Antitumor Research Articles

Real-world pharmacovigilance study of drug-induced autoimmune hepatitis from the FAERS database

This study aims to identify and evaluate the most common drugs associated with the risks of autoimmune hepatitis (AIH) using the FDA Adverse Event Reporting System (FAERS) database. Adverse drug events (ADEs) associated with drug-induced AIH (DI-AIH) were retrieved from the FAERS database (January 2004–June 2024). Disproportionality analysis was performed to identify drugs significantly linked to DI-AIH, and time-to-onset (TTO) analyses were conducted to evaluate the timing and risk profiles of DI-AIH adverse reactions. Our study identified 2,511 ADEs linked to autoimmune hepatitis. Disproportionality analysis identified 22 drugs significantly associated with AIH risk, including 4 antibiotics, 3 antivirals, 4 cardiovascular drugs, 5 antitumor agents, 2 immunomodulators, 2 nonsteroidal anti-inflammatory drugs, and 1 drug each from the respiratory and nervous system categories. The highest DI-AIH risks were observed with minocycline (ROR = 53.97), nitrofurantoin (ROR = 57.02), and doxycycline (ROR = 16.12). Antitumor drugs had the shortest median TTO (77.00 days), whereas cardiovascular drugs exhibited the longest (668.30 days). Through a comprehensive analysis of the FAERS database, our study identified drugs strongly associated with AIH. Preventing DI-AIH requires careful drug selection and monitoring. This study provides evidence-based insights into implicated drugs, aiming to optimize clinical management and mitigate risks.

Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m6A protein synthesis routes

Plitidepsin is an antitumoral compound safe for treating COVID-19 that targets the translation elongation factor eEF1A. Here we detect that plitidepsin decreases de novo cap-dependent translation of SARS-CoV-2 and non-viral RNAs but affects less than 13% of the host proteome, thus preserving cellular viability. In response to plitidepsin, cells upregulate EIF2AK3 and proteins that reduce translation, but also proteins that support proteostasis via ribosome synthesis and cap-independent translation by eIF4G2 and IGF2BP2. While plitidepsin inhibits cap- or internal ribosome entry sites (IRES)-mediated translation, its impact on N6-methyladenosine (m6A) translation is limited. In agreement, plitidepsin blocks members of Coronaviridae, Flaviviridae, Pneumoviridae and Herpesviridae families. Yet, it fails to inhibit retroviruses that exploit m6A synthesis routes and are blocked by drugs targeting IGF2BP2 m6A reader. By deciphering the molecular fingerprint of cells treated with therapies targeting translation we identify a rational approach to select broad-spectrum antivirals with potential to counteract future pandemic viruses.

New Polyketides From Trichoderma harzianum and Their Antifungal Activity.

Chemical investigation of the marine-derived fungus Trichoderma harzianum ZN-4 led to the isolation and identification of seven new secondary metabolites, harzianolides K-Q (1-7). The complete structures of seven new compounds were determined by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopic analyses coupled with electronic circular dichroism calculations. The seven isolates were inactive as antibacterial and antitumor agents. However, harzianolides K (1), L (2), M (3) and O (5) exhibited weak to moderate anti-Pestalotiopsis theae activity with minimum inhibitory concentration values at the range of 25-100µg/mL.

A pan-cancer analysis of homeobox family: expression characteristics and latent significance in prognosis and immune microenvironment

BackgroundThe Homeobox (HOX) gene family are conserved transcription factors that are essential for embryonic development, oncogenesis, and cancer suppression in biological beings. Abnormally expressed HOX genes in cancers are directly associated with prognosis.MethodsPublic databases such as TCGA and the R language were used to perform pan-cancer analyses of the HOX family in terms of expression, prognosis, and immune microenvironment. The HOX score was defined, and potential target compounds in cancers were predicted by Connective Map. Immunohistochemistry was employed to validate protein expression levels. Gene knockdowns were used to verify the effects of HOXB7 and HOXC6 on the proliferation and migration of lung adenocarcinoma (LUAD) cells.ResultsHOX genes play different roles in different cancers. Many HOX genes, especially HOXB7 and HOXC6, have higher expression and lower overall survival in specific cancers and are predicted as risk factors. The high expression of most HOX genes is mainly related to immune subtypes C1-C4 and C6. Potential anti-tumor compounds for down-regulating HOX gene expression were identified, such as HDAC inhibitors and tubulin inhibitors. LUAD Cell migration and proliferation were inhibited when HOXB7 or HOXC6 was knocked down.ConclusionsMany HOX genes may act as both oncogenes and tumor suppressor genes, necessitating precision medicine based on specific cancers. The HOX gene family plays a crucial role in the development of certain cancers, and their expression patterns are closely related to cancer prognosis and the tumor microenvironment (TME), which may affect cancer prognosis and response to immunotherapy. Compounds that are negatively correlated with the expression levels of the HOX family in various cancers, such as HDAC inhibitors, are potential anti-cancer drugs. HOXB7 and HOXC6 may serve as potential targets for cancer treatment and the development of targeted compounds in the future.

Multifunctional Novel Lanthanide Complexes Based on Chromone Moiety for Corrosion Inhibition, Molecular Docking, and Anticancer and Antimicrobial Applications

ABSTRACTTwo novel multifunctional complexes [M(CCAM)2(NO3)](NO3)2·C2H5OH (M = Dy (III)/Er (III); CCAM = 2‐cyano‐N′‐((4‐oxo‐4H‐chromen‐3‐yl)methylene)acetohydrazide) were synthesized and characterized via elemental and thermal analyses, molar conductivity, UV–vis., and FT‐IR spectroscopy, revealing a 1:2 metal‐to‐ligand stoichiometry. The CCAM ligand coordinated with Dy(III) or Er(III) ions through nitrogen of azomethine and oxygen of the carbonyl and γ‐pyran groups. Corrosion inhibition studies for Dy(CCAM), Er(CCAM), and CCAM on carbon steel (C‐steel) in 1‐M HCl showed Dy(CCAM) and Er(CCAM) as highly efficient, with Er(CCAM) offering the best protection. In a 1‐M HCl solution, Fe2+ at the C‐steel surface interacts with the CCAM, Dy(CCAM), and Er(CCAM) compounds, as demonstrated by UV–vis spectroscopy. At a concentration of 10−3 M, the Dy(CCAM) and Er(CCAM) compounds showed greater performance efficiency in the weight loss test in 1‐M HCl solution, reaching 93.34% and 95.67%, respectively. The Langmuir adsorption isotherm pronounced the mixed adsorption mechanisms. The surface characteristics SEM, EDX, AFM, and contact angle measurements confirmed surface shielding. In vitro antibacterial and antifungal activity of the prepared compounds against organisms, including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis as bacteria, and Candida albicans and Aspergillus fumigatus as fungi is carried out. Er(CCAM) inhibitor exhibits the greatest action against different tested antimicrobials. Additionally, the in vitro cytotoxicity of the produced complexes as growth inhibitory effects against Erlish Acities Carcinoma was ascertained. Er(CCAM) and Dy(CCAM) were found to have cytotoxic levels with (IC50 of 64 and 65 μM), respectively. As a result, Er(CCAM) inhibitor is a more effective therapeutic approach for the creation of novel antimicrobial and antitumor agents. For Er(CCAM) superior corrosion protection, the theoretical studies of molecular docking and DFT and MD simulations validated the experimental results.

A case report: interstitial pneumonia following treatment of gastric cancer with sintilimab in combination with S-1

BackgroundInterstitial pneumonia is a group of pathologies affecting the pulmonary interstitium, characterized by interstitial fibrosis and extensive alveolar consolidation. This disease can extend to the surrounding blood vessels and pulmonary interstitium, sometimes affecting the entire lung, resulting in functional limitations, including restrictive ventilatory defect, impaired gas exchange, and hypoxemia. Severe interstitial pneumonia can lead to death. Antitumor drugs can induce interstitial pneumonia. Sintilimab is an immune checkpoint inhibitor, a recombinant fully human immunoglobulin G-type programmed death protein-1 monoclonal antibody inhibitor. S-1 is a compound preparation consisting of gimeracil, oteracil potassium, and ftorafur. There have been cases of interstitial pneumonia caused by treatment with sintilimab or S-1 in clinical settings, but no cases of interstitial pneumonia caused by treatment with a combination of sintilimab and S-1 have been reported.Case reportA patient diagnosed with gastric cancer underwent nine courses of treatment using a chemotherapy regimen of combined oxaliplatin S-1., Due to severe bone marrow suppression and gastrointestinal adverse reactions, the treatment was switched to sintilimab in combination with S-1therapy., This change resulted in the development of interstitial pneumonia, as revealed by non-contrast chest Computed Tomography scans. Following a review of blood test results and a multidisciplinary consultation, we suspect that the interstitial pneumonia may have been caused either by Sintilimab alone or by the combined effects of sintilimab and S-1. The treatment was discontinued, and after receiving adequate glucocorticoid therapy, the pulmonary lesions showed slight improvement.ConclusionThis case provides a clinical reference, indicating that prior touse of sintilimab in combination with S-1 antitumor regimen, a comprehensive baseline assessment should be conducted, including blood routine examination, enzyme tests, and pulmonary imaging examination, with close monitoring of the patient’s pulmonary condition. If drug-induced lung injury is suspected, the medication should be discontinued immediately, and appropriate treatment should be initiated promptly.

Cellular and Molecular Evidence of the Synergistic Antitumour Effects of Hydroxytyrosol and Metformin in Prostate Cancer

Prostate cancer (PCa) is the tumour pathology with the second highest incidence among men worldwide. PCa is strongly influenced by obesity (OB), which increases its aggressiveness. Hence, some metabolic drugs like metformin have emerged as potential anti-tumour agents against several endocrine-related cancers. Likewise, a high adherence to the Mediterranean diet has been associated with lower rates of OB and a reduction in PCa aggressiveness since this diet contains phenolic bioactive compounds such as hydroxytyrosol (HT) that is mainly present in extra virgin olive oil. Thus, we decided to analyse the therapeutic potential of the combination of HT + metformin in different PCa cell models. Specifically, combinations of different doses of HT and metformin were evaluated by analysing the proliferation rate of LNCaP, 22Rv1, DU-145, and PC−3 cells using the SynergicFinder method. The results revealed a synergistic effect of HT + metformin in significantly reducing proliferation, especially in LNCaP cells. This anti-tumour effect of HT + metformin was also confirmed in migration and tumoursphere formation assays in LNCaP. The effects on the cell cycle and apoptosis were also assessed by flow-cytometry, and a cycle arrest in the G1 phase and an increase in late apoptosis were observed with the combination of HT + metformin. The phosphorylation levels of critical components of different oncogenic pathways were measured which revealed that the combination of HT + metformin significantly reduced the activity of multiple components of the MAPK, AKT, and TGF-β pathways. Overall, the combination of HT + metformin might represent a new therapeutic avenue for the management of PCa patients, an observation that certainly warrants further investigation through a well-designed clinical trial.

Responsive Zwitterionic Materials for Enhanced Drug Delivery.

Zwitterionic materials have traditionally been recognized as exceptional antifouling agents, imparting nanocarriers with extended circulation times in vivo. Despite much studies on antifouling ability, the responsive zwitterionic materials that change physicochemical properties stimulated by mild signals are much less explored. As is known, there are multiple biological barriers in antitumor drug delivery, including the blood circulation barrier, non-specific organ distribution, elevated tumor interstitial pressure, tumor cytomembrane barrier, and lysosomal barrier. Multiple biological barriers restrict the delivery efficiency of nanocarriers to tumors, leading to a reduced therapeutic effect and increased side effects. Therefore, it is far from satisfactory to overcome the blood circulation barrier alone for classical zwitterionic antitumor materials. To address this challenge, recently developed responsive zwitterionic materials have been engineered to overcome multiple biological barriers, thereby enabling more effective antitumor drug delivery. Furthermore, responsive zwitterionic materials could respond to signals by themselves without the need of incorporating extra stimuli-responsive groups, which maintains the simplicity of the molecular structure. In this mini-review, the recent progress of antitumor zwitterionic materials responding to pH, temperature, enzyme, or reactive oxygen species is summarized. Furthermore, prospects and challenges of responsive zwitterionic materials are provided to promote better development of this field.

A review on intrathecal administration of medications for leptomeningeal metastases in solid tumors

Leptomeningeal disease (LMD) is a particular mode of central metastasis in malignant tumors. It occurs when tumor cells infiltrate the subarachnoid space and cerebrospinal fluid (CSF), spreading throughout the central nervous system (CNS). LMD is a rare but devastating complication of malignant tumors. It can occur in various types of cancers, with lung and breast cancer being the most frequently associated. The treatment approach for LMD includes a combination of supportive care, surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, and intrathecal (IT) therapy, among other modalities. Despite the challenges in determining the optimal treatment for LMD, IT therapy remains one of the primary therapeutic strategies. This therapy can directly circumvent the blood–brain barrier. Moreover, a low-dose medication can achieve a higher drug concentration in the CSF, resulting in better cytotoxic effects. Chemotherapy drugs such as methotrexate, cytarabine, and thiotepa have been widely studied as traditional IT therapies. In recent years, the advent of novel anti-tumor drugs has led to a growing number of agents being employed for IT administration in the treatment of malignant tumors with LMD. This article presents a comprehensive review of the current advancements in IT administration of chemotherapy, targeted, and immunotherapy drugs for the treatment of LMD in solid tumors. In addition, we also discuss the safety issues associated with IT therapy, summarize the advantages of IT administration of different types of anti-tumor drugs, and put forward some suggestions for reducing adverse reactions. It is hoped that future research will focus on exploring more potentially effective anti-tumor drugs for IT treatment, conducting in-depth pharmacokinetic studies, and developing long-acting and low-toxic IT administration regimens for the treatment of meningeal metastases.

Targeted inhibition of the PTEN/PI3K/AKT pathway by YSV induces cell cycle arrest and apoptosis in oral squamous cell carcinoma

BackgroundTyroservatide (YSV), a bioactive tripeptide, holds potential as an anti-tumor agent. However, its specific effects on oral squamous cell carcinoma (OSCC) have not been elucidated. This study aims to investigate the inhibitory effects of YSV on OSCC and explore the underlying molecular mechanisms.MethodsA series of in vitro experiments were conducted to assess the impact of YSV on OSCC cell viability, colony formation, cell cycle, and apoptosis. RNA sequencing (RNA-seq), molecular docking, and western blotting were employed to investigate the molecular mechanisms. Additionally, a subcutaneous tumor model was established to validate the in vitro findings. Furthermore, PI3K inhibitors LY294002 and PI3K-IN-1, were used to confirm the role of the PTEN/PI3K/AKT pathway in YSV-mediated OSCC inhibition. Cell cycle and apoptosis were analyzed to assess the combined effect of YSV and LY294002.ResultsYSV significantly inhibited OSCC proliferation by inducing cell cycle arrest and apoptosis. RNA-seq and molecular docking revealed that YSV regulated the PTEN/PI3K/AKT signaling pathway. Western blotting confirmed the modulation of this pathway both in vitro and in vivo. The use of PI3K inhibitors, LY294002 and PI3K-IN-1, further validated the involvement of the PTEN/PI3K/AKT pathway in YSV-induced anti-tumor effects. Notably, the combination of YSV and LY294002 synergistically enhanced cell cycle arrest and apoptosis, demonstrating effective anti-tumor activity. In vivo experiments also supported these findings.ConclusionYSV inhibited the progression of OSCC by promoting cell cycle arrest and apoptosis through the regulation of the PTEN/PI3K/AKT signaling pathway. The combination of YSV and PI3K inhibitors, such as LY294002, exhibited enhanced anti-tumor activity, suggesting potential therapeutic strategies for OSCC treatment.Graphical abstract

Implantable Polymer Scaffolds Loaded with Paclitaxel–Cyclodextrin Complexes for Post-Breast Cancer Tissue Reconstruction

The side effects associated with the chemotherapy of triple-negative breast cancer (TNBC), such as nucleotide-binding oligomerization domain (NOD)-like receptor family (NLR), pyrin domain containing 3 (NLRP3) inflammasome activity, are responsible for the treatment failure and high mortality rates. Therefore, advanced delivery systems have been developed to improve the transport and targeted administration of anti-tumor agents at the tumor sites using tissue engineering approaches. Implantable delivery systems based on biodegradable polymers are an effective alternative due high biocompatibility, porosity, and mechanical strength. Moreover, the use of paclitaxel (PTX)-cyclodextrin complexes increases the solubility and permeability of PTX, enhancing the bioavailability and efficacy of the drug. All of these properties contribute to the efficient encapsulation and controlled release of drugs, preventing the damage of healthy tissues. In the current study, we detailed the synthesis process and evaluation of 3D scaffolds based on gelatin functionalized with methacryloyl groups (GelMA) and pectin loaded with PTX–cyclodextrin inclusion complexes on TNBC pathogenesis in vitro and in vivo. Bio-physio-chemical analysis of the proposed scaffolds revealed favorable mechanical and biological properties for the cellular component. To improve the drug solubility, a host–guest interaction was performed by the complexation of PTX with a cyclodextrin derivative prior to scaffold synthesis. The presence of PTX suppressed the growth of breast tumor cells and promoted caspase-1 activity, the release of interleukin (IL)-1β, and the production of reactive oxygen species (ROS), conditioning the expression levels of the genes and proteins associated with breast tumorigenesis and NLRP3 inflammasome. The in vivo experiments suggested the activation of pyroptosis tumor cell death, confirming the in vitro experiments. In conclusion, the bio-mechanical properties of the GelMA and pectin-based scaffolds as well as the addition of the PTX–cyclodextrin complexes allow for the targeted and efficient delivery of PTX, suppressing the viability of the breast tumor cells via pyroptosis cell death initiation.

The potential of MAO inhibitors as chemotherapeutics in cancer: A literature survey.

Drug resistance in cancer is determined by genetic mutations and adaptations of tumor cells to drug treatments, raising a challenge in the treatment of cancer. Factors such as prolonged drug exposure, genetic variability among patients, and tumor heterogeneity have been established as contributors to rising incidence of drug resistance, prompting ongoing research into alternative therapies and combination treatments to overcome this challenge. Monoamine oxidases (MAOs), including both isoforms MAO-A and MAO-B, are mitochondrial enzymes responsible for the catabolism of monoamine neurotransmitters such as dopamine, norepinephrine, and serotonin. While these enzymes play a pivotal role in the nervous system, their role in tumorigenesis has garnered increasing attention in the last years. Recent studies, in fact, have highlighted the potential of MAO inhibitors (MAOIs) as antitumor agents, emphasizing their use as standalone treatments or in synergy with traditional anticancer therapies, focusing on pathways involved in tumorigenesis. This review aims to provide a comprehensive overview of MAOIs currently under study for their potential antitumor activity, focusing on their structural characteristics, mechanisms of action, and efficacy in preclinical and clinical settings, referencing key articles in the field.

Abiraterone acetate fixed-dosed combinations with ibuprofen-based therapeutic eutectic and deep eutectic solvents.

In recent years, deep eutectic solvents (DESs) with their outstanding solubilization properties have emerged as strong candidates for oral enabling formulations of poorly soluble drugs. This study explores the use of drug-based therapeutic DESs (THEDESs) to solubilize a poorly soluble compound with the aim of providing a fixed-dose combination of two complementary therapeutic agents. Specifically, potential anticancer effects of ibuprofen (IBU) are harnessed in a novel type of THEDES to dissolve higher amounts of abiraterone acetate (AbAc), an antitumor agent. Four IBU-based combinations were studied: 1:4M ratio with octanoic acid (OctA), 1:5 with nonanoic acid (NonA), 1:3 with decanoic acid (DeA) or 1:2 with dodecanoic acid (DoA). Fatty acids of different chain lengths were analyzed and discussed considering surface charge densities obtained via quantum chemistry. The THEDESs listed could apparently dissolve AbAc amounts up to 1311.0±125.4mg/g in IBU:OctA THEDES, 1151.7±22.2mg/g in IBU:NonA, 1160.4±33.5mg/g in IBU:DeA, and 231.3±10.7mg/g in IBU:DoA. In vitro dissolution of the simultaneously released drugs reached 37.8±9.0% to 64.2±1.0% for IBU and 5.0±3.3% to 19.4±0.1% for AbAc. This increased to between 60.4±2.8% and 79.4±5.0% of released IBU, and 23.6±1.0% to 57.3±5.8% of released AbAc, with 20% (w/w) Tween 80 added to the formulations. This showed the significant potential of drug-containing THEDESs as solubilizing agents for poorly soluble drugs, in the form of fixed-dose combinations of synergistic APIs.

Design, synthesis and biological evaluation of novel β-carbolines as antitumor agents via targeting autophagy in colorectal cancer

A series of novel β-carbolines with a flexible amino side chain at positions 1 and 3, respectively, were designed, synthesized and evaluated as potential antitumor agents. The results revealed that most of the compounds exhibited a broad spectrum of antiproliferative activity with IC50 value lower than 20μM against human tumor cell lines. Among them, compound 2f was the most potent antiproliferative agent with IC50 value below 5.0μM against human tumor cell lines. Subsequent studies on the in vivo antitumor efficacy of the representative compound 2f demonstrated its ability to hinder tumor progression and significantly diminish tumor mass in a mouse model of colorectal cancer. Further investigation on mechanisms of action showed that compound 2f induced autophagy via the ATG5/ATG7 pathway in HCT116cells. These compounds may contribute to the development of therapeutic agents for colorectal cancer.

Lactoferrin-functionalized PEGylation liposomes loaded with norcantharidin acid for targeted therapy of hepatocellular carcinoma.

Norcantharidin (NCTD), an antitumor agent with an increased leukocyte function, has been used for the treatment of hepatocellular carcinoma (HCC) in clinical. However, the clinical application of NCTD is limited due to its inadequate hydrophilicity and lipophilicity, short half-life (t1/2), as well as adverse effects such as vascular irritation, cardiotoxicity, and nephrotoxicity. Herein, a lactoferrin (Lf) and DSPE-mPEG2000 functionalized liposomes loaded with norcantharidic acid (NCA), an active metabolite of NCTD, was constructed for the targeted therapy of HCC. In this study, blank PEGylated liposomes were prepared using the film hydration method, and the NCA was loaded by calcium acetate active loading method to increase the encapsulation efficiency (EE). Subsequently, lactoferrin was covalently coupled to DSPE-PEG2000-COOH activated by EDC and NHS. In addition, the in vivo pharmacokinetics and pharmacodynamics were investigated in Sprague-Dawley (SD) rats and H22 tumor-bearing BALB/c mice, respectively. As expected, the encapsulation efficiency measurement showed that the encapsulation efficiency of the NCA liposomes was 89.3±1.25%, and the coupling efficiency of lactoferrin was more than 65.97%. Additionally, the variations in both the dynamic size and encapsulation efficiency of norcantharidic acid liposomes in long-term storage stability and serum stability studies did not exceed 10%. Furthermore, the pharmacokinetics and pharmacodynamics results showed that, the NCA-Lips-Lf were able to significantly improve antitumor activity by enhancing tumor-targeting accumulation and prolonging circulation time in the body compared to the sodium demethylcantharidate for injection (Na2DCA). Notably, the AUC0-48 and the t1/2 of NCA-Lips-Lf increased 4.28-time and 5.17-time in comparison to those of NCA-sol, respectively. The tumor inhibition rate of NCA-Lips-Lf (85.29%) was significantly higher than that of sodium demethylcantharidate for injection (Na2DCA) (59.13%), without obvious vascular irritation, cardiotoxicity and nephrotoxicity. In conclusion, NCA-Lips-Lf have the potential to eliminate hepatocellular carcinoma more effectively with fewer side effects than Na2DCA, which further advances the clinical application of norcantharidin-related drugs.

In silico Prediction of Pranlukast as a Stabilizer of PD-L1 Homodimers.

Tumors can be targeted by modulating the immune response of the patient. Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are critical immune checkpoints in cancer biology. The efficacy of certain cancer immunotherapies has been achieved by targeting these molecules using monoclonal antibodies. Small-molecule drugs have also been developed as inhibitors of the PD-1/PD-L1 axis, with a mechanism of action that is distinct from that of antibodies: they induce the formation of PD-L1 homodimers, causing their stabilization, internalization, and subsequent degradation. Drug repurposing is a strategy in which new uses are sought after for approved drugs, expediting their clinical translation based on updated findings. In this study, we generated a pharmacophore model that was based on reported small molecules that targeted PD-L1 and used it to identify potential PD-L1 inhibitors among FDA-approved drugs. We identified 12 pharmacophore-matching compounds, but only 4 reproduced the binding mode of the reference inhibitors in docking experiments. Further characterization by molecular dynamics showed that pranlukast, an antagonist of leukotriene receptors that is used to treat asthma, generated stable and energyfavorable interactions with PD-L1 homodimers and induced homodimerization of recombinant PD-L1. Our results suggest that pranlukast inhibits the PD-1/PD-L1 axis, meriting its repurposing as an antitumor drug.

Palindrome-mediated DNA nanotubes with cell-specific aptamers to improve targeted antitumor effects and reduce toxicity on non-small cell lung cancer.

Chemotherapy is regarded as a widely used and effective treatment strategy for lung cancer, although most conventional chemotherapeutics cause severe toxic side-effects due to their indiscriminate attacks on both cancerous and normal cells. Although nucleic acid nanomaterials are emerging as a promising drug delivery strategy, their clinical applications are limited by rapid degradation by nucleases and difficulties in targeting cancer cells. In this study, we have developed a Rhein-loaded aptamer-based DNA nanotube (DNT-S6@Rhein) for the targeted and efficient therapy of non-small cell lung cancer. Through the palindrome segments, two specified oligonucleotides were hybridized and folded into the well-defined nanotubes (DNT-S6), with the S6 aptamer distributed outside. The obtained nanotubes exhibited excellent serum stability and targeting ability towards A549 cells due to the firm structure and decoration of the S6 aptamer. Rhein, as an antitumor drug and DNA intercalator, can be effectively inserted into the DNT-S6. The drug-loaded nanotubes rapidly disassembled in intracellular environment and then the released Rhein was found to activate cellular apoptotic process and significantly suppress proliferation, migration and invasion of A549 cells. Moreover, DNT-S6@Rhein could efficiently accumulate in tumor regions, offering compelling therapeutic efficacy and biocompatibility under both in vitro and in vivo settings. These findings of this study provide a promising strategy for mitigating the inevitable systemic side-effects of chemotherapy and expand the potential application of DNA nanostructure on targeted drug delivery.

Pregnancy outcomes in Greek women with inflammatory bowel disease: a longitudinal national retrospective study.

Inflammatory bowel disease (IBD) commonly affects patients of reproductive age. The effect of disease activity on the outcome of pregnancy and its impact on neonatal health are areas of intense research. Α national retrospective study of pregnancies in women with IBD between 2010 and 2020 was carried out in 22 IBD reference centers in Greece. 223 pregnancies in 175 IBD patients [122 Crohn's disease (CD)] were included. Mean age at diagnosis was 26 years (12-44) with a mean duration of 7.4 (0-23). Pregnancy as a result of IVF occurred in 15 cases (6.7%). At the beginning of gestation, 165 patients (74%) were under treatment: 48 (29%) with anti-tumor necrosis factor alpha agents, 43 (26%) with azathioprine, 101 (61%) with 5-aminosalicylates, and 12 (7%) with steroids. Forty-nine cases (22%) of IBD flares were recorded: Two-thirds ( n = 30) were in clinical remission at the onset of pregnancy, whereas treatment with corticosteroids was required in 22 (45%). Patients with ulcerative colitis were at greater risk for flare compared to those with CD ( P < 0.001). All but two pregnancies (99.1%) resulted in an uncomplicated delivery. In 147 cases (67.1%), c-section was performed. Two late fetal deaths (0.9%) were reported, both in patients with persistently active disease. After delivery, 75 patients (34%) presented with a disease flare, associated with active disease at the beginning of pregnancy ( P < 0.001). The majority of Greek patients with IBD have a favorable pregnancy outcome. Active inflammation during gestation and a diagnosis of ulcerative colitis are negatively associated with pregnancy outcomes.

Physicochemical characterization and antitumor activity in vitro of a polysaccharide from Christia vespertilionis.

CVP-2 is a homogeneous polysaccharide extracted from the whole plant of Christia vespertilionis, with an average molecular weight of approximately 92,920 Da. Its main chain consists of repeating units of [3,5)-α-L-Araf-(1]2 → [5)-α-L-Araf-(1]2→, with branches at the C-3 position: branch 1 is α-L-Araf-(1→, and branch 2 is α-L-Araf-(1 → 4)-. Additionally, the structure includes β-D-Gclp-(1 → [4)-β-D-Glap-(1]2 → 5)-α-L-Araf-(1→. In vitro experiments conducted on cancer and normal cell lines demonstrated that the purified polysaccharide exhibited a significant pro-apoptotic effect on lung and liver cancer cells, while having no impact on the growth of normal tissue cells at dosage concentrations ranging from 125 to 1000 μg/mL. The inhibition of cell viability at 1000 μg/mL CVP-2 was 49.63 % for A549, 2.6 % for 16HBE, 28.56 % for HepG2, and 12.64 % for LX-2. Compared to the drug-free group, the death rates of A549, 16HBE, HepG2, and LX-2 cells increased by 37.13 %, 4.15 %, 26.00 %, and 4.41 %, respectively. CVP-2 was found to inhibit the G1/S phase of the cell cycle. The potential anticancer mechanism of CVP-2 involves a reduction in the Bcl-2/Bax protein in cancer cells, with no significant effect on the growth of normal cells. Therefore, CVP-2 holds great promise as a broad-spectrum antitumor agent and dietary supplement.

Design, Synthesis and Biological Evaluation of Novel 9H Purine Derivatives as Potent CDK9 Inhibitors.

Cyclin-dependent kinase 9 (CDK9) is considered as an important target in the research of antitumor drugs. Taking the CDK2/9 inhibitor CYC065 as the positive control and an in-house library compound (64) as the lead compound, four classes of 22 target compounds with 9H purine as the core structure were designed to establish structure-activity relationships (SAR). In general, SAR of 9H purine CDK9 inhibitors is systematically described in this paper, resulting in the discovery of two compounds (B2 and B5) with further research value. After conducting selectivity testing against CDK2/9 kinase, compound B5 demonstrated approximately five-fold greater selectivity towards CDK9-cyclinT1 over CDK2-cyclinE2. This work also provides a reference basis for the subsequent research on CDK9 inhibitors.