Introduction

Medicinal plants and their phytoconstituents (natural products) are source for therapeutic applications and play a pivotal role in maintaining proper health for human beings and in controlling various diseases (Gurib-Fakim 2006). “Natural products” are chemical compounds that are isolated from living organisms such as plants, animals, fungi, microorganisms, marine organisms, and terrestrial vertebrates and invertebrates (Newman et al. 2000). Newman and Cragg published several reviews under the topic “Natural products as sources of new drugs,” covering the years 1981 to 2019 (Newman and Cragg 2007; Newman and Cragg 2012; Newman and Cragg 2016; Newman and Cragg 2020; Newman et al. 2003). The reviews focus on the fact that many drugs in the market are derived from natural origin. The reviews revealed that, out of the 1328 new chemical entities approved as drugs between 1981 and 2016, only 359 were of synthetic origin and a little less than half of those new drugs (549, exactly) were from natural origin or natural product derivatives. Furthermore, out of 136 approved nonbiological anticancer compounds in the period (1981–2014), only 23 were of synthetic origin (i.e., not derived from natural compounds nor natural derivatives) (Newman and Cragg 2016).

Over the past 20 years, the top pharmaceutical companies such as Merck, Pfizer, and Bristol Myers Squibb have declined the in-house research programs on natural products (Beutler 2009). This approach has been observed in the USA, while a few European and Japanese pharmaceutical companies continue to support research on natural product drug discovery (Atanasov et al. 2021; Thomford et al. 2018). Beutler (2009) has enumerated several reasons for this trend, (i) process of drug discovery from natural products is slow; (ii) all of the easy natural product drug discoveries have been made; (iii) synthesis of complex structure of natural products is difficult; (iv) maintaining continuous supply of natural products is difficult; (v) high throughput chemistry is viewed as better than natural products; and (vi) sometimes, natural product formula may not be patentable in the USA. Of the abovementioned reasons, search in natural products still holds out the best options for finding novel agents/active templates, which when worked on in parallel with chemists and biologists offer the potentials to discover novel structures with therapeutic activity against variety of human illnesses (Newman and Cragg 2020). In addition, natural products, mainly from plant sources, still provide and demonstrate important structural diversity, and showed a wide variety of novel and templates to the Western medicine (Balunas and Kinghorn 2005; Harvey 2008; Newman et al. 2003). Recent reports revealed the significance of natural products in health care system, providing that 80% of the world population still use plant-derived products (Butler 2008; Farnsworth et al. 1985). It is also reported that about 50% of all therapeutic drugs in clinical use are of natural origin, or their derivatives, or their analogs (Balandrin et al. 1993), and 74% of the most important drugs consist of plant-derived active ingredients (Arvigo and Balick 1993).

This review summarizes recently published studies on russelioside B (1), a major pregnane glycoside isolated from Caralluma species focusing on its biological and pharmacological activities.

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Search Strategy

A systematic search in the literature was performed through Egyptian Knowledge Bank database, Google Scholar, J-Global, Scopus, Dr. Duke’s Phytochemical and Ethnobotanical Databases, PubMed, Web of Science, and Elsevier databases. The search was done using all available MeSH terms for russelioside B, structure, isolation, solubility, bioavailability, uses, biological activity, toxicity, pharmacokinetics, clinical investigations, and mechanism. The article search time was from inception to the year 2021.

Discussion

Natural Sources

Russelioside B (1) was isolated from the following species: Caralluma retrospiciens (Ehrenb.) N.E.Br., syn. C. russelliana (Courb. Ex Brongn.) Cufod. Boucerosia russelliana Courbon ex Brongn.) (Abdul-Aziz Al-Yahya et al. 2000); C. quadrangula (Forssk.) N.E.Br., syn. B. quadrangula, Decne., Ceropegia quadrangula (Forssk.) Bruyns and Monolluma quadrangula (Forssk.) Plowes (Abdel-Sattar et al. 2016; Abdel-Sattar et al. 2017); C. tuberculata N.E.Br., syn. Apteranthes tuberculata (N.E.Br.) Meve & Liede, and Borealluma tuberculata (N.E.Br.) Plowes, and Borealluma aucheriana (N.E.Br.) Plowes (Abdel-Sattar et al. 2013); and, finally, C. europaea (Guss.) N.E.Br., syn. C. negevensis Zohary ex Feinbrun, A. europaea subsp. negevensis (Zohary ex Feinbrun) M.B. Crespo, and A. negevensis (D. Zohary) Plowes (Braca et al. 2002). The 20R isomer of 1 was isolated from C. umbellata Haw [Syn: Stapelia umbellata Roxb, C. campanulata N.E.Br.] (Ray et al. 2011); C. indica; C. adscendens var. gracilis Gravely & Mayur (Reddy et al. 2011); and C. paucilfora (Wright) N.E. Brown (Gummadi et al. 2021). The summary of plants containing russelioside B, parts used (Fig. S1), and uses/biological activities is shown in Table S1.

Chemical Structure

Russelioside B (1) was first separated by our group from C. russelliana (Abdul-Aziz Al-Yahya et al. 2000) and later from C. quadrangula (Abdel-Sattar et al. 2016; Abdel-Sattar et al. 2017) and identified by LC-MS in C. tuberculata (Abdel-Sattar et al. 2013). It was isolated as colorless crystals, had the molecular formula C40H66O17 as determined using ESI-MS (m/z 841 [M + Na]+) data, and confirmed by its 13C NMR (Abdul-Aziz Al-Yahya et al. 2000). It showed no UV activity and the IR (KB, cm−1) spectrum showed strong absorptions at 3562 (OH alcohol), 2865 (-C=C-), and the absence of carbonyl groups. The presence of glucose and 3-O-methyl-6-deoxygalactose moieties was proved by acid hydrolysis and from detailed NMR analysis, which showed the presence of three anomeric protons and carbons (1H and 13C NMR spectra). The linkages of sugar to aglycone and sugar to sugar were proved through HMBC correlations. The stereocenters of russelioside B structure was determined from the analysis of the NOESY correlations, and it was concluded that the side chain is oriented with carbon C-20 having the S configuration (Table S1). The russelioside B was elucidated as calogenin 20 (S)-O-β-d-glucopyranosyl-3-O-[β-d-glucopyranosyl-(1 → 4)-β-d-(3-O-methyl-6-deoxy)] galactoside.

Physicochemical Properties

Russelioside B was isolated as colorless crystals with melting point of 202–204 °C, and had [α]25D − 15.4°. It is soluble in water, methanol, and ethanol and insoluble in chloroform and ether. Other physicochemical properties of russelioside B were predicted and reported by ChemAxon, viz. logP (10−1.3 g/l), pKa (strongest acidic: 11.78), pKa (strongest basic: − 3.2), and refractivity of 196.68 m3·mol−1 (https://chemaxon.com/products/calculators-and-predictors#logp_logd).

Quantification

Quantification of russelioside B was performed using LC-MS analysis in the methanolic extract of C. tuberculata (Abdel-Sattar et al. 2013). The analysis was performed on HPLC system of an Agilent 1200 system composed of solvent delivery module, quaternary pump, autosampler, and column compartment. The column effluent was connected with Agilent 6320 Ion Trap LC-ESI-MS. Analytes were separated on Agilent Zorbax SB-C18 (150 mm length × 4.6 mm i.d., 3.5 mμ). A volume of 1 μl from each standard or sample solution was injected 3 times for LC-ESI-MS analysis applying two-segment and positive mode. The developed method used 20% formic acid (0.1%) and 80% acetonitrile as eluting system and flow rate 0.5 ml/min over 25 min. Russelioside B (tR 2.73 min) was determined along with russelioside C (tR 4.53 min) and caratuberside C (tR 17.57 min) in the methanolic extract of C. tuberculata from the corresponding calibration curve using the peak area of each m/z extracted (Abdel-Sattar et al. 2013). LC-MS analysis showed that russelioside B, russelioside C, and caratuberside C present in amounts of 239, 12.8, and 42.8 mg/g, respectively.

Biological Activity

Acute Toxicity (LD50)

The toxicity of russelioside B (1) was carried out by determining its LD50 in male albino mice. After acclimatization (5 days), the animals were fasted overnight prior dosing. A batch consisting of 10 male mice was administered with a single dose orally once with varied concentrations (500 up to 5000 mg//kg bw) of 1, in parallel with control group. All the animals in all groups were observed for 15 days. Observations were made at least once during the first 30 min and every 4 h in the first day and once every day for the next 14 days. The results showed no signs of toxicity up to 5000 mg/kg body wt.

Anti-hyperglycemic Activity

Diabetes mellitus has emerged as a major public health problem worldwide, which is predicted to worsen in the coming decades, particularly in developing countries. The global prevalence of DM among adults (aged 18–99 years) was estimated to reach 451 million people in 2017. These figures were expected to reach 693 million adults by 2045 (Cho et al. 2018). Nearly half of this figure remains with undiagnosed diabetes (type 2) and there was an estimated 374 million people with impaired glucose tolerance. In those who are diagnosed, diabetes control is not up to the maximum, which potentially increases the risk of associated complications, resulting in poor health outcomes. Approximately 5 million deaths globally were attributable to DM in the age of 20–99 range. In 2017, the global health expenditure on people with diabetes was estimated to be USD 727 billion (Atlas 2015). An alternative approach of the use of western medicine to treat diabetes mellitus is the use of various natural agents possessing hypoglycemic effect or their derivatives. Several species of the genus Caralluma are rich in pregnane glycosides and showed promising blood glucose-lowering effects of their extracts or their corresponding fractions, namely, C. russelliana (Zari and Al-Thebaiti 2018), C. dalzielii N.E.Br. (Tanko et al. 2012), C. adscendens var. attenuata (Wight) Grav. & Mayur. (Singh and Kori 2014; Venkatesh et al. 2003), C. arabica N.E.Br. (Radhakrishnan et al. 1999; Wadood et al. 1989), C. edulis (Edgew.) Benth. ex Hook.f. (Sayantan and Abhishek 2012; Wadood et al. 1989), C. umbellate Haw. (Kumar 2016), C. tuberculata N.E.Br. (Abdel-Sattar et al. 2011; Abdel-Sattar et al. 2013), C. sinaica (Decne.) A.Berger (Habibuddin et al. 2008), C. adscendens var. fimbriata (Wall.) Gravely & Mayur. (Latha et al. 2014), and C. quadrangula (Abdel-Sattar et al. 2017; Al-Adhreai et al. 2018).

Russelioside B (1) was evaluated in STZ-induced diabetic rats for its anti-hyperglycemic activity (15 and 25 mg/kg), alongside with the MeOH extract C. quadrangula and related fractions (CHCl3, n-butanol and remaining water) (Abdel-Sattar et al. 2017). The effect of 1 on body weight, fasting blood glucose (FBG) level, serum insulin level, and hepatic glucose-6-phosphatase activity was measured. Compound 1 (25 mg/kg) recovered the body weight nearly comparable to that of glibenclamide (5 mg/kg), the reference drug. The administration of 1 at 25 mg/kg showed a significant decrease in fasting blood glucose level in diabetic treated rats similar to the effect of glibenclamide. Compound 1 (25 mg/kg) resulted in the decrease of fasting serum glucose (FSG) from 600.3 ± 33.96 mg/dl (diabetic control) to 322.66 ± 20.4 mg/dl. The treatment of diabetic rats with the various extracts and fractions and RB showed different activities on serum insulin level. The MeOH extract (200 mg/kg), CHCl3, and n-butanol fractions (100 mg/kg) showed significant increase in the insulin levels in the diabetic treated rats, which is similar to that of glibenclamide, while 1 showed a moderate effect. On the other hand, the activity of gluconeogenic enzyme, G-6-Pase, was significantly increased in the diabetic rats compared to those in normal control. The MeOH extract (200 mg/kg), chloroform, n-butanol fractions (100 mg/kg), and RB (25 mg/kg) showed significant reduction in hepatic G-6-Pase activity by about 51.1, 57.7, 51.8, and 54.8%, respectively.

Anti-hyperglycemic Mechanism of Action

The suggested mechanism of the anti-hyperglycemic activity of 1, at least partly, may be due to stimulation of insulin secretion, inhibition of glucose-6-phosphatase activity, enhancement of glucose utilization, and inhibition of glucose absorption. The change in body weight was not strong in all tested fractions and 1; this may be due to the effect of their pregnane glycosidic content which showed appetite suppressant activity (Abdel-Sattar et al. 2018).

In another study, compound 1 showed improvement effect on glucose metabolism in the liver of STZ-induced diabetic rats (Abdel-Sattar et al. 2016). The daily oral administration of 1 (50 mg/kg) for a period of 30 days resulted in the improvement of the FSG level, glycated hemoglobin percent, serum insulin level, and lipid profile. Administration of 1 showed a significant decrease in the levels of serum total glycerides, and atherogenic index with a significant increase in the level of high-density lipoprotein cholesterol when compared with the diabetic group. A significant improvement was also observed on the activities of glucokinase, glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, and glycogen phosphorylase enzymes in the liver of STZ-diabetic rats, the key player enzymes of carbohydrate metabolism. Furthermore, administration of 1 reverted gene expression of glucokinase, glucose-6-phosphatase, glycogen synthase, and glycogen synthase kinase-3β to near-normal levels.

The hypoglycemic action of russelioside B (1) may have two mechanisms of actions; this pregnane glycoside may reduce the blood glucose level by decreasing the intestinal glucose absorption, or/and by stimulation of insulin secretion from the pancreas. Yoshikawa (2002) proposed that steroidal glycosides partially stay on the surface of the small intestine and lower glucose absorption, thus regulating the increase in blood glucose levels (Yoshikawa 2002). The decline in total glyceride (TG) and total cholesterol (TC) in russelioside B–treated diabetic animals could be due to the increase in insulin secretion potentiated by 1. It was suggested that it also inhibits cholesterol biosynthesis and promoted the activity of lipolytic enzymes in hyperlipidemic animals (Sethi et al. 2007). The reduction of serum TG following treatment with 1 might also facilitate glucose oxidation. In addition, the increase in insulin secretion by RB is reflected by the rise in intracellular glycogen deposition particularly in liver tissues due to stimulation of glycogen synthase (GS) and inhibiting glycogen phosphorylase and GSK-3β expression. Russelioside B (1) affects also hepatic glucose metabolism by increase of GK activity as well as its expression, which could be attributed to the increase in insulin concentration (Morinaga et al. 2008).

Anti-obesity Activity

Obesity and overweight have become a major common health problem globally, experiencing increasing rates in both developed and developing countries (Shao et al. 2014). In 2016, it was estimated that 1.9 billion adults were overweight and 650 million out of 1.9 billion overweight were classified as obese (Shuaib et al. 2021). The worldwide prevalence of obesity has nearly tripled between 1975 and 2016 (Abarca-Gómez et al. 2017).

In obesity, the imbalance between energy intake and expenditure results in excessive body fat accumulation. This may lead to serious non-communicable diseases, such as type 2 diabetes mellitus, hypertension, dyslipidemia, cerebro- and cardiovascular diseases, sleep apnea, and some cancers (Son and Kim 2020). The key strategy to control overweight and obesity is a combination of change in lifestyle and physical activity, in addition to the use of pharmacological therapy to prevent chronic positive impairments in the energy equation by elevating average daily metabolic rate and increasing energy expenditure (Schrauwen and Westerterp 2000). The pharmaceutical drugs for the control of obesity include the use of thermogenetic agents, lipase inhibitors and compounds that suppress appetite or stimulate the CNS (Shashoua and Hesse 1996), which may have undesirable harmful side effects.

Natural products (including crude drug, extracts, or isolated compounds) that induce body weight loss and prevent diet-induced obesity are widely consumed in control of the metabolic disorders (Hanl et al. 2005). Plants of genus Caralluma have long been used to control weight gain and as appetite suppressant, namely C. fimbriata, C. attenuate, C. tuberculata, C. indica, C. stalagmifera, C. umbellata, C. lasiantha, and C. edulis (Adnan et al. 2014). Commercial products containing C. fimbriata extract are available in the international markets. The use of C. fimbriata extract (100 mg/kg/day) showed significant weight loss and improved lipid profile as compared with hypercaloric diet control group in rats, resulting in suppressing appetite and preventing fat accumulation (Ambadasu and DSWRW, 2013). This effect is due to inhibition the formation of enzymes responsible for fat synthesis (Naingade et al. 2013). The appetite-suppressing effects of C. fimbriata have been ascribed to its content of pregnane glycosides (Adnan et al. 2014). This hypothesis was confirmed by the isolation of P57 (2), an oxypregnane steroidal glycoside isolated from Hoodia gordonii (Masson) Sweet ex Decne., Apocynaceae, a succulent plant consumed traditionally by the Khoi-San of South Africa and Namibia as a hunger and thirst suppressant (appetite suppressant) (Vermaak et al. 2011).

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Caralluma quadrangula and C. tuberculata, the source of russelioside B (1), have been consumed by Bedouins of Saudi communities in cases of thirst and hunger and for the treatment of diabetes, and when food supplies were low. Abdel-Sattar and coauthors (2016) observed the failure of 1 to restore the fall in body weight in diabetic rats induced by STZ and was explained possibly by the appetite suppressant effect of pregnane glycoside (Abdel-Sattar et al. 2016; Liu et al. 2013; Tucci 2010; Vermaak et al. 2011). This observation encouraged the authors to investigate the possible appetite suppressant activity of RB. Abdel-Sattar and coauthors (2018) designed experimental protocol to examine the potential role of RB in controlling weight gain associated with high-fat (HF) diet in rats focusing on the influence of RB on adipose tissue expression for adipokines as well as energy expenditure. The assessment of the effect RB was carried out using male Wistar rats (fed on high-fat diet for 16 weeks) at two oral doses (25 and 50 mg/kg). Animal parameters like weight gain, blood glucose, serum lipids, and liver enzyme activities were measured, in addition to liver and adipose tissue indices. Adipose tissues were processed for histopathological examination (Fig. 1), and for measurement of mRNA expression of uncoupling protein-1 (UCP-1), visfatin, adiponectin, leptin, and carnitine palmitoyl transferase-1 (CPT-1). In addition, serum levels of insulin, interleukins (IL-1b and IL-6), tumor necrosis factor-α (TNF-α), adiponectin, resistin, and leptin were assessed. Fig. 1 shows tissue sections from the adipose tissues. The adipose tissue from HF diet control rats showed larger diameter for adipocyte spaces. Treatment with 1 (50 mg/kg) significantly reduced the diameter of the adipocyte spaces. The modulation of all these parameters confirmed the potential benefits of russelioside B (1) in diminishing weight gain and improving the inflammatory perturbations and energy expenditure in HF diet-fed rats.

Fig. 1
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Effect of russelioside B (1) on the diameter of adipocyte spaces in the lumbar adipose tissue. a Tissue section from normal rat adipose tissue showing low-diameter adipocyte space. b Tissue section from adipose tissue from high-fat diet control rats showing larger diameter adipocyte spaces. c, d Tissue sections from adipose tissues from high-fat diet-fed rats treated with 1 at 25 and 50 mg/kg, respectively. e Box plots showing the medians and quartiles for diameters (μm) of adipocyte spaces. ∗Significant versus normal group. #Significant versus high-fat diet control group. Comparison was performed by non-parametric ANOVA followed by Dunn’s test at p < 0.05. Reproduced from Abdel-Sattar et al. (2018)

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Anti-obesity Mechanism of Action

This study confirmed the potential therapeutic benefits of russelioside B (1) in decreasing weight gain, improved lipid profile, and insulin resistance as indicated by the HOMA-IR index. The authors highlighted that RB regulated enzymes involved in carbohydrate metabolism in the liver of diabetic rats (Abdel-Sattar et al. 2016). Furthermore, the data revealed the upregulation of both UCP-1 and CPT-1 genes and increased their protein level in the brown adipose tissue in treated rats with 1, which results in fatty acid β-oxidation, and activation of the brown adipose tissue (Gonzalez-Hurtado et al. 2018). This action leads to improve glucose homeostasis and modulate insulin resistance (Zaitone et al. 2015). The authors reported that the upregulation of UCP-1, in addition to CPT-1, plays a crucial role in controlling of obesity (Rameshreddy et al. 2018), through enhancement of lipolysis and decreased total glycerides. The released free fatty acids are transported to the mitochondria via the activated CPT-1 enzyme, with simultaneous induction of the thermogenic activity of UCP-1, which suggested to reduce visceral fat mass (Han et al. 2017).

The study also revealed the amelioration effect of russelioside B (1) on pro-inflammatory cytokines (IL-1B, IL-6, and TNF-α), adipokines (leptin, adiponectin, resistin, visfatin), and their mRNA expression in the pathology of insulin resistance. Interestingly, compound 1 elevated serum leptin, resistin, and visfatin, and reduced adiponectin levels. This led to suppression of appetite and improvement of thermogenesis, insulin sensitivity, and insulin resistance. Therefore, the overall anti-obesity action of 1 may be, at least partly, attributed to its anti-inflammatory and adipokine modulation, in addition to it is beneficial effect on energy expenditure.

Antiparasitic Activity

Malaria and trypanosomiasis are vector-borne diseases caused by Plasmodium and Trypanosoma parasites, respectively. Both diseases continue to be the main reasons of community health problem for many millions of people in both tropical and subtropical zones of the world (Ashley et al. 2018). The recent malaria report (WHO 2020) considered almost half of the world’s population was at risk of malaria infection; the number of malaria deaths increased up to 409,000; and approximately 229 million new malaria cases occurred in 2019 worldwide. On the other hand, human African trypanosomiasis (HAT) showed great decrease in the new cases in the last 10 years; however, there are more than 57 million people who still remain at risk from the disease in 36 countries (Kassebaum et al. 2016). Many of the antiparasitic drugs currently in use showed serious toxicity and upsurge of drug resistance or a lack of adherence to treatment. Therefore, there is an urgent and global need to discover new effective drugs. The biological assays to discover new antiparasitic drugs from natural products showed great promise due to their efficacy and good selectivity (Kayser et al. 2003).

Abdel-Sattar and co-workers tested 42 Saudi plants and some fractions obtained thereof for their antiplasmodial and antitrypanosomal activity. Among these plants, C. tuberculata showed some moderate activity against chloroquine-resistant strain (K1) and sensitive strain (FCR3) of Plasmodium falciparum, and against Trypanosoma brucei brucei GUTat 3.1 strain. Application of biologically guided fractionation approach on C. tuberculata methanolic extract led to isolation of six pregnane glycosides from the moderately active chloroform fraction (Abdel-Sattar et al. 2008). Five compounds showed weak antimalarial activity against Plasmodium falciparum (K1, drug resistant) with IC50 < 12.5 and > 6.25 μg/ml, and one was inactive (IC50 > 12.5 μg/ml) in comparison to chloroquine (IC50 0.17 μg/ml), the positive control. Regarding in vitro antitrypanosomal activity, only one compound showed promising activity with IC50 1.85 μg/ml (IC90 3.4 μg/ml) using melarsoprol (IC50 0.000011) as positive control.

The previous results represent the first report on the antitrypanosomal activity of pregnane glycosides, which encouraged the authors to test some of the previously isolated pregnane glycosides. The study carried by Abdel-Sattar et al. (2009) revealed that all the acylated glycosides showed variable activity, except for penicilloside B isolated from C. penicillata that was inactive (Abdel-Sattar et al. 2001), while penicilloside E (3) isolated from C. tuberculata (Abdel-Sattar et al. 2008) was the most active (IC50 1.01 μg/ml). However, all the tested non-acylated glycosides (russeliosides B–D) including russelioside B were completely inactive. The authors suggested the urgent need to test the previously acylated pregnane glycosides, in addition to their alycones.

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Gastroprotective and Antiulcer Activity

Gastric ulcer is an acid-induced injury of the lining mucosa of the digestive tract. It results in a serious health problem, which could lead to the high morbidity and mortality rates due to perforation, bleeding, and obstruction (Lanas and Chan 2017). The estimated prevalence of peptic ulcer disease globally is 5–10%, but recently, it showed a decrease in the incidence of new cases, and mortality associated with peptic ulcer (Lanas et al. 2011).

Three species of genus Caralluma including C. edulis, C. tuberculata, and C. umbellata are traditionally used for the treatment of gastric ulcers (Adnan et al. 2014). Several species showed antigastric effect, cytoprotective or ulcer heal activity, like C. arabica (Zakaria et al. 2002), C. adscendens var. fimbriata (Dakshayani et al. 2014), C. flava N.E.Br. (Al-Naqeb 2017; Raees 2018), C. tuberculata (Alharbi et al. 1994), C. attenuata (Garg et al. 2016), C. quadrangula (Ibrahim et al. 2016) and C. penicillata (Deflers) N.E.Br. (Albaser et al. 2014).

The traditional uses of several Caralluma species in the treatment of gastric ulcer, in addition to the biological studies which confirmed these uses, encouraged El-Shiekh and coauthors (2021c) to evaluate the possible gastroprotective effect of russelioside B in rat model of gastric ulcer. The study aimed to evaluate the possible protective effect of russelioside B in ethanol-induced gastric mucosal injury of rat model (El-Shiekh et al. 2021c). Russelioside B (50 mg/kg) as well as antodine (20 mg/kg) as positive standard were given by oral gavage 1 h before ulcer induction using absolute ethanol (5 ml/kg). Pretreatment with russelioside B attenuated the gastric mucosal ulceration as proved by a decrease of ulcer index, and histological scores. The significant decrease of cytokine levels (TNF-α and IL-6 levels) and lowering myeloperoxidase activity proved its inhibition of gastric inflammation. In addition, the administration of russelioside B suppressed the gastric oxidative stress through inhibition of lipid peroxides by maintaining reduced glutathione and by lowering malondialdehyde. It was able also to ameliorate the sharp decline in the levels of vascular endothelial growth factor, heat shock protein-70, prostaglandin E2, and carbonic anhydrase inhibition activity induced by ethanol.

Gastroprotective Mechanism of Action

The potential of ulcer healing action of russelioside B (1) was mainly exerted through multi-mechanistic actions: cytoprotective, antiulcerogenic effects, suppression of gastric oxidative stress, and anti-inflammatory properties. It acts also through anti-apoptotic activities and enhanced gastric mucosal protection by upregulation of endothelial growth factor, normalization of heat shock protein-70, and prostaglandin E2. These actions were comparable in part to classical antiulcer drugs such as antodine. Therefore, russelioside B could be a powerful candidate for the treatment of gastric ulcer and as potent antiulcer drug, but further studies are required to prove its safety and efficacy relative to the synthetic drugs.

Anti-arthritic Activity

Rheumatoid arthritis (RA) is a long-term, chronic autoimmune inflammatory disorder that causes chronic synovial inflammation (synovitis), joint erosion, and cartilage damage (Lwin et al. 2020) and may lead to disability in many patients. RA can also affect most organs of the body, leading to higher mortality and morbidity rates (Zielinski et al. 2019). The estimates of global prevalence of RA range from 0.24 to 1%, although rates vary by region and country (Cross et al. 2014).

Several Caralluma extracts showed anti-inflammatory and/or analgesic activities, viz. C. tubreculata (Ahmed et al. 1993), C. attenuata (Ramesh et al. 1998), C. arabica (Zakaria et al. 2001), C. adscendens (Naik and Jadge 2009), C. dalzielii (Umar et al. 2013), and C. umbellata (Ramanjaneyulu et al. 2016). In a limited study, carumbelloside-III (4) (Ray et al. 2011) and carumbelloside-IV (5) (Ray et al. 2012) showed significant anti-inflammatory activity in carrageenan-induced left hind paw edema model in Wistar rats with 41.8% (10 mg/kg), 52.3% (20 mg/kg), and 60.4% (mg/kg) of inhibition (indomethacin: 69.7% at dose 10 mg/kg). Carumbelloside-III (4) was separated and identified as the 20R isomer of 1 (20S isomer) previously separated from C. russelliana under the name russelioside B (Abdul-Aziz Al-Yahya et al. 2000).

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Russelioside B (1) was assessed for its anti-arthritic effect in adjuvant-induced arthritis (AIA) model established in rats by intradermal injection of complete Freund’s adjuvant (CFA) (El-Shiekh et al. 2021a). Compound 1 was evaluated at two doses (25 and 50 mg/kg) in parallel with ibuprofen (5 mg/kg) as positive standard. The treatment was started from day 16 and continued to the day 40. Serum diagnostic rheumatoid markers, such as rheumatoid factor (RF); anti-cyclic citrullinated peptides (anti-CCP); high-sensitivity C-reactive protein (hr-CRP); inflammatory cytokines, as nuclear factor-kappa-B (NF-κB), TNF-α, IL-6, and IL-1β; oxidative stress biomarkers: total antioxidant capacity (TAC) and myeloperoxidase (MPO); and cartilage and bone degeneration enzymes, were assessed. Compound 1 (50 mg/kg) showed significant decreases in the activities of hyaluronidase and β-glucuronidase enzymes as well as significant decreases in the levels of NF-κB, TNF-α, IL-6, and IL-1β compared to the arthritic group. The oxidative stress biomarkers like TAC and MPO activities were significantly restored to normal values. Bone histomorphometry and histopathological examination (Fig. 2) revealed that treatment with 1 significantly attenuated the CFA-induced bone loss and pronounced regression of the pathological alterations (El-Shiekh et al. 2021a).

Fig. 2
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Photomicrograph (hematoxylin and eosin staining, scale bar, 100 μm) of ankle joint of a and b normal group, c and d CFA group, e and f CFA + Ibuprofen group, g and h CFA + russelioside B group (25 mg/kg b. wt.), i and j CFA + russelioside B group (50 mg/kg b. wt.) (n = 8 rats per group). a Normal articular cartilage with smooth surface. b Normal chondrocytes embedded within normal cartilage matrix. c Deterioration of cartilage and subchondral bone. d numerous osteoclasts (arrows). e Smooth articular surface. f Necrosis of chondrocytes (arrows). g Smooth articular surface. h Focal loss of cartilaginous matrix (arrow). i Normal cartilage matrix. j Necrosis of individual chondrocytes (arrow). Abbreviation: CFA, complete Freund’s adjuvant-induced arthritic rats; IBU, ibuprofen treated group; NOR, normal group; RB, russelioside B (1)–treated groups. Reproduced from El-Shiekh et al. (2021a)

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Anti-arthritic Mechanism of Action

These findings suggested that the anti-arthritic effect of RB was mediated through the reduction of the rheumatoid markers, anti-inflammatory and antioxidant action, inhibition of cartilage, and bone degenerative enzymes as well as attenuation of bone loss and osteoclastogenesis.

Antibacterial Activity

Several Caralluma species were tested for their antimicrobial and antifungal activity and showed moderate or weak activity (Babu et al. 2014; BinMowyna and Alsayadi 2020; Farouk et al. 2016; Kumar et al. 2008; Makeen et al. 2020; Malladi et al. 2017). The activity most probably is due to their content from flavonoids and to less extent to pregnane glycosides (Reddy et al. 2013). The juice of C. quadrangula collected from Al-Shafa Taif, Kingdom of Saudi Arabia, was extracted with different solvents (water, Zamzam water, ethyl alcohol, acetone and Tris-HCl, pH 8.7). The different extracts were tested against Gram-positive, Gram-negative bacteria and fugi using the agar diffusion method. The most sensitive tested microorganisms were Micrococcus luteus, Candida albicans, Escherichia coli, and Pseudomonas aeruginosa strains. The acetonic and ethyl alcohol extract showed the highest activity. On the drying juice exuded from cutting aerial parts of C. quadrangula, it showed major spot identified as russelioside B (unpublished data by Abdel-Sattar). Therefore, testing russelioside B (1) for its antimicrobial and antibiofilm activity is of a great challenge for the authors.

Methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MDRAB) are serious public health threat. It becomes a big challenge because of their capability to cause biofilm resistance to commonly used antibiotics producing chronic infections and hindering the process of wound healing. The antibacterial activity of C. quadrangula extracts (MeOH, and its fractions CH2Cl2 and n-butanol) was investigated against multidrug-resistant MRSA USA300 and MDRAB AB5057 (El-Shiekh et al. 2021b). In vitro, all the tested samples of C. quadrangula significantly suppressed biofilm formation and destroyed the established biofilm of MRSA and MDRAB at all concentrations tested (0.625, 0.313, and 0.156 mg/ml). In addition, both C. quadrangula MeOH extract and the CH2Cl2-soluble fraction succeeded in lowering bacterial loads in MRSA-infected skin lesions in mice topically treated (Fig. 3). The chromatographic separation of the bioactive n-butanol led to the isolation of four pregnane glycosides (1, 6–8) and one flavone glycoside (9). All the isolated compounds, coded as Rus A–E (1, 6–9) were subjected to biofilm inhibition and biofilm detachment assays. Rus C (8) was the most active compound (IC50 0.139 mmole), while Rus E (9) was the least active (IC50 0.818 mmole). These results support the potential use of C. quadrangula extracts or their isolated compounds for inhibiting the biofilm attachment and the virulence of MRSA and MDRAB and their application as a topical antimicrobial preparation in MRSA skin infections.

Fig. 3
figure 3

Efficacy of Caralluma quadrangula MeOH extract (Cq1) and n-butanol fraction (Cq3) in a murine model of MRSA skin infection in vivo. Thirty-two BALB/C mice were divided into four groups (n = 8), three treated groups (Cq1, Cq3, and vehicle), and the fourth group remained untreated as the negative control. A Efficacy of C. quadrangula extracts (Cq1 and Cq3) on MRSA skin infection in the posterior upper backs of mice at the end of the experiment. B Efficacy of C. quadrangular extracts on the bacterial load in murine model MRSA skin infection. Results are expressed as mean ± standard error. The dotted line represents the limit of detection of the viable count (log10 of 50 CFU = 1.7). * and *** indicate that the difference is significant at p < 0.05 and p < 0.0009, respectively (one-way ANOVA, Tukey’s post hoc test). Reproduced from El-Shiekh et al. (2021b)

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Perspectives and Future Directions

Russelioside B (1) is considered a good lead for the development of a new phytoparmaceutical for the treatment of different ailments. In the previous studies, there is a lack for an ideal method for the isolation of russelioside B that generates a higher yield, in a shorter time and at a lower cost other than solvent-solvent extraction using n-butanol. In addition, russelioside B was determined only by LC-ESI for its quantification. Analytically, there is a need for simple methods for its metabolites, specifically in biological fluids. Compound 1 has shown different biological activities, such as antidiabetic, antibacterial, antiparasitic, anti-obesity, and gastroprotective potentials, but further detailed safety and pharmacokinetic studies are necessary. To date, there are no trials for the synthesis of 1; therefore, it is also necessary to prepare its derivatives and investigate their activity and construct structure-activity relationships and understand their mechanisms of action. Based on its activity on inflammatory biomarkers, compound 1 needs to be tested against COVID-19 infection.

Conclusions

This review presents updated report on russelioside B (1), a major pregnane glycosides isolated from different Caralluma species with a promising pharmacological preclinical potential. Russelioside B possesses anti-inflammatory, anti-obesity, antidiabetic, antibacterial, antigastric ulcer, and antibiofilm properties, as well as it could be useful for the treatment of rheumatic arthritis. The main limitation for its therapeutic use is the lack of detailed assessment of its safety profile on different organs, which are also required for a better evaluation of its potential for future clinical applications. Further deeper mechanistic studies underlying these beneficial properties are needed in a near future to elucidate the interaction between russelioside B and the receptors of the specific genes. This review suggests that russelioside B may find direct medicinal application as a phytophamaceutical agent or as chemical template for the design, synthesis, and semi-synthesis of new drug for the treatment of contemporary human diseases.