A Review of Recent Studies on the Antioxidant and Anti-Infectious Properties of Senna Plants

The use of phytochemicals is gaining interest for the treatment of metabolic syndromes over the synthetic formulation of drugs. Senna is evolving as one of the important plants which have been vastly studied for its beneficial effects. Various parts of Senna species including the root, stem, leaves, and flower are found rich in numerous phytochemicals. In vitro, in vivo, and clinical experiments established that extracts from Senna plants have diverse beneficial effects by acting as a strong antioxidant and antimicrobial agent. In this review, Senna genus is comprehensively discussed in terms of its botanical characteristics, traditional use, geographic presence, and phytochemical profile. The bioactive compound richness contributes to the biological activity of Senna plant extracts. The review emphasizes on the in vivo and in vitro antioxidant and anti-infectious properties of the Senna plant. Preclinical studies confirmed the beneficial effects of the Senna plant extracts and its bioactive components in regard to the health-promoting activities. The safety, side effects, and therapeutic limitations of the Senna plant are also discussed in this review. Additional research is necessary to utilize the phenolic compounds towards its use as an alternative to pharmacological treatments and even as an ingredient in functional foods.


Introduction
Senna-a genus belonging to family Fabaceae, subfamily Caesalpinioideae, tribe Cassieae ser. Aphyllae-has roughly 350 species of tree shrubs and subshrubs [1,2]. It was set apart from Cassia s. l. with the identification of three definite genera, viz., Senna, Cassia L. (s.s), and Chamaecrista Moench [3,4]. This genus can be found in wide-ranging habitats, in distinct climatic conditions, latitudes, and continents such as America, Africa, and Oceania and to a minor extent in Asia and Pacific islands [5]. Senna plants colonized forests (both humid and dry), deserts (both cold and dry), and rock outcrops [6]. Some ornamental species are widely used for landscape gardening due to the attractive yellow inflorescences and the high adaptability in terms of soil and environmental conditions [7]. Recently, some species from desert climates were proposed to prevent or block desertification in arid zones. The use of Cassia species is reported in the ancient Ayurvedic literature as a laxative, antimalarial, relaxant, and anti-inflammatory [8]. To date, the genus is also commonly recognized for its biologically active compounds and medicinal properties [9,10].
The cosmopolitan presence of the Senna genus and its medicinal properties lead to its various traditional medicinal uses and health-promoting effects. These beneficial effects of the Senna genus are contributed by the diverse group of phytoconstituents present in its leaves, stem, and seeds. By phytochemical research, more than 350 compounds were extracted from Senna, together with forty secondary metabolites extracted from Senna spectabilis (DC.) H.S.Irwin & Barneby. These phytochemicals majorly included classes of pentacyclic triterpenes and piperidine alkaloids displaying health-promoting properties [11]. Many of the parts such as leaves, pods, roots, and fruits of the natural plants have beneficial pharmacological properties against diseases. The studied pharmacological activities of Senna plants include anti-infectious, antioxidant, anticryptococcus, antitumor, antimutagenic, antiplasmodial, anti-inflammatory, anticancer, antidiabetic, wound healing, and antihelmintic activities [12,13]. Some studies have shown the antidiabetic activity of Senna plants due to the content of phenols and flavonoids [14]. The antidiabetic effects have as mechanisms the decrease of the expression levels of different adipokines and the reduction of glucose absorption [15].
Its anti-infectious and antioxidant properties are established using various experiments, i.e., in vitro or in vivo.
The current review is focused on the traditional medicinal uses, phytoconstituents, antioxidant and anti-infectious properties, clinical trials, and toxicological data of Senna species.
in which it grows naturally. Giving a unique description of general botanical characteristics is tedious given the numerous species included in this genus. Senna has paripinnate compound leaves, with leaflets facing opposite, and globose, cylindrical, or clavate glands on rachis, petiole, or stalk [18]. The flowers are generally yellow and appear in dense racemes. It has large, lateral, terminal inflorescences with branched leafy panicles and can be up to 15-30 cm long. The flowers have fragrance and are made of 5 bristly bracts that usually are oval, 4-5 mm long, and caduceus and pedicles (2-3 mm). The sepals/calyx are unequal, oval to circular, coloured yellow-orange, and 5-7 mm long in size. The flower has 5 (uneven) golden-yellow-coloured petals and an ellipsoidal or spoon-like structure and is 2-3.5 cm in length. Anthers are opening by apical pores and a slit. It has sterile stamens that are 7 large and 3 small, while the pistil is curvy, slender, and hairless. The ovary is smooth and recurved with an inconspicuous style and stigma. The fruits of Senna are green in colour that turns black or dark with ripening, and their shape is cylindrical or column-like long pods. These pods are hard, end in a short, none splitting [7]. The size of the seeds is nearly 5 mm in diameter as they are brown coloured with flattened shapes.
The flowers of genus Senna present an interesting structural specialization that includes outstanding androecial diversity and several floral asymmetry patterns [7]. Classification of Senna flower traits becomes even more complicated due to its extraordinary level of specialization of the buzz-pollination. Ten stamens are present in heterantherous flowers of Senna, out of which 3 adaxial stamens are staminodial and the rest are fertile. These are further divided into two sets, viz., one set of four middle stamens from which the bees buzz and extract pollen, while another set includes 2-3 abaxial stamens, and the pollen from here is deposited on bees through the buzzing and is carried to the stigma of another flower [19]. Senna genus has 3-colporate pollen grains, ranging from size small to medium, and is euripalynic, radiosymmetric, and isopolar; however, the shape is oblates-spheroidic to prolate, nearly circular, and copli is long, subtriangular to triangular. Floral asymmetry is also due to the corolla and androecium. Extrafloral nectaries represent an "archaic feature" of numerous Senna species [5]. This appears in ca. 76% of the American species, several Australian species, scarcely in African, and none in Southeast Asian species. These glands secreting nectar can draw insects like ants that eat the nectar thus protecting the plant from the herbivores [20]. The fruits of Senna are long, enlarged, and tubular/cylindric, with the pods having 25-32 cm size, and the colour is black that has brown seeds equipped with pleurogram [11].
Senna can be propagated by seeds that remain viable for several years [21]. Most of the species of Senna require the scarification of the seeds to favour germination. The plant has numerous lateral roots and a robust primary root that contribute to the colonization of different substrates. Among the several species of Senna the series Aphyllae (Benth.) H.S.Irwin & Barneby is a taxonomically complex group of xeromorphic shrubs and subshrubs of the caesalpinioid legume Senna Mill., from arid, semiarid, and xerophilous areas of southern South America. Among all the Senna species, these seven are morphologically distinct. Fully grown mature plants are without leaves, and stems are junciform, green, and photosynthetic, while roots are woody and deep. These xerophytic attributes assist their survival in harsh conditions [22].
The monophyletic nature of Senna was revealed by phylogenetic investigations making it occupy the place next to Cassia sensu stricto and Chamaecrista [6], and all of these together form the subtribe Cassiinae are morphologically identified based on traits of their androecium, floral architecture, corolla, bracteoles, and fruits [23]. To date, taxonomy is not simply based on floral and vegetative characters, but on several other information, such as anatomy, cytology, serological, and molecular biology, that is useful for determining relationships and affinities among the Senna genus. DNA sequencing of various chloroplast gene sections of Senna plants (matK, rpL16, rpS16) depicted that majority of them are polyphyletic [5]. The chromosome counts exist only for about 20% of Senna species, with a prevalence of 2n = 28. There are also records of 2n = 22, 24, and 26 [24,25] [27]. Recently, Cordeiro and Felix [23] demonstrated that the karyotypic differences noted in Senna, either interspecific or intraspecific, are making this genus among the most representative taxa of the Fabaceae in several world territories [22].
Plants of Senna genus are present in all the tropical regions and grow well on wasteland, river banks, damp/ moist uncultivated fields, or similar areas in the low-lying coastal region; they also grow at places with altitudes up to 1000-1400 meters [28] (Figure 1).
Senna's evolutionary history is also linked to the arid lands that this genus currently populates, such as deserts and xerophilous regions of South America in southern Bolivia, southeastern Paraguay, and central and northwestern Argentina [22]. Several types of research conducted in plants of genus Senna, growing in diverse climatic conditions, revealed a variation in phenotype between individuals within species that could arise from phenotypic plasticity.
Geographical separation and/or morphological variation among individuals of Senna causes the formation of species and subspecies in a different habitat, thanks to the adaptive strategies. America has the majority of Senna species (74%), followed by Australia with 13 percent of species and Africa and/or Madagascar having 10 percent, while only a few species are obtained from Near East, South-East Asia, and on the Pacific Islands [29]. Soladoye et al. [30] reported about 19 species in the West African floristic region with the whole 19 species in Nigeria and at least 8 species in South-Western Nigeria, with a high variety in habits, ranging from trees (approaching 34 m in height) to prostrate annual herbs. There are about 18 species of Senna in southern Africa, of which the majority is naturalized, but only Senna italica subsp. arachoides (Burch.) Lock and Senna petersiana (Bolle) Lock are native [31].

Ethnobotanical Uses
Senna genus is widely used in southern countries in different spheres of life such as building, decoration, rituals, nutrition, poisons, and medicine. Some plants of Senna genus are used as building wood and as a shade plant and landscape ornamental [33,34]. S. alata bark decoction has been applied by the west and east Africans while tribal mark incision and tattoo was making on to the cuts [12].
In Uganda Senna obtusifolia (L.) H.S.Irwin & Barneby is used as a good luck charm before travelling [35]. Shoots and leaves of S. garrettiana and S. siamea are cooked in a dish called kaeng khi lek (a kind of curry) which is found in two forms-with and without coconut milk [33].
Other species consumed as boiled vegetables along with chili sauce include S. timoriensis for its tender leaves and flowers and S. sophera for its tender fruits and shoots [33]. The crude pounded bark of S. alata is used as fish poison [36]. And the most popular usage of Senna genus is as a traditional medicine used as a remedy for a vast range of diseases in various countries and cultures (Table 1).

Antioxidant Activity of Senna Plants
Antioxidants are chemical compounds which are naturally present in food and also in human body [173][174][175]. These substances play a vital role for preventing cell damage caused by oxidative destruction as a result of free radical generation [176][177][178].
According to the literature, there are different pathways to acting as antioxidant agents [179,180]: (1) Inhibiting the spread of free radicals or peroxide radicals by exchange of one or more protons (2) Reducing or blocking free radical formations with help of "metal chelating agents" (3) Reduction in reactive oxygen species (ROS) formation (4) Decreasing cellular ROS creation by hindering the oxidant enzymes (5) Influencing the complete antioxidant mechanism in the body by synergies of different antioxidant-rich ingredients ROS are considered causative for various detrimental effects and persistent diseases like cancer, cardiovascular diseases (CVD), neurodegenerative dysfunction, like Alzheimer's, Parkinson's, and Huntington's diseases, sepsis, and diabetes [181][182][183].
Neutralization of free radicals by the contained polyphenols justifies the antioxidant activities of the genus Senna. These polyphenols also quench singlet, and triplet oxygen, or decompose peroxides [187]. The antioxidant capacity and total polyphenol content of genus Senna were investigated by conducting both in vitro and in vivo experiments ( Figure 3).
Commonly used in vitro techniques for determining the antioxidant activities of extracts are DPPH (2,2-diphenyl-1picrylhydrazyl radical) and FRAP (ferric reducing antioxidant power) assay. The literature study indicates that various species under Senna genus were investigated using different methodologies, and they are indicated in Table 2. According to the study of Silva et al. [188] with four species of Senna from northeast Brazil, some of the phenolic compounds such as anthraquinones and flavonoids which are detected in the phytochemical screening especially in root extracts more than other parts can act as radical scavengers by donating hydrogen. They also mentioned that root extract of S. trachypus had a higher radical scavenging activity level than two standards (butylated hydroxyanisole (BHA) and quercetin) used in the assays.
Campos et al. [185] examined the chemical makeup of Senna velutina (Vogel) H.S.Irwin & Barneby leaf extracts (ethanol) and antioxidant activities with the DPPH method. In this study, IC 50 (minimum sample concentration needed for scavenging 50 percent free radicals) values of the extract of S. velutina leaf extract; ascorbic acid and butylated hydroxytoluene (BHT) were found (6.3 μg/mL, 2.6 μg/mL, and 21.3 μg/mL, respectively). This indicates that the antioxidant activity of S. velutina leaves is higher with a 3.5-fold than BHT but lower than ascorbic acid according to these results.
Ita and Ndukwe [189] studied the antioxidant activity of S. alata roots in different in vitro models. They used three different solvents such as acetone, ethanol, and water for  11 Oxidative Medicine and Cellular Longevity extraction and measured its ferric reducing power, DPPH, ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical-scavenging abilities, and metal chelating activity to determine antioxidant properties of roots. Researchers stated that ethanol extract had high amounts of total phenolics and flavonoids with values of 78.21 mg gallic acid equivalent (GAE)/g and 39.29 mg quercetin equivalent (QE)/g and exhibited the best antioxidant capacity in terms of DPPH and ABTS protocols. Besides, the aqueous extract showed more potential in metal chelating and reducing power. Khalaf et al. [88] analyzed the phenolic compounds, antioxidant, antimicrobial, and anticancer activities of S. italica aerial parts extracted using ethyl acetate and n-butanol. The researchers isolated and identified six compounds from this plant as they did bioguided fractionation. The names of these compounds are as follows: quercetin 3-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside (rutin), physcion, emodin, 1-hydroxy-2-acetyl-3-methyl-6-hydroxy-8-methoxynaphthalene (tinnevellin), 2-methoxy-emodin-6-O-β-D-glucopyranoside, and 1,6,8-trihydroxy-3-methoxy-9,10dioxo-9,10-dihydroanthracene. Antioxidant activity was measured with ABTS method, and the ethyl acetate and nbutanol extracts showed 82.9% and 85.7% inhibition against ABTS radical, respectively, in comparison with ascorbic acid (89.2% inhibition). According to the literature, anthraquinone compounds which are already in this plant are given to their antioxidant potentials. Therefore, the researchers said that these anthraquinone-rich extracts (ethyl acetate and n-butanol) might be the reasons behind the high antiradical capacity. At last, it is noted that the aerial parts of S. italica may possess antioxidant activity and can serve as natural sources of antimicrobial and anticancer factors.
Phaiphan and Baharin [190] focused on determining effects of various extraction methods on some bioactive properties of S. siamea leaf. Researchers focused the study on comparing the solvent extraction with that of ultrasound-assisted extraction with regard to total phenolic content and antioxidant and antibacterial activity. In solvent extraction and ultrasound-assisted extraction (UAE), ethanol/water mixture (49%) and ethanol/water mixture (40%) were used, respectively, under the optimized conditions which were predetermined. The study showed that extracts from the ultrasound-assisted extraction had higher yield, total phenolic content (TPC), and antioxidant activities than those acquired from the solvent extraction. Furthermore, UAE extracts had greater antibacterial activity compared to solvent extracts. This can be attributed to the fact that the cavitational effect caused by ultrasound resulted in a more porous cell wall causing more release of phenolic bioactive in the solvent. It is evident from the literature that higher concentrations of bioactive have a direct correlation with antioxidant activity and antimicrobial activity. Similarly, Laghari et al. [191] investigated the comparison between 5 different extraction methods (microwave, Soxhlet, marination, reflux, and sonication) during the extraction of flavonoids to evaluate the antioxidative properties of S. alexandrina. As a result of this study, a greater quantity of flavonoids was obtained with microwave extraction in the aqueous ethanol (70%) fractions of S. alexandrina flowers and leaves.

Leaves-ethanol
Chemiluminescence measurement [192] Senna alata (L.) Roxb. Root, stem, seed, leaves and flower-methanol/water FRAP-Folin-Ciocalteu FRAP (g/100 g) TPC (g/100 g) [195] Root  14 Oxidative Medicine and Cellular Longevity In some of the studies, the antioxidant activity of some plants is compared with each other. In a study, five different medicinal plants (S. alata, Eleusine indica (L.) Gaertn., Eremomastax speciosa (Hochst.) Cufod., Carica papaya L., and Polyscias fulva (Hiern) Harms) collected from Cameroon were examined according to their scavenger activities against superoxide anion and hydrogen peroxide [192]. The results show that S. alata plant extracts at less than 12.5 μg had the best scavenger activity with a 67% reduction in luminol-amplified chemiluminescence signal.
Navarro et al. [193] obtained and characterized (UPLC-DAD-EST-TQ-MS) phenolic extracts from Petiveria alliaceae L., Phyllanthus niruri L., and S. reticulata. Researchers also evaluated the antioxidant potential via conducting DPPH and ORAC (oxygen radical absorbance capacity) assay, and TPC was measured by the Folin-Ciocalteu method. Correlation analysis was carried out as well. It was reported that P. niruri has the highest phenolic content with 328.8 GAE/g, followed by S. reticulata with 79.3 GAE/g. In addition, P. niruri exhibited the best DPPH and ORAC values among these three plants. About the phenolic acid's characterization, for S. reticulata, the main compound was ferulic acid (52.6%) followed by 4-hydroxybenzoic acid, caffeic acid, vanillic acid, p-coumaric acid, and protocatechuic acid. S. reticulata had IC 50 of 72.9 μg/mL for DPPH and 2.68 mmol Trolox equivalents (TE)/g for ORAC. It was concluded that as TPC and UPLC increased ORAC values increased indicating a strong correlation.
Mak et al. [194] investigated the antioxidant capacity and antibacterial properties of ethanolic and distilled water extracts of hibiscus (Hibiscus rosa-sinensis L.) and S. bicapsularis flower. DPPH radical scavenging activity and FRAP were used as antioxidant assay while total phenolic content was analyzed by using the Folin-Ciocalteu method. DPPH inhibition values were 99:51 ± 0:2 for ethanol extracts and 96:51 ± 0:3 for aqueous extracts. The FRAP values found in the study were like 2403:15 ± 307:3 μmol Fe (II)/100 g for ethanol extract and 1966:30 ± 12:7 for aqueous extract. Total phenolics were also determined in the study, and results are as follows: 26223:78 ± 450:3 mg GAE/100 g for ethanol extract and 9468:18 ± 91:9 mg GAE/100 g for aqueous extract. Researchers stated that these results were significantly different from each other and the other hibiscus flower extracts. Similarly, too many studies in literature, Cassia flower extracts (ethanolic) exhibited the highest TPC, total flavonoid, and flavonol content, which in turn had the highest DPPH radical scavenging activity. In addition to that, they suggested that all hibiscus and cassia flowers-because of their significant antioxidant activities-can be used as a natural preservative in formulations of new and creative functional products or nutraceuticals.
Channa et al. [195] studied medicinal properties, biochemical parameters, and antibacterial activity of S. alata's various sections such as roots, stem, seed, leaves, and flower. To analyze the antioxidant capacity, the FRAP method was chosen and 80% methanol-water was used as a solvent. Researchers noted that the seeds were found rich in phenolic compounds compared to other parts. The seeds of S. alata contained a sufficient amount of total flavonoid whereas the leaves of the plant were quite rich in tannins. However, flowers were found the strongest antioxidative content. As a result, researchers suggested that these extracts have important potential for health benefits, so the plant needs to be isolated and test in detail.
Madubunyi and Ode [196] investigated the antioxidant potential of the S. singueana leaves with an in vivo malondialdehyde test. Malondialdehyde is an oxidative stress marker which is the end product of lipid peroxidation in the cells. In this study, all doses (0.25, 0.50, and 1.00 g/kg feed) of S. singueana extract significantly decreased malondialdehyde (MDA) level in the blood samples of test rats in comparison to the control group up to day 56. Similar to that study, treating rats using the methanolic extract of S. singueana root extracts was able to decrease malondialdehyde levels, the same as aspartate aminotransferase, alanine aminotransferase, and bilirubin level which are the indices of liver damage and lipid peroxidation, in all tissues especially in the liver and kidney [197].
7. Anti-infectious Activity of Senna Plants 7.1. Antibacterial and Antifungal. The most studied genus Senna for its anti-infectious activity was found to be S. alata. Different parts of S. alata are used as a vermicide, astringent, purgative, and expectorant and for treating skin diseases such as eczema, pruritus, itching, ulcers, scabies, and especially ringworm [198,199]. Other species having antimicrobial activity are S. spectabilis, S. alexandrina, S. occidentalis, S. podocarpa, S. tora, S. racemosa, and S. siamea. The bioactive substances that provide bioactivity to genus Senna are steroids, flavonoids, anthraquinones, anthrones, and miscellaneous other compounds. They are located in the leaves, stems, roots, flowers, bark, seeds, and fruits.
Especially antibacterial and antifungal activities of Senna extracts are obtained from the extraction of leaves mostly. In the studies generally, minimum inhibitory concentration (MIC) is calculated which is described as the smallest concentration of sample necessary to prevent microbial growth. The MIC value of 100-200 μg/mL is generally acceptable for plant materials [200]. Although the extracts of the parts of the genus Senna could not reach such MIC values, when the bioactive compounds are isolated from the extracts, MIC values decrease, and the antimicrobial properties increase [201]. Some of these bioactive components include stigmasterol, beta-sitosterol, kaempferol, luteolin, santal, alatonal, aloe-emodin, alquinone, chrysophanol, emodin, physcion, rhein, alarone, benzoquinone, coumarin, ellagitannin, naphthalene, phenolic acid, purine, xanthone, and cassine [202]. Anti-infectious effects of genus Senna are presented in Table 3.
The antifungal and antibacterial activity of the genus Senna varies depending on the species of the plant, the species of the microorganism, and the factors that affect the yield of the extraction process, such as the extraction method, the solvent used, the portion of the plant, and the secondary metabolite.
Ogunjobi and Abiala [203] investigated in vitro antimicrobial effect of different solvent extracts of S. alata leaves  [201] Antibacterial

Senna occidentalis
Whole plant ethanol extract ND [212] Klebsiella pneumoniae Agar disk diffusion method, zone of inhibition

Proteus mirabilis
The cup plate agar diffusion method

Senna occidentalis
Whole plant ethanol extract 7-10 mm [212] Pseudomonas aeruginosa The cup plate agar diffusion method

Senna italica
Aerial part-ethyl acetate extract 8.6 mm [88] Shigella flexneri The cup plate agar diffusion method

Staphylococcus aureus
The cup plate agar diffusion method

Streptococcus pyogenes
The cup plate agar diffusion method

Aspergillus niger
The cup plate agar diffusion method

Candida albicans
The cup plate agar diffusion method

Herpes simplex
Plaque-inhibition method, reduction factor was measured

Brassica chinensis
Percent inhibition germination at 10,000 ppm

Senna spectabilis
Leaf-dichloromethane 21 Oxidative Medicine and Cellular Longevity by using the agar well diffusion method. Except for Aspergillus niger inhibition, ethanol extract of S. alata showed a more inhibition zone than water extract. The best antimicrobial properties of S. alata ethanolic extract were shown in A. niger with a 25.2 mm zone of inhibition, and the least was Salmonella typhimurium with a 12.1 mm inhibition zone. Makinde et al. [204] research was about the methanolwater extract of S. alata leaves, and extract was assessed for antimicrobial activity by using a disc diffusion method (in vitro assay). The results indicated that S. alata leaves are more effective against fungi. S. alata phenolics and terpenoids, alkaloid salt, alkaloid base, and aqueous extract showed antimicrobial activity against Microsporum canis, Blastomyces dermatitidis, Trichophyton mentagrophytes, C. albicans, and A. flavus with 10-30 mm zone of inhibition. Phenolics and terpenoids, alkaloid salt, and alkaloid base extract of S. alata leaves had provided 5 mm of inhibition of S. aureus, Corynebacterium parvum, Nocardia asteroides, and Clostridium septicum; however, the aqueous extract had not shown antimicrobial activity of these bacteria. Phenolic and terpenoids and aqueous extract of S. alata leaf had 5-10 mm inhibition zone of Dermatophilus congolensis. Alkaloid salt and alkaloid base S. alata extract's inhibition zone of D. congolensis was 10-20 mm and 20-30 mm. Besides, S. alata antimicrobial activity was not observed against Proteus vulgaris and Bacillus pumilus.
Ehiowemwenguan et al. [205] examined the S. alata leaves and roots antimicrobial effect by using the cup plate agar diffusion method. Except for Streptococcus pyogenes, all inhibition zone is less than 5 mm; moreover, hot water extract, methanol extract, and acetone extract S. alata root and leaves did not differentiate among their inhibition zone. S. pyogenes had the highest zone inhibition at 5-6 mm both root and leaf extract independent of solvent type. S. alata root and leaves exhibited antimicrobial and antifungal reaction against E. coli, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella typhi, Shigella flexneri, S. aureus, A. flavus, A. niger, C. albicans, and Cryptococcus neoformans. S. alata root extract's MIC level was changed (5-8 mg/mL) for bacteria species except for S. pyogenes (3 mg/mL); however, fungi needed more concentration, approximately 25-50 mg/mL for inhibition except for C. neoformans (6 mg/ mL). The results of MIC level of leaves for bacteria were similar to root extract; yet, MIC range was between 6 and 10 mg/ mL for bacteria. The leaf extract MIC was 35-50 mg/mL except C. neoformans (13 mg/mL). The minimum microbial concentration of S. alata leaf extract for bacteria was determined between 6 and 10 mg/mL, and fungi had more minimum microbial concentration at 25-50 mg/mL except C. neoformans (13 mg/mL). The minimum microbial concentration of root extract results was similar to leaf extract except for S. pyogenes (3 mg/mL) and C. neoformans (6 mg/mL).
Channa et al. [195] also detected antibacterial activity in root, stem, seeds, leaves, and flower extracts (methanol, ethanol, and water) of S. alata. In this study, a good diffusion method was used, and the results were between 8 and 34 mm. The least inhibition zone, 8 mm, was observed against S. aureus and Klebsiella pneumoniae by root-methanol, root-ethanol, leave-ethanol, stem-ethanol, and stemwater extraction. The maximum inhibition zone was observed against E. coli by leaves-methanol extraction. Furthermore, the results showed that flowers and leaves of S. alata possess antibacterial activity as compared to commercial drugs such as ciprofloxacin, penicillin, ampicillin, tetracycline, and gentamicin.
Sule et al. [206] experimented to determine in vitro antifungal activities of S. alata crude stem bark extract by using the agar diffusion method. Zones of inhibition were observed at 5 mg/mL and 10 mg/mL ethanol solvent of S. alata crude steam bark except for T. mentagrophytes. T. mentagrophytes has the highest inhibition zone with 17 mm at 5 mg/mL concentration. The inhibition zone followed the order as Epidermophyton floccosum with 15.5 mm, Trichophyton verrucosum with 15.0 mm, and Microsporum canslaslomyces with 12.0 mm at 5 mg/mL concentration. T. verrucosum and E. floccosum showed the best inhibition of zone with 21.0 mm and 20.5 mm at 10 mg/mL concentration. M. canslaslomyces had again the least zone of inhibition with 13.50 mm at a concentration of 10 mg/ mL. However, a concentration of 10 mg/mL was effective against T. mentagrophytes with 19 mm inhibition of the zone. In addition, T. mentagrophytes was the only fungi that affected the inhibition at 2.5 mg/mL concentration with 10 mm zone. The MIC was evaluated at 5 mg/mL for all fungi. Minimum 5 mg/mL fungicidal concentration was appropriate for inhibition of fungi, except E. floccosum. The minimum fungicidal concentration of E. floccosum was determined at 10.0 mg/mL.
Abubacker et al. [198] conducted a study for in vitro antifungal properties of S. alata aqueous flower extracts, using three different fungal groups including fungi that produce aflatoxin (A. flavus and Aspergillus parasiticus), plant pathogenic fungi (Fusarium oxysporum and Helminthosporium oryzae), and human pathogenic fungi (C. albicans and Microsporum audouinii). The results highlighted the strong antifungal activity of S. alata. While 15 mg/mL of flower extract concentration provides 100% inhibition of all the fungus, 10 mg/mL was enough in inhibiting A. flavus. The MIC values of the flower extract of S. alata ranged from 5.75 to 8.0 mg/mL.
In a different investigation, Timothy et al. [207] assessed leaf extracts of S. alata (aqueous and ethanol) against five pathogenic fungi which are C. albicans, M. canis, T. mentagrophyte, Penicillium notatum, and A. niger. According to the calculated zones of inhibition, there was no inhibition 22 Oxidative Medicine and Cellular Longevity for water extract of leaves whereas ethanol extracts exhibited inhibition for all tested microorganisms. Furthermore, MIC of ethanol extracts for all tested fungi was lower than the water extract indicating that ethanol extract includes more bioactive compounds than the water extract. The reason ethanol is being more effective than the water was told to be because of the presence of anthraquinone which is not found in the water extraction. Intense antifungal activities of S. alata were depicted from the study outcomes. Wuthi-udomlert et al. [208] remarked on the importance of anthraquinone derivatives in the in vitro evaluation. Anthraquinone glycosides including emodin, rhein, and chrysophanol found in S. alata are the source of laxative effects. In the study, extraction of leaves is obtained in five different ways using anthraquinone aglycone, anthraquinone glycoside, anthraquinone aglycone from glycosidic fraction, crude ethanol, and anthraquinone aglycone from crude ethanol extract. Extraction yields were monitored by thin-layer chromatography, and the highest yield is obtained from crude ethanol extraction which was 34.94% w/w. As a result of the in vitro antifungal activity against Trichophyton rubrum, T. mentagrophytes, E. floccosum, and Microsporum gypseum by diffusion and broth dilution methods, anthraquinone aglycone from glycosidic fraction presented greater activity among five different extracts.
Phongpaichit et al.'s [209] experiment was about antifungal activities of S. alata and S. tora. Except Penicillium marneffei, 10 mg/mL methanolic extract obtained from leaves of S. alata and S. tora were enough in inhibiting all the M. gypseum, and T. rubrum. 10 mg/mL S. alata leaves inhibited only 77% of P. marneffei; still, S. tora extract was sufficient to inhibit all P. marneffei. In addition, IC 50 result of T. rubrum followed the order as S. alata at 0.5 mg/mL and S. tora at 1.2 mg/mL. S. alata with 0.8 mg/mL IC 50 value was the best inhibition for M. gypseum; also S. tora have an IC 50 value at 1.8 mg/mL. The IC 50 values of P. marneffei of S. alata and S. tora were 6.6 mg/mL and 1.8 mg/mL, respectively.
Malmir et al. [113] drew attention to the bioactive substance called "rhein" isolated from S. podocarpa root hydroethanol extract. In their study, S. podocarpa root extracts were evaluated for in vitro anti-Neisseria gonorrhoeae activity. Gonorrhoea is a widespread sexually transmitted infectious disease induced by N. gonorrhoeae bacterium infection. N. gonorrhoeae infects the mucous membranes of the reproductive organs that include the fallopian tubes, uterus, and cervix in women, while in men and boys it infects the urethra. N. gonorrhea can also harm the mucous membranes of the mouth, throat, and eyes [210]. S. podocarpa root demonstrated anti-N. gonorrhoeae activity against all strains. MIC ranged from 100 to 400 mg/L. The most active fractions having 50-100 mg/L MIC values, had rhein, emodin, chrysophanol, and physician as their key compounds as detected by LC-UV/DAD cochromatography with reference standards. Among all the isolates, rhein (MIC: 3.13 mg/L against all test strains) was the most effective. In addition to rhein, Sansores-Peraza et al. [117] highlighted the antibacterial and antifungal activity of cassine, isolated from S. racemosa, with MIC of 2.5 mg/mL against S. aureus and Bacillus subtilis and 5.0 mg/mL for C. albicans.
Albayrak et al. [211]  As a result of in vitro antibacterial analysis conducted by Jain et al. [212], although Klebsiella aerogenes exhibited resistance to all extracts, ethanol extracts of flowers and pods of S. occidentalis provide inhibition of growth of E. coli and P. vulgaris. In addition, a descending sort among bioactive compounds according to the antibacterial activities against test bacteria which are E. coli, K. aerogenes, P. vulgaris, and S. aureus was reported as anthraquinones>sennosides>flavonoids. Antifungal activity of ethanol extracts of S. occidentalis was found to be higher than the antibacterial activity. Among the metabolite-rich fractions, the maximum inhibition was shown by sennosides against A. flavus, followed by anthraquinones and flavonoids against Curvularia lunata. 7.2. Antiviral. Antiviral activity of genus Senna is generally found quite low; however, the extraction yield and the isolation of bioactive compounds provide an increase in the antiviral activity.
Jain et al. [212] investigated the antimicrobial, antitumor, and antiviral activity of ethanol extracts of S. occidentalis. They conducted in vitro analysis for antiviral and in vivo analysis for antitumor activity. The antiviral activity against Herpes simplex was quite inadequate; the reduction factor of titre was found 10 μg/mL. In addition, S. occidentalis did not exhibit any antitumor activity or cytotoxicity.
Another genus which is analyzed for the antiviral activity is S. alata. Shaheen et al. [215] determined the antiviral activity of methanol, chloroform, ethyl acetate, n-butanol, and aqueous extracts of S. alata by in vitro and in vivo experiments. The results justified the antiviral activity of Senna; all extracts exhibited antiviral effects against cardiac coxsackievirus B3. As a result of in vitro analysis, the therapeutic index varied between 0.2 and 12. In vivo, virus titer values were between 0 log 10 and 2.5 log 10 . Both in vitro and in vivo analyses exhibited that the most effective extracts against cardiac coxsackievirus B3 were aqueous extracts. 23 Oxidative Medicine and Cellular Longevity Woradulayapinij et al. [216] investigated in vitro HIV-1 reverse transcriptase inhibitory activity of ethanol and water extracts of aerial part of S. alata. Even though the results were quite close to each other, water extract depicted higher activity than the ethanol extract; inhibition ratios were 37 and 35.86% for water and ethanol extracts, respectively.

Antiprotozoal.
Numerous studies reported antiprotozoal activities of genus Senna. de Castro et al. [201] conducted a study about the schistosomicidal activity of S. spectabilis flower extracts. Schistosoma is an intestinal parasite that causes a chronic disease called Schistosomiasis. The disease has been reported in 78 countries; especially, 90% of the cases have been reported in Africa where access to safe drinking water is a challenge. According to the WHO [217], at least 229 million people needed the treatment of Schistosoma in 2018. de Castro et al. [201] extracted and isolated (-)-cassine and (-)-spectaline substances from S. spectabilis flowers. In vitro activity of extracts, their fractions, and the mixture of (-)-cassine and (-)-spectaline against S. mansoni worms were analyzed. Obtained data indicated that the mixture of (-)-cassine and (-)-spectaline exhibited a multitarget mechanism against the excretory activity, tegument lesions, and neuromotor activity. It also showed a toxic effect on the larval period of cercariae. Therefore, S. spectabilis flower extracts (-)-cassine and (-)-spectaline have a great potential for their schistosomicidal activity. Furthermore, de Albuquerque Melo et al. [218] mentioned about leishmanicidal activity of S. spectabilis and the two major alkaloidal metabolites (−)-cassine/(−)-spectaline. Caamal-Fuentes et al. [219] studied antiprotozoal properties of S. racemosa against Giardia intestinalis and observed that methanolic extracts of S. racemosa bark in both in vitro and in vivo experiments had activity against G. intestinalis [219,220]. Eguale et al. [221] mentioned the in vitro anthelmintic activity of S. occidentalis, and the extract concentration required to inhibit 50% (ED50) of the eggs of Haemonchus contortus was found to be 0.13 mg/mL and 0.17 mg/mL for aqueous and hydroalcoholic extracts, respectively.
A scheme with anti-infectious properties of Senna plants is summarized in Figure 4.

Other Biological Properties.
Villaseñor et al. [222] also conducted research on S. alata leaf extracts with hexane, chloroform, and ethyl acetate to investigate antimutagenic, antifungal, analgesic, anti-inflammatory, and hypoglycemic activities. Chloroform extract exhibited a reduction in the mutagenic activity of tetracycline by 65.8% at a dosage of 2 mg/20 g mouse as a result of the in vivo analysis. Against fungi, T. mentagrophytes chloroform extract was the most effective. The hexane extract was having the highest analgesic property which provides a decrease of 59.9% at a dosage of 5 mg/20 g mouse among other extracts. The analgesic activity of hexane extract was similar to the activity of mefenamic acid which is a widely known analgesic. For the antiinflammatory activity, all three extracts are observed hourly, for three hours. At the end of three hours, hexane and ethyl acetate extracts demonstrated 65.5% and 68.2% inhibition, respectively, at a dosage of 5 mg/20 g mouse. Ethyl acetate extract also showed hypoglycemic activity more effectively than the other extracts by providing a 56.7% reduction in blood glucose level.

Clinical Studies
Health-promoting effects of Senna and its other species have been evaluated by a large number of researchers around the world while clinical trials have been conducted in limited

24
Oxidative Medicine and Cellular Longevity cases (Table 4). Therefore, in this section, we are presenting quantified data on Senna and its clinical trials (previous and latest).
Mcnicol [225] performed a clinical experiment to evaluate the activity of tablets prepared using Senna (standardized preparation) on human bowel function and its possible side effects. The experiment was carried out in two phases: (a) first is the administration of the drug to 52 ward patients; (b) the drug was administered to 126 volunteer medical students. The Senna tablets were prepared in two different batches. The results demonstrated that the mean values for "speed of action" of Senna preparation (3 tablets) were recorded as 9.7 hours with ward patients and 12.15 hours among student volunteers, respectively. The frequency of griping, looseness of stool, and multiple bowel movements in ward patients have been recorded in dose-dependent patterns (increased with rising dosage). In addition, results confirmed that there is no significant difference between male and female responses. Thamlikitkul et al. [226] performed a randomized controlled experiment to evaluate the efficacy of S. alata against constipation. A total of 80 candidates participated in this study, and the differences observed between both groups (placebo & mist. Alba; and placebo & S. alata) were statistically highly significant (p < 0:001).
Kinnunen et al. [227] evaluated the safety and efficacy profile of laxatives containing Senna in treating constipation patients using lactulose as standard medication. The present study was carried out in a total of 30 patients (mainly bedridden due to degenerative diseases, age: 65-94 years). One week run-in without laxatives was followed by 5 weeks (a) of a daily dose of 14.8 mg (20 mL) laxative plus Senna or 20.1 mg (30 mL) lactulose and (b) crossed medicines (5-week period). The results indicated that bulk laxative plus Senna (14.8 mg dose) when given daily resulted in significantly (p < 0:005) more frequent bowel habits (4.5 vs. 2.2-19/week) compared to that of lactulose (daily dose of 14.8 mg). In other words, bulk laxative plus Senna produced efficiently treated constipation patients.
Damodaran and Venkataraman [228] from India reported the therapeutic effectiveness of S. alata leaves against Pityriasis versicolor in humans. The study was completed among 200 candidates (age: 16-60 years) of Tamil Nadu (Indian State) within 10 years. Different concentrations of plant extract (80%, 90%, and 100%) were used at affected areas (trunk, neck, hands, and face) of the body. The results indicated that S. alata leaf extract could be employed as a herbal remedy having no side effects, for curing P. versicolor.
Ramesh et al. [229] carried out a controlled comparative study of Misrakasneham (Ayurvedic formulation) and laxative Senna tablets (purified Senna extract) against opioidinduced constipation. Misrakasneham (a combination of 21 different types of herbs, castor oil, purified butter, and milk) is a centuries-old Ayurvedic medicine. The present study was conducted in 50 patients with advanced cancer aged 15 years and categorized into two groups (25 each). The first group received Misrakasneham while the second group received Senna tablets in three steps during the 14day study. The results demonstrated that 85% of the Misra-kasneham group and 69% of the laxative Senna group had satisfactory bowel movements with no statistical difference (p > 0:2). In addition, Misrakasneham data showed interesting results in terms of efficacy and was recommended as a possible candidate for opioid-induced constipation.
van Gorkom et al. [230] reported the effects of sennosides on histology of colonic mucosa and bowel preparation. In this experiment, a total of 171 candidates participated who were further split into two groups: (a) n = 84 candidates treated with 1 mL/kg of a syrup containing 2 mg/mL sennosides A and B and 3-5 L of a lavage solution and (b) n = 87 candidates treated with 3-5 L of lavage solution. The results demonstrated that both groups showed no difference in tolerance or quality of bowel preparation. In addition, group a (10/19) also showed a rapid increase of mononuclear infiltrate in the lamina propria compared to group b (2/21), respectively (p = 0:0005).

Safety and Side Effects
In traditional medicine, the leaves of Senna traditionally are used as laxatives in the form of pellets prepared with dried figs and plums. The anthraquinone laxatives like Senna are extremely useful drugs, but appropriate usage is highly important, although most of the reported side effects are mild and transit.
Senna is generally safe and well tolerated but can cause adverse events when it is used in high doses and for a long period ( Figure 5). Most of the adverse effects are mild and transient. The liver injury, including hepatotoxicity, has been reported in several case studies when Senna has been used prolonged, and the symptoms were mild-to-moderate in severity and solved rapidly with discontinuation [243][244][245]. In all cases, the correlation between side effects was explained by abuse of Senna in laxative purpose.
Derivatives of sennosides present in the leaves and pods may affect increasing irritability on the intestinal mucosa, which could cause abdominal pain and spasm in a sensitive person. It can also lead to diarrhoea, intensification of menstrual bleeding, and dark urine. It is recommended to take herbal tea or capsules/tablets/syrup of Senna in the evening before sleep, as effects start 6 to 12 hours later. Also, drugs that contain Senna are available in the form of rectal suppositories.
The prolonged use of Senna causing the spasm is the sign that it is necessary to stop future taken. In rare cases, vomiting and nausea may occur. Chronic use of Senna and other laxative herbs leads to increased potassium excretion, resulting in spasms, muscle weakness, and heart failure. However, in very well-explained patient conditions, these types of herbal drugs should be avoided. However, the full safety profile of these herbals is controversial like the opponent attitude of FDA and EMA regarding their consumption in some vulnerable groups of people.

Therapeutic Perspectives and Clinical Gaps
Traditional and modern medicines, in case of decreasing the intestine motility, take into consideration two classes of 25 Oxidative Medicine and Cellular Longevity

Senna
Control single-blinded randomized study Assessing the efficacy and safety of gum chewing added to high dose Senna before colonoscopy promotes bowel cleaning 129 candidates participated and were further divided into two groups (a) n = 65 patients treated with Senna solution (150 mL) and sennoside tablet (80 mg) daily for 3 days before the colonoscopy (b) n = 64 patients were additionally advised to chew sugarless gum half an hour (three times) daily for 3 days The results demonstrated that gum chewing enhanced colonoscopy bowel preparation quality and is considered a physiologically sound, safe, and impassive part of the colonoscopy bowel preparation. The gum chewing group showed better cleaning compared to other groups Turkey [234] Senna Placebo-controlled, double-blinded, randomized study Evaluating the use of Senna with docusate for constipation after pelvic surgery 96 candidates completed a baseline seven-day bowel diary pre-and postsurgery. After pelvic surgery, candidates were divided into two groups: (a) n = 45 in the placebo group and (b) n = 48 in Senna (8.6 mg) with docusate (50 mg) group. The findings demonstrated that the use of Senna with docusate decreases the time to first bowel movement in those undergoing pelvic surgery than placebo (3.00 vs. 4.05 days; p = 0:001).

Senna
Case study Case of a 31-year-old female patient who, after prolonged ingestion of Senna extract, developed severe weight loss, cyclic oedema, and dyspepsia, accompanied by an asymptomatic increase in markers of liver and muscle damage, dyslipidemia, electromyographic alterations, and mitochondrial myopathy in the muscle biopsy This clinical case is of particular significance, given that Senna is widely used for its pharmacological properties, with failure to consider its potentially toxic effects Portugal [236] Senna Single-blinded randomized study The effectiveness of Senna tables and sodium phosphate solution for bowel preparation before colonoscopy was examined for its efficiency A total of 134 candidates were treated with Senna tablets (180 mg) and sodium phosphate solution (95 mL) on the day before colonoscopy The results demonstrated that the mean cleanliness scores in the four segments of the colon (rectum, sigmoid segments, descending colon, and transverse colon) except the cecum were higher in the sodium phosphate group than in the Senna group (7.9 vs. 8.3, 8.0 vs. 8.5, 7.9 vs. 8.5, 7.9 vs. 8.2, and 7.2 vs. 6.9, respectively) The taste of Senna was more effective compared to sodium phosphate solutions Thailand [237] Senna tora (L.) Roxb.
Experimental study Supplementation of S. tora fibre on the serum lipid profile of diabetic Korean patients was evaluated. S. tora fibre supplement of a combination of soluble fibre extracted from S. tora (2 g), alpha-tocopherol (200 mg), ascorbic acid (500 mg), and maltodextrin (300 mg) was prepared in a pack and given to a total of 15 candidates 2 packs per day up to 2 months The results demonstrated that S. tora fibre products were safe for consumption and additionally provided the necessary amount of dietary fibre for helping in the maintenance of lipid status in diabetic (type II) patients Korea [238] Senna Controlled randomized single-blinded study Evaluating efficiency and acceptability of high dose Senna tablets and its comparison with standard polyethylene glycol in adult patients 192 patients participated and were treated into two groups: (a) n = 91 in polyethylene glycol group and (b) n = 101 in Senna group The Senna tablet group showed acceptable results for colon cleansing and tolerance compared to the polyethylene glycol group (p < 0:001) -

[239]
Senna Controlled study Highly purified Senna extract was evaluated against cell proliferation, crypt length in the entire colon and gene expression (p53 and bcl-2). 171 patients (84 with sennosidecontaining syrup and 87 without sennoside-containing syrup) were included 15 patients with Senna and 17 without Senna from 32 randomized patients were used for biopsies Proliferation activity in four areas of colon and gene expression (p53 and bcl-2) was evaluated by using 5-bromo-2′-deoxyuridine labelling, immunohistochemistry, and immunohistochemical The results demonstrated that crypts were shorter in the Senna group than without Senna group in the transverse and sigmoid colon. In the entire colon, the labelling index was higher in the Senna group than without the Senna group. In addition, bcl-2 expression was higher in both groups when crypts were shorter and proliferation was enhanced while no difference was recorded in p53 expression Netherlands [240] 27 Oxidative Medicine and Cellular Longevity curative substances: drugs that increase the volume of the gut contents and facilitate mass flow [246,247]. Among herbal substances, here, we have substances rich in sugars (dried plums and figs) and herbals with mucus, such as flax seeds. Another approach is medicines that contain substances that have a mild irritant effect on the intestinal mucosa to promote intestinal motility [248,249]. Among these remedies are the species from the genus Senna.
Genus Senna is well recognized as the most used laxative herbal treatment, also available without a prescription. Even before we knew its composition, Senna was used for centuries in phytotherapy for the same purpose. The main type of Senna genus used in medicine is S. alexandrina, known in commerce as Alexandria Senna, and Tinnevelly Senna [250]. Senna plants are widely used herbal medicine in the treatment of functional constipation. As the beneficial parts of the plant in phytotherapy, both the mature pods and the dried leaves are used. They contain natural chemical compounds, called anthraquinone, which are glycoside derivatives of anthracene, and the major compounds are sennosides A and B, which are available in the market [251]. The sennosides A and B have been broken down by the bacterial flora in the colon and result in the production of the main active metabolites rhein and rheinanthrone [252]. The working of anthraquinones includes the hindrance of NaCl absorption in the colon and the stimulation of Cl secretion, by inhibiting the (Na + , K + )-ATPase [253].
Additionally, S. alexandrina is used in case of bowel irritable colon, as a pretreatment before diagnostic tests like colonoscopy [254] and as a supplement for weight reduction [255]. While the treatment with active compounds from genus Senna is widely used in different laxative drugs taken orally in liquid or solid dosage forms, in the form of instant tea and herbal tea, however, there are controversies in their usage.
European Medical Agency (EMA) reference the use of Senna [256] only in cases of periodical constipation, while long term is not recommended due to acute dehydration which is followed by loss of electrolytes. Also, EMA do not recommend Senna in case of pregnancy, breast feeding, dehydration, different forms of intestinal obstructions, ulcers, and ulcerative colitis, inflammatory bowel disease including Crohn's disease, pain and spasm in stomach, unknown etiology, and rectal bleeding.
EMA does not recommend using the Senna as a laxative treatment in children under 12, but off-label use has been reported ( Figure 5). On the other hand, the USA Food and Drug Administration (FDA) prescribes 17.2 mg (7.5 to 30 mg) per day for people 12 years and older and 8.5 mg for children under 12 and allowing the usage of botanical laxatives containing Senna in children under 12. Based on a recently published review on Senna side effects as a longterm therapy in children by Vilanova-Sanchez et al. [257], Senna can be a safely employed option in treating functional constipation in children. However, more evidences are needed to confirm this conclusion and to change the attitude of EMA, who recently revised the herbal monography of Senna still stated that Senna is not recommended for children under 12 years [256].
Although some researches of Senna have found that it is effective in a short-term usage of constipation treatment in pregnancy [258][259][260] and does not have the teratogenic potential [261], intake of Senna during the pregnancy is allowed only in some countries like the USA.
Senna is still contraindicated by EMA recommendation because of experimental data that indicated possibly a A double-blinded, double-dummy, randomized, and controlled trial Trial registration: NCT01695850 The protocol evaluated the effectiveness of MaZiRenWan (MZRW) with laxative Senna for functional constipation 291 candidates were recruited, and after a 2-week run-in period, the suitable candidates were randomly grouped into the three viz (a) Chinese medicine arm (MZRW and western medicine placebo) (b) Western medicine arm (Senna and Chinese medicine placebo) (c) Placebo arm (Chinese medicine placebo and western medicine placebo) The results of the eight-week treatment showed the increased responder rate for a complete spontaneous bowel movement (CSBM ≧ 1/week) in the course of the treatment while the eight-week follow-up period showed changes of colonic transit, individual and global symptom assessments, and adverse effects China [241] Senna and MaZiRenWan (MZRW) (2nd phase) A double-blind, double-dummy, randomized, and controlled trial Trial registration: NCT01695850 Evaluating the efficacy and safety of Chinese herbal medicine MZRW and its comparison with the stimulant laxative Senna and placebo against functional constipation Primary and secondary outcomes demonstrated that the MZRW showed well-accepted effects in increasing complete spontaneous bowel movement per week compared to the Senna group (68.0% vs. 57.7%, with p = 0:14) during the treatment. After the eight-weekfollow-up period, 47.4% of patients had a complete response to MZRW, 20.6% had a complete response to Senna, and 17.5% had a complete response to placebo (p < 0:005 for MZRW vs. placebo) China [242] 28 Oxidative Medicine and Cellular Longevity genotoxic risk of several anthranoids, e.g., emodin and aloeemodin [262]. While the use of Senna in breastfeeding women is not recommended, there is evidence that anthraquinone drugs in lactating mothers do not carry a risk of producing a laxative effect in the infant [263][264][265]. However, there are available data from other studies in which laxative effect on the bowels was observed in infants [258]. Despite controversial findings, still, the official recommendation is to avoid the use of it. Senna should not be used for a longer period, no longer than 1-2 weeks, nor with medicines that lead to loss of potassium (diuretics, cardiotonic drugs, and corticosteroids). The caution should be exercised when used with antiarrhythmic and cardiotonic drugs and medicinal products inducing QTprolongation, as it may potentiate their effect. All of these effects are correlated with hypokalemia [266,267]. It has been found that usage of sennosides and digoxin in combination is linked with a modestly increased risk of digoxin toxicity in heart failure patients [268].
Particular attention, based on the animal studies, should be exerted in the patients with kidney and liver disorders during chronic use of Senna-based products [269]. Additionally, studies performed on rats showed that long-term administration of extracts of Senna does not promote gastrointestinal, liver, kidney, or adrenal tumors in the rats [270][271][272].

Concluding Remarks
This review showed that various parts of the Senna plant such as roots, stem, leaves, and seeds are traditionally used to treat many ailments and its extract has antioxidant, antimicrobial, and important health-promoting activities. These biological activities are attributed to the many phytochemicals contained in the genus Senna. Epicatechin, proanthocyanidins, scutellarein, rutin, and sennoides are just a few bioactive compounds of the genus Senna that are responsible for their bioactivity. Numerous studies in vitro and in vivo have been performed to establish the anti-infective and antioxidant properties of Senna extracts. Studies on the consumption of Senna over a period have shown that Senna is safe, but chronic use has adverse and limiting effects in medical practice. Among them, the laxative disease is a condition related to the massive use of Senna-based laxatives with an increased loss of potassium ions and the possibility of interaction with other drugs prescribed for heart disease. Based on the analysis of the studies selected in the study, this review opens new therapeutic perspectives of the Senna plant for antioxidant and especially anti-infective effects in the digestive tract.

Data Availability
The data supporting this review are from previously reported studies and datasets, which have been cited. The processed data are available from the corresponding authors upon request.