Bioactive Components of Salvia and Their Potential Antidiabetic Properties: A Review

The utilization of therapeutic plants is expanding around the globe, coupled with the tremendous expansion of alternative medicine and growing demand in health treatment. Plants are applied in pharmaceuticals to preserve and expand health—physically, mentally and as well as to treat particular health conditions and afflictions. There are more than 600 families of plants identified so far. Among the plants that are often studied for their health benefit include the genus of Salvia in the mint family, Lamiaceae. This review aims to determine the bioactive components of Salvia and their potential as antidiabetic agents. The search was conducted using three databases (PubMed, EMBASE and Scopus), and all relevant articles that are freely available in the English language were extracted within 10 years (2011–2021). Salvia spp. comprises many biologically active components that can be divided into monoterpenes, diterpenes, triterpenes, and phenolic components, but only a few of these have been studied in-depth for their health benefit claims. The most commonly studied bioactive component was salvianolic acids. Interestingly, S. miltiorrhiza is undoubtedly the most widely studied Salvia species in terms of its effectiveness as an antidiabetic agent. In conclusion, we hope that this review stimulates more studies on bioactive components from medicinal plants, not only on their potential as antidiabetic agents but also for other possible health benefits.


Introduction
According to World Health Organization's 2019 Global Health Estimates, it was estimated that non-communicable diseases contribute to about 7 out of 10 causes of death globally. The prevalence of diabetes was noticed more rapidly in low and middle-income countries. Chronic diabetic complications are associated with various long-term complications that include prolonged injuries, organ failure, vision loss, renal impairment, peripheral neuropathy with foot ulcer risk and even amputation [1]. Currently, there are various therapies available to control diabetes, such as insulin, pharmaco and diet therapy. Despite the availability of multiple drugs that exert antidiabetic effects via various pathways, however, optimal treatment effects are yet to be achieved. In recent times, medicinal plant-based therapies have gained attention given their rich constituents (e.g., carotenoids, terpenoids, alkaloids, glycosides, flavonoids) that portray antidiabetic effects [2,3].
In the US, the development of herbal-based products as prescription drugs is subject to Food and Drug Administration approval. For example, Veregen ® (sinecatechins), a product derived from green tea (Camellia sinensis) intended for external genital or perianal warts, was first approved in the year 2008 [4]. In 2012, another product Crofelemer was introduced targeted for diarrhea relief among HIV/AIDS patients [5]. The extensive benefits of herbal plants have attracted much interest in their possible application-focused for health benefits, where it is usually commenced with chemical composition, in vitro and/or in vivo before any intervention studies. Chemical composition characterization assists researchers in ensuring the most efficient dosage that is required for evident changes of certain disease mechanism assists in lowering after-meal glucose effects that suggest their potential in the prevention of diabetes occurrence [21]. Acarbose also has been reported as a competitive inhibitor of α-amylase, where they are composed of the pseudo-sugar ring and glycosidic nitrogen linkage that mimics transition state for enzymatic cleavage of glycosidic bond and thus, inhibits α-amylase competitively [22]. The mechanisms of starch hydrolysis into glucose via the action of α-amylase and α-glucosidase are presented in Figure 1. Hydrolysis of starch to glucose as catalyzed by α-amylase and α-glucosidase (adapted from [23]).
In vivo studies will require experimental animals to be induced as a diabetic model. Alloxan and streptozotocin (STZ) are the most common diabetogenic agents used to assess antidiabetic and hypoglycemic components. These materials inflate and eventually degenerate β-cells from the Langerhans islets [24]. Injection of the anterior hypophysis extract is a less effective approach for developing diabetes [25]. The final signs of insulin deficiency are seen in STZ-chemically impaired rats [26]. An autoimmune process that destroys the β-cells of the Langerhans islets will begin once a 60 mg/kg STZ dose was given to the rats. The use of 60 mg/kg STZ dose resulted in the toxicity of β-cells with the emergence of clinical diabetes within 2-4 days [27]. Alloxan is lower in cost and more readily available than STZ. On this basis, in experimental diabetes research, one would logically assume a preference for using alloxan. Chemically known as 5,5-dihydroxyl pyrimidine-2,4,6-trione, alloxan is an organic compound, a derivative of urea, a carcinogen and an analog of cytotoxic glucose [28]. Nevertheless, alloxan has poor diabetogenicity and is very normal with intraperitoneal (IP) doses of 150 mg/kg and below [29,30] for fast auto-reversal of alloxan-induced hyperglycemia.
In this review, we intend to conduct evidence-based evaluations on the potential of Salvia spp. as an antidiabetic agent focused on their chemical constituents, in vitro, in vivo and intervention-based studies.

Search Strategy
The original articles were identified through searches of three databases (PubMed, Embase and Scopus) from 2011 to 2021 using the medical subject heading (MeSH) terms "Salvia", crossed with the term "diabetes". Publications with available abstracts were reviewed and limited to studies published in the English and Malay languages. Papers on chemical composition, in vitro, in vivo and human studies, and related to diabetes were included. However, review articles and letters to the editor were excluded. Duplicate articles were eliminated.

Results
After conducting a comprehensive literature review, the articles were selected and divided into several categories. A total of 58 articles were included in our first screening that consists of 6 articles on a combination of chemical composition and in vitro studies, 45 articles on a combination of chemical composition and in vivo studies, and 8 intervention studies. Upon second screening to include only articles with details of chemical components, only 28 articles were included as presented in Table 1. Among these, 6 articles were focused on a combination of chemical composition and in vitro studies, 18 articles on a combination of chemical composition and in vivo studies, and 4 articles on intervention studies. All the related articles were printed out for further evidence-based assessment to explore the effectiveness of Salvia spp. as a potential antidiabetic agent. • Eucalyptol inhibited glucose-induced expression of the mesenchymal markers of N-cadherin and α-smooth muscle actin • Enhanced induction of E-cadherin and attenuated the induction of connective tissue growth factor and collagen IV by glucose • Oral administration of eucalyptol blunted hyperglycemia and proteinuria, reversed tissue levels of E-cadherin, N-cadherin and P-cadherin and the collagen fiber deposition in diabetic kidneys. Furthermore, attenuated the induction of Snail1, β-catenin and integrin-linked kinase 1 (ILK1) in glucose-exposed tubular cells and diabetic kidneys, reversely enhanced glycogen synthase kinase (GSK)-3β expression • Eucalyptol may antagonize hyperglycemia-induced tubular epithelial derangement and tubulointerstitial fibrosis through blocking ILK1-dependent transcriptional interaction of Snail1/β-catenin

Ref.
Objective Methods Findings Conclusion [46] To investigate the effect of cryptotanshinone on myocardial fibrosis in diabetic rats • Male Wistar rats were separated into three groups (control, vehicle-treated STZ-treated rats, and cryptotanshinone-treated STZ-treated rats) • In STZ-treated rats, FBG levels and heart weight/body weight ratio were markedly increased, but both were not modified by cryptotanshinone • Cardiac performance in catheterized STZ-treated rats was improved. The histological results from Masson staining showed that cryptotanshinone attenuated cardiac fibrosis in STZ-treated rats • Both the messenger ribonucleic acid (mRNA) and protein levels of the signal transducer and activator of transcription 3 (STAT3), matrix metalloproteinase-9, and connective tissue growth factor were reduced by cryptotanshinone in high glucose-cultured cardiomyocytes • STAT3 regulates matrix metalloproteinase-9 and connective tissue growth factor expression in diabetic rats with cardiac fibrosis, cryptotanshinone inhibited fibrosis to improve cardiac function by suppressing the STAT3 pathway [47] To screen and explore bioactive constituents from the root of S. miltiorrhiza Bunge acting on renin activity and evaluates its osteoprotective efficacy in diabetic mice • DSS reduced the mean escape latency and increased the percentage of time spent in the target quadrant • DSS partly blocked the expression of receptor of glycation end (RAGE), p-p38, and cyclooxygenase 2 (COX-2), and nuclear factor kappa-light-chain-enhancer of B cells (NF-κB) activation, and inhibited the increase of TNF-α, interleukin 6 (IL-6), and prostaglandin E 2 (PGE 2 ) • DSS may provide a potential alternative for the prevention of cognitive impairment associated with diabetes by attenuating AGE-mediated neuroinflammation • Tricardin was found to be a safe and effective treatment option for the management of diabetic polyneuropathies

Chemical Composition of Salvia spp. and Their Antidiabetic Effect via In Vitro and In Vivo Studies
Chemical composition analysis is acknowledged as the main focus, especially in studies investigating their potential benefits in the prevention or treatment of diseases. Normally, drug candidates will be examined by in vitro, in vivo and preclinical investigations to prove their safety and efficacy before they can be tested in humans. However, chemical constituents remain as the root that exerts their specific effects. Based on our findings, S. virgata, S. viridis, S. urmiensis, S. syriaca and S. nemorosa were some of the common species discussed with the presence of polyphenols, flavonoids and terpenoids identified as the major components [11,[31][32][33][34]. Rosmarinic acid (RA), salvianolic acids, ursolic acid, oleanolic acid, chlorogenic acid, 1,8-cineole, thujone, β-pinene, spathulenol, linalool, linalyl acetate, rutin and caryophyllene oxide were among the main chemical constituents characterized based on the included studies from the various Salvia spp. The chemical structures of several major constituents are presented in Figure 2. Chemical characterization was mainly performed using high-performance liquid chromatography (HPLC) and gas chromatography (GC) techniques equipped with various relevant detection systems, such as diode array detector (DAD), mass spectrometry (MS) and flame ionization detector (FID) [11,[32][33][34]. Also, total phenolic content and total flavonoid contents were analyzed by the commonly applied Folin-Ciocâlteu and colorimetric techniques [33,34]. Research on S. virgata involved a fractionation study that involved various other techniques, such as column chromatography, preparative layer chromatography and nuclear magnetic resonance (NMR) [31]. In general, almost all included articles focusing on chemical profiling were followed by either in vitro or in vivo investigations. A study by Nickavar and Abolhasani in 2013 [31] reported that the ethanolic extract of S. virgata showed a dose-dependent α-amylase inhibition with IC50 of 19.08 mg/mL. One significant finding of this study is on the isolation and identification of active flavonoid chrysoeriol that also inhibited α-amylase activity (IC50 = 1.21-1.33 Mm). It was documented that the presence of a -OMe group at 3 -position of B-ring improves the ability to inhibit α-amylase activity [69]. In 2019, Zengin and colleagues [32] evaluated phytochemical composition and enzyme inhibitory potential of S. viridis ethanolic root extracts that were obtained by various methods. The choice of extraction technique was seen to influence phenolic and flavonoid composition, where UAE gave the highest concentration. UAE technique is based on applying high-frequency sounds and a limited amount of solvent to produce an effective extraction of the components contained in a solid matrix [70]. Among all extracts, the main components identified were mostly comprised of salvianolic acids, polyphenols, flavonoids and terpenoids. The enzyme inhibition potential of S. viridis was higher against α-glucosidase (1.61-1.65 mmol ACAE/g) compared to α-amylase (0.56-0.73 mmol ACAE/g), which presented a possible therapeutic approach for diabetes management [32].
An antidiabetic potential of essential oils (EOs) from Salvia sp. has also been investigated in several studies. Bahadori and team [11] evaluated EO composition and antidiabetic properties of S. urmiensis. EO analysis indicated a high presence of ester compounds in leaves (ethyl linoleate, methyl hexdecanoate and methyl linoleate), while 6,10,14-trimethyl-2-pentadecanonen was the major identified compound in flowers. Enzyme inhibition assays performed with EO and various extracts showed that methanolic extract gave the highest α-glucosidase and α-amylase inhibition with the lowest IC50 values (IC50 = 8.3 and 24 µg/mL). S. urmiensis EO was classified as a weak inhibitor that could be correlated with the presence of esters, ketone and alkane compounds. Similarly, another study attempted to investigate the phytochemical composition of S. syriaca EO and methanolic extract as well as antidiabetic properties. Spathulenol, isospathulenol and bornyl acetate were the major identified compounds in EO, while rutin, quercetin, apigenin, RA, and ferulic acid were the most abundant phenolic compounds. Contradictory to S. urmiensis, EO of S. syriaca exhibited the strongest activity in both α-glucosidase (IC50 = 1.18 mg/mL) and α-amylase assays (IC50 = 1.54 mg/mL) compared to all other tested extracts [33]. In the year 2017, Bahadori et al. [34] studied the chemical composition of S. nemorosa EO and phenolic compounds of methanolic extract along with α-glucosidase inhibition assay. The results demonstrated the strongest inhibition assay for the methanolic extract. RA was detected as the major compound of extract, whereas oxygenated sesquiterpenes constitute the highest proportion in EO. It was reported that the presence of RA correlates proportionally to α-amylase inhibition, where higher inhibition is observed with increased RA concentration [71].
Two structurally isomeric pentacyclic triterpenes compounds (ursolic acid and oleanolic acid) isolated from many Salvia spp. also have gained massive attention in relevance to their potent inhibition effects on α-glucosidase activity [72,73]. However, the analysis of these compounds encountered difficulties due to their structural similarities. A study by Janicsak et al. [74] presented the largest data of these acids among Salvia sp. in Turkey, although the study was restrained in terms of its quantitative evaluation. To counteract this gap, a group of researchers in 2018 embarked on investigating and developing techniques for the simultaneous analysis of both acids among fourteen Salvia spp. (S. adenocaulon, S. aucheri var. aucheri, S. blepharochlaena, S. cilicica, S. absconditiflora, S. divaricate, S. euphratica var. euphratica, S. heldreichiana, S. huberi, S. hypargeia, S. limbate, S. rosifolia, S. sclarea and S. virgata), along with their α-glucosidase enzyme inhibitory effects. The finding showed that S. aucheri var. aucheri and S. adenocaulon were the two species with the best α-glucosidase activities (IC50 = 17.6 and 25.9 µg/mL), respectively. Moreover, a strong negative correlation was reported for both ursolic and oleanolic acid with IC50 results of r = −0.623 and r = −0.695, respectively. Based on the collective findings, the authors concluded that α-glucosidase inhibitory activity could be attributed to the presence of both triterpenoids, suggesting their potential use as antidiabetic agents [35].
In addition to in vitro evaluation, potentials of Salvia spp. were also investigated through in vivo approaches using several species (S. miltiorrhiza, S. fruticosa, S. sclarea) as well as specific compounds, such as salvianolic acids, tanshinone IIA (TSIIA) and RA. Studies involving these specific compounds are mostly conducted using those that are commercially available. On the other hand, extract from respective plants varied from water extract, ethanol extract and EOs. The doses were given through intraperitoneal injection from 3 up to 24 weeks, and some were administered orally [38,39,42,44,47].
Salvianolic acids, as water-soluble compounds, are abundantly present in S. miltiorrhiza, with more than 10 different forms. Among these, salvianolic acid A (SalA) and B (SalB) are recognized as the most abundant compound [75]. Danshensu (DSS) ((R)-3-(3, 4dihydroxyphenyl)-2-hydroxypropanoic acid) is the basic chemical structure that forms the various salvianolic acids [76,77]. Specifically, SalA is formed by a combination of DSS with two molecules of caffeic acid, whereas three molecules of DSS and one molecule of caffeic acid forms the SalB [75,78]. Previous researchers demonstrated extensive pharmacological effects of SalA that include antioxidative, anti-platelet aggregation, anti-cerebral, myocardial ischemia, and ameliorates diabetes complications [36,[79][80][81]. On the other hand, SalB showed excellent protection against high-fat-diet-induced obesity, protects β-cells against cytotoxicity, prevents high glucose-induced apoptosis and also exerts hepatoprotective effects [82][83][84][85]. In a study conducted by Qiang et al. [38], the antidiabetic effect of SalA was indicated by the improvement of mitochondrial roles and stimulating AMP-activated protein kinase (AMPK) via the CaMKKβ/AMPK signaling pathway. This study proposed that SalA could potentially be applied for diabetes treatment in relevance to its appealing effects by reducing mitochondrial membrane potential (MMP) while increasing adenosine triphosphate (ATP) synthesis.
Based on the study by Yu and colleagues [37], the beneficial effect of SalA on peripheral nerve function was reported in diabetic rats. This result might be attributed to improvements in glucose metabolism by regulating the AMPK-proliferator-activated reaction-α-sirtuin 3 (PGC1α-Sirt3) axis. AMPK functions as a fuel sensor in several tissues, including skeletal muscle [86]. AMPK enhances peroxisome expression in the mRNA AMPK activation, PGC1α and manganese superoxide dismutase (MnSOD) [87]. In addition, PGC-1α serves as an important transcriptional coactivator for Sirt3 expression [88] and a pivotal factor for mitochondrial function [86]. As a member of the sirtuin family, Sirt3 regulation of silent matting-type information is located in the mitochondria and controls several pivotal pathways via targeted central metabolism enzymes [89].
SalA was found to lower fasting blood glucose (FBG) and fed blood glucose in a dosedependent manner, as well as reduced 24-h food and water intake in a study conducted by Qiang et al. [38] using alloxan-induced type 1 diabetic mice with an HFD and low-dose STZ-induced T2DM rats. By using the HepG2 cells and L6 myotubes, SalA caused a dose-dependent increase in glucose consumption and enhanced glucose uptake. Moreover, SalA also decreased mitochondrial function, increased ATP production and decreased MMP via the CaMKKβ/AMPK signaling pathway. Intriguingly, SalA did not show any effect on insulin secretagogue and activation of PI3K/Akt signaling pathway. The pathway PI3K/AKT regulates the proliferation, differentiation and transformation of cells, as well as the metabolism and cytoskeletonization, which result in apoptosis and the survival of cancer cells. Therefore, numerous disorders, such as obesity, diabetes and cancer, are associated with this pathway. Thus, SalA has this unique function as it does not activate phosphorylation of Akt based on the recorded result by Western blot analysis.
SalB is also recognized for its potential use as antidiabetic agent where it resulted in significant reduction of serum glucose (p < 0.05-0.01) and MDA (p < 0.05), while serum insulin, glutathione (GSH) (p < 0.05) and catalase activity (p < 0.01) increased upon continuous administration of 20 or 40 mg/kg (IP injection) up to 3 weeks with no evident changes on nitrite of STZ-induced diabetic rats [39]. Raoufi and colleagues [39] presented the mechanism of the antidiabetic effects of SalB evaluated with multiple low-dose STZinduced diabetes models where it was concluded that the action could be via protection of pancreatic β-cells against chemicals followed by improvement of the β-cells insulin secretion. Normally, SalB accounts for 3-5% of the total herbs dry weight [90]. Oral treatment of SalB at a much higher concentration (50 and 100 mg/kg) in a spontaneous model of T2DM mice (db/db) was found to decrease FBG, TG and free fatty acid levels, reduced hepatic gluconeogenic gene expression and improved insulin intolerance. Huang and his friends also found that high dose SalB significantly improved glucose intolerance, increased hepatic glycolytic gene expression and muscle glycogen content, and ameliorated histopathological alterations of the pancreas, similar to metformin [40]. In contrast, serum insulin was found to be higher in this study than the other study done by Raoufi and his colleagues [39].
Although many researchers focused on SalA for antidiabetic study, SalB was thought to have much more commercial value for food and medicine purposes due to the containment of the highest amounts in S. miltiorrhiza [91,92]. In another study that used a much higher concentration of SalB (50, 100, and 200 mg/kg), a significant decrease of blood glucose and insulin, along with increased ISI, was noticed at 100 and 200 mg/kg. They also found a significant decrease in TC, LDL, non-esterified fatty acids, hepatic glycogen, and muscle glycogen, and increased HDL, which was originally altered by HFD and STZ. Moreover, SalB (200 mg/kg) markedly decreased TG and MDA and increased superoxide dismutase, which was originally altered by HFD and STZ [41].
As previously mentioned, RA is also a chemical constituent in Salvia sp. RA can be found particularly in Lamiaceae and Boraginaceae family [93], and it was detected as one major component among two species, namely S. nemorosa and S. syriaca. RA occurs in nature as a phenolic compound. It is an ester of caffeic acid and 3,4-dihydroxy phenyl lactic acid with noteworthy biological roles, such as antioxidant, antidiabetic, anti-inflammatory, cardioprotective, hepatoprotective, nephroprotective and many others [94]. RA was shown to be metabolized in the intestines and liver upon absorption. Metabolites, such as caffeic acid, ferulic acid and coumaric acid, were noticed to be present along with RA upon its administration to rats. A study conducted by Azevedo and colleagues [42] investigated the effects of SFT treatment and RA as its major phenolic constituent against SGLT1, the facilitative GLUT2 and GLP-1. It was reported that without significant changes in total levels of cell transport proteins, RA from SFT was capable of increasing SGLT1. Nevertheless, there was no impact on GLUT 2, Na + /K + -ATPase or GLP-1 levels by SFT. The findings of this study showed that SFT and RA specifically regulate SGLT1 transporter levels at the brush border membranes (BBM). SGLT1 transporter levels are controlled by decreasing their level in diabetic conditions and with an increased presence of digestible carbohydrates. This phenomenon is also in parallel with lower blood glucose where RA was recognized as the active component [42].
1,8-cineole, also known as eucalyptol, is a bicyclic monoterpene that can be obtained from various plant EOs, including Salvia sp. [95,96]. 1,8-cineole has been reported for its extensive pharmacological benefits, such as antimicrobial, anti-inflammatory and pain relief. A study by Kim and colleagues [43] investigated the potentials of eucalyptol in opposing diabetic kidney disease characteristics represented by renal tubular epithelial derangement and tubulointerstitial fibrosis. The findings of this study presented eucalyptol as a potent inhibitor of Snail1 and β-catenin in diabetic models of renal tubular cells and kidneys. Linalool is a volatile flavor and exists in two forms known as R (−)-linalool (licareol) or S (π)-linalool (coriandrol) that varies according to climate conditions. This compound has been acknowledged for strong antidiabetic characteristics based on previous investigations. Raafat and Habib [44] attempted to study the antidiabetic effect of S. sclarea EO from two different regions in Lebanon; Beirut (SS-Bt) and Taanayel (SS-TI). The phytochemical analysis found that SS-Bt was characterized by high linalool concentration, while linalyl acetate constitutes the SS-TI. This research monitored the acute and subchronic antidiabetic properties of EOs along with linalool and linalyl acetate, where the most active chemotype was determined. Results of this study indicate better activities with chemotype 1 that is characterized by higher linalool content.
Other compounds that can be found in Salvia spp. include lithospermic acid, cryptotanshinone, and TSIIA [45][46][47][48]. It was found that the treatment with LAB prevented vascular leakage and basement membrane thickening in retinal capillaries in diabetic rats, which indirectly thwart developing diabetic retinopathy in this animal [45]. On the other hand, cryptotanshinone did not affect FBG levels in STZ-induced rats. However, its action is more pronounce in inhibiting developing fibrosis to improve cardiac function by reducing the mRNA and protein levels of the STAT3, matrix metalloproteinase-9, and con-nective tissue growth factor in Type 1-like diabetic rats as well as in high glucose-cultured cardiomyocytes [46]. While TSIIA was found to display inhibitory effects on renin activity of HEK-293 cells; moreover, it downregulated protein expression of ANG II in human renin-expressed HEK-293 cells [47]. The determination of plasma renin activity has been widely used to evaluate the renin-ANG system in disease states. Therefore, measurement of plasma renin activity has been suggested as an important aid in the differential diagnosis of primary and secondary aldosteronism [97,98]. A differentiation between low and high renin hypertensive states may also help select antihypertensive as well as antidiabetic medications. Based on the animal study, treatment of diabetic mice with TSIIA at two different doses (10 and 30 mg/kg) found to decrease the significant level of ANG II in serum (from 16.56 ± 1.70 to 10.86 ± 0.68 and 9.14 ± 1.31 pg/mL) and managed to reduce the expression of ANG II in bone, consequently improving trabecular bone mineral density and microstructure of proximal tibial end and increasing trabecular bone area of distal femoral end in diabetic mice [47]. The potential antidiabetic effect is not only performed by the individual compound in Salvia. The total PAF of S. miltiorrhiza Bunge that contains SalA, SalB, RA, cryptotanshinone, TSIIA and other polyphenolic acids were also found to induce a significant decrease in FBG, FINS, TC, TG and BUN, along with an obvious ISI increase in STZ-induced diabetic rats [49].
Combined supplementation of Pae with DSS prevented vascular damage and improved vascular reactivity in STZ-induced diabetic rats. Moreover, phenylephrine (PE)induced contraction response was also decreased in the treated groups. The combination showed significant protective effects by reducing oxidative stress and intracellular Ca 2+ regulatory mechanisms [50]. Another study attempted to evaluate the effect of DSS on cognitive decline and AGE-mediated neuroinflammation in learning and memory deficits of STZ-induced diabetic mice. The outcome of this study presented the potential of DSS in ameliorating cognitive decline via attenuation of AGE-mediated neuroinflammation, which suggests its application as an alternative in preventing diabetes-associated cognitive impairment [51].
Jiangtang decoction (JTD), a patented drug that contains Euphorbia humifusa Willd, S. miltiorrhiza Bunge, Astragalus mongholicus Bunge, Anemarrhena asphodeloides Bunge and Coptis chinensis Franch, has also been studied for its antidiabetic properties. JTD exhibited a significant amelioration in glucose and lipid metabolism dysfunction, reduced morphological changes in the renal tissue, decreased urinary albumin excretion, and normalized creatinine clearance. JTD therapy decreased AGE, and RAGE accumulation improved IRS-1 and increased both PI3K (p85) and Akt phosphorylation suggesting the involvement in the PI3K/Akt pathway activation. JTD administration further decreased the high rates of renal inflammatory mediators and reduced NF-κB p65 phosphorylation [52]. The schematic pathway showing developing diabetic nephropathy, cardiomyopathy and nephropathy through the modulation of nitric oxide, protein kinase G (PKG-1), thrombospondin 1 (TSP1), transforming growth factor-β1 (TGF-β1) and NF-κB is shown in Figure 3.
It is known by the scientific community that diabetes is linked to various metabolic deranges, such as overproduction of reactive oxygen, hypoxic conditions, mitochondrial dysfunction and inflammation [88]. Poor diabetes control could damage blood vessel clusters in the kidney, resulting in kidney damage and elevated blood pressure. Prolonged stress conditions induce further strain to the kidney's filtration system that could completely damage the kidney function. Orally given decoction from HDD significantly decreases excretion of urinary albumin and improvement in db/db mice at a dose of 6.8 g/kg/day for 12 weeks. HDD is composed of Astragali Radix (Huang-qi) and S. miltiorrhizae Radix et Rhizoma. The study by Liu and colleagues [53] reported that HDD treatment reversed the effects of enhanced mitochondrial fission and PINK1/Parkin-mediated mitophagy in the db/db mice. This finding suggested that administration of HDD tends to suppress PINK1/Parkin mediated mitophagy, and this mechanism plays a vital role in the protection of possible kidney injuries. The representation of PINK1/Parkin-mediated mitophagy is presented in Figure 4.

Salvia spp. in Intervention Studies
Four intervention studies were included in this review. On the whole, several Salvia spp. were investigated for their potential as antidiabetic agents. S. miltiorrhiza is the most studied, with three articles focusing on this species. In a study by Lian et al. [54], the safety and effectiveness of danshen-containing Chinese herbal medicine intended for diabetic retinopathy (DR) were conducted via randomized, double-blind, placebocontrolled multicenter clinical trial. This research involves a dose-ranging study where varying doses of CDDP were given for selected nonproliferative DR patients. The findings indicated that the observed effects were significantly better with those of high-dose and mid-dose treatment groups comparatively to low-dose treatment groups. However, the researchers stressed the study limitation whereby short clinical duration may not be sufficient enough that raises the need for future trials to evaluate if the extended duration also exerts a similar effect. Nevertheless, the positive outcomes observed the proposed potential role of Chinese herbal medicines in NPDR treatment and delaying possible progression [54].

Salvia spp. in Intervention Studies
Four intervention studies were included in this review. On the whole, several Salvia spp. were investigated for their potential as antidiabetic agents. S. miltiorrhiza is the most studied, with three articles focusing on this species. In a study by Lian et al. [54], the safety and effectiveness of danshen-containing Chinese herbal medicine intended for diabetic retinopathy (DR) were conducted via randomized, double-blind, placebo-controlled multicenter clinical trial. This research involves a dose-ranging study where varying doses of CDDP were given for selected nonproliferative DR patients. The findings indicated that the observed effects were significantly better with those of In the year 2019, another study by Tassadaq and Wahid [55] attempted to evaluate the efficiency of Tricardin (danshenform 250 mg dripping pills capsules) along with physical rehabilitation among diabetic patients with polyneuropathies. Diabetic polyneuropathy was recognized as one of the major complications that induce pain, numbness or loss of sensation, which could ultimately result in amputation [102,103]. Apart from good glycemic control, proper use of footwear, as well as physical activities, are deemed vital in diabetes management, especially neuropathies [104]. This study highlighted that the addition of Tricardin pills to their usual treatment regime significantly led to an improved quality of life post-treatment, compared to the control group that only practiced conventional therapy.
Hence, Tricardin is considered a safe and alternative option in the management of diabetic polyneuropathies, although long-term efficacy studies should be performed with a larger population [55].
In contrast to danshen pills, the effect of S. miltiorrhiza injection combined with telmisartan in DN was studied in 2018 [56]. This case-control study showed that increased levels of ColIV and FN are partially accountable for the progress of DN. This induction could be successfully altered via S. miltiorrhiza injection with telmisartan that attenuates both ColIV and FN, postpones the ultrastructure changes of the glomerular basement membrane and reverses the hyperglycemia state along with low adverse reactions. Nevertheless, future studies are suggested to be conducted longer with larger sample size and dose and time-dependent based approaches [56].
S. officinalis is another species of Salvia that also has been widely investigated with hypoglycemic activity. S. officinalis is comprised of volatile oils, tannins, diterpenes, triterpenes, steroids, flavones and flavonoids [13,105,106]. They are well-known for various medicinal benefits (antioxidant, anti-inflammatory, anti-hyperglycemic, anti-dyslipidemia as well as culinary uses [107][108][109][110][111][112]. A study by Kianbakht et al. [57] investigated the effects of S. officinalis leaf extract in combination with statin therapy in hypercholesterolemic T2DM patients, with positive findings that were deemed safe and further improved lipid profiles. These effects observed with glycemic control and lipid profile are portrayed as beneficial in preventing cardiovascular-associated complications among the patients [57].

Conclusions
The significance of Salvia spp. potentials in diabetes management were noticed based on the included studies ranging from chemical composition analysis, in vitro, in vivo, and clinical investigation. Collectively, Salvia spp. has gained much recognition, especially in China, and it is anticipated that more investigations are performed to establish their potential usage in all parts of the world. However, we would like to state the limitation of this review where some studies were conducted with commercially available compounds that we believe may differ in certain purity compared to the original extract. The mechanism of action for specific compounds remained elusive, and therefore, we cannot conclude the most effective Salvia spp. in diabetic management from our perspective. Despite this challenge, Salvia spp. have shown the huge potential to be explored as an alternative strategy in diabetic therapies, and we hope that this review will instigate more interest among researchers around the globe to further explore bioactive components from Salvia spp., as well as other medicinal plants for their potential not only as antidiabetic agents but also for other possible health benefits.