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Background: CD37, an antigen highly expressed in B-cell malignancies, served as the target in the LYMRIT-37-01 Part B (PARADIGME) and Part C studies employing a single intravenous injection of the radioimmunoconjugate ¹⁷⁷Lu-lilotomab satetraxetan (Betalutin^®). Methods: Patients with follicular lymphoma (FL), grades I-IIIa, who had received at least two previous lines of therapy and were refractory to at least one previous regimen with rituximab or an anti-CD20 agent, were included. They were randomized to receive either a 40 mg lilotomab pretreatment and an activity dosage of 15 MBq/kg Betalutin ("40/15" regimen) or 100 mg/m² of lilotomab and 20 MBq/kg of Betalutin ("100/20" regimen). In total, 109 patients were enrolled and received Betalutin, 72 of whom received the 40/15 regimen and 28 received the 100/20 regimen. An additional heavily pretreated "special population" of nine patients received 40/12.5 (i.e., a reduced Betalutin dosage) due to low platelets and/or a previous autologous stem cell transplant. Part C was a small expansion cohort of four patients, all receiving the 40/15 regimen, and was designed to obtain supplementary pharmacokinetic data. Results: The efficacy analysis set comprised a total of 100 patients from the PARADIGME study. The overall response rates were 38.9% and 32.1%, and the complete response rates were 20.8% and 14.3% in the 40/15 and 100/20 groups, respectively. Correspondingly, the median response durations were 8.5 months and 3.4 months in the two groups. Hence, increasing the Betalutin activity dose by using the stronger protective CD37 pre-dosing ("100/20") did not improve the therapeutic benefit. The most common grade ≥ 3 adverse events were hematologic, including neutropenia (11.5%) and thrombocytopenia (8.0%), with nadirs occurring around weeks 5-7 and recovery by week 11. Conclusions: A single-dose administration of Betalutin had a mild toxicity profile with a clinically relevant response rate. It represents a viable treatment alternative in FL patients who are not suitable for more toxic and long-lasting treatments. Trial Registration: This trial was registered at clinicaltrials.gov under #NCT01796171.

Background: Non-small cell lung carcinoma (NSCLC) is the most prevalent form of lung cancer, and its progression is closely associated with constitutive activation of signal transducer and activator of transcription 3 (STAT3). This study used surface plasmon resonance (SPR) technology to develop a STAT3-targeting recognition system and identify natural STAT3-targeting compounds from the traditional Chinese medicine Psoralea corylifolia and to evaluate their anti-NSCLC activities, with particular attention to reactive oxygen species (ROS) regulation. Methods: The SPR biosensor immobilized with STAT3 was used to screen and enrich STAT3-binding constituents of Psoralea corylifolia, and to determine ligand-STAT3 affinities. Molecular docking was performed to characterize interactions within the STAT3 SH2 domain. Functional effects were assessed in A549 cells using proliferation and scratch migration assays. Antioxidant capacity was evaluated via hydroxyl radical and superoxide anion scavenging assays, and intracellular ROS levels were measured in hydrogen peroxide (H₂O₂)-induced oxidative stress models in human umbilical vein endothelial cells (HUVECs) and A549 cells. Results: SPR analysis showed that psoralen and isopsoralen bind to STAT3, with equilibrium dissociation constants (KD) of 80.92 µM and 28.11 µM, respectively. Molecular docking further confirmed their interaction with the STAT3 SH2 domain. Both compounds inhibited A549 proliferation and reduced migration. Beyond direct STAT3 inhibition, both compounds demonstrated notable free radical scavenging activity. In a H₂O₂-induced oxidative stress model, pretreatment with psoralen or isopsoralen significantly reduced ROS levels in HUVECs, while increasing ROS accumulation in A549 lung cancer cells. Conclusions: This work identifies psoralen and isopsoralen as novel dual-function STAT3 inhibitors that exert anti-NSCLC effects through combined STAT3 suppression and context-dependent ROS modulation, and demonstrates the utility of SPR for screening bioactive natural products.

Background/Objectives: Silicosis is a chronic disease caused by long-term exposure to high levels of silica dust, which leads to extensive nodular fibrosis in the lungs. The disease is currently a serious occupational health hazard globally. Xuanfei Baidu decoction (XFBD) is a mature Chinese herbal medicine in China that has shown anti-inflammatory and anti-fibrotic effects in mouse experiments, making it a promising candidate for addressing the persistent inflammation and fibrosis in silicosis. Methods: Silicosis was induced in male C57BL/6J mice using crystalline silica (CS). XFBD's early anti-inflammatory role was verified in vitro in peritoneal macrophages (PMs) and in vivo in silicosis mice, while its late anti-collagen deposition and anti-fibrotic activities were further investigated. Results: In vitro, XFBD effectively inhibits the activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome in CS-induced lipopolysaccharide (LPS)-primed PMs, decreases the release of inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), and modulates the phenotypic transition of macrophages from the M2 to the M1 phenotype. In vivo studies further validated that XFBD significantly downregulates the expression of NLRP3 and Cleaved-Caspase-1 proteins in the lung tissues of mice afflicted with silicosis. Additionally, XFBD enhanced pulmonary function, inhibited collagen deposition and pulmonary fibrosis in silicosis mice, and reversed epithelial-mesenchymal transition (EMT) by regulating key EMT-related proteins to slow fibrosis. Conclusions: The beneficial effects of XFBD on CS-induced pulmonary fibrosis can be attributed to the induction of macrophage polarization-mediated anti-inflammatory responses during the early stage of fibrotic development, as well as its anti-collagen deposition and anti-fibrotic activities during the intermediate stage of fibrotic development. This study provides preclinical evidence supporting XFBD as a promising candidate for prevention or adjunctive therapy, and its multi-target, time-phase mechanism offers a novel rationale and theoretical foundation for the development of new strategies against silicosis.

Background: Multiple sclerosis (MS) is a neuroinflammatory disease characterized by autoimmune-driven inflammation in the central nervous system that damages axons and destroys myelin. It is difficult to diagnose multiple sclerosis due to its complexity, and different people may react differently to different treatments. While the exact cause of multiple sclerosis (MS) and the reasons for its increasing prevalence remain unclear, it is widely believed that a combination of genetic predisposition and environmental influences plays a significant role. Methods: Finding biomarkers for complicated diseases like multiple sclerosis (MS) is made more promising by the emergence of network and system biology technologies. Currently, using tools like Network Analyst to apply network-based gene expression profiling provides a novel approach to finding potential medication targets followed by molecular docking and MD Simulations. Results: There were 1200 genes found to be differentially expressed, with CD44 showing the highest degree score of 15, followed by CDC42 and SNAP25 genes, each with a degree score of 14. To explore the regulatory kinases involved in the protein-protein interaction network, we utilized the X2K online tool. The present study examines the binding interactions and the dynamic stability of four ligands (Obeticholic acid, Chlordiazepoxide, Dextromethorphan, and Hyaluronic acid) in the Hyaluronan binding site of the human CD44 receptor using molecular docking and molecular dynamics (MD) simulations. Docking studies demonstrated a significant docking score for Obeticholic acid (-6.3 kcal/mol), underscoring its medicinal potential. MD simulations conducted over a 100 ns period corroborated these results, revealing negligible structural aberrations (RMSD 1.3 Å) and consistent residue flexibility (RMSF 0.7 Å). Comparative examinations of RMSD, RMSF, Rg, and β-factor indicated that Obeticholic acid exhibited enhanced stability and compactness, establishing it as the most promising choice. Conclusions: This integrated method underscores the significance of dynamic validations for dependable drug design aimed at CD44 receptor-mediated pathways. Future experimental techniques are anticipated to further hone these findings, which further advance our understanding of putative biomarkers in multiple sclerosis (MS).

Background: Thirty-five analogues of a promising antiosteoporotic drug, incadronate, have been synthesized and evaluated for their antiproliferative activity against mouse macrophage-like J774E cells. These cells originated from identical precursors as osteoclasts and served to select the most active compounds. Two of them, n-heptyl- and n-octyl-aminomethylenebispohosphonic acids, were then used for the medication of sheep with induced osteoporosis. They demonstrated mild antiosteoporotic activity that was documented using bone histopathology. Additionally, a decrease in the immunological response to Corynebacterium pseudotuberculosis was observed as a major side effect accompanied by this medication. Methods: Aminomethylenebisphosphonates may be obtained in the three-component reaction of aliphatic amine, triethyl orthoformate and diethyl phosphite with the further acid hydrolysis of crude esters. The obtained N-substituted alkiloaminomethylenebisphosphonic acids are presented alongside with their in vitro activity toward mouse macrophages J774E. Results: The new families of aminomethylenebisphosphonic compounds synthesized by our approach may be of practical importance due to the significant cytotoxic activity in the cell cultures investigated. Two of them were chosen for further evaluation in the treatment of induced osteoporosis in sheep. Conclusions: In vivo studies confirmed the mild therapeutic effects of compounds 4 (N-(n-heptylamino)methylenebisphosphonic acid and 5 (N-(n-octylamino)methylenebisphosphonic acid; however, they are not suitable analogues of incadronate for consideration as potential drugs.

Background/Objectives: Topical treatment of cutaneous tuberculosis (CTB) requires reliable models to evaluate dermal drug release and diffusion, particularly for fixed-dose combinations (FDCs) with contrasting physicochemical properties. Human skin remains the reference standard but poses ethical, logistical, and reproducibility challenges. This study investigated the suitability of Strat-M^® synthetic membranes as an alternative to human skin for assessing the simultaneous release and diffusion of clofazimine (CFZ) and pyrazinamide (PZA) from a topical FDC, and aimed to develop an optimized dermal emulsion using a Quality-by-Design (QbD)-informed formulation development tool. Methods: Self-emulsifying dermal emulsions containing CFZ and PZA were developed following QbD principles. Preformulation studies included drug solubility screening, oil phase selection, and pseudoternary phase diagram construction to identify stable emulsion regions. Formulations were characterized for droplet size, polydispersity index, zeta potential, viscosity, self-emulsification efficiency, and thermodynamic stability. Eight stable emulsions were identified, of which four were selected for in vitro drug release studies. The peppermint oil-based emulsion (PPO415) was further evaluated in comparative diffusion studies using Strat-M^® membranes and ex vivo human skin (Caucasian and African). Results: PPO415 demonstrated favorable physicochemical properties, including high CFZ solubility, uniform droplet distribution, and suitability for dermal application. Comparative diffusion studies showed that Strat-M^® underestimated the partitioning of lipophilic CFZ while overestimating the diffusion of hydrophilic PZA relative to human skin. These differences were attributed to compositional and structural disparities between synthetic membranes and biological skin. Conclusions: Strat-M^® membranes show potential as a reproducible and ethical in vitro screening tool during early-stage formulation development for topical FDCs. However, ex vivo human skin remains essential for accurately predicting dermal drug distribution and therapeutic performance.

Background: Combination chemotherapy using nanotechnology-based delivery is a promising approach to improve cancer treatment, but the added value of co-loaded polymeric nanocarriers has not been comprehensively appraised. This review synthesizes preclinical evidence on polymeric systems co-encapsulating antitumor agents. Methods: A narrative literature review identified 33 preclinical studies (2015-2025) employing polymer-based nanocarriers to co-load at least two antitumor drugs. Study characteristics and in vitro and in vivo outcomes were qualitatively analyzed. Results: Most studies addressed breast, lung, or ovarian cancer and used micelles or nanospheres. Co-loaded formulations consistently enhanced in vitro cytotoxicity and, in vivo, produced marked tumor growth inhibition relative to free drugs or single-loaded systems; in several reports, near-complete or complete tumor regression was achieved. Synergy was frequently suggested but not consistently quantified, more than half of the studies did not report a combination index. Most formulations showed favorable tolerability, with few reports including mild hepatic toxicity, renal, or weight-related effects. Beyond conventional drug pairs, examples of co-delivering chemotherapeutics with resistance modulators, gene therapy agents, or targeted ligands illustrated how tailored release profiles and active targeting can potentiate efficacy. Nevertheless, heterogeneity in models, dosing schedules, endpoints, and limited long-term safety data hamper cross-study comparison and translation. Conclusions: Co-loaded polymeric nanocarriers constitute a promising platform to optimize combination chemotherapy, improving preclinical antitumor efficacy with generally limited toxicity, but more standardized and mechanistically driven studies are required to support clinical development.

Background: Liver fibrosis is a major global public health issue that is only getting worse. The underlying molecular mechanisms of Yindanpinggan Capsule (YDPG), a traditional Chinese medication, are still unknown, although it has shown notable effectiveness in treating fibrosis and other forms of liver injury. Methods: To evaluate the impact of YDPG on liver fibrosis, a mouse model of liver damage caused by carbon tetrachloride (CCL₄) was used. Proteomics, deep learning, network pharmacology, and later biological process validation using Western blot were used to elucidate the possible mechanism of YDPG in reducing liver damage. Results: Following YDPG treatment, we observed a decrease in the fibrosis index and an improvement in liver function. Network pharmacology, deep learning, and proteomics collectively identified the ferroptosis and peroxisome proliferator-activated receptor (PPAR) signaling pathways as pivotal in the anti-fibrosis effects of YDPG on the liver. Further experimental results showed that YDPG inhibited Malondialdehyde (MDA) and Fe²⁺ content and increased Glutathione (GSH) activity in fibrotic liver. Mechanistically, both SLC7A11/GSH pathway-mediated ferroptosis and oxidative stress up-regulated by the PPAR γ/GPx4 pathway were alleviated following YDPG treatment. Conclusions: Our present study corroborates that YDPG limits the progression of liver fibrosis by regulating the PPARγ-GPX4-ferroptosis pathway. These results indicate that YDPG could be a potential medication for hepatic fibrosis.

Background/Objectives: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are essential antidiabetic medications. However, their side effects warrant careful consideration. The search for novel SGLT2 inhibitors with high affinity remains an ongoing endeavor. Medicine food homology (MFH) herbs show promise for drug development due to their nutritional and medicinal value. Methods: This study aims to address the shortcomings of existing virtual screening models for SGLT2 inhibitors by optimizing feature selection and integrating multidimensional molecular fingerprints. Subsequently, an integrated virtual screening pipeline is constructed to identify potential SGLT2 inhibitors from eight selected MFH herbs. Results: The results indicate that the optimal model (LightGBM and RF) achieved an accuracy of 0.97 and an AUC of 0.98. Following rigorous filtering, a total of 44 potential SGLT2 inhibitors were identified, among which, Isoononin (from Gancao) and Ononin (from Huangqi, Gegen, and Gancao) exhibit favorable drug likeness and safety. Molecular docking demonstrate that both compounds can effectively bind to the SGLT2 active site, establishing stable hydrophobic interactions with critical residues such as Phe98 and Phe453. Furthermore, molecular dynamics simulations confirm the stability of the interactions between the two compounds and SGLT2. Conclusions: This study significantly enhances the accuracy and stability of SGLT2 inhibitor virtual screening models by addressing deficiencies in structural characterization and feature selection. It provides candidate molecules for the development of novel SGLT2 inhibitors and offers new scientific evidence for the application of MFH herbs in the prevention and treatment of chronic metabolic diseases.

Nanoemulgels have emerged as a promising hybrid drug delivery system that integrates the advantages of nanoemulsions and gels, offering enhanced drug penetration, prolonged residence time, and improved patient compliance. This review provides a comprehensive overview of the therapeutic applications of nanoemulgels in wound healing, microbial infections, skin cancer, and various dermatological disorders. The article begins with an overview of skin architecture and its implications for cutaneous drug delivery, followed by a clear distinction between transdermal and topical drug delivery systems. The mechanisms of drug transport into and through the skin are discussed in detail, highlighting the role of nano-sized carriers, particularly nanoemulsions, in overcoming the stratum corneum barrier. Mechanistic insights into nanocarrier-mediated cutaneous drug transport and their versatility as dermal delivery platforms are described. The formulation aspects of nanoemulgels, including their components and both high-energy and low-energy methods for nanoemulsion preparation, are critically discussed to elucidate their impact on formulation performance. An overview of in vitro characterization techniques and biological screening methods employed to evaluate nanoemulgel performance is presented, along with a tabulated compilation of relevant patents to highlight translational progress. Finally, current challenges, regulatory considerations, and future perspectives are discussed, underscoring the potential of nanoemulgels as a versatile and effective platform for advanced topical drug delivery.