Molecular Drug Research Articles

Covalent Affibody-Molecular Glue Drug Conjugate Nanoagent for Proximity-Enabled Reactive Therapeutics.

Sulfur-fluoride exchange (SuFEx) reaction is an emerging class of click chemistry reaction. Owing to its efficient reactivity under physiological conditions, SuFEx reaction is used to construct covalent protein drugs. Herein, a covalent affibody-molecular glue drug conjugate nanoagent is reported, which can irreversibly bind with its target protein through proximity-enabled SuFEx reaction. As a proof of concept, a latent bioreactive unnatural amino acid fluorosulfate-L-tyrosine (FSY) is first introduced at site 36 of the affibody with cysteine mutation (ZHER2:342-Cys) to produce ZHER2:342-36FSY-Cys. Subsequently, ZHER2:342-36FSY-Cys is coupled with a molecular glue drug (CR8) to yield an amphiphilic conjugate of ZHER2:342-36FSY-CR8, which can self-assemble into affibody-drug conjugate nanoagent (ZHER2:342-36FSY-CR8 ADCN) in PBS. When ZHER2:342-36FSY-CR8 ADCN specific binds to human epidermal growth factor receptor 2 (HER2) on cancer cells, the FSY36 of ZHER2:342 approaches to the His490 of HER2 and ultimately reacts with each other to form a covalent bond via SuFEx reaction. Such a covalent binding mode endows ZHER2:342-36FSY-CR8 ADCN with permanent binding ability to effectively increase the concentration of drugs in tumor. Eventually, the covalent ZHER2:342-36FSY-CR8 ADCN exhibits an outstanding tumor inhibition ratio of 90.03±4.29% in HER2-positive ovary tumor models, strikingly higher than that of the noncovalent one (64.25±7.71%).

Establishment and Validation of the Diagnostic Value of Oligodendrocyte-related Genes in Alzheimer's Disease.

AD is a demyelinating disease. Myelin damage initiates the pathological process of AD, resulting in abnormal synaptic function and cognitive decline. The myelin sheath formed by oligodendrocytes (OL) is a crucial component of white matter. Investigating AD from the perspective of OL may offer novel diagnostic and therapeutic perspectives. This study aimed to analyze the association between OL-related genes and Alzheimer's disease (AD) using bioinformatics and verify this association via molecular biology experiments. The AD datasets were acquired from the Gene Expression Omnibus (GEO) database of NCBI. Consensus clustering was employed to determine the subtypes of AD, followed by evaluating the clinical characteristics of these subtypes. Subsequently, immune infiltration analysis of relevant genes and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identify modules and hub genes associated with AD progression. The intersection of genes obtained was analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. To narrow down the scope and identify OL-related genes with diagnostic potential, three machine learning algorithms were utilized. In addition, the eXtreme Sum (XSum) algorithm was used to screen small molecule drug candidates based on the connectivity map (CMAP) database. Finally, these identified genes were validated using Real-time fluorescence quantitative PCR (RT-qPCR). Among the three subtypes of AD, Cluster A and Cluster C exhibited increased levels of Braak and neurofibrillary tangles compared to Cluster B. The proportion of females was greater than that of males among the three subclasses of AD. There were no significant differences in age among the three subclasses, but significant differences in gene expression existed. Through WGCNA analysis, 108 genes were identified. Among these, 16 genes were identified as shared genes by the least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machines (SVM) algorithms, and logistic regression further determined 11 genes. The establishment of a nomogram demonstrated the significance of these 11 genes in AD. The "XSum" algorithm revealed five drugs with therapeutic potential for AD. qPCR analysis revealed the upregulation and downregulation of the highlighted genes. According to this study, 11 genes related to OL were also found to be associated with immune cell infiltration in AD patients. These genes demonstrated potential diagnostic value for AD. Additionally, we screened five small molecular drugs that exhibit potential therapeutic effects on AD. This research provides a new perspective for personalized clinical management and treatment of AD.

Integration of histone modification-based risk signature with drug sensitivity analysis reveals novel therapeutic strategies for lower-grade glioma

BackgroundLower-grade glioma (LGG) exhibits significant heterogeneity in clinical outcomes, and current prognostic markers have limited predictive value. Despite the growing recognition of histone modifications in tumor progression, their role in LGG remains poorly understood. This study aimed to develop a histone modification-based risk signature and investigate its relationship with drug sensitivity to guide personalized treatment strategies.MethodsWe performed single-cell RNA sequencing analysis on LGG samples (n = 4) to characterize histone modification patterns. Through integrative analysis of TCGA-LGG (n = 513) and CGGA datasets (n = 693 and n = 325), we constructed a histone modification-related risk signature (HMRS) using machine learning approaches. The model's performance was validated in multiple independent cohorts. We further conducted comprehensive analyses of molecular mechanisms, immune microenvironment, and drug sensitivity associated with the risk stratification.ResultsWe identified distinct histone modification patterns across five major cell populations in LGG and developed a robust 20-gene HMRS from 129 candidate genes that effectively stratified patients into high- and low-risk groups with significantly different survival outcomes (training set: AUC = 0.77, 0.73, and 0.71 for 1-, 3-, and 5-year survival; P < 0.001). Integration of HMRS with clinical features further improved prognostic accuracy (C-index >0.70). High-risk tumors showed activation of TGF-β and IL6-JAK-STAT3 signaling pathways, and distinct mutation profiles including TP53 (63% vs 28%), IDH1 (68% vs 85%), and ATRX (46% vs 20%) mutations. The high-risk group demonstrated significantly elevated immune and stromal scores (P < 0.001), with distinct patterns of immune cell infiltration, particularly in memory CD4+ T cells (P < 0.001) and CD8+ T cells (P = 0.001). Drug sensitivity analysis revealed significant differential responses to six therapeutic agents including Temozolomide and targeted drugs (P < 0.05).ConclusionOur study establishes a novel histone modification-based prognostic model that not only accurately predicts LGG patient outcomes but also reveals potential therapeutic targets. The identified associations between risk stratification and drug sensitivity provide valuable insights for personalized treatment strategies. This integrated approach offers a promising framework for improving LGG patient care through molecular-based risk assessment and treatment selection.

Polymeric Nanoparticles Revolutionizing Brain Cancer Therapy: A Comprehensive Review of Strategies and Advances.

Brain cancer continues to be one of the most formidable malignancies to manage, mainly attributable to the presence of the blood-brain barrier (BBB) limiting the permeability of drugs and the diverse characteristics of brain tumors complicating treatment. The management of brain tumors has been hampered by many different factors, including the impermeability of the BBB, which restricts the delivery of chemotherapeutic agents to the tumor site, as well as intertumoral heterogeneity and the influence of brain tumor stem cells. In addition, small molecular weight drugs cannot specifically accumulate in malignant cells and have a limited circulation half-life. Nanoparticles (NPs) can be engineered to traverse the BBB and transport therapeutic medications directly into the brain, enhancing their efficacy compared with the conventional delivery of unbound drugs. Surface modifications of NPs can boost their efficiency by increasing their selectivity towards tumor receptors. This review covers treatment methods for malignant gliomas, associated risk factors, and improvements in brain drug administration, emphasizing the future potential of polymeric NPs and their mechanism for crossing the BBB. To surmount these obstacles, the newly formulated drug-delivery approach utilizing NPs, particularly those coated with cell membranes, has demonstrated potential in treating brain cancer. These NPs provide targeted tumor specificity, biocompatibility, extended circulation, enhanced BBB penetration, and immune evasion. This review focuses on coating strategies for PLGA NPs, particularly dual-targeting methods, to enhance BBB permeability and tumor-targeted delivery of drugs in brain cancer.

The continually evolving landscape of novel therapies in oncogene-driven advanced non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is a highly heterogeneous disease that is frequently associated with a host of known oncogenic alterations. Advances in molecular diagnostics and drug development have facilitated the targeting of novel alterations such that the majority of NSCLC patients have driver mutations that are now clinically actionable. The goal of this review is to gain insights into clinical research and development principles by summary, analysis, and discussion of data on agents targeting known alterations in oncogene-driven, advanced NSCLC beyond those in the epidermal growth factor receptor (EGFR) and the anaplastic lymphoma kinase (ALK). A search of published and presented literature was conducted to identify prospective trials and integrated analyses reporting outcomes for agents targeting driver gene alterations (except those in EGFR and ALK) in molecularly selected, advanced NSCLC. Clinical efficacy data were extracted from eligible reports and summarized in text and tables. Findings show that research into alteration-directed therapies in oncogene-driven, advanced NSCLC is an extremely active research field. Ongoing research focuses on the expansion of new agents targeting both previously identified targets (particularly hepatocyte growth factor receptor (MET), human epidermal growth factor receptor 2 (HER2), and Kirsten rat sarcoma viral oncogene homolog (KRAS)) as well as novel, potentially actionable targets (such as neuregulin-1 (NRG1) and phosphatidylinositol 3-kinase (PI3K)). The refinement of biomarker selection criteria and the development of more selective and potent agents are allowing for increasingly specific and effective therapies and the expansion of clinically actionable alterations. Clinical advances in this field have resulted in a large number of regulatory approvals over the last 3 years. Future developments should focus on the continued application of alteration therapy matching principles and the exploration of novel ways to target oncogene-driven NSCLC.

Molecular interaction, Drug suitability and Protein-Ligand Interaction on 4-chloro-4’-methylbutyrophenone by spectroscopic and DFT approaches

Molecular interaction, Drug suitability and Protein-Ligand Interaction on 4-chloro-4’-methylbutyrophenone by spectroscopic and DFT approaches

Synthesis and photocatalytic efficiency of novel ZnO-CBS-Ni complex for diclofenac sodium under irradiation of light

The use of diclofenac sodium, a small molecular drug, is essential for treating inflammation in pharmacology. However, its extensive use can lead to environmental and water pollution. To address this issue, a new area of research involving nanomaterials and polymer-metal complexes for photo-degradation processes has emerged. As part of this research, we have developed nano-composites consisting of a biodegradable polymeric metal complex – a chitosan nickel metal complex coupled with a ZnO nanoparticle to eliminate the harmful effects of pharmaceutical residues in the environment is vital for achieving long-term sustainability and protecting natural resources. These nanocomposites have been successfully synthesized and analysed for their structure and optical properties using XRD, FT-IR, SEM, UV–visible, and band gap analysis techniques. The band gap value of the nano-composite falls within the semiconductor range. These synthesized nano-composites have been tested for the photo-degradation of diclofenac sodium in three different sources at various pH levels. The catalyst exhibited better activity in sunlight at acidic pH. We also explored the possible mechanism of photo-activity with the catalyst by combining the results of photo-degradation and the optical characterization of the nano-composite.

Coaxial bioprinting of a three-layer vascular structure exhibiting blood-brain barrier function for neuroprotective drug screening.

The in vitro blood-brain barrier (BBB) structures can offer advantages for studying cerebrovascular functions and developing neuroprotective drugs. However, currently developed BBB models are overly simplistic and inadequate for replicating the complex three-dimensional architecture of the in vivo BBB. In this study, a method is introduced for fabricating a three-layer vascular structure exhibiting BBB function using a coaxial extrusion bioprinting technique with a two-layer nozzle. Photocurable materials were incorporated into the inner layer of the coaxial nozzle, and photoinitiators from the outer layer diffused into the inner layer. As a result, only the materials in the inner layer at the interface between the inner and outer layers underwent crosslinking upon UV exposure. After removing the uncrosslinked materials, a two-layer vascular structure can be formed. Subsequently, a three-layer structure was established after seeding endothelial cells. The perfusion experiments demonstrated that the vascular structure facilitated the continuous flow of culture medium, thereby providing nutrients and oxygen to the surrounding neural tissue. The drug screening analysis indicated that this vascular structure could possess barrier function, allowing the passage of small molecular drugs while effectively blocking macromolecular drugs. Overall, these results suggest that the three-layer vascular structure exhibits excellent perfusion capacity and barrier function, making it a promising candidate for neuroprotective drug screening.

Drug retention after intradiscal administration

Intradiscal drug delivery is a promising strategy for treating intervertebral disk degeneration (IVDD). Local degenerative processes and intrinsically low fluid exchange are likely to influence drug retention. Understanding their connection will enable the optimization of IVDD therapeutics. Release and retention of an inactive hydrophilic fluorine-19 labeled peptide (19F-P) as model for regenerative peptides was studied in a whole IVD culture model by measuring the 19F-NMR (nuclear magnetic resonance) signal in culture media and IVD tissue extracts. In another set-up, noninvasive near-infrared imaging was used to visualize IR-780, as hydrophobic small molecular drug model, retention upon injection into healthy and degenerative caudal IVDs in a rat model of disk degeneration. Furthermore, IR-780-loaded degradable polyester amide microspheres (PEAM) were injected into healthy and needle pricked degenerative IVDs, subcutaneously, and in knee joints with and without surgically-induced osteoarthritis (OA). Most 19F-P was released from the IVD after 7 days. IR-780 signal intensity declined over a 14-week period after bolus injection, without a difference between healthy and degenerative disks. IR-780 signal declined faster in the skin and knee joints compared to the IVDs. IR-780 delivery by PEAMs enhanced disk retention beyond 16 weeks. Moreover, in degenerated IVDs the IR-780 signal was higher over time than in healthy IVDs while no difference between OA and healthy joints was noted. We conclude that the clearance of peptides and hydrophobic small molecules from the IVD is relatively fast. These results illustrate that development of controlled release formulations should take into account the target anatomical location and local (patho)biology.

Molecular Docking and Drug Kinetics Assessment for Structure-Based Drug Design of New Piperazine-Containing Hydrazone Derivatives as Effective Alzheimer Inhibitors

The neurodegenerative condition known as Alzheimer's disease (AD) impairs cognitive function and produces dementia in older people. The disease's precise mechanism is still a mystery. Four drugs are available. However, they all have a long list of adverse effects and only help people with their warning signs. Medicinal chemists are searching for ways to treat this disease. There is discussion about creating and using a new class of multifunctional small molecule inhibitors. The hydrazone scaffold was used to create a wide range of chemicals. This is because hydrazone derivatives may disrupt the self-assembly of amyloid beta (A), one of the factors that cause fibrils and oligomers. They may also reverse the effects of harmful compounds like free radicals on effective therapeutic agents like medications that penetrate the central nervous system. Structure-based drug design methods were used in this investigation. A protein target (code ID 4EY7) was selected based on published literature research and factors like a lower resolution value (2.35), no mutation, Homo sapiens, and the X-ray diffraction technique. Fifteen Hydrazone derivatives with increased interactions, higher binding scores, and improved drug-like properties and drug kinetic parameters were designed using the protein target, engineered to interact with compounds of interest (a lead compound with a higher binding energy). Promising pharmacotherapeutic drugs for AD treatment may be developed using the results of these investigations.

A novel three-dimensional model of Infantile Haemangioma.

Infantile Haemangioma (IH) is vascular tumour in infants exhibiting rapid proliferation and angiogenesis followed by gradual involution.10% of cases are associated with disfiguring complications and requires medical interventions with β-blockers such as propranolol, surgery, or laser therapy. An in vitro IH three-dimensional (3D) model will improve our understanding of the disease mechanism(s). We have isolated and expanded CD31+ endothelial cells (HemEC) from patient-derived IH cell lines, and then grown as spheroids in StemDIFF Endothelial expansion media. These were then embedded in extracellular matrix hydrogel with reduced growth factors to initiate angiogenic sprouting. HemEC spheroids expressed CD31, GLUT1, VEGFR2, CD44, Vimentin, CD133 but not SMA, indicating their similarity to immature IH blood vessels and their angiogenic potential. Proteomic analysis revealed similar homology in terms of protein expression in spheroids and IH tissue. The high-throughput application of this 3D angiogenesis model was tested using propranolol to inhibit sprouting of spheroids with increased toxicity response. This study reports the development of a 3D model of IH that recapitulates angiogenic features of IH for molecular analysis and drug screening.

Fundamental research and practical application of GDNF as a neuroprotective agent in neurodegenerative diseases

Glial cell line-derived neurotrophic factor (GDNF) is under extensive investigation as a therapeutic agent for treating age-related neurodegenerative diseases and traumatic neuronal injury. The compelling results from preclinical studies contrast with the disappointing outcomes of phase II clinical trials in Parkinson’s disease, highlighting the need for further fundamental research. Several hypotheses have been proposed to explain these discrepancies, including challenges with the delivery of high molecular weight drugs, GDNF’s high affinity for heparin and heparin-like molecules, which limits its biodistribution in the brain parenchyma, the use of protein forms differing from the native GDNF, and the existence of multiple isoforms of the protein. These issues underscore the necessity for further investigation into GDNF at the genetic, RNA, and protein levels. This review aims to consolidate the latest data on GDNF, address the challenges identified, and explore its potential for therapeutic application in human neurodegenerative diseases.

Modulating Phosphorylation by Proximity-Inducing Modalities for Cancer Therapy.

Abnormal phosphorylation of proteins can lead to various diseases, particularly cancer. Therefore, the development of small molecules for precise regulation of protein phosphorylation holds great potential for drug design. While the traditional kinase/phosphatase small-molecule modulators have shown some success, achieving precise phosphorylation regulation has proven to be challenging. The emergence of heterobifunctional molecules, such as phosphorylation-inducing chimeric small molecules (PHICSs) and phosphatase recruiting chimeras (PHORCs), with proximity-inducing modalities is expected to lead to a breakthrough by specifically recruiting kinase or phosphatase to the protein of interest. Herein, we summarize the drug targets with aberrant phosphorylation in cancer and underscore the potential of correcting phosphorylation in cancer therapy. Through reported cases of heterobifunctional molecules targeting phosphorylation regulation, we highlight the current design strategies and features of these molecules. We also provide a systematic elaboration of the link between aberrantly phosphorylated targets and cancer as well as the existing challenges and future research directions for developing heterobifunctional molecular drugs for phosphorylation regulation.

Identification of hub genes and biological pathways related to central post-stroke pain in ischemic stroke.

This investigation aims to screen ischemic stroke (IS)-related hub genes of central post-stroke pain (CPSP) from public databases and predict their potential roles through bioinformatics analysis to better interpret CPSP in IS. First, based on differential analysis, Venn analysis, and enrichment analyses, we identified 13 differently expressed genes in CPSP (CPSP-DEGs) related to the TNF signaling pathway, Vascular smooth muscle contraction, and IL-17 signaling pathway. Subsequently, through screening and analysis of the PPI network constructed by the Search Tool for the Retrieval of Interacting Genes (STRING) database, we obtained 3 CPSP-related hub genes (CD163, MMP9, and ARG1). They were all highly expressed in the IS group, exhibiting good diagnostic performance, with area under curve (AUC) value > 0.85. The immune-related analysis demonstrated that the infiltration levels of various immune cells in the IS group and the normal group were substantially different. In addition, by utilizing some online websites, we not only predicted some microRNAs (miRNAs) and transcription factors (TFs) that may target hub genes but also mined small molecular drugs that may target differentially expressed genes (DEGs) in IS. In conclusion, this project first investigated the role of CPSP-related genes in IS and identified 3 hub genes. At the same time, we predicted some miRNAs, TFs, and candidate drugs that may target hub genes. Our research uncovered the potential mechanism of CPSP-related genes in IS from multiple perspectives. Furthermore, it also laid a research foundation for the future study of the mechanisms of IS disease.

Reversing protonation of weakly basic drugs greatly enhances intracellular diffusion and decreases lysosomal sequestration.

For drugs to be active they have to reach their targets. Within cells this requires crossing the cell membrane, and then free diffusion, distribution, and availability. Here, we explored the in-cell diffusion rates and distribution of a series of small molecular fluorescent drugs, in comparison to proteins, by microscopy and fluorescence recovery after photobleaching (FRAP). While all proteins diffused freely, we found a strong correlation between pKa and the intracellular diffusion and distribution of small molecule drugs. Weakly basic, small-molecule drugs displayed lower fractional recovery after photobleaching and 10- to-20-fold slower diffusion rates in cells than in aqueous solutions. As, more than half of pharmaceutical drugs are weakly basic, they, are protonated in the cell cytoplasm. Protonation, facilitates the formation of membrane impermeable ionic form of the weak base small molecules. This results in ion trapping, further reducing diffusion rates of weakly basic small molecule drugs under macromolecular crowding conditions where other nonspecific interactions become more relevant and dominant. Our imaging studies showed that acidic organelles, particularly the lysosome, captured these molecules. Surprisingly, blocking lysosomal import only slightly increased diffusion rates and fractional recovery. Conversely, blocking protonation by N-acetylated analogues, greatly enhanced their diffusion and fractional recovery after FRAP. Based on these results, N-acetylation of small molecule drugs may improve the intracellular availability and distribution of weakly basic, small molecule drugs within cells.

Multi-Locus Sequence Typing-Based Genetic Analysis, Antifungal Resistance, and Clinical Prognosis of Cryptococcus neoformans Infections in HIV-Infected Patients in Northern China.

This study aimed to investigate the molecular epidemiological characteristics and drug sensitivity of Cryptococcus from HIV-infected patients and their relationship with patients' prognosis. Seventy-six strains were collected and identified to the species level by matrix-assisted laser desorption ionization-time of flight mass spectrometry, confirmed by internal transcribed spacer sequencing. Multi-locus sequence typing was used for the typing of Cryptococcus, and its antifungal susceptibility was tested using FUNGUS 3. The clinical outcomes of the patients were reviewed at 3-, 6-, 9-, and 12-month follow-ups. All strains were Cryptococcus neoformans var. grubii classified into seven sequence types (STs) dominated by ST5, ST31, and a new ST702 strain. The 6- and 9-month survival rates were highest for patients infected with ST31, ST32, and ST174. The antifungal resistant rates were 13.2%, 2.6%, and 1.4% for fluconazole, amphotericin B, and 5-fluorocytosine. Except itraconazole, the minimum inhibitory concentration (MIC) values and wild type (WT)/non-wild type (NWT) of Cryptococcus for antifungal drugs were not related to the clinical prognosis of HIV-infected patients with cryptococcal infection. ST5 was the main ST type, and the new ST702 type was found in a patient who died in a short period of time. Cryptococcus neoformans var. grubii had a relatively high antifungal drug resistance rate to fluconazole. The WT strain accounted for the highest proportions for 5-fluorocytosine, amphotericin B, fluconazole, voriconazole, and itraconazole. The MIC values of Cryptococcus for first-line antifungal drugs showed no relationship with clinical prognosis, implying that MIC values cannot be used to predict the clinical outcome of these patients.

Multi-omics and in-silico approach reveals AURKA, AURKB, and RSAD2 as therapeutic biomarkers in OSCC progression

Oral squamous cell carcinoma (OSCC), a prevalent form of head and neck cancer, poses a significant health challenge with limited improvements in patient outcomes over the years. Its development is influenced by a complex interplay of genetic alterations and environmental factors. While progress has been made in understanding the molecular mechanisms driving OSCC, pinpointing critical molecular markers and potential drug candidates has proven elusive. This study uniquely endeavors to conduct a meta-analysis to unveil therapeutic genes responsible for OSCC tumorigenesis. A multi-omics approach identified 951 differentially expressed genes (DEGs) associated with OSCC by analyzing microarray data from the NCBI GEO database. Weighted gene co-expression network analysis (WGCNA) detected a significant hub gene module comprising 805 genes, followed by the construction of protein-protein interaction network resulting in two small clusters of 7 gene-encoded proteins each. These clusters were filtered out based on top 10 significant pathways and gene ontology terms to identify six key target proteins with elevated expression levels, acting as potential therapeutic biomarkers for OSCC. Notably, RSAD2 emerged as a novel biomarker linked to OSCC progression. Furthermore, we identified potential inhibitors targeting AURKA, AURKB, and RSAD2 proteins and validated their interactions through molecular dynamics simulation studies. The simulations confirmed the stability of receptor-ligand complexes, suggesting ZINC03839281, ZINC04026167, and ZINC00718292 compounds hold promise as potential inhibitors for therapeutically targeting AURKA, AURKB, and RSAD2 as significant OSCC biomarkers. We recommend further comprehensive studies, including experimental and preclinical investigations, to validate the effectiveness of these lead compounds for OSCC treatment.

Group graph: a molecular graph representation with enhanced performance, efficiency and interpretability

The exploration of chemical space holds promise for developing influential chemical entities. Molecular representations, which reflect features of molecular structure in silico, assist in navigating chemical space appropriately. Unlike atom-level molecular representations, such as SMILES and atom graph, which can sometimes lead to confusing interpretations about chemical substructures, substructure-level molecular representations encode important substructures into molecular features; they not only provide more information for predicting molecular properties and drug‒drug interactions but also help to interpret the correlations between molecular properties and substructures. However, it remains challenging to represent the entire molecular structure both intactly and simply with substructure-level molecular representations. In this study, we developed a novel substructure-level molecular representation and named it a group graph. The group graph offers three advantages: (a) the substructure of the group graph reflects the diversity and consistency of different molecular datasets; (b) the group graph retains molecular structural features with minimal information loss because the graph isomorphism network (GIN) of the group graph performs well in molecular properties and drug‒drug interactions prediction, showing higher accuracy and efficiency than the model of other molecular graphs, even without any pretraining; and (c) the molecular property may change when the substructure is substituted with another of differing importance in group graph, facilitating the detection of activity cliffs. In addition, we successfully predicted structural modifications to improve blood‒brain barrier permeability (BBBP) via the GIN of group graph. Therefore, the group graph takes advantages for simultaneously representing molecular local characteristics and global features.Scientific contribution The group graph, as a substructure-level molecular representation, has the ability to retain molecular structural features with minimal information loss. As a result, it shows superior performance in predicting molecular properties and drug‒drug interactions with enhanced efficiency and interpretability.

Activation of glycolysis alleviates mitochondrial impairments caused by social isolation in Drosophila

Social isolation (SI) in humans can lead to various psychological and physical abnormalities. However, the molecular mechanisms and potential drug treatments for this illness are not well understood. Drosophila, a social organism, exhibits distinct behavioral defects under SI conditions, such as reduced sleep and loss of sugar intake preference. By examining the transcriptional profiles of SI flies, we discovered significant impacts on metabolic pathways. Notably, serotonin (5-HT) levels were reduced in the brains of SI flies. Treatment with 5-HT reversed the behavioral defects in SI flies. 5-HT is known to regulate mitochondrial synthesis in mouse brain, and we found it also enhances mitochondrial biogenesis in flies. Further investigation revealed that the 5-HT7 receptor subtype was involved in SI behavior. To activate mitochondrial metabolism, we overexpressed phosphoglycerate kinase (Pgk), an enzyme in the glycolytic pathway, in neurons. This overexpression rescued the behavioral defects in SI flies. Additionally, terazosin, an alpha-1 adrenergic receptor antagonist known to activate Pgk, produced a similar rescue effect. Our study elucidates a key principle of SI-induced psychological damage and proposes a drug targeting strategy for future validation.

Pyroptosis-related lncRNAs are potential biomarkers for predicting prognoses and immune landscapes in patients with gastric adenocarcinoma

ObjectivesThe purpose of this study was to investigate the significance of pyroptosis-related lncRNAs (PRlncRNA) in predicting prognoses and immune landscapes of patients with gastric adenocarcinoma (STAD).MethodsTranscriptomic data and clinicopathological data were obtained from The Cancer Genome Atlas database. Based on correlation analysis and univariate Cox regression, prognostic PRlncRNA were identified. Subsequently, a PRlncRNA prognostic signature (PRLPS) was generated via least absolute shrinkage and selection operator (LASSO) regression, Kaplan–Meier method, receiver operating characteristic (ROC) curves, principal component analysis, and univariate and multivariate regression. Besides, the clinicopathological characteristics, tumor microenvironment (TME) scores, the immune landscapes in different risk subgroups were explored. Moreover, based on three PRlncRNA, we constructed a competing endogenous RNA (ceRNA) network. Additionally, Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) and Gene Ontology (GO) analysis were performed for biological functional analysis based on the difference between high- and low- risk groups, which also used to screen out potential STAD drugs.Results21 PRlncRNA made up the prognostic signature, which had significant value in predicting the overall survival (OS), clinicopathological features, TME, immune checkpoint genes expression, and the response to immune checkpoint inhibitors of patients with STAD. In a addition, we constructed a ceRNA network comprising 3 PRlncRNAs and 69 mRNAs. The function of PRlncRNA was related to cancer-associated pathways. Ten small molecular drugs that might improve the prognosis of patients were screened out by connectivity maps.ConclusionsUsing PRlncRNA as a prognostic indicator for STAD, we identified predictive biomarkers and immunotherapy targets while refreshing our understanding.