Multifaceted mesoporous silica-based nanoplatform to co-deliver honokiol and baicalin for integrative therapy of drug-resistant bacteria infection.

Background/Objectives: This study aimed to further enhance the properties of paclitaxel (PTX) and honokiol (HNK) through encapsulation in planetary ball-milled nanoparticles (PBM NPs) and specific targeting of breast cancer (BrCa) cells via MUC1 targeting using an aptamer (S2.2) coating. Methods: Tissue microarray (TMA) analysis was utilized to measure MUC1 expression in stages 1, 2, 3, and 4 BrCa tissue samples. Pharmacokinetic simulations were performed to explore the potential advantages of using PTX and HNK in combination while targeting MUC1 for BrCa treatment. To investigate the efficacy of the PBM NPs for MUC1 targeting, we synthesized the aptamer-conjugated PTX and HNK PBM NPs (PTX-S2.2-PBM NPs, HNK-S2.2-PBM NPs) using N-hydroxysuccinimide (NHS) coupling. Dynamic light scattering (DLS), Fourier-transform infrared (FTIR), and high-performance liquid chromatography (HPLC) were utilized to characterize the NPs. MTT and live/dead cell assays were used to evaluate the cytotoxicity of the NPs. Results: TMA sample analysis confirmed the upregulation of MUC1 in BrCa tissues, which increased with the stage of BrCa. DLS analysis revealed that the PTX-S2.2 and HNK-S2.2 NPs have a desirable size (83.4 nm and 163 nm, respectively) and zeta potential (−9.74 mV and −7.16 mV, respectively), which are suitable for systemic circulation and improved therapeutic outcomes. FTIR and HPLC analysis suggest proper conjugation was achieved, and an encapsulation efficiency of PTXS2.2 and HNKS2.2 NPs at 77% and 84%, respectively, was achieved. Cell viability assays demonstrated that PTX-S2.2-PBM and HNK-S2.2-PBM NPs exhibit cytotoxicity comparable to or greater than free PTX and HNK, respectively. Conclusions: These findings support the belief that using PTX-S2.2 and HNK-S2.2 PBM NPs could be a promising treatment option for BrCa.

Honokiol-loaded nanoparticles for targeted bacterial eradication and treatment of MRSA infection

Background/Objectives: Honokiol (HK), a bioactive phenolic compound, exhibits significant anti-cancer properties. This study aimed to investigate the anti-cancer effects of HK in colorectal cancer (CRC) cells by focusing on its direct interaction with heat shock protein 27 (Hsp27) as a molecular target, and to elucidate the underlying mechanisms involved. Methods: HK was isolated via silica/ODS chromatography. Anchorage-independent growth of CRC cells was quantified using a soft agar assay with increasing HK concentrations. Apoptosis and cell cycle were analyzed by flow cytometry, and cell viability by MTS assay. Hsp27 binding to HK was validated by pull-down assay with HK-conjugated Sepharose 4B beads. Hsp27 knockdown was performed using lentiviral shRNA in CRC cells. Molecular docking of HK-Hsp27 interaction employed Schrödinger Suite 2016. Protein expressions, including chaperone and apoptotic proteins, were evaluated by Western blotting. Results: HK dose-dependently suppressed anchorage-independent growth of CRC cells and induced G0/G1 arrest. It triggered apoptosis through cytochrome c release, PARP cleavage, and Bcl-2 downregulation. HK directly bound to the α-crystallin domain of Hsp27 at Asn102 and His103 residues, confirmed by computational molecular docking and site-directed mutagenesis. Hsp27 knockdown in CRC cells dramatically reduced anchorage-independent growth. HK markedly decreased Hsp27 protein levels while having less effect on other heat shock proteins in CRC cells. Conclusions: HK exerts anti-cancer effects in CRC cells, associated with Hsp27 inhibition, resulting in suppressed cell growth and increased apoptosis. This interaction between HK and Hsp27 may support a mechanistic foundation supporting the potential utility of HK as a natural therapeutic agent for CRC.

Honokiol ameliorates hepatic fibrosis by inducing lysosomal membrane permeabilization and impairing lipophagy in hepatic stellate cells.

Self-assembled GSH-responsive polycyclophosphazene loaded honokiol nano-drug for enhanced cancer therapy.

Honokiol protects against heavy-ion radiation-induced oxidative damage via the thioredoxin system.

Activation of SIRT3 / PRDX5 signaling inhibits apoptosis after acute spinal cord injury in mice.

In the wood industry, soy protein adhesives offer promising eco-friendly alternatives to formaldehyde-based resins. However, their widespread application is hindered due to disadvantages such as poor water resistance and mold resistance. This study presents a sustainable soy protein isolate (SPI) adhesive modified with honokiol (HK), a natural polyphenol derived from Houpoea officinalis. The results show that when the HK content is 0.4%, the dry and wet shear strength reaches 2.12 MPa and 1.24 MPa, respectively, which is 28.92% and 39.32% higher than the unmodified SPI. This is attributed to the biphenyl structure and phenolic hydroxyl groups of the HK facilitated cross-linking interactions with active sites in soy protein, forming a robust network within the adhesive. Furthermore, the modified adhesive exhibited outstanding mold resistance, with uncured and cured formulations resisting mildew for 27 and 40 days, respectively. Structural analyses confirmed enhanced cross-linking density and reduced hydrophilicity, while thermogravimetric analysis revealed improved thermal stability. This work provides a green, high-performance solution for soy protein adhesives.

Synergistic chemoimmunotherapy in a green framework: pH-responsive natural plant polysaccharide-based nanoparticles.

Honokiol (HON) and magnolol (MAG), structural isomers from Magnolia officinalis, exhibit notable anticancer activity, particularly against head and neck squamous cell carcinoma (HNSCC). However, due to their high lipophilicity, their intravenous administration is challenging. This study aimed to develop HON- and MAG-loaded intravenous (IV) nanoemulsions using commercial lipid preparations with varying fatty acid compositions. The formulations were physicochemically characterized and evaluated in vitro using FaDu and SCC-040 HNSCC cell lines. HON and MAG were sterilized via ionizing radiation at doses of 25, 100, and 400 kGy. Their suitability for IV use was assessed through PXRD, DSC, TGA, EPR, FT-IR, NMR, and HPLC analyses. All formulations met safety criteria for IV administration, with mean droplet diameters below 241 nm and encapsulation efficiencies exceeding 95%. They significantly reduced cancer cell viability, with a synergistic effect observed in combined HON and MAG formulations compared to single-compound nanoemulsions. Clinoleic-based formulations showed enhanced anticancer efficacy, likely due to the pro-apoptotic properties of oleic acid. Notably, radiation sterilization at the standard 25 kGy dose preserved the thermal, crystalline, and structural stability of HON and MAG, whereas higher doses (400 kGy) induced degradation. Although free radicals were detected via EPR, their transient nature and rapid decay confirmed the method’s safety. HON/MAG-loaded nanoemulsions exhibited strong anticancer potential, while radiation sterilization at 25 kGy ensured sterility without compromising stability. These findings provide a preliminary in vitro basis for future in vivo studies investigating HON and MAG as potential adjuvant therapies for HNSCC.

BackgroundWe demonstrated that Honokiol (HKL), a natural compound from Magnolia officinalis, exerts neuroprotection in APP/PS1 mice by increasing the expression of Sirtuin 3 (SIRT3), which activates mitochondrial autophagy. We also found that the liver may play a significant role in the pathogenesis of Alzheimer's disease (AD). However, it remains unclear whether HKL exerts its protection on AD through hepatic pathways.ObjectiveWe aimed to elucidate the impact of HKL on the liver of AD mice and its mechanisms.MethodsAPP/PS1 transgenic mice were utilized as AD models and administered with HKL and 3-TYP (an inhibitor of SIRT3). Congo-red staining and immunohistochemistry were conducted to detect the Aβ1-42 plaque deposition in the brain. Hematoxylin-eosin and Oil red O staining were employed to observe alterations in hepatic morphology. Liver function markers were tested to assess the metabolic function. qRT-PCR was employed to examine the level of SIRT3 mRNA. Western blot was performed to evaluate the expression of SIRT3, insulin degrading enzyme (IDE), GpLD1, lipoprotein receptor related protein 1 (LRP-1), ANGPTL8, and superoxide dismutase 2 (SOD2).ResultsHKL mitigated the Aβ1-42 plaque deposition in the brains of AD mice. It also reduced hepatic morphological damage. Additionally, HKL decreased the levels of ALT, AST, ALP, TBIL, and DBIL, and enhanced the levels of TP and ALB. It increased the levels of SIRT3 mRNA, and also the expression of SIRT3, IDE, GpLD1, and SOD2, while suppressing the expression of LRP-1 and ANGPTL8. 3-TYP could reverse all these effects of HKL on AD mice.ConclusionsHKL might alleviate liver damage of AD mice by upregulating SIRT3.

Aptamer-modified GSH-degradable honokiol polyprodrug nanoparticles for ovarian cancer-specific targeting therapy.

Background: The study evaluates the immunomodulatory potential of secukinumab (SECU) and honokiol (HONK) in a murine model of allergic asthma complicated by acute lung injury (ALI), with an emphasis on modulating key inflammatory pathways. The rationale is driven by the necessity to attenuate Th17-mediated cytokine cascades, wherein IL-17 plays a critical role, as well as to explore the adjunctive anti-inflammatory effects of HONK on Th1 cytokine production, including IL-6, TNF-α, and Th2 cytokines. Methods: Mice were sensitized and challenged with ovalbumin (OVA) and lipopolysaccharide (LPS) was administrated to exacerbate pulmonary pathology, followed by administration of SECU, HONK (98% purity, C18H18O2), or their combination. Quantitative analyses incorporated OVA-specific IgE measurements, differential cell counts in bronchoalveolar lavage fluid (BALF), and extensive cytokine profiling in both BALF and lung tissue homogenates, utilizing precise immunoassays and histopathological scoring systems. Results: Both SECU and HONK, when used alone or in combination, display significant immunomodulatory effects in a murine model of allergic asthma concomitant with ALI. The combined therapy synergistically reduced pro-inflammatory mediators, notably Th1 cytokines, such as TNF-α and IL-6, as measured in both BALF and lung tissue homogenates. Conclusions: The combined therapy showed a synergistic attenuation of pro-inflammatory mediators, a reduction in goblet cell hyperplasia, and an overall improvement in lung histoarchitecture. While the data robustly support the merit of a combinatorial approach targeting multiple inflammatory mediators, the study acknowledges limitations in cytokine diffusion and the murine model's translational fidelity, thereby underscoring the need for further research to optimize clinical protocols for severe respiratory inflammatory disorders.

Osteoarthritis (OA) is a multifactorial disease characterized by joint inflammation and cartilage degeneration, with no disease-modifying drugs available. The vicious cycle between the inflammatory microenvironment (inflamed soil) and dysfunctional chondrocytes (degeneration-related seeds) drives the chronic progressive deterioration of OA. Here, we report a genetically engineered chondrocyte-mimetic nanoplatform (termed HKL-GECM@MPNPs) comprising a honokiol (HKL)-loaded mitochondrion-targeting nanoparticle core coated with an interleukin-1 receptor type 2 (IL-1R2)-overexpressing chondrocyte membrane. HKL-GECM@MPNPs fuse with OA chondrocytes, transferring IL-1R2 onto the plasma membrane and reprogramming the inflamed microenvironment through IL-1β blockade. Mitochondrion-targeting cores then directly deliver HKL to restore mitochondrial sirtuin-3 in OA chondrocytes, reprogramming the cells' pathological phenotype. Intra-articular injection of HKL-GECM@MPNPs in OA mice reduces inflammation, alleviates joint pain, and mitigates cartilage damage through a synergistic effect. Moreover, HKL-GECM@MPNPs effectively reverse cartilage degeneration in human OA cartilage explants. This approach highlights the potential of HKL-GECM@MPNPs to combine IL-1β blockade and mitochondrial sirtuin-3 restoration as a promising strategy for OA treatment.

Fibromyalgia (FM) is a chronic condition characterized by widespread musculoskeletal pain, fatigue, psychological disturbances, and sleep issues. Honokiol (HNK) is a bioactive compound known for its medicinal properties. This study evaluated HNK's effectiveness in alleviating pain, depression, and anxiety in a reserpine-induced FM rat model. Thirty male rats were divided into three groups: control, RES (FM-induced), and RES + HNK. HNK was supplemented to RES + HNK in a dose of 8mg/kg for 21 days. Behavioral assessments included the open field, elevated plus maze, and forced swim tests, while pain was evaluated using treadmill endurance, tail flick latency, paintbrush, and rotarod tests. Brain homogenates were analyzed for neurotransmitters, antioxidants, pro-inflammatory cytokines, and gene expressions. Histopathological evaluation of spinal cords assessed markers of inflammation and apoptosis. Results showed that HNK administration improved behavior and reduced pain. This was linked to reduced levels of malondialdehyde, tumor necrosis factor-α, and prostaglandin E2, alongside increased superoxide dismutase and interleukin-10. Additionally, HNK downregulated the expression of calcitonin gene-related peptide and the JAK/STAT3 gene. These findings suggest that HNK alleviates FM symptoms through its antioxidant, anti-inflammatory, neuroprotective, and anti-apoptotic properties, indicating its potential as a therapeutic agent for FM.

Honokiol in the treatment of triple-negative breast cancer: a network pharmacology approach and experimental validation.

Honokiol (HKL), one of the major bioactive components of the traditional Chinese medicine Magnolia officinalis, has garnered significant attention because of its extensive pharmacological activities. Numerous studies have demonstrated that SIRT3 plays a crucial regulatory role in the disease intervention mechanisms mediated by HKL. HKL can bind to the SIRT3 protein, not only directly increasing its deacetylase activity but also forming a positive feedback loop by activating its transcription factors, thereby further promoting SIRT3 expression. This dual regulatory mechanism effectively restores the function of downstream proteins, activates intracellular protective mechanisms, and combats a variety of pathological processes, including aging, oxidative stress, inflammation, cell death, mitochondrial dysfunction, and metabolic disorders. It has shown broad prospects in the prevention and treatment of chronic diseases such as neurodegenerative diseases, cardiovascular diseases, degenerative bone and joint diseases, lung diseases, and metabolic disorders. Although HKL is a highly recognized SIRT3 activator, there is currently no comprehensive review systematically summarizing the research on HKL as a SIRT3 activator. This review comprehensively summarizes the research progress over the past decade since the discovery of HKL as a SIRT3 activator. Through in-depth analysis of the literature, we focused on elucidating the biological functions of HKL through SIRT3 activation in various disease models and the signaling pathways involved. These findings emphasize the therapeutic development value and significant application potential of HKL as a SIRT3 activator, providing a theoretical basis for the development of natural products that target SIRT3.

Rationale: Coronary collateral circulation (CCC) is essential for myocardial recovery after infarction, yet effective strategies to enhance CCC formation are scarce. In this study, we aimed to identify potential FDA-approved drugs that can promote CCC after MI injury.Methods: Candidate drugs were screened through multiple analyses using cMap and public CCC-related databases. Male C57BL/6J mice underwent myocardial infarction (MI) surgery, and 3D micro-CT imaging and immunostaining for smooth muscle actin (SMA) in the watershed region of the heart were employed to evaluate CCC formation. Cardiac function was assessed through Masson's trichrome staining and cardiac ultrasonography. Macrophage polarization was analyzed using flow cytometry, qRT‒PCR, and immunostaining. Additionally, a macrophage and THP-1 cell coculture system was established to simulate the in vivo microenvironment, and mitochondrial morphology was assessed using electron microscopy.Results: Our screen revealed that methimazole (MMI) efficiently promotes CCC formation by driving the polarization of macrophages from the proinflammatory M1-like phenotype to the proangiogenic M2-like phenotype. In vitro, MMI enhanced the differentiation of THP-1 cells into M2-like macrophages and increased VEGFA secretion. Mechanistically, molecular docking studies confirmed a direct interaction between MMI and MAPK1, leading to the suppression of the MAPK1/ROS axis and inhibition of ferroptosis, which facilitated M2 polarization. Furthermore, in vivo, honokiol (HK), a MAPK activator, reversed the effects of MMI on CCC, confirming the pivotal role of the MAPK1 pathway.Conclusions: This study reveals a novel therapeutic role for MMI in promoting CCC formation following MI through the modulation of macrophage polarization via the MAPK1/ROS axis-mediated inhibition of ferroptosis. These findings highlight the potential of MMI as a strategy for enhancing cardiac repair and advancing collateral circulation therapies for ischemic heart disease.

This study investigates the antimicrobial properties of honokiol (HNK), a naturally occurring polyphenol, when conjugated with short-chain fatty acids (SCFAs) such as butyrate. We examined the effects of HNK-SCFA ester conjugates on Enterococcus faecalis, a gut bacterium that metabolizes levodopa, a drug used to manage Parkinson’s disease symptoms. Our findings indicate that HNK-SCFA-esters (e.g., HNK-acetate, HNK-propionate, HNK-butyrate, and HNK-hexanoate) inhibit E. faecalis growth in a dose-dependent manner, followed by a temporary recovery period during which levodopa remains intact and unmetabolized. Notably, HNK-SCFAs exhibit enhanced cellular permeability and are hydrolyzed within bacterial cells, releasing HNK and SCFAs. These results suggest that HNK-SCFAs may reversibly modulate the gut metabolism of levodopa to dopamine, potentially enhancing its therapeutic efficacy in treating Parkinson’s disease.