Naunyn-Schmiedeberg's archives of pharmacology最新文献

Acetaminophen (APAP) is a widely used over-the-counter medication for pain and fever, but its overuse can lead to liver toxicity, hepatocyte apoptosis, and necrosis. Despite therapeutic advances in drug-induced hepatotoxicity, APAP-induced liver damage still poses a medical challenge. Recently, natural products have emerged as potential options for mitigating the effects of APAP hepatotoxicity. Curcumin, a natural compound with antioxidant and anti-inflammatory properties, has shown promising results in drug-induced hepatotoxicity. However, further investigations are needed to assess the clinical benefits of curcumin. In this review, we discuss the mechanisms of APAP-induced liver damage and the role of curcumin in preventing liver necrosis, oxidative stress, inflammation, and apoptosis caused by APAP overdose. Through its ability to scavenge free radicals, prevent lipid peroxidation, restore glutathione (GSH) levels, and inhibit apoptosis, curcumin has been found to significantly reduce oxidative stress and protect liver tissue from APAP toxicity in various studies. This paper also reviews the potential of novel nanoformulations to enhance the bioavailability of curcumin for improved therapeutic outcomes. Overall, the evidence suggests that curcumin could be a promising intervention to mitigate the harmful effects of APAP overdose and improve liver health. However, further research is required to assess the optimal dosing and timing of curcumin administration in APAP toxicity.

In addition to being able to fight cancer, betanin (BTN) has amazing natural antioxidant and peroxy-radical scavenging properties. 7,12-Dimethylbenz[a]anthracene (DMBA) can impair the activities of enzymes accountable for breaking down xenobiotics and can also cause lipid peroxidation. The study's goal was to find out if betanin could protect against these problems. We determined 100% tumor incidence, abnormal tumor volume, inclined tumor burden, and deduced body weight in DMBA-induced hamsters. We observed diminished lipid peroxidation and enzymatic and nonenzymatic antioxidant activities in DMBA-induced hamsters. The histological study showed that the hamster that receives only DMBA undergoes hyperkeratosis, epithelial hyperplasia, dysplasia, and well-differentiated oral squamous cell carcinoma (OSCC). The hamsters received three different dosages of BTN (10, 20, and 40 mg/kg b.w.) via intragastric intubation for 14 weeks, on alternate days of DMBA painting. The levels of antioxidants, xenobiotic enzymes, and lipid peroxidation (LPO) were significantly restored and inhibited tumor development in a dose-dependent manner. The molecular docking study found high levels of binding affinity in Bax (PDB ID: 2K7W), Caspase-3 (PDB ID: 4JJ8), Caspase-9 (PDB ID: 2AR9), PI3K (PDB ID: 5XGI), AKT (PDB ID: 6BUU), p53 (PDB ID: 1YCS), SMAD-2 (PDB ID: 1DEV), SMAD-4 (PDB ID: 1YGS), SMAD-7 (PDB ID: 2DJY), TGFβ-I (PDB ID: 1PY5), and TGFβ-II (PDB ID: 1M9Z). So, therefore, in vivo and in silico studies were providing prominent anticancer activity of betanin against DMBA-induced oral cancer.

Testicular dysfunction is a significant long-term side effect of the chemotherapeutic drug cisplatin (CDDP), primarily due to DNA damage and oxidative stress. Lisinopril (LSP), an angiotensin-converting enzyme (ACE) inhibitor commonly used for hypertension treatment, has a debated impact on reproductive function. This study investigates, for the first time, the ability of LSP to counteract CDDP-induced inflammation, oxidative stress, apoptosis, and steroidogenic disturbances in rat testis. In addition, LSP's effect on testicular Nrf2/Keap1/HO-1 and PPARγ signaling is examined. Rats were divided into Control, LSP, CDDP, and LSP + CDDP groups. Rats were treated with 10 mg/kg of LSP orally for 10 days, and blood and testis samples were collected after sacrifice for histopathological, biochemical, and genetic analysis. Our results revealed that LSP administration with CDDP effectively increased luteinizing, follicle-stimulating, and testosterone hormone levels (effect size f = 2.56, 2.32, and 3.02; respectively, and power = 1.00) and upregulated testicular expression of CYP11a1, HSD17B3, and StAR genes. LSP counteracted the histopathological aberrations induced by CDDP. The LSP + CDDP group also showed increased levels of reduced glutathione and superoxide dismutase (effect size f = 1.72 and power = 0.99) and decreased levels of malondialdehyde (effect size f = 3.07 and power = 1), interleukin-1β, tumor necrosis factor-α, interleukin-6, nuclear factor kappa B, cyclooxygenase-2, and cleaved caspase 3 (effect size f = 4.61 and power = 1). On the molecular level, the LSP + CDDP group showed a reduction in Keap1 protein level but an increase in Nrf2 (effect size f = 5.50 and power = 1), HO-1 (effect size f = 3.66 and power = 1), and PPARγ protein levels, compared to the CDDP group. In conclusion, LSP revealed prominent anti-oxidant, anti-apoptotic, and anti-inflammatory effects protecting against CDDP-induced testicular damage. Moreover, it preserved the steroidogenic process and testicular tissue characteristics. LSP modulated the expression of Nrf2/Keap1/HO-1 and PPARγ signaling. Therefore, our data presents LSP as a promising candidate for enhancing reproductive health in patients undergoing CDDP treatment.

Cholestasis is defined as an impairment in the flow of bile, resulting in the accumulation of its components. Despite ursodeoxycholic acid (UDCA) being the only FDA-approved drug for cholestasis, it has little value in treating or preventing cholestasis; hence, new medications are required to treat these illnesses. The farnesoid X receptor (FXR) maintains bile acid (BA) homeostasis. It exists as heterodimers with retinoid X receptor (RXR) and responds to ligands that bind to any one of the partners and are activated synergistically in the presence of both. The hepatoprotective effect of bexarotene (Bex) against cholestasis liver injury induced by α-naphthyl isothiocyanate (ANIT) was evaluated in male Wistar albino rats. Our study demonstrates that compared to the ANIT group, Bex improves liver function tests, liver histology, and considerably reduces inflammatory mediators. Additionally, antioxidant levels increased significantly. Besides that, Bex upregulates the gene expression of FXR, bile salt export pump, hepatocyte nuclear factor 1α, and small heterodimer partner. Moreover, it enhances antioxidative nuclear factor erythroid 2-related factor gene expression and the expression of the NAD(P)H quinone oxidoreductase 1, and heme-oxygenase 1 protein targets in the rats' livers, reinforcing its hepatoprotective potential. Furthermore, Bex increases protein expressions of FXR, The bile salt export pump, and sirtuin 1 levels in the rats' livers. This study demonstrates that Bex protects against ANIT-induced cholestasis. This protective strategy involves controlling BA metabolism, inhibiting inflammatory mediators, and reducing oxidative stress.

Breast cancer is the most common malignant tumor in women. Among its subtypes, triple-negative breast cancer (TNBC) is more aggressive and poses a serious threat to women's health. Rosmarinic acid (RA) is a natural polyphenolic compound known for its diverse pharmacological activities, with its antioxidant and anticancer properties being particularly notable. This study investigated the effects of RA on TNBC cell lines and explored its potential mechanisms. CCK-8 and colony formation assays were used to evaluate the potential inhibitory effects of RA on TNBC cells and to measure intracellular reactive oxygen species (ROS) levels. Flow cytometry was employed to analyze the cell cycle and apoptosis. RNA-seq analysis was performed to investigate the potential mechanisms of RA on MDA-MB-231 cells. RA inhibited the proliferation of TNBC cells in a concentration-dependent manner and reduced intracellular ROS levels. RA induced cell cycle arrest at the G1/G0 phase and promoted apoptosis by decreasing mitochondrial membrane potential. RNA-seq differential expression analysis, identified 1,929 differentially expressed genes, including 601 upregulated genes and 1,328 downregulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) showed that these differentially expressed genes were significantly enriched in pathways associated with ferroptosis, ABC transporters, and fatty acid metabolism. Additionally, RA significantly upregulated the expression of dynamin-related protein 1 (DRP1) in MDA-MB-231 cells, promoting mitochondrial fission, disrupting mitochondrial dynamics, and leading to dysfunction. Furthermore, RA increased the expression of intracellular ferroportin and heme oxygenase 1 (HMOX-1), resulting in elevated intracellular iron levels. The study suggests that RA inhibits the proliferation of TNBC cells through multiple mechanisms and may have potential therapeutic effects in the treatment of TNBC.

One of the most common gastrointestinal tumors is gastric cancer (GC), which has a high lethality and a poor prognosis. Recently, it was discovered that mature tRNAs, which are expressed differently in a variety of malignancies, give rise to a novel class of tRNA-derived small RNAs (tsRNAs). In this study, we investigated the role of short RNAs produced from tRNA in GC and possible therapeutic uses. edgeR was used to screen the differentially expressed tsRNAs from the TCGA database and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was used to verify the levels of tsRNAs in GC samples. tRF-24-6VR8K09LE9 downregulated in GC was confirmed by detecting serum samples from 114 patients with gastric cancer, 40 patients with gastritis, and 100 healthy controls. The chi-square test displayed that tRF-24-6VR8K09LE9 was highly related to differentiation grade (P = 0.029), T-stage (P = 0.036), lymph node status (P = 0.036), TNM staging (P < 0.0001), and neurological/vascular invasion (P = 0.033). The receiver operating characteristic (ROC) curve indicated that tRF-24-6VR8K09LE9 is more effective than the current diagnostic markers for GC. Furthermore, mechanistic studies verified that tRF-24-6VR8K09LE9 affected the malignant progression of GC through the PI3K/AKT signaling pathway. In conclusion, tRF-24-6VR8K09LE9 can be served as a molecular marker for early GC auxiliary diagnosis. Over-expression of tRF-24-6VR8K09LE9 inhibits the malignant progression of GC, which may provide a new strategy for the adjuvant treatment of GC.

Lymphoma, the most common form of blood cancer, affects primarily the intricate network of tissues and organs known as the lymphatic system. Globally, it ranks among the leading causes of cancer-related deaths. Although conventional therapies have led to significant advancements, they are accompanied by adverse side effects and present challenges in cases of multidrug resistance, refractory patients, and relapses. This highlights a pressing need for innovative treatment approaches. Extensive research on the anti-lymphoma properties of natural compounds has particularly focused on marine organisms as valuable sources for potential medicinal agents. Among these, anticancer peptides have garnered attention due to their multiple beneficial effects against cancer, coupled with reduced toxicity to normal cells. This review focuses on the molecular mechanisms underlying the anti-lymphoma effects of marine peptides, examining the diverse pathways through which these peptides impact physiological processes. Key effects include modulation of cell viability, induction of apoptosis, cell cycle arrest, antimitotic activity, immunotherapeutic properties, disruption of mitochondrial function and induction of oxidative stress, cancer cell membrane destruction, and interference with microtubule stability. The review also highlights the antibody-drug conjugates (ADCs) derived from marine peptides and their synergistic effects with other anti-lymphoma medications. This knowledge should inspire future study and development of these prospective therapeutic modalities and hasten the investigation and creation of novel lymphoma remedies derived from marine sources.

Arterial thrombosis is one of the main causes of mortality and mortality worldwide. Platelets are effectively targeted by antithrombotic strategies. However, current antiplatelet agents are often associated with a bleeding risk and single antiplatelet agent may not completely prevent thrombosis. Platelets, neutrophils, and neutrophil extracellular traps (NETs) have been found to play crucial synergistic roles in the pathological process of arterial thrombosis in recent years. Platelets play a key regulatory role in the formation of NETs, and NETs can enhance platelet aggregation and activation, further aggravating the process of arterial thrombosis. Targeting the interaction mechanisms of platelets and NETs may provide a promising approach to better prevent arterial thrombosis. This review highlights the current insight in the interaction of platelets and neutrophil-forming NETs and their mechanisms involved in the process of arterial thrombosis. Finally, we discuss the potential of interventions targeting platelets and NETs to treat arterial thrombosis.

Titanium dioxide is a prevalent food ingredient for human ingestion. We investigated the nephrotoxic effects of titanium dioxide in Wistar albino rats subjected to oral exposure for 14 days. The rats were categorized into four groups (n = 8): (1) control (saline solution), (2) exposure to titanium dioxide (30 mg/kg), (3) exposure to resveratrol (100 mg/kg), and (4) exposure to both titanium dioxide and resveratrol. The investigations revealed that the administration of titanium dioxide resulted in considerable histological abnormalities and a significant prevalence of apoptotic cells marked by caspase-3 in the titanium dioxide group, with a markedly elevated quantity and strong staining of cells reacting with 4-HN across the tissue in the kidney. Blood serum assessments revealed that BUN and creatinine levels were elevated in the titanium group relative to the other three groups, with a reduction in these levels observed in the group receiving both titanium and resveratrol (P < 0.05). The assessment of oxidative stress markers in kidney tissue revealed that GSH-Px and SOD activity considerably decreased in the titanium dioxide group relative to the other experimental groups. In contrast, MDA levels increased markedly (P < 0.05). The activities of GSH-Px and SOD were significantly elevated in the group receiving both titanium dioxide and resveratrol compared to the titanium dioxide-only group (P < 0.05). The analysis of inflammation markers TNF-α and IL-6 revealed a substantial rise in their levels in the titanium dioxide group compared to the other groups (P < 0.05).

Drinking water disinfection byproducts (DBPs) can adversely affect human health. Iodoacetic acid (IAA) is a DBP associated with most cytotoxic, genotoxic, and mutagenic disorders. However, its effects on the osteogenic differentiation of adipose-derived mesenchymal stem cells, ADMSCs, remain unknown. In this study, the cytotoxicity, cytokine response, phenotype, and osteogenic differentiation potential of the ADMSCs were evaluated in the presence and absence of IAA. It was revealed that IAA induces a toxic response at a concentration of 2 µM. Flow cytometry confirmed no significant alterations in ADMSCs' phenotype after treatment with 10 nM and 1 µM IAA for 48 h. IAA led to a decreased secretion of IL-8, a dose-dependent secretion of IL-10, and no significant change in the secretion of IL-6 compared to the control group. The osteogenic differentiation ability of ADMSCs in the presence of different concentrations and exposure times to IAA was evaluated by measurement of alkaline phosphatase activity, calcium content, Alizarin Red S, real-time PCR, and immunocytochemistry assays. The findings show that the osteogenic differentiation of ADMSCs decreased at higher concentrations of IAA and extended exposure time, confirming the potential disruption of the osteogenic differentiation of ADMSCs.