Gaurav Gupta

Introduction: This review aims to comprehensively discuss the emerging role of artificial intelligence (AI) and three-dimensional (3D) printing in the design and development of personalized polymeric nanocomposite-based drug delivery systems. The focus is on how integrating these technologies enhances the precision, efficacy, and customization of pharmacotherapy compared with conventional formulations. Methods: An extensive literature survey was conducted using databases such as PubMed, Scopus, Web of Science, and ScienceDirect, focusing on publications from the past decade. Peer-reviewed studies, reviews, and reports on polymeric nanocomposites, AI-based formulation design, and 3Dprinted drug delivery systems were critically analyzed. The collected data were synthesized to elucidate design principles, fabrication methods, and the synergistic application of AI and 3D printing in personalized medicine. Results: Polymeric nanocomposites have demonstrated superior performance in targeted and controlled drug release due to their adaptable physicochemical properties and biocompatibility. The application of AI enables predictive modeling, optimization of formulation parameters, and patient stratification through data-driven algorithms. Concurrently, 3D printing enables the fabrication of patient-specific dosage forms and implants with programmable drug-release profiles. Together, these technologies enable the development of individualized therapeutic systems that enhance treatment outcomes and minimize adverse effects. Discussion: This synergistic incorporation of AI and additive manufacturing tackles some of the main obstacles in precision medicine by diminishing trial-and-error in formulation, enhancing reproducibility, and promoting better outcomes during treatment. Such multidisciplinary applications are most promising in cancer, diabetes, neurodegenerative, infectious, and cardiovascular diseases. Conclusion: The integration of AI and 3D printing represents a transformative advancement in personalized nanocomposite drug delivery. These interdisciplinary approaches collectively enable precise control over drug release kinetics, dosage customization, and formulation design. Future developments focusing on regulatory standardization, ethical data use, and large-scale clinical translation will further accelerate the adoption of AI- and 3D-printing-assisted personalized drug delivery systems in clinical practice. While these technologies hold great potential for personalized and precise therapeutics, their clinical translation remains challenged by regulatory validation, manufacturing reproducibility, and data transparency requirements.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an integral pathogenic factor in inflammatory lung pathologies including asthma, COPD, and lung cancer. As a pro-inflammatory cytokine, GM-CSF triggers the division and stimulation of granulocytes and macrophages, exacerbating the inflammatory response and promoting lung tissue damage. GM-CSF is an essential factor in promoting the production of the corresponding cytokines, levelling the effect of local activity by stimulating the infiltration of immune cells and maintaining chronic inflammation. Therefore, its neutralization in many ways leads to the cessation of the progression and exacerbation of inflammation in the lungs of patients with corresponding pathologies. Inhibitory therapy associated with GM-CSF reduces the number of immune cells and activates them at the inflammatory focus. The use of neutralizing antibodies to treat an acute inflammatory process is promising because they relatively quickly neutralize the effect of pathogenic GM-CSF. However, the immunocyte response can also be inhibited at the level of formation. Therapy with GM-CSF inhibitors can significantly reduce acute inflammation but can lead to adverse changes in the innate immunity of the patient. This review highlights GM-CSF's dual function of GM-CSF as a pathogenic contributor and possible treatment targets.

Rheumatoid arthritis (RA) is a chronic autoimmune disease with a global prevalence of 0.5% to 2%, causing serious impairment and early mortality. Presently approved therapeutics comprising non‐steroidal anti‐inflammatory drugs (NSAIDs), disease‐modifying anti‐rheumatic drugs (DMARDs), corticosteroids, etc. only lower pain, edema, and inflammation. Most of these therapeutics have been administered orally, intravenously, and intra‐articularly, minimizing patient adherence. Additionally, high doses of these drugs need to be taken for a long duration and have poor specificity, causing fatal side effects. The conventional and nanocarrier (NCs)‐based topical cargo delivery pose challenges like poor residence, possibility of skin reactions, and low patient adherence. Therefore, transdermal delivery of these therapeutics using microneedles (MNs) can be promising to improve permeability, bioavailability, targeting, and patient compliance while minimizing side effects. Moreover, NCs‐assisted MNs, biomimetic NCs‐based MNs, and MNs for biologics delivery have also emerged as a promising platform for targeting RA efficiently. This review attempts to give an overview on the transdermal drug delivery using MNs and NCs‐based MNs in the efficient management of RA. Thus, different MNs and their amalgamation with NCs could effectively deliver and manage RA via the transdermal route.

EXCLI Journal - Experimental and Clinical Sciences, International Online Journal for Advances in Sciences

Cancer cells frequently evade therapies that depend on apoptosis, necessitating the exploration of alternative cell death mechanisms. Ferroptosis, an iron-dependent regulated cell death characterized by lethal lipid peroxidation, has emerged as a promising strategy for cancer treatment. Recent studies have identified berberine, an isoquinoline alkaloid derived from Coptis chinensis and Berberis species, as an inducer of ferroptosis in various malignancies through its multitarget effects. This review systematically elucidates the molecular pathways through which berberine induces ferroptosis. These pathways include the inhibition of the System Xc−/glutathione/glutathione peroxidase 4 antioxidant axis, disruption of iron homeostasis via ferritinophagy, inhibition of mitochondrial complex I, and regulation of the upstream regulators p53, nuclear factor erythroid 2-related factor 2, and Gli1/signal transducer and activator of transcription 3 axis. Evidence specific to various cancer types, including nasopharyngeal, lung, colorectal, gastric, hepatocellular, pancreatic, prostate cancer, and osteosarcoma, was critically evaluated. Translational strategies, such as combination therapy, nanodelivery systems, and machine learning-directed structural optimization, have been examined. Additionally, the challenges of low bioavailability, resistance to ferroptosis, and complex immunological responses are discussed. Preclinical evidence suggests that berberine exhibits significant epigenetic activity, including the inhibition of DNA methyltransferases (DNMT1/DNMT3), histone modifications (H3K9me3 via SETDB1, H3K27me3 via EZH2), and modulation of oncogenic/tumor-suppressor microRNAs (e.g., miR-21, miR-155). These actions enhance its ferroptotic effects and may synergistically increase the sensitivity of cancer cells to lipid peroxidation. Although primarily based on preclinical findings, these epigenetic mechanisms represent a crucial and underexplored aspect of berberine's anticancer potential.

Introduction: The global increase in antimicrobial resistance presents a significant public health challenge and calls for the discovery of new antimicrobial agents with innovative mechanisms of action. Spirocyclic compounds, characterized by two or more rings connected via a single shared atom, have attracted interest due to their rigid three-dimensional structures and promising pharmacological activities. This review aims to summarize research published between 2019 and 2025 on the antibacterial potential of natural, semisynthetic, and synthetic spirocyclic compounds, emphasizing their activity against Gram-positive, Gramnegative, and resistant bacterial strains. It also highlights promising therapeutic scaffolds and explores Structure- Activity Relationships (SAR) where available. Methods: Relevant literature was gathered from peer-reviewed scientific databases. Studies reporting antibacterial evaluations of spirocyclic derivatives were included. Reported compounds were classified based on their core scaffold type, and their antibacterial activities, synergistic effects with standard antibiotics, and insights from computational docking were examined. Results: Several spirocyclic scaffolds demonstrated antibacterial potential, including spiro β-lactams, spiro chromanes, spiro thiazolidines, and especially spiro oxindoles, which were the most extensively studied (44 research articles). Many compounds showed notable antibacterial activity against drug-resistant strains, and synergistic effects were observed when combined with conventional antibiotics. One spiro pyrimidinetrione derivative was approved recently by the US FDA, indicating translational potential. Molecular docking studies supported mechanistic understanding by predicting possible bacterial targets. Discussion: Due to their wide applications across various scaffolds, spiro frameworks could be a valuable strategy in defeating bacteria. This architecture offers structurally unique compounds by expanding the threedimensional chemical space that may address antimicrobial resistance. Further exploration through Mechanistic validations and systematic structure-activity relationships studies is required to fully understand the potential of spiro compounds. Conclusion: Spirocyclic compounds are a valuable class of antibacterial agents owing to their structural diversity and efficacy. This review offers insights into their therapeutic potential and provides a foundation for future drug development targeting antimicrobial resistance.

Circadian rhythms are endogenous time-keeping mechanisms that organize physiological and cellular functions into approximately 24-hour cycles. These rhythms are generated by conserved molecular clocks composed of interconnected transcription–translation feedback loops involving core regulators such as CLOCK, BMAL1, PERIOD, CRYPTOCHROME, REV-ERB, and ROR proteins. While circadian regulation is best known for governing sleep–wake behavior, mounting evidence demonstrates that peripheral clocks exert critical control over organ-specific physiology. The lung represents a highly rhythmic tissue in which local circadian oscillators coordinate airway tone, immune surveillance, inflammatory signaling, epithelial repair, and metabolic homeostasis. Disruption of circadian timing arising from genetic alterations, environmental stressors, shift work, irregular light exposure, or chronic inflammation has emerged as an important contributor to the development and progression of multiple respiratory diseases, including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, acute lung injury, sleep-disordered breathing, and lung cancer. At the mechanistic level, dysregulation of clock genes alters inflammatory pathways, oxidative stress responses, mitochondrial metabolism, and cell-cycle control, thereby exacerbating tissue injury and impairing resolution and repair. Recognition of these temporal influences has prompted growing interest in circadian-based therapeutic strategies. Chronotherapy, which aligns drug administration with endogenous biological rhythms, and pharmacological targeting of clock components such as REV-ERBs and RORs, offer promising avenues to improve treatment efficacy while limiting adverse effects. This review integrates current insights into circadian clock architecture, lung-specific regulation, disease mechanisms, and therapeutic potential, highlighting circadian biology as a critical yet underutilized dimension of respiratory medicine.

The use of CRISPR-Cas9 to engineer cancer cell lines has made it possible to precisely examine how cancer cells react to different drugs and therapies. Some of the key improvements are in the use of Mediator Complex Subunit 12 (MED12)-knockout cells to study cell resistance to BRAF inhibitors, CRISPR models of epithelial-mesenchymal transition for breast cancer, and pharmacogenomic analysis in various cancer cell lines. CRISPR is used in immunotherapy to help Chimeric Antigen Receptor T (CAR-T) cells function better by disrupting the immune checkpoints like Programmed Cell Death Protein 1 (PD-1) and Cytotoxic T-lymphocyte- associated protein 4 (CTLA-4) and to adapt T cells to react with various antigens. As a result of these innovations, it is now possible to track how cancers like non-small cell lung cancer (NSCLC) and ovarian cancer evolve, change their epigenetic features, and find strategies to reverse their resistance. Moving forward, integrating AI analytics, single-cell multi-omics, patient-derived organoids, and CRISPR mechanisms will help improve precision oncology and speed up effective treatment planning.

Introduction: Japanese encephalitis virus (JEV) hijacks the host cell's endoplasmic reticulum (ER) to form assembly and replication complexes during replication, leading to the production of multiple copies of JEV negative-sense and positive-sense RNA strands. The nonstructural protein NS5 RNA-dependent RNA polymerase (RdRp) is conserved across all Flavivirus species, and its inhibition can suppress Flavivirus replication. The objective of this study is to evaluate the inhibitory potential of 126 Aegle marmelos-derived compounds on JEV NS5 RdRp using computational methods. Methods: A computational (in silico) approach was employed to assess the binding efficacy and inhibitory effects of Aegle marmelos compounds against the NS5 RdRp of JEV. Molecular docking and virtual screening techniques were used to identify potential inhibitors. Results: The analysis revealed that several compounds, specifically IMPHY015072, IMPHY015047, IMPHY014838, and IMPHY011609, demonstrated significant binding affinity towards NS5 RdRp. These compounds effectively reduced JEV replication in silico, compared to control compounds. Furthermore, the selected compounds may potentially lower IL-1β serum levels and mitigate structural abnormalities in brain tissue. Discussion: The in silico analysis in this study demonstrated the potential of Aegle marmelosderived compounds to inhibit Japanese encephalitis virus (JEV) replication by targeting the conserved NS5 RNA-dependent RNA polymerase (RdRp). The selected compounds— IMPHY015072, IMPHY015047, IMPHY014838, and IMPHY011609—showed strong binding affinity and effectively reduced JEV replication compared to control compounds. Conclusion: The study suggests that specific Aegle marmelos-derived compounds exhibit promising inhibitory effects against JEV NS5 RdRp and could serve as potential therapeutic candidates to treat JEV infection and reduce associated inflammation and neuronal damage.