Acta Pharmaceutica最新文献

Riolozatrione (RZ) is a diterpenoid compound isolated from a dichloromethane extract of the Jatropha dioica root. This compound has been shown to possess moderate antiherpetic activity in vitro. However, because of the poor solubility of this compound in aqueous vehicles, generating a stable formulation for potential use in the treatment of infection is challenging. The aim of this work was to optimize and physio-chemically characterize Eudragit^® L100-55-based polymeric nanoparticles (NPs) loaded with RZ (NPR) for in vitro antiherpetic application. The NPs formulation was initially optimized using the dichloromethane extract of J. dioica, the major component of which was RZ. The optimized NPR formulation was stable, with a size of 263 nm, polydispersity index < 0.2, the zeta potential of -37 mV, and RZ encapsulation efficiency of 89 %. The NPR showed sustained release of RZ for 48 h with release percentages of 95 and 97 % at neutral and slightly acidic pH, respectively. Regarding in vitro antiherpetic activity, the optimized NPR showed a selectivity index for HSV-1 of ≈16 and for HSV-2 of 13.

Cancer-associated fibroblasts (CAFs) play critical roles in the tumor microenvironment and exert tumor-promoting or tumor-retarding effects on cancer development. Astragaloside IV has been suggested to rescue the pathological impact of CAFs in gastric cancer. This study aimed to investigate the potential mechanism of astragaloside IV in the regulation of CAF pathological functions in gastric cancer development. Homeobox A6 (HOXA6), and Zinc Finger and BTB Domain Containing 12 (ZBTB12) are highly expressed in gastric CAFs compared with normal fibroblasts (NFs) based on the GSE62740 dataset. We found that astragaloside IV-stimulated CAFs suppressed cell growth, migration, and invasiveness of gastric cancer cells. HOXA6 and ZBTB12 were downregulated after astragaloside IV treatment in CAFs. Further analysis revealed that HOXA6 or ZBTB12 knockdown in CAFs also exerted inhibitory effects on the malignant phenotypes of gastric cells. Additionally, HOXA6 or ZBTB12 overexpression in CAFs enhanced gastric cancer cell malignancy, which was reversed after astragaloside IV treatment. Moreover, based on the hTFtarget database, ZBTB12 is a target gene that may be transcriptionally regulated by HOXA6. The binding between HOXA6 and ZBTB12 promoter in 293T cells and CAFs was further confirmed. HOXA6 silencing also induced the downregulation of ZBTB12 mRNA and protein in CAFs. Astragaloside IV was demonstrated to regulate the expression of ZBTB12 by mediating the transcriptional activity of HOXA6. Our findings shed light on the therapeutic value of astragaloside IV for gastric cancer.

Epinephrine is the first-line emergency drug for cardiac arrest and anaphylactic reactions but is reported to be associated with many challenges resulting in its under- or improper utilization. Therefore, in this meta-analysis, the efficacy and safety of epinephrine as a first-line cardiac emergency drug for both out-of-hospital and in-hospital patients was assessed. Pertinent articles were searched in central databases like PubMed, Scopus, and Web of Science, using appropriate keywords as per the PRISMA guidelines. Retrospective and prospective studies were included according to the predefined PICOS criteria. RevMan and MedCalc software were used and statistical parameters such as odds ratio and risk ratio were calculated. Twelve clinical trials with a total of 208,690 cardiac arrest patients from 2000 to 2022 were included, in accordance with the chosen inclusion criteria. In the present meta-analysis, a high odds ratio (OR) value of 3.67 (95 % CI 2.32-5.81) with a tau² value of 0.64, a chi² value of 12,446.86, df value of 11, I2 value of 100 %, Z-value 5.53, and a p-value < 0.00001 were reported. Similarly, the risk ratio of 1.89 (95 % CI 1.47-2.43) with a tau² value of 0.19, chi² value of 11,530.67, df value of 11, I2 value of 100 %, Z-value of 4.95, and p-value < 0.000001. The present meta-analysis strongly prefers epinephrine injection as the first cardiac emergency drug for both out-of-hospital and in-hospital patients during cardiac arrest.

Herein, thermal and non-thermal techniques were used to elucidate the putative physical and chemical interactions between poorly water-soluble Kaempferia methoxyflavones and PEG400/propylene glycol. Additionally, the biocompatibility of methoxyflavone-glycol solutions was evaluated using Caco-2 cells whereas the absorptive transport was investigated by measuring the apparent permeability coefficient (P _app) of the methoxyflavones and transepithelial electrical resistance (TEER) of the Caco-2 cell monolayer. Data from differential scanning calorimetry, Fourier-transform infrared (FTIR), and proton nuclear magnetic resonance (¹H NMR) spectroscopic analysis revealed physico-chemical compatibility between the three methoxyflavones and PEG400/propylene glycol. Furthermore, PEG400 and propylene glycol solutions of the methoxyflavones were shown to be compatible with Caco-2 cells at pharmacologically effective concentrations. In vitro transport studies across the Caco-2 cell monolayer revealed high P _app values of 24.07 × 10^-6 to 19.63 × 10^-6 cm s^-1 for PEG400 solutions of the methoxyflavones. The TEER values of the Caco-2 cell monolayers indicated that the increased drug transport was partly due to increased tight junction openings, but without compromising the epithelial barrier integrity. The good pharmaceutical and biocompatibility profiles, as well as improved transport of the methoxyflavones in PEG400 and propylene glycol solutions, are suggestive of the worthiness of this approach for further consideration pertaining to the development of these drugs into oral liquid dosage forms.

The advancements in proteomics have provided a better understanding of the functionality of apolipoproteins and lipoprotein-associated proteins, with the HDL lipoprotein fraction being the most studied. The focus of this study was to evaluate the HDL proteome in dyslipidemic subjects without an established cardiovascular disease, as well as to test whether rosuvastatin treatment alters the HDL proteome. Patients with primary hypercholesterolemia or mixed dyslipidemia were assigned to 20 mg/day rosuvastatin and blood samples were drawn at study entry and after 12 weeks of treatment. A label-free LC-MS/MS protein profiling was conducted, coupled with bioinformatics analysis. Sixty-nine HDL proteins were identified, belonging to four main biological function clusters: lipid transport and metabolism; platelet activation, degranulation, and aggregation, wound response and wound healing; immune response; inflammatory and acute phase response. Five HDL proteins showed statistically significant differences in the abundance (Anova ≤ 0.05), before and after rosuvastatin treatment. Platelet factor 4 variant (PF4V1), Pregnancy-specific beta-1-glycoprotein 2 (PSG2), Profilin-1 (PFN1) and Keratin type II cytoskeletal 2 epidermal (KRT2) showed decreased expressions, while Integrin alpha-IIb (ITGA2B) showed an increased expression after treatment with rosuvastatin. The ELISA validation of PFN1 segregated the subjects into responders and non-responders, as PFN1 levels after rosuvastatin were shown to mostly depend on the subjects' inflammatory phenotype. Findings from this study introduce novel insights into the HDL proteome and statin pleiotropism.

The constitutive proteasome and the immunoproteasome represent validated targets for pharmacological intervention in the context of various diseases, such as cancer, inflammation, and autoimmune diseases. The development of novel chemical scaffolds of non-peptidic nature, capable of inhibiting different catalytically active subunits of both isoforms, is a viable approach against these diseases. Such compounds are also useful as leads for the development of biochemical probes that enable the studies of the roles of both isoforms in various biological contexts. Here, we present a ligand-based computational design of (immuno)proteasome inhibitors, which resulted in the amino-substituted N-arylpiperidine-based compounds that can inhibit different subunits of the (immuno)proteasome in the low micromolar range. The compounds represent a useful starting point for further structure-activity relationship studies that will, hopefully, lead to non-peptidic compounds that could be used in pharmacological and biochemical studies of both proteasomes.

The current work was conducted to elucidate the pharmacological effect of pyrazole-conjugated imidazo[1,2-a]pyrazine derivatives against acute lung injury in rats in sepsis and their mechanism of action. Various pyrazole-conjugated imidazo[1,2-a]-pyrazine derivatives have been synthesized in a straightforward synthetic route. They exhibited a diverse range of inhibitory activity against NF-ĸB with IC ₅₀ ranging from 1 to 94 µmol L-1. Among them, compound 3h [(4-(4-((4-hydroxyphenyl)sulfonyl) phenyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl) (8-(methylamino)imidazo[1,2-a]pyrazin-2-yl)methanone] was identified as the most potent NF-κB inhibitor with IC ₅₀ of 1.02 µmol L^-1. None of the synthesized compounds was found cytotoxic to normal cell-line MCF-12A. The pharmacological activity of the most potent NF-ĸB inhibitor 3h was also investigated in cecal ligation and puncture (CLP)-induced sepsis injury of the lung in rats. Compound 3h was administered to rats after induc tion of lung sepsis, and various biochemical parameters were measured. Results suggested that compound 3h significantly reduced lung inflammation and membrane permeability, as evidenced by H&E staining of lung tissues. It substantially reduced the generation of pro-inflammatory cytokines (TNF-α, IL-1B, IL-6) and oxidative stress (MPO, MDA, SOD). It showed attenuation of NF-ĸB and apoptosis in Western blot and annexin--PI assay, resp. Compound 3h also reduced the production of bronchoalveolar lavage fluid from the lung and provided a protective effect against lung injury. Our study showed the pharmacological significance of pyrazole-conjugated imidazo[1,2-a] pyrazine derivative 3h against acute lung injury in sepsis rats.

Colorectal cancer (CRC) is one of the most common types of malignant cancers worldwide. Although molecularly targeted therapies have significantly improved treatment outcomes, most of these target inhibitors are resistant. Novel inhibitors as potential anticancer drug candidates are still needed to be discovered. Therefore, in the present study, we synthesized a novel 4-(1,3,4-thiadiazole-2-ylthio)pyrimidine derivative (compound 4) using fragment- and structure-based techniques and then investigated the anticancer effect and underlying mechanism of anti-CRC. The results revealed that compound 4 significantly inhibited HCT116 cell proliferation with IC ₅₀ values of 8.04 ± 0.94 µmol L^-1 after 48 h and 5.52 ± 0.42 µmol L^-1 after 72 h, respectively. Compound 4 also inhibited colony formation, migration, and invasion of HCT116 cells in a dose-dependent manner, as well as inducing cell apoptosis and arresting the cell cycle in the G2/M phase. In addition, compound 4 was able to inhibit the activation of the MEK/ERK signaling in HCT116 cells. And compound 4 yielded the same effects as the MEK inhibitor U0126 on cell apoptosis and MEK/ERK-related proteins. These findings suggested that compound 4 inhi bited cell proliferation and growth, and induced cell apoptosis, indicating its use as a novel and potent anticancer agent against CRC via the MEK/ERK signaling pathway.

Despite the importance of process parameters in the printing of solid dosage forms using fused deposition modelling (FDM) technology, the field is still poorly explored. A design of experiment study was conducted to understand the complete set of process parameters of a custom developed FDM 3D printer and their influence on tablet disintegration time. Nine settings in the Simplify 3D printing process design software were evaluated with further experimental investigation conducted on the influence of infill percentage, infill pattern, nozzle diameter, and layer height. The percentage of infill was identified as the most impactful parameter, as increasing it parabolically affected the increase of disintegration time. Furthermore, a larger nozzle diameter prolonged tablet disintegration, since thicker extruded strands are generated through wider nozzles during the printing process. Three infill patterns were selected for in-depth analysis, demonstrating the clear importance of the geometry of the internal structure to resist mechanical stress during the disintegration test. Lastly, layer height did not influence the disintegration time. A statistical model with accurate fit (R ² = 0.928) and predictability (Q ² = 0.847) was created. In addition, only the infill pattern and layer height influenced both the uniformity of mass and uniformity of the disintegration time, which demonstrates the robustness of the printing process.

In women, ovarian cancer is a common gynecological cancer associated with poor prognosis, reoccurrence and chemoresistance. Scoulerine, a benzylisoquinoline alkaloid, has been reported effective against several carcinomas. Thus, we investigated the impact of scoulerine on ovarian cancer cells (OVCAR3). Cell viability was assessed by MTT assay, migration was determined by Boyden Chamber assay, while the invasion was monitored by Boyden Chamber assay using the matrigel. The stemness properties of OVCAR3 cells were observed by tumorsphere assay. Epithelial to mesenchymal transition (EMT) and stemness-related protein markers were monitored by real-time PCR analysis and immunoblotting. Scoulerine inhibits the viability of OVCAR3 cells with the IC ₅₀ observed at 10 µmol L^-1 after 48 h treatment. Scoulerine inhibited the colony-forming ability, migration and invasiveness of OVCAR3 cells in a dose-dependent fashion. Scoulerine treatment also drastically reduced the spheroid-forming ability of OVCAR3 cells. The mesenchymal and stemness--related markers like N-cadherin, vimentin, CD-44, Oct-4, Sox-2 and Aldh1A1 were downregulated, whereas the epithelial markers like E-cadherin and CD-24 were upregulated in scoulerine-treated cells. The upstream PI3K/Akt/mTOR-axis was downregulated in scoulerine-treated cells. We concluded that scoulerine successfully perturbs the cancerous properties of OVCAR3 cells by targeting the PI3K/Akt/mTOR axis. In vivo studies revealed a substantial decrease in tumor mass and volume after scoulerine treatment. Furthermore, scoulerine treatment was found to decrease oxidative stress factors in ovarian cancer mice model. Scoulerine is a potential anticancer agent against ovarian cancer and can be considered as a lead molecule for this malignancy, provided further investigations are performed.