Chronic neuroinflammation has become a major concern due to its ability to propagate into multiple neurodegenerative disorders which severely reduce the life expectancy of the patients. Many molecular targets have been identified which include amyloid beta (Aβ) peptides and oligomers, protofibrils, tau proteins, MID1/ TRIM18, Beclin1 protein, Puma, NMDA receptors, RyanR2, 5-HT2B, α7nAChR, TLR4, ERRα, CysLT(1)R, PDGFβR, DRD1, β2-AR, caspases, calpain, cytochrome c, CDK5, p38-MAPK, BACE1, γ-secretase, 5-lipoxygenase, NADPH oxidase 2 and 4, JNK, MMPs, NLRP3, GSAP, PARP-1, PARG, TRPM2, H2O2, NO (excess), LTB4, LTD4, NF-κB (NF-kBp50/RelA dimers and NF-κB p65), TNF-α,IL-1β, IL-6, IL-10, ApoE2, ApoE4, Bax,Bcl-2, miR-9, miR-29, miR-29a/b-1, miR-101, miR-124, miR-107, miR-298, miR-149, miR-328, miR-34a-5p, miR-15b, miR-16, miR-125b-5p, miR-124, and miR-374b-5p, miR-181c-5p, linc00507, LncRNA 51A, LncRNA 17A, LncRNA BC200, LncRNA NDM29, LncRNA NEAT1, LncRNA EBF3-AS, LncRNA NAT-Rad18, LcRNA TUG1, LncRNA MALAT1, LncRNA WT1-AS, LncRNA MAGI2-AS3, XBP-1, SERCA, Na+/Ca2+exchanger, plasma-membrane Ca2+-ATPase, HSP27, mtHSP60/HSPD1-mtHSP10/HSPE1, HSPD1, HSPE1, HSP70, Hsp90, Sirt1, Sirt3, TIMP-123 (composite of TIMP-1, TIMP-2, and TIMP-3), TIMP-4, AChEI, BDNF. Identification of the molecular targets enabled the identification of phytoconstituents which could modulate majority of these molecular targets. A herbal formulation which is expected to alleviate neuroinflammation includes many phytoconstituents such as curcumin, (-)-epigallocatechin-3-gallate, baicalein, baicalin, resveratrol, cis-resveratrol, berberine, quercetin, apigenin, corosolic acid, ursolic acid, oleanolic acid, luteolin, albigenin, withanolide A, celastrol, gallotannin, nobotanin B, kaempferol, naringenin, rutin, withaferin A, crocetin, katsumain H, geranylgeranylacetone and huperzine. A compatibility study with different phytoconstituents will determine the suitability of the formulation.
The opportunistic pathogen Acinetobacter baumannii, a major cause of nosocomial infections, has exhibited a rapid increase in resistance to conventional antimicrobial therapies, emphasizing the urgent need for alternative strategies such as anti-virulence approaches. The response regulator BfmR is a critical mediator of biofilm formation and virulence, making it an attractive yet underexplored therapeutic target. In this study, we established a comprehensive in silico pipeline to identify potential BfmR inhibitors through large-scale virtual screening and advanced computational analyses. The crystal structure of BfmR (PDB ID: 5HM6) was prepared using Schrödinger's Protein Preparation Wizard with the OPLS3 force field. A compound library comprising 66,734 molecules from CMNPD, Enamine, ChemDiv, and Asinex databases was processed using LigPrep and Epik to generate appropriate protonation states and stereoisomers at physiological pH. Virtual screening was performed using GLIDE in a hierarchical workflow including HTVS, SP, and XP docking. Pharmacokinetic and toxicity profiles were assessed using QikProp to ensure drug-likeness. Top-scoring compounds were further evaluated using triplicate 500 ns molecular dynamics simulations in GROMACS 2023 with the CHARMM36 force field, employing TIP3P water models and system neutralization. Post-simulation analyses included RMSD, PCA, free energy landscape mapping, dynamic cross-correlation matrices, covariance analysis, and MM-PBSA binding energy calculations. Six lead compounds demonstrated stable binding, favorable energetics, and consistent interactions with key regulatory residues THR23, ARG29, and VAL109, highlighting their potential as promising anti-virulence agents against A. baumannii.
Protein kinases play a key role in cellular signalling and are key drivers of neoplasia. In comparison, their role in neurodegenerative diseases used to be considered as secondary or downstream effects of neuronal damage. A growing body of data based on genetics, biochemistry, structural biology, and systems-level analysis has completely changed this view and placed kinase dysregulation as a common and unifying pathogenic pathway throughout cancer and neurodegeneration. The current chapter summarizes the recent progress that places kinases in a context-dependent state of molecular switches with disease-specific outcomes determined by structural conformation, spatiotemporal regulation, and network integration as opposed to kinase identity. The structural insights of high-resolution have changed the classical models that were based on pathways into models based on conformation and have shown that pathological kinase signalling is often caused by stabilisation of individual states of activity or regulation. These structural concepts describe the efficacy and drawbacks of first-generation ATP-competitive inhibitors, thereby leading to the development of allosteric, covalent, multi-target, and network-directed therapeutic approaches. The chapter also contrasts oncogenic kinase activation with oncogenic kinase dysfunction in post-mitotic neurons to demonstrate how the same signalling modules can be used to drive cell proliferation, cell survival, or cell degeneration depending on cellular context and microenvironment. The chapter also applies the knowledge in oncology, including mechanisms of resistance, adaptive signalling rewiring, and precision medicine, to neurodegenerative studies, but highlights the need for disease-specific adaptation due to the susceptibility and longevity of neurons.
Oceanic environments represent a unique source of biologically active substances, which has a large spectrum of chemical composition, and has significant therapeutic potential. Marine-derived bioactive compounds have emerged as accuracy regulators of molecular signals and offer new options to modern therapeutics design. Unlike normal small molecules, these compounds are often highly specific in terms of interaction with challenging targets, including proteases, chaperones, protein-protein interaction crossroads, transcription factors, and epigenetic regulators. It is becoming clear that they have the ability to shape disease specific gene expression and cellular phenotypes through chromatin architecture, altering complex signaling networks, and immunological checkpoints. Such system level regulation is particularly relevant in multifactorial diseases including neurological diseases, cancer, and chronic inflammatory states. The advances in structural biology, computational drug design and the omics technologies have minimized reliance on direct marine harvesting and accelerated the discovery and optimization of marine biological agents. Moreover, the concept of marine-inspired scaffolds is integrated into the framework of precision medicine more often, making it possible to develop a personalized therapeutical strategy that is less risky and more efficient. This review highlights recent mechanistic findings, targets, and translational advancements of marine-derived bioactives with a focus on the importance of these advancements in the development of next-generation therapeutics based on their revolutionary nature.
Autism Spectrum Disorder (ASD), Bipolar Disorder (BD), and Schizophrenia (SCZ) are major neuropsychiatric conditions that contribute substantially to global disability. Although traditionally considered distinct disorders, increasing evidence suggests overlapping molecular mechanisms across these conditions. In this study, we applied a cross-disorder transcriptomic framework to identify shared molecular dysregulation across ASD, BD, and SCZ. Publicly available RNA-sequencing datasets for each disorder were analysed independently using disorder-specific case-control comparisons. Differentially expressed genes were ranked within each disorder using a composite magnitude-confidence score integrating effect size and statistical significance, and the top 500 ranked genes per disorder were selected for cross-disorder analysis. Genes recurrently dysregulated in at least two disorders were prioritised based on their mean cross-disorder score. This approach identified 20 high-confidence recurrent genes, with pronounced transcriptional convergence observed between BD and SCZ. Notably, genes such as TPRX1, NPC1L1, and SLC12A3 emerged among the highest-ranked cross-disorder candidates, reflecting consistent and robust dysregulation across disorders. Directionality analysis revealed predominantly concordant expression patterns, with limited disorder-specific divergence. Functional annotation highlighted biological processes related to cellular homeostasis, immune regulation, metabolic pathways, and signal transduction. Overall, this study provides a systematic and quantitative framework for identifying shared molecular signatures across major neuropsychiatric disorders. The prioritised genes identified here represent promising candidates for further functional investigation and contribute to a deeper understanding of transdiagnostic disease biology.
The therapeutic manipulation concerning towards wound healing meets the different macroscopic levels such as immunological mechanisms, molecular signalling networks, developmental biology (regeneration) and drug discovery. From the epidermal skin infection to the deprived wound conditions, they are turned around into either scar or regenerated tissues. The restoration of tissue networks meets an intrinsic and dynamic rewinding processes from gene signals to several enzymes secretion led healing actions. Several advancements made in the wound healing materials and therapeutic assistive kits. Nanoparticle got high significant potential does not allow the drug waste rather it enhance target specific modifiers that either increase or decrease inflammatory response depend on the acute and chronic condition. And, there intrinsic pathways and growth regulators where activated in the entire process of wound healing. This review, encompasses from the rudimentary process to mechanism of highly advanced.
Staphylococcus aureus is the leading pathogen responsible for hospital- and community-acquired infections. The increasing prevalence of nosocomial infections in healthcare settings presents a significant challenge, particularly due to the strong biofilm-forming capability of clinical strains, which contributes to biofilm-mediated multidrug resistance. The biofilm-associated protein (BAP) plays a pivotal role in the initial adhesion and maturation of biofilms, significantly increasing the likelihood of failure of conventional antimicrobial therapies. Given its crucial function in biofilm formation, BAP represents a promising target for anti-biofilm drug development. A high-throughput virtual screening technique was implemented to identify potent BAP inhibitors, utilizing triple-mode docking with the Glide module of the Schrödinger Maestro suite. About 28,831 compounds from the ENAMINE-targeted antibacterial library were screened against BAP in S. aureus. Among the selected ligands, Z1430813924 and Z1738791774 exhibited the lowest binding energy, demonstrating superior docking scores alongside favorable ADME and physicochemical properties, which suggests an enhanced inhibitory potential. To validate the docking findings, a 100-ns molecular dynamics simulation was employed to assess the stability of the protein-ligand complex within a dynamic environment. The essential dynamics analysis, including free energy landscape (FEL) and principal component analysis (PCA) evaluations, affirmed the stability and efficacy of the top compounds, Z1430813924 and Z1738791774, as promising BAP inhibitors. These insights provide a strong foundation for subsequent experimental validation and the potential development of novel anti-biofilm therapeutics targeting S. aureus infections.
Chordoma is a rare, locally aggressive bone tumor originating from notochordal remnants. Despite advances in surgical and radiation-based approaches, effective systemic therapies remain limited, and recurrence rates are high. This chapter explores the current clinical landscape of chordoma management with an emphasis on the integration of molecular insights into therapeutic decision-making. In particular, we highlight emerging strategies targeting brachyury and receptor tyrosine kinases, as well as promising immunotherapies, including PD-1/PD-L1 immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapies. We further underscore the pivotal role of institutional and multi-center biobanking efforts in enabling biomarker discovery, enhancing diagnostic accuracy, and facilitating patient prognostication. Alongside these efforts, clinical trial development and public health considerations provide a comprehensive overview of the present scope and future potential of precision medicine in chordoma. By emphasizing the translational potential of molecular profiling together with advances in the clinical, institutional, and public health infrastructures that support its implementation, this chapter outlines a pathway toward more personalized and effective care for patients with chordoma.
The increased recognition of intrinsically disordered proteins (IDPs) as critical mediators in viral infections has shifted attention toward fuzzy drug targets, challenging the conventional structure-based paradigms of drug discovery due to their inherent conformational flexibility. The binding of viral IDPs and IDRs to host factors occurs in dynamic, multivalent, and context-dependent interactions and constitute flexible complexes, which form the basis of pathogenicity and immune evasion. In this review, the disordered proteins of viruses are considered with a combination of molecular, computational, and translational insights to assess the next-generation antiviral targets. In this, we have discuss about the energetic landscapes that control the disorder, functional disorder order transitions and the fuzzy interfaces as centers of the networks of virus-host interactions. Special focus is kept on the new lines of computational and AI-directed technologies such as ensemble-based docking, machine-learning computational models of IDP ligand recognition, and multi-omics-driven target prioritization. The experimental approaches that are modified to characterize disordered systems, including NMR spectroscopy and hybrid structural biology, are also reviewed. The translational applicability of the targeting of viral fuzziness is highlighted by case studies of HIV-1, influenza, SARS-CoV-2, and emerging viral pathogens. We also provide directions about the future involving adaptive pharmacophores, customized antiviral approaches, and AI-driven ensemble targeting making disordered viral proteins a paradigm shift in antiviral drug discovery.
Molecularly targeted nanomedicine has emerged as a transformative approach in modern drug delivery by integrating nanotechnology with molecular biology to achieve site-specific therapeutic action. Conventional pharmacotherapy often suffers from poor selectivity, systemic toxicity, limited bioavailability, and off-target effects, particularly in the treatment of complex diseases such as cancer, inflammatory disorders, and neurodegenerative conditions. Advances in the understanding of disease-specific molecular targets and pathological microenvironments have driven the development of nanocarriers capable of precise targeting and controlled drug release. This chapter provides a comprehensive overview of recent strategies and approaches employed in the design of molecularly targeted nanomedicines. It discusses fundamental principles of nanocarrier design, physicochemical properties influencing biological performance, and the mechanisms of passive and active targeting. Various classes of nanocarriers, including lipid-based, polymeric, inorganic, hybrid, and biomimetic systems, are critically examined with respect to their targeting potential. Additionally, the chapter highlights the role of targeting ligands, stimuli-responsive systems, and tumor microenvironment-specific strategies in enhancing therapeutic efficacy while minimizing adverse effects. Current challenges, translational barriers, and future perspectives are also addressed, emphasizing the potential of molecularly targeted nanomedicine to advance precision therapy and improve clinical outcomes.
Hormone-dependent malignancies, including breast, ovarian, thyroid, and prostate cancers, are driven by dysregulated endocrine signaling but exhibit marked heterogeneity in molecular architecture and therapeutic response. Whether these cancers share conserved transcriptional programs that transcend tissue-of-origin remains incompletely understood. In this study, we applied a systematic, direction-aware transcriptomic framework to identify shared gene expression signatures across hormone-driven malignancies using RNA-sequencing data with matched non-malignant controls. Differential expression analysis was performed independently for each cancer type using DESeq2, identifying 15,648 significant differentially expressed genes (DEGs). Integration of DEGs across cancers using a presence-direction matrix revealed limited universal overlap, with only one gene shared across all four cancers. Leave-one-out sensitivity analysis demonstrated that prostate cancer exhibited reduced transcriptional concordance relative to other malignancies. Exclusion of prostate cancer resulted in the highest overlap and direction-consistent dysregulation, identifying 10,948 shared DEGs across breast, ovarian, and thyroid cancers, including 1043 genes with consistent regulatory direction. Restriction to genes common to all three retained cancers defined a core pan-hormone transcriptional signature comprising 270 genes. These genes were prioritized using a composite statistical score integrating mean absolute log2 fold change and Fisher-combined adjusted p-values across cancers. Functional enrichment analysis of the top 100 ranked genes using g:Profiler revealed significant enrichment of immune-related biological processes, cytokine signaling, membrane-associated signal transduction, and protein-protein interaction functions. Collectively, this study identifies a conserved immune-signaling-centric transcriptional program shared across breast, ovarian, and thyroid cancers.
Advancing therapeutic strategies for chordoma requires a deep molecular understanding of tumor biology, supported by robust and reproducible experimental models. This chapter reviews recent progress in the development of in vitro and in vivo chordoma systems, including novel cell lines, genetically engineered models, and patient-derived xenografts. We detail the molecular and epigenetic features that underpin chordoma pathogenesis and resistance to therapy. Special attention is given to the design and testing of combinatorial therapeutic approaches-including immunotherapies, epigenetic modulators, and hydrogel-based drug delivery systems-that target distinct molecular vulnerabilities. Together, these innovations provide a translational framework for next-generation therapies tailored to the unique biology of chordoma.
Telomeric sequences are hotspots for ultraviolet light (UV) induced cyclobutane pyrimidine dimers (CPD) and pyrimidine(6-4)pyrimidone photoproducts (6-4 PP), due to pyrimidine runs on both the TTAGGG and CCCTAA containing strands. Photoproducts are repaired by global genome nucleotide excision repair (GG-NER) or by transcription-coupled (TC-NER) in regions of active transcription. Since telomeres are transcribed into long telomeric repeat-containing RNA (TERRA) molecules, here we tested roles for both TC-NER and GG-NER in telomere stability following UVC irradiation. XPC-deficient cells, incapable of GG-NER, failed to exhibit significant reductions in 6-4 PPs and CPDs at telomeres during recovery times, indicating that TC-NER cannot compensate for detectable photoproduct removal at telomeres when GG-NER is absent. TERRA analysis confirmed active telomere transcription in these cell lines. Loss of total NER or specifically GG-NER in XPA-deficient or XPC-deficient cells, respectively, increased telomere losses and telomere fragility following UV irradiation. These data provide direct evidence that NER is required to prevent UV damage-induced telomere aberrations and that transcription at telomeres is likely insufficient to drive substantial TC-NER-mediated photoproduct removal.
BACKGROUND/AIM:This study aimed to evaluate the anticancer efficacy of 5-Fluorouracil (5-FU) in Caco-2 human colorectal adenocarcinoma cells treated with siRNA-mediated MLH1 gene inhibition, in terms of cell viability, apoptosis, and related gene/protein expression. MATERIALS AND METHODS:Caco-2 cells were treated with a dose of 10 µM 5-FU. Cell viability was assessed by CVDK-8 analysis, and apoptosis was determined by flow cytometry using Annexin V-FITC/PI staining. Expression levels of MLH1, CDK2, CDK4, CDK5, CDK6, PTEN, EGFR, mTOR, PI3K, AKT3, ERK, PARP1, and GAPDH genes were examined by RT-qPCR analysis. Protein expression levels were analyzed using Western blot for PI3K, p-AKT, AKT1, mTOR, MAPK-p38, Caspase-3, Bcl-2, STAT3, JAK2, MLH1, MDR1, p53, and proteins; β-Actin was used as an internal control. RESULTS:CVDK-8 analysis showed that application of 10 µM 5-FU significantly reduced cell viability in Caco-2 cells. Flow cytometry results revealed a significant increase in both early- and late-apoptotic cell populations following 5-FU treatment. DISCUSSION:Gene and protein expression analyses showed significant changes in signaling pathways associated with apoptosis and cell proliferation. In this study, the effects of combining MLH1 gene silencing with 5-FU on colorectal cancer cells were comprehensively evaluated using Cell viability, RT-qPCR, flow cytometry, and Western blot analyses. It was determined that the combined application significantly reduced cell viability and increased apoptosis. Molecular-level findings on gene and protein expression support this effect. The results suggest that MLH1 gene silencing may increase sensitivity to 5-FU, offering a potential combination therapy approach in colorectal cancer.
Neglected tropical diseases (NTDs) comprise a heterogeneous group of infections that disproportionately affect populations in low- and middle-income countries, where limited access to diagnostics, therapeutics, and surveillance perpetuates disease burden. Conventional strategies based on antibodies and small-molecule drugs face major challenges, including high production costs, limited stability, cross-reactivity, toxicity, and the emergence of drug resistance. In this context, aptamers, short single-stranded nucleic acids selected by SELEX, have emerged as versatile immunomodulatory tools with significant potential for the diagnosis and treatment of NTDs. This chapter provides a comprehensive overview of aptamer-based strategies targeting major NTDs, with particular emphasis on human African trypanosomiasis and arboviral infections such as dengue, Zika, and chikungunya. Aptamers directed against conserved parasite and viral epitopes demonstrate the capacity to circumvent immune evasion mechanisms, including antigenic variation and serotype diversity, while enabling highly specific recognition and internalization. In African trypanosomes, RNA aptamers targeting variant surface glycoproteins exploit the flagellar pocket for targeted drug delivery, offering a novel approach to overcome therapeutic resistance. In arboviral diseases, aptamers have been successfully integrated into advanced diagnostic platforms, including competitive ELISA, electrochemical, and capacitive biosensors, achieving high sensitivity, rapid response times, and minimal cross-reactivity among closely related flaviviruses. Beyond diagnostics, selected aptamers exhibit neutralizing activity and immunomodulatory effects by interfering with host-pathogen interactions and innate immune signaling pathways.
Bladder cancer (BC) poses a significant global health and economic burden due to its high recurrence rates, progression risks, and the need for lifelong surveillance. Despite advances in diagnosis and treatment, reliable molecular biomarkers for prognosis and therapeutic targeting remain limited. In this study, we used an integrative bioinformatics approach to identify key dysregulated nuclear genes in BC, focusing on histone variants because of their essential role in chromatin organization and gene regulation. Using RNA-seq data, we performed a quality assessment, aligned reads with STAR, and conducted differential expression analysis using DESeq2. A unique gene expression pattern was seen between the cancer and control groups. From the DEGs, nuclear genes were curated using the NCBI Gene database and analysed their network topology via STRING and Cytoscape. MCODE found the complex cluster, and CytoHubba identified key hub genes, notably histone genes HIST1H3D (H3C4), HIST1H4E (H4C5), and HIST1H4B (H4C2). Functional enrichment via clusterProfiler highlighted roles in chromatin assembly, nucleosome organization, and centromeric dynamics. Notably, pathway analysis revealed links to systemic lupus erythematosus (SLE), neutrophil extracellular trap formation, and transcriptional misregulation, suggesting immunomodulatory roles. Kaplan-Meier survival analysis of patient cohorts using the KM-plotter tool revealed that higher expression of HIST1H4E and HIST1H4B was associated with improved survival outcomes. These findings emphasize the epigenetic and immunological roles of nuclear histone genes in BC progression and lay the groundwork for future translational research aimed at diagnostic and therapeutic advancements.
