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Type 2 diabetes mellitus (T2DM) involves insulin resistance and elevated blood sugar levels, causing complications. Red ginseng extract powder (RGEP) from Panax ginseng Meyer shows promise for diabetes treatment. However, its efficacy in managing T2DM remains unclear. Therefore, this study aims to evaluate the effectiveness of RGEP in a mouse model of T2DM. The efficacy of RGEP in treating T2DM was assessed in db/db mice. Mice were divided into seven groups: control, db/db, metformin, and RGEP at 50, 100, 200, and 400 mg/kg. Administered orally for 9 weeks, RGEP effects on glucose regulation and insulin sensitivity were assessed through various metabolic parameters. In addition, mRNA expression levels of genes associated with hepatic gluconeogenesis and insulin sensitivity were examined. Fasting blood sugar showed a significant decrease in all RGEP concentration groups, but OGTT and insulin tolerance test showed a significant decrease at the RGEP concentration of 400 mg/kg, indicating enhanced glycemic control. Moreover, RGEP dose-dependently decreased serum glucose, HbA1c levels, and homeostatic model assessment of insulin resistance values, suggesting its effectiveness in reducing insulin resistance in db/db mice. Furthermore, RGEP downregulated mRNA expression of key components in the gluconeogenesis pathway (G6Pase, FOXO1, GLUT4, and PEPCK), insulin sensitivity (leptin, insulin1, PTP1B, GLP-1, and DPP-4), and mitochondria energy metabolism (PGC1) in either the liver or pancreas, while simultaneously upregulating GLP-1 expression. In conclusion, these findings highlight the potential of RGEP as a complementary therapy for T2DM, indicating therapeutic efficacy in managing diabetic complications through improved metabolic parameters.

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The present study examined the underlying mechanisms of mechanical allodynia and thermal hyperalgesia induced by the intracisternal injection of angiotensin (Ang) II. Intracisternal Ang II injection decreased the air puff threshold and head withdrawal latency. To determine the operative receptors for each distinct type of pain behavior, we intracisternally injected Ang II receptor antagonists 2 h after Ang II injection. Losartan, an Ang II type 1 receptor (AT1R) antagonist, alleviated mechanical allodynia. Conversely, PD123319, an Ang II type 1 receptor (AT2R) antagonist, blocked only thermal hyperalgesia. Immunofluorescence analyses revealed the co-localization of AT1R with the astrocyte marker GFAP in the trigeminal subnucleus caudalis and co-localization of AT2R with CGRP-positive neurons in the trigeminal ganglion. Intracisternal pretreatment with minocycline, a microglial inhibitor, did not affect Ang II-induced mechanical allodynia, whereas L-α-aminoadipate, an astrocyte inhibitor, significantly inhibited Ang II-induced mechanical allodynia. Furthermore, subcutaneous pretreatment with botulinum toxin type A significantly alleviated Ang II-induced thermal hyperalgesia, but not Ang II-induced mechanical allodynia. These results indicate that central Ang II-induced nociception is differentially regulated by AT1R and AT2R. Thus, distinct therapeutic targets must be regulated to overcome pain symptoms caused by multiple underlying mechanisms.

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Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death and has a poor 5-year overall survival. The superior therapeutic benefits of combination or co-administration of drugs as intraperitoneal chemotherapy have increased interest in developing strategies to deliver chemotherapeutic agents to patients safely. In this study, we prepared a gel comprising the thermosensitive poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) polymer and gemcitabine (GEM), which is currently used as the primary chemotherapy for PDAC and rapamycin (RAPA), a mammalian TOR (mTOR) inhibitor, to deliver the drug through intraperitoneal injection. We performed in vitro cytotoxicity experiments to verify the synergistic effects of the two drugs at different molar ratios and characterized the physicochemical properties of the GEM, RAPA, and GEM/RAPA-loaded thermosensitive PLGA-PEG-PLGA gels, hereafter referred to as (g(G), g(R), and g(GR)), respectively. The g(GR) comprising PLGA-PEG-PLGA polymer (25% w/v) and GEM and RAPA at a molar ratio of 11:1 showed synergism and was optimized. An in vitro cytotoxicity assay was performed by treating Panc-1-luc2 tumor spheroids with g(G), g(R), or g(GR). The g(GR) treatment group showed a 2.75-fold higher inhibition rate than the non-treated (NT) and vehicle-treated groups. Furthermore, in vivo drug release assay in mice by intraperitoneal injection of g(G), g(R), or g(GR) showed a more rapid release rate of GEM than RAPA, similar to the in vitro release pattern. The drugs in the gel were released faster in vivo than in vitro and degraded in 48 h. In addition, g(GR) showed the highest anti-tumor efficacy with no toxicity to mice. These results provide evidence for the safety and efficacy of g(GR) for intraperitoneal drug delivery. This study will assist in developing and clinically administering topical anti-cancer formulations.

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Ovarian cancer has a high mortality rate due to difficult detection at an early stage. It is necessary to develop a novel anticancer treatment that demonstrates improved efficacy while reducing toxicity. Here, using the freeze-drying method, micelles encapsulating paclitaxel (PTX) and sorafenib (SRF) with various polymers were prepared, and the optimal polymer (mPEG-b-PCL) was selected by measuring drug loading (%), encapsulation efficiency (%), particle size, polydispersity index, and zeta potential. The final formulation was selected based on a molar ratio (PTX:SRF = 1:2.3) with synergistic effects on two ovarian cancer cell lines (SKOV3-red-fluc, HeyA8). In the in vitro release assay, PTX/SRF micelles showed a slower release than PTX and SRF single micelles. In pharmacokinetic evaluation, PTX/SRF micelles showed improved bioavailability compared to PTX/SRF solution. In in vivo toxicity assays, no significant differences were observed in body weight between the micellar formulation and the control group. The anticancer effect of PTX/SRF combination therapy was improved compared to the use of a single drug. In the xenografted BALB/c mouse model, the tumor growth inhibition rate of PTX/SRF micelles was 90.44%. Accordingly, PTX/SRF micelles showed improved anticancer effects compared to single-drug therapy in ovarian cancer (SKOV3-red-fluc).

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Paclitaxel (PTX), etoposide (ETP), and rapamycin (RAPA) have different mechanisms, allowing multiple pathways to be targeted simultaneously, effectively treating various cancers. However, these drugs have a low hydrosolubility, limiting clinical applications. Therefore, we used pH-sensitive polymeric micelles to effectively control the drug release in cancer cells and to improve the water solubility of PTX, ETP, and RAPA. The synergistic effect of PTX, ETP, and RAPA was evaluated in gastric cancer, and the combination index values were evaluated. Thin-film hydration was used to prepare PTX/ETP/RAPA-loaded mPEG-pH-PCL micelles, and various physicochemical properties of these micelles were evaluated. In vitro cytotoxicity, pH-sensitivity, drug release profiles, in vivo pharmacokinetics, and biodistribution studies of PTX/ETP/RAPA-loaded mPEG-pH-PCL micelles were evaluated. In the pH-sensitivity evaluation, the size of the micelles increased more rapidly at a pH of 5.5 than at a pH of 7.4. The release rate of each drug increased with decreasing pH values in PTX/ETP/RAPA-loaded mPEG-pH-PCL micelles. In vitro and in vivo studies demonstrated that PTX/ETP/RAPA-loaded mPEG-pH-PCL micelles exhibit different drug release behaviors depending on the pH of the tumor and normal tissues and increased bioavailability and circulation time in the blood than solutions. Therefore, we propose that PTX/ETP/RAPA- loaded mPEG-pH-PCL micelles are advantageous for gastric cancer treatment in drug delivery systems.

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PURPOSE: We aimed to develop a nanocarrier formulation incorporating fenbendazole (FEN) and rapamycin (RAPA) with strong efficacy against A549 cancer cells. As FEN and RAPA are poorly soluble in water, it is difficult to apply them clinically in vivo. Therefore, we attempted to resolve this problem by encapsulating these drugs in polymeric micelles. METHODS: We evaluated drug synergy using the combination index (CI) values of various molar ratios of FEN and RAPA. We formed and tested micelles composed of different polymers. Moreover, we conducted cytotoxicity, stability, release, pharmacokinetic, and biodistribution studies to investigate the antitumor effects of FEN/RAPA-loaded mPEG-b-PCL micelles. RESULTS: We selected mPEG-b-PCL-containing FEN and RAPA at a molar ratio of 1:2 because these particles were consistent in size and had high encapsulation efficiency (EE, %) and drug loading (DL, %) capacity. The in vitro cytotoxicity was assessed for various FEN, RAPA, and combined FEN/RAPA formulations. After long-term exposures, both the solutions and the micelles had similar efficacy against A549 cancer cells. The in vivo pharmacokinetic study revealed that FEN/RAPA-loaded mPEG-b-PCL micelles had a relatively higher area under the plasma concentration-time curve from 0 to 2 h (AUC0-2 h) and 0 to 8 h (AUC0-8 h) and plasma concentration at time zero (Co) than that of the FEN/RAPA solution. The in vivo biodistribution assay revealed that the IV injection of FEN/RAPA-loaded mPEG-b-PCL micelles resulted in lower pulmonary FEN concentration than the IV injection of the FEN/RAPA solution. CONCLUSION: When FEN and RAPA had a 1:2 molar ratio, they showed synergism. Additionally, using data from in vitro cytotoxicity, synergism between a 1:2 molar ratio of FEN and RAPA was observed in the micelle formulation. The FEN/RAPA-loaded mPEG-b-PCL micelle had enhanced bioavailability than the FEN/RAPA solution.

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Venous insufficiency results from several factors responsible for the progression of inflammation and oxidative damage of veins. Recently, natural extracts have been proposed for the treatment of venous insufficiency, but their efficacies have not been fully elucidated. In the present study, we evaluate the combinatorial effects on anti-inflammatory and anti-vascular leakage potential of mixed compositions containing different proportions of Centella asiatica extract (CE) and Vitis vinifera L. leaf extract (VVE) using an inflammation model of lipopolysaccharide- (LPS-) stimulated RAW264.7 cells and various vascular permeability models in mice (acetic-acid-induced peritoneal vascular model, mustard-oil-stimulated ear vascular model, and carrageenan-induced paw edema model). Pretreatment of CE and VVE in a 1 : 3 combination dose dependently inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2) and mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) through downregulation of the nuclear factor-κB (NF-κB) pathway in LPS-stimulated RAW264.7 macrophages. In vascular permeability-related mouse models, pretreatment with the CE-VVE 1 : 3 combination significantly reduced the permeability of peritoneal or ear veins caused by acetic acid and mustard oil, respectively. Furthermore, pretreatment of the CE-VVE 1 : 3 combination ameliorated inflammation and edema of the hind paw caused by carrageenan injection. Thus, the combination of CE and VVE showed significant anti-inflammatory qualities and anti-vascular leakage effects. These findings indicate that an optimal combination of CE and VVE may have a more synergistic effect than that of CE or VVE alone as a putative agent against vascular incompetence.

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Docetaxel (DTX), a taxane-based anticancer drug, and osthol (OTH), a coumarin-derivative compound, have shown anticancer effects against different types of cancers through various mechanisms. However, these drugs have low solubility in water and low oral bioavailability, and thus their clinical application is difficult. To overcome these problems, we encapsulated DTX and OTH in methoxy poly(ethylene glycol)-b-poly(caprolactone) (mPEG-b-PCL) and conducted studies in vitro and in vivo. We selected a 1:4 ratio as the optimal ratio of DTX and OTH, through combination index analysis in A549 cancer cells, and prepared micelles to evaluate the encapsulation efficiency, drug loading, particle size, and zeta potential. The in vitro drug-release profile showed that DTX/OTH-loaded mPEG-b-PCL micelles could slowly release DTX and OTH. In the clonogenic assay, DTX/OTH-loaded mPEG-b-PCL micelles showed 3.7 times higher inhibitory effect than the DTX/OTH solution. Pharmacokinetic studies demonstrated that micelles in combination with DTX and OTH exhibited increased area under curve and decreased clearance values, as compared with single micelles.

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Fenbendazole (FEN), a broad-spectrum benzimidazole anthelmintic, suppresses cancer cell growth through various mechanisms but has low solubility and achieves low blood concentrations, which leads to low bioavailability. Solubilizing agents are required to prepare poorly soluble drugs for injections; however, these are toxic. To overcome this problem, we designed and fabricated low-toxicity Soluplus® polymeric micelles encapsulating FEN and conducted toxicity assays in vitro and in vivo. FEN-loaded Soluplus® micelles had an average particle size of 68.3 ± 0.6 nm, a zeta potential of -2.3 ± 0.2 mV, a drug loading of 0.8 ± 0.03%, and an encapsulation efficiency of 85.3 ± 2.9%. MTT and clonogenic assays were performed on A549 cells treated with free FEN and FEN-loaded Soluplus® micelles. The in vitro drug release profile showed that the micelles released FEN more gradually than the solution. Pharmacokinetic studies revealed lower total clearance and volume of distribution and higher area under the curve and plasma concentration at time zero of FEN-loaded Soluplus® micelles than of the FEN solution. The in vivo toxicity assay revealed that FEN-loaded Soluplus® micelle induced no severe toxicity. Therefore, we propose that preclinical and clinical safety and efficacy trials on FEN-loaded Soluplus® micelles would be worthwhile.

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Bisphenol A (BPA), an endocrine-disrupting chemical, has been used as a basic raw material for the production of polycarbonate plastics. As concern over the toxic effects of BPA grows, it is gradually being replaced in many consumer products with compounds such as bisphenol F (BPF) and bisphenol S (BPS). In this study, online solid-phase extraction-high-performance liquid chromatography-tandem mass spectrometry was used to analyze the urinary concentrations of BPA, BPF, and BPS in 2487 Korean urine samples collected between 2017 and 2018. The detection rates and geometric mean (GM) concentrations were as follows: BPA (82.1 %; 0.65 µg/L), BPF (11.1 %; not calculated), and BPS (63.6 %; 0.20 µg/L), respectively. The mean daily intake based on urinary BPA concentrations was 0.013 µg/kg bw/day (95th percentile, 0.089 µg/kg bw/day), which is lower than the tolerable daily intake. This is the first study observing urinary BPA, BPF, and BPS concentrations based on a nationally representative Korean population and could contribute to the evaluation of bisphenol analogue exposure levels in risk assessments.

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Insufficient efficacy of current single drug therapy of cancers have led to the advancement of combination drug-loaded formulations. Specifically, polymeric micelles have been focused on as efficient injectable vehicles for the delivery of several anticancer drugs simultaneously to cancer cells. These nano delivery systems have evolved with advancements in the area of nanotechnology. The current review presents a summary of the past events that have led to the procession of nanomicelles and novel nanotechnologies for combinatorial drug delivery. It also focuses on the advantages, disadvantages, and considerations for the design of nanotechnologies for combinatorial drug delivery systems. The opportunities and challenges of nanotechnologies in drug delivery to overcome current disadvantages are also discussed. Furthermore, we have added findings regarding the trends and perspectives regarding nanotechnologies for combinatorial anticancer drug delivery.

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Alpinumisoflavone, a major compound in unripe Cudrania tricuspidata fruit is reported to exhibit numerous beneficial pharmacological activities, such as osteoprotective, antibacterial, estrogenic, anti-metastatic, atheroprotective, antioxidant, and anticancer effects. Despite its medicinal value, alpinumisoflavone is poorly soluble in water, which makes it difficult to formulate and administer intravenously (i.v.). To overcome these limitations, we used methoxy poly(ethylene glycol)-b-poly(d,l-lactide) (mPEG-b-PLA) polymeric micelles to solubilize alpinumisoflavone and increase its bioavailability, and evaluated their toxicity in vivo. Alpinumisoflavone-loaded polymeric micelles were prepared using thin-film hydration method, and their physicochemical properties were characterized for drug release, particle size, drug-loading (DL, %), and encapsulation efficiency (EE, %). The in vitro drug release profile was determined and the release rate of alpinumisoflavone from mPEG-b-PLA micelles was slower than that from drug solution, and sustained. Pharmacokinetic studies showed decreased total clearance and volume of distribution of alpinumisoflavone, whereas area under the curve (AUC) and bioavailability were significantly increased by incorporation in mPEG-b-PLA micelles. In vivo toxicity assay revealed that alpinumisoflavone-loaded mPEG-b-PLA micelles had no severe toxicity. In conclusion, we prepared an intravenous (i.v.) injectable alpinumisoflavone formulation, which was solubilized using mPEG-b-PLA micelles, and determined their physicochemical properties, pharmacokinetics, and toxicity profiles.

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Assembly of neuronal SNARE protein complexes is essential for fusion of synaptic vesicles with the presynaptic plasma membrane, which releases neurotransmitters into the synaptic cleft and mediates neurotransmission. However, despite the potential of pharmacological regulation of this process for the treatment of various neurological disorders, only a few reagents, including botulinum neurotoxins, are currently available. Here, we report that buforin-1, an antimicrobial peptide from the Asian toad Bufo gargarizans, inhibits neuronal SNARE complex assembly, resulting in neuronal SNARE-mediated membrane fusion in vitro via its direct association with neuronal t-SNAREs syntaxin-1 and SNAP-25. Consistently, buforin-1 significantly inhibited neuronal-SNARE-mediated exocytosis in PC-12 cells. Thus, buforin-1 has potential for the treatment of neurological disorders caused by dysregulated neurotransmission.

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We reconstructed the three-dimensional (3D) surface displacement field of the 24 August 2014 M6.0 South Napa earthquake using SAR data from the Italian Space Agency's COSMO-SkyMed and the European Space Agency's Sentinel-1A satellites. Along-track and cross-track displacements produced with conventional SAR interferometry (InSAR) and multiple-aperture SAR interferometry (MAI) techniques were integrated to retrieve the east, north, and up components of surface deformation. The resulting 3D displacement maps clearly delineated the right-lateral shear motion of the fault rupture with a maximum surface displacement of approximately 45 cm along the fault's strike, showing the east and north components of the trace particularly clearly. These maps also suggested a better-constrained model for the South Napa earthquake. We determined a strike of approximately 338° and dip of 85° by applying the Okada dislocation model considering a single patch with a homogeneous slip motion. Using the distributed slip model obtained by a linear solution, we estimated that a peak slip of approximately 1.7 m occurred around 4 km depth from the surface. 3D modelling using the retrieved 3D maps helps clarify the fault's nature and thus characterize its behaviour.