Biomedicine & Pharmacotherapy 170 (2024) 116051

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Dioscin: Therapeutic potential for diabetes and complications

Haoyang Gao a, b, 1, Ze Wang a, b, 1, Danlin Zhu a, b, Linlin Zhao a, b, c, *, Weihua Xiao a, b, *
a
Shanghai Key Lab of Human Performance (Shanghai University of sport), Shanghai University of Sport, Shanghai 200438, China
b
The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China
c
School of Physical Education, Shanghai Normal University, Shanghai 200234, China

A R T I C L E I N F O A B S T R A C T

Keywords: Diabetes mellitus is a widespread metabolic disorder with increasing incidence worldwide, posing a considerable
Dioscin threat to human health because of its complications. Therefore, cost-effective antidiabetic drugs with minimal
Therapeutics side effects are urgently needed. Dioscin, a naturally occurring compound, helps to reduce the complications of
Diabetes mellitus
diabetes mellitus by regulating glucose and lipid metabolism, protecting islet β cells, improving insulin resis­
Diabetic complications
tance, and inhibiting oxidative stress and inflammatory response. Plant-derived dioscin reduces the risk of
toxicity and side effects associated with chemically synthesized drugs. It is a promising option for treating
diabetes mellitus because of its preventive and therapeutic effects, which may be attributed to a variety of un­
derlying mechanisms. However, data compiled by current studies are preliminary. Information about the mo­
lecular mechanism of dioscin remains limited, and no high-quality human experiments and clinical trials for
testing its safety and efficacy have been conducted. As a resource for research in this area, this review is expected
to provide a systematic framework for the application of dioscin in the treatment of diabetes mellitus and its
complications.

Abbreviations: DM, Diabetes mellitus; T1DM, Type 1 diabetes mellitus; T2DM, Type 2 diabetes mellitus; IR, insulin resistance; IDF, International Diabetes
Federation; TCM, Traditional Chinese medicine; Dio, Dioscin; TLR4, toll-like receptor 4; MyD88, myeloid differentiation factor 8; TGF-β, transforming growth factor
β; ADME, pharmacokinetic; GLUT-4, glucose transporter-4; GSK-3β, glycogen synthase kinase-3β; PEPCK, phosphoenolpyruvate carboxykinase; G6Pase, glucose 6-
phosphatase; HFD, High-fat diet; SREBP-1c, sterol regulatory element binding protein-1c; FAS, fatty acid synthase; ACC, acetyl-CoA carboxylase; SCD1, stearoyl-CoA
desaturase-1; AMPK, AMP-activated protein kinase; MAPK, mitogen-activated protein kinase; C/EBP, CCAAT/enhancer-binding protein; PPARγ, peroxisome
proliferator-activated receptor γ; IRS, insulin receptor substrate; PI3K, phosphatidylinositol 3-kinase; Akt/PKB, protein kinase B; PA, palmitic acid; SIRT1, sirtuin 1;
FoxO1, forkhead box protein O1; ROS, reactive oxygen species; PKC, protein kinase C; SOD, superoxide dismutase; Nrf2, nuclear factor E2-related factor-2; HO-1,
heme oxygenase-1; GSH-Px, glutathione peroxidase; CAT, catalase; MDA, malondialdehyde; IL-1β, Interleukin-1β; IL-6, Interleukin-6; TNF-α, tumor necrosis factor-α;
IKKβ/IKBβ, inhibitor of nuclear factor kappa-B kinaseβ; NF-κB, nuclear factor kappa-B; JNK, c-Jun N-terminal kinase; COX2, Cyclooxygenase-2; STZ, streptozotocin;
TSDN, total saponins from D. nipponica Makino; DKD, Diabetic kidney disease; CKD, Chronic Kidney Disease; mtDNA, mitochondrial DNA; nDNA, nuclear DNA;
mTOR, mammalian target of rapamycin; DN, Diabetic neuropathy; DPN, diabetic peripheral neuropathy; DSPN, distal symmetric polyneuropathy; NGF, Nerve
growth factor; PDPN, Painful diabetic peripheral neuropathy; DC, Diabetic cardiomyopathy; TGF, transforming growth factor; NO, nitric oxide; sGC, soluble gua­
nylate cyclase; cGMP, cyclic guanosine monophosphate; PKG, cGMP-dependent protein kinase; DR, Diabetic retinopathy; AGEs, advanced glycation end products;
NPDR, nonproliferative; PDR, proliferative diabetic retinopathy; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor;
HRMECs, human retinal microvascular endothelial cells; AS, atherosclerosis; oxLDL, oxidized low-density lipoprotein; LOX‑1, lectin‑like oxidized low‑density li­
poprotein receptor‑1; DCs, dendritic cells; SR-A, class A scavenger receptors; DCD, Diabetes cognitive dysfunction; P2×7R, purinergic 2 × 7 receptor; NLRP3, NOD-
like receptor thermal protein domain associated protein 3; BMD, bone mineral density; ASC, recruitment domain; RANKL, receptor activator for nuclear factor-κ B
ligand; TRAF6, TNF receptor associated factor 6; TSRD, total saponins extracted from Rhizoma Dioscorea bulbifera; CYP, cytochrome P450; AhR, aromatic hy­
drocarbon receptor; DPP-4, Dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT-2, sodium-glucose co-transporter-2.
* Corresponding author at: Shanghai Key Lab of Human Performance (Shanghai University of Sport), Shanghai University of Sport, 650 Qingyuan RingRoad,
Yangpu District, Shanghai 200438, China.
E-mail addresses: linlinzhao666@163.com (L. Zhao), xiaoweihua@sus.edu.cn (W. Xiao).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.biopha.2023.116051
Received 15 October 2023; Received in revised form 13 December 2023; Accepted 15 December 2023
Available online 28 December 2023
0753-3322/© 2023 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
H. Gao et al. Biomedicine & Pharmacotherapy 170 (2024) 116051

1. Introduction effect of “activating blood circulation and reducing tendon, dissipating

food and promoting water, eliminating phlegm, and halting malaria”
Diabetes mellitus (DM) is a chronic metabolic disease characterized [11]. Modern medical research has also shown that Dio has antitumor,
by persistent hyperglycemia caused by insufficient insulin secretion and anti-inflammatory, immunomodulatory, lipid-lowering, antiviral, anti­
defective insulin action and is accompanied by carbohydrate, fat, and fungal, and anti-allergic effects, which can protect the liver, kidney,
protein metabolism disorders. It is classified into type 1 DM (T1DM), brain, and gastrointestinal tract from damage by inhibiting inflamma­
type 2 DM (T2DM), and other particular types according to etiology. tion, apoptosis, necrosis, lipid peroxidation, and mitochondrial
T1DM, also known as insulin-dependent DM, is usually caused by the dysfunction [12]. Furthermore, Dio exhibits therapeutic potential
damage of islet β cells, resulting in insufficient insulin production in the against metabolic diseases, such as DM, osteoporosis, obesity, and
body. It affects over 1.2 million of children and adolescents and is the nonalcoholic fatty liver disease, by influencing lipid accumulation,
prevalent type in these age groups [1]. Meanwhile, T2DM is the most oxidative damage, autophagy, and glucose metabolism [12,13]. The
prevalent type of DM, constituting approximately 90–95 % DM cases underlying mechanisms of these diverse therapeutic actions may involve
[2]. It is mainly caused by insulin resistance (IR) and the relative defi­ the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88
ciency of insulin. Other specific types of DM have complex and diverse (MyD88), sirtuin 1 (Sirt1)/nuclear factor E2-related factor-2 (Nrf2),
causes associated with various factors, including genetics, medications, FXR, and transforming growth factor β (TGF-β)/Smads signal pathways
or diseases [2]. The prevalence of DM has been increasing worldwide. In [12]. To date, Dio has not been found to have serious side effects [13].
fact, the International Diabetes Federation stated that approximately As an economical and easy-to-obtain natural ingredient, Dio has had
537 million people have DM in 2021, and this number is projected to sound therapeutic effects on DM in vitro and in vivo. The conclusions of
reach 643 million by 2030 and 783 million by 2045 [3]. In 2021, a systematic review confirmed the potential of yam extracts, including
approximately 6.7 million adults died due to DM or its complications, Dio, as a functional food for treating T2DM in the rodent models of DM
accounting for 12.2 % of the overall mortality in this age group [3,4]. by improving fasting plasma glucose levels and insulin sensitivity [14].
Among these, about one-third of the patients with DM are less than 60 This article reviews and analyzes recent studies on Dio in treating DM
years old [3,4]. These, DM has become an essential threat to human and its complications to provide the theoretical basis for further phar­
health worldwide. macological research and subsequent clinical research and treatment of
Persistent hyperglycemia causes severe damage to various tissues DM (Fig. 1).
and organs, especially blood vessels and nerves, and then generate a In this review, we conducted a comprehensive search of major da­
variety of acute or chronic complications [5–7]. DM is a high-risk factor tabases (PubMed, Google Scholar, Web of Science, CNKI) up to
for many fatal diseases [8]. For example, patients with DM are two or November 2023, using the keywords “Dioscin,” “Dioscin AND diabetes,”
three times more likely than the general population to develop cardio­ “Dioscin AND diabetic complications,” and “Dioscin AND antidiabetic
vascular and cerebrovascular diseases, which presents a serious risk to effects.” Research on the therapeutic efficacy and mechanism of action
their health, seriously affects quality of life, and exerts profoundly of Dio in DM and diabetic complications was emphasized, and the
negative effect on individuals and families [9]. Therefore, the treatment literature from the last 5–10 years was included to ensure access to
of DM, especially T2DM, has always been a top priority for researchers current information. A total of 147 documents were eventually included.
and clinicians worldwide. Additionally, we described the pharmacological properties and phar­
Traditional Chinese medicine (TCM) is widely used to treat many macokinetics of Dio; the therapeutic effects of Dio on DM and various
diseases, including DM. Dioscin (Dio) with a chemical name (3β,25 R) diabetic complications; its potential mechanism of action, interactions
-spirost-5-en-3-ylo-6-deoxy-α-L-mannopyranosyl-(1− 2)-[6-deoxy-α-L- with cellular components at the cellular level, toxicological properties,
mannopyranosyl-(1− 4)]-β-D-glucopyranoside is a natural steroidal and potential side effects; and the progress in the clinical application of
saponin found in Dioscorea, Liliaceae, Solanaceae, and leguminous plants. Dio. Finally, we summarized the contents of this paper and discussed the
Dio is abundant in the rhizomes of Dioscorea, such as Dioscorea zingi­ future direction for research.
berensis and Dioscorea nipponica Makino [10]. TCM believes it has the

Fig. 1. Chemical structure of dioscin and its various sources (from www.iplant.cn). Dioscin with a chemical name (3β,25R) -spirost-5-en-3-ylo-6-deoxy-α-L-
mannopyranosyl-(1− 2)-[6-deoxy-α-L-mannopyranosyl-(1− 4)]-β-D-glucopyranoside is a natural steroidal saponin found in Dioscorea, Liliaceae, Solanaceae, and
leguminous plants. Dio is abundant in the rhizomes of Dioscorea, such as Dioscorea zingiberensis and Dioscorea nipponica Makino.

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2. Pharmacological properties and pharmacokinetics of dioscin biological activities and is essential to the regulation of
inflammation-related pathways [25,26]. When adipose dysfunction oc­
In clinical practice, Dio is mainly administered orally. A pharmaco­ curs, adipokine production and secretion disorder cause chronic
kinetic study that used the UPLC-QTOF-MS method demonstrated that low-grade inflammation, eventually leading to IR and T2DM [26–28].
Dio is absorbed from the digestive tract into the blood circulation slowly Therefore, regulating lipid metabolism disorders and controlling obesity
(>1 h) but gradually increased and lasted longer (>36 h) after oral and lipid accumulation are of great value in T2DM prevention and
administration in rats [15]. In animal models, the absolute bioavail­ treatment. Dio has lipase-inhibiting activity, inhibits fat absorption, and
ability of Dio after oral administration is extremely low (0.2 %) [16]. has shown anti-obesity potential in rodents [29]. Liu et al. [30] found
Manda et al. [17] conducted a systematic study of the in vitro phar­ that Dio promoted fatty acid β-oxidation and induced cell autophagy in
macokinetic (ADME) properties of Dio, including its stability in bio­ mice and ob/ob mice fed with high-fat diet (HFD). In addition, Dio can
logical fluids, gastrointestinal absorption stability, and metabolic inhibit the synthesis of triglycerides and cholesterol, thereby reducing
stability; their experimental results showed that (1) Dio had poor sta­ body weight and liver lipid accumulation in mice in a dose-dependent
bility in the digestive tract fluids, the degradation rates of Dio in gastric manner [30]. By regulating the miR-125a-5p/STAT3 pathway, Dio
and intestinal fluids were as high as 28.3 % and 12.4 %, respectively. (2) inhibited the transcription of hepatic sterol regulatory element binding
Dio has a moderate level of intestinal permeability. (3) The metabolic protein-1c (SREBP-1c) reduced the expression of downstream adipo­
stability of Dio is good, with a half-life of 25.6 h after oral administra­ genic genes, including fatty acid synthase (FAS), acetyl-CoA carboxylase
tion. In a drug interaction study [18], humans did not cause inhibition of (ACC), and stearoyl-CoA desaturase-1 (SCD1), and ultimately reduced
important enzyme activities in vivo [18]. This indicates that Dio has lipid production and accumulation [23]. In addition, Dio also exerted a
good pharmacological compatibility and that combination therapy lipid-lowering effect in a rabbit model; it considerably reduced choles­
makes it possible to affect the metabolism of other drugs almost or very terol diet-induced increase in rabbit serum cholesterol level and lipid
weakly. deposition in the liver and arteries [31]. Its mechanism may involve the
activation of AMP-activated protein kinase (AMPK) phosphorylation,
3. Preventive and therapeutic effects and mechanisms of dioscin inactivation of ACC, and acceleration of lipid catabolism [31]. In addi­
on diabetes mellitus tion, Dio promotes the phosphorylation of AMPK and inhibits
mitogen-activated protein kinase (MAPK), thereby inhibiting adipocyte
3.1. Regulation of glucose metabolism differentiation by down-regulating of adipogenic transcription factors,
such as CCAAT/enhancer-binding protein (C/EBP) α, C/EBP β/δ, and
Persistently high blood glucose level is a crucial feature of DM and a peroxisome proliferator-activated receptor γ(PPARγ), a attenuating the
fundamental factor enabling DM to cause severe damage to the body. expression of adipogenesis-associated genes in 3T3-L1 cells, and regu­
Dio improves glucose metabolism disorders and lowers blood glucose. lating fat accumulation in obese mice [32].
Carbohydrates in food are broken down and eventually absorbed by the
small intestine into the bloodstream as glucose. However, glucose 3.3. Protection of islet β cells and alleviation of insulin resistance
transport and absorption require many enzymes and carriers, including
α-glucosidase, α-amylase, disaccharidases, Na+-K+-ATPase, sodium- Islet β cells are the specific sites of insulin secretion and critical
glucose co-transporter 1 (SGLT-1), and glucose transporter-4(GLUT-4) factors along with insulin in the pathogenesis of various types of DM.
[19]. Therefore, inhibiting the activity of enzymes or carriers related T1DM occurs when pancreatic β cells are damaged, and insulin secretion
to glucose transport and absorption will lower blood glucose level. is deficient because of genetic or pharmacological factors. However,
Zhang et al. [20] showed that Dio from plants inhibits α-glucosidase patients with T2DM have insufficient insulin, and thus their islet β cells
activity and has relatively low toxicity. Dio extracted from fenugreek are forced to secrete large amounts of insulin. This condition leads to the
can inhibit SGLT-1 activity and SGLT-1-mediated glucose absorption, dysfunction and substantial damage of islet β cells [33]. IR refers to
thereby delaying glucose absorption [21]. In addition to its role in the decrease in the sensitivity of tissues and organs [34] and renders insulin
digestion and absorption of glucose, Dio exerts a significant effect on the unable to effectively increase glucose uptake and utilization, thereby
regulation of glucose metabolism in vivo. As early as 2007, Yoshikawa reducing blood glucose levels organs [34]. IR is a pathological phe­
et al. [22] confirmed that the oral administration of Dio can inhibit in­ nomenon and predisposing factor of great diagnostic significance in
crease in blood glucose level in rats with sucrose load, and this effect is T2DM, usually precedes the progression of T2DM, and is a key compo­
dose dependent. Notably, this study showed that 50 mg/kg Dio admin­ nent of metabolic syndrome [35]. However, IR’s specific mechanism and
istered orally is more effective than the classic antidiabetic drug met­ etiology remain unclear. Dio treatment can reduce the apoptosis of
formin hydrochloride [22]. Xu et al. [23] explored the potential RNAKT-15 pancreatic cells with high glucose levels by down-regulating
mechanism underlying Dio’s effects that alleviate glucose and lipid the expression of p-GSK3β and β-catenin through the Wnt/ β-catenin
metabolism disorders in T2DM by establishing a T2DM mouse model signaling pathway, exerting a protective effect on islet β cells and pro­
and conducting in vitro experiments; the results showed that Dio low­ moting their proliferation [36]. Adipose tissue is a target tissue for the
ered blood glucose level by regulating glycogen synthase kinase-3β glucose-lowering effect of insulin. The binding of insulin to the insulin
(GSK-3β), phosphoenolpyruvate carboxykinase (PEPCK) and glucose receptor substrate (IRS) on adipocytes activates two major related
6-phosphatase (G6Pase) activity and other related enzymes promoted signaling pathways: phosphatidylinositol 3-kinase (PI3K)/protein ki­
glycogen synthesis and inhibited gluconeogenesis. The mechanisms nase B (AKT) pathway, which is critical for most of the metabolic effects
involved elevating the level of miR-125a-5p and inhibiting the expres­ of insulin and Ras-MAPK signaling pathway [25]. Dio significantly re­
sion of the STAT3 gene [23]. duces IR in adipose tissues by up-regulating the expression of the
IRS-1/PI3K/AKT pathway and may be used as a therapeutic agent for
3.2. Regulation of lipid metabolism treating IR in adipose tissue [37]. As the core organ of glucose and lipid
metabolism, the liver is an important target organ of insulin. The
Dyslipidemia induced by lipid metabolism disorder is an important excessive accumulation of liver fat can induce IR in the liver and further
pathological feature of T2DM. Oesity is a major high-risk trigger of aggravate metabolic dysfunction. Xu et al. [23] reported that Dio
T2DM and plays an essential role in the pathogenesis of T2DM [24]. improved glucose and lipid metabolic homeostasis in insulin-induced
Adipose tissue is not only traditional energy reservoirs but also an HepG2 cells and palmitic acid-induced AML12 cells. Dio improves he­
endocrine organ that can secrete various bioactive proteins, including patic insulin sensitivity in HFD- and streptozocin (STZ)-induced T2DM
adipokines and cytokines. It has anti-inflammatory or proinflammatory in rats and spontaneous T2DM KK-Ay mice. It can inhibit STAT3

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signaling by up-regulating miR-125a-5p and then promote the phos­ FOXO1 in the liver of mice. Their results also indicated the potential of
phorylation of PI3K and AKT, thereby alleviating hepatic IR [23]. In­ Dio in anti-obesity and indirect prevention of T2DM by inhibiting liver
sulin is secreted and released by the endocrine part of the pancreas. inflammatory response. In adipose tissue, adiponectin is an adipokine
When IR occurs, the endocrine function of islet cells falls into a vicious secreted by adipocytes with anti-inflammatory and insulin-sensitizing
cycle, leading to the damage of pancreatic cells and tissues [38]. Dio can effects. Studies have shown that Dio can increase the production and
alleviate IR and markedly reduce pancreatic tissue damage in T2DM rats secretion of adiponectin in adipocytes, thereby mediating an indirect
[39]. The underlying mechanism may be mediated by increasing the anti-inflammatory effect [32].
level of SIRT1 and decreasing the level of forkhead box protein O1 In summary, Dio (1) regulates glucose metabolism and alleviates
(FOXO1), and enhancing autophagy in pancreatic tissues [39]. hyperglycemia; (2) regulates lipid metabolism and alleviates hyperlip­
idemia; (3) protects islet β cells, promotes insulin secretion, alleviates
3.4. Regulation of oxidative stress IR, and improves the sensitivity of tissues and organs to insulin; (4)
regulates oxidative stress-related signaling pathways and biological
An imbalance between oxidative reaction and antioxidant action in molecules and reduces oxidative stress injury; (5) regulates
the body usually causes oxidative stress. The accumulation of free rad­ inflammation-related signaling pathways and the secretion and release
icals through excessive oxidation is an essential pathogenesis of many of inflammatory factors and inhibits harmful inflammatory response.
diseases and can cause tissue and cell damage. Sustained hyperglycemia These mechanisms have shown effects that potentially prevent and treat
directly increases reactive oxygen species (ROS) level and a variety of DM (Fig. 2). Table 1.
inflammatory markers, and the progression of oxidative stress and
inflammation impairs IR and insulin secretion and eventually lead to the 4. Preventive and therapeutic effects and mechanisms of dioscin
occurrence of DM [40]. In addition, ROS directly oxidize and damage for diabetic complications
DNA, proteins, and lipids and triggers a series of biochemical reactions,
such as the nonenzymatic glycosylation of proteins in the body, 4.1. Diabetic kidney disease
increased activity of the body’s poly-alcohol pathway, and activation of
protein kinase C (PKC), which plays a critical role in the pathogenesis of Diabetic kidney disease (DKD) is a common complication of diabetic
advanced diabetic complications [41]. Therefore, controlling oxidative microangiopathy caused by persistent hyperglycemia. DKD occurs in
stress is of great practical significance to DM prevention and treatment. approximately 40 % of diabetic patients and is the leading cause of
Dio has an excellent protective effect against oxidative stress in various chronic kidney disease (CKD) and end-stage renal disease worldwide. It
tissues and organ injury models. The mechanisms involved promoting is a major but underrecognized contributor to the global burden of
the expression of superoxide dismutase (SOD), Nrf2, heme oxygenase-1 disease [51,52].
(HO-1), glutathione peroxidase (GSH-Px), catalase (CAT) and other Chronic inflammation is an important pathologic mechanism in DKD
endogenous antioxidant enzymes expression, In addition, it also signif­ and plays a central role in its progression, and persistent inflammation
icantly reduced the contents of peroxidation products ROS and malon­ determines the continued progression of kidney injury [53]. Cai et al.
dialdehyde (MDA) [42–45]. It scavenged excess free radicals, improved [53] reported that in STZ-induced DKD mouse model, the continuous
antioxidant capacity, reduced oxidative stress damage, and improved oral administration of Dio for 8 weeks reduced the inflammatory
glucose and lipid metabolism disorders and IR in diabetic mice [30,46]. response and alleviated STZ-induced kidney injury in diabetic mice by
inhibiting the activation of the TLR4/NF-κB pathway and the production
3.5. Inhibition of inflammatory response of inflammatory cytokines. Moreover, in the present study, TLR4 plays
an indispensable role in STZ-induced DKD because the knockdown of
Inflammation is the body’s defense response to harmful stimuli. It is TLR4 directly ameliorates renal injury caused by STZ [53]. Oxidative
mediated by proinflammatory cytokines, such as interleukin-1β (IL-1β), stress is an important initiating factor in the pathogenesis of DKD.
interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) [47]. Inflam­ Continuous oxidative stress damage can cause mitochondrial DNA
matory response is involved in the occurrence and development of DM. (mtDNA) and nuclear DNA (nDNA) damage in renal parenchymal cells,
Obesity and excessive lipid accumulation cause disorders in the secre­ further leading to mitochondrial dysfunction and apoptosis. Zhong et al.
tion function of adipose tissues, the release of adipokines, and the [54] confirmed the renoprotective effect of Dio on HFD + STZ-induced
release of proinflammatory cytokines. Adipose tissues store proin­ diabetic rats; renal and mitochondrial function improved, and renal
flammatory factors, which is transported to tissue cells throughout the oxidative stress, inflammation, apoptosis, and autophagy were reduced;
body through the bloodstream. The proinflammatory cytokines then their experimental results showed that Dio inhibited renal oxidative
cause an inflammatory response and the activation and infiltration of stress injury and inflammatory response by reducing the production of
macrophages in various tissues, including adipose tissues. IR subse­ ROS and expression of inflammatory factors and enhancing antioxidant
quently occurs in adipose tissues, liver, skeletal muscles, and other tis­ enzyme activity [54]. In addition, Dio can inhibit mitochondrial and
sues and organs related to glucose metabolism, eventually leading to endoplasmic reticulum stress-mediated apoptosis and enhance auto­
T2DM [48–50]. The molecular mechanism involved may be the obesity- phagy by activating the AMPK/mammalian target of rapamycin(mTOR)
and HFD-induced activation of the inhibitor of nuclear factor kappa-B signaling pathway [54]. Mitochondrial quality control processes include
kinaseβ (IKKβ/IKBβ)/ nuclear factor kappa-B (NF-κB) and c-Jun N-ter­ mitophagy and mitochondrial dynamics (fusion and fission). The
minal kinase (JNK) signaling pathways in adipocytes, hepatocytes, and enhancement of mitophagy and the inhibition of mitochondrial fission
associated macrophages [50]. Yu et al. [46] reported the protective ef­ by Dio contributes to its protective effect against DKD [54]. In the high
fect of diosgenin with Dio as the main active ingredient on T2DM rats; fructose-induced rat kidney injury model, Dio restored the expression of
after 12 weeks of drug intervention, fasting blood glucose, blood lipids, Sirt3, partially reversed renal oxidative stress injury, inflammatory
serum insulin levels, and other biochemical indicators markedly response, renal fibrosis, and lipid metabolism disorder mediated by its
improved; the marked decrease in the expression levels of TNF-α and inhibition, and rescued renal pathological changes induced by fructose,
IL-6 genes suggested that the antidiabetic activity of Dio is partially showing an excellent multitarget renal-protective effect [55]. Maithili
mediated by clearing excessive inflammatory factors and inhibiting in­ et al. [56] tested the antidiabetic effect of the ethanol extract of Dio­
flammatory response. Similarly, Liu et al. [30] found that Dio treatment scorea alata tubers in alloxan-induced diabetic rats; they showed that
significantly down-regulated the activation of NF-κB, Cyclooxygenase-2 rats treated with the extract had a near-normal reversal of serum lipid,
(COX2), and other inflammation-related proteins in HFD mice and total protein, albumin, and creatinine levels compared with diabetic
ob/ob mice and inhibited the mRNA expression of TNF-α, IL-1, IL-6 and control rats. This result suggested that renal function in the diabetic rats

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(caption on next page)

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H. Gao et al. Biomedicine & Pharmacotherapy 170 (2024) 116051

Fig. 2. Dioscin for the treatment of diabetes through multiple targets and multiple mechanisms. A. Dio regulates glucose metabolism and alleviates hy­
perglycemia. Dio inhibits the activity of α-glucosidase and SGLT-1, thereby impeding the transport and absorption of exogenous glucose. Additionally, Dio regulates
the miR-125a-5p/STAT3 pathway, activating GSK-3β to promote glycogen synthesis. Dio down-regulates the activities of PEPCK and G6Pase, suppressing gluco­
neogenesis. B. Dio regulates lipid metabolism and alleviates hyperlipidemia. Dio inhibits the absorption of exogenous fat by inhibiting the activity of pancreatic
lipase. Dio activates key enzymes in the process of fatty acid transport and oxidative catabolism, and promotes the β-oxidation of fatty acids. Dio can inhibit the
transcription of SREBP-1c in the liver, down-regulate the expression of FAS, ACC, SCD1 and other genes, and inhibit lipid synthesis through miR-125a-5p/STAT3
pathway. Dio promotes the phosphorylation of AMPK and inhibits the phosphorylation of MAPK, down-regulates the expression of downstream adipogenesis
related genes, thereby promoting lipid catabolism and inhibiting the differentiation and adipogenesis of adipocytes. C. Dio protects islet β cells, promotes insulin
secretion, alleviates IR, and improves the sensitivity of tissues and organs to insulin. Dio inhibits apoptosis and promotes proliferation of pancreatic β cells by down-
regulating Wnt/ β-catenin signaling pathway. Dio increases the level of SIRT1 and decrease the level of FOXO and enhances autophagy in pancreatic tissues. Dio
improves adipose tissue IR by activating IRS-1/PI3K/AKT pathway. Dio promotes the phosphorylation of PI3K and AKT by regulating the miR-125a-5p/STAT3
pathway and improves hepatic IR.D. Dio regulates oxidative stress-related signaling pathways and biological molecules and reduces oxidative stress injury; Dio
promote the expression of SOD, Nrf2, HO-1, GSH-Px, CAT and other endogenous antioxidant enzymes expression, In addition, it also significantly reduced the
contents of peroxidation products ROS and MDA. Dio can scavenge excess free radicals, improved antioxidant capacity, reduced oxidative stress damage; E. Dio
regulates inflammation-related signaling pathways and the secretion and release of inflammatory factors and inhibits harmful inflammatory response. Dio inhibits
the activation of IKKβ/ NF-κB signaling pathway in adipocytes, hepatocytes and macrophages, promotes the production and release of anti-inflammatory factor-
adiponectin in adipose tissue, and down-regulates the expression of inflammatory factors such as TNF-α, IL-1, IL-6, FOXO1 and COX2, thereby inhibiting inflam­
matory response.

Table 1
Table of studies of Dioscin treatment for diabetic.
Experimental model/cell line Dosage Anti-diabetes function References
In vivo In vitro

sucrose-loaded rats Dioscin 50 mg/kg, p.o Inhibited the increase of serum glucose levels. [22]
HFD andSTZ induced Insulin-inducedHepG2 cells, Rats:Diocin 15,30 and 60 mg/kg, Mice:Diocin 20,40 Promotes glycogen synthesis. Inhibits [23]
T2DMrats, and T2DM palmitic acidinduced AML-12 and 80 mg/kg,gavage daily for 8 weeks Cell:Diocin gluconeogenesis and lipogenesisImprove
KK-Ay mice cells 50,100 and 200nmol/L for 24h insulin resistance.
HFD induced mice and Diocin 20,40 and 80 mg/kg,gavage daily for 8 weeks Promote fatty β-oxidation. Inhibits liver lipid [30]
ob/ob mice accumulation.Inhibits oxidative stress.Inhibits
inflammatory.
cholesterol-fed rabbit 50 g kg− 1 50 mesh-size DP flour or 50 g Promote the acceleration of lipid catabolism [31]
kg− 1nanoscale DP flour for for 8 weeks
HFD induced mice 3T3-L1 cells Mice:Diocin 50mg/kg,gavage for 7 weeks Cells: Inhibits adipocyte differentiation and [32]
Diocin 4μmol/L adipogenesis
High glucose-induced Diocin 25,50μmol/L for 24h Promotes proliferation of islet βcellsInhibits [36]
RNAKT-15 cells apoptosis of islet βcells
HFD induced mice Dioscin 5, 10 and 20 mg/kg gavage for18weeks Improve insulin resistance in adipose tissues [37]
HFD andSTZ induced Dioscin 5, 10 and 20 mg/kg gavage for 4 weeks Promotes insulin sensitivityInhibits pancreatic [39]
T2DM rats tissue damage Improve insulin resistance
HFD andSTZ induced TSDN 200, 100 and 50mg/kg body weight, p.o for 12 Inhibits oxidative stressInhibits inflammatory [46]
T2DM rats weeks

improved after Dio treatment. and T2DM-induced death of neurons. Notably, phase II clinical trials for
treating DN with DA-9801 was completed in the United States in 2015.
This achievement is a crucial step toward transformation to clinical
4.2. Diabetic neuropathy
treatment [62].
Painful DPN (PDPN) is a neuropathic pain caused by sensory neu­
Diabetic neuropathy (DN) is a common chronic complication of DM.
ropathy in DPN and characterized by spontaneous pain, hyperalgesia,
The central, peripheral, and autonomic nervous systems can be affected
decreased pain threshold, and a certain degree of sensory loss. It causes
by DN. In diabetic peripheral neuropathy (DPN), distal symmetric pol­
great pain and place mental burden on patients. Given the unclear
yneuropathy is a typical pathological manifestation and starts from the
pathogenesis of PDPN and lack of specific drugs, symptomatic analgesia
distal end of the lower limbs and gradually develops to the proximal end,
is the primary treatment. Dio has an analgesic effect on PDPN. Leng et al.
showing a “glove and sock” distribution of sensory disorders with or
[63] found that Dio in the extract of Pangolanthus longus reduced his­
without motor and autonomic disorders [57,58]. Sensory and motor
tamine and 5-hydroxytryptamine levels in the sera of diabetic rats; they
dysfunctions caused by DN increase the risk of falls, induce foot lesions,
used databases, software, and other technical means to construct an
and cause abnormal pain, seriously affecting quality of life [59].
“active ingredients-target-signaling pathway” network diagram through
Nerve growth factor (NGF), a member of the neurotrophins family,
target prediction, drug-like analysis, GO gene enrichment analysis, and
plays a crucial role in the onset of DN [60]. DA-9801, a drug with Dio as
KEGG pathway annotation analysis. They predicted the potential
the main active ingredient, exhibits anti-DN potential. Moon et al. [61]
mechanism by which Dio regulates signaling pathways related to
studied the therapeutic effect of DA-9801 on DN in vitro and in vivo; the
inflammation, immunity, and oxidative stress [64].
results of the in vivo experiments showed that DA-9801 greatly
decreased the blood glucose level in db/db mice, increased the secretion
of NGF from primary astrocytes, increased the levels of NGF in sciatic 4.3. Diabetic cardiomyopathy
nerve and plasma, and improved changes in nerve conduction velocity
and ultrastructure; the results of the in vitro experiments showed that DC is defined as a human pathophysiological condition in which
DA-9801 promoted neurite outgrowth and the mRNA expression of patients with DM develop heart failure in the absence of coronary artery
Tieg1/Klf10, which is an NGF target gene, in PC12 cells; There study disease, hypertension, and valvular heart disease [65]. IR, T2DM hy­
suggested that DA-9801 ameliorates peripheral neuropathy by promot­ perglycemia, and hyperinsulinemia are significant independent risk
ing the production and secretion of NGF and inhibiting the degeneration factors for DC and lead to cardiac pathophysiological changes, including

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myocardial fibrosis, myocardial hypertrophy, myocardial inflammation, 4.5. Diabetic atherosclerosis

oxidative stress, cellular calcium transport defects, and changes in
myocardial contractile proteins and metabolic substrates. All these ab­ The risk of cardiovascular disease considerably increases in patients
normalities lead to changes in myocardial structure and myocardial with DM. One of the most important factors is the microvascular and
dysfunction and systolic heart failure [66]. macrovascular complications of DM caused by high glucose, which
The chronic inflammation of cardiomyocytes is one of the main seriously damage human blood vessels’ standard structure and function
pathological changes of DC. Dio prevented DC damage by improving left [5]. Generalized systemic vascular dysfunction, including significant
ventricular function and myocardial histological pathological changes artery stiffness, endothelial dysfunction, and vascular smooth muscle
in STZ-induced diabetic rats. It reduces the levels of inflammatory fac­ dysfunction, is the main feature and basis of diabetic angiopathy [79].
tors transforming growth factor (TGF)-β1, TNF-α, and IL-1β [67]. These Macrophage-derived foam cells have a critical regulatory role in the
positive changes may be mediated by the up-regulation of nitric oxide development of atherosclerosis (AS). In 2017, Wang et al. [80] first re­
(NO)–soluble guanylate cyclase enzyme (sGC)–cyclic guanosine mono­ ported the anti-AS activity of Dio in vivo and in vitro; Dio considerably
phosphate (cGMP)–cGMP-dependent protein kinase (PKG) signaling reduced plasma lipids and inflammatory factors, such as TNF-a, IL-1β,
pathway [67]. In addition to direct studies related to DC, several studies and IL-6 in HFD-induced AS rats and delayed the progression of AS. The
have reported Dio’s molecular mechanism and effects on cardiomyop­ in vitro studies showed that Dio directly inhibited foam cell formation in
athy caused by other factors. Zhao et al. [42] found that Dio reduces macrophages treated with oxidized low-density lipoprotein (oxLDL) and
adriamycin-induced cardiotoxicity by inhibiting myocardial oxidative reduced intracellular cholesterol accumulation and TNF-α, IL-1β, and
stress mediated by miR-140–5p. The results of similar studies have IL-6 secretion [80]. Mechanistically, Dio significantly reduced lec­
provided valuable insights into Dio and DC, providing ideas and theo­ tin‑like oxidized low‑density lipoprotein receptor‑1 (LOX‑1) and NF-κB
retical support to future research. expression in aortic tissues and oxLDL-treated macrophages; these re­
sults suggested that Dio mediates the protective effect of oxLDL uptake
4.4. Diabetic retinopathy by macrophages and DM-associated AS by down-regulating the
oxLDL/LOX-1/NF-κB axis [80]. Apart from macrophages, dendritic cells
Diabetic retinopathy(DR) is one of the chronic complications of DM (DCs) are essential in AS. DCs can accumulate in the vessel wall, mediate
with high specificity and is a common and severe ocular complication of vascular inflammation and monocyte adhesion in atherosclerotic pla­
DM-induced neurovascular diseases affecting the eye [68]. It is the ques, and play a role in the development of AS [81]. Li et al. [81] found
leading cause of blindness in adults aged 20–74 in developed countries that Dio down-regulated the expression of class A scavenger receptors
[69]. Patients with DM are susceptible to glaucoma, cataract, and other (SR-A) and CD36 and LOX-1 genes and reduced the content of p38
eye diseases [69]. Moreover, DR negatively affects quality of life, and MAPK protein in DCs induced by high glucose level. Dio decreased the
the occurrence and development of DR usually increase the risk of production of ROS, inflammatory cytokine secretion, and oxLDL uptake
life-threatening systemic vascular complications [70]. in DCs, playing a positive role in the prevention AS caused by diabetic
The pathogenesis of DR is complex, which is often caused by the hyperglycemia [81].
accumulation of advanced glycation end products(AGEs), oxidative
stress damage, inflammation, and other factors. DR is divided into two 4.6. Diabetes cognitive dysfunction
stages according to whether neovascularization is present: non­
proliferative(NPDR) and proliferative diabetic retinopathy(PDR) [71]. Diabetes cognitive dysfunction (DCD) refers to the DM-induced
The former is characterized by local ischemia and hypoxia induced by impairment of memory, learning ability, executive function, and other
basement membrane thickening, tight junction damage, and blood­ cognitive functions. Age (aging) is a prominent risk factor for the
–retinal barrier destruction. In the progression of ischemia and hypoxia, development of DCD [82]. Although DCD is not considered a typical
retinal neovascularization accelerates in the PDR stage, leading to serum complication of DM, it may reflect changes in the brain caused by DM.
leakage, hemorrhage, and fibrovascular proliferation at the vitreoretinal Therefore, DCD in elderly patients with DM needs to be further explored.
interface and ultimately to vitreous hemorrhage and tractional retinal Lu et al. [83] investigated the effect of Dio on DCD by using a
detachment [72]. Although the physiopathological mechanism of DR methylglyoxal-treated PC12 cell model and STZ-induced rat model; they
has not been fully elucidated, substantial evidence has shown that the found that Dio inhibited purinergic 2 × 7 receptor (P2×7R)/NOD-like
activated overexpression of vascular endothelial growth factor (VEGF) receptor thermal protein domain associated protein 3 (NLRP3) signaling
has a clear and substantial link to the progression of DR [73]. The levels pathway and alleviated cognitive impairment induced by T2DM,
of VEGF in ocular humor and sera of patients with DR significantly demonstrating the value of Dio in DCD prevention.
increased, especially in patients with PDR [74,75]. Under physiological
conditions, VEGF maintains regular vascular endothelial activity and 4.7. Diabetic bone disease
function. In PDR, high levels of VEGF stimulate ocular pathological
neovascularization. Under hypoxic conditions, VEGF is overexpressed In addition to soft tissues, bones are vital target organs involved in
by retinal endothelial cells, pericytes, and pigment epithelial cells; this diabetic complications. Inferior bone quality, increased fracture risk,
increase promotes the activation of inflammatory factors, increases and prolonged fracture healing time are some of the complications of
capillary permeability, adhesion, and infiltration of inflammatory cells, DM [84]. Bone tissues in patients with DM are usually characterized by
and leads to retinal hemorrhage, exudation, macular edema, and neo­ bone microstructure destruction, negative bone metabolism balance,
vascularization [76,77]. Thus, angiogenesis underlies the pathophysi­ and decreased bone turnover rate [85–87]. However, the pathological
ology of PDR pathogenesis, and VEGF plays a critical role in this process phenotype of bone vary by DM type. For example, patients with T1DM
[77]. usually show bone mass loss and low bone mineral density (BMD). By
Targeting VEGF is a practical approach for preventing and treating contrast, patients with T2DM typically have normal or even high BMD
DR. A study by Wang et al. [78] showed that Dio inhibited the activation but have severely impaired bone microstructure and biomechanical
of VEGFA-vascular endothelial growth factor receptor (VEGFR)2 properties [88–92].
signaling pathway and cell proliferation in human retinal microvascular One study showed that the oral administration of Dio partly treated
endothelial cells (HRMECs) cultured in a high glucose environment; bone loss caused by T2DM and improved BMD levels in T2DM rats [46].
subsequently, their in vivo study confirmed that Dio administration However, the mechanism is still unclear. NLRP3 inflammasome is a
inhibited retinal vascular injury and pro-angiogenic factor expression in cytosolic signaling protein complex containing caspase activation and
diabetic db/db mice. recruitment domain (ASC) and caspase-1 and NLRP3, which is

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particularly important for the activation and maturation of IL-1β and multitarget drug. Dio can prevent and treat a variety of complications,
IL-18. It is a critical component of the innate immune system [93]. As an such as DKD, DN, DC, DR, AS and DCD, by regulating various targets and
immune-mediated disease or inflammatory disease, DM has been closely signaling pathways. In addition, Dio has shown full therapeutic poten­
related to NLRP3 inflammasome in recent years [94]. High glucose level tial for DM-related lung and bone lesions (Fig. 3). Table 2.
is a critical initiating factor for NLRP3 activation, and a high-glucose
environment can induce the production of large amounts of ROS in 5. Molecular interaction between dioscin and cell components
bone tissues, activate NLRPS inflammasome, and induce DM-related
bone loss or a complex bone regeneration [95,96]. Therefore, the for­ The cell is the basic unit of life activity. Dio can influence the func­
mation and activation of NLRP3 is a crucial initiating factor for tion and homeostasis of subcellular structures within a cell, which in
DM-related bone disease. Dio can indirectly inhibit NLRP3 expression by turn shows biological activity.
directly inhibiting the activation of NLRP3 inflammasome or regulating
multiple related signaling pathways [97] and has a direct regulatory 5.1. Cell membrane
effect on bone metabolism. Moreover, Dio can promote the expression of
osteogenesis-related factors, increase the formation of mineralized The cell membrane is a semipermeable membrane composed of
nodules, and significantly reduce the number of Receptor Activator for phospholipid bilayer with physiological functions, such as bio­
Nuclear Factor-κ B Ligand (RANKL)-induced TRAP-positive multinu­ recognition and material transport, and is extremely important for the
cleated cells in MC3T3-E1 cells. It considerably reduces RANKL-induced normal homeostasis of cells. Studies have shown that Dio has a
TNF receptor associated factor 6 (TRAF6) and downstream signaling destructive effect on cell membranes. Exposure to high concentrations of
molecules [98,99]. These results indicated that Dio can promote osteo­ Dio often leading to hemolysis by rupture of red blood cells [115]. In
blast proliferation, inhibit osteoclast formation, and positively regulate addition, the hepatotoxicity of Dio has also been confirmed to be related
bone metabolic homeostasis. It promotes the differentiation and matu­ to the destructive effect of Dio on liver cell membrane [116]. Lin et al.
ration of bone marrow mesenchymal stem cells into chondrocytes [100]. [117] showed that exogenous Dio can first penetrate the lipid bilayer
Therefore, Dio is a promising drug for treating DM-related bone and move toward and aggregate in the microstructural domains of lipid
diseases. rafts, where it formed complexes with cholesterol, destabilized lipid
rafts, and led to the severe bending of the lipid bilayer and ultimately to
4.8. Diabetic lung disease the collapse and rupture of the cell membrane. Nevertheless, this
complex-forming feature of Dio is necessary for its pharmacological
The lungs have rich alveolar capillary networks and connective tis­ functions, such as antibacterial, antiparasitic, and antitumor. Interest­
sues. Researchers had long believed that the lungs are not the main ingly, the strength of Dio’s disruptive effect on the plasma membrane is
organs affected by DM. However, a growing number of clinical cases and influenced by the number of sugar units in the Dio molecule and the
research have shown that DM is significantly related to pulmonary osmotic pressure environment in which a cell is exposed [118,119].
dysfunction and accelerates cardiovascular disease in patients with DM
[101–103]. High blood glucose level and damage due to AGE accumu­ 5.2. Mitochondria
lation induce an inflammatory response in the lungs, leading to pul­
monary fibrosis. Increased lung volume and weight; increased collagen, Mitochondria are the primary site of aerobic respiration in the cell
elastin, and hydroxyproline content; and decreased glycated connective and they perform many functions, such as biosynthesizing molecules,
tissue protein breakdown in STZ-induced T1DM rat models [104,105]. balancing redox equivalents, and processing metabolic wastes [120].
Hyper glucose-induced pulmonary fibrosis in STZ-induced diabetic Thus, mitochondria are indispensable to the balance of cellular meta­
mouse models is more severe than in mice treated with bleomycin, bolism. Studies on various tumors, including lung cancer, gastric cancer,
which is the standard drug for experimental pulmonary fibrosis induc­ and glioblastoma, have confirmed that Dio can directly target the
tion in animal models [104]. Studies have confirmed that lung tissue mitochondria of tumor cells and exert significant anticancer activity
fibrosis is a key pathological feature of progressive lung injury in dia­ [121–126]. Specifically, Dio induces the production of ROS in cells and
betic patients [106]. structural changes in mitochondria, increases mitochondrial membrane
Dio, which has anti-inflammatory and antioxidant effects, effectively permeability, and decreases mitochondrial membrane potential. These
provides protection against lipopolysaccharide-induced acute lung effects result in the release of cytochrome C from mitochondria and the
injury by down-regulating TLR4/MyD88 signaling pathway and inhib­ activation of cysteine proteases (caspases) and ultimately induces
iting oxidative stress injury and inflammation [107–109]. In addition, mitochondrion-derived apoptosis in tumor cells. The pathogenesis of
Dio treats silicosis induced by silica particles. Cheng et al. [110] re­ many diseases is closely related to the impairment of mitochondrial
ported that Dio exerts a protective effect on crystalline silica–induced function, and Dio can promote the recovery of mitochondrial function in
pulmonary inflammation and fibrosis in mice by reducing the secretion normal or damaged cells. For example, Shen et al. [127] reported that
of proinflammatory and profibrotic cytokines and regulating innate and Dio maintains mitochondrial function and thereby attenuates cardiac
adaptive immune responses. Dio promotes autophagy in alveolar mac­ dysfunction induced by myocardial infarction by maintaining mito­
rophages and cell survival, mitigating macrophage-mediated inflam­ chondrial Kreb’s cycle and respiratory chain enzyme activity and
matory cytokine production, inactivating mitochondrion-dependent inhibiting ROS accumulation in cardiomyocytes. In metabolism-related
apoptotic pathways, and providing protection against mitochondrial diseases, Dio has also been shown to have a therapeutic effect on DKD by
dysfunction by terminating ROS production [43]. Dio directly inhibits inhibiting mitochondrial stress and improving impaired mitochondrial
TGF-β/Smads signaling and fibroblast activation [110,111]. The autophagy and mitochondrial kinetics [54].
TGF-β/Smads signaling pathway is an important molecular mechanism
in the development of diabetic pulmonary fibrosis. In lung tissues, TGF-β 5.3. Cell nucleus
plays a crucial role in the epithelial–mesenchymal transition of alveolar
epithelial cells by activating the Smad signaling pathway [112,113]. It Histones are proteins localized in the nuclei of eukaryotic cells and
was highly activated in the lung tissues of STZ-induced diabetic [114]. bound to DNA. Dio can regulate the expression levels of histones and
In conclusion, Dio has the potential of diabetes pulmonary complica­ exert biological activities. For example, it can up-regulate the level of
tions and is a potential alternative drug for the prevention and treatment P53 protein in HEp-2 and TU212 tumor cells and exert anticancer effects
of diabetic pulmonary complications. [128]. In addition, molecular docking experiments reported that Dio has
In summary, Dio shows its excellent properties as a natural a high affinity for NF-κB p65, and Dio inhibited the progression of

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Fig. 3. (a) Dioscin for the treatment of diabetic complications through multiple targets and multiple pathways. Dio can prevent and treat diabetic kidney
disease, diabetic neuropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic atherosclerosis and diabetes cognitive dysfunction, by regulating various
targets and signaling pathways. In addition, Dio has shown full therapeutic potential for DM-related lung and bone lesions. (b) To summarize Dioscin for the
treatment of diabetic complications through multiple targets and multiple pathways.

inflammatory response by down-regulating the expression of NF-κB p65 6. Toxicological properties and side effects of dioscin
[129]. It has therefore been suggested that Dio can alter gene expression
levels and cause structural changes at the nuclear level [13]. However, The livers of humans or rodents can take up Dio via the OATP family
evidence showing that Dio can enter the nucleus and interact with DNA, transport system [131]. The level of Dio in the liver was 10- or 7-fold
RNA, and proteins in the nucleus is insufficient. that in the plasma within 24 h after the oral or intravenous adminis­
tration of Dio in rats[16]. The liver is an essential organ for the uptake
5.4. Other components of the cytoplasm and metabolism of Dio, but Dio is metabolized slowly in the liver.
Therefore, Dio may show certain hepatotoxicity.
The endoplasmic reticulum is an organelle located in the cytoplasm Several preclinical studies have supported this conclusion [116,
of a cell and is the main site of protein synthesis. Recently, A study on 132–134]. Xu et al. [133] evaluated the subchronic toxicity of Dio in
Cryptobacterium hidradii reported that Dio can enhance the innate im­ rats. They designed four dosages (0, 75, 150, and 300 mg/kg/day) for
mune response by activating the unfolded protein response of the oral administration for 90 days; assessed body weight and food and
endoplasmic reticulum, functioning as an anti-infective agent [130]. In water consumption; conducted urinalysis, hematology, clinical,
addition to organelles, the cytoplasm is rich in proteins and other active biochemical examination, and pathology [133]. The results showed that
molecules, which play a key role in the regulation of the various life Dio was nontoxic to female rats at a dose of 300 mg/kg/day but
activities of cells. In tumor cells, Dio targets various cell cycle proteins exhibited some degree of chronic toxicity in male rats, as evidenced by a
located in the cytoplasm, such as cyclin-dependent kinase 2 and cyclin dose-dependent increase in ghrelin levels and gastrointestinal dilatation
A, and induces cell cycle arrest, thereby inhibiting the proliferation of and hemolytic anemia [133]. Another study revealed that mice
cancer cells and infiltration of tumor tissues [121,122,128]. administered oral doses of 1125 mg/kg or higher of total saponins
In summary, interactions between Dio and various subcellular extracted from Dioscorea zingiberensis C.H. Wright steroids exhibited
structures can occur at multiple levels, including the cell membrane, severe dose-dependent destruction of liver tissue morphology, and in
cytoplasm, nucleus, and other sites. These interactions may explain the some cases, proved fatal [134]. Notably, 1125 mg/kg is much higher
various pharmacological effects of Dio at the cellular level. However, than the dose normally prescribed in clinical practice (112.5 mg/kg);
current studies are still underdeveloped. The molecular mechanism of thus, the results indicated the safety of Dio [134]. In a subchronic
action of Dio at the cellular level and its mutual specific mode of toxicity study 510 mg/kg/day dosage of steroidal saponins significantly
interaction for various subcellular components have not been reported, increased serum levels of total bilirubin and significantly decreased
and the exact mechanism of interaction still needs to be elucidated. protein content in the liver of Sprague–Dawley rats [134]. It is suggested
that prolonged high doses of steroidal saponins may damage the liver
and gallbladder system, leading to the release of bilirubin and impaired

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Table 2
Table of studies of Dioscin treatment for various types of diabetic complications.
Disease Experimental model/cell line Dosage Upregulation/ Downregulation/ References
activation Inhibition
In vivo In vitro

Diabetic kidney HFD and STZ Dioscin 15,30 and 60 mg/kg, TLR4/NF-κB pathway, [53]
disease induced T2DM gavage daily for 8 weeks inflammatory cytokines
rats
HFD and STZ Dioscin20 mg/kg bwdaily for 8 Antioxidant enzyme ROS production,apoptosis, [54]
induced T2DM weeks activity, autophagy, mitochondrial fission
rats mitophagy,
High fructose- Diocin15,30 and 60 mg/kg, AMPK-mTOR Oxidative stress, inflammatory, [55]
induced rat kidney gavage daily for 8 weeks pathway Sirt3 renal fibrosis, lipid metabolism
injury models disorder
Alloxan-induced DA extract:100 and 200 mg/kg Renal function [56]
diabetic rats p.o. daily for 21 days
Diabetic db/db mice PC12 cells. Mice:DA-9801:30 and 100 mg/ Neurite outgrowth, Degeneration and death of neurons [61]
neuropathy kg, daily, p.o. for 12 weeks; NGF, Tieg1/Klf10
Cells:10, 100, and 200 μg/ml
for 6 h
STZ induced Dioscin 36.18 mg/(kg⋅d), Histamine,5-hydroxytryptamine [63]
diabeticrats gavage daily for 8 weeks
Diabetic STZ-induced Dioscin Left ventricular Inflammator-y factors, [67]
cardiomyopathy diabetic rats 100 and 200 ug/kg, gavage function NO-sGC-cGMP-PKG pathway
daily for 6 weeks
Diabetic db/db mice High-glucose Mice: Retinal vascular injury, [78]
retinopathy induced HRMECs Dioscin cell proliferation,
oral administration 80 mg/kg VEGFA-VEGFR2 pathway
and ocular delivery 0.32 μg/kg
daily for 16 weeks；
Cells:
1, 10, and 100 μmol/L
Diabetic HFD-induced AS Macrophag-es Rats:Dioscin 25, 50 and Foam cell formation, inflammatory [80]
atherosclerosis rats treated with oxLD 100 mg/kg/d daily for 4 factors, oxLDL/LOX-1/NF-κB axis
weeks； Cells: 1,2,4 μM for
48 h
High-glucose Dioscin 30 mM for 24 h Production of ROS,inflammatory [81]
induced DCs cytokine secretion,oxLDL uptake by
DCs,SR‑A, CD36, LOX‑1,p38 MAPK
Diabetes cognitive STZ-induced Methylglyoxal- Rats P2×7R/NLRP3 signaling pathway [83]
dysfunction diabetic rats treated PC12 cells Dioscin
15,30 and 60 mg/kg, gavage
daily for 12 weeks;
Cells
230 nM
Diabetic bone HFD and STZ TSDN 200, 100 and 50mg/kg BMD [46]
disease induced T2DM body weight, p.o for 12 weeks
rats
Diabetic bone NLRP3 inflammaso-me [97]
disorders
Diabetic lung Not Pulmonary inflammation [107–111]
disease diabetic model pulmonary fibrosis,
TLR4/ MyD88 signaling pathway,
TGF-β/Smads signaling pathway

hepatic protein synthesis. of HepG2 cell viability [132].

On a mechanistic level, numerous studies have provided evidence In clinical practice, there have been reported cases of hepatotoxicity
that the hepatotoxic effects associated with high doses of Dio may stem and gastrointestinal adverse reactions associated with Dio. As early as
from Dio-induced oxidative stress damage and an upregulation of cy­ 1999, Zhou et al. [135] reported two cases of liver damage attributed to
tochrome P450 (CYP) expression [116,132]. Fan et al. [116] observed the consumption of Di’aoxin Kang (with Dio as the main active ingre­
that administration of high-dose Dio induced oxidative stress, upregu­ dient). A total of 800 patients with hypertension took Dio tablets
lated cytochrome P450s (CYPs), and increased hepatocellular apoptosis (80 mg, 3 times/day) orally for 3.5 months; six patients developed in­
in rats. This led to liver function impairment and disruption of bile acid dividual hepatic impairment and showed elevated levels of serum ami­
homeostasis. In vitro study revealed a dose-dependent and notransferases; liver enzymes gradually returned to normal after Dio
time-dependent reduction in the viability of L-02 cells upon exposure to was discontinued, and treatment with hepatoprotective and
high doses of Dio [116]. Further experimental results confirmed that Dio enzyme-lowering therapies were performed [136]. In addition to hep­
induces intracellular oxidative stress and upregulates the expression of atotoxicity and gastrointestinal discomfort, palpitations, back pain, and
CYPs, thereby disrupting the functionality of cell membranes and generalized weakness were reported after Dio treatment, which were
mitochondrial membranes, ultimately resulting in cellular apoptosis alleviated 4 h after the administration of the drug was stopped [137].
[116]. Similarly, Zhang et al. [132] reported that treatment with Dio at The above studies suggest that long-term or high-dose use of Dio may
concentrations ranging from 4 to 32 μmol/L for 12 h induced oxidative lead to hepatic impairment and should be guarded against during clin­
stress and membrane damage in HepG2 cells. Dio activated the aryl ical application of related drugs.
hydrocarbon receptor (AhR) and upregulated the expression of cyto­ In addition, the disruptive effects of high doses of Dio on cell mem­
chrome P450 1A (CYP1A), ultimately leading to a significant inhibition branes can lead to the rupture of erythrocytes and hemolysis. Dio

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H. Gao et al. Biomedicine & Pharmacotherapy 170 (2024) 116051

penetrates the lipid bilayer, accumulates in the microstructural domains are the pathological basis of complications. Traditional antidiabetic
of lipid rafts, and forms complexes with cholesterol, which destabilizes drugs often target the regulation of blood glucose but cannot effectively
the rafts and causes the severe bending of the lipid bilayer and leads to inhibit inflammatory response. Dio has good anti-inflammatory and
the hemolysis of erythrocytes [117]. Erythrocytes are susceptible to antioxidant effects, which make it a promising treatment for multi-organ
hemolysis in the presence of hyperosmolar disorders, such as hyper­ complications. In summary, the comprehensive effects of Dio on
natremia, hyperglycemia, and acute renal failure, and the hemolytic different aspects of DM and its complications can be attributed to its
effect of Dio and the rate of hemolysis gradually decrease with osmo­ multitarget feature. In addition, compared with traditional drugs, plant-
lality [119]. Fortunately, by engineering the original chemical structure derived Dio reduces the risk of the toxicity and side effects of chemically
of Dio, researchers have been able to reduce the cytotoxicity and he­ synthesized drugs and safe.
molytic activity of Dio while retaining its pharmacological activity Dio is effective and safe, and drugs with Dio as the main component
[138]. have been partially used in the treatment of cardiovascular diseases.
In summary, many animal and clinical experiments have recognized Di’ao Xinxuekang capsule, a TCM preparation with Dio as the main
the toxicological properties and safety of Dio and its related drug active ingredient, has been used for the treatment of cardiovascular
preparations. However, in clinical settings, potential adverse reactions diseases in China for more than 30 years and was marketed in the
caused by long-term use of Dio preparations or high doses of the drug Netherlands in 2012, which was a milestone event in the clinical
should be alert (Table 3). translation of Dio [145]. Two other drugs, Dioscorea saponin tablets and
Dunyeguanxinning tablets, which are the active ingredients of Dio, have
7. Clinical application of dioscin also been approved for the treatment of cardiovascular diseases [146].
However, no drug with Dio as a single component has been used in
The ultimate goal of drug research is the effective use of a drug in clinical practice. Notably, DA-9801, a pure Dioscorea extract, has now
clinical treatment, and thus extensive basic research in the early stage is been approved by the FDA and entered phase III clinical trial stage,
necessary to apply novel drugs to clinical settings. Nearly 10 kinds of which is also a large step forward from clinical application [62].
drugs have been developed for the clinical treatment of T2DM. To date, However, Dio is a compound with poor water solubility and stability,
commonly used noninsulin drugs include metformin, glinides, sulfo­ which are the primary problems that limit its large-scale clinical appli­
nylureas, thiazolidinediones, α-glucosidase inhibitors, Dipeptidyl cation [147]. Therefore, research should focus on developing economic
peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) ago­ and compatible Dio drug delivery vectors through bioengineering.
nists, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors are
commonly used [139,140]. Although the introduction of various types 8. Conclusion and prospect
of antidiabetic drugs has benefited many patients with DM, the side
effects and significant efficacy are becoming prominent. After taking Dio has attracted considerable interest in recent years because it is
certain antidiabetic drugs for a long time, some patients may suffer from safe and economical and has a broad spectrum of pharmacological ef­
adverse reactions, such as hypoglycemia, gastrointestinal reactions, fects. The results indicated that Dio exerts antidiabetic effects through
infection, and heart failure, and liver and kidney toxicity may also occur mechanisms, such as lowering blood glucose levels, inhibiting lipid
[141–144]. deposition, protecting pancreatic β-cells, and inhibiting abnormal
Despite this, Dio is not yet approved for use as a first-line therapy for oxidative stress and inflammatory responses. In abnormal glucose–lipid
DM or its complications. In contrast to the problems posed by the metabolism and systemic chronic inflammation caused by DM, sec­
commonly used drugs mentioned above, Dio offers distinct benefits. ondary multi-organ complications that cause harm to patients. Dio has
Different from traditional single-target drugs, Dio has multiple meta­ good therapeutic and alleviates diabetic complications. Dio has a wide
bolic regulation effects, including glucose metabolism, lipid meta­ range of regulatory effects on a variety of molecular targets and
bolism, and insulin signaling pathways. Chronic inflammation and signaling pathways. Through a systematic review of related studies, we
oxidative stress are systemic reactions in abnormal metabolic state and found that Dio has a protective effect on a variety of tissues and organs,

Table 3
Table of studies of the side effects and adverse reactions of Dioscin.
Side effect Object of study Dose Mechanism References
(adverse reactions occur)

Hepatotoxicity Wistar rats， L-O2 cells Rat: SRD 30 g/kg body weightgavage for 10，30，60 days Oxidative stress, Upregulates the [116]
Cells: Dioscin 4mg/mL for 12 h, 24h and 48 h expression of CYPs, Mitochondrial
damage, Cell membrane damage,
Cellular apoptosis
HepG2 cells Diocin 4 -32 μmol/L for 12 hours Oxidative stress, Upregulates the [132]
expression of AhR and CYP1A1, Cell
membrane damage
Male Sprague-Dawley rats Dioscin administered orally 300 mg/kg/day for 90 days [133]
Kunming mice, Sprague- Mice: total saponins extracted from Dioscorea zingiberensis [134]
Dawley rats C.H. Wright steroidsadministered oral doses of 1125 mg/kg
or higher in single doses Rat: steroidal saponins 510 mg/kg/
day for 30 days
Six patients with hypertension Take dioscin tablets (80 mg, 3 times/day) orally for 3.5 [135]
months
Two patients with Take Di’aoxin Kang orally for more than 2 months [136]
cardiovascular or
cerebrovascular disease
Hemolysis HL-60 cells Steroidal saponins isolated from liliaceous plants 0.1—20 Cell membrane damage [115]
mg/ml for 72 h
Male Sprague-Dawley rats Dioscin administered orally 300 mg/kg/day for 90 days Hemolytic anemia [133]
Palpitation,Back pain, A 56-year-old female patient 5 min after first oral administration of Dioscin 80 mg [137]
Generalized with stable angina pectoris
Weakness and hypertension

11
H. Gao et al. Biomedicine & Pharmacotherapy 170 (2024) 116051

such as the kidney, heart, retina, nervous system, blood vessels, and China (32371185); the Shanghai Science and Technology Plan Project
bones and can improve the function of vital organs. Therefore, Dio im­ (23010504200); the "Shuguang Program" (20SG50) funded by Shanghai
proves or delays the progression of diabetic complications, such as DKD, Education Development Foundation and Shanghai Municipale Educa­
DN, DC, DR, DCD, AS. The potential mechanisms of action include tion Commission; the Shanghai Talent Development Fund (2020125);
inhibiting the activation of inflammatory signaling pathways, such as the Key Lab of Exercise and Health Sciences of Ministry of Education
TLR4/NF-κB and NLRP3, inhibiting ROS production, improving mito­ (Shanghai University of Sport) (2022KF001); and the Shanghai Key Lab
chondrial function, and inhibiting tissue and organ fibrosis. In addition, of Human Performance (Shanghai University of Sport) (NO.
for diabetic pulmonary complications and bone diseases, Dio inhibit 11DZ2261100).
lung inflammation and fibrosis.
However, research into Dio as the main active ingredient for DM and
Consent for publication
its complications is still in its infancy. Dio has been examined, and many
problems should be resolved. First, Dio’s role at a variety of cellular and
The manuscript has been approved by all authors for publication.
molecular levels, knowledge of its detailed molecular mechanisms is still
limited. For example, at the subcellular level, it remains to be investi­
gated how Dio enters the cytoplasm or nucleus and then regulates the Ethics approval and consent to participate
physiological activities of individual cells. In-depth exploration of the
molecular targets and signaling pathways regulated by Dio and its spe­ Not applicable.
cific mechanism of action against DM and various diabetic complica­
tions is a direction for future research. Furthermore, most studies on References
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