Introduction
According to the United Nations report, the global population of over sixty-five years old is expected to increase every year (Ref. Reference Nations1). The aging process increases the incidence and prevalence of age-related disorders in organs such as the eyes, intestines and brain, due to physiological factors. The main cause of aging-related diseases is an increase in intracellular inflammatory and immune response, which are highly correlated with an increase in oxidative stress. That is, oxidative stress induces the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κ B), interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF) α, cyclooxygenase (COX)-2, and inducible NO synthase to cause an inflammatory response, which can cause to cataracts, metabolic diseases, Alzheimer's disease, dementia, etc (Ref. Reference Chung2) (Fig. 1). Thus, it is growing interest to treat or prevent the age-related diseases.
An illustration of link between aging-related diseases and Cassia tora L. Aging changes pathological phenomena by induction of oxidative stresses and inflammatory responses thus causes to aging-related diseases including cataract, metabolic disease and neuronal disease, and Cassia tora Linn improves the diseases.
Phytomedicine is an herbal extract which is derived from a plant in whole or in part. It is generally more meaningful in the current medical system as it is a useful cause of an advantage over synthetic compounds in toxicity, and new interest has been established in finding the relationship between herbal extracts and disease prevention (Refs Reference Hwang3–Reference Benchennouf5).
Cassia tora Linn. (C. tora) is an annual plant involved in Fabaceae family and grows in Asia including, China, India and Nepal (Refs Reference Tzeng6, Reference Xie7) and its seed commonly drinks as a tea. Extracts from leaves and seed parts are using for medicinal activities such as anti-allergic, anti-asthenic, anti-oxidant, anti-hepatotoxic, anti-diabetic and anti-mutagenic (Refs Reference Tzeng6–Reference Park8). The cream containing C. tora improved the ultraviolet-induced psoriasis in rats (Ref. Reference Niculet9). Sushant Aryal et al., investigated the anti-oxidant potential activities of C. tora with IC50 = 9.898 μg/ml of DPPH radical scavenging activity and IC50 = 22.52 μg/ml of hydroxyperoxide scavenging activity (Ref. Reference Aryal10). Latestly, Khalifa Sam et al., screened the natural extracts or components for treatment of coronavirus infections, and C. tora was listed as a candidate for preclinical and clinical study (Ref. Reference Khalifa11). According to the different extraction solvents including acetonitrile, ethylacetate, 70% or 90% of ethanol and methanol, and parts of C. tora, such as root, leaves, stems and seeds, the major components are different like rotenoids, anthraquinones, naphthopyran glycosides naphthalene glycoside and ononitols (Refs Reference Sreelakshmi and Abraham12–Reference Ko15).
Effects of Cassia tora L. on aging-related diseases
Cataract
Vision is important throughout life, however as we age, functional impairments, including cataracts with clouding of the lens, can be appeared by oxidative stress, one of the major factors. Ethyl acetate extracts of C. tora leaves showed antioxidant effects on selenite-induced cataract rat model (Ref. Reference Sreelakshmi and Abraham16). The extracts decreased activities of myeloperoxidase and calpain which are catalyzer of reactive oxidant species (ROS) formation and increased activities of superoxide dismutase and catalase which are scavenger of ROS production. Also, selenite-induced lens damage was prevented by upregulation of cytochrome C oxidase 1 activity and ATP level as well as ubiquitin-activating enzyme (Ube)1 and Ube2 expression (Ref. Reference Sreelakshmi and Abraham16). Meanwhile ethyl acetate extracts of C. tora leaves including chrysophanol, emodin, kaemferol, quercetin, stigmasterol and isoquercetin reduced mRNA level of NFκB and early growth response protein (Egr)-1, and induced activities of superoxide dismutase, catalase and Na + K + -ATPase thus inhibited selenite-induced cataractogenesis in rat pups (Ref. Reference Sreelakshmi and Abraham12). It might be caused by acetate extracts enhanced reduced-glutathione level, and gamma glutamylcysteine synthase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase activities (Ref. Reference Sreelakshmi and Abraham17) (Figs 1 and 2, Table 1).
Therapeutic effects of Cassia tora L. on aging-related diseases. Cassia tora L. exhibits pharmacological activities for anti-cataract, anti-metabolic disease, anti-neuronal disease and others including anti-malaria, anti-bacterial, and anti-allergy by depletion of oxidative stresses and inflammatory factors. MPO, myeloperoxidase; CCO 1, cytochrome c oxidase 1; ATP, adenosine triphosphate; Ube, ubiquitin-activating enzyme; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; Egr-1, early growth response protein 1; STAT6, signal transducer and activator of transcription 6; LTB4R, Leukotriene B4 Receptor; BDNF, brain derived neurotrophic factor; ROS, reactive oxygen species; COX-2, cyclooxygenase-2; DPPH, 2,2-diphenyl-1-picrylhydrazyl.
Preclinical activities of Cassia tora L
Metabolic disease
According to the development of economics and expended life-span, patients with metabolic dysfunctions such as obesity and diabetes are emerged and increased. It is closely related with inflammation and immune responses as well as oxidative stresses (Ref. Reference Colca and Scherer18).
Ethanol (70%) extracts of C. tora seed ameliorated high fat diet (HFD)-induced obesity and -hyperlipidemia as well as -insulin resistance and secretion in mice model. Because hyperinsulinemia induced mitochondrial dysfunction in pancreas, treatment of ethanol extracts recovered the mitochondrial biogenesis of pancreas by increasing mitochondrial complexes expression and activity. It means that ethanol extracts of C. tora seed will be useful for treatment of type2 diabetes metabolic disease (Ref. Reference Ko15).
Ononitol monohydrate, a kind of glycoside form extracted from C. tora leaves inhibited lipid accumulation and adipocyte maturation by enhancing mitochondrial membrane potential (Ref. Reference Subash-Babu and Alshatwi13). In the adipogenic factors which are inflammatory mediators, adiponectin level was increased, and leptin, CCAAT/enhancer binding protein α and leukotriene B4 Receptor (LTB4R) levels were decreased. Ononitol monohydrate induced the expression of uncoupling protein-1, PR/SET domain 16, peroxisome proliferator activated receptor gamma coactivator 1 alpha and sterol-regulatory element binding protein-1C for adipocyte browning. Moreover, ononitol monohydrate suppressed signal transducer and activator of transcription (STAT) 6 and LTB4R expression which are involved in insulin resistance of adipocytes.
Ethanol (90%) extracts of C. tora seeds in a dose of 500 mg/kg reduced plasma and liver level of total cholesterol, phospholipids and triglyceride and induced post heparin lipolytic and lipoprotein lipase activity in both triton WR-1339-medicated acute and cholesterol rich HFD- induced hyperlipidemia rat model (Ref. Reference Awasthi19)
Ethanol (95%) extracts of C. tora seeds with orally administration of 500 mg/kg down-regulated levels of blood glucose, total cholesterol, phospholipid, triglyceride and free fatty acid and up-regulated post-heparin lipolytic activity (Ref. Reference Kumar20). In addition, ethanol extracts inhibited oxygen free radicals such as O2− anions and OH− radical by extracts treatment of 400 mg/kg, in vivo.
Anthraquinone and naphthalene derivatives containing 7-methoxy-obtusifolin, aurantio-obtusin, chrysoobtusin, obtusin, obtusifolin, emodin, physcion, chrysophanol, cassiaside, rubrofusarin-6-O-gentiobiosideol, obtusifolin-2-glucoside, chryso-obtusin-2-O-glucoside, cassitoroside, toralactone-9-O-gentiobioside, physcion-8-O-gentiobioside and glucoaurantio-obtusin from ethyl acetate and butanol fractions of C. tora seed significantly inhibited soluble epoxide hydrolase activity which is a key lipid mediator for vasodilatation, blood pressure regulation and heart dysfunction (Ref. Reference Lee21) (Figs 1 and 2, Tables 1 and 2).
Components from different solvents and parts of Cassia tora
Neuronal disease
As an aging society, neurodegeneration disease decreases the quality of life. Neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease are unavoidable progressions caused by oxidative damage, mitochondrial dysfunction, bioenergetic changes and neuroinflammatory responses (Ref. Reference Shamji22).
Ethyl acetate extracts of C. tora leaves inhibited acetylcholinesterase activity and fibrillations in vitro in doses of 20–100 μg/ml and 25 or 50 μg/ml (Ref. Reference Ravi23). In human neuroblastoma cells, SH-SY5Y and SK-N-SH, ethyl acetate extracts rescued the cell viability from the Aβ 1−42-mediated cell death and prevented the ROS production at 50 and 100 μg/ml (Ref. Reference Ravi23).
Chethana K. R reported that methanol fraction among methanol, n-hexane, petroleum ether and aqueous extracts from C. tora leaves exhibited inhibitory effects on acetylcholinesterase and butyralycholinesterase activities and fibrillation (Ref. Reference Chethana24).
Methanol extracts from C. tora leaves containing mainly flavonoids such as quercetin, rutin and kaempferol, and minorly phenolic compounds such as vanillic acid, gallic acid, p-coumaric acid and ferulic acid inhibited Aβ 1–42 aggregates formation of monomer, oligomer and fibril by quantifying of thioflavin-T assay in vitro at 100 μg/ml (Ref. Reference Ravi25), and reduced the time of escape latency, northwestern latency and time spent in the target quadrant and induced the number of crosses of the original platform location by analysis of Morris water maze tests in aluminium-induced Alzheimer's disease rat model at 100 or 400 mg/kg, daily for 60 days. Also, methanol extracts restored the locomoter and exploratory activities. Furthermore, it was recovered antioxidant enzyme activity such as catalase, glutathione peroxidatse and glutathione S-transferase and inhibited lipid peroxidation as well as acetylcholinesterase activity in hippocampus and frontal cortex. In the underlying mechanism, methanol extracts decreased the expression of inflammatory cytokines such as interleukin (IL)-1β, IL-6, TNF-α and increased brain-derived neurotrophic factor (BDNF) (Ref. Reference Ravi25).
Ethyl acetate or methanol extracts from C. tora leaves induced DPPH scavenging activity and reduced paraquat-induced Parkinson's disease cell model via inhibiting ROS production, cell death, DNA damage and lipid peroxidation (malanoldehyde formation) (Ref. Reference Ravi26) (Figs 1 and 2, Table 1).
Effects of Cassia tora L. on other diseases
Allergy
Allergy in the immune system is an acquired hypersensitivity response to external stimuli and substances, which can cause allergic asthma, conjunctivitis, rhinitis, urticaria, etc. Remarkably, mast cells show an important role in triggering immunoglobulin E (IgE)-mediated allergic reactions and its activation can be induced by interaction of allergen-IgE linked with high-affinity IgE receptor thus release inflammatory cytokines (Ref. Reference Shamji22).
Ethanol (95%) extracts (5, 10 or 20 μg/ml) from C. tora seeds extracts containing gluco-aurantioobtusin, gluco-obtusifolin, aurantio-obtusin, chryso-obtusin, obtusin and obtusifolin inhibited secretion of histamine, β-hexosaminidase (degranulation marker) and prostaglanding E2 (inflammatory arachidonic pathway product), and COX-2 expression and reactive oxygen species production in antidinitrophenyl-IgE-sensitised RBL-2H3 cells and dinitrophenyl-IgE-induced passive cutaneous anaphylaxis mouse in vivo (Ref. Reference Kim27). The inflammatory cytokines level such as TNF-α and interleukin-4 was decreased following the reduction of high-affinity receptor mediated cascades for the Fc region of Ig E. Furthermore, it was identified that aurantio-obtusin is the most active and major fraction component among the six compounds of extracts, and the activity of aurantio-obtusin at 20 μM was shown to clearly similar tendency in the above pharmacological examinations (Ref. Reference Kim27).
AF-343, a hot-water extraction mixture of Cassia tora L., Ulmus pumila, L., and Taraxacum officinale, and each mixture inhibited compound 48/80-induced degranulation and inflammation in RBL-2H3 cells by measuring β-hexosaminidase release and inflammatory cytokine production such as interleukine-4 and TNF-α (Ref. Reference Lee28). While AF-343 and each mixture induced 1,1-diphenyl-2picrylhydrazyl (DPPH) scavenging activity and reduced ROS production in compound 48/80-induced oxidative stresses of RBL-2H3 cells (Fig. 2, Table 1).
Malaria
Malaria which can be severe to death, is caused by the Plasmodium parasite, and infected female Anopheles mosquito transmitted to people by biting. P. falciparum and P. vivax are the most threat and prevalent on African continent and countries outside of sub-Saharan Africa (Ref. Reference Organization29). Rotenoids containing sumatrol, rotenone, tephrosin, rotenol, deguelin and elliptone were extracted from C. tora root under acetonitrile saturated with n-hexane and showed anti-larvicidal activity with LC50 = 120.61 ppm to larvae of A. stephensi (Ref. Reference Vats14). While fatty acid methyl ester fractions from C. tora leaves and stem inhibited the bacteria activities including methicillin-resistant staphylococcus aureus, methicillin-sensitive staphylococcus aureus and bacillus subtilis (gram-positive) and pseudomonas aeruginosa (gram-negative) (Ref. Reference Shukla30). Ethyl acetate extracts which contained major active components aurantio-obtusin and obtusin from C. tora seed inhibited mosquito larvicidal activity to LD50 = 2.5 ppm (Ref. Reference Mbatchou31). (Fig. 2, Table 1)
Discussion and perspectives
From the querying in Pubmed for Cassia tora, the publications are only 120 although its high potential activities for anti-oxidants and anti-inflammation. With recent five years' publication, we found the major target diseases of Cassia tora Linn., such as cataract, obesity, diabetes, Alzheimer's disease, and Parkin's disease in vitro and in vivo preclinical studies which are highly related with aging-disease. Others were allergy, malaria and bacteria. For extending the clinical study, we may consider the toxicity. From the quantitative structure activity relationship study for hepato- and nephrotoxicity, chryso-obtusin, 1,7,8-methoxyl-2-hydroxyl-3-methyl-anthraquinone and chryso-obtusin-2-β-D-glucoside was supposed hepatotoxicity and 1,7,8-methoxyl-2-hydroxyl-3-methyl-anthraquinone, emodin, chrysophanol, aloe-emodin, rhein, rhein-8-O-β-D-glucoside, obtusifoline-2-O-β-D-glucoside and 9,10-anthracenedione were expected nephrotoxicity, and triptolide, a positive control, were showed renal and hepatic cytotoxicity (Ref. Reference Yang32). Especially emodin showed the IC50 = 139.90 μM or 88.97 μM of cytotoxicity in HK-2 normal kidney cells with single culture or co-culture, respectively and hepatoxicity in rat with 500 mg/kg orally by induction of CYP3A and depletion of GSH levels (Refs Reference Yang32, Reference Jiang33). While ethanol extracts from C. tora seeds also was evaluated no toxicity in rat with oral administration of 500, 1000 and 2000 mg/kg/day for 13 weeks (Ref. Reference Lee34).
Additionally, more preclinical evidences are required such as pharmacokinetic and pharmacodynamic analysis based on the standardisation of extraction methods, and efforts are needed to modification of formulation for improving the solubility. Then it could be successfully applied for the prevention and therapy of aging-related diseases.
Search strategy and selection criteria
This review was prepared by searching in PubMed with the query key words: Cassia tora and Cassia tora Linn. The search was conducted for research articles including in vitro and in vivo preclinical reports, up to 15 June 2022 within the past five years.
Acknowledgements
This work was supported by a Korea Innovation Foundation (INNIPOLIS) grant funded by the Korean government (Ministry of Science and ICT) through a science and technology project that opens the future of the region, grant number: 2021-DD-UP-0380, and the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (No. 2022R1A5A2029546 and No. 2022R1A5A8033794).
Authors’ contribution
SYH, CSN and BCM contributed to the literature search and collection of articles, assisted with designing the figures and writing; MHL and JHS designed the structure of manuscript, edited the manuscript, supervised the studies and allocated the funding.
Conflicts of interests
No potential conflicts of interest are disclosed.
