Advanced pharmaceutical bulletin最新文献

Liver fibrosis (LF) is a pathological condition resulting from a chronic inflammatory response to multiple etiological factors, including viral infections, excessive alcohol consumption, and metabolic disorders. The important role of macrophages in this process, especially the M2 subtype, has attracted attention as a potential target for macrophage-based immunotherapy. M2 macrophages have anti-inflammatory and reparative properties that enable them to modulate the immune response and facilitate repairing damaged tissues. They participate in reducing fibrogenic features in term of gene expression and histological markers associated with LF. These cells phagocytose apoptotic cells and matrix components. M2 macrophage-based immunotherapy has shown great potential in ameliorating LF through mechanisms involving the IL-10/STAT3 and TGF-β/SMAD signaling pathways, which are essential in suppressing the pro-inflammatory response and supporting tissue regeneration. However, significant challenges such as individual resistance to therapy and the potential for promoting fibrosis suggest that further development and research are needed to optimize the safety and efficacy of this therapy in clinical applications. This study provides comprehensive insights into the role of M2 macrophages in LF and explores their potential as an innovative therapeutic approach in treating LF.

Lipid nanocapsules (LNCs) are an emerging nanocarrier platform for cancer therapy as they can co-deliver multiple drugs, promote synergistic action, and provide targeted drug delivery. The phase inversion temperature (PIT) process is most used for LNC formulation, which has the advantage of process simplicity, thermodynamic stability, and the employment of non-toxic solvents without requiring high energy input. Surface functionalization with targeting ligands like folic acid and peptides increases tumor specificity and reduces off-target toxicity. The nanoscale dimensions and stealth properties of LNCs also take advantage of the enhanced permeability and retention (EPR) effect for enhanced tumor accumulation. LNCs provide precise cancer therapy through the ability to deliver drugs selectively, improve bioavailability, and reduce systemic toxicity. Their nanometer dimensions and surface characteristics allow for effective lymphatic uptake and passive tumor targeting. LNCs offer a potential platform for site-specific treatment, particularly in metastatic cancer with lymphatic involvement. LNCs have become multifunctional platforms with accurate, effective, and patient-friendly delivery systems for cancer treatments. This review critically examines new developments in LNC-based cancer therapies, focusing on optimization of physicochemical properties, improved targeting efficiency, and facilitation of combination therapy. In addition, it draws attention to the translational advantages of LNCs in alleviating systemic toxicity, enhancing pharmacokinetics, and overcoming multidrug resistance in cancer treatment.

Carbon-based nanoparticles possess distinctive chemical, physical, and biological characteristics that render them suitable for biomedical uses. This paper reviews recent advancements in carbon-based nanomaterial (CBs) synthesis methods, emphasizing the importance of careful modification for biomedical uses, particularly in the passivation of drugs and chemicals on their surfaces. This review article examines information from 2021-2024 regarding carbon-based nanoparticles and the biomedical uses of graphene, fullerene, carbon nanotubes, nano horns, nanodiamonds, quantum dots, and graphene oxide. Initially, a total of 5,612 relevant data points from various databases such as PubMed, ScienceDirect, and Web of Science were analyzed. After eliminating duplicates, nearly 3,905 data points were found to meet the inclusion criteria for this study, with the latest research indicating that 1,791 (45.8%) of these databases pertained to graphene. Carbon nanotubes accounted for approximately 928 (25.14%) databases, while graphene oxide represented around 837 (21.43%) databases, placing them in second and third positions, respectively. Nanohorns and fullerene were found in very minor quantities, specifically 34 (0.87%) and 06 (0.15%) in the database. CBNs, have the capacity to revolutionize biological medicine by improving regenerative treatments, personalized healthcare, and therapeutic outcomes. They are utilized in scaffolding, drug delivery, tissue engineering, bioimaging, and additional fields. Nonetheless, successful integration necessitates tackling scale and regulatory limitations.

Nanotechnology has revolutionized drug delivery, which offers innovative ways to maximize treatment efficacy while decreasing side effects. The lyotropic liquid crystalline nanoparticles (LLCNP), such as cubosomes and hexosomes, have gained substantial interest because of their distinctive molecular arrangements. Lipophilic, hydrophilic, and amphiphilic drugs can be encapsulated by cubosomes, making them versatile carriers in drug delivery systems. Different types of cubosomes, such as pH-responsive, temperature-responsive, light-responsive, enzyme-responsive, and multi-stimuli-responsive, have been discussed in this review detailing their preparation methods and therapeutic applications. Cubosomes possess high surface area, are biocompatible, and provide enhanced drug protection. However, formulation stability and scalability are the main challenges. This paper highlights the potential of cubosomes for targeted drug delivery, focusing on their ability to optimize bioavailability and controlled drug release.

Purpose: Spinal cord ischemia-reperfusion injury (SCII) is initiated following the occlusion of supporting blood vessels, leading to the loss of neurological function. Here, we aimed to study the regenerative properties of tourniquet-induced hindlimb ischemia exosomes (Exos) in SCII Wistar rats.

Methods: Exos were isolated from rats following tourniquet-induced hindlimb ischemia. CellTracker^TM CM-DiI-labeled Exos were injected systematically into SCII rats subjected to 60 min of abdominal aorta occlusion. The distribution of Exos was monitored using an immunofluorescence assay. Using histological examination and real-time PCR analysis, glial cell number, pyknotic and swollen neurons, and expression of apoptosis genes were studied. Oxidative stress was examined by measuring the SOD, GPx activity, MDA, and TAC levels. The neurological assessments were also performed 72 hours after the Exo injection.

Results: Data revealed cup-shaped spherical Exos with average size and zeta potential of 279.3 nm and 15.6 mV, respectively. The isolated particles were CD9+, CD63+, and CD81+, indicating the existence of typical Exo biomarkers. Histological analysis showed reduced gliosis, pyknotic, and swollen neurons compared to SCII rats after Exos injection (P<0.05). Data indicated the existence of Exos at the site of injury 24 hours after systemic injection. The injection of hypoxic Exos led to inhibition of apoptosis [Bax (~0.6-fold↓), and Bcl-2 (~3.97-fold↑)] and reduction of oxidative stress [MDA (~58%↓), SOD (~310%↑), GPx (~260%↑), and TAC (~300%↑)] compared to SCII rats (P<0.05). Neurological assessments revealed the reduction of withdrawal response and motor deficit index in SCII rats after injection of hypoxic Exos.

Conclusion: Hypoxic Exos are valid regenerative tools for the alleviation of spinal cord injury (SCI) following ischemic/reperfusion.

Purpose: The survival and progression of multiple myeloma (MM) cells rely heavily on supportive factors and cells within the MM microenvironment, notably macrophages. The PI3K signaling pathway plays a crucial role in both myeloma cells survival and macrophage polarity, making it a potential target for altering the MM microenvironment dynamics.

Methods: In this study, the impact of LY294002, a PI3K signaling pathway inhibitor, on the viability of U266 myeloma cells in mono-culture and MM patient-derived bone marrow mononuclear cells (BM-MNCs) in co-culture was investigated. Additionally, the effect of treatments on the M1/M2 macrophage ratio was assessed. Cultures were conducted in both two-dimensional (2D) matrix-free and fibrin gel-based three-dimensional (3D) environments.

Results: The treatment significantly increased U266 cell death in 2D cultures, dose-dependently compared to control. However, this effect was not replicated in 3D cultures. In both 2D and 3D cultures, the percentages of cells in G0/G1 phase were dose-dependently increased, compared to the untreated control. However, the percentages of cells in S and G2/M phases in both 2D and 3D cultures were dose-dependently decreased, compared to control. Treatment of BM-MNCs with LY294002 showed patient- and culture-dependent patterns of CD138⁺ myeloma cell death and M1/M2 macrophage ratio, contrasting the observed consistent responses in U266 mono-culture.

Conclusion: LY294002 affected U266 cell viability and cell cycle in a dose-dependent manner in 2D mono-cultures. However, its impact varied in 3D cultures. Treatment of MNCs showed varied responses based on individuals and culture conditions, underscoring the need for more similar tumor microenvironment (TME) recapitulation for drug screening.

Purpose: The central nervous system plays a crucial role in regulating food intake and energy expenditure to maintain energy homeostasis in the body. With rising obesity rates, alternative therapeutic strategies, including herbal-based interventions, are gaining attention. Elateriospermum tapos a plant that rich in flavonoids, has shown potential supporting weight reduction. This study aimed to evaluate the effects of E. tapos seed and shell supplementation on the hypothalamic feeding pathway in obese female rats and their offspring.

Methods: Thirty adult female Sprague-Dawley rats were used in this study. Obesity was induced in 24 rats via high-fat diet (HFD) for five weeks. Six rats were maintained on a normal diet as the control group (DCG). The obese rats were then divided into four groups: negative control (DNG, HFD only), positive control (DPG, HFD+orlistat 200 mg/kg), treatment 1 (DTX1, HFD+E. tapos seed 200 mg/kg), and treatment 2 (DTX2, HFD+E. tapos shell 200 mg/kg). Treatments were administered daily for six weeks before mating. On postnatal day 21 (PND21), blood and hypothalamus samples were collected from female rats and their female offspring. Plasma leptin levels were measured using ELISA, and expression of leptin receptor (Obr), proopiomelanocortin (POMC), and neuropeptide Y (NPY) in the hypothalamus was assessed by western blotting.

Results: DTX2 and offspring (OTX2) groups showed significantly (P<0.05) lower levels of leptin. Western blot results indicate Obr, POMC and NPY protein significantly (P<0.05) higher expression in DNG and ONG compared to the other groups.

Conclusion: In conclusion, the E. tapos shell significantly reduced maternal obesity in female offspring at PND21 compared to its seed.

The formation of urate crystals in the joints causes severe, erratic flare-ups of joint pain, swelling, and erythema in gout, one kind of inflammatory arthritis. The standard treatment currently available involves the use of nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, allopurinol, febuxostat, and corticosteroids which require lifelong management via oral or parenteral route. The challenge is the therapy adherence as the symptoms become better, patients may quit taking them, which could result in more episodes. In addition, conventional therapy regimes demonstrate insufficient effectiveness and minimal safety owing to these drug molecule's biopharmaceutical limitations, including inadequate chemical stability and an insufficient capacity to target the pathophysiological pathways. Therefore, developing an alternative drug carrier system that can meet the challenge is necessary. In recent years, the use of lipid-based nanocarriers has increased due to their properties of enhancing solubility and bioavailability of poor-soluble drugs, site-specific targeting, and sustained release. In this review, an attempt has been made to highlight the challenges of available therapies for gout along with its pathophysiology, the mechanism of lipoidal nanocarriers permeation via topical route, and recent advancements in gout therapy using lipid nanocarriers based on preclinical experiments. In addition, patents and clinical trials of lipid-based nanocarriers have also been discussed. Lipid-based nanocarriers present a potential strategy specifically for topical gout therapy as this can offer localized therapy with minimal systemic exposure. Even though lipid-based nanocarriers show promise for gout topical therapy, several issues that need to be looked after, including economically viable scalability and regulatory approvals.

Purpose: Combinatorial therapies are essential for treating advanced non-small cell lung cancer (NSCLC), particularly overcoming resistance to third-generation epidermal growth factor receptor (EGFR) like osimertinib (OSI). The Hippo signaling pathway, a critical regulator of cell proliferation, apoptosis, and tumor progression, is often dysregulated in NSCLC and contributes to chemo-resistance. This study investigated the potential of epigallocatechin-3-gallate (EGCG), a green tea polyphenol, to overcome OSI resistance by modulating the Hippo signaling pathway, specifically through inhibition of the YAP-1 (Yes-associated protein)-TEAD (TEA domain transcription factor)-CTGF (connective tissue growth factor) axis.

Methods: Using stepwise dose escalation, OSI-resistant (OR) clones were developed from EGFR T790M-mutated H460 cells. The anti-proliferative effects of EGCG were assessed, and synergistic interactions between OSI and EGCG were analysed using combination index (CI) values and the median effect concept. Mechanistic studies evaluated the co-treatment's impact on the Hippo signaling pathway, focusing on the inhibition of the YAP/TEAD/CTGF signaling axis.

Results: The OR clones exhibited significantly higher IC₅₀ values for OSI (25.12-28.48 µM) compared to parental H460 cells (2.74±0.2µM). EGCG treatment reduced cell viability in a concentration-dependent manner, with IC₅₀ values of 102.54±0.23μM for H460 cells and 225.79-237.36 µM for OR clones. Combination treatment of OSI and EGCG showed strong synergy at a 1:2 molar ratio, with CI values indicating synergism across a range from IC₅₀ to IC₉₅. Mechanistically, co-treatment suppressed the overexpression of the YAP/TEAD/CTGF axis, restoring Hippo pathway activity and reversing OSI resistance.

Conclusion: This study provides evidence that EGCG effectively targets the Hippo signaling pathway to overcome OSI resistance in NSCLC. The inclusion of EGCG in combinatorial therapies holds promise as a novel approach to combat therapeutic resistance and improve outcomes for patients with EGFR-mutated NSCLC.