Chinese ligustrum berry

Chinese Ligustrum Berry (Fructus Ligustri Lucidi): A Comprehensive Reference

1. Identity and Botanical Description

Botanical and Pharmacognostic Names

The Chinese Ligustrum berry is known as Nüzhenzi (女貞子) in traditional Chinese medicine and is the dried mature fruit of Ligustrum lucidum W.T. Aiton. Ligustrum, commonly known as privet, belongs to the genus of flowering plants in the olive family, Oleaceae. In pharmacognostic literature, the drug is identified by the Latin name Fructus Ligustri Lucidi (abbreviated FLL). The herb is also known under the synonyms Nu Zhen Zi, Privet, Chinese privet, Dong Qing Zi, To-Nezumimochi, Trueno, White Wastree, and Ligustrum.

Plant Description and Geographic Origin

The evergreen plant Ligustrum lucidum, often called glossy privet, is native to China and is grown for both decorative and therapeutic uses all over the world. The shrub contains large clusters of white flowers with bluish-purple berries that are used medicinally. It is mainly produced in Hu'nan, Sichuan, Jiangsu, and Zhejiang provinces in China, and is harvested in winter by plucking the ripe fruits. The fruit is harvested in December when it turns black.

This medicinal material is mainly distributed in regions such as China, the Korean Peninsula, India, and Nepal, and is traditionally valued for nourishing the liver and kidneys, improving vision, strengthening tendons and bones, and delaying aging.

Adulteration and Species Confusion

Care must be taken not to confuse glossy privet (Ligustrum lucidum) with other species of privet such as Japanese privet, border privet, Chinese privet (Ligustrum sinense), common privet, golden privet, and others. One common adulterant is Xiao La (Ligustrum sinense)—the fruits of which are more spherical and slightly larger with a smoother surface, and the species has different and weaker therapeutic properties.

Common Preparations and Dosage Forms

Ligustri Lucidi Fructus has been used as a common herbal medicine in clinical practice in China for nearly 2,000 years; in most cases, it is prescribed in decoctions in the form of processed products rather than crude drugs. FLL is currently administered as a Chinese medicine powder or as traditional decoctions. The classical processing method in TCM involves repeated steaming with rice wine; modern pharmaceutical forms include standardized hydroalcoholic extracts, capsules, and dropping pills. Among the phenylethanoid glycosides, salidroside is considered to be the quality control marker in wine-steamed L. lucidum, which should be quantified based on Chinese Pharmacopeia.

Wine-processing (酒蒸) reduces the herb's cool, moistening nature, which can otherwise cause loose stools in people with weak, cold digestion. A comparative pharmacokinetic study of raw and wine-processed Ligustri Lucidi Fructus in rats found that the AUC_0–24 and C_max of salidroside, hydroxytyrosol, and nuezhenidic acid were increased significantly after processing, while the values for specnuezhenide and oleanolic acid were decreased, suggesting processing affects the absorption and bioavailability of constituents.

2. Traditional and Historical Use

Foundational Texts and Chronology

FLL was first recorded in Shen Nong's Classic Materia Medica (written during the period from 100 BCE to 200 CE), and was labeled as a "top-tier" medicine—the ancient term "top-tier" was given to herbs without observable toxicity. Over time, Chinese physicians such as Li Shizhen in the Ming Dynasty detailed its uses in the Compendium of Materia Medica, highlighting its benefits for kidney health, vision, and hair vitality.

TCM Theoretical Framework

Since ancient times, ligustrum has been used as a yin tonic in traditional Chinese medicine. In TCM theory, the concept of yin refers broadly to the body's cooling, moistening, and nourishing reserves; tonics that replenish yin are considered restorative rather than stimulating. Nu Zhen Zi is described as sweet, bitter, and cool in nature; it nourishes kidney and liver yin, clears deficiency heat, and supports vision and hair health. In TCM organ-system theory, the fruit is said to enter the Kidney and Liver channels.

Classical Indications

Classic Chinese medical indications include deficiency of the liver-yin and kidney-yin manifested as dizziness, tinnitus, blurring of vision, weakness of the loin and knees, fever, nocturnal emission, alopecia, and poliosis (premature greying of the hair). More recent traditional use has included seborrheic alopecia, central retinitis, early cataract treatment, and insufficiency of heart-yin manifested as insomnia, palpitation, and precordial pain.

In the 2020 version of the Chinese Pharmacopoeia, the herb's primary officially recognized roles are to nourish the liver and kidneys, enhance vision, and darken the hair.

Classical Formulas

Erzhi Wan, also known as the "Two Solstices Pill," is a classical formula containing ligustrum; it consists of winter-harvested ligustrum berries (harvested at the winter solstice) and Eclipta alba harvested at the summer solstice. This formulation has been used to prevent and treat various kidney diseases by tonifying the body's essential fluid, enhancing tendons and bones, and arresting hemorrhage. In the 2020 Edition of the Chinese Pharmacopoeia, more than 100 prescriptions contain L. lucidum, among them classical preparations including Er Zhi Wan and the Zhenqi fuzheng formula, which are used in the treatment of various cancers.

Ligustrum was often used in combination with astragalus to treat various conditions, including tinnitus and premature aging.

3. Key Constituents and Phytochemistry

A total of 206 compounds have been isolated and identified from L. lucidum; they mainly include flavonoids, phenylpropanoids, iridoid glycosides, and triterpenoids. The four principal chemical classes are described in detail below.

Triterpenoids

At present, more than 20 triterpenes have been extracted and identified from FLL, with oleanolic acid being the highest in content among the triterpenes. The two primary bioactive components in L. lucidum, oleanolic acid and ursolic acid, exhibit various biological effects, including anti-inflammatory, antioxidant, hepatoprotective, antiprotozoal, antimutagenic, and anticancer capabilities. Oleanolic acid belongs to oleanane-type pentacyclic triterpenes and is widely distributed in nearly 200 species of plants, including Ligustrum lucidum, grape, and elderberry. The active ingredient with the highest FLL content is oleanolic acid, a triterpenoid compound that is practically insoluble in water. Under optimized microwave-assisted extraction conditions, the yields of oleanolic acid and ursolic acid from the fruit were 4.4 ± 0.20 mg/g and 5.8 ± 0.15 mg/g, respectively.

Other isolated triterpenoids include crategolic acid, lupeol, betulin, dammarenediol-II, and a range of dammarane-type triterpenes.

Secoiridoid Glycosides (Iridoids)

Among all obtained chemical constituents from FLL, secoiridoids are often used as the characteristic compound for the identification of the FLL genus; moreover, they are considered the main active ingredients in many pharmacological effects, and have recently been the focus of study. The iridoids in FLL mainly include specnuezhenide, nuezhenide, ligustroflavone, neuzhengalaside, nuezhenoside G13, oleuropein, oleuropeinic acid, oleoside dimethyl ester, and other compounds. Specnuezhenide, with a content of 0.70–3.06%, is one of the main reference compounds for FLL in the 2015 Chinese Pharmacopoeia.

Phenylethanoid Glycosides

A total of fourteen phenylethanoid glycosides have been isolated and elucidated from the fruit and leaves of L. lucidum with unambiguous structures and significant bioactive characteristics. Among these, salidroside is the characteristic chemical with broad pharmacological application prospects and has been considered the quality control marker in wine-steamed L. lucidum; verbascoside and echinacoside are the most frequently reported components and have been proven to possess strong biological effects, including anti-inflammatory, anti-hyperglycemic, anti-osteoporotic, liver protection, and anti-Alzheimer's disease activities. The content of salidroside in crude FLL powder determined by HPLC ranges from 5.7 to 6.9 mg/g.

Flavonoids

Fifteen flavonoids have been isolated and identified from the fruit, leaves, and flowers of L. lucidum. Key antioxidant constituents such as oleuropein, echinacoside, and verbascoside have been identified, with their antioxidant activity closely related to their catechol groups.

Other Constituents

The berries also contain a variety of nutrients including calcium, fructose, glucose, iron, magnesium, and potassium.

4. Mechanisms of Action

Hepatoprotection

The in vivo antioxidant activities of various FLL fractions were assessed by examining effects on carbon tetrachloride (CCl₄)-induced hepatotoxicity in mice; pretreatment with oleanolic acid-enriched fractions could protect against CCl₄-induced hepatotoxicity. Hepatoprotective effects are due to oleanolic acid and are perhaps mediated by an increase in hepatic glutathione regeneration capacity. At the cellular level, oleanolic acid has been shown to activate the Nrf2 pathway and upregulate antioxidant defenses, thereby enhancing cellular resistance to oxidative damage.

Bone Metabolism and Anti-Osteoporotic Effects

Data from animal and cell experiments demonstrate that FLL is able to improve bone metabolism and bone quality in ovariectomized, growing, aged, and diabetic rats through the regulation of PTH/FGF-23/1,25-(OH)₂D₃/CaSR, Nox4/ROS/NF-κB, and OPG/RANKL/cathepsin K signaling pathways. FLL extract and its two primary components, oleanolic acid and ursolic acid, significantly suppressed RANKL-induced tartrate-resistant acid phosphatase (TRAP) activity and multinucleate osteoclast formation without inducing cytotoxicity. Specnuezhenide, an iridoid glycoside isolated from FLL, is an herb prescribed for the treatment of senile osteoporosis. Administration of specnuezhenide (SPN) increased bone mass of d-galactose-induced mice and attenuated cell senescence, with the mechanism linked to improvement of bone formation and inhibition of bone resorption.

Immunomodulation and Antitumor Effects

In vitro studies suggest that antitumor effects occur via immunomodulation and by reverting macrophage suppression brought about by tumors, or are due to increases in phagocytes and lymphokine-activated killer cells. Ligustrum may also induce apoptosis in human hepatocellular carcinoma cells via p21 upregulation. Salidroside improved the cellular immunity of tumor-bearing mice, which led to an anti-hepatocellular carcinoma effect; it was proposed that increasing cellular immunity and fighting cancer work in concert.

Antidiabetic and Metabolic Effects

The fruits of Ligustrum lucidum are known for their effectiveness in lowering blood glucose levels in normal and diabetic mice, attributed to the active constituent oleanolic acid. The primary hypoglycemic compounds are oleanolic acid and salidroside, which also control blood lipid levels. Studies in alloxan-induced diabetic rats demonstrated that oleanolic acid from L. lucidum reduced blood glucose levels in both the short term (2 h after administration) and long term (40 days), lowered total cholesterol, triglycerides, and LDL cholesterol, and increased HDL cholesterol.

Antiviral Activity

The secoiridoid glucoside oleuropein has demonstrated antiviral activity against respiratory syncytial virus and parainfluenza type 3 virus, while other secoiridoid compounds showed activity against influenza A virus.

Vision-Related Mechanisms

The compound specnuezhenide may confer vision improvement effects via inhibition of the HIF-1alpha/VEGF signaling pathway. In a murine model of diabetes-induced osteoporosis, ligustroflavone from Ligustrum fruit appeared to have protective effects via regulation of parathyroid hormone levels and improved calcium balance by acting on calcium-sensing receptors.

Antioxidant Activity

Secoiridoid glucosides showed antioxidant effects against free radical-associated hemolysis of erythrocytes. Oleanolic acid has been shown in multiple studies to possess pharmacological effects including liver protection, antioxidation, hypolipidemia, antitumor, anti-inflammatory, and antiviral activities.

5. Scientific Evidence by Health Area

5.1 Osteoporosis and Bone Health

FLL is assumed to exhibit anti-osteoporotic effects by improving liver and kidney deficiencies and reducing lower back soreness in TCM; it has been clinically used to treat osteoporotic bone pain and rheumatic bone for more than 1,000 years. Oleanolic acid, ursolic acid, salidroside, and nuzhenide have been reported in preclinical experiments to exhibit the anti-osteoporosis effect. Acute and subacute toxicity studies show that FLL is well tolerated and presents no safety concerns at doses tested in these protocols.

A 2017 comprehensive review published in Molecules (PMC6151717) concluded that FLL has attracted increasing attention as an alternative medicine in the prevention and treatment of osteoporosis, and the review provided a general overview of traditional applications, phytochemical constituents, pharmacokinetics, pharmacology in bone-improving effects, and safety. The evidence base is primarily animal and cell-based; human clinical trials specifically examining FLL's anti-osteoporotic effects are lacking.

One multi-herb study involving FLL used a combination of Herba Epimedii, Fructus Ligustri Lucidi, and Fructus Psoraleae (ELP). A dosing effect with concentrations of 1 g/day, 0.5 g/day, and 0.175 g/day was tested in ovariectomized and calcium deficiency-induced osteoporotic rats. No directly equivalent human data for FLL alone have been verified in authoritative sources at the time of writing.

5.2 Hepatoprotection

Hepatoprotective effects have been documented primarily in animal models. A study published in Phytotherapy Research (2001) examined oleanolic acid-enriched extracts of FLL in mice challenged with carbon tetrachloride. Oleanolic acid pretreatment produced dose-dependent protection against CCl₄ hepatotoxicity, and this hepatoprotection was associated with an enhancement of hepatic glutathione regeneration capacity. The classical combination formula Er Zhi Wan (EZP), which contains FLL, is most frequently mentioned as an anti-aging, hepatoprotective, promoting hematopoietic, and antioxidant agent for menopausal symptoms in clinical application in Taiwan and China. EZP has shown marked effects in preclinical and clinical settings for the treatment of liver injury, fatty liver, and aging-associated symptoms. In clinical practice, FLL is widely used to treat hepatitis, diabetes, hyperlipidemia, atherosclerosis, menopausal syndrome, infertility, and tumors. The quality of human evidence for FLL's hepatoprotective effects when used as a single agent remains limited; most data derive from animal studies or multi-herb formulations.

5.3 Immune Function and Cancer Support

Ligustrum lucidum has not been shown to treat cancer in humans. It is a Chinese medicinal herb used to increase immune function in cancer patients. In vitro studies suggest that the fruits of Ligustrum lucidum have antitumor, immunomodulatory, antidiabetic, antiosteoporotic, antiviral, antimutagenic, hepatoprotective, and cytotoxic effects.

Human Clinical Evidence: Data in humans are quite limited. In a small study of non-small cell lung cancer patients undergoing chemotherapy, a formula containing reishi mushroom and ligustrum was found to help maintain quality of life. The combination of Astragalus membranaceus and Ligustrum lucidum (AL) has been investigated in China as an adjunct to standard anticancer therapies in numerous clinical studies of variable quality reported in the Chinese literature; however, independent assessment of its effects on safety, tolerability, and efficacy are lacking. Ligustrum combined with Siberian ginseng may have protective effects against chemotherapy-induced myelosuppression, according to animal studies.

Overall, in vitro studies suggest L. lucidum has anticancer properties, but clinical evidence is lacking; data from lab studies suggest L. lucidum may change immune response. Preliminary studies have suggested that ligustrum may be a beneficial adjuvant therapy for chemotherapy patients; however, there is little meaningful scientific evidence.

5.4 Blood Glucose and Metabolic Health

Preclinical (animal) evidence is the predominant evidence class for antidiabetic effects. A decoction of Ligustrum lucidum Ait. was administered in alloxan-induced diabetic mice to test type-1 diabetes mellitus, in which a reduced level of fasting blood glucose was found. The primary mechanism identified is oleanolic acid's effect on glucose and lipid metabolism, as described in the preceding mechanistic section. No controlled human clinical trials for blood glucose control using FLL as a single agent have been verified in authoritative sources.

5.5 Vision and Ocular Health

Ligustrum lucidum is used in Chinese medicine to treat dizziness, but clinical evidence is lacking. In animal models, ligustrum compounds showed antiosteoporotic and vision-sparing effects. The specnuezhenide-mediated inhibition of the HIF-1alpha/VEGF signaling pathway represents a biologically plausible mechanism for reported vision benefits, but this has not been confirmed in human trials. Traditional use for conditions such as early cataract and central retinitis is documented in classical texts, but these claims are not substantiated by controlled human research at the time of writing.

5.6 Antiviral Activity

Evidence for antiviral properties is entirely preclinical (in vitro). Oleuropein has demonstrated antiviral activity against respiratory syncytial virus and parainfluenza type 3 virus in laboratory studies, while other secoiridoid compounds showed activity against influenza A virus. These findings have not been translated to human clinical trials.

5.7 Neuroprotection

FLL methanol extracts have been reported to suppress the development of glioma cells in vitro by altering the Akt/mTOR/survivin pathway. Echinacoside, one of the most frequently reported phenylethanoid glycosides, has been proven to possess anti-Alzheimer's disease biological effects. These are in vitro findings and have not been confirmed in human trials.

Overall Evidence Assessment

The compounds of L. lucidum exert anti-osteoporosis, anti-tumor, liver protective, antioxidant, anti-inflammatory, and immunomodulatory effects in preclinical systems. Modern pharmacological research has been concentrated on the anti-osteoporotic and hepatoprotective activity, with relatively weaker applications established in antioxidant and immunomodulatory actions. More large-scale human trials are needed to definitively establish clinical efficacy and safety in various therapeutic applications; some clinical trials and preclinical studies have examined the pharmacological effects of ligustrum, focusing on its immune-boosting, anti-inflammatory, and hepatoprotective properties.

6. Body Systems and Health Areas

Based on pharmacological and traditional evidence in the reviewed literature, the following body systems and areas have been investigated in connection with Chinese Ligustrum berry:

• Hepatic system: Hepatoprotection, support in hepatitis and fatty liver disease, enhancement of glutathione metabolism.
• Musculoskeletal system: Prevention and treatment of osteoporosis via osteoclast inhibition and osteoblast promotion, bone quality improvement.
• Immune system: Immunomodulation, macrophage activation, reversal of tumor-induced immune suppression, potential adjunct in cancer care.
• Endocrine/metabolic system: Blood glucose regulation, lipid-lowering activity, support in metabolic syndrome and diabetes.
• Ophthalmic system: Traditional use in blurred vision, early cataracts, and retinitis; preclinical angiogenesis inhibition in the retina.
• Nervous system: Traditional use in dizziness and tinnitus; preclinical anti-neuroinflammatory and anti-Alzheimer's activity.
• Cardiovascular system: Lipid-lowering effects; traditional use in palpitations; preclinical cardioprotective data for salidroside.
• Integumentary system: Traditional use in premature greying and hair health.

The classical combination EZP has shown documented effects in the treatment of diabetic cardiomyopathy, benign prostatic hyperplasia, liver injury, Alzheimer's disease, osteoporosis, rheumatoid arthritis, fatty liver, and aging-associated symptoms in preclinical or early clinical research.

7. Dosage Forms and Reported Dosages

FLL is widely used in clinical practice in China; it is currently administered as a Chinese medicine powder or as traditional decoctions. In TCM, Ligustrum Fruit is used for the treatment of dizziness and tinnitus, soreness and weakness of the waist and knees, premature greying of the hair, dimness of the eyes, internal heat and thirst, bone steam and hot flashes, and other symptoms.

Traditional practitioners recommend patients taking powdered berries between 5–15 grams per day. Because it is mild and well tolerated, it is often taken over extended periods as part of a gradual restoration of vitality.

In one osteoporosis-related preclinical study, dosing with the multi-herb formula ELP at several concentrations (1 g/day, 0.5 g/day, and 0.175 g/day) was tested in ovariectomized and calcium deficiency-induced osteoporotic rats. No standard human clinical dosage ranges for isolated FLL have been established in reviewed peer-reviewed sources.

8. Safety Considerations and Interactions

General Tolerability

Acute and subacute toxicity studies show that FLL is well tolerated and presents no safety concerns at doses evaluated in animal protocols. Ligustrum is generally considered safe when used appropriately in recommended doses, but it may cause mild gastrointestinal upset in some individuals.

Digestive Effects

The main concern noted in TCM is not toxicity but rather the herb's cool, moistening nature, which can cause loose stools or mild diarrhea in people with weak, cold digestion; wine-processing reduces this tendency.

Pregnancy and Lactation

Traditional herbal sources indicate the herb is not for use during pregnancy or lactation.

Contraindications

Ligustrum lucidum is contraindicated in individuals with known hypersensitivity to the plant. Because it belongs to the Oleaceae family, cross-reactivity with other family members (including olive and ash pollen) may be a consideration in atopic individuals, as documented in allergy research on the family.

Gaps in Toxicological Knowledge

Ligustrum lucidum is typically applied in multi-herb formulations or integrated with conventional drugs in long-standing clinical applications. However, most modern pharmacological and toxicological research has been performed on single L. lucidum or its main compositions, which critically ignores effects induced by medicine interactions. Toxicological studies and the detailed bioavailability, distribution, metabolism, and excretion of its main compositions in the body are still insufficient, thereby limiting its wider applications.

Bioavailability Limitations

The clinical use of oleanolic acid, the major active triterpenoid, is restricted because it is water-insoluble and has limited dosage forms of administration. The traditional decoction is prepared by decocting with water, which is not conducive to the extraction and dissolution of oleanolic acid; thus, this method of administration will affect the absorption of oleanolic acid in the body, resulting in poor bioavailability that affects efficacy.

Pharmacokinetic Distribution

Wide tissue distribution is shown by pharmacokinetic investigations, with the liver serving as the main site of accumulation.

References

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