Naunyn-Schmiedeberg's archives of pharmacology最新文献

Paraquat (PQ) is a highly toxic herbicide that causes rapid and severe lung injury via oxidative stress and inflammatory activation. The present study aimed to investigate the protective effects of curcumin on PQ inhalation-induced lung injury in a mice model. Therefore, the intranasal route of PQ administration was selected, where mice were euthanized after 48 h of PQ exposure. Enhanced oxidative damage and the formation of neutrophil extracellular traps were released by activated neutrophils, along with elevated inflammatory mediators. Oxidative stress-induced lung injury was accompanied with increased DNA damage and reduced antioxidant defenses. Lung injury severity was higher with intranasal PQ in terms of inflammatory cell infiltration and early fibrotic changes, with collagen deposition around the bronchioles. Reduced E-cadherin, a marker of epithelial cells, and enhanced α-SMA were noted, showing enhanced epithelial to mesenchymal transition (EMT) in PQ-induced groups, which was reduced in intranasal curcumin treatment groups. Substantially reduced oxidative stress, NF-kB expression, and enhanced Nrf2 levels were noted, indicative of restored antioxidant enzymes and limited inflammatory responses, signifying a protective effect against PQ-induced lung injury. Immunofluorescence and protein expression analysis revealed fibrotic changes in the lungs, where enhanced alpha smooth muscle actin (α-SMA) and MMP9 expressions were reduced with intranasal curcumin treatment.

Sacubitril/valsartan is a combined neprilysin inhibitor/angiotensin II receptor blocker which simultaneously potentiates the beneficial effects of natriuretic peptides while blocking angiotensin II accumulation. Numerous studies suggest that sacubitril/valsartan has better renal protective effects compared to valsartan but the evidence remains inconsistent. This study compared renal and blood pressure (BP)-lowering effects of sacubitril/valsartan versus valsartan in rats with adenine-induced chronic kidney disease (CKD). This model replicates slow progression and structural and functional characteristics of human CKD. Male Wistar rats (n = 24) were divided into four groups and treated for 35 days as follows: group 1 served as control; group 2 received 0.25% adenine; group 3 received adenine plus sacubitril/valsartan; group 4 received adenine plus valsartan. Adenine significantly increased systolic BP. It also significantly increased the urinary albumin/creatinine ratio, N-acetyl-β-D-glucosaminidase (NAG), plasma urea, creatinine, uric acid, and neutrophil gelatinase-associated lipocalin (NGAL) while reducing creatinine clearance. Additionally, adenine significantly increased inflammatory markers, decreased antioxidant activity, and induced tubular necrosis, dilatation, and interstitial inflammation. Sacubitril/valsartan significantly reduced systolic BP, with greater effects than valsartan. Both treatments reversed adenine-induced alterations in urinary albumin/creatinine ratio, NAG, plasma urea, creatinine, NGAL, and creatinine clearance, with more pronounced improvements in urea, NAG, and creatinine clearance observed with valsartan. Furthermore, both treatments ameliorated inflammatory and antioxidant changes to a comparable extent. Both treatments showed histopathological improvements, but these were more marked with valsartan. To conclude, both sacubitril/valsartan and valsartan effectively mitigated adenine-induced CKD changes, with sacubitril/valsartan producing greater systolic BP reduction and valsartan showing more pronounced renoprotective effects.

Nowadays, the media make a major contribution to the medical education of the population. However, people who are not experts are hardly able to assess the accuracy of the situations depicted. To test the reliability of the statements made, this paper deals with the analysis of the accuracy of the pharmacological content in the television series Dr. House. The database is currently around 20 years old. The series was first broadcasted in the United States in 2004. The aim of this study was to check the quality of the pharmacological content. In addition, it analyzed the education by the TV series Dr. House in the field of pharmacological knowledge. Ten episodes containing 105 pharmacological items were analyzed. The analysis was illustrated with eleven comparable parameters of the items. This includes, for example, naming the drugs, evaluating the indication, assessing the therapy, and presenting the drug within the scene. In addition, the course of the series was analyzed for the first and eleventh episodes of each season. This resulted in 131 additional pharmacological contents. The study shows a high usage rate of international non-proprietary names (INN). The indications are often correctly stated, and an appropriate therapy is initiated. A particular and quite unusual feature of the series is that drugs are used as diagnostic tools to come to the correct diagnosis. Antibacterial drugs and psychotropic drugs are strongly presented. The analysis also highlights differences in the use of drugs between various genres in which drugs play an important role. Due to the cynical character traits of Dr. House, there were issues of concerns such as lack of patient information and use of dangerous/experimental therapies. There were also several medication errors. The way of drug administration often remained unclear and the mechanism of action was not explained. A comparison of the seasons throughout the series reveals a decline in the quality of naming, explanation, and accuracy of indications and presentation of pharmacological content. The lowest quality is evident in season 6, with a marked improvement in seasons 7 and 8. Despite some concerns regarding ethical issues, the TV series Dr. House makes a valuable contribution to introducing to the public a broad diversity of pharmacological topics.

Despite the rising burden of hypertension (HTN) across Africa, the rate of blood pressure (BP) control among hypertensive patients remains unacceptably low. One of the key contributors to this treatment gap is therapeutic inertia (TI) the failure to initiate or intensify therapy when clinically indicated. However, evidence on the magnitude and determinants of TI in Ethiopia remains scarce. Objective: To assess the prevalence of therapeutic inertia and identify associated factors among hypertensive patients attending the outpatient department of Wolaita Sodo University Comprehensive Specialized Hospital. A hospital-based cross-sectional study was conducted among 189 hypertensive patients from August to November 2023. Participants were selected through consecutive sampling. Data were collected via interviews with patients and physicians, along with a review of medical charts. Descriptive statistics (frequencies, percentages, means ± SD, and medians with interquartile ranges) were used to summarize patient characteristics. Bivariate and multivariable logistic regression analyses were performed to identify factors associated with TI. Adjusted odds ratios (AORs) with 95% confidence intervals (CIs) were reported. Of the 189 patients, 50.8% were male, with a mean age of 53.8 years. The prevalence of therapeutic inertia was 58.7% (95% CI: 52.3%-65.4%). Factors significantly associated with lower odds of TI included treatment with amlodipine (AOR = 0.137; 95% CI: 0.019-0.975), use of NPH insulin (AOR = 0.174; 95% CI: 0.036-0.833), and higher diastolic BP readings (AOR = 0.910; 95% CI: 0.839-0.986). In contrast, physician-reported reasons for not intensifying treatment such as "BP being close to the target value" (AOR = 6.074; 95% CI: 1.315-28.060) and "concerns about patient adherence" (AOR = 5.487; 95% CI: 1.061-28.362) were positively associated with TI. Therapeutic inertia was observed in nearly 6 out of 10 cases of uncontrolled hypertension in this setting, highlighting a significant gap in clinical decision-making. Addressing therapeutic inertia through improved adherence to hypertension treatment guidelines and strengthened physician education may help improve blood pressure control in similar settings. Stakeholders should implement systems that support timely treatment intensification and encourage adherence to evidence-based management strategies.

Angiogenesis, the production of new blood capillaries from pre-existing vasculature, is an important mechanism necessary for cancer progression and metastasis. This process may be regulated by the balance of pro-angiogenic and anti-angiogenic factors. The disruption of this balance leads to the induction of angiogenesis. Thus, there is a high necessity to identify these angiogenesis-related genes. In this study, we have used GeneCards database to obtain a list of angiogenesis-related genes followed by construction of protein-protein interaction (PPI) network using STRING database. Out of 37 angiogenesis-related genes, a single-gene cluster containing 27 genes was identified using MCODE analysis. The top ten hub genes were identified as FGF2, HIF1A, VEGFC, VEGFA, MMP9, THBS1, MMP2, KDR, IL6, and NOS, which were further analyzed. FunRich application was used to perform gene enrichment analysis and identify top interactors by constructing an interaction map. PPI map of each individual hub gene was constructed using search tool for the retrieval of interacting genes/proteins (STRING) database. The expression levels of each individual hub gene in HCC (liver hepatocellular carcinoma-LIHC dataset) and normal tissue were analyzed using the gene expression profiling interactive analysis 2 (GEPIA2) portal. The prognostic value of the hub genes was analyzed using Kaplan-Meier survival plot. The translational-level expression was analyzed using the IHC section images from the Human Protein Atlas (HPA) database. Thus, targeting these factors for therapy, diagnosis, or prognosis could be a key strategies in the field of oncology.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by relapsing mucosal inflammation. Medicine-food homologous (MFH) substances represent a promising source of therapeutic compounds. This study aimed to identify promising key MFH-derived bioactives for UC intervention. Transcriptomic datasets from GEO were analyzed to overlap differentially expressed genes (DEGs) between UC and controls with UC-related target genes from public disease databases, generating candidate genes for functional enrichment analysis. Bioactive compounds from 110 MFH substances were compiled via dual-database integration. Compound-protein interactions were predicted using GraphBAN, followed by drug-likeness and toxicity evaluations to identify candidate key compounds and their corresponding potential key genes. An MFH substance-compound-gene tripartite network was constructed. Molecular docking and molecular dynamics (MD) simulations were performed, and the expression of candidate key genes was assessed in an independent UC/control tissue dataset. We identified 266 candidate genes enriched in immune response, inflammation, and cell adhesion pathways. MOL008417 was prioritized as the candidate key compound, with CHRM3, CYP17A1, CYP3A5, MPO, and NOS1 prioritized as potential key genes. Network analysis highlighted Dangshen (Codonopsis root) as a key MFH substance. Docking suggested a feasible binding between MOL008417 and CHRM3 (- 5.3 kcal/mol), and MD simulations indicated complex stability. Gene expression analysis demonstrated significant CHRM3 upregulation and CYP3A5 downregulation in inflamed UC tissues compared with non-inflamed UC tissues and control samples. Our integrated computational workflow suggests that the MFH-derived compound MOL008417 may have multi-target potential for UC treatment through interactions with potential key genes. These predictive findings offer a mechanistic hypothesis for the development of MFH-based interventions and could inform the design of novel, UC therapeutics, pending future experimental validation.

Convallatoxin (CNT), a cardiac glycoside purified from a traditional Chinese herb Adonis amurensis Regel et Radde, has been reported to exert anti-inflammatory and antitumor effects. However, its therapeutic effect on rheumatoid arthritis (RA), a chronic inflammatory disorder, remains unexplored. Thus, this study aimed to investigate the impact of CNT on regulating key functions of fibroblast-like synoviocytes (FLS) from patients with RA, evaluate its therapeutic efficacy on collagen induced arthritis (CIA) mouse model and further elucidate the underlying molecular mechanisms. Cell viability, proliferation and apoptosis were assessed using CCK8, EdU and Annexin V-AF647/ PI assays, respectively. RA FLS migration and invasion were evaluated using wound healing assay, Transwell and Matrigel assays. mRNA and protein levels of proinflammatory cytokines and matrix metalloproteinases (MMPs) were analyzed by RT-qPCR and ELISA, respectively. Protein expression in RA FLS and synovial tissues was examined via Western blotting and immunohistochemistry. Furthermore, RNA sequencing was employed to identify the potential downstream targets of CNT. The in vivo therapeutic efficacy of CNT was investigated using a CIA mouse model. In vitro experiments demonstrated that CNT (7.5, 15 and 30 nM) dose dependently inhibited migration, invasion and expression of IL-6, CCL2, MMP-2 and MMP-13 of RA FLS, without affecting proliferation and apoptosis. In vivo study showed that CNT treatment (50ug/kg/d and 150ug/kg/d) attenuated synovial inflammation and joint destruction in mice with CIA. Mechanistically, IDH1 was identified as the potential downstream target of CNT in RA FLS. IDH1 expression was significantly elevated in RA FLS and RA synovial tissues. Moreover, both CNT treatment and IDH1 knockdown suppressed AKT and NF-κB p65 phosphorylation. CNT inhibits aggressive behavior and inflammatory response of RA FLS by inhibiting IDH1-mediated activation of the AKT and NF-κB signaling pathways. Our findings suggest that CNT may be a potential novel therapeutic agent for RA.

The association between respiratory drugs (RDs) and pediatric psychiatric adverse events (pAEs) remains insufficiently characterized. We aimed to characterize pAEs associated with RDs use in pediatric patients. RD-related pAE reports were retrieved from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. Analysis focused on pediatric patients aged 0 to 17 years. Disproportionality analysis was conducted using four algorithms, with a focus on anxiety disorders and symptoms, depressed mood disorders and disturbances, and suicidal and self-injurious behaviors. Descriptive and clinical outcome analyses were performed, along with subgroup analyses to explore potential risk differentials by age and gender. Among 6,994 cases of RD-related pAEs in pediatric patients, 16 drugs with positive signals were identified across all four algorithms, with antiallergics accounting for 75.00%. Montelukast was the most frequently reported drug (n = 6,168), primarily associated with anxiety (21.84%, reporting odds ratio [ROR] = 15.08), depression (15.86%, ROR = 12.90), and suicidal ideation (14.27%, ROR = 13.63). Promethazine demonstrated strong signals for intentional self-injury (62.99%, ROR = 127.36). The highest mortality rates were observed with hydroxyzine (50.94%) and caffeine (50.00%), while oxytetracycline (4/4, 100%) showed the highest proportions of life-threatening events. Montelukast generated signals in all age and gender groups, with the highest disproportionality observed in children aged 0 to 4 years. This study identifies statistical associations between RDs and pAEs in pediatric patients, particularly with montelukast and promethazine. The highest mortality rates were observed with hydroxyzine. These findings provide a foundation for further research but require confirmation through large-scale prospective studies.