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REVIEW ARTICLE
Year : 2023 | Volume
: 9
| Issue : 4 | Page : 369-398
Phytochemistry, pharmacology, and clinical applications of Centella asiatica (L.) Urban
Zhong-Hong Yan1, Xing-Yang Shi1, Hai Jiang2
1 School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, 150040, PR China
2 Key Laboratory of Chinese Materia Medica, Heilongjiang University of Chinese Medicine, Ministry of Education, Harbin, 150040, PR China
Correspondence Address:
Prof. Hai Jiang
Heilongjiang University of Chinese Medicine, Harbin
PR China
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/2311-8571.376900
Centella asiatica, a traditional Chinese medicine belonging to the Umbelliferae family, was recorded in the Eastern Han Dynasty. Owing to its wide developmental prospects, many scholars have extensively explored C. asiatica and made significant progress in recent years. In this study, we summarize the phytochemistry, pharmacology, and clinical applications of C. asiatica (L.) Urban based on Google Scholar, PubMed, and CNKI databases. Triterpenes and their glycosides, flavonoids, terpenoids, and volatile oils occur in herbs. The pharmacological effects mainly comprise improving cognition and memory impairment in Alzheimer's disease and anti-inflammation activity. Clinical applications include the treatment of chronic kidney diseases, malignant intestinal obstruction, radiation dermatitis, precancerous lesions, chronic prostatitis, Alzheimer's disease, and other diseases. This review provides insights into the phytochemistry, pharmacology, and clinical applications of C. asiatica and summarizes the shortcomings of the research in recent years to provide a reference for future research.
Keywords: Clinical applications, pharmacology, phytochemistry, review
Centella asiatica (L.) Urban, commonly known as “Luo De Da” or “Beng Da Wan,” belongs to the family Umbelliferae. It is widely distributed in South Central and southwest China, Japan, India, Indonesia, Malaysia, Sri Lanka, Oceania, Central Africa, and South Africa.[1]C. asiatica was first recorded in China in Sheng Nong's Herbal Classic. It grows in mountains and river valleys.[2] Li Chan, a famous doctor during the Ming Dynasty in China, summarized the main therapeutic effects of C. asiatica in his book Introduction to Medicine as follows, “Jixuecao is mainly used to treat all of the heat toxin, carbuncle-abscess poison, malign sore, rubella ringworm, acute febrile skin, children erysipelas with hot or cold, and heat bind in abdomen.[3]” The plant has a vast repository of compounds, including triterpenes, glycosides, flavonoids, terpenoids, and volatile oils, as confirmed by phytochemical screening.
C. asiatica was first listed in Chinese Pharmacopoeia in 1977. According to Chinese Pharmacopoeia, the plant is cold in property, bitter or acrid in taste, and distributed in the liver, spleen, or kidney channel. It is used in traditional Chinese medicine (TCM) for treating damp-heat jaundice, sunstroke and diarrhea, urolithiasis and blood strangury, carbuncle, and injuries from the impact and has effects such as clearing heat, removing dampness, detoxicating, and relieving swelling.[4]C. asiatica has been incorporated in medicines for chronic kidney diseases, malignant bowel obstruction, radiodermatitis, precancerous lesions, and chronic prostatitis and is also widely used in medical cosmetology and the production and processing of skin care products. In 2021, researchers found that the triterpenes of C. asiatica, 2,3-dihydroxyurs-12-en-28-oic acid, corosolic acid, and pomolic acid have a high binding affinity for the RdRp protein and can inhibit the replication of the novel coronavirus SARS-CoV-2.[5] In recent years, based on the pharmacopeia, academic papers, and some ancient Chinese medical books, scholars have made many discoveries in phytochemistry, pharmacology, and clinical applications of C. asiatica, illustrating the potential and developmental prospects in the resistance to novel coronavirus SARS-CoV-2.[5] This study aimed to review the progress in phytochemistry, pharmacology, and clinical applications of C. asiatica and identify loopholes and provide a scientific premise for future research on this plant.
PhytochemistryTriterpenes and their glycosides
The main components of C. asiatica are triterpenes and their glycosides, including triterpenoid saponins, triterpene acids, and triterpenoid steroids, which are mainly urosane-type and oleanane-type pentacyclic triterpenes. Triterpenoid saponins are common secondary plant metabolites that produce, via the isoprenoid pathway, hydrophobic triterpenes with hydrophilic sugar chains, the main component of C. asiatica with significant antibacterial activity. The content of triterpenoids in the leaves of C. asiatica is more than twice that in the petiole. In contrast, the content of triterpenes in the hairy root culture of hairy petiole root infected by Agrobacterium tumefaciens was 1.4 times higher than that in the leaf hairy root culture, and the yield of triterpenes in hairy roots of leaves and petioles was higher than that in adventitious roots. The hairy root culture of C. asiatica leaves and petioles could increase the content of triterpenoids in C. asiatica.[6] Ren et al.[7] isolated two ursane-type triterpene saponins, asiaticoside H and I, elucidated using 1D and 2D NMR and HRESIMS spectroscopic data and chemical derivation. Recent studies demonstrated that C. asiatica contains rare ginsenosides, such as Rk1, Rg5, and Rd2. Two dammarane saponins, centellosides A and B, and ginsenoside Rk1, ginsenoside Rg5, (20R)-ginsenoside Rg3, notoginsenoside Ft1, ginsenoside F2, (20S)-ginsenoside Rg3, notoginsenoside ST-4, ginsenoside Mc, ginsenoside Y, gypenoside ιβ, notoginsenoside Fe, ginsenoside Rd2, and gypenoside η were reported from whole plants of C. asiatica. Some of these compounds reportedly have remarkable antitumor effects on HepG2 (human hepatocellular carcinoma), K562 (human chronic myeloid leukemia), and BGC-823 (human gastric carcinoma) cells.[8][Figure 1] and [Table 1] summarize the triterpenoids and their glycosides from C. asiatica.
Figure 1: Structures of triterpenoids and their glycosides isolated from Centella asiatica
Table 1: Triterpenoid and its glycosides isolated from Centella asiaticaFlavonoids
In 2008, Subban et al.[26] first detected two flavonoids from C. asiatica, castillicetin and castilliferol. Li et al.[27] used several types of chromatography and referred to the physical and chemical properties and spectral data to study the chemical composition of C. asiatica. Patuletin was isolated from the plant and identified in this study. Research has been conducted on the isolation and structural elucidation of kaempferol, quercetin, astragalin, and isoquercetin from C. asiatica leaves.[23] The structures and details of these flavonoids are presented in [Figure 2] and [Table 2].
Terpenoids and volatile oil
C. asiatica is also an excellent source of terpenoids and volatile oils, such as β-caryophyllene, trans-β-farnesene, germacrene-D, and linalool. β-caryophyllene is the main active component of the volatile oil in C. asiatica and possesses antidepression activity.[29] The volatile constituents of C. asiatica are mainly monoterpenes (51.4%). Sesquiterpenoids account for approximately 41.9% of essential oils extracted from C. asiatica, which include elemene and β-caryophyllene.[30][Figure 3] and [Table 3] summarize the terpenoids and volatile oils found in C. asiatica.
Figure 3: Structures of terpenoids and volatile oil isolated from Centella asiaticaOther phytoconstituents
In addition to these major phytoconstituents, C. asiatica possesses other compounds with diverse biological activities. These include phenylpropanoids, polyacetylenes, phenolic acids, amino acids, tannic acid, vitamins, minerals, and alkaloids. Ravi et al.[26] isolated isochlorogenic acid from the whole plants of C. asiatica. 1, 3, 7, 9-tetrahydroxy-6H-dibenzo[β-D] pyran-6-one was isolated from C. asiatica. Dihydroartomunoxanthone, artonol A, cyclocomunomethonol, artochamin B, schweinfurthin E, and vedelianin have also been reported.[32] Araliadiol isolated from this plant has significant therapeutic effects against glutamate and tunicamycin damage in improving memory and cognitive abilities in mice.[33] Three polyacetylenes and their structures have been reported, including 6-acetoxy-trideca-1,7-dien-4-yn-3-ol (centellin), p-benzoyloxy methyl-butyl benzoate (asiaticin), and 1-(2',3'-dihydroxypropyl)-2-en3-methyl- 6-hydroxy-9-yn-undecanoate (centellicin).[34] Methyl 5-[(E)-9-hydroxy-1-(1-hydroxyhexyl)-2-methoxyundeca- 3,10-diene-5,7-diynyloxy] pentanoate, isolated from the aerial parts of C. asiatica, reportedly induced apoptosis independent of the cell cycle regimen in mouse lymphoma cells (P388D1) and reduced nitric oxide production in lipopolysaccharide-activated mouse macrophages with no measurable cytotoxicity.[35] The structures and additional details of other compounds are listed in [Figure 4] and [Table 4].
According to the current statistics on 137 compounds, the chemical constituents of C. asiatica are mainly triterpenoids and terpenoids, whereas flavonoids, polyenes, phenylpropanoids, and other compounds need to be further isolated and explored. In addition, the chemical composition and mechanism of action of C. asiatica can be further investigated and studied using molecular biology and network pharmacology, emphasizing the development of new active components and pharmacological effects. Finally, it lays the foundation for more effective and in-depth development and utilization of C. asiatica.
PharmacologyNumerous experimental studies have indicated that C. asiatica and its representative components exhibit potential effects on central nervous system disease and myocardial injury, delay the fibrosis process of many organs in the body, and show anticarcinogenic, anti-inflammatory, antibacterial, and antioxidative activities. Furthermore, C. asiatica can regulate the metabolism of skin tissue, treat wounds and ulcers, and accelerate wound healing.[38] Specific pharmacological effects are presented in [Table 5].
Effects on the central nervous system
Nootropic effects and restorative memory activity
Firdaus et al.[39],[40] found that the ethanolic extract of C. asiatica could alleviate D-gal-induced behavioral and cognitive dysfunction, thus reducing neurotoxicity. This ethanolic extract also protected the rat brain from AlCl3-induced cognitive dysfunction and reduced behavioral, biochemical, and neuroanatomical impairments, thereby reducing memory loss and cognitive impairment. Pham et al.[41] investigated the protective role of an n-butanol extract of C. asiatica against neurodegeneration caused by trimethyltin (TMT). This study demonstrated that C. asiatica extract treatment attenuated memory impairment in TMT mice and prevented neuronal damage in the CA1 and CA3 regions. In a previous study, Gadahad et al.[104] demonstrated that C. asiatica juice stimulated the proliferation and morphological changes of neuronal cells located in CA1 and CA3 in adult rats. Sirichoat et al.[105] reported that asiatic acid from C. asiatica improves hippocampus-dependent memory deficits through neuronal proliferation. C. asiatica extract may also prevent neuronal cell death or stimulate neuronal cell proliferation in the hippocampus of TMT-treated mice.
An increase in oxidative and endoplasmic reticulum stress is observed in the brains of patients with AD, and these factors may contribute to neuronal cell death and cognitive dysfunction. Ascorbic acid and resveratrol isolated from plants are antioxidants that enhance cellular antioxidant capacity by inducing mild oxidative stress; however, araliadiol inhibits reactive oxygen species (ROS) production and glutamate-induced cell death triggered by caspase-3/7. In addition, C. asiatica and araliadiol prevent tunicamycin-induced cell death, mainly by suppressing PERK phosphorylation. After 7 days of oral araliadiol administration, mice with cognitive impairment caused by scopolamine showed an improved arm alternation ratio in the Y-maze test. Araliadiol may have an effect similar to other polyalkynes owing to its polyacetylene structure, but its mechanism requires further study.[33]C. asiatica decoction showed significant spatial learning memory ability in an Alzheimer's disease mouse model by increasing choline acetyltransferase (ChAT) content, glutathione peroxidase (GSH-Px) activity, and malondialdehyde content in brain tissue.[42] Asiaticoside reportedly reduced interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels and promoted peroxisome proliferator-activated receptor-gamma (PPAR-γ) production in the hippocampus of Alzheimer's disease model rats. PPAR-γ protein is produced in patients with early Alzheimer's disease. PPAR-Î3 is an anti-inflammatory molecule. PPAR-γ production plateaus during the later stages of Alzheimer's disease.[43] Sbrini et al.[44] showed that long-term administration of C. asiatica increased brain-derived neurotrophic factor (Bdnf) expression in the prefrontal cortex. Bdnf is primarily involved in memory formation and neural plasticity. In addition, the increase in mBDNF protein level with increased Bdnf transcription in rats treated with C. asiatica proved that C. asiatica could effectively improve synaptic function, similar to the effect on mBDNF after long-term administration of the antidepressant duloxetine. In addition, rats administered C. asiatica for an extended period performed better cognitively in the novel object recognition test than untreated rats. The mechanism of caffeoylquinic acid and triterpenoids in C. asiatica in Bdnf regulation remains unclear and requires further investigation. According to Matthews et al.,[45]C. asiatica water extract exhibited effects on hippocampal-dependent memory and prefrontal cortex-mediated executive function.[45] The expression of synaptophysin and Psd95 in the hippocampus increased in response to compounds in C. asiatica, suggesting that triterpenoids may benefit synapses. In male mice with Alzheimer's disease, triterpenes and caffeoylquinic acid from C. asiatica help improve their conditioned fear response. Songvut et al.[106] found that C. asiatica extract significantly increased the choline levels. Cognitive and memory benefits have been proven to be associated with choline, an endogenous metabolite. The effects of C. asiatica extract on cognition may be mitigated by modulating human metabolites.
Cholinergic agents, such as acetylcholine precursors, acetylcholinesterase inhibitors, and selective cholinergic receptor agonists, are used to improve cognitive function in Alzheimer's disease. Some drugs can reduce β-amyloid polypeptide levels, which is the primary goal of treating Alzheimer's disease. However, there are no obvious therapeutic benefits.[107]C. asiatica contains several complex chemical constituents. Research has demonstrated that it improves cognitive and memory function at the biochemical, cellular, and behavioral levels. Further studies on the chemical constituents of C. asiatica in relation to Alzheimer's disease are warranted.
Improvement of cerebral ischemia–reperfusion injury
Zhou et al.[46] used the Rice–Vannucci method to establish a hypoxic–ischemic brain injury model. Asiaticoside ameliorated histological damage induced by hypoxia–ischemia in a dose-dependent manner, inhibited apoptosis, and reduced oxidative damage and levels of pro-inflammatory cytokines (intercellular adhesion molecule-1(ICAM-1), IL-18, and IL-1β) and Toll-like receptor 4 (TLR4). The decrease in Toll-like receptors and IL-18 inhibited the phosphorylation of nuclear factor-kappa B (NF-κB), decreased TNF-α, IL-6, and p-STAT3, and led to the inactivation of the NF-κB/STAT3 pathway. Zhang et al.[47] investigated the effects of asiaticoside on cerebral ischemia–reperfusion injury in vivo and in vitro. Asiaticoside could reverse neural function injury, brain edema, apoptosis, infarct size, apoptosis-related protein expression, and NOD2/mitogen-activated protein kinase (MAPK)/NF-κB signaling pathway protein expression in a rat cerebral ischemia–reperfusion model. Feng et al.[48] reported that rats treated with asiaticoside showed a reduction in caspase-3 and caspase-9 protein expression, oxidative stress, and hypoxic–ischemic brain damage. Wang et al.[49] found that asiaticoside could reduce oxidative stress response in Sprague–Dawley (SD) rats by upregulating nuclear factor-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) axis, so as to reduce brain injury. The Nrf2/HO-1 signaling pathway plays a key role in reducing oxidative stress. Zeng et al.[50] found that asiaticoside could maintain the normal morphology of brain cells after cerebral ischemia–reperfusion, reduce the volume of cerebral infarction, decrease the level of microglia activated by Iba1+ in the cerebral cortex, activate the Nrf2 antioxidant stress pathway, and inhibit the thioredoxin-interacting protein/NOD-like receptor protein 3 (NLRP3) pathway, reduce oxidative stress and inflammation, and cerebral ischemia–reperfusion injury.
The therapeutic effect of asiaticoside on cerebral ischemia–reperfusion injury may involve more mechanisms, which is worth further exploration to enrich the pharmacological mechanism of asiaticoside and lay a foundation for its clinical application. At present, studies at home and abroad have preliminarily verified the therapeutic effects of C. asiatica and asiaticoside on cerebral ischemia–reperfusion injury. However, they have mainly focused on in vivo effects, and the related therapeutic mechanisms still need to be verified in vitro. In addition, there may be additional mechanisms of C. asiatica in cerebral ischemia–reperfusion injury.
Protection and repair of the central nervous system
Wahab et al.[51] found that after treatment with C. asiatica, the levels of lactic acid, isoleucine, proline, methionine, valine, leucine, and glutamine were significantly increased in rats, suggesting that C. asiatica can promote neuronal activity, neurotransmitter synthesis, synaptogenesis, and antioxidant activity in the rat brain and promote the growth and development of rats. Nafiisah et al.[52] found a significant positive correlation between pyramidal apoptosis and Bcl-2 immune expression after craniocerebral injury in rats treated with different doses of C. asiatica. A study by Giribabu et al.[53] concluded that the water extract of C. asiatica could reduce the expression of inflammatory markers NF-κBp65, p-Ikkβ, Ikkβ, iNOS, COX-2, TNF-α, IL-6, and IL-1β; reduce the expression of apoptosis markers caspase-3, caspase-9, and Bax; and increase the expression of anti-apoptosis marker Bcl-2 and the activity levels of Na+/K+, Mg2+, and Ca2+-adenosine triphosphate (ATP) in the brains of diabetic rats. Thus, it can reduce inflammation and apoptosis in the brain of diabetic rats. Li et al.[54] confirmed that asiaticoside could increase the expression of cell proliferation marker protein Ki67 and anti-apoptotic protein Bcl-2 in the brain tissue of rats with focal cerebral infarction. Thus, it inhibited the activity of apoptotic protein Bax, inhibited the increase of mitochondrial cell membrane permeability, inhibited apoptosis, and released cytochrome C. It can also reduce brain injury by inhibiting oxidative stress in brain tissue. In addition, asiaticoside can activate the Phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, increasing the vascular endothelial growth factor level and promoting angiogenesis. According to Jia and Chen,[55] madecassoside decreased the expression of N-methyl-D-aspartate receptor 2 B subunit (NR2B), Excitatory neurotoxic injury molecules (pNR2B), caspase-3, and Bax and increased that of Bcl-2, alleviating excitatory neurotoxic injury and inhibiting apoptosis.
Apoptosis, a type of programmed cell death regulated by genes, plays an important role in the growth and development of multicellular organisms and the maintenance of the dynamic balance of cell numbers. Abnormal apoptosis often leads to structural and functional disorders.[108] The extracts of asiaticoside and madecassoside from C. asiatica can significantly inhibit the abnormal apoptosis of brain cells caused by traumatic brain injury, cerebral infarction, and brain injury caused by diabetes and promote angiogenesis. Its antioxidant effects also help to alleviate inflammation in the brain. Further studies are needed to determine the optimal administration time, route, and dose of related treatments.
Effect against myocardial injury
A study by Qiu et al.[56] found that asiatic acid significantly reduced myocardial infarct size and ischemic myocardial injury, improved cardiac function, and prevented cardiac death after myocardial infarction. It can also promote mitochondrial autophagy and alleviate mitochondrial edema, mainly characterized by increased myocardial mitochondrial phagosomes and mitochondrial light chain 3-II colocalization in cardiomyocytes treated with oxygen-glucose deprivation (ODG) in vitro. Zhang et al.[57] reported that asiaticoside increased the survival rate of H9c2 cells injured by oxygen–glucose deprivation/reoxygenation, inhibited apoptosis, protected cardiomyocytes from oxidative stress, reversed the decrease in glucose consumption and lactic acid production, and mechanically induced hexokinase 2 expression in H9c2 cells injured by oxygen–glucose deprivation/reoxygenation. Knockout of hexokinase 2 could block the protective effect of asiaticoside. Yang et al.[58] discovered that asiaticoside could maintain myocardial tissue structure, inhibit cardiomyocyte apoptosis, and delay the occurrence of myocardial infarction. Western blotting showed that asiaticoside reduced the levels of GRP78, PERK, CHOP, and caspase-12, suggesting that asiaticoside could reduce apoptosis by inhibiting the GRP78-PERK-CHOP pathway. CHOP promotes apoptosis by inhibiting Bcl-2. Asiaticoside reverses this process by protecting cardiomyocytes. Yang et al.[59] found that asiaticoside promotes cardiomyocyte proliferation, inhibits cardiomyocyte apoptosis, reduces myocardial oxidative stress, reduces the ratio of Bax/Bcl-2, p-ERK1/2/ERK1/2, and P-P38MAPK/p38MAPK, and reduces myocardial injury in rats with myocardial ischemia–reperfusion injury. Wang[60] reported that asiaticoside reduced the expression of TGF-β1 in the myocardium of rats with myocardial infarction, thus inhibiting the formation of collagen type I (ColI) and III (ColIII) in noninfarcted areas and controlling the progression of left ventricular myocardial fibrosis. However, it could not reduce the infarct size. Wang and Zhang[61] reported that asiaticoside could reduce the level of NF-κB in neonatal rat cardiomyocytes injured by ischemia and hypoxia, thereby reducing the release of inflammatory factors and formation of oxygen-free radicals and inhibiting cardiomyocyte apoptosis. In a study by Jin et al.,[62] asiaticoside increased the level of Nrf2 mRNA in cardiomyocytes of diabetic cardiomyopathy rats, inhibited the oxidative stress response downstream of Nrf2, reduced the expression of caspase-3 protein, improved the evaluation index of heart function and heart failure, and inhibited organic heart disease. Yang et al.[63] found that asiaticoside reduced Bax and caspase-3 mRNA and increased the expression of Bcl-2, Notch1, and Hes1 in a diabetic cardiomyopathy mouse model. Notch1 and Hes1 reportedly inhibit apoptosis and maintain cardiac structure and function in many ways.
Asiaticoside in C. asiatica can reduce myocardial oxidative stress, inhibit cardiomyocyte apoptosis, and protect the myocardial structure and function from multiple targets and links. Some studies have found that the asiaticoside content is highest in the heart of SD rats.[109] In recent years, there have been many experimental studies on the effect of asiaticoside on myocardial injury caused by myocardial infarction and diabetic cardiomyopathy. However, there is a lack of relevant clinical research and data support on the application of asiaticoside in myocardial injury. Related experiments and clinical studies are expected to follow up further to enrich and improve the therapeutic effect of asiaticoside on myocardial injury.
Effects on kidney
Relieving diabetic nephropathy
C. asiatica extract may inhibit renal damage in diabetic rats by inhibiting the increase in urine volume, glycosuria, and kidney weight.[64] In another report, C. asiatica downregulated the expression of TGF-β1, TβR1, TβR2, Smad2/3 mRNA, and phosphorylation of Smad2/3 protein; increased the expression of Smad7; inhibited the activation of TGF-β1/Smad signaling pathway; reduced renal interstitial fibrosis; and delayed the progression of diabetic nephropathy.[62] Currently, research on the mechanism of C. asiatica in treating diabetic nephropathy does not involve regulating blood glucose levels, and the pathogenesis of diabetic nephropathy is unclear. The therapeutic mechanism of C. asiatica in diabetic nephropathy requires further investigation. Crosstalk occurs between the Smad and non-Smad pathways in the TGF-β1 pathway. Further studies on the mechanism of C. asiatica on signal crosstalk between the TGF-β1/Smad and non-Smad pathways are of great significance for studying the role of C. asiatica in treating diabetic nephropathy.
Relieving renal ischemia–reperfusion injury
Arfian et al.[66] reported that C. asiatica extract could accelerate the transition from apoptosis, desquamation, lumen obstruction, and inflammation to the balance stage of apoptosis and repair of renal tubular cells, and reduce renal tubular injury caused by renal ischemia–reperfusion injury. C. asiatica extract can also downregulate the expression of TLR4 mRNA to reduce the accumulation of macrophages. TLR4 is an innate immune response that can cause inflammation in renal ischemia–reperfusion injury. Another study confirmed that asiaticoside reduces the levels of serum creatinine and urea nitrogen in renal ischemia–reperfusion model rats, reduces renal tissue injury, activates silent information regulatory factor 1-forkhead box O3-PTEN-inducible kinase protein 1-E3 ubiquitin ligase pathway, promotes mitochondrial autophagy, and reduces renal injury caused by renal ischemia–reperfusion.[67] In the future, it will be necessary to explore further the relationship between the specific degree of mitochondrial autophagy and ischemia–reperfusion time in renal ischemia–reperfusion injury and multiple autophagy regulatory pathways involved in renal ischemia–reperfusion injury, thereby providing new methods and ideas for the prevention and treatment of the renal ischemia–reperfusion injury.
Relieving renal injury caused by unilateral ureteral obstruction
Zhang et al.[68] showed that asiatic acid can improve renal insufficiency, renal interstitial fibrosis, and oxidative stress caused by unilateral ureteral occlusion by inhibiting TGF-β/Smad and Wnt/β-catenin signaling pathways. Thiazolidinedione and PPAR-γ agonists reduced renal interstitial fibrosis and inflammation by inhibiting the expression of TGF-β. In contrast, continuous use of the PPAR-γ antagonist GW9662 for 7 days counteracted the protective effect of asiatic acid on renal injury and fibrosis. Wang[69] showed that asiaticoside reduced the urinary protein content in rats with unilateral ureteral obstruction, increased the creatinine clearance rate within 24 h, reduced the expression of connective tissue growth factor, reduced the formation and deposition of renal interstitial ColIII, and improved renal interstitial fibrosis caused by unilateral ureteral obstruction. According to Feng et al.,[70]C. asiatica can alleviate tubulointerstitial fibrosis caused by unilateral ureteral obstruction by downregulating the expression of Smad3 in the TGF-β pathway and upregulating Smad7 protein expression with no obvious nephrotoxicity. Smad7 can be used as a TGF-β antagonist to inhibit the TGF-β/Smad pathway.
Inhibition of the TGF-β/Smad signaling pathway may interfere with the normal function of the body, but the research results are only from cellular and animal experiments, which are still far from clinical application.
Anti-inflammatory effects
Baby et al.[71] evaluated the anti-inflammatory activity of C. asiatica against human erythrocyte membranes in vitro by inhibiting hypotonic-induced erythrocyte membrane lysis. It was found that different concentrations of C. asiatica ethanol extract could effectively inhibit the thermogenic hemolysis of human erythrocytes. As the concentration of C. asiatica increased, the hemolysis rate of the membrane decreased and the stability of the membrane increased. The anti-inflammatory activity of the extract was concentration dependent. Praengam et al.[72] reported that C. asiatica inhibited the expression of IL-6, IL-8, and TNF-α in human intestinal Caco-2 cells after simulated gastrointestinal digestion in vitro and the formation of ROS in a dose-dependent manner. C. asiatica ethanol extract has anti-inflammatory and antioxidant activities in intestinal cells and maintains these activities even after digestion. Hernayanti et al.[73] studied the anti-inflammatory effect of C. asiatica extract in cadmium-induced hepatitis model rats. C. asiatica extract neutralized cadmium, reduced TNF-α and Cox-2 levels, increased glutathione and glutathione S-transferase levels, and reduced cadmium-induced hepatitis response. Yun et al.[74] found that madecassic acid can inhibit the activation of γT17 cells through the PPAR-γδ-PTEN/AKT/GSK3PTEN/AKT/γβ/NFAT pathway, reduce IL-17 levels in the colonic tissue of colitis mice, and improve colitis induced by sodium dextran sulfate in mice. Madecassic acid and other PPAR-γ agonists can be used to prevent and treat γδT17-related inflammatory bowel disease or other diseases. In another experiment, Cho et al.[75] reported that the methanol extract of C. asiatica significantly inhibited the production of nitric oxide and the expression of inducible nitric oxide synthase in RAW264.7 macrophages through the treatment of the middle cerebral artery. It downregulated the expression of cyclooxygenase-2, reduced the production of prostaglandin E2, reduced the levels of TNF-α and IL-6, alleviated LPS/D-GalN-induced acute hepatitis in mice, reduced the phosphorylation level of inhibitory κBα (IκBα) at Ser32/36, blocked the degradation of IκBα, and inhibited the phosphorylation of the TXY motif in the MAPK-activated ring. Further studies showed that the methanol extract of C. asiatica exerted anti-inflammatory effects by downregulating the IRAK1-TAK1 signaling pathway in mouse macrophages.
Yang[110] found that the main absorption window of madecassoside is in the small intestine, and the duodenum is the best absorption site. Xia and Dong[111] studied the absorption characteristics of madecassoside in each segment of the rat intestine. It was found that the absorption of madecassoside in the rat small intestine was greater than that in the large intestine, and its absorption rate was in the order of ileum > jejunum ≥ duodenum > colon. C. asiatica has a positive effect on digestive system inflammation, but the specific anti-inflammatory components of C. asiatica are unclear. The author speculated that treating digestive system inflammation, except in the colon, may be related to madecassoside, and madecassoside in C. asiatica is the key ingredient in treating colitis. However, there are few studies on madecassic acid in treating colitis. Therefore, further studies are required.
Effect on skin
One study showed that after administering C. asiatica extract cream to female rats, the average skin collagen content and moisture increased. The concentration and time positively affected the collagen level and hydration in female rats.[76] Lee et al.[77] found that the ethanol extract of C. asiatica attenuated skin inflammation in mice with atopic dermatitis induced by 2-dinitrochlorobenzene, mainly by reducing immune cell infiltration and Th1 and Th2 responses in subsequent atopic dermatitis, and interferon-γ/TNF-α, pro-inflammatory cytokines, and chemokines in keratinocytes. C. asiatica can also significantly inhibit histopathological changes in mice, including the expression of cytokines and the protein levels of TNF-α, COX-2, MAC-1, and IL-6. Another study reported that asiaticoside accelerated wound healing and collagen maturation and reduced scar formation in scalded rats by affecting the expression of heat shock protein 47. As a molecular chaperone of collagen, asiaticoside binds specifically to procollagen in the endoplasmic reticulum and participates in the folding, assembly, modification, and transport of procollagen, which is closely related to collagen synthesis.[78] Huang[79] found that asiatic acid could downregulate the expression of TNF-α in psoriatic mice induced by imiquimod, decrease the expression of the nuclear antigen PCNA, upregulate the expression of the apoptotic protein Bax, inhibit the proliferation of HaCaT cells induced by TNF-α, block the cell cycle in G2 phase, inhibit NF-κB phosphorylation induced by TNF-α, prevent its translocation into the nucleus, and increase the production of ROS in HaCaT cells, causing the mitochondrial membrane potential to collapse and inhibiting the formation of intracellular ATP from inducing apoptosis of keratinocytes. Zhang et al.[80] showed that asiaticoside could accelerate skin healing in diabetic skin ulcer model rats, produce more granulation tissue, and accelerate angiogenesis after granulation formation. On the 14th day, the damaged epidermis of the rats was nearly intact, and the fibroblasts in the effector cells proliferated rapidly.
In recent years, research on the effect of C. asiatica on the skin has mainly focused on inhibiting scar formation and promoting skin repair, and there are many studies on the related mechanism. C. asiatica has good antioxidant and anti-inflammatory effects. Some studies have also found that C. asiatica has a therapeutic effect on skin inflammation; however, there is still a lack of experimental research on treating dermatitis with C. asiatica and its active components, and the related pathways and targets still need to be explored.
Anticancer effects
Liu et al.[81] found that after asiaticoside acted on breast cancer MCF-7 cells, there were vacuoles, cytoplasmic spillover, and nuclear shrinkage. Another study reported that after the effect of C. asiatica on the human ovarian cancer cell line A2780, the cells shrank and became round. It could upregulate the expression of Bcl-2 mRNA and downregulate the expression of Bax mRNA.[82] 1, 3, 7, 9-tetrahydroxy-6H-dibenzo[β-D] pyran-6-one and other known components were isolated from the whole plant of C. asiatica. Liu et al.[83] evaluated the cytotoxicity of all isolates to four human cancer cell lines MCF-7, HepG2, HeLa, and A549. 1, 3, 7, 9-tetrahydroxy-6H-dibenzo[β-D] pyran-6-one is significantly cytotoxic to MCF-7 and HepG2 cancer cells, but there is no other literature on the pharmacological effects of this compound; therefore, the pharmacological effects need to be further studied. Liu et al.[84] found that asiatic acid reduced the viability of cisplatin-resistant nasopharyngeal carcinoma cell lines cis-NPC-039 and cis-NPC-BM. It is induced by apoptosis in a dose- and time-dependent manner through endogenous and exogenous apoptotic pathways, including changes in mitochondrial membrane potential, activation of death receptors, increased Bax expression, and upregulated caspase-3, caspase-8, and caspase-9. In addition, the phosphorylation of p38 is a crucial mediator of apoptosis induced by asiatic acid in cisplatin-resistant human nasopharyngeal carcinoma cells. Asiaticoside inhibited the proliferation of hepatocellular carcinoma cell lines QGY-7703 and Bel-7402 in a dose- and time-dependent manner. Asiaticoside significantly induced apoptosis in QGY-7703 and Bel-7402 cells. Treatment with asiaticoside also caused G1 cell cycle arrest in QGY-7703 and Bel-7402 cells. Western blot analysis showed that the potential mechanism of asiaticoside was related to the inhibition of PI3K/Akt and MAPK/ERK pathway activities. Asiaticoside can also antagonize P-gp-mediated multidrug resistance in hepatocellular carcinoma cells.[85] Wu and Jiang[86] found that asiaticoside inhibited the proliferation of human osteosarcoma Saos-2 cells, increasing the apoptosis rate and proportion of S-phase cells. It can also reduce the expression of phosphatidylinositol 3-kinase (PI3K), threonine kinase (AKT), p-threonine kinase (p-AKT), glycogen synthase kinase-3β (GSK-3β), and p-GSK-3β. In addition, asiaticoside had an antioxidant effect on Saos-2 cells. Jiang et al.[87] reported that madecassoside can induce apoptosis in human cervical cancer C-33A/CaSki cells, mainly by increasing the expression of Bax and downregulating the expression of Bcl-2 and Bcl-xl, destroying the outer membrane of mitochondria, and promoting the apoptosis of C-33A/CaSki cells.
Some of the active components of C. asiatica can promote apoptosis of tumor cells and inhibit drug resistance in vivo. There is abundant literature on the anticancer effect of asiatic acid. In recent years, many researchers have begun to study asiaticoside and madecassoside, but the mechanism of C. asiatica and its active components in some cancer cells and the drug resistance pathways are unclear. The anticancer effect of the newly isolated compounds from C. asiatica lacks theoretical support in the pharmacological literature related to this compound. The anticancer effect of C. asiatica may involve more pathways and targets, and further experimental studies are still needed.
Effect on bone
Wu et al.[88] applied asiatic acid to a femur fracture model mice for 8 weeks by subcutaneous injection and found that the mice were treated with complete bone scab formation at the fracture site, uniform density of bone trabeculae, complete mineralization of the fracture end, and improved biomechanical properties of the femur. Fu et al.[89] showed that asiaticoside reduces the apoptosis rate of chondrocytes induced by IL-1β and downregulates the expression of Bax, IL-6, and TNF-α by inhibiting the expression of miR-342-5p or AQP3. Hong et al.[90] found that asiatic acid can inhibit the differentiation of multinucleated tartrate-resistant acid phosphatase-positive osteoclasts and osteoclast-induced bone loss, reduce the expression of lower cascade target genes such as CTSK, NFATC1, Calcr, and Atp6v0d2, and inhibit NF-κB and NFATc1 signal transduction mediated by an NF-κB ligand–receptor activator. In vivo studies have shown that asiatic acid can reduce bone loss induced by estrogen deficiency in ovariectomized mice. Micheli et al.[91] found that C. asiatica extract 14G1862 reduced the production of nitric oxide and the expression of inducible nitric oxide synthase induced by lipopolysaccharide solution in vitro. In vivo, 14G1862 significantly reduced mechanical allodynia and hyperalgesia, spontaneous pain and motor alterations starting on day 14 up to day 60. Qiao et al.[92] found that oral administration of madecassoside significantly relieved the symptoms of collagen-induced arthritis in rats, but its primary metabolite, madecassoside, did not have this effect. Madecassoside also increased the number of Treg cells in the ileum, upregulated the expression of Foxp3 and IL-10, and reversed the changes in intestinal flora under arthritis. Lu et al.[93] showed that madecassoside could reduce the inflammatory response caused by the activation of the NLRP3 inflammatory complex and the joint action of NLRP3, ASC, and caspase-1. Caspase-1 can lead to the abnormal production and extracellular accumulation of IL-1β after activation, which aggravates the inflammatory response. Activation of the NLRP3 signaling pathway is related to gouty arthritis. Madecassoside can inhibit the expression of inflammatory factors, such as IL-1β, by inhibiting the NLRP3 inflammatory body axis and signaling pathway-related molecules to improve gouty arthritis.
According to TCM, C. asiatica is cold in property, bitter or acrid in taste, distributing to the kidney channel, clearing heat, removing dampness, detoxicating and relieving swelling, and can be used to treat bruises and injuries. This is related to modern research. It has anti-inflammatory properties, promotes fracture healing, and reduces bone loss. In the last decade, some scholars have also started to focus on the direction of C. asiatica in the treatment of osteoarthritic diseases, the research literature and experimental data are insufficient, and there is currently a good research prospect for this field, which we hope to pay attention to in future studies.
Effect on liver
One study showed that the alcohol extract of C. asiatica can inhibit the secretion of pro-inflammatory chemokines, cytokines, and apoptosis markers in hepatocytes by activating β2-adrenergic receptors, improving the secretion of pro-inflammatory factors and cytokines, and reducing hepatocyte apoptosis in rats under electric shock stress.[94] Akrom et al.[95] evaluated the hepatoprotective effect of chewable tablets of C. asiatica extract in high-fat diet-induced Wistar rats and found that chewable tablets of C. asiatica extract decreased serum triglyceride levels and SGPT activity. Huang et al.[96] observed the effect of asiaticoside on oxidative stress in a nonalcoholic fatty liver rat model. Middle and high doses of asiaticoside could reduce the expression of alanine aminotransferase (ALT), aspartate aminotransferase, TNF-α, and liver cytochrome P4502E1 in the serum, and a high amount of asiaticoside could antagonize the oxidative reaction of liver tissue. Lin et al.[97] found that asiaticoside could reduce the levels of serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, total cholesterol/high-density lipoprotein cholesterol, liver total cholesterol, and triglyceride in golden hamsters with hyperlipidemia induced by a high-fat diet. It also increased the levels of superoxide dismutase and GSH-Px in the liver and decreased the serum glutamic-oxaloacetic transaminase content.
Asiaticoside in C. asiatica can improve fatty liver caused by a high-fat diet and nonalcoholic causes; significantly reduce serum total cholesterol, triglycerides, and low-fat protein; reduce oxidation and inflammation in liver tissue; and reduce apoptosis in liver tissue. However, other components in C. asiatica may also play a role in improving fatty liver. The mechanism of C. asiatica extract and asiaticoside on the fatty liver is unclear, and the related pathways and targets need further exploration and confirmation.
Anti-fibrosis effects
Wang et al.[98] found that asiaticoside downregulated the expression of MMP-2, COL-I, COL-III, α-SMA, TGF-β1, p-Smad2, p-Smad3, and miR-564 in human hypertrophic scar fibroblasts; significantly reduced the proliferation and collagen secretion of hypertrophic scar fibroblasts; and promoted their apoptosis. Liu et al.[99] found that asiaticoside inhibited the proliferation of alveolar epithelial cells induced by TGF-β1, reduced the expression of vimentin, increased the expression of epithelial marker cadherin E, and downregulated the expression of nitric oxide synthase protein and the expression of IL-6, TNF-α, IL-4, and vascular endothelial growth factor, thus antagonizing pulmonary fibrosis. Zhu and Shen[100] found that asiaticoside significantly reduced the lung index and the expression of IL-6, TNF-α, IL-1β, and TGF-β mRNA in mice and rats with pulmonary fibrosis induced by pingyangmycin, maintained alveolar structure, and inhibited fibroblast proliferation and inflammatory cell infiltration.
Early studies have found that C. asiatica can delay or improve the fibrosis process of the lung, kidney, liver, skin, and other tissues, control oxidative stress in tissues, and inhibit the formation of fibroblasts and collagen. Related signaling pathways and target studies also improve, but the causes of fibrosis in some body organs are very complex. Because of the complex biological characteristics of tissues and cells and the complex internal environment in the body, the mechanism of C. asiatica in treating tissue and organ fibrosis still needs to be elucidated.
Antibacterial and antifungal effects
Bhuyar et al.[101] studied the antifungal activity of C. asiatica using disk diffusion and medium dilution methods. It was found that the methanol extract of C. asiatica had an inhibitory effect on fungal infections, especially on Candida albicans, Aspergillus niger, and Penicillium sp. Azmi et al.[102] used the liquid dilution method to determine the minimum inhibitory concentration of an ethanol extract of C. asiatica against Streptococcus pyogenes and Pseudomonas aeruginosa. The minimum bactericidal concentrations for S. pyogenes and P. aeruginosa were 60%. Zhang et al.[103] reported that the ethanol extract of C. asiatica had a strong inhibitory effect on the pathogenic microorganisms of many autoimmune inflammatory diseases. The chloroform and n-hexane extracts of C. asiatica also strongly inhibited the growth of Klebsiella pneumoniae. In a joint test with K. pneumoniae, the methanol extract of C. asiatica restored the significant growth inhibitory activity of chloramphenicol and tetracycline. In contrast, two antagonistic effects were found for the combination containing gentamicin, indicating that the combination of C. asiatica extract and gentamicin should be avoided in treating infections caused by K. pneumoniae. C. asiatica has a bacteriostatic effect on Staphylococcus aureus and Proteus. Asiaticoside has a strong bacterial scavenging effect on Escherichia coli in mice with ascending bladder renal infection and has good antibacterial activity in vivo and in vitro.[112] According to Chinese Pharmacopoeia, Sanjin tablets contain C. asiatica, mainly used to treat urinary diseases, such as cystitis and urinary tract infection.[4]C. asiatica extract also has a good inhibitory effect on some fungi, such as C. albicans, A. niger, and Penicillium, as well as bacteria, such as K. pneumoniae. However, due to the complex pathogenic processes and mechanisms of pathogenic microorganisms, in recent years, there has been a lack of in vivo experimental data, and further research is needed to determine the bacteriostatic effect in vivo.
Clinical ApplicationsTraditional usages
The plant does not wither even if there is cold snow in winter, so it is named “Jixuecao.” C. asiatica is cold in property, bitter, or acrid in taste, and is distributed to the liver, spleen, or kidney channel. This plant is believed to be effective in clearing heat, removing dampness, detoxicating, and relieving swelling. It is used in TCM for treating damp-heat jaundice, sunstroke and diarrhea, urolithiasis and blood strangury, carbuncle, and injuries from the impact. C. asiatica was first recorded in Sheng Nong's Herbal Classic in China: “Jixuecao bitter in taste and cold, is mainly used to treat severe heat, sore, abscess, eczema with itching, red erysipelas, febrile skin, and fever. It grows in the mountains and river valleys.[2]” Chen-tsang-chi, known as the “ancestor of tea therapy,” mentioned that “Jixuecao (C. asiatica) is used for the treatment of sudden heat, cold, and fever in children, hot knot in the abdomen, ramming juice to take it.” In the theory of medicinal properties written by Zhen Quan in the Tang Dynasty, C. asiatica can be used to “treat scrofula alternately in cold and hot conditions.” In Tang Materia Medica, C. asiatica can be mashed and applied to sites of pyretic erysipelas. In Song Dynasty, it is recorded in Rihuazi Materia Medica that “apply (C. asiatica) with salt to reduce swelling and poison and treat rubella scabies.”[113] Kou Zongyi recorded “smashing, sticking on all the heat toxin carbuncle, etc.” in Materia Medica Yan Yi. In the Introduction to Medicine, Li Chan mentioned the main therapeutic effects of C. asiatica: “Jixuecao is mainly used to treat all of the heat toxin, carbuncle-abscess poison, malign sore, rubella ringworm, acute febrile skin, children erysipelas with hot or cold, and heat bind in abdomen.” In the Southern Yunnan Materia Medica written by Lanmao during the Ming Dynasty, C. asiatica
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