Berberine: Benefits, supplements, side effects, dosage, and ...

06 May.,2024

 

Berberine: Benefits, supplements, side effects, dosage, and ...

Although berberine appears to be safe and causes few side effects, a person should speak with a doctor before taking it.

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Studies of berberine have indicated that it can treat several metabolic health conditions, including diabetes, obesity, and heart problems. It may also improve gut health.

Berberine has been a part of Chinese and Ayurvedic medicine for thousands of years . It works in the body in multiple ways and is able to make changes within the body’s cells.

Berberine, or berberine hydrochloride, is a compound in several plants. It may help to treat diabetes, high cholesterol, and high blood pressure, among other conditions. However, side effects can include upset stomach and nausea.

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The following are conditions that berberine may help treat, according to research.

Bacterial infections

Berberine could be an effective antimicrobial agent. A 2022 study found that berberine helped inhibit the growth of Staphylococcus aureus.

S. aureus can cause many health problems, including:

  • sepsis
  • pneumonia
  • meningitis
  • a range of skin conditions

Another study found that berberine has the ability to damage the DNA and protein of certain bacteria.

Inflammation

Inflammation is a key factor in several health conditions, including heart disease and diabetes.

Research suggests that berberine has anti-inflammatory properties, which means it could help treat diabetes and other inflammation-related health conditions.

Diabetes

Research has shown that berberine may work as a diabetes treatment. Studies have found that it can have positive effects on:

One literature review indicated that berberine was better than a placebo at lowering blood sugar.

The same analysis found that a combination of berberine and blood-sugar-lowering drugs is more effective than the drugs alone.

According to 2014 research, berberine shows promise as a potential diabetes treatment, especially for those who cannot take existing anti-diabetic drugs due to heart disease, liver failure, or kidney problems.

Another literature review found that berberine combined with lifestyle changes worked better to lower blood glucose than lifestyle changes alone.

Berberine appears to activate AMP-activated protein kinase, which can help regulate how the body uses blood sugar. Researchers believe this activation can help treat diabetes and related health issues, such as obesity and high cholesterol.

Another 2020 meta-analysis showed benefits in body weight and metabolic parameters, without significant elevation in liver enzymes.

However, scientists need to conduct more large, double-blind studies to fully determine berberine’s safety and efficacy.

Speak with a doctor before taking berberine for diabetes. It may not be right for everyone and could interact with other medications.

High cholesterol

High levels of low-density lipoprotein (LDL) cholesterol and triglycerides may increase the risk of heart disease and stroke.

Some evidence suggests that berberine could help lower LDL cholesterol and triglyceride levels. According to one review, studies in both animals and humans indicate that berberine has cholesterol-lowering effects.

It may help reduce LDL, or “bad” cholesterol, and increase high-density lipoprotein, or “good” cholesterol.

A literature review found that berberine combined with lifestyle changes works better than lifestyle changes alone in treating high cholesterol.

Researchers believe that the effects of berberine might be similar to those of drugs that reduce high cholesterol, while berberine does not cause the same side effects.

High blood pressure

High blood pressure is a leading cause of heart disease.

A literature review found that berberine combined with a blood-pressure-lowering drug was more effective than the drug alone.

Also, results of a study of rats indicate that berberine could delay the onset of high blood pressure and, when it does develop, help reduce its severity.

Obesity

Obesity is a common condition that can increase the risk of:

One review reported that people who took 750 milligrams (mg) of barberry twice a day for 3 months had a significant decrease in weight. Barberry is a plant that contains high amounts of berberine.

Also, a double-blind study found that individuals with metabolic syndrome who took 200 mg of barberry three times a day experienced decreases in their body mass index readings.

The team behind another study observed that berberine may activate brown adipose tissue. This tissue helps the body turn food into body heat, and increased activation may help treat obesity and metabolic syndrome.

Some research suggests that berberine works similarly to the drug metformin, which doctors often prescribe to treat type 2 diabetes. In fact, berberine may have the ability to change the bacteria in the gut, which could help treat both obesity and diabetes.

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) occurs when a female has high levels of certain male hormones. The syndrome is a hormonal and metabolic imbalance that can lead to infertility and other health issues.

PCOS is linked with many issues that berberine may help address. For example, a person with PCOS may also have:

  • high levels of insulin, diabetes, or both
  • high blood pressure
  • high cholesterol
  • more body weight

Doctors sometimes prescribe metformin, a diabetes drug, to treat PCOS. As berberine appears to have similar effects to metformin, it may also be a good treatment option for PCOS.

A systematic review found that berberine has promise as a treatment for PCOS with insulin resistance. However, the authors state that confirming these effects will require further studies.

Cancer

Berberine can create changes within the molecules of cells, and this could have another potential benefit: fighting cancer.

One review found that berberine has “clear inhibitory effects” on the following cancers:

Another study states that berberine helps treat cancer by interfering with its progression and its typical life cycle. It may also play a role in killing cancer cells.

Based on this evidence, the authors state that berberine is “highly expected to be effective, safe, and affordable” as a cancer-fighting agent.

However, it is important to remember that researchers have only studied berberine’s effects on cancer cells in a laboratory, not in people.

Gut health

If berberine can help treat cancer, inflammation, diabetes, and other conditions, it may be because of a beneficial effect on gut microbiota, according to some research published in 2020. Scientists have found links between the gut microbiome — colonies of bacteria in the gut — and these conditions.

Berberine has an antibacterial action that seems to remove the harmful bacteria in the gut, and thus enhance the growth of healthy bacteria.

While studies in humans and rodents have suggested this could be true, scientists caution that more research is needed to confirm how berberine affects humans and whether it is safe to use.

Berberine: Botanical Occurrence, Traditional Uses ...

Abstract

Berberine-containing plants have been traditionally used in different parts of the world for the treatment of inflammatory disorders, skin diseases, wound healing, reducing fevers, affections of eyes, treatment of tumors, digestive and respiratory diseases, and microbial pathologies. The physico-chemical properties of berberine contribute to the high diversity of extraction and detection methods. Considering its particularities this review describes various methods mentioned in the literature so far with reference to the most important factors influencing berberine extraction. Further, the common separation and detection methods like thin layer chromatography, high performance liquid chromatography, and mass spectrometry are discussed in order to give a complex overview of the existing methods. Additionally, many clinical and experimental studies suggest that berberine has several pharmacological properties, such as immunomodulatory, antioxidative, cardioprotective, hepatoprotective, and renoprotective effects. This review summarizes the main information about botanical occurrence, traditional uses, extraction methods, and pharmacological effects of berberine and berberine-containing plants.

Keywords:

berberine, botanical occurrence, traditional uses, extraction methods, biological activities

Introduction

Berberine

Berberine(5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolo[5,6-a] quinolizinium) Figure , is a nonbasic and quaternary benzylisoquinoline alkaloid, a relevant molecule in pharmacology and medicinal chemistry. Indeed, it is known as a very important natural alkaloid for the synthesis of several bioactive derivatives by means of condensation, modification, and substitution of functional groups in strategic positions for the design of new, selective, and powerful drugs (Chen et al., 2005).

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Traditional use of berberine-containing species

In the Berberidaceae family, the genus Berberis comprises of ~450–500 species, which represent the main natural source of berberine. Plants of this genus are used against inflammation, infectious diseases, diabetes, constipation, and other pathologies (Singh A. et al., 2010). The oldest evidence of using barberry fruit (Berberis vulgaris) as a blood purifying agent was written on the clay tablets in the library of Assyrian emperor Asurbanipal during 650 BC (Karimov, 1993). In Asia, the extensive use of the stem, stem bark, roots, and root bark of plants rich in berberine, particularly Berberis species, has more than 3000 years of history. Moreover, they have been used as raw material or as an important ingredient in Ayurvedic and traditional Chinese medicine (Birdsall, 1997; Kirtikar and Basu, 1998; Gupta and Tandon, 2004; Kulkarni and Dhir, 2010). In Ayurveda, Berberis species have been traditionally used for the treatment of a wide range of infections of the ear, eye, and mouth, for quick healing of wounds, curing hemorrhoids, indigestion and dysentery, or treatment of uterine and vaginal disorders. It has also been used to reduce obesity, and as an antidote for the treatment of scorpion sting or snakebite (Dev, 2006). Berberine extracts and decoctions are traditionally used for their activities against a variety of microorganisms including bacteria, viruses, fungi, protozoa, helminthes, in Ayurvedic, Chinese, and Middle-Eastern folk medicines (Tang et al., 2009; Gu et al., 2010).

In Yunani medicine, Berberis asiatica has multiple uses, such as for the treatment of asthma, eye sores, jaundice, skin pigmentation, and toothache, as well as for favoring the elimination of inflammation and swelling, and for drying ulcers (Kirtikar and Basu, 1998). Decoction of the roots, and stem barks originating from Berberis aristata, B. chitria, and B. lycium (Indian Berberis species), have been used as domestic treatment of conjunctivitis or other ophthalmic diseases, enlarged liver and spleen, hemorrhages, jaundice, and skin diseases like ulcers (Rajasekaran and Kumar, 2009). On the other hand, the use of decoction of Indian barberry mixed with honey has also been reported for the treatment of jaundice. Additionally, it has been reported the use of decoction of Indian barberry and Emblic myrobalan mixed with honey in the cure of urinary disorders as painful micturition (Kirtikar and Basu, 1998). Numerous studies dealing with its antimicrobial and antiprotozoal activities against different types of infectious organisms (Vennerstrom et al., 1990; Stermitz et al., 2000; Bahar et al., 2011) have been assessed so far. Moreover, it has been used to treat diarrhea (Chen et al., 2014) and intestinal parasites since ancient times in China (Singh and Mahajan, 2013), and the Eastern hemisphere, while in China it is also used for treating diabetes (Li et al., 2004).

Nowadays, a significant number of dietary supplements based on plants containing berberine (Kataoka et al., 2008) are used for reducing fever, common cold, respiratory infections, and influenza (Fabricant and Farnsworth, 2001). Another reported use for berberine-containing plants is their application as an astringent agent to lower the tone of the skin. Also, positive effects were observed on the mucous membranes of the upper respiratory tract and gastrointestinal system with effects on the associated ailments (Chen et al., 2014; Yu et al., 2016).

In southern South America leaves and bark of species of the genus Berberis are used in traditional medicine administered for mountain sickness, infections, and fever (San Martín, 1983; Houghton and Manby, 1985; Anesini and Perez, 1993).

Furthermore, there are other genera which contain berberine. The genus Mahonia comprises of several species that contain berberine. Within them, M. aquifolium has been traditionally used for various skin conditions. Due to its main alkaloid (berberine), is known to be used in Asian medicine for its antimicrobial activity. Coptidis rhizoma (rhizomes of Coptis chinensis), another plant which contains berberine, is a famous herb very frequently used in traditional Chinese medicine for the elimination of toxins, “damp-heat syndromes”, “purge fire”, and to “clear heat in the liver” (Tang et al., 2009). Table gathers a synthesis of the main traditional uses of species containing berberine.

Table 1

FamilyScientific nameTraditional usesReferencesAnnonaceaeAnnickia chlorantha (Oliv.) Setten & Maas (ex-Enantia chlorantha Oliv.)Treat jaundice, hepatitis A, B, C, and D, conjunctivitis, leishmaniasis, medicine for cuts and infected wounds, sores and ulcers, antipyretic for various fevers, tuberculosis, vomiting of blood, urinary tract infections, treatment of fatigue, rheumatism, treat malaria symptoms, aches, wounds, boils, vomiting, yellow bitter, chills, sore, spleen in children and body pains, skin ailments, intercostal pain and to promote conception, intestinal worms, intestinal spasms, malaria and sexual asthenia, treat coughs and wounds; rickettsia fever, treat of sleeping sickness and dysentery, hemostatic and rickettsia, treat yellow fever and typhoid fever, treat diabetes, treat syphilis, and other infectious diseases, poliomyelitis, treat hypertension, treat HIV and prostate cancerOliver, 1960; Sandberg, 1965; Bouquet, 1969; Hamonniere et al., 1975; Onwuanibe, 1979; Burkill, 1985; Gill and Akinwumi, 1986; Gbile et al., 1988; Vennerstrom and Klayman, 1988; Vennerstrom et al., 1990; Adjanohoun et al., 1996; Nguimatsia et al., 1998; Kayode, 2006; Odugbemi et al., 2007; Ehiagbonare and Onyibe, 2008; Jiofack et al., 2008, 2009; Kadiri, 2008; Ogbonna et al., 2008; Olowokudejo et al., 2008; Betti and Lejoly, 2009; Ndenecho, 2009; Adeyemi et al., 2010; Noumi, 2010; Noumi and Anguessin, 2010; Noumi and Yumdinguetmun, 2010; Bele et al., 2011; Din et al., 2011; Ngono Ngane et al., 2011; Oladunmoye and Kehinde, 2011; Gbolade, 2012; Musuyu Muganza et al., 2012; Tsabang et al., 2012; Betti et al., 2013; Borokini et al., 2013; Fongod, 2014; Ishola et al., 2014; Ohemu et al., 2014Annickia pilosa (Exell) Setten & Maas (ex-Enantia pilosa Exell)Medicine for cutsVersteegh and Sosef, 2007Annickia polycarpa (DC.) Setten & Maas ex I.M.Turner (ex-Enantia polycarpa (DC.) Engl. & Diels)Treat cuts, antiseptic to treat sores, stomach ulcers, leprosy and ophthalmia, treatment of skin infections and sores, treat jaundice, and treat fever including malaria and to promote wound healing, against intestinal problemsIrvine, 1961; Bouquet and Debray, 1974; Ajali, 2000; Govindasamy et al., 2007; Versteegh and Sosef, 2007Rollinia mucosa (Jacq.) Baill.Treat of tumorsHartwell, 1982Xylopia polycarpa (DC.) Oliv.Treat wounds, ulcers, leprosy, rheumatism, stomach and gall-bladder problems, eye diseases, for conception, diarrhea, malaria, fevers and sleeping disordersNeuwinger, 1996BerberidaceaeBerberis actinacantha Mart.AntipyreticSan Martín, 1983Berberis aquifolium PurshSkin conditions, treat eczema, acne, conjunctivitis and herpes, alleviate the symptoms of psoriasis, treat diarrhea and in higher doses to treat constipation, improvement of blood flow to the liver, stimulate intestinal secretions and bile flow, treat jaundice, hepatitis, cirrhosis and general digestive problems, treatment of gall bladder disease, hemorrhages and a few forms of cancer, fungal infections, dysentery, anti-inflammatory properties, stomach problems, sore womb following childbirth and/or menstruationKing, 1898; Ritch-Krc et al., 1996Berberis aristata DC.Treat allergies, metabolic disorders, ophthalmia, and other eye diseases, treat bleeding piles, anti-osteoporosis, treat skin diseases, menorrhagia, fever, diarrhea, dysentery, cholera, jaundice, ear and urinary tract infections, anti-bacterial, anti-fungal, anti-inflammatory, analgesic, anti-pyretic, jaundice, piles, malaria, laxative, anti-scorbutic, anti-diabetic, and anti-hepatopathicBhattacharjee et al., 1980; Duke and Beckstrom-Sternberg, 1994; Küpeli et al., 2002; Acharya and Rokaya, 2005; Chhetri et al., 2005; Kunwar and Adhikari, 2005; Sharma et al., 2005; Joshi and Joshi, 2007; Meena et al., 2009; Shahid et al., 2009; Phondani et al., 2010; Saraf et al., 2010; Tiwary et al., 2010; Sati and Joshi, 2011; Yogesh et al., 2011Berberis asiatica Roxb. ex DC.Jaundice, diabetes mellitus, wound healing, asthma; drying unhealthy ulcers, anti-inflammatory, swelling, treat pneumococcal infections, eye (conjunctivitis) and ear diseases, rheumatism, fever, stomach disorders, skin disease (hyperpigmentation), malarial fever, laxative, teeth problems (toothache), and headacheWatt, 1883; Kirtikar and Basu, 1933; Samhita, 1963; Hashmi and Hafiz, 1986; Bhandari et al., 2000; Shah and Khan, 2006; Uniyal et al., 2006; Uprety et al., 2010; Maithani et al., 2014Berberis buxifolia Lam.Treat infectionsAnesini and Perez, 1993; Mølgaard et al., 2011Berberis chitria Buch.-Ham. ex Lindl.Treat skin disease, jaundice, rheumatism, affection of eyes (household treatment for conjunctivitis, ophthalmic, bleeding piles), ulcers, skin diseases, enlarged liver and spleenWatt, 1883; Kirtikar and Basu, 1933; Sir and Chopra, 1958Berberis darwinii Hook.Antipyrectic, anti-inflammatory, treat stomach pains, indigestion, and colitisMontes and Wilkomirsky, 1987Berberis empetrifolia Lam.Treat mountain sicknessSan Martín, 1983Berberis integerrima Bunge.Antipyretic, treat diabetes, bone fractures, rheumatism, radiculitis, heart pain, stomach aches, kidney stones, tuberculosis, chest pain, headaches, constipation, and woundKhalmatov, 1964; Khodzhimatov, 1989; Baharvand-Ahmadi et al., 2016Berberis jaeschkeana C. K. Schneid.Treat eye diseasesKala, 2006Berberis koreana Palib.Antipyretic, treat gastroenteritis, sore throats, and conjunctivitisAhn, 2003Berberis leschenaultia Wall. ex Wight & Arn.Antipyretic, cold and complications during post-natal periodRajan and Sethuraman, 1992Berberis libanotica Ehrenb. ex C. K. Schneid.Treat rheumatic and neuralgic diseases, anti-inflammatory, treat arthritis and muscular painEl Beyrouthy et al., 2008; Esseily et al., 2012Berberis lycium RoyleTreat eye diseases, febrifuge, jaundice, diarrhoea, menorrhagia, piles, backache, dysentery, earache, fracture, eye ache, pimples, boils, wound healing, cough and throat pain, intestinal colic, diabetes, throat pain, scabies, bone fractures, sun blindness, against stomachache and intestinal problemsZaman and Khan, 1970; ul Haq and Hussain, 1993; Bushra et al., 2000; Kaur and Miani, 2001; Hamayun et al., 2003; Ahmed et al., 2004; Abbasi et al., 2005, 2009, 2010; Shah and Khan, 2006; Zabihullah et al., 2006; Hussain et al., 2008; Sood et al., 2010Berberis microphylla G. Forst. (ex-Berberis heterophylla Juss. ex Poir.)Febrifuge, anti-inflammatory and treat diarrheaMuñoz, 2001Berberis oblonga (Regel) C. K. SchneidHeart tonic, treat neurasthenia, antipyretic, antidiarrheal, treat rheumatism, eye diseases and wounds of the mouth, jaundice, stomach aches, back pain and arthralgiaKhalmatov, 1964; Sezik et al., 2004; Pak, 2005Berberis petiolaris Wall. ex G. DonTreat malarial fever, diarrhea, conjunctivitis, and jaundiceKarimov, 1993Berberis pseudumbellata R. ParkerDiuretic, treat jaundice, intestinal disorders, eye diseases, oxytocic and throat ache, stomach problems and ulcersKala, 2006; Khan and Khatoon, 2007; Singh et al., 2009; Khan et al., 2016Berberis thunbergii DC.Anti-inflammatoryKüpeli et al., 2002Berberis tinctoria Lesch.Antimicrobial for skin disease, jaundice, affection of eyes, treat menorrhagia, diarrhea, and rheumatismFyson, 1975; Satyavati et al., 1987Berberis umbellata Wall. ex G. DonTreating fever, jaundice, nausea, eye disorders and skin problems, tonicSingh et al., 2012Berberis vulgaris L.Antiarrhythmic, sedative, anticancer, heal internal injuries, remove kidney stones, treat sore throat and feverTantaquidgeon, 1928; Chaudhury et al., 1980; Zovko Koncić et al., 2010Caulophyllum thalictroides (L.) MichauxMenstrual cramps, relieve the pain of childbirth, promote prompt delivery, treat colics, cramps, hysteria, rheumatism, uterine stimulant, inducer of menstruation, and antispasmodicCastleman, 1991; Hutchens, 1992Jeffersonia diphylla (L.) Pers.Antispasmodic, diuretic, emetic, expectorant, treat diarrhea, dropsy, gravel and urinary problems, emetic, expectorant, treat sores, ulcers and inflamed partsUphof, 1959; Duke and Ayensu, 1985; Foster and Duke, 1990; Coffey, 1993; Moerman, 1998; Lust, 2014Mahonia fortunei (Lindl.) FeddeAnticancer, febrifuge, antiodontalgic, treat testicular swelling and arthritic painDuke and Ayensu, 1985; He and Mu, 2015Mahonia napaulensis DC.Diuretic, demulcent, treat dysentery and inflammations of the eyesChopra et al., 1986; Manandhar, 2002Nandina domestica Thunb.Antitussive, astringent, febrifuge, stomachic and tonic, treat of fever in influenza, acute bronchitis, whooping cough, indigestion, acute gastro-enteritis, tooth abscess, pain in the bones, muscles and traumatic injuries, and antirheumaticKariyone and Koiso, 1971; Duke and Ayensu, 1985; Fogarty, 1990Sinopodophyllum hexandrum (Royle) T. S. YingRegulate menstruation, promote the circulation of blood, treat amenorrhea, difficult labor and retention of dead fetus or placentaKong et al., 2010MenispermaceaeTinospora sinensis (Lour.) Merr (ex-Tinospora cordifolia (Willd.) Miers)Tonic, antiperiodic, anti-spasmodic, anti-inflammatory, antiarthritic, anti-allergic, anti-diabetic, improve the immune system, antistress, anti-leprotic and anti-malarial activitiesSingh et al., 2003PapaveraceaeArgemone albiflora Hornem (ex-Argemone alba F. Lestib.)Anthydropic, cathartic, diaphoretic, diuretic, demulcent, emetic, purgative, treat jaundice, skin ailments, colds, colics and woundsSmyth, 1903; Foster and Duke, 1990Argemone mexicana L.Analgesic, antispasmodic, sedative, treat warts, cold sores, cutaneous affections, skin diseases, itches, treat cataracts, treat dropsy, jaundice, treat chronic skin diseases, expectorant, treat coughs and chest complaints, demulcent, emetic, expectorant, laxative and antidote to snake poisoningUphof, 1959; Pesman, 1962; Usher, 1974; Stuart and Smith, 1977; Emboden, 1979; Chopra et al., 1986; Coffey, 1993; Chevallier, 1996Argemone platyceras L.Treat respiratory ailments as asthma, cough, bronchitis and pneumoniaEmes et al., 1994Bocconia frutescens L.Treat skin conditions (ulcers and eruptions) and respiratory tract infections (bronchistis and tuberculosis)Martinez, 1977, 1984Chelidonium majus L.Treat ophthalmic diseases (remove films from the cornea of the eye), mild sedative, antispasmodic, relaxing the muscles of the bronchial tubes and intestines, treat warts, alterative, anodyne, antispasmodic, cholagogue, diaphoretic, diuretic, hydrogogue, narcotic, purgative, treat bronchitis, whooping cough, asthma, jaundice, gallstones and gallbladder pains, anticancer, analgesic, treat stomach ulcer, treat get rid of warts, ringworm and cornsLaunert, 1981; Grieve, 1984; Phillips and Foy, 1990; Phillips and Rix, 1991; Chevallier, 1996; Lust, 2014Corydalis solida subsp. brachylovaAnodyne, antibacterial, antispasmodic, hallucinogenic, calm the nerves, sedative for insomnia, CNS stimulant, painkiller, treat painful menstruation, lowering the blood pressure, traumatic injury and lumbagoLaunert, 1981; Bown, 1995Corydalis solida subsp. slivenensis (Velen.) Hayek (ex-Corydalis slivenensis Velen.)Corydalis solida subsp. tauri colaCorydalis turtschaninovii Besser (ex-Corydalis ternata (Nakai) Nakai)Treat memory dysfunction, treat gastric, duodenal ulcer, cardiac arrhythmia disease, rheumatism and dysmenorrheaTang and Eisenbrand, 1992; Kamigauchi and Iwasa, 1994; Orhan et al., 2004; Houghton et al., 2006Eschscholzia californica Cham.Sedative, diuretic, relieve pain, relax spasms, promote perspiration, treat nervous tension, anxiety, insomnia, urinary incontinence (especially in children), narcotic, relieve toothache, antispasmodic, analgesic and suppress the flow of milk in lactating womenCoffey, 1993; Bown, 1995; Chevallier, 1996; Moerman, 1998Glaucium corniculatum (L.) Rud. subsp. corniculatumReduce warts, antitusive, treat CNS disturbances, sedative, cooling, and mild laxativeAl-Douri, 2000; Al-Qura'n, 2009; Hayta et al., 2014Macleaya cordata (Willd.) R.Br.Analgesic, antioedemic, carminative, depurative, diuretic, treat insect bites, and ringwormGrieve, 1984; Duke and Ayensu, 1985Macleaya microcarpa (Maxim.) FeddeTreat some skin diseases and inflammationDeng and Qin, 2010Papaver dubium L.Sudorific, diuretic, expectorant and ophthalmiaChopra et al., 1986Papaver dubium var. lecoquiiPapaver rhoeas L. var. chelidonioidesAilments in the elderly and children, mild pain reliever, treat irritable coughs, reduce nervous over-activity, anodyne, emollient, emmenagogue, expectorant, hypnotic, slightly narcotic, sedative, treat bronchial complaints and coughs, insomnia, poor digestion, nervous digestive disorders and minor painful conditions, treat jaundice, fevers, and anticancerUphof, 1959; Launert, 1981; Grieve, 1984; Duke and Ayensu, 1985; Phillips and Foy, 1990; Bown, 1995; Chevallier, 1996Papaver hybridum L.Treat dermatologic diseases, anti-infective, diuretic, sedative, and antitussiveRivera Núñez and Obon de Castro, 1996; Ali et al., 2018RanunculaceaeCoptis chinensis Franch.Control of bacterial and viral infections, relax spasms, lower fevers, stimulate the circulation, treat diabetes mellitus, analgesic, locally anaesthetic, antibacterial, antipyretic, bitter, blood tonic, carminative, cholagogue, digestive, sedative, stomachic, vasodilator, treat diarrhoea, acute enteritis and dysentery, treat insomnia, fidget, delirium due to high fever, leukaemia and otitis media, treat conjunctivitis, skin problems (acne, boils, abscesses and burns whilst), mouth, tongue ulcers, swollen gums, and toothacheUphof, 1959; Usher, 1974; Duke and Ayensu, 1985; Yeung, 1985; Bown, 1995Coptis japonica (Thunb.) MakinoControl of bacterial and viral infections, relax spasms, lower fevers, stimulate the circulation, locally analgesic and anaesthetic, anti-inflammatory, stomachic, treat conjunctivitis, intestinal catarrh, dysentery, enteritis, high fevers, inflamed mouth and tongueKariyone and Koiso, 1971; Usher, 1974; Grieve, 1984; Bown, 1995Coptis teeta Wall.Control of bacterial and viral infections, relaxes spasms, lowers fevers and stimulate the circulation, locally analgesic, anaesthetic, ophthalmic and pectoral diseases, effective antibacterial, treat dysenteryStuart and Smith, 1977; Duke and Ayensu, 1985; Bown, 1995Hydrastis canadensis L.Treat disorders of the digestive system and mucous membranes, treat constipation, antiperiodic, antiseptic, astringent, cholagogue, diuretic, laxative, stomachic, tonic, treat disorders affecting the ears, eyes, throat, nose, stomach, intestines, and vaginaUphof, 1959; Weiner, 1980; Grieve, 1984; Mills, 1985; Foster and Duke, 1990; Coffey, 1993; Bown, 1995; Chevallier, 1996; Lust, 2014Xanthorhiza simplicissima MarshallTreat mouth ulcers, stomach ulcers, colds, jaundice, treat piles, and digestive disordersWeiner, 1980; Foster and Duke, 1990; Moerman, 1998RutaceaePhellodendron amurense Rupr.Treat gastroenteritis, abdominal pain and diarrhea, antiinflammator, immunostimulator and treat cancer (antitumor activities)Uchiyama et al., 1989; Park et al., 1999
  • Phellodendron chinense C. K. Schneid.

  • Phellodendron chinense var. glabriusculum C. K. Schneid.

  • (ex-Phellodendron wilsonii Hayata & Kaneh.)

Act strongly on the kidneys, detoxicant for hot damp conditions, treat meningitis, conjunctivitis, antibacterial, antirheumatic, aphrodisiac, bitter stomachic, cholagogue, diuretic, expectorant, febrifuge, hypoglycaemic, treat ophtalmia, skin, vasodilator and tonic, treat acute diarrhoea, dysentery, jaundice, vaginal infections (with Trichomonas vaginalis), acute urinary tract infections, enteritis, boils, abscesses, night sweats and skin diseases, and expectorantKariyone and Koiso, 1971; Usher, 1974; Stuart and Smith, 1977; Grieve, 1984; Yeung, 1985; Bown, 1995; Chevallier, 1996Zanthoxylum monophyllum Tul.Treat eye infections and dark vomitusHirschhorn, 1981; Eric Brussell, 2004Open in a separate window

Botanical sources of berberine

Berberine has been detected, isolated, and quantified from various plant families and genera including Annonaceae (Annickia, Coelocline, Rollinia, and Xylopia), Berberidaceae (Berberis, Caulophyllum, Jeffersonia, Mahonia, Nandina, and Sinopodophyllum), Menispermaceae (Tinospora), Papaveraceae (Argemone, Bocconia, Chelidonium, Corydalis, Eschscholzia, Glaucium, Hunnemannia, Macleaya, Papaver, and Sanguinaria), Ranunculaceae (Coptis, Hydrastis, and Xanthorhiza), and Rutaceae (Evodia, Phellodendron, and Zanthoxyllum) (Table ). The genus Berberis is well-known as the most widely distributed natural source of berberine. The bark of B. vulgaris contains more than 8% of alkaloids, berberine being the major alkaloid (about 5%) (Arayne et al., 2007).

Table 2

FamilyScientific nameCommon nameUsed partReferencesAnnonaceaeAnnickia chlorantha (Oliv.) Setten & Maas (ex-Enantia chlorantha Oliv.)African whitewood, african yellow wood Epfoué, Péyé, Nfol, PoyoBarkMell, 1929Annickia pilosa (Exell) Setten & Maas (ex-Enantia pilosa Exell)–BarkBuzas and Egnell, 1965Annickia polycarpa (DC.) Setten & Maas ex I. M. Turner (ex-Enantia polycarpa (DC.) Engl. & Diels)African yellow woodBarkBuzas and Egnell, 1965Coelocline polycarpa A.DC.Yellow-dye tree of SoudanBarkHenry, 1949Rollinia mucosa (Jacq.) Baill.Biriba, wild sweet sop, wild cashinaFruitChen et al., 1996Xylopia macrocarpa A.Chev.JangkangStem barkWillaman and Schubert, 1961Xylopia polycarpa (DC.) Oliv.–Stem barkWillaman and Schubert, 1961BerberidaceaeBerberis aetnensis C.Presl–RootsBonesi et al., 2013LeavesMusumeci et al., 2003RootHenry, 1949Berberis amurensis Rupr.BarberryStem & rootsTomita and Kugo, 1956Berberis aquifolium PurshOregon grapeRootsParsons, 1882Berberis aristata DC.Tree turmericBarkChakravarti et al., 1950RootsSingh A. et al., 2010StemRaw herbSingh R. et al., 2010ExtractFruitKamal et al., 2011RootsAndola et al., 2010a,cRootsRashmi et al., 2009RootsSingh and Kakkar, 2009RootsSrivastava et al., 2004RootsSrivastava et al., 2001BarkWillaman and Schubert, 1961Berberis asiatica Roxb. ex DC.Chutro, rasanjan (Nep); marpyashi (Newa); daruharidra, darbi (Sans)RootsAndola et al., 2010bRootsAndola et al., 2010cRootsSrivastava et al., 2004Roots, stem, barkWillaman and Schubert, 1961Berberis barandana Vidal.–NDWillaman and Schubert, 1961Berberis beaniana C. K. Schneid.Kang song xiao bo (pinyin, China)–Steffens et al., 1985Berberis chitria Buch.-Ham. ex Lindl.Chitra, indian barberryWhole plantHussaini and Shoeb, 1985RootsSrivastava et al., 2006a,b,cBerberis concinna Hook.f.BarberryStem barkTiwari and Masood, 1979Berberis congestiflora GayMichayLeaves and stemTorres et al., 1992Berberis coriaria Royle ex Lindl.–Stem barkTiwari and Masood, 1979Berberis croatica Mart. ex Schult. & Schult.f.Croatian barberryRootsKončić et al., 2010RootsKosalec et al., 2009Berberis darwinii Hook.Michai, calafateRootsRichert, 1918LeavesUrzúa et al., 1984Stem-barkHabtemariam, 2011Berberis densiflora Raf.–LeavesKhamidov et al., 1997bBerberis floribunda Wall. ex G.DonNepal barberryRootsChatterjee, 1951Berberis fortunei Lindl.Fortune's MahoniaWoodWillaman and Schubert, 1961Berberis guimpelii K. Koch & C. D. Bouché–RootsPetcu, 1965aBerberis heteropoda Schrank–Root barkWillaman and Schubert, 1961Berberis himalaica Ahrendt–Stem-barkChatterjee et al., 1952Berberis horrida Gay–Leaves and stemTorres et al., 1992Berberis iliensis Popov–Young shootsKarimov and Shakirov, 1993RootsDzhalilov et al., 1963Berberis integerrima Bunge.–RootKarimov et al., 1993LeavesKarimov et al., 1993; Khamidov et al., 1996c, 1997bBerberis jaeschkeana C. K. Schneid.Jaeschke's Barberry–Rashid and Malik, 1972Berberis jamesonii Lindl (ex-Berberis glauca Benth)––Willaman and Schubert, 1961Berberis japonica R.BrJapanese MahoniaWood, rootWillaman and Schubert, 1961Berberis kawakamii Hayata–RootsYang and Lu, 1960aBerberis koreana Palib.Korean barberryBark of the stemPetcu, 1965bBark of the rootsSeedsStemRoots–Kostalova et al., 1982RootsYoo et al., 1986LeavesBerberis lambertii R. Parker–RootsChatterjee and Banerjee, 1953Berberis laurina ThunbLaurel barberryRootsGurguel et al., 1934; Willaman and Schubert, 1961Berberis leschenaultii Wall. ex Wight & Arn (ex-Mahonia leschenaultii (Wall. ex Wight & Arn.) Takeda)–BarkWillaman and Schubert, 1961Berberis libanotica Ehrenb. ex C. K. Schneid.–RootBonesi et al., 2013Berberis lycium RoyleBoxthorn barberryRootsAndola et al., 2010cBerberis microphylla G. Forst. (ex-Berberis heterophylla Juss. ex Poir. Berberis buxifolia Lam.)Patagonian barberry, magellan barberry, calafateRootsFreile et al., 2006–Rashid and Malik, 1972Berberis mingetsensis Hayata–RootsYang and Lu, 1960bBerberis nummularia BungeNummular barberryYoung shootsKarimov et al., 1993Berberis morrisonensis Hayata–RootsYang, 1960a,bStem–Berberis nepalensis Spreng. (ex-Mahonia acanthifolia Wall. ex G.Don)––Willaman and Schubert, 1961Berberis nervosa PurshDwarf Oregon-grape–Willaman and Schubert, 1961Berberis oblonga (Regel) C. K. SchneidOblong barberryStemKarimov and Lutfullin, 1986; Gorval' and Grishkovets, 1999LeavesKhamidov et al., 2003RootsTadzhibaev et al., 1974Berberis petiolaris Wall. ex G. DonChocharRootsHuq and Ikram, 1968Berberis pseudumbellata R. Parker–RootsAndola et al., 2010bStem bark–Pant et al., 1986Berberis repens Lindl.Creeping mahonia, creeping Oregon grape, creeping barberry, or prostrate barberry–Willaman and Schubert, 1961Berberis sargentiana C. K. Schneid.Sankezhen–Liu, 1992Berberis swaseyi Buckley––Willaman and Schubert, 1961Berberis thunbergii DC.Japanese barberryStemKhamidov et al., 1997aLeavesKhamidov et al., 1997aBerberis tinctoria Lesch.Nilgiri barberryRootsSrivastava and Rawat, 2007Berberis trifolia (Cham. & Schltdl.) Schult. & Schult.f.–Root, stemWillaman and Schubert, 1961Berberis turcomanica Kar. ex Ledeb.–LeavesKhamidov et al., 1996a,b,cBerberis umbellata Wall. ex G.DonHimalayan barberryRootsSingh et al., 2012Berberis vulgaris L.BarberryStems and rootsImanshahidi and Hosseinzadeh, 2008RootsKončić et al., 2010RootsKosalec et al., 2009Berberis waziristanica Hieron.–Root barkAtta-ur-Rahma and Ahmad, 1992Caulophyllum thalictroides (L.) Michaux (ex-Leontice thalictroides L.)Blue cohosh–Willaman and Schubert, 1961Jeffersonia diphylla (L.) Pers.Twinleaf–Willaman and Schubert, 1961Mahonia borealis Takeda––Willaman and Schubert, 1961Mahonia fortunei (Lindl.) FeddeFortune's MahoniawoodWillaman and Schubert, 1961Mahonia napaulensis DC. (ex- Mahonia griffithii; ex-Mahonia manipurensis Takeda; Mahonia sikkimensis Takeda)Nepal BarberrybarkWillaman and Schubert, 1961Mahonia simonsii Takeda––Willaman and Schubert, 1961Nandina domestica Thunb.Nandina, heavenly bamboo or sacred bamboobark, rootWillaman and Schubert, 1961Sinopodophyllum hexandrum (Royle) T.S.YingHimalayan May Apple, Indian may appleRoot, rhizomeWillaman and Schubert, 1961MenispermaceaeTinospora sinensis (Lour.) Merr. (ex-Tinospora cordifolia) (Willd.) MiersGulbel, indian tinosporaStemSrinivasan et al., 2008–Singh et al., 2003PapaveraceaeArgemone albiflora Hornem. (ex-Argemone alba F.Lestib.)White prickly poppy, Bluestem pricklypoppyAerial part and rootsSlavikova et al., 1960Foote, 1932Israilov and Yunusov, 1986Argemone hybrida R.Otto & Verloove–Leaves and stemIsrailov and Yunusov, 1986Argemone mexicana L.Prickly poppyApigeal parts, seedsHaisova and Slavik, 1975; Israilov and Yunusov, 1986; Fletcher et al., 1993LeavesBapna et al., 2015SeedsFletcher et al., 1993–Singh, 2014–Majumder et al., 1956; Hakim et al., 1961; Misra et al., 1961Superterranean partsSlavikova and Slavik, 1955Roots–Santos and Adkilen, 1932; de Almeida Costa, 1935; Misra et al., 1961; Doepke et al., 1976; Abou-Donia and El-Din, 1986; Monforte-Gonzalez et al., 2012RootsPathak et al., 1985; Kukula-Koch and Mroczek, 2015Leaves and capsulesSchlotterbeck, 1902Whole plantBose et al., 1963; Haisova and Slavik, 1975LatexSantra and Saoji, 1971Argemone ochroleuca SweetChicaloteSeedsFletcher et al., 1993Argemone platyceras L.Chicalote poppy, crested poppyLeaves and stemIsrailov and Yunusov, 1986Argemone subintegrifolia Ownbey–Aerial partStermitz et al., 1974Argemone squarrosa GreeneHedgehog pricklypoppyAerial partStermitz, 1967Bocconia frutescens L.Plume poppy, tree poppy, tree celandine, parrotweed, sea oxeye daisy, john crow bushLeavesSlavik and Slavikova, 1975Roots, stalks, leavesTaborska et al., 1980Chelidonium majus L.Celandine poppyRootsJusiak, 1967Corydalis chaerophylla DC.FitweedRootsJha et al., 2009Corydalis ophiocarpa Hook. f. et ThomsFitweedManske, 1939Corydalis solida subsp. brachylobaFitweedAerial partsSener and Temizer, 1988, 1991Corydalis solida subsp. slivenensis (Velen.) Hayek (ex-Corydalis slivenensis Velen.)Fitweed–Kiryakov et al., 1982a,bCorydalis solida subsp. tauricolaFitweed–Kiryakov et al., 1982bRhizomeSener and Temizer, 1990Corydalis turtschaninovii Besser. (ex-Corydalis ternata (Nakai) Nakai)FitweedTubersLee and Kim, 1999Eschscholzia californica Cham.Californian poppyRootsGertig, 1964Glaucium corniculatum (L.) Rud. subsp. corniculatumBlackspot HornpoppyAerial partsDoncheva et al., 2014–Slavik and Slavikova, 1957Glaucium grandiflorum Boiss. & A.HuetRed Horned Poppy, Grand-flowered Horned PoppyAerial partPhillipson et al., 1981Hunnemannia fumariifolia SweetMexican Tulip Poppy, Golden CupRootsSlavikova and Slavik, 1966Macleaya cordata (Willd.) R.Br.Plume poppy–Kosina et al., 2010Macleaya microcarpa (Maxim.) FeddePoppyRootsPěnčíková et al., 2011Papaver dubium L.Long-Head PoppyRootsSlavik et al., 1989Papaver dubium var. lecoquiiLong-Head PoppyLatexEgels, 1959Papaver rhoeas L. var. chelidonioidesCorn PoppyRootsSlavík, 1978Papaver hybridum L.PoppyAerial partPhillipson et al., 1981Sanguinaria canadensis L.BloodrootGreathouse, 1939RanunculaceaeCoptis chinensis Franch.Chinese goldthreadRootsJin and Shan, 1982RootsLou et al., 1982Coptis japonica (Thunb.) MakinoJapanese goldthreadRhizomeKubota et al., 1980Coptis teeta Wall.Gold threadRhizomeChen and Chen, 1988RhizomeZhang et al., 2008RootsHydrastis canadensis L.Goldenseal–Baldazzi et al., 1998–Leone et al., 1996Xanthorhiza simplicissima MarshallYellowrootRoot, stem, and leavesOkunade et al., 1994RutaceaeEvodia meliaefolia (Hance ex Walp.) Benth.–BarkPerkin and Hummel, 1895Phellodendron amurense Rupr.Amur cork treeBarkChiang et al., 2006Root barkZhang et al., 2008Trunk barkPerennial Branch barkAnnual branchesLeavesPhellodendron chinense C. K. Schneid.Chinese cork treeBarkChan et al., 2007Phellodendron chinense var. glabriusculum C. K. Schneid. (ex-Phellodendron wilsonii Hayata & Kaneh.)Chinese cork treeBark, branch, leaf and heartwoodChen, 1981–Tan et al., 2013BarkChen, 1982Phellodendron lavallei DodeLavalle corktreeBarkYavich et al., 1993Zanthoxylum monophyllum (Lam.) P. WilsonPalo rubioStem and branchesStermitz and Sharifi, 1977Zanthoxylum quinduense Tul.––Ladino and Suárez, 2010Open in a separate window

Berberine is also widely present in barks, leaves, twigs, rhizomes, roots, and stems of several medicinal plants species, including Argemone mexicana (Etminan et al., 2005), Berberis aristata, B. aquifolium, B. heterophylla, B. beaniana, Coscinium fenestratum (Rojsanga and Gritsanapan, 2005), C. chinensis, C. japonica, C. rhizome, Hydratis canadensis (Imanshahidi and Hosseinzadeh, 2008), Phellodendron amurense, P. chinense, Tinospora cordifolia (Khan et al., 2011), Xanthorhiza simplicissima (Bose et al., 1963; Knapp et al., 1967; Sato and Yamada, 1984; Steffens et al., 1985; Inbaraj et al., 2001; Liu et al., 2008a; Srinivasan et al., 2008; Vuddanda et al., 2010). Several researches found that berberine is widely distributed in the barks, roots, and stems of plants, nevertheless, bark and roots are richer in berberine compared to other plant parts (Andola et al., 2010a,b). In the Papaveraceae family, Chelidonium majus is another important herbal source of berberine (Tomè and Colombo, 1995). An important number of plants for medicinal use, such as Coptidis rhizoma and barberry, are the natural sources with the highest concentration of berberine. Barberries, such as Berberis aristata, B. aquifolium, B. asiatica, B. croatica, B. thunbergii, and B. vulgaris, are shrubs grown mainly in Asia and Europe, and their barks, fruits, leaves, and roots are often widely used as folk medicines (Imanshahidi and Hosseinzadeh, 2008; Kosalec et al., 2009; Andola et al., 2010c; Kulkarni and Dhir, 2010). Different research groups have reported that maximum berberine concentration accumulates in root (1.6–4.3%) and in most of the Berberis species, plants that grow at low altitude contain more berberine compared to higher altitude plants (Chandra and Purohit, 1980; Mikage and Mouri, 1999; Andola et al., 2010a). However, a correlation could not be established within the results of berberine concentration regarding to species and season of the year (Srivastava et al., 2006a,c; Andola et al., 2010c; Singh et al., 2012). Comparative studies of berberine concentration contained in different species of the same genus have been reported, e.g., higher berberine content in B. asiatica (4.3%) in comparison to B. lycium (4.0%), and B. aristata (3.8%). Meanwhile, Srivastava et al. (2004) documented a higher berberine content in root of B. aristata (2.8%) compared with B. asiatica (2.4%) (Andola et al., 2010a). Seasonal variation of berberine concentration has been reported, e.g., the maximum yield of berberine for B. pseudumbellata was obtained in the summer harvest, and was 2.8% in the roots and 1.8% for the stem bark, contrary to that reported in the roots of B. aristata, where the berberine concentration (1.9%) is higher for the winter harvest (Rashmi et al., 2009). These variations may be caused to multiple factors, among which stand out: (i) the intraspecific differences, (ii) location and/or, (iii) the analytical techniques used. Table gathers a synthesis of the main species containing berberine.

Extraction methods

Berberine, a quaternary protoberberine alkaloid (QPA) is one of the most widely distributed alkaloid of its class. Current studies suggest that isolation of the QPA alkaloids from their matrix can be performed using several methods. The principles behind these methods consist of the interconversion reaction between the protoberberine salt and the base. The salts are soluble in water, stable in acidic, and neutral media, while the base is soluble in organic solvents. Thus during the extraction procedure, the protoberberine salts are converted in their specific bases and further extracted in the organic solvents (Marek et al., 2003; Grycová et al., 2007).

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In the case of berberine, the classical extraction techniques like maceration, percolation, Soxhlet, cold or hot continuous extraction are using different solvent systems like methanol, ethanol, chloroform, aqueous, and/or acidified mixtures. Berberine's sensitivity to light and heat is the major challenge for its extraction. Hence, exposure to high temperature and light could lead to berberine degradation and thus influencing its matrix recovery. In his study Babu et al. (2012) demonstrated that temperature represent a crucial factor in both extraction and drying treatments prior extraction. The yield of berberine content in C. fenestratum stem tissue samples was higher in case of samples dried under the constant shade with 4.6% weight/weight (w/w) as compared to samples dried in oven at 65°C (1.32% w/w) or sun drying (3.21% w/w). As well hot extraction procedure with methanol or ethanol at 50°C gave lower extraction yields when compared with methanol or ethanol cold extraction at −20°C. Thus, berberine content in the shade-dried samples was 4.6% (w/w) for methanolic cold extraction and 1.29% (w/w) for methanolic hot extraction (Babu et al., 2012).

Along with extraction temperature, the choice of solvents is considered a critical step in berberine extraction as well (Figure ). As seen in Table , methanol, ethanol, aqueous or acidified methanol or ethanol are the most used extraction solvents. The acidified solvents (usually with the addition of 0.5% of inorganic or organic acids) are used to combine with free base organic alkaloids and transform them in alkaloid salts with higher solubility (Teng and Choi, 2013). The effect of different inorganic acids like hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid as well as the effect of an organic acid like acetic acid were tested on berberine content and other alkaloids in rhizomes of Coptis chinensis Franch by Teng and Choi (2013). In this case, 0.34% phosphoric acid concentration was considered optimal. Moreover, when compared to other classical extraction techniques like reflux and Soxhlet extraction, the cold acid assisted extraction gave 1.1 times higher berberine yields.

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Table 3

Sample (weight)Extraction methodDetection methodReferencesDried stem powder Coscinium fenestratum (Gaertn.) (1 g)Extraction solvents (ES): water, methanol–water (1:1. v/v), and methanol
Sonication (15 min, room temperature)
Centrifugation (2,800 rpm, 15 min)
Filtration and evaporation
Extracts resolubilization (methanol:water, 9:1 v/v)HPLC - DAD Column: ODS, Chromolith, RP-18e,100 × 4.6 mm Mobile Phases: Methanol/Deionized Water (90:10, v/v) Flow: 0.5 mL/min, Temperature: 25°C UV Spectrophotometric AnalysisAkowuah et al., 2014C. fenestratum (Gaertn.) (10 g)ES: methanol
Hot extraction: sample refluxed with ES for 3 h
Filtration and evaporation.
Extracts resolubilization (methanol)TLC
Adsorbent: Silica Gel GF 254
Solvent system: n-Butanol: Ethyl acetate: Acetic acid (2.5:1.5:1, v/v/v)
Detection: 254 and 366 nmArawwawala and Wickramaar, 2012Cold extraction: sample extraction with ES for 24 h
Filtration and evaporation.
Extracts resolubilization (methanol)Dried C. fenestratum (0.1 g)ES: absolute methanol
Cold extraction: sample extraction at −20°C
Hot extraction: water bath sample extraction at 50°C
ES: absolute ethanol
Cold extraction sample extraction at −20°C
Hot extraction: water bath sample extraction at 50°C
Samples centrifugation (10 min at 10°C after cooling down)
Samples filtrationHPLC
Column: C18, 250 × 4.6 mm, 5 μm
Mobile Phases: Acetonitrile/0.1% Trifluro-acetic acid (50:50, v/v)
Detection: 344 nm
Flow: 0.8 mL/minBabu et al., 2012C. fenestratum (1,000g)


Capsules (containing 62.5 mg C. fenestratum)ES: petroleum ether, chloroform, methanol (1L each)
Soxhlet extraction: with each ES for 3 days at (30–40°C)
ES: methanol (10 mL)
Extraction for 1 h
Filtration and evaporation
Resolubilisation in methanol (5 mL)HPLC
Column: Luna C18, 150 × 4.6 mm, 5 μm, Phenomenex
Mobile Phases: (A) Potassium dihydrogen phosphate
(pH −2.5) and (B) Acetonitrile
Detection: 220 nm
Flow: 1 mL/min
HPTLC
Adsorbent: Silica Gel 60F 254
Solvent system: n-Butanol: Glacial acetic acid: Water
(8:1:1, v/v/v)
Detection: 350 nm for all measurementsJayaprakasam and Ravi, 2014Tinospora cordifolia (Willd.), Tribulus terrestris (L.), Emblica officinalis (Gaertn.) (3 g)ES: chloroform
Dried sample trituration with ammonia solution
Drying at room temperature
Extraction with ES for 1h
Chloroform phase extraction with 5% sulfuric acid (x 3)
Basification of acid extract with sodium carbonate (pH −9)
Extraction of basified solution with chloroform (X 3)
Evaporation of chloroform phase (temperature under 50°C)
Residue solubilization with methanolUV-VIS
UV absorbance: 348 nmJoshi and Kanaki, 2013Cortex phellodendri (2 g)Ultrahigh pressure extraction (UPE)
Optimal parameters: ES: ethanol (69.1%), liquid-solid ratio−31.3, extracting pressure−243.30 MPa, extraction time−2 minHPLC
Column: Hypersil ODS C18, 250 × 4.6 mm, 5 μm
Mobile Phases: (A) 0.3% triethanolamine aqueous solution
(pH − 3.5)
Detection: 265 nm
Temperature: 30°C
Flow: 1 mL/minGuoping et al., 2012Rhizome of Coptis chinensis Franch (1 g)Supercritical fluid extraction
Extraction time: up to 3 h
Temperature: 60°C
Pressure: from 200 to 500 bar
Flow-rate of carbon dioxide (gaseous state): 1 L/min
Flow-rate of modifier: 0.4 mL/min.
Organic solvent modifier systems:
ethanol-modified supercritical carbon dioxide, methanol-modified supercritical carbon dioxide, 1,2-propanediol-modified supercritical carbon dioxide, 5% Tween 80 in methanol-modified supercritical carbon dioxide, 5% Tween in ethanol-modified supercritical carbon dioxideHPLC
Column: Diamonsil C18, 250 × 4.6 mm, 5 μm
Mobile Phases: 33 mM Potassium dihydrogen phosphate : acetonitrile (70:30, v/v)
Detection: 345 nm
Flow: 1 mL/minLiu et al., 2006Soxhlet extraction
ES: hydrochloric acid: methanol (1: 100, v/v)
Time: 8 hCortex pellodendri amurensis (1 g)Ultrahigh pressure extraction
ES: ethanol (50 %), liquid-solid ratio −30: 1, extracting pressure −400 MPa, extraction time −4 min, extraction temperaturte −40°C
Ultrasonic extraction
ES: 70% ethanol
Sample soaking for 24 h in 40 ml ES
Sonic extraction for 60 min at 30°CHPLC- DAD
Column: Daisopak SP-120-5-ODS_BP, 250 × 4.6 mm, 5 μm
Mobile Phases: (A) acetonitrile and (B) phosphoric acid: water (0.7:100, v/v)
Detection: 345 nm
Temperature: 25°C
Flow: 1 mL/minLiu et al., 2013Heat reflux extraction
ES: 70% ethanol
Sample soaking for 24 h in 40 ml ES
Sample extraction for 4 h at boiling stateSoxhlet extraction
ES: 70% ethanol
Sample soaking for 24 h in 40 ml ES
Sample extraction: 4 hGoldenseal (Hydrastis canadensis L.) (2, 5, 5 g)Pressurized hot water extraction
ES: water at 140°C,
Optimal parameters: pressure: 50 bars and flow rate: 1 mL/min, Time: 15 min
Reflux extraction
ES: methanol (200 mL)
Sonication: 4 h at 80°C
Ultrasonic extraction
ES: methanol (50 mL)
Reflux: 6 h with continuous stirringHPLC-DAD
Column: Zorbax eclipse Plus C 18, 75 x 4.6 mm, 3.5 μm
Mobile phases: (A) 0.1 % Formic Acid (pH 2.7) and (B) methanol
Detection: 242 nm
Temperature: 35°C
Flow: 1 mL/min
MS
Detection: ESI (+)
Capillary temperature: 200°C, Sheath gas: 80, Capillary voltage: 20 V, Tube lens voltage: 5VMokgadi et al., 2013Berberis aristata DC (1.5 g), Berberis aristata herb extract (0.1 g), Ayurvedic form (6 g)Crude herb reflux extraction
ES: methanol (100 mL) for 1 h in a water bath
Filtratio
Reextraction with ES (50 mL) for 30 min (× 2)
Filtrates combination and concentration to 50 mL
Herb extracts ultrasonic extraction
ES: methanol (up to 10 mL)
Sonication
FiltrationHPLC
Column: Zorbax ODS II, 250 x 4.6 mm, 5 μm
Mobile phase: potassium hydrogen phosphate buffer (pH 2.5)/ acetonitrile
Detection: 346 nm
Temperature: 40°C
Flow: 1 mL/minSingh R. et al., 2010Ayrvedic form ultrasonic extraction
ES: methanol (up to 25 mL)
SonicationBerberis aristata DC rootSoxhlet extraction
ES: ethanol
Berberine isolation
Ethanolic extract concentration to obtain a syrup mass
Dissolvation in hot water and filtration
Acidification (36.5% w/v hydrochloric acid)
Cool: ice bath - 30 min, overnight in refrigeratorHPTLC
Stationary phase: precoated silica gel 60GF254
Mobile phases: n-butanol: glacial acetic acid: water (12:3:4 v/v/v)
Temperature: 33 ± 5°C
Detection: 350 nmPatel, 2013Mahonia manipurensis (Takeda) stem bark (100 g)Cold extraction
ES: 80% methanol (1,000 mL)
Stirring at room temperature
Extract concentrationTLC
Stationary phase: precoated silica gel G F254
Mobile phase: hexane: ethyl acetate: methanol (56:20:5)
Fraction purification: positive test using Dragendroff's reagent
Further analysis of purified fraction
Mobile phase: chloroform: ethyl acetate: diethylamine: methanol: 20% ammonium hidroxide (6:24:1.5:6:0.3)Pfoze et al., 2014HPLC
Column: Water Symmetry C18, 250 x 4.6 mm, 5 μm
Mobile phase: methanol/ formic acid buffer (0.1%, v/v)
Detection: 346 nm
Flow: 1 mL/minUV-VIS
UV spectra: 200–500 nmESI-MSCoscinium fenestratum (100 g)Maceration
ES: 80% ethanol (500 ml), 160 h
Shaken: 80 h (200 rpm), stand: 80 h
Reextraction: 48 h, shaken: 24 h, stand: 24 h
Combined extracts concentration
Evaporation to dryness (dry extract)
Resolubilisation in 80% ethanol (10 mg dry extract/mL)TLC
Stationary phase: Silica gel GF254
Mobile phase: ethyl acetate : butanol : formic acid : water (50:30:12:10);
Detection: 366 nmRojsanga and Gritsanapan, 2005Argemone mexicanaSoxhlet extraction
ES: methanol
Evaporation to dryness
Resolubilisation in methanol (known concentration)HPTLC
Stationary phase: precoated silica gel 60F254
Mobile phases: toluene: ethyl acetate (9:3, v/v).
Detection: 266 nmSamal, 2013Tinospora cordifolia (20 g)Microwave assisted extraction (MAE)
ES: 80% ethanol
Irradiation power: 60%, Extraction time: 3 min
Soxhlet extraction
ES: ethanol, for 3 h
Filtration
ConcentrationHPTLC
Mobile phases: methanol: acetic acid: water (8: 1: 1, v/v/v).
Detection: 366 nmSatija et al., 2015Maceration
ES: ethanol (200 mL), 7 days, occasional stirringBerberis aristata, Berberis tinctoria (800 g)Hot extraction
ES: methanol (2.5 L) (X2)
Extraction time: 3 h
Temperature: 50°C
Extract concentration under vacuumHPLC
Column: Unisphere C18, 150 x 4.6 mm, 5 μm
Mobile phase: (A) 0.1% trifluoroacetic acid and (B) acetonitrile (60:40, v/v)
Detection: 350 nm
Temperature: 30°C
Flow: 1 mL/minShigwan et al., 2013Coptis chinensis Franch. (1g)Acid assisted extraction
ES: several inorganic acids (hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid) and one organic acid (acetic acid)
Extraction time:1–8 h, Acid concentrations: 0–1%
Solvent to sample ratios: 20–60 mL/g
Maceration at 25°C
Filtration
Dilution to 100 mL final volumeHPLC
Column: XTerra C18, 250 x 4.6 mm
Mobile phase: (A) acetonitrile and (B) 25 mmol/L potassium dihydrogen phosphate,(27:75, v/v)
Detection: 345 nm
Temperature: 30°CTeng and Choi, 2013Soxhlet extraction
ES: 50% ethanol (100 mL), 4 h at 70°C
Extract evaporation to dryness
Resolubilization in ES (up to 100 mL final volume)Heating reflux extraction
ES: 50% ethanol
Soaked for 1 h
Extraction: 4 h at 70°C (heated water bath)
Filtration
Dilution (up to 100 mL final volume)Rabbit plasma (100 μl)Mixing 100 μl sample with 3% formic acid in acetonitrile (200 μl)
Vortex: 30 s
Centrifugation: 10 min at 4°C
Evaporation of supernatant: under nitrogen stream at 40°CLC-ESI-MS
HPLC system
Column: Capcell Pakc18 MG, 100 × 2.1 mm, 5 μm with
Security Guard C18, 4 × 2 mm, 5 μm
Mobile Phases: (A) 0.4% formic acid solution and (B) 0.2 % formic acid solution in methanol (60:40, v/v)Liu et al., 2011Residue solubilization: in 100 μl of 20% methanolTemperature: 25°C
Flow: 0.4 mL/min
MS detection:
Source: ESI (+)
Quantification: MRM modeRat plasmaSolid phase extraction (SPE)
Cartridges: Oasis HLB (1 cc, 30 mg)
Pre-conditioning: 2 mL methanol
Equilibrtating:UPLC-MS/MS
UPLC system
Column: 120 EC-C18, 50 × 4.6 mm, 2.7 μm with
Security Guard C18, 4 × 2 mm, 5 μm
Mobile Phases: (A) 10 mM ammonium acetate in water (pH- 4.5) and (B) acetonitrile
Temperature: 35°C
Flow: 0.8 mL/min
MS detection:
Source: ESI (+)
Quantification: MRM modeLiu M. et al., 2015Rat plasma
Rat tissueRat plasma
ES: methanol
Mixing sample (200 μl) with internal standard (40 μl) and ES (560 μl)
Vortex: 20 s
Centrifugation: 10 min, 12,000x g
FiltrationUPLC-MS/MS
UPLC system
Column: Acquity BEH C18, 50 × 2.1 mm, 1.7 μm
Mobile Phases: (A) acetonitrile and (B) formic acid: water (0.1:99.9, v/v)
Flow: 0.25 mL/min
MS detection:
Source: ESI (+)
Quantification: MRM modeWang et al., 2016Rat tissue
Grinding: 3 mL physiological saline with 600 mg tissue
Centrifugation: 10 min, 12,000x g, 4°C
Mixing supernatant (200 μl) with internal standard (40 μl) and ES (560 μl)
Vortex: 20 s
Centrifugation: 10 min, 12,000x g
FiltrationRat plasmaEvaporation of 10 ul IS in the working tube
Mixing sample (200 μl) with internal evaporated standard Vortex: 1 min
Mixing sample with 10 μl 1% formic acid and 200 μl acetone
Vortex: 2 min
Centrifugation: 10 min, 10,000 rpm
Mixing supernatant with 200 μl methanol
Vortexing, centrifugation
Mixing supernatant wit 400 μl acetonitrile
Vortexing, centrifugation
Evaporation to dryness (37°C, under nitrogen stream)
Resolubilization in methanolLC-MS/MS
LC system
Column: Zorbax Eclipse XDB-C18, 150 × 2.1 mm, 3.5 μm
Mobile Phases: (A) acetonitrile and (B) water with 1% acetic acid and 0.001 mol/L ammonium acetate
Flow: 0.2 mL/min
MS detection:
Source: ESI (+)
Quantification: MRM modeXu et al., 2015Rat plasmaES: 90% methanol
Mixing sample (100 μl) with internal standard (10 μl) and ES (100 μl)
Vortex: 1 min
Centrifugation: 10 min, 12,000 rpm, 4°C
Supernatant evaporation to dryness under nitrogen stream
Resolubilization (100 μl ES)UPLC-MS/MS
UPLC system
Column: Acquity UPLC BEH C18, 50 × 2.1 mm, 1.7 μm
Mobile Phases: (A) formic acid: water (0.1:99.9, v/v) and (B) acetonitrile
Flow: 0.4 mL/min
MS detection:
Source: ESI
Quantification: MRM modeYang et al., 2017Open in a separate window

Large solvent volumes and long extraction time represent other drawbacks of conventional extraction methods (Mokgadi et al., 2013). For example, Rojsanga and Gritsanapan (2005) used maceration process to extract 100 g of C. fenestratum plant material with a total volume of 3,200 mL solvent (80% ethanol) over a period of 416 h. Furthermore, in a different study, Rojsanga et al. (2006) used several classical extraction techniques like maceration, percolation, and Soxhlet extraction to extract the berberine from C. fenestratum stems. This time even if the extracted plant material was in a lower amount than the previous study (30 vs. 100 g), large solvent volumes (2,000 mL for maceration, 5,000 mL for percolation, and 600 mL for Soxhlet extraction) over long time periods (7 days for maceration and 72 h for Soxhlet extraction) were employed (Rojsanga and Gritsanapan, 2005; Rojsanga et al., 2006).

Large solvent volumes are characteristic for other conventional methods too. Shigwan et al. (2013) extracted berberine from Berberis aristata and B. tinctoria powdered stem bark (800 g) using hot extraction (50°C for 3 h) with 2,500 mL methanol (Shigwan et al., 2013).

Even though conventional methods are widely used in berberine extraction, a number of other different methods have been developed lately. This led to an improved extraction efficiency, a decreased extraction time and solvents' volumes used in the extraction. Thus, ultrasound assisted solvent extraction (USE), microwave-assisted solvent extraction (MAE), ultrahigh pressure extraction (UPE), and supercritical fluid extractions (SFE), pressurized liquid extraction (PLE) have been successfully used as alternative extraction techniques with better results when compared with classical extraction methods.

Ultrasonically and microwave-assisted extraction are considered green, simple, efficient, and inexpensive techniques (Alupului et al., 2009).

Teng and Choi (2013) extracted berberine from Rhizome coptidis by optimized USE. Using response surface methodology, they identified that the optimal extraction conditions were 59% ethanol concentration, at 66.22°C within 46.57 min. A decrease in the extraction time (39.81 min) was obtained by Chang (2013). He used the combination of ionic liquids solutions as green solvents with USE to extract berberine from Coptis chinensis in order to apply an environmentally friendly approach (Chang, 2013). Moreover, in their study, Xu et al. (2017) compared several extraction tehniques like USE, distillation, and Soxhlet extraction in order to establish an high-efficient method for phellodendrine, berberine, and palmatine extraction from fresh Phellodendron bark (Cortex phellodendri). In the case of berberine, the combination of simple or acidified solvent (water, ethanol, and methanol) with the adjustment of the specific setting characteristics to each extraction type enabled them to determine the highest extraction yield. They concluded that the use of USE and hydrochloric acid-acidified methanol were the most efficient in extracting berberine. The USE extraction yield was significantly higher when compared to distillation and Soxhlet extraction, with values of ~100 mg/g toward 50 and 40 mg/g berberine, respectively (Xu et al., 2017).

The important reduction in organic solvent and extraction time determined the increasing interest in MAE, too. Lately, MAE was used as a green and cost-effective alternative to conventional methods. Using central composite design, Satija et al. (2015) successfully optimized the MAE parameters in terms of irradiation power, time, and solvent concentration to extract berberine form Tinospora cardifolia. They compared two classical extraction techniques like maceration and Soxhlet extraction with MAE under optimized conditions (60% irradiation power, 80% ethanol concentration, and 3 min extraction time). The results showed that MAE extraction had the highest yield of berberine content with 1.66% (w/w) while Soxhlet and maceration had 1.04 and 0.28% (w/w), respectively. Their study is emphasizing the dramatic time reduction in case of MAE (3 min) when compared with Soxhlet extraction (3 h) and maceration (7 days) together with solvent and energy consumption (Satija et al., 2015).

Another novel extraction technique considered to be environmentally friendly is UPE. The interest toward this extraction technique is increasing because it presents several advantages toward classical extraction techniques like increased extraction yields, higher quality of extracts, less extraction time, and decreased solvent consumption (Xi, 2015). These are achieved at room temperature by applying different pressure levels (from 100 to 600 MPa) between the interior (higher values) and the exterior of cells (lower values) in order to facilitate the transfer of the bioactive compounds through the plant matrices in the extraction solvent (Liu et al., 2006, 2013). In the study regarding berberine content in Cortex phellodendri, Guoping et al. (2012) made a comparison between UPE, MAE, USE, and heat reflux extraction techniques. They observed that the higher extraction yield and the lower extraction time was obtained in case of UPE with 7.7 mg/g and 2 min extraction time toward reflux, USE and MAE with 5.35 mg/g and 2 h, 5.61 mg/g and 1 h. and 6 mg/g and 15 min, respectively (Guoping et al., 2012).

Super critical fluid extraction is another environmentally friendly efficient technique used in phytochemical extraction. Because the extraction is performed in the absence of light and oxygen, the degradation of bioactive compounds is reduced. Also, the inert and non-toxic carbon dioxide used as a main extraction solvent in combination with various modifiers (e.g., methanol) and surfactants (e.g., Tween 80) at lower temperatures and relatively low pressure, allows the efficient extraction of bioactive compounds (Liu et al., 2006; Farías-Campomanes et al., 2015). In case of berberine extraction from the powdered rhizome of Coptis chinensis Franch, the highest recovery of berberine was obtained when 1,2-propanediol was used as a modifier of supercritical CO2 (Liu et al., 2006).

Pressurized liquid extraction, also known as pressurized fluid extraction, pressurized solvent extraction, and accelerated solvent extraction (ASE) is considered a green technology used for compounds extraction from plants (Mustafa and Turner, 2011). Compared with conventional methods, PLE increases the extraction yield, decreases time and solvent consumption, and protects sensitive compounds. In their study, Schieffer and Pfeiffer (2001) compared different extraction techniques like PLE, multiple USE, single USE, and Soxhlet extraction in order to extract berberine from goldenseal (Hydrastis canadensis). When compared in terms of extraction yield the results are comparable, ~42 mg/g berberine, except single USE with slightly lower content (37 mg/g berberine). Big differences were observed in the extraction time, PLE requiring only 30 min for a single sample extraction compared to 2 h for multiple extraction techniques or 6 h for Soxhlet extraction (Schieffer and Pfeiffer, 2001).

When referring to berberine extraction from biological samples, the extraction process is relatively simple and involves several steps like sample mixing with extraction solvents (e.g., methanol, acetone, acetonitrile), vortex, centrifugation followed by supernatant evaporation under nitrogen stream (Table ). Other extraction techniques like solid phase extraction (SPE) can also be applied.

Analytical techniques

After extraction and purification, the separation and quantification of berberine are commonly resolved by chromatographic methods. According to literature studies, berberine determination in plants was predominantly performed using methods like UV spectrophotometry (Joshi and Kanaki, 2013), HPLC (Babu et al., 2012; Akowuah et al., 2014), HPTLC and TLC (Rojsanga and Gritsanapan, 2005; Arawwawala and Wickramaar, 2012; Samal, 2013), capillary electrophoresis (Du and Wang, 2010), while berberine content in biological fluids was mainly achieved by using LC-MS (Deng et al., 2008; Feng et al., 2010), UPLC-MS (Liu M. et al., 2015; Liu L. et al., 2016), UHPLC/Q-TOF-MS (Wu et al., 2015).

UV-Vis spectrophotometry can be considered as one of the most rapid detection methods for berberine quantitative analysis from plant extracts. Based on the Beer-Lambert law, berberine concentration can be determined according to its absorption maxima at 348 nm. Joshi and Kanaki (2013) quantified berberine in Rasayana churna samples in the range of 2–20 μg/mL, the interference with other compounds being avoided by the specific isolation of the alkaloid fraction (Joshi and Kanaki, 2013).

Next, high-performance liquid chromatography (HPLC) is a versatile, robust, and widely used technique for the qualitative and quantitative analysis of natural products (Sasidharan et al., 2011). This approach is widely used in berberine identification and quantification. Generally, the choices of stationary phase in berberine separation are variants of C18-based silica column (Table ) with a mobile phase consisting of simple or acidified solvents like water, methanol, or acetonitrile, used as such or in combination with phosphate buffers. Normally, the identification and separation of berberine can be accomplished using either isocratic or gradient elution system. Berberine identification is further accomplished using high sensitivity UV or DAD (diode array detectors) detectors. For example, Shigwan et al. (2013) developed in his study a reverse phase HPLC method with photodiode array detection (PDA) to quantify berberine from Berberis aristata and B. tinctoria. They used a Unisphere-C18 column (5 μm, 4.6 × 150 mm) with an isocratic gradient of acidified water (with 0.1% trifluoroacetic acid) and acetonitrile (60:40, v/v) to elute berberine within 5 min. The developed method was reproducible, validated, precise, and specific for berberine quantification (with a concentration range between 0.2 and 150 μg/mL; Shigwan et al., 2013).

Two other commonly used techniques in berberine quantification are thin layer chromatography (TLC) and high performance thin layer chromatography (HTPLC). Sometimes, these methods are preferred over HPLC, offering the possibility of running several samples simultaneously along with the use of small amount of both samples and mobile phases (Samal, 2013). For these reasons, Samal (2013) used an HPTLC method to quantify berberine from A. mexicana L. using toluene and ethyl acetate (9:3, v/v) as mobile phases, and a silica gel plate as stationary phase, they developed a simple, rapid, and cost-effective method for berberine quantification. The LOD (0.120 μg) and LOQ (0.362 μg) of the method are in accordance with high-quality requirements.

Following the same principles (small sample volume, high separation efficiency, and short analysis time), capillary electrophoresis (CE) was successfully used in berberine analysis. Du and Wang (2010) used CE with end-column electrochemiluminescence (ECL) detection for berberine analysis in both tablets and Rhizoma coptidis. Using a 4 min analysis time, a small sample volume (3.3 nL) and a LOD of (5 × 10−9 g/mL), the developed method proved to be highly sensitive and with good resolution (Du and Wang, 2010).

Besides UV, HPLC, HTPLC, TLC, and CE, other detection methods like liquid chromatography coupled with mass spectrometry (LC/MS) are currently employed to quantify berberine in biological fluids. Generally, it is considered a powerful technique for the analysis of complex samples because it offers rapid and accurate information about the structural composition of the compounds, especially when tandem mass spectrometry (MSn) is applied. For example, Xu et al. (2015) developed a sensitive an accurate LC-MS/MS method to determine berberine and other seven components in rat plasma using multiple reactions monitoring (MRM) mode. Compounds separation was optimized using six different types of reverse-phase columns, and two different mobile phases (methanol–water and acetonitrile–water with different additives). Additives like formic acid, acetic acid, and ammonium acetate were added in different concentrations as follows: 0.1, 0.5, 1, and 2% for formic acid, 0.1, 0.5, 1, and 2% for acetic acid and 0.0001, 0.001, 0.01 mol/L for ammonium acetate. The method was also tested in terms of specificity, linearity, lower limit of quantification (LLOQ), precision, accuracy, and stability (Xu et al., 2015).

Antioxidant effect

Under normal conditions, the body maintains a balance between the antioxidant and pro-oxidant agents (reactive oxygen species—ROS and reactive nitrogen species—RNS; Rahal et al., 2014).

The imbalance between pro and antioxidants occurs in case of increased oxidative stress (Bhattacharyya et al., 2014).

The oxidative stress builds up through several mechanisms: an increase in the production of reactive species, a decrease in the levels of enzymes involved in blocking the actions of pro-oxidant compounds, and/or the decrease in free radical scavengers (Pilch et al., 2014).

An experimental study demonstrated the effect of berberine on lipid peroxidation after inducing chemical carcinogenesis in small animals (rats). An increase in LPO (lipid peroxidation) was observed after carcinogenesis induction, but also its significant reversal after berberine administration (30 mg/kg). Berberine shows therefore at least partial antioxidant properties, due to its effect on lipid peroxidation (Thirupurasundari et al., 2009).

Other mechanisms involved in the antioxidant role of berberine are: ROS/RNS scavenging, binding of metals leading to the transformation/oxidation of certain substances, free-oxygen removal, reducing the destructiveness of superoxide ions and nitric oxide, or increasing the antioxidant effect of some endogenous substances. The antioxidant effect of berberine was comparable with that of vitamin C, a highly-potent antioxidant (Shirwaikar et al., 2006; Ahmed et al., 2015).

The increase in blood sugar leads to oxidative stress not by generating oxygen reactive species but by impairing the antioxidant mechanisms. Administration of berberine to rats with diabetes mellitus increased the SOD (superoxide dismutase) activity and decreased the MDA (malondialdehyde) level (marker of lipid peroxidation). This antioxidant effect of berberine could explain the renal function improvement in diabetic nephropathy (Liu et al., 2008b).

The oxidative stress plays an important role in the pathogenesis of many diseases. The beneficial effect of berberine is presumed to reside mostly in its antioxidant role.

Cardiovascular effects of berberine

Effect on cardiac contractility

The beneficial effect of berberine in cardiac failure was demonstrated in a study on 51 patients diagnosed with NYHA (New York Heart Association) III/IV cardiac failure with low left ventricular ejection fraction (LVEF) and premature ventricular contractions and/or ventricular tachycardia. These patients received tablets containing 1.2 g berberine/day, together with conventional therapy (diuretics, ACEI—angiotensin-converting-enzyme inhibitors, digoxin, nitrates) for 2 weeks. An increase in LVEF was observed in all patients after this period, but also a decrease in the frequency and complexity of premature ventricular contractions. The magnitude of the beneficial effect was in direct proportion with the plasma concentration of berberine (Zeng, 1999).

The cardioprotective effect during ischemia

Berberine can provide cardio-protection in ischemic conditions by playing various roles at different levels: modulation of AMPK (AMP—activated kinase) activity, AKT (protein kinase B) phosphorylation, modulation of the JAK/STAT (Janus kinase/signal transducers and activators of transcription) pathway and of GSK3β (glycogen synthase kinase 3β; Chang et al., 2016). AMPK is an important enzyme playing an essential role in cellular metabolism and offering protection in ischemic conditions by adjusting the carbohydrate and lipid metabolism, the function of cell organelles (mitochondria, endoplasmic reticulum) and the apoptosis (Zaha et al., 2016).

Berberine activates the PI3K (phosphoinositide 3-kinase)/AKT pathway which is considered a compensatory mechanism limiting the pro-inflammatory processes and apoptotic events in the presence of aggressive factors. The activation of this pathway is associated with a reduction of the ischemic injury through the modulation of the TLR4 (toll-like receptor 4)-mediated signal transduction (Hua et al., 2007).

Several supporting data indicate that the JAK2/STAT3 signaling plays an important role in cardioprotection against ischemia-reperfusion injury (Mascareno et al., 2001).

GSK3β is a serine/threonine protein-kinase, an enzyme involved in reactions associated to important processes at the cellular level: metabolization, differentiation, proliferation, and apoptosis. Berberine inhibits this kinase, thereby exercising its cardioprotective effect (Park et al., 2014).

Effects on the endothelium

Berberine induces endothelial relaxation by increasing NO production from arginine through the activity of eNOS (endothelial nitric oxide synthase) which is considered a key element in the vasodilation process. Besides increasing the NO level, it also up-regulates eNOS mRNA. Furthermore, berberine facilitates the phosphorylation of eNOS and its coupling to HSP 90 (heat shock proteins), which consequently increases NO production (Wang et al., 2009).

Moreover, berberine reduces endothelial contraction by reducing COX-2 expression. Any imbalance in COX 1 or 2 activity may alter the ratio between prothrombotic/antithrombotic and vasodilator/vasoconstrictor effects (Liu L. et al., 2015).

The beneficial effect of berberine on the TNFα-induced endothelial contraction was also recorded, as well as an increase in the level of PI3K/AKT/eNOS mRNA (Xiao et al., 2014).

The role of berberine in atherosclerosis

Atherogenesis is a consequence of high blood lipid levels and is associated with inflammatory changes in the vascular wall. Berberine interferes with this process by up-regulating the expression of SIRT1 (silent information regulator T1) and by inhibiting the expression of PPARγ (peroxisome proliferator-activated receptor-γ). SIRT1 is a NAD-dependent deacetylase. The SIRT1 enzyme has many targets (PPARγ, p53), all playing different roles in atherogenesis (Chi et al., 2014).

The role of berberine in lipid metabolism

The effects of berberine on lipid metabolism are also the consequence of its effects on LDL cholesterol receptors. On one hand, these receptors are stabilized by an extracellular signal-regulated kinase (ERK)-dependent pathway, and on the other, berberine increases the activity of LDL receptors through the JNK pathway (Cicero and Ertek, 2009).

Moreover, berberine has an effect on ACAT (cholesterol acyltransferases), a class of enzymes that transform cholesterol into esters, thus playing an essential role in maintaining cholesterol homeostasis in different tissues. There are two types of ACAT enzymes, ACAT1, and ACAT2. ACAT1 is a ubiquitous enzyme, while ACAT2 can be found only in hepatic cells and enterocytes. Berberine influences the activity of ACAT2 without an effect on ACAT1, therefore reducing the intestinal absorption of cholesterol and decreasing its plasmatic level (Chang et al., 2009; Wang et al., 2014).

The hypolipidemic effect of berberine is also a result of its action on PCSK9 (proprotein convertase subtilisin kexin 9). This enzyme can attach itself to LDL receptors, leading to a decrease in LDL metabolization and an increase in its blood level (Xiao et al., 2012).

In a clinical trial, 63 patients with dyslipidemia were randomly divided in three groups. The first group was treated with berberine (1,000 mg/day), the second with simvastatin (20 mg/day) and the third with a combination of berberine and simvastatin. The authors reported a 23.8% reduction in LDL-C levels in patients treated with berberine, a 14.3% reduction in those treated with simvastatin and a 31.8% LDL-C reduction in the group treated with both simvastatin and berberine. This result demonstrates that berberine can be used alone or in association with simvastatin in the treatment of dyslipidemia (Kong et al., 2008).

The role of berberine in glucose metabolism

Many studies demonstrated that berberine lowers blood sugar, through the following mechanisms:

  • - Inhibition of mitochondrial glucose oxidation and stimulation of glycolysis, and subsequently increased glucose metabolization (Yin et al., 2008a ).

  • - Decreased ATP level through the inhibition of mitochondrial function in the liver, which may be the probable explanation of gluconeogenesis inhibition by berberine (Xia et al., 2011 ).

  • - Inhibition of DPP 4 (dipeptidyl peptidase-4), a ubiquitous serine protease responsible for cleaving certain peptides, such as the incretins GLP1 (glucagon-like peptide-1) and GIP (gastric inhibitory polypeptide); their role is to raise the insulin level in the context of hyperglycemia. The DPP4 inhibition will prolong the duration of action for these peptides, therefore improving overall glucose tolerance (Al-masri et al., 2009 ; Seino et al., 2010 ).

Berberine has a beneficial effect in improving insulin resistance and glucose utilization in tissues by lowering the lipid (especially triglyceride) and plasma free fatty acids levels (Chen et al., 2011).

The effect of berberine (1,500 mg day) on glucose metabolism was also demonstrated in a pilot study enrolling 84 patients with type 2 diabetes mellitus. The effect, including on HbA1c, was comparable to that of metformin (1,500 mg/day), one of the most widely used hypoglycemic drugs. In addition, berberine has a favorable influence on the lipid profile, unlike metformin, which has barely any effect (Yin et al., 2008b).

Hepatoprotective effect of berberine

The hepatoprotective effect of berberine was demonstrated on lab animals (mice), in which hepatotoxicity was induced by doxorubicin. Pretreatment with berberine significantly reduced both functional hepatic tests and histological damage (inflammatory cellular infiltrate, hepatocyte necrosis; Zhao et al., 2012).

The mechanism by which berberine reduces hepatotoxicity was also studied on CCl4 (carbon tetrachloride)-induced hepatotoxicity. Berberine lowers the oxidative and nitrosamine stress and also modulates the inflammatory response in the liver, with favorable effects on the changes occurring in the liver. Berberine prevents the decrease in SOD activity and the increase in lipid peroxidation and contributes to the reduction in TNF-α, COX-2, and iNOS (inducible nitric oxide synthase) levels. The decrease in transaminase levels supports the hypothesis according to which berberine helps maintain the integrity of the hepatocellular membrane (Domitrović et al., 2011).

Nephroprotective effect of berberine

The chronic kidney damage occurring in time in patients with HT (hypertension) and DM (diabetes mellitus) is well known; it is mainly due to the atherosclerosis of the renal artery, caused by inflammation and oxidative stress. The protective effect of berberine on kidneys was studied on 69 patients suffering from both HT and DM, with blood pressure and blood sugar levels controlled with conventional medication. The patients received 300 mg berberine/day for 24 months, with 2-week interruptions every 5 months. The authors recorded lower CRP (C-reactive protein), MDA and SOD levels after treatment, but without significant changes in creatinine, arterial pressure, or glycaemia levels. These results support the renal protective effect of berberine through its anti-inflammatory and antioxidant effects (Dai et al., 2015).

Another animal study tested the renoprotective effect of berberine after administration of HgCl2 (mercury chloride). This substance induces hepato-renal damage by increasing the oxidative stress (increases lipid peroxidation and NO levels, and lowers glutathione and SOD levels as well as the activity of other protective enzymes). Administration of HgCl2 increased the AST (aspartate aminotransferase), ALT (alanine aminotransferase), and ALP (alkaline phosphatase) levels, compared to the control group. However, pretreatment with berberine lowered these enzymes significantly. In addition, both urea and creatinine levels were significantly increased in the HgCl2 group vs. the control group, and again pretreatment with berberine prevented these changes. Additionally, the authors recorded higher pro-oxidant and lower antioxidant levels in the intervention group. These data support the hepatic and renal protective effects of berberine. Other studies performed on animal models with CCl4−induced hepatotoxicity demonstrated the same effect (Othman et al., 2014).

In addition, berberine can lower the nephrotoxicity caused by cisplatine. In an animal study, berberine was administered in progressive doses of 1, 2, 3 mg/kg, orally, for 2 successive days, starting 2 days after cisplatine administration. After the last doses of berberine, the animals were sacrificed and the kidneys were examined by the pathologist. The results showed significant histological improvement and a reduction in NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells), TNF α, COX2 an iNOS levels, all of which support the anti-inflammatory effect of berberine (Domitrović et al., 2013).

Immunomodulatory effect of berberine

The immunomodulatory effect of berberine was demonstrated in many experimental and clinical contexts.

In an experimental autoimmune myocarditis model, berberine contributed to mitigate the cardiac damage by: limiting the rise in anticardiac myosin antibodies, modulating the activity of certain STATs and blocking Th1 and Th2 cell differentiation, which play an important role in the pathogenesis of myocarditis (Liu X. et al., 2016).

Experimental autoimmune neuritis is an experimental animal model equivalent to the Guillain-Barre syndrome in humans. This neurologic syndrome is characterized by autoimmune injury of the peripheral nervous system. The beneficial effect of berberine on this animal model resided in its influence on cellular and humoral immunity through the inhibition of lymphocyte proliferation (especially CD4), and the decrease in pro-inflammatory cytokines (IL-6 and TNF α; Li et al., 2014).

Experimental autoimmune encephalomyelitis is an established model of multiple sclerosis. Multiple sclerosis is a one of the most common diseases of the central nervous system (CNS) and involves neurodegenerative and inflammatory processes, and autoimmune demyelination (Ransohoff et al., 2015). The blood-brain barrier permeability and changes in matrix metalloproteinase (MMP) levels in the cerebrospinal fluid and brain were studied using this model (Ma et al., 2010). MMPs may be involved in demyelination and their activity in tissues depends on the balance between their level and their tissue inhibitors. MMP2 and MMP9 are the main endoproteinases involved in the migration of lymphocytes in CNS and in altering the BBB (blood brain barrier) (Avolio et al., 2003). Berberine has a beneficial effect in experimental autoimmune encephalomyelitis by inhibiting the activity of MMP9, reducing BBB permeability and, consecutively, by decreasing the inflammatory cellular infiltration of the CNS (Ma et al., 2010).

The current therapy used for inflammatory bowel diseases, including glucocorticoids and immunosuppressive agents, has a low level of safety. The effect of berberine was studied in combination with 5-ASA (5-aminosalicylic acid) vs. 5-ASA alone using an experimental animal model with DSS (dextran sulfate sodium)-induced colitis. The authors analyzed the level of proinflammatory cytokines in the animal gut. A decrease in COX2, IL6, and IL23 mRNA levels was observed in animals treated only with 5-ASA, whereas animals treated with both 5-ASA and berberine had a reduction in mRNA levels for COX2, IL6, IL23 as well as for TNF alfa and IL12b. This beneficial effect could partially be attributed to the inhibition of NF-kB and the reduction in JAK2 phosphorylation (through the influence on the JAK/STAT pathway) by both 5-ASA and berberine (Li et al., 2015; Figure ).

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Another study demonstrated that berberine increases the corticosteroid level in rats with experimentally-induced colitis. This engendered the theory that its beneficial effect may also be attributed to the increase in endogenous glucocorticoid levels, compounds with well-known therapeutic effect in inflammatory bowel disease (Minaiyan et al., 2011).

Conclusion

A review of the available scientific literature shows that the traditional medical uses of berberine-containing plants have been evaluated by modern pharmacological studies. Different species of berberine-rich plants have multiple pharmacological and therapeutic actions, such as antioxidant and immunomodulatory effects, protective action on the cardiovascular system, liver and kidney, endothelial relaxation, regulator on glucose metabolism and atherosclerosis, which can all be explained by the presence of berberine as well as other phyto constituents (when dealing with berberine-containing plant extracts). Moreover, the effects of berberine vary according to its origin (different plants or pharmaceutical products) and its concentration, depending on the very diverse extraction and detection techniques already described. Over time, modern extraction techniques were increasingly preferred to classical ones. Since classical methods are generally time- and solvent-consuming processes, modern extraction techniques such as USE, MAE, UPE, SFE, and PLE are seen as better alternatives to overcome these limitations. Furthermore, berberine, due to its antioxidant and anti-inflammatory effects, has several clinical applications in many disorders, from inflammatory conditions to the metabolic syndrome. However, there are some traditional uses that have not yet been completely elucidated, and further studies are needed. Therefore, extensive studies on the potential of plants containing berberine that have shown aforementioned pharmacological activities should go through additional in vitro and in vivo studies.

Author contributions

MN, AM, JE, and RP have conceived and designed the structure of the manuscript, data collection, and drafting, as well as its revision. CB, GC, and AB have critically reviewed the manuscript. All authors have seen and agreed on the final version of the manuscript.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This article was published under the frame of the internal grant no. 4945/15/08.03.2016 of the Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.

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