Current Medicinal Chemistry - Online First

Follicular lymphoma (FL) is the most prevalent form of indolent lymphoma, characterized by intermittent relapse and remission periods. This study aims to identify potential biomarker genes for FL and elucidate their roles in the disease.

FL-related microarray datasets were downloaded from the Gene Expression Omnibus database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were conducted to identify potential hub genes. Various machine learning algorithms were applied to improve gene selection accuracy and predictive performance. Mendelian randomization (MR) analysis was carried out to identify genes with causal relationships to FL. Functional enrichment analysis was performed to explore the underlying mechanisms. Finally, the identified biomarker gene was validated in clinical samples using quantitative real-time PCR.

A total of 60 hub genes were identified through differential expression analysis and WGCNA. Subsequently, 11 characteristic genes were identified using machine learning algorithms. MR analysis revealed 173 genes with causal effects on FL, leading to the identification of one key co-expressed gene, N-myc downstream-regulated gene 2 (NDRG2), as a potential biomarker for FL. NDRG2 demonstrated strong predictive performance. Functional enrichment analysis revealed significant associations between NDRG2 and immune-related pathways in FL. Validation in clinical samples confirmed the relevance of NDRG2 as a biomarker.

The integration of machine learning and MR successfully identified NDRG2 as a promising biomarker with a causal relationship to FL. Validation in clinical samples reinforced the reliability of these findings in clinical practice.

By combining machine learning, MR, and experimental validation, NDRG2 was identified and validated as a promising biomarker for FL.

This study aimed to evaluate cyclophilin (CypA) levels in patients with diabetes mellitus (DM) before and after treatment. Metabolic variables, such as weight, blood pressure, and plasma glucose, were assessed in these patients.

This prospective cross-sectional study was conducted over 24 weeks. We included 38 patients with DM. After confirming the diagnosis of type 2 diabetes, SGLT2i (empagliflozin vs. dapagliflozin) therapy was prescribed to the patients. Weight, body mass index (BMI), waist circumference, body fat ratio, fasting plasma glucose, glycated hemoglobin (HbA1c, %), and CypA levels were measured at 0, 12, and 24 weeks. Patients in the drug subgroup were divided into 2 groups: Empagliflozin (Empa, n=16) and Dapagliflozin (Dapa, n=22).

Weight (p<0.001), body mass index (p<0.001), percentage of body fat (p<0.001), diastolic blood pressure (p=0.006), fasting plasma glucose (p<0.001), HbA1c (p<0.001), serum creatinine (p<0.001), and CypA (p<0.001) levels after the SGLT2i therapy were statistically decreased compared to pre-treatment values in all patients. When comparing drug subgroups, significant decreases in weight (p=0.013) and percentage body fat (p=0.01) were observed in the Empa group compared with the Dapa group at 24 weeks. Changes in FPG (p=0.399), HbA1c (p=0.102), and CypA (p=0.329) between the two groups seemed to be similar.

In a 24-week study, significant reductions in weight, BMI, body fat percentage, HbA1c, FPG, and diastolic blood pressure with SGLT2i have been reported in those patients. Furthermore, we also observed that cyclophilin A, an oxidative marker of atherosclerosis, plays a destructive role in cardiomyocyte levels, which are decreased during the SGLT2i therapy.

Beyond the improvement of metabolic parameters, SGLT2 treatment reduced CypA levels in patients with DM regardless of drug subgroups. These drugs may further prevent the presence of cardiovascular diseases.

Papillary thyroid carcinoma (PTC), the most common thyroid malignancy, presents with multiple variants. This study aimed to identify potential biomarkers and therapeutic candidates for PTC through computational analyses and molecular docking.

Gene expression data related to PTC were obtained from the TCGA-THCA and GEO datasets (GSE35570 and GSE33630) to identify differentially expressed genes (DEGs). Functional enrichment analysis was performed on the DEGs, followed by construction of a protein-protein interaction (PPI) network. Hub genes were identified using recursive feature elimination (RFE) and LASSO regression analyses. A nomogram incorporating these hub genes was developed, and its diagnostic performance was evaluated using receiver operating characteristic (ROC) curves. Furthermore, the relationship between hub genes and immune cell infiltration was investigated. Potential drug candidates targeting the hub genes were predicted and validated through molecular docking.

Common DEGs across the three datasets were enriched in pathways such as ECM-receptor interaction, proteoglycans in cancer, and cell adhesion molecules. Significantly enriched GO terms included ‘binding,’ ‘receptor activity,’ ‘integral component of membrane,’ ‘cytoplasm,’ ‘cell adhesion,’ and ‘immune response.’ A PPI network was constructed by intersecting the common DEGs with PTC-related targets. Machine learning algorithms identified three hub genes: SRY-box transcription factor 4 (SOX4), cyclin D1 (CCND1), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1). These hub genes exhibited differential expression in PTC and were used to construct a reliable diagnostic model. Furthermore, molecular docking revealed stable binding between CCND1 and Tipifarnib, suggesting potential therapeutic relevance.

While previous studies have applied bioinformatics and molecular docking in PTC research, this study uniquely integrates both approaches to identify the hub gene CCND1 and its potential targeting drug, Tipifarnib, as promising molecular markers and therapeutic candidates for PTC.

The hub gene CCND1 and its targeting drug candidate Tipifarnib may contribute to PTC treatment.

Ischemic stroke (IS) is a major cause of death and disability worldwide. The transcriptional mechanism of neutrophil extracellular trap-related genes (NRGs) and their diagnostic potential remain unknown. This study aims to explore the mechanism of NRGs in IS through machine learning and single-cell RNA sequencing (scRNA-seq).

We conducted differential analysis and functional enrichment analysis on the GEO dataset. Machine learning algorithms were used to identify NRGs related to IS. ScRNA-seq analysis was employed to verify the expression of NRGs in different cell types, and cellchat was used to explore the interactions between cell types in the IS. The expression of Eno1 was also verified in the mouse model of middle cerebral artery occlusion (MCAO).

We identified 26 differentially expressed NRGs (DE-NRGs). The diagnostic models constructed from five DE-NRGs (ENO1, HMGB1, ILK, ORAI1, SUCNR1) demonstrated high predictive ability. Single-cell analysis revealed that NRGs were highly expressed in the IS group. The experiment verified the significant upregulation of Eno1.

This study employed machine learning and scRNA-seq to identify the DE-NRGs-related diagnostic model, providing a certain theoretical basis for IS risk stratification. More experiments are needed to verify the role of DE-NRGs in IS in the future.

This study identified DE-NRGs with diagnostic capabilities in IS and verified their high expression through scRNA and experimental methods. DE-NRGs may be potential therapeutic targets for IS.

More robust 4-substituted 7-chloroquinolines have been investigated for their diverse properties. However, there is still no systematic study that correlates the effects of the side chain at the 4-position of chloroquine and hydroxychloroquine derivatives with their lipophilicity, antimicrobial and toxicity properties.

To this end, a cleaner and facile approach was planned to obtain nineteen 4- substituted 7-chloroquinolines, whose influence of the substituent group and side chain extension at the 4-position on their properties was studied.

4-Alkoxy/amino-7-chloroquinolines were prepared by a nucleophilic aromatic substitution (SNAr) reaction between 4,7-dichloroquinoline and alcohols/amines, evaluated for their in silico ADMET test, in vitro antimicrobial activity against Gram-(+) and Gram-(−) bacteria, and Candida albicans fungus, and in vitro toxicity on Artemia salina larvae.

4-Alkoxy/amino-7-chloroquinolines were obtained in yields ranging from 81 to 100%. The best results showed antimicrobial activity against Pseudomonas aeruginosa for 4-amino-7-chloroquinolines 6-8, with halos greater than 20 mm, and against C. albicans for 4-amino-7-chloroquinolines 1-3, with halos close to 30 mm. A correspondence between Minnow toxicity prediction and in vitro toxicity on A. salina larvae was observed, where compounds 3 and 14, with R = Pent, were both predicted to have high acute toxicity (log LC50 < -0.3) and classified as highly toxic (LC50 < 100 µg mL^-1). It seems that increased lipophilicity in the side chain is harmful to A. salina larvae.

Considering the results for compounds 1-3 and 6-8 with greater activity against C. albicans and P. aeruginosa, respectively, especially for 4-amino-7-chloroquinolines 6 and 7, which are slightly toxic on A. salina larvae (LC50 500-1000 µg mL^-1), their antimicrobial studies deserve to be continued by the determination of Minimum Inhibitory Concentration (MIC) values.

The absence of physiologically relevant models for neuroinflammatory brain disorders, such as multiple sclerosis (MS), highlights the need for improved drug screening platforms. To bridge this gap, this study aimed to develop a human brain organoid (hBO) model incorporating essential neural cell types, including astrocytes, microglia, and oligodendrocytes.

hBOs were generated from H9 stem cells, and neuroinflammatory characteristics were elicited by lipopolysaccharide (LPS). The expression of specific neuronal and inflammatory markers was assessed through qRT-PCR, immunofluorescence staining (IFS), and ELISA.

IFS of mature hBOs with anti-SOX2, anti-SATB2, anti-MAPT, anti-GFAP, anti-MBP, and anti-IBA1 antibodies and images collected with the confocal microscope confirmed the differentiation of H9 cells into cortical neurons, astrocytes, microglia, and oligodendrocyte cell types. Elevated GFAP, IBA1, NF-κB, and IL-6 levels, along with reduced CNPase expression with LPS treatment, were considered reflective of MS-like pathology and were used to test fingolimod and its derivatives. Fingolimod and all its derivatives, specifically ST-1505, decreased MAPT (2.1-fold in ELISA, 1.7-fold in IFS), GFAP (1.8-fold in IFS), TNFα (5.4-fold in qRT-PCR), and FABP (1.5-fold in ELISA) levels, and increased IL-10 (11-fold in qRT-PCR) and MBP (2.9-fold in IFS) levels.

The present data collectively showed LPS to evoke neuroinflammation in the hBO model, while fingolimod and its derivatives, particularly ST-1505, exhibited significant anti-inflammatory and neuroprotective properties by counteracting these evoked changes in the hBO model.

The findings supported the applicability of brain organoids as a model system for drug screening studies for neuroinflammatory brain diseases.

Several pathological conditions, including glaucoma, malignant brain tumors, and renal, gastric, and pancreatic carcinomas, are commonly associated with carbonic anhydrase type II (CA-II). Additionally, CA-II plays a critical role in regulating bicarbonate concentration in the eyes. The inhibition of CA-II reduces aqueous humor production and thus lowers intraocular pressure associated with glaucoma.

This study aimed to synthesize potent CA-II inhibitors, 5-nitro-1H-benzo[d]imidazole-2(3H)-thione (5NBIT) and acylhydrazone derivatives (1-13).

In this study, a new series of potent CA-II inhibitors, 5-nitro-1H-benzo[d]imidazole-2(3H)-thione (5NBIT) and acylhydrazone derivatives (1-13), were synthesized and characterized by IR, NMR, UV and mass spectroscopy and evaluated against bovine carbonic anhydrase-II (bCA-II).

Interestingly, most of the compounds showed better inhibition than the standard drug, acetazolamide (IC50: 18.2±0.51 µM), such as compounds 1 (IC50: 10.5±0.81 µM), 2 (IC50: 11.3±0.36 µM), 3 (IC50: 16.5±0.53 µM), 4 (IC50: 15.8±1.02 µM), 5 (IC50: 13.7±1.03 µM), and 9 (IC50: 12.2±1.03 µM). Among the synthesized compounds, compound 7 (IC50: 8.2±0.32 µM) exhibited the highest and compound 6 (IC50: 27.6±0.39 µM) showed the lowest inhibition. Structure-activity relationships suggest that the presence of nitro group on the phenyl ring contributed significantly to the overall inhibitory activity. Molecular docking of all the active compounds was performed to predict their binding behavior, which indicated good agreement between docking and experimental findings. Moreover, the MD simulation of compound 7 also showed excellent binding behavior and binding energy within the binding cavity of bCA-II.

These findings suggest that the synthesized 5NBIT and acylhydrazone derivatives exhibited potent CA-II inhibition, with several compounds outperforming the standard drug acetazolamide. These results provide valuable insights for the development of novel CA-II inhibitors with potential therapeutic applications in glaucoma and other related conditions.

“Penumbra freezing” aims to extend vascular recanalization treatment to acute ischemic stroke (AIS) patients beyond the standard time window by preserving the ischemic penumbra. Efficient biomarkers are crucial for identifying patients eligible for AIS treatment.

This study enrolled 141 AIS patients who exceeded the conventional treatment window. Using CT perfusion imaging, patients were categorized into “penumbra freezing” and “non-penumbra freezing” groups based on the EXTEND criteria. Multiple regression analysis assessed the association of nine baseline factors and five blood lipid indicators with “penumbra freezing.” Diagnostic accuracy was evaluated using ROC curves. Mendelian randomization (MR) analysis validated these findings using blood lipid indicators as exposures and penumbra biomarkers as outcomes.

Among AIS patients beyond the treatment window, males exhibited better penumbra preservation (OR=0.243, 95% CI=0.072-0.813, p=0.022), while those with hyperlipidemia showed poorer preservation (OR=2.429, 95% CI=1.027-7.747, p=0.043). In the “penumbra freezing” group, ApoA1 levels were significantly lower (1.29 ± 0.03 g/L) compared to the “non-penumbra freezing” group (1.42 ± 0.06 g/L, p=0.034). Conversely, Lp(a) levels were significantly higher in the “penumbra freezing” group (304.63 ± 52.44 mg/L) than in the “non-penumbra freezing” group (110.26 ± 40.71 mg/L, p=0.034). Higher ApoA1 levels increased the likelihood of “non-penumbra freezing” beyond the time window (OR=3.206, 95% CI=1.034-9.938, p=0.044), while elevated Lp(a) levels reduced this likelihood (OR=0.075, 95% CI=0.007-0.848, p=0.036). MR analysis confirmed genetic associations of ApoA1 and Lp(a) with penumbra biomarkers.

ApoA1 and Lp(a) may be linked to ischemic penumbra status, but further validation is needed due to limitations in sample size and study methodology.

ApoA1 and Lp(a) are promising biomarkers for identifying AIS patients eligible for “penumbra freezing,” suggesting the potential to extend the treatment window.

Coronary atherosclerotic disease (CAD), clinically manifesting as progressive coronary atherosclerosis (As), involves endothelial cell (EC) dysfunction. HYMAI may contribute to atherogenesis by acting on ECs, but its regulation of endothelial injury and role in As pathogenesis remain unclear.

HYMAI expression was assessed via PCR array in blood samples from healthy individuals, patients with premature coronary atherosclerotic disease (PCAD), and patients with mature coronary atherosclerotic disease (MCAD) (each group consisting of 4 males and 2 females). Using male ApoE^−/− and LDLR^−/− mice fed with a high-fat diet (HFD) to model As, we evaluated the effects of endothelial-specific HYMAI overexpression on aortic lesions. Autophagy and apoptosis were analyzed in ox-LDL-treated human coronary artery endothelial cells (HCAECs).

HYMAI levels increased sequentially in healthy individuals, PCAD, and MCAD patients. In HFD-fed ApoE^−/− and LDLR^−/− mice, aortic atherosclerosis progressed with age, while HYMAI expression in aortic tissue declined. HYMAI overexpression in ECs promoted autophagy and attenuated atherosclerosis. In vitro, ox-LDL suppressed HYMAI, triggering autophagic inhibition and apoptotic activation in HCAECs. HYMAI overexpression rescued ox-LDL-impaired autophagy and suppressed apoptosis through the miR-19a-3p/ATG14 pathway. MiR-19a-3p overexpression reversed autophagic rescue and promoted apoptosis by repressing ATG14.

HYMAI upregulation counteracts ox-LDL-treated endothelial autophagic inhibition via the miR-19a-3p/ATG14 pathway, rescuing apoptosis and attenuating As in both in vivo and in vitro settings.

Our results demonstrated that HYMAI attenuated As progression in As mice and ox-LDL-treated HCAECs by enhancing endothelial autophagy through the miR-19a-3p/ATG14 axis. These findings establish HYMAI as a novel regulatory mechanism and provide a potential druggable target for As and CAD.

Klotho is a multifunctional protein with anti-aging properties that plays a role in regulating vitamin D and phosphate metabolism. Sarcopenia is characterized by the loss of muscle mass and strength and is an important public health concern due to its negative effects on health. The aim of this study was to investigate the association between α-Klotho levels and the frequency of sarcopenia in a diverse population.

This study analyzed data from 1,250 participants in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2016. Participants were divided into four subgroups based on serum α-Klotho levels. Sarcopenia was assessed using skeletal muscle index and handgrip strength measurements. Multivariable logistic regression analysis was used to determine the association between serum α-Klotho levels and sarcopenia.

There was a significant difference in serum α-Klotho levels between patients with sarcopenia and patients without sarcopenia. In an unadjusted multivariable logistic regression model, higher α-Klotho serum levels were associated with a lower risk of sarcopenia (p < 0.05). This trend was maintained in the partially adjusted model, indicating that higher levels of α-Klotho were associated with a lower risk of sarcopenia. However, the fully adjusted model did not show significance.

Several factors significantly influence the relationship between serum α-Klotho levels and sarcopenia, including sex, ethnicity, alcohol consumption, body mass index (BMI), vitamin D levels, and disease status. Our findings indicate that the risk of sarcopenia is elevated in individuals within the lowest quartile of serum α-Klotho levels. Furthermore, a negative correlation exists between α-Klotho levels and grip strength, observed in both the overall sample and the aging-related subgroup. These results highlight the necessity for further investigation into the complex interplay between α-Klotho and grip strength, particularly in the context of sarcopenia associated with renal disease.

Serum α-Klotho levels in different populations are negatively correlated with the risk of sarcopenia, suggesting that α-Klotho may be involved in the occurrence and development of sarcopenia. Therefore, measuring α-Klotho levels in clinical practice may be a valuable diagnostic tool to identify individuals at high risk of developing sarcopenia.

Hepatocellular Carcinoma (HCC) exhibits high recurrence rates, particularly when accompanied by Microvascular Invasion (MVI). We identified MVI-related biomarkers and established a prognostic model for personalized HCC treatment.

Data were downloaded from The Cancer Genome Atlas (TCGA) and HCCDB databases. Key radiomics features were identified using the support vector machine-recursive feature elimination (SVM-RFE) algorithm, and differential expression analysis was performed with DESeq2. This was followed by functional enrichment analysis using the clusterProfiler package. Through univariate and Lasso regression analyses, we constructed a robust RiskScore model to effectively stratify HCC patients into distinct risk groups based on the median RiskScore value. The model prediction performance was evaluated using ROC curves and Kaplan-Meier (KM) analysis. We used the CIBERSORT algorithm to characterize immune cell infiltration patterns and conducted GSEA to identify differentially activated pathways between the risk groups.

Radiomic analysis revealed four significant features strongly associated with MVI, enabling the construction of a nomogram model with robust classification performance (AUC = 0.742). Subsequent analysis identified 241 overlapping MVI-related Differentially Expressed Genes (DEGs) enriched in critical tumor proliferation and invasion pathways. A 10-gene RiskScore model was developed, demonstrating excellent prognostic discrimination in training and validation cohorts. CIBERSORT analysis revealed significant correlations between specific immune cell infiltration and the 10 genes. GSEA analysis showed significant enrichment of cell cycle regulation pathways in the high-risk group, suggesting their important role in MVI.

The RiskScore was established using MVI-related features for prognosis assessment in HCC.

Our findings provided novel biomarkers and a theoretical basis for the early diagnosis and personalized treatment of HCC.

To identify the critical genes, biological mechanisms, and signaling pathways involved in the therapeutic effects of quercetin on diabetic foot ulcers using network pharmacology and molecular docking approaches.

We identified pathological targets of diabetic foot ulcers (DFU) from GeneCards, OMIM, and TTD, and pharmacological targets of quercetin from STP, TCMSP, and PharmMapper. Intersection analysis revealed potential therapeutic targets. Core targets were determined via GO/KEGG enrichment, PPI network construction, and Cytoscape screening algorithms (Degree, Closeness, Betweenness). Molecular docking and dynamics simulations assessed quercetin-core target interactions and binding affinity.

After screening and intersecting the targets of quercetin and diabetic foot ulcers, 236 genes related to quercetin's anti-diabetic foot ulcer effects were identified, with six key genes emerging as critical: SRC, TP53, MAPK1, JUN, HSP90AA1, and AKT1. Enrichment analysis suggested that quercetin may modulate inflammatory imbalance(HSP90AA1), immunosuppression(JUN), and oxidative stress(SRC, TP53, MAPK1, and AKT1) during diabetic foot ulcer progression.

The relationship between these core targets and biological pathways in diabetic foot ulcers requires further experimental validation. Notably, molecular docking and dynamics simulation results confirmed strong binding affinity between quercetin and the core targets, supporting their potential therapeutic relevance.

Quercetin exerts anti-diabetic foot ulcer effects by regulating SRC, TP53, MAPK1, JUN, HSP90AA1, and AKT1. These hub genes may serve as promising candidates for future therapeutic interventions in diabetic foot ulcers.

The receptor for pyroglutamylated RF amide peptide (QRFPR) is a G protein-coupled receptor that plays a role in various physiological and pathological processes. However, a gap remains in our understanding of QRFPR's pan-cancer properties.

This study performs an extensive pan-cancer analysis of QRFPR utilizing large-scale genomic datasets, including The Cancer Genome Atlas (TCGA). We evaluated QRFPR expression levels in multiple malignancies and examined their correlations with clinical outcomes. Additionally, we investigated associations between QRFPR expression and immune cell infiltration using bioinformatics tools.

Our results reveal significant alterations in QRFPR expression across several cancer types, particularly breast, colorectal, and prostate cancers. Elevated levels of QRFPR are linked to poor prognosis in certain malignancies, such as uterine corpus endometrial carcinoma (UCEC) and mesothelioma (MESO), and correlate with increased infiltration of immune cells, especially T cells and macrophages. Pathway enrichment analyses suggest that QRFPR may impact critical signaling pathways associated with cell growth, apoptosis, and immune regulation.

The observed variations in QRFPR expression across cancer types suggest its diverse roles in tumor biology. Its association with unfavorable clinical outcomes in specific cancers, as well as its link to immune cell infiltration, highlights its multifaceted impact on tumor progression and microenvironment modulation.

Our findings underscore the potential of QRFPR as a prognostic biomarker and therapeutic target in cancer biology. Further investigations into its functional mechanisms could pave the way for precision medicine approaches in oncology.

Cholesterol plays a key role in maintaining tumor cell homeostasis. Reduced IGFBP6 expression is associated with an increased risk of breast cancer recurrence. Previous studies showed that IGFBP6 knockdown decreases cholesterol levels in the MDA-MB-231 cell line. This study aimed to investigate how IGFBP6 influences genes involved in cholesterol metabolism.

We used MDA-MB-231 breast cancer cells with IGFBP6 knockdown. Transcriptomic and proteomic analyses were performed, with selected gene expression validated by RT-PCR. Correlations between IGFBP6 and cholesterol-related genes were evaluated using public RNA-seq datasets.

IGFBP6 knockdown in MDA-MB-231 cells resulted in a threefold decrease in low-density lipoprotein receptor (LDLR) expression and a twofold reduction in LDLR adaptor protein (LDLRAP1) mRNA levels, both responsible for exogenous cholesterol uptake. Meanwhile, PCSK9 expression increased 11-fold (p-adj = 1.4E-93), further limiting uptake. Despite the upregulation of genes involved in endogenous cholesterol synthesis (HMGCS1, HMGCR, FDFT1, SQLE, DHCR24), total cholesterol content in knockdown cells decreased, leading to activation of the sterol-dependent transcription factor SREBF1 (OR = 6.44; p-adj = 0.036). Correlation analysis revealed a significant association between IGFBP6 expression and cholesterol synthesis genes in basal-like breast cancer.

The altered expression profile of multiple cholesterol metabolism-related genes with known prognostic value aligns with a transcriptional program typical of poor-outcome basal-like tumors. These findings support the role of IGFBP6 as a regulator of lipid metabolism and a potential biomarker for therapeutic stratification.

The results of this study indicate that the reduction in cholesterol levels observed in breast cancer cells following IGFBP6 knockdown is primarily due to decreased exogenous uptake. These findings highlight the role of IGFBP6 in regulating cholesterol metabolism and further explain its clinical significance in predicting breast cancer recurrence and progression.

Breast cancer has become the most commonly diagnosed cancer in women worldwide, with advanced cases often leading to bone metastases that significantly affect prognosis and quality of life. This meta-analysis and systematic review aims to evaluate and compare the diagnostic performance of [¹⁸F]FDG PET/CT and bone scintigraphy for detecting bone metastases in breast cancer patients.

A systematic search was conducted across PubMed, Embase, Web of Science, and Scopus for studies published up to February 2025. Relevant articles were identified using a combination of subject-specific and free-text keywords, including “breast cancer,” “positron emission tomography,” “bone scintigraphy,” and “bone metastasis.” Studies assessing the diagnostic utility of [¹⁸F]FDG PET/CT and bone scintigraphy in detecting bone metastases were included. A bivariate random-effects model was used to calculate pooled estimates of sensitivity, specificity, and diagnostic accuracy with 95% confidence intervals (CIs). Potential sources of heterogeneity were explored using meta-regression analysis. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was applied to evaluate the methodological quality of the included studies.

A total of 1407 publications were initially retrieved, and 13 studies involving 892 patients met the inclusion criteria. The pooled diagnostic performance for [¹⁸F]FDG PET/CT demonstrated a sensitivity of 0.91 (95% CI: 0.81-0.96) and a specificity of 0.98 (95% CI: 0.93-1.00), with an area under the curve (AUC) of 0.99 (95% CI: 0.97-0.99). In comparison, bone scintigraphy showed a sensitivity of 0.82 (95% CI: 0.72-0.89), specificity of 0.81 (95% CI: 0.73-0.87), and an AUC of 0.88 (95% CI: 0.85-0.91). Despite its higher diagnostic accuracy, PET/CT exhibited notable heterogeneity across studies, potentially influenced by differences in patient populations and imaging interpretation criteria.

Our meta-analysis demonstrated the superior diagnostic performance of [¹⁸F]FDG PET/CT over bone scintigraphy, likely attributable to its enhanced sensitivity for osteolytic lesions and integrated anatomical-functional imaging. Nevertheless, considerable inter-study heterogeneity and incomplete clinical data reporting limit the generalizability and robustness, warranting further standardized prospective investigations.

The findings suggest that [¹⁸F]FDG PET/CT offers superior diagnostic accuracy compared to bone scintigraphy for detecting bone metastases in breast cancer patients. However, its clinical application requires further validation through large-scale, prospective studies. Additionally, considerations such as cost-effectiveness and accessibility must be addressed before widespread clinical adoption.

Current osteoporosis medications often prove ineffective for various reasons. Alongside optimizing available agents, new genetic targets should be proposed for drug development. Mendelian randomization (MR) may resolve throughput and confounding issues in traditional observational studies for druggable targets.

We employed two-sample MR with protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) data as exposures and six bone mineral density (BMD) sites as outcomes. By meta-analyzing pQTL evidence, validating eQTL evidence, conducting MR sensitivity tests, and assessing druggability, key druggable targets for BMD were identified. Additionally, we performed functional analysis, drug repurposing annotation, transcriptome analysis, in-house PCR, ELISA, and micro-CT validation to further investigate the functionality and expression levels of these targets across different tissues and conditions.

Out of 5,928 pQTLs from deCODE and UKB-PPP datasets, 16 were identified as prioritized targets with significant meta pQTL evidence. Tyrosine-protein kinase Lyn (LYN, meta beta -0.09, 95% CI -0.13 to -0.05), Chondroadherin (CHAD, meta beta -0.39, 95% CI -0.18 to -0.20), Tumor necrosis factor receptor superfamily member 19 (TNFRSF19, meta beta -0.03, 95% CI -0.05 to -0.02), and Transforming growth factor beta induced (TGFBI, meta beta -0.04, 95% CI -0.06 to -0.03) were identified as key druggable targets for BMD. R-spondin-3 (RSPO3) and SPARC-related modular calcium-binding protein 2 (SMOC2) were also suggested with consistent MR associations with previous studies.

We identified four novel BMD-related targets (CHAD, LYN, TGFBI, TNFRSF19) through pQTL meta-analysis, and validated RSPO3/SMOC2's positive effects. By integrating multi-tissue transcriptomics and OVX experiments, we further revealed elevated expression of TNFRSF19/TGFBI negatively correlated with BMD, providing new therapeutic insights.

This large-scale Proteome-Wide MR study introduced novel targets for BMD and osteoporosis at transcriptional and translational levels, presenting new prospects for drug repurposing and development.

This study aims to elucidate the mechanisms contributing to the transition from acute to chronic inflammation, particularly in the context of atherosclerosis, by investigating the pro-inflammatory responses of cybrid cell lines derived from patients with coronary heart disease.

Acute inflammatory reactions are essential components of the innate immune response, typically resolving within hours or days. However, disruptions in this process can lead to chronic inflammation, which is linked to significant morbidity and mortality. Atherosclerosis, characterized by chronic vascular inflammation, poses a major health threat, underscoring the need for understanding its underlying mechanisms.

The primary objective is to analyze the pro-inflammatory cytokine responses of 14 cellular lines, including 13 cybrids and one maternal line (THP-1), to identify intolerant and tolerant responses to key cytokines associated with inflammation.

We utilized cybrid cell lines created by fusing THP-1 monocytic cells with platelets from patients diagnosed with atherosclerosis. Cytokine responses were assessed through quantitative analysis of IL-1β, IL-6, MPC-1, IL-8, and TNF-α secretion. Gene expression profiles were analyzed to correlate cytokine secretion with specific gene regulation patterns, focusing on epigenetic mechanisms influencing immune responses.

Distinct intolerant and tolerant responses were observed across the cellular lines for key cytokines. Specifically, TC-HSMAM1 and TCP-521 were intolerant to IL-1β, TC-HSMAM1, TC-LSM2, and TC-522 were intolerant to IL-6, six lines exhibited intolerance to MPC-1, and eight lines were intolerant to IL-8. No intolerant responses were noted for TNF-α. Gene expression analysis revealed that at least ten genes correlated with increased cytokine secretion in intolerant reactions, while 23 genes showed higher expression during these intolerant responses, indicating significant roles for DNA modification and chromatin remodeling. An important finding emerged from the study of agents affecting histone modification. Specifically, unlike other agents, sodium butyrate not only exhibited a stronger suppression of the inflammatory response in cells but also eliminated their intolerance to inflammatory stimulation. Therefore, in the near future, sodium butyrate could be regarded as a fundamentally new anti-inflammatory preventive and therapeutic agent, with its mechanism of action rooted in the prevention and suppression of chronic inflammation.

In chronic non-infectious diseases like atherosclerosis the intolerant response or trained immunity can worsen inflammation. This study shows that both genetic and epigenetic regulation contribute to this intolerant response. It was also found that sodium butyrate can prevent the intolerant response, suggesting it may become a new anti-inflammatory agent that suppresses chronic inflammation.

Our findings have suggested that the interplay between pro-inflammatory cytokine responses and epigenetic regulation mechanisms is critical in determining whether a cell exhibits a normal or intolerant immune response. Understanding these dynamics may provide insights into the chronic inflammatory processes associated with atherosclerosis and other related conditions.

Coronavirus disease (COVID-19) is a highly infective disease caused by SARS-CoV-2. The SARS-CoV-2 spike protein binds with the human ACE2 receptor to facilitate viral entry into the host cell; therefore, spike protein serves as a potential target for drug development.

Keeping in view the significance of SARS-CoV-2 spike protein for viral replications, in the current study, we identified the potent inhibitors against SARS-CoV-2 spike protein in order to combat the viral infection.

In the current study, we screened an in-house library of ~900 natural and synthesized compounds against the spike protein receptor binding domain (RBD) using a structure-based virtual approach, followed by an in-vitro inhibition bioassay.

Seven (C1-C7) potent compounds were identified with docking scores ≥ −6.66 Kcal/mol; their drug-likeness, pharmacokinetic, and pharmacodynamic characteristics were excellent with no toxic effect. Those molecules were subjected to a triplicate simulation for 200 ns, which further confirmed their stable binding with RBD. This tight packing of complexes was reflected by calculated binding free energy, which disclosed higher binding free energy of C4, C7 and C6 than C1-C3, while predicted entropic energy demonstrates higher values for C4, C7 and C1 than the rest of the compounds, indicating more thermodynamic stability in protein due to conformational changes in spike protein induced by binding of C4, C7 and C1. These computational analyses were later validated through in-vitro bioassay. Remarkably, C2-C7 displayed significant inhibitory potential with >76 to 89% inhibition and C3, C4, C6 and C7 demonstrated the highest inhibition of RBD.

The current findings suggest that compounds C3 and C6 effectively disrupt the function of RBD of SARS-CoV-2 spike protein and can serve as potential drug candidates for spike protein.

GLP-1 receptor peptide agonists have revolutionized type 2 diabetes mellitus and obesity treatment, primarily through injection-based therapies. Small-molecule GLP-1 receptor agonists allow oral administration, but none are clinically established. Pfizer's danuglipron and lotiglipron, presented in 2018-2019, were “first-in-class” drug candidates, becoming prototypes for “next-in-class” drug development.

This review summarizes “next-in-class” GLP-1 receptor agonists developed, identifying different relationships between the molecular structure and functional activity of agonists.

Patents containing danuglipron- and lotiglipron-like agonists from January 2021 to July 2024 were browsed in databases, such as Espacenet and Google Patents, using specified keywords. Over 5,000 compounds from 67 patent publications were analyzed.

Our analysis identified some key general SAR trends. The presence of a carboxyl group leads to highly active agonists, but replacing it with bioisosteric analogs may improve the ADME profile of the target compounds. The introduction of specific privileged fragments, as well as the replacement of 1H-benzo[d]imidazole nucleus or (S)-oxetan-2-ylmethyl substituent in the prototype structure with bioisosteric heterocycles, may be viable approaches. The replacement of 1,4-disubstituted piperidine linker with its (S)-2-methyl-substituted homologue or O, N-disubstituted piperidin-4-ol may also result in highly potent agonists. Additionally, the classic 2,4-EWG-disubstituted benzyl alcohol residue allows significant variability.

Despite the limited clinical success of danuglipron and lotiglipron, as well as the inherent problems associated with the complex nature of GLP-1R signaling, the current state of research and the abundance of novel, promising chemotypes of highly potent compounds suggest that approved GLP-1R agonists may emerge in the coming years.