Drug Development Research[JOURNAL]
Sun
200 papers
Emerging in Diabetic Cardiomyopathy: Molecular Pathways and Targets for Therapeutic Intervention.
Trivedi MV, Jadhav HR, Gaikwad AB
Drug Dev Res · 2025 Nov · PMID 41183131 · Publisher ↗
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...
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.
Integration of Machine Learning, Bioinformatics, and Experimental Validation to Identify Novel Diagnostic and Prognostic Biomarkers Associated With Succinylation in Lung Adenocarcinoma.
Wu S, Pan J, Zheng Y … +2 more , Pan Q, Tan Y
Drug Dev Res · 2025 Nov · PMID 41169155 · Publisher ↗
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 systematic...
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.
Kaurenoic Acid Suppresses Osteosarcoma Progression by Reprogramming Tumor-Associated Macrophages to M1 Phenotype.
Tang Y, Guo Y, Wu Y … +9 more , Chen M, Yu P, Wang Y, Li X, Zhu Z, Qian S, Zhang J, Li Z, Yao N
Drug Dev Res · 2025 Nov · PMID 41158091 · Publisher ↗
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...
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.
CRISPR Targeting the 5' Regulatory Region of FOXM1 Will Also Disrupt RHNO1.
Karpf AR, Jirapongwattana N
Drug Dev Res · 2025 Nov · PMID 41158086 · Publisher ↗
Abstract loading — click title to view on PubMed.
Neuroprotective Effect of Empagliflozin/Rivastigmine in Alzheimer's Disease Rat Model: Optimization of Multifaceted Mechanism of Action.
Abdel-Lah ES, Hamad N, Taha AF … +7 more , Mohamed WH, Fawy MA, Attaai AH, Abbas FYA, Sherkawy HS, Abdelwarith A, Gamea MG
Drug Dev Res · 2025 Nov · PMID 41140062 · Publisher ↗
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 comb...
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.
Curcumin Alleviates Sepsis-Associated Acute Kidney Injury Potentially by Inhibiting Ferroptosis Through the ACSL4/GPX4 Signaling Pathway.
Wang L, Wu N, Zhang W … +2 more , Huang D, Li Y
Drug Dev Res · 2025 Nov · PMID 41140036 · Full text
This study aimed to investigate the protective effect of curcumin against sepsis-associated acute kidney injury (SA-AKI) in vitro and in vivo, and to clarify the role of ferroptosis in this protection. Human renal tubula...
This study aimed to investigate the protective effect of curcumin against sepsis-associated acute kidney injury (SA-AKI) in vitro and in vivo, and to clarify the role of ferroptosis in this protection. Human renal tubular epithelial cell (RTEC) line HK-2 was stimulated with lipopolysaccharide (LPS). Ferroptosis was further induced with erastin. In vivo, a rat SA-AKI model was produced by cecal ligation and puncture (CLP) and allocated to the Sham, sepsis, and curcumin (Cur) + sepsis (Sep) groups. Glutathione (GSH), malondialdehyde (MDA), and pro-inflammatory cytokines were quantified by ELISA. Western blot analysis was used to evaluate the ferroptosis-related proteins, including long-chain acyl-coenzyme synthetases 4 (ACSL4) and glutathione peroxidase 4 (GPX4). Apoptosis of RTECs was assessed with TUNEL staining, and ultrastructural changes were examined by transmission electron microscopy (TEM). Compared with the Sepsis group, the Cur + Sep group showed significantly lower Paller damage scores, reduced Scr, BUN, TNF-α, IL-1β, IL-6, MDA, Fe levels, and ACSL4 protein expression (all p < 0.05). Conversely, GSH and GPX4 levels were significantly elevated in the Cur + Sep group (both p < 0.05). TUNEL staining revealed fewer apoptotic RTECs in the Cur + Sep group compared with the Sepsis group (p < 0.05). TEM demonstrated swollen mitochondria with condensed membranes and vanished cristae in the sepsis group, changes that were markedly alleviated by curcumin. In HK-2 cells, erastin abolished curcumin's protective effect against LPS-induced injury. Curcumin attenuates SA-AKI, likely by suppressing inflammation and ferroptosis via the ACSL4/GPX4 signaling pathway.
Correction to "Dioscin Induces Osteosarcoma Cell Apoptosis by Upregulating Ros-Mediated P38 Mapk Signaling".
Drug Dev Res · 2025 Nov · PMID 41103106 · Publisher ↗
Abstract loading — click title to view on PubMed.
RBM15B/IGF2BP2-m6A Mediated Upregulation of FNBP1 Promotes the Progression of Glioblastoma by Promoting Smad3-Mediated Glycolysis.
Zhang L, Li F, Zhang L … +9 more , Ma J, Liu B, Chen Y, Jiang X, Gao W, Wei Y, Xue L, Zhao H, Xu J
Drug Dev Res · 2025 Nov · PMID 41086050 · Publisher ↗
Glioblastoma (GBM) is the most common and lethal primary intracranial tumor, and glycolysis has been reported to play a critical role in its progression. Formin-binding protein 1 (FNBP1) has been implicated in GBM progre...
Glioblastoma (GBM) is the most common and lethal primary intracranial tumor, and glycolysis has been reported to play a critical role in its progression. Formin-binding protein 1 (FNBP1) has been implicated in GBM progression; however, the precise molecular mechanisms remain unclear. In this study, we demonstrated that FNBP1 expression was significantly higher in GBM tissues compared with adjacent tissues. Elevated FNBP1 expression was correlated with higher tumor grade and reduced 5-year survival in GBM patients. In vitro, knockdown of FNBP1 inhibited proliferation, invasion, and glycolysis, while promoting apoptosis in GBM cells. Mechanistically, RNA-binding motif protein 15B (RBM15B) increased the m6A modification level of FNBP1 mRNA, and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) recognized this m6A mark and enhanced the stability of FNBP1 mRNA. Furthermore, FNBP1 interacted with LIM and SH3 Domain Protein 1 (LASP1), upregulating LASP1 protein expression and subsequently activating the Smad3 signaling pathway to promote glycolysis. In vivo, subcutaneous xenograft models were established using U251/U87 cells, and a lung metastasis model was generated via tail vein injection of U87 cells. FNBP1 knockdown significantly suppressed tumor growth in the subcutaneous model and reduced the number of lung nodules in the metastasis model. In conclusion, FNBP1, regulated by the RBM15B-m6A-IGF2BP2 axis, promotes GBM progression by interacting with LASP1 to activate Smad3-mediated glycolysis.
β-Elemene Suppresses Proliferation, Migration, and Stemness in Triple-Negative Breast Cancer by Inhibiting SIX-1.
Liu J, Yan X, Wang M … +4 more , Yu Q, Jia L, Chen C, Xia J
Drug Dev Res · 2025 Nov · PMID 41078324 · Publisher ↗
Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options and poor prognosis. This study investigated the therapeutic potential of β-Elemene, a sesquiterpene from traditional Chinese...
Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options and poor prognosis. This study investigated the therapeutic potential of β-Elemene, a sesquiterpene from traditional Chinese medicine, against TNBC. We first confirmed that SIX-1 was significantly upregulated in TNBC tissues and cell lines. Our findings demonstrated that β-Elemene inhibited TNBC cell proliferation in a dose- and time-dependent manner. It also attenuated cell migration and invasion by reducing the expression and activity of MMP-2 and MMP-9. Furthermore, β-Elemene reversed epithelial-to-mesenchymal transition (EMT), as shown by the downregulation of N-cadherin, Snail, and TGF-β1, upregulation of E-cadherin, and a morphological shift towards an epithelial phenotype. The compound also diminished cancer stemness, evidenced by reduced spheroid formation and decreased expression of OCT4 and SOX2. Mechanistically, β-Elemene suppressed the β-Catenin/ID2 signaling pathway, an effect that was reversed by SIX-1 overexpression. In conclusion, β-Elemene suppresses TNBC proliferation, migration, invasion, and stemness in vitro by modulating the SIX-1/β-Catenin/ID2 axis, suggesting its promise as a candidate for further therapeutic development.
Mechanism of Berberine Ameliorating Severe Pneumonia by Targeting PTGS2 Inhibition to Regulate C-Type Lectin Receptor Pathway, Mitochondrial Function and Cellular Focalization.
Wang K, Zhao W, Yin XH … +5 more , Jiang YP, Tu F, Yang JL, Cheng L, Liu J
Drug Dev Res · 2025 Nov · PMID 41063474 · Publisher ↗
Severe pneumonia remains a major global health burden owing to its high morbidity and mortality, placing substantial strain on healthcare systems. Although berberine shows therapeutic potential against lung infections, i...
Severe pneumonia remains a major global health burden owing to its high morbidity and mortality, placing substantial strain on healthcare systems. Although berberine shows therapeutic potential against lung infections, its effects and mechanisms in severe pneumonia are not fully defined. This study investigated how berberine ameliorates severe pneumonia by regulating the C-type lectin receptor (CLR) pathway, mitochondrial function, and cellular pyroptosis via inhibition of prostaglandin endoperoxide synthase 2 (PTGS2). Network pharmacology and bioinformatics were used to predict downstream targets of berberine for molecular docking and enrichment analysis. A severe pneumonia rat model and a cellular infection model were established, comprising a control group, a Klebsiella pneumoniae infection group, and berberine treatment groups at different doses. Hematoxylin-eosin staining, enzyme-linked immunosorbent assay, immunohistochemistry, and TUNEL staining were performed to evaluate lung pathology, inflammatory cytokines, expression and localization of related proteins, apoptosis, and pyroptosis. Docking indicated tight binding of berberine to PTGS2 and modulation of multiple inflammation-related pathways. In vivo, berberine improved lung histopathology, reduced inflammatory cytokines, downregulated PTGS2 and proteins in the CLR pathway, enhanced mitochondrial function, and decreased pyroptosis-related protein levels; consistent effects were observed in vitro. These findings indicate that berberine targets the CLR pathway, inhibits PTGS2, and restores mitochondrial and cellular homeostasis, thereby reducing inflammation and tissue damage in severe pneumonia.
Multi-Target Rational Design and Synthesis of Some 2-Quinolinone Antitumor Candidates Downregulating the Expression of EGFR, VEGFR-2, and Telomerase With Apoptotic Potential.
El-Helw EAE, Mousa MHA, Ghareeb EA … +7 more , Mahmoud NFH, Sharaky M, El-Bordany EA, Khatib AOA, Soliman EA, Alnajjar R, Al-Karmalawy AA
Drug Dev Res · 2025 Nov · PMID 41054290 · Publisher ↗
The literature represented that the 2-quinolone moiety is present in diverse potent EGFR, VEGFR-2, and telomerase cellular downregulators. Accordingly, it was incorporated in new scaffolds (2, 3, 5, and 8-12), keeping in...
The literature represented that the 2-quinolone moiety is present in diverse potent EGFR, VEGFR-2, and telomerase cellular downregulators. Accordingly, it was incorporated in new scaffolds (2, 3, 5, and 8-12), keeping in mind its attachment to the requested pharmacophores of more than one target receptor to produce novel multi-target ligands. First, the growth inhibition % (GI%) of all candidates was recorded in seven diverse human cancer cell lines. Second, the IC values of compounds (5, 6, and 12) were determined against six cancer cell lines. Interestingly, analogue (6) displayed the highest cytotoxicity, particularly against CaCo2, with an IC value of 21.99 µM. Then, the EGFR, VEGFR-2, and telomerase inhibitory potentials of compounds (5, 6, and 12) were recorded. Notably, compound 6 showed the highest EGFR, VEGFR-2, and telomerase inhibitory potentials with 0.34, 0.31, and 0.54-fold changes, respectively. Additionally, the apoptotic potency of analogue (6) was evaluated by measuring the expression of caspases 3, 8, and 9 (proapoptotic markers), besides CDK 2, 4, and 6 (antiapoptotic markers) proteins. To sum up, compound 6 showed remarkable upregulation of the caspases 3, 8, and 9, while it showed detrimental results against the CDK 2, 4, and 6 proteins. This further emphasizes the potent apoptotic potential of compound 6 in CaCo2 cancer cells. Moreover, compound 6's impact on cell cycle progression in CaCo2 showed a notable increase in cell cycle arrest in the G0 and G1 phases, equivalent to 28.72% and 68.20%, respectively, relative to control cells with 25.77% and 60.49%, respectively. Furthermore, the superior antitumor analogue (6) was tested by in silico molecular docking and dynamic simulations (for 200 ns) against EGFR, VEGFR-2, and telomerase targets to investigate its affinity and interactions. A structure-activity relationship (SAR) was performed to determine the anticancer potential of the tested candidates through modifications to the 2-oxoquinoline-3-carbaldehyde scaffold.
Cardiovascular Safety of VIAN-c4551, an Antiangiogenic Peptide Derived From Vasoinhibin.
García-González MA, Miguel-Martínez AD, González-Hernández A … +11 more , Zamora M, Adán-Castro E, Ruíz-Herrera X, Carbajo-Mata MA, Triebel J, Bertsch T, Lopez-Lopez JG, Martínez de la Escalera G, Robles JP, Clapp C, Villalón CM
Drug Dev Res · 2025 Nov · PMID 41054285 · Full text
Vasoinhibin is a potent antiangiogenic protein that blocks the activation of endothelial nitric oxide synthase (eNOS) in response to vascular endothelial growth factor, bradykinin, and acetylcholine (ACh). In this regard...
Vasoinhibin is a potent antiangiogenic protein that blocks the activation of endothelial nitric oxide synthase (eNOS) in response to vascular endothelial growth factor, bradykinin, and acetylcholine (ACh). In this regard, VIAN-c4551, a new synthetic vasoinhibin analog, has therapeutic potential for targeting angiogenesis in oncology and ophthalmology. Given that cardiovascular actions are common complications of antiangiogenic drugs and eNOS inhibitors, this multidisciplinary study investigated the cardiovascular safety of VIAN-c4551. Administered acutely, VIAN-c4551 inhibited ACh-induced eNOS phosphorylation/activation in cultured endothelial cells and in lung tissue treated in vivo, as well as the ACh-induced relaxation of rat aortic segments. However, daily intravenous (i.v.) injections of VIAN-c4551 (1 or 3 mg kg) for 5 days failed to significantly modify the vasodepressor responses to ACh and the baseline values of blood pressure in anesthetized rats (intact, vagotomized, or pithed). Furthermore, daily i.v. injections of 1 mg kg VIAN-c4551 (for 5 days) did not alter: (i) blood pressure or heart rate values in awake rats; (ii) cardiac autonomic and histological outcomes in anesthetized animals; or (iii) inflammatory (tumor necrosis factor-α [TNF-α] and interleukin-6 [IL-6]) and apoptotic (caspase-3) markers. Although VIAN-c4551 inhibited ACh-induced eNOS activation in vitro and in vivo and vasorelaxation in ex vivo assays, in vivo experiments consistently showed no significant cardiovascular effects produced by this synthetic peptide. Thus, VIAN-c4551 appears to be cardiovascularly safe for targeting angiogenesis-related diseases.
Targeting mTOR Kinase for Cancer Treatment: A Comprehensive Review With Clinical Insights.
Hossain MT, Hossain MA
Drug Dev Res · 2025 Nov · PMID 41046532 · Publisher ↗
Cancer remains a significant global health challenge, with increasing incidence and mortality rates worldwide. The mechanistic target of rapamycin (mTOR) pathway, a central regulator of cell growth, proliferation, metabo...
Cancer remains a significant global health challenge, with increasing incidence and mortality rates worldwide. The mechanistic target of rapamycin (mTOR) pathway, a central regulator of cell growth, proliferation, metabolism, and survival, has emerged as a promising therapeutic target in cancer. Dysregulation of mTOR signaling is implicated in various cancers, including breast, colon, lung, renal cell carcinoma, and multiple myeloma, making it an attractive target for inhibition. This review provides a comprehensive analysis of mTOR-targeted therapies, focusing on the clinical outcomes, efficacy, safety, and adverse effects of mTOR inhibitors. We explore the mechanisms of mTOR regulation, the impact of mTOR mutations on drug sensitivity, and the development of resistance to mTOR inhibitors. The review also highlights the potential of combination therapies and next-generation inhibitors to overcome resistance and improve therapeutic outcomes. Key mTOR inhibitors, including rapalogs (e.g., sirolimus, everolimus) and ATP-competitive inhibitors (e.g., MLN0128, PP242), are discussed in detail, along with their clinical applications and limitations. Additionally, we summarize the findings from major clinical trials, including FDA-approved mTOR inhibitors like everolimus and temsirolimus, and non-FDA-approved inhibitors such as sapanisertib and ridaforolimus. The review underscores the importance of understanding mTOR signaling and its role in cancer progression, offering insights into the future of mTOR-targeted therapies in oncology.
Baicalin Promotes Recovery Following Intracerebral Hemorrhage by Inhibiting Ferroptosis in Brain Tissue Through Modulation of AKT/Nrf2/GPX4 Axis.
Yu Z, Qian X, Wu W … +2 more , Zhang M, Li Y
Drug Dev Res · 2025 Nov · PMID 41024642 · Publisher ↗
Intracerebral hemorrhage (ICH) is a serious acute cerebrovascular disease with a high death and disability rate. Baicalin plays a neuroprotective role in various diseases, but its regulatory mechanism on ICH remains uncl...
Intracerebral hemorrhage (ICH) is a serious acute cerebrovascular disease with a high death and disability rate. Baicalin plays a neuroprotective role in various diseases, but its regulatory mechanism on ICH remains unclear. In this study, we investigated the protective effects and mechanisms of baicalin in ICH using an ICH mouse model. ICH mouse model was established by injection of collagenase type IV into intracranial in C57BL/6 mice. Neurological function was evaluated by neurological severity scores and the rotarod test. Hemorrhagic foci of brain was evaluated by TTC and hematoxylin-eosin staining. Iron ion deposition in brain was detected by Prussian blue staining. Ferroptosis was evaluated by measuring expression of FTH-1, SLC7A11, GPX4, and TFRC, as well as detecting iron content and levels of glutathione (GSH) and malondialdehyde (MDA). GPX4 expression and apoptosis of brain were detected by immunofluorescence staining and TUNEL assay. Results showed that baicalin improved neurological function and reduced the area of hemorrhagic foci of brain in ICH mouse model. Baicalin decreased iron ion deposition, inhibited ferroptosis and apoptosis, and upregulated GPX4 in brain of ICH mouse model. Moreover, baicalin increased AKT1 phosphorylation and the protein level of Nrf2 in brain of ICH mouse model. Notably, AKT1 inhibitor LY294002 and Nrf2 inhibitor reversed the effects of baicalin on the activation of AKT1/Nrf2/GPX4 axis and the inhibition of ferroptosis in brain of ICH mouse model. Collectively, we demonstrated that baicalin promotes ICH recovery by inhibiting ferroptosis in brain tissue through activation of AKT/Nrf2/GPX4 axis. These results may provide new insights for the study of baicalin in the treatment of ICH.
Rational Discovery of BACE1-Selective Inhibitors as Potential Therapeutics for Alzheimer's Disease.
Varma T, Kamble P, Garg P
Drug Dev Res · 2025 Nov · PMID 41024640 · Publisher ↗
Alzheimer's disease (AD) remains a major neurodegenerative disorder with limited therapeutic medication. Despite intensive efforts, the clinical development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) i...
Alzheimer's disease (AD) remains a major neurodegenerative disorder with limited therapeutic medication. Despite intensive efforts, the clinical development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors has been hindered by off-target effects, poor brain penetration, and toxicity, which is often due to a lack of selectivity over BACE2. In this study, we conducted a comprehensive analysis of over 9,000 reported BACE1 inhibitors to identify key physicochemical properties and interaction fingerprints associated with effective binding. These criteria were used to filter a library of 1.4 million commercially available compounds, prioritizing candidates with better safety and blood-brain barrier (BBB) permeability properties. The top-ranked molecules were evaluated through molecular docking and molecular dynamics (MD) simulations, followed by selectivity assessments against BACE2 and additional off-targets. Among these, two compounds, MCULE-5138978734 and MCULE-2333131051, exhibited strong and stable binding to BACE1 with markedly reduced affinity for BACE2, suggesting improved selectivity. This integrative in silico framework demonstrates a rational strategy for the discovery of selective BACE1 inhibitors and highlights promising lead candidates for further experimental validation in the development of AD therapeutics.
Synthesis, Biological Evaluation and Molecular Docking Studies of New 4-(Cyanomethyl)-N'-Substituted Benzohydrazide Derivatives as Anti-Alzheimer Agents.
Tok F, Baltaş N, Abas Bİ … +4 more , Kozan B, Kaya S, Tatar-Yılmaz G, Çevik Ö
Drug Dev Res · 2025 Nov · PMID 41024623 · Publisher ↗
Although the incidence of Alzheimer's disease increases with age, the number of effective drugs in the fight against this disease remains insufficient. In this regard, a new series of hydrazide-hydrazone derivative compo...
Although the incidence of Alzheimer's disease increases with age, the number of effective drugs in the fight against this disease remains insufficient. In this regard, a new series of hydrazide-hydrazone derivative compounds (3a-3n) was synthesized and their structures were elucidated using spectral techniques. Then, all compounds were tested for their in vitro antioxidant and anticholinesterase activities. Compound 3i was found to have the highest antioxidant activity in the series with 63.750 ± 0.033 µM and 44.210 ± 0.058 µM SC values in the DPPH and ABTS methods, respectively. Compound 3i exhibited significantly higher inhibitory properties than the reference standard donepezil with IC values of 1.850 ± 0.013 µM and 3.680 ± 0.034 µM against AChE and BChE enzymes, respectively. The cytotoxicity and AChE inhibition potential of the compounds on the SH-SY5Y cell line were also evaluated. Compounds 3i and 3l were found to have the highest AChE inhibition (81.03 ± 2.05% and 83.84 ± 2.46%) in SH-SY5Y cells, respectively. Compound 3l also maintained cell viability at 100 µM concentration. The most active compounds in the series were investigated as competitive or noncompetitive inhibitors against AChE and BChE by enzyme kinetic studies. Moreover, molecular docking and MD simulation studies were used to describe the enzyme-ligand interactions and their stability.
Oleuropein Modulates Mitophagy and Metabolism in Cardiomyocyte Via the PINK1/Parkin Signaling Pathway.
Ling H, Song C
Drug Dev Res · 2025 Nov · PMID 41001689 · Publisher ↗
Oleuropein (OLEU), a natural polyphenol, exhibits cardioprotective potential through mitochondrial modulation, yet its precise mechanisms remain elusive. This study elucidates OLEU's role in alleviating oxidative stress...
Oleuropein (OLEU), a natural polyphenol, exhibits cardioprotective potential through mitochondrial modulation, yet its precise mechanisms remain elusive. This study elucidates OLEU's role in alleviating oxidative stress and regulating mitochondrial quality control via the PINK1/Parkin pathway. In vitro, H9C2 cardiomyocytes exposed to H₂O₂-induced oxidative stress were treated with OLEU (0-200 μM), and analyses included cell viability, ROS, SOD, MDA, ΔΨm, ATP, PINK1/Parkin expression and detection of Mitophagic Flux. In vivo, myocardial infarction (MI) was induced in SD rats via coronary ligation, followed by OLEU administration, with assessments of cardiac function, histopathology, and mitophagy using echocardiography, electron microscopy, immunohistochemistry and immunofluorescence. Results showed that OLEU (≤200 μM) dose-dependently restored cell viability, reduced ROS, and normalized SOD/MDA (p < 0.05), while mitigating ΔΨm collapse and ATP depletion, indicating enhanced mitochondrial bioenergetics. OLEU upregulated PINK1/Parkin, promoting mitophagic clearance of damaged mitochondria, and metabolomic analysis revealed modulation of arginine/proline and lipid pathways. In MI rats, OLEU attenuated ROS, preserved myocardial structure, and improved cardiac function, supported by elevated mitophagy in electron microscopy. These findings demonstrate that OLEU protects cardiomyocytes by suppressing oxidative stress, stabilizing mitochondrial integrity, and activating PINK1/Parkin-mediated mitophagy, highlighting its therapeutic potential for myocardial injury and mitochondrial dysfunction.
Pyrrolidine-2-carbonitrile Derivatives as Multifunctional Antidiabetic Agents: Inhibition of α-Amylase, α-Glucosidase, and DPP-IV With Structure-Activity Relationships, HSA Binding, and Molecular Docking Studies.
Bhat AA, Singh I
Drug Dev Res · 2025 Nov · PMID 41000067 · Publisher ↗
A series of pyrrolidine-2-carbonitrile derivatives was designed, synthesized, and evaluated for their antidiabetic potential. The synthesized compounds exhibited notable inhibitory activity, with IC₅₀ values ranging from...
A series of pyrrolidine-2-carbonitrile derivatives was designed, synthesized, and evaluated for their antidiabetic potential. The synthesized compounds exhibited notable inhibitory activity, with IC₅₀ values ranging from 9.36 to 21.54 µg/mL for α-amylase, 13.32 to 46.14 µg/mL for α-glucosidase, and 22.87 to 42.12 µg/mL for DPP-IV. Among the evaluated derivatives, compounds bearing para-methyl (6b) and para-chloro (6c) substituents demonstrated the most potent inhibitory activity across all three enzymatic targets. To elucidate the underlying trends, a SAR analysis was conducted, revealing that both electronic properties and steric effects of the substituents significantly influenced enzyme inhibition potency. The molecular docking studies showed strong and specific interactions between the active compounds and key residues within the catalytic sites of the target enzymes. In addition, UV-visible absorption and fluorescence spectroscopy studies demonstrated high binding affinities for both 6b and 6c with HSA, having binding constant (K) values of 7.31 × 10⁵ M⁻¹ and 7.43 × 10⁵ M⁻¹, respectively. Taken together, these findings highlight compounds 6b and 6c as promising lead candidates for the development of multitarget antidiabetic agents.
Antiproliferative Effects of the Triterpene Ursolic Acid Natural Product in Bladder and Ovarian Tumor Cell Lines.
Silva LWPE, Almeida TC, Teixeira MSDS … +4 more , Cerrutti CMV, Agostini LDC, Brandão GC, da Silva GN
Drug Dev Res · 2025 Nov · PMID 41000061 · Publisher ↗
Bladder and ovarian cancers impose a significant burden on healthcare systems due to their high incidence, mortality rates, and the challenges associated with early diagnosis. Current chemotherapy regimens, which typical...
Bladder and ovarian cancers impose a significant burden on healthcare systems due to their high incidence, mortality rates, and the challenges associated with early diagnosis. Current chemotherapy regimens, which typically involve combinations of drugs, often cause severe side effects that negatively impact patient adherence and treatment efficacy. Recently, studies have explored the use of herbal medicines to mitigate the adverse effects of chemotherapy. One such herbal compound is ursolic acid (UA), a triterpene known for its anti-inflammatory, antioxidant, and antitumor properties. This study aimed to evaluate the effects of UA on bladder and ovarian cancer cells harboring TP53 mutations through various assays, including cytotoxicity, clonogenic survival, cell migration, morphological changes, apoptosis, cell cycle analysis, JHDM1D expression and selectivity using MRC-5 cells, along with in silico evaluation. The treatment demonstrated selectivity for tumoral cells and significant antiproliferative effects in both cell types, leading to decreased cell viability, reduced colony-forming ability, inhibited cell migration, morphological changes characteristic of cell death, and increased expression of JHDM1D. In conclusion, UA exhibited antiproliferative activity against bladder and ovarian cancer cell lines with different TP53 mutation sites, suggesting its potential as a promising therapeutic alternative. Moreover, our study demonstrated for the first time the presence of UA in the species F. formosa.
Neuroprotective Effects of Liraglutide and/or Rivastigmine Combination on the Rat Hippocampus.
Abdel-Aal RA, Hareedy MS, Badary DM … +2 more , Abdelnabi S, Hussein AMR
Drug Dev Res · 2025 Nov · PMID 41000001 · Publisher ↗
This study evaluated the neuroprotective potential of a combination therapy using liraglutide (LIRA), an antidiabetic agent, and rivastigmine (RIVA), a standard treatment for Alzheimer's disease (AD), in a rat model of a...
This study evaluated the neuroprotective potential of a combination therapy using liraglutide (LIRA), an antidiabetic agent, and rivastigmine (RIVA), a standard treatment for Alzheimer's disease (AD), in a rat model of aluminum chloride (AlCl₃)-induced AD. Male rats were divided into five groups: control, AD (AlCl₃,75 mg/kg for 60 days), RIVA-treated (1 mg/kg daily for 6 weeks), LIRA-treated (300 µg/kg daily for 6 weeks), and combination-treated (LIRA + RIVA). Cognitive function was assessed behaviorally, and hippocampal biomarkers related to AD-such as microtubule-associated protein Tau (MAPt), Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1), Sequestosome 1 (SQSTM1/p62), and acetylcholinesterase (AChE) activity-were evaluated. Histopathological changes, immunohistochemistry, and transmission electron microscopy were also assessed. The levels of MAPt, BACE1, SQSTM1/p62, and AChE in the LIRA + RIVA group were 11.32 ± 0.467 ng/mL, 1069 ± 80.1 pg/mL, 408.7 ± 19.41 pg/mL, and 0.805 ± 0.342 µmol of acetylthiocholine iodide hydrolyzed/min/g of tissue, respectively. These levels were significant (p < 0.01) when compared with the AlCl group. Histological findings supported these biochemical data, indicating enhanced neuroprotection. LIRA may have a potential neuroprotective effect due to the rise in AChE, BACE1, (SQSTM1/p62) amyloid beta (Aβ), and caspase-3 levels induced by AlCl. Co-administration of LIRA and RIVA provided superior neuroprotective effects compared with RIVA alone, suggesting a promising therapeutic strategy for preserving cognitive function in AD.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe