Continuous atmospheric pressure interfaced ion trap mass spectrometry with thermal desorption for detection of nonvolatile drugs.

The escalating need for prompt and highly sensitive on-site detection of trace-level drugs is fueling the advancement of miniature, high-performance mass spectrometers and analytical methodologies. In this study, a miniature continuous atmospheric pressure interfaced ion trap mass spectrometer integrated with thermal desorption acetone-assisted photoionization (TD-CAPI-ITMS) was developed for highly sensitive detection of nonvolatile drugs in saliva and blood. By strategically extending the sampling time of the TD-CAPI-ITMS to cover the entire desorption process, a remarkable two-order-of-magnitude enhancement in the signal intensity of individual drugs was observed. Moreover, the simultaneous detection of drug mixtures with widely varying boiling points and saturation vapor pressures was accomplished. Optimization of the parameters yielded a limit of detection (LOD) for ketamine and 5F-EMB-PICA of 1 pg/µL accompanied by a robust stability, as evidenced by a relative standard deviation (RSD) of 5.30 %. Combined with straightforward liquid-liquid extraction, the sensitivity of drugs in saliva as low as 10 pg/µL was achieved, which met the requirements of Chinese national standard GA1333-2017. Owing to its exceptional sensitivity, the matrix effect present in blood samples was significantly alleviated through dilution, allowing for accurate monitoring of antibiotic concentrations. The results underscore the substantial potential of the TD-CAPI-ITMS for lab-free applications in drug-related forensic analysis, therapeutic drug monitoring, and pharmacokinetic studies.

Dissection of triple-negative breast cancer microenvironment and identification of potential therapeutic drugs using single-cell RNA sequencing analysis.

Breast cancer remains a leading cause of mortality in women worldwide. Triple-negative breast cancer (TNBC) is a particularly aggressive subtype characterized by rapid progression, poor prognosis, and lack of clear therapeutic targets. In the clinic, delineation of tumor heterogeneity and development of effective drugs continue to pose considerable challenges. Within the scope of our study, high heterogeneity inherent to breast cancer was uncovered based on the landscape constructed from both tumor and healthy breast tissue samples. Notably, TNBC exhibited significant specificity regarding cell proliferation, differentiation, and disease progression. Significant associations between tumor grade, prognosis, and TNBC oncogenes were established via pseudotime trajectory analysis. Consequently, we further performed comprehensive characterization of the TNBC microenvironment. A crucial epithelial subcluster, E8, was identified as highly malignant and strongly associated with tumor cell proliferation in TNBC. Additionally, epithelial-mesenchymal transition (EMT)-associated fibroblast and M2 macrophage subclusters exerted an influence on E8 through cellular interactions, contributing to tumor growth. Characteristic genes in these three cluster cells could therefore serve as potential therapeutic targets for TNBC. The collective findings provided valuable insights that assisted in the screening of a series of therapeutic drugs, such as pelitinib. We further confirmed the anti-cancer effect of pelitinib in an orthotopic 4T1 tumor-bearing mouse model. Overall, our study sheds light on the unique characteristics of TNBC at single-cell resolution and the crucial cell types associated with tumor cell proliferation that may serve as potent tools in the development of effective anti-cancer drugs.

Metabolic Reprogramming in Glioblastoma Multiforme: A Review of Pathways and Therapeutic Targets.

Glioblastoma (GBM) is an aggressive and highly malignant primary brain tumor characterized by rapid growth and a poor prognosis for patients. Despite advancements in treatment, the median survival time for GBM patients remains low. One of the crucial challenges in understanding and treating GBMs involves its remarkable cellular heterogeneity and adaptability. Central to the survival and proliferation of GBM cells is their ability to undergo metabolic reprogramming. Metabolic reprogramming is a process that allows cancer cells to alter their metabolism to meet the increased demands of rapid growth and to survive in the often oxygen- and nutrient-deficient tumor microenvironment. These changes in metabolism include the Warburg effect, alterations in several key metabolic pathways including glutamine metabolism, fatty acid synthesis, and the tricarboxylic acid (TCA) cycle, increased uptake and utilization of glutamine, and more. Despite the complexity and adaptability of GBM metabolism, a deeper understanding of its metabolic reprogramming offers hope for developing more effective therapeutic interventions against GBMs.

Barriers to access of precision guided therapies for children with high-risk cancer.

INTRODUCTION: Accessing compassionate access schemes to obtain novel therapeutic agents for children with hard-to-treat cancers can be fraught with challenges such as regulatory barriers and limited resources. This study aimed to explore clinician perspectives on the barriers, impacts and ethical considerations of accessing novel therapeutic agents within the context of a paediatric oncology precision medicine trial. METHODS: We gathered data from 37 semi-structured interviews with paediatric oncologists participating in the PRecISion Medicine for Children with Cancer (PRISM) study, a precision medicine clinical trial in Australia. The interviews, conducted over 2 years, focused on paediatric oncologist's experiences with the PRISM trial. Interviews were re-analysed to identify themes related to access pathways and any challenges in obtaining novel agents through thematic analysis. The resulting thematic framework was discussed and refined by a multidisciplinary team. RESULTS: Three main themes were identified: (i) barriers to access, including poor drug availability, lack of evidence and the time burden of the application process; (ii) impacts of inaccessibility, encompassing medical consequences and financial burden on families; and (iii) ethical considerations, centred around balancing realistic expectations and providing compassionate care to patients and families. Paediatric oncologists expressed frustration with the complex regulatory landscape and the lack of systematic reporting on applications and outcomes of obtaining novel agents. Lengthy wait times for decision notifications were also highlighted, raising concerns about missed therapeutic opportunities for patients. CONCLUSION: This study provides insight to the challenges faced when seeking access to novel therapies for paediatric oncology patients. There is a clear need for improved communication, streamlining processes and increased resources to facilitate access to novel agents. Further resource development is necessary to address these complexities in accessing novel therapy agents to ultimately ensure equitable and timely access.

Vascular endothelium: The interface for multiplex signal transduction.

As the innermost monolayer of the vasculature, endothelial cells (ECs) serve as the interface for multiplex signal transduction. Directly exposed to blood-borne factors, both endogenous and exogenous, ECs actively mediate vascular homeostasis and represent a therapeutic target against cardiometabolic diseases. ECs act as the first-line gateway between gut-derived substances and vasculature. Additionally, ECs convert blood flow-exerted hemodynamic forces into downstream biochemical signaling to modulate vascular pathophysiology. Besides, ECs can sense other forms of stimuli, like cell extrusion, thermal stimulation, photostimulation, radiation, magnetic field, noise, and gravity. Future efforts are still needed to deepen our understanding on endothelial biology.

Endothelial cell dysfunction and targeted therapeutic drugs in sepsis.

Sepsis is a life-threatening organ dysfunction caused by an abnormal host response to microbial infections. During its pathogenesis, vascular endothelial cells (ECs) play a pivotal role as essential components in maintaining microcirculatory homeostasis. This article aims to comprehensively review the multifaceted physiological functions of vascular ECs, elucidate the alterations in their functionality throughout the course of sepsis, and explore recent advancements in research concerning sepsis-related therapeutic drugs targeting ECs.

Corrigendum: A novel model based on necroptosis to assess progression for polycystic ovary syndrome and identification of potential therapeutic drugs.

[This corrects the article DOI: 10.3389/fendo.2023.1193992.].

Therapeutic Effects of Natural Products on Liver Cancer and Their Potential Mechanisms.

Liver cancer ranks third globally among causes of cancer-related deaths, posing a significant public health challenge. However, current treatments are inadequate, prompting a growing demand for novel, safe, and effective therapies. Natural products (NPs) have emerged as promising candidates in drug development due to their diverse biological activities, low toxicity, and minimal side effects. This paper begins by reviewing existing treatment methods and drugs for liver cancer. It then summarizes the therapeutic effects of NPs sourced from various origins on liver cancer. Finally, we analyze the potential mechanisms of NPs in treating liver cancer, including inhibition of angiogenesis, migration, and invasion; regulation of the cell cycle; induction of apoptosis, autophagy, pyroptosis, and ferroptosis; influence on tumor metabolism; immune regulation; regulation of intestinal function; and regulation of key signaling pathways. This systematic review aims to provide a comprehensive overview of NPs research in liver cancer treatment, offering a foundation for further development and application in pharmaceuticals and functional foods.

Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review.

Tau protein is a microtubule-associated protein that is widely distributed in the central nervous system and maintains and regulates neuronal morphology and function. Tau protein aggregates abnormally and forms neurofibrillary tangles in neurodegenerative diseases, disrupting the structure and function of neurons and leading to neuronal death, which triggers the initiation and progression of neurological disorders. The aggregation of tau protein in neurodegenerative diseases is associated with post-translational modifications, which may affect the hydrophilicity, spatial conformation, and stability of tau protein, promoting tau protein aggregation and the formation of neurofibrillary tangles. Therefore, studying the role of tau protein in neurodegenerative diseases and the mechanism of aberrant aggregation is important for understanding the mechanism of neurodegenerative diseases and finding therapeutic approaches. This review describes the possible mechanisms by which tau protein promotes neurodegenerative diseases, the post-translational modifications of tau protein and associated influencing factors, and the current status of drug discovery and development related to tau protein, which may contribute to the development of new therapeutic approaches to alleviate or treat neurodegenerative diseases.

Novel Therapies for ANCA-associated Vasculitis: Apilimod Ameliorated Endothelial Cells Injury through TLR4/NF-κB Pathway and NLRP3 Inflammasome.

BACKGROUND: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a rapidly progressive form of glomerulonephritis for which effective therapeutic drugs are currently lacking, and its underlying mechanism remains unclear. AIMS: This study aimed to investigate new treatment options for AAV through a combination of bioinformatics analysis and cell molecular experiments. METHODS: The research utilized integrated bioinformatics analysis to identify genes with differential expression, conduct enrichment analysis, and pinpoint hub genes associated with AAV. Potential therapeutic compounds for AAV were identified using Connectivity Map and molecular docking techniques. In vitro experiments were then carried out to examine the impact and mechanism of apilimod on endothelial cell injury induced by MPO-ANCA-positive IgG. RESULTS: The findings revealed a set of 374 common genes from differentially expressed genes and key modules of WGCNA, which were notably enriched in immune and inflammatory response processes. A proteinprotein interaction network was established, leading to the identification of 10 hub genes, including TYROBP, PTPRC, ITGAM, KIF20A, CD86, CCL20, GAD1, LILRB2, CD8A, and COL5A2. Analysis from Connectivity Map and molecular docking suggested that apilimod could serve as a potential therapeutic cytokine inhibitor for ANCA-GN based on the hub genes. In vitro experiments demonstrated that apilimod could mitigate tight junction disruption, endothelial cell permeability, LDH release, and endothelial activation induced by MPO-ANCA-positive IgG. Additionally, apilimod treatment led to a significant reduction in the expression of proteins involved in the TLR4/NF-κB and NLRP3 inflammasome-mediated pyroptosis pathways. CONCLUSION: This study sheds light on the potential pathogenesis of AAV and highlights the protective role of apilimod in mitigating MPO-ANCA-IgG-induced vascular endothelial cell injury by modulating the TLR4/ NF-kB and NLRP3 inflammasome-mediated pyroptosis pathway. These findings suggest that apilimod may hold promise as a treatment for AAV and warrant further investigation.

Pan-cancer exploration of oncogenic and clinical impacts revealed that HOXA9 is a diagnostic indicator of tumorigenesis.

Homeodomain transcription factor A9 (HOXA9) is a member of the HOX cluster family of transcription factors that are crucially involved in embryo implantation, morphogenesis, body axis development, and endothelial cell differentiation. Despite numerous reports on its aberrant expression in a few malignancies, the molecular and functional complexity of HOXA9 across cancers remains obscure. We aimed to analyze the dynamic role of HOXA9 across cancers by identifying, analyzing, and understanding its multiple modes of regulation and functional implications and identifying possible therapeutic avenues. We conducted a comprehensive analysis to determine the role of HOXA9 across cancers. This approach involved the integration of large-scale datasets from public repositories such as the Genomic Data Commons, specifically the Cancer Genome Atlas (GDC-TCGA), across 33 different cancer types. The multiple modes of HOXA9 regulation by genetic and epigenetic factors were determined using online tools, which comprised experimentally validated observations. Furthermore, downstream pathways were identified by predicting the targets of HOXA9 and by performing functional enrichment analysis. We also assessed the clinical significance of HOXA9 in terms of prognosis and stage stratification. This study evaluated the correlation between HOXA9 and tumor-infiltrating molecules and discussed its association with therapeutically approved antineoplastic drugs. HOXA9 was significantly upregulated in 9 tumors and downregulated in 2 cancers. The deregulation of HOXA9 is primarily attributed to epigenetic factors, including promoter DNA methylation and noncoding RNAs (ncRNAs). The HOXA9 transcription factor interacts with PBX/MEIS cofactors and regulates multiple genes involved in cancer-associated EMT, autophagy, the cell cycle, metabolic pathways, Wnt signaling, TGF-ß signaling, the AMPK pathway, PI3K/AKT signaling, and NF-κB signaling, thereby establishing control over downstream mechanisms. Differential expression in various clinical stages across cancers was shown to have prognostic significance and to be correlated with tumor-infiltrating immune molecules. The assessment of the correlation of HOXA9 expression with approved antineoplastic drugs revealed that targeting HOXA9 could be the most reliable strategy for preventing cancer progression. HOXA9 is upregulated in the majority of malignancies and drives cancer progression by regulating multiple signaling mechanisms. Hence, HOXA9 could be a reliable diagnostic indicator and a potential therapeutic candidate for solid cancer types.

DDCM: A Computational Strategy for Drug Repositioning Based on Support-Vector Regression Algorithm.

Computational drug-repositioning technology is an effective tool for speeding up drug development. As biological data resources continue to grow, it becomes more important to find effective methods to identify potential therapeutic drugs for diseases. The effective use of valuable data has become a more rational and efficient approach to drug repositioning. The disease-drug correlation method (DDCM) proposed in this study is a novel approach that integrates data from multiple sources and different levels to predict potential treatments for diseases, utilizing support-vector regression (SVR). The DDCM approach resulted in potential therapeutic drugs for neoplasms and cardiovascular diseases by constructing a correlation hybrid matrix containing the respective similarities of drugs and diseases, implementing the SVR algorithm to predict the correlation scores, and undergoing a randomized perturbation and stepwise screening pipeline. Some potential therapeutic drugs were predicted by this approach. The potential therapeutic ability of these drugs has been well-validated in terms of the literature, function, drug target, and survival-essential genes. The method's feasibility was confirmed by comparing the predicted results with the classical method and conducting a co-drug analysis of the sub-branch. Our method challenges the conventional approach to studying disease-drug correlations and presents a fresh perspective for understanding the pathogenesis of diseases.

A systematic review: Sinomenine.

Sinomenine (SIN), an alkaloid derived from the traditional Chinese medicine, Caulis Sinomenii, has been used as an anti-inflammatory drug in China for over 30 years. With the continuous increase in research on the pharmacological mechanism of SIN, it has been found that, in addition to the typical rheumatoid arthritis (RA) treatment, SIN can be used as a potentially effective therapeutic drug for anti-tumour, anti-renal, and anti-nervous system diseases. By reviewing a large amount of literature and conducting a summary analysis of the literature pertaining to the pharmacological mechanism of SIN, we completed a review that focused on SIN, found that the current research is insufficient, and offered an outlook for future SIN development. We hope that this review will increase the public understanding of the pharmacological mechanisms of SIN, discover SIN research trial shortcomings, and promote the effective treatment of immune diseases, inflammation, and other related diseases.

Receptor-Mediated and Receptor-Independent Actions of Melatonin in Vertebrates.

Melatonin (N-acetyl-5-methoxytryptamine) is an indolamine that is synthesized from tryptophan in the pineal glands of vertebrates through four enzymatic reactions. Melatonin is a quite unique bioactive substance, characterized by a combination of both receptor-mediated and receptor-independent actions, which promote the diverse effects of melatonin. One of the main functions of melatonin, via its membrane receptors, is to regulate the circadian or seasonal rhythm. In mammals, light information, which controls melatonin synthesis, is received in the eye, and transmitted to the pineal gland, via the suprachiasmatic nucleus, where the central clock is located. Alternatively, in many vertebrates other than mammals, the pineal gland cells, which are involved in melatonin synthesis and secretion and in the circadian clock, directly receive light. Recently, it has been reported that melatonin possesses several metabolic functions, which involve bone and glucose, in addition to regulating the circadian rhythm. Melatonin improves bone strength by inhibiting osteoclast activity. It is also known to maintain brain activity during sleep by increasing glucose uptake at night, in an insulin-independent manner. Moreover, as a non-receptor-mediated action, melatonin has antioxidant properties. Melatonin has been proven to be a potent free radical scavenger and a broad-spectrum antioxidant, even protecting organisms against radiation from space. Melatonin is a ubiquitously distributed molecule and is found in bacteria, unicellular organisms, fungi, and plants. It is hypothesized that melatonin initially functioned as an antioxidant, then, in vertebrates, it combined this role with the ability to regulate rhythm and metabolism, via its receptors.

Research status of pathogenesis of anxiety or depression after percutaneous coronary intervention and Traditional Chinese Medicine intervention.

ETHNIC PHARMACOLOGICAL RELEVANCE: Anxiety or depression after percutaneous coronary intervention (PCI) is a common clinical disease. Currently, conventional pharmacotherapy primarily involves the administration of anxiolytic or antidepressant medications in conjunction with anticoagulants, antiplatelet agents, and other cardiovascular drugs. However, challenges such as drug dependence, adverse reactions and related concerns persist in the treatment of this disease. Numerous pertinent studies have demonstrated that Traditional Chinese Medicine (TCM) exhibits significant therapeutic efficacy and distinctive advantages in managing post-PCI anxiety or depression. AIM OF THIS REVIEW: This review attempted to summarize the characteristics of TCM for treating anxiety or depression after PCI, including single Chinese herbs, Chinese medicine monomers, compound TCM prescriptions, TCM patented drugs, and other TCM-related treatment methods, focusing on the analysis of the relevant mechanism of TCM treatment of this disease. METHODS: By searching the literature on treating anxiety or depression after PCI with TCM in PubMed, Web of Science, CNKI, and other relevant databases, this review focuses on the latest research progress of TCM treatment of this disease. RESULTS: In the treatment of anxiety or depression after PCI, TCM exerts significant pharmacological effects such as anti-inflammatory, antioxidant, anti-anxiety or anti-depression, cardiovascular and cerebrovascular protection, and neuroprotection, mainly by regulating the levels of related inflammatory factors, oxidative stress markers, neurotransmitter levels, and related signaling pathways. TCM has a good clinical effect in treating anxiety or depression after PCI with individualized treatment. CONCLUSIONS: TCM has terrific potential and good prospects in the treatment of anxiety or depression after PCI. The main direction of future exploration is the study of the mechanism related to Chinese medicine monomers and the large sample clinical study related to compound TCM prescriptions.

Unraveling the underlying mechanisms of reduced amyloidogenic properties in human calcitonin via double mutations.

The therapeutic efficacy of peptide-based drugs is commonly hampered by the intrinsic propensity to aggregation. A notable example is human calcitonin (hCT), a peptide hormone comprising 32 amino acids, which is synthesized and secreted by thyroid gland parafollicular cells (C cells). This hormone plays a vital role in regulating blood calcium levels and upholding bone integrity. Despite its physiological importance, utilizing hCT as a drug is hampered by its inclination to form amyloid. To address this limitation, an alternative is provided by salmon calcitonin (sCT), which possesses a lower aggregation propensity. Although sharing the same disulfide bond at the N terminus as hCT, sCT differs from hCT at a total of 16 amino acid positions. However, due to the dissimilarity in sequences, using sCT as a clinical replacement occasionally results in adverse side effects in patients. Earlier investigations have highlighted the significant roles of Tyr-12 and Asn-17 in inducing the formation of amyloid fibrils. By introducing double mutations at these sites, the ability to hinder aggregation can be significantly augmented. This study delves into the oligomerization and helical structure formation of the hCT double mutant (Y12LN17H hCT, noted as DM hCT), as well as two single mutants (Y12L and N17H), aiming to elucidate the mechanism behind hCT fibrillization. In addition, computational prediction tools were employed again to identify potential substitutes. Although the results yielded were not entirely satisfactory, a comparison between the newly examined and previously found hCT double mutants provides insights into the reduced aggregation propensity of the latter. This research endeavor holds the promise of informing the design of more effective therapeutic peptide drugs in the future.

Synergetic approaches of fucoidan and trabectedin complex coated PLGA nanoparticles effectively suppresses proliferation and induce apoptosis for the treatment on non-small cell lung cancer.

Traditional methods of treating lung cancer have not been very effective, contributing to the disease's high incidence and death rate. As a result, Fn/Tn-PLGA NPs, a novel directed fucoidan and trabectedin complex loaded PLGA nanoparticle, were produced to investigate the role of developing therapeutic strategies for NSCLC and A549 cell lines. Quantitative real-time polymerase chain reaction was used to examine protein expression and mRNA expression, respectively. Protein activity was knocked down using specific inhibitors and short disrupting RNA transfection. Lastly, cancer cell lines H1299 and A549 were subjected to an in vitro cytotoxicity experiment. Commercial assays were used to assess the levels of cell viability, ROS and proliferation found that Fn/Tn-PLGA NPs effectively killed lung cancer cells. To examine cell death, annexin flow cytometry was employed. In addition, a scratch-wound assay was conducted to assess the migration effects of Fn/Tn-PLGA NPs in a laboratory setting. Finally, PLGA NPs covered with a mix of fucoidan and trabectedin could be a good vehicle for targeting cancerous tissues with chemotherapeutic drugs.