Naunyn-Schmiedeberg's archives of pharmacology最新文献

Cancer presents a global health challenge with rising incidence and mortality. Despite treatment advances in cancer therapy, radiotherapy and chemotherapy remained the most common treatments for all types of cancers. However, resistance phenotype in cancer cells leads to unsatisfactory results in the efficiency of therapeutic strategies. Therefore, researchers strive to propose effective solutions to overcome treatment failure, which requires a deep knowledge of treatment-resistant mechanisms. The progression and occurrence of tumors can be attributed to gene mutation. Over the past decade, the emergence of clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9) genome editing has revolutionized cancer research. This versatile technology enables cancer modeling, manipulation of specific DNA sequences, and genome-wide screening. CRISPR/Cas9 is an effective tool for identifying radio- and chemoresistance genes and offering potential adjunctive treatments to overcome tumor recurrence after chemo- and radiotherapy. This article aims to explain the potential of the CRISPR/Cas9 system in improving the effectiveness of chemo- and radiotherapy and ultimately overcoming treatment failure.

Dysregulated expression of ribosomal protein S3A (RPS3A) is associated with the tissue infiltration of immune-related cells in a variety of cancers. However, the role of RPS3A in immune cell infiltration in glioma remains unclear. This study aimed to explore the role of RPS3A in the glioma immune microenvironment. RPS3A expression was detected in tumor tissues from patients with glioma. U251 cells were transfected with RPS3A shRNA (sh-RPS3A) and overexpression vector (pcDNA-RPS3A) and then co-cultured with PMA-induced THP-1 cells. Cell viability, invasion, and apoptosis were detected by Edu staining, Transwell, and flow cytometry, respectively. The expression of tumor-associated macrophage (TAM) M1 and M2 markers was detected with RT-qPCR. Next, the interaction between RPS3A and E4 transcription factor 1 (E4F1) was verified by Co-IP analysis, and the binding of E4F1 to colony-stimulating factor 1 (CSF1) promoter was verified by ChIP analysis. Overexpression vectors of CSF1 and E4F1 were used to treat sh-RPS3A-transfected U251 cells for reversal experiments. Finally, U251 cells transfected with sh-RPS3A adenovirus vectors were subcutaneously injected into nude mice to construct a xenograft tumor model, and the growth and metastasis of glioma in vivo were monitored. RPS3A was significantly upregulated in glioma tissues. Overexpression of RPS3A promoted glioma cell proliferation and invasion and inhibited apoptosis. Moreover, overexpression of RPS3A promoted TAM proliferation, invasion, and M2 polarization. Silencing RPS3A had the opposite effect. Silencing RPS3A inhibited autophagy in U251 cells, whereas rapamycin, an activator of autophagy, reversed the inhibitory effect of RPS3A silencing on TAM M2 polarization. Meanwhile, RPS3A promoted its expression by interacting with E4F1, and E4F1 promoted CSF1 transcriptional activation. Overexpression of CSF1 promoted the proliferation and invasion of U251 cells and reversed the inhibitory effect of RPS3A silencing on TAM proliferation and invasion, but had no effect on TAM M2 polarization. The results of in vivo experiments showed that knockdown of RPS3A significantly inhibited glioma tumor growth and metastasis in vivo. This study revealed that RPS3A recruited TAMs by upregulating E4F1-mediated transcription activation of CSF1, and promoted the M2 polarization of TAMs through autophagy, promoting glioma cell malignant growth and tumor progression.

The increasing resistance of Plasmodium parasites to currently available antiplasmodial therapies poses a significant challenge in treating malaria. Since ancient times, plants have served as a primary source of novel pharmacologically active compounds for drug development. Therefore, this study aimed to explore the antiplasmodial properties of pentacyclic triterpenes isolated from Ziziphus mucronata bark, with an emphasis on their mechanism of action. Dichloromethane and ethyl acetate extracts of the stem bark were subjected to silica gel column chromatography, which led to the isolation of three known triterpenoids: betulinic acid, methyl betulinate, and lupeol. The compounds were then evaluated for antiplasmodial activity against Plasmodium falciparum NF54 strains using the Plasmodium lactate dehydrogenase (pLDH) assay. In silico evaluation of the isolated compounds was conducted through molecular docking and further validated with in vitro experiments against a purified protein target, Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT). Betulinic acid, methyl betulinate, and lupeol exhibited potent antiplasmodial activities with IC₅₀ values of 20, 10.11, and 7.56 µg/mL, respectively. Lupeol exhibited the highest binding energy of - 7.6 kcal/mol. Differential scanning fluorimetry revealed that lupeol decreases the T_m of PfHGXPRT, thus decreasing the protein's thermal stability. At high concentrations, lupeol also increased protein absorbance, indicating the detection of hydrophobic amino acids and protein unfolding. This study proves that Z. mucronata could serve as a reservoir of effective agents for treating malaria, while also scientifically validating its use in traditional medicine. However, further experimental studies are required to substantiate its relevant therapeutic effects.

We investigated the potential diuretic effectiveness of the selective arginine vasopressin 2 receptor antagonist tolvaptan in critically ill patients including cardiac and noncardiac populations. This was a single-center retrospective observational study. We analyzed the data of our hospital's critically ill adult patients (n = 473) including noncardiac as well as cardiac populations who had an ICU stay ≥ 4 days in 2019-2020 and who did not undergo renal transplantation or permanent renal replacement therapy before their ICU admission. Adjusting for several confounders (the patients' disease severity, comorbidities including cardiac disease, and diuretics used), we estimated the predictors for the patients whose daily urine volume had increased by up to twofold or more compared to the minimal value (the primary endpoint) by applying a multivariable logistic regression model. We also investigated tolvaptan's effect on time-course changes in the serum creatine (sCr) level (the secondary endpoint) by using a generalized estimating equation model. Tolvaptan use was significantly correlated with increased urine volume (odds ratio [OR] 1.86, 95%CI 1.13-3.06, p = 0.015) but was not significantly associated with time-course changes in the sCr level: beta estimator [95%CI], 0.07 [- 0.01 to 0.15], p = 0.08. Tolvaptan independently increased the urine volume, apparently without worsening the renal function in critically ill patients including cardiac and noncardiac populations.

This review aims to evaluate the efficacy of alpha-lipoic acid (ALA) in combating toxic elements, such as aluminum, arsenic, lead, mercury, and cadmium. The primary research question addressed is whether ALA can effectively mitigate the toxic effects of these metals through its antioxidant and chelating properties. Articles published between 1995 and 2024 were collected from Scopus, PubMed, Google Scholar, and Web of Science. Using Boolean (AND and OR), English-language publications were selected based on medical subject headings, titles, or abstracts that contained keywords related to ALA, metals, toxicity, antioxidants, and chelation. ALA supplementation significantly enhances cellular defense mechanisms and antioxidant enzyme activity. It effectively mitigates the adverse effects of aluminum exposure, counters arsenic toxicity in various cells and organs, and reduces cadmium toxicity, resulting in lower mortality rates among treated groups. Although ALA acts as a lead chelator, its efficacy is less than standard chelators. In the case of mercury, ALA shows beneficial effects in long-term therapy, although its capacity to reduce mercury concentration is limited. Overall, ALA emerges as a promising alternative for alleviating metal toxicity by enhancing antioxidant defenses, chelating toxic metals, and reversing their harmful effects. Further research in this area is encouraged to explore the full potential of ALA in mitigating the toxic effects of metals on biological systems.

Background: Silver nanoparticles (AgNPs) are increasingly known to have anticancer effects, but few studies have examined their adverse effects, so the underlying mechanisms are not yet fully understood. The current study investigated the critical influence of AgNPs on angiogenesis in 4T1 breast cancer-bearing mice.

Methods: The sub-lethal dose of AgNPs (0.25 mg/kg) was carried out. Female BALB/c mice (N = 35) were divided into 7 groups; normal control, cancer control, AgNPs control (one dose of (0.25 mg/kg) AgNPs), single dose AgNPs before cancer, single dose AgNPs after cancer, 5 doses AgNPs after cancer, and doxorubicin. 4T1 breast cancer cell induction was performed subcutaneously on the left flank. Intraperitoneal (IP) administration of AgNPs and doxorubicin was carried out for all studied groups.

Results: Weight gain was normal in all study groups except the doxorubicin-treated group. Administering AgNPs before cancer induction promotes tumorigenesis, raises MMP-2 and MMP-9 activity, and increases CD31 and Ki67 expression. The cancer control group experienced the same outcomes. On the other hand, depending on the administered doses, the injection of AgNPs after tumor induction resulted in a notable decrease in tumor volume. In the doxorubicin-treated group, similar results were observed, while a dose of AgNPs‌ before cancer induction lead to increasing tumor volume compared to the cancer control group. The differences of biochemical markers including LDH, ALP, AST, ALT, BUN, and Cr between different groups were not significant. Significant differences were seen among all studied groups except doxorubicin and single dose AgNPs before cancer groups for serum TAC levels.

Conclusions: It appears that AgNPs are considered a double-edged sword in the fight against cancer. AgNPs not only have anti-cancer effects on tumor size and angiogenesis, but they also might have cancer-stimulating roles. To confirm this conclusion, more detailed investigations are needed.

Nowadays, the cryopreservation process can produce reactive oxygen species (ROS), which cause damage to the motility, cell membrane, and DNA integrity of sperm. This study is aimed at evaluating the impact of carvacrol, as a powerful antioxidant, on sperm features and improving oxidative stress throughout the cryopreservation procedure. In this prospective study, semen samples from 25 patients with asthenozoospermia were separated into three groups: fresh, freezing, and freezing + carvacrol (a dose of 100 µM). The subsequent parameters were evaluated using standard methods in all three groups: sperm motility according to WHO criteria, sperm morphology using Papanicolaou staining, sperm viability with eosin-nigrosin staining, DNA integrity with acridine orange staining, levels of antioxidant enzymes (catalase, glutathione, and superoxide dismutase), total antioxidant capacity (TAC), and malondialdehyde (MDA) using ELISA. Also, DNA fragmentation was analyzed by the SDFA kit, and mitochondrial membrane potential (MMP) was assessed by rhodamine staining. Average sperm viability, motility, mitochondrial membrane potentiality, integrity of sperm membrane, and antioxidant enzyme levels are meaningfully reduced in the freezing group in contrast to the control group. The freezing group showed a meaningful rise in the mean MDA levels and DNA fragmentation compared to the control group. In the freezing group supplemented with carvacrol, a meaningful rise could be visible in mean percentages of viability, motility, and antioxidant enzyme levels, whereas mean levels of MDA and DNA fragmentation meaningfully declined in contrast to the freezing group. The results demonstrate that carvacrol, a potent antioxidant, offers significant protection against the loss generated by the freeze-thaw procedure, thereby improving sperm quality.

The occurrence and death rates of primary hepatocellular carcinoma (HCC) are increasing, and there remains a shortage of effective oral medications with minimal side effects. We aim to identify potential biomarkers and compounds from Radix Astragali (RA) and Pueraria Mirifica (PM) to treat liver cancer and improve prognosis. Differentially expressed genes (DEGs) associated with HCC were identified by bioinformatics analysis of three datasets, GSE112791, GSE101685, and GSE45114. Using public databases to predict the bioactive components and possible targets of RA and PM. Target crossover from Gene Expression Omnibus (GEO) and public databases were used to identify potential biomarkers for HCC. Subsequently, validation and prognostic value analyses were performed using the Gene Expression Profile Interaction Analysis (GEPIA) platform. The Cytoscape software created a network of "compound targets" to pinpoint compounds linked to the biomarkers. Molecular docking techniques were utilized to validate the connection between these compounds and the identified biomarkers. Ultimately, the HepG2 liver cancer cell line was chosen to assess the inhibitory effect of Hederagenin (HDG) and to confirm the expression of ADH1B through Western blot analysis. In this study, four key biomarkers (NR1I2, ADH1B, NQO1, GHR) were identified. Molecular docking showed that these four core targets could form stable conformations with the corresponding compounds. As the drug concentration decreases, the inhibitory effect on HepG2 diminishes, and the survival rate of HepG2 cells significantly declines following the administration of 100 µmol/L HDG. Compared to the control, the expression of ADH1B protein is significantly increased in HepG2 cells treated with 100 µmol/L HDG. The study identified four key biomarkers (ADH1B, GHR, NQO1, NR1I2) that have prognostic ability for HCC. This study provides biomarkers and potential targeted monomeric medicines for treating HCC.

Breast cancer remains one of the leading causes of cancer-related deaths among women worldwide. Genistein (Gen), a phytoestrogen soy isoflavone, has emerged as a promising agent in the prevention and treatment of breast cancer due to its ability to function as a natural selective estrogen receptor modulator (SERM). This review explores the multifaceted mechanisms through which Gen and its derivatives exert their anticancer effects, including modulation of the PI3K/Akt signaling pathway, regulation of apoptosis, inhibition of angiogenesis, and impacts on DNA methylation and enzyme functions. We discuss the dual roles of Gen in both enhancing and inhibiting estrogen receptor (ER)-dependent pathways., highlighting its complex interactions with ERα and ERβ. Furthermore, the review examines the synergistic effect of combining Gen with conventional chemotherapeutic agents such as doxorubicin, cisplatin, and selenium, as well as other natural compounds like lycopene. Clinical studies suggest that while isoflavones may not significantly influence breast cancer progression in general, the high consumption of soy isoflavones is associated with reduced recurrence rates in breast cancer survivors. Importantly, Gen's ability to modulate key signaling pathways and enhance the efficacy of existing treatments improves its potential as a valuable adjunct in breast cancer therapy. In conclusion, Gen and its derivatives offer a novel and promising approach for treatment of breast cancer. Continued research into their mechanisms of action and clinical applications will be essential in optimizing their therapeutic potential and translating these findings into effective clinical interventions.

This study evaluated the potential efficacy of eco-friendly biofabricated zinc oxide nanoparticles (GS-ZnONP) (10 mg/kg b.wt) to reduce the impacts of long-term oral acrylamide (ALD) exposure (20 mg/kg b.wt) on the blood cells, immune components, splenic oxidative status, and expression of CD20, CD3, CD4, CD8, TNF-α, caspase-3, microRNA-181a-5p, and microRNA-125-5p in rats in a 60-day experiment. The study findings revealed that GS-ZnONP significantly corrected the ALD-induced hematological alterations. Additionally, the ALD-induced increase in the serum C3, splenic ROS, CD4, CD8, and MDA and histological alterations were significantly repressed in the ALD + GS-ZnONP-treated rats. Instead, the depleted splenic antioxidants and Zn contents were markedly reestablished in the ALD + GS-ZnONP-treated group. Additionally, a significant upregulation of expression of splenic CD3, CD4, CD8, CD20, TNF-α, and caspase-3, but downregulation of microRNA-181a-5p and microRNA-125-5p was detected in the ALD-exposed group. Yet, the former deviations in the gene expressions were corrected in the ALD + GS-ZnONP-treated rats. Furthermore, GS-ZnONP treatment significantly minimized the increased caspase-3 and TNF-α immunoexpression in the splenic tissues of ALD-exposed rats. Conclusively, the study findings proved the efficacy of GS-ZnONP in rescuing ALD-induced disturbances in blood cell populations, immune function, splenic antioxidant status, and immune-related gene expression.