Probing into the plasma stability and microsomal stability of thiol-based prodrug derivatives: Using IYS-15, an HDAC inhibitor as the model thiol.

Thiols have interesting bio-chemical properties and can be found in a number of approved drugs. However, some thiols exhibited poor plasma stability and microsomal stability, leading to poor in vivo activity and poor oral bio-availability, in spite of their potent activity in vitro. Prodrug is a classic strategy to improve drug pharmacokinetics.

Aspirin-based PROTACs as COX-2 degraders for anti-inflammation.

Cyclooxygenase-2 (COX-2) is a key enzyme in the biosynthesis of prostaglandins and plays a special role in the process of inflammatory response. COX-2 is a target of non-steroidal anti-inflammatory drugs (NSAIDs), which can effectively relieve inflammation, pain and fever responses by inhibiting COX-2. Despite the significant study progress of inhibitors targeting COX-2, the development of COX-2 degraders remains insufficient.

Characterization of main degradation products from dendrobine under stress conditions by multistage cleavage of UPLC-ESI-IT-TOF.

Dendrobine is a sesquiterpene alkaloid primarily used in the treatment of inflammatory diseases, immune system disorders, and conditions related to oxidative stress. To understand the possible degradation pathways of dendrobine for its quality control, we conducted an in-depth investigation of its degradation products using forced degradation methods. The separation of dendrobine and its degradation products was achieved on a Shim-pack XR-ODS III (75 mm × 2 mm, 1.

Sucralose uses reward pathways to promote acute caloric intake.

Non-nutritive sweeteners (NNSs) are used to reduce caloric intake by replacing sugar with compounds that are sweet but contain little or no calories. In this study, we investigate how non-nutritive sweetener sucralose to promote acute food intake in the fruit fly Drosophila melanogaster. Our results showed that acute exposure to NNSs sweetness induces a robust hyperphagic response in flies.

A novel importance scores based variable selection approach and validation using a MIR and NIR dataset.

Variable selection is important in spectral analysis for improving interpretation quality and accuracy. This study introduces a novel variable selection process, named "VMHBSC", which consists of six steps, with each letter representing one step. To demonstrate its process and advantages, two datasets were employed, a mid-infrared spectral (MIR) dataset (234 × 7468, sample number × variables) of Chenpi samples (a traditional Chinese medicinal material derived from the dried peel of mature tangerines) and a near-infrared spectral (NIR) dataset (16000 × 256) for modeling competition.

Protocatechuic aldehyde ameliorates psoriasis-like skin inflammation and represses keratinocyte-derived IL-1α and CXCL9 via inhibiting STAT3 activation.

Psoriasis is a chronic inflammatory skin disease. Consistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) in epidermal keratinocyte transactivates various keratinocyte-derived pro-inflammatory cytokines and elicits spontaneous psoriasis-like skin inflammation. In the current study, we first report that topical application of protocatechuic aldehyde (PA), the bioactive compound from Salvia miltiorrhiza (Danshen), significantly improved psoriasis-like skin symptoms and reduced immune cell infiltration in psoriatic lesions.

Unlocking the catalytic precision of ligand-controlled enzymatic halogenation.

A single-component flavin-dependent halogenase, AetF, has emerged as an attractive biocatalyst for catalyzing halogenation. However, its flavin chemistry remains unexplored and cannot be predicted due to its uniqueness in sequence and structure compared to other flavin-dependent monooxygenases. Here, we investigated the flavin reactions of AetF using transient kinetics.

Risk factors of short-term poor functional outcomes and long-term durability of ruptured large or giant intracranial aneurysms.

Objective: Aneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality rates. In particular, functional outcomes of SAH caused by large or giant (≥ 10 mm) ruptured intracranial aneurysms are worsened by high procedure-related complication rates. However, studies describing the risk factors for poor functional outcomes specific to ruptured large/giant aneurysms are sparse.

Quantitative LC-MS/MS Analysis of Endogenous Isomeric Metabolites Biliverdin IX Alpha, Beta, and Delta in Cell Culture Supernatant, Cell Pellet, and Lung Tissue.

() utilizes heme as an iron source from the host during infection. Biliverdin beta and delta (BVIXβ and BVIXδ) are generated by HemO, specific to , while biliverdin alpha is generated from the bacterial BphO system and by mammalian heme oxygenases. Here, we have developed and characterized a quantitative LC-MS/MS assay for the separation of three endogenous isomers, BVIXα, BVIXβ, and BVIXδ.

Prediction of Thermodynamic Properties of C-Based Fullerenols Using Machine Learning.

Traditional machine learning methods face significant challenges in predicting the properties of highly symmetric molecules. In this study, we developed a machine learning model based on graph neural networks (GNNs) to accurately and swiftly predict the thermodynamic and photochemical properties of fullerenols, such as C(OH) ( = 1 to 30). First, we established a global method for generating fullerenol isomers through isomer fingerprinting, which can generate all possible isomers or produce diverse structural types on demand.

Anti-Mycobacterial Activity of Bacterial Topoisomerase Inhibitors with Dioxygenated Linkers.

Developing new classes of drugs that are active against infections caused by is a priority for treating and managing this deadly disease. Here, we describe screening a small library of 20 DNA gyrase inhibitors and identifying new lead compounds. Three structurally diverse analogues were identified with minimal inhibitory concentrations of 0.

Machine Learning-Driven Prediction, Preparation, and Evaluation of Functional Nanomedicines Via Drug-Drug Self-Assembly.

Small molecules as nanomedicine carriers offer advantages in drug loading and preparation. Selecting effective small molecules for stable nanomedicines is challenging. This study used artificial intelligence (AI) to screen drug combinations for self-assembling nanomedicines, employing physiochemical parameters to predict formation via machine learning.

Discovery of Novel Small-Molecule Inhibitors Disrupting the MTDH-SND1 Protein-Protein Interaction.

MTDH-SND1 protein-protein interaction (PPI) plays an important role in the initiation and development of tumors, and it is a target for the treatment of breast cancer. In this study, we identified and synthesized a series of novel small-molecule inhibitors of MTDH-SND1 PPI. The representative compound showed potent activity against MTDH-SND1 PPI with an IC of 487 ± 99 nM and tight binding to the SND1-purified protein with a value of 279 ± 17 nM.

Comparative efficacy and safety of sitagliptin or gliclazide combined with metformin in treatment-naive patients with type 2 diabetes: A single-center, prospective, randomized, controlled, noninferiority study with genetic polymorphism analysis.

Background: This study evaluates the efficacy and safety of sitagliptin versus gliclazide, combined with metformin, in treatment-naive patients with type 2 diabetes mellitus (T2DM) and glucotoxicity.

Methods: In this single-center, randomized, controlled noninferiority trial, 129 treatment-naive patients with T2DM with glucotoxicity (fasting plasma glucose [FPG] ≥ 200 mg/dL and glycated hemoglobin ≥ 9.0%) were randomized to receive sitagliptin plus metformin (n = 66) or gliclazide plus metformin (n = 63) for 12 weeks.

Public perceptions and attitudes of drive-through pharmacy services: Insights from a cross-sectional survey in Saudi Arabia.

Disease-related fatalities in Saudi Arabia (SA) are on the rise, with 28% of all deaths attributed to cardiovascular diseases, followed by cancer, diabetes, and chronic respiratory disorders. In response to this issue, pharmacy dispensing practices have been significantly altered. One such innovative approach is the drive-through pharmacy service.

Hepatocellular Carcinoma Cells in Humans Exhibit Resistance to Suberoylanilide Hydroxamic Acid (SAHA) Owing to the Diminished Level of Hsa-miR-125a-5p.

Hepatocellular carcinoma (HCC) presents an escalating public health challenge globally. However, drug resistance has emerged as a major impediment to successful HCC treatment, limiting the efficacy of curative interventions. Despite numerous investigations into the diverse impacts of hsa-miR-125a-5p on tumor growth across different cancer types, its specific involvement in chemotherapy resistance in HCC remains elusive.

Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature.

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons.

Safety, Efficacy and Pharmacokinetics of daily optimised doses of Rifampicin for the Treatment of Tuberculosis: A Systematic Review and Bayesian Network Meta-Analysis.

Background: Higher than standard doses of rifampicin could improve the treatment outcome of drug-susceptible tuberculosis without compromising the safety of patients.

Methods: We performed a systematic review of prospective clinical studies including adults with pulmonary and extrapulmonary TB receiving rifampicin doses above 10mg/kg/day. We extracted the data on overall adverse events (AE), hepatic AE, sputum culture conversion (SCC) at week 8, recurrence, mortality, and pharmacokinetics.

Differential Responses of Methylobacterium and Sphingomonas Species to Multispecies Interactions in the Phyllosphere.

The leaf surface, known as the phylloplane, presents an oligotrophic and heterogeneous environment due to its topography and uneven distribution of resources. Although it is a challenging environment, leaves support abundant bacterial communities that are spatially structured. However, the factors influencing these spatial distribution patterns are not well understood.

The adaptor protein Miro1 modulates horizontal transfer of mitochondria in mouse melanoma models.

Recent research has shown that mtDNA-deficient cancer cells (ρ cells) acquire mitochondria from tumor stromal cells to restore respiration, facilitating tumor formation. We investigated the role of Miro1, an adaptor protein involved in movement of mitochondria along microtubules, in this phenomenon. Inducible Miro1 knockout (Miro1) mice markedly delayed tumor formation after grafting ρ cancer cells.

Examining Whole Blood, Total and Free Plasma Tacrolimus in Elderly Kidney Transplant Recipients.

Background: Therapeutic monitoring is routinely performed to ensure tacrolimus whole-blood concentrations fall within a predefined target. Despite this, patients still experience inefficacy and toxicity that could be related to variability in free (unbound) tacrolimus exposure. Therefore, the aim of this study was to compare tacrolimus-free plasma (C u ), total plasma (C p ), and whole-blood (C wb ) concentrations in adult kidney transplant recipients and to characterize tacrolimus disposition across different matrices.

Exploration of Novel Metabolic Mechanisms Underlying Primary Biliary Cholangitis Using Hepatic Metabolomics, Lipidomics, and Proteomics Analysis.

Metabolic reprogramming is important in primary biliary cholangitis (PBC) development. However, studies investigating the metabolic signature within the liver of PBC patients are limited. In this study, liver biopsies from 31 PBC patients and 15 healthy controls were collected, and comprehensive metabolomics, lipidomics, and proteomics analysis were conducted to characterize the metabolic landscape in PBC.

Isolation, identification and genetic variation analysis of avian orthoreovirus in commercial broilers in China from 2016 to 2021.

In the last decade, the emergence of variant strains of avian orthoreovirus (ARV) has caused an enormous economic impact on the poultry industry across China and other countries. This study aimed to evaluate the molecular evolution of the ARV lineages detected in Chinese commercial broiler farms. Firstly, ARV isolation and identification of commercial broiler arthritis cases from different provinces in China from 2016 to 2021 were conducted.