs of the body.9, 12, 12, 12, and 14 ginsenosides were detected in the brain (Rb1 ) by a single intravenous bolus dose of Shenmai injection (SMI) [19].Te ginsenoside content of the kidney (8.33∼6250 ng/g) was highest, followed by the spleen (1.87∼2117 ng/g), heart (0.31∼1785 ng/g), liver (0.09∼1297 ng/g), and brain (0.16∼132 ng/g) [19,20].Te systemic exposure of PDS was signifcantly greater than that of PTS after oral administration of ginsenosides.However, systemic exposure has obvious diferences between PPD and PPT that needs widespread attention in clinical for optimizing dosage regimens and predicting outcomes in patients receiving ginseng-based therapy.

Hydrolytic Metabolism
Most ginsenosides of PDS and PTS are deglycosylated in the gastrointestinal tract via the action of intestinal bacteria, acid, alkali, and/or enzyme.Reports suggested that the hydrophilic ginsenosides (nR1, Rb1, Rg1, Rc, Re, and R1) were deglycosylated into hydrophobic secondary ginsenosides or aglycones (Rd, Rh2, CK, PPT, and PPD) by Lactobacillus plantarummediated fermentation [22,23].β-glucosidases were the important enzymes in the biological transformation process of ginsenosides, which could hydrolyze Rb1/Rb2/Rb3/Rc to generate the deglycosylation minor ginsenosides Rd, F2, CK, Rg3, Rh2, and PPD in the intestinal bacteria (Figure 2) [24,25].β-glucosidases also hydrolyzed Re to generate the minor ginsenosides Rg1, Rg2, F1, Rh1, and PPT (Figure 3) [26].All the metabolites are nonpolar compared to the parental components, which are easier to absorb to cell membranes and exhibit stronger bioavailability; these properties further determine their pharmacological efcacies.Meanwhile, some researchers found that several intestinal bacteria were essential to hydrolyze ginsenosides, such as Lactobacillus, Bacteroides, Bifdobacterium, Eubacterium, Prevotella, and Streptococcus [27,28].Ginseng polysaccharides enhance the systemic exposure, metabolism, and intestinal absorption of ginsenosides by afecting gut microbial [29,30].[31].Te antioxidative activity of Rg2 (IC50 value 14.12) was better than Rb1 (IC50 value 9.67) in AAPH-induced hemolysis; meanwhile, the antioxidation of the Z-confguration was greater than the E-confguration of pseudo-Rg2, pseudo-Rh2, pseudo-Rg3, and pseudo-Rh1 [32].Te orders of antioxidative efect were Rc > Rb1 and Re > Rd > R1 > Rg1 > Rb3 > Rh1 [31].Tese results showed that the antioxidative efect of PDS was stronger than that of PTS, most of the Z confguration was better than the E confguration, and the antioxidative activity of ginsenosides with low-sugar chain was higher than ginsenosides with high-sugar chain in PDS.Rb1, Rb2, Re, and Rg1 mainly reduced astrocytic death and ROS formation by increasing the activity of superoxide dismutase (SOD), glutathione peroxidases (GPx), and glutathione reductase (GR) [33].Rg3 signifcantly inhibited oxidative stress in cyclophosphamide-induced mice and exerted antioxidant efects by increasing the activities of catalase (CAT), SOD, and lysozyme and decreasing levels of xanthine oxidase and malondialdehyde (MDA) [34]    Advances in Pharmacological and Pharmaceutical Sciences SIRT1 expression and mitochondrial activity [35].CK protected human retinal pigment epithelial (RPE) cells from oxidative stress-stimulated damage by activating the Nrf2/HO-1 signaling [36].PTS well improved DNA damage and excessive activation of the DNA repair enzyme PARP-1 and inhibited depletion of the intracellular substrate NAD+ of endothelial cells induced by H2O2, which also reversed the decrease of the ATP/ADP ratio and the GSH/GSSG ratio by increasing the activities of GR and glutathione peroxidase (GSH-Px) [37].Rg1 exerted the antioxidant efect by activating the Akt/GSK3β/NRF2 pathway and reducing the cell apoptosis in the D-galinduced model mice [38].Rh4 increased the levels of SOD, glutathione (GSH), and nitric oxide (NO) and decreased the levels of MDA, tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and interleukin1β (IL-1β) in ethanolinduced gastric ulcer model rat, which inhibited the infammation and oxidative stress by blocking the MAPK/ NF-κB pathway [39].Tese results show that the antioxidative efect of PDS is stronger than PTS in vivo and in vitro.[40].Rg3 increased the serum levels of total cholesterol (TC), serum triglyceride (TG), and LDH and elevated the activity of SOD of skeletal muscles by activating SIRT1 and inhibiting the p53 transcription factor [41].Meanwhile, 20(R)-Rg3 entrapped in chitosan microspheres exerted antifatigue efects by increasing the residence time of Rg3 and promoting its absorption by nasal mucosa [42].Rg1 exerted the antifatigue efect by impacting the metabolism of taurine and mannose 6phosphate by epidermal growth factor receptor (EGFR) [43].Some ginsenosides targeted the creatine kinase muscle type (CKMM) in skeletal muscle [44].PPD and PPT were the fnal metabolites of PDS and PTS.Cheng et al. reported that PPD was the best activator of CKMM among the 12 dammarane-type compounds, and exerted an antifatigue efect by increasing the level of tissue phosphocreatine and delaying exercise-induced lactate accumulation.Te cyclization of the side chain, the hydroxyl group of C 6 , and the glycosylation of C-3, C-6, and C-20 in PDS and PTS reduced the activation efect of ginsenosides on the CKMM compared to PPD and PPT [44,45].Tese results show that PDS and PTS have antifatigue efects.In some results, the antifatigue efect of PDS is stronger than that of PTS, and the antioxidant activity of ginsenosides with low-sugar chain was higher than ginsenosides with high-sugar chain in PDS and PTS.  and Rg1 reduced ROS production, increased CAT activity, elevated the mtDNA content and ATP level, and attenuated the MMP depolarization of primary mouse astrocytes injury induced by oxygen-glucose deprivation/reoxygenation (OGD/R).Te protective efect of Rb1 on OGD/R-induced injury was stronger than that of Rg1 [47].Rb1 attenuated metabolic disorders of the aging-induced mouse by regulating the cell cycle and apoptotic pathway of cardiomyocytes [48].Rg1 exerted an antiaging function on hematopoietic stem cells by activating the SIRT3/SOD2 pathway, the p16(INK4a)-Rb and p19(Arf )-p53-p21(Cip/ Waf1) signaling pathways [49], increasing the lengths and activity of the telomere, and restraining mitochondrial pathway-mediated apoptosis in aging rat induced by D-gal [50].Also, Rg1 attenuated the cognitive capacity, senescence-related markers, and hippocampal neurogenesis and inhibited the expression of cellular senescenceassociated genes p53, p21Cip1/Waf1, and p19Arf of the hippocampus in D-gal-induced aging rat [51].Rh4 could target SIRT1 to inhibit oxidative stress and infammation of aging skeletal muscle cells by activating the PGC-1α-TFAM and HIF-1α-c-Myc pathways and enhancing mitochondrial homeostasis [52].Rg1, Re, and Rb1 were the major ginsenoside monomers that prolonged lifespan by activating NRF2/SKN-1, SIRT1/SIR 2.1, and FOXO/DAF-16 signaling pathways [53].Ginsenosides could also exert antiaging effects by delaying the occurrence of infammation.Te transformed ginsenosides Rd, GypXVII, Rg2, and PPT signifcantly inhibited TNF-α and IL-6 production induced by LPS compared to Rb1, Re, and Rg1; meanwhile, the antiinfammatory efect of Rd was stronger than that of PPT, Re, and Rg1 [54].Rb1 inhibited the extracellular matrix degradation, matrix metalloproteinase (MMP) production, infammatory cell infltration, and vascular smooth muscle cell (VSMC) dysfunction induced by Ang II through inhibiting the JNK and p38 signaling pathways; however, Rg1 could not improve the above indices [55].Zhang et al. reported that CK on acute arthritis showed the best antiinfammatory efect among Rg1, Rg3, Rg5, Rb1, Rh2, and CK [56].Tese results show that PDS on the antiaging efect is stronger than that of PTS.

Immunomodulatory Efect.
Te immune system is our main defense barrier against the invasion of pathogens.It detects and removes foreign substances and kills pathogens and other microorganisms.PDS (including Rg3, Rh2, Rb1, Rb2, Rc, Rd, CK, and PPD) and PTS (including Rg1, Rg2, Rh4, Re, and nR1) could activate the immune responses in some diseases, such as lung injury, liver injury, and asthma (Figure 4); however, PDS (including Rg3, Rb1, Rd, and CK) and PTS (R1 and R6) showed immunosuppressive properties in some diseases, such as rheumatoid arthritis (RA), septic shock, and sepsis (Figure 5) [57].Zhang et al. reported that both PDS and PTS protected the immunomodulatory of bone marrow, thymus, and spleen in immunosuppressed mice induced by cyclophosphamide (CP), they improved the hematopoiesis-related cytokines and infammatory cytokines, promoted the cell cycle and inhibited the apoptosis of bone marrow, and increased the CD4 + cell of spleen.However, the prevention efect of PDS was stronger than PTS in some parameters, including red blood cells, hemoglobin, IL-1β, IL-4, IL-10, TNF-α, CD4 + , and thymus index [58].CP is a chemotherapy drug that causes myelosuppression and immunosuppression, which disrupts the balance between T1 and T2.PDS and PTS promoted lymphocyte, macrophage, and endothelial cells to release cytokines, which regulated the immune response and the dynamic balance between T1 and T2.Rb1 regulated the immune function by enhancing the T-lymphocytes subsets (CD4 + and CD8 + ), the expressions of cytokines (IL-2, IL-6, IFN-c, and TNF-α), and the production of immunoglobulins (IgA, IgM, and IgG) of immune injury mice induced by deoxynivalenol [59].Rb2 bound to target proteins of immune regulation to improve the pathological characteristics of immunosuppression mice induced by CP, which enhanced the viability of natural killer cells and boosted the expression of IFN-c, TNF-α, IL-2, and IgG [60].CK inhibited the macrophage phagocytosis by decreasing overexpression of β-arrestin2, Gαi, TLR4, and NF-κB in the collagen-induced arthritis (CIA) mouse, which reduces the proportion of M1 by inhibiting the colocalization of β-arrestin2 with Gαi and TLR4 with Gαi and promoting TLR4 coupling with Gas [61]; meanwhile, CK downregulated dendritic cells (DCs) priming of T-cell activation and suppressed migration and of signaling CCL21/CCR7mediated T cells and DCs in mouse with collagen-induced arthritis (CIA) [62].Rg1 regulated the innate immune response in macrophages by diferentially modulating the expression of related cytokine and the NF-κB and PI3K/Akt/ mTOR pathways [63].Rg1 attenuates IL-1β-induced infammation and apoptosis of podocytes by increasing the NRF2 pathway [64].Re inhibited the production of IFN-c and immunity-related GTPase family M (IRGM) in CD4+ T cell; however, they had no changes in other autophagyrelated signaling molecules (including ERK, p38, and AKT-mTOR-p70S6k) [65].Minor ginsenosides Rg2 and Rh1 reduced LPS-induced PKCδ expression and translocation to the membrane, resulting in p38-STAT1 activation and NF-κB translocation; especially, the combined Rg2 and Rh1 further enhanced the blocking efect and reduced the levels of TNF-α, IL-1β, and IFN-β [66].PDS and PTS have good immune regulation by regulating ARK, MAPK, and ERK1/2 signaling pathways and balance between T1 and T2; PDS showed strong immune regulatory efects compared to PTS in some parameters.[68], and the presence of sugars in PPD and PPT aglycone structures reduced the toxicity on the human leukemia cells (THP-1) [69].

Anticancer
Te anticancer efects of PPD, CK, Rh2, Rb1, and Rb2 in PDS are popular research, and Rg1 and PPT are also studied (Figure 6).At present, PPD shows pleiotropic anticancer capabilities in most cancer cell lines [70], which activated caspase-3, -7, -8, and -9 to induce rapid apoptosis and autophagy of human glioma cell SF188 and U87MG through caspase-dependent and -independent mechanisms, respectively [71].PPD initiated the intrinsic and extrinsic apoptotic pathway of HepG2 cells by activating DR5, caspase-3, -8, -9, promoting the cleavage of PARP, and inhibiting the expression of Bcl-2 and Bcl-xl proteins.Zhu et al. found that ER was the molecular target of PPD, and   PPD induces cancer cell apoptosis through the ER stress pathway [72] [82] and inhibiting TGF-β1-induced EMT [83], NF-κB-mediated regulation of MMP-9 expression [84] in thyroid cancer, HepG2, and MCF-7 cells, respectively.PPT reduced the expression of tyrosinase-related protein-1 and -2 to inhibit the melanin synthesis and dendrite elongation of B16 melanoma cells through the CREB-MITF-tyrosinase signaling pathway [85].Most ginsenosides in PDS showed strong anticancer efects; however, Rg1 and PPT in PTS had anticancer efects.

Efect on the Cardiovascular System.
Cardiovascular disease is the main cause of morbidity and mortality in the world, and afects tens of millions of people every year.Atherosclerosis (AS) is the main foundation of pathology in heart attacks, strokes, and cerebral infarction.AS begins with infammation and thrombosis, which are considered to be caused by the damage of the vascular endothelial cells (ECs) and the deposition of lipids [86].In addition, hypercholesterolemia, hypertension, and diabetes can induce EC dysfunction to develop atherosclerosis.Over time, some infammation factors and proatherogenic transcriptional factors promote the formation of atherosclerotic lesions, which cause vascular remodeling, occlusion of the vascular lumen, thrombus, and bleeding, subsequently leading to acute myocardial infractions or stroke or acute ischemia of any nearby organ [87].Te underlying mechanism of ginsenoside treatment of atherosclerosis is the inhibition of key steps in the development of the pathology, such as vascular smooth muscle cell (VSMC) proliferation, endothelial dysfunction, lipid deposition, oxidative stress, hyperlipidemia, chronic infammation, and macrophage polarization [88].We summarized the efect of PDS and PTS on the cardiovascular system from the following two areas: antiplatelet aggregation efects and abnormal vascular remodeling.] i mobilization, and ATP release of collagen-induced platelets by the PI3K/Akt pathway [90].Ro showed the calcium antagonist efect, which inhibited platelet aggregation and [Ca 2+ ] i mobilization of human platelets induced by thrombin [91].Te antiplatelet aggregation and antithrombosis efects of PTS including Rg1, R1, and Re were stronger than those of total saponins from Panax notoginseng in the middle cerebral artery occlusion model rat by regulating the glycoprotein Ib-α to reduce von Willebrand factor-mediated platelet adhesion [92].PTS also inhibited platelet aggregation induced by collagen, thrombin, and ADP via inhibiting [Ca 2+ ] i mobilization and ERK2/ p38 activation [93].Rg1 inhibited platelet aggregation induced by various agonists including thrombin, ADP, collagen, and U46619 through afecting αIIbβ3-mediated outside-in signaling, and Rg1 also attenuated the arterial thrombus formation by inhibiting the activation and adhesion of platelets [94].Gao et al. compared the efect of some monomer saponins on ADP-induced platelet aggregation; they found that Rg2, Rh2, Rg3, Rg1, Re, Rd, and nFc obviously inhibited platelet aggregation; however, nFt1, PPD, nFe, and nR1 could promote ADP-induced rat platelet aggregation [95].Zhang et al. verifed the abovementioned results of PPD and 20(S)-panaxadiol (PD); they could induce the platelet aggregation and activation of human and rat platelets with 1 mM Ca 2+ , but the process required the participation of calcium ions.PD and PPD only slightly increased the platelet activation and cannot directly induce the platelet aggregation in vitro [96,97].To summarize, we thought that ginsenosides and aglycone exhibited opposite activity on the platelet.

Efects on the Abnormal Vascular Remodeling.
Abnormal vascular remodeling is a vital pathological event in cardiovascular disease.Ginsenosides obviously improved vasodilation dysfunction and abnormal vascular remodeling in cardiovascular diseases by afecting calcium ion channels [98].Rb1 and Rd inhibited mitochondrial swelling of cardiomyocytes induced by Ca 2+ , which protected the heart against I/R and H/R injury by inhibiting mitochondrial Advances in Pharmacological and Pharmaceutical Sciences permeability transition pore (mPTP) opening and restoring subsequent loss of mitochondrial membrane potential [99].
Rd was a voltage-independent Ca 2+ entry blocker that inhibited basilar hypertrophic remodeling in stroke-prone renovascular hypertensive rats [100].PPD caused vasodilation of endothelium-intact aortic rings by activating the Ca 2+ -activated K + channel [101].Rg1 signifcantly inhibited [Ca 2+ ] i overload, loss of mitochondrial membrane potential, and ROS production of astrocytes induced by H 2 O 2 .Angiogenesis plays an important role in ischemic cardiovascular disease, which recuperates the blood fow in the ischemic boundary and improves endogenous neurogenesis and neurological function.Rg1, a potent proangiogenic agent, induced the angiogenesis by targeting RUNX2 and increasing the vascular endothelial growth factor receptor-2 (VEGFR-2) in ischemic injury [102,103], which reduced the myocardial fbrosis and left ventricular hypertrophy by increasing the expression of HIF-1 and VEGF [104].R1 signifcantly restored cerebral blood fow and mitochondrial energy metabolism and promoted angiogenesis after ischemic stroke by regulating the NAMPT-NAD + -SIRT1 cascade and Notch/VEGFR-2 signaling pathways [105].Re showed the antiangiopathy efects by activating the p38 MAPK, ERK1/2, and JNK signaling in the T1DM and T2DM rats [106,107].PDS and PTS showed diferent therapeutic efects on cardiovascular diseases.Some ginsenosides of PTS, such as R1, Rg1, and Re showed proangiogenic action by regulating the VEGF-KDR/Flk-1 and PI3K-Akt-eNOS signaling pathways in ischemic cardiovascular disease [107,108].However, some ginsenosides of PDS, such as Rg3, Rh2, and Rd, inhibited the proliferation, migration, and vessel-like tube formation of HUVECs induced by VEGF via inhibiting VEGFR2-Gab1 signaling and Akt/mTOR/P70S6 kinase signaling [109,110].Migration of VSMC from their primary site and proliferate, which will lead to neointimal formation with subsequent vascular remodeling via a series of cellular cascades.Rg3 exhibited stronger antiproliferation and antimigration efects of VSMC in diabetic atherosclerosis [111].Rk1 increases the phosphorylation of myosin light chain and cortactin to reduce the vessel leakiness of the retina in DM mice [112].PTS mainly infuences vascular remodeling of the heart and brain, and the antiangiogenesis of PDS is more conducive to treat diabetes and cancer.[113].Rg3 attenuated Hcy-induced neurotoxicity and protected the vascular endothelial cells via Nmethyl-D-aspartate receptor (NMDAR) activation and the estrogen receptor (ER), respectively [114].Rg1 could exert an estrogenic efect by activating extracellular regulated protein kinases (ERK) and Akt signaling, and fnally improve memory [115].Rg1 also signifcantly improved the neurological defcit, attenuated the damage of the bloodbrain barrier by downregulating the expression of aquaporin 4, and reduced the neurological damage induced by cerebral ischemia/reperfusion injury in rats [116].Rb1 improved neurobehavioral function and neuroprotection after subarachnoid hemorrhage-induced brain injury [117] and also signifcantly promoted neurite growth in hippocampal neurons and protected neurons from Aβ-induced neurotoxicity [118].Rd and Re exerted neuroprotective efects by reducing cell loss and degeneration and protecting the length and number of neurites in tyrosine hydroxylase (TH+) cells [119].Rd could improve learning and memory ability and exhibit neuroprotective efects in model mice, probably through inhibiting the transcription activity of NF-κB, reducing proinfammatory cytokines, and generating protective factors [120].Rb1 and Rg1 improved the cognitive impairment induced by simulated microgravity in rats; the protective efects of Rb1 are superior to Rg1 in some    [123], and PDS obviously inhibited the activity of BACE1.Rb1 could relieve cognitive defcits by decreasing expressions of IL-1β, Aβ, and glial fbrillary acidic protein (GFAP) and alter the amyloidogenic process of APP into the nonamyloidogenic process in AD rats by exerting anti-infammatory [128].Disturbed energy metabolism adversely afects AD pathology.CK was used as a prophylactic or therapeutic agent for AD by promoting the activity of glucose transporters (GLUTs) to increase ATP levels and inhibiting neuronal damage by Aβ peptides through activation of energy metabolism signaling pathways and Nrf2/Keap1 signaling pathway [129,130].Both PDS and PTS improve Alzheimer's disease; however, they act through diferent mechanisms.

Efect on the
5.6.Antidiabetes.Diabetes is one of the major global health problems and there is an especially high rate of incidence in the elderly population.It has been shown that ginsenosides, especially PDS and PTS possess antihyperglycemic activity in vitro and in vivo.Deng et al. reported that PDS and PTS treated the high-fat diet/streptozocin-induced type 2 diabetes mellitus (T2DM) mice by inhibiting expression of hepatic metabolism genes (peroxisome proliferatoractivated receptor gamma coactivator 1-alpha, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase) and promoting the expression of lipid metabolism genes (microsomal triglyceride transfer protein).PDS exhibited a better efect on the improvement of T2DM than PTS in most indicators, such as body weight, blood glucose, ITT, serum insulin content, C peptide, TNF-α, and IL-6 [131].Rb1 reduced 11β-hydroxysteroid type I dehydrogenase (11β-HSD1) levels in liver and adipose tissue, attenuated insulin sensitivity and elevated blood glucose in T2DM mice [132].Rg1 improved blood glucose levels and insulin resistance index, as well as lipid distribution and liver function of T2DM mice [133].20(R)-Rg3 treatment not only attenuated fasting blood glucose (FBG) levels and advanced glycation end products (AGEs) levels but also improved insulin (INS) levels, blood lipids, oxidative stress, and renal function by regulating MAPKs and NF-κB signal pathways in diabetic nephropathy mice [134].Rg3 enhanced islet cell function and attenuated islet cell apoptosis in mice, and insulin secretion was 2.3-fold higher in the 4 μM Rg3-treated islet cells compared with the untreated reference islet cells [135].Rb1 exerted protective efects on diabetes and diabetic complications by regulating mitochondrial energy metabolism, improving insulin resistance, and alleviating the occurrence of complications [136].Rb1 also regulated the glycolipid metabolism and improved the insulin and leptin sensitivities to exert the antiobesity and antihyperglycemic.Re reversed the insulin resistance and glucose transporter 4 translocation in high-fat diet-induced rats; however, the efect of Re on insulin-stimulated glucose transport was specifc, which did not change the skeletal muscle glucose transport induced by contraction and hypoxia [137].Chen et al. thought that the antidiabetic efects of ginsenosides are positive for T2DM but have no signifcant improvement in prediabetes or healthy adults [138].

Conclusions and Future Perspectives
In conclusion, PDS and PTS are important active ingredients of ginseng with strong pharmacological activities, including antioxidant, antifatigue, antiaging, immunomodulation, antitumor, cardiovascular, neuroprotection, and antidiabetic.In recent years, the chemical composition, pharmacokinetics, hydrolytic metabolism, and pharmacological activities of PDS and PTS have been extensively studied, and some important progresses have been made.Due to the diference in chemical structure between PDS and PTS, the absorption, distribution, elimination metabolism, and bioavailability of PDS and PTS are obviously diferent in vivo and in vitro.Te absorption and bioavailability of PDS is higher than those of PTS in vivo; and the elimination rate of PTS is faster than that of PDS.Meanwhile, the absorption and bioavailability of ginsenosides were increased with a reduction in the number of glycosides.Te systemic Advances in Pharmacological and Pharmaceutical Sciences exposure of PDS was signifcantly greater than that of PTS after oral administration of ginsenosides, such PDS needs widespread attention in clinical for optimizing dosage regimens and predicting outcomes in patients receiving ginseng-based therapy.We summarized the absorption, metabolism, biotransformation, and pharmacological efects of PDS and PTS, and pharmacokinetic parameters of PDS and PTS are closely related to drug activity.It is hoped that the information gathered will facilitate further discussion and research on PDS and PTS.Poly ADP-ribose polymerase RUNX2:

Figure 1 :
Figure 1: Te structures of PPD-type ginsenosides core and PPT-type ginsenosides core.

Figure 3 :
Figure 3: Schematic diagram of PTS in vivo metabolism.

Figure 5 :
Figure 5: Te immunosuppressive role of ginsenosides in vivo.

Table 1 :
Structure characteristics of PDS and PTS.

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[46]nces in Pharmacological and Pharmaceutical Sciences 5.1.3.Antiaging.Aging is mainly characterized by a progressive dysfunction of metabolism and various physiological roles.PDS and PTS are important antiaging drugs that could promote the metabolism and proliferation of stem cells, protect the skin, brain, heart, and nerves, enhance mitochondrial function and telomerase activity, and maintain the intestinal fora[46].Xu et al. reported that Rb1 . CK, the important metabolite of PDS in the body, was almost nonexistent in ginseng.CK induced the cancer cell apoptosis by multiple signal pathways.Te Akt/ mTOR/c-Myc signaling pathway is involved in aerobic glycolysis and tumor growth.Shin et al.