A Review on the Main Phytoconstituents, Traditional Uses, Inventions, and Patent Literature of Gum Arabic Emphasizing Acacia seyal

Acacia seyal is an important source of gum Arabic. The availability, traditional, medicinal, pharmaceutical, nutritional, and cosmetic applications of gum acacia have pronounced its high economic value and attracted global attention. In addition to summarizing the inventions/patents applications related to gum A. seyal, the present review highlights recent updates regarding its phytoconstituents. Traditional, cosmetic, pharmaceutical, and medicinal uses with the possible mechanism of actions have been also reviewed. The patent search revealed the identification of 30 patents/patent applications of A. seyal. The first patent related to A. seyal was published in 1892, which was related to its use in the prophylaxis/treatment of kidney and bladder affections. The use of A. seyal to treat cancer and osteoporosis has also been patented. Some inventions provided compositions and formulations containing A. seyal or its ingredients for pharmaceutical and medical applications. The inventions related to agricultural applications, food industry, cosmetics, quality control of gum Arabic, and isolation of some chemical constituents (L-rhamnose and arabinose) from A. seyal have also been summarized. The identification of only 30 patents/patent applications from 1892 to 15 November 2021 indicates a steadily growing interest and encourages developing more inventions related to A. seyal. The authors recommend exploring these opportunities for the benefit of society.


Introduction
The genus Acacia (also known as wattles) is a large genus formed mainly of shrubs and trees that belong to the subfamily Mimosoideae and the pea family (Fabaceae). Plant species of this genus grow natively in the tropical and subtropical regions of the world, including Africa, Australia, middle America, the Middle East, and south Asia. The genus name "Acacia" was introduced by Philip Miller in 1754 [1] and is derived from the Greek name (

Introduction
The genus Acacia (also known as wattles) is a large genus formed mainly of shrubs and trees that belong to the subfamily Mimosoideae and the pea family (Fabaceae). Plant species of this genus grow natively in the tropical and subtropical regions of the world, including Africa, Australia, middle America, the Middle East, and south Asia. The genus name "Acacia" was introduced by Philip Miller in 1754 [1] and is derived from the Greek name ( ἀ κακία) "akakia", a term used by Dioscorides (40-90 AC) for a prepared extract from leaves and pods of Acacia nilotica "Vachellia nilotica". The genus Acacia formerly contained 1540 species as recognized in 2011. However, these plant species were varied in species count and habitat: Acaciella Britton & Rose (15 species) and Mariosousa Seigler & Ebinger (13 species) are confined to the Americas. Vachellia Wight & Arn. (163) and Senegalia Raf. (194 species) are pantropical (mainly in Africa and India). The largest clade, corresponding to Acacia following the Vienna Congress, comprises 1021 species, almost all of which are Australian [6]. However, there are a great number of botanists who conserve the old nomenclature and disagree with this recent classification [7].
Acacia seyal Del. (homotypic synonym: Vachellia seyal Del.; another synonym: Acacia stenocarpa Hochst.; English name: Whistling thorn; Arabic Name: Taleh or Talha) [8] wellknown species belongs to the genus Acacia (or Vachellia), Family Fabaceae. Besides the ecological, social, and economic importance of Acacia species. A. seyal is a well-known traditional medicinal plant that has a wide range of medicinal applications related to its different phytoconstituents from organized parts, e.g., fruits, barks, stem, and roots, and unorganized parts, e.g., gum acacia, which is called "taleh or talha gum" [6].
The bark of A. seyal can be easily recognized where A. seyal var. seyal has thin redbrown bark, while the bark of A. seyal var. fistula is smooth and whitish. Both varieties have long, slender, and white thorns that occur in pairs; the thorns of A. seyal var. fistula are sometimes swollen at the base by ant galls. The inflorescence of A. seyal is almost yellow, pedunculate with a globose head. Pods are 7-20 cm long, thin, and slightly curved [9]. Some reviews on A. seyal and A. senegal have been documented, which have been cited at the appropriate places of this manuscript. This review has been written to provide recent updates regarding the phytoconstituents, traditional, cosmetic, pharmaceutical, and medicinal uses of A. seyal with the possible mechanism of actions along with an insight of the inventions/patents applications related to gum A. seyal.
According to Eltayeb et al. 2017 [21], the Sudanese A. seyal stem and stem wood contain tannins, terpenoids, cardiac glycosides, reducing sugars, flavonoids, alkaloids, steroids. The stem barks extract shows only positive results for tannins, terpenoids, cardiac glycosides, and reducing sugars, while all test materials are free from saponins. The dry distillates of the stem materials of A. seyal (known in Sudan as Dokhan) are used as fumigants for their cosmetic, aromatic, and medicinal values. The GC-MS analysis of this dry distillate revealed the presence of more than 130 volatile constituents, while the major vol. constituents were solerone, furfural, catechol, syringol, allo-inositol, mequinol, furfuralcohol, 3-methyl-1,2cyclopentanedione, phenol, homovanillyl alcohol, 1,3-dimethyl-5-methoxypyrazol, and 1,2-anhydro-3,4,5,6-alloinositol. [21]. Gum Arabic (GA) or acacia gum is dried gummy exudate (mainly shaped in tears, spherical, or subspherical forms) obtained pathologically, mainly by incision, from the stems and stem branches of acacia trees, especially A. senegal and A. seyal, family Fabaceae. A. senegal gum is called "hashab gum" and has a milky white appearance and is hard; while A. seyal gum is known as "Talha gum", which has mainly amber yellow color and is friable [22]. GA is an arabinogalactan-protein complex (known as arabin) which is composed mainly of calcium, magnesium, and potassium salts of Arabic acid. Arabic acid is composed mainly of 1-3-linked β-D-galactopyranosyl units with branches that consist of two to five β-D-galactopyranosyl residues linked together through 1,3-ether linkages and attached to the fundamental β-D-galactopyranosyl chain ( Figure 2) through 1,6-linkages. Both fundamental and branches contain additional αl -arabinofuranosyl and α-l-rhamnopyranosyl units and terminated with β-D-glucopyranosyl and 4-O-methyl-β-Dglucopyranosyl residues (Figure 3).  Compared with A. senegal gum, A. seyal gum is more compact and friable, less charged, less hydrolyzable by enzymes, less surface-active, more unstable in solution, richer in minerals and polyphenols, and less rich in proteins [23]. In a study reported by Karamalla 1999 [24], GA contains about 10.75% as an average moisture content, which determines the hardness of the gum and average ash content as 3.27% for A. senegal var. senegal samples, while the average moisture and ash content of A. seyal gum was reported to be 14.41% and 3.5%, respectively [25]. The protein content is responsible for the emulsification properties of GA. For good-quality GA, the European specifications and the United States pharmacopeia define that at least 3% of GA should be protein content [11]. However, the percentage of GA proteins is varied according to the geographical source, the constitution of soil, time of collection, and the plant species; for example, the protein contents in GA from Nigerian A. senegal contain approximately double the content found in Nigerian A. seyal gum, which could explain the instability of the oil in water emulsification properties of A. seyal gum [11,26]. A. senegal gum contains high amounts of hydroxyproline, serine, leucine, threonine, histidine, and aspartic amino acids compared with lower amino acid contents present in A. seyal gum [27]. GA is acidic; its pH is 4.66, as described by Karamalla 1999. [24] The average optical rotation of hashab gum (A. senegal gum) is −30 • , while the [α]D values of talha gum (A. seyal gum) are ranged between +45 • to +54 • [28].
Although polysaccharides macromolecules are mainly sparingly soluble in water, GA is soluble easily in hot and cold water, forming aqueous concentrated solutions of up to 50% concentration. Like most polysaccharides, GA is insoluble in non-polar organic solvent and oils, but it can be soluble in aqueous ethanol solutions up to 60% ethanol concentration [29]. The mineral types and concentrations in gum Arabic attract important attention as they are responsible for the polarity of the arabinogalactan protein complex and, in turn, have an impact on the solubility, hydration compactness, and stability of the colloidal solution of the gum [11].

Traditional Uses
Unorganized parts (e.g., acacia gum and acacia extracts) and organized parts (e.g., fruits, stem barks, and roots) of acacia trees have been used since ancient times for medical, nutrition, and economic benefits. From the first Egyptian Dynasty (3400 B.C.), gum Arabic (or gum acacia) was used in crafts for the production of ink (mixture of carbon, gum, and water) and also in human and veterinary medicine [25]. Traditionally, African herbalists also used gum acacia to bind pills and stabilize emulsions and in aromatherapy for applying essential oils. The fruits and bark of the acacia tree had also been used by the local people of Sudan to tan leather or as a dye [33]. A. seyal (Del.) is a multi-purpose tree that is cultivated for animal fodder, wood, and charcoal in many countries, such as Sudan, Egypt, Somalia Mozambique, and Namibia [34,35]. Presently, gum acacia is used widely in the food and pharmaceutical industries as an important naturally occurring oil-in-water emulsifier. After many years of vacillation, in June 1999, the Codex Alimentarius and the FAO Joint Expert Committee issued the specification for gum acacia [33]. Commercially, it is also used as a film-forming agent in peel-off masks and candies and as emulsifying agents for the production of beverages and flavor concentrates [18,33,36]. Due to the low emulsification properties of A. seyal gum, Bi et al. (2017) [37] have incorporated A. seyal gum with β-lactoglobulin through Millard reaction to obtain high-quality conjugate.

Medicinal Uses
Several studies conducted in recent decades revealed that extracts from the bark of A. seyal have antibacterial action [25,38,39], antimalarial effect [40], antimycobacterial effect, cyclooxygenase inhibition effect [41], molluscicidal activity [42], and anticancer activities [43,44]. Acacia gum has been established to possess several therapeutic actions, such as hypoglycemic, antidiabetic, antioxidant, immunomodulatory, and cytoprotective antiulcer, and has prebiotic properties [18,25]. Table 2 shows the traditional uses of the different parts of A. seyal in different countries for the treatment of various conditions, such as pneumonia, malaria, joint pain, bleeding, rheumatic arthritis, jaundice, chest pain, diarrhea, skin necrosis, bleeding leprosy, dysmenorrhea, eye infection, stomach ulcers, and respiratory tract infection.

Pharmacological Relevance and Industrial Applications
Gum Arabic from Acacia trees, especially from A. seyal and A. senegal, has a wide range of pharmacological activities and applications in modern and traditional medicine (Table 3).
These activities were reported in their original articles after biological experiments using the total content (not pure individual compounds) of gum Arabic, which contain mainly macro-polysaccharide contents (more than 80% w/w) and a small amount of protein (1-3.5% w/w) in addition to traces of other phytoconstituents, e.g., flavonoids, saponins, polyphenolic compounds/tannins and others. The pharmacological activities of gum Arabic are attributed mainly to the polysaccharide contents, but we cannot also neglect the biological activities of other phytoconstituents or at least their synergistic effects, especially we have no confirmed results of the direct relation between specific Acacia phytoconstituent and its direct biological activities. Table 3. The pharmacological relevance of gum Arabic.

Pharmacological Activity
Possible Mechanism of Action Refs.
Antiulcerative effect It provides an antisecretory and cytoprotective effect on GIT. [56,57] Wound healing effect Inhibits periodontic bacterial growth and early deposition of plaque. [58] Protective effect on the reproductive system GA protects the ovary from oxidative stress damage in mice fed with a high-fat diet and increases sperm and semen qualities in the diabetic rat. [59] Hepatoprotective effect GA decreases serum bilirubin level and other liver function markers (ALT, AST) and decreases symptoms of liver damage by restoring the architecture of liver tissue. [60] Activity against adenine-induced renal failure GA mitigates the adenine-induced inflammation and generation of free radicals, resulting in reduced concentrations of plasma urea and creatinine. [61] Activity against Hg-induced nephrotoxicity It prevented Hg-induced degenerative changes of kidney tissues. [62] Activity on renal function It has a significant reduction in blood urea and creatinine concentrations in diabetic nephropathy patients. [63,64] Improvement of chronic renal failure GA can activate colonic bacteria to produce ureases that hydrolyze urea to NH3 and CO2, NH3 excreted in feces through incorporation into bacterial protein. GA increases serum level of butyrate, which prevents the generation of pro-fibrotic cytokine TGF-B1 that contributes to renal fibroblast. [65] Activity against doxorubicin induced-cardiotoxicity It has significant reduction effects on serum creatine kinase and cardiac lipid peroxides. [66] Health benefits on the cardiovascular system GA showed a significant decrease in systolic and diastolic blood pressure. It has a hypocholesterolemic effect, decreasing low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL). [67] Antioxidant activity GA increases the activity of superoxide dismutase, catalase, and glutathione peroxidase in the liver of diabetic rats by either directly scavenging free radicals or reactive oxygen metabolites or via increasing the synthesis of antioxidant biomolecules. [59,61,68,69] Anti-inflammatory effects GA fibers decreased inflammatory markers and disease severity scores among rheumatoid arthritis patients. [70] Supportive treatment of gout GA reduces in a dose-dependent manner the serum levels of uric acid, urea, creatinine, and erythrocyte sedimentation rate level while increasing the hemoglobin and packed cell volume. [71] Effects on fat metabolism and obesity GA lowers sugar and fat absorption and lowers the caloric density of the diet. It improves the fat utilization in adipose tissues, alternating the expression of mRNA levels of genes involved in lipid metabolism. It has a downregulation effect on 11β-hydroxysteroid dehydrogenase type 1 and increases the viscosity of gastrointestinal contents, thus delaying the evacuation of GIT and contributing to a feeling of satiety. GA influences the gut hormones and enzymes that regulate food intake, satiety, and pancreatic functions. It has metabolic energy dilution, bulking, and satiety effects and aids fermentation to produce short-chain fatty acids and increase GLP-1 and PYY. GA diminishes intestinal SGLT1 expression and activity and glucose-actuated overweight.

Pharmacological Activity Possible Mechanism of Action Refs.
Antihypercholesterolimic effect GA decreases plasma triglyceride, total cholesterol, low-density lipoprotein (LDL), and very-low-density lipoprotein. GA disrupts the enterohepatic circulation of bile acids, leading to increased bile acid excretion. [75,[80][81][82] Antidiabetic effect The gel-forming and viscosity of GA inhibit intestinal absorption of macronutrients, enhancement of insulin sensitivity, and modification of certain gut hormones secretion affects a variety of metabolic and inflammatory biomarkers.
[ 79,89] Anti-sickle-cell anemia GA increases fetal hemoglobin (HbF) level, mean corpuscular volume, and hematocrit level. [90] Antimalaria effect GA metabolites (short-chain fatty acids) increase the level of HbF, which is known to hamper the intra-erythrocytic growth of Plasmodium parasites. [59,91] Anticarcinogenic effect GA modifies cancer-related genes' mRNA expression. Antioxidant amino acids contents of GA have radical scavenging activities. GA is involved as a nanomaterial for the preparation of anticancer nano-pharmaceuticals, e.g., gold nanoparticles and selenium nanoparticles. GA decreased the colonic mRNA levels of the angiogenetic factors and diminished ss-catenin expression. [59,69,79,92,93] Dermatological activity It is used as an antiallergic, smoothing, protective, binding, and/or stabilizing agent in cosmetic preparations. It has an anti-inflammatory effect against Kwashiorkor skin lesions and decreases skin inflammation (redness).
[ [94][95][96] Water and electrolyte up-taking GA increases water and electrolyte movement from the intestinal lumen to the bloodstream. [97] Gut probiotic effect GA increases the growth of colonic beneficial strains of Lactobacillus and Bifidobacterium. GA selectively nourishes gut microbiota and aid to produces short-chain fatty acids, especially butyrate, and inhibits pathogenic organisms, e.g., the Clostridium histolyticum group, that are commonly associated with gut dysbiosis. [98,99] Dentistry applications It upgrades dental re-mineralization and has some antimicrobial effects. It showed antiplaque on the gums and teeth and anti-gingivitis actions. [68,100] Besides various pharmacological applications of A. seyal, it also has diverse applications in the pharmaceutical and food industries. Table 4 summarizes various pharmaceutical and food applications of A. seyal. Table 4. Importance of gum Arabic in food and pharmaceutical industries.

Industrial Relevance
Its Role Refs.

Adjustment of medication delivery
GA microspheres facilitate absorption and expand the bioavailability of drugs. [101] Nanotechnology GA is a renewable, biocompatible, biodegradable, and non-harmful nanomaterial. GA has the optimum capacity to experience simple synthetic alterations with higher economic values. [102]

Industrial Relevance Its Role Refs.
Additive in Food and pharmaceutical industry GA has many applications as an emulsifier, stabilizer, thickener, processing aid, firming agent, texturizer, adhesive, plasticizer, and formulation aid. GA protects against unstable oils and flavors from the development of rancidity and off-tastes.

Nutritive Value
A. seyal gum is composed mainly of a complex polysaccharide that contains a small number of nitrogenous compounds (proteins). Although it has a low nutritive value as an indigestible polysaccharide complex, it has significant nutritional value as a rich source of soluble dietary fibers. Polysaccharide contents of A. seyal gum have low caloric contents that are resistant to digestion by intestinal enzymes [73]. However, it can be fermented by colonic microflora to produce short-chain fatty acids, especially butyrate, with high medicinal values [56]. Furthermore, the soluble dietary fiber contents of A. seyal gum can retard the absorption of sugars and fats and consequently has antihyperglycemic and antihyperlipidemic activities [72]. Gum Arabic can absorb and retain a reasonable amount of water inside the gastrointestinal tract and, therefore, can aid digestion, improve gastrointestinal movements, treat diarrhea, and soften the hard stool (treats constipation) in addition to its ability to absorb heavy metals and bacterial toxin from the GIT and decreasing their passage into the systemic circulation. The soluble dietary fibers of gum Arabic has a prebiotic effect that can help the growth of probiotic microflora, e.g., Lactobacillus and Bifidobacterium [99].

Patent Literature
The following keywords, namely Vachellia seyal, Acacia seyal, seyal, and Vachellia, were selected for patent searching using free databases, such as Espacenet (https://worldwide. espacenet.com/patent/search), Patentscope (https://patentscope.wipo.int/search/en/search. jsf), and USPTO (https://patft.uspto.gov/netahtml/PTO/index.html) database). The keywords were entered into all fields/any field section of the databases on 15 November 2021. The number of references obtained by Espacenet (Vachellia seyal = 19; Acacia seyal = 469; seyal = 528; Vachellia = 61), Patentscope (Vachellia seyal = 28; Acacia seyal = 1058; seyal = 1162; Vachellia = 96), and USPTO (Vachellia seyal = 3; Acacia seyal = 474; seyal = 569; Vachellia = 68) were recorded. All the patent references were combined, and duplicate references were removed. The remaining patents/patent applications were segregated according to their patent family, and one patent of each patent family was analyzed because the specification of all members of one patent family remains the same. The patents/patent applications that explicitly/implicitly cover A. seyal were analyzed, and others were excluded. The patent summary, along with the applicant's name, filing date, priority country, legal status, and patent classification, is provided in Table 5. It claims a solid composition for intra-oral/buccal delivery of insulin encompassing insulin, a hydrophilic polymer (such as gum Talha or A. seyal) matrix, and a phospholipid (such as lecithin or phosphotidylcholin), providing insulin bioavailability of 5-20% [115]. It claims a sweetener composition comprising rebaudioside A (purity > 97%), erythritol, and a sweet taste improving polymer (such as gum A. senegal and gum A. seyal) or combinations thereof [116]. It claims an oral device to dispense substances in an oral cavity comprising a natural gum (gum Arabic such as A. senegal and A. seyal) or a combination of natural gum with a medicament [122].  It claims a plant proteoglycan (molecular weight of 900,000-3,500,000; total aldehyde content = 2.0 µmol equivalent/g or less) obtained from A.
senegal or A. seyal [132]. It claims a water-dispersible microencapsulated composition containing 10-20% of cannabinoid and at least one gum Acacia (A. senegal and A. seyal) for use as an ingredient in food and cosmetics [136].

Discussion
The traditional uses (Table 2), pharmacological relevance (Table 3), and the applications in food and pharmaceutical industries (Table 4) of gum Arabic, including A. seyal gum, make it a substance of high commercial importance. A total of 30 patents/patent applications on A. seyal gum belonging to 29 patent families were identified ( Table 5). The first patent related to A. seyal was published in 1892, wherein the 30th patent application was published on 2 September 2021. The inventions (patents/patent applications) of A. seyal can be categorized based on their utility.
Three inventions were related to the prophylaxis/treatment of kidney and bladder affections [107], angiogenesis inhibitors [118], and osteoporosis [120] using A. seyal or its equivalents. However, these publications [107,118,120] did not provide the utility of A. seyal with experimental evidence for all types of kidney/bladder diseases, cancers, and osteoporosis/bone diseases. This opens an area of research to assess the activity of A. seyal for different types of cancers, kidney diseases, and bone diseases.
Five inventions provided pharmaceutical compositions and devices containing A. seyal or its equivalents. These include patient compliant solid composition for intra-oral/buccal delivery of insulin [115], sweetener composition with improved palatability [116,117], an oral device to dispense medicament in an oral cavity [122], and dental synbiotic lozenge offering a controlled time-release of the prebiotics, and probiotic organisms [130]. There exist many non-compliant dosage forms and pharmaceutical devices of different drugs. Therefore, new formulations of such dosage forms utilizing A. seyal or its equivalents are foreseeable.
Two inventions were related to the agricultural applications of A. seyal, and its equivalents have been published. These were related to bloat-safe forage crops with altered nutritional value/increased disease resistance [109], and isolated plant gum polynucleotide or synthetic genes that help to improve gum Arabic production [110]. The authors trust that many new agriculture-related inventions on A. seyal are possible in the future.
The quality of A. seyal and its equivalents is important for consumer safety as it is used in the food and pharmaceutical industry. This problem has been solved by simple inventions that provide a method for determining the quality of gum Arabic using a nearinfrared spectrophotometer in a short time [133]. The gum of A. seyal encompasses many chemical constituents, which can be isolated. Accordingly, two inventions related to the process for preparing L-rhamnose [108] and recovering arabinose [114] from gum Arabic have been identified.
The publication of only 30 patents/patent applications during the period of 1892-2021 means a small work has been conducted on the inventions related to A. seyal. This creates a scope to develop more inventions related to A. seyal. The priority patent applications of the identified patents/patent application were filed in different countries (USA = 12; Japan = 5; China = 4; Germany = 2; Europe = 2; United Kingdom = 1; Australia = 1; Israel = 1; Canada = 1; Italy = 1). It is interesting to note that A. seyal is called gum Arabic, but no patent application has been filed from any Gulf/Arabic country. Accordingly, we anticipate A. seyal-related patent application filings from the Arabic countries.

Conclusions
The pharmaceutical/medicinal/traditional/cosmetic uses and nutritive values of gum Arabic from both A. senegal and A. seyal have pronounced the economic or commercial importance of these acacia trees. In Sudan (the main source of GA worldwide), A. seyal gum contributed an average of 10% of gum products until 2011. However, due to its availability and economic values, the average contribution percentage of A. seyal gum jumped to almost 60% within the last few years. This is the first review that reveals the inventions and patent data of A. seyal, which signals that a lot of innovations are possible for A. seyal related to the food/pharmaceutical/cosmetic industries and medical field. The authors recommend exploring these opportunities for the benefit of society.

Conflicts of Interest:
The authors declare no conflict of interest.
Sample Availability: Not applicable.