Naunyn-Schmiedeberg's archives of pharmacology最新文献

Pseudomonas aeruginosa is a significant opportunistic pathogen in healthcare-associated infections. Its intrinsic resistance and ability to acquire resistance genes pose therapeutic challenges, particularly with the emergence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan-drug-resistant (PDR) strains. This study aimed to assess the prevalence, antimicrobial susceptibility, and metallo-β-lactamase (MBL) resistance genes (blaNDM, blaOXA48) in P. aeruginosa isolates from clinical samples over 14 months. A total of 4410 clinical samples were processed, yielding 241 non-duplicate P. aeruginosa isolates. Antimicrobial susceptibility testing (AST) identified MDR, XDR, and PDR isolates. Carbapenemase production was detected using the eCIM test, and blaNDM and blaOXA48 genes were identified via PCR. Among the 241 isolates, 128 (53.1%) were from female patients and 113 (46.9%) from males. The most common sample sources were pus 111 (46.1%), sputum 36 (14.9%), and urine 35 (14.5%). The highest prevalence was observed in the Medicine department (45, 18.7%) and TB & Chest (42, 17.4%). Inpatients contributed 126 (52.3%) isolates, while 115 (47.7%) were from outpatients. AST showed the highest sensitivity to piperacillin/tazobactam (70.2%), piperacillin (67.2%), and tobramycin (67.6%), while imipenem (47.7%) and ceftazidime (33.6%) exhibited the lowest sensitivity. MDR was identified in 88 (36.5%) isolates, XDR in 29 (12.0%), and PDR in 9 (3.7%). MDR isolates were most common in pus (33, 13.6%), while XDR and PDR were frequently found in bronchoalveolar lavage (6, 2.4%) and urine (3, 1.2%), respectively. Among 20 eCIM-positive isolates, all carried the blaNDM gene, and 17 (85.0%) harbored blaOXA48. Males accounted for 70.0% of blaNDM and 70.6% of blaOXA48 cases. The highest prevalence of blaNDM (35.0%) was in the 41-60 age group, while blaOXA48 was equally distributed between the 20-40 and 41-60 age groups (35.3% each). Sputum (25.0% blaNDM, 23.5% blaOXA48) and urine (20.0% each) were the most common specimen sources. This study demonstrates the presence of antimicrobial resistance in P. aeruginosa isolates, including MDR, XDR, and PDR strains. The detection of carbapenemase-producing isolates carrying blaNDM and blaOXA-48 genes emphasizes the importance of effective infection control measures, antimicrobial stewardship, and ongoing surveillance to monitor and manage resistance trends.

Enhancer of zeste homolog 2 (EZH2) serves as the enzymatic catalytic subunit of the polycomb repressive complex 2 (PRC2), which is capable of modifying the expression of downstream target genes through the trimethylation of Lys-27 on histone 3 (H3K27me3). In addition to its role in H3K27me3 modification, EZH2 may influence gene expression through alternative mechanisms. The involvement of EZH2 in cellular processes such as proliferation, apoptosis, and senescence has been established. Its significant contributions to the pathophysiology of cancer have garnered considerable attention. Consequently, pursuing EZH2 as a target for cancer therapy has become a prominent area of research, leading to the development of various EZH2 inhibitors. A growing number of efforts are being made to investigate the possible application of small interfering RNA (siRNA) in medical applications after the practical application of this technique to decrease gene expression in various research models. Pharmacological inhibition of EZH2 induces apoptosis in cancer cells, while siRNA-mediated downregulation of EZH2 suppresses cancer cell growth. The cell cycle is modulated by siRNA-induced suppression of EZH2, yet its precise cause is unclear. Furthermore, inadequate research has been done on the signaling route affecting cancer cells' cell cycle following EZH2 suppression with siRNA. Investigating the molecular basis of EZH2 siRNA's anticancer activity will aid in developing fresh methods for identifying, managing, and preventing cancer.

The study aims to clarify the therapeutic effect and underlying mechanisms of wogonin (WOG) against acute lung injury (ALI). Lipopolysaccharide-induced in vivo ALI mice model and in vitro RAW264.7 cell model were established. Lung histopathologic changes were assessed by H&E staining. Inflammatory cell infiltration in lung tissues and bronchoalveolar lavage fluid (BALF) was determined using H&E staining and flow cytometry. Inflammatory cytokines, reactive oxygen species (ROS), and antioxidant mediators were quantified. Potential targets of WOG were identified by bioinformatics and network pharmacology and further verified by Western blotting. WOG treatment (10 mg/kg, 20 mg/kg, 40 mg/kg) alleviated lung injury of ALI mice by ameliorating infiltration of inflammatory cells in lung tissues and BALF, inhibiting inflammatory cytokines, elevating antioxidant mediator levels, and attenuating lung edema. In RAW264.7 cells, WOG treatment (10 μM, 20 μM, 40 μM) also suppressed inflammatory response and oxidative stress. Peroxisome proliferator-activated receptor α (PPARα), protein kinase B (AKT), and nuclear factor erythroid 2-related factor 2 (NRF2) were predicted to be the targets of WOG against ALI by integrating the network pharmacology database and the GSE1871 dataset. Interestingly, WOG markedly promoted the expression and activation of PPARα and NRF2, while it inhibited the expression and phosphorylation of AKT both in vivo and in vitro. We provided a comprehensive insight into investigating the therapeutic effect of WOG against ALI via ameliorating inflammation and oxidative stress through regulating PPARα, AKT, and NRF2.

Nanoplastics (NPs) and pharmaceutical residues are environmental pollutants that can bioaccumulate in the food chain, thus increasing the risk of harmful effects due to concomitant exposure in both humans and animals. However, the impact of such co-exposure on target tissue toxicity and mechanism remains unclear. In this study, we aimed to investigate the effect of combined exposure to widespread polystyrene NP (Ps-NP) contaminant and a widely used antibiotic, gentamicin (GEN) on nephrotoxicity in adult rat. A total of 40 male Wistar rats were assigned into four groups; control group (C), GEN exposed-group (100 mg/kg/day, i.p.), Ps-NPs exposed-group (2.5 mg/kg/day, orally) and co-exposure-group (100 mg Ps-NPs/kg/day orally + 2.6 mg GEN/kg/day i.p.) for 15 consecutive days. Kidneys were excised at sacrifice on day 15 for the examination of: (i) renal function parameters and renal oxidative stress (oxidant and antioxidant markers); (ii) mRNA expression of key regulators of oxidative stress and inflammation response (NF-κB, TNF-α, IL-6 and NRF-2) and mitochondrial apoptosis pathway (Bax, Bcl-2, caspase-9 and caspase-3); (iii) histopathology. Levels of urea and creatinine in serum of NPs or/and GEN-treated rats were significantly increased with marked histopathological changes in the kidney. Additionally, the oxidative stress markers (MDA, PCO and NO) were increased with a decrease of antioxidant enzyme activities. Furthermore, Ps-NPs or/and GEN-treated rats exhibited increased expression of mRNA related to oxidative stress (NRF-2), inflammation (TNF-α, IL-6) and apoptosis (Bax, Bcl-2, caspase-9 and caspase-3). Our results revealed that co-exposure of adult rats to Ps-NPs and GEN had a synergic-adverse effect on the kidney function. This study highlights a new finding regarding the combined toxicity of NPs and pharmaceutical pollutants on kidney function, suggesting potential synergistic interaction between these substances.

The rise of bacterial resistance threatens the treatment of infections and is closely linked to the consumption of antibacterial drugs. The EU's 'One Health' approach aims to address this issue by requiring Member States to reduce consumption by 20% by 2030. This study analyses antibacterial consumption trends in the total care of European and non-European OECD countries, compares the community and hospital sector, uses ARIMA modelling and correlation analysis to provide long-term forecasts, assesses patterns of consumption and evaluates whether current trends are in line with the EU target. Projections to 2040 show increases for Spain (+36.6%; 30.7 DID), Greece (+31.4%; 37.5 DID), Czechia (+29.7%; 19.4 DID), Bulgaria (+28.3%; 33. 7 DID), Malta (+26.5%; 28.8 DID), Denmark (+25.7%; 19.8 DID), Croatia (+17.4%; 24.9 DID), Italy (+13.7%; 26.3 DID), Germany (+7.6%; 12.6 DID), Australia (+12.4%, 18.2 DID), Canada (+8.0%, 14.8 DID), Chile (+90.1%, 66.7 DID), Costa Rica (+0.4%, 19.7 DID), Japan (+22.7%, 12.8 DID) and Korea (+24.3%, 31.9 DID). Declines are forecast for Belgium (-0.5%; 20.5 DID), Romania (-0.6%; 27.2 DID), Cyprus (-1.0%; 33.2 DID), Luxembourg (-2.2%; 19.8 DID), Norway (-3.4%; 15.1 DID), Latvia (-5.5%; 14.1 DID), Lithuania (-6.4%; 17.5 DID), the Netherlands (-8.4%; 8. 8 DID), Portugal (-10.6%; 16.1 DID), Estonia (-12.1%; 11.2 DID), Slovakia (-16.1%; 16.8 DID), France (-17.7%; 19.8 DID), Hungary (-20.4%; 11.3 DID), Slovenia (-21.9%; 10.5 DID), Finland (-24.8%; 9.7 DID), Iceland (-24.9%; 13.9 DID), Sweden (-30.4%; 7.0 DID) and Israel (-70.7%, 4.7 DID). A significant positive correlation was found between current versus projected consumption levels and changes, highlighting stable prescribing patterns in many countries. Northern and Central Europe maintain low levels of consumption with decreasing trends, whereas Latin America, Eastern and Southern Europe show higher levels with projected increases. Western Europe and Asia shows a mixed pattern, with varying trends of increase and decrease. Alarmingly, only Sweden is projected to meet the 20% reduction target by 2030. Even in the best-case scenario, only a proportion of European countries are projected to meet the target, including Austria, Belgium, Croatia, Cyprus, Finland, France, Greece, Hungary, Italy, Iceland, Lithuania, Luxembourg, Latvia, Portugal, Slovenia, Slovakia and Spain, while 11 countries show no potential for a successful reduction. The reliability of the projections is considered good to moderate. Divergent trends between the community and hospital sectors further complicate the assessment of progress and underline the need for targeted interventions. Current trends suggest that the EU targets are unlikely to be met, highlighting the urgent need to strengthen stewardship programmes. Further research is needed to address other objectives of the 'One Health' approach, including the use of classes of antibacterial drugs and the development of bacterial resistance.

Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by progressive cognitive decline. Among various experimental models, scopolamine-induced amnesia is widely used to mimic memory dysfunction. Pioglitazone (PG), a thiazolidinedione derivative, has recently demonstrated neuroprotective potential in neurodegenerative conditions. This study aimed to evaluate the potential benefits of PG in mitigating scopolamine-induced cholinergic dysfunction and the associated memory and learning deficits in male Wistar rats. Fifty male Wistar rats were randomly assigned to five groups: (1) Control, (2) Scopolamine, and (3-5) three treatment groups receiving daily injections of PG at doses of 20, 40, or 60 mg/kg for three weeks in addition to scopolamine administration. Cognitive impairment was induced using scopolamine in all groups except the control. Cognitive function was assessed using the Morris water maze (MWM) and passive avoidance (PA) tests. Biochemical analyses were conducted to measure malondialdehyde (MDA), superoxide dismutase (SOD), total thiol levels, and acetylcholinesterase (AChE) activity in the cortex and hippocampus. Additionally, mRNA expression levels of inflammatory markers (TNF-α, IL-1β, IL-6) were evaluated in the hippocampus. Scopolamine induced cognitive impairment, increased MDA levels and AChE activity, decreased SOD activity and thiol levels, and elevated mRNA expression of inflammatory cytokines. PG significantly reversed these effects by enhancing performance in the MWM and PA tests, reducing MDA levels and AChE activity, and increasing SOD activity and total thiol concentration. Additionally, PG downregulated TNF-α, IL-1β, and IL-6 expression in brain tissue. The present behavioral and neurochemical findings suggest that PG ameliorates scopolamine-induced memory impairment by reducing oxidative stress and neuroinflammation while enhancing cholinergic function.

Glutathione S-transferase P1 (GSTP1) plays a significant role in cancer progression and chemotherapy resistance, with its overexpression diminishing chemotherapeutic efficacy across various tumor types. This study evaluates the inhibitory effects of 6-thio-2'-deoxyguanosine (6-thio-dG) and its dimeric form (6-thio-2'-dG-Dimer) on GSTP1. Enzyme inhibition assays with recombinant human GSTP1, kinetic analysis, molecular docking, and molecular dynamic simulations were employed. Enzymatic assays were performed in 0.1 M phosphate buffer (pH 6.5) at 30 °C, containing 1 mM EDTA, 1 mM GSH, and 1 mM CDNB. The compounds 6-thio-dG and its dimer were dissolved in 2.5% DMSO for the experiments. The IC₅₀ values indicated that the dimer exhibited a higher potency (IC₅₀: 0.339 μM) than the monomer (IC₅₀: 15.14 μM). Kinetic analysis revealed noncompetitive inhibition with glutathione (Ki: 12.26 μM) and mixed inhibition with CDNB (Ki: 11.41 μM) for the monomer, whereas the dimer showed mixed inhibition with glutathione (Ki: 0.972 μM) and competitive inhibition with CDNB (Ki: 0.723 μM). Molecular docking confirmed the higher binding affinity of the dimer (binding energy: - 7.9 kcal/mol, Ki: 1.595 μM) compared to the monomer (binding energy: - 6.2 kcal/mol, Ki: 28.21 μM). The dimer form of 6-thio-dG shows strong potential to enhance chemotherapeutic efficacy by effectively inhibiting GSTP1 and overcoming drug resistance. Its superior inhibitory properties make it a valuable candidate for targeted cancer therapies.

Gastric cancer (GC) is one of the most fatal types of solid neoplasms involving individuals globally due to its chemo-resistant and metastatic nature. 5-Fluorouracil (5-FU) resistance is a complex procedure concerning the prognosis of patients with GC treated with this agent. Metformin has recently been highlighted as a member of anti-diabetic agents for its potential anti-cancer influences. In this study, we investigated the chemo-sensitivity and cell death mechanisms by which metformin moderates its effects by targeting ABCB1 (MDR1), DKK1, WNT5A, and chemo-resistance proteins (P-gp and CD44) on 5-FU-resistant gastric cancer cells. MTT assay exhibited that the combined metformin treatment with 5-FU had a more cytotoxic effect than 5-FU alone. DAPI staining proved that metformin, 5-FU, and co-treatment of them exerted an apoptotic effect on GC cells. Immunocytochemistry illustrated that metformin and its combination with 5-fluorouracil reduced the protein expressions of CD44 and P-gp, compared to the control group. The outcomes of this research displayed that the co-treatment of metformin with 5-FU significantly diminished the expressions of ABCB1, WNT5A, and DKK1 in comparison to the control. The co-treatment of these agents also decreased the expression of WNT5A and ABCB1 compared to 5-FU alone group. Overall, this study's findings demonstrated that co-treating metformin with 5-FU could overcome chemoresistance in GC cells by reducing the expression of WNT5A, MDR1, P-gp, and CD44 levels.

Diabetic retinopathy (DR) represents a significant and serious complication associated with diabetes mellitus (DM), often resulting in considerable visual impairment or even blindness. The intricate pathological processes underlying DR complicate the effectiveness of current treatment modalities. Studies have highlighted the potential of natural products in the treatment of DR via several beneficial effects including anti-inflammatory, antioxidant, anti-neovascular, and anti-apoptotic properties. Flavonoids, saponins, saccharides, and alkaloids exhibited various beneficial effects in DR in in vivo and in vitro studies. However, the clinical utilization of these natural compounds is hindered by issues such as inadequate specificity, low bioavailability, and potential toxicity. Therefore, there is a pressing need for rigorous clinical studies to confirm the efficacy of natural products in preventing or mitigating the progression of DR.