Rhamnus nakaharai

Rhamnus nakaharai: A Comprehensive Reference

1. Identity, Botanical Classification, and Natural Source

Rhamnus nakaharai (Hayata) Hayata is a woody shrub belonging to the family Rhamnaceae — the same family as the medicinally well-known cascara sagrada (R. purshiana) and alder buckthorn (R. frangula). Rhamnus is a genus of about 140 accepted species of shrubs or small trees, commonly known as buckthorns, native mainly to East Asia and North America but found throughout the temperate and subtropical Northern Hemisphere. The genus belongs to the Rhamnaceae family, which contains approximately 137 species, traditionally used as folk medicine in East Asia, North and South America, and subtropical regions of Africa.

Rhamnus nakaharai, also known as Nakahara's buckthorn, is a plant used in some East Asian traditional medicine systems, particularly in Taiwan and China. The species epithet honors the Japanese-Taiwanese botanist who contributed significantly to the documentation of Formosan flora. Within the classification system accepted by the Royal Botanic Gardens at Kew, the species is recorded under Rhamnus L., of the tribe Rhamneae, order Rosales. The genus Rhamnus enters the tribe Rhamneae, the family Rhamnaceae, of the order Rosales.

Systematic phytochemical investigation of R. nakaharai has focused on multiple plant parts. A new anthraquinone glycoside and a new naphthalene glycoside have been isolated from the root bark of Rhamnus nakaharai; these compounds were characterized as chrysophanol 8-O-xylosyl-(1→6)-glucoside and 2-acetyl-3-methyl-6-methoxynaphthalene-1,8-diol 8-O-xylosyl-(1→6)-glucoside, respectively. Additionally, the stem bark, heartwood, and root bark have each yielded distinct chemical profiles in published studies. The species grows in Taiwan, where it has been the subject of most documented ethnobotanical and phytochemical research.

In experimental research, the plant material has been processed into methanol extracts, ethanol extracts, and further fractionated using ethyl acetate, n-butanol, and similar solvents to isolate pure compounds. No standardized commercial extract or pharmacopeial monograph exists for R. nakaharai specifically.

2. Traditional and Historical Use

Rhamnus nakaharai (Hayata) Hayata (Rhamnaceae) is used as a folk medicine for treating constipation, inflammation, tumors, and asthma in Taiwan. This ethnomedical record — preserved in Formosan folk medicine traditions — formed the primary rationale for modern phytochemical investigation of the species.

It is a herb used as a traditional medicine for gastrointestinal ailments, inflammation, tumors, and asthma in Taiwan. This herb belongs to the family Rhamnaceae. The use of Rhamnus species broadly for digestive complaints is well documented across East Asian traditions. The genus is used traditionally to treat diseases such as cancer, wound, jaundice, hepatitis, gonorrhea, laxative use, hypertension, malaria, stomach ache, snake bite, and diarrhea.

In traditional Chinese medicine (TCM) and related East Asian herbal practices, herbs from the Rhamnus genus are sometimes used to "support the Spleen," which in TCM theory refers to enhancing digestive function, energy, and nutrient absorption. The Spleen concept in TCM does not directly correspond to the anatomical spleen in Western medicine but instead encompasses digestive and metabolic processes.

Historical texts and modern herbal compendia list Rhamnus nakaharai as having properties such as clearing heat, promoting urination, and reducing swelling, with occasional citations for its use in digestive disorders and as a mild laxative.

Although Rhamnus nakaharai has been used historically in Taiwan in folk medicines, not enough information is available about the percentage of chemical constituents present in the plant, proper dosages, and safety. No formal pharmacopeial or governmental monograph for R. nakaharai specifically has been identified in the available literature.

3. Key Constituents and Active Compounds

Phytochemical study of R. nakaharai has identified a range of structurally distinct secondary metabolites spanning anthraquinones, naphthalenes, and flavonoids. Anthraquinones and flavonoids are the most cited compounds from the genus, of which polyphenols are abundant. Each chemical class in R. nakaharai has been characterized in peer-reviewed publications originating primarily from Taiwanese research groups.

3.1 Anthraquinones and Anthraquinone Glycosides

This herb is reported to contain naphthalenic compounds such as 6-methoxysorigenin, different glycosides, and acylates — specifically 6-methoxysorigenin-8-O-glucoside, alpha-sorinin, 6-methoxysorigenin-8-rutinoside, peracetate, and perpropionate — in the stem bark, along with several known compounds.

In continuing study on the heartwood of Rhamnus nakaharai, a new alaternin-8-O-glucoside, namely 1,2,6,8-tetrahydroxy-3-methylanthraquinone-8-O-β-glucopyranoside, together with known compounds, was further isolated and characterized by 1-D, 2-D NMR and other spectral evidence. The free radical scavenging and antityrosinase activities of the isolates, including alaternin, emodin, emodin-8-O-β-glucopyranoside, 6-methoxysorigenin-8-O-β-glucopyranoside, and 6-methoxysorigenin, were tested.

Lin and Wei (1993) characterized anthraquinone and naphthalene glycosides from Rhamnus nakaharai, published in Phytochemistry (33:905–908). This work established the presence of the anthraquinone glycoside chrysophanol 8-O-xylosyl-(1→6)-glucoside in the root bark of the species.

3.2 Naphthalene Derivatives

A new naphthalene derivative, isotorachrysone, was isolated from the stem bark of Rhamnus nakaharai along with several known compounds and showed potent antiplatelet effects on arachidonic acid (AA-) and collagen-induced platelet aggregation. This compound was the subject of antioxidant and antiplatelet investigations published from Taiwanese laboratories.

The naphthalenic compound 6-methoxysorigenin is one of the most extensively studied isolates from this species. The naphthalenic compounds 6-methoxysorigenin and its glycosides — 6-methoxysorigenin-8-O-glucoside, alpha-sorinin, and 6-methoxysorigenin-8-rutinoside — isolated from Rhamnus nakaharai, together with two acylates (peracetate and perpropionate), were evaluated for antioxidant activities using DPPH, metal chelating, and electron spin resonance (ESR) assays, as well as an anti-lipid peroxidation assay.

3.3 Flavonoids

Rhamnus nakaharai is a source of several flavonoids such as quercetin, quercetin 3-O-methyl ether (3-O-methylquercetin), and kaempferol; it also contains isotorachyrsone and derivatives. The flavonol 3-O-methylquercetin (3-MQ) — also called quercetin 3-O-methyl ether — has been the most pharmacologically studied compound from this plant, particularly in the context of airway inflammation and smooth muscle relaxation.

3-O-Methylquercetin is a flavone isolated from Rhamnus nakaharai Hayata (Rhamnaceae) and functions as an inhibitor of cAMP- and cGMP-phosphodiesterases (PDE) with IC₅₀ values of 13.8 μM and 14.3 μM, respectively.

Quercetin from Rhamnus nakaharai and frangulin B from Rhamnus formosana displayed strong inhibition against the formation of TNF-α in LPS-stimulated RAW 264.7 macrophage cells, with IC₅₀ values of 49.7 ± 6.1 μM and 24.2 ± 12.8 μM, respectively.

4. Mechanisms of Action of Key Constituents

4.1 Anti-inflammatory Mechanism: 3-O-Methylquercetin and Nitric Oxide Suppression

3-O-Methylquercetin was found to suppress inflammation by managing nitric oxide production induced by lipopolysaccharide through the inhibition of inducible nitric oxide synthase (iNOS) DNA transcription. 3-O-Methylquercetin was also reported to inhibit total cAMP- and cGMP-phosphodiesterase of guinea pig trachealis.

4.2 Bronchodilating Mechanism: PDE Inhibition

In experiments on isolated guinea pig tracheal segments recorded isometrically, 3-MQ concentration-dependently relaxed histamine-, carbachol-, and KCl-induced precontractions, and inhibited cumulative histamine- and carbachol-induced contractions in a non-competitive manner. 3-MQ also concentration-dependently and non-competitively inhibited cumulative Ca²⁺-induced contractions in depolarized guinea-pig trachealis. The mechanisms of relaxant action of 3-MQ may be due to its inhibitory effects on both PDE activities and a subsequent reducing effect on intracellular calcium [Ca²⁺]i of the trachealis.

3-MQ and the positive control IBMX, at various concentrations (10–300 μM), concentration-dependently and significantly inhibited cAMP- and cGMP-PDE activities of the trachealis.

4.3 Antioxidant Mechanisms

6-Methoxysorigenin possesses the most potent DPPH radical scavenging, metal chelating, and anti-lipid peroxidation activities, with IC₅₀ values of 3.48, 615.90, and 5.95 μg/mL, respectively. The glycosides showed decreasing antioxidant activity related to increased substitution at the 1,8-dihydroxyl position with sugar molecules, suggesting the importance of the 1,8-dihydroxyl group in the antioxidative effect.

Isotorachrysone was reported to inhibit iron-induced lipid peroxidation in rat brain homogenates with an IC₅₀ value of 1.64 ± 0.08 µM. Results were comparable in potency to butylated hydroxytoluene and more potent than alpha-tocopherol or desferrioxamine.

Alaternin exhibited mild DPPH radical scavenging activity with about half the potency of vitamin C, while both alaternin and emodin-8-O-β-glucopyranoside exhibited stronger SOD-like activity than that of the reference antioxidant BHA.

4.4 Anti-tyrosinase Mechanism

6-Methoxysorigenin, a reported potential antioxidant, and its 8-O-glucoside both performed significant inhibitory effect on mushroom tyrosinase with about twice the potency of kojic acid, the positive control. This inhibition of tyrosinase — the key enzyme in melanin biosynthesis — has prompted interest in the compound's potential relevance to pigmentation-related conditions.

A prominent anti-tyrosinase effect was displayed by 6-methoxysorigenin reported from R. nakaharai, with an IC₅₀ value of 42.2 μM, which was twofold more potent than kojic acid with an IC₅₀ value of 82.1 μM.

4.5 Antiplatelet Mechanism

A new naphthalene derivative, isotorachrysone, isolated from the stem bark of Rhamnus nakaharai, showed potent antiplatelet effects on arachidonic acid (AA-) and collagen-induced platelet aggregation. The specific pathway of this antiplatelet activity was characterized by Lin et al. (1995) in the Journal of Natural Products.

5. Scientific Evidence by Area of Use

5.1 Respiratory / Anti-asthmatic Effects

Evidence Level: Preliminary — in vitro and isolated tissue models only; no human clinical data.

The suppressive effects of 3-O-methylquercetin 5,7,3′,4′-O-tetraacetate (QMTA), a more potent PDE3/4 inhibitor than quercetin 3-O-methyl ether, were investigated against ovalbumin-induced airway hyperresponsiveness (AHR). The IC₅₀ value of QMTA for PDE3 was significantly less than that for PDE4. According to Lineweaver-Burk analysis, QMTA (1–10 μM) competitively inhibited PDE3 and PDE4 activities, with Ki values of 0.9 ± 0.3 μM and 3.9 ± 0.5 μM respectively, suggesting higher affinity for PDE3 than for PDE4. QMTA (3–10 μM) concentration-dependently relaxed the baseline level and significantly inhibited cumulative OVA-induced contractions in isolated sensitized guinea pig trachealis, suggesting bronchodilator and mast cell degranulation-inhibiting effects.

These in vitro and in vivo studies have confirmed anti-inflammatory and bronchodilating effects of 3-O-methylquercetin. However, no randomized controlled trials, dose-response studies in humans, or clinical pharmacokinetics data specific to R. nakaharai extract or its isolated constituents in asthmatic patients have been identified in the published literature.

5.2 Anti-inflammatory Effects

Evidence Level: Preliminary — in vitro cell culture models only; no clinical trials.

The primary mechanistic data for anti-inflammatory activity derive from macrophage cell-line studies. 3-O-Methylquercetin was found to suppress inflammation by managing nitric oxide production induced by lipopolysaccharide through the inhibition of inducible nitric oxide synthase DNA transcription. The cell model used in this investigation was the RAW 264.7 murine macrophage line stimulated with LPS, which is a standard but non-human surrogate for inflammation.

Additionally, quercetin from Rhamnus nakaharai displayed strong inhibition against the formation of TNF-α in LPS-stimulated RAW 264.7 macrophage cells with IC₅₀ values of 49.7 ± 6.1 μM. No human trial data exist for anti-inflammatory applications of R. nakaharai as a whole extract.

5.3 Antioxidant Activity

Evidence Level: Preliminary — in vitro biochemical assays and isolated tissue models; no human clinical data.

Naphthalenic compounds including 6-methoxysorigenin and its glycosides — 6-methoxysorigenin-8-O-glucoside, alpha-sorinin, and 6-methoxysorigenin-8-rutinoside — isolated from Rhamnus nakaharai, along with two acylates (peracetate and perpropionate), were evaluated for antioxidant activities using DPPH, metal chelating, and ESR assays as well as anti-lipid peroxidation assay. 6-Methoxysorigenin possessed the most potent DPPH radical scavenging, metal chelating, and anti-lipid peroxidation activities with IC₅₀ values of 3.48, 615.90, and 5.95 μg/mL, respectively.

The iron chelation result further explains the main cause of increasing antioxidant activity in 6-methoxysorigenin. The acylates, although lacking a free hydroxyl, also exhibited significant anti-lipid peroxidation effect. ESR results further demonstrated strong antioxidant activities. The study concluded that 6-methoxysorigenin is a potent antioxidant and may also be used for designing new iron chelators for clinical applications.

Hsiao et al. (1996) evaluated antioxidant activities of isotorachrysone isolated from root bark extracts of R. nakaharai using iron-induced lipid peroxidation in rat brain homogenates, with butylated hydroxytoluene (BHT), alpha-tocopherol, and desferrioxamine as positive controls. The study revealed that isotorachrysone exhibited an IC₅₀ value of 1.64 μM, comparable to the IC₅₀ of 1.08 μM exhibited by BHT and more potent than alpha-tocopherol and desferrioxamine with IC₅₀ values of 3.71 and 97.10 μM.

5.4 Anti-tyrosinase / Depigmentation Activity

Evidence Level: Preliminary — in vitro enzyme assay only; no clinical evidence in humans.

Continuing study on the heartwood of Rhamnus nakaharai isolated a new alaternin-8-O-glucoside (1,2,6,8-tetrahydroxy-3-methylanthraquinone-8-O-β-glucopyranoside). The isolates including alaternin, emodin, emodin-8-O-β-glucopyranoside, 6-methoxysorigenin-8-O-β-glucopyranoside, and 6-methoxysorigenin were tested for free radical scavenging and antityrosinase activities. Alaternin exhibited mild DPPH radical scavenging activity, while both alaternin and emodin-8-O-β-glucopyranoside showed stronger SOD-like activity than BHA. 6-Methoxysorigenin and its 8-O-glucoside both performed significant inhibitory effect on mushroom tyrosinase with about twice the potency of kojic acid. The relevance of the mushroom tyrosinase enzyme assay to human melanogenesis is a recognized limitation, and no dermatological clinical studies of R. nakaharai have been published.

5.5 Antiplatelet and Cardiovascular-Related Activity

Evidence Level: Preliminary — in vitro platelet aggregation assays; no human pharmacological data.

Lin, Lu, Lin, Ko, and Teng (1995) published "Novel antiplatelet naphthalene from Rhamnus nakaharai" in the Journal of Natural Products (58:1934–1940). This study characterized isotorachrysone and demonstrated its antiplatelet properties in ex vivo assays. No clinical cardiovascular studies or human pharmacokinetic investigations have been published for this compound or for R. nakaharai extracts.

5.6 Gastrointestinal / Laxative Use

Evidence Level: Traditional use only; no formal clinical trials on R. nakaharai.

The primary use of Rhamnus nakaharai in East Asian traditional medicine systems has focused on effects as a mild laxative and digestive aid. Evidence supporting these uses is largely anecdotal, with documentation found in ethnobotanical surveys and traditional texts. There is a lack of robust scientific studies such as randomized controlled trials or pharmacological analyses directly examining the efficacy or mechanism of Rhamnus nakaharai for digestive conditions.

While related species in the Rhamnus genus — such as Rhamnus purshiana (cascara sagrada) — have recognized laxative effects due to anthraquinone glycosides, the specific bioactive compounds and their actions in R. nakaharai are not well-characterized in modern literature.

6. Body Systems and Health Areas Associated with R. nakaharai

• Respiratory system: Traditional use for asthma; in vitro and animal model evidence for bronchodilating and anti-airway-hyperresponsiveness activity via PDE3/PDE4 inhibition by 3-O-methylquercetin.
• Immune / Inflammatory system: In vitro suppression of nitric oxide and TNF-α production in macrophage models by 3-O-methylquercetin and quercetin.
• Gastrointestinal system: Traditional use for constipation, gastrointestinal ailments, and digestive disorders; anthraquinone content consistent with genus-wide laxative activity.
• Cardiovascular / Platelet system: Antiplatelet activity of isotorachrysone demonstrated in vitro.
• Integumentary / Pigmentation: Anti-tyrosinase activity of 6-methoxysorigenin in biochemical assays.
• Oxidative stress: Multiple antioxidant mechanisms demonstrated in vitro for 6-methoxysorigenin, isotorachrysone, and alaternin.

7. Dosage Forms and Dosages Reported in Studies

Not enough information is available about the percentage of chemical constituents present in the plant, proper dosages, and safety in the existing literature on Rhamnus nakaharai. As a result, no standardized dosage has been established for the whole plant or any standardized extract. The following dosage-related figures come directly from reported in vitro studies and are not clinical recommendations:

• 6-Methoxysorigenin demonstrated DPPH radical scavenging with an IC₅₀ of 3.48 μg/mL, metal chelating with IC₅₀ of 615.90 μg/mL, and anti-lipid peroxidation with IC₅₀ of 5.95 μg/mL in biochemical assays.
• Isotorachrysone inhibited iron-induced lipid peroxidation in rat brain homogenates with an IC₅₀ of 1.64 ± 0.08 µM.
• 3-O-Methylquercetin concentration-dependently relaxed induced precontractions in guinea pig tracheal tissue and also concentration-dependently inhibited cumulative Ca²⁺-induced contractions in depolarized guinea-pig trachealis.
• The Ki values for QMTA (a 3-MQ derivative) for PDE3 and PDE4 competitive inhibition were 0.9 ± 0.3 μM and 3.9 ± 0.5 μM, respectively.
• Anti-tyrosinase IC₅₀ for 6-methoxysorigenin: 42.2 μM (compared to kojic acid at 82.1 μM).
• 3-O-Methylquercetin inhibits cAMP- and cGMP-phosphodiesterases with IC₅₀ values of 13.8 μM and 14.3 μM, respectively.

No human pharmacokinetic studies, bioavailability data, or dose-ranging clinical trials for Rhamnus nakaharai as a whole plant preparation have been published in the peer-reviewed literature identified.

8. Safety Considerations

Although Rhamnus nakaharai has been used historically in Taiwan in folk medicines, not enough information is available about the percentage of chemical constituents present in the plant, proper dosages, and safety. Formal toxicological studies specific to R. nakaharai have not been published. However, several safety considerations arise from its constituent profile:

8.1 Anthraquinone-Related Concerns

Rhamnus nakaharai contains anthraquinone compounds including emodin, alaternin, and chrysophanol glycosides, which are chemically homologous to the anthraquinones found in other Rhamnus species that carry documented toxicological signals. Anthraquinones are a group of functionally diverse chemicals structurally related to anthracene, known to be present in the roots and bark of numerous plants of the genus Rhamnus such as senna, cascara, aloe, frangula, and rhubarb, used for their laxative properties.

It has been reported that anthraquinones exert a wide range of biological activities including antifungal, antimicrobial, and anticancer properties in addition to the well-known laxative action on the gastrointestinal apparatus. Alongside health benefits, anthraquinones were also reported to have a cell toxicity effect.

A case report in the PMC literature documented nephrotoxicity associated with another Rhamnus species (R. alaternus): this nephropathy was most likely aggravated by the potential toxic effect of anthraquinone glycosides found in Rhamnus alaternus infusion extract. While this case involved a different species, the anthraquinone-containing nature of R. nakaharai renders this finding scientifically relevant for safety assessment.

Anthraquinone glycosides can alter the body's normal balance of fluids and minerals, which can cause dehydration, severe hypokalemia, hyponatremia, asthenia, and anorexia.

8.2 Emodin

R. nakaharai contains emodin, which is a widely distributed anthraquinone in the Rhamnus genus. Given the potential toxicity associated with emodin, sub-chronic toxicity studies have been conducted in mice at emodin-infused diet concentrations of approximately 20 mg/kg, 40 mg/kg, and 80 mg/kg for 12 weeks. These studies pertain to emodin as an isolated compound rather than to whole-plant R. nakaharai preparations.

8.3 Antiplatelet Interaction Potential

The demonstration that isotorachrysone from R. nakaharai exhibits antiplatelet activity against both arachidonic acid–induced and collagen-induced platelet aggregation in vitro raises the theoretical possibility of interaction with anticoagulant or antiplatelet pharmaceutical agents, although no clinical pharmacokinetic or drug-interaction studies have been published for R. nakaharai.

8.4 Absence of Clinical Safety Data

There is little to no modern scientific research validating the use of Rhamnus nakaharai for most claimed indications. The evidence for efficacy comes almost exclusively from traditional texts rather than clinical trials or pharmacological studies. In the absence of formal human toxicology studies, no maximum safe dose or tolerable upper intake level can be stated for R. nakaharai preparations.

9. State of Research and Evidence Summary

The overall body of published research on Rhamnus nakaharai is preliminary and preclinical. The available evidence consists predominantly of in vitro phytochemical and mechanistic studies, with some isolated tissue (ex vivo) work. A moderate body of research data for Rhamnus nakaharai is available. 6-Methoxysorigenin, glycosides, and acylates derivatives have been studied for antioxidant activity; 6-methoxysorigenin was found to possess strong radical scavenging, metal chelating, and anti-lipid peroxidation activities compared to other derivatives.

Pharmacological activity evaluation of the extracts and isolated compounds revealed anti-inflammatory, antioxidant, antimalarial, antibacterial, anti-mutagenic, anti-genotoxic, hepatoprotective, anticancer, and anti-proliferative activity across the genus Rhamnus broadly; however, for R. nakaharai specifically, only antioxidant, anti-inflammatory, bronchodilatory, antiplatelet, and anti-tyrosinase activities have been formally reported at the in vitro level. There are no published randomized controlled trials, systematic reviews, or evidence-based monographs for R. nakaharai as a whole plant extract or dietary supplement.

References

• Bioactivity Monograph: Rhamnus nakaharai — Archives of Medicine and Health Sciences (2016)
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• Ko WC et al. Mechanisms of relaxant action of 3-O-methylquercetin in isolated guinea pig trachea — PubMed
• Lu TM, Ko HH. A new anthraquinone glycoside from Rhamnus nakaharai and anti-tyrosinase effect of 6-methoxysorigenin. Natural Product Research 2016;30:2655–2661
• Lin C, Wei B. Anthraquinone and naphthalene glycosides from Rhamnus nakaharai. Phytochemistry 1993;33:905–908 — ScienceDirect
• Lin CN, Lu CM, Lin HC, Ko FN, Teng CM. Novel antiplatelet naphthalene from Rhamnus nakaharai. Journal of Natural Products 1995;58:1934–1940 — ACS Publications
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• Traditional Medicinal Uses, Phytochemicals, and Pharmacological Activities of Genus Rhamnus: A Review — ResearchGate
• Ko WC et al. Suppressive effects of 3-O-methylquercetin on ovalbumin-induced airway hyperresponsiveness. Planta Medica 2004;70:1123–7 — Thieme
• Toxic Effects of Rhamnus alaternus: A Rare Case Report — PMC / Case Reports in Emergency Medicine 2015
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