Cholinergic dysfunction is a key feature of cognitive impairment, and currently available acetylcholinesterase (AChE) inhibitors provide limited symptomatic benefit and are often associated with adverse effects. This study evaluated the cognitive-protective effects of bavachin (BVC), a prenylated flavonoid from Psoralea corylifolia, and its interaction with Donepezil (DNP) in a scopolamine (SCP)-induced amnesia model. Male Swiss albino mice were pretreated with BVC (10-40 mg/kg), DNP (2.5 mg/kg), or their combination for 7 days prior to SCP challenge, followed by assessment using multiple behavioral paradigms, including novel object recognition, elevated plus maze, passive avoidance, Y-maze, and Morris water maze. BVC attenuated SCP-induced memory deficits in a dose-dependent manner, with the 40 mg/kg dose producing performance statistically comparable to, though not formally demonstrated to be equivalent to, the normal control across tests. Bliss independence analysis of behavioral endpoints indicated predominantly additive interactions, with occasional greater-than-additive trends. Biochemical evaluation demonstrated that BVC inhibits AChE in vitro (IC50 = 27.7 µM) and attenuates SCP-induced elevations of AChE activity ex vivo in the frontal cortex and hippocampus. Combination treatment showed a greater-than-additive interaction in the frontal cortex (ΔBliss = 0.054) and an approximately additive effect in the hippocampus (ΔBliss = 0.013). Molecular docking and molecular dynamics simulations further suggested stable binding of BVC within the active sites of AChE and butyrylcholinesterase (BChE). Collectively, these findings indicate that BVC attenuates cognitive deficits, at least in part, through cholinesterase inhibition, and exhibits additive effects with DNP, supporting its potential as an adjunctive candidate for cognitive disorders.

Owing to the intrinsic instability of mRNA, its routes of administration are limited, and to date, only injectable delivery has been clinically applied. In contrast, oral administration exposes mRNA to a variety of substances in the gastrointestinal (GI) tract. Despite these challenges, oral delivery remains the most familiar and convenient route for patients, making the development of orally administrable mRNA-encapsulated lipid nanoparticles (mRNA-LNPs) highly desirable. However, no studies have directly examined how mRNA-LNPs are affected within the GI environment. In the present study, we investigated the effects of representative GI components on mRNA-LNPs. Among several digestive enzymes, pepsin markedly reduced the protein-expression efficiency of the particles, whereas amylase had no effect. Pepsin-treated particles exhibited increased size, suggesting that structural alterations contributed to the observed functional loss. Lipase at high concentrations impaired nanoparticle function. Because lipase hydrolyzes ester bonds in lipids, we examined LNPs incorporating C12-200, an ionizable lipid lacking ester bonds, instead of SM-102. The C12-200 formulation showed reduced susceptibility to lipase-induced functional loss, indicating that enzymatic lipid degradation underlay the observed effects. Simulated gastric fluid also significantly diminished particle functionality. A detailed analysis of the relationship between functionality and pH revealed that impairment primarily occurred at approximately pH 1 but not at pH ≥ 3. Collectively, these findings identify the key GI factors that compromise mRNA-LNP integrity and provide important insights into the rational design of orally administrable mRNA-LNP formulations.

Lipopolysaccharide (LPS) induces endotoxemia-associated inflammatory cardiac injury rather than classical viral or autoimmune myocarditis. Sphingosine-1-phosphate (S1P) regulates cardiovascular and immune responses, predominantly through S1P receptors, but whether it also modulates macrophage-associated inflammatory signaling during LPS-induced cardiac injury remains incompletely understood. This study investigated the role of the RASGRP1-S100A9-NLRP3 signaling axis in the cardioprotective effects of S1P. Transcriptomic and single-cell RNA-sequencing analyses were used to identify inflammation-associated candidate genes and their cellular distribution. Male Sprague-Dawley rats received a single intraperitoneal injection of LPS (8 mg/kg) followed by S1P treatment for 6 weeks. Histopathology, echocardiography, serum cardiac-injury markers, oxidative-stress indices, inflammatory cytokines, Western blotting, and cellular metabolic-flux assays were evaluated. RAW264.7 macrophages were used for mechanistic cellular studies. RASGRP1 or NLRP3 overexpression and S100A9-R101Q mutation were used to assess functional contributions. Molecular docking and molecular-dynamics simulations were complemented by SPR, MST, CETSA, DARTS, and Co-IP assays to evaluate S1P-RASGRP1 target engagement and pathway-associated protein interactions. Bioinformatic analyses identified RASGRP1 as a macrophage-enriched, inflammation-associated hub gene. In LPS-treated rats, S1P reduced myocardial inflammatory injury and collagen deposition, improved ejection fraction and fractional shortening, and decreased cardiac-injury, oxidative-stress, and inflammatory markers. In RAW264.7 macrophages, S1P attenuated inflammatory and oxidative-stress responses, restored oxidative phosphorylation and glycolytic capacity, and reduced the abundance of RASGRP1, S100A9, NLRP3, and ASC. SPR and MST supported a concentration-dependent biophysical interaction between S1P and RASGRP1; CETSA and DARTS provided complementary target-stability evidence. The molecular-dynamics trajectory showed substantial rearrangement of S1P from the starting pose before reaching a plateau and therefore supports conformational sampling rather than preservation of the original docked pose. Co-IP supported protein associations within the proposed inflammatory network. RASGRP1 or NLRP3 overexpression attenuated several S1P-associated protective effects. The S100A9-R101Q mutation also weakened several S1P-associated protective responses. SPR indicated a lower apparent dissociation constant for R101Q than for WT S100A9 after model-specific fitting, which is consistent with stronger or more persistent NLRP3 binding rather than loss of the S100A9-NLRP3 interaction. S1P mitigates LPS-induced inflammatory cardiac injury in association with altered macrophage RASGRP1-S100A9-NLRP3 signaling. Biophysical and target-stability assays support direct engagement of RASGRP1 by S1P. However, these findings do not establish RASGRP1 as the sole mediator of S1P activity, exclude contributions from canonical S1P receptor signaling, or demonstrate a strictly linear RASGRP1-S100A9-NLRP3 signaling cascade. Because the LPS model primarily represents endotoxemia-associated inflammatory cardiac injury, extrapolation of these findings to classical viral or autoimmune myocarditis should be made with caution.

BRAF is a cytoplasmic serine-threonine protein kinase that plays a critical role in the MAPK signaling pathway. BRAF is the only member of the RAF family activated by mutation in human cancers. Many classes of B-Raf small molecule inhibitors have been identified. In this review, we will highlight typical BRAF inhibitors developed during these decades and provide a reference for the exploration of more potential BRAF inhibitors in the future.

Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and reduce flux through the mevalonate pathway, which supplies both cholesterol and the non-sterol isoprenoids required for prenylation of small GTPases. Because this pathway is frequently activated in cancer, statins have become one of the most intensively studied candidates for oncological drug repurposing. Preclinical work indicates that statins can lower the threshold for apoptosis, modulate autophagy in either a pro-death or a cytoprotective direction, induce pyroptosis, and sensitize cells to ferroptosis, while also acting on CD8[+] T cells, macrophages, dendritic cells, and cancer-associated fibroblasts within the tumor microenvironment. Clinical evidence, however, remains discordant with the strength of these mechanistic claims: favorable observational associations are susceptible to immortal-time bias, healthy-user bias, and confounding by indication, and randomized trials have been largely neutral for tumor-directed endpoints. This narrative review appraises the mechanistic, preclinical, and clinical literature using an explicit five-tier evidence hierarchy, and treats two constraints as analytical tools rather than closing caveats: the pharmacological heterogeneity of individual statins, and the one-to-two order-of-magnitude gap between concentrations used in cancer-cell experiments and free drug concentrations achievable in patients. We conclude that statins are biologically plausible but clinically unproven anticancer agents whose evaluation should proceed through biomarker-selected, pharmacodynamically validated combination trials rather than unselected add-on designs.

Hepatocellular carcinoma (HCC) is a major contributor to cancer-related mortality worldwide and is closely linked to oxidative stress and progressive hepatic dysfunction. This study investigated the effects of plumbagin on antioxidant defense systems and hepatic function markers in an N-nitrosodiethylamine-thioacetamide (NDEA-TAA)-induced experimental model of HCC and compared its efficacy with that of sorafenib. Male Wistar rats were assigned to five groups: normal control, plumbagin-only, HCC control, HCC treated with plumbagin, and HCC treated with sorafenib. Hepatocarcinogenesis was induced using NDEA-TAA, after which antioxidant parameters including reduced glutathione (GSH), glutathione-S-transferase (GST), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) were evaluated alongside hepatic function markers alanine aminotransferase (ALT) and albumin (ALB). The HCC control group exhibited significant reductions in GSH, GST, GPx, CAT, and SOD activities, accompanied by elevated MDA and ALT levels and decreased ALB concentrations (p ≤ 0.05), indicating severe oxidative stress and hepatic injury. Treatment with plumbagin significantly restored antioxidant enzyme activities, reduced lipid peroxidation, and improved hepatic function relative to the untreated HCC group. These effects were comparable to, and in certain parameters exceeded, those observed following sorafenib administration. The findings demonstrate that plumbagin possesses substantial antioxidative and hepatoprotective properties capable of mitigating oxidative damage and improving liver function in experimental HCC. These findings support further investigation of plumbagin as a redox-modulating candidate in HCC and a basis for future studies incorporating combination treatment, molecular validation and translational models.

Hepatocellular carcinoma (HCC) is a common malignant tumor of the digestive system. The liver is the primary organ for cholesterol production and metabolism in the body. Abnormal cholesterol levels can promote the initiation and progression of liver cancer, as well as influence treatment and patient prognosis. Damulin A and damulin B, a pair of isomeric dammarane-type saponins isolated from heat-treated Gynostemma pentaphyllum, have been shown to inhibit HCC cell proliferation and migration, arrest the cell cycle at the G0/G1 phase, induce apoptosis, and reduce intracellular cholesterol levels in vitro. Damulin B exhibited more potent effects in these assays. RNA sequencing and Western blot analysis revealed that both compounds downregulate the expression of key cholesterol biosynthesis-related genes, namely isopentenyl-diphosphate delta isomerase 1 (IDI1) and geranylgeranyl diphosphate synthase 1 (GGPS1). However, damulin A uniquely increased the expression of other cholesterol pathway genes: farnesyl diphosphate synthase (FDPS), farnesyl-diphosphate farnesyltransferase 1 (FDFT1), and lanosterol synthase (LSS). These findings indicate that damulin A and damulin B regulate intracellular cholesterol biosynthesis through distinct mechanisms, which may account for their differential inhibitory effects on hepatocellular carcinoma.

Inflammation is a tightly regulated response that maintains tissue homeostasis; however, its dysregulation in the lung contributes to acute lung injury (ALI), characterised by excessive cytokine production, oxidative stress, epithelial-endothelial barrier disruption, and impaired gas exchange. In the current study, we report the synthesis of 1,2,3,4-tetrahydro-β-carboline (THβC)-based spirocyclic peptides by an efficient cascade strategy involving N-Boc deprotection and Pictet-Spengler cyclization, which was developed for tryptophan-containing peptides using 9-fluorenone, enabling the synthesis of THβC peptides. The reaction proceeds under mild conditions [C6F5OH (pentafluorophenol) catalyst, HFIP (1,1,1,3,3,3-Hexafluoro-2-propanol) solvent] to generate a novel spiro-β-carboline scaffold, with broad substrate scope across aromatic, aliphatic, and alicyclic ketones. Further, the anti-inflammatory potential of THβC derivatives was evaluated in LPS-stimulated macrophages and lung epithelial cells. Initial screening demonstrated that compounds 3a, 3aa, 3c,3e, and 3 g (20 μM) significantly reduced Il-1β levels compared with the LPS control. Subsequent structure-activity relationship studies identified compounds 3aa and 3ag as potent inhibitors of Il-1β expression, while compounds 3aa, 3ad, 3af and 3ag effectively suppressed Ccl-2 and Cox-2 expression. Based on their ability to attenuate intracellular ROS levels, compounds 3aa and 3ag were selected for further dose-response evaluation and assessment in lung epithelial cells. These compounds significantly downregulated key inflammatory mediators in both macrophages and epithelial cells. Immunocytochemical analyses further revealed that compounds 3aa and 3ag reduced LPS-induced VCAM expression and restored caveolin levels, indicating improved barrier integrity. Collectively, compounds 3aa and 3ag attenuate LPS-induced inflammation and oxidative stress while preserving epithelial barrier integrity, supporting their potential as leads for pulmonary inflammatory disorders.

c-Jun-N-terminal kinase 3 (JNK3) inhibitors are emerging as promising therapeutic agents for the treatment of Alzheimer's disease (AD). Predominantly expressed in the central nervous system (CNS), JNK3 plays a crucial role in neuronal apoptosis and inflammation, processes that are often dysregulated in neurodegenerative conditions. In recent years, a diverse range of heterocycle scaffolds has been explored as selective JNK3 inhibitors, demonstrating significant potential in modulating disease pathology. Structure-activity relationship (SAR) studies have further facilitated the rational design and optimization of these compounds, improving their potency, selectivity, and pharmacokinetic profiles. By selectively inhibiting JNK3, these small compounds can mitigate neuroinflammation and promote neuronal survival. The development of small molecule JNK3 inhibitors offers a targeted approach that may minimize side effects. This article explores various heterocyclic molecules such as pyrazoles, thiazoles, imidazoles, and thiophenes, evaluated for JNK3 inhibition. This review will help medicinal chemists to design and develop new molecules based on established data on isoform-selective JNK3 inhibitors.

Vascular endothelial growth factor receptor-2 (VEGFR-2) is a vital mediator of angiogenesis. Therefore, VEGFR-2 inhibition is considered a promising therapeutic target to combat cancer. In the present study, a series of 22 imidazo[4,5-b]pyridine-acrylonitrile-based derivatives was designed and synthesized. All compounds were evaluated for their VEGFR-2 inhibitory activity. Seven of the tested compounds showed high inhibitory activity against VEGFR-2 with IC50 (0.029-0.087 µM) compared to reference drug sorafenib IC50 = 0.091 µM. Four of these derivatives were selected for in vitro cytotoxic activity against breast cancer (MCF-7) and hepatocellular (HepG2) carcinoma cell lines, showing IC50 (0.073-0.196 µM) and (0.20-0.21 µM), respectively, relative to sorafenib IC50 0.16 and 0.19 µM, respectively. Compound 2f exhibiting a superior VEGFR-2 inhibition (IC50 = 0.029 µM compared to sorafenib IC50 = 0.091 µM) and cytotoxicity against MCF-7 and HepG2 (IC50 = 0.073 µM and IC50 = 0.09 µM, respectively), was subjected to cell cycle analysis, apoptosis assay, and molecular modeling studies, which strongly supported the results. It caused cell cycle arrest at G2/M phase by 13.67% and a promising apoptosis induction. 2f exhibited a promising binding score and pose inside the VEGFR-2 active sites. It also showed a good safety profile with a moderate selectivity index. Based on the prediction of physicochemical and pharmacokinetic properties for 2f, it showed excellent prediction results to be orally bioavailable.

Mosquito-borne arboviruses, including dengue virus (DENV), Zika virus (ZIKV), and chikungunya virus (CHIKV), represent a growing global health burden, yet no specific antiviral therapies are currently available for most of these infections. This unmet need highlights the importance of identifying novel antiviral compounds from biologically relevant sources such as plant-derived natural products. In this study, a bioactivity-guided approach was applied to methanolic extracts from eight Solanaceae species to identify compounds with antiviral activity against DENV-2 in Vero cells. Five extracts significantly reduced viral infectivity, with Solanum ovalifolium and Cestrum sp. achieving complete inhibition at non-cytotoxic concentrations. Subsequent fractionation and purification led to the isolation of four spirostane-type steroidal saponins, structurally characterized by UPLC-DAD-MS and 1D/2D NMR spectroscopy. Functional assays demonstrated that these compounds inhibit DENV replication, as evidenced by marked reductions in viral RNA levels, NS1 and NS3 protein expression, and infectious viral titers. Stage-specific analyses revealed that their antiviral activity is primarily associated with intracellular phases of the viral life cycle, consistent with inhibition of viral replication and/or protein processing. Molecular docking analyses supported these findings by predicting favorable interactions with key viral enzymes, particularly NS5 RNA-dependent RNA polymerase and NS3 helicase/protease. Importantly, the isolated compounds retained antiviral activity against ZIKV and CHIKV, indicating cross-arboviral efficacy. Together, these findings identify spirostane saponins as promising antiviral scaffolds and support their further development as broad-spectrum antiviral agents.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and cholinergic dysfunction is considered one of the fundamental pathological factors of this disease. Guided by the clinically used acetylcholinesterase (AChE) inhibitor donepezil, we explored trimetazidine dihydrochloride as an accessible starting scaffold to generate donepezil-like features and to develop new anti-AD candidates. Accordingly, 20 novel hydrazone derivatives were designed and synthesized based on trimetazidine dihydrochloride, and their structures were confirmed by spectroscopic methods. The compounds were evaluated for in vitro inhibition of AChE and butyrylcholinesterase (BChE) using donepezil and tacrine as reference inhibitors, respectively. Several derivatives displayed pronounced AChE inhibition, whereas most compounds showed weak or negligible activity toward BChE, indicating a generally favorable AChE-selective profile. Among the series, compounds 3p, 3q and 3r exhibited selective inhibitory activity against AChE comparable to donepezil, with IC50 values of 0.030 ± 0.001 μM, 0.085 ± 0.003 μM and 0.034 ± 0.001 μM, respectively. To rationalize the observed activity trends, molecular docking studies were performed, suggesting that the most active ligands adopt donepezil-like binding modes spanning the catalytic and peripheral anionic sites and are further stabilized by π-π/π-cation contacts and hydrogen-bonding interactions within the active gorge. Overall, these findings identify trimetazidine-derived hydrazide-hydrazones as a promising chemotype for the development of selective AChE inhibitors and provide a basis for further optimization and advanced biological validation.

Multi-drug insensitivity (MDI) to various antibiotics and the rapid dissemination of antibiotic resistance markers among the microorganisms, particularly bacteria, has become a global concern. Annually, MDI microorganisms cause 7 × 10[6] deaths worldwide, which are expected to increase in an exponential manner in the future. The development of novel drugs for MDI microorganisms is very demanding, often taking approximately 17 years to complete. Drug repurposing refers to the discovery of drugs for MDI microorganisms from drugs that are already approved for the treatment of other diseases. Drug repurposing has emerged as an alternative approach to tackling MDI microorganisms because it decreases the duration and cost of the drug. Among various non-antibiotic compounds, psychotropic drugs have been found to be effective against drug-resistant Gram-positive and Gram-negative pathogens, fungi, parasites, and viruses. Innumerable reports have been published about the antimicrobial potential of psychotropic drugs against HAIs caused by various pathogens through various mechanisms, and they are helpful in lowering complications associated with these infections. The objective of the current perspective review is to highlight all available data on psychotropic drugs' antimicrobial activity, discussing the molecular targets of psychotropic drugs and the impact of psychotropic drugs on the gut microbiome.

Pectolinarigenin (PEC) is a natural flavonoid compound derived from Chinese herbal medicines. Previous studies have demonstrated its significant inhibitory effects against various malignancies. However, the effect and molecular mechanism of PEC in esophageal squamous cell carcinoma (ESCC) as well as its potential for combination with clinical chemotherapeutics for ESCC treatment is still obscure. Here, we systematically explored the anti-ESCC effects of PEC, elucidated its molecular mechanism, and evaluated its synergistic therapeutic potential with paclitaxel (PTX), a first-line chemotherapeutic agent for ESCC. The results showed that PEC obviously restrained proliferation and migration, and induced apoptosis of ESCC cells. Mechanistically, we found that PEC targets the non-canonical pathway of NF-κB, specifically preventing nuclear translocation of p52 and RELB, thus suppressing the transcriptional activity of this pathway. Moreover, we confirmed that PEC markedly inhibited tumor growth and exhibited a strong synergistic effect on the progression of ESCC when combined with PTX using a xenograft model of nude mice. Our research results have revealed a new molecular mechanism for the anti-ESCC efficiency of PEC. This study highlights PEC potential as a promising candidate for ESCC monotherapy or combination therapy with PTX and points out a new strategy for the clinical treatment of natural flavonoids to ESCC.

Chemotherapy-induced adverse effects and drug resistance remain major obstacles limiting the therapeutic efficacy of cancer treatment, underscoring an urgent need for novel anticancer agents. Among promising candidate molecules, antimicrobial peptides (AMPs) exhibit considerable therapeutic potential owing to their unique mechanisms of action, potent anticancer activity, minimal off-target toxicity, and low propensity to induce drug resistance. In this review, we summarize recent advances in the anticancer properties of AMPs, with a focus on their effects on both cancer cells and immune cells across diverse cancer types, clinical applications, as well as current challenges and future prospects. This review highlights the promise of AMPs as highly effective anticancer candidates for combination cancer therapy.