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1.
Luminescence ; 39(8): e4849, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39099225

ABSTRACT

Pesticides in environmental samples pose significant risks to ecosystems and human health since they require precise and efficient detection methods. Imidacloprid (IMI), a widely used neonicotinoid insecticide, exemplifies these hazards due to its potential toxicity. This study addresses the urgent need for improved monitoring of such contaminants by introducing a novel fluorometric method for detecting IMI using nitrogen-doped graphite carbon dots (N-GCDs). The sensor operates by quenching fluorescence through the interaction of Cu2+ ions with N-GCDs. Subsequently, IMI binds to the imidazole group, chelates with Cu2+, and restores the fluorescence of N-GCDs. This alternating fluorescence behavior allows for the accurate identification of both Cu2+ and IMI. The sensor exhibits linear detection ranges of 20-100 nM for Cu2+ and 10-140 µg/L for IMI, with detection limits of 18 nM and 1.2 µg/L, respectively. The high sensitivity of this sensor enables the detection of real-world samples, which underscores its potential for practical use in environmental monitoring and agricultural safety.


Subject(s)
Copper , Environmental Monitoring , Fluorometry , Graphite , Neonicotinoids , Nitro Compounds , Nitrogen , Quantum Dots , Neonicotinoids/analysis , Neonicotinoids/chemistry , Nitro Compounds/chemistry , Nitro Compounds/analysis , Copper/chemistry , Copper/analysis , Nitrogen/chemistry , Graphite/chemistry , Quantum Dots/chemistry , Insecticides/analysis , Insecticides/chemistry , Imidazoles/chemistry
2.
Cancer Biol Ther ; 25(1): 2385517, 2024 Dec 31.
Article in English | MEDLINE | ID: mdl-39087955

ABSTRACT

BACKGROUND: CDK4 is highly expressed and associated with poor prognosis and decreased survival in advanced neuroblastoma (NB). Targeting CDK4 degradation presents a potentially promising therapeutic strategy compared to conventional CDK4 inhibitors. However, the autophagic degradation of the CDK4 protein and its anti-proliferation effect in NB cells has not been mentioned. RESULTS: We identified autophagy as a new pathway for the degradation of CDK4. Firstly, autophagic degradation of CDK4 is critical for NVP-BEZ235-induced G0/G1 arrest, as demonstrated by the overexpression of CDK4, autophagy inhibition, and blockade of autophagy-related genes. Secondly, we present the first evidence that p62 binds to CDK4 and then enters the autophagy-lysosome to degrade CDK4 in a CTSB-dependent manner in NVP-BEZ235 treated NB cells. Similar results regarding the interaction between p62 and CDK4 were observed in the NVP-BEZ235 treated NB xenograft mouse model. CONCLUSIONS: Autophagic degradation of CDK4 plays a pivotal role in G0/G1 cell cycle arrest in NB cells treated with NVP-BEZ235.


Subject(s)
Autophagy , Cyclin-Dependent Kinase 4 , G1 Phase Cell Cycle Checkpoints , Neuroblastoma , Cyclin-Dependent Kinase 4/metabolism , Neuroblastoma/metabolism , Neuroblastoma/pathology , Neuroblastoma/drug therapy , Neuroblastoma/genetics , Humans , Animals , Mice , Autophagy/drug effects , G1 Phase Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Xenograft Model Antitumor Assays , Quinolines/pharmacology , Resting Phase, Cell Cycle/drug effects , Cell Proliferation/drug effects , Imidazoles/pharmacology , Mice, Nude , Proteolysis
3.
Int J Med Sci ; 21(10): 1814-1823, 2024.
Article in English | MEDLINE | ID: mdl-39113885

ABSTRACT

Background: BMS-1166, a PD-1/PD-L1 inhibitor, inhibits the binding of PD-L1 to PD-1, restores T cell function, and enhances tumor immune response. However, mutations in the tumor suppressor or impaired cellular signaling pathways may also lead to cellular transformation. In this study, the SW480 and SW480R cell lines were used as the model to elucidate the treatment with BMS-1166, BEZ235, and their combination. Methods: MTT and colony-formation assays were used to evaluate cell proliferation. Wound-healing assay was used to assess cell migration. Cell cycle and apoptosis were analyzed by flow cytometry. The phosphorylation level of the key kinases in the PI3K/Akt/mTOR and MAPK pathways, PD-L1, and the protein levels related to the proliferation, migration, and apoptosis were assessed using western blotting. Results: BEZ235 enhanced BMS-1166-mediated cell proliferation and migration inhibition in SW480 and SW480R cells and promoted apoptosis. Interestingly, the downregulation of the negative regulator PTEN raised the PD-L1 level, which was abolished by the inhibition of Akt. BMS-1166 promoted PI3K, Akt, mTOR, and Erk phosphorylation. However, the combination of BEZ235 with BMS-1166 suppressed the expression of PI3K, p-Akt, p-mTOR, and p-Erk in SW480 and SW480R cells compared to BMS-1166 or BEZ235 single treatment by inhibiting the binding of PD1 to PD-L1. Conclusions: PD-1 binds to PD-L1 and activates the PI3K/mTOR and MAPK pathways, which might be the molecular mechanism of acquired resistance of CRC to BMS-1166. The combination of the two drugs inhibited the phosphorylation of PI3K, Akt, and Erk in the PI3K/mTOR and MAPK pathway, i.e., BEZ235 enhanced the BMS-1166 treatment effect by blocking the PI3K/mTOR pathway and interfering with the crosstalk of the MAPK pathway. Therefore, these findings provide a theoretical basis for BMS-1166 combined with BEZ235 in the trial treatment of colorectal cancer.


Subject(s)
Apoptosis , Cell Movement , Cell Proliferation , Colorectal Neoplasms , Imidazoles , Phosphoinositide-3 Kinase Inhibitors , Quinolines , TOR Serine-Threonine Kinases , Humans , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , B7-H1 Antigen/metabolism , B7-H1 Antigen/antagonists & inhibitors , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Drug Synergism , Imidazoles/pharmacology , MTOR Inhibitors/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Quinolines/pharmacology , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors
4.
J Mater Sci Mater Med ; 35(1): 46, 2024 Aug 08.
Article in English | MEDLINE | ID: mdl-39115576

ABSTRACT

An antifungal agent, luliconazole, is commercially available in cream or gel form. The major limitation of these conventional formulations is less residence time at the infection site. The primary objective of this work was to develop luliconazole-loaded polyvinyl alcohol (Luz-PVA) nanofibers for mycotic skin conditions with a longer retention. Luz-PVA nanofibers were prepared by plate electrospinning and optimized for polymer concentration and process parameters. The optimized batch (Trial 5) was prepared by 10% PVA, processed at 22.4 kV applied voltage, and 14 cm plate and spinneret distance to yield thick, uniform, and peelable nanofibers film. There was no interaction observed between Luz and PVA in the FTIR study. DSC and XRD analysis showed that luliconazole was loaded into fabricated nanofibers with a reduced crystallinity. FESEM studies confirmed the smooth, defect-free mats of nanofibers. Luz-PVA nanofibers possessed a tensile strength of 21.8 N and a maximum elongation of 10.8%, representing the excellent elasticity of the scaffolds. For Luz-PVA nanofibers, the sustained and complete drug release was observed in 48 h. In antifungal activity using Candida albicans, the Luz-PVA nanofibers showed a greater zone of inhibition (30.55 ± 0.38 mm and 29.27 ± 0.31 mm) than marketed cream (28.06 ± 0.18 mm and 28.47 ± 0.24 mm) and pure drug (27.57 ± 0.17 mm and 27.50 ± 0.47 mm) at 1% concentration in Sabouraud dextrose agar and yeast malt agar, respectively. Therefore, Luz-PVA nanofibers exhibited good mechanical properties, longer retention time, and better antifungal activity than marketed products and, therefore, can be further examined preclinically as a potential treatment option for topical mycotic infection.


Subject(s)
Antifungal Agents , Candida albicans , Imidazoles , Microbial Sensitivity Tests , Nanofibers , Polyvinyl Alcohol , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacokinetics , Candida albicans/drug effects , Nanofibers/chemistry , Polyvinyl Alcohol/chemistry , Imidazoles/chemistry , Imidazoles/pharmacology , Administration, Topical , Spectroscopy, Fourier Transform Infrared , Tensile Strength , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/pharmacology , X-Ray Diffraction
6.
Anticancer Drugs ; 35(8): 761-763, 2024 Sep 01.
Article in English | MEDLINE | ID: mdl-39115059

ABSTRACT

The combination of BRAF and MEK inhibitors demonstrated significant clinical benefit in patients with BRAF-mutant non-small cell lung cancer (NSCLC). However, the molecular mechanisms of acquired resistance to BRAF and MEK inhibition in NSCLC are still unknown. Herein, we report a case of a 76-year-old man with a history of smoking who was diagnosed with BRAF V600E-mutant lung adenocarcinoma (PD-L1 > 50%) and subsequently candidate to first-line therapy with pembrolizumab. After 18 months since the start of immunotherapy, computed tomography scan showed disease progression and a second-line therapy with dabrafenib and trametinib was initiated. Seven months later, due to a suspect disease progression, a left supraclavicular lymphadenectomy was performed and next-generation sequencing analysis revealed the appearance of MET exon 14 skipping mutation, while fluorescence in situ hybridization analysis showed MET amplification. The patient is still on BRAF and MEK inhibitor treatment. Our case highlights the relevance of performing tumor tissue rebiopsy at the time of progression during treatment with BRAF/MEK inhibition with the aim of identifying putative mechanisms of resistance.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , Drug Resistance, Neoplasm , Imidazoles , Lung Neoplasms , Mutation , Oximes , Proto-Oncogene Proteins B-raf , Proto-Oncogene Proteins c-met , Pyridones , Pyrimidinones , Humans , Pyridones/administration & dosage , Pyrimidinones/administration & dosage , Male , Oximes/administration & dosage , Aged , Proto-Oncogene Proteins B-raf/genetics , Imidazoles/administration & dosage , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Proto-Oncogene Proteins c-met/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
7.
J Phys Chem B ; 128(32): 7792-7802, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-39092664

ABSTRACT

The present study utilizes molecular dynamics simulations to examine how different anions compete for protein solvation in aqueous solutions of ionic liquids (ILs). Ubiquitin is used as model protein and studied in IL mixtures sharing the same cation, 1-ethyl-3-methylimidazolium (EMIM), and two different anions in the same solution, from combinations of dicyanamide (DCA), chloride (Cl), nitrate (NO3), and tetrafluoroborate (BF4). Our findings reveal that specific interactions between anions and the protein are paramount in IL solvation, but that combinations of anions are not additive. For example, DCA exhibits a remarkable ability to form hydrogen bonds with the protein, resulting in a significantly stronger preferential binding to the protein than other anions. However, the combination of DCA with NO3, which also forms hydrogen bonds with the protein, results in a smaller preferential solvation of the protein than the combination of DCA with chloride ions, which are weaker binders. Thus, combining anions with varying affinities for the protein surface modulates the overall ion accumulation through nonadditive mechanisms, highlighting the importance of the understanding of competition for specific interaction sites, cooperative binding, bulk-solution affinity, and overall charge compensations, on the overall solvation capacity of the solution. Such knowledge may allow for the design of novel IL-based processes in biotechnology and material science, where fine-tuning protein solvation is crucial for optimizing performance and functionality.


Subject(s)
Anions , Ionic Liquids , Molecular Dynamics Simulation , Water , Ionic Liquids/chemistry , Anions/chemistry , Water/chemistry , Ubiquitin/chemistry , Hydrogen Bonding , Solubility , Imidazoles/chemistry
8.
ACS Synth Biol ; 13(8): 2347-2356, 2024 Aug 16.
Article in English | MEDLINE | ID: mdl-39109930

ABSTRACT

Aerobic methanotrophs, or methane-consuming microbes, are strongly dependent on copper for their activity. To satisfy this requirement, some methanotrophs produce a copper-binding compound, or chalkophore, called methanobactin (MB). In addition to playing a critical role in methanotrophy, MB has also been shown to have great promise in treating copper-related human diseases, perhaps most significantly Wilson's disease. In this congenital disorder, copper builds up in the liver, leading to irreversible damage and, in severe cases, complete organ failure. Remarkably, MB has been shown to reverse such damage in animal models, and there is a great deal of interest in upscaling MB production for expanded clinical trials. Such efforts, however, are currently hampered as (1) the natural rate of MB production rate by methanotrophs is low, (2) the use of methane as a substrate for MB production is problematic as it is explosive in air, (3) there is limited understanding of the entire pathway of MB biosynthesis, and (4) the most attractive form of MB is produced by Methylocystis sp. strain SB2, a methanotroph that is genetically intractable. Herein, we report heterologous biosynthesis of MB from Methylocystis sp. strain SB2 in an alternative methanotroph, Methylosinus trichosporium OB3b, not only on methane but also on methanol. As a result, the strategy described herein not only facilitates enhanced MB production but also provides opportunities to construct various mutants to delineate the entire pathway of MB biosynthesis, as well as the creation of modified forms of MB that may have enhanced therapeutic value.


Subject(s)
Imidazoles , Methylocystaceae , Methylosinus trichosporium , Oligopeptides , Methylosinus trichosporium/metabolism , Methylosinus trichosporium/genetics , Imidazoles/metabolism , Oligopeptides/metabolism , Methylocystaceae/metabolism , Methylocystaceae/genetics , Methane/metabolism , Metabolic Engineering/methods
9.
Molecules ; 29(15)2024 Jul 27.
Article in English | MEDLINE | ID: mdl-39124951

ABSTRACT

The development of targeted drug delivery systems has been a pivotal area in nanomedicine, addressing challenges like low drug loading capacity, uncontrolled release, and systemic toxicity. This study aims to develop and evaluate dual-functionalized mesoporous silica nanoparticles (MSN) for targeted delivery of celecoxib, enhancing drug loading, achieving controlled release, and reducing systemic toxicity through amine grafting and imidazolyl polyethyleneimine (PEI) gatekeepers. MSN were synthesized using the sol-gel method and functionalized with (3-aminopropyl) triethoxysilane (APTES) to create amine-grafted MSN (MSN-NH2). Celecoxib was loaded into MSN-NH2, followed by conjugation of imidazole-functionalized PEI (IP) gatekeepers synthesized via carbodiimide coupling. Characterization was conducted using Fourier-transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance (1H-NMR). Drug loading capacity, entrapment efficiency, and in vitro drug release at pH 5.5 and 7.4 were evaluated. Cytotoxicity was assessed using the MTT assay on RAW 264.7 macrophages. The synthesized IP was confirmed by FTIR and 1H-NMR. Amine-grafted MSN demonstrated a celecoxib loading capacity of 12.91 ± 2.02%, 2.1 times higher than non-functionalized MSN. In vitro release studies showed pH-responsive behavior with significantly higher celecoxib release from MSN-NH2-celecoxib-IP at pH 5.5 compared to pH 7.4, achieving a 33% increase in release rate within 2 h. Cytotoxicity tests indicated significantly higher cell viability for IP-treated cells compared to PEI-treated cells, confirming reduced toxicity. The dual-functionalization of MSN with amine grafting and imidazolyl PEI gatekeepers enhances celecoxib loading and provides controlled pH-responsive drug release while reducing systemic toxicity. These findings highlight the potential of this advanced drug delivery system for targeted anti-inflammatory and anticancer therapies.


Subject(s)
Amines , Celecoxib , Delayed-Action Preparations , Drug Liberation , Nanoparticles , Polyethyleneimine , Silicon Dioxide , Celecoxib/chemistry , Celecoxib/pharmacology , Silicon Dioxide/chemistry , Mice , Nanoparticles/chemistry , Animals , Polyethyleneimine/chemistry , RAW 264.7 Cells , Amines/chemistry , Delayed-Action Preparations/pharmacology , Delayed-Action Preparations/chemistry , Drug Carriers/chemistry , Porosity , Cell Survival/drug effects , Drug Delivery Systems , Spectroscopy, Fourier Transform Infrared , Imidazoles/chemistry , Hydrogen-Ion Concentration
10.
Molecules ; 29(15)2024 Aug 02.
Article in English | MEDLINE | ID: mdl-39125070

ABSTRACT

The COVID-19 pandemic highlighted the need to create and study new substances with improved lipophilicity and antimicrobial properties, such as ionic liquids (ILs), with easily tunable physicochemical properties. Most ILs possess strong antibacterial effects, but ILs containing the imidazolium cation are even more effective than the positive control. Thus, in this study, three ionic liquids with 1-butyl-3-methylimidazolium cation and various carboxylate anions (phenylacetate, benzoate, and 4-methoxyphenylacetate) were synthesized and fully characterized. The interactions between the cations and anions were discussed based on the experimental density, viscosity, and electrical conductivity. From the measured electrical conductivity and viscosity, the Walden plot is constructed and ionicity of the studied ILs is discussed. The similarities and dissimilarities among the studied ILs and their physicochemical properties are analyzed by applying the hierarchical cluster analysis and in silico calculated properties. The antimicrobial activity of the studied ionic liquids is tested on two bacterial (E. coli and P. aeruginosa) and three fungi (P. verrucosum, A. flavus, and A. parasiticus) strains, finding that they showed improved antimicrobial activity compared to the individual components.


Subject(s)
Anti-Infective Agents , Carboxylic Acids , Ionic Liquids , Ionic Liquids/chemistry , Ionic Liquids/pharmacology , Anti-Infective Agents/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/chemical synthesis , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Viscosity , Imidazoles/chemistry , Imidazoles/pharmacology , Imidazoles/chemical synthesis , Electric Conductivity , Microbial Sensitivity Tests , Computer Simulation , Escherichia coli/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , COVID-19/virology
11.
Langmuir ; 40(32): 16909-16920, 2024 Aug 13.
Article in English | MEDLINE | ID: mdl-39087886

ABSTRACT

We have prepared a novel assembly with copper nanoclusters (CuNCs) and imidazolium-based gemini surfactants (different chain lengths). These novel mimic enzymes formed through the assembly of nanocluster-gemini surfactants have been utilized in creating colorimetric sensors to detect biomolecules. Yet, understanding the method for detecting glutathione (GSH) and its sensing mechanism using this specific assembly-based colorimetric sensor poses a significant challenge. Because of the role of surface ligands, the complexes of cysteine-capped CuNCs (Cys-CuNCs) and gemini surfactants exhibit strong amphiphilicity, enabling them to self-assemble like a molecular amphiphile. We have investigated the kinetics and catalytic capabilities of this Cys-CuNCs@gemini surfactant assembly through peroxidase-like activity. Additionally, a sensitive and simple-to-use colorimetric sensing approach for glutathione (GSH) is also disclosed here, demonstrating a low limit of detection, by using this peroxidase-like activity of Cys-CuNCs@gemini surfactant assemblies. Thus, the remarkable advantages of the Cys-CuNCs@gemini surfactant nanozyme make it suitable for the precise colorimetric detection of GSH, demonstrating excellent sensitivity and reliable selectivity. Additionally, it performs well in detecting GSH in various soft drinks.


Subject(s)
Colorimetry , Copper , Cysteine , Glutathione , Metal Nanoparticles , Surface-Active Agents , Copper/chemistry , Glutathione/analysis , Glutathione/chemistry , Colorimetry/methods , Surface-Active Agents/chemistry , Cysteine/analysis , Cysteine/chemistry , Metal Nanoparticles/chemistry , Imidazoles/chemistry , Peroxidase/chemistry , Peroxidase/metabolism
12.
Anal Chem ; 96(32): 13166-13173, 2024 Aug 13.
Article in English | MEDLINE | ID: mdl-39092810

ABSTRACT

For the approval of a drug, the stability data must be submitted to regulatory authorities. Such analyses are often time-consuming and cost-intensive. Forced degradation studies are mainly carried out under harsh conditions in the dissolved state, often leading to extraneous degradation profiles for a solid drug. Oxidative mechanochemical degradation offers the possibility of generating realistic degradation profiles. In this study, a sustainable mechanochemical procedure is presented for the degradation of five active pharmaceutical ingredients (APIs) from the sartan family: losartan potassium, irbesartan, valsartan, olmesartan medoxomil, and telmisartan. High-resolution mass spectrometry enabled the detection of impurities already present in untreated APIs and allowed the elucidation of degradation products. Significant degradation profiles could already be obtained after 15-60 min of ball milling time. Many of the identified degradation products are described in the literature and pharmacopoeias, emphasizing the significance of our results and the applicability of this approach to predict degradation profiles for drugs in the solid state.


Subject(s)
Benzimidazoles , Biphenyl Compounds , Losartan , Telmisartan , Tetrazoles , Valsartan , Benzimidazoles/chemistry , Benzimidazoles/analysis , Tetrazoles/chemistry , Telmisartan/chemistry , Valsartan/chemistry , Losartan/chemistry , Losartan/analysis , Biphenyl Compounds/chemistry , Irbesartan/chemistry , Irbesartan/analysis , Imidazoles/chemistry , Benzoates/chemistry , Valine/chemistry , Valine/analysis , Solvents/chemistry , Drug Stability
13.
Trials ; 25(1): 534, 2024 Aug 13.
Article in English | MEDLINE | ID: mdl-39135126

ABSTRACT

BACKGROUND: Low back pain is one of the most common symptoms of osteoporosis. The pain can seriously affect patients' mood and quality of life; it can also further aggravate bone loss, causing a serious social burden. Minodronate is an oral bisphosphonate that needs to be administered daily. It significantly reduces levels of bone turnover markers (BTMs) and rapidly improves symptoms of low back pain in patients with osteoporosis. Osteoporosis requires long-term treatment, and daily dosing reduces patient compliance. Minodronate has a better safety profile than other bisphosphonates. The objective of the trial is to explore the efficacy and safety of minodronate in the treatment of low back pain in postmenopausal osteoporosis patients. METHODS: This is a single-centre, randomized, open-label controlled trial with a 24-week duration. Seventy-two eligible patients will be randomly divided into 4 groups. Subjects will be randomized at a 1:1 ratio to receive either minodronate (1 mg/day) or alendronate (10 mg/day) every day; senior women (≥ 75 years old) and older women (< 75 years old) will be at a ratio of 1:2. The primary outcome is the time required for the visual analogue scale (VAS) score to decline by ≥ 10 from baseline. The secondary outcome is the changes in VAS scores from baseline, the frequency and dosage of rescue medication, BTMs, bone mineral density (BMD), and variations in upper gastrointestinal (GI) symptom scores from baseline (including heartburn, pain, and bloating). DISCUSSION: This study will provide objective evidence for the efficiency and safety of minodronate. Furthermore, it will be helpful to evaluate the quantitative relationship between BTMs and BMD in patients with osteoporosis under different ages. TRIAL REGISTRATION: This study protocol has been registered with ClinicalTrials.gov ID NCT05645289 ( https://clinicaltrials.gov/search?term=NCT05645289 ) on December 8, 2022. The registry name is Peking University Third Hospital. This study protocol was reviewed and approved by the Peking University Third Hospital Medical Science Research Ethics Committee (M2022465, 2022.08.09, V2.0). The results will be published in scientific peer-reviewed journals. TRIAL STATUS: The protocol was registered at ClinicalTrials.gov (registration number: NCT05645289). Recruitment has started in January 2023 and is still ongoing.


Subject(s)
Bone Density Conservation Agents , Diphosphonates , Imidazoles , Low Back Pain , Osteoporosis, Postmenopausal , Randomized Controlled Trials as Topic , Humans , Female , Osteoporosis, Postmenopausal/drug therapy , Bone Density Conservation Agents/therapeutic use , Bone Density Conservation Agents/adverse effects , Bone Density Conservation Agents/administration & dosage , Aged , Diphosphonates/therapeutic use , Diphosphonates/adverse effects , Diphosphonates/administration & dosage , Treatment Outcome , Low Back Pain/drug therapy , Middle Aged , Imidazoles/therapeutic use , Imidazoles/adverse effects , Imidazoles/administration & dosage , Pain Measurement , Bone Density/drug effects , Alendronate/therapeutic use , Alendronate/adverse effects , Alendronate/administration & dosage
14.
BMC Cardiovasc Disord ; 24(1): 344, 2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38977993

ABSTRACT

BACKGROUND: The link between diabetes mellitus and chronic hepatitis C infection remains well established. It is estimated that up to one third of chronic hepatitis C patients have type II diabetes mellitus. Hepatitis C virus infection is one of the main global health burdens. Sofosbuvir and Daclatasvir are used as effective antiviral inhibitors of hepatitis C virus. The cardiovascular effects of those drugs are not well studied. We used electrocardiography and echocardiography with global longitudinal strain assessment by speckle tracking to detect their effect on cardiac function. METHODS AND RESULTS: One hundred diabetic patients with hepatitis C infection were included in the study. Abdominal ultrasound and laboratory work up were carried out for all participants. Left ventricular systolic and diastolic function were assessed by 2D-echocardiography and global longitudinal strain, before and 3 months after treatment. Results showed significant decrease in global longitudinal strain 3 months after therapy (-21 ± 4 vs. -18 ± 7; P < 0.001) but other echocardiographic findings showed no significant changes. CONCLUSIONS: Sofosbuvir and Daclatasvir were associated with early left ventricular systolic dysfunction as assessed by global longitudinal strain in diabetic patients. More deterioration in left ventricular systolic function was detected among those with Child-Pough class B. Further long-term follow-up may be required.


Subject(s)
Antiviral Agents , Carbamates , Diabetes Mellitus, Type 2 , Hepatitis C, Chronic , Imidazoles , Pyrrolidines , Sofosbuvir , Valine , Ventricular Dysfunction, Left , Ventricular Function, Left , Humans , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/complications , Male , Female , Middle Aged , Sofosbuvir/therapeutic use , Sofosbuvir/adverse effects , Valine/analogs & derivatives , Valine/therapeutic use , Pyrrolidines/therapeutic use , Imidazoles/therapeutic use , Treatment Outcome , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/diagnosis , Carbamates/therapeutic use , Ventricular Function, Left/drug effects , Ventricular Dysfunction, Left/physiopathology , Ventricular Dysfunction, Left/diagnostic imaging , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/etiology , Ventricular Dysfunction, Left/diagnosis , Time Factors , Aged , Electrocardiography , Adult
16.
Int J Nanomedicine ; 19: 6603-6618, 2024.
Article in English | MEDLINE | ID: mdl-38979533

ABSTRACT

Objective: Ovarian cancer cells are prone to acquire tolerance to chemotherapeutic agents, which seriously affects clinical outcomes. The development of novel strategies to enhance the targeting of chemotherapeutic agents to overcome drug resistance and minimize side effects is significant for improving the clinical outcomes of ovarian cancer patients. Methods: We employed folic acid (FA)-modified ZIF-90 nanomaterials (FA-ZIF-90) to deliver the chemotherapeutic drug, cisplatin (DDP), via dual targeting to improve its targeting to circumvent cisplatin resistance in ovarian cancer cells, especially by targeting mitochondria. FA-ZIF-90/DDP could rapidly release DDP in response to dual stimulation of acidity and ATP in tumor cells. Results: FA-ZIF-90/DDP showed good blood compatibility. It was efficiently taken up by human ovarian cancer cisplatin-resistant cells A2780/DDP and aggregated in the mitochondrial region. FA-ZIF-90/DDP significantly inhibited the mitochondrial activity and metastatic ability of A2780/DDP cells. In addition, it effectively induced apoptosis in A2780/DDP cells and overcame cisplatin resistance. In vivo experiments showed that FA-ZIF-90/DDP increased the accumulation of DDP in tumor tissues and significantly inhibited tumor growth. Conclusion: FA-modified ZIF-90 nanocarriers can improve the tumor targeting and anti-tumor effects of chemotherapeutic drugs, reduce toxic side effects, and are expected to be a novel therapeutic strategy to reverse drug resistance in ovarian cancer.


Subject(s)
Antineoplastic Agents , Apoptosis , Cisplatin , Drug Resistance, Neoplasm , Folic Acid , Imidazoles , Ovarian Neoplasms , Zeolites , Female , Cisplatin/pharmacology , Cisplatin/chemistry , Cisplatin/pharmacokinetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Humans , Drug Resistance, Neoplasm/drug effects , Animals , Zeolites/chemistry , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/administration & dosage , Folic Acid/chemistry , Folic Acid/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Imidazoles/administration & dosage , Apoptosis/drug effects , Drug Delivery Systems/methods , Mitochondria/drug effects , Mice , Mice, Inbred BALB C , Mice, Nude , Drug Carriers/chemistry , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/pharmacology , Xenograft Model Antitumor Assays
17.
Neuroreport ; 35(12): 753-762, 2024 Aug 07.
Article in English | MEDLINE | ID: mdl-38980926

ABSTRACT

We aimed to study the reparative effects of orientin against spinal cord injury (SCI) in rats and explore its potential mechanisms. Sprague-Dawley rats were divided into Sham, SCI, Orientin, and SB203580 [an inhibitor of p38 mitogen-activated protein kinase (p38MAPK)] groups. In the SCI group, rats underwent Allen's beat. SCI animals in Orientin and SB203580 groups were respectively treated with 40 mg kg-1 orientin and 3 mg kg-1 SB203580 once daily. Functional recovery was evaluated based on Basso, Beattie, and Bresnahan scoring. Histopathological analysis was performed using hematoxylin-eosin and Nissl staining. Cell apoptosis was examined by TUNEL staining. The relative quantity of apoptosis-related proteins, glial fibrillary acidic protein (GFAP), neurofilament 200 (NF200), and brain derived neurotrophic factor (BDNF) was detected via western blotting. The indices related to inflammation and oxidation were measured using agent kits. The p38MAPK/inducible nitric oxide synthase (iNOS) signaling activity was detected using real-time quantitative PCR, western blotting, and immunohistochemical staining. Orientin was revealed to effectively mitigate cell apoptosis, neuroinflammation, and oxidative stress in impaired tissues. Meanwhile, orientin exerted great neuroprotective effects by abating GFAP expression, and up-regulating the expression of NF200 and BDNF, and significantly suppressed the p38MAPK/iNOS signaling. Orientin application could promote the repair of secondary SCI through attenuating oxidative stress and inflammatory response, reducing cell apoptosis and suppressing p38MAPK/iNOS signaling.


Subject(s)
Apoptosis , Flavonoids , Glucosides , Neuroprotective Agents , Rats, Sprague-Dawley , Spinal Cord Injuries , Animals , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/pathology , Neuroprotective Agents/pharmacology , Flavonoids/pharmacology , Rats , Apoptosis/drug effects , Glucosides/pharmacology , Glucosides/therapeutic use , Male , p38 Mitogen-Activated Protein Kinases/metabolism , Oxidative Stress/drug effects , Recovery of Function/drug effects , Recovery of Function/physiology , Imidazoles/pharmacology , Pyridines
18.
Per Med ; 21(4): 205-209, 2024.
Article in English | MEDLINE | ID: mdl-38958204

ABSTRACT

We report the case of an 87-year-old female patient who was diagnosed with metastatic non-small-cell lung cancer harboring MET exon 14 skipping mutation (MET ex14) and PD-L1 expression of 60%. A first-line treatment with atezolizumab was started with primary resistance. Then, a second-line treatment with capmatinib, a selective type Ib MET tyrosine kinase inhibitor, was started, achieving a partial response. The patient is still alive and on treatment with capmatinib 300 mg twice daily after 20 months, with a good tolerability and no evidence of disease progression.In summary, our patient experienced a long-lasting response (>18 months) with capmatinib as second-line treatment. Further analyses evaluating the efficacy and tolerability of MET tyrosine kinase inhibitors are warranted, especially in the elderly, a non-small-cell lung cancer population whose tumors could more frequently harbor MET ex14 mutation.


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Subject(s)
Carcinoma, Non-Small-Cell Lung , Exons , Lung Neoplasms , Mutation , Proto-Oncogene Proteins c-met , Humans , Female , Proto-Oncogene Proteins c-met/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Aged, 80 and over , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation/genetics , Exons/genetics , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/administration & dosage , Benzamides/therapeutic use , Benzamides/adverse effects , Treatment Outcome , Acrylamides/therapeutic use , Acrylamides/administration & dosage , Acrylamides/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Imidazoles , Triazines
19.
Nature ; 631(8020): 409-414, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38961288

ABSTRACT

Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase1,2. However, BDQ also inhibits human ATP synthase3. At present, how these compounds interact with either M. tuberculosis ATP synthase or human ATP synthase is unclear. Here we present cryogenic electron microscopy structures of M. tuberculosis ATP synthase with and without BDQ and TBAJ-587 bound, and human ATP synthase bound to BDQ. The two inhibitors interact with subunit a and the c-ring at the leading site, c-only sites and lagging site in M. tuberculosis ATP synthase, showing that BDQ and TBAJ-587 have similar modes of action. The quinolinyl and dimethylamino units of the compounds make extensive contacts with the protein. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers' understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs.


Subject(s)
Antitubercular Agents , Diarylquinolines , Imidazoles , Mitochondrial Proton-Translocating ATPases , Mycobacterium tuberculosis , Piperidines , Pyridines , Humans , Antitubercular Agents/pharmacology , Antitubercular Agents/chemistry , Binding Sites , Cryoelectron Microscopy , Diarylquinolines/chemistry , Diarylquinolines/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Mitochondrial Proton-Translocating ATPases/antagonists & inhibitors , Mitochondrial Proton-Translocating ATPases/chemistry , Mitochondrial Proton-Translocating ATPases/metabolism , Mitochondrial Proton-Translocating ATPases/ultrastructure , Models, Molecular , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/drug effects , Piperidines/chemistry , Piperidines/pharmacology , Protein Subunits/metabolism , Protein Subunits/chemistry , Protein Subunits/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology
20.
Int J Mol Sci ; 25(13)2024 Jun 29.
Article in English | MEDLINE | ID: mdl-39000295

ABSTRACT

Olprinone (OLP) is a selective inhibitor of phosphodiesterase III and is used clinically in patients with heart failure and those undergoing cardiac surgery; however, little is known about the effects of OLP on hepatoprotection. The purpose of this study aimed to determine whether OLP has protective effects in in vivo and in vitro rat models of endotoxin-induced liver injury after hepatectomy and to clarify the mechanisms of action of OLP. In the in vivo model, rats underwent 70% partial hepatectomy and lipopolysaccharide treatment (PH/LPS). OLP administration increased survival by 85.7% and decreased tumor necrosis factor-α, C-X-C motif chemokine ligand 1, and inducible nitric oxide synthase (iNOS) mRNA expression in the livers of rats treated with PH/LPS. OLP also suppressed nuclear translocation and/or DNA binding ability of nuclear factor kappa B (NF-κB). Pathological liver damage induced by PH/LPS was alleviated and neutrophil infiltration was reduced by OLP. Primary cultured rat hepatocytes treated with the pro-inflammatory cytokine interleukin-1ß (IL-1ß) were used as a model of in vitro liver injury. Co-treatment with OLP inhibited dose-dependently IL-1ß-stimulated iNOS induction and NF-κB activation. Our results demonstrate that OLP may partially inhibit the induction of several inflammatory mediators through the suppression of NF-κB and thus prevent liver injury induced by endotoxin after liver resection.


Subject(s)
Disease Models, Animal , Hepatectomy , Hepatocytes , Imidazoles , NF-kappa B , Nitric Oxide Synthase Type II , Pyridones , Animals , Hepatectomy/adverse effects , Hepatocytes/drug effects , Hepatocytes/metabolism , Rats , Male , Pyridones/pharmacology , Pyridones/therapeutic use , NF-kappa B/metabolism , Imidazoles/pharmacology , Nitric Oxide Synthase Type II/metabolism , Phosphodiesterase 3 Inhibitors/pharmacology , Phosphodiesterase 3 Inhibitors/therapeutic use , Interleukin-1beta/metabolism , Lipopolysaccharides/adverse effects , Lipopolysaccharides/toxicity , Sepsis/drug therapy , Rats, Sprague-Dawley , Cells, Cultured , Tumor Necrosis Factor-alpha/metabolism , Chemokine CXCL1/metabolism , Liver/drug effects , Liver/pathology , Liver/metabolism
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