Intracellular bacteria exploit host cell niches, such as lysosomes, phagosomes, cytosol, entire cells, and even erythrocytes, to evade immune clearance and escape conventional antibiotics. These environments pose numerous therapeutic challenges, including crossing host cell membranes, navigating endosomal trafficking, tolerating acidic and redox conditions, bypassing efflux mechanisms, and countering phenotypic tolerance. Although recent advancements in nanotechnology-such as carriers, prodrugs, and host-directed therapies-offer promising solutions, current strategies remain narrowly focused on "getting the drug inside the cell", leaving therapeutic agents vulnerable to off-site targeting, degradation, and functional failure. This review introduces a next-generation approach for intracellular antibacterial therapy, incorporating subcellular targeting, dual-function delivery systems, innovative biomimetic carriers, precise intracellular pharmacokinetics/pharmacodynamics (PK/PD) assessment, and artificial intelligence-assisted drug design. Highlighting frameworks for multimodal regimens targeting intracellular bacteria, we advocate a transition from solely facilitating cellular entry to achieving precise spatiotemporal regulation of drug activity within infected host cells. This paradigm informs the development of therapeutics designed to persist within the intracellular bacterial niche, minimizing relapse and reducing the emergence of antimicrobial resistance.

Developing new antimicrobial drugs is crucial for combating global drug resistance caused by microbial infections. Here, a new series of pyrazole and isoxazole derivatives were synthesized using a multicomponent reaction based on ethylvanillin and active methylene group as well as binucleophile reagents under basic conditions. The designed derivatives were confirmed using FT-IR, H NMR, C NMR, Mass spectrum, and elemental analysis. Subsequently, all the designed derivatives were evaluated against four bacterial and one fungal strain. The synthesized derivatives demonstrated significant to good antimicrobial activity with low MIC values against the tested strains, especially against Bacillus subtilis, Staphylococcus aureus, and Candida albicans. Notably, four compounds 14, 17, 20, and 24 showed promising MIC values ranging from 7.8 to 62.5 µg/mL) against gram-positive strains and for gram-negative strains (MIC = 31.25-125 µg/mL), compared to gentamycin (15.62 and 31.25 µg/mL), respectively. In addition, these derivatives revealed MIC values from 15.62 to 31.25 µg/mL compared to fluconazole (MIC = 15.62 µg/mL) against C. albicans. Additionally, the structure activity relationships (SAR) were discussed. Moreover, the MBC and MFC values were evaluated and the results exhibited bactericidal and fungicidal properties, except for 5-hydroxy-1H-pyrazole-1-carbothioamide derivative 14 that demonstrated bacteriostatic activity against B. subtilis. Moreover, the biofilm inhibitory activity of the most promising derivatives demonstrated a dose-dependent effect and inhibit biofilm formation from 96.17 ± 0.004% to 66.04 ± 0.004%. Among these compounds, the 5-hydroxy-1H-pyrazole-1-carbothioamide derivative 14 emerged as the most active, exhibiting a biofilm inhibitory percentage (BIP) of 96.17 ± 0.004% compared to gentamicin's BIP of 96.44 ± 0.004% at 75% MIC. Finally, a docking simulation of the most promising derivatives was conducted within the active site of Las R, suggesting a potential mode of action, where these derivatives displayed different binding interaction with low binding affinity. Moreover, in-silico oral bioavailability and toxicity profile was predicted for the most promising derivatives and exhibited promising physicochemical properties with a safe toxicity profile, opening up the possibility of the discovery of new antibiotics.

Periodontal disease is a chronic inflammatory problem that has destructive effects on the tooth-supporting tissues. This disease affects a large portion of the population, influencing overall health and quality of life, and significant socioeconomic burden. Therefore, efforts to more effectively manage the problems caused by this disease are a necessity. This review describes the therapeutic potential of Trolox (a water-soluble analogue of vitamin E) and its modified derivatives as potential candidates for managing periodontal disease, highlighting their multifaceted pharmacological properties. Unlike the lipophilic molecule vitamin E, Trolox can be formulated into aqueous solutions, gels, mouthwashes, or rinses, ensuring optimal bioavailability at sites of inflammation and infection in the oral cavity. This compound can also help treat periodontal disease by combating oxidative stress, where its antioxidant properties neutralize harmful reactive oxygen species (ROS), reducing tissue damage and bone loss caused by undesired conditions such as bacterial imbalance. In addition to antioxidant and anti-inflammatory properties, Trolox and its derivatives exhibit various pharmacological activities against diabetes, Alzheimer's disease, Plasmodium falciparum malaria infection, and periodontopathogens, all of which are associated with the development of periodontal disease. In conclusion, this review suggests that Trolox and some of its derivatives with favorable activity/toxicity profiles have significant potential to be considered as new drug candidates for combating periodontal diseases.

Type 2 diabetes (T2D) is a major cause of morbidity in developed countries and involves insulin resistance, a failure to correctly respond to insulin. Numerous studies in rodent T2D models suggested that the short-chain fatty acid butyrate, produced by gut microbiota species through fermentation of dietary fibers, improves T2D symptoms. Here, we explored the potential antidiabetic effects of butyrate by measuring the transcription of selected T2D-implicated genes in human B lymphocyte-derived lymphoblastoid cell lines (LCLs) from 17 unrelated adult healthy donors. Human LCLs were cultured with and without sodium butyrate (1 mM for 48 h), followed by RNA extraction and real-time PCR analysis of the selected T2D-related genes. Butyrate significantly upregulated the expression of MT2A, RRAGD, IGF1R, OXTR, and INSR, while no changes were observed in the expression of other selected genes implicated in insulin signaling. Our findings, which should be considered preliminary until demonstrated by in vivo T2D animal models, suggest that butyrate is a potential modulator of metabolic pathways relevant to insulin resistance. Future studies should explore the tentative therapeutic potential of butyrate and its upregulated genes using proteomics and metabolomics in relevant tissues of T2D animal models, possibly followed by controlled clinical trials.

Mitochondrial targeting is of particular interest to researchers, as it presents as a personalized medicine approach in cancer cell metabolism and survival. By specifically targeting mitochondria, targeted therapies can disrupt energy production, induce apoptosis, and overcome drug resistance in cancer cells, potentially improving therapeutic outcomes. This review discusses the advancements in mitochondrial drug delivery over the last decade. It explores the potential of mitochondrial targeting using mitocurcumin (MTC), a novel small molecule curcumin analog that has been engineered to specifically target mitochondria in cancer cells, thereby augmenting its therapeutic efficacy. The antiproliferative activity of MTC demonstrates its ability to induce reactive oxygen species (ROS) production and promote oxidative stress-mediated apoptosis, oxidative damage, and cellular senescence in diverse cancer cell lines, thereby enhancing its specificity for cancer cells. Despite these encouraging attributes, current research on MTC remains limited. Further comprehensive investigations are imperative to fully elucidate the efficacy and potential applications of mitochondrial targeting, especially MTC, in oncological therapeutics, including in vivo efficacy trials, pharmacokinetic profiling, toxicology studies, and combination therapy assessments. Although mitochondrial targeting presents a promising avenue for cancer therapy, rigorous scientific inquiry is essential to validate its clinical potential and optimize its therapeutic application for improved patient compliance.

Targeted protein degradation (TPD) is an emerging drug discovery approach aimed at enabling the selective removal of disease-associated proteins. While proteolysis-targeting chimeras (PROTACs) have advanced intracellular degradation via the ubiquitin-proteasome system, their limitation to cytosolic proteins excludes ~40% of the human proteome that is extracellular or membrane-bound. Lysosome-targeting chimeras (LYTACs) address this gap by harnessing lysosomal trafficking receptors, thereby mediating the degradation of extracellular and membrane proteins. More recently, methylarginine-targeting chimeras (MrTACs) have extended lysosomal strategies to certain intracellular targets, bypassing proteasomal dependence. This review critically examines the mechanistic underpinnings, design strategies, and bioanalytical challenges associated with lysosome-mediated degradation platforms. Emphasis is placed on their therapeutic implications, analytical evaluation, and potential for expanding druggable targets. Together, these emerging lysosomal chimeras offer a paradigm shift in TPD, with far-reaching applications in precision medicine and chemical biology.

The unique physicochemical and structural flexibility of ionic liquids (ILs) allows for fine modulation of biological activity, thus offering potential as the next-generation anticancer lead compounds with improved selectivity and efficacy. In this study, a new series of benzyl functionalised imidazolium ILs with varying para substituents (R = H, CH, F, Cl, Br, NO, CN) is reported. Their cytotoxicity against human neuroblastoma (SHSY-5Y), estrogen-positive breast cancer cells (MCF-7), neuroblastoma (SHSY-5Y), lung carcinoma (A549), liver cancer cells (HepG2), colorectal adenocarcinoma (HT-29), and mouse embryonic fibroblasts (NIH 3T3) was evaluated. The ILs were cytotoxic against all tested cell lines but were generally more selective toward MCF-7. ILs bearing H, CH, F, Cl, and Br exhibited similar growth inhibition strength against MCF-7 (IC ranged between 3.99 and 5.20 µM) that was superior to that of tamoxifen (IC = 15.41 µM). However, the presence of NO (IC = 8.10 µM) and CN (IC = 17.52 µM) significantly reduced their growth inhibition potentials (two- to four-fold) in NIH 3T3 (IC > 40 µM). The NO-containing IL had a broad safety window against MCF-7 (selectivity index > 4). All the ILs have high drug-likeness (complied with all criteria stated in Lipinski's rule of five and Veber's rule). The most selective IL against MCF-7 (R = NO) induced caspase-dependent but reactive oxygen species independent pro-apoptosis in MCF-7 cells. Substituent modifications in the benzyl group regulated cytotoxicity and selectivity, thus reinforcing ILs as a valuable platform for the development of a new class of effective anticancer lead compounds.

Alzheimer's Disease (AD) is a neurological disorder characterized by progressive cognitive impairment and memory loss. In vitro artificial membrane permeability assays targeting the blood-brain barrier (BBB), such as the parallel artificial membrane permeability assay (PAMPA), are useful for pre-evaluating the BBB penetration of molecules during the early stages of drug development. Inhibitors of glycogen synthase kinase-3β (GSK-3β), casein kinase-1δ (CK-1δ), and acetylcholinesterase (AChE) exhibit neuroprotective effects, indicating a potential therapeutic approach for AD. This study aimed to assess the ability of 23 phenolic compounds derived from natural sources to penetrate the central nervous system (CNS) and examine their potential neuroprotective effects. Following the prediction of BBB penetration of the compounds by PAMPA, neuroprotective effects of CNS+ compounds were evaluated through in vitro inhibition of GSK-3β, CK-1δ, and AChE. Based on the data obtained, five flavonoids (hispidulin, nepetin, platanoside, apigenin, and kaempferol) and two furanocoumarins (isopimpinellin and bergapten) were predicted to penetrate the CNS. Apigenin (API) and kaempferol (KEM) exhibited the most potent dual inhibitory activity against CK-1δ and GSK-3β. Furthermore, API and KEM did not exhibit cytotoxic effects in SH-SY5Y cells. Molecular modeling studies, including molecular docking, molecular dynamics simulations, and dynophore analysis, were performed to understand the binding mechanism of these most potent compounds to their target enzymes. Overall, the current study offers a rational approach to designing new molecules inspired by natural compounds to treat Alzheimer's Disease.

Angelicin (AGN), an angular furocoumarin, exhibits notable anti-inflammatory and biological activities. However, its potential for managing pain and diarrhea, and the underlying mechanisms, remain poorly explored. This study aimed to investigate the analgesic and antidiarrheal properties of AGN and elucidate its possible mechanisms of action through in vivo and in silico approaches. Mice received AGN (2.5, 5, and 10 mg/kg, i.p), DFS (25 mg/kg, p.o), LOP (3 mg/kg p.o), and BSS (10 mg/kg, p.o), after 30 min of administration, for an analgesic test; 0.7% acetic acid at 10 mL/kg (i.p) induced writhing, observed latency, and number of writhing. Antidiarrheal activity was assessed by using castor oil (0.5 mL, p.o) induced diarrhea in mice, observing latency and number of diarrhea secretions over 3 h. Additionally, Molecular docking studies were performed to analyze AGN's interactions with cyclooxygenase (COX-1/2) enzymes and the µ-opioid receptor (MOR). Drug-likeness and toxicity profiles were predicted using SwissADME and ProTox-III. AGN demonstrated significant, dose-dependent analgesic and antidiarrheal effects. Its combination with standard drugs (DFS, LOP, BSS) showed enhanced efficacy. Molecular docking revealed strong binding affinities of AGN for COX-1 (-7.4 kcal/mol), COX-2 (-8.0 kcal/mol), and MOR (-7.1 kcal/mol). Pharmacokinetic predictions indicated good drug-likeness, and toxicity profiling suggested a favorable safety margin. These results strongly suggest that AGN is a promising dual-action therapeutic candidate for pain and diarrhea, likely mediated through COX inhibition and MOR interaction. Further studies are warranted to validate these mechanisms and develop optimized AGN-based formulations for clinical translation.

Insulin-like growth factor-1 (IGF-I) promotes breast cancer (BC) progression by activating the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which enhances invasion and migration through β-catenin-mediated epithelial-mesenchymal transition (EMT). Triple-negative breast cancer (TNBC), an aggressive BC subtype lacking hormone receptors and HER2 expression, exhibits high metastatic potential, poor prognosis, and limited therapeutic options. The recombinant fungal immunomodulatory protein from Ganoderma microsporum (rFIP-GMI) possesses anti-inflammatory, anti-allergic, and anticancer activities; however, its role in suppressing tumor invasion and migration remains unclear. In this study, we investigated the molecular mechanism of rFIP-GMI in TNBC cell lines, Hs578T and MDA-MB-231. Cell invasion and migration were evaluated using Boyden chamber and Transwell migration assays, while Western blot analysis and nuclear/cytoplasmic fractionation were employed to analyze protein expression and β-catenin localization. rFIP-GMI significantly inhibited IGF-1-induced invasion and migration in both TNBC cell lines. Mechanistically, rFIP-GMI suppressed PI3K and Akt phosphorylation, thereby activating glycogen synthase kinase-3 beta (GSK3β) and promoting β-catenin phosphorylation and degradation. This led to reduced nuclear β-catenin accumulation and downregulation of oncogenic targets, including c-Myc, cyclin D1, and MMP-9. Conversely, treatment with the proteasome inhibitor MG132 confirmed that rFIP-GMI stabilized cytoplasmic β-catenin phosphorylation and blocked its nuclear translocation. Collectively, these findings demonstrate that rFIP-GMI inhibits IGF-1-driven invasion and migration in TNBC by inactivating the PI3K/Akt/β-catenin axis, highlighting its potential as a therapeutic agent for this aggressive TNBC subtype.

Among multiple complications of Kawasaki disease (KD), coronary artery lesions (CALs) emerge as the clinically paramount concern. Aspirin therapy can reduce the incidence of KD with CAL, yet its mechanism remains unclear. This study principally investigated the mechanism by which aspirin is effective in treating KD with CAL. Peripheral blood samples from healthy, KD, and KD + CAL children were analyzed using RT-qPCR, western blot, and ELISA to assess the levels of TNF receptor associated factor 6 (TRAF6), signal transducer and activator of transcription 3 (STAT3), and Th17 cells. Spleen CD4 T cells extracted from mouse were initially activated and subsequently differentiated into Th17 cells for subsequent experiments. After aspirin treatment and the downregulation of TRAF6, IF, ELISA, western blot, and RT-qPCR assessed Th17 differentiation and TRAF6/STAT3 expression. Conversely, the effects of TRAF6 overexpression coupled with MG132 treatment on STAT3 expression were evaluated using RT-qPCR and western blot. Additionally, IP and IF assays were conducted to detect the interaction and ubiquitination modifications between TRAF6 and STAT3. The STRING online tool predicted the interacting proteins of TRAF6, which were then validated through cell experiments. In KD with CAL children, elevated Th17 cell count, reduced TRAF6 expression, and heightened STAT3 expression were observed in the peripheral blood. In cell experiments, aspirin boosted TRAF6 expression, downregulated STAT3, inhibited Th17 differentiation. Dampening TRAF6 expression in cells reversed the impact of aspirin. TRAF6 facilitated the ubiquitination of STAT3, triggering its protein degradation, while UBE2N interacted with TRAF6 to modulate STAT3 expression. This study found that aspirin upregulates TRAF6 to ubiquitinate STAT3, inhibiting Th17 differentiation and improving KD with CAL.

Designing novel selenium-containing compounds (organoselenium compounds, OSe) has shown growing interest owing to their chemoprotective and antioxidant properties. Consequently, by harnessing a fragment merging approach, a series of novel OSe hybrid compounds bearing selanyl phenyl acetamide and thiazolidinedione scaffolds were designed and synthesized (8-10, 11a-c, 12a-c, 13a-c, and 14). The growth inhibition percentages (GI%) of the newly afforded OSe were evaluated using seven human cancer cells along with one normal cell line to ensure selectivity and safety. Interestingly, it was revealed that compound 9 exhibited the best mean GI% (75.54%), surpassing the doxorubicin (Dox) mean GI% of 72.28%. In addition, the inhibitory concentration 50 (IC) values of the frontier compounds 9, 13a, 13c, 12b, and 12c were assessed against cancer cell lines PC3, MCF7, and HCT. Compound 13c displayed the lowest IC value (5.195 µM) at the PC3 cancer cell line, surpassing doxorubicin (8.065 µM). Besides, compounds 9 and 12c revealed the lowest IC values (21.045 and 13.575 µM) against MCF7 and HCT, respectively. Moreover, analogues 9 and 13c were chosen to examine their ability to induce apoptosis and showed the upregulation of proapoptotic proteins: Caspases (3, 7, and 9) and BAX, besides the downregulation of the antiapoptotic BCL2, MMP2, and MMP9 proteins. Furthermore, in silico molecular docking studies targeting BCL-2, along with ADMET analyses, were performed. The results indicated that the tested compounds demonstrated favourable binding affinity to the selected target and exhibited acceptable pharmacokinetic properties. Consequently, these compounds can be considered promising lead candidates for inducing apoptosis in cancer cells, warranting further optimization.

Sulfonamides, the oldest synthetic antibacterial agents, specifically target the enzyme dihydropteroate synthase (DHPS), which is essential for the folic acid biosynthesis pathway. In contrast, humans do not use this mechanism as they produce no endogenous folic acid and therefore lack the DHPS enzyme. Despite this unique mechanism and selective action against bacteria, their crucial role in fighting bacterial infections has been diminished by the rise of resistance and allergies to sulfa drugs. To overcome these factors that restrict the application of antibacterial sulfonamides, molecular modification of approved sulfa drugs, such as sulfanilamide, sulfathiazole, and sulfadiazine, appears to be a promising strategy for drug design. This review, for the first time, focuses on the molecular modifications directly performed on sulfa drugs to develop new antibacterial agents that address the resistance and safety problems associated with clinical sulfonamides. These modifications involve the conjugation of commercial sulfa drugs with various heterocycles (triazole, thiazole, thiophene, etc.), functional groups (hydrazone, Schiff base, azo dye, urea/thiourea), phytochemicals (thymol, eugenol, etc.), and drug molecules, leading to new antibacterial candidates and insights into their structure-activity relationships. Given the growing global threat of antibiotic resistance, this review may help restore the importance of traditional sulfa drugs in treating bacterial infections through effective chemical modifications.

Metal-based complexes have greatly advanced anticancer therapy, but limitations of traditional drugs like cisplatin have driven the search for more stable and targeted metallodrugs. In this study, two novel Ir(III) complexes, PNIC and PNIT, incorporating a rigid Schiff base ligand (PNN) derived from 1,10-phenanthroline-5,6-dione and N,N-bis(4-formylphenyl)-N, N-diphenylbenzidine, were synthesized and characterized by NMR, FT-IR, HRMS, and UV-Vis spectroscopy. Both complexes exhibited large Stokes shifts (60 and 47 nm), high stability in GSH and PBS, and strong binding affinity toward DNA and HSA through hydrophobic and hydrogen bonding interactions. They also exhibited notable antioxidant activity and potent cytotoxicity against A549 lung cancer cells, with IC values of 19.69 µM for PNIC and 16.86 µM for PNIT, and good selectivity toward normal HEK293 cells (SI = 10.5 and 13.6, respectively). These findings highlight the potential of both PNIC and PNIT as multifunctional Ir(III)-based anticancer candidates possessing excellent bio-stability and target selectivity.

This study assessed the neuroprotective potential of empagliflozin (EMPA) as antidiabetic drug on glucose metabolism, comparing it to rivastigmine (RIVA) as standard treatment for Alzheimer's disease (AD), and their combination. Male rats were sorted into five groups. Group I served as the control, while groups II, III, IV, and V received the scopolamine plus heavy metal mixture for AD induction. Groups III and IV were administered RIVA and EMPA, respectively, and group V received both treatments. Cognitive function was evaluated behaviorally. Subsequently, glucose levels, acetylcholinesterase, oxidative stress, and inflammatory markers were assessed. Alongside the brain histopathological changes, the expression of phosphorylated tau protein was assessed. Moreover, glycolytic enzymes and glucose transporters were assessed using PCR analysis. The findings were attributed to a notable suppressive impact of EMPA on lipid peroxidation, acetylcholinesterase, glucose levels, phosphorylated tau protein, pro-inflammatory cytokines, and neuropathological changes, while enhancing antioxidant and interleukin-10 levels. It also improves glucose metabolism. The findings suggest that EMPA may be a viable candidate for future therapeutic exploration in AD, which has a multifaceted mechanism of action encompassing anti-neuroinflammation, antioxidant stress, and enhanced glucose metabolism, as well as decreased acetylcholinesterase activity and phosphorylated tau protein levels. Interestingly, combined treatment showed a superior effect than EMPA alone.

Osteosarcoma (OS) is the most prevalent primary malignant bone tumor. M2 type tumor-associated macrophages (TAMs) are the predominant infiltrating cells within the OS microenvironment and play a key role in promoting OS progression. Although kaurenoic acid (KA) has demonstrated notable antitumor properties, it remains vacant whether KA exerts its effects against OS by modulating TAM. In vitro, THP-1 monocytes were polarized into different macrophage phenotypes using specific cytokines and supernatants from OS cells. qRT-PCR, ELISA and flow cytometry assays were conducted to investigate the effects of KA on macrophage reprogramming. The effects of KA on the proliferation, migration, invasion and vasculogenic mimicry of OS cells in the context of M2 macrophages were examined in vitro. Western blot, immunofluorescence staining, and rescue experiments were performed to explore the molecular mechanism underlying the effect of KA. The K7M2 OS mouse model was employed to scrutinize the effects of KA on OS growth and TAM polarization in vivo. The results demonstrated that KA induced a dose-dependent shift of M2 macrophages toward the M1 phenotype, as evidenced by the downregulation of M2 markers, upregulation of M1 markers, and enhanced macrophage-mediated phagocytosis. Additionally, KA inhibited M2 macrophage-mediated enhancement of malignant behaviors in OS cells. We discovered that the activation of the MAPK and NF-κB signaling pathways was involved in KA-induced macrophage polarization. In vivo data demonstrated that KA suppressed OS growth and switched TAMs to the M1 phenotype, while exhibiting low toxicity. These findings suggest that KA can reprogram M2 macrophages into M1 phenotype and inhibit the progression of OS, highlighting its potential as a new macrophage-based therapeutic agent against OS.

Lung adenocarcinoma (LUAD) is the most prevalent and lethal subtype of non-small cell lung cancer (NSCLC), with its progression closely associated with aberrant succinylation modifications. This study aimed to systematically identify succinylation-related genes in LUAD and evaluate their diagnostic and prognostic significance. By integrating four Gene Expression Omnibus (GEO) datasets, 45 differentially expressed succinylation-related candidate genes were identified. Feature selection using three machine learning methods-Lasso regression, support vector machine recursive feature elimination (SVM-RFE), and Random Forest-yielded seven core genes: TIMP1, SLC2A1, JUP, F12, B3GALNT1, DSP, and MMP1. ROC analysis showed that all core genes achieved AUC values greater than 0.7, indicating strong diagnostic potential. A diagnostic model constructed from these seven genes achieved an AUC of 0.912 in the training cohort, significantly outperforming single-gene models, and was validated in The Cancer Genome Atlas (TCGA) cohort (AUC = 0.893). Prognostic analysis revealed that Kaplan-Meier curves for all seven core genes demonstrated p < 0.05 and HR > 1, indicating that high expression was associated with poor outcomes. A risk prediction nomogram was also developed based on these genes. SHAP analysis clarified each gene's contribution to the model, while drug enrichment and transcriptional regulatory network analyses provided further insights into potential therapeutic targets. Notably, JUP exhibited the highest diagnostic efficacy (AUC = 0.921) and was significantly correlated with immune cell infiltration and tumor microenvironment regulation. Molecular docking suggested stable binding between JUP and potential therapeutic compounds, single-cell analysis confirmed its marked overexpression in tumor and epithelial cells, and experimental validation further established its oncogenic role. In conclusion, this study systematically defines the diagnostic and prognostic value of seven succinylation-related core genes in LUAD, with JUP playing a particularly pivotal role. These findings provide robust evidence supporting its potential as a novel biomarker and therapeutic target.

Amongst various complications presented by diabetes, diabetic cardiomyopathy (DCM) is one of the most prominent and vexing complications. Due to the absence of consensus on prevention and treatment strategies, along with limitations in current therapies, a fresh perspective is essential and a requirement of the time. The succeeding review explores research that provides insights into novel molecular targets that could possibly evolve as breakthroughs in restraining the pathological hallmarks of DCM, such as inhibition of cardiomyocyte fibrosis or modulation of various inflammatory pathways, apoptotic pathways such as PANoptosis, cuproptosis, and ferroptosis, and mitochondrial dysfunction. This review shall also explore various RNA-targeting therapeutic areas that can combat the consecution of DCM. Therapeutic intervention targeting Phosphodiesterase 4D (PDE4D), LGR6 (G-protein-coupled receptor containing leucine-rich repeats 6), Interferon gamma inducible protein 16 (IFI16), Growth differentiation factor 11(GDF11), Transcription factor EB(TFEB), Secreted frizzled-related protein 1 (SFRP1), Fibroblast growth factor -21 (FGF21), Takeda G protein-coupled receptor-5 (TGR5), Nuclear receptor of the subfamily 4 (NR4A3), Enhancer of zeste homolog 2 (EZH2), and RNA-based therapeutics such as piR112710 and TUG1 are reviewed. Moreover, how these molecular targets intersect with DCM pathology, and how they can be further explored in a drug discovery paradigm for DCM management, is discussed.

Cancer affects one in three to four people globally, with over 20 million new cases and 10 million deaths annually, projected to rise to 35 million cases by 2050. Developing effective cancer treatments is crucial, but the drug discovery process is a highly complex and expensive endeavor, with success rates sitting well below 10% for oncologic therapies. More recently, there has been a growing interest in Artificial intelligence (AI) due to its potential to significantly enhance the success rates by processing large data sets, identifying patterns, and making autonomous decisions. The primary aim of this literature review is to examine the potential that state-of-the-art AI tech-nologies have to enhance and complement well-established research methods used in cancer drug development, such as QSAR, interactions prediction, and ADMET prediction, among others. The basic technical aspects of computational technologies are clarified, and key terms commonly asso-ciated with AI are defined. Current applications and case studies from academia and industry are presented to highlight AI's potential to accelerate progress in cancer drug research. Challenges and disadvantages of AI are also acknowledged, and it is discussed that future research should focus on overcoming its limitations to maximize its impact in cancer treatment.

Enzyme-responsive magnetic nanoparticles (MNPs) represent an emerging class of multifunctional drug delivery systems that combine spatial precision with biochemical selectivity. By integrating magnetic guidance with enzyme-triggered activation, these nanocarriers address a critical limitation of conventional chemotherapy, namely the lack of specificity that often leads to systemic toxicity and reduced therapeutic efficacy. Enzymes such as proteases, phospholipases, and oxidoreductases are frequently dysregulated in pathological tissues, providing endogenous signals that can be harnessed for site-specific drug release. Enzyme-responsive MNPs exploit these biochemical signatures by incorporating cleavable linkers, enzyme-sensitive coatings, or catalytic cascades, ensuring that therapeutic payloads are released selectively in tumor microenvironments, inflamed regions, or infection sites. Advances in nanoparticle synthesis have further enabled fine-tuning of magnetic cores, polymer shells, and functionalized surfaces, thereby enhancing stability, drug loading capacity, and responsiveness. Preclinical studies demonstrate substantial benefits, including enhanced tumor accumulation, alleviation of hypoxia, improved drug penetration through stromal barriers, and reduction of off-target toxicity. Applications extend beyond oncology to infectious diseases, where pathogen-derived enzymes activate antibiotic release, and to metabolic disorders, where glucose oxidase-based systems regulate insulin delivery. Despite these promising outcomes, translation to clinical practice is constrained by manufacturing challenges, variable enzyme expression, limited in vivo data, and stringent regulatory requirements. This review critically examines the principles, design strategies, release mechanisms, and biomedical applications of enzyme-responsive MNPs, while highlighting unresolved barriers and future directions. Ultimately, enzyme-responsive MNPs exemplify the potential of precision nanomedicine, offering a platform for highly adaptable, multimodal, and patient-tailored therapeutic interventions.