Inhibitory Effects Of Honokiol Research Articles

Inhibitory Effects of Honokiol on Substantia Gelatinosa Neurons of the Trigeminal Subnucleus Caudalis in Juvenile Mice

Inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA) and glycine are known to be abundant in the substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc). Thus, it has been recognized as an initial synaptic site for regulating orofacial nociceptive stimuli. Honokiol, a principal active ingredient derived from the bark of Magnolia officinalis, has been exploited in traditional remedies with multiple biological effects, including anti-nociception on humans. However, the anti-nociceptive mechanism of honokiol on SG neurons of the Vc remains fully elusive. In this study, effects of honokiol on SG neurons of the Vc in mice were investigated using the whole-cell patch-clamp method. In a concentration-dependent manner, honokiol significantly enhanced frequencies of spontaneous postsynaptic currents (sPSCs) that were independent of action potential generation. Notably, honokiol-induced increase in the frequency of sPSCs was attributed to the release of inhibitory neurotransmitters through both glycinergic and GABAergic pre-synaptic terminals. Furthermore, higher concentration of honokiol induced inward currents that were noticeably attenuated in the presence of picrotoxin (a GABAA receptor antagonist) or strychnine (a glycine receptor antagonist). Honokiol also exhibited potentiation effect on glycine- and GABAA receptor-mediated responses. In inflammatory pain model, the increase in frequency of spontaneous firing on SG neurons induced by formalin was significantly inhibited by the application of honokiol. Altogether, these findings indicate that honokiol might directly affect SG neurons of the Vc to facilitate glycinergic and GABAergic neurotransmissions and modulate nociceptive synaptic transmission against pain. Consequently, the inhibitory effect of honokiol in the central nociceptive system contributes to orofacial pain management.

Honokiol Inhibits HIF-1α-Mediated Glycolysis to Halt Breast Cancer Growth

Background: Hypoxia-inducible factor-1α (HIF-1α) induces the expression of glycolysis-related genes, which plays a direct and key role in Warburg effect. In a recent study, honokiol (HNK) was identified as one of the potential agents that inhibited the HIF-1α signaling pathway. Because the HIF- 1α pathway is closely associated with glycolysis, we investigated whether HNK inhibited HIF-1α-mediated glycolysis. Methods: The effects of HNK on HIF-1α-mediated glycolysis and other glycolysis-related genes’ expressions, cancer cells apoptosis and tumor growth were studied in various human breast cancer models in vitro and in vivo. We performed the following tests: extracellular acidification and oxygen consumption rate assays, glucose uptake, lactate, and ATP assays for testing glycolysis; WST-1 assay for investigating cell viability; colony formation assay for determining clonogenicity; flow cytometry for assessing cell apoptosis; qPCR and Western blot for determining the expression of HIF-1α, GLUT1, HK2 and PDK1. The mechanisms of which HNK functions as a direct inhibitor of HIF-1α were verified through the ubiquitination assay, the Co-IP assay, and the cycloheximide (CHX) pulse-chase assay. Results: HNK increased the oxygen consumption rate while decreased the extracellular acidification rate in breast cancer cells; it further reduced glucose uptake, lactic acid production and ATP production in cancer cells. The inhibitory effect of HNK on glycolysis is HIF-1α-dependent. HNK also downregulated the expression of HIF-1α and its downstream regulators, including GLUT1, HK2 and PDK1. A mechanistic study demonstrated that HNK enhanced the self-ubiquitination of HIF-1α by recruiting two E3 ubiquitin ligases (UFL1 and BRE1B). In vitro, HNK inhibited cell proliferation and clonogenicity, as well as induced apoptosis of cancer cells. These effects were also HIF1α-dependent. In vivo, HNK inhibited tumor growth and HIF-1α-mediated glycolysis. Conclusion: HNK has an inhibitory effect on HIF-1α-mediated glycolysis in human breast cancer. Our research revealed a new mechanism of HNK as an anti-cancer drug, thus representing a novel strategy to improve the prognosis of cancer.

Honokiol Suppresses Perineural Invasion of Pancreatic Cancer by Inhibiting SMAD2/3 Signaling

BackgroundPerineural invasion (PNI) is an important pathologic feature of pancreatic cancer, and the incidence of PNI in pancreatic cancer is 70%-100%. PNI is associated with poor outcome, metastasis, and recurrence in pancreatic cancer patients. There are very few treatments for PNI in pancreatic cancer. Honokiol (HNK) is a natural product that is mainly obtained from Magnolia species and has been indicated to have anticancer activity. HNK also has potent neurotrophic activity and may be effective for suppressing PNI. However, the potential role of HNK in the treatment of PNI in pancreatic cancer has not been elucidated.MethodsIn our study, pancreatic cancer cells were treated with vehicle or HNK, and the invasion and migration capacities were assessed by wound scratch assays and Transwell assays. A cancer cell-dorsal root ganglion coculture model was established to evaluate the effect of HNK on the PNI of pancreatic cancer. Western blotting was used to detect markers of EMT and neurotrophic factors in pancreatic tissue. Recombinant TGF-β1 was used to activate SMAD2/3 to verify the effect of HNK on SMAD2/3 and neurotrophic factors. The subcutaneous tumor model and the sciatic nerve invasion model, which were established in transgenic engineered mice harboring spontaneous pancreatic cancer, were used to investigate the mechanism by which HNK inhibits EMT and PNI in vivo.ResultsWe found that HNK can inhibit the invasion and migration of pancreatic cancer cells. More importantly, HNK can inhibit the PNI of pancreatic cancer. The HNK-mediated suppression of pancreatic cancer PNI was partially mediated by inhibition of SMAD2/3 phosphorylation. In addition, the inhibitory effect of HNK on PNI can be reversed by activating SMAD2/3. In vivo, we found that HNK can suppress EMT in pancreatic cancer. HNK can also inhibit cancer cell migration along the nerve, reduce the damage to the sciatic nerve caused by tumor cells and protect the function of the sciatic nerve.ConclusionOur results demonstrate that HNK can inhibit the invasion, migration, and PNI of pancreatic cancer by blocking SMAD2/3 phosphorylation, and we conclude that HNK may be a new strategy for suppressing PNI in pancreatic cancer.

Inhibitory effect of honokiol on furin-like activity and SARS-CoV-2 infection

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a pandemic and has caused damage to the lives of the people and economy of countries. However, the therapeutic reagents against SARS-CoV-2 remain unclear. The spike (S) protein of SARS-CoV-2 contains a cleavage motif at the S1/S2 boundary, known to be cleaved by furin. As cleavage is essential for S protein activation and viral entry, furin was selected as the target compound. In this study, we examined the inhibitory effects of two lignans (honokiol and magnolol) on furin-like enzymatic activity using a fluorogenic substrate with whole-cell lysates. Of two compounds tested, honokiol partially inhibited furin-like enzymatic activity. We further examined the anti-SARS-CoV-2 activity of honokiol using VeroE6 cell line, which is stably expressing a transmembrane protease serine 2 (TMPRSS2). It was shown that honokiol exhibited remarkable inhibition of SARS-CoV-2 infection. Therefore, honokiol and crude drugs which contain honokiol such as Magnolia species have a potential therapeutic reagents for SARS-CoV-2.

Honokiol ameliorates oxidative stress-induced DNA damage and apoptosis of c2c12 myoblasts by ROS generation and mitochondrial pathway

ABSTRACT Honokiol is one of the main active components of Magnolia officinalis, and has been demonstrated to have multiple pharmacological activities against a variety of diseases. Recently, this phenolic compound is known to have antioxidant activity, but its mechanism of action remains unclear. The purpose of the current study was to evaluate the preventive effects of honokiol against oxidative stress-induced DNA damage and apoptosis in C2C12 myoblasts. The present study found that honokiol inhibited hydrogen peroxide (H2O2)-induced DNA damage and mitochondrial dysfunction, while reducing reactive oxygen species (ROS) formation. The inhibitory effect of honokiol on H2O2-induced apoptosis was associated with the up-regulation of Bcl-2 and down-regulation of Bax, thus reducing the Bax/Bcl-2 ratio that in turn protected the activation of caspase-9 and -3, and inhibition of poly (ADP-ribose) polymerase cleavage, which was associated with the blocking of cytochrome c release to the cytoplasm. Collectively, these results demonstrate that honokiol defends C2C12 myoblasts against H2O2-induced DNA damage and apoptosis, at least in part, by preventing mitochondrial-dependent pathway through scavenging excessive ROS.

Inhibitory Effects of Honokiol and Magnolol on Biofilm Formation by Acinetobacter baumannii

Acinetobacter baumannii is a nosocomial pathogen that can survive unfavorable conditions, such as, desiccation, nutrient starvation, and antimicrobial treatment, and this is primarily due to its ability to form biofilms on biotic and abiotic surfaces like tissues and medical devices. In this study, honokiol and magnolol were investigated for antibiofilm activity against A. baumannii ATCC 17978. Both were found to inhibit biofilm formation dose-dependently and to disperse matured biofilms. Honokiol and magnolol were found to inhibit biofilm formation by five and four of eight additional clinical A. baumannii isolates, respectively. Furthermore, honokiol and magnolol effectively suppressed pellicle formation and the surface motilities of the A. baumannii and prolonged the survival of infected nematode Caenorhabditis elegans. These results demonstrate that honokiol and magnolol may be useful for controlling A. baumannii infections.

Honokiol enhanced the antitumor activity of Sorafenib through inhibiting glycolysis

Objective To investigate the synergetic inhibitory effects of Honokiol and Sorafenib on hepatocellular carcinoma cell line HepG2 in vitro. Methods The expression of lactate dehydrogenase A (LDHA) in liver cancer tissue was detected by immunohistochemistry (IHC), the glycolysis level was evaluated by detecting the expression of LDHA in tumor cells and the level of lactate in the culture supernatants by immunofluorescence (IF) and colorimetry, respectively. The inhibitory effect of honokiol combined with sorafenib on growth of tumor cells was tested by methyl thiazol tetrazolium (MTT) and clonogenic assays, and apoptosis was examined by annexin V staining and caspase-3 activity detecting. Results LDHA expression increased in hepatocellular carcinoma as compared with normal liver tissues (3.74±0.98 vs. 1.92±0.63) (P=0.024). Treatment with 2.5 μmol/L Sorafenib for 2 days induced enhancement of aerobic glycolysis, reflecting by an increased levels of LDHA in cells and lactate in cell supernatants [from (17.23±3.42) mmol/L to (28.34±8.19) mmol/L](P=0.001). As compared with Sorafenib monotherapy, the significant reduction of cell growth rate [(74.35±13.64)% vs. (38.16±5.75)%](P=0.008) and increase of apoptosis rate (47% vs. 18%) (P=0.029) were observed in the tumor cells treated with Sorafenib plus Honokiol. Conclusion Honokiol enhances the killing effect of Sorafenib on hepatoma cell line HepG2, which may be related to the inhibition of tumor cell glycolysis and induction of apoptosis. Key words: Carcinoma, hepatocellular; Sorafenib; Lactate dehydrogenase A; Glycolysis; Honokiol

Inhibitory Effects of Honokiol on the Voltage-Gated Potassium Channels in Freshly Isolated Mouse Dorsal Root Ganglion Neurons.

Voltage-gated potassium (KV) currents, subdivided into rapidly inactivating A-type currents (I A) and slowly inactivating delayed rectifier currents (I K), play a fundamental role in modulating pain by controlling neuronal excitability. The effects of Honokiol (Hon), a natural biphenolic compound derived from Magnolia officinalis, on KV currents were investigated in freshly isolated mouse dorsal root ganglion neurons using the whole-cell patch clamp technique. Results showed that Hon inhibited I A and I K in concentration-dependent manner. The IC50 values for block of I A and I K were 30.5 and 25.7µM, respectively. Hon (30µM) shifted the steady-state activation curves of I A and I K to positive potentials by 17.6 and 16.7mV, whereas inactivation and recovery from the inactivated state of I A were unaffected. These results suggest that Hon preferentially interacts with the active states of the I A and I K channels, and has no effect on the resting state and inactivated state of the I A channel. Blockade on K+ channels by Hon may contribute to its antinociceptive effect, especially anti-inflammatory pain.

Effect of honokiol on proliferation and apoptosis in HL-60 cells and its potential mechanism

This study was aimed to investigate the effect of Honokiol (HNK) on proliferation and apoptosis of acute myeloid leukemia HL-60 cells and its potential mechanism. Inhibitory effect of HNK on the HL-60 cell proliferation was detected by MTT assay. Flow cytometry was used to detect the change of cell cycle and AnnexinV/PI staining was used to detect apoptosis. Western blot was applied to analyze the cell cycle protein (cyclins), cyclin-dependent kinase (CDK), P53, P21, P27, BCL-2, BCL-XL, Bax, caspase-3/9 and proteins for MAPK signal pathway. The results showed that HNK could inhibit the proliferation of HL-60 cells in time- and dose dependent ways. HNK arrested HL-60 cells in G0/G1 phase, and S phase cells decreased significantly (P < 0.05). The expression of cyclin D1, cyclin A, cyclin E and CDK2/4/6 were significantly down-regulated (P < 0.05), the expression of P53 and P21 was significantly upregulated after treating for 24 h with HNK (P < 0.05). After 24 h treatment with HNK, HL-60 cell apoptosis increased significantly with the upregulation of activated caspase-3, -9, BAX expression and the downregulation of BCL-2, BCL-XL expression. The MAPK subfamily, P38 and JNK were not significantly changed, but the expression of MEK1/2-ERK1/2 was significantly downregulated (P < 0.05). It is concluded that HNK arrestes the cells at G0/G1 phase and induces HL-60 cell apoptosis through the intervention of MEK1/2-ERK1/2 signaling pathway.

Inhibitory effect of honokiol and magnolol on cytochrome P450 enzyme activities in human liver microsomes

Honokiol and magnolol, the major bioactive neolignans of magnolia officinalis, are the most important constituents of the crude drug prescriptions that are used in the therapy of neuroses and various nervous disorders. There have been limited reports on the effects of neolignoid compounds on human cytochrome P450 activity. Therefore, the inhibitory effects of honokiol and magnolol on seven human cytochrome P450 s were evaluated in human liver microsomes. Honokiol and magnolol showed the most potent inhibition of CYP1A2-mediated phenacetin O-deethylase activity (<TEX>$IC_{50}$</TEX> values of 3.5 and 5.4 mM, respectively) among the seven P450s tested. These in vitro data indicate that neolignan compounds can inhibit the activity of CYP1A2 and suggest that these compounds should be examined for potential pharmacokinetic drug interactions in vivo.

Honokiol: an effective inhibitor of tumor necrosis factor-&amp;alpha;-induced up-regulation of inflammatory cytokine and chemokine production in human synovial fibroblasts

In this study, we investigated the mechanisms underlying the anti-inflammatory effects of honokiol in tumor necrosis factor (TNF)-α-stimulated rheumatoid arthritis synovial fibroblasts (RASFs). RASFs pre-treated with honokiol (0-20 μM) were stimulated with TNF-α (20 ng/ml). The levels of prostaglandin E2 (PGE2), nitric oxide (NO), soluble intercellular adhesion molecule-1 (sICAM-1), transforming growth factor-β1 (TGF-β1), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1α (MIP-1α) in supernatants were determined by enzyme-linked immunosorbent assay (ELISA) and Griess assay. In addition, protein expression levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and phosphorylated Akt, nuclear factor kappa B (NFκB), and extracellular signal-regulated kinase (ERK)1/2 were determined by western blot. The expression of NFκB-p65 was assessed by immunocytochemical analysis. TNF-α treatment significantly up-regulated the levels of PGE2, NO, sICAM-1, TGF-β1, MCP-1, and MIP-1α in the supernatants of RASFs, increased the protein expression of COX-2, iNOS, and induced phosphorylation of Akt, IκB-α, NFκB, and ERK1/2 in RASFs. TNF-α-induced expression of these molecules was inhibited in a dose-dependent manner by pre-treatment with honokiol. The inhibitory effect of honokiol on NFκB-p65 activity was also confirmed by immunocytochemical analysis. In conclusion, honokiol is a potential inhibitor of TNF-α-induced expression of inflammatory factors in RASFs, which holds promise as a potential anti-inflammatory drug.

Honokiol inhibits hypoxia-inducible factor-1 pathway

Purpose: Hypoxia-inducible factor-1α (HIF-1α) plays a pivotal role in the reaction of a tumour to hypoxia. In this study, we examined the inhibitory effect of a natural compound, honokiol, on HIF-1α activity and tumour growth in combination with radiation.Methods: The inhibitory effect of honokiol on hypoxia-responsive element (HRE) controlled luciferase activity and HIF-1α accumulations stimulated by CoCl2, or hypoxia was examined. Effect of honokiol on HIF-1α levels within hypoxic tumour microenvironment was investigated by immunohistochemical and in vivo bioluminescent studies. The in vivo radiosensitising activity of honokiol was evaluated with subcutaneous murine colon carcinoma, CT26, xenografts of BALB/c mice treated with honokiol, radiation, or both.Results: Suppression of luciferase (luc) activity in HRE-luc stable cells by honokiol was in agreement with the results of decreased HIF-1α accumulation. In CT26-HRE-luc tumour-bearing mice, the inhibitory effect of intraperitoneally injected honokiol on HIF-1α-regulated luciferase activities induced by either CoCl2 or radiation could be monitored non-invasively. Lastly, honokiol in combination with irradiation produced synergistic delay of CT26 tumour growth.Conclusions: Our data suggest that honokiol can exert its anticancer activity as a HIF-1α inhibitor by reducing HIF-1α protein level and suppressing the hypoxia-related signaling pathway. The animal experiment indicates that honokiol improves the therapeutic efficacy of radiation.

Honokiol: a promising small molecular weight natural agent for the growth inhibition of oral squamous cell carcinoma cells

Honokiol (HNK) is a small organic molecule purified from magnolia species and has demonstrated anticancer activities in a variety of cancer cell lines; however, its effect on oral squamous cell carcinoma (OSCC) cells is unknown. We investigated the antitumor activities of HNK on OSCC cells in vitro for the first time. The inhibitory effects of HNK on the growth and proliferation of OSCC cells were demonstrated via in vitro 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and propidium iodide (PI) assays, and the apoptotic cells were investigated by the observation of morphological changes and detection of DNA fragmentation via PI, TdT-mediated dUTP-biotin nick end labeling (TUNEL), and DNA ladder assays, as well as flow cytometry assay. The results showed that HNK inhibited the growth and proliferation of OSCC cells in vitro in a time and dose-dependent manner. The inhibitory effect was associated with the cell apoptosis induced by HNK, evidenced by the morphological features of apoptotic cells, TUNEL-positive cells and a degradation of chromosomal DNA into small internucleosomal fragments. The study also demonstrated here that the inhibition or apoptosis mediated by 15 μg·mL−1 or 20 μg·mL−1 of HNK were more stronger compared with those of 20 μg·mL−1 5-fluorouracil (5-Fu, the control) applied to OSCC cells, when the ratio of OSCC cell numbers were measured between the treatment of different concentrations of HNK to the 5-Fu treatment for 48 h. HNK is a promising compound that can be potentially used as a novel treatment agent for human OSCC.

Inhibitory effects of honokiol on lipopolysaccharide-induced cellular responses and signaling events in human renal mesangial cells

Honokiol has been shown to possess a lot of pharmacologic benefits, including antioxidative, antiangiogenic and antineoplastic effects. In the present study, we investigated the anti-inflammatory effects of honokiol and the signaling mechanisms involved in lipopolysaccharide (LPS)-induced conditions in human renal mesangial cells (HRMCs). Honokiol did not significantly change HRMC viability when used at a concentration of <20μmol/l but markedly altered cell viability at concentrations of >40μmol/l. In this study, LPS treatment led to a marked upregulation of the levels of IL-1β, IL-18, TNF-α, TGF-β1, CCL2, CCL3, and CCL5 in HRMCs. The expression of COX-2, iNOS, and their products PGE2 and NO also increased. The upregulation of these molecules was significantly abolished by honokiol in a dose-dependent manner. Moreover, honokiol almost completely reversed IL-1β, CCL3, and NO expression at 10μmol/l, and IL-18, TNF-α, TGF-β1, and COX-2 expression at 20μmol/l. In addition, phospho-NF-κB p65 at Ser536, phospho-Akt, and phospho-p42/44 were dramatically suppressed by honokiol in LPS-treated HRMCs. These results indicate that honokiol can inhibit the LPS-induced expression of inflammatory cytokines and mediators in HRMCs. The anti-inflammatory mechanisms of honokiol are partly due to the suppression of the phospho-NF-κB p65, phospho-Akt and phospho-p42/44 pathways.

Abstract 1871: Honokiol, a natural plant product, inhibits ultraviolet radiation-induced skin tumorigenesis in mice through inhibition of inflammation and inflammatory mediators

Abstract Chronic exposure of solar ultraviolet (UV) radiation is the major etiologic agent for over one million new cases of non-melanoma skin cancers in the US each year. These cutaneous malignancies thus have a tremendous impact on public health and healthcare expenditures. The use of natural plant products has received considerable interest to protect skin from adverse biological effects of UV radiation since the protective clothing and use of sunscreens are not adequate for skin photoprotection. The photoprotective effect of honokiol, a plant product from Magnolia species, therefore assessed using SKH-1 hairless mouse model. To determine the skin cancer chemopreventive effect and associated mechanism of honokiol, a hydrophilic cream based topical formulation was developed. Different groups of mice (n=20) treated with or without honokiol were subjected to photocarcinogenesis protocol. Mice were irradiated to UVB (180 mJ/cm2) three times a week. At the termination of the experiment at 24th week, we found that topical application of honokiol (1mg &amp; 3mg/mouse) inhibited UVB-induced skin tumor development in terms of tumor incidence (10-20%), tumor multiplicity (40-60%) and tumor size (50-75%). Since UV-induced inflammation plays a crucial role in the development of skin tumors, we examined the effect of honokiol on UVB-induced biomarkers of inflammation, such as the expression levels of cyclooxygenase-2 (COX-2), prostaglandins (PG), proliferating cell nuclear antigen (PCNA), infiltration of inflammatory leukocytes, development of edema and epidermal hyperplastic response using immunostaining, western blotting and RT-PCR. Our data revealed that topical application of honokiol before each exposure of UVB radiation resulted in a dose-dependent inhibition of UVB-induced expression of COX-2, PGE2, developments of edema and infiltration of leukocytes at the UVB-irradiated skin sites. Honokiol also inhibited the levels of PCNA (hyperplastic potential) in epidermal keratinocytes of UVB-exposed skin. The inhibitory effects of honokiol on inflammatory mediators were also found in skin tumor samples. The results of this study suggest that honokiol has the ability to inhibit UVB radiation-induced skin tumor development in mice and it is associated with the inhibition of UVB-induced inflammation and inflammatory mediators in mouse skin and skin tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1871.

Inhibitory effects of honokiol on LPS and PMA-induced cellular responses of macrophages and monocytes

The regulatory effects of honokiol on the cellular responses of macrophages and monocytes were evaluated. Specifically, we investigated the effects of honokiol with respect to lipopolysaccharide (LPS)-induced cytotoxicity, LPS- or phorbol-12-myristate-13-acetate (PMA)-mediated morphological changes, and relevant events (FITC-dextran-induced phagocytic uptake). Honokiol blocked the LPS-induced cytotoxicity of RAW264.7 cells in a dose-dependent manner. In addition, honokiol appeared to block the production of cytotoxic cytokines such as interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, nitric oxide (NO), and reactive oxygen species (ROS). Moreover, honokiol strongly prevented the morphological changes in RAW 264.7 and U937 cells that were induced by LPS and PMA. The surface levels of marker proteins, which are up-regulated under the morphological changes of RAW264.7 and U937 cells, were also diminished. The data presented here strongly suggest that the honokiol modulates various cellular responses managed by macrophages and monocytes. [BMB reports 2009; 42(9): 574-579].

The mechanism of honokiol-induced and magnolol-induced inhibition on muscle contraction and Ca2+ mobilization in rat uterus.

The effects of honokiol and magnolol extracted from the Magnolia officinalis on muscular contractile responses and intracellular Ca(2+) mobilization were investigated in the non-pregnant rat uterus. Honokiol and magnolol (1-100 micromol/l) were observed to inhibit spontaneous and uterotonic agonists (carbachol, PGF(2alpha), and oxytocin)-, high K(+)-, and Ca(2+) channel activator (Bay K 8644)-induced uterine contractions in a concentration-dependent manner. The inhibition rate of honokiol on spontaneous contractions appeared to be slower than that of magnolol-induced response. The time periods that were required for honokiol and magnolol, at 100 micromol/l, to abolish 50% spontaneous contractions were approximately 6 min. Furthermore, honokiol and magnolol at 10 micromol/l also blocked the Ca(2+)-dependent oscillatory contractions. Consistently, the increases in intracellular Ca(2+) concentrations ([Ca(2+)](i)) induced by PGF(2alpha) and high K(+) were suppressed by both honokiol and magnolol at 10 micromol/l. After washout of these treatments, the rise in [Ca(2+)](i) induced by PGF(2alpha) and high K(+) was still partially abolished. In conclusion, the inhibitory effects of honokiol and magnolol on uterine contraction may be mediated by blockade of external Ca(2+) influx, leading to a decrease in [Ca(2+)](i). Honokiol and magnolol may be considered as putative Ca(2+) channel blockers and be of potential value in the treatment of gynecological dysfunctions associated with uterine muscular spasm and dysmenorrhea.

In vitro and in vivo protective effect of honokiol on rat liver from peroxidative injury

Honokiol, a compound extracted from the Chinese medicinal herb Magnolia officinalis, has a strong antioxidant effect on the inhibition of lipid peroxidation in rat heart mitochondria. To investigate the protective effect of honokiol on hepatocytes from peroxidative injury, oxygen consumption and malondialdehyde formation for in vitro iron-induced lipid peroxidation were assayed, and the mitochondrial respiratory function for in vivo ischemia-reperfusion injury were evaluated in rat liver, respectively. The inhibitory effect of honokiol on oxygen consumption and malondialdehyde formation during iron-induced lipid peroxidation in liver mitochondria showed obvious dose-dependent responses with a concentration of 50% inhibition being 2.3 × 10 −7M and 4.96 × 10 −7M, respectively, that is, 550 times and 680 times more potent than α-tocopherol, respectively. When rat livers were introduced with ischemia 60 min followed by reperfusion for 60 min, and then pretreated with honokiol (10 ug/kg BW), the mitochondrial respiratory control ratio (the quotient of the respiration rate of State 3 to that of State 4) and ADP/O ratio from the honokiol-treated livers were significantly higher than those of non-treated livers during reperfusion. The dose-dependent protective effect of honokiol on ischemia-reperfusion injury was 10 μg-100 μg/Kg body weight. We conclude that honokiol is a strong antioxidant and shed insight into clinical implications for protection of hepatocytes from ischemia-reperfusion injury.