Naunyn-Schmiedeberg's archives of pharmacology最新文献

Triple-negative breast cancer (TNBC) has become one of the most challenging cancers to date due to its great variability in biological features, high growth rate, and rare options for treatment. This review examines several innovative strategies for tailored treatment of TNBC, focusing mainly on the most recent developments and potential directions. The molecular landscape of TNBC is covered in the first section, which keeps the focus on transcriptome and genomic profiling while highlighting key molecular targets like mutations in the BRCA1/2, PIK3CA, androgen receptors (AR), epidermal growth factor receptors (EGFR), and immunological checkpoint molecules. This review also covers novel therapies that aim to block well-defined pathways, including immune checkpoint inhibitors (ICI), EGFR inhibitors, drugs that target AR, poly ADP ribose polymerase (PARP) inhibitors, and drugs that disrupt the PI3K/AKT/mTOR pathway. Additionally, it covers novel strategies focusing on combination therapy, targeting the DNA damage response pathway, and epigenetic modulators. Conclusively, it emphasizes perspectives and directions on topics such as personalized medicine, artificial intelligence (AI), predictive biomarkers, and treatment planning with the inclusion of machine learning (ML).

MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in regulating gene expression by binding to target messenger RNAs (mRNAs), leading to their degradation or translational repression. Over the past few years, significant progress has been made in understanding the role of miRNAs in various biological processes, including viral infections such as human immunodeficiency virus (HIV). HIV infection is characterized by a complex interaction between the virus and the host's immune system, where miRNAs have emerged as key regulators. MiRNAs influence HIV infection by modulating both viral replication and the host immune response. Researchers have identified several host miRNAs that suppress or enhance HIV replication by targeting viral genes or host factors essential for the virus life cycle. Conversely, HIV has evolved mechanisms to manipulate the host's miRNA machinery to its advantage. The virus can downregulate or upregulate specific host miRNAs to create a more favorable environment for replication and persistence. Moreover, HIV infection can alter the expression profiles of various miRNAs in infected cells, which can contribute to immune dysregulation and disease progression. Dysregulation of miRNAs is associated with HIV-associated complications, such as neurocognitive disorders and cardiovascular diseases. Understanding the specific roles of miRNAs in HIV pathogenesis could lead to the development of novel therapeutic strategies, such as miRNA-based therapies, to control HIV infection and its associated comorbidities. Understanding the role of miRNAs in HIV infection reveals their significant influence on the complex interactions between the virus and the host, impacting the course of infection and disease progression. Also, continued research in miRNA-mediated mechanisms in HIV holds the potential for uncovering new insights into viral pathogenesis and developing innovative therapeutic approaches.

Magnesium is the fourth most abundant cation in the human organism. As a key-player in many enzymatic reactions, magnesium homeostasis disbalance can cause severe disorders. In the early 2000s, the transient receptor potential melastatin channel 6 (TRPM6) was identified as a critical protein in renal Mg²⁺-reabsorption in the distal convoluted tubule (DCT). As the key-interface responsible for salt/water adaptation to environmental changes, the kidney is a highly dynamic system. Therefore, renal TRPM6 expression and Mg²⁺-reabsorption might not be restricted to the DCT, as previously indicated. To address this, protein targeting is mandatory since genomic detection is insufficient to conclude on functional expression. For this purpose, we used a polyclonal TRPM6 antibody from an established manufacturer and detected immunostaining in murine proximal and distal tubules. As a matter of fact, the specificity of most commercially available TRPM6 antibodies is insufficiently validated which relies on the lack of constitutive trpm6 knockouts. Therefore, conditional trpm6 knockout mice were used for control experiments. Similar signals were observed in the knockout tissue when compared to wildtype using the TRPM6 antibody. Overlaps with TRPM7 epitopes or other peptides are conceivable. Thus, TRPM6 immunohistochemistry and immunofluorescence results are difficult to interpret, and the spectrum of renal TRPM6 expression is not yet elucidated.

Age-related eye diseases (AREDs), such as dry eye disease (DED), age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR), are significant worldwide health concerns due to their rising prevalence and debilitating effects. Despite substantial research on the pathobiology of AREDs, the impact of immune-related alterations caused by aging is still not well understood. Tissue-resident cells and invading immune cells in the eye control innate responses in the event of damage or infection. However, as cells age, they gradually lose their ability to perform their protective duties and develop abnormal characteristics. Therefore, the disrupted regulation of immune responses in the eyes of older individuals enhances their vulnerability to and the intensity of eye disorders. Cytokines, immune system components, have a role in developing AREDs by contributing to inflammation. This paper examines the deficiencies in the pathogenic and therapeutic aspects of pro-inflammatory cytokines in AREDs that require further investigation in future studies.

Acute kidney injury (AKI) can occur primarily by exposing kidneys to uranium (U). Insulin-like growth factor binding protein 7 (IGFBP7) can regulate sepsis-induced AKI and epithelial-mesenchymal transition through ERK1/2 signaling. In vitro, the IGFBP7's role and mechanism of action in uranium-induced NRK-52E cells, however, remains unknown. To evaluate the effect of U exposure on kidneys, rat kidney proximal cell line NRK-52E was treated with different concentrations (200, 400, and 800 µmol/L) of it. Subsequently, three siRNAs targeting IGFBP7 were transfected with the HiPerFect reagent. The role of the JNK/ERK signaling pathway in uranium-induced kidney cytotoxicity was examined by a series of cell function experiments, including CCK-8 assay, TUNEL staining, RT-qPCR, Western blot, and flow cytometry analysis. Uranium inhibited NRK-52E cell viability and enhanced IGFBP7 expression in a dose-dependent manner. Silencing of IGFBP7 promoted cell cycle progression and inhibited cell apoptosis of uranium-treated cells. Mechanistically, silencing of IGFBP7 inhibited the uranium-activated JNK/ERK signaling pathway. The ERK1/2 signaling inhibitor PD98059 suppressed the IGFBP7-activated JNK/ERK signaling pathway. Furthermore, knockdown of IGFBP7 exerted a similar effect with PD98059 on uranium-induced NRK-52E cell cycle arrest and apoptosis. Silencing IGFBP7 inhibited the JNK/ERK signaling pathway to attenuate uranium-induced cytotoxicity and necrosis of NRK-52E cells.

Acetylsalicylic acid (ASA), commonly known as aspirin, is an organic compound with the formula C₉H₈O₄ obtained from the natural compound salicylic acid, recognized for its analgesic, anti-inflammatory, antipyretic, and anticancer properties. Its role in medicine and plant biology is well-established, but its emerging potential in cancer treatment has garnered increased attention. This review aims to provide a comprehensive overview of the therapeutic applications of ASA as an anticancer agent, focusing on its mechanisms, effectiveness, and role as an adjuvant therapy, preventive compound, and radioprotective agent. Recent research papers, including mechanistic studies, preclinical investigations, and clinical trials related to the effects of ASA on various cancer types, were reviewed. The review places particular emphasis on the enhancement of traditional chemotherapy drugs by ASA and considers toxicological aspects. The analysis of recent studies highlights the potential of ASA to improve the effectiveness of chemotherapy and its role in cancer inhibition through specific molecular pathways. Mechanistic insights suggest that ASA may influence cellular processes that contribute to cancer growth suppression and increased sensitivity to conventional treatments. ASA exhibits promising potential as an adjunct therapy in cancer treatment, with evidence supporting its benefits in improving therapeutic outcomes when used alongside conventional chemotherapy. Further studies are needed to clarify its mechanisms and ensure its safe and effective application in clinical settings.

Alantolactone (ALA), a sesquiterpene lactone compound obtained from Inula helenium root, is known to have anticancer activity in many types of cancer. Paclitaxel (PAX) is an effective first-line chemotherapeutic drug and is widely used in the treatment of lung cancer. The in vitro anticancer efficacy of combined treatment of ALA with PAX was investigated in the A549 human lung cancer cell line. The results show that ALA potentiated the effect of PAX-induced growth restriction and apoptosis in A549 cells. The combined administration more effectively decreased the Bcl-2 expression and increased Bax gene expression in cells compared to ALA or PAX alone. Also, co-treatment of ALA and PAX caused apoptotic nuclear formations. Additionally, coadministration increased the caspase-3 and caspase-9 levels more than PAX or ALA alone. The increase in NF-κB gene expression levels suggests that an NF-κB-independent apoptotic trigger mechanism operates in cells. Together, the present in vitro findings suggest that ALA may contribute as a potential therapeutic strategy in the treatment of lung cancer.

This study investigated the effect of myo-inositol on apoptosis-related genes expression in cumulus cells of polycystic ovary syndrome (PCOS) patients undergoing intracytoplasmic sperm injection (ICSI), and its relationship with the of quality oocyte and embryo. In the study of placebo-controlled clinical trial, sixty infertile women with PCOS undergoing ICSI were randomly assigned to two groups: 1) the placebo (PLA) group obtained a placebo involving 1 mg of folic acid twice a daily for 6 weeks. 2) The MYO group obtained 2000 mg Myo-inositol + 1 mg folic acid twice a daily for the same duration, beginning concurrently with the ICSI cycle. Real-time polymerase chain reaction (real-time PCR) was used to assess the expression of Survivin, Bcl-2, Caspase-3, Caspase-7, and TNF-α in cumulus cells. Although the levels of Survivin and Bcl-2 expression were significantly increased in the MYO group compared to the placebo, levels of Caspase-3, Caspase-7, and TNF-α expression were significantly lower. A strong correlation was found between the expression levels of these genes and embryos with good quality. These findings suggest that Myo-inositol administration in PCOS patients undergoing ICSI may improve of apoptosis-related genes expression (Survivin, Bcl-2, Caspase-3, Caspase-7, and TNF-α) in cumulus cells. Nevertheless, additional expected surveys are essential to verify these results and create their clinical applicability. (Registration details: Date: 2022.10.19, Registry: https://irct.behdasht.gov.ir/trial/66005 , and Trial registration: IRCT202220921056008N1).

Recent studies have demonstrated that antioxidants like lutein considerably lower the prevalence of age-related macular degeneration (AMD), which has been connected to blindness in numerous older adults. By halting oxidation, antioxidants reduce the damage that free radicals do. However, the short residence time, low stability, and poor solubility of lutein limit their ocular bioavailability following topical application. This study aimed to develop and characterize a micelle nanogel formulation for the ocular delivery of lutein. The micelle nanogel delivery system suggests a novel therapeutic strategy for administering ocular drugs due to its longer retention on the ocular surface, improved corneal permeability, and lowering the need for frequent administration. We developed a nanosized lutein micelle and incorporated it into a gel base to increase the solubility and ocular permeability. The micelle nanoformulation underwent evaluations like mean particle size, entrapment efficiency (EE), zeta potential, in vitro release investigations, ex vivo permeation tests, cell line studies, and Hen's egg test chorioallantoic membrane (HET-CAM). This nanoformulation exhibited favorable particle size (205.2 ± 15.36 nm), PDI (0.3 ± 0.20), and zeta potential (- 14.2 to + 11.3 mV) with 84.5 ± 1.75% entrapment efficiency. Fourier transform infrared spectroscopy confirmed compatibility, while TEM showed nanoscale spherical structures. F4 demonstrated effective corneal penetration, enhanced fibroblast viability, antioxidant activity (IC₅₀: 55.11 µg/mL), and mild ocular irritancy and better wound healing properties. Based on the results, the formulations were proven safe and efficient for drug delivery to the eyes.

Cancer is a critical health issue that remains a predominant cause of mortality globally. It is a complex disease that may effectively regulate many signaling pathways and modify the metabolism of the body to evade the immune system. Understanding neoplastic metabolic reprogramming as a hallmark of cancer has facilitated the creation of innovative metabolism-targeted treatment strategies. Various signaling cascades, such as the PI3K/Akt/mTOR, ERK, JAK/STAT, MAPK/p38, NF-κB/Nrf2, and apoptotic pathways, are commonly involved in this process. It is now widely recognized that an inadequate response and the subsequent development of resistance are frequently caused by the highly selective blockage of these pathways in tumor cells. Consequently, to enhance the overall efficacy of anticancer agents, it is crucial to employ multi-target compounds that can concurrently inhibit multiple vital processes within tumor cells. The utilization of plant-derived bioactive compounds for this purpose is particularly promising, owing to their varied structures and numerous targets. Among these bioactive compounds, terpenoids have exhibited significant anticancer efficacy by targeting various altered signaling pathways. Thus, this review examines the terpenoid class of plant-derived compounds exhibiting potential anticancer activity, including their impact on metabolism and interconnected deregulated signaling pathways in human tumor cells. Accordingly, current research will help in the rational design and critical evaluation of innovative anticancer therapeutics utilizing plant-derived terpenoids for the modulation of cross-linked signaling pathways of cancer metabolism.