Frontiers in Pharmacology最新文献

Current treatments for gynecological cancers include surgery, radiotherapy, and chemotherapy. However, these treatments often have significant side effects. Phytochemicals, natural compounds derived from plants, offer promising anticancer properties. Coumarins, a class of benzopyrone compounds found in various plants like tonka beans, exhibit notable antitumor effects. These compounds induce cell apoptosis, target PI3K/Akt/mTOR signaling pathways, inhibit carbonic anhydrase, and disrupt microtubules. Additionally, they inhibit tumor multidrug resistance and angiogenesis and regulate reactive oxygen species. Specific coumarin derivatives, such as auraptene, praeruptorin, osthole, and scopoletin, show anti-invasive, anti-migratory, and antiproliferative activities by arresting the cell cycle and inducing apoptosis. They also inhibit metalloproteinases-2 and -9, reducing tumor cell migration, invasion, and metastasis. These compounds can sensitize tumor cells to radiotherapy and chemotherapy. Synthetic coumarin derivatives also demonstrate potent antitumor and anticancer activities with minimal side effects. Given their diverse mechanisms of action and minimal side effects, coumarin-class phytochemicals hold significant potential as therapeutic agents in gynecological cancers, potentially improving treatment outcomes and reducing side effects. This review will aid in the synthesis and development of novel coumarin-based drugs for these cancers.

Background: Kidney injuries often carry a grim prognosis, marked by fibrosis development, renal function loss, and macrophage involvement. Despite extensive research on macrophage polarization and its effects on other cells, like fibroblasts, limited attention has been paid to the influence of non-immune cells on macrophages. This study aims to address this gap by shedding light on the intricate dynamics and diversity of macrophages during renal injury and repair.

Methods: During the initial research phase, the complexity of intercellular communication in the context of kidney injury was revealed using a publicly available single-cell RNA sequencing library of the unilateral ureteral obstruction (UUO) model. Subsequently, we confirmed our findings using an independent dataset from a renal ischemia-reperfusion injury (IRI) model. We treated two different types of endothelial cells with TGF-β and co-cultured their supernatants with macrophages, establishing an endothelial cell and macrophage co-culture system. We also established a UUO and an IRI mouse model. Western blot analysis, flow cytometry, immunohistochemistry and immunofluorescence staining were used to validate our results at multiple levels.

Results: Our analysis revealed significant changes in the heterogeneity of macrophage subsets during both injury processes. Amyloid β precursor protein (APP)-CD74 axis mediated endothelial-macrophage intercellular communication plays a dominant role. In the in vitro co-culture system, TGF-β triggers endothelial APP expression, which subsequently enhances CD74 expression in macrophages. Flow cytometry corroborated these findings. Additionally, APP and CD74 expression were significantly increased in the UUO and IRI mouse models. Immunofluorescence techniques demonstrated the co-localization of F4/80 and CD74 in vivo.

Conclusion: Our study unravels a compelling molecular mechanism, elucidating how endothelium-mediated regulation shapes macrophage function during renal repair. The identified APP-CD74 signaling axis emerges as a promising target for optimizing renal recovery post-injury and preventing the progression of chronic kidney disease.

Non-coding RNAs (ncRNAs), which are usually considered not to encode proteins, are widely involved in important activities including signal transduction and cell proliferation. However, recent studies have shown that small peptides encoded by ncRNAs (SPENs) have important roles in the development of malignant tumors. Some SPENs participate in the regulation of skeleton reorganization, intercellular adhesion, signaling and other processes of tumor cells, with effects on the invasive and migratory abilities of the cells. Therefore, SPENs have potential applications as therapeutic targets and biomarkers of malignant tumors. Invasion and migration of malignant tumor cells are the main reasons for poor prognosis of cancer patients and represent the most challenging aspects of treatment of malignant tumors. Currently, the main treatments for tumors include surgery, radiotherapy, targeted drug therapy. Surgery, however, is reserved for early stages of cancer and carries risks and costs. Radiotherapy and targeted therapy have serious side effects. This review describes the mechanisms of SPENs and their roles in tumor invasion and migration, with the aim of providing new targets for tumor diagnosis and treatment.

Following the legalization of recreational Cannabis in Canada in 2018, the associated waste, including Cannabis roots, has significantly increased. Cannabis roots, comprising 30%-50% of the total plant, are often discarded despite their historical use in Ayurvedic medicine for treating inflammatory and infectious disorders. This study evaluates the phytochemical and therapeutic properties of Cannabis root extracts from a high tetrahydrocannabinolic acid, low cannabidiolic acid cultivar (variety Alien Gorilla Glue). We performed ultra high-performance liquid chromatography coupled with mass spectrometry (UPLC-QTOF-MS) to identify the chemical components of the Cannabis roots. Extracts using water, ethanol and acid-base solvents were tested for antioxidant activity through free radical scavenging, metal chelation, and lipoperoxidation inhibition assays. Mitochondrial membrane protection was assessed using flow cytometry with the MitoPerOx probe in THP-1 monocytic leukemia cells. Anti-inflammatory potential was evaluated by measuring interleukin-6 levels in lipopolysaccharide-stimulated THP-1 cells. Bactericidal/fungicidal efficacy against Escherichia coli, Staphylococcus aureus, and Candida albicans was determined using the p-iodonitrophenyltetrazolium assay. Additionally, we investigated the anticholinesterase activity of Cannabis root extracts, given the potential role of plant alkaloids in inhibiting cholinesterase, an enzyme targeted in Alzheimer's disease treatments. UPLC-QTOF-MS analysis suggested the presence of several phenolic compounds, cannabinoids, terpenoids, amino acids, and nitrogen-containing compounds. Our results indicated significant antioxidant, bactericidal, and anticholinesterase properties of Cannabis root extracts from both soil and hydroponic cultivation. Extracts showed strong antioxidant activity across multiple assays, protected mitochondrial membrane in THP-1 cells, and exhibited anti-inflammatory and bactericidal/fungicidal efficacy. Notably, soil-cultivated roots displayed superior anti-inflammatory effects. These findings demonstrate the remarkable antioxidant, anti-inflammatory, and anti-microbial activities of Cannabis roots, supporting their traditional uses and challenging their perception as mere waste. This study highlights the therapeutic potential of Cannabis roots extracts and suggests avenues for further research and application.

Background: The standardized extract of milk thistle seeds, known as silibinin, has been utilized in herbal medicine for over two centuries, with the aim of safeguarding the liver against the deleterious effects of various toxic substances. However, the role of silibinin in Particulate Matter (PM2.5)-induced intrahepatic triglyceride accumulation remains unclear. This study seeks to investigate the impact of silibinin on PM2.5-induced intrahepatic triglyceride accumulation and elucidate potential underlying mechanisms.

Methods: A model of intrahepatic triglyceride accumulation was established in male C57BL/6J mice through intratracheal instillation of PM2.5, followed by assessment of liver weight, body weight, liver index, and measurements of intrahepatic triglycerides and cholesterol after treatment with silibinin capsules. Hep G2 cells were exposed to PM2.5 suspension to create an intracellular triglyceride accumulation model, and after treatment with silibinin, cell viability, intracellular triglycerides and cholesterol, fluorescence staining for Nile Red (lipid droplets), and DCFH-DA (Reactive Oxygen Species, ROS), as well as proteomics, real-time PCR, and mitochondrial function assays, were performed to investigate the mechanisms involved in reducing triglycerides.

Results: PM2.5 exposure leads to triglyceride accumulation, increased ROS production, elevated expression of inflammatory factors, decreased expression of antioxidant factors, and increased expression of downstream genes of aryl hydrocarbon receptor. Silibinin can partially or fully reverse these factors, thereby protecting cells and animal livers from PM2.5-induced damage. In vitro studies show that silibinin exerts its protective effects by preserving oxidative phosphorylation of mitochondrial complexes I and II, particularly significantly enhancing the function of mitochondrial complex II. Succinate dehydrogenase (mitochondrial complex II) is a direct target of silibinin, but silibinin A and B exhibit different affinities for different subunits of complex II.

Conclusion: Silibinin improved the accumulation of intrahepatic triglycerides induced by PM2.5, and this was, at least in part, explained by an enhancement of oxidative phosphorylation in mitochondrial Complexes I and II.

Introduction: Semen Cuscutae is a traditional Chinese medicine (TCM) that tonifies the kidneys and prevents miscarriage. According to Chinese medicine theory, kidney deficiency is one of the main causes of recurrent spontaneous abortion (RSA). The previous studies showed that raw product of Semen Cuscutae (SP) and Semen Cuscutae processed with salt solution (YP) have ameliorative effects on RSA, and that YP is superior to SP. However, the active components of YP to ameliorate RSA remain unclear and require further studies. The objective of this study is to investigate the active components of YP in ameliorating RSA.

Methods: First, a rat model of RSA was established using hydroxyurea in combination with mifepristone. Aqueous decoction of YP was given by gavage to rats. Second, pregnant rats were sampled on days 5, 7, 9, 10 and 12 during the modelling period. The content of Hyperin (HY), astragalin (AS) and kaempferol-3-O-β-D-glucuronide (KA) in blood and liver, heart, spleen, lung and kidney tissues were detected by liquid chromatography-mass spectrometry (LC-MS). The pharmacodynamic indicators including progesterone (P), chorionic gonadotropin β (β-HCG), estradiol (E2), tumor necrosis factor-α (TFN-α), interleukin 4 (IL-4), and tryptophan (TRP) were measured by enzyme-linked immunosorbent assay (ELISA) Pearson's correlation analysis and grey relational analysis were used to establish the relationship between the pharmacodynamic indexes and chemical constituents.

Results: The pharmacokinetic results showed that the area under curve (AUC) value of KA was the largest. The tissue distribution results showed that astragalin was widely distributed in liver, heart, spleen, lung and kidney in the RSA model rats, while HY was detected only in the uterus, and KA was detected only in the kidney. The pearson correlationl analysis showed that KA was significantly and positively correlated with the contents of E2, P, β-HCG and TRP. Both AS and HY were significantly negatively correlated with the content of TNF-α, respectively.

Discussion: This study reveals the pharmacokinetics and tissue distribution of KA, AS and HY in rats with RSA. It was elucidated that all three were involved in the regulation of progesterone levels and immune function. It initially revealed the mechanism of action of YP in enhancing the improvement of RSA, and it provided a theoretical basis for the quality assessment of YP.

Background: Fufang Yinhua Jiedu (FFYH) granules are recommended for treating coronavirus pneumonia (COVID-19) in China. However, its anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity and clinical efficacy against COVID-19 remain to be confirmed.

Aims: Our study aimed to investigate the anti-SARS-CoV-2 effect and potential mechanism of FFYH.

Materials and methods: The activity of FFYH against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was evaluated via cell pathogenic effects, immunoblotting, immunofluorescence staining, and qRT-PCR. The potential mechanism of FFYH against SARS-CoV-2 was investigated by immunoblotting. One head-to-head randomized controlled trial was designed to evaluate the clinical efficacy of FFYH in mild COVID-19. Two hundred patients were randomly recruited to receive either FFYH or LHQW (Lianhua Qingwen) granules.

Results: The in vitro results indicated that FFYH effectively inhibited SARS-CoV-2 replication by suppressing CPE and decreasing viral RNA and protein expression. A time-of-drug-addition assay confirmed that FFYH mainly targeted the binding and replication stages of the SARS-CoV-2 life cycle. Mechanistic studies revealed that blocking SARS-CoV-2-triggered autophagy may be the primary mechanism by which FFYH protects against SARS-CoV-2 infection by regulating the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. Clinical results confirmed that FFYH effectively shortened the recovery time of clinical symptoms and viral nucleic acid negativity, improved abnormal hematology parameters, and controlled excessive cytokine responses in mild COVID-19 patients. Subgroup analysis revealed that FFYH improved the recovery time of clinical symptoms, improved hematological parameters, and controlled excessive cytokine storms to a greater extent in the mild COVID-19 male subgroup, abnormal hematology subgroup, and 32-42-year-old subgroup than in the corresponding LHQW subgroup (P < 0.05). No patients progressed to severe or critical cases.

Conclusion: Our results indicate that FFYH not only has good anti-viral activity against SARS-CoV-2 but also has significant efficacy against COVID-19, indicating that FFYH may be a novel complementary option for treating COVID-19.

Breast cancer (BC) has the second highest incidence among cancers and is the leading cause of death among women worldwide. The human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20%-30% of BC patients. The development of HER2-targeted drugs, including monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), has improved the operation rate and pathological remission rate and reduced the risk of postoperative recurrence for HER2-positive early-stage BC (HER2+ EBC) patients. This review systematically summarizes the mechanisms, resistance, therapeutic modalities and safety of HER2-targeted drugs and helps us further understand these drugs and their use in clinical practice for patients with HER2+ EBC.

Introduction: Premature ovarian insufficiency (POI) has affected about 3.7% of women of reproductive age and is a major factor contributing to infertility. Bushen Huoxue formula (BHF), a traditional Chinese medicine prescription, is clinically used to treat POI in China. This study aims to investigate the potential mechanisms of BHF in combating POI using corticosterone-induced rats and palmitic acid (PA)-challenged human ovarian granulosa cells (GCs).

Methods: Initially, ultra performance liquid chromatography tandem mass spectrometry was employed to analyze the components of BHF. The pharmacodynamic parameters evaluated included body weight, ovaries index, and serum hormone in rats. Follicle numbers were observed using H&E staining. Additionally, PCNA and TUNEL staining were used to assess GCs proliferation and apoptosis, respectively. Lipid accumulation and ROS levels were examined using Oil Red O and ROS staining. Protein expressions were determined by western blot. To probe mechanisms, cell viability and E₂ levels in BHF-treated, PA-stimulated GCs were determined using MTT and ELISA, respectively. Cell apoptosis and ROS levels were assessed using TUNEL and ROS staining. Proteins related to lipid metabolism and autophagy in PA-stimulated GCs were studied using agonists.

Results: Our results shown that BHF effectively normalized serum hormone levels, including follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), estradiol (E₂), and luteinizing hormone (LH). Concurrently, BHF also significantly reduced follicular atresia and promoted cell proliferation while inhibiting apoptosis in POI rats. Furthermore, BHF mitigated ovarian lipid accumulation by modulating lipid metabolism, which included reducing lipid synthesis (expression of peroxisome proliferator-activated receptor γ and CCAAT/enhancer binding protein α), increasing lipid catabolism (expression of adipose triglyceride lipase), and enhancing lipid oxidation (expression of carnitine palmitoyl transferase 1A). Mechanistically, the therapeutic effects of BHF on POI were linked with alleviation of lipid deposition-induced reactive oxygen species (ROS) accumulation and excessive autophagy, corroborating the results in PA-challenged GCs. After treatment with elesclomol (a ROS inducer) and rapamycin (an autophagy inducer) in GCs, the effects of BHF were almost counteracted under model conditions.

Conclusion: These findings suggest that BHF alleviates the symptoms of POI by altering lipid metabolism and reducing lipid accumulation-induced ROS and autophagy, offering evidence for BHF's efficacy in treating POI clinically.