Drug Development Research[JOURNAL]
Sun
200 papers
Scopoletin Mitigates DSS-Induced Ulcerative Colitis by Attenuating NF-κB/MMP-9 Mediated Inflammation and Activating the Nrf2 Pathway to Preserve Colonic Barrier Integrity.
Gowtham A, Mishra T, Gungha T … +1 more , Kaundal RK
Drug Dev Res · 2025 Nov · PMID 40995618 · Publisher ↗
Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon, characterized by persistent mucosal inflammation and epithelial barrier disruption. This study investigated the therapeutic efficacy of Scopoletin,...
Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon, characterized by persistent mucosal inflammation and epithelial barrier disruption. This study investigated the therapeutic efficacy of Scopoletin, a natural coumarin derivative with established anti-inflammatory and antioxidant properties, in a DSS-induced colitis model in Balb/c mice. A total of five experimental groups were established: a normal control, a DSS+ vehicle group, two Scopoletin-treated groups (10 and 30 mg/kg), and a reference group treated with Sulfasalazine (200 mg/kg). Network pharmacology analyses identified key inflammatory and immune-regulatory pathways potentially modulated by Scopoletin. In vivo assessments encompassed body weight monitoring, DAI scoring, colon length measurement, and histopathological evaluation using H&E, PAS, and Alcian blue staining. Scopoletin (30 mg/kg) treatment significantly ameliorated clinical and histological manifestations of colitis, including body weight loss and colonic shortening. Mechanistically, Scopoletin (30 mg/kg) attenuated the expression of pro-inflammatory cytokines such as TNF-α and IL-1β, suppressed NF-κB activation, MMP-9, COX-2 and enhanced the Nrf2 expression, leading to upregulation of antioxidant enzymes HO-1 and NQO1. Notably, Scopoletin (30 mg/kg) restored the expression of tight junction proteins such as Occludin and ZO-1, indicating reinforcement of epithelial barrier integrity. These findings demonstrated that Scopoletin protects against UC by suppressing inflammation, enhancing antioxidant defenses, and preserving mucosal barrier integrity, highlighting its potential as a therapeutic candidate for UC.
Nanoparticle-Integrated Transdermal Patches: A Platform for Next-Generation Drug Delivery.
Mohan N, Nair RPAN, Narayanasamy D
Drug Dev Res · 2025 Nov · PMID 40990940 · Publisher ↗
Nanoparticle-mediated transdermal systems can bypass the skin's natural outer barrier (stratum corneum), allowing drugs to enter the body more effectively. This technology improves how much drug reaches the bloodstream a...
Nanoparticle-mediated transdermal systems can bypass the skin's natural outer barrier (stratum corneum), allowing drugs to enter the body more effectively. This technology improves how much drug reaches the bloodstream and how long it acts, which can make drug delivery noninvasive and more comfortable for patients. These technologies are engineered to markedly enhance drug permeability and bioavailability, while improving patient adherence and reducing systemic side effects. The incorporation of nanocarriers into transdermal systems can augment drug permeability across the skin by 2- to 10-fold, contingent upon the physicochemical characteristics of both the drug and the nanocarrier type, as demonstrated in multiple preclinical investigations. This review rigorously analyzes various nanocarriers, including liposomes, niosomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), polymeric nanoparticles, and inorganic nanostructures, and their effects on cutaneous and transdermal drug delivery. Improvements in entrapment efficiency of up to 90% and a three- to fivefold enhancement in drug retention within the epidermis have been recorded. Optimized nanoparticle-based formulations have also demonstrated sustained release characteristics lasting up to 72 h. Additionally, innovative technologies such as dissolving microneedles, nanoneedle arrays, luminous patches, and 3D-printed transdermal systems are examined regarding their capacity to enhance dosage accuracy, bioadhesion, and therapeutic efficacy. The study examines formulation characteristics such as polymer matrices, rate-controlling membranes, excipient compatibility, and penetration enhancers that affect the clinical efficacy and stability of nanoparticle-integrated patches. Significant attention is directed towards the impact of formulation choices on drug loading, release kinetics, and skin interaction patterns. Notwithstanding advancements, no nanoparticle-encapsulated transdermal patch has attained FDA approval to yet. The review delineates the principal translational obstacles-regulatory ambiguity, safety assessment, and GMP-scale production-and emphasizes the necessity for cohesive pharmacokinetic modeling, human skin correlation investigations, and real-time stability data to enhance clinical translation.
Design, Synthesis, and 2D QSAR Analysis of Some Novel Pyrazolo[1,5-a]pyrimidine Derivatives as Pim-1 Kinase Inhibitors for the Treatment of MCF-7 Breast Cancer.
Mohammed EZ, El-Dydamony NM, Mehany ABM … +3 more , Fahim SH, Abdel Aziz HA, Ibrahim NM
Drug Dev Res · 2025 Nov · PMID 40990904 · Publisher ↗
In the current study, new pyrazolo [1,5-a]pyrimidine-3-carbonitriles were synthesized and evaluated for their inhibitory activity against Pim-1 kinase. The most potent inhibitors were 4d, 5d, and 9a with IC values (0.61,...
In the current study, new pyrazolo [1,5-a]pyrimidine-3-carbonitriles were synthesized and evaluated for their inhibitory activity against Pim-1 kinase. The most potent inhibitors were 4d, 5d, and 9a with IC values (0.61, 0.54 and 0.68 μM) compared to quercetin (IC = 0.91 μM), with some selectivity towards Pim-1 and Pim-3 over Pim-2. Compound 4d exhibited a 1.5-fold increased cytotoxic activity compared to doxorubicin against the MCF-7 cell line, whereas compound 9a showed an analogous activity to doxorubicin. Furthermore, compounds 4d, 5d, and 9a arrested the cell cycle at G2-M phase with a decrease in the G1-phase population. Compounds 4d, 5d, and 9a induced apoptosis in MCF-7 cells by a 94-, 64-, and 78-fold increase in the entire apoptotic and necrotic cells compared to the untreated control cells and increased the levels of wild p53 in MCF-7 cells by 6.5, 6, and 5.7-fold indicating that these compounds may induce apoptosis via increasing the expression level of p53. Moreover, a promising safety profile was shown for compound 4d on MCF-10A normal breast cells. Besides, docking of the desired compounds into Pim-1 ATP binding site showed a noteworthy binding mode for the enzyme inhibition. Additionally, a 2D QSAR identified the potential structural features controlling the Pim-1 inhibitory activity attained via the targeted pyrazolo[1,5-a]pyrimidines.
CCAR2 Drives Glioma Cell Survival by Positively Regulating SIRT1 and Activating the Notch1/c-Myc Pathway.
Ma L, Liu C, Zhang Y … +1 more , Chen Z
Drug Dev Res · 2025 Nov · PMID 40986003 · Publisher ↗
Cell cycle and apoptosis regulator 2 (CCAR2) is a transcriptional regulator involved in diverse types of cancer. However, its role in human glioma is unclear. This study aimed to investigate whether CCAR2 could function...
Cell cycle and apoptosis regulator 2 (CCAR2) is a transcriptional regulator involved in diverse types of cancer. However, its role in human glioma is unclear. This study aimed to investigate whether CCAR2 could function as a regulator in glioma. Database analysis results showed that CCAR2 expression was greatly higher in glioma tissues than that in control brain tissues. Besides, CCAR2 expression was upregulated in glioma cell lines. CCAR2 knockdown inhibited cell viability and proliferation and promoted apoptosis in glioma cells. The Notch1/c-Myc pathway was found to be inactivated by CCAR2 knockdown in glioma cells, while Notch1 overexpression reversed the inhibitory effect of CCAR2 knockdown on glioma cell survival. Further investigations showed that CCAR2 interacted with SIRT1 and regulated its expression. SIRT1 overexpression also attenuated the tumor-suppressing role of CCAR2 knockdown, as well as prevented CCAR2 knockdown-caused inactivation of Notch1/c-Myc pathway. Taken together, this study demonstrated that CCAR2 depletion exerted a tumor-suppressing role in glioma through regulating SIRT1-mediated Notch1/c-Myc pathway. These findings provide evidence for the therapeutic implication of CCAR2 in glioma treatment.
Exploring Novel Tetrahydropyrimidine and Fused Pyrimidine-Based Compounds as DHFR Inhibitors and Antimicrobial Agents: Synthesis, In Vitro, In Vivo, and In Silico Studies.
Sherif MM, Mansour B, El-Antrawy MA … +3 more , Abdelaziz HA, Badr SMI, Nasr MNA
Drug Dev Res · 2025 Nov · PMID 40986002 · Publisher ↗
New series of 2-imino/oxo-tetrahydropyrimidines (4a-4j), and fused pyrimidines (5a-5i and 6a-6h) were designed and synthesized as attractive scaffolds to be investigated in vitro and in vivo for antimicrobial activity ag...
New series of 2-imino/oxo-tetrahydropyrimidines (4a-4j), and fused pyrimidines (5a-5i and 6a-6h) were designed and synthesized as attractive scaffolds to be investigated in vitro and in vivo for antimicrobial activity against gram-positive Staphylococcus aureus, gram-negative Escherichia coli and Klebsiella pneumoniae, and fungus Candida albicans. In the in vitro antimicrobial screening using agar diffusion method, compounds 4 d, 4 f, 6a and 6 d showed broad-spectrum antimicrobial activity against all the tested strains when compared to levofloxacin as a reference drug. Moreover, compound 4 f showed higher antibacterial activity against all the tested microorganisms with MIC = 22-45 µM compared with levofloxacin with MIC = 50- > 708 µM. Compound 5 g exhibited lower IC than that of reference trimethoprim (TMP) towards the DHFR enzyme inhibition. Additionally, compounds 4 d, 4 f, 4 g, 6 d and 6 f had kept the superiority over the reference drug with IC ranging from 4.10 to 4.77 µM. Compounds 4 f and 6a were subjected to in vivo evaluation for their antibacterial activity. They caused a significant reduction in abscess volume and area in the skin of mice inoculated with S. aureus. Moreover, compound 4 f had reduced the immune-expression of interleukin-1β in the isolated tissues of the infected skin. Molecular docking results were in a good agreement with the DHFR enzyme assay results and justified the binding profiles and affinities profile of all tested compounds. Conclusively, compounds 4 d, 4 f, 5 g, 6a and 6 d are very promising candidates for further antimicrobial studies.
Atopic Dermatitis: Updated Insights Into Pathophysiology and Emerging Therapies.
Xie M, Kong L, Li G … +3 more , Chen Y, Hou L, Hou J
Drug Dev Res · 2025 Nov · PMID 40985984 · Publisher ↗
Atopic dermatitis (AD) is a chronic, relapsing skin ailment characterized by intense itching and diverse clinical manifestations. Its pathogenesis is complex, involving genetic, microbial, and immunological factors. Rece...
Atopic dermatitis (AD) is a chronic, relapsing skin ailment characterized by intense itching and diverse clinical manifestations. Its pathogenesis is complex, involving genetic, microbial, and immunological factors. Recently, significant therapeutic advancements have been made in AD, including topical phosphodiesterase-4 (PDE-4) inhibitors, Janus kinase (JAK) inhibitors, and biologics targeting cytokines and signaling molecules such as Interleukin-13 (IL-13), Interleukin-31(IL-31), thymic stromal lymphopoietin (TSLP), and OX40/OX40L. This review comprehensively demonstrates the genetic, microbial, and immunological factors underlying AD, with a particular emphasis on the gut-skin axis. Furthermore, it summarizes recently approved drugs and potential therapeutic agents currently under clinical trials. Besides, the review highlights the emerging role of the gut-skin axis in AD pathogenesis and the breakthroughs in novel targeted therapies. These include inhibitors of IL-13 and IL-31, which have shown remarkable efficacy in reducing disease severity and improving quality of life in patients with moderate-to-severe AD. Additionally, the review contains the potential of targeting the OX40/OX40L pathway, which holds promise for future therapeutic development. Based on these advancements, the review provides an outlook on the potential for individualized treatment strategies or precision medicine approaches in AD, aiming to optimize therapeutic outcomes and patient management.
Phytol Enhances Anticonvulsant Effect of Carbamazepine and Diazepam Against PTZ-Induced Convulsion in Chicks, Possibly Through Voltage-Gated Sodium Channel and GABA Interaction Pathways.
Islam MT, Ahammed S, Al Hasan MS … +8 more , Alshahrani MY, Chowdhury R, Sheikh S, Mia E, Rohan F, Rakib IH, Hosain MS, Mandal P
Drug Dev Res · 2025 Nov · PMID 40976776 · Publisher ↗
The chlorophyll-derived diterpenoid phytol (PHY) is evident for its diverse biological effects, including neuroprotective activities in experimental animals. This study aims at the evaluation of anticonvulsant effects al...
The chlorophyll-derived diterpenoid phytol (PHY) is evident for its diverse biological effects, including neuroprotective activities in experimental animals. This study aims at the evaluation of anticonvulsant effects along with the possible mechanism of action of PHY through animal and in silico studies. For this, we performed pentylenetetrazole (PTZ)-induced convulsion tests in chicks and in silico studies against GABA receptor subunits and voltage-gated sodium channel (VGSC) receptors. PHY was tested at 25, 50, and 75 mg/kg with or without the standard drugs diazepam (DZP: 5 mg/kg) and carbamazepine (CAR: 80 mg/kg) using a vehicle as a control. Acute oral toxicity was evaluated in chicks per OECD guidelines by administering PHY (500-2000 mg/kg, p.o.) and monitoring for 48 h for mortality, toxicological signs, and behavioral changes. PHY exhibited a dose-dependent anticonvulsant effect, significantly increasing latency and reducing convulsion frequency and duration at 75 mg/kg. PHY (75 mg/kg) combined with CAR and DZP showed the most potent reduction in convulsion frequency and duration, indicating a synergistic effect. Acute toxicity tests in chicks confirmed safety up to 2000 mg/kg. In silico studies demonstrated that PHY had good binding affinity with both the GABA receptor (-6.5 kcal/mol) and VGSC (-7.0 kcal/mol), potentially contributing to its anticonvulsant action through GABAergic and sodium channel modulation. PHY showed significant anticonvulsant activity, likely via GABA and VGSC modulation, warranting further studies to clarify its mechanisms and assess its adjunct potential in drug-resistant convulsion management.
Design, Synthesis, and Biological Evaluation of 8-Phenyl-THIQ as Antidepressive Agents.
Wei X, Yang F, Xu N … +2 more , Huang X, Qiao W
Drug Dev Res · 2025 Sep · PMID 40919677 · Publisher ↗
The structural modification and derivatization of natural products represent an essential pathway for pharmaceutical innovation in the management of depression. The 8-phenyl tetrahydroisoquinoline, as a parent core, was...
The structural modification and derivatization of natural products represent an essential pathway for pharmaceutical innovation in the management of depression. The 8-phenyl tetrahydroisoquinoline, as a parent core, was obtained from magnoflorine by a structural simplification strategy. The present report details the synthesis and antidepressant activity studies of 8-phenyl-THIQ analogs. Among them, compounds 1e and 1j exhibited significant antidepressant activity in addition to high synthetic accessibility and adequate predictive ADME/T properties.
Lazertinib: A Cardio-Safer Alternative to Osimertinib for Epidermal Growth Factor Receptor L858R/T790M Double-Mutant Tyrosine Kinase Resistant Non-Small Cell Lung Cancer.
Gawli CS, Nagpure NR, Patil BR … +3 more , Ochi N, Takigawa N, Patel HM
Drug Dev Res · 2025 Sep · PMID 40919674 · Publisher ↗
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with "epidermal growth factor receptor (EGFR)" mutations playing a pivotal role in tumor progression and carcinogenesis. "Third-gene...
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with "epidermal growth factor receptor (EGFR)" mutations playing a pivotal role in tumor progression and carcinogenesis. "Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs)," such as Osimertinib, have significantly improved treatment outcomes by overcoming resistance mechanisms like the T790M mutation. However, Osimertinib's clinical application is limited by cardiotoxicity concerns, necessitating safer alternatives. Lazertinib, a structurally optimized third-generation EGFR-TKI, exhibits superior selectivity for mutant EGFR while sparing wild-type EGFR, thereby reducing off-target toxicities. This current opinion highlights the pharmacological properties of Lazertinib, its enhanced binding interactions, and its efficacy in overcoming resistance while demonstrating an improved safety profile. Comparative analyses reveal that Lazertinib offers stronger inhibition of key EGFR mutations, superior pharmacokinetics, and lower cardiotoxicity risks compared to Osimertinib. Additionally, Lazertinib's improved central nervous system (CNS) penetration enhances its therapeutic potential in patients with brain metastases. As ongoing clinical trials further elucidate its role, Lazertinib emerges as a promising next-generation EGFR inhibitor, offering a safer and more effective alternative for NSCLC treatment.
Triazole-Pyrimidine Hybrids as EGFR Inhibitors via Synthesis, In Silico, In Vitro, and In Vivo Evaluation as Anticancer Agents.
Dubey R, Gupta S, Singh R … +5 more , Chandel S, Thakur S, Irani M, Gupta GD, Asati V
Drug Dev Res · 2025 Sep · PMID 40919645 · Publisher ↗
The epidermal growth factor receptor (EGFR) is a common diver gene for lung cancer (NSCLC), which leads to an increasing death rate worldwide. This study reports the design, synthesis, and biological evaluation of triazo...
The epidermal growth factor receptor (EGFR) is a common diver gene for lung cancer (NSCLC), which leads to an increasing death rate worldwide. This study reports the design, synthesis, and biological evaluation of triazole-clubbed pyrimidine derivatives (RDa-RDm) as potential anticancer agents. Thirteen compounds were synthesized and screened against the A549 lung cancer cell line. RDg emerged as the most potent derivative, exhibiting an IC of 15.70 µM, compared with the standard drug erlotinib (IC = 10.10 µM). Notably, all derivatives displayed moderate to excellent anticancer activity at 100 µM, with IC values ranging from 15.70 to 88.27 µM. RDg, characterised by a 4-chlorophenyl group, demonstrated strong in vitro activity and induced cell-cycle arrest at the sub-G0 phase. In vivo study using the Ehrlich ascites carcinoma (EAC) mouse model confirmed the superior anticancer efficacy of RDg. At a 5 mg/kg dose, RDg achieved a 52% reduction in tumour volume and 54% reduction in tumour weight compared with erlotinib 26% tumour volume reduction. Furthermore, RDg demonstrated a 90% tumour inhibition rate compared with erlotinib 75%, attributed to its enhanced cellular uptake and sustained release properties. In silico analyses provided insights into RDg mechanism of action, revealing strong interactions with EGFR binding sites, including hydrogen bonding with Met-793 and π-sulphur interaction with Met-790. Molecular dynamics simulations demonstrated RDg stabilising effect on EGFR, as evidenced by reduced protein flexibility and compact conformational space. The combination of promising in vitro, in vivo and in silico results showed RDg may be used as a lead compound for further development of novel compounds as EGFR inhibitors.
Isolation, Purification, and Preparation of Taxinine-Loaded Liposomes for Improved Anti-Hepatocarcinogenic Activity.
Wang Q, Wang X, Hua Q … +10 more , Shi F, Jiang X, Gong M, Li T, Li J, Toreniyazov E, Yu J, Adu-Frimpong M, Cao X, Xu X
Drug Dev Res · 2025 Sep · PMID 40919640 · Publisher ↗
Liver cancer is the fourth most deadly cancer worldwide, but existing treatment options are insufficient, thus highlighting the urgent need for new therapeutic agents. Taxanes, known for their anticancer properties, prov...
Liver cancer is the fourth most deadly cancer worldwide, but existing treatment options are insufficient, thus highlighting the urgent need for new therapeutic agents. Taxanes, known for their anticancer properties, provide a promising avenue for intervention. In this study, a tetracyclic taxane compound with antitumor activity (taxinine) was extracted and isolated from Taxus chinensis (T. chinensis) seeds. It was then formulated into liposomes using lecithin, cholesterol, and D-α-tocopheryl polyethylene glycol succinate (TPGS) as excipients to enhance its solubility and antitumor efficacy. The isolation of taxinine was achieved through ultrasound-assisted ethanol extraction, followed by silica gel column chromatography, MTT activity screening, and recrystallization. Afterward, the structure of taxinine was confirmed using nuclear magnetic resonance and mass spectrometry. Taxinine liposomes were prepared via the thin film dispersion method, while the particle size, polydispersity index, zeta potential, and encapsulation efficiency of the nanoliposomes were discovered to be 186.76 ± 0.08 nm, 0.226 ± 0.012, -44.34 ± 0.77 mV, and 93.75 ± 1.29%, respectively. They also showed good stability with a release rate of 85.77% ± 2.43% in phosphate-buffered solution (PBS, pH 7.4). Toxicity tests conducted on zebrafish larvae indicated that taxinine liposomes were safe in vivo. Tissue distribution study showed that the concentration of taxinine liposomes increased to varying degrees in tissues (especially liver). In vitro experiments demonstrated that taxinine liposomes significantly enhanced the inhibitory effect of taxinine on HepG2 cell growth. Overall, the nanoliposomal formulation improved the anti-liver cancer activity of taxinine, thus suggesting its potential as a therapeutic agent.
Co-Loaded Nanoparticles of Empagliflozin and Rutin for Pancreatitis Prevention and Anticancer Activity.
Maan O, Al-Samydai A, Alqaraleh M … +4 more , Nsairat H, Alsanabrah A, Awwad O, Al-Hiari Y
Drug Dev Res · 2025 Sep · PMID 40919612 · Publisher ↗
Cancer treatment faces challenges like nonselective toxicity and drug resistance, prompting the need for innovative therapies. This study aimed to develop liposomal formulations for co-delivery of empagliflozin and rutin...
Cancer treatment faces challenges like nonselective toxicity and drug resistance, prompting the need for innovative therapies. This study aimed to develop liposomal formulations for co-delivery of empagliflozin and rutin, evaluating their anticancer and antioxidant efficacy. PEGylated empagliflozin-loaded nanoliposomes (Empa-NLs) and empagliflozin-rutin co-loaded nanoliposomes (Empa-Rut NLs) were synthesized using the thin-film hydration technique. The formulations were characterized for particle size, zeta potential, polydispersity index (PDI), encapsulation efficiency, and stability. Antiproliferative activity was assessed through MTT assay, and inflammatory and oxidative stress markers were evaluated using ELISA. Empa-NLs had a size of 118.9 ± 0.97 nm, zeta potential of -0.135 ± 0.74mV, and PDI of 0.198 ± 0.11, while Empa-Rut NLs measured 133.4 ± 1.01 nm, zeta potential of -8.78 ± 0.85 mV, and PDI of 0.13 ± 0.01, with significant differences (p ≤ 0.01). Encapsulation efficiency was 10.8 ± 0.103% for empagliflozin and 66.92 ± 0.05% for rutin. Both drugs displayed a biphasic release profile. Free empagliflozin showed stronger antiproliferative activity at lower concentrations, while Empa-Rut NLs were more effective at higher concentrations. Empa-NLs upregulated IL-1β and downregulated catalase, while Empa-Rut NLs and rutin reduced IL-1β and increased catalase. VEGF levels were elevated with empagliflozin but decreased in the presence of rutin and Empa-Rut NLs. Co-loading empagliflozin and rutin in nanoliposomes enhanced anticancer efficacy and modulated inflammatory and oxidative stress responses, suggesting that this combined drug delivery system may improve cancer therapy outcomes.
Theaflavins Inhibit Proliferation and Glycolysis of Colorectal Cancer Cells by Downregulating DDIT4.
Li H, Bei S, Mo Y … +1 more , Feng L
Drug Dev Res · 2025 Sep · PMID 40911331 · Publisher ↗
Colorectal cancer (CRC) is a common malignancy often characterized by metastasis and poor prognosis. This study attempts to ascertain the anticancer impacts of theaflavin (TF) on CRC cells and examine the fundamental mol...
Colorectal cancer (CRC) is a common malignancy often characterized by metastasis and poor prognosis. This study attempts to ascertain the anticancer impacts of theaflavin (TF) on CRC cells and examine the fundamental molecular mechanisms, focusing on the function of DDIT4 in CRC progression. This study utilized RNA sequencing for gene expression profiling, differential expression analysis, and Venn diagram analysis for overlapping genes. Protein interactions were explored, while cell viability was evaluated using colony formation assays and Cell Counting Kit-8 (CCK-8). Flow cytometry was employed for apoptosis analysis, and Transwell assays measured cell migration and invasion. ATP synthesis, lactate production, and glucose uptake were analyzed to evaluate metabolic changes, with protein and RNA expression identified by Western blot and quantitative real-time polymerase chain reaction (qRT-PCR). This study reveals that TF effectively inhibits CRC cell invasion, migration, and proliferation in a dose- and time-dependent manner. TF induces apoptosis by suppressing the antiapoptotic protein Bcl-2 and enhancing proapoptotic proteins (Cleaved Caspase-3, Bax, and Caspase-9). Through bioinformatics analysis, DDIT4 was identified as a key target gene. Additionally, correlation analysis highlighted a positive relationship between DDIT4 and the glycolysis/gluconeogenesis pathway. TF downregulates DDIT4 expression, which suppresses CRC cell proliferation and glycolysis. Moreover, DDIT4 overexpression partially reverses the suppressive impacts of TF on glycolysis and cell viability. These observations imply that TF suppresses CRC progression by targeting DDIT4 and regulating glycolytic activity, highlighting its promise as a medicinal substance for the treatment of CRC.
Exploring the Topoisomerase II Inhibitory Potential of Steroidal Drugs as a Recommended Mechanism of Action for Their Anticancer Activity: In Silico and In Vitro Assessments.
Al-Karmalawy AA, Eissa ME, Elmaaty AA … +7 more , Yousef TA, Khatib AOA, Alnajjar R, Farouk F, Belal A, Alzahrani AYA, Sharaky M
Drug Dev Res · 2025 Sep · PMID 40911302 · Publisher ↗
Herein, and based on the pharmacophoric features of doxorubicin (Dox); 133 steroids were screened to assess their ability to act as TOP II inhibitors for the discovery of those with promising anticancer activity. The cyt...
Herein, and based on the pharmacophoric features of doxorubicin (Dox); 133 steroids were screened to assess their ability to act as TOP II inhibitors for the discovery of those with promising anticancer activity. The cytotoxic inhibitory concentration 50 (IC) of the investigated steroids was determined against H1299, CaCo2, MDA-MB-468, and FaDu cancer cell lines and compared to Dox. Fluticasone propionate and fusidic acid exhibited the most potent antiproliferative effect against the MDA-MB-468 with IC values of 10.4 ± 0.7 and 10.6 ± 1.7 μM, respectively. On the other hand, the outstanding antitumor members (beclomethasone dipropionate, fluticasone propionate, prednisolone, dexamethasone, and fusidic acid) were further investigated for their TOP II inhibitory potentials. Where the protein expression of TOP II was downregulated by 0.79, 0.76, and 0.67-fold change for fusidic acid, fluticasone propionate, and dexamethasone, respectively, compared to the control. Besides, the examined steroidal candidates were subjected to a molecular docking study towards the TOP II receptor in comparison to Dox and the co-crystallized ligand (EVP) as references. Moreover, molecular dynamics (MD) simulations were conducted on the aforementioned steroids along with Dox and EVP for 200 ns to validate the docking results. Consequently, steroids, in particular fusidic acid, fluticasone propionate, and dexamethasone, can be regarded as promising lead compounds targeting TOP II for cancer treatment along with their typical anti-inflammatory effects.
Effects of a Dendritic Cell Vaccine Loaded With Whole Tumor Antigen on Bladder Cancer Model in hu-PBL-SCID Mice.
Wang B, Wu K, Cui Y … +2 more , Han X, Xing T
Drug Dev Res · 2025 Sep · PMID 40910989 · Publisher ↗
The aim of this study was to establish a humanized immune system model in severe combined immunodeficient (SCID) mice, assess dendritic cell (DC) phenotype, and evaluate the therapeutic efficacy of a DC-based vaccine in...
The aim of this study was to establish a humanized immune system model in severe combined immunodeficient (SCID) mice, assess dendritic cell (DC) phenotype, and evaluate the therapeutic efficacy of a DC-based vaccine in a bladder cancer model. Bladder cancer was induced in SCID mice by injection of T24 cells, followed by human peripheral blood leukocyte (hu-PBL) inoculation to reconstitute the human immune system. DCs were generated in vitro by culturing hu-PBL for 5 days and matured on the eighth day. The DC vaccine was produced by coculturing with whole tumor antigen which was purified through freezing and melting T24 cells. The therapeutic efficacy of a DC vaccine was evaluated by administering the vaccine to SCID mice at Weeks 5 and 6 after T24 cell injection. Immune reconstitution, phenotype of DCs, tumor weight, and matrix metalloproteinase-7 (MMP-7) mRNA expression were assessed. All SCID mice successfully developed bladder cancer, confirmed as urothelial carcinoma. After hu-PBL inoculation, human IgG was detectable in mouse serum at Week 5, and spleen weight increased over time, indicating successful human immune system reconstitution. Phenotypic analysis of DCs showed high expression of maturation markers, including CD1a (78.07% ± 9.43%), CD80 (60.11% ± 20.50%), and CD83 (46.82% ± 14.15%), indicating functional and mature DCs. Therapeutic intervention with the DC vaccine significantly reduced tumor weight and MMP-7 mRNA expression, with statistical significance (p = 0.0004 for tumor weight and p = 0.0008 for MMP-7). This study successfully established a humanized immune system model in SCID mice and demonstrated that a DC-based vaccine effectively inhibits tumor growth in a bladder cancer model. These results support the potential of DC vaccines as a promising immunotherapeutic strategy for bladder cancer.
Targeted Inhibition of NOTCH2 and Importin-β Promotes Osteogenic Differentiation of Osteosarcoma Cells.
Wei Z, Chen Y, Liu G … +3 more , Deng S, Wang Z, Zou F
Drug Dev Res · 2025 Sep · PMID 40904201 · Publisher ↗
Osteosarcoma (OS) is a common malignant bone tumor, frequently associated with impaired osteogenic differentiation of tumor cells. Recent studies have suggested that the NOTCH signaling pathway plays a crucial role in ma...
Osteosarcoma (OS) is a common malignant bone tumor, frequently associated with impaired osteogenic differentiation of tumor cells. Recent studies have suggested that the NOTCH signaling pathway plays a crucial role in maintaining tumor cell stemness and may influence their differentiation status. This study investigates the role of NOTCH2, a key receptor in the NOTCH family, in regulating osteogenic differentiation in OS. By analyzing public datasets, we compared the expression patterns and functional relevance of NOTCH1-4 in OS and identified NOTCH2 as the most significant. Using MG-63 and Saos-2 OS cell lines, we found that NOTCH2 silencing suppressed cell proliferation, invasion, and stem-like properties, while promoting osteogenic differentiation under inductive conditions. This was accompanied by increased expression of osteogenic markers. Further experiments demonstrated that Importazole, an Importin-β inhibitor, blocked the nuclear translocation of NOTCH2. Treatment with Importazole alone inhibited OS cell proliferation and invasion, reduced stem-like features, and enhanced osteogenic differentiation. When combined with NOTCH2 knockdown, Importazole exerted a synergistic effect, further inhibiting tumor progression and promoting differentiation. In vivo, xenograft models confirmed that the combination treatment more effectively suppressed tumor growth and induced osteoblast-like characteristics compared to either intervention alone. These findings indicate that NOTCH2 is a critical regulator of OS cell behavior, and that targeting NOTCH2 - especially in combination with Importazole - may offer a promising therapeutic strategy to promote differentiation and suppress tumor progression in OS.
Recent Development in Celiac Disease: Pathophysiology, Animal Models and Treatments.
Patel V, Joharapurkar A, Jain M
Drug Dev Res · 2025 Sep · PMID 40888352 · Publisher ↗
Celiac disease (CD) is an autoimmune disorder which is triggered by gluten in genetically susceptible individuals. There is no successful therapy for CD. A strict gluten-free diet (GFD) is the only remedy used in clinica...
Celiac disease (CD) is an autoimmune disorder which is triggered by gluten in genetically susceptible individuals. There is no successful therapy for CD. A strict gluten-free diet (GFD) is the only remedy used in clinical practice, which highlights the need to develop pharmacotherapeutic approaches to treat CD. This review discussed the data from genetic, biochemical, and immunological research, which has identified the mechanisms that causes activation of gluten which cause sequential immunological cascade through antigen presenting cell (APC) and human leukocyte antigen (HLA) dependent pathway. Recent studies aim to develop medications that stimulate repair of intestinal barrier, modify gluten peptides to make less immunogenic, regulate immune responses, and reduce CD associated symptoms. These approaches are mostly investigated in addition to GFD. In addition to these approaches, therapies that may work without gluten restriction need to be prioritized for patients who continue to experience symptoms despite strict adherence to GFD.
Sestrin2 Regulates Mitochondrial Function and Autophagy via Nrf2/SIRT3 Signaling to Ameliorate Hypoxia/Reoxygenation-Induced Rat's Cardiomyocyte Injury.
Liu T, Kong J, Li Z … +2 more , Xi S, Liu L
Drug Dev Res · 2025 Sep · PMID 40878255 · Publisher ↗
Mitigating myocardial ischemia-reperfusion (I/R) injury poses a significant challenge, necessitating the exploration of novel therapeutic targets. Sestrin2 (Sesn2), a stress-induced protein, has emerged as a potential ca...
Mitigating myocardial ischemia-reperfusion (I/R) injury poses a significant challenge, necessitating the exploration of novel therapeutic targets. Sestrin2 (Sesn2), a stress-induced protein, has emerged as a potential candidate for attenuating I/R injury, yet its precise mechanisms remain elusive. The role of Sesn2 was investigated using an in vitro model of H9C2 cardiomyocytes subjected to hypoxia-reoxygenation (H/R). Sesn2 expression was modulated through overexpression techniques, and cellular responses, including cell viability, inflammatory factor production, mitochondrial function, oxidative stress, autophagy, and apoptosis, were assessed. Furthermore, the role of the Nrf2/SIRT3 signaling pathway in the mechanism was explored via treating cells with Nrf2 inhibitor ML385. Sesn2 overexpression significantly improved cell viability, attenuated inflammatory factor production, preserved mitochondrial function, and mitigated oxidative stress in H/R-exposed cardiomyocytes. Additionally, Sesn2 enhanced autophagy and modulated the Nrf2/SIRT3 signaling pathway. Moreover, Sesn2-mediated protection was reversed upon inhibition of Nrf2 signaling, underscoring the importance of this pathway in Sesn2-induced protection. Our findings may elucidate the mechanism of Sesn2-mediated protection and highlight its potential as a therapeutic target to ameliorate H/R-induced cardiomyocyte injury.
Targeting the Enzymatic Site of Botulinum Neurotoxin Type E With 8-Hydroxyquinolinol-Based Inhibitors: In Silico, In Vitro, and In Vivo Evaluation.
Sonkar P, Kushwah VC, Agnihotri S … +3 more , Disoriya D, Vimal M, Dhaked RK
Drug Dev Res · 2025 Sep · PMID 40852871 · Publisher ↗
Botulinum neurotoxins are the most potent toxins responsible for causing flaccid paralysis of muscles by blocking the release of acetylcholine at the neuromuscular junction. There are no postexposure therapeutics and eff...
Botulinum neurotoxins are the most potent toxins responsible for causing flaccid paralysis of muscles by blocking the release of acetylcholine at the neuromuscular junction. There are no postexposure therapeutics and effective active/passive prophylaxis available for the treatment. Therefore, it is highly desirable to develop a potential antidote to counter botulinum neurotoxicity. In this study, ~800 molecules were mined by a structure similarity search from open databases and docked into the pocket of the catalytic domain of botulinum toxin type E using AutoDock 4.2. Twenty-four small molecules with the best scoring function were selected and evaluated using in vitro and in vivo assays. Among these, two molecules, NSC1011 and NSC1012, were identified as inhibiting the catalytic activity of BoNT/E, with IC values of 31.25 ± 1.0 μM and 55.45 ± 5.2 μM and K of 5.54E-07 and 6.51E-06 M, respectively. To find inhibitors that can reverse the neurotoxicity more effectively, we have derived and synthesized 12 analogs of NSC1011. These compounds showed higher inhibition than the parent molecules, with IC and K values of 4.375 ± 2.3 µM and 1.61E-08 M (C25.12) and 10.25 ± 3.0 µM and 4.70E-08 M (C25.9). Compounds C25.9 and C25.12 completely protected mice in premixed doses and led to significant extension in survival of up to 60 h with therapeutic treatment. This study showed that these 8-HQ derivatives had the potency to inhibit BoNT/E by interacting with the active site. Further studies could lead to the development of undiscovered postexposure therapeutics against this deadly neurotoxin.
Berberine as a Multi-Targeted Therapeutic Agent in Melanoma: Mechanisms, Efficacy, and Combination Therapies.
Wang RR, Wu H, Feng ML … +3 more , Zhong JL, Li RX, Zhou BX
Drug Dev Res · 2025 Sep · PMID 40827003 · Publisher ↗
Melanoma is a type of aggressive cancer distinguished by its high propensity for recurrence, the development of metastases, and an unfavorable outlook for recovery. Treatment modalities for melanoma encompass surgery, im...
Melanoma is a type of aggressive cancer distinguished by its high propensity for recurrence, the development of metastases, and an unfavorable outlook for recovery. Treatment modalities for melanoma encompass surgery, immunotherapy, and targeted therapies. In recent decades, berberine has garnered attention for its significant anticancer properties across various cancer types. This review systematically examines the molecular mechanisms of berberine in melanoma, particularly its modulation of critical signaling pathways, including B-RAF/MEK/ERK, PI3K/AKT, and NF-κB, which are essential for regulating melanoma cell proliferation and promoting apoptosis. Furthermore, berberine activates AMP-activated protein kinase, leading to the inhibition of cyclooxygenase-2, thereby reducing melanoma cell migration and invasion through decreased inflammation and enhanced cellular energy regulation. It also induces mitochondrial dysfunction and oxidative stress, promoting apoptosis while simultaneously inhibiting epithelial-to-mesenchymal transition, a key process in metastasis. Additionally, berberine modulates the immune microenvironment through Toll-like receptors, cytokine networks, and the regulation of various immune cells, thereby enhancing its antitumor effects. Recent studies have shown that the therapeutic effect of berberine is enhanced when used in combination with other therapies, especially immune checkpoint inhibitors, to improve antitumor immune responses. These findings highlight the potential of berberine as a multi-targeted agent for the treatment of melanoma, providing an avenue for further clinical exploration and integration into therapeutic strategies.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe