Intermediate filaments are cytoskeletal proteins that are vital for proper cell structure formation and functioning. There are six types of these proteins. Type I includes acidic keratins, Type II includes basic and neutral keratins, both of which are present in epithelial cells. Type III includes vimentin, desmin, glial fibrillary acidic protein and peripherin, among which the last two are highly involved in neurodegenerative diseases. Type IV includes three types of neurofilament proteins, NF-L, NF-M and NF-H, where L signifies light, M signifies medium and H signifies heavy. The fourth protein in this category is α-internexin. All of these proteins are highly involved in neurodegenerative diseases, especially the neurofilament proteins. The type V intermediate filament proteins are lamins. The type VI intermediate filaments are nestins. Their involvement in a variety of neurodegenerative diseases has been observed, including Alzheimer's disease, Cerebral Ischemia, Multiple Sclerosis, Alexander Disease, Neuronal IF inclusion disease (NIFID) and Amyotrophic Lateral Sclerosis (ALS). Alzheimer's disease is a neurodegenerative disease in which two proteins are mainly involved, the Tau protein and the Amyloid-β protein. This review discusses the crosstalk of the intermediate filament proteins with the pathological proteins involved in the neurodegenerative diseases. For the case of the Alzheimer's disease, many of the intermediate filament proteins are involved in the disease pathology and are vital markers for the disease. One of the category of proteins involved is neurofilaments, among which NF-L is a marker for the disease. Keratin 9 and the glial fibrillary acidic protein (GFAP) are other intermediate filament proteins that are being explored as markers for the Alzheimer's disease.
Marine-derived polysaccharides and peptides have emerged as innovative immunomodulatory agents offering distinct structural features and multimodal biological activities not commonly found in terrestrial sources. Environmental pressures in marine ecosystems drive the evolution of diverse sulfated polysaccharides, antimicrobial peptides, and bioactive macromolecules capable of modulating both innate and adaptive immune responses. Polysaccharides such as fucoidan, carrageenan, ulvan, chitin, and chitosan demonstrate potent engagement of pattern recognition receptors, enhancement of antigen presentation, and immunological reprogramming of macrophages, dendritic cells, and natural killer cells. Marine peptides derived from fish, mollusks, and marine microbes combine direct antimicrobial effects with regulation of cytokine balance, T-cell differentiation, and tissue repair pathways. Synergistic strategies integrating polysaccharides and peptides in nanoscale delivery systems and conjugate vaccines show increased immunogenicity and therapeutic benefit across oncology, infectious diseases, and inflammatory disorders. Despite this promise, translation of marine immunomodulators into clinical practice is restricted by structural heterogeneity, limited bioavailability, and a lack of harmonized analytical and regulatory frameworks. Advances in multi-omics technologies, systems immunology, and machine learning, guided design are enabling deeper mechanistic understanding and rational optimization of marine bioactives. Concurrently, the development of sustainable aquaculture, biorefinery systems, and controlled bioprocessing supports scalable and environmentally responsible production. This chapter provides the recent molecular insights, therapeutic opportunities, and emerging translational strategies for marine-derived polysaccharides and peptides, while outlining key challenges and future priorities. Together, these innovations position marine immunomodulators as promising candidates for next-generation immunotherapy, vaccine adjuvant development, and global health applications.
Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily marked by the degeneration of dopaminergic neurons in the substantia nigra and the pathological accumulation of misfolded α-synuclein in Lewy bodies. This chapter explores the underrecognized role of microtubule (MT) dysregulation in PD pathogenesis, linking disruptions in cytoskeletal integrity to impaired axonal transport and neuronal survival. The fundamental biology of MTs, their dynamics, and their regulation by motor proteins and associated proteins like MT-associated proteins (MAPs), tau, and gamma-tubulin complexes. Special attention is given to how mutations linked to PD, such as those in SNCA (α-synuclein), Parkin, PINK1 (PTEN-induced kinase 1), and LRRK2 (leucine-rich repeat kinase 2), lead to MT destabilization, impaired mitophagy, and disruptions in axonal transport. A self-perpetuating cycle of MT disruption and α-synuclein aggregation is proposed, resulting in synaptic failure and dopaminergic neuron loss. The chapter also evaluates emerging therapeutic strategies targeting MT stabilization, including LRRK2 inhibitors, MT-stabilizing agents like Epothilone D, and approaches to modulate α-synuclein aggregation. Challenges such as the blood-brain barrier, off-target effects of MT-targeting drugs, and patient-specific variability in drug response are critically discussed. The future directions include CRISPR-Cas9-based gene therapies and personalized medicine, emphasizing the need for a deeper understanding of PD-related molecular pathways. This comprehensive overview highlights MT dynamics not just as collateral damage but as a central element in PD pathology, offering novel insights into potential avenues for intervention.
Neurodegenerative diseases (NDs) are a heterogeneous group of progressive disorders characterized by the selective loss of neuronal structure or function, often leading to cognitive and/or motor dysfunction. Although NDs present clinical diversity, several of these diseases share a common pathological characteristic, which consists of the aggregation of cytoskeletal proteins in specific regions of the central nervous system (CNS). The cytoskeleton is an intricate network of filamentous proteins within the cytoplasm and plays a critical role in maintaining neuronal polarity, axonal transport, synaptic integrity, and overall cellular architecture. Structural and functional abnormalities in the cytoskeleton, especially in neuronal intermediate filament (IF) proteins and microtubule-associated protein tau (MAPT), can compromise neuronal function, inciting inflammation and leading to neuron cell death. So, cytoskeletal protein species can be considered biomarkers and provide guidance for treatments associated with NDs. Considering the complexity of the biological matrix and the molecular mechanisms involved, the identification and characterization of cytoskeletal protein abnormalities require robust and sensitive analytical tools, comprising sample preparation protocol, advanced instrumental techniques and data processing algorithms. So, this chapter provides a comprehensive review of the bioanalytical approaches employed in the investigation of cytoskeletal proteins involved in the pathogenesis of NDs. Also, some tools applied in data processing are discussed here, considering the combination of classical data analysis algorithms with artificial intelligence focused on the discovery of cytoskeletal biomarker proteins. Furthermore, a general discussion of the possible molecular mechanisms related to neuronal degeneration involving the main cytoskeletal proteins is presented.
Systemic Lupus Erythematosus (SLE) is a complex autoimmune disorder characterized by chronic inflammation, multi-organ involvement, and a strong type I interferon (IFN) signature. To elucidate immune-specific molecular drivers of SLE, we performed transcriptomic profiling using RNA sequencing (RNA-seq) data from 117 samples (99 SLE patients, 18 healthy controls) obtained from the European Nucleotide Archive (PRJNA294187). Following quality control, alignment to GRCh38, and read quantification, differential expression analysis with DESeq2 identified 2150 differentially expressed genes (DEGs), including 1361 upregulated and 789 downregulated genes (FDR<0.01, |log₂FC=>1). Reactome pathway enrichment isolated 41 immune-related DEGs enriched in cytokine signaling, interferon response, antigen processing, and innate immune activation. Notably, interferon-stimulated genes (ISGs) such as EIF2AK2, ISG15, CXCL10, CXCL11, IFI44L, RSAD2, and HERC5 emerged as central nodes in immune regulatory networks. Gene Ontology analysis highlighted overactivation of defense response, chemokine-mediated cell trafficking, and Jak-STAT signaling pathways typically induced by viral infection but aberrantly sustained in SLE, driving chronic inflammation and autoimmunity. Several genes, including HERC5, HERC6, and IL5RA, exhibited regulatory roles in ubiquitination and cytokine receptor signaling, suggesting potential as biomarkers for disease activity. These findings support targeting type I IFN signaling and related immune circuits as therapeutic strategies, aligning with emerging clinical success of IFN-blockade in SLE. By prioritizing immune-focused DEGs and integrating pathway-level interpretation, our study refines the transcriptomic landscape of SLE and provides actionable molecular insights for precision medicine approaches aimed at disease modulation and patient stratification.
It was shown experimentally that the motility of different families of kinesin motors can be differentially regulated by microtubule-associated tau proteins. However, the underlying mechanism is unclear. To address the mechanism, here we take three kinesin motors-kinesin-1, kinesin-3 and kinesin-8-as examples to study theoretically the motility of the kinesin motor within the tau island and at the island boundary. The theoretical results show that after landing within the tau island, a kinesin-8 motor can move processively for a long time of about 80 s and for a long run length of about 1.6 µm, a kinesin-1 motor can dissociate in a short time of about 0.35 s, while a kinesin-3 motor can dissociate in a much shorter time of about 0.01 s. The kinesin-8 motors can induce the receding of the tau island with a velocity similar to a kinesin-8 stepping within the island, kinesin-1 motors can hardly induce the island receding, while kinesin-3 motors have a much lower probability to induce the island receding than kinesin-1 motors. The theoretical results explain well the available experimental data. The studies indicate that the tau island differentially regulating the motility of different kinesin motors is due mainly to different residence times of the motors with a stationary small obstacle on the front tubulin.
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.
Systemic lupus erythematosus (SLE) is a complex autoimmune condition characterized by multifactorial pathogenesis involving dysregulated immune responses. It has been associated with an elevated risk of various cancers, notably cervical cancer (CC), one of the most common cancers in women globally. Despite this association, the molecular mechanisms linking SLE and CC remain incompletely defined. To investigate this intersection, we employed integrative bioinformatics approaches to analyze transcriptomic datasets relevant to both SLE and CC, including GSE112087, GSE154851, GSE46907, GSE49454, GSE50772, GSE63514, GSE64217, GSE63678, GSE7803, and GSE9750 . We performed differential gene expression analysis, constructed Protein-Protein Interaction (PPI) networks, and carried out functional annotation to pinpoint pivotal hub genes and signaling pathways implicated in both diseases. Our analysis revealed significant differentially expressed genes (DEGs) in SLE, predominantly associated with cytokine and interferon alpha/beta signaling pathways, as well as the innate immune response. Notable hub genes included MX1, ISG15, and STAT1. In CC, DEGs were chiefly enriched in the mitotic cell cycle and cytokine signaling processes, with CDK1 and DLGAP5 standing out as key hub genes. The cross-disease analysis identified shared DEGs between SLE and CC, particularly in the interferon-alpha/beta and cytokine signaling pathways. This suggests a shared molecular architecture that underlies both autoimmune and cancer pathogenesis. Our study underscores the common molecular pathways between SLE and CC, highlighting the significance of interferon and cytokine signaling in the pathogenesis of both diseases. These insights set the stage for future research into potential therapeutic targets for the treatment of both SLE and CC.
Antimicrobial peptides (AMPs) are tiny proteins essential for innate immunity in various taxa, including mammals and insects. They provide defence against a wide range of pathogens, including bacteria, viruses, fungi, and parasites. Apart from their antimicrobial properties, new studies have revealed the roles of AMPs in brain ageing, neurodegeneration, and neuroinflammation. With an emphasis on their dysregulation in glial and neuronal tissues and their role in neuroinflammation, mitochondrial dysfunction, and neuronal loss, we reviewed the new function of AMPs beyond their antimicrobial activity. Findings from Drosophila models of Huntington's disease, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Ataxia-telangiectasia show that immune pathways, like Toll and immune deficiency, drive persistent or ectopic AMP expression, which is similar to the inflammatory processes seen in human neurodegenerative diseases. Furthermore, the dual function of AMPs as mediators of sterile inflammation and protective immunological agents reveals a universal paradox. The translational relevance of these findings is further supported by comparisons with human AMPs, such as LL-37 and β-defensins. LL-37 and β-defensins levels were found to be increased in the cerebrospinal fluid of patients suffering from meningitis. LL-37 is released from neurons and activates glial cells, boosting the production of inflammatory cytokines and decreasing neuronal survival. This chapter redefines AMPs as not only sentinels of microbial defence but also as important participants in preserving or disturbing brain homeostasis by establishing them as a link between immunity and neurobiology.
A wide range of neurological conditions known as Tauopathies are distinguished by a peculiar accumulation of Tau protein and its effect on the central nervous system (CNS) and beyond. In Tauopathies, Tau aggregation has a primary role in the neurodegenerative process. Clinically, individuals exhibit various symptoms, such as cognitive or behavioural anomalies, mobility issues, memory loss, and language problems. The major Tau isoforms (3R, 4R, or an equal 3R:4R ratio) identified in the inclusion bodies of the brain are used to classify Tauopathies pathologically. We address various Tauopathies, differentiating between primary and secondary forms, the involvement of Tau isoforms, the affected brain areas, and the corresponding neuropathological features. This review emphasizes the pathological and physiological role of Tau protein, providing a comprehensive analysis of the molecular processes enabling Tau aggregation and its subsequent effect on neuronal structure and function. Additionally, the review highlights the complex interactions that exist between Tau and other neurodegenerative proteins, including amyloid-beta in Alzheimer's disease, alpha-synuclein in Parkinson's disease, huntingtin protein in Huntington's disease, and how these relationships worsen Tau pathology and advance neurodegeneration. The organ-specific impact of Tauopathy, including the brain and other peripheral organs, has been discussed. The significance of these findings for future treatment techniques aiming at addressing Tau disease and mitigating its organ-specific repercussions.
Alzheimer's Disease is characterized by significant alterations in the cytoskeleton, driven by hyperphosphorylation of the microtubule-associated protein Tau. This modification impairs Tau's ability to stabilize microtubules, leading to structural instability, disrupted axonal transport, and neuronal degeneration. Hyperphosphorylated Tau aggregates into neurofibrillary tangles and oligomers, exacerbating cellular dysfunction. The cytoskeleton, composed of actin filaments, microtubules, and intermediate filaments, is vital for maintaining cellular structure, intracellular transport, and signalling. G-protein coupled receptors, widely expressed in neuroglial cells, play critical roles in neuroinflammation, synaptic pruning, and cytoskeletal dynamics in neurodegenerative diseases. Extracellular Tau species interact with GPCRs, particularly in microglia and astrocytes, triggering neuroinflammatory responses and cytoskeletal remodelling. Key kinases such as Glycogen Synthase Kinase-3β and Cyclin-Dependent Kinase-5 regulate Tau phosphorylation. Hyperactivation of these kinases, influenced by GPCRs signalling pathways, promotes Tau hyperphosphorylation, contributing to Tauopathies. Stress-related GPCRs like CRFR1, β2AR, and AT2R, along with glutamate-driven activation of mGluR2, exacerbate Tau pathology by enhancing kinase activity. Conversely, certain GPCRs, such as mAChRs, can mitigate Tau hyperphosphorylation by inhibiting GSK-3β activity. Understanding the interplay between Tau, GPCRs, and associated signalling pathways provides insights into the molecular mechanisms driving AD and highlights potential therapeutic targets for mitigating Tauopathies and neurodegeneration.
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.
Cytoskeleton represents a set of specific proteins uniquely organized in a complex network of protein filaments within cells that has a multitude of crucial roles, acting as a structural framework, facilitating intracellular transport, enabling various cellular processes, such as cell division, intracellular cargo transport, and cell movement, as well as providing mechanical support and maintaining cellular structure. The cytoskeleton is particularly vital in neurons, as their shape, axonal transport, and synaptic transmission are controlled by this complex interacting meshwork. Therefore, it is not surprising that aberrations in cytoskeleton and dysregulations of the neuronal cytoskeletal proteins are linked to a wide spectrum of neurodegenerative diseases. Vast literature exists about physiological and pathological roles of neuronal cytoskeleton. It is clear that the specific structural organization of different cytoskeletal forms and associated distinctive sets of specific functions and dysfunctions are determined by the proteins forming specific filaments (microfilaments, microtubules, and intermediate filaments) and by the proteins interacting with those filament formers. Therefore, one deals here with large and complex proteinaceous machines composed of multiple highly diversified components. Commonly, multifunctionality and complexity of proteins are associated with the intrinsic disorder phenomenon. Analysis of such structure-disorder-function connections in neuronal cytoskeleton represents a subject of this study. We are showing here that the overall organization of the elements of the neuronal cytoskeleton represents an intertwined unity of order and disorder and can be described as supramolecular sticks with whips assembled from macromolecular sticks with whips.
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.
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease are characterized by progressive neuronal dysfunction and loss. A growing body of evidence implicates cytoskeletal disruption as a central pathological mechanism in these conditions. Cytoskeletal proteins, including microtubules, actin filaments, tau, neurofilaments, and alpha-synuclein, not only provide structural integrity but also regulate axonal transport, synaptic connectivity, and neuroplasticity. Its dysfunction will lead to impaired intracellular trafficking, protein aggregation, and neuronal degeneration. This chapter explores clearly about the specific cytoskeletal abnormalities that are evident in major neurodegenerative disorders, highlighting the biological mechanisms such as tauopathy-induced microtubule instability in Alzheimer's, actin cytoskeleton dysregulation in Parkinson's, and neurofilament aggregation in ALS. Current therapeutic strategies aimed at the stabilizing cytoskeletal components, enhancing protein clearance, and restoring transport dynamics are examined, alongside the cutting-edge approaches including the gene therapy, CRISPR/Cas9 editing, and nanotechnology-based delivery systems. Challenges such as limited blood-brain barrier penetration, off-target toxicity, and patient heterogeneity are also discussed with the focus on need for precision medicine. Additionally, we have also explored the future directions that specifically focused on the biomarker development, combination therapies, and strategies to promote neuroregeneration and structural plasticity. Targeting cytoskeletal pathways holds significant promise not only for suppressing the disease progression but also for rebuilding the structural foundation of the nervous system, potentially reversing the neurodegenerative decline.
Neurodegenerative diseases, such as Alzheimer's disease, vascular dementia, Parkinson's disease, frontotemporal dementia, and cognitive decline associated with stroke, have a similar clinical trait involving the alteration of microtubule dynamics and cytoskeletal integrity. The neuronal cytoskeleton is essential for facilitating axonal transport, synaptic connections, and providing structural support. In Alzheimer's disease and vascular dementia, tau protein undergoes hyperphosphorylation and dissociates from microtubules, forming insoluble aggregates that obstruct intracellular transport and destabilize microtubule structure. Additionally, region-specific posttranslational changes of tubulin are modified, further impairing cytoskeletal control. In Parkinson's disease, the aggregation of α-synuclein induces oxidative damage and directly impairs microtubule polymerization, especially in the dopaminergic neurons of the substantia nigra. Stroke induces acute ischemia and reperfusion injury, resulting in surges of reactive oxygen and nitrogen species, disruption of the blood-brain barrier, and neuroinflammatory cascades that rapidly destroy cytoskeletal proteins and alter microglial phenotypes. Cardiovascular conditions, including hypertension, heart failure, and atherosclerosis, lead to persistent cerebral hypoperfusion, which promotes progressive neuronal damage and alters tubulin expression and organization. Cardiovascular complications intensify oxidative stress and impair neurovascular coupling, establishing a detrimental cycle that accelerates cytoskeletal disintegration and neural impairment. Collectively, such conditions demonstrate a heart-brain axis in which cardiovascular problems directly lead to microtubule disintegration and dementia. Understanding these pathways provides a unified framework for cytoskeletal biomarkers and novel therapeutic approaches to preserve neuronal structure in various neurological conditions.
The Hippocratic adage "all disease starts in the gut" remains pertinent as research uncovers how the gut microbiome and its products influence immunity and gastrointestinal cancers. The immune system's remarkable paradox lies in its ability to distinguish and tolerate trillions of beneficial microbes while defending against harmful pathogens to maintain health. Disruptions to this delicate balance, known as dysbiosis, contribute to chronic inflammation and create a favourable tumour development and progression environment. Microbial metabolites, such as- short-chain fatty acids and secondary bile acids further modulate inflammation, gut barrier integrity, and immune checkpoint pathways. Emerging microbial biomarkers show promise in diagnosis and prognosis and compete with traditional clinical factors. Innovative therapeutic strategies are being explored to harness the microbiome's immunomodulatory potential. Integrating microbiome profiling into personalised medicine offers new opportunities to prevent, detect, and treat gastrointestinal cancers, shifting the microbiome from a passive disease marker to an active agent that modulates and influences the disease. This chapter discusses the emerging understanding of microbiomes and microbial products in gastrointestinal cancers, highlighting diagnostic advances and novel therapeutic approaches that leverage microbial interactions to improve patient outcomes.
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.
Immunotherapy has reshaped modern medicine, especially in oncology, yet uneven patient responses, treatment resistance, and immune-related toxicities still limit its impact. This chapter focuses on synthetic immunomodulators, engineered agents that steer immune activity with tighter control than broad immunosuppressants or many first-generation biologics. We first revisited why classical immunomodulation was often blunt and toxic, and how advances in chemistry, synthetic biology, and nanotechnology now enable more selective immune tuning. We then organized the field into practical classes such as small molecules, synthetic peptides and peptidomimetics, cytokine mimetics, nucleic acid-based modulators, and synthetic checkpoint modulators, and explained how each can either strengthen protective immunity (for example, antitumor responses) or calm damaging inflammation in autoimmune and chronic inflammatory settings. We highlighted use cases that matter at the bedside, including vaccine adjuvants, reprogramming suppressive tumor microenvironments, sustaining cytotoxic and memory responses, and building rational combinations with chemotherapy, radiotherapy, and targeted therapy. Finally, we summarized the clinical direction and key translational bottlenecks, including delivery and biodistribution, toxicity ceilings from overactivation, and the need for biomarker-guided patient selection and sequencing. Overall, synthetic immunomodulators are moving the field from simply turning immunity up or down to tuning it with better timing, location, and cell-type precision. We concluded with practical markers that can track whether a strategy is working, including interferon response signatures, antigen-presenting cell activation, and early shifts in cytotoxic lymphocyte populations in patients over time.
The formation of filopodia and podosome-like structures as a part of the Alzheimer's disease pathology has been examined over the recent past. Podosomes are structures rich in F-actin, which are involved in adhesion and mechanosensing. To assist the podosomes in its roles, it has an advanced and dynamic structure, comprised of actin filaments as a part of its core, the ring region composed of integrin and integrin-actin linkers and the cap composed of tropomyosin 4. The podosomes organize from clusters to rings to belts. Various components are involved in the formation of podosomes, including phosphatidylinositol, Src kinases, PI3 kinase, the adaptor TKS5, integrins, cortactin, paxillin, Iba1, Sk3, PAM, EB1, CDC42, WASP and Arp2/3. Podosomes play a role in cell adhesion by attaching cells to the ECM, while also contributing to the latter's degradation. Many studies have also shown that podosomes and invadosomes are involved in pathogen clearance. Various factors responsible for the formation of podosomes have also been linked to the Alzheimer's disease, including TKS5 and ADAM12 which have been liked to Amyloid-β. TKS5 and Arp2 are involved in the interactions between the P2Y12 receptor and Tau, which lead to the formation of podosomes. It is suggested that these podosomes are involved in the microglial migratory process.