**1. Introduction**

The Traditional Medicine/Complementary and Alternative Medicine (TCAM) concept includes any practice, knowledge and belief in health that incorporates medicine based on plants, animals and/or minerals, spiritual therapies, manual techniques and exercises applied individually or in combination to improve human health. The World Health Organization (WHO) considers that TCAM have shown favorable factors that contribute to an increasing acceptance worldwide, such as easy access, diversity, relatively low cost and, most importantly, relatively low adverse toxic effects in comparison with allopathic

**Citation:** Madrigal-Santillán, E.; Portillo-Reyes, J.; Madrigal-Bujaidar, E.; Sánchez-Gutiérrez, M.; Mercado-Gonzalez, P.E.; Izquierdo-Vega, J.A.; Vargas-Mendoza, N.; Álvarez-González, I.; Fregoso-Aguilar, T.; Delgado-Olivares, L.; et al. *Opuntia* genus in Human Health: A Comprehensive Summary on Its Pharmacological, Therapeutic and Preventive Properties. Part 1. *Horticulturae* **2022**, *8*, 88. https:// doi.org/10.3390/horticulturae8020088

Academic Editors: Dasha Mihaylova and Aneta Popova

Received: 17 November 2021 Accepted: 8 January 2022 Published: 19 January 2022

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medicine where these effects are frequently attributed to synthetic drugs. For this reason, TCAM continues to be used by different populations to treat and/or prevent the onset and progression of chronic diseases including obesity, diabetes, hypertension, atherosclerosis, and cancer [1–3].

Throughout human history, plants and their phytochemicals have played an important role at improving human health care. *Opuntia* spp. species have specifically shown many beneficial properties and high biotechnological capacity. These plants classified as angiosperm dicotyledonous are the most abundant of the Cactaceae family and are importantly distributed in America, Africa, Asia, Australia, and in the central Mediterranean area. Due to their capacity to store water in one or more of their organs, they are considered "succulent plants" whose cultivation is ideal in arid areas since they are very efficient to generate biomass in water scarcity conditions [4–7].

Most opuntioid cacti have flat and edible stems called cladodes (CLD), paddles, nopales or stalks. Generally, young CLDs (also called nopalitos) are eaten as a vegetable in salads, while their fruits [called cactus pear fruits (tunas) or prickly pear fruits (PPFs)] are widely eaten as fresh seasonal fruit. Prickly pears are oval berries with lots of seeds throughout all the pulp and a semi-hard bark that contains thorns. They are grouped in different colors (red, purple, orange/yellow, and white). Generally, the fruit with white flesh and green skin is the most consumed as food [4–7]. Some evidences indicate that *Opuntia* plants have been consumed by humans for more than 8000 years and due to their easy adaptation and spread in different types of soil, their domestication process in man-made environments has increased favoring the constant collection of CLD and PPFs [7–10].

### **2.** *Opuntia* **genus in Mexico**

*Opuntia* spp. is a diverse and widely distributed genus in the American Continent. However, Mexico has the largest number of wild species. The most representaive are *O. streptacantha* (OS), *O. hyptiacantha* (OH), *O. albicarpa* (OA), *O. megacantha* (OM) and *O. ficus-indica*. The latter is highly cultivated and domesticated species due to its nutritional, medicinal, pharmaceutical, and economic impacts. It is believed to be a secondary crop with fewer thorns derived from OM, (a native species from central Mexico) [4,7,8,10,11]. Currently, *O. ficus-indica* (OFI) has become as important a vegetable crop as corn and agave*tequila*; its economic relevance is significantly increasing in our country and in other parts of the world, especially for improving health when nopal and prickly pear are included in a diet. Therefore, the OFI domestication process has favored changes in the texture, flavor, size, color, quantity and quality of the cladodes and their fruits [4,7,8]. Mexico and Italy are the main producing and consuming countries of the approximately 590,000 ha cultivated around the world. The Annual Mexican production can reach 350,000 tons; for this reason, our country represents approximately 90% of the total production worldwide. In addition, Mexico is the main producer of prickly pear, representing more than 45% of world production; however, only 1.5% of this production is exported [4,7,11,12].

#### **3. Nutritional Value, Bioactive Compounds and Main Mechanisms of Action Involved**

Various investigations where different extraction methods were used have documented the nutritional value of *Opuntia* spp. Most of these studies coincide in the differences among the phytochemical composition of their plant parts (fruits, roots, cladodes, flowers, seeds and stems) and the wild and domesticated species. These can be attributed to environmental conditions (climate, humidity), the type of soil that prevails in the cultivation sites, the age of maturity of the cladodes, and the harvest season [5–7]. In general, opuntioid cacti contain a large amount of water (80 and 95%), carbohydrates (3–7%), proteins (0.5–1%), soluble fiber (1–2%), fatty acids (palmitic, stearic, oleic, vaccenic and linoleic) and minerals [Potassium (K), calcium (Ca), phosphorus (P), magnesium (Mg), chrome (Cr) and sodium (Na)]. They also have viscous and/or mucilaginous materials [made up of D-glucose, Dgalactose, L-arabinose, D-xylose and polymers such as β-D-galacturonic acid linked to (1–4)


Specifically, the CLDs and prickly pears of OFI have shown several kinds of bioactive compounds, among which flavonoids (such as quercetin, kaempferol, isorhamnetin), essential amino acids [Glutamine (Glu), arginine (Arg), leucine (Leu), isoleucine (Ile), lysine (Lys), valine (Val), and phenylalanine (Phe)], vitamins (B1, B6, E, A, and C), minerals (mainly K and Ca), and betalains [such as betaxanthins (betanin and indicaxanthin) and betacyanins (betanidin, isobetanin, isobetanidine, and neobetanin) (Table 1) [5–7,13–16].

**Table 1.** Main bioactive compounds in different anatomical parts of *O. ficus-indica.*



asso-However,it is relevant to comment that the Cactaceae family contains approximately 130 genera and 1500 species, which favors a wide genetic diversity that in conjunction with environmental conditions (climate, humidity), soil type, age of maturity of the cladodes and the harvest season generates differences in the phytochemical composition between wild and domesticated specie, inducing changes in their nutritional values and/or functional properties. This first review (Part 1), focuses on information from published research (in vitro, in vivo and clinical studies) on its action in atherosclerotic cardiovascular diseases, diabetes and obesity, hepatoprotection, effects on human infertility and chemopreventive and/or antigenotoxic capacity; which will be discussed below.

### **4. Pharmacological, Therapeutic and Preventive Properties**

### *4.1. Effects on Atherosclerotic Cardiovascular Diseases*

The term atherosclerotic cardiovascular diseases (ASCVD) encompasses conditions that affect the blood vessels and the heart as a consequence of the thickening and hardening of medium and large-caliber arteries. ASCVD involves diseases of the cardiovascular system that share similar characteristics regarding their cause, pathophysiology, prognosis, and treatment. They are one of the main causes of mortality in the world (including Mexico) and unfortunately, their incidence is increasing [18].

In general, atherosclerosis is an inflammatory and chronic process characterized by the progressive occlusion of arteries where there is retention, oxidation, and modification of lipids in the form of fatty stretch marks, whose development can generate endothelial dysfunction, inflammation, and thrombosis. When serum concentrations of LDL-cholesterol (LDL-Cho) rises significantly, it penetrates the arterial walls to accumulate among the cells where reactive oxygen species (ROS) are induced and produce oxidation of LDL

(Low-density lipoprotein) that generates the release of pro-inflammatory cells (such as monocytes and neutrophils).

Specifically, monocytes become macrophages, which promote the progression of the lesion by stimulating an inflammatory cascade. Various situations that cause endothelial damage have been identified, such as hypercholesterolemia, hypertension, diabetes, obesity, and smoking [7,18,19], which together with genetic predisposition are considered traditional risk factors; Several of these factors are related to changes in lifestyle, which has contributed to generating certain strategies (especially those focused on smoking and poor nutritional habits) that reduce the possibility of cardiovascular risk. In this context, both CLD and PPFs from *Opuntia* spp. have shown antiatherogenic, antihyperlipidemic, and antihypercholesterolemic properties due to their soluble fiber content, flavonoids, phenolic compounds and fatty acids. In the case of fiber, composed of substances (such as cellulose, hemicelluloses, pectin, lignin and gums) resistant to digestive enzymes, the hypolipidemic effect is attributed to them due to their binding to dietary fat which promotes its excretion by fecal route with the consequent reduction of body fat [7,14,20,21].

On the other hand, some flavonoids, phenolic compounds and fatty acids, are considered phytochemicals with the same activity and anti-inflammatory effects. Such properties are supported by its antioxidant capacity. Specifically, quercetin 3-methyl ether, obtained from cladode extracts of OFI, has shown potential to lower cholesterol (Cho); while omega-6 linoleic acid from cactus seed oil is considered a precursor of arachidonic acid with a hypocholesterolemic effect [6,7]. Also, betalains [such as betanin and indicaxanthin (Ind)] from PPFs have evidenced to protect the vascular endothelium from inflammation and cytokine-induced oxidative alteration [such as tumor necrosis factor alpha (TNFα)] by inhibiting intercellular adhesion molecule-1 (ICAM-1) [22].

Table 2 shows the most relevant studies of the hypolipidemic, hypocholesterolemic and antiatherogenic properties of *Opuntia* spp. In summary, from 1996 to date, 4 out of 17 have been in vitro studies; 7, using laboratory animals (mainly rodents); 5, developed with patients (clinical studies) and only one where a systematic review was made. Garcia-Diez et al. (1996) were the first researchers to explore a diet supplemented with pectin (extracted from nopal) in the metabolism of Cho and bile acids of Wistar rats. After four weeks, they obtained lower concentrations of Cho in serum and liver; as well as a higher activity of the regulatory enzymes of Cho [3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) and cholesterol 7 alpha-hydroxylase (Cho7AH) [23]. Possibly, these results prompted other researchers to analyze the intake of PPFs (in pulp form) in patients suffering from isolated heterozygous familial hypercholesterolaemia [24] and primary hypercholesterolaemia [25]; as well as to extract a glycoprotein (GOFI) from the nopal to be orally administered to mice for two weeks and to show that in both cases the plasma levels of triglycerides (TG), tCho and LDL were reduced [26]. In 2012, the lethal dose 50 (LD50) of a methanolic extract of *O. joconostle* (OJ) seeds was found to be greater than 5000 mg/kg and that mice fed with a hypercholesterolemic diet along with this oral extract could reduce the concentrations of TG, tCho and LDL-Cho [27]. A similar phenomenon took place when evaluating a food supplement (*NeOpuntia*) obtained from dehydrated leaves of OFI on blood lipid parameters of 59 women after 6 weeks of treatment [28].

Regarding the antiatherogenic potential, during 2015 this property was tested by using different powdered cladodes of *Opuntia* (OS, OH, OA, OM, OFI) against the oxidation of LDL caused by vascular endothelial cells and the toxicity of 4- hydroxynonenal under normal conditions (Apc +/+) and in immortalized preneoplastic epithelial colon cells (Apc min/+). The conclusion was that all powders significantly inhibited the oxidation induced by incubation with murine endothelial cells and the formation of foam cells of murine macrophages RAW 264.7 [29].


**Table 2.** Studies testing for hypolipidemic and antiatherogenic effects of *Opuntia* spp.




### *4.2. Effects on Diabetes and Obesity*

The metabolic syndrome is the set of carbohydrate and lipid metabolic abnormalities that describes the increasing incidence of type 2 diabetes mellitus (DM2) associated with abdominal obesity (AO), insulin resistance, and cardiovascular disease [14,39]. DM2 is a multifactorial disease that includes genetic determinants of individual susceptibility and environmental factors of lifestyle. It is considered a serious public health problem, being among the leading causes of death worldwide.

The high social costs and implications for hospital systems are some of the relevant consequences. The worldwide increase of the metabolic syndrome is estimated to 360 million people by 2030. It is characterized by a decrease in glucose uptake stimulated by insulin (insulin resistance) and once the disease is established and there is poor control in the patients, macrovascular complications may develop (including atherosclerosis) as well as microvascular abnormalities (such as retinopathy, nephropathy, and neuropathy). Furthermore, in the long term, grave problems may result in the kidney and the heart [5,7,14,39].

On the other hand, obesity (also considered a public health problem) has significantly increased as a result of rapid urbanization, growing technology, altered eating habits, and decreasing physical activity. Specifically, Mexico faces a challenging situation due to its high incidence. The statistical data indicate that in adults it occurs in 33% (higher prevalence in women) and approximately 15% in children [7].

There is a close relationship between AO and insulin resistance. This is due to the fact that AO implies an increase in fat at the visceral level (mainly in the liver, muscles and pancreas), which induces the formation of adipokines in the fat tissue and favors proinflammatory and prothrombotic states, which contribute to the development of insulin resistance, hyperinsulinemia and endothelial dysfunction (cardiovascular disease) [5,39].

Adiponectin, in particular, decreased; which is a situation associated with an increase in TG, a decrease in HDL, an elevation of apoliprotein B, and the presence of dense LDL particles, contributing to the atherothrombotic state that represents the inflammatory profile of visceral adiposity [39]. It is also known that oxidative stress (OXs) is related to insulin resistance and obesity and that a high concentration of ROS can induce and/or favor the development of both diseases.

An interesting observation is that low levels of adiponectin are usually the result of this high concentration; also, the production of ROS in adipocytes is associated with insulin resistance and alterations in serum levels of adiponectin with the consequent inflammatory response [5,40].

The herbal treatments and traditional plant-based medicines are increasingly popular due to their low-cost with apparently fewer side effects for treating DM2 and AO. In general, four possible mechanisms of action have been directed at *Opuntia* spp.

The first is related to its content of fiber, pectin and mucilage that slow down the speed of digestion and/or intestinal absorption of glucose and fatty acids [5,7,25,34,41,42]. The second focuses on improving the postprandial glucose response and stimulating insulin secretion through a direct action on pancreatic β cells after a dietary intake that includes nopal [43–45].

Another hypothesis lies on its antioxidant properties. As it is mentioned above, OXs plays a fundamental role in the development of atherosclerosis and cardiovascular diseases, the main complications of DM2 and AO [40]. A relevant data on this mechanism is its content of polysaccharides (arabinose, xylose, fructose, glucose, galacturonic acid and rhamnose) that have demonstrated anti-inflammatory activity and ability to isolate ROS. This supports the fact that these polysaccharides can reduce hepatic lipoperoxidation, maintaining the tissue function and improving the target cells response to insulin [46,47]. The final proposal is that Cr (III), present in the CLD of nopal and extracts of the pulp of PPFs, is an important element in mammals to maintain the balance of carbohydrates and lipids. Some studies have validated this property, finding a positive effect of Cr (III) on insulin signaling and/or function; helping to improve its systemic sensitization and reduce plasma glucose under fasting conditions [48–50].

After the studies related to cardiovascular diseases, the greatest scientific interest in *Opuntia* spp. has focused on its ability to treat DM2 and AO. Approximately 47 scientific articles have been published since the 1980s; 10 of which belong to clinical investigations, 4 are in vitro studies, 24 in vivo tests (using rodents, rabbits and pigs), and 9 of them are systemic reviews.

Initially, the research of Ibañez and Meckes (1983) stands out, who evaluated the hypoglycemic effect of a semi-purified fraction of OS in rabbits and observed that the powder obtained would produce an effect similar to the traditional extract of OS stems [51]. Years later, with the same animal model, another study confirmed that OS decreased the area under the glucose tolerance curve and the hyperglycemic peak [52].

Likewise, they observed that the red juice obtained from *O. dillenii Haw* (OdHw) increased plasma insulin levels in normoglycemic and alloxane (Allox) -induced diabetic rabbits [53]. Another frequently used experimental model is the administration of streptozocin (STZ) to induce diabetes in rodents. A dose of 1.0 mg/kg/day of a purified extract of *O. fuliginosa* (Of) decreased blood glucose levels and glycosylated hemoglobin (HbA1c) in diabetic rats [54].

Not only the species Of has demonstrated this property, since the juice of OdHw, a rich source of fiber, minerals and vitamins, has also reduced glucose levels [55]. On the other hand, four extracts of *O. Milpa Alta* [Aqueous, petroleum ether, ethyl acetate (EtOAc), and butanol (BuOH)] were tested in STZ-induced diabetic mice and they also managed to lower glucose levels [56].

Hahm et al. (2011) studied the intake of three doses of OHF (150, 250 and 500 mg/kg/day) for 7 weeks on the regulation of blood glucose in diabetic rats; their conclusion was that all doses reduced this blood parameter to values comparable to the DM control group. In particular, the group treated with 500 mg/kg showed a considerable increase in the relative volume of β pancreatic cells [31].

This final result was also confirmed by Yoon et al. (2011) who, when administering an OFI extract for 4 weeks to db/db mice and performing a histopathological analysis, observed that the morphology of the pancreatic islets were significantly improved [57].

In studies related to AO, the absorption of fat in the diet decreased through natural treatments, such as Litramine IQP-G-002AS (fiber derived from OFI). The results of four randomized clinical studies sugges<sup>t</sup> that it is effective in promoting fat excretion and weight loss when taken at a daily dose of 3 g for seven days [58].

Another relevant study showed that an OFI extract included in a high-fat diet and administered for 12 weeks to C57BL/6 mice, prevented the rise of body weight and blood levels of LDL-Cho, HDL-Cho, tCho. In addition, the extract stimulated insulin secretion produced by their pancreatic islets [59].

Given that the information is very extensive, only the most significant documents will be analyzed, so the summary of the rest of the investigations, including in vitro and in vivo trials, clinical studies, and systematic reviews are included in Table 3.


**Table 3.** Main studies of *Opuntia* spp. on its effects in diabetes and obesity.




