Drug Development Research最新文献

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.

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.

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 IC₅₀ 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 IC₅₀ 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.

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_A 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_A 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_A and VGSC modulation, warranting further studies to clarify its mechanisms and assess its adjunct potential in drug-resistant convulsion management.

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.

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 IC₅₀ of 15.70 µM, compared with the standard drug erlotinib (IC₅₀ = 10.10 µM). Notably, all derivatives displayed moderate to excellent anticancer activity at 100 µM, with IC₅₀ 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.

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.

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.

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.

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.