bakuchiol and Disease-Models--Animal

Bakuchiol (BAK) has been reported to have a diverse pharmacological property as an antibiotic, anti-cancer, anti-hypolipidemic, anti-inflammatory and anti-convulsant agent. This study aimed to elucidate the immunomodulation and anti-inflammatory mechanism of bakuchiol using lipopolysaccharide stimulated RAW 264.7 macrophages and various animal models. The present study has shown that BAK significantly suppressed the pro-inflammatory cytokine expression in a dose-dependent manner and its oral administration significantly decreased delayed hypersensitivity responses as compared to control group. The assessment of immunomodulatory activity was carried out by the testing Hemagglutinating antibody (HA) titer, delayed type hypersensitivity (DTH) responses and phagocytic index by carbon clearance test. On the other hand, it showed significant decrease in circulating antibody titer and carbon clearance assay in a concentration-dependent manner. BAK has significantly potentiated the cellular immunity as well as humoral immunity by facilitating the footpad thickness responses in sheep RBCs in sensitized mice by significantly decreasing circulating antibody titer. Molecular studies revealed that BAK inhibited the activation of upstream mediator nuclear factor-κB by suppressing the phosphorylation of IκBα and p65. The responses were statistically significant as compared with the control (*p < 0.05, **p < 0.01).

Topics: Animals; Anti-Inflammatory Agents; Cell Proliferation; Cytokines; Disease Models, Animal; Female; Graft Rejection; Hypersensitivity, Delayed; Immunity, Humoral; Immunosuppressive Agents; Inflammation; Inflammation Mediators; Lipopolysaccharides; Lymphocyte Activation; Macrophages; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Phagocytosis; Phenols; Phosphorylation; RAW 264.7 Cells; Sheep; Signal Transduction; Skin Transplantation

Cerebral ischemia/reperfusion (I/R) injury is a common cerebrovascular disease with high mortality. Bakuchiol (BAK), extracted from the seeds of psoralea corylifolia, exhibits anti-inflammatory effects on lung, kidney and heart injuries. However, the effect of BAK on brain I/R injury remains elusive. In our study, a cerebral I/R model in mice was established by 1-h middle cerebral artery occlusion and 24-h reperfusion (1-h MCAO/24-h R). Prior to it, mice were gavaged with BAK (2.5 or 5 mg/kg) per day for 5 days. BAK pre-treatment improved neurological deficit, and reduced infarct volume, cerebral edema and neuronal injury in MCAO/R-injured mice. BAK decreased the number of Iba1-immunoreactive cells in the brain, indicating a reduction of microglial activation. BAK also reduced the expressions of NLRP3, ASC, cleaved-caspase-1, IL-1β and IL-18. BAK triggered Nrf2 nuclear accumulation and elevated HO-1 level. Further, the role of BAK was explored in BV-2 microglia with 3-h oxygen-glucose deprivation/24-h reperfusion (3-h OGD/24-h R). It was found that the functions of BAK in vitro were consistent with those in vivo, as manifested by reduced NLRP3 inflammasome and activated Nrf2 signaling. In addition, BV-2 cells were treated with Brusatol, an Nrf2 inhibitor. Results showed that Brusatol partially reversed the protective effect of BAK on OGD/R-injured BV-2 cells, further confirming that BAK might exhibit its anti-inflammatory property via activating Nrf2 signaling. In short, BAK is more meaningful in improving cerebral ischemic injury through suppressing NLRP3-mediated inflammatory response and activating the Nrf2 signaling pathway.

Topics: Animals; Brain Edema; Brain Ischemia; Disease Models, Animal; Infarction, Middle Cerebral Artery; Inflammasomes; Male; Mice; Mice, Inbred C57BL; Neuroinflammatory Diseases; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Phenols; Reperfusion Injury; Signal Transduction

Bakuchiol (BAK) is a prenylated phenolic mono-terpene extracted from the fruit of Psoralea corylifolia L., which exerts a protective effect on organs. However, whether BAK has a protective effect on sepsis-induced acute kidney injury (S-AKI) is not clear. In our study we have demonstrated for the first time that pretreatment with BAK significantly reduced bacterial load, inflammation and renal oxidative stress in caecal ligation and puncture (CLP)-induced sepsis. Moreover, CLP-induced renal histological damage, mortality and clinical signs were markedly attenuated by BAK. Additionally, BAK inhibited sepsis-induced activation of NF-κB and p38 MAPK signaling in the kidneys. The evidence presented here has confirmed that BAK exerts multifunctional activity in protection against S-AKI. This action of BAK is probably due to the blockade of the NF-κB and p38 MAPK signaling pathways. Our findings offer a novel potential for BAK in protection against sepsis and S-AKI.

Topics: Acute Kidney Injury; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antioxidants; Bacterial Load; Disease Models, Animal; Kidney; Male; Mice, Inbred C57BL; NF-kappa B; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phenols; Psoralea; Sepsis

Estrogen replacement therapy (ERT) is utilized as a major regime for treatment of postmenopausal osteoporosis at present. However, long-term supplement of estrogen may cause uterine hyperplasia and hypertension leading to a high risk of endometrial cancer and breast cancer. Psoralea corylifolia L. has long been used as tonic and food additives in many countries. Previous studies had found two ingredients in P. corylifolia L.: bavachin and bakuchiol exhibited osteoblastic activity. The present study was designed to investigate the protective effect of bakuchiol and bavachin on ovariectomy-induced bone loss and explore the possible mechanism. In vivo, bakuchiol and bavachin could prevented estrogen deficiency-induced bone loss in ovariectomized rats without uterotrophic activity. In vitro studies suggested that bakuchiol and bavachin induced primary human osteoblast differentiation by up-regulating the Wnt signalling pathway. This study suggests that such a bone-protective role makes them a promising and safe estrogen supplement for the ERT.

Topics: Animals; Cell Differentiation; Cells, Cultured; Disease Models, Animal; Female; Flavonoids; Humans; Osteoblasts; Osteoclasts; Osteoporosis; Ovariectomy; Phenols; Plant Extracts; Psoralea; Rats; Up-Regulation; Wnt Signaling Pathway

Bakuchiol was an active antifungal compound isolated from Psoraleae Fructus by means of bioassay-guided fractionation in our previous study. The present work aimed to investigate the underlying mechanisms and the therapeutic effect of bakuchiol in Trichophyton mentagrophytes-induced tinea pedis. After exposure to bakuchiol at 0.25-fold, 0.5-fold and 1-fold of minimum inhibitory concentration (MIC) (3.91 μg/ml) for 24h, the fungal conidia of T. mentagrophytes demonstrated a significant dose-dependent increase in membrane permeability. Moreover, bakuchiol at 1-fold MIC elicited a 187% elevation in reactive oxygen species (ROS) level in fungal cells after a 3-h incubation. However, bakuchiol did not induce DNA fragmentation. In a guinea pig model of tinea pedis, bakuchiol at 1%, 5% or 10% (w/w) concentration in aqueous cream could significantly reduce the fungal burden of infected feet (p<0.01-0.05). In conclusion, this is the first report to demonstrate that bakuchiol is effective in relieving tinea pedis and in inhibiting the growth of the dermatophyte T. mentagrophytes by increasing fungal membrane permeability and ROS generation, but not via induction of DNA fragmentation.

Topics: Animals; Antifungal Agents; Cell Membrane Permeability; Disease Models, Animal; DNA Fragmentation; Dose-Response Relationship, Drug; Female; Guinea Pigs; Microbial Sensitivity Tests; Phenols; Reactive Oxygen Species; Tinea Pedis; Trichophyton

Liver fibrosis and cirrhosis may be reversible, possibly through the selective clearance of activated hepatic stellate cells/myofibroblasts by apoptosis. Hepatic stellate cells transdifferentiate into myofibroblast-phenotype cells in culture, a process that recapitulates hepatic stellate cell activation in vivo. Bakuchiol, a prenylated phenolic terpene isolated from the seed of Psoralea corylifolia L. (Leguminosae), reduced activated hepatic stellate cells when treated to rats during liver injury recovery period as demonstrated by alpha-smooth muscle actin immunostaining in rat liver and induced apoptosis in activated hepatic stellate cells/myofibroblasts as demonstrated by DNA fragmentation, activation of caspase-3, release of cytochrome c into the cytoplasm, translocation of Bax into mitochondria, and the proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) in vitro. Bakuchiol-induced apoptosis was prevented by z-DEVD-fmk, a specific inhibitor of caspase-3, and z-VAD-fmk, a general caspase inhibitor, suggesting that bakuchiol-induced apoptosis occurs through a caspase-3-dependent pathway in vitro. Bakuchiol treatment stimulated the activation of extracellular signal-regulated kinase 1/2 (ERK), c-Jun NH2-terminal protein kinase (JNK), and p38 mitogen-activated protein kinases (MAPK) in vitro. Pretreatment with SP600125 attenuated the bakuchiol-induced translocation of Bax into mitochondria, cytochrome c release into the cytosol, caspase-3 activation, and PARP cleavage. In contrast, preincubation with SB203580, a p38 MAPK inhibitor, and U0126, an ERK inhibitor, had no effect on bakuchiol-induced cell death and caspase-3 activity. Taken together, these findings indicate that bakuchiol induces caspase-3-dependent apoptosis through the activation of JNK, followed by Bax translocation into mitochondria in rat liver myofibroblasts.

Topics: Actins; Animals; Apoptosis; bcl-2-Associated X Protein; Carbon Tetrachloride; Caspase 3; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cytochromes c; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Fibroblasts; JNK Mitogen-Activated Protein Kinases; Liver; Liver Diseases; Male; MAP Kinase Signaling System; Mitochondria, Liver; Phenols; Protective Agents; Protein Transport; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Time Factors