Herbs, immunity and COVID

Centella asiatica or Gotu kola is a traditional medicine used in China, possessing extensive medicinal value, widely used in Southeast Asian countries. The main chemical components responsible for its pharmacological activity are triterpenes, mostly asiaticoside, asiatic acid, madecassoside, and madecassic acid.

A study summarized the effects of C. asiatica and its main components on neurological diseases, endocrine diseases, skin diseases, cardiovascular diseases, gastrointestinal diseases, immune diseases, and gynecological diseases. 

Effects on Neurological Diseases

C. asiatica is known to enhance the function of the nervous system. It can be dissolved in methanol, ethanol, and water. C. asiatica and its triterpenes were found to relieve a variety of neurological diseases, most importantly Alzheimer’s disease (AD) and Parkinson’s disease. The pathogenesis of AD and Parkinson’s disease involve neuroinflammatory activities, oxidative stress, mitochondrial dysfunction, and dysfunction in a brain-derived neurotrophic factor.

Superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase act as free radical scavengers, that affects the level of reactive oxygen species (ROS), and the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) prevents oxidative stress, which is all altered in AD and Parkinson’s disease. T. Studies have found that C. asiatica and its triterpenoids effectively increase SOD and GPX activities, activate nuclear factor erythroid-2-related factor 2, and improve the cognitive impairment of animals, thus alleviating the symptoms of related diseases.

Mitochondrial dysfunction, due to increased ROS production is closely related to the occurrence of AD and Parkinson’s disease. Studies have demonstrated that C. asiatica and its triterpenoids could reduce ROS production, thus restoring mitochondrial dysfunction and recovering neuronal function in AD and Parkinson’s disease.

Brain-derived neurotrophic factor, which is closely related to neuron maintenance, neuron survival, and neurotransmitter regulation, is reduced in the brain of patients with neurodegenerative diseases. C. asiatica extract, asiatic acid, and asiaticoside are known to effectively increase the content of brain-derived neurotrophic factors (BDNF).

Thus the main effect of C. asiatica and its triterpenoids in improving neurological diseases is probably through regulating mitogen-activated protein kinase (MAPK) signalling pathway, phosphotidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signalling pathway, where all of these signalling pathways are known to be dysregulated in many diseases of the brain.

Hence, C. asiatica and its extracts show a positive effect on neurological diseases. They improve neurological diseases by reducing inflammatory factors, balancing oxidative stress, repairing abnormal expression of mitochondrial-related proteins, and improving the content of BDNF. Additionally, they also reduce related nerve cell apoptosis, increase synaptic density, and improve the survival rate of neural cells.

Effects on Endocrine Diseases

C. asiatica extracts are considered effective in treating endocrine diseases, especially type 2 diabetes and obesity. 

Lipid peroxidation causes oxidative stress which is the main indicator of the pathogenesis and development of Type 2 diabetes mellitus (T2DM). Oxidative stress causes microvascular and macrovascular complications. In addition, the inflammation response may cause the occurrence of T2DM by inducing insulin resistance.

Both the diabetic animal model and the obesity animal model have demonstrated that the C. asiatica extract increases the GSH, CAT, and SOD activities, thereby improving the enzyme antioxidant system. Additionally, animal experiments have shown that the C. asiatica extract can effectively decrease related inflammation factors (TNF-α, IL-1β, and IL-4) and blood glucose and blood lipid levels. Extracts of C. asiatica are known to lower the food and water intake and body weight, suggesting the role of C. asiatica extract in affecting obesity by influencing the feeding center controlled by the central nervous system. 

Moreover, asiatic acid acts as an anti-obesity agent by suppressing weight gain and enhancing the sensitivity of leptin and insulin. It can also increase the level of enzymatic antioxidants (CAT, GPx and SOD), reverse the expression of CPT-1 and UCP-2 that are suppressed by a high-fat diet. Therefore, it is correct to conclude that asiatic acid can repair oxidative stress damage caused by obesity, and can also suppress weight gain by promoting fatty acid oxidation.

Additionally, madecassoside can inhibit the expression of osteoporosis-related genes by affecting the NF-κB and MAPK signalling pathways (NFATc1, c-Fos, Acp5, CTSK, VATPase-d2), inhibiting the generation of osteoclasts, weakening the absorption activity of osteoclasts. Thus madecassoside can serve as a potential candidate for the treatment of osteoporosis.

Hence, C. asiatica extract and asiatic acid could (1) lower blood glucose levels, (2) improve insulin resistance, (3) inhibit weight gain (4) ameliorate inflammation, and (5) improve oxidative stress. And madecassoside can improve osteoporosis by weakening the absorption of osteoclasts and reducing osteoclast formation. 

This proves C. asiatica extract and related components (asiatic acid, madecassoside) to be an excellent candidate for treating endocrine diseases such as diabetes, obesity and osteoporosis.

Effects on Skin Diseases

The C. asiatica extract and its triterpenoids have shown therapeutic and relieving effects on acne, baldness, vitiligo, atopic dermatitis, and wounds.

Many studies have investigated the best formulation and concentration of C. asiatica for numerous skin conditions. Previously reported animal and cell experiments have found that C. asiatica and its triterpenoids improves the degree of re-epithelialization, increases collagen synthesis, reduces the inflammation around wounds and cause no obvious skin irritation.

In the treatment of atopic dermatitis, C. asiatica has demonstrated a significant reduction in the inflammation response (TNF-α ↓, IL-1β ↓, IL-8 ↓, IL-4 ↓, and IL-13 ↓), and also the local immune response (IgE ↓). titrated extract of C. asiatica (TECA) and ethanol extract of C. asiatica, both showed inhibition of hyperkeratosis, mast cell and inflammatory cell infiltration, along with inhibiting the expression of iNOS and COX-2 and NF -κB activity. Thus, confirming the role of C. asiatica extract for the treatment of atopic dermatitis.

Madecassoside can reduce dermatitis by reducing the pro-inflammatory cytokines (IL-1β, TLR2), and promoting the secretion of AQP3, LOR, IVL in HaCaT keratinocytes and the secreting HA in human skin fibroblasts, thus significantly enhancing skin hydration.

Madecassoside have also shown to improve vitiligo by reducing the oxidative stress response and weakening the damage to mitochondria by oxidative stress [matrix metalloproteinase (MMP) ↑ and [Ca2+]i ↓]. Additionally, it is suggested that the LC3-II/LC3-I ratio of melanocytes treated with madecassoside increases significantly, thus enhancing the autophagy activation of the cells, thereby protecting skin cells from physiological and pathological ageing damage. 

Furthermore, C. asiatica has also demonstrated a positive activation effect on dermal papilla, by improving the viability of dermal papilla cells and increasing the expression of characteristic genes related to hair growth in the cells, thus proving effective for baldness.

Thus the prime mechanism of action of C. asiatica and its ingredients in the treatment of skin diseases are anti-inflammation, anti-oxidation, and weakening of the damage to mitochondria by oxidative stress, which is consistent with the pathogenesis of these diseases.

Effects on Cardiovascular Diseases

C. asiatica has shown a positive effect on cardiovascular diseases. The main components that affect the cardiovascular system are asiaticoside and asiatic acid.

A clinical prospective, placebo-controlled, randomized, dose range trial demonstrated that 4 weeks of treatment with C. asiatica improves total triterpenes (TTFCA), the capillary filtration rate, ankle circumference and ankle edema of patients with venous hypertension, and the dose 180 mg/day is most effective in improving the symptoms.

Clinical studies have demonstrated that following 4 years of intervention in patients with Pycnogenol® 100 mg/day plus C. asiatica (100 mg/day), patients showed reduced plaque progression, reduced oxidative stress, and mild transient brain deficiency as compared to the control group. The incidence of angina events was less than 3%, compared to 6.25% in the control group. Thus C. asiatica has a role in preventing preclinical atherosclerosis. 

Effects on Digestive Diseases

C. asiatica and its triterpenoids have shown therapeutic effects on digestive disorders, which is mainly reflected by improved liver fibrosis, colitis, gastric mucosal damage and reduced Helicobacter pylori gastric colonization.

C. asiatica extract can effectively ameliorate the drug-induced liver toxicity, improved gastric mucosal injury, and reduced H. pylori infection by reducing related inflammation factors (IL−1β ↓, IL−2 ↓, IL−6 ↓, IL−10 ↓, IL−12 ↓, and TNF−α ↓) and increasing the level of antioxidant stress factors (SOD ↑, CAT ↑, and GPx ↑). 

C. asiatica is also known to reduce MDA and COX-2 levels, thereby ameliorating gastric mucosal damage. It has also demonstrated certain therapeutic effects on gastrointestinal tumors by- reducing the level of pro-apoptotic factors (B-cell lymphoma 2(Bcl-2) ↑, Bcl-2-associated X protein(Bax) ↓, caspase-3 ↓), and related inflammation factors (TGF-β1 ↓, TNF-α ↓, IL-6 ↓, IL-1β ↓), and increasing the level of anti-oxidative stress factors (SOD ↑, GSH-Px ↑, CAT ↑, GST ↑, GSH ↑). 

Asiatic acid can also affect the expression of epithelial-mesenchymal transition marker proteins in colon cancer cells thus proving to be a potential therapeutic drug for liver cancer and colon cancer.

Thus C. asiatica can improve liver, colon and stomach related digestive disorders by reducing inflammation, ameliorating oxidative stress, and improving mitochondrial function.

Effects on Respiratory Diseases

The effects of C. asiatica on respiratory diseases are described by its ability to improve pulmonary fibrosis, ameliorate chronic obstructive pulmonary disease, and decrease lung injury and certain anti-lung cancer effects.

Effective components of C. asiatica on reducing respiratory diseases are asiatic acid and asiaticoside, and the major mechanism is anti-inflammation, consistent with the pathological mechanism of the several respiratory diseases. The potential therapeutic effect of C. asiatica and asiatic acid on lung cancer has also been demonstrated in some studies by promoting apoptosis and inhibiting differentiation of tumor cells, which warrants further investigation.

Effects on Gynecological Diseases

C. asiatica is known to effectively improve endometriosis and relief pelvic inflammatory disease, as well as exert anti-ovarian cancer and anti-breast cancer functions.

The therapeutic effect of C. asiatica on gynaecological diseases mainly relies on the improvement of inflammation. Asiatic acid works by affecting apoptosis, reducing the production of inflammatory factors and influencing the cell cycle progression. Therefore, it can be a potential agent in the treatment of gynecological diseases, with further clinical trials demanded to verify its efficacy.

Effects on Rheumatoid Arthritis

Animal and cell experiments have confirmed an anti-rheumatoid effect of madecassoside by reducing the level of inflammatory factors.

Effects on Other Diseases

C. asiatica and its triterpenoids have also shown positive effects in (1) protecting retinal blood vessels, (2) reducing toxic and side effects of drugs, (3) reducing drug resistance, and (4) promoting periodontal tissue regeneration. C. asiatica could also alleviate oral submucous fibrosis, sepsis, migraine, glaucoma, periodontitis, leukemia, and osteolytic bone diseases.

Thus it can be summarized as C. asiatica and its triterpenoids have broad therapeutic potential, with specific mechanism involving the following four aspects: (1) anti-inflammatory; (2) antioxidant; (3) anti-apoptosis; and (4) anti-fibrosis.