Nonalcoholic fatty liver disease (NAFLD) is a chronic condition caused by fat accumulated in the liver over time, in the absence of excessive alcohol use. The disease can be classified into the types of non-inflammatory fatty liver (NAFl) and inflammatory nonalcoholic steatohepatitis (NASH)(1).
Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of cirrhosis and liver cancer.
According to world statistics, nonalcoholic fatty liver disease (NAFLD) is normally known as a disease of the Western world(2). However, due to the economic prosperity of Southeast Asian(3), the disease also was found in a large number of population in the cities, causing concerns of many scientists in the region(4)(6).
According to the joint assessment of the prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the US, led by the Stanford University School of Medicine, "The prevalence of NAFLD in the United States (U.S.) has risen from 18% in 1988–1991 to 31% in 2011–2012. Estimates of NAFLD prevalence for adults in Western countries is 20–30%, with much higher prevalence in adults with obesity (80–90%), diabetes (30–50%), and hyperlipidemia (90%)"(5).
Among the more affluent regions of China, the prevalence rate of non-alcoholic fatty liver disease (NAFLD) is approximately 15%(6). The number may decrease substantially if the poor rural populations where obesity is non-existence are also taking into account(7).
The exact causes of NAFLD aren't well understood. Some researchers suggested that certain risk factors such as long-term use of certain medications(8), genetic preposition(8), insulin resistance(8), high cholesterol(8) and triglycerides(8) in the blood, polycystic ovary syndrome(8), metabolic syndrome(8), obesity(8), and type 2 diabetes(8) are associated with the onset of the disease.
Recent studies also found that people with obstructive sleep apnea(11), underactive thyroid (hypothyroidism(10) and underactive pituitary gland (hypopituitarism) (9) also at an increased risk of the NALFD.
Some researchers suggested that unhealthy diet such as high-fat diet may also have a strong implication on NAFLD(12)(13).
Dr. Jensen VS, the lead scientist in the study high-fat diet-induced non-alcoholic fatty liver disease, wrote, "In humans and animal models, excessive intake of dietary fat, fructose, and cholesterol has been linked to the development of non-alcoholic fatty liver disease (NAFLD)"(13).
And, " Only HFr-fed rats developed dyslipidemia as characterized by higher levels of plasma triglycerides compared to all other groups (p < 0.0001). Hepatic dysfunction and inflammation was confirmed in HFD-fed rats by elevated levels of hepatic MCP-1 (p < 0.0001), TNF-alpha (p < 0.001) and plasma β-hydroxybutyrate (p < 0.0001), and in NASH-fed rats by elevated levels of hepatic MCP-1 (p < 0.01), increased hepatic macrophage infiltration (p < 0.001), and higher plasma levels of alanine aminotransferase (p < 0.0001) aspartate aminotransferase (p < 0.05), haptoglobin (p < 0.001) and TIMP-1 (p < 0.01) compared to Control"(13).
According to the statistics, in the US, over 100 million people have non-alcoholic fatty liver disease and the condition is more double over the past 20 years(14). The disease also is the most prevalent liver disease in children(14).
The prevalence rate of NAFLD is varied among different ethnic groups in the US. Dr. Rich NE, the lead scientist in the investigation of the ethnicity and NAFLD, wrote, "NAFLD prevalence was highest in Hispanics, intermediate in Whites, and lowest in Blacks, although differences between groups were smaller in high-risk cohorts (range 47.6%-55.5%) than population-based cohorts (range, 13.0%-22.9%)(15)".
And, "Among patients with NAFLD, the risk of NASH was higher in Hispanics (relative risk, 1.09; 95% CI, 0.98-1.21) and lower in Blacks (relative risk, 0.72; 95% CI, 0.60-0.87) than Whites"(15).
The progression of NAFLD and NASH led to cirrhosis, the late stage of liver scarring are well defined, as the liver tries to heal itself by halting inflammation(16), leading to symptoms of ascites(16)(18), swell esophageal varices(16)(19), hepatic encephalopathy(16)(17) and complications of liver cancer(16)(17) and liver failure(16)(17).
Most people at the early stage NAFLD are asymptomatic, however, as the disease progression into the later stage, most patients experience symptoms of right upper abdominal discomfort(20), fatigue(20), and/or malaise(20), and jaundice(20) with yellowing of the skin and eyes(20).
Most patients with NAFLD have elevated levels of liver enzymes gamma-glutamyl transferase (GGT)(21) and/or Aspartate Aminotransferase (AST)(21) to platelet ratio index (APRI) score(21), and/or Alanine Aminotransferase (ALT) (21) which are the markers used to predict the severity of liver disease including the fatty liver. A blood test is required if you suspected to have developing nonfatty liver disease.
Conventionally, as of today, there is no effective treatment of NAFLD(22)(23). Weight loss for overweight and obese patients(22) has been recommended through our the industry accompanied by the change of lifestyles(22) such as moderate exercise and reduced intake of alcohol, depending on individuals.
Patients who are hepatitis virus B and C carriers are also recommended to be vaccinated(22).
Given the nature of the nonalcoholic fatty liver disease, the search for effective treatment for NAFLD from the natural sources used over thousands of years in traditional medicine for the treatment of liver disease has been intensified(23). Many secondary metabolites, whole foods, and herbal medicine have been found to be effective in vivo, vitro and small human trials(24). However, most of them were stopped due to a simple reason. Who will spend billions to prove the thing which has no commercial values? Secondary metabolites, whole foods, and herbal medicine cannot be patented.
Herbal medicines
Herbal medicines have been used as medicines over thousands of year in human history.
1. Herbal Anise
Herbal anise is a flowering plant of the species of Pimpinella anisum, genus Pimpinella, belongings to the family Apiaceae native to Egypt and the Mediterranean region, used in traditional herbal medicine as a fragrance in soaps, oils, and mouth fresheners and stomachic, antiseptic, anti-spasmodic (61).
In animal NAFLD induced by choline-deficient diet for 90 days, 30 days treatment with hydroethanolic extract (AE) at 25, 50, 100, and 200 mg/kg/day and essential oil (AO) at 0.125, 0.25, and 0.5 mg/kg/day, reversed plasma levels of total cholesterol962), low-density lipoprotein(62), and triacylglycerol(62) and decrease in high-density lipoprotein level(62) caused by choline-deficient diet in dose-dependent manner.
Additionally, anise AE and AO demonstrated a strong effect in ameliorated lipid peroxidation induced by oxidative stress(62) indicated by elevation of plasma level of 8-isoprostane(62) which is correlated to the prevalence of non-alcoholic fatty liver disease (NAFLD).
3. Sida rhomboidea Roxb
Sida rhomboidea Roxb is a shrubby weed found growing throughout India belonging to the Malvaceae family, used in North-East India for the treatment of hypolipidemia and diabetes properties(66).
In a high-fat diet (HFD) induced insulin resistance in C57BL/6J mice, Sida rhomboidea ROXB. (S. rhomboidea ROXB., SR) compared to mice fed with rosiglitazone (ROS) lowered the plasma(67) and hepatic TC(67), TG(67) and FFA(67) were also significantly lowered (p<0.05) in HFD+SR groups.
According to the efficient clearance of glucose in intraperitoneal glucose tolerance test (IPGTT), Sida rhomboidea ROXB also lowered the plasma insulin(67) and fasting insulin resistance(67) levels in HFD+SR groups.
Furthermore, In vivo, sida rhomboidea. Roxb leaf extract (SRLE) supplementation with SRLE significantly prevented HFD induced increment in body weight(68), plasma lipids(68) and leptin(68), visceral adiposity(68)and adipocyte hypertrophy(68) by modulation of related genes expression(68).
In vitro, Roxb leaf extract (SRLE) decreased triglyceride accumulation(68), leptin release(68) and glyceraldehyde-3-Phosphate dehydrogenase activity(68) along with higher glycerol release(68) without significant alteration of the viability of 3T3L1 pre-adipocytes(68).
4. Teucrium polium (Golden Germander)
Teucrium polium, known popularly as felty germander, is a sub-shrub and herb, belonging to the Lamiaceae family, native to the western Mediterranean, found abundantly in South-Western Asia, Europe, and North Africa. and used in traditional medicine for the treatment of abdominal pain, indigestion, common cold, and type 2 diabetes(69).
Moreover, in N-Mary rats induced NASH by methionine and choline-deficient (MCD) diet for 8 weeks, injection of ethyl acetate fraction of T. polium orally for 3 weeks, lowered the elevated levels of proteins(71) associated with inflammation and malondialdehyde (MDA)(71) in the liver.
The extract increased the levels of antioxidants enzymes activities such as superoxide dismutase (SOD)(71), glutathione peroxidase (GPx)(71) and hepatic glutathione (GSH)(71).
In other words, the ethyl acetate fraction of T. poium effectively protected the liver by reversing NASH(71), through its strong antioxidant(71) and anti-inflammatory properties(71).
5. Grape seed extract
Grape Seed Extract is the commercial extracts from whole grape seeds that contains many concentrations, including vitamin E, flavonoids, linoleic acid, oligomeric proanthocyanidins(OPCs), and used in traditional medicine as antioxidant, anti-inflammatory agents and to treat skin wounds with less scarring, allergies, macular degeneration, arthritis, enhance circulation of blood vessels, lower cholesterol(72)
Additionally, injection of resveratrol (RSV) also found to induced production of hepatic low-density lipoprotein(74) which has been found to process similarly activity as high-density lipoprotein that returns cholesterol to the liver.
6. Milk thistles
Milk Thistle is a flowering plant, in the genus Silybum Adans, belonging to the family Asteraceae, native to the Mediterranean. The herb has been used in traditional medicine for the treatment of liver, kidney, and gall bladder problems(75).
According to the study lead by First Hospital of Jilin University in the review of eight RCTs involving 587 patients with NAFLD, Silymarin (SIL), an active extraction of milk thistle, significantly reduced liver oxidative stress(76) associated with the AST(76) and ALT levels(76).
9. Cissus quadrangularis (Asthisamharaka)
Cissus quadrangularis is a perennial plant, belonging to the grape family, native to India, Srilanka, Malaysia, Thailand, and Africa used in the traditional medicine for the treatment of obesity, diabetes, and metabolic syndrome(83)
On oxidant-antioxidant balance and insulin resistance (IR) in rats fed high fat–high fructose diet (HFFD) and free-radical scavenging property in vitro, CQEt addition for for 45 days restored insulin sensitivity (84), liver damage(84), and oxidative changes(84), on (HFFD) rats by and bring back the antioxidants and lipids towards normal(84).
Furthermore, CQEt protected the liver by improving the histopathology(84)of the liver.
In vivo, CQEtin also exerted liver protective effect(84) comparable with that of standard drug, metformin.
In vitro, CQEt exhibited radical scavenging ability(84) in a dose-dependent manner.
In other words, dietary supplementation of CQ extract (10%) for 45 days significantly improved insulin sensitivity(84), reduced liver damage(84), prevented oxidative changes(84).
10. Clerodendron glandulosum
Clerodendron glandulosum is comprised of small trees, shrub sand herbs belonging to the Verbenaceae family, native the tropical and sub-tropical regions of the world us in the traditional medicine for the treatment of hypertension, fever, diabetes, and abdominal pain(85).
On hyperlipidemic chronically rat fed by a high-fat diet (HL), administration of aqueous extract of Clerodendron glandulosum. Caleb (CG) (400 mg/kg/day) for 90 days, showed to improve the levels of LDL-C (81.36%) (86)and VLDL-C (43%)(86) along with an increase in HDL-C (52.84%)(86).
On alteration in lipid and cholesterol metabolism in high-fat diet fed hyperlipidemic rats, compared to hypolipidemic drug Lovastatin (LVS), injection of ECG exerted a strong effect in experimental hyperlipidemia(86) by a significant alteration in plasma and tissue lipid profiles(86).
Further differentiation of the efficacy of researchers found that ECG reduced absorption(86), improved elimination(86) and augmented catabolism(86) of lipids and cholesterol.
11. Curcuma longa (Turmeric)
Turmeric, principal curcuminoid of the popular Indian spice, a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae, native to tropical South Asia used in traditional medicine for the treatment of varies illness, including metabolic syndrome and inflammatory conditions(87).
According to the experimental results, GBE reduced the elevations of hepatic triglyceride contents(91) and the increased hepatic fatty acids(91) in rat livers caused by HFD.
Furthermore, GBE also enhanced the expression palmitoyltransferase I (CPT I) and total activity of the fatty acid β-oxidation rate-limiting enzyme, in the regulation of whole-body metabolism, inflammatory vigor, and pathogenesis of nonalcoholic fatty liver disease(91).
2. Hawthorn Fruit
Hawthorn is shrubs and trees of the genus Crataegus, belonging to the family Rosaceae, native to temperate regions of the Northern Hemisphere in Europe, Asia and North America(63) used in traditional medicine to treat heart disease and symptoms of heart diseases(63) such as irregular heartbeat(63), high blood pressure(63), chest pain(63), hardening of the arteries(63), circulatory disorders and respiratory illnesses(63).
Researchers at The First Affiliated Hospital of Wenzhou Medical College, in the concerns that nonalcoholic fatty liver disease (NAFLD) is emerging as a widespread condition worldwide, and reaffirm the natural treatments of nonalcoholic fatty liver disease (NAFLD) in the traditional Chinese medicine (TCM), launched an investigation to find natural medicines for the treatment of NAFLD without prominent side effects, suggested that hawthorn fruit was one the favorite herb used in TCM for the treatment of NAFLD compared to other herbs(64).
Researchers at The First Affiliated Hospital of Wenzhou Medical College, in the concerns that nonalcoholic fatty liver disease (NAFLD) is emerging as a widespread condition worldwide, and reaffirm the natural treatments of nonalcoholic fatty liver disease (NAFLD) in the traditional Chinese medicine (TCM), launched an investigation to find natural medicines for the treatment of NAFLD without prominent side effects, suggested that hawthorn fruit was one the favorite herb used in TCM for the treatment of NAFLD compared to other herbs(64).
Furthermore, the search of the database of PubMed and China National Knowledge Infrastructure from January 1995 to June 2010 for RCTs comparing either traditional Chinese medicine (TCM) formulations alone or in combination with placebo, a formula containing hawthorn normalized alanine aminotransferase(65) and disappearance of radiological steatosis(65) in patients with NAFLD, without inducing any side effects(65).
3. Sida rhomboidea Roxb
Sida rhomboidea Roxb is a shrubby weed found growing throughout India belonging to the Malvaceae family, used in North-East India for the treatment of hypolipidemia and diabetes properties(66).
In a high-fat diet (HFD) induced insulin resistance in C57BL/6J mice, Sida rhomboidea ROXB. (S. rhomboidea ROXB., SR) compared to mice fed with rosiglitazone (ROS) lowered the plasma(67) and hepatic TC(67), TG(67) and FFA(67) were also significantly lowered (p<0.05) in HFD+SR groups.
According to the efficient clearance of glucose in intraperitoneal glucose tolerance test (IPGTT), Sida rhomboidea ROXB also lowered the plasma insulin(67) and fasting insulin resistance(67) levels in HFD+SR groups.
Furthermore, In vivo, sida rhomboidea. Roxb leaf extract (SRLE) supplementation with SRLE significantly prevented HFD induced increment in body weight(68), plasma lipids(68) and leptin(68), visceral adiposity(68)and adipocyte hypertrophy(68) by modulation of related genes expression(68).
In vitro, Roxb leaf extract (SRLE) decreased triglyceride accumulation(68), leptin release(68) and glyceraldehyde-3-Phosphate dehydrogenase activity(68) along with higher glycerol release(68) without significant alteration of the viability of 3T3L1 pre-adipocytes(68).
4. Teucrium polium (Golden Germander)
Teucrium polium, known popularly as felty germander, is a sub-shrub and herb, belonging to the Lamiaceae family, native to the western Mediterranean, found abundantly in South-Western Asia, Europe, and North Africa. and used in traditional medicine for the treatment of abdominal pain, indigestion, common cold, and type 2 diabetes(69).
In nonalcoholic steatohepatitis induced in male N‐Mary rats by a methionine/choline‐deficient (MCD) diet, ethyl acetate (EtOAc) extract of Teucrium polium, inhibited inflammation(70) and ballooning degeneration by 80%(70) of the rats treated by MCD diet.
Furthermore, EtOAc extract also lowered the lipoprotein profiles(70) and levels of liver oxidative stress(70) markers such as alkaline phosphatase(70), aspartate aminotransferase(70), and alanine aminotransferase(70) by improving the liver superoxide dismutase(70), glutathione peroxidase(70), and glutathione reductase enzymes(70).
Moreover, in N-Mary rats induced NASH by methionine and choline-deficient (MCD) diet for 8 weeks, injection of ethyl acetate fraction of T. polium orally for 3 weeks, lowered the elevated levels of proteins(71) associated with inflammation and malondialdehyde (MDA)(71) in the liver.
The extract increased the levels of antioxidants enzymes activities such as superoxide dismutase (SOD)(71), glutathione peroxidase (GPx)(71) and hepatic glutathione (GSH)(71).
In other words, the ethyl acetate fraction of T. poium effectively protected the liver by reversing NASH(71), through its strong antioxidant(71) and anti-inflammatory properties(71).
5. Grape seed extract
Grape Seed Extract is the commercial extracts from whole grape seeds that contains many concentrations, including vitamin E, flavonoids, linoleic acid, oligomeric proanthocyanidins(OPCs), and used in traditional medicine as antioxidant, anti-inflammatory agents and to treat skin wounds with less scarring, allergies, macular degeneration, arthritis, enhance circulation of blood vessels, lower cholesterol(72)
In rats fed a high-fat diet induced non-alcoholic fatty liver disease(NAFLD), resveratrol (RSV) administration reversed the abdominal obesity(73), NAFLD(73), and insulin resistance (IR)(73) by 10 weeks.
In vitro, RSV treatment inhibited the triacylglycerol (TG) accumulation(73) in HepG2 cells incubated with a high concentration of glucose(73) and insulin(73).
In other words, resveratrol (RSV) improved NAFLD(73) and IR(73) by suppressing the 2 lipogenesis genes(73) associated with the elevation of NAFLD(73) and IR expression (73).
Additionally, injection of resveratrol (RSV) also found to induced production of hepatic low-density lipoprotein(74) which has been found to process similarly activity as high-density lipoprotein that returns cholesterol to the liver.
6. Milk thistles
Milk Thistle is a flowering plant, in the genus Silybum Adans, belonging to the family Asteraceae, native to the Mediterranean. The herb has been used in traditional medicine for the treatment of liver, kidney, and gall bladder problems(75).
In other words, SIL improved the liver parameters(76) by reducing transaminases levels(76) in NAFLD patients.
Furthermore, on hepatic steatosis and oxidative stress during the development of nonalcoholic fatty liver disease (NAFLD), administration of SMO decreased the histological injury of the liver(77) and the levels of hepatic triglyceride(77), cholesterol(77) and free fatty acid(77) in HFD-fed mice.
Moreover, SMO administration elevated the activities of superoxide dismutase (SOD)(77) and catalase (CAT)(77) and reduced the level of malondialdehyde (MDA)(77) and lowered the levels of proteins(77) involved in the production of pro-inflammatory cytokines(77) in the liver, thus preventing the onset of NAFLD.
7. Acanthopanax senticosus (Siberian Ginseng)
Acanthopanax senticosus or Siberian Ginseng is an oriental herb belonging to the Araliaceae family commonly distributed throughout the North Eastern parts of Asia, used in traditional Chinese medicine for the treatment of arthritis, hypertension, heart disease, gastric ulcers, and tumors(78).
In obesity in 10 C57BL/6J mice of 10 fed either a normal diet (10 kcal fat%) or high fat diet (60 kcal fat%) given with or without oral administration of A. senticosus extract (ASE; 0.5 g/kg of body weight) for 12 weeks, restored the significantly higher low-density lipoprotein (LDL)-cholesterol in serum(79) and higher triglyceride accumulation in liver(79), of mice high fat diet without altering the levels of carnitine status(79).
Collectively, oral administration of ASE lowered the weight gain(79), serum LDL-cholesterol concentration(79), and liver triglycerides accumulation(79) in mice with obesity induced by high-fat diets.
In insulin-resistant ob/ob mice with fatty livers, 50% ethanol extract ofAcanthopanax senticosus stem bark (ASSB) reversed the hepatomegaly(80), bt reducing the % liver weight/body weight ratio(80) in 8 weeks.
The ASSB ethanol extract also specifically lowered circulating glucose(80) and lipids(80) and enhanced insulin(80) action in the liver and triglyceride synthesis(80) in non-adipose tissues including liver and skeletal muscle(80).
Genes expression of glucose 6-phosphatase and lipogenic enzymes associated with the development of hepatic steatosis(80) also were reduced by the injection of ASSB ethanol extract.
8. Alisma Orientalis (Alismatis rhizome) or Ze Xie in traditional Chinese Medicine
Ze Xie is also known as Alisma. The sweet, bland and cold herb has been used in TCM as anti-pyretic, as anti-bacterial, hypoglycemic, hypotensive, antitumor, and anti-allergic medicine(81).
Furthermore, on hepatic steatosis and oxidative stress during the development of nonalcoholic fatty liver disease (NAFLD), administration of SMO decreased the histological injury of the liver(77) and the levels of hepatic triglyceride(77), cholesterol(77) and free fatty acid(77) in HFD-fed mice.
Moreover, SMO administration elevated the activities of superoxide dismutase (SOD)(77) and catalase (CAT)(77) and reduced the level of malondialdehyde (MDA)(77) and lowered the levels of proteins(77) involved in the production of pro-inflammatory cytokines(77) in the liver, thus preventing the onset of NAFLD.
7. Acanthopanax senticosus (Siberian Ginseng)
Acanthopanax senticosus or Siberian Ginseng is an oriental herb belonging to the Araliaceae family commonly distributed throughout the North Eastern parts of Asia, used in traditional Chinese medicine for the treatment of arthritis, hypertension, heart disease, gastric ulcers, and tumors(78).
In obesity in 10 C57BL/6J mice of 10 fed either a normal diet (10 kcal fat%) or high fat diet (60 kcal fat%) given with or without oral administration of A. senticosus extract (ASE; 0.5 g/kg of body weight) for 12 weeks, restored the significantly higher low-density lipoprotein (LDL)-cholesterol in serum(79) and higher triglyceride accumulation in liver(79), of mice high fat diet without altering the levels of carnitine status(79).
Collectively, oral administration of ASE lowered the weight gain(79), serum LDL-cholesterol concentration(79), and liver triglycerides accumulation(79) in mice with obesity induced by high-fat diets.
In insulin-resistant ob/ob mice with fatty livers, 50% ethanol extract ofAcanthopanax senticosus stem bark (ASSB) reversed the hepatomegaly(80), bt reducing the % liver weight/body weight ratio(80) in 8 weeks.
The ASSB ethanol extract also specifically lowered circulating glucose(80) and lipids(80) and enhanced insulin(80) action in the liver and triglyceride synthesis(80) in non-adipose tissues including liver and skeletal muscle(80).
Genes expression of glucose 6-phosphatase and lipogenic enzymes associated with the development of hepatic steatosis(80) also were reduced by the injection of ASSB ethanol extract.
8. Alisma Orientalis (Alismatis rhizome) or Ze Xie in traditional Chinese Medicine
Ze Xie is also known as Alisma. The sweet, bland and cold herb has been used in TCM as anti-pyretic, as anti-bacterial, hypoglycemic, hypotensive, antitumor, and anti-allergic medicine(81).
On rats fed with high‐fat diet for six weeks induced nonalcoholic fatty liver disease (NAFLD), followed by AOME for another six weeks, administration of AOME (150,300 and 600 mg kg−1) markedly decreased the serum and liver lipids(82), fasting serum glucose(82) and improved insulin resistance(82).
AOME lessened the lipid peroxidation(82) and activated antioxidant enzymes(82) through inhibiting the oxidative stress in the liver(82).
Furthermore, according to the tested assays, AOME also protected the liver against injury(82) by reducing the aminotransferase abnormalities(82) and enhanced the hepatomegaly(82).
9. Cissus quadrangularis (Asthisamharaka)
Cissus quadrangularis is a perennial plant, belonging to the grape family, native to India, Srilanka, Malaysia, Thailand, and Africa used in the traditional medicine for the treatment of obesity, diabetes, and metabolic syndrome(83)
On oxidant-antioxidant balance and insulin resistance (IR) in rats fed high fat–high fructose diet (HFFD) and free-radical scavenging property in vitro, CQEt addition for for 45 days restored insulin sensitivity (84), liver damage(84), and oxidative changes(84), on (HFFD) rats by and bring back the antioxidants and lipids towards normal(84).
Furthermore, CQEt protected the liver by improving the histopathology(84)of the liver.
In vivo, CQEtin also exerted liver protective effect(84) comparable with that of standard drug, metformin.
In vitro, CQEt exhibited radical scavenging ability(84) in a dose-dependent manner.
In other words, dietary supplementation of CQ extract (10%) for 45 days significantly improved insulin sensitivity(84), reduced liver damage(84), prevented oxidative changes(84).
10. Clerodendron glandulosum
Clerodendron glandulosum is comprised of small trees, shrub sand herbs belonging to the Verbenaceae family, native the tropical and sub-tropical regions of the world us in the traditional medicine for the treatment of hypertension, fever, diabetes, and abdominal pain(85).
On hyperlipidemic chronically rat fed by a high-fat diet (HL), administration of aqueous extract of Clerodendron glandulosum. Caleb (CG) (400 mg/kg/day) for 90 days, showed to improve the levels of LDL-C (81.36%) (86)and VLDL-C (43%)(86) along with an increase in HDL-C (52.84%)(86).
On alteration in lipid and cholesterol metabolism in high-fat diet fed hyperlipidemic rats, compared to hypolipidemic drug Lovastatin (LVS), injection of ECG exerted a strong effect in experimental hyperlipidemia(86) by a significant alteration in plasma and tissue lipid profiles(86).
Further differentiation of the efficacy of researchers found that ECG reduced absorption(86), improved elimination(86) and augmented catabolism(86) of lipids and cholesterol.
11. Curcuma longa (Turmeric)
Turmeric, principal curcuminoid of the popular Indian spice, a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae, native to tropical South Asia used in traditional medicine for the treatment of varies illness, including metabolic syndrome and inflammatory conditions(87).
On C57BL/6 mice fed an HFD for 16 weeks, daily oral administration (os) of the NDS restored the steatosis(88), aortic lesions(88) or carotid artery thickening(88) induced by the HFD.
Furthermore, NDS inhibited dyslipidemia(88) compared to untreated animals.
In other words, NDS prevented the onset of NAFLD and atherogenesis(88) by modulating the expression of different genes(88) involved in NAFLD.
According to the double-blind randomized controlled clinical trial conducted on 46 patients with NAFLD (21males and 25 females) aged 20-60 years old and body mass index (BMI) between 24.9 and 40 kg/m2, turmeric group (n = 23) given six turmeric capsules daily for 12 weeks with each capsule contained 500 mg turmeric powder (6×500 mg) showed the decreased serum levels of glucose(89), insulin(89), HOMA-IR(89), and leptin(89) compared to the placebo group without affecting the weight, BMI and liver enzymes.
Collectively, turmeric supplementation inhibited NAFLD complications by improving glucose indexes(89) and serum leptin levels(89).
12. Ginkgo biloba (Maidenhair Tree)
Ginkgo biloba is the oldest living tree species, genus Ginkgo, belonging to the family Ginkgoaceae, native to China, from the temperate zone to subtropical zone and some parts of North America. It Has been used in traditional herbal medicine in treating impotence, memory loss, respiratory diseases, circulatory disorders, and deafness as well as preventing drunkenness, and bedwetting(90).
Collectively, turmeric supplementation inhibited NAFLD complications by improving glucose indexes(89) and serum leptin levels(89).
12. Ginkgo biloba (Maidenhair Tree)
Ginkgo biloba is the oldest living tree species, genus Ginkgo, belonging to the family Ginkgoaceae, native to China, from the temperate zone to subtropical zone and some parts of North America. It Has been used in traditional herbal medicine in treating impotence, memory loss, respiratory diseases, circulatory disorders, and deafness as well as preventing drunkenness, and bedwetting(90).
In vivo, on Male Wistar rats divided into 4 groups (the control group, GBE group, high-fat diet [HFD] group, and HFD + GBE group) researchers examined the effect of Ginkgo biloba extract (GBE) on nonalcoholic fatty liver disease (NAFLD).
Based on the finding, researchers wrote, "The triglyceride-lowering effect of GBE on the HFD rat liver is closely associated with the increased expression and activity of CPT1A, and the flavonoid ingredients are the major contributors of GBE".
13. Linum usitatissimum (Linseed/Flaxseed)
Flaxseed is native to the region of the eastern Mediterranean to India and also known as common flax or linseed. Flax is an erect annual plant, it can grow to 1.2 m tall. The leaves are 20–40 mm long and 3 mm broad, used in traditional medicine for the treatment of constipation(92).
A double-blinded, randomized, and placebo-controlled study in moderately hypercholesterolemic men suggested that oral administration of SDG (20 or 100 mg) decreases the level of blood cholesterol(93) and liver disease risk factors(93) induced by hypercholesterolemia in humans.
In a study of 30 men with total cholesterol levels of 4.65 to 6.21 mmol/L (180-240 mg/dL), SDG exhibited a significant reduction in the ratio of low-density lipoprotein/high-density lipoprotein cholesterol(93) compared to baseline at week 12.
Furthermore, injection of SDG also showed a significant percentage decrease in the levels of glutamic pyruvic transaminase(93) and γ-glutamyl transpeptidase(93) associated with liver injury markers relative to the levels at baseline.
In other words, daily administration of 100 mg SDG may be effective in reducing the levels of blood cholesterol(93) and hepatic diseases risk(93) in moderately hypercholesterolemic men.
In the testing of 7-d diets including a low-fiber control diet (Control), a diet with flaxseed fiber drink (3/day) (Flax drink), and a diet with flaxseed fiber bread (3/day) (Flax bread), researchers found that compared to control, Flax drink lowered fasting total-cholesterol and LDL-cholesterol by 12 and 15%(94), respectively.
Fecal fat and energy excretion increased by 50 and 23% with Flax drink consumption compared to control(94).
In other words, Flax drink decreased plasma total and LDL-cholesterol(94) and increased fat excretion(94).
14. Nelumbo nucifera (Lotus)
Nelumbo nucifera (Lotus) is a perennial plant belonging to the Nymphaeaceae family produced individual leaves and flowers directly from the root system and used in traditional medicine for the treatment of respiratory, hepatic, digestive, and reproductive diseases(95).
Fecal fat and energy excretion increased by 50 and 23% with Flax drink consumption compared to control(94).
In other words, Flax drink decreased plasma total and LDL-cholesterol(94) and increased fat excretion(94).
14. Nelumbo nucifera (Lotus)
Nelumbo nucifera (Lotus) is a perennial plant belonging to the Nymphaeaceae family produced individual leaves and flowers directly from the root system and used in traditional medicine for the treatment of respiratory, hepatic, digestive, and reproductive diseases(95).
In 3T3-L1 preadipocytes and high-fat diet (HFD)-induced obese SD rats, injection of N. nucifera leaves extract. N. nucifera alkaloid (NNA) decreased cell population growth of 3T3-L1 preadipocytes(96) and increased the apoptotic cells(96) in a time- and dose-dependent manner and reduced the body weight(96), the lee's index(96), adipose tissue weight(96), and plasma lipid levels((96) in HFD-induced obese rats.
In vivo, C57BL/6 mice induced obesity by a high-fat diet (HFD), oral administration of NLFE reduced the body weight(97), body lipid accumulation(97), and activities of fatty acid synthase (FAS)(97), glutamic oxaloacetic transaminase(97), and glutamic pyruvic transaminase(97) associated with the risk of NAFLD.
Summary
Taken altogether, phytochemicals, herbal medicines, healthy foods found in the research paper may be considered remedies for the prevention and treatment of non-alcoholic fatty liver disease, pending to large sample size and multicenter human study.
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Author Biography
Kyle J. Norton (Scholar, Master of Nutrition, All right reserved)
Health article writer and researcher; Over 10.000 articles and research papers have been written and published online, including worldwide health, ezine articles, article base, health blogs, self-growth, best before it's news, the karate GB daily, etc.,.
Named TOP 50 MEDICAL ESSAYS FOR ARTISTS & AUTHORS TO READ by Disilgold.com Named 50 of the best health Tweeters Canada - Huffington Post
Nominated for shorty award over last 4 years
Some articles have been used as references in medical research, such as international journal Pharma and Bioscience, ISSN 0975-6299.
Sources
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1 Homie Razavi, 1 Rohit Loomba, 2 Zobair Younossi, 3 and Arun J. Sanyal. (PMC)(8) Symptoms & Causes of NAFLD & NASH by NIH
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(15) Racial and Ethnic Disparities in Nonalcoholic Fatty Liver Disease Prevalence, Severity, and Outcomes in the United States: A Systematic Review and Meta-analysis by Rich NE1, Oji S1, Mufti AR1, Browning JD1, Parikh ND2, Odewole M1, Mayo H3, Singal AG. (PubMed)
(16) Emerging Trends Conference: EMERGING TRENDS IN NON-ALCOHOLIC FATTY LIVER DISEASE by AASLD
(17) Hepatic Encephalopathy by the Canadian Liver Foundation
(18) LIVER DISEASE AND ASCITES by Sequana Medical
(19) Nonalcoholic fatty liver disease manifesting esophageal variceal bleeding by Tang CP1, Huang YS, Tsay SH, Chang FY, Lee SD. (PubMed)
(20) Non-alcoholic fatty liver disease by Genetic Home Reference. (NIH)
(21) Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis by J K Dowman,*† J W Tomlinson,‡ and P N Newsome. (PMC)
(22) Current treatment options for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis by Melanie D Beaton, MD FRCPC. (PMC)
(23) Herbal medicines and nonalcoholic fatty liver disease by Hong Yao, Yu-Jie Qiao, Ya-Li Zhao, Xu-Feng Tao, Li-Na Xu, Lian-Hong Yin, Yan Qi, and Jin-Yong Peng. (PMC)
(24) An Overview of Herbal Products and Secondary Metabolites Used for Management of Type Two Diabetes by Ajda Ota and Nataša P. Ulrich. (PubMed)
(61) Popular #Herbs - Anise Kyle J. Norton
(62) Pimpinella anisum L. fruit: Chemical composition and effect on a rat model of nonalcoholic fatty liver disease by Asadollahpoor A1, Abdollahi M2, Rahimi R3,(PubMed)
(63) Popular Herbs - Hawthorn (Crataegus)
(64) Traditional Chinese medicines benefit to nonalcoholic fatty liver disease: a systematic review and meta-analysis by Shi KQ, Fan YC, Liu WY, Li LF, Chen YP, Zheng MH. (PubMed)
(65) The relationship between obesity and the severity of non-alcoholic fatty liver disease: systematic review and meta-analysis by Lu FB1, Hu ED1, Xu LM1, Chen L1, Wu JL1, Li H1, Chen DZ2, Chen YP. (PubMed)
(66) Sida rhomboidea. Roxb Leaf Extract Down-Regulates Expression of PPARγ2 and Leptin Genes in High Fat Diet-Fed C57BL/6J Mice and Retards in Vitro 3T3L1 Pre-Adipocyte Differentiation by Menaka C. Thounaojam,1 Ravirajsinh N. Jadeja,1 Umed V. Ramani,2 Ranjitsinh V. Devkar,1,*and A. V. Ramachandran. (PMC)
(67) Prevention of High Fat Diet-Induced Insulin Resistance in C57BL/6J Mice by Sida rhomboidea ROXB. Extract by Menaka Chanu Thounaojam, Ravirajsinh Navalsinh Jadeja, Ansarullah, Ranjitsinh Vijaysinh Devkar, A. V. Ramachandran. (Journal of Health Science)
(68) Sida rhomboidea. Roxb Leaf Extract Down-Regulates Expression of PPARγ2 and Leptin Genes in High Fat Diet-Fed C57BL/6J Mice and Retards inVitro 3T3L1 Pre-Adipocyte Differentiation
Menaka C. Thounaojam 1, Ravirajsinh N. Jadeja 1, Umed V. Ramani 2, Ranjitsinh V. Devkar 1,* and. V. Ramachandran. ( International Journal of Molecular Science)
(69) Phytochemistry and medicinal properties of Teucrium polium L. (Lamiaceae) by Bahramikia S1, Yazdanparast R. (PubMed)
(70) Teucrium polium in the prevention of steatohepatitis in rats by Rahim Amini, Narges Nosrati, Razieh Yazdanparast, Mahsa Molaei. ( Liver International)
(71) Teucrium polium reversed the MCD diet-induced liver injury in rats by Rahim Amini, Razieh Yazdanparast and Safiyeh Aghazadeh. (Sage Journal)
(72) Popular Herbs - Grapefruit Seed Extract by Kyle J. Norton
(73) Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase by Shang J1, Chen LL, Xiao FX, Sun H, Ding HC, Xiao H. (PubMed)
(74) SIRT1 as a potential therapeutic target for the treatment of nonalcoholic fatty liver disease by Colak Y1, Ozturk O, Senates E, Tuncer I, Yorulmaz E, Adali G, Doganay L, Enc FY. (PubMed)
(75) Popular #Herbs - Milk Thistle by Kyle J. Norton
(76) The therapeutic effect of silymarin in the treatment of nonalcoholic fatty disease: A meta-analysis (PRISMA) of randomized control trials by Zhong S1, Fan Y, Yan Q, Fan X, Wu B, Han Y, Zhang Y, Chen Y, Zhang H, Niu J. (PubMed)
(77) Silybum marianum oil attenuates hepatic steatosis and oxidative stress in high fat diet-fed mice by Zhu SY1, Jiang N2, Yang J3, Tu J4, Zhou Y3, Xiao X3, Dong Y. (PubMed)
(78) Popular #Herbs - #Ginseng, Asian (Panax ginseng) and Ginseng, North America by Kyle J. Norton
(79) Acanthopanax senticosus Extract Prepared from Cultured Cells Decreases Adiposity and Obesity Indices in C57BL/6J Mice Fed a High Fat Diet by Youn-Soo Cha, Soon-Jae Rhee, and Young-Ran Heo. (Journal of Medicinal Food)
(80) Acanthopanax senticosus reverses fatty liver disease and hyperglycemia in ob/ob mice by Sang, Hyun Park, Sang Gil Lee, Sung Keel Kang, and Sung Hyun Chung. (Springer Link)
(81) Chinese Herbs – Ze Xie by Kyle J. Norton
(82) Protective effects of the Alisma Orientalis extract on the experimental nonalcoholic fatty liver disease byXuezhi Hong, Huiqing Tang, Limao Wu, and Lianda Li. (Wiley Online Library)
(83) Cissus quadrangularis by Wikipedia
(84) Cissus quadrangularis stem alleviates insulin resistance, oxidative injury and fatty liver disease by Chidambaram, Jaya, Carani Venkatraman, and Anuradha. (Science Direct)
(85) Cissus quadrangularis - Wikipedia
(86) Clerodendron glandulosum Coleb., Verbenaceae, ameliorates high fat diet-induced alteration in lipid and cholesterol metabolism in rats by Jadeja RN; Thounaojam MC; Ansarullah; Devkar RV*; Ramachandran AV. (Scielo)
(87) Popular #Herbs - Turmeric (Curcuma longa) by Kyle J. Norton
(88) NAFLD and Atherosclerosis Are Prevented by a Natural Dietary Supplement Containing Curcumin, Silymarin, Guggul, Chlorogenic Acid and Inulin in Mice Fed a High-Fat Diet by Amato A1, Caldara GF2, Nuzzo D3, Baldassano S4, Picone P5, Rizzo M6, Mulè F7, Di Carlo M. (PubMed)
(89) Turmeric Supplementation Improves Serum Glucose Indices and Leptin Levels in Patients with Nonalcoholic Fatty Liver Diseases by Navekar R1, Rafraf M1, Ghaffari A1, Asghari-Jafarabadi M2, Khoshbaten M. (PubMed)
(90) Popular Herbs - Ginkgo biloba by Kyle J. Norton
(91) Inhibitory effect of Ginkgo biloba extract on fatty liver: Regulation of carnitine palmitoyltransferase 1a and fatty acid metabolism by Shi Dong Wang, Zuoquan Xie, Jia Chen and Ke Wang. (Research Gate)
(92) Superfoods - Flaxseed oil by Kyle J. Norton
(93) Flaxseed lignan lowers blood cholesterol and decreases liver disease risk factors in moderately hypercholesterolemic men by Fukumitsu S1, Aida K, Shimizu H, Toyoda K. (PubMed)
(94) Flaxseed dietary fibers lower cholesterol and increase fecal fat excretion, but the magnitude of the effect depends on food type by Kristensen M1, Jensen MG, Aarestrup J, Petersen KE, Søndergaard L, Mikkelsen MS, Astrup A. (PubMed)
(95) A comprehensive review on Nymphaea stellata: A traditionally used bitter by M. K. Mohan Maruga Raja, Neeraj Kumar Sethiya, and S. H. Mishra. (PMC)
(96) Nelumbo nucifera alkaloid inhibits 3T3-L1 preadipocyte differentiation and improves high-fat-diet-induced obesity and body fat accumulation in rats by Xie Bin, Wan Jin, Wang Wenqing, and Shi Chunyang. (Research Gate)
(97) Improvement in High-Fat Diet-Induced Obesity and Body Fat Accumulation by a Nelumbo nucifera Leaf Flavonoid-Rich Extract in Mice by Cheng-Hsun Wu, Mon-Yuan Yang, Kuei-Chuan Chan, and Pei-Jun Chung. (Research Gate)
(62) Pimpinella anisum L. fruit: Chemical composition and effect on a rat model of nonalcoholic fatty liver disease by Asadollahpoor A1, Abdollahi M2, Rahimi R3,(PubMed)
(63) Popular Herbs - Hawthorn (Crataegus)
(64) Traditional Chinese medicines benefit to nonalcoholic fatty liver disease: a systematic review and meta-analysis by Shi KQ, Fan YC, Liu WY, Li LF, Chen YP, Zheng MH. (PubMed)
(65) The relationship between obesity and the severity of non-alcoholic fatty liver disease: systematic review and meta-analysis by Lu FB1, Hu ED1, Xu LM1, Chen L1, Wu JL1, Li H1, Chen DZ2, Chen YP. (PubMed)
(66) Sida rhomboidea. Roxb Leaf Extract Down-Regulates Expression of PPARγ2 and Leptin Genes in High Fat Diet-Fed C57BL/6J Mice and Retards in Vitro 3T3L1 Pre-Adipocyte Differentiation by Menaka C. Thounaojam,1 Ravirajsinh N. Jadeja,1 Umed V. Ramani,2 Ranjitsinh V. Devkar,1,*and A. V. Ramachandran. (PMC)
(67) Prevention of High Fat Diet-Induced Insulin Resistance in C57BL/6J Mice by Sida rhomboidea ROXB. Extract by Menaka Chanu Thounaojam, Ravirajsinh Navalsinh Jadeja, Ansarullah, Ranjitsinh Vijaysinh Devkar, A. V. Ramachandran. (Journal of Health Science)
(68) Sida rhomboidea. Roxb Leaf Extract Down-Regulates Expression of PPARγ2 and Leptin Genes in High Fat Diet-Fed C57BL/6J Mice and Retards inVitro 3T3L1 Pre-Adipocyte Differentiation
Menaka C. Thounaojam 1, Ravirajsinh N. Jadeja 1, Umed V. Ramani 2, Ranjitsinh V. Devkar 1,* and. V. Ramachandran. ( International Journal of Molecular Science)
(69) Phytochemistry and medicinal properties of Teucrium polium L. (Lamiaceae) by Bahramikia S1, Yazdanparast R. (PubMed)
(70) Teucrium polium in the prevention of steatohepatitis in rats by Rahim Amini, Narges Nosrati, Razieh Yazdanparast, Mahsa Molaei. ( Liver International)
(71) Teucrium polium reversed the MCD diet-induced liver injury in rats by Rahim Amini, Razieh Yazdanparast and Safiyeh Aghazadeh. (Sage Journal)
(72) Popular Herbs - Grapefruit Seed Extract by Kyle J. Norton
(73) Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase by Shang J1, Chen LL, Xiao FX, Sun H, Ding HC, Xiao H. (PubMed)
(74) SIRT1 as a potential therapeutic target for the treatment of nonalcoholic fatty liver disease by Colak Y1, Ozturk O, Senates E, Tuncer I, Yorulmaz E, Adali G, Doganay L, Enc FY. (PubMed)
(75) Popular #Herbs - Milk Thistle by Kyle J. Norton
(76) The therapeutic effect of silymarin in the treatment of nonalcoholic fatty disease: A meta-analysis (PRISMA) of randomized control trials by Zhong S1, Fan Y, Yan Q, Fan X, Wu B, Han Y, Zhang Y, Chen Y, Zhang H, Niu J. (PubMed)
(77) Silybum marianum oil attenuates hepatic steatosis and oxidative stress in high fat diet-fed mice by Zhu SY1, Jiang N2, Yang J3, Tu J4, Zhou Y3, Xiao X3, Dong Y. (PubMed)
(78) Popular #Herbs - #Ginseng, Asian (Panax ginseng) and Ginseng, North America by Kyle J. Norton
(79) Acanthopanax senticosus Extract Prepared from Cultured Cells Decreases Adiposity and Obesity Indices in C57BL/6J Mice Fed a High Fat Diet by Youn-Soo Cha, Soon-Jae Rhee, and Young-Ran Heo. (Journal of Medicinal Food)
(80) Acanthopanax senticosus reverses fatty liver disease and hyperglycemia in ob/ob mice by Sang, Hyun Park, Sang Gil Lee, Sung Keel Kang, and Sung Hyun Chung. (Springer Link)
(81) Chinese Herbs – Ze Xie by Kyle J. Norton
(82) Protective effects of the Alisma Orientalis extract on the experimental nonalcoholic fatty liver disease byXuezhi Hong, Huiqing Tang, Limao Wu, and Lianda Li. (Wiley Online Library)
(83) Cissus quadrangularis by Wikipedia
(84) Cissus quadrangularis stem alleviates insulin resistance, oxidative injury and fatty liver disease by Chidambaram, Jaya, Carani Venkatraman, and Anuradha. (Science Direct)
(85) Cissus quadrangularis - Wikipedia
(86) Clerodendron glandulosum Coleb., Verbenaceae, ameliorates high fat diet-induced alteration in lipid and cholesterol metabolism in rats by Jadeja RN; Thounaojam MC; Ansarullah; Devkar RV*; Ramachandran AV. (Scielo)
(87) Popular #Herbs - Turmeric (Curcuma longa) by Kyle J. Norton
(88) NAFLD and Atherosclerosis Are Prevented by a Natural Dietary Supplement Containing Curcumin, Silymarin, Guggul, Chlorogenic Acid and Inulin in Mice Fed a High-Fat Diet by Amato A1, Caldara GF2, Nuzzo D3, Baldassano S4, Picone P5, Rizzo M6, Mulè F7, Di Carlo M. (PubMed)
(89) Turmeric Supplementation Improves Serum Glucose Indices and Leptin Levels in Patients with Nonalcoholic Fatty Liver Diseases by Navekar R1, Rafraf M1, Ghaffari A1, Asghari-Jafarabadi M2, Khoshbaten M. (PubMed)
(90) Popular Herbs - Ginkgo biloba by Kyle J. Norton
(91) Inhibitory effect of Ginkgo biloba extract on fatty liver: Regulation of carnitine palmitoyltransferase 1a and fatty acid metabolism by Shi Dong Wang, Zuoquan Xie, Jia Chen and Ke Wang. (Research Gate)
(92) Superfoods - Flaxseed oil by Kyle J. Norton
(93) Flaxseed lignan lowers blood cholesterol and decreases liver disease risk factors in moderately hypercholesterolemic men by Fukumitsu S1, Aida K, Shimizu H, Toyoda K. (PubMed)
(94) Flaxseed dietary fibers lower cholesterol and increase fecal fat excretion, but the magnitude of the effect depends on food type by Kristensen M1, Jensen MG, Aarestrup J, Petersen KE, Søndergaard L, Mikkelsen MS, Astrup A. (PubMed)
(95) A comprehensive review on Nymphaea stellata: A traditionally used bitter by M. K. Mohan Maruga Raja, Neeraj Kumar Sethiya, and S. H. Mishra. (PMC)
(96) Nelumbo nucifera alkaloid inhibits 3T3-L1 preadipocyte differentiation and improves high-fat-diet-induced obesity and body fat accumulation in rats by Xie Bin, Wan Jin, Wang Wenqing, and Shi Chunyang. (Research Gate)
(97) Improvement in High-Fat Diet-Induced Obesity and Body Fat Accumulation by a Nelumbo nucifera Leaf Flavonoid-Rich Extract in Mice by Cheng-Hsun Wu, Mon-Yuan Yang, Kuei-Chuan Chan, and Pei-Jun Chung. (Research Gate)
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