Birch (Betula pendula) and Arthritis / joint pain: evidence and sources

Ethnopharmacological relevance Trees and shrubs of the genus Betula (Betulaceae) inhabit various ecosystems in temperate and boreal climate zones of the northern hemisphere. The healing properties of Betula bark and bark extracts have been known for a long time in traditional medicine in different parts of the world. Several species of Betula have traditionally been used for the treatment of various inflammatory diseases including arthritis. The purpose of this review is to provide updated, comprehensive and categorized information on the botany, traditional uses, phytochemistry and pharmacological and toxicological research of Betula species in order to explore their therapeutic potential and evaluate future research opportunities. Materials and methods All the available information on various species belonging to the genus Betula was collected via electronic search (using Pubmed, SciFinder, Scirus, Google Scholar, JCCC@INSTIRC and Web of Science) and a library search for articles published in peer-reviewed journals. Results Although over a hundred Betula species are found distributed globally, about 7 different species of Betula have been documented for their traditional uses. Phytochemical research on Betula species has led to the isolation of triterpenoids, diarylheptanoids, phenylbutanoids, lignans, phenolics and flavonoids. Crude extracts, fractions and phytochemical constituents isolated from Betula showed a wide spectrum of in vitro and in vivo pharmacological activities like immunomodulatory, anti-inflammatory, antimicrobial, antiviral, antioxidant, antidiabetic, dermatological, gastroprotective and hepatoprotective. Antiarthritic and anticancer are the two major areas of research conducted on these species. The anti-carcinogenic effects of Betula bark, betulin as well as betulinic acid have been extensively studied. Conclusions Several species belonging to the genus Betula are widely used in traditional medicine. Betula platyphylla and Betula pendula have specifically been found to be potentially useful in the treatment of degenerative joint disease. There is convincing evidence in experimental animal models in support of their anti-carcinogenic effects. However, it would be worthwhile to investigate the biochemical and physiological mechanisms as well as detailed preclinical toxicity, bioavailability, pharmacokinetics and pharmacodynamics of the different biologically active extracts as well as molecules in sufficient detail. An integrated and holistic approach is required for tapping the full potentials of this important genus.

Ethnopharmacological relevance Leaf extracts of Betula pendula have been traditionally used for the treatment of patients with rheumatoid arthritis (RA) or osteoarthritis. Aim of the study We investigated the anti-proliferative capacity of an aqueous leaf extract of Betula pendula (BPE) on human primary lymphocytes in vitro, because activated lymphocytes play a major role in the initiation and maintenance of RA. Materials and methods Lymphocyte proliferation and cell division was measured by the activity of mitochondrial dehydrogenases and by using the membrane-permeable dye carboxyfluorescein diacetate succinimidyl ester (CFSE), respectively. Apoptosis was analyzed by surface staining of phosphatidylserine and intracellular activation of effector caspases 3 and 7 in comparison to the drug methotrexate using flow cytometric and photometrical analysis. In addition, the impact of the extract on cell cycle distribution was investigated by propidium iodide staining of DNA. For the bioassays BPE concentrations of 10-160 μg/mL were investigated. A phytochemical analysis, using LC-MS and HPLC, was conducted to identify the polyphenolic constituents of the birch leaf extract. Results Leaf extracts of Betula pendula inhibited the growth and cell division (CD8(+): 40 μg/mL: 45%; 80 μg/mL: 60%; 160 μg/mL: 87%) (CD4(+): 40 μg/mL: 33%; 80 μg/mL: 54%; 160 μg/mL: 79%) of activated, but not of resting T lymphocytes in a significant dose-dependent manner. The inhibition of lymphocyte proliferation due to apoptosis induction (compared to untreated control: 40 μg/mL: 163%; 80 μg/mL: 240%; 160 μg/mL: 348%) and cell cycle arrest was comparable to that of methotrexate. LC-MS analyses showed that the extract contains different quercetin-glycosides. Conclusion Our results give a rational basis for the use of Betula pendula leaf extract for the treatment of immune disorders, like rheumatoid arthritis, by diminishing proliferating inflammatory lymphocytes.

Ethnopharmacological relevance Betula pendula subsp. Mandshurica (Regel) Ashburner & McAll. Cortex (birch bark) is a globally traditional medicine for treating multiple inflammatory diseases. Its records are included in the Compendium of Materia Medica and other ancient medical literatures. However, uncovering its chemical profile and exploring novel biologically active compounds from birch bark remains a significant challenge. Aim of the study To uncover the anti-inflammatory, -oxidative, and -proliferative mechanisms and potentially effective compounds of birch bark extract by combing chemical profiling, isolation, identification, together with in vivo, in vitro, and silico evaluation. Materials and methods Ultra-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS/MS) was used to obtain the chemical profile of birch bark extract. The new compounds were obtained via column chromatography and analyzed using X-ray diffraction and electronic circular dichroism for absolute configuration confirmation. The zebrafish caudal fin inflammation-induced model, qPCR, and Western blot analysis were used to explore the effects and underlying mechanisms of birch bark extract. In vitro cytotoxicity assays and kinases screening conducted to gain preliminary insight into the anti-proliferative effects of birch bark extract and its isolated compounds. In addition, in-silico molecular docking was performed to investigate the putative mechanism. Results UPLC-QTOF-MS/MS chemical profiles revealed 105 compounds in birch bark extract, with 80 of these were first reported in B. pendula subsp. Mandshurica cortex. We selected five compounds speculated as novel and isolated three ones (one triterpenoid derivative and two lupine series triterpenoids) for further analysis. Birch bark extract exerted antioxidative and anti-inflammatory effects on zebrafish, as shown by the downregulated reactive oxygen species levels and COX-2α, IL-1β, and TNF-α expression, which occurred through NF-ĸB signaling pathway activation. The in vitro anti-proliferative effects of birch bark extract and compound 44 were also unveiled. Moreover, the putative anti-tumor mechanism of compound 44 was revealed using kinase screening and in-silico molecular docking. Conclusions This study provided a predictable chemical profile and demonstrated the pharmacological effects of birch bark extract, elucidated the mechanism of this traditional Chinese medicine and suggested it as a novel anti-cancer candidate.