Current Medicinal Chemistry - Online First

The ITIH family, crucial for extracellular matrix stability and cancer progression, is underexplored in multi-omic profiles and immune microenvironments; this study analyzes their roles across cancers and ITIH1’s function in gastric cancer to reveal diagnostic, prognostic, and therapeutic potential.

We analyzed RNA-seq, protein expr ession, and clinical data from 33 cancer types and 24 non-cancerous conditions using TCGA, GTEx, GEO, CPTAC, and IMvigor210 datasets. Methods included differential expression analysis, ROC curve assessment for diagnostic potential, Cox regression and Kaplan-Meier survival analyses for prognostic value, GSEA for pathway enrichment, and molecular docking for ITIH1-targeted small molecule screening. Immune microenvironment interactions, tumor mutational burden (TMB), microsatellite instability (MSI), and immunotherapy response were evaluated. in vitro experiments validated ITIH1’s role in gastric cancer using qRT-PCR, Western blotting, siRNA knockdown, and functional assays.

ITIH family genes exhibited differential expression across cancers and non-cancerous conditions, with ITIH1, ITIH4, and ITIH5 showing high diagnostic potential (AUC > 0.90 in multiple cancers). ITIH1 was a risk factor for poor survival in gastric cancer (p < 0.05). Lower ITIH scores correlated with improved survival in patients receiving immune checkpoint inhibitors (p < 0.05). ITIH genes showed strong correlations with immune checkpoints (PD-1, CTLA-4), TMB, and MSI. Molecular docking identified six small molecules, including Entinostat, with high binding affinity for ITIH1 (-8.4 kcal/mol). ITIH1 knockdown in gastric cancer cell lines (HGC-27, AGS) significantly reduced proliferation, migration, and invasion (p < 0.01).

This study underscores the ITIH family's critical role as diagnostic and prognostic biomarkers across various cancers and non-cancerous conditions, with ITIH1's therapeutic potential in gastric cancer highlighted through its impact on tumor progression, though limitations include discrepancies in some ITIH gene expressions between in vitro and in vivo settings, necessitating further validation.

Our findings highlight the ITIH family's potential as diagnostic biomarkers, prognostic indicators, and therapeutic targets, particularly in gastric cancer. The identification of ITIH1 inhibitors and their association with immune checkpoints, TMB, and MSI paves the way for improved diagnostics, targeted therapies, and immunotherapy predictions, enhancing patient outcomes across diseases.

Cervical cancer, primarily driven by high-risk human papillomavirus (HPV) infection, remains a global health challenge due to limited therapeutic efficacy and adverse effects of conventional treatments. Jinbai Heat-Clearing Prescription (JBHCP), a Traditional Chinese Medicine (TCM), exhibits potential against HPV-associated cervical cancer, yet its molecular mechanisms are unclear. This study aimed to elucidate JBHCP’s multitarget regulatory mechanisms in HPV-induced cervical carcinogenesis.

Network pharmacology, UHPLC-Q-TOF-MS-based metabolomics, and microarray data analysis were integrated to identify the bioactive components and therapeutic targets of JBHCP. Molecular docking and 60 ns Molecular Dynamics (MD) simulations were used to assess the interactions between key compounds (JBHCP673, JBHCP727) and cyclin-dependent kinases (CDK1/CDK2). Gene Ontology (GO), KEGG pathway enrichment, and Protein-Protein Interaction (PPI) network analyses were performed to explore biological functions and signaling pathways.

UHPLC-Q-TOF-MS identified 816 compounds in JBHCP, with 86 meeting drug-likeness criteria. Network analysis revealed 215 shared targets between JBHCP and HPV-induced cervical cancer, including CDK1 and CDK2 as core regulators. Enrichment analysis highlighted JBHCP’s involvement in cell cycle regulation, PI3K/AKT, and STAT3 signaling pathways. Molecular docking demonstrated strong binding affinities of JBHCP727 with CDK1 (-7.36 kcal/mol) and CDK2 (-6.13 kcal/mol). MD simulations confirmed stable binding of JBHCP727 to CDK1/2, while JBHCP673 exhibited instability. ADMET predictions supported JBHCP727’s drug-like properties.

JBHCP exerts anticancer effects by targeting CDK1/2, disrupting cell cycle progression, and modulating oncogenic pathways (PI3K/AKT, STAT3). The stability of JBHCP727-CDK complexes suggests its role in inhibiting HPV-driven proliferation. Multi-component synergy enables JBHCP to act on diverse pathways, aligning with TCM’s “multitarget” paradigm.

This study provides the first systematic evidence of JBHCP’s multi-pathway mechanism against HPV-associated cervical cancer, emphasizing CDK1/2 inhibition as a key therapeutic strategy. JBHCP727 emerges as a promising lead compound. Further in vivo and clinical validation is warranted to translate these findings into clinical applications.

Gastroesophageal reflux disease (GERD) is a prevalent digestive disorder, yet the causal roles of modifiable risk factors remain unclear. This study aims to investigate the causal relationships between 28 modifiable risk factors (including obesity traits, mental health disorders, sleep traits, metabolic comorbidities, and serum parameters) and GERD using two-sample Mendelian randomization (MR). Gastroesophageal reflux disease (GERD). Our findings aim to inform targeted prevention and treatment strategies for GERD.

This study obtained data from extensive genome-wide association studies (GWAS). Pooled data associated with gastroesophageal reflux associations were obtained from the 23andMe Research team’s research, which included a total of 129,080 cases of gastroesophageal reflux and 473,524 controls of European ancestry. We conducted a univariable Mendelian randomization (MR) analysis to ascertain whether genetic evidence of exposure demonstrated a statistically significant association with the risk of GERD. Subsequently, a multivariable MR analysis was carried out to estimate the independent effects of the exposures on GERD.

Univariable MR analysis utilizing extensive GWAS data suggested that genetic factors such as BMI, Waist circumference, Arm fat mass (left and right), Leg fat mass (left and right), Attention Deficit and Hyperactivity Disorder (ADHD), Major Depressive Disorder (MDD), Schizophrenia, Negative emotions (including nervousness, anxiety, tension, or depression), Insomnia, Sleep apnea syndrome, Sleep duration, and Snoring, as well as Total cholesterol levels and Apolipoprotein B levels, are associated with the development of GERD. Multivariate Mendelian randomization of BMI and Negative emotion as correction factors showed that Waist circumference, Arm fat mass (left and right), Leg fat mass (left and right), ADHD, Insomnia, Sleep apnea syndrome, and Snoring were associated with an increased risk of GERD (p< 0.05). Conversely, longer sleep duration was associated with a reduced risk of GERD (p< 0.05).

This MR study reveals novel causal mechanisms in GERD pathogenesis: (1) Peripheral adiposity (arm/leg fat mass) exerts independent effects beyond central obesity, indicating site-specific fat distribution significance; (2) ADHD emerges as a distinct psychiatric risk factor independent of mental disorders; (3) Sleep apnea operates through BMI-independent pathways. Collectively, these findings redefine GERD pathophysiology, highlighting fat depot specificity and brain-gut interactions as critical mechanistic drivers.

Overall, our findings suggest that multiple risk factors are associated with the risk of GERD. These results provide a theoretical basis for controlling body weight and plasticity, improving sleep habits, and preventing and timely seeking medical attention to reduce the occurrence of psychiatric disorders, which will be important strategies to prevent and alleviate GERD.

Seven new 4-[2-(dichloromethyl)pyrazolo[1,5-a][1,3,5]triazine derivatives were investigated for anticancer activity, possible molecular mechanisms of anticancer action, and ADMET properties.

The 4-benzenesulfonamide derivatives of pyrazolo[1,5-a][1,3,5]triazine were synthesized using the condensation of N-(2,2-dichloro-1-cyanovinyl)-amides IV with 1H-pyrazol-5-amine. Compound antitumor activities were evaluated using the NCI-60 human cancer cell line. AutoDockTools and AutoDock Vina software were used for molecular modeling. Using the ADMETlab 3.0 and pkCSM web sources, the ADMET properties of compounds 4, 5, and 7 were calculated.

Seven new pyrazolo[1,5-a][1,3,5]triazine derivatives were synthesized. The compounds 4, 5, and 7 exhibit high activity >1 µM against leukemia, colon, and renal cancer. Compound 4 exhibited the most potent activity, with IC50 values of 0.32  µM against leukemia, 0.49-0.89  µM against colon cancer, and 0.92  µM against renal cancer. Molecular modeling has demonstrated a potential antitumor mechanism involving CDK. The predicted ADMET profile of compounds 4, 5, and 7 is favorable.

The seven novel pyrazolo[1,5-a][1,3,5]triazines, as purine bioisosteres, were developed, synthesized, and investigated by in vitro and in silico methods.

Seven novel pyrazolo[1,5-a][1,3,5]triazine derivatives exhibited anticancer activity against the NCI-60 cancer cell lines. The compounds 4, 5, and 7 demonstrated strong anticancer activity, with growth inhibition (GI) values exceeding 50% across all nine cancer types tested. The most active compound, 4, is against leukemia, colon cancer, renal cancer, and lung cancer. All compounds exhibit low toxicity, with LC50 values of 100 µM or greater. The molecular docking of compounds 4, 5, and 7 revealed the potential to inhibit cancer-associated cyclin-dependent kinases. The predicted ADMET profiles of their compounds are favorable, providing a basis for further improvement of their anticancer activity.

Metabolic dysregulation, encompassing conditions such as type 2 diabetes mellitus, obesity, metabolic syndrome, and dyslipidemia, poses an increasing global health burden. The dysregulation of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a key enzyme in glucocorticoid metabolism, has been strongly implicated in the pathogenesis of these disorders by influencing glucose homeostasis, lipid metabolism, and insulin sensitivity. Consequently, targeting 11β-HSD1 offers a promising therapeutic strategy for mitigating metabolic dysregulation and its associated complications.

The study aimed to identify resveratrol derivatives with high binding affinity and inhibitory potential against 11β-HSD1, using computational approaches to evaluate their pharmacokinetic and toxicity profiles.

A library of resveratrol derivatives was screened using molecular docking to identify high-affinity compounds. The hit compounds were further evaluated for absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, followed by molecular dynamics simulations to assess their stability.

The resveratrol cis-dehydrodimer emerged as the most promising candidate, demonstrating high binding affinity, favorable ADMET properties, and stability over a 200 ns simulation period. These findings suggest its potential as a small-molecule inhibitor of 11β-HSD1.

The resveratrol cis-dehydrodimer represents a viable candidate for further experimental validation as a therapeutic agent for metabolic disorders. Future studies should include synthetic validation and in vivo testing to confirm its efficacy.

Long COVID-19 (LC) is a condition that follows SARS-CoV-2, an acute infection defined by persistent fatigue, dyspnea, and impaired cognitive function. LC presents a complex array that imposes ongoing challenges on global health, patients' quality of life, and functional capacity. Many inconsistencies surround its pathophysiology, diagnosis, prevention, and treatment. This review aims to cover missed gaps in LC with a special focus on therapeutic strategies concerning non-pharmacological, pharmacological, experimental, and innovative approaches for better patient management and outcomes, as well as to evaluate their effectiveness and guide future research.

An online search was conducted using five digital repositories: PubMed, Scopus, Google Scholar, Web of Science, and the Cochrane Library. A combination of keywords associated with LC therapy was employed: “long COVID, “pharmacological options,” “non-pharmacological options,” “innovative strategies,” “experimental”, and” quality of life (QOL).” Relevant data were extracted and synthesized to categorize therapeutic approaches into subtypes. A critical analysis was conducted on their mechanism of action, indication, outcome, and limitations.

The pooled prevalence of LC was 42%, and the symptom duration ranged from 3 months to 2 years. The most important risk factors for LC were female sex, unvaccinated status, and cases with co-morbidities. Diagnosis of LC was challenging due to a lack of diagnostic standardization and reliable biomarkers.

Non-pharmacological strategies were employed first, showing diverse efficacies; however, the reported literature was hindered by small sampling. Pharmacological agents show promising results but need further validation. Experimental and innovative strategies need longer studies and validations.

LC has imposed a significant burden on community health, necessitating the appropriate allocation of health resources and community support. Preventive and therapeutic interventions show promise, but the variability in patient response underscores the need for personalized approaches and more well-designed trials. Collaborative research and multi-disciplinary teams are needed to mitigate the long-term effects of LC and improve patient outcomes.

Circadian rhythm genes (CRGs) play a significant role in the pathogenesis of various cancers, yet their impact on bladder cancer (BC) remains to be fully elucidated. EZH2, as a potential oncological biomarker, lacks clear delineation regarding its prognostic significance in BC. Furthermore, the effect of anesthesia on circulating tumor cells (CTCs) in cancer patients is scarcely studied.

In this study, we developed a bioinformatics signature based on CRGs to assess the prognosis of BC patients and investigated the expression of EZH2 in BC and its correlation with patient outcomes through clinical sample analysis. Furthermore, we collected blood samples from BC patients before anesthesia and two hours post-anesthesia, enriched for CTCs, and analyzed the expression of EZH2 to evaluate the impact of anesthesia on the quantity of CTCs and their EZH2 expression status.

Our prognostic model identified EZH2 as a key determinant of BC prognosis, with the high expression of EZH2 significantly associated with poor patient outcomes. Experimental validation revealed a significant increase in the number of EZH2⁺ CTCs after anesthesia in BC patients. These findings suggest that anesthesia may facilitate BC metastasis by increasing the number of EZH2⁺ CTCs.

The findings highlight the prognostic value of CRGs and EZH2 in BC, providing new insights into tumor biology and metastasis. Furthermore, this study suggests anesthesia may influence tumor progression by modulating EZH2 expression in CTCs, underscoring the need for careful anesthetic selection in BC patients.

This study unveils the potential value of CRGs and EZH2 in the prognostic assessment of BC and reports for the first time that anesthesia may influence tumor metastasis by modulating the expression of EZH2 in CTCs. These results offer new biomarkers for the prognosis and treatment of BC and provide novel insights into the role of anesthesia in cancer metastasis.

Neurodevelopmental disorders (NDDs) represent a diverse and heterogeneous group of conditions, including global developmental delay (GDD), autism spectrum disorder (ASD), and neurodevelopmental encephalopathy with epilepsy (NDEE). While these disorders often share phenotypic similarities, their underlying genetic causes can vary widely, making clinical diagnosis challenging.

In this study, we performed whole-genome sequencing (WGS) on a family having an autosomal recessive neurodevelopmental disorder. The proband (II-2) underwent WGS, followed by variant filtering through an in-house bioinformatics pipeline. Sanger sequencing and 3D protein modeling were performed to confirm the pathogenicity of the identified variant.

A novel biallelic missense variant in the NAV3 (c.3430T>C; p.Ser1144Pro) was detected using WGS and Sanger sequencing. Subsequently, 3D protein modeling revealed significant alterations in the secondary structure of NAV3, indicating a potential pathogenic effect.

The identification of a novel biallelic missense variant in NAV3 adds a new layer to our understanding of its potential contribution to autosomal recessive neurodevelopmental disorders. This case expands the mutational landscape of NAV3 and underscores its emerging significance in neurodevelopment.

This study reports a novel NAV3 variant in association with autosomal recessive NDD, contributing to the growing body of evidence supporting the involvement of NAV3 in human neurodevelopment. Functional validation and identification of additional patients will be essential to establish definitive genotype-phenotype correlations and uncover the mechanistic pathways underlying NAV3-associated disorders.

Ovarian reserve reflects the functional capacity of a woman’s ovaries, encompassing factors such as follicle quantity, egg quality, and fertilization potential. Assessment of ovarian reserve is essential in reproductive medicine, particularly for fertility evaluation and assisted reproductive technologies (ART). While traditional biochemical markers such as anti-Müllerian hormone (AMH) and follicle-stimulating hormone (FSH) are commonly used, instrumental diagnostic methods like ultrasound and magnetic resonance imaging (MRI) provide valuable morphological and functional insights. This systematic review without a comprehensive meta-analysis evaluates the role of ultrasound and MRI in assessing ovarian reserve and their potential applications in clinical and research settings.

A comprehensive literature search was conducted across multiple databases to identify relevant studies evaluating ovarian reserve using ultrasound and MRI. Studies were screened based on predefined inclusion criteria, focusing on imaging parameters such as ovarian volume, follicular count, stromal characteristics, and vascularization. The effectiveness of these imaging techniques was analyzed in comparison to established biochemical markers. Due to heterogeneity in the included studies, a systematic review was performed without a formal meta-analysis.

Ultrasound, particularly transvaginal ultrasound (TVUS), remains the gold standard for ovarian reserve assessment, allowing real-time visualization of antral follicle count (AFC), ovarian volume, and follicular morphology. Doppler ultrasound provides additional insights into ovarian blood flow, which correlates with follicular development and ovarian function. MRI offers high-resolution, three-dimensional imaging, enabling detailed assessment of ovarian structure, follicular density, and stromal composition. While MRI provides superior soft-tissue contrast, its role in routine ovarian reserve assessment is limited due to cost and accessibility. The findings indicate that although both modalities are valuable for ovarian reserve evaluation, there is no consensus on standardized imaging parameters for defining ovarian functional viability. The available literature also presents inconsistencies in the correlation between imaging findings and ovarian function.

Ultrasound and MRI are essential tools for assessing ovarian reserve, providing complementary morphological and functional data. However, the lack of standardized imaging parameters limits their ability to definitively determine ovarian functional viability. Further research is needed to establish validated diagnostic criteria and integrate imaging techniques with biochemical markers to enhance the accuracy of ovarian reserve assessment in clinical practice and reproductive research.