Lipophilic Research Articles

Enhanced in vivo Stability and Antitumor Efficacy of PEGylated Liposomes of Paclitaxel Palmitate Prodrug.

The clinical use of paclitaxel (PTX) in cancer treatment is limited by its poor water solubility, significant toxicity, and adverse effects. This study aimed to propose a straightforward and efficient approach to enhance PTX loading and stability, thereby offering insights for targeted therapy against tumors. We synthesized a paclitaxel palmitate (PTX-PA) prodrug by conjugating palmitic acid (PA) to PTX and encapsulating it into liposomal vehicles using a nano delivery system. Subsequently, we investigated the in vitro and in vivo performance as well as the underlying mechanisms of PTX-PA liposomes (PTX-PA-L). PTX had a remarkable antitumor effect in vivo and significantly decreased the myelosuppressive toxicity of PTX. Moreover, the introduction of PA increased the lipid solubility of PTX, forming a phospholipid bilayer as a membrane stabilizer, prolonging the circulation time of the drug and indirectly increasing the accumulation of liposomes at the tumor site. Our in vivo imaging experiments demonstrated that PTX-PA-L labeled with DiR has greater stability in vivo than blank liposomes and that PTX-PA-L can target drugs to the tumor site and efficiently release PTX to exert antitumor effects. In a mouse model, the concentration of PTX at the tumor site in the PTX-PA-L group was approximately twofold greater than that of Taxol. However, in a nude mouse model, the concentration of PTX at the tumor site in the PTX-PA-L group was only approximately 0.8-fold greater than that of Taxol. Furthermore, the originally observed favorable pharmacodynamics in normal mice were reversed following immunosuppression. This may be caused by differences in esterase distribution and immunity. This prodrug technology combined with liposomes is a simple and effective therapeutic strategy with promising developmental prospects in tumor-targeted therapy owing to its ability to convert PTX into a long-circulating nano drug with low toxicity, high pharmacodynamics, and good stability in vivo.

Clog P-Guided Development of Multi-Colored Buffering Fluorescent Probes for Super-Resolution Imaging of Lipid Droplet Dynamics.

Super-resolution fluorescence imaging of live cells increasingly demands fluorescent probes capable of multi-color and long-term dynamic imaging. Understanding the mechanisms of probe-target recognition is essential for the engineered development of such probes. In this study, it is discovered that the molecular lipid solubility parameter, Clog P, determines the staining performance of fluorescent dyes on lipid droplets (LDs). Fluorescent dyes with Clog P values between 2.5 and 4 can form buffering pools outside LDs, replacing photobleached dyes within LDs to maintain constant fluorescence intensity in LDs, thereby enabling dynamic super-resolution imaging of LDs. Guided by Clog P, four different colored buffering LD probes spanning the visible light spectrum have been developed. Using Structured Illumination Microscopy (SIM), the role of LD dynamics have been tracked during cellular ferroptosis with the secretion, storage, and degradation of overexpressed ACSL3 proteins. It is found that LDs serve as storage sites for these proteins through membrane fusion, and further degrade overexpressed proteins via interactions with organelles like lysosomes or through lipophagy, thereby maintaining cellular homeostasis.

8660 Bodipy Labeled Vitamin D3 Associates With Lipid Droplets In Adipocytes

Abstract Disclosure: N. Ucar: None. J.T. Deeney: None. R. Pickering, PhD: None. M.T. Kirber: None. T. Fan: None. R. Loo, PhD: Research Investigator; Self; Carbogen Amcis BV. M.F. Holick: Grant Recipient; Self; Carbogen Amcis BV. Research Investigator; Self; Carbogen Amcis BV. Obese patients are often found to be deficient in vitamin D, requiring higher levels of supplementation than normal weight subjects. While this has been attributed to vitamin D3‘s lipid solubility and accumulation in fat tissue, little is known about how vitamin D3 enters adipocytes and associates with the intracellular lipid droplet. The goal of this study was to investigate this association using a novel fluorescently labelled vitamin D3. Bodipy, 4,4-difluoro-1,3,5, 7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY 493/503), was covalently linked to vitamin D3 and its structure was confirmed by NMR and mass spectroscopy. Murine 3T3L1 and primary adipocytes were used for our study. Mouse 3T3L1 preadipocytes were cultured in multiwell plates or glass bottom dishes in high glucose DMEM media and differentiated for 7-14 days. Primary adipocytes were obtained by collagenase digestion after surgical extraction of adipose tissue from male/female C57BL/6J mice and attached to glass bottom dishes. The cultured adipocytes were exposed to 10 microM BODIPY labelled Vitamin D3 (vitD-B). BODIPY was added to cultured cells and served as the control. Cells were imaged at various times on a wide-field epifluorescence microscope and analysed with NIH ImageJ software. VitD-B adipocyte uptake and accumulation in lipid droplets was observed over 24 hrs. Isolated lipid droplets were also incubated with vitD-B and BODIPY. VitD-B in mature 3T3L1 cells was observed in lipid droplets after 1h incubation and increased fluorescent intensity was observed over the next 24 hrs. BODIPY was observed in the lipid droplets after 15-20 mins. As a negative control, non-differentiated 3T3L1 cells did not exhibit staining by BODIPY even after 24-hrs. When vitD-B was added to primary cultured adipocytes, it appeared in the adipocytes within 1-hr. Fluorescence intensity of primary adipocytes was increased 1.2-fold at 8 hrs and 5.7-fold at 24 hrs compared to 1 hr. For comparison the positive control treated with BODIPY exhibited rapid fluorescence uptake into primary adipocytes that was increased 29-fold higher than that of vitD-B at 1 hr. VitD-B and BODIPY both demonstrated rapid uptake into isolated lipid droplets (less than 2 min) based on fluorescence microscopy.These results hold promising implications for understanding of the interaction between vitamin D and intracellular lipid droplets. Keywords: Adipocyte, Vitamin D3, BODIPY, adipocytes, lipid droplet, fluorescent labelled vitamin D3 Presentation: 6/2/2024

OPTIMISATION METHOD FOR OBTAINING A BIOLOGICALLY ACTIVE SUBSTANCES FROM THE PLANT PETROSIMONIA BRACHIATA

Kazakhstan is rich in medicinal plants, so it needs to be studied. Ten species of the Petrosimonia belonging to the Chenopodiaceae family are growing in Kazakhstan. These plants have been adapted to harsh climatic conditions in the country’s salty, saline, and desert areas. Petrosimonia plants are a new species that has not been fully studied. Chinese scientists studied Petrosimonia sibirica species and found that the plant contains alkaloids, steroids, terpenes, flavonoids, and phenolic acids and has antibacterial activity (Wen, 2015; Ying, 2016). The qualitative and quantitative compositions of biologically active substances in P. sibirica, P. Glaucescens, P. triandra, and P. brachiata growing in Kazakhstan were studied. To prepare phytopreparations from P. Sibirica, P. Glaucescens and P. triandra plants were extracted using the classical maceration method, and individual representatives of biologically active compounds were isolated (Toktarbek, 2021; Seitimova, 2022). In this study, a phytochemical study of P. brachiata was conducted. The method for obtaining biologically active complexes with high efficiency was optimised by using supercritical fluid and ultrasonic extraction methods. These methods have a short extraction time, can be carried out at room temperature, are cost effective, and are a modern green chemical approach. Using supercritical fluid CO2 extraction (180 bar, 2 hours), the plant was purified from lipophilic substances. Further, a biologically active complex was obtained by pouring 70% ethanol-water solvent into the plant raw material and performing ultrasound extraction. The obtained complex was analysed by thin-layer chromatography using different organic solvent systems. Based on our analysis, steroids, terpenes, phenolic acids, and flavonoid glycosides were found in the extract. Hexane and ethyl acetate fractions were obtained as a result of liquid-liquid extraction of the extract using organic solvents. Stigmasterol 3-O-β-D-galactopyranoside, isovanillic acid, quercetin 3-O-β-D-glucopyranoside, and isorhamnetin 3-O-α-L-rhamnopyranoside were isolated by washing the hexane and ethyl acetate fractions in a silica gel column with an organic solvent system. The isolated compounds will be tested for biological activity.

The penetration of therapeutics across the blood-brain barrier: Classic case studies and clinical implications.

The blood-brain barrier (BBB) plays central roles in the maintenance and health of the brain. Its mechanisms to safeguard the brain against xenobiotics and endogenous toxins also make the BBB the primary obstacle to the development of drugs for the central nervous system (CNS). Here, we review classic examples of the intersection of clinical medicine, drug delivery, and the BBB. We highlight the role of lipid solubility (heroin), saturable brain-to-blood (efflux: opiates) and blood-to-brain (influx: nutrients, vitamins, and minerals) transport systems, and adsorptive transcytosis (viruses and incretin receptor agonists). We examine how the disruption of the BBB that occurs in certain diseases (tumors) can also be modulated (osmotic agents and microbubbles) and used to deliver treatments, and the role of extracellular pathways in gaining access to the CNS (albumin and antibodies). In summary, this review provides a historical perspective of the key role of the BBB in delivery of drugs to the brain in health and disease.

Isolation of valuable substances from berry seeds and pomace by the green high-pressure methods, their evaluation and application in cosmetic creams

Berry seeds and pomace generated as a by-product of fruit processing contain valuable nutrients and bioactive compounds; however, nowadays it is inefficiently recycled or even discarded as a waste. Valorisation of such by-products for the development of higher value ingredients would substantially increase the sustainability of the sector. For this purpose, green extraction methods with supercritical CO2 (SFE-CO2) and pressurized liquid (PLE) extraction with hydro-ethanol were consecutively applied to strawberry, blackberry and elderberry seeds and rowanberry pomace for the isolation of lipophilic and higher polarity substances. SFE-CO2 extracts were rich in unsaturated fatty acids (oleic, 10.76 − 23.25 %; linoleic, 39.11 −59.74 %; linolenic, 1.32 − 43.83 %), tocopherols (31 – 637 μg/g), phytosterols (1992 – 3775 μg/g), carotenoids (65.06 – 2147 μg β-carotene/g) and chlorophylls (27.95 – 130.4 μg/g). Anthocyanins (22.7 – 697.6 mg cyanidin-3-O-glucoside equivalents/100 g), flavonoids (2.75 – 7.43 mg quercetin eqv./g), proanthocyanidins (122.2 – 199.4 catechin monohydrate eqv./g), antioxidant and antibacterial properties were evaluated for the PLE extracts. The extracts were tested in cosmetic creams at 2 % concentrations and strawberry seed extracts were selected for the evaluation of cream properties. In general, PLE extract addition had slight effect on antioxidant properties and sun protection factor of creams. However, considering the presence of high value constituents both in the lipophilic and hydrophilic extracts and the studies showing the benefits of the use of these constituents in cosmetic products, it may be expected that the extracts may be promising ingredients in developing new natural cosmetic products, including cosmeceuticals. In addition, the extracts may be promising ingredients in the formulation of nutraceuticals.

Preclinical Evaluation of a Radiolabeled Pan-RAF Inhibitor for RAF-Specific PET/CT Imaging.

Abnormalities in the RAS-RAF signaling pathway occur in many solid tumors, leading to aberrant tumor proliferation, invasion, and metastasis. Due to the elusive pharmacology of RAS, RAF inhibitors have become the main targeted therapeutic drugs. Naporafenib (LXH-254) is a high-affinity pan-RAF inhibitor with FDA Fast Track Qualification. We sought to develop an 18F-labeled molecular probe from LXH-254 for PET imaging of tumors overexpressing RAF to noninvasively screen patients for susceptibility to targeted RAF therapy. To reduce the lipid solubility, LXH-254 was designed with triethylene glycol di(p-toluenesulfonate) (TsO-PEG3-OTs) to obtain the precursor (LXH-254-OTs) and a nucleophilic substitution reaction with 18F to obtain the tracer ([18F]F-LXH-254). [18F]F-LXH-254 exhibited good molar activity (7.16 ± 0.81 GBq/μmol), radiochemical purity (>95%), and stability. Micro-PET imaging revealed distinct radioactivity accumulation of [18F]F-LXH-254 in tumors in the imaging groups, whereas in the blocked group, the tumor radioactivity level was consistent with the background tissue, illustrating the affinity and specificity of [18F]F-LXH-254 in targeting RAF. Overall, [18F]F-LXH-254 is a promising radiotracer for screening and diagnosing patients with RAF-related disease and monitoring their treatment. This is the first attempt at using an 18F-labeled RAF-specific radiotracer.

Comparative efficacy and safety of tenofovir amibufenamide vs tenofovir alafenamide in the initial 48-week treatment of high viral load chronic hepatitis B: A single-centre retrospective study.

Tenofovir amibufenamide (TMF) employs innovative ProTide technology and a methylation strategy to enhance the lipid solubility and plasma stability of the amide bond, providing advantages over tenofovir alafenamide (TAF). Despite promising Phase III clinical trial results demonstrating its antiviral efficacy, real-world data on TMF remains scarce. This study evaluates the antiviral efficacy and safety of TMF compared to TAF as the initial treatment in patients with high viral loads of chronic hepatitis B (CHB). We retrospectively collected clinical data from March 1 2022 to June 30 2022 for highly viremic CHB patients who received either TMF (n = 58) or TAF (n = 32) as their initial monotherapy at Beijing YouAn Hospital. To understand the efficacy and safety of TMF over 48 weeks, we compared the virological response rates and HBeAg/HBsAg serological clearance rates between TMF and TAF groups. Also, the changes in serum creatinine, eGFR and serum lipid levels were assessed. Baseline median HBV DNA levels were 7.85 (6.89, 8.36) IgIU/ml for TMF and 7.44 (6.89, 8.03) IgIU/ml for TAF. Median ALT levels were 102.0 (56.0, 210.0) U/L for TMF and 195.0 (73.5, 371.0) U/L for TAF, with HBeAg positivity rates of 70.7% and 75.0%, respectively. At 48 weeks, virological response rates (HBV DNA <10 IU/ml) were 43.5% (20/46) for TMF and 42.9% (12/28) for TAF (p = 1.000). ALT normalization rates were 87.9% for TMF and 90.6% for TAF (p = .969), and HBeAg serological clearance rates were 21.1% and 18.2%, respectively (p = 1.000). No patients achieved HBsAg clearance. Compared with the baseline, LDL-C levels increased, while eGFR decreased, with no significant differences in serum creatinine, triglycerides and total cholesterol levels noted at week 48 for both TMF and TAF groups. TMF demonstrates comparable antiviral efficacy to TAF when used as initial therapy in highly viremic CHB patients, with similar impacts on renal function and lipid profiles.

Facile Preparation of Silica/Tannic Acid/Zein Microcapsules Templated from Non-Aqueous Pickering Emulsions and their Application in Cargo Protection.

Microcapsules have attracted significant attention in academia and industry due to their unique properties for protecting and controlling the release of active substances. However, based on water-insoluble biopolymers, developing a straightforward approach to prepare microcapsules with improved biocompatibility and functional shells remains a great challenge. In this study, zein, a water-insoluble protein, is employed to prepare robust microcapsules facilely using oil-in-aqueous ethanol Pickering emulsions as templates. First, the emulsion template is stabilized by hydrophobic silica nanoparticles with in situ surface modification of tannic acid. The zein is then precipitated at the interface in a controlled manner using antisolvent approach to obtain silica/tannic acid/zein (STZ) microcapsules. It is found that the concentration of zein and the presence of tannic acid played a significant role in the formation of STZ microcapsules with well-defined morphology and a robust shell. The uniform deposition of zein on the surface of template droplets is facilitated by the interactions between tannic acid and zein via hydrogen bond and electrostatic force. Finally, the resulting STZ microcapsules showed super resistance to ultraviolet (UV) radiation and high temperature for the unstable, lipophilic, and active substance of β-carotene.

METHOXYFLURANE: A HISTORICAL REVIEW AND SAFETY ANALYSIS OF ITS USE AS AN ANALGESIC IN EMERGENCY AND OUTPATIENT PROCEDURES

OMethoxyflurane, introduced as an anesthetic agent in the 1960s, quickly gained popularity due to its potent properties. However, its use as an anesthetic was discontinued due to significant side effects, particularly nephrotoxicity, manifested as acute renal failure with high diuresis. By the mid-1970s, methoxyflurane was withdrawn from the anesthetic market in North America and gradually worldwide. It was later discovered that low-dose methoxyflurane had powerful analgesic properties, allowing its use for short-term pain relief in traumatic injuries and during ambulatory procedures. Australian emergency services began using portable methoxyflurane inhalers for emergency care. Clinical trials confirmed the effectiveness of this agent, with no significant side effects such as renal or hepatic toxicity reported. The physicochemical properties of methoxyflurane, particularly its high lipid solubility and low vapor pressure, provide a slow onset of sedation, limiting its sedative effects when used short-term. Clinical studies have confirmed the safety and efficacy of methoxyflurane in conducting ambulatory procedures such as colonoscopy and burn wound dressing changes. Methoxyflurane reduces anxiety and pain, allowing patients to return to normal activities more quickly. Thus, methoxyflurane, used as a low-dose inhaled analgesic, can be an effective and safe pain relief option during ambulatory medical and surgical procedures, particularly in patients at high risk of complications from traditional sedation methods. Further research, including large randomized controlled trials, may provide additional evidence to support the potential benefits of methoxyflurane.

Application of Nanotechnology to Enhance the Effectiveness and Stability of Essential Oils

The global demand for essential oils is expanding as a result of their numerous applications and increasing consumer exposure in the international market. Essential oils (EOs) are mixtures of volatile compounds including, but not limited to, phenolics, esters, ketones, terpenes, alcohols, and amides. The majority of EOs have excellent antioxidant, antibacterial, and functional activities. These natural products have conquered space in the food, drug, and cosmetic commercial arena. Unfortunately, like many lipophilic and aromatic active substances, EO presents some drawbacks such as low water solubility, strong organoleptic characteristics, low stability, and limited administration routes, which confines their Industrial use. EOs can be nanoencapsulated to increase their persistence, and bioavailability in the biological process by employing the optimum encapsulation polymers. Additionally, these particles are capable of controlling the release of the EOs promoting a prolonged preservative effect in cosmetics and foods, as well as a potential advantage for pharmaceutical dosage forms. The current research focuses on the essential features of EOs as well as their encapsulation methods. Furthermore, the potential applications of applying nanoencapsulated essential oils in the healthcare field were addressed.

Comparison of the Efficacy Between Ultrasound-Guided Paravertebral Block and Erector Spinae Block for Postoperative Analgesia in Percutaneous Nephrolithotomy Using Levobupivacaine: A Prospective and Randomized Study.

Introduction Various techniques have been developed in the current era of regional anesthesia practice. With the advent of ultrasound, the visualization of needle and pleura in real time enables a better outcome with negligible adverse events. This study was designed to compare the efficacy between ultrasound-guided erector spinae plane block (ESPB) and paravertebral block (PVB) in percutaneous nephrolithotomy (PCNL) for the duration of postoperative analgesia with levobupivacaine, a local anesthetic with higher lipid solubility, making it more potent and resulting in a longer duration of action. Methods This prospective randomized single-blinded study enrolled 50 patients of ASA grades I and II, aged between 20 and 60 years, who were scheduled for PCNL under general anesthesia. Patients were divided into two groups of 25 each: group ESPB andgroup PVB, and 25 mL of 0.25% levobupivacaine was administered to both groups. They were primarily evaluated for the duration of postoperative analgesia. Total rescue analgesic requirements, hemodynamic parameters, and any adverse effects were also assessed. Results Both ESPB and PVB provided a significant duration of analgesia postoperatively. Demographic characteristics in both groups were comparable. The duration of postoperative analgesia in group ESPB was 746 ± 58.6 minutes when compared to group PVB, which is 768 ± 68.6 minutes (p = 0.08). Intravenous (IV) paracetamol was used as a rescue analgesic. The doses used were also comparable in both groups, with the visual analog score (VAS) being high after around 12 hours of surgery. The total rescue analgesic requirement was similar in both groups (group ESPB, 2.0 ± 1.6; group PVB, 2.2 ± 1.4; p = 0.51). There were no significant hemodynamic or other adverse effects in either group. Conclusion We conclude that both ESPBand PVB using isobariclevobupivacaine 0.25% as a local anesthetic are equally efficacious in providing effective postoperative analgesia in patients undergoing PCNL under generalanesthesia.

Rapid pyrolysis of cellulose: Revealing the role of volatile matter and char structure evolution

The complexity of the cellulose structure hinders its energy conversion and utilization. Pyrolysis is not only an independent thermochemical conversion technology but also a necessary stage in the gasification process. The real-time capture of volatile components in cellulose pyrolysis is difficult, and the evolution of char structures is lacking, which is extremely challenging. In this work, elemental analysis, industrial analysis, thermogravimetric analysis, infrared spectroscopy (FTIR), Raman spectroscopy (Raman), and X-ray diffraction spectroscopy (XRD) were used to characterize the raw materials and products. Combined with rapid pyrolysis experiments, the pathways of cellulose pyrolysis volatiles and char structure evolution were explored. Dehydrated sugars are the initial products formed below 350 ℃, which quickly dehydrate to form furan compounds at 400 ℃ and then break CC bonds at 600 ℃ to generate fatty aldehydes, ketones, and carboxylic acids. Biochar generated at low temperatures (<300°C) has strong lipid solubility. An increase in pyrolysis temperature leads to a continuous decrease in the content of H and O in biochar, which destroys its functional groups and physical structure, and ultimately tends to form graphite-type char with aromatic structures. Based on the correlation between the volatile matter release characteristics and the evolution of the semichar structure, a cellulose pyrolysis pathway was established, providing theoretical support for the high-value utilization of cellulose.

Highly Hydrophilic TiO2 Nanoparticles as Stabilizers of Pickering Emulsions with Photosensitive Lipophilic Compounds: Synthesis and Application.

Pickering emulsions are a very promising system for encapsulating and photoprotecting active ingredients. The highest photoprotection efficiency can be achieved when bare TiO2 nanoparticles are used as stabilizers. However, the main problem when using highly hydrophilic TiO2 nanoparticles is their inability to adsorb at the oil-water interface. Here, we developed emulsions stabilized by bare, highly hydrophilic TiO2 nanoparticles for the encapsulation and photoprotection of active lipophilic compounds. Emulsion stabilization occurs due to the formation of hydrogen bonds between hydroxyl groups on the particle surface and the carbonyl groups of the oil molecules. The stability and rheological properties of emulsions are explained by the properties of the initial hydrosols. The resulting Pickering emulsions demonstrated effective UV protection of α-lipoic acid. Our results pave the way for the formulation of Pickering emulsions with a widely used cosmetic oil and show for the first time the possibility of photoprotection of a lipophilic active substance using unmodified TiO2 nanoparticles.

Myxodiaspory in Adenostemma brasilianum (Asteraceae): morphological and histochemical strategies for diaspore dispersion

Abstract Myxodiaspory, the extrusion of sticky substances by the diaspores (seeds, fruits, anthocarps, and parts of infrutescences), has several selective advantages, one of which is aiding the adherence of diaspores between feathers/fur of animals that transport them over short or long distances. The diaspores of Asteraceae have three structures that can contain sticky substances: exocarp epidermal cells, exocarp trichomes, and viscid pappus. The South American species Adenostemma brasilianum (Asteraceae) has all three features. We examined the anatomy, secreted substances, and mode of adhesion of the diaspores of A. brasilianum to understand its strategies for dispersion. The fruit comprises an exocarp with glandular trichomes arranged spirally and scarce nonglandular trichomes, two layers of mesocarp separated by phytomelanin, and an endocarp. The pappus has a basal ring, a stalk, and a head with glandular trichomes. The mucilage, secreted by the glandular trichomes of fruit and pappus, reacted positively to tests for pectins, essential oils, lipophilic substances, and gums. The test for tannins gave a homogeneous positive reaction in the phytomelanin area, and as droplets, in the outer mesocarp layer and in the exocarp. The whole capitulum of A. brasilianum is adapted for successful transportation of its diaspores via diaspore release, secretion, and positioning. We discuss the idea that the dispersal adaptive traits found here evolved as phylogenetic parallelisms in the family.

Synthesis, characterization, and mechanistic insights into the enhanced anti-inflammatory activity of baicalin butyl ester via the PI3K-AKT pathway.

To investigate the anti-inflammatory activity and mechanism of Baicalin derivative (Baicalin butyl ester, BE). BE was synthesized and identified using UV-Vis spectroscopy, FT-IR spectroscopy, mass spectrometry (MS) and high-performance liquid chromatography (HPLC) methods. Its anti-inflammatory potential was explored by an in vitro inflammation model. Network pharmacology was employed to predict the anti-inflammatory targets of BE, construct protein-protein interaction (PPI) networks, and analysis topological features and KEGG pathway enrichment. Additionally, molecular docking was conducted to evaluate the binding affinity between BE and its core targets. qRT-PCR analysis was conducted to validate the network pharmacology results. The organizational efficiency was further evaluated through octanol-water partition coefficient and transmembrane activity analysis. UV-Vis, FT-IR, MS, and HPLC analyses confirmed the successfully synthesis of BE with a high purity of 93.75%. In vitro anti-inflammatory research showed that BE could more effectively suppress the expression of NO, COX-2, IL-6, IL-1β, and iNOS. Network pharmacology and in vitro experiments validated that BE's anti-inflammatory effects was mediated through the suppression of SRC, HSP90AA1, PIK3CA, JAK2, AKT1, and NF-κB via PI3K-AKT pathway. Molecular docking results revealed that the binding affinities of BA to the core targets were lower than those of BE. The Log p-value of BE (1.7) was markedly higher than that of BA (-0.5). Furthermore, BE accumulated in cells at a level approximately 200 times greater than BA. BE exhibits stronger anti-inflammatory activity relative to BA, possibly attributed to its better lipid solubility and cellular penetration capabilities. The anti-inflammatory mechanism of BE may be mediated through the PI3K-AKT pathway.

Borneol and lactoferrin dual-modified crocetin-loaded nanoliposomes enhance neuroprotection in HT22 cells and brain targeting in mice

Crocetin (CCT), a natural bioactive compound extracted and purified from the traditional Chinese medicinal herb saffron, has been shown to play a role in neurodegenerative diseases, particularly depression. However, due to challenges with solubility, targeting, and bioavailability, formulation development and clinical use of CCT are severely limited. In this study, we used the emulsification-reverse volatilization method to prepare CCT-loaded nanoliposomes (CN). We further developed a borneol (Bor) and lactoferrin (Lf) dual-modified CCT-loaded nanoliposome (BLCN) for brain-targeted delivery of CCT. The results of transmission electron microscope (TEM) and particle size analysis indicated that the size of BLCN (∼140 nm) was suitable for transcellular transport across olfactory axons (∼200 nm), potentially paving a direct path to the brain. Studies on lipid solubility, micropolarity, and hydrophobicity showed that BLCN had a relatively high Lf grafting rate (81.11 ± 1.33 %) and CCT entrapment efficiency (83.60 ± 1.04 %) compared to other liposomes, likely due to Bor improving the lipid solubility of Lf, and the combination promoting the orderly arrangement of liposome membrane molecules. Microplate reader and fluorescence microscopy analysis showed that BLCN efficiently promoted the endocytosis of fluorescent coumarin 6 into HT22 cells with a maximal fluorescence intensity of (13.48 ± 0.80 %), which was significantly higher than that of CCT (5.73 ± 1.17 %) and CN (12.13 ± 1.01 %). BLCN also exhibited sustained function, remaining effective for more than 12 h after reaching a peak at 1 h in cells, while CN showed a significant decrease after 4 h. The uptake mechanisms of BLCN in HT22 cells mainly involve energy-dependent, caveolae-mediated, and microtubule-mediated endocytosis, as well as micropinocytosis. Furthermore, BLCN displayed a significant neuroprotective effect on HT22 cells in glutamate-, corticosterone-, and H2O2-induced models. Tissue fluorescence image analysis of mice showed that BLCN exhibited substantial retention of fluorescent DiR in the brain after nasal administration for 12 h. These findings suggest that CCT has the potential for cellular uptake, neuroprotection, and targeted delivery to the brain following intranasal administration when encapsulated in Bor and Lf dual-modified nanoliposomes.

Specific intermolecular interaction with sodium glycocholate generates the co-amorphous system showing higher physical stability and aqueous solubility of Y5 receptor antagonist of neuropeptide Y, a brick dust molecule

Drugs with poor water and lipid solubility are termed “brick dust.” We previously successfully developed a co-amorphous system of a novel neuropeptide Y5 receptor antagonist (AntiY5R), a brick dust molecule, using sodium taurocholate (NaTC) as a co-former. However, the maximum improvement in AntiY5R dissolution by the co-amorphous system was only approximately 10 times greater than that of the crystals. Therefore, in the current study, other bile salts, including sodium cholate (NaC), sodium chenodeoxycholate (NaCC), and sodium glycocholate (NaGC), were examined as co-formers to further improve AntiY5R dissolution. NaC, NaCC, and NaGC have glass transition temperatures above 150°C. All three co-amorphous systems prepared successfully retained the amorphous form of AntiY5R for 3 months at 40°C, but the co-amorphous system with NaGC (AntiY5R-NaGC; 1:9 molar ratio) provided the highest improvement in AntiY5R dissolution, which was approximately 50 times greater than that of the crystals. Possible intermolecular interactions via the glycine moiety of NaGC more than the other bile salts would contribute to the highest dissolution enhancement with AntiY5R-NaGC. Thus, NaGC would be a promising co-former for formulating stable co-amorphous systems to enhance the dissolution behavior of brick dust molecules.

Absorption enhancement of peach kernel oil on hydroxysafflor yellow A in safflower extracts and its mechanisms

Carthamus tinctorius L. (Safflower) is extensively used as a functional food and herbal medicine, with its application closely associated with hydroxysafflor yellow A (HSYA). However, the low oral bioavailability of HSYA in safflower extract (SFE) limits its health benefits and application. Our study found that co-administration of 250, 330, and 400 mg/kg peach kernel oil (PKO) increased the oral bioavailability of HSYA in SFE by 1.99-, 2.11-, and 2.49-fold, respectively. The enhanced bioavailability is attributed to improved lipid solubility and intestinal permeability of HSYA in SFE due to PKO. PKO is believed to modify membrane fluidity and tight junctions, increase paracellular penetration, and inhibit the expression and function of P-glycoprotein, enhancing the transcellular transport of substrates. These mechanisms suggest that PKO is an effective absorption enhancer. Our findings provide valuable insights for developing functional foods with improved bioavailability.

Tailoring oleogel-in-hydrogel pickering emulsion fluid gels as an oral delivery system for different levels of dysphagia: From microstructure to rheological properties

Dysphagia-affected populations are facing crucial challenges on oral administration of medicines and health products because of swallowing malfunction with a high risk of aspiration. The current countermeasures that relied mainly on modification of existing formulations with thickened liquids comes with potential hazards, e.g., bioavailability alterations and unsatisfactory safety. Thus, dysphagia-specific oral delivery system is in critical need of development. Herein, a swallowing dynamics-inspired, oleogel-in-hydrogel Pickering emulsion fluid gel was proposed as a versatile oral delivery system for patients with dysphagia. With the dual structure of high acyl gellan gum (HAG) fluid gel and whey protein isolate (WPI) stabilized oleogel-in-hydrogel Pickering emulsion gel, the novel system demonstrated the potential to tackle both swallowing and drug encapsulation challenges. Specifically, it displayed good shear flowability during shearing and appropriate extensional capabilities after shearing which are well-matched with swallowing dynamics to facilitate ease and safe swallowing. Moreover, the oleogel-in-hydrogel Pickering emulsion gel structure enables its versatile loading potential for both hydrophilic and lipophilic substances. Remarkably, the microstructure and the related rheological properties of this novel system could be tailored by controlling critical determinants in the formation of fluid gels, namely HAG content and process mixing rate. By adjusting these two parameters, the fluid gels could be customized as preparations with different thickness level for mild, moderate and severe dysphagia, respectively. In conclusion, this proposed approach offers a promising rheologically-tunable oral delivery system for administering bioactives to patients with different levels of dysphagia.