Effects Of Honokiol Research Articles

The application prospects of honokiol in dermatology.

Honokiol is one of the natural extracts of Magnolia officinalis. It is a small molecule, lipophilic compound with extensive biological effects. It has been used in the treatment of multisystem diseases, including digestive diseases, endocrine diseases, nervous system diseases, and various tumors. This paper reviews the biological effects of honokiol on the treatment of skin diseases in recent years, including anti‐microbial, anti‐oxidant, anti‐inflammatory, anti‐tumor, anti‐fibrosis, anti‐allergy, photo‐protection, and immunomodulation. Most current researches are focused on the effects of anti‐melanoma and photo‐protection. Therefore, we summarized the specific mechanisms about these two effects. On the other side of treating skin diseases, the advantages of topical drugs cannot be replaced. As a small molecule fat‐soluble compound, honokiol is suitable for external use. We reviewed the advantages and disadvantages of the topical mixed cream and various improved methods. These improvements include physical and chemical penetration enhancers, drug carriers, and chemical derivatives. In conclusion, honokiol has a wide range of effects, and its topical preparation provides a safe and effective way for treating skin diseases.

The Modulation of Arachidonic Acid Metabolism and Blood Pressure-Lowering Effect of Honokiol in Spontaneously Hypertensive Rats.

Background: Cardiovascular diseases have consistently been the leading cause of death in the United States over the last two decades, with 30% of the adult American population having hypertension. The metabolites of arachidonic acid (AA) in the kidney play an important role in blood pressure regulation. The present study investigates the antihypertensive effect of honokiol (HON), a naturally occurring polyphenol, and examines its correlation to the modulation of AA metabolism. Methods: Spontaneously hypertensive rats (SHR) were randomly divided into four groups. Treatment groups were administered HON intraperitoneally at concentrations of 5, 20, and 50 mg/kg. Blood pressure was monitored at seven-day intervals. After a total of 3 weeks of treatment, the rats were euthanized and the kidney tissues were collected to examine the activity of the two major enzymes involved in AA metabolism in the kidney, namely cytochrome P450 (CYP)4A and soluble epoxide hydrolase (sEH). Results: Rats treated with HON did not experience the rise in blood pressure observed in the untreated SHR. High-dose HON significantly reduced blood pressure and inhibited the activity and protein expression of the CYP4A enzyme in the rat kidney. The activity of the sEH enzyme in renal cytosol was significantly inhibited by medium and high doses of HON. Conclusion: Our data demonstrate the antihypertensive effect of HON and provide a novel mechanism for its underlying cardioprotective properties.

PCAT19 Regulates the Proliferation and Apoptosis of Lung Cancer Cells by Inhibiting miR-25-3p via Targeting the MAP2K4 Signal Axis.

Both PCAT19 and miR-25-3p have been reported in lung cancer studies, but whether there is a correlation between the two and whether they jointly regulate the progress of lung cancer have not been reported yet. Therefore, this study carried out a further in-depth research. The expression of PCAT19 was detected in lung cancer (LC) tissues and cells by quantitative real-time polymerase chain reaction (qRT-PCR). The effect of PCAT19 on tumor growth was detected in a tumor-bearing model of nude mice. PCAT19-transfected cells were treated with Honokiol and anisomycin. The effects of PCAT19 on proliferation, apoptosis, and cycle of LC cells were investigated by biomolecule experiments. The effects of PCAT19 on the expressions of mitogen-activated protein kinase- (MAPK-) related proteins were evaluated by western blotting. The expression of PCAT19 was decreased in LC tissues and related to patient survival, tumor size, and pathology. In addition, upregulation of PCAT19 hindered LC cell proliferation, miR-25-3p expression, and the activation of extracellular regulated protein kinases (ERK) 1/2, p38, and c-Jun N-terminal kinase (JNK), while facilitating LC cell apoptosis. Furthermore, upregulation of PCAT19 reversed the effects of Honokiol and anisomycin on promoting cell proliferation and inhibiting cell apoptosis. Collectively, our findings show that upregulated PCAT19 suppresses proliferation yet promotes the apoptosis of LC cells through modulating the miR-25-3p/MAP2K4 signaling axis.

Honokiol ameliorates cisplatin-induced acute kidney injury via inhibition of mitochondrial fission.

Mitochondrial damage and oxidative stress are crucial contributors to the tubular cell injury and death in acute kidney injury. Novel therapeutic strategies targeting mitochondria protection and halting the progression of acute kidney injury are urgently needed. Honokiol is a small-molecule polyphenol that exhibits extraordinary cytoprotective effects, such as anti-inflammatory and anti-oxidative. Thus, we investigated whether honokiol could ameliorate cisplatin-induced acute kidney injury via preventing mitochondrial dysfunction. Acute kidney injury was induced by cisplatin administration. Biochemical and histological analysis were used to determine kidney injury. The effect of honokiol on mitochondrial function and morphology were determined using immunohistochemistry, transmission electron microscopy, immunoblot and immunofluorescence. To investigate the mechanism by which honokiol alters mitochondrial dynamics, remodelling and resistance to apoptosis, we used transfection experiments, immunoblotting, immunoprecipitation and flow cytometry assay. We demonstrated that the prominent mitochondrial fragmentation occurred in experimental models of cisplatin-induced nephrotoxicity, which was coupled to radical oxygen species (ROS) overproduction, deterioration of mitochondrial function, release of apoptogenic factors and the consequent apoptosis. Honokiol treatment caused notable reno-protection and attenuated of these cisplatin-induced changes. Mechanistically, honokiol treatment recovered the expression of SIRT3 and improved AMPK activity in tubular cells exposure to cisplatin, which preserved the Drp1 phosphorylation at Ser637 and blocked its translocation in mitochondria, consequently preventing mitochondrial fragmentation and subsequent cell injury and death. Our results indicate that honokiol may protect against cisplatin-induced acute kidney injury by preserving mitochondrial integrity and function by SIRT3/AMPK-dependent mitochondrial dynamics remodelling.

Honokiol improves endothelial function in type 2 diabetic rats via alleviating oxidative stress and insulin resistance

We aimed to examine the effect of Honokiol (HKL) on endothelial dysfunction in type 2 diabetic rats and its possible mechanism. A high-fat diet and streptozotocin (STZ) were used to establish the type 2 diabetic model in rats. Part of these rats were intraperitoneally injected with HKL 10 mg/kg daily. Then the expression of Ser1177 phosphorylation of endothelial nitric oxide synthase (p-eNOS), eNOS, and CD31, vasodilation function, insulin signaling, indicators of oxidative stress and relative signaling pathway were measured. Human umbilical vein endothelial cells (HUVECs) were used to explore the underlying mechanism of the effect of HKL on high glucose-related endothelial injury in vitro. The data showed that HKL could reverse the decline of the expression of p-eNOS and CD31, endothelium-related vasodilation dysfunction, insulin resistance and activation of oxidative stress induced by type 2 diabetes in vivo. The similar results were obtained in vitro. In summary, our study demonstrates that HKL improves endothelial function and diminishes insulin resistance and oxidative stress, suggesting that HKL could be used as a treatment option for diabetes in the future.

Honokiol suppresses 2,6-dinitrochlorobenzene-induced atopic dermatitis in mice

Ethnopharmacological relevanceMagnolia officinalis constitutes a traditional Korean medicine used for the treatment of atopic dermatitis, and honokiol is an active diphenyl compound present in Magnolia officinalis.Aim of the study: The aim of the study was to investigate the therapeutic effects of honokiol on atopic dermatitis in vivo. Materials and methodsThe therapeutic effects of honokiol were evaluated in a 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis model. ResultsAdministration of honokiol (10 mg/kg) significantly suppressed mast cell accumulation and inflammation induced by DNCB in skin tissues. Moreover, DNCB-induced increases in serum immunoglobulin E levels were reversed by honokiol treatment. In addition, DNCB-induced elevation of inflammatory cytokines (interleukin (IL)-4, IL-13, IL-17, and interferon-γ) in the skin and lymph nodes was significantly ameliorated by honokiol administration. Furthermore, the increase in lymph nodes sizes induced by DNCB treatment was reduced by honokiol administration. ConclusionDNCB-induced atopic responses in the ears and lymph nodes were significantly suppressed by honokiol treatment. These results suggested that honokiol is a potential therapeutic agent for atopic dermatitis.

Targeting histone deacetylase-3 blocked epithelial-mesenchymal plasticity and metastatic dissemination in gastric cancer

Background and purposeHistone deacetylase (HDAC) inhibitors (HDIs) can modulate the epithelial-mesenchymal transition (EMT) progression and inhibit the migration and invasion of cancer cells. Emerging as a novel class of anti-cancer drugs, HDIs are attracted much attention in the field of drug discovery. This study aimed to discern the underlying mechanisms of Honokiol in preventing the metastatic dissemination of gastric cancer cells by inhibiting HDAC3 activity/expression.Experimental approachClinical pathological analysis was performed to determine the relationship between HDAC3 and tumor progression. The effects of Honokiol on pharmacological characterization, functional, transcriptional activities, organelle structure changes, and molecular signaling were analyzed using binding assays, differential scanning calorimetry, luciferase reporter assay, HDAC3 activity, ER stress response element activity, transmission electron microscopy, immune-blotting, and Wnt/β-catenin activity assays. The in vivo effects of Honokiol on peritoneal dissemination were determined by a mouse model and detected by PET/CT tomography.Key resultsHDAC3 over-expression was correlated with poor prognosis. Honokiol significantly abolished HDAC3 activity (Y298) via inhibition of NFκBp65/CEBPβ signaling, which could be reversed by the over-expression of plasmids of NFκBp65/CEBPβ. Treatments with 4-phenylbutyric acid (a chemical chaperone) and calpain-2 gene silencing inhibited Honokiol-inhibited NFκBp65/CEBPβ activation. Honokiol increased ER stress markers and inhibited EMT-associated epithelial markers, but decreased Wnt/β-catenin activity. Suppression of HDAC3 by both Honokiol and HDAC3 gene silencing decreased cell migration and invasion in vitro and metastasis in vivo.Conclusions and implicationsHonokiol acts by suppressing HDAC3-mediated EMT and metastatic signaling. By prohibiting HDAC3, metastatic dissemination of gastric cancer may be blocked.Graphical abstractConceptual model showing the working hypothesis on the interaction among Honokiol, HDAC3, and ER stress in the peritoneal dissemination of gastric cancer. Honokiol targeting HDAC3 by ER stress cascade and mitigating the peritoneal spread of gastric cancer. Honokiol-induced ER stress–activated calpain activity targeted HDAC3 and blocked Tyr298 phosphorylation, subsequently blocked cooperating with EMT transcription factors and cancer progression. The present study provides evidence to demonstrate that HDAC3 is a positive regulator of EMT and metastatic growth of gastric cancer cells. The findings here imply that overexpressed HDAC3 is a potential therapeutic target for honokiol to reverse EMT and prevent gastric cancer migration, invasion, and metastatic dissemination.• Honokiol significantly abolished HDAC3 activity on catalytic tyrosine 298 residue site. In addition, Honokiol-induced ER stress markedly inhibited HDAC3 expression via inhibition of NFκBp65/CEBPβ signaling.• HDAC3, which is a positive regulator of metastatic gastric cancer cell growth, can be significantly inhibited by Honokiol.• Opportunities for HDAC3 inhibition may be a potential therapeutic target for preventing gastric cancer metastatic dissemination.

Magnolol and Honokiol Inhibited the Function and Expression of BCRP with Mechanism Exploration.

Breast cancer resistance protein (BCRP), one of the ATP-binding cassette (ABC) transporters, was associated with the multidrug resistance (MDR) of chemotherapy. Magnolol (MN) and honokiol (HK) are major bioactive polyphenols of Magnolia officinalis. This study investigated the effects of MN and HK on the function and expression of BCRP for the purpose of developing BCRP inhibitor to overcome MDR. Cell lines including MDCKII-BCRP and MDCKII-WT were used for evaluating the function and expression of BCRP. The results showed that MN (100–12.5 µM) and HK (100–12.5 µM) significantly decreased the function of BCRP by 80~12% and 67~14%, respectively. In addition, MN and HK were verified as substrates of BCRP. Furthermore, MN and HK reduced the protein expression of BCRP, and inhibited the phosphorylation of epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K). In conclusion, both MN and HK decreased the function and expression of BCRP via EGFR/PI3K signaling pathway. Therefore, both compounds were promising candidates for reversing the MDR of chemotherapy.

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.

Ultra-Performance Liquid Chromatography/Mass Spectrometry-Based Metabolomics for Discovering Potential Biomarkers and Metabolic Pathways of Colorectal Cancer in Mouse Model (ApcMin/+) and Revealing the Effect of Honokiol.

Endogenous metabolites are a class of molecules playing diverse and significant roles in many metabolic pathways for disease. Honokiol (HNK), an active poly-phenolic compound, has shown potent anticancer activities. However, the detailed crucial mechanism regulated by HNK in colorectal cancer remains unclear. In the present study, we investigated the therapeutic effects and the underlying molecular mechanisms of HNK on colorectal cancer in a mouse model (ApcMin/+) by analyzing the urine metabolic profile based on metabolomics, which is a powerful tool for characterizing metabolic disturbances. We found that potential urine biomarkers were involved in the metabolism of compounds such as purines, tyrosines, tryptophans, etc. Moreover, we showed that a total of 27 metabolites were the most contribution biomarkers for intestinal tumors, and we found that the citrate cycle (TCA cycle) was regulated by HNK. In addition, it was suggested that the efficacy of HNK was achieved by affecting the multi-pathway system via influencing relevant metabolic pathways and regulating metabolic function. Our work also showed that high-throughput metabolomics can characterize the regulation of metabolic disorders as a therapeutic strategy to prevent colorectal cancer.

Honokiol inhibits proliferation of colorectal cancer cells by targeting anoctamin 1/TMEM16A Ca2+ -activated Cl- channels.

Ca2+ -activated Cl- channels (Ano1 channels) contribute to the pathogenesis of colorectal cancer. Honokiol is known to inhibit cell proliferation and tumour growth in colorectal cancer. However, the molecular target of honokiol remains unclear. This study aimed to investigate whether honokiol inhibited cell proliferation of colorectal cancer by targeting Ano1 channels. Patch-clamp techniques were performed to study the effect of honokiol on Ca2+ -activated Cl- currents in HEK293 cells overexpressing Ano1- or Ano2-containing plasmids or in human colorectal carcinoma SW620 cells. Site-directed mutagenesis was used to identify the critical residues for honokiol-induced Ano1 inhibition. Proliferation of SW620 cells or human intestinal epithelial NCM460 cells by CCK-8 assays. Honokiol blocked Ano1 currents in Ano1-overexpressing HEK293 cells and SW620 cells. Honokiol more potently inhibited Ano1 currents than Ano2 currents. Three amino acids (R429, K430 and N435) were critical for honokiol-induced Ano1 inhibition. The R429A/K430L/N435G mutation reduced the sensitivity of Ano1 to honokiol. Honokiol inhibited SW620 cell proliferation, and this effect was reduced by Ano1-shRNAs. Furthermore, Ano1 overexpression promoted proliferation in NCM460 cells with low Ano1 endogenous expression and resulted in an increased sensitivity to honokiol. Overexpression of the R429A/K430L/N435G mutation reduced WT Ano1-induced increase in the sensitivity of NCM460 cells to honokiol. We identified a new anticancer mechanism of honokiol, through the inhibition of cell proliferation, by targeting Ano1 Ca2+ -activated Cl- channels.

Honokiol: A naturally occurring lignan with pleiotropic bioactivities.

Honokiol is the dominant biphenolic compound isolated from the Magnolia tree, and has long been considered as the active constituent of the traditional Chinese herb, 'Houpo', which is widely used to treat symptoms due to 'stagnation of qi'. Pharmacological studies have shown that honokiol possesses a wide range of bioactivities without obvious toxicity. Honokiol protects the liver, kidneys, nervous system, and cardiovascular system through reducing oxidative stress and relieving inflammation. Moreover, honokiol shows anti-diabetic property through enhancing insulin sensitivity, and anti-obese property through promoting browning of adipocytes. In vivo and in vitro studies indicated that honokiol functions as an anti-cancer agent through multiple mechanisms: inhibiting angiogenesis, promoting cell apoptosis, and regulating cell cycle. A variety of therapeutic effects of honokiol may be associated with its physiochemical properties, which make honokiol readily cross the blood brain barrier and the blood-cerebrospinal fluid barrier, with high bioavailability. In the future, more clinical researches on honokiol are needed to fully authenticate its therapeutic values.

Honokiol inhibits arecoline-induced oral fibrogenesis through transforming growth factor-β/Smad2/3 signaling inhibition

The habit of areca nut chewing has been regarded as an etiological factor of precancerous oral submucous fibrosis (OSF). In the present study, we aimed to evaluate the anti-fibrosis effect of honokiol, a polyphenolic component derived from Magnolia officinalis. The cytotoxicity of honokiol was tested using normal and fibrotic buccal mucosal fibroblasts (fBMFs) derived from OSF tissues. Collagen gel contraction, Transwell migration, invasion, and wound healing capacities were examined. Besides, the expression of TGF-β/Smad2 signaling as well as α-SMA and type I collagen were measured as well. Honokiol exerted higher cytotoxicity of fBMFs compared to normal cells. The arecoline-induced myofibroblast activities, including collagen gel contractility, cell motility and wound healing capacities were all suppressed by honokiol treatment. In addition, the expression of the TGF-β/Smad2 pathway was downregulated along with a lower expression of α-SMA and type I collagen in honokiol-receiving cells. Our data suggest that honokiol may be a promising compound to alleviate the progression of oral fibrogenesis and prevent the transformation of OSF oral epithelium into cancer.

Honokiol attenuates oxidative stress-induced cytotoxicity in human keratinocytes via activating AMPK signaling

Objective: To investigate the effect of honokiol on oxidative damage in HaCaT human keratinocytes. Methods: HaCaT cells were exposed to hydrogen peroxide (H2O2), following pretreatment with various concentrations of honokiol. The alleviating effects of honokiol on HaCaT cell viability and cell death, reactive oxygen species (ROS) production, DNA damage, mitochondrial dynamics, and inhibition of adenosine triphoaphate production against H2O2 were investigated. Western blotting analysis was used to analyze the expression levels of specific proteins. Results: Honokiol suppressed H2O2-induced cytotoxicity and DNA damage by blocking abnormal ROS accumulation. Honokiol also prevented apoptosis by inhibiting loss of mitochondrial membrane potential and release of cytochrome c from the mitochondria into the cytosol, decreasing the Bax/Bcl-2 ratio, and reducing the activity of caspase-3 in H2O2-stimulated HaCaT cells. In addition, honokiol attenuated H2O2-induced reduction of adenosine triphosphate content, and activation of AMP-activated protein kinase (AMPK) was markedly promoted by honokiol in H2O2-stimulated cells. Importantly, the anti-apoptosis and anti-proliferative activity of honokiol against H2O2 was further enhanced by adding an activator of AMPK, indicating that honokiol activated AMPK in HaCaT keratinocytes to protect against oxidative damage. Conclusions: The present results indicate that honokiol may be useful as a potential therapeutic agent against various oxidative stress-related skin diseases.

Honokiol exerts protective effects on neural myelin sheaths after compressed spinal cord injury by inhibiting oligodendrocyte apoptosis through regulation of ER-mitochondrial interactions

Objective To investigate the effect of honokiol on demyelination after compressed spinal cord injury (CSCI) and it's possible mechanism. Design Animal experiment study. Setting Institute of Neuroscience of Chongqing Medical University. Interventions Total of 69 Sprague–Dawley (SD) rats were randomly divided into 3 groups: sham group (n=15), honokiol group (n=27) and vehicle group (n=27). After established CSCI model by a custom-made compressor successfully, the rats of sham group were subjected to the limited laminectomy without compression; the rats of honokiol group were subjected to CSCI surgery and intraperitoneal injection of 20 mg/kg honokiol; the rats of vehicle group were subjected to CSCI surgery and intraperitoneal injection of an equivalent volume of saline. Outcome measures: The locomotor function of each group was assessed using the Basso, Beattie and Bresnahan (BBB) rating scale. The pathological changes of myelinated nerve fibers of spinal cord in 3 groups were detected by osmic acid staining and transmission electron microcopy (TME). Immunofluorescence and Western blot were used to research the experessions of active caspase-3, caspase-12, cytochrome C and myelin basic protein (MBP) respectively. Results In the vehicle group, the rats became paralyzed and spastic after injury, and the myelin sheath became swollen and broken down along with decreased number of myelinated nerve fibers. Western blot analysis manifested that active caspase-3, caspase-12 and cytochrome C began to increase 1 d after injury while the expression of MBP decreased gradually. After intervened with honokiol for 6 days, compared with the vehicle group, the locomotor function and the pathomorphological changes of myelin sheath of the CSCD rats were improved with obviously decreased expression of active caspase-3, caspase-12 and cytochrome C. Conclusions Honokiol may improve locomotor function and protect neural myelin sheat from demyelination via prevention oligodendrocytes (OLs) apoptosis through mediate endoplasmic reticulum (ER)-mitochondria pathway after CSCI.

Synergistic Therapeutic Effect of Honokiol and 5-Fluorouracil on the Induced-Tongue Cancer in Rats.

Introduction: 5-Fluorouracil (5-FU) is a common chemotherapeutic drug for treatment of oral squamous cell carcinoma. However, its toxicity to normal tissues has limited its role as an effective cancer therapy. Aim: This research aimed to investigate the effect of combining 5-FU with honokiol (HNK) on enhancing the anticancer activity of 5-FU without increasing its toxicity. Material and methods: HNK was used in combination with 5-FU for treatment of tongue carcinoma induced chemically by 4-nitroquinoline 1 oxide (4-NQO) in albino rats. Rats were divided into five groups (10 animals each) including control, 4-NQO, 5-FU, HNK, and combined 5-FU with HNK. Serial sections of the tongues from all animals were examined microscopically and real-time PCR quantification of P53 gene expression was also assessed. Results: The results showed that treatment with both 5-FU + HNK had significantly regressed the number and size of malignant lesions seen in the carcinogen-only group. Data analysis revealed a statistically significant decrease in the expression levels of mutant P53 in the combined treatment group compared to control groups. Conclusion: This study reported that HNK and 5-FU had a synergistic cytotoxic effect on this model, without notable intensification of the side effects associated with 5-FU treatment. Introduction: 5-Fluorouracil (5-FU) is a common chemotherapeutic drug for treatment of oral squamous cell carcinoma. However, its toxicity to normal tissues has limited its role as an effective cancer therapy. Aim: This research aimed to investigate the effect of combining 5-FU with honokiol (HNK) on enhancing the anticancer activity of 5-FU without increasing its toxicity. Material and methods: HNK was used in combination with 5-FU for treatment of tongue carcinoma induced chemically by 4-nitroquinoline 1 oxide (4-NQO) in albino rats. Rats were divided into five groups (10 animals each) including control, 4-NQO, 5-FU, HNK, and combined 5-FU with HNK. Serial sections of the tongues from all animals were examined microscopically and real-time PCR quantification of P53 gene expression was also assessed. Results: The results showed that treatment with both 5-FU + HNK had significantly regressed the number and size of malignant lesions seen in the carcinogen-only group. Data analysis revealed a statistically significant decrease in the expression levels of mutant P53 in the combined treatment group compared to control groups. Conclusion: This study reported that HNK and 5-FU had a synergistic cytotoxic effect on this model, without notable intensification of the side effects associated with 5-FU treatment.

Honokiol antagonizes doxorubicin resistance in human breast cancer via miR-188-5p/FBXW7/c-Myc pathway.

Honokiol, a natural phenolic compound derived from Magnolia plants, is a promising anti-tumor compound that exerts a wide range of anti-cancer effects. Herein, we investigated the effect of honokiol on doxorubicin resistance in breast cancer. Doxorubicin-sensitive (MCF-7 and MDA-MB-231) and doxorubicin-resistant (MCF-7/ADR and MDA-MB-231/ADR) breast cancer cell lines were treated with doxorubicin in the absence or presence of honokiol; then, the following tests were performed: flow cytometry for cell apoptosis, WST-1 assay for cell viability, qPCR and western blot for the expression of miR-188-5p, FBXW7, and c-Myc. MiR-188-5p mimic, miR-188-5p inhibitor, siFBXW7, and c-Myc plasmids were transfected into cancer cells to evaluate whether miR-188-5p and FBXW7/c-Myc signaling are involved in the effect of honokiol on doxorubicin resistance in breast cancer. A dual luciferase reporter system was used to study the direct interaction between miR-188-5p and FBXW7. Honokiol sensitized doxorubicin-resistant breast cancer cells to doxorubicin-induced apoptosis. Mechanically, upregulation of miR-188-5p was associated with doxorubicin resistance, and honokiol enhanced doxorubicin sensitivity by downregulating miR-188-5p. FBXW7 was confirmed to be a direct target gene of miR-188-5p. FBXW7/c-Myc signaling was involved in the chemosensitization effect of honokiol. Honokiol induced apoptosis in MCF-7/ADR and MDA-MB-231/ADR cells. However, FBXW7 silencing or c-Myc transfection resulted in resistance to the honokiol-induced apoptotic effect. These findings suggest that downregulation of miR-188-5p by honokiol enhances doxorubicin sensitivity through FBXW7/c-Myc signaling in human breast cancer. Our study finds an important role of miR-188-5p in the development of doxorubicin resistance in breast cancer, and enriches our understanding of the mechanism of action of honokiol in cancer therapy.

Honokiol regulates mitochondrial substrate utilization and cellular fatty acid metabolism in diabetic mice heart

Type 2 diabetes mellitus is strongly associated with cardiac mitochondrial dysfunction, which is one of the main reasons for cardiovascular diseases. Among the mitochondrial metabolic changes, fatty acid metabolism is of great importance as cardiac tissues depend primarily on fatty acids. Honokiol, a constituent of Magnolia tree bark extract, is reported to strongly influence cardiac mitochondrial functions, via various mechanisms. The current study showed that honokiol decreased fatty acid-mediated complex I respiration and increased carbohydrate-mediated complex I and II respiration in diabetic C57BL/6 mice cardiac mitochondria. It was also found that honokiol treatment decreased expression of Cluster of Differentiation 36, AMP-activated kinases and nuclear transcription factors like, Peroxisome proliferator-activated receptor γ co-activator 1α/β and Peroxisome proliferator-activated receptor α, surrogating the evidence of decreased fatty acid-mediated complex I respiration. Honokiol treatment also reduced the levels of mitochondrial acetylated proteins, suggesting the possible action of honokiol via acetylation/deacetylation mechanism of regulation of protein functions in diabetic mitochondria. The antioxidant effect of honokiol is evidenced by the augmented expression of Manganese super oxide dismutase. In conclusion, honokiol imparts beneficial effect on diabetic cardiac mitochondria by decreasing the oxidant burden via regulating mitochondrial fatty acid respiration and expression of oxidant response factors.

Honokiol regulates endoplasmic reticulum stress by promoting the activation of the sirtuin 1-mediated protein kinase B pathway and ameliorates high glucose/high fat-induced dysfunction in human umbilical vein endothelial cells.

Honokiol plays an important role in anti-oxidation, but its role in diabetic vascular complications is unclear. In this study, the effects of honokiol in high glucose/high fat (HG/HF)-induced human umbilical vein endothelial cells (HUVECs) were explored. After pre-treatment with honokiol, the cells were transferred to an HG/HF medium, and cell viability and apoptosis were respectively measured by methyl tetrazolium and flow cytometry. Moreover, the contents of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured. The expressions of C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78), phosphorylated-protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), phosphorylated-inositol requiring enzyme-1α (p-IRE1α), cleaved caspase-3 and SIRT1 were determined by Western blot or quantitative reverse transcription PCR, respectively. Finally, the viability, apoptosis, and the contents of ROS, MDA, and SOD, as well as the expressions of CHOP, GRP78, p-PERK, p-IRE1α, cleaved caspase-3, Akt, p-Akt, and SIRT1 in the cells transfected with small interfering RNA SIRT1 (siSIRT1) were detected by the previously mentioned methods. Honokiol reversed the effect of HG/HF on promoting cell apoptosis, ROS and MDA contents, and the expressions of CHOP, GRP78, p-PERK, p-IRE1α and cleaved caspase-3, and also reversed the inhibitory effect of HG/HF on cell viability, SOD content and SIRT1 expression. However, siSIRT1 reversed the above effects caused by honokiol. Honokiol activated SIRT1 promoter. SIRT1 interacted with Akt, consequently promoting the activity of Akt. Therefore, honokiol activates the Akt pathway by regulating SIRT1 expression to regulate endoplasmic reticulum stress, promotes cell viability and inhibits the apoptosis of HG/HF-induced HUVECs.

Honokiol inhibits the growth of SKBR3 cells.

BackgroundBreast cancer is one of the most malignant tumors in the reproductive system and has a poor prognosis. Finding drugs with high efficiency, low side-effects, and low cost has become a research hotspot.MethodsIn the present study, we treated SK-BR-3 cells with different doses of honokiol. Crystal violet staining method was used to detect changes in the total number of living cells; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to detect the effect of honokiol on SK-BR-3 cell proliferation. Cell migration ability change was determined by wound healing assay. Cell invasion ability change was determined by Transwell migration assay. Flow cytometry was used to detect the apoptotic rate of SK-BR-3 cells, and Western blot was used to detect the expression levels of proliferation-associated protein (PCNA); migration- and invasion-related protein matrix metalloproteinase-2 (MMP-2); vimentin; apoptosis-related proteins Bcl-xl, caspase 3, and cleaved caspase 3 (CC3); and β-catenin and its downstream target molecule c-Myc.ResultsCompared with the control group, different doses of honokiol have different degrees of inhibitory effects on cells, including proliferation and invasion and migration (P<0.01). After treatment with 50 or 60 µmol·L–1 honokiol, the apoptotic rate of SK-BR-3 cells increased (both P<0.01); PCNA expression was significantly downregulated (P<0.01). Intracellular accumulation of apoptosis-related proteins Bcl-xl and caspase-3 decreased but C-C3 increased. We also found downregulation of MMP-2 expression, a protein related to invasion and migration (P<0.01), and a decrease in the expression levels of the Wnt/β-catenin signaling pathway-related proteins β-catenin and c-Myc (P<0.01).ConclusionsHonokiol can promote the apoptosis of SK-BR-3 cells and can inhibit the proliferation, migration, and invasion of human breast cancer SK-BR-3 cells. The underlying mechanism may be through inhibiting the activation of the Wnt signaling pathway.