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Nutrients 2019, 11(7), 1581; https://doi.org/10.3390/nu11071581

Review
Natural Hydrogen Sulfide Donors from Allium sp. as a Nutraceutical Approach in Type 2 Diabetes Prevention and Therapy
1
Department of Chemical Science and Technologies, University of Rome “Tor Vergata”, via della Ricerca Scientifica 1, 00133 Rome, Italy
2
CIMER Center for Regenerative Medicine, University of Rome Tor Vergata, via Montpellier 1, 00166 Rome, Italy
3
Department of Pharmacy, University of Medicine Tirana, rruga Dibra, 371 Tirana, Albania
*
Author to whom correspondence should be addressed.
Received: 2 June 2019 / Accepted: 10 July 2019 / Published: 12 July 2019

Abstract

:
Type 2 diabetes mellitus (DM) is a socially relevant chronic disease with high prevalence worldwide. DM may lead to several vascular, macrovascular, and microvascular complications (cerebrovascular, coronary artery, and peripheral arterial diseases, retinopathy, neuropathy, and nephropathy), often accelerating the progression of atherosclerosis. Dietary therapy is generally considered to be the first step in the treatment of diabetic patients. Among the current therapeutic options, such as insulin therapy and hypoglycemic drugs, in recent years, attention has been shifting to the effects and properties—that are still not completely known—of medicinal plants as valid and inexpensive therapeutic supports with limited side effects. In this review, we report the relevant effects of medicinal plants and nutraceuticals in diabetes. In particular, we paid attention to the organosulfur compounds (OSCs) present in plant extracts that due to their antioxidant, hypoglycemic, anti-inflammatory, and immunomodulatory effects, can contribute as cardioprotective agents in type 2 DM. OSCs derived from garlic (Allium sp.), due to their properties, can represent a valuable support to the diet in type 2 DM, as outlined in this manuscript based on both in vitro and in vivo studies. Moreover, a relevant characteristic of garlic OSCs is their ability to produce the gasotransmitter H2S, and many of their effects can be explained by this property. Indeed, in recent years, several studies have demonstrated the relevant effects of endogenous and exogenous H2S in human DM, including by in vitro and in vivo experiments and clinical trials; therefore, here, we summarize the effects and the underlying molecular mechanisms of H2S and natural H2S donors.
Keywords:
OSCs; garlic; phytochemicals; inflammation; oxidative stress; H2S; diabetes; plants; nutraceuticals

1. Introduction

Diabetes mellitus (DM), as reported in the WHO 2016 global report, is a chronic disease with high incidence worldwide, creating a crucial social issue that represents one of four major noncommunicable diseases as outlined in world forums. The International Diabetes Federation recently estimated that DM affects about 425 million people and that this number will increase to 629 million in 2045. Type 2 DM is the most frequent form of the disease (over 90% of DM patients), characterized by hyperglycemia due to insulin resistance or inadequate insulin secretion [1]. Progressive hyperglycemia is one of the main causes of oxidative stress and is recognized to be principally responsible for type 2 DM complications [2,3,4]. Inflammation and oxidative stress are determinants for the loss of endothelial function and dysfunction of the vascular endothelium leading to macrovascular (cerebrovascular or heart pathologies), as well as at the microvascular complications (degenerative defects of the kidney or retina, with subsequent complications such as limb amputation or neurological defects) [5,6]. Dementia, depression, sexual dysfunction, and high risk for cancers of the liver, pancreas, colon, and rectum are other complications stemming from chronic diabetic conditions [7]. Epidemiological evidence suggests that type 2 DM is frequently under-diagnosed according to a recent review in seven countries, which estimated that 24% to 62% of people with DM were undiagnosed and untreated [8]. The main causes of type 2 DM are related to genetic factors and lifestyle (patterns of diet and physical activity) [9]. Obesity and physical inactivity are known, by epidemiological evidence, to be risk factors for insulin resistance and type 2 DM. Accordingly, several studies have examined the effect of a combination of diet and physical activity, often referred to as a lifestyle intervention, in reducing the progression of Impaired Glucose Tolerance to type 2 DM [10,11,12,13,14,15]. The U.S. Diabetes Prevention Program (DPP), Finnish Diabetes Prevention Study (FDPS), and Da-Qing Investigation have produced evidence that the risk of developing type 2 DM can be reduced by changes in one’s lifestyle. In both the FDPS and DPP studies, the estimated risk reduction was about 58% after three years [15].
To achieve good and long-term metabolic control in DM, to reduce its complications, and to maintain quality of life, a combination of changes in lifestyle and pharmacological treatment is required. According to both the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA), the lifestyle changes, including Medical Nutrition Therapy (MNT), physical exercise, smoking cessation, and weight loss, are important approaches in the management of type 2 DM [16]. In recent years, there have been a great number of hypoglycemic drugs available for the treatment of type 2 DM, mainly by oral administration, which possess different mechanisms of action. These include, for example, decreasing endogenous glucose production, insulin secretagogue, alpha-glucosidase inhibitor, dipeptidyl peptidase-4 inhibitor, and sodium glucose co-transporter-2 inhibitor 1. Metformin still remains the major frontline drug for the treatment of type 2 DM [17]. Many available drugs for the treatment of DM have significant adverse effects and do not prevent its complications. The high prevalence of type 2 DM and its multiple complications highlight the requirement for further investigations aiming for the improvement of existing anti-diabetic therapeutic regimens or for the development of a new therapeutic strategy based on the current understanding of the pathophysiology and biochemical pathways of insulin resistance. In this context, natural products are a very important source of bioactive compounds acting on distinct molecular mechanisms able to affect several biochemical pathways, providing benefits in diabetic management as part of complementary and alternative therapies or as important new lead molecules for drug design [18,19].
Dietary therapy is generally considered to be the first step in the prevention and treatment of diabetic patients. Among the current therapeutic options, such as insulin therapy and hypoglycemic drugs, attention in recent years has been shifting to the effects and properties—still not completely known—of medicinal plants as valid and inexpensive therapeutic supports lacking or almost completely devoid of side effects.

2. Therapeutic Potential of Nutraceuticals Consumed in Type 2 DM

Plants and plant extracts have been used for the treatment of DM since ancient times, and they still remain an important source of herbal remedies in DM therapy, and possible tools for the development of new drugs [20].
The antihyperglycemic biguanide metformin was developed from investigation of the plant Galega officinalis, traditionally used to treat DM [21,22]. Herbal remedies are very popular, particularly in developing countries, and play a supportive role as a complementary medical intervention with limited toxic effects and reduced financial cost. Over 400 plants and their compounds have been studied for type 2 DM treatment, and several reviews summarize these studies [23,24,25,26]. According to efficacy, the most active plants in the management of DM are Trigonella foenum greacum, Momordica charantia, Gymnema sylvestre, Ocimum tenuiflorum, Panax ginseng and quinquefolius, Coccinia grandis, Opuntia spp., Allium spp., etc. [26,27,28]. Many studies in human and animal models of type 2 DM have confirmed the potential beneficial effects of plants to correct the metabolic disorder and to delay the development of diabetic complications. However, the therapeutic efficacy of herbal plants in mitigating the deleterious effect of DM remains insufficient (and, in some cases, controversial) to actively recommend the use of herbal medicine to treat either high blood glucose or other related risk factors [20,29]. Table 1 summarizes the effects of the most important plants and their active compounds, for which there is clinical evidence of their efficacy as nutraceuticals or food supplements in the prevention or cure of diabetes. In general, the antidiabetic activity of these plants is attributed to the presence of bioactive compounds, such as polyphenols, terpenoids, alkaloids, coumarins, and other constituents, which have demonstrated a reduction in blood glucose levels. The most common hypoglycemic mechanisms of action found for these plant extracts and their pure compounds include the reduction of α-glucosidase activity, inhibition of protein tyrosine phosphatase 1β and antioxidant activity, activation of the peroxisome proliferator-activated receptors (PPARs), reduction of glucose uptake and glucose transport, and induction of pancreatic insulin secretion [25,30]. The synergistic effect of different phytochemicals in the plant extracts is very important, so that the herbs have multiple mechanisms in the control of the diabetic condition and its complications. In some cases, they lower the blood glucose steady-state level, and they also reduce hypertension and the blood lipid profile [31]. Many plant preparations and derived compounds are used as nutraceuticals or food supplements to prevent DM or as an adjuvant in combined therapy with antidiabetic drugs to treat DM and its complications. Frequently, clinical evidence has demonstrated that supplementary treatment of diabetic subjects with functional foods and nutraceuticals derived from vegetables could increase the effectiveness of DM management [32]. Most nutraceuticals are dietary phytochemicals, such as polyphenols compounds (phenolic acids, flavonoids and their derivatives, stilbenes, tannins), glycosinolates, phytoestrogen, dietary fibers, and carotenoids. Dietary polyphenols possess several biological and beneficial properties and are considered an important class of antioxidant with a beneficial role in opposing the effects of excess reactive oxygen species involved in the pathogenesis of type 2 DM [33,34]. Most epidemiological papers connect dietary polyphenol consumption to reduced risk of type 2 DM [35,36]. Many studies evidentiate that dietary polyphenolic compounds may exert hypoglycemic effects in multiple ways, such as by inhibiting intestinal carbohydrate hydrolyzing enzymes α-amylase and α-glucosidase, reducing intestinal absorption of dietary carbohydrate, protecting β-cell function from glucotoxicity, activating 5-adenosine monophosphate-activated protein kinase (AMPK), increasing insulin-dependent glucose uptake, or showing antioxidative and anti-inflammatory properties [34,37,38,39,40,41]. Phenolic-rich extracts, anthocyanins, and isoflavones have shown protective effects on pancreatic β cells against oxidative damage through enhancing the natural antioxidant system [42,43,44,45]. Flavonoids have been found to lower glucose levels, mainly through inhibiting intestinal α-glucosidase and α-amylase [46,47], upregulating the liver glucokinase (GK) via PPARγ, upregulating adipocyte Glucose transporter-4 (GLUT4) [48,49], inhibiting intestinal glucose absorption by inhibiting GLUT2 [50], or through reduction or decrease the lipid peroxidation [51]. Furthermore, proanthocyanidin extracts from grape seeds have drawn great interest as natural treatments for DM and some long-term DM complications. According to clinical studies, these extracts seem to delay the development of retinopathy, nephropathy, and neurodegenerative damage in diabetic subjects [52,53]. Other studies indicate that epigallocatechin-3-gallate (ECGC) from green tea may act on glucose intestinal and cellular uptake, on inflammation to inhibit adipocyte proliferation, and on oxidative stress [54,55,56,57,58]. ECGCs suppress apoptosis via several mechanisms, including the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in subsequent enhancement of expression of the antioxidant response elements (ARE), providing more resistance to reactive oxygen species (ROS) damage via neutralizing enzymes and ROS scavengers. However, for the prevention of type 2 diabetes and obesity, it is important to have slow absorption of the green tea ECGCs, which could be obtained using polyethylene glycol-3350 or poly-γ-glutamate to extend their intestinal effects [57,59]. Therefore, additional trials are needed to support green tea consumption for DM therapy, with larger sample size and greater statistical power.

3. OSCs from Garlic as Nutraceuticals for Prevention and Therapy in Type 2 DM

Among the nutraceuticals described above, the plant extracts with organosulfur compounds (OSCs) deserve particular interest. Several studies have shown that OSCs and their different formulations inhibit insulin resistance and hyperglycemia, and they subsequently protect DM patients from several clinical effects, including cardiovascular complications. There are two main groups of vegetables characterized by the presence of OSCs with special properties: Brassicaceae and Amaryllidaceae. The first family includes cabbage, cauliflower, and Brussels sprouts, and kale and rucola (also known as rocket salad) are part of the Eruca genus of the mustard or cruciferous family; all of these produce S-methyl cysteine-l-sulfoxide [113]. The second one includes shallot, garlic, leek, onion, and chives; they belong to the Allium genus and produce S-alk(en)yl-l-cysteine sulfoxides. OSCs, contained in both these vegetable families, can be used as nutraceuticals and the mechanisms of action of either original produced sulfoxides or their derivatives have been studied in detail for their therapeutic effects. According to these investigations, type 2 DM patients eating broccoli sprouts, containing sulforaphane (1-isothiocyanato-4-(methylsulfinyl)butane), show increased total antioxidant capacity in their blood, serum insulin, and insulin resistance, with reduced lipid peroxidation, serum triglycerides, oxidative stress index, oxidized low-density lipoprotein (LDL)/LDL cholesterol ratio, and blood high-sensitivity C-reactive protein (CRP) [114]. Therefore, sulforaphane seems to reduce nephropathy, diabetic fibrosis, and vascular complications. The underlying molecular mechanism of sulforaphane seems to involve the Nrf2-related antioxidant response, elevation of phase 2 enzymes and PPARs, reduction of oxidative stress, and NF-κB (nuclear factor kappa light chain enhancer of activated B cells) activity reduction (with reduction of its related inflammation). According to these investigations, sulforaphane, as a component of young broccoli sprouts, is an excellent food additive for diabetic patients [114]. One of the most important glycemic-controlled herbal medicines with OSCs is garlic (A. sativum L.) [115,116]. Epidemiological and preclinical studies support the effects of garlic extract and its OSCs as cardiovascular-protective agents [117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133], due to the properties of these compounds, which are summarized in Figure 1.
Garlic shows powerful effects in DM, such as hypoglycemia, hyperinsulinemia, hypotriglyceridemia, anti-glycation, hypocholesterolemia, and anti-lipidperoxidation effects [116,117] (Figure 2). Garlic, either dried or fresh, and its derivatives show antihyperglycemic effects in genetic animal models of DM [116,134,135,136,137] and clinically in humans [138,139]. Garlic improves insulin sensitivity and the associated metabolic syndrome in animal models [134], and its derivatives reduce both insulin resistance [67] and blood glucose in streptozotocin-induced and alloxan-induced DM mellitus in rats and mice [140,141]. These beneficial effects are attributed to the presence of OSCs, such as derivatives from alliin and sulfoxide amino acids. The effect of garlic homogenate in reducing heart hypertrophy and fructose-induced myocardial oxidative stress is due to activation of the PI3K/Akt/Nrf2-Keap1-dependent pathway [142]. Diabetic erectile dysfunction may be associated with an elevated level of ROS in penile tissue [143] and ROS formation prevention and the restoration of the erectile function by S-allyl cysteine (SAC), the main OSC in aged garlic extract, in diabetic rats was obtained by modulation of NADPH oxidase expression. Recent studies on SAC demonstrated its antidiabetic, antioxidant, anti-inflammatory, and neuroprotective properties [144,145]. Trials using raw garlic on type 2 DM patients have reported a significant lowering of glycaemia and lipid metabolism with a concomitant amelioration of redox metabolism (SOD, catalase, and GPx in erythrocytes) [146]. Similar effects have been reported by other trials following administration of garlic or garlic compounds [147,148]. Although several investigations using garlic or its extracts, both in animal models and in clinical trials, have shown a clear beneficial effect in the treatment of patients with DM, nonetheless, additional investigations are needed to further explore the benefits of garlic for patients with type 2 DM.
Garlic OSCs are spontaneously derived from allicin after cutting of the garlic cloves (Figure 3) and are the principal active ingredients that are responsible for the beneficial effects of the garlic extracts. The alliin (S-allyl-cysteine sulfoxide) is metabolized to allicin (diallyl thiosulfinate) by alliinase, a carbon-sulfur lyase enzyme that can be released only by breaking the garlic cells. Subsequently, allicin rapidly undergoes nonenzymatic decomposition that transforms into a series of OSCs, such as diallyl monosulfide (DAS) and oil-soluble polysulfides, including diallyl disulfide (DADS) as a main product and diallyl trisulfide (DATS) (Figure 3).
These first compounds are responsible for the characteristic pungency of garlic [152]. Among the compounds with notable current interest, there are the so-called polysulfites, which are abundant constituents, especially in the essential oils of garlic. Zhao and colleagues [153] identified 16 compounds as the main components of commercial garlic essential oil, accounting for 97.44% of the total oil of A. sativum. These were diallyl trisulfide (DATS; 50.43%), diallyl disulfide (DADS; 25.30%), diallyl sulfide (DAS; 6.25%), diallyl tetrasulfide (DATES; 4.03%), 1,2-dithiolane (3.12%), allyl methyl disulfide (3.07%), 1,3-dithiane (2.12%), and allyl methyl trisulfide (2.08%).
Originally, the antidiabetic properties of allicin were demonstrated in rabbits by a reduction of fasting blood glucose, with comparable efficacy to the standard drug tolbutamide [154]. The heart-related complications in DM, such as suppression of myocardial fibrosis progression in streptozotocin-induced diabetic rats, can be reduced by allicin administration. The attenuation of apoptosis and fibrosis after allicin treatment was related to the inhibition of Bcl-2, CD95, connective tissue growth factor (CTGF), and transforming growth factor β1 (TGF-β1) protein expression, eventually preventing DM-induced cardiac complication progression [155]. Bcl-2 and CD95 drive the cell fate, while CTGF and TGF-β1 are highly sensitive myocardial fibrosis markers. Allicin substantially down-regulates both Bcl2 and CD95 in diabetic rats, and thereby reverses myocardial apoptosis remodeling [155]. Moreover, ventricular arrhythmias activated by Bcl-2 treatment in diabetic rats can be considerably suppressed by allicin. Electrophysiology experiments have also demonstrated that allicin attenuated the action potential duration by inhibiting the L-type calcium current (ICa-L) and improving the inward rectifier potassium current (IK1) [156]. Nephropathy is also a disease linked to DM and it is typically related to a high kidney weight/body ratio, blood urea, and creatinine, with a reduced creatinine clearance rate. Allicin treatment efficiently ameliorated the diabetic nephropathy in rats by preventing the effects on the TGF-1/p-ERK1/2 signaling pathway [157].
In order to ameliorate the efficacy and stability of allicin, it was conjugated with captopril to produce S-allyl-mercapto-captopril (CPSSA). Prolonged CPSSA administration reduces body weight gain, blood pressure, and blood glucose levels in Cohen- Rosenthal Diabetic Hypertensive mice.
All these data demonstrate that allicin can provide an important contribution to reducing obesity, hypertension, and diabetes, which are also important risk factors for cardiac and metabolic disease [158]. Therefore, allicin can prevent insulin resistance and other complications [159]. The molecular mechanism by which allicin reduces the pathologies related to the DM was also investigated, and it was related to its ability to scavenge ROS. Free radical generation, which is also due to hyperglycemia, could in fact be one of the primary causes of insulin resistance in DM and its related complications [160].
In vitro studies have demonstrated that allicin attenuated nicotinamide adenine dinucleotide phosphate oxidase (NOX) activation and ROS production when oxidized LDL-cholesterol was exposed to endothelial cells [159,161].
Other derivatives from allicin have been studied for their properties as adjuvants in diabetic pathologies. One of these derivatives is allyl methyl sulfide (AMS), which is one of the major bioactive components in garlic present in the volatile garlic fraction with antibacterial [162], antioxidant [163], and anticancer properties [164]. The administration of AMS to experimental hyperglycemic rats considerably enhanced glutathione (GSH) and vitamin C and E levels [165]. Moreover, AMS treatment, by way of its free radical scavenging property and control of free radicals in the liver, is able to increase the activities of antioxidant enzymes.
Antioxidants and anti-inflammatory phytochemicals have a crucial role in the prevention of acute liver damage [166]. Due to the hepatoprotective effects of AMS, its administration can reduce the elevation of hepatic injury enzymes [165]. Several studies have shown that AMS treatment improves hepatic cellular damage, thereby conquering diabetic complications. Beneficial effects in alleviating diabetic liver damage and improving the hepatic function were obtained, in addition to exertion of a better glycemic control through stimulating insulin secretion in the remnant β-cells and ameliorating inflammatory markers. Dietary administration of AMS exhibited significant preservation of the structural and functional integrity of hepatocytes, probably due to the attenuation of hyperglycemia-mediated oxidative stress [165]. Further in vivo and clinical studies are necessary to confirm the possibility of using this phytochemical for dietary treatment in DM.
Garlic OSCs and their conjugates are also optimal slow H2S-releasing agents [167,168,169] and are able to release H2S in a non-enzymatic reaction with intracellular GSH (Figure 4B) [169]. A growing body of evidence has shown that H2S plays an important role in the disordered glucose metabolism [170,171] that is the most important features of DM. Therefore, garlic-derived OSC supplementation could increase H2S levels, help to restore kidney function, and represent a natural therapeutic strategy.

4. H2S-Releasing Agents for Prevention and a Therapeutic Approach in Type 2 DM

Hydrogen sulfide is one of three important endogenous gasotransmitters and is released in tissues from the metabolism of L-cysteine or polysulfides [170] (Figure 4A,B). Principally, the enzymatic production of H2S in mammalian cells is due to the cytosolic pyridoxal 5’-phosphate (PLP)-dependent enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) and to the 3-mercaptopyruvate sulfurtransferase (MST) that is present in both the cytosol and mitochondria. H2S exerts relevant protective effects and has essential roles in the central nervous, respiratory, and cardiovascular systems. H2S is a physiological mediator able to limit inflammation and free radical damage by reacting with multiple oxidant stressors, including peroxynitrite [172], superoxide radical anion [173], and hydrogen peroxide [174], and by producing glutathione persulfide (GSSH) in mitochondria [175,176,177], a more efficient H2O2 scavenging molecule than GSH. Its antioxidant activity is also due to activation of the Nrf2-ARE pathway [178] (Figure 5A). In the last few years, H2S donors have shown great therapeutic potential for widely diffused pathologies, such as cardiovascular [179,180,181], neurodegenerative [182,183,184], and gastrointestinal diseases [185,186]. Moreover, H2S seems to be able to protect islet beta cells from damage elicited by distinct toxic or stress events [187,188]. Both exogenous administration of H2S (NaHS) and stimulating endogenous H2S generation with L-cysteine seem to reduce programmed cell death [187]. The pathological loss of beta cells, but also the chronic inflammation of damaged islet cells, is the primary cause of several DM complications. DM can be, therefore, considered an inflammatory response disease, suggesting a possible anti-inflammatory therapy [189,190,191]. Of note is that the NaHS administration can significantly inhibit pro-inflammatory-factor-induced injury in primary cultured pancreatic beta cells and MIN6 cells [192]. The reduction of H2S by knockout of CSE in high-fat-diet-induced type 2 DM mice exhacerbates oxidative insults without insulin secretion or reduction of blood glucose levels [193]. Actually, endogenous H2S does not always work as a friend. Conversely, other authors demonstrated that H2S contributes to ER stress-mediated cellular apoptosis through activation of the p38 MAPK pathway [194], not fully in keeping with the work by Taniguchi et al. [192].
Basal CSE expression is quite low in islet β cells, but can be increased by high concentrations of glucose. H2S can affect insulin-secreting β cells, both inhibiting secretion of insulin from the cells [195,196] and protecting them against cellular apoptosis induced by various stimuli [193,197]. Deregulated production of insulin is the major reason for glycometabolism disorder, and therefore DM; this is because insulin is the only hormone that is able to decrease blood glucose. Some studies have demonstrated that the expression of CSE and CBS is significantly upregulated in both liver and pancreas in streptozotocin-induced diabetic rats compared to the control [198]. H2S administration to beta cell lines INS-1E and HIT-T15 cells attenuated insulin secretion triggered by a high concentration of glucose [195]. This inhibitory effect of H2S on insulin secretion is related to the opening of KATP channels [199]. During diabetic hyperglycemia, high levels of endogenous H2S can open KATP channels in islet β cell membrane, causing elevated polarization of the membrane potential and lower insulin secretion [195] (Figure 5B). Moreover, exogenous H2S by NaHS inhibits L-type voltage-dependent Ca2C channels, further lowering insulin secretion in a KATP channel-independent manner [196]. Therefore, H2S inhibits insulin secretion by targeting several biochemical processes, such as activation of KATP channels, inhibition of ATP synthesis, and inactivation of L-type voltage-dependent Ca2C channels [170]. Of note is that the physiological synthesis of H2S inhibition in Zucker DM rats increased insulin release and reduced hyperglycemia [200]. Altogether, the above strongly support that the downregulation of the H2S system apparently promotes diabetic prevention and treatment. The regulation of endogenous H2S production can be very relevant in DM, i.e., at the early phases of diabetes, the administration of H2S may be beneficial, while at its late stage, inhibiting H2S generation may be a possible therapeutic strategy.
On these bases, we can conclude that the effects of H2S on insulin secretion can change at different phases of diabetic development. Therefore, in the early phases of the disease, hyperglycemia-induced CSE upregulation seems a beneficial mechanism for the patients and the increased H2S levels protect islet β cells by reducing oxidation and inflammation, and by inhibiting the autoimmune response. The development of diabetes leads to a further increase of H2S that can inhibit insulin secretion and reduce the overload of diabetic beta cells by the reduction of the ATP content, activation of KATP channels, or inhibition of L-type voltage-dependent calcium channels [201]. In persistent hyperglycemia conditions, an increase in endogenous H2S can trigger an ER stress response, and consequently apoptosis [194]. Although endogenous H2S production could have different effects in the stages of DM, several studies have demonstrated that the treatment with H2S-releasing agents can be important in reducing the damage induced by DM. Oxidative stress in DM leads to excessive autophagy with consequent vascular endothelial cell (EC) dysfunction. Several studies have shown that exogenous H2S administration is able to prevent arterial EC dysfunction by inhibition of excessive autophagy through the Nrf2-ROS-AMPK signaling pathway [202]. NaHS treatment ameliorated myocardial autophagy, and more generally, the myocardial fibrosis, which is a predominant pathological characteristic of diabetic myocardial damage, by PI3K/Akt1 pathway activation [203]. High blood glucose levels and DM are implicated in neurodegeneration, and one of the hallmarks of this pathology is protein aggregation; H2S treatment could represent a novel strategy against protein aggregation in the diabetic brain [204]. Other common complications of DM are reduced angiogenesis and intractable wound lesions. H2S has been reported to have pro-angiogenic effects and H2S donors are able to promote diabetic wound healing by restoring endothelial progenitor cell (EPC) function and inducing an upregulation of in-wound skin tissue and EPCs [205]. In diabetic skin complications, H2S provided by NAC or NSHD-1, a synthetic slow H2S-releasing donor, can exert protective effects against DM-like injury [206,207]. More recently, several groups have produced slow H2S-releasing materials able to promote cell proliferation and migration and tissue repair, also reducing oxidative stress due to ROS [208,209]. A microparticle system comprising hydrophobic phase-change materials able to release H2S, termed [email protected], was produced for wound healing applications in DM [210]. In this study, significantly accelerated re-epithelialization and wound closure in diabetic mice was obtained using Tegaderm integrated with [email protected] Other H2S-releasing biomaterials for potential application in wound healing in DM have been obtained using OSCs derived from garlic. Wang et al. [211] demonstrated that mesoporous silica nanoparticles (MSNs) loaded with DATS, named DATS-MSN, and able to release H2S can stimulate endothelial cells proliferation and migration and have cytoprotective effects, reducing the inflammatory cytokines production and adhesion molecule expression. Other formulations of slow H2S-releasing microfibrous mats were produced by functionalization or doping with OSCs or oil-soluble extracts derived from garlic, named DADS-PFM/PFM+DADS and GaOS-PFM/ PFM+GaOS [212], and were shown to scavenge hydrogen peroxide, increasing pro-cell survival signaling, and at the same time, decreasing pro-apoptotic signaling. The development of slow H2S-releasing biomaterials opens new perspectives for applications of OSC H2S-releasing donors for the fabrication of biomedical devices. Functionalized biomaterials could then be used inside or outside the body for both non-implantable devices and patches for wound dressing and implantable vascular grafts and implants in order to reduce damage due to DM, improving the patient’s health.

5. Conclusions

Currently the worldwide attention is focused on the development of prevention and treatment of diseases by daily consume of nutraceuticals, which can have a supportive role in preserving the life quality of the public. In this review we revised the state of the art on the use of nutraceuticals for prevention and adjuvant therapy of type 2 DM and its complications, focusing our attention in particular on nutraceuticals with sulfur and derived from Allium spp. The peculiarity of these nutraceuticals is their ability to release the gasotrasmitter H2S. Although endogenous H2S, as a signaling molecule, can show different effects at different stages of DM, several in vitro and in vivo studies have demonstrated that H2S donors can reduce the onset of DM and the damage it causes. However, more clinical studies are requested to support the validity of OSCs administration in the prevention and therapy of DM. In general, although several studied have demonstrated the beneficial effects of nutraceuticals in DM, one of the most important problems with natural compounds, including garlic OSCs, is their stability over time. Indeed, many garlic OSCs, such as allicin and its derivatives, can rapidly degrade even at low temperatures. Accordingly, several groups are developing promising strategies of administration of these natural compounds, such as capsules containing garlic oil self-nanoemulsifying systems [213] or nano-emulsions obtained in combination with other nutraceuticals, as we previously have shown with omega 3 and proteins [214], for improving their stability and bioavailability. Therefore, the production of new formulations with other nutraceuticals, having synergistic effects, may be relevant to obtaining good administration and reproducibility in clinical trials. Moreover, the variability of the chemical composition of the vegetables, which can vary with the environmental conditions and countries where they are produced, represents another relevant problem. Therefore, trials on the use of vegetables containing H2S donors should include information on their chemical composition and standardized preparations. In this context, the possibility to increase the production of the optimal H2S-releasing agents in the OSC-rich-vegetables should be explored in order to produce optimized food for daily usage as a prevention strategy and adjuvant cure for type 2 DM.
The study of OSCs and the vegetables containing them represents a stimulating field of research, in which the redox biology, inflammation, detoxification, tissue repair, and regeneration are interconnected for beneficial effects on human health.

Author Contributions

Writing—original draft preparation, S.M.; writing—review and editing, S.M., V.T.P., S.L.; supervision, S.M., V.T.P.; conceptualization and project administration, S.M.

Funding

This research received no external funding.

Acknowledgments

We thank the Italian Ministry of Foreign Affair (MAECI) for the Grant-GR-project Italia-Albania 2011-2014 that supported our collaboration.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

3-MP: 3-mercaptopyruvateCD95: Cluster of differentiation 95
ADA: American Diabetes AssociationCPSSA: S-allyl-mercapto-captopril
AMS: allyl methyl sulfideCRP: C-reactive protein
Ang-1: angiopoietin-1CSE: cystathionine γ-lyase
ARE: antioxidant response elementsCTGF: connective tissue growth factor;
Bcl2: B-cell lymphoma 2DADS: diallyl disulfide;
BMI: Body mass indexDAS: diallyl monosulfide;
CBS: cystathionine β-synthaseFDPS: Finnish Diabetes Prevention Study
DATES: diallyl tetrasulfideGIP: Glucose-dependent insulinotropic polypeptide
DATS: diallyl trisulfideGK: glucokinase
DM: diabetes mellitusGLUT2: Glucose transporter-2
DPP: Diabetes Prevention ProgramGLUT4: Glucose transporter-4
ECs: vascular endothelial cellsGPx: Glutathione peroxidase
ECGC: epigallocatechin-3-gallateGSH: reduced Glutathione
eNOS: endothelial nitric oxide synthaseGSSH: glutathione persulfide
EPC: endothelial progenitor cellGST: Glutathione-S-transferase
FBG: Fast blood glucoseH2S: Hydrogen sulfide
HbA1c: Glycated hemoglobinMSNs: mesoporous silica nanoparticles
HDL: Hight density lipoproteinMST: 3-mercaptopyruvate sulfurtransferase
ICa-L: L-type calcium currentNK cells: Natural killer cells
IK1: inward rectifier potassium currentNO: Nitric oxide
IL-6: Interleukin 6TGF- β1: transforming growth factor β1
INS-1E: Insulinoma cell line 1ENrf2: nuclear factor erythroid 2-related factor 2
IRs: Insulin ReceptorsOSCs: organosulfur compounds
LDL: Light density lipoproteinPUFAs: Polyunsaturated fatty acids
MIN6: mouse insulinoma cell line 6ROS: Reactive oxygen species
p38 MAPK: p38 mitogen-activated protein kinasesSAC: S-allyl cysteine
PFM: polylactic fibrous membranesSAMC: S-allylmercaptocysteine
PLP: pyridoxal 5’-phosphateSAMG: S-allylmercaptoglutatione
PPARs: peroxisome proliferator-activated receptorsTNF-α: Tumor necrosis factor
PPBG: Postprandial blood glucoseVEGF: Vascular endothelial growth factor
SGLT1: Sodium glucose transporter protein 1VLDL: Very low density lipoprotein
SOD: Superoxide dismutaseWHO: World Health Organization.
TG: Triglyceride
AMPK: activating 5-adenosine monophosphate-activated protein kinase
P13k/Akt: phosphoinositide-3-kinase/ Protein Kinase B
p-ERK1/2: phosphorylated extracellular signal–regulated kinases 1/2
NF-κB: nuclear factor kappa light chain enhancer of activated B cells
EASD: European Association for the Study of Diabetes
NOX: nicotinamide adenine dinucleotide phosphate oxidase
HIT-T15: insulin release from a cloned hamster B-cell line

References

  1. Akkati, S.; Sam, K.G.; Tungha, G. Emergence of promising therapies in diabetes mellitus. J. Clin. Pharmacol. 2011, 51, 796–804. [Google Scholar] [CrossRef] [PubMed]
  2. Aronson, D. Hyperglycemia and the pathobiology of diabetic complications. Adv. Cardiol. 2008, 45, 1–16. [Google Scholar] [CrossRef] [PubMed]
  3. Baynes, J.W.; Thorpe, S.R. Role of oxidative stress in diabetic complications: A new perspective on an old paradigm. Diabetes 1999, 48, 1–9. [Google Scholar] [CrossRef] [PubMed]
  4. Maritim, A.C.; Sanders, R.A.; Watkins, J.B., 3rd. Diabetes, oxidative stress, and antioxidants: A review. J. Biochem. Mol. Toxicol. 2003, 17, 24–38. [Google Scholar] [CrossRef] [PubMed]
  5. López-Candales, A. Metabolic syndrome X: A comprehensive review of the pathophysiology and recommended therapy. J. Med. 2001, 32, 283–300. [Google Scholar] [PubMed]
  6. Ritz, E.; Rychlík, I.; Locatelli, F.; Halimi, S. End-stage renal failure in type 2 diabetes: A medical catastrophe of worldwide dimensions. Am. J. Kidney Dis. 1999, 34, 795–808. [Google Scholar] [CrossRef]
  7. Forbes, J.M.; Cooper, M.E. Mechanisms of diabetic complications. Physiol. Rev. 2013, 93, 137–188. [Google Scholar] [CrossRef]
  8. Gakidou, E.; Mallinger, L.; Abbott-Klafter, J.; Guerrero, R.; Villalpando, S.; Ridaura, R.L.; Aekplakorn, W.; Naghavi, M.; Lim, S.; Lozano, R.; et al. Management of diabetes and associated cardiovascular risk factors in seven countries: A comparison of data from national health examination surveys. Bull. World Health Organ. 2011, 89, 172–183. [Google Scholar] [CrossRef]
  9. Golbidi, S.; Badran, M.; Laher, I. Antioxidant and Anti-Inflammatory Effects of Exercise in Diabetic Patients. Exp. Diabetes Res. 2012, 2012, 1–16. [Google Scholar] [CrossRef]
  10. Eriksson, K.F.; Lindgarde, F. Prevention of Type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study. Diabetologia 1991, 34, 891–898. [Google Scholar] [CrossRef]
  11. Pan, X.; Li, G.; Hu, Y.; Wang, J.X.; Yang, W.Y.; An, Z.X.; Hu, Z.X.; Lin, J.; Xiao, J.Z.; Cao, H.B.; et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: The Da Qing IGT and Diabetes Study. Diabetes Care 1997, 20, 537–544. [Google Scholar] [CrossRef] [PubMed]
  12. Tuomilehto, J.; Lindstrom, J.; Eriksson, J.G.; Valle, T.T.; Hämäläinen, H.; Ilanne-Parikka, P.; Keinänen-Kiukaanniemi, S.; Laakso, M.; Louheranta, A.; Rastas, M.; et al. Prevention of Type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 2001, 344, 1343–1350. [Google Scholar] [CrossRef] [PubMed]
  13. Knowler, W.C.; Barrett-Connor, E.; Fowler, S.E.; Hamman, R.F.; Lachin, J.M.; Walker, E.A.; Nathan, D.M. Reduction in the incidence of Type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 2002, 346, 393–403. [Google Scholar] [CrossRef] [PubMed]
  14. Ramachandran, A.; Snehalatha, C.; Mary, S.; Mukesh, B.; Bhaskar, A.D.; Vijay, V. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent Type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 2006, 49, 289–297. [Google Scholar] [CrossRef] [PubMed]
  15. Orozco, L.J.; Buchleitner, A.M.; Gimenez-Perez, G.; Roque, I.F.M.; Richter, B.; Mauricio, D. Exercise or exercise and diet for preventing Type 2 diabetes mellitus. Cochrane Database Syst. Rev. 2008, 16. [Google Scholar] [CrossRef] [PubMed]
  16. Davies, M.J.; D’Alessio, D.A.; Fradkin, J.; Kernan, W.N.; Mathieu, C.; Mingrone, G.; Rossing, P.; Tsapas, A.; Wexler, D.J.; Buse, J.B. Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018, 41, 2669–2701. [Google Scholar] [CrossRef] [PubMed]
  17. Marín-Peñalver, J.J.; Martín-Timón, I.; Sevillano-Collantes, C.; Cañizo-Gómez, F.J. Update on the treatment of type 2 diabetes mellitus. World J. Diabetes 2016, 7, 354–395. [Google Scholar] [CrossRef] [PubMed]
  18. Kar, A.; Choudhary, B.K.; Bandyopadhyay, N.G. Comparative evaluation of hypoglycaemic activity of some Indian medicinal plants in alloxan diabetic rats. J. Ethnopharmacol. 2003, 84, 105–108. [Google Scholar] [CrossRef]
  19. Heinrich, M.; Barnes, J.; Gibbons, S.; Williamson, E. Fundamentals of Pharmacognosy and Phytotherapy, 2nd ed.; Elsevier: Atlanta, GA, USA, 2012; ISBN 9780702033889. [Google Scholar]
  20. Evans, W.C. Trease and Evans Pharmacognosy, 16th ed.; Saunders: Philadelphia, PA, USA, 2009; ISBN-13: 978-0702029332. [Google Scholar]
  21. Cusi, K.; DeFronzo, R.A. Metformin: A review of its metabolic effects. Diabetes Rev. 1998, 6, 89–131. [Google Scholar]
  22. Evans, J.L.; Bahng, M.K. Non-pharmaceutical Intervention Options for type 2 Diabetes: Diets and Dietary Supplements (Botanicals, Antioxidants, and Minerals). In Diabetes Mellitus and Carbohydrate Metabolism; MDText.com, Inc.: South Dartmouth, MA, USA, 2014; Volume 16, pp. 1–13. [Google Scholar]
  23. Modak, M.; Dixit, P.; Londhe, J.; Ghaskadbi, S.; Devasagayam, T.P. Indian herbs and herbal drugs used for the treatment of diabetes. J. Clin. Biochem. Nutr. 2007, 40, 163–173. [Google Scholar] [CrossRef]
  24. Marles, R.J.; Farnsworth, N.R. Antidiabetic plants and their active constituents. Phytomedicine 1995, 2, 137–189. [Google Scholar] [CrossRef]
  25. Ota, A.; Ulrih, N.P. An Overview of Herbal Products and Secondary Metabolites Used for Management of Type Two Diabetes. Front. Pharmacol. 2017, 8, 436. [Google Scholar] [CrossRef] [PubMed]
  26. Governa, P.; Baini, G.; Borgonetti, V.; Cettolin, G.; Giachetti, D.; Rosa Magnano, A.; Miraldi, E.; Biagi, M. Phytotherapy in the Management of Diabetes: A Review. Molecules 2018, 23, 105. [Google Scholar] [CrossRef] [PubMed]
  27. Cefalu, W.T.; Ye, J.; Zuberi, A.; Ribnicky, D.M.; Raskin, I.; Liu, Z.; Wang, Z.Q.; Brantley, P.J.; Howard, L.; Lefevre, M. Botanicals and the metabolic syndrome. Am. J. Clin. Nutr. 2008, 87, 481S–487S. [Google Scholar] [CrossRef] [PubMed]
  28. Ghorbani, A. Best herbs for managing diabetes: A review of clinical studies. Braz. J. Pharm. Sci. 2013, 49, 413–422. [Google Scholar] [CrossRef]
  29. Cefalu, W.T.; Stephens, J.M.; Ribnicky, D.M. Herbal Medicine: Biomolecular and Clinical Aspects, 2nd ed.; CRC Press/Taylor & Francis: Boca Raton, FL, USA, 2011; p. 9. [Google Scholar]
  30. Rios, J.L.; Francini, F.; Schinella, G.R. Natural products for the treatment of type 2 Diabetes mellitus. Planta Med. 2015, 81, 975–994. [Google Scholar] [CrossRef]
  31. Choudhury, H.; Pandey, M.; Hua, C.K.; Mun, C.S.; Jing, J.K.; Kong, L.; Ern, L.Y.; Ashraf, N.A.; Kit, S.W.; Yee, T.S.; et al. An update on natural compounds in the remedy of diabetes mellitus: A systematic review. J. Tradit. Complement. Med. 2018, 8, 361–376. [Google Scholar] [CrossRef]
  32. Bahadoran, Z.; Mirmiran, P.; Azizi, F. Dietary polyphenols as potential nutraceuticals in management of diabetes: A review. J. Diabetes Metab. Disord. 2013, 12, 43. [Google Scholar] [CrossRef]
  33. Han, X.; Loa, T. Dietary polyphenols and their biological significance. Int. J. Mol. Sci. 2007, 8, 950–988. [Google Scholar] [CrossRef]
  34. Pandey, K.B.; Rizvi, S.I. Plant polyphenols as dietary antioxidants in human health and disease. Oxid. Med. Cell. Longev. 2009, 2, 270–278. [Google Scholar] [CrossRef]
  35. Song, Y.; Manson, J.E.; Buring, J.E.; Sesso, H.D.; Liu, S. Associations of dietary flavonoids with risk of type 2 diabetes, and markers of insulin resistance and systemic inflammation in women: A prospective study and cross-sectional analysis. J. Am. Coll. Nutr. 2005, 24, 376–384. [Google Scholar] [CrossRef] [PubMed]
  36. Xiao, J.B.; Högger, P. Dietary polyphenols and Type 2 diabetes: Current insights and future perspectives. Curr. Med. Chem. 2015, 22, 23–38. [Google Scholar] [CrossRef] [PubMed]
  37. Sales, P.M.; Souza, P.M.; Simeoni, L.A.; Silveira, D. α-Amylase inhibitors: A review of raw material and isolated compounds from plant source. J. Pharm. Pharm. Sci. 2012, 15, 141–183. [Google Scholar] [CrossRef] [PubMed]
  38. Shori, A.B. Screening of antidiabetic and antioxidant activities of medicinal plants. J. Integr. Med. 2015, 13, 297–305. [Google Scholar] [CrossRef]
  39. Kim, Y.; Keogh, J.B.; Clifton, P.M. Polyphenols and Glycemic Control. Nutrients 2016, 8, 17. [Google Scholar] [CrossRef] [PubMed]
  40. Lin, D.; Xiao, M.; Zhao, J.; Li, Z.; Xing, B.; Li, X.; Kong, M.; Li, L.; Zhang, Q.; Liu, Y.; et al. An overview of plant phenolic compounds and their importance in human nutrition and management of type 2 diabetes. Molecules 2016, 21, 1374. [Google Scholar] [CrossRef]
  41. Solayman, M.; Ali, Y.; Alam, F.; Islam, M.A.; Alam, N.; Khalil, M.I.; Gan, S.H. Polyphenols: Potential Future Arsenals in the Treatment of Diabetes. Curr. Pharm. Des. 2016, 22, 549–565. [Google Scholar] [CrossRef]
  42. Yin, P.; Zhao, S.; Chen, S.; Liu, J.; Shi, L.; Wang, X.; Liu, Y.; Ma, C. Hypoglycemic and hypolipidemic effects of polyphenols from burs of Castanea mollissima Blume. Molecules 2011, 16, 9764–9774. [Google Scholar] [CrossRef]
  43. Zhang, B.; Kang, M.; Xie, Q.; Xu, B.; Sun, C.; Chen, K.; Wu, Y. Anthocyanins from Chinese bayberry extract protect β cells from oxidative stress-mediated injury via HO-1 upregulation. J. Agric. Food Chem. 2011, 59, 537–545. [Google Scholar] [CrossRef]
  44. Liu, Z.M.; Chen, Y.M.; Ho, S.C. Effects of soy intake on glycemic control: A meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 2011, 93, 1092–1101. [Google Scholar] [CrossRef]
  45. Fu, Z.; Zhang, W.; Zhen, W.; Lum, H.; Nadler, J.; Bassaganya-Riera, J.; Jia, Z.; Wang, Y.; Misra, H.; Liu, D.; et al. Genistein induces pancreatic beta-cell proliferation through activation of multiple signaling pathways and prevents insulin-deficient diabetes in mice. Endocrinology 2010, 151, 3026–3037. [Google Scholar] [CrossRef] [PubMed]
  46. Priscilla, D.H.; Roy, D.; Suresh, A.; Kumar, V.; Thirumurugan, K. Naringenin inhibits a-glucosidase activity: A promising strategy for the regulation of postprandial hyperglycemia in high fat diet fed streptozotocin induced diabetic rats. Chem. Biol. Interact. 2014, 210, 77–85. [Google Scholar] [CrossRef] [PubMed]
  47. Meng, Y.; Su, A.; Yuan, S.; Zhao, H.; Tan, S.; Hu, C.; Deng, H.; Guo, Y. Evaluation of total flavonoids, myricetin, and quercetin from Hovenia dulcis Thunb. as inhibitors of α-amylase and α-glucosidase. Plant Foods Hum. Nutr. 2016, 71, 444–449. [Google Scholar] [CrossRef] [PubMed]
  48. Roy, S.; Ahmed, F.; Banerjee, S.; Saha, U. Naringenin ameliorates streptozotocin-induced diabetic rat renal impairment by downregulation of TGF-b1 and IL-1 via modulation of oxidative stress correlates with decreased apoptotic events. Pharm. Biol. 2016, 54, 1616–1627. [Google Scholar] [CrossRef]
  49. Jung, U.J.; Lee, M.K.; Park, Y.B.; Kang, M.A.; Choi, M.S. Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mrna levels in type-2 diabetic mice. Int. J. Biochem. Cell Biol. 2006, 38, 1134–1145. [Google Scholar] [CrossRef] [PubMed]
  50. Kwon, O.; Eck, P.; Chen, S.; Corpe, C.P.; Lee, J.H.; Kruhlak, M.; Levine, M. Inhibition of the intestinal glucose transporter GLUT2 by flavonoids. FASEB J. 2007, 21, 366–377. [Google Scholar] [CrossRef] [PubMed]
  51. Coskun, O.; Kanter, M.; Korkmaz, A.; Oter, S. Quercetin, a flavonoid antioxidant, prevents and protects streptozotocin-induced oxidative stress and b-cell damage in rat pancreas. Pharmacol. Res. 2005, 51, 117–123. [Google Scholar] [CrossRef]
  52. Li, B.Y.; Cheng, M.; Gao, H.Q.; Ma, Y.B.; Xu, L.; Li, X.H.; Li, X.L.; You, B.A. Back-regulation of six oxidative stress proteins with grape seed proanthocyanidin extracts in rat diabetic nephropathy. J. Cell. Biochem. 2008, 104, 668–679. [Google Scholar] [CrossRef]
  53. Cui, X.P.; Li, B.Y.; Gao, H.Q.; Wei, N.; Wang, W.L.; Lu, M. Effects of grape seed proanthocyanidin extracts on peripheral nerves in streptozocin-induced diabetic rats. J. Nutr. Sci. Vitaminol. 2008, 54, 321–328. [Google Scholar] [CrossRef]
  54. Ortsäter, H.; Grankvist, N.; Wolfram, S.; Kuehn, N.; Sjöholm, A. Diet supplementation with green tea extract epigallocatechin gallate prevents progression to glucose intolerance in db/db mice. Nutr. Metab. 2012, 14, 9–11. [Google Scholar] [CrossRef]
  55. Wang, C.T.; Chang, H.H.; Hsiao, C.H.; Lee, M.J.; Ku, H.C.; Hu, Y.J.; Kao, Y.H. The effects of green tea (−)-epigallocatechin-3-gallate on reactive oxygen species in 3T3-L1 preadipocytes and adipocytes depend on the glutathione and 67 kDa laminin receptor pathways. Mol. Nutr. Food Res. 2009, 53, 349–360. [Google Scholar] [CrossRef] [PubMed]
  56. Kobayashi, Y.; Suzuki, M.; Satsu, H.; Arai, S.; Hara, Y.; Suzuki, K. Green tea polyphenols inhibit the sodium-dependent glucose transporter of intestinal epithelial cells by a competitive mechanism. J. Agric. Food Chem. 2000, 48, 5618–5623. [Google Scholar] [CrossRef] [PubMed]
  57. Park, J.H.; Bae, J.H.; Im, S.S.; Song, D.K. Green tea and type 2 diabetes. Integr. Med. Res. 2014, 3, 4–10. [Google Scholar] [CrossRef] [PubMed]
  58. Igarashi, K.; Honma, K.; Yoshinari, O.; Nanjo, F.; Hara, Y. Effects of dietary catechins on glucose tolerance, blood pressure and oxidative status in Goto-Kakizaki rats. J. Nutr. Sci. Vitaminol. 2007, 53, 496–500. [Google Scholar] [CrossRef] [PubMed]
  59. Park, J.H.; Jin, J.Y.; Baek, W.K.; Park, S.H.; Sung, H.Y.; Kim, Y.K.; Lee, J.; Song, D.K. Ambivalent role of gallated catechins in glucose tolerance in humans: A novel insight into non-absorbable gallated catechin-derived inhibitors of glucose absorption. J. Physiol. Pharmacol. 2009, 60, 101–109. [Google Scholar] [PubMed]
  60. Ismail, M.Y.M. Clinical evaluation of antidiabetic activity of Trigonella seeds and Aegle marmelos leaves. World Appl. Sci. J. 2009, 7, 1231–1234. [Google Scholar]
  61. Ismail, M.Y.M. Clinical Evaluation of Antidiabetic Activity of Bael Leaves. World Appl. Sci. J. 2009, 6, 1518–1520. [Google Scholar]
  62. Sankhla, A.; Sharma, S.; Sharma, N. Hypoglycemic effect of bael leaves (Aegle marmelos) in NIDDM patients. J. Dairy. Food HS 2009, 28, 233–236. [Google Scholar]
  63. Mathew, P.T.; Augusti, K.T. Hypoglycaemic effects of onion, Allium cepa Linn. on diabetes mellitus—A preliminary report. Indian J. Physiol. Pharmacol. 1975, 19, 213–217. [Google Scholar]
  64. Eldin, I.M.T.; Ahmed, E.M.; Elwahab, H.M.A. Preliminary Study of the Clinical Hypoglycemic Effects of Allium cepa (Red Onion) in Type 1 and Type 2 Diabetic Patients. Environ. Health Insights 2010, 4, 71–77. [Google Scholar] [CrossRef]
  65. Bayan, L.; Koulivand, H.P.; Gorji, A. Garlic: A review of potential therapeutic effects. Avicenna J. Phytomed. 2014, 4, 1–14. [Google Scholar] [PubMed]
  66. Gautam, S.; Pal, S.; Maurya, R.; Srivastava, A.K. Ethanolic extract of Allium cepa stimulates glucose transporter typ 4-mediated glucose uptake by the activation of insulin signaling. Planta Med. 2015, 81, 208–214. [Google Scholar] [CrossRef] [PubMed]
  67. Padiya, R.; Banerjee, S.K. Garlic as an anti-diabetic agent: Recent progress and patent reviews. Recent Pat. Food Nutr. Agric. 2013, 5, 105–127. [Google Scholar] [CrossRef] [PubMed]
  68. Méndez-Del Villar, M.; Puebla-Pérez, A.M.; Sánchez-Peña, M.J.; González-Ortiz, L.J.; Martínez-Abundis, E.; González-Ortiz, M. Effect of Artemisia dracunculus administration on glycemic control, insulin sensitivity, and insulin secretion in patients with impaired glucose tolerance. J. Med. Food 2016, 19, 481–485. [Google Scholar] [CrossRef] [PubMed]
  69. Zheng, X.X.; Xu, Y.L.; Li, S.H.; Hui, R.; Wu, Y.J.; Huang, X.H. Effects of green tea catechins with or without caffeine on glycemic control in adults: A meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 2013, 97, 750–762. [Google Scholar] [CrossRef] [PubMed]
  70. Van Dieren, S.; Uiterwaal, C.S.P.M.; van der Schouw, Y.T.; van der A, D.L.; Boer, J.M.; Spijkerman, A.; Grobbee, D.E.; Beulens, J.W. Coffee and tea consumption and risk of type 2 diabetes. Diabetologia 2009, 52, 2561–2569. [Google Scholar] [CrossRef]
  71. Iso, H.; Date, C.; Wakai, K.; Fukui, M.; Tamakoshi, A. The relationship between green tea and total caffeine intake and risk for self-reported type 2 diabetes among Japanese adults. Ann. Intern. Med. 2006, 144, 554–562. [Google Scholar] [CrossRef]
  72. Khan, A.; Safdar, M.; Ali Khan, M.M.; Khattak, K.N.; Anderson, R.A. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care 2003, 26, 3215–3218. [Google Scholar] [CrossRef]
  73. Akilen, R.; Tsiami, A.; Devendra, D.; Robinson, N. Cinnamon in glycemic control: Systematic review and meta analysis. Clin. Nutr. 2012, 31, 609–615. [Google Scholar] [CrossRef]
  74. Subash Babu, P.; Prabuseenivasan, S.; Ignacimuthu, S. Cinnamaldehyde-A potential antidiabetic agent. Phytomedicine 2007, 14, 15–22. [Google Scholar] [CrossRef]
  75. Munasinghe, M.A.A.K.; Abeysena, C.; Yaddehige, I.S.; Vidanapathirana, T.; Piyumal, K.P.B. Blood sugar lowering effect of Coccinia grandis (L.) J.Voigt: Path for a new drug for diabetes mellitus. Exp. Diabetes Res. 2011, 2011, 1–4. [Google Scholar] [CrossRef] [PubMed]
  76. Kuriyan, R.; Rajendran, R.; Bantwal, G.; Kurpad, A.V. Effect of supplementation of Coccinia cordifolia extract on newly detected diabetic patients. Diabetes Care 2008, 31, 216–220. [Google Scholar] [CrossRef] [PubMed]
  77. Ludvik, B.; Neuffer, B.; Pacini, G. Efficacy of Ipomoea batatas (Caiapo) on diabetes control in type 2 diabetic subjects treated with diet. Diabetes Care 2004, 27, 436–440. [Google Scholar] [CrossRef] [PubMed]
  78. Ludvik, B.; Hanefeld, M.; Pacini, G. Improved metabolic control by Ipomoea batatas (Caiapo) is associated with increased adiponectin and decreased fibrinogen levels in type 2 diabetic subjects. Diabetes Obes. Metab. 2008, 10, 586–592. [Google Scholar] [CrossRef] [PubMed]
  79. Tiwari, P.; Mishra, B.N.; Sangwan, N.S. Phytochemical and Pharmacological Properties of Gymnema sylvestre: An Important Medicinal Plant. Biomed. Res. Int. 2014, 2014, 1–18. [Google Scholar] [CrossRef]
  80. Kumar, S.N.; Mani, U.V.; Mani, I. An open label study on the supplementation of Gymnema sylvestre in type 2 diabetics. J. Diet. Suppl. 2010, 7, 273–282. [Google Scholar] [CrossRef] [PubMed]
  81. Paliwal, R.; Kathori, S.; Upadhyay, B. Effect of Gurmar (Gymnema sylvestre) powder intervention on the blood glucose levels among diabetics. Stud. Ethno-Med. 2009, 3, 133–135. [Google Scholar] [CrossRef]
  82. Al-Romaiyan, A.; Liu, B.; Asare-Anane, H.; Maity, C.R.; Chatterjee, S.K.; Koley, N.; Biswas, T.; Chatterji, A.K.; Huang, G.-C.; Amiel, S.A.; et al. A novel Gymnema sylvestre extract stimulates insulin secretion from human islets in vivo and in vitro. Phytother. Res. 2010, 24, 1370–1376. [Google Scholar] [CrossRef]
  83. Mani, U.V.; Mani, I.; Biswas, M.; Kumar, S.N. An open-label study on the effect of flax seed powder (Linum usitatissimum) supplementation in the management of diabetes mellitus. J. Diet. Suppl. 2011, 8, 257–265. [Google Scholar] [CrossRef]
  84. Thakur, G.; Mitra, A.; Pal, K.; Rousseau, D. Effect of flaxseed gum on reduction of blood glucose and cholesterol in type 2 diabetic patients. Int. J. Food Sci. Nutr. 2009, 60, 126–136. [Google Scholar] [CrossRef]
  85. Rahman, I.; Malik, S.A.; Bashir, M.; Khan, R.; Iqbal, M. Serum sialic acid changes in noninsulin dependant diabetes mellitus (NIDDM) patients following bitter melon (Momordica charantia) and rosiglitazone (Avandia) treatment. Phytomedicine 2009, 16, 401–405. [Google Scholar] [CrossRef] [PubMed]
  86. Fuangchan, A.; Sonthisombat, P.; Seubnukarn, T.; Chanouan, R.; Chotchaisuwat, P.; Sirigulsatien, V.; Ingkaninan, K.; Plianbangchang, P.; Haines, S.T. Hypoglycemic effect of bitter melon compared with metformin in newly diagnosed type 2 diabetes patients. J. Ethnopharmacol. 2011, 134, 422–428. [Google Scholar] [CrossRef] [PubMed]
  87. Grover, J.K.; Yadav, S.P. Pharmacological actions and potential uses of Momordica charantia: A review. J. Ethnopharmacol. 2004, 93, 123–132. [Google Scholar] [CrossRef] [PubMed]
  88. Tan, M.-J.; Ye, J.-M.; Turner, N.; Hohnen-Behrens, C.; Ke, C.-Q.; Tang, C.-P.; Chen, T.; Weiss, H.-C.; Gesing, E.-R.; Rowland, A.; et al. Antidiabetic activities of triterpenoids isolated from bitter melon associated with activation of the AMPK pathway. Chem. Biol. 2008, 15, 263–273. [Google Scholar] [CrossRef] [PubMed]
  89. Cheng, H.L.; Huang, H.K.; Chang, C.I.; Tsai, C.P.; Chou, C.H. A cell-based screening identifies compounds from the stem of Momordica charantia that overcome insulin resistance and activate AMP-activated protein kinase. J. Agric. Food Chem. 2008, 56, 6835–6843. [Google Scholar] [CrossRef]
  90. Rodrigues, E.L.; Marcelino, G.; Silva, G.T.; Figueiredo, P.S.; Garcez, W.S.; Corsino, J.; Guimarães, R.C.A.; Freitas, K.C. Review Nutraceutical and Medicinal Potential of the Morus Species in Metabolic Dysfunctions. Int. J. Mol. Sci. 2019, 20, 301. [Google Scholar] [CrossRef]
  91. Hwang, S.H.; Li, H.M.; Lim, S.S.; Wang, Z.; Hong, J.S.; Huang, B. Evaluation of a Standardized Extract from Morus alba against α-Glucosidase Inhibitory Effect and Postprandial Antihyperglycemic in Patients with Impaired Glucose Tolerance: A Randomized Double-Blind Clinical Trial. Evid. Based Complement. Altern. Med. 2016, 2016, 1–10. [Google Scholar] [CrossRef]
  92. Choi, K.H.; Lee, H.A.; Park, M.H.; Han, J.S. Mulberry (Morus alba L.) Fruit Extract Containing Anthocyanins Improves Glycemic Control and Insulin Sensitivity via Activation of AMP-Activated Protein Kinase in Diabetic C57BL/Ksj-db/db Mice. J. Med. Food 2016, 19, 737–745. [Google Scholar] [CrossRef]
  93. Agrawali, P.; Rai, V.; Singh, R.B. Randomized placebo-controlled, single blind trial of holy basil leaves in patients with noninsulin-dependent diabetes mellitus. Int. J. Clin. Pharmacol. Ther. 1996, 34, 406–409. [Google Scholar]
  94. Rai, V.; Mani, U.V.; Iyer, U.M. Effect of Ocimum sanctum leaf powder in blood lipoproteins, glycated proteins and total amino acids in patients with non-insulin-dependent diabetes mellitus. J. Nutr. Environ. Med. 1997, 7, 113–118. [Google Scholar] [CrossRef]
  95. Kochhar, A.; Sharma, N.; Schdeva, R. Effect of supplementation of tulsi (Ocimum sanctum) and neem (Azadirachta indica) leaf powder on diabetic symptoms, anthropometric parameters and blood pressure of non insulin dependent male diabetics. Stud. Ethno-Med. 2009, 3, 5–9. [Google Scholar] [CrossRef]
  96. Satapathy, S.; Das, N.; Bandyopadhyay, D.; Mahapatra, S.C.; Sahu, D.S.; Meda, M. Effect of Tulsi (Ocimum sanctum Linn.) Supplementation on Metabolic Parameters and Liver Enzymes in Young Overweight and Obese Subjects. Indian J. Clin. Biochem. 2017, 32, 357–363. [Google Scholar] [CrossRef] [PubMed]
  97. Leem, K.H.; Kim, M.G.; Hahm, Y.T.; Kim, H.K. Hypoglycemic Effect of Opuntia ficus-indica var. saboten is Due to Enhanced Peripheral Glucose Uptake through Activation of AMPK/p38 MAPK Pathway. Nutrients 2016, 8, 800. [Google Scholar] [CrossRef]
  98. López-Romero, P.; Pichardo-Ontiveros, E.; Avila-Nava, A.; Vázquez-Manjarrez, N.; Tovar, A.R.; Pedraza-Chaverri, J.; Torrez, N. The effect of nopal (Opuntia ficus indica) on postprandial blood glucose, incretins, and antioxidant activity in Mexican patients with type 2 diabetes after consumption of two different composition breakfasts. J. Acad. Nutr. Diet. 2014, 114, 1811–1818. [Google Scholar] [CrossRef] [PubMed]
  99. Frati, A.C.; Gordillo, B.E.; Altamirano, P.; Ariza, C.R.; Cortés-Franco, R.; Chavez-Negrete, A. Acute hypoglycemic effect of Opuntia streptacantha Lemaire in NIDDM. Diabetes Care 1990, 13, 455–456. [Google Scholar] [CrossRef] [PubMed]
  100. Vuksan, V.; Stavro, M.P.; Sievenpiper, J.L.; Beljan-Zdravkovic, U.; Leiter, L.A.; Josse, R.G.; XU, Z. Similar postprandial glycemic reductions with escalation of dose and administration time of American ginseng in type 2 diabetes mellitus. Diabetes Care 2000, 23, 1221–1226. [Google Scholar] [CrossRef] [PubMed]
  101. Sotaniemi, E.A.; Haapakoski, E.; Rautio, A. Ginseng therapy in non-insulin-dependent diabetic patients. Diabetes Care 1995, 18, 1373–1375. [Google Scholar] [CrossRef]
  102. Jiang, S.; Ren, D.; Li, J.; Yuan, G.; Li, H.; Xu, G.; Han, X.; Du, P.; An, L. Effects of compound K on hyperglycemia and insulin resistance in rats with type 2 diabetes mellitus. Fitoterapia 2014, 95, 58–64. [Google Scholar] [CrossRef]
  103. Kajimoto, O.K.S.; Shimoda, H.; Kawahara, Y.; Hirata, H.; Takahashi, T. Effects of a diet containing Salacia reticulata on mild type 2 diabetes in humans. A placebo controlled, cross over trial. J. Jpn. Soc. Food Sci. 2000, 53, 199–205. [Google Scholar] [CrossRef]
  104. Shivaprasad, H.N.; Bhanumathy, M.; Sushma, G.; Midhun, T.; Raveendra, K.R.; Sushma, K.R.; Venkateshwarlu, K. Salacia reticulata improves serum lipid profiles and glycemic control in patients with prediabetes and mild to moderate hyperlipidemia: A double-blind, placebo-controlled, randomized trial. J. Med. Food 2013, 16, 564–568. [Google Scholar] [CrossRef]
  105. Stohs, S.J.; Ray, S. Anti-diabetic and Anti-hyperlipidemic Effects and Safety of Salacia reticulata and Related Species. Phytother. Res. 2015, 29, 986–995. [Google Scholar] [CrossRef] [PubMed]
  106. Huseini, H.F.; Larijani, B.; Heshmat, R.; Fakhrzadeh, H.; Radjabipour, B.; Toliat, T.; Raza, M. The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: A randomized, double-blind, placebo-controlled, clinical trial. Phytother. Res. 2006, 20, 1036–1039. [Google Scholar] [CrossRef] [PubMed]
  107. Lirussi, F.; Beccarello, A.; Zanette, G.; De Monte, A.; Donadon, V.; Velussi, M.; Crepaldi, G. Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant agent. Diabetes Nutr. Metab. 2002, 15, 222–231. [Google Scholar] [PubMed]
  108. Velussi, M.; Cernigoi, A.M.; De Monte, A.; Dapas, F.; Caffau, C.; Zilli, M. Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients. J. Hepatol. 1997, 26, 871–879. [Google Scholar] [CrossRef]
  109. Ebrahimpour Koujan, S.; Gargari, B.P.; Mobasseri, M.; Valizadeh, H.; Asghari-Jafarabadi, M. Effects of Silybum marianum (L.) Gaertn. (silymarin) extract supplementation on antioxidant status and hs-CRP in patients with type 2 diabetes mellitus: A randomized, triple-blind, placebo-controlled clinical trial. Phytomedicine 2015, 22, 290–296. [Google Scholar] [CrossRef] [PubMed]
  110. Hannan, J.M.A.; Ali, L.; Rokeya, B.; Khaleque, J.; Akhter, M.; Flatt, P.R.; Abdel-Wahab, Y.H.A. Soluble dietary fibre fraction of Trigonella foenum-graecum (fenugreek) seed improves glucose homeostasis in animal models of type 1 and type 2 diabetes by delaying carbohydrate digestion and absorption, and enhancing insulin action. Br. J. Nutr. 2007, 97, 514–521. [Google Scholar] [CrossRef] [PubMed]
  111. Neelakantan, N.; Narayanan, M.; De Souza, R.J.; Van Dam, R.M. Effect of fenugreek (Trigonellafoenum-graecum L.) intake on glycemia: A meta-analysis of clinical trials. Nutr. J. 2014, 13, 7. [Google Scholar] [CrossRef]
  112. Shidfar, F.; Rajab, A.; Rahideh, T.; Khandouzi, N.; Hosseini, S.; Shidfar, S. The effect of ginger (Zingiber officinale) on glycemic markers in patients with type 2 diabetes. J. Complement. Integr. Med. 2015, 12, 165–170. [Google Scholar] [CrossRef]
  113. Munday, R. Harmful and beneficial effects of organic monosulfides, disulfides, and polysulfides in animals and humans. Chem. Res. Toxicol. 2012, 25, 47–60. [Google Scholar] [CrossRef]
  114. Bahadoran, Z.; Mirmiran, P.; Azizi, F. Potential efficacy of broccoli sprouts as a unique supplement for management of type 2 diabetes and its complications. J. Med. Food 2013, 16, 375–382. [Google Scholar] [CrossRef]
  115. Cicero, A.F.G.; Derosa, G.; Gaddi, A. What do herbalists suggest to diabetic patients in order to improve glycemic control? Evaluation of scientific evidence and potential risks. Acta Diabetol. 2004, 41, 91–98. [Google Scholar] [CrossRef] [PubMed]
  116. Thomson, M.; Al-Qattan, K.K.; Divya, J.S.; Ali, M. Anti-diabetic and anti-oxidant potential of aged garlic extract (AGE) in streptozotocin-induced diabetic rats. BMC Complement. Altern. Med. 2016, 16, 17. [Google Scholar] [CrossRef] [PubMed]
  117. Iciek, M.; Kwiecieñ, I.; Włodek, L. Biological properties of garlic and garlic-derived organosulfur compounds. Environ. Mol. Mutagen. 2009, 50, 247–265. [Google Scholar] [CrossRef] [PubMed]
  118. Dirsch, V.M.; Gerbes, A.L.; Vollmar, A.M. Ajoene, a compound of garlic, induces apoptosis in human promyeloleukemic cells, accompanied by generation of reactive oxygen species and activation of nuclear factor kappaB. Mol. Pharmacol. 1998, 53, 402–407. [Google Scholar] [CrossRef] [PubMed]
  119. Knowles, L.M.; Milner, J.A. Allyl sulfides modify cell growth. Drug Metabol. Drug Interact. 2000, 17, 81–107. [Google Scholar] [CrossRef] [PubMed]
  120. Lea, M.A. Organosulfur compounds and cancer. Adv. Exp. Med. Biol. 1996, 401, 147–154. [Google Scholar] [PubMed]
  121. Lea, M.A.; Randolph, V.M.; Patel, M. Increased acetylation of histones induced by diallyl disulfide and structurally related molecules. Int. J. Oncol. 1999, 15, 347–352. [Google Scholar] [CrossRef]
  122. Li, G.; Qiao, C.; Lin, R.; Pinto, J.; Osborne, M.; Tiwari, R. Antiproliferative effects of garlic constituents in cultured human breast-cancer cells. Oncol. Rep. 1995, 2, 787–791. [Google Scholar] [CrossRef]
  123. Pinto, J.T.; Qiao, C.; Xing, J.; Rivlin, R.S.; Protomastro, M.L.; Weissler, M.L.; Tao, Y.; Thaler, H.; Heston, W.D. Effects of garlic thioallyl derivatives on growth, glutathione concentration, and polyamine formation of human prostate carcinoma cells in culture. Am. J. Clin. Nutr. 1997, 66, 398–405. [Google Scholar] [CrossRef]
  124. Pinto, J.T.; Rivlin, R.S. Antiproliferative effects of allium derivatives from garlic. J. Nutr. 2001, 131, 1058S–1060S. [Google Scholar] [CrossRef]
  125. Sakamoto, K.; Lawson, L.D.; Milner, J.A. Allyl sulfides from garlic suppress the in vitro proliferation of human A549 lung tumor cells. Nutr. Cancer 1997, 29, 152–156. [Google Scholar] [CrossRef] [PubMed]
  126. Scharfenberg, K.; Wagner, R.; Wagner, K.G. The cytotoxic effect of ajoene, a natural product from garlic, investigated with different cell lines. Cancer Lett. 1990, 53, 103–108. [Google Scholar] [CrossRef]
  127. Scharfenberg, K.; Ryll, T.; Wagner, R.; Wagner, K.G. Injuries to cultivated BJA-B cells by ajoene, a garlic-derived natural compound: Cell viability, glutathione metabolism, and pools of acidic amino acids. J. Cell. Physiol. 1994, 158, 55–60. [Google Scholar] [CrossRef] [PubMed]
  128. Sigounas, G.; Hooker, J.L.; Li, W.; Anagnostou, A.; Steiner, M. S-allylmercaptocysteine, a stable thioallyl compound, induces apoptosis in erythroleukemia cell lines. Nutr. Cancer 1997, 28, 153–159. [Google Scholar] [CrossRef] [PubMed]
  129. Sundaram, S.G.; Milner, J.A. Impact of organosulfur compounds in garlic on canine mammary tumor cells in culture. Cancer Lett. 1993, 74, 85–90. [Google Scholar] [CrossRef]
  130. Sundaram, S.G.; Milner, J.A. Diallyl disulfide induces apoptosis of human colon tumor cells. Carcinogenesis 1996, 17, 669–673. [Google Scholar] [CrossRef] [PubMed]
  131. Takeyama, H.; Hoon, D.S.; Saxton, R.E.; Morton, D.L.; Irie, R.F. Growth inhibition and modulation of cell markers of melanoma by S-allyl cysteine. Oncology 1993, 50, 63–69. [Google Scholar] [CrossRef] [PubMed]
  132. Welch, C.; Wuarin, L.; Sidell, N. Antiproliferative effect of the garlic compound S-allyl cysteine on human neuroblastoma cells in vitro. Cancer Lett. 1992, 63, 211–219. [Google Scholar] [CrossRef]
  133. Nian, H.; Delage, B.; Pinto, J.T.; Dashwood, R.H. Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter. Carcinogenesis 2008, 29, 1816–1824. [Google Scholar] [CrossRef]
  134. Padiya, R.; Khatua, T.N.; Bagul, P.K.; Kuncha, M.; Banerjee, S.K. Garlic improves insulin sensitivity and associated metabolic syndromes in fructse fed rats. Nutr. Metab. 2011, 8, 53. [Google Scholar] [CrossRef]
  135. Shiju, T.M.; Rajkumar, R.; Rajesh, N.G.; Viswanathan, P. Aqueous extract of Allium sativum L bulbs offer nephroprotection by attenuating vascular endothelial growth factor and extracellular signal-regulated kinase-1 expression in diabetic rats. Indian J. Exp. Biol. 2013, 51, 139–158. [Google Scholar] [PubMed]
  136. Al-Qattan, K.K.; Thomson, M.; Jayasree, D.; Ali, M. Garlic Attenuates Plasma and Kidney ACE-1 and AngII Modulations in Early Streptozotocin-Induced Diabetic Rats: Renal Clearance and Blood Pressure Implications. Evid. Based Complement. Altern. Med. 2016, 2016, 1–11. [Google Scholar] [CrossRef] [PubMed]
  137. Sathibabu Uddandrao, V.V.; Brahmanaidu, P.; Saravanan, G. Therapeutical Perspectives of S-Allylcysteine: Effect on diabetes and other disorders in Animal Models. Cardiovasc. Hematol. Agents Med. Chem. 2018, 15, 71–77. [Google Scholar] [CrossRef]
  138. Ashraf, R.; Khan, R.A.; Ashraf, I. Effects of garlic on blood glucose levels and HbA1c in patients with type 2 diabetes mellitus. J. Med. Plants Res. 2011, 5, 2922–2928. [Google Scholar]
  139. Atkin, M.; Laight, D.; Cummings, M.H. The effects of garlic extract upon endothelial function, vascular inflammation, oxidative stress and insulin resistance in adults with type 2 diabetes at high cardiovascular risk. A pilot double blind randomized placebo controlled trial. J. Diabetes Complicat. 2016, 30, 723–727. [Google Scholar] [CrossRef]
  140. Sheela, C.G.; Kumud, K.; Augusti, K.T. Anti-diabetic effect of onion and garlic sulfoxide amino acids in rats. Planta Med. 1995, 61, 356–357. [Google Scholar] [CrossRef]
  141. Lee, C.W.; Lee, H.S.; Cha, Y.J.; Joo, W.H.; Kang, D.O.; Moon, J.Y. In vivo investigation of anti-diabetic properties of ripe onion juice in normal and streptozotocin-induced diabetic rats. Prev. Nutr. Food Sci. 2013, 18, 169–174. [Google Scholar] [CrossRef]
  142. Padiya, R.; Chowdhury, D.; Borkar, R.; Srinivas, R.; Pal Bhadra, M.; Banerjee, S.K. Garlic attenuates cardiac oxidative stress via activation of PI3K/AKT/Nrf2-Keap1 pathway in fructose-fed diabetic rat. PLoS ONE 2014, 9, e94228. [Google Scholar] [CrossRef]
  143. Yang, J.; Wang, T.; Yang, J.; Rao, K.; Zhan, Y.; Chen, R.B.; Liu, Z.; Li, M.C.; Zhuan, L.; Zang, G.H.; et al. S-allyl cysteine restores erectile function through inhibition of reactive oxygen species generation in diabetic rats. Andrology 2013, 1, 487–494. [Google Scholar] [CrossRef]
  144. Baluchnejadmojarad, T.; Kiasalari, Z.; Afshin-Majd, S.; Ghasemi, Z.; Roghani, M. S-allyl cysteine ameliorates cognitive deficits in streptozotocin-diabetic rats via suppression of oxidative stress, inflammation, and acetylcholinesterase. Eur. J. Pharmacol. 2017, 794, 69–76. [Google Scholar] [CrossRef]
  145. Zarezadeh, M.; Baluchnejadmojarad, T.; Kiasalari, Z.; Afshin-Majd, S.; Roghani, M. Garlic active constituent s-allyl cysteine protects against lipopolysaccharide-induced cognitive deficits in the rat: Possible involved mechanisms. Eur. J. Pharmacol. 2017, 795, 13–21. [Google Scholar] [CrossRef] [PubMed]
  146. Mirunalini, S.; Krishnaveni, M.; Ambily, V. Effects of raw garlic (Allium sativum) on hyperglycemia in patients with type 2 diabetes mellitus. Pharmacologyonline 2011, 2, 968–974. [Google Scholar] [CrossRef]
  147. Eidi, A.; Eidi, M.; Esmaeili, E. Antidiabetic effect of garlic (Allium sativum L.) in normal and streptozotocin-induced diabetic rats. Phytomedicine 2006, 13, 624–629. [Google Scholar] [CrossRef] [PubMed]
  148. Liu, C.T.; Wong, P.L.; Lii, C.K.; Hse, H.; Sheen, L.Y. Antidiabetic effect of garlic oil but not diallyl disulfide in rats with streptozotocin-induced diabetes. Food Chem. Toxicol. 2006, 44, 1377–1384. [Google Scholar] [CrossRef] [PubMed]
  149. Liu, H.; Mao, P.; Wang, J.; Wang, T.; Xie, C.H. Allicin protects PC12 cells against 6OHDA-induced oxidative stress and mitochondrial dysfunction via regulating mitochondrial dynamics. Cell. Physiol. Biochem. 2015, 36, 966–979. [Google Scholar] [CrossRef] [PubMed]
  150. Kumar, R.; Chhatwal, S.; Sahiba Arora, S.; Sharma, S.; Singh, J.; Singh, N.; Bhandari, V.; Khurana, A. Antihyperglycemic, antihyperlipidemic, anti-inflammatory and adenosine deaminase–lowering effects of garlic in patients with type 2 diabetes mellitus with obesity. Diabetes Metab. Syndr. Obes. 2013, 6, 49–56. [Google Scholar] [CrossRef]
  151. Sobenin, I.A.; Nedosugova, L.V.; Filatova, L.V.; Balabolkin, M.I.; Gorchakova, T.V.; Orekhov, A.N. Metabolic effects of time-released garlic powder tablets in type 2 diabetes mellitus: The results of double-blinded placebo-controlled study. Acta Diabetol. 2008, 45, 1–6. [Google Scholar] [CrossRef]
  152. Locatelli, D.A.; Nazareno, M.A.; Fusari, C.M.; Camargo, A.B. Cooked garlic and antioxidant activity: Correlation with organosulfur compound composition. Food Chem. 2017, 220, 219–224. [Google Scholar] [CrossRef]
  153. Zhao, N.N.; Zhang, H.; Zhang, X.C.; Luan, X.B.; Zhou, C.; Liu, Q.Z.; Shi, W.P.; Liu, Z.L. Evaluation of acute toxicity of essential oil of garlic (Allium sativum) and its selected major constituent compounds against overwintering Cacopsylla chinensis (Hemiptera: Psyllidae). J. Econ. Entomol. 2013, 106, 1349–1354. [Google Scholar] [CrossRef]
  154. Augusti, K.T.; Jose, R.; Sajitha, G.R.; Augustine, P. A rethinking on the benefits and drawbacks of common antioxidants and a proposal to look for the antioxidants in allium products as ideal agents: A review. Indian J. Clin. Biochem. 2012, 27, 6–20. [Google Scholar] [CrossRef]
  155. Liu, H.; May, K. Disulfide bond structures of IgG molecules: Structural variations, chemical modifications and possible impacts to stability and biological function. MABS 2012, 4, 17–23. [Google Scholar] [CrossRef] [PubMed]
  156. Huang, W.; Wang, Y.; Cao, Y.G.; Qi, H.P.; Li, L.; Bai, B.; Liu, Y.; Sun, H.L. Antiarrhythmic effects and ionic mechanisms of allicin on myocardial injury of diabetic rats induced by streptozotocin. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2013, 386, 697–704. [Google Scholar] [CrossRef] [PubMed]
  157. Huang, H.; Jiang, Y.; Mao, G.; Yuan, F.; Zheng, H.; Ruan, Y.; Wu, T. Protective effects of allicin on streptozotocin- induced diabetic nephropathy in rats. J. Sci. Food Agric. 2017, 97, 1359–1366. [Google Scholar] [CrossRef] [PubMed]
  158. Younis, F.; Mirelman, D.; Rabinkov, A.; Rosenthal, T. S-Allyl-Mercapto-Captopril: A novel compound in the treatment of cohen-rosenthal diabetic hypertensive rats. J. Clin. Hypertens. 2010, 12, 451–455. [Google Scholar] [CrossRef] [PubMed]
  159. Chen, X.; Pang, S.; Lin, J.; Xia, J.; Wang, Y. Allicin prevents oxidized lowdensity lipoprotein-induced endothelial cell injury by inhibiting apoptosis and oxidative stress pathway. BMC Complement. Altern. Med. 2016, 16, 133. [Google Scholar] [CrossRef] [PubMed]
  160. Asaba, K.; Tojo, A.; Onozato, M.L.; Goto, A.; Quinn, M.T.; Fujita, T.; Wilcox, C.S. Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney Int. 2005, 67, 1890–1898. [Google Scholar] [CrossRef]
  161. Ma, L.; Chen, S.; Li, S.; Deng, L.; Li, Y.; Li, H. Effect of allicin against ischemia/ hypoxia-induced H9c2 myoblast apoptosis via eNOS/NO pathway-mediated antioxidant activity. Evid. Based Complement. Altern. Med. 2018, 2018, 1–10. [Google Scholar] [CrossRef]
  162. Becker, P.M.; Van Wikselaar, P.G.; Mul, M.F.; Pol, A.; Engel, B.; Wijdenes, J.W.; Vander Peet-Schwering, C.M.; Wisselink, H.J.; Stockhofe-Zurwieden, N. Actinobacillus pleuropneumoniae is impaired by the garlic volatile allyl methyl sulfide (AMS) in vitro and in-feed garlic alleviates pleuropneumonia in a pig model. Vet. Microbiol. 2012, 154, 316–324. [Google Scholar] [CrossRef]
  163. Yin, M.C.; Hwang, S.W.; Chan, K.C. Nonenzymatic antioxidant activity of four organosulfur compounds derived from garlic. J. Agric. Food Chem. 2003, 50, 6143–6147. [Google Scholar] [CrossRef]
  164. Wargovich, M.J. Diallylsulfide and Allyl methyl sulfide are uniquely effective among organosulfur compounds in inhibiting CYP2E1 protein in animal models. J. Nutr. 2006, 136, 832–834. [Google Scholar] [CrossRef]
  165. Sujithraa, K.; Srinivasan, S.; Indumathi, D.; Vinothkumar, V. Allyl methyl sulfide, an organosulfur compound alleviates hyperglycemia mediated hepatic oxidative stress and inflammation in streptozotocin -ninduced experimental rats. Biomed. Pharmacother. 2018, 107, 292–302. [Google Scholar] [CrossRef] [PubMed]
  166. Ganesan, K.; Jayachandran, M.; Xu, B.A. Critical review on hepatoprotective effects of bioactive food components. Crit. Rev. Food Sci. Nutr. 2018, 7, 1165–1229. [Google Scholar] [CrossRef] [PubMed]
  167. Bhuiyan, A.I.; Papajani, V.T.; Paci, M.; Melino, S. Glutathione-garlic sulfur conjugates: Slow hydrogen sulfide releasing agents for therapeutic applications. Molecules 2015, 20, 1731–1750. [Google Scholar] [CrossRef] [PubMed]
  168. Martelli, A.; Testai, L.; Breschi, M.C.; Blandizzi, C.; Virdis, A.; Taddei, S.; Calderone, V. Hydrogen sulphide: Novel opportunity for drug discovery. Med. Res. Rev. 2012, 32, 1093–1130. [Google Scholar] [CrossRef] [PubMed]
  169. Benavides, G.A.; Squadrito, G.L.; Mills, R.W.; Patel, H.D.; Isbell, T.S.; Patel, R.P.; Darley-Usmar, V.M.; Doeller, J.E.; Kraus, D.W. Hydrogen sulfide mediates the vasoactivity of garlic. Proc. Natl. Acad. Sci. USA 2007, 104, 17977–17982. [Google Scholar] [CrossRef] [PubMed]
  170. Wallace, J.L.; Wang, R. Hydrogen sulfide-based therapeutics: Exploiting a unique but ubiquitous gasotransmitter. Nat. Rev. Drug Discov. 2015, 14, 329–345. [Google Scholar] [CrossRef] [PubMed]
  171. Untereiner, A.; Wu, L. Hydrogen sulfide and glucose homeostasis: A tale of sweet and the stink. Antioxid. Redox Signal. 2018, 28, 1463–1482. [Google Scholar] [CrossRef]
  172. Whiteman, M.; Armstrong, J.S.; Chu, S.H.; Siau, J.-L.; Wong, B.S.; Cheung, N.S.; Halliwell, B.; Moore, P.K. The novel neuromodulator hydrogen sulfide: An endogenous peroxynitrite ‘scavenger’? J. Neurochem. 2004, 90, 765–768. [Google Scholar] [CrossRef]
  173. Mitsuhashi, H.; Yamashita, S.; Ikeuchi, H.; Kuroiwa, T.; Kaneko, Y.; Hiromura, K.; Ueki, K.; Nojima, Y. Oxidative stress-dependent conversion of hydrogen sulfide to sulfite by activated neutrophils. Shock 2005, 24, 529–534. [Google Scholar] [CrossRef]
  174. Geng, B.; Chang, L.; Pan, C.; Qi, Y.; Zhao, J.; Pang, Y.; Du, J.; Tang, C. Hydrogen sulfide regulation of myocardial injury induced by isoproterenol. Biochem. Biophys. Res. Commun. 2004, 318, 756–763. [Google Scholar] [CrossRef]
  175. Hildebrandt, T.M.; Grieshaber, M.K. Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria. FEBS J. 2008, 275, 3352–3361. [Google Scholar] [CrossRef] [PubMed]
  176. Tiranti, V.; Viscomi, C.; Hildebrandt, T.; Di Meo, I.; Mineri, R.; Tiveron, C.; Levitt, M.D.; Prelle, A.; Fagiolari, G.; Rimoldi, M.; et al. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat. Med. 2009, 15, 200–205. [Google Scholar] [CrossRef] [PubMed]
  177. Viscomi, C.; Burlina, A.B.; Dweikat, I.; Savoiardo, M.; Lamperti, C.; Hildebrandt, T.; Tiranti, V.; Zeviani, M. Combined treatment with oral metronidazole and Nacetylcysteine is effective in ethylmalonic encephalopathy. Nat. Med. 2010, 16, 869–871. [Google Scholar] [CrossRef] [PubMed]
  178. Koike, S.; Ogasawara, Y.; Shibuya, N.; Kimura, H.; Ishii, K. Polysulfide exerts a protective effect against cytotoxicity caused by t-butylhydroperoxide through Nrf2 signaling in neuroblastoma cells. FEBS Lett. 2013, 587, 3548–3555. [Google Scholar] [CrossRef] [PubMed]
  179. Tang, G.; Wu, L.; Liang, W.; Wang, R. Direct stimulation of K(ATP) channels by exogenous and endogenous hydrogen sulfide in vascular smooth muscle cells. Mol. Pharmacol. 2005, 68, 1757–1764. [Google Scholar] [CrossRef] [PubMed]
  180. Bucci, M.; Papapetropoulos, A.; Vellecco, V.; Zhou, Z.; Pyriochou, A.; Roussos, C.; Roviezzo, F.; Brancaleone, V.; Cirino, G. Hydrogen sulfide is an endogenous inhibitor of phosphodiesterase activity. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 1998–2004. [Google Scholar] [CrossRef] [PubMed]
  181. Sen, U.; Mishra, P.K.; Tyagi, N.; Tyagi, S.C. Homocysteine to hydrogen sulfide or hypertension. Cell Biochem. Biophys. 2010, 57, 49–58. [Google Scholar] [CrossRef] [PubMed]
  182. Dawe, G.S.; Han, S.P.; Bian, J.S.; Moore, P.K. Hydrogen sulphide in the hypothalamus causes an ATP-sensitive K+ channel-dependent decrease in blood pressure in freely moving rats. Neuroscience 2008, 152, 169–177. [Google Scholar] [CrossRef]
  183. Kimura, H. Signaling of hydrogen sulfide and polysulfides. Antioxid. Redox Signal. 2015, 22, 347–349. [Google Scholar] [CrossRef]
  184. Eto, K.; Asada, T.; Arima, K.; Makifuchi, T.; Kimura, H. Brain hydrogen sulfide is severely decreased in Alzheimer’s disease. Biochem. Biophys. Res. Commun. 2002, 293, 1485–1488. [Google Scholar] [CrossRef]
  185. Wallace, J.L. Physiological and pathophysiological roles of hydrogen sulfide in the gastrointestinal tract. Antioxid. Redox Signal. 2010, 12, 1125–1133. [Google Scholar] [CrossRef] [PubMed]
  186. Mard, S.A.; Neisi, N.; Solgi, G.; Hassanpour, M.; Darbor, M.; Maleki, M. Gastroprotective effect of NaHS against mucosal lesions induced by ischemia-reperfusion injury in rat. Dig. Dis. Sci. 2012, 57, 1496–1503. [Google Scholar] [CrossRef] [PubMed]
  187. Kaneko, Y.; Kimura, T.; Taniguchi, S.; Souma, M.; Kojima, Y.; Kimura, Y.; Kimura, H.; Niki, I. Glucose-induced production of hydrogen sulfide may protect the pancreatic beta-cells from apoptotic cell death by high glucose. FEBS Lett. 2009, 583, 377–382. [Google Scholar] [CrossRef] [PubMed]
  188. Taniguchi, S.; Niki, I. Significance of hydrogen sulfide production in the pancreatic beta-cell. J. Pharmacol. Sci. 2011, 116, 1–5. [Google Scholar] [CrossRef] [PubMed]
  189. Donath, M.Y. Targeting inflammation in the treatment of type 2 diabetes: Time to start. Nat. Rev. Drug Discov. 2014, 13, 465–476. [Google Scholar] [CrossRef] [PubMed]
  190. Donath, M.Y. Multiple benefits of targeting inflammation in the treatment of type 2 diabetes. Diabetologia 2016, 59, 679–682. [Google Scholar] [CrossRef] [PubMed]
  191. Esser, N.; Paquot, N.; Scheen, A.J. Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease. Expert Opin. Investig. Drugs 2015, 24, 283–307. [Google Scholar] [CrossRef]
  192. Taniguchi, S.; Kang, L.; Kimura, T.; Niki, I. Hydrogen sulphide protects mouse pancreatic beta-cells from cell death induced by oxidative stress, but not by endoplasmic reticulum stress. Br. J. Pharmacol. 2011, 162, 1171–1178. [Google Scholar] [CrossRef]
  193. Okamoto, M.; Yamaoka, M.; Takei, M.; Ando, T.; Taniguchi, S.; Ishii, I.; Tohya, K.; Ishizaki, T.; Niki, I.; Kimura, T. Endogenous hydrogen sulfide protects pancreatic beta-cells from a high-fat diet-induced glucotoxicity and prevents the development of type 2 diabetes. Biochem. Biophys. Res. Commun. 2013, 442, 227–233. [Google Scholar] [CrossRef]
  194. Yang, G.; Yang, W.; Wu, L.; Wang, R. H2S, endoplasmic reticulum stress, and apoptosis of insulin-secreting beta cells. J. Biol. Chem. 2007, 282, 16567–16576. [Google Scholar] [CrossRef]
  195. Yang, W.; Yang, G.; Jia, X.; Wu, L.; Wang, R. Activation of KATP channels by H2S in rat insulin-secreting cells and the underlying mechanisms. J. Physiol. 2005, 569, 519–531. [Google Scholar] [CrossRef] [PubMed]
  196. Tang, G.; Zhang, L.; Yang, G.; Wu, L.; Wang, R. Hydrogen sulfideinduced inhibition of L-type Ca2C channels and insulin secretion in mouse pancreatic beta cells. Diabetologia 2013, 56, 533–541. [Google Scholar] [CrossRef] [PubMed]
  197. Lipson, K.L.; Fonseca, S.G.; Urano, F. Endoplasmic reticulum stress-induced apoptosis and auto-immunity in diabetes. Curr. Mol. Med. 2006, 6, 71–77. [Google Scholar] [CrossRef] [PubMed]
  198. Yusuf, M.; Kwong Huat, B.T.; Hsu, A.; Whiteman, M.; Bhatia, M.; Moore, P.K. Streptozotocin-induced diabetes in the rat is associated with enhanced tissue hydrogen sulfide biosynthesis. Biochem. Biophys. Res. Commun. 2005, 333, 1146–1152. [Google Scholar] [CrossRef]
  199. Ali, M.Y.; Whiteman, M.; Low, C.M.; Moore, P.K. Hydrogen sulphide reduces insulin secretion from HIT-T15 cells by a KATP channel-dependent pathway. J. Endocrinol. 2007, 195, 105–112. [Google Scholar] [CrossRef] [PubMed]
  200. Wu, L.; Yang, W.; Jia, X.; Yang, G.; Duridanova, D.; Cao, K.; Wang, R. Pancreatic islet overproduction of H2S and suppressed insulin release in Zucker diabetic rats. Lab. Investig. 2009, 89, 59–67. [Google Scholar] [CrossRef]
  201. Okamoto, M.; Ishizaki, T.; Kimura, T. Protective effect of hydrogen sulfide on pancreatic beta-cells. Nitric Oxide 2015, 46, 32–36. [Google Scholar] [CrossRef] [PubMed]
  202. Liu, J.; Wu, J.; Sun, A.; Sun, Y.; Yu, X.; Liu, N.; Dong, S.; Yang, F.; Zhang, L.; Zhong, X.; et al. Hydrogen sulfide decreases high glucose/palmitate-induced autophagy in endothelial cells by the Nrf2-ROS-AMPK signaling pathway. Cell. Biosci. 2016, 6, 33. [Google Scholar] [CrossRef]
  203. Xiao, T.; Luo, J.; Wu, Z.; Li, F.; Zeng, O.; Yang, J. Effects of hydrogen sulfide on myocardial fibrosis and PI3K/AKT1-regulated autophagy in diabetic rats. Mol. Med. Rep. 2016, 13, 1765–1773. [Google Scholar] [CrossRef]
  204. Talaei, F.; Van Praag, V.M.; Shishavan, M.H.; Landheer, S.W.; Buikema, H.; Henning, R.H. Increased protein aggregation in Zucker diabetic fatty rat brain: Identification of key mechanistic targets and the therapeutic application of hydrogen sulfide. BMC Cell Biol. 2014, 15, 1. [Google Scholar] [CrossRef]
  205. Liu, F.; Chen, D.D.; Sun, X.; Xie, H.H.; Yuan, H.; Jia, W.; Chen, A.F. Hydrogen sulfide improves wound healing via restoration of endothelial progenitor cell functions and activation of angiopoietin-1 in type 2 diabetes. Diabetes 2014, 63, 1763–1778. [Google Scholar] [CrossRef] [PubMed]
  206. Yang, C.T.; Zhao, Y.; Xian, M.; Li, J.H.; Dong, Q.; Bai, H.B.; Xu, J.D.; Zhang, M.F. A novel controllable hydrogen sulfide-releasing molecule protects human skin keratinocytes against methylglyoxal-induced injury and dysfunction. Cell. Physiol. Biochem. 2014, 34, 1304–1317. [Google Scholar] [CrossRef] [PubMed]
  207. Yang, C.T.; Meng, F.H.; Chen, L.; Li, X.; Cen, L.J.; Wen, Y.H.; Li, C.C.; Zhang, H. Inhibition of methylglyoxal-induced AGEs/RAGE expression contributes to dermal protection by N-acetyl-L-cysteine. Cell. Physiol. Biochem. 2017, 41, 742–754. [Google Scholar] [CrossRef] [PubMed]
  208. Sidik, K.; Mahmood, A.; Salmah, I. Acceleration of Wound Healing by Aqueous Extract of Allium sativum in Combination with Honey on Cutaneous Wound Healing in Rats. Int. J. Mol. Med. Adv. Sci. 2006, 2, 231–235. [Google Scholar]
  209. Mauretti, A.; Neri, A.; Kossover, O.; Seliktar, D.; Nardo, P.D.; Melino, S. Design of a Novel Composite H2S-Releasing Hydrogel for Cardiac Tissue Repair. Macromol. Biosci. 2016, 16, 847–858. [Google Scholar] [CrossRef]
  210. Lin, W.C.; Huang, C.C.; Lin, S.J.; Li, M.J.; Chang, Y.; Lin, Y.J.; Wan, W.L.; Shih, P.C.; Sung, H.W. In situ depot comprising phase-change materials that can sustainably release a gasotransmitter H2S to treat diabetic wounds. Biomaterials 2017, 145, 1–8. [Google Scholar] [CrossRef] [PubMed]
  211. Wang, W.; Sun, X.; Zhang, H.; Yang, C.; Liu, Y.; Yang, W.; Guo, C.; Wang, C. Controlled release hydrogen sulfide delivery system based on mesoporous silica nanoparticles protects graft endothelium from ischemia-reperfusion injury. Int. J. Nanomedicine 2016, 11, 3255–3263. [Google Scholar] [CrossRef]
  212. Cacciotti, I.; Ciocci, M.; Di Giovanni, E.; Nanni, F.; Melino, S. Hydrogen Sulfide-Releasing Fibrous Membranes: Potential Patches for Stimulating Human Stem Cells Proliferation and Viability under Oxidative Stress. Int. J. Mol. Sci. 2018, 19, 11. [Google Scholar] [CrossRef]
  213. Phadatare, A.G.; Viswanathan, V.; Mukne, A. Novel strategies for optimized delivery of select components of Allium sativum. Pharmacogn. Res. 2014, 6, 334–340. [Google Scholar] [CrossRef]
  214. Ciocci, M.; Iorio, E.; Carotenuto, F.; Khashoggi, H.A.; Nanni, F.; Melino, S. H2S-releasing nanoemulsions: A new formulation to inhibit tumor cells proliferation and improve tissue repair. Oncotarget 2016, 7, 84338–84358. [Google Scholar] [CrossRef]
Figure 1. Scheme of the effects of organosulfur compounds (OSCs) derived from Allium sp.
Figure 1. Scheme of the effects of organosulfur compounds (OSCs) derived from Allium sp.
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Figure 2. Scheme of the inter-relationship between hyperglycemia, iperlipidemia, oxidative stress, vascular inflammation, and the ability of garlic extract to modulate macrovascular and microvascular complications in type 2 DM [139,149,150,151]. Abbreviations: DM = Diabetes mellitus; P13k/Akt = phosphoinositide-3-kinase/Protein Kinase B; IRs = Insulin Receptors; SAC = S-allyl cysteine; allicin = dyallil thiosulfinate; SAMG = S-allylmercaptoglutatione; SAMC = S-allylmercaptocysteine; NO = Nitric oxide; IL-6 = Interleukin 6; TNF-α = Tumor necrosis factor; NK cells, Natural killer cells; GST = Glutathione-S-transferase; GSH = Glutathione reduced; SOD = Superoxide dismutase; GPx = Glutathione peroxidase; eNOS = endothelial Nitric oxide synthase.
Figure 2. Scheme of the inter-relationship between hyperglycemia, iperlipidemia, oxidative stress, vascular inflammation, and the ability of garlic extract to modulate macrovascular and microvascular complications in type 2 DM [139,149,150,151]. Abbreviations: DM = Diabetes mellitus; P13k/Akt = phosphoinositide-3-kinase/Protein Kinase B; IRs = Insulin Receptors; SAC = S-allyl cysteine; allicin = dyallil thiosulfinate; SAMG = S-allylmercaptoglutatione; SAMC = S-allylmercaptocysteine; NO = Nitric oxide; IL-6 = Interleukin 6; TNF-α = Tumor necrosis factor; NK cells, Natural killer cells; GST = Glutathione-S-transferase; GSH = Glutathione reduced; SOD = Superoxide dismutase; GPx = Glutathione peroxidase; eNOS = endothelial Nitric oxide synthase.
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Figure 3. Scheme of the spontaneous OSCs production from garlic.
Figure 3. Scheme of the spontaneous OSCs production from garlic.
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Figure 4. Scheme of the enzymatic (A) and non-enzymatic (B) production of H2S in mammalian cells. The figure B displays the non-enzymatic production of H2S starting from DADS that reacts with GSH through a nucleophilic substitution at the α-carbon. Abbreviations: CBS = cystathionine β-synthase; CSE = cystathionine γ-lyase; 3-MP = 3-mercaptopyruvate; GSH = reduced glutathione; GSSG = oxidized glutathione; GSSH = glutathione persulfide; Nutrients 11 01581 i001 = allyl-thiol; Nutrients 11 01581 i002 = S-allyl-glutathione; Nutrients 11 01581 i003 = allyl-glutathione disulfide.
Figure 4. Scheme of the enzymatic (A) and non-enzymatic (B) production of H2S in mammalian cells. The figure B displays the non-enzymatic production of H2S starting from DADS that reacts with GSH through a nucleophilic substitution at the α-carbon. Abbreviations: CBS = cystathionine β-synthase; CSE = cystathionine γ-lyase; 3-MP = 3-mercaptopyruvate; GSH = reduced glutathione; GSSG = oxidized glutathione; GSSH = glutathione persulfide; Nutrients 11 01581 i001 = allyl-thiol; Nutrients 11 01581 i002 = S-allyl-glutathione; Nutrients 11 01581 i003 = allyl-glutathione disulfide.
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Figure 5. (A) Scheme of the effects and pathway activation of H2S-donors in cell: Akt activation, Erk1/2 activation, Nutrients 11 01581 i004 Ang-1 upregulation, Nutrients 11 01581 i005 NF-kB sulfidration, Nutrients 11 01581 i006 Nrf2 activation by sulfidration of Keep1 Nutrients 11 01581 i007 and upregulation of CBS, CSE and antioxidant enzyme (NQO1, HO1, etc.), opening Nutrients 11 01581 i008 KATP channels; (B) effects of H2S on insulin Nutrients 11 01581 i009 release under hyperglycemic conditions ( Nutrients 11 01581 i010 inhibition) at late stage of diabetes in beta cells: upregulation of CSE Nutrients 11 01581 i011 and CBS Nutrients 11 01581 i012; MST Nutrients 11 01581 i013; closure Nutrients 11 01581 i014 of L-type voltage-dependent Ca2C channels Nutrients 11 01581 i015, opening of KATP channels Nutrients 11 01581 i016, and hyperpolarization.
Figure 5. (A) Scheme of the effects and pathway activation of H2S-donors in cell: Akt activation, Erk1/2 activation, Nutrients 11 01581 i004 Ang-1 upregulation, Nutrients 11 01581 i005 NF-kB sulfidration, Nutrients 11 01581 i006 Nrf2 activation by sulfidration of Keep1 Nutrients 11 01581 i007 and upregulation of CBS, CSE and antioxidant enzyme (NQO1, HO1, etc.), opening Nutrients 11 01581 i008 KATP channels; (B) effects of H2S on insulin Nutrients 11 01581 i009 release under hyperglycemic conditions ( Nutrients 11 01581 i010 inhibition) at late stage of diabetes in beta cells: upregulation of CSE Nutrients 11 01581 i011 and CBS Nutrients 11 01581 i012; MST Nutrients 11 01581 i013; closure Nutrients 11 01581 i014 of L-type voltage-dependent Ca2C channels Nutrients 11 01581 i015, opening of KATP channels Nutrients 11 01581 i016, and hyperpolarization.
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Table 1. The most relevant plants and vegetables and their phytochemicals/nutraceuticals with significant effects on type 2 DM via clinical or in vivo studies.
Table 1. The most relevant plants and vegetables and their phytochemicals/nutraceuticals with significant effects on type 2 DM via clinical or in vivo studies.
Plants/Vegetables SpeciesPhytochemicals/NutraceuticalsEffects on Type 2 DMReferences
Aegle marmelos
(Common name: bael)
coumarins (umbelliferone β-D-galactopyranoside) alkaloids, and steroids ↓ PPBG and lipid peroxidation;
↑ hypoglycemic effect of standard oral drugs in type 2 DM patients and antioxidant activity
[60,61,62]
Allium cepa and A. sativum.
(Common names: onion and garlic)
OSCs and flavonoids (quercetin and its glycosides) ↓ FBG and intestinal glucosidase inhibition, serum cholesterol and triacylglycerol and LDL-cholesterol; ↓ blood glucose and lipid levels;
↑ GLUT-4 translocation, glucose uptake and insulin action, SOD, GPx and catalase activity
[63,64,65,66,67]
Artemisia dracunculus
(Common name: Russian tarragon)
essential oils, coumarins, flavonoids, and phenolic acids ↓ systolic blood pressure;
↓ HbA1c and total insulin secretion;
↑ HDL-cholesterol levels
[68]
Camellia sinensis
(Common name: green tea)
Polyphenols: catechins like EGCG, epigallocatechin,epicatechin-3-gallate and epicatechin↓ FBG and blood glucose;
↑ insulin sensitivity and secretion;
↓ intestinal glucose absorption by SGLT1 inhibition and oxidative stress;
↑ immune response
[54,55,56,69,70,71]
Cinnamomum spp.
(Common name: cinnamon)
cinnamaldehyde, procyanidin oligomers ↓ FBG, HbA1c, triglyceride, LDL cholesterol and total cholesterol;
↑ glucose up-take (GLUT4 translocation) and insulin release
[72,73,74]
Coccinia indica/grandis
(Common name: ivy gourd)
triterpenoid, saponin coccinioside, flavonoid glycoside↓ levels of the enzymes glucose-6-phosphatase, lactate dehydrogenase;
↑ lipase activity and insulin-secreting through glucose metabolism
[75,76]
Ipomoea batatas
(Common name: caiapo)
acidic glycoprotein, coumarins, caffeic acid, and flavonoids ↓ FBG and HbA1c;
↑ insulin sensitivity and adiponectin;
↓ fibrinogen levels
[77,78]
Gymnema sylvestre
(Common name: gurmar)
gymnemic acids, gymnema saponins, and gurmarin
dihydroxy gymnemic triacetate
↓ FBG, PPBG and HbA1c of type 2 DM patients;
↑ insulin secretion and C-peptide;
↓ intestinal glucose absorption;
↑ plasma insulin and muscle and liver glycogen in diabetic rats;
↑ islet β cell regeneration
[79,80,81,82]
Linum ussitatisimum
(Common name: flaxseed)
PUFAs (α-linoleic and linolenic acid), polyphenols, triterpenoids ↓ fasting blood glucose, HbA1c, triglycerides, total and LDL cholesterol, apolipoprotein B;
↑ HDL cholesterol levels
[83,84]
Momordica charantia
(Common name: bitter melon)
cucurbitane triterpenoids, charantin etc.
polypeptide-p
↓ FBG and PPBG levels in type 2 DM; ↓ total cholesterol;
↓ related complications (retinopathy and myocardial infarction);
↑ glucose uptake through stimulation of GLUT-4 translocation, AMPK system;
↓ α-glucosidase activity
[85,86,87,88,89]
Morus alba
(Common name: morus)
Phenols, flavonoids, anthocyanins, alkaloids↑ the postprandial glycemic control;
↓ plasma glucose, α-glucosidase;
↑ AMPK and plasma membrane GLUT4 levels in skeletal muscle
[90,91,92]
Ocimum sanctum
(Common name: holy basil)
tannins and essential oil (eugenol, methyleugenol, and caryophyllene)↓ FBG and PPBG;
↓ total cholesterol level;
↓ insulin resistance and normalization of serum lipid profile, body weight and BMI, diabetic symptoms, lipid peroxidation;
↑ activity of antioxidant enzymes
[93,94,95,96]
Opuntia spp.
(Common name: nopal)
flavonoids, phenolic acids, betalains, phytosterol, PUFAs↓ PPBG and serum insulin, glucose absorption from the intestine and plasma GIP levels;
↑ increase antioxidant activity and glucose uptake (through the AMPK/p38 MAPK signaling pathway and GLUT4 translocation in muscle cells)
[97,98,99]
Panax ginseng and P. quinquefolius (Common name: Asian and American ginseng)triterpene saponins, (ginsenosides, protopanaxadiol and protopanaxatriol-
type saponins, compound K
↓ FBG and body weight;
↑ glucose metabolism and VEGF expression;
↑ angiogenesis by eNOS activation;
↓ insulin resistance and apoptosis;
↑ fasting serum insulin and insulin sensitivity
[100,101,102]
Salacia reticulata
(Common name: Kothala himbutu)
polyphenols (mangiferin, catechins, and tannins)↓ FBG, HbA1c and lipid levels (cholesterol, LDL, VLDL and triglyceride levels)[103,104,105]
Silybum marianum
(Common name: milk thistle)
flavonolignans (silymarin complex: silybin and isosilybin, silychristin and silydianin), the flavonol taxifolin↓ glucose and lipids levels, FBG, HbA1c, total cholesterol, LDL, TG and hepatic enzymes;
↓ PPBG, insulin resistance and insulin production;
↑ antioxidant system (SOD and GPx activities and total antioxidant capacity);
↓ C reactive protein
[106,107,108,109]
Trigonella foenum graecum
(Common name: fenugreek)
steroid saponins (diosgenin, yamogenin, tigogenin), protoalkaloids, trigonelline, 4-hydroxyisoleucin, soluble fiber fraction ↓ PPBG, FBG, HbA1c, TG, VLDL, lipid;
↓ intestinal glycosidase;
↑ lipogenic enzymes, glucose uptake, HDL level and insulin sensitivity
[110,111]
Zingiber officinale
(Common name: ginger)
metabolites ginger oleoresin, 8-gingerol, 10-gingerol and 6-shogaol ↓ serum glucose, HbA1c and insulin resistance;
↑ total antioxidant capacity
[112]
Abbreviations: PPBG = Postprandial blood glucose; FBG = Fast blood glucose; AMPK = activating 5-adenosine monophosphate-activated protein kinase; HbA1c = Glycated hemoglobin; TG = Triglyceride; LDL = Light density lipoprotein; HDL = Hight density lipoprotein; PUFAs = Polyunsaturated fatty acids; GIP = glucose-dependent insulinotropic polypeptide; SOD = Superoxide dismutase; GPx = Glutathione peroxidase; eNOS = endothelial nitric oxide synthase; SGLT1 = Sodium glucose transporter protein 1; VEGF = Vascular endothelial growth factor; BMI = Body mass index; ↓ = decrease; ↑ = increase.

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