Frontiers in Pharmacology最新文献

Aim: This is a retrospective cohort study aimed to investigate the association of adverse drug related (ADR)-related hospital admissions with adverse clinical outcomes, including in-hospital mortality, length of stay (LOS), and hospital readmission among older adults with diabetes.

Methods: All individuals aged 65 years and older with diabetes who were admitted to the three major public hospitals in Tasmania, Australia, between July 2017 and December 2023 were identified using International Classification of Diseases codes. Patients with at least one ADR-related hospital admission were propensity score matched with and those without ADR-related admissions based on age, sex, year of index admission, diagnosis-related groups, socioeconomic status, and comorbidities. Adjusted logistic regression was used to assess in-hospital mortality. Length of stay was analysed using a generalised linear model with a Gamma distribution, and readmission risk at 30, 60, and 90 days was assessed using Cox proportional hazards models.

Results: After matching, a total of 5,038 older patients with diabetes were included in the in-hospital mortality analysis, and 4,674 were included in the LOS and readmission analyses. Patients with ADR-related hospitalisations had a significantly higher risk of in-hospital mortality (adjusted odds ratio = 1.31; 95% CI: 1.03-1.66; p < 0.05), longer LOS (adjusted ratio = 1.24 (1.13-1.37); p < 0.001, and a greater risk of readmission (the highest adjusted hazard ratio was at 60 days = 1.29 (1.14-1.45); p < 0.001) compared to those without ADR-related hospital admissions.

Conclusion: ADR-related hospital admissions were associated with poorer clinical outcomes in older adults with diabetes, including greater mortality, prolonged hospital stays, and increased risk of readmission. These findings underscore the importance of early ADR detection, structured medication review, ongoing monitoring, and patient-centered education to improve medication safety and optimise outcomes in this high-risk group.

Background: Sonchus arvensis L. is a traditional Chinese food and medicine, and the primary plant metabolites are polysaccharides (SAP). In this study, we aimed to investigate the protective effect of SAP in a colitis model and the potential underlying molecular mechanisms.

Methods: C57BL/6 mice were randomly assigned to three groups: the negative control, model, and SAP treatment groups. The influence of SAP on ulcerative colitis (UC) was evaluated by water and food intake, body weight change, diarrhea, bloody stool, colon length, histological analysis, disease activity index, and immune parameters. The effects of SAP on the gut microbiota (GM) were investigated using 16S rRNA sequencing. The impact of SAP on metabolites was evaluated using non-targeted metabolomics analysis.

Results: SAP attenuated colitis and modified immune parameters. 16S rRNA sequencing showed that the abundance of Akkermansia, Rikenella, Rikenellaceae_RC9_gut_group, and unidentified_Clostridia_vadinBB60_group in the model mice was remarkably reversed after SAP treatment. The correlation analysis of GM and the metabolites showed that SAP could regulate five metabolites correlated with GM.

Conclusion: The protective effect of SAP on the model mice may be related to GM diversity and metabolites.

Natural products continue to be fundamental to contemporary drug discovery. Aloe-emodin, a natural anthraquinone molecule sourced from plants including aloe and rhubarb, has attracted considerable interest owing to its diverse pharmacological properties. This review analyzes the complex modes of action of AE, emphasizing its significant anti-cancer effects by targeting critical signaling pathways like PI3K/Akt, MAPK, and NF-κB, which induce apoptosis and cell cycle arrest, regulate autophagy, and inhibit metastasis. In addition to oncology, AE exhibits potent anti-inflammatory, neuroprotective, and antiviral effects primarily by reducing oxidative stress and regulating inflammatory responses. Notwithstanding its encouraging preclinical performance, the practical application of AE has been impeded by considerable obstacles, notably its inadequate bioavailability, possible toxicity, and absence of target selectivity. We rigorously assess these challenges and examine novel tactics designed to improve its therapeutic index, including nanotechnology-based drug delivery devices and alterations to chemical structures. This review seeks to reconcile the intricate pharmacology with clinical applicability, offering a prospective outlook on the use of AE as a next-generation therapeutic agent for cancer and other complex disorders.

The concept of the intensive care unit (ICU) was developed around 70 years ago, and this has become essential for caring for a hospital's sickest patients. A commonality for many patients' critical illness is the systemic inflammatory state with multiple-organ injury precipitated by infectious causes and/or other pathophysiologic insults. Therapeutic modalities to address these complications remain unclear, and there are no FDA-approved drugs to treat these often-devastating clinical situations. Clinical deterioration may be associated with the release of "damage-associated molecular patterns" (DAMPs), such as extracellular adenosine triphosphate (eATP), from stressed and dying cells. Pharmacological dosing or boosting of CD73, an ectoenzyme that can convert pro-inflammatory adenosine monophosphate (AMP) to anti-inflammatory adenosine, in this setting of critical illness has been shown to have a survival benefit with decreased time in the hospital and ICU. Whether there are clinical benefits of extracellular nucleotide (eATP) scavenging over adenosine generation within the setting of inflammatory diseases remains unclear. Upcoming pre-clinical developments testing soluble forms of CD39 to hydrolyze eATP to AMP in sepsis and following cardiac surgery should clarify this question. We conclude by suggesting that exogenous CD39, CD73, and/or other ectonucleotidases may provide therapeutic benefits in critically ill patients.

Objective: This study aims to evaluate the antioxidant, anti-aging, and mitochondrial protective effects of JadeAging, a Chinese medicine-based longevity formulation, using the model organism Caenorhabditis elegans.

Methods: We used C. elegans to assess the impact of JadeAging and its individual components (rehmannia, poria, and ginseng) on various health metrics. RNA sequencing (RNA-seq) was performed to identify differentially expressed genes and their effects on biological pathways. Lifespan and healthspan assays were performed to evaluate cell vitality, whereas mitochondrial health was assessed using mitochondrial fragmentation analysis. Antioxidant capacity was determined by measuring protection against reactive oxygen species.

Results: Treatment with JadeAging did not significantly extend lifespan but showed improvements in healthspan, with treated animals exhibiting more vigorous movement over their lifespan. JadeAging and its components demonstrated significant antioxidant capacity, protecting C. elegans from the deleterious effects of paraquat-induced oxidative stress. Furthermore, JadeAging treatment significantly reduced mitochondrial fragmentation, indicating enhanced mitochondrial health. RNA-Seq data revealed downregulation of daf-2 and rsks-1 and upregulation of cpr-1, suggesting the activation of the Target of Rapamycin pathway and promotion of autophagy.

Conclusion: JadeAging exerts protective effects against oxidative stress and age-related mitochondrial decline, likely by modulating key longevity pathways. These findings support the positive effects of JadeAging and its components on health.

Introduction: Globally, respiratory infections remain a leading cause of mortality, with treatment efficacy increasingly challenged by antimicrobial resistance. This study aimed to investigate the role of serum metabolites in the prognosis of severe human pneumonia.

Methods: Untargeted and targeted serum metabolomics were performed on intensive care unit (ICU) patients. Experimental validation was conducted in a murine bacterial infection model and cellular models. RNA sequencing was used for mechanistic exploration to identify the signaling pathways regulated by the key metabolite.

Results: Valeric acid, a short-chain fatty acid, was significantly elevated in survivors compared with non-survivors of severe pneumonia. In the murine Klebsiella pneumoniae model, valeric acid treatment alleviated infection severity, reduced body weight loss, lung inflammation, and bacterial load. Mechanistically, RNA sequencing revealed that valeric acid suppresses IL-17-associated inflammation and upregulates pathways related to mucociliary clearance. We further delineated the underlying mechanism, finding that valeric acid acts as a histone deacetylase (HDAC) inhibitor, specifically targeting HDAC3. This inhibition activates the canonical Wnt/β-catenin signaling pathway, leading to the upregulation of the master transcriptional regulator Foxj1 and subsequent promotion of cilia assembly and function in airway epithelia.

Discussion: The findings establish a protective role for the gut microbiome-derived valeric acid in respiratory infections via the novel HDAC-Wnt-FOXJ1 axis, revealing its potential as a therapeutic agent to improve clinical outcomes.

Ischemia/reperfusion injury (IRI) refers to a condition in which ischemia is followed by reperfusion, leading to an exacerbation of the initial tissue damage. Currently, there are no specific therapeutic methods for IRI. Phytochemicals from natural products have the potential to develop noble drugs for IRI. Naringenin (NGE) and naringin (NG) are natural dietary flavonoids derived from ethnobotanical plants in Southeast and South Asia. NGE and NG have a wide range of pharmacological properties, including antioxidant, anti-apoptotic, and anti-inflammatory effects. As research on NGE and NG deepens, it has been found that they protect against IRI. We first summarize plant species containing NGE and NG from Southeast and South Asia in this article. Then, we highlight recent advances in NGE and NG for treating IRI in the myocardium, brain, intestines, kidneys, retinal, liver, spinal cord, skeletal muscles, and testicles. We find that NGE and NG possess antioxidant, anti-inflammatory, anti-apoptotic, anti-endoplasmic reticulum stress, anti-ferroptosis, anti-pyroptosis, and autophagy regulatory properties that protect organs from IRI. In addition, NGE and NG alleviate organ IRI through certain signaling pathways, including nuclear factor-κB, nuclear factor erythroid 2-related factor 2, phosphatidylinositol 3-kinase/AKT, cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes, sirtuin (SIRT) 1/SIRT 3, and hypoxia-inducible factor-1α. Furthermore, we investigate the interactions between these signaling pathways and inflammation, oxidative stress, and programmed cell death. Nevertheless, NGE and NG still face challenges related to pharmacokinetic interactions, bioavailability, and clinical safety assessments. Further studies will be needed to verify their safety and efficacy in clinical settings.

The immunomodulator Transferon Oral^® (TO) is a human Dialyzable Leukocyte Extract (hDLE), id est, a complex mixture of peptides smaller than 10 kDa derived from human buffy coats. TO reduces TNF-α, IL-6, and IgE; and induces IFN-γ levels, which makes it useful in the treatment of allergies, autoimmunity, and infections. Its complex composition has made it difficult to characterize its pharmacokinetic profile, target organs, and mechanism of action. This study focused on describing the biodistribution profile of TO peptides indirectly using in vivo imaging. The TO peptides were coupled to the fluorophore Alexa 488 and administered intravenously (IV), subcutaneously (SC), intraperitoneally (IP), intramuscularly (IM), and oropharingelly (ORO) to female and male Crl: Nu-Foxn1nu Nu/Nu nude mice. It was verified that the TO peptides linked to the fluorophore maintained their biological activity (increment of survival in a murine model of HSV-1 infection) as a critical quality control. The fluorescence was acquired using an IVIS imaging system. Parenteral administration routes showed consistent biodistribution of TO peptides from the site of administration to the cervical and axillary areas, except for the IM route, where no biodistribution pattern was observed. The IV route of administration reached maximum fluorescence the fastest, at 15 min, and the peptides remained in the study subjects for around 180 min in all routes. Interestingly, the TO peptides were absorbed via ORO and exhibited a biodistribution pattern similar to that of the parenteral routes. Elimination via glomerular filtration was observed for all administration routes, and accumulation of TO peptides in the axillary and lymph nodes, as well as the heart, was confirmed by ex vivo analysis. The results of this work are relevant because they identify how the peptide components of an hDLE are absorbed enterally and parenterally and consistently accumulate in immunologically relevant organs where they exert their immunomodulatory function. Furthermore, it sets the first precedent for indirectly describing the absorption, distribution, metabolism, and excretion processes of a drug composed of a myriad of molecules using in vivo imaging.

Background: The role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), which is one of the primary targets of statin drugs, in prostate cancer (PCa) remains controversial. This study aimed to investigate the causal relationship of genetically instrumented HMGCR inhibition with the therapeutic role of PCa through Mendelian randomization (MR) and validate the findings by cell experiments.

Methods: We selected single nucleotide polymorphisms (SNPs) associated with statins use by targeting HMGCR. We used three genome-wide association studies (GWASs) datasets for PCa: PCa (GWAS ID:ieu-b-85, Sample size = 140,254), PCa (GWAS ID:ieu-b-4809, Sample size = 182,625), PCa (GWAS ID:ebi-a-GCST006085, Sample size = 140,254). The inverse variance weighted (IVW) method served as the primary MR approach to validate the suitability of the selected SNPs and to explore the causal relationship between statins use and PCa. To assess the robustness of the MR findings, a comprehensive sensitivity analysis, steiger directionality tests and colocalization analyses were performed. Finally, we validated the MR findings by treating two PCa cell lines with Atorvastatin.

Results: We ultimately selected 7 SNPs associated with HMGCR. The IVW results indicated that HMGCR inhibition decreased the risk of PCa. Per 1 standard deviation (SD, mg/dL) decrease in low-density lipoprotein cholesterol (LDL-C) was associated with a 16.7% reduction in PCa risk: PCa (GWAS ID: ieu-b-85, Sample size = 140,254) (odds ratio (OR) = 0.833; 95% confidence interval (CI) = 0.726-0.954; P-adjusted = 0.014); Per 1 SD (mg/dL) decrease in LDL-C was associated with a 1.5% reduction in PCa risk: PCa (GWAS ID: ieu-b-4809, Sample size = 182,625) (OR = 0.985; 95% CI = 0.973-0.998; P-adjusted = 0.023) and 16.2% reduction in PCa risk: PCa (GWAS ID: ebi-a-GCST006085, Sample size = 140,254) (OR = 0.838; 95% CI = 0.734-0.956; P-adjusted = 0.014). Results of sensitivity analysis showed MR finding was robust. However, our colocalization results indicated that no shared genetic variants were found in the HMGCR region. Results of cell experiments also demonstrated that statins use could promote apoptosis of PCa cells.

Conclusion: HMGCR inhibition reduces the risk of PCa, and this protective effect is independent of its lipid-lowering action. Our findings provide strong genetic support for initiating RCTs to investigate the therapeutic potential of statins for partial PCa patients.

Hyperuricemia is a significant risk factor for gout, cardiovascular disease, and chronic kidney disease, and its global prevalence has continued to rise. Genome-wide association studies (GWAS) have made significant advances in elucidating the genetic basis of serum uric acid levels, identifying key loci such as SLC2A9, ABCG2, SLC22A12, GCKR, and HNF4A, while also revealing population heterogeneity and gene-environment interactions. Concurrently, traditional Chinese medicine (TCM) has demonstrated multi-component, multi-pathway regulatory effects on uric acid production, renal and intestinal excretion, inflammatory responses, and gut microbiota. This review summarizes recent GWAS advances in hyperuricemia and compiles experimental and mechanistic studies on TCM regulation of uric acid homeostasis over the past 5 years. Furthermore, the discussion section outlines current limitations in both GWAS and TCM research, proposes potential connections between them in specific regulatory processes, and explores possible directions for future mechanistic studies and the development of intervention strategies.