搜索结果：Frontiers in pharmacology

Protein tyrosine phosphatase non-receptor type 12 (PTPN12), a crucial enzymatic protein involved in cellular signaling, remains understudied in colorectal cancer (CRC). This study investigates this biological macromolecule's potential as a biomarker, examining its protein-protein interactions, therapeutic relevance, and immunomodulatory functions in CRC. We conducted a comprehensive analysis of PTPN12 using public datasets and clinical samples. Bioinformatics tools were employed to predict regulators and signaling pathways associated with PTPN12. Immune infiltration analysis and re-analysis of publicly available single-cell RNA sequencing (scRNA-seq) datasets were performed to explore the immunomodulatory role of PTPN12. The relationship between PTPN12 protein levels and drug susceptibility was evaluated. Functional assays validated PTPN12's role in CRC cells and its impact on oxaliplatin resistance. PTPN12 protein is significantly upregulated in CRC tissues, with its elevated expression correlating with poor prognosis. PTPN12 correlates with increased genomic instability. PTPN12 is involved in various biological processes, including the regulation of cellular and developmental processes. Furthermore, high PTPN12 expression is positively correlated with stromal cell infiltration, suggesting a potential role in modulating the immune response. These findings collectively suggest that PTPN12 may have potential as a therapeutic candidate and immunotherapy-related biomarker. Knockdown of PTPN12 inhibited CRC cell proliferation, migration, and invasion. Notably, PTPN12 protein was overexpressed in oxaliplatin-resistant CRC cells, and its inhibition restored chemosensitivity in in vitro models.​. PTPN12 shows promise as a potential biomarker and therapeutic target candidate in CRC. Our study provides preliminary insights into the role of PTPN12 in CRC pathogenesis, treatment response, and chemoresistance, which may lay the groundwork for future development of personalized therapeutic strategies pending further in vivo validation.

Knee osteoarthritis (KOA) is a degenerative bone and joint disease. Jingu Zhitong Gel (JGZTG) exhibits a promising therapeutic effect in the clinical treatment of knee osteoarthritis (KOA). However, the mechanism of JGZTG in treating KOA remains unclear. We established a rat model of KOA through surgery and treated rats with JGZTG for 21 days. The pain threshold was measured by the Ugo Basile joint pain tester, the weight bearing on the right foot was detected by a bipedal balance tester, the inflammatory factor levels were measured by ELISA kits, and the joint morphology score was evaluated. Hematoxylin and eosin staining (H&E) was used to evaluate the pathological lesions, while toluidine blue staining was used to observe the proteoglycan depletion. Transcriptomic analysis was conducted to elucidate the potential mechanisms of JGZTG in treating KOA. Real-time quantitative Polymerase Chain Reaction (RT-qPCR), and immunofluorescence (IF) assays were conducted to validate transcriptomic results and investigate the analgesic mechanisms. After 21 days of treatment, JGZTG significantly increased the pain threshold and the weight bearing on the right foot in KOA rats, furthermore, reduced the levels of inflammatory factors (TNF-α, IL-6, IL-1β, and PGE2) in the serum and joint lavage fluid. In addition, JGZTG significantly decreased the joint morphology score, reduced synovial damage, alleviated cartilage injury, and reduced proteoglycan depletion in KOA models. The results of transcriptomic analysis showed that the anti-inflammatory effect of JGZTG in treating KOA was associated with the IL-17 signaling pathway. Further validation revealed that the relative mRNA and protein expression of IL-17RB, FosB, MMP1b, MMP3, MMP13, CCL17, and CXCL6 were regulated by JGZTG. In addition, JGZTG can reduce the mRNA and protein overexpression of NGF, Ntrk1, Trpv1, Ptgs2, PGE2, EP4, TAC1, and Calca, which are the key factors of the NGF-TrkA and COX-2/PGE2 pathways. JGZTG exhibits pain-relieving and anti-inflammatory effects in KOA, which were linked to altered IL-17, NGF-TrkA, and COX-2/PGE2 pathways. These findings have provided experimental evidence for the mechanisms underlying the therapeutic effects of JGZTG in KOA.

Physiological changes during pregnancy substantially alter opioid pharmacokinetics, yet clinical pharmacokinetic data in pregnant populations remain limited. Pharmacometric modeling using population pharmacokinetic (PopPK) and physiologically based pharmacokinetic (PBPK) approaches offers a quantitative framework to characterize these changes and to estimate maternal and fetal drug exposure. Despite increasing application of these methods, the methodological quality, reproducibility, and clinical relevance of existing opioid models in pregnancy have not been systematically evaluated. This systematic review aimed to critically appraise published PopPK and PBPK models of opioid medications in pregnancy, identify recurring structural and methodological features, and outline priorities for improving model development and reporting. A structured PubMed search (database inception to September 2025) identified studies modeling opioid disposition in pregnant individuals using PopPK or PBPK frameworks. Data on model structure, parameterization, assumptions, evaluation strategies, and reported limitations were extracted and synthesized. Ten studies met inclusion criteria, with fentanyl having the most studies. PopPK analyses consistently identified pregnancy as a significant covariate associated with increased clearance. PBPK models showed substantial heterogeneity in physiological detail, ranging from simplified fetoplacental compartments to permeability-limited placenta representations and multi-compartment fetal systems. Reproducibility emerged as a concern, with at least one PBPK model unable to be independently replicated due to incomplete reporting. Across studies, common gaps included limited verification datasets, incomplete representation of gestational physiology, and reliance on single-time-point umbilical cord concentrations at delivery. Overall, pharmacometric modeling provides valuable mechanistic insight into opioid disposition during pregnancy, but its translational impact is constrained by inconsistent reporting practices, sparse empirical data, and limited incorporation of fetal and neonatal exposure. Future progress will be accelerated by standardized documentation, improved pregnancy-specific physiological data, integration of genetic and developmental variability, and closer linkage between pharmacokinetics and clinically relevant outcomes to support model-informed perinatal opioid therapy.

Renal cell carcinoma (RCC) is a highly heterogeneous malignant tumor, characterized by a globally increasing incidence and mortality rate. Although surgical resection serves as the standard treatment for localized RCC, recurrence and metastasis remain major clinical challenges. Based on patient sample analysis and signaling pathway investigation, the present study identifies peroxiredoxin 1 (PRDX1) as a potential therapeutic target for RCC. Patient microarray analysis, combined with data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, revealed the expression pattern of PRDX1 in clear cell renal cell carcinoma (ccRCC) and confirmed its prognostic and diagnostic significance. Cell proliferation was evaluated using Cell Counting Kit-8 (CCK-8) assay, while cell motility was assessed via wound healing and transwell assays. Gene expression profiles and signaling pathways were analyzed through bioinformatics approaches including Western blot, immunohistochemistry and immunoprecipitation. A xenograft mouse model was utilized to investigate the in vivo effects of PRDX1. The analysis of 90 pairs of ccRCC samples demonstrated that elevated PRDX1 expression was significantly associated with higher malignancy in ccRCC and correlated with tumor prognosis and clinical stage. Comprehensive bioinformatics analysis identified a close relationship between PRDX1 inhibition and relative epidermal growth factor receptor (EGFR) pathways. Mechanistically, co-immunoprecipitation (Co-IP) assays revealed that PRDX1 could act as a molecular chaperone by binding to the juxta-membrane (JM) domain of EGFR to induce EGFR phosphorylation. The downregulation of PRDX1 significantly reduced their proliferation and migration capacities in renal cell lines ACHN and 786-O, whereas PRDX1 overexpression exerted the opposite effect. Importantly, the inhibitory effects of PRDX1 knockdown on ccRCC could be attenuated by EGF activation in vitro, as well as the oncogenic functions enhanced by increasing PRDX1 was blocked by gefitinib, a specific inhibitor of EGFR. Treatment with PRDX1 inhibitor showed that PRDX1 inhibition restrain the growth and metastasis of ccRCC. In summary, the findings of this study revealed a novel role of PRDX1 in triggering ccRCC progression by inducing the phosphorylation of EGFR, supporting that PRDX1 may serve as a potential therapeutic target for the clinical management of ccRCC.

Verbascum thapsus L. is a prized medicinal plant from the Kashmir Himalaya traditionally utilized to treat many ailments, yet its active metabolites against antimicrobial mechanisms remain unclear. This work envisages an integrated in-silico and in-vitro approach to mechanistically investigate broad-spectrum antimicrobial activity of carpachromene, a supradecorated phytochemical from V. thapsus. Carpachromene was isolated through cold extraction from V. thapsus, followed by silica gel column chromatography with an optimized polarity solvent system, yielding a whitish amorphous solid confirmed by XRD, FTIR, 1H NMR and 13C NMR spectroscopy. In-silico analyses encompassed molecular docking of carpachromene against key microbial drug targets like sterol 14-α demethylase (CYP51), Dihydropteroate synthase (DHPS), GyrB ATPase domain, and Penicillin-Binding Protein 1 (PBP-1) followed by 100 ns molecular dynamics simulations assessing RMSD, RMSF, dynamic cross-correlation matrix (DCCM), principal component analysis (PCA), radius of gyration (Rg), and solvent accessible surface area (SASA). In-vitro antimicrobial activity was assessed using the agar well-diffusion method against clinical isolates: bacterial pathogens (Escherichia coli OP268610, Staphylococcus aureus OP268597, Salmonella enterica OP268585, Pseudomonas aeruginosa OP268614, Klebsiella pneumoniae OP268611, Bacillus cereus OP268602) and fungal pathogens (Aspergillus niger MTCC183, A. fumigatus MTCC282, Candida albicans MTCC343), evaluating concentration-dependent inhibition zones relative to standard controls (ciprofloxacin for bacteria; fluconazole for fungi). Docking studies revealed robust binding affinities for carpachromene, ranging from -9.3 to -10.5 kcal/mol across targets (CYP51: -10.5 kcal/mol; E. coli DHPS: -9.6 kcal/mol; S. aureus GyrB: -9.4 kcal/mol; PBP-1: -9.3 kcal/mol) driven by hydrogen bonding (e.g., with active-site residues like Asp 73, Thr 165, Gly 77 in GyrB ATPase) and other hydrophobic interactions. MD simulations affirmed complex stability (RMSD: 1.2-1.5 Å; RMSF: 0.69-1.07 Å), with persistent intermolecular contacts, and coordinated residue motions via DCCM/PCA. In-vitro results revealed potent, dose-dependent activity, yielding maximum inhibition zones of 21 mm against S. enterica (50 μg/mL) and 10 mm against C. albicans. The mechanistic insights from computational analysis corroborated with in-vitro observations, highlighting carpachromene as a promising multi-target antimicrobial scaffold. These findings support supradecoration strategies for advancing carpachromene toward novel drug development against antimicrobial resistance.

Curcuma caesia Roxb (Black Turmeric) is an underexploited medicinal species with recognized ethnobotanical use in gastrointestinal disorders. This study integrates morphological characterization, validated camphor quantification, and computational anti-ulcer evaluation across 21 genotypes collected from diverse Indian agro-climatic zones. Genotypes were cultivated at Coimbatore and Bhavanisagar and characterized using DUS guidelines. Significant morphological variation was observed in plant height (27.81-107.08 cm), rhizome traits, and essential oil yield (0.20%-0.62%), indicating high genetic diversity. GC-MS profiling identified 30 bioactive metabolites, with camphor emerging as the predominant constituent. Quantification using D-camphor standard revealed substantial genotypic variation in camphor content, ranging from 5.19% (GKK-6) to 33.84% (GTE-18), with high concentrations also recorded in GMR-2 (30.35%), GMN-10 (26.41%), and GCA-5 (24.44%). Molecular docking studies against ulcer-associated targets predicted camphor's superior binding affinity for MMP9 (-7.8 kcal/mol) compared to ranitidine (-6.3 kcal/mol), with stable hydrogen bonding interactions involving TYR A:111 and TYR A:458. Molecular dynamics simulations over 100 ns confirmed stable camphor-MMP9 interactions with minimal RMSD deviation (0.20-0.25 nm) and persistent hydrogen bonding, providing computational support for investigating its potential gastroprotective role in mucosal healing. While in silico predictions suggest plausible mechanisms aligning with traditional ethnomedicinal use, these computational findings require experimental validation through in vitro enzyme inhibition assays and in vivo gastric ulcer models. This study provides a phytochemical and computational foundation for hypothesis-driven investigation of camphor's potential gastroprotective properties, identifying elite C. caesia genotypes (GTE-18, GMR-2, GMN-10) for breeding programs targeting enhanced camphor content and subsequent biological validation.

Cisplatin-induced nephrotoxicity is a major dose-limiting complication of chemotherapy. However, effective protective strategies remain limited. Licochalcone A (LicoA), a flavonoid isolated from Glycyrrhiza inflata, exhibits multi-target bioactivity against oxidative stress, inflammation, and metabolic disorders. In vivo murine cisplatin-induced model and in vitro HK-2 cells were employed. HE/Masson staining, renal function, oxidative stress, ferroptosis markers (Fe2+, GSH, MDA, lipid peroxidation), and mitochondrial health were assessed. Mechanistic studies were conducted using metabolomic approaches, molecular docking, cellular thermal shift assay, Western blot, immunofluorescence, and Nrf2-knockdown assays. LicoA significantly ameliorated cisplatin-induced renal dysfunction and attenuated the progression from acute kidney injury (AKI) to chronic kidney disease (CKD), as evidenced by reduced tubular injury and fibrosis. Metabolomic analysis revealed that LicoA restored energy metabolism and glutathione homeostasis. LicoA effectively alleviated cisplatin-induced ferroptosis by inhibiting Fe2+ accumulation, reducing lipid peroxidation, restoring cellular redox homeostasis, and consequently diminishing membrane blistering. Molecular docking and cellular thermal shift assay confirmed the binding affinity between LicoA and both Nrf2 and GPX4. Crucially, Nrf2 knockdown abolished the protective effects of LicoA, demonstrating the essential role of the Nrf2 pathway. LicoA alleviated cisplatin-induced renal injury by activating the Nrf2/GPX4 axis, thereby suppressing ferroptosis and mitigating mitochondrial damage. These findings highlight the therapeutic potential of LicoA in preventing cisplatin nephrotoxicity and impeding the AKI-to-CKD transition.

Acute Kidney Injury (AKI) is a critical clinical syndrome with high morbidity and mortality, yet effective therapeutic agents are lacking. The Rheum-Salvia miltiorrhiza (R-S) combination, a traditional Chinese herbal pair, has been used to treat acute kidney injury, but its mechanisms remain unclear. This study aimed to evaluate the nephroprotective effects of the R-S combination on cisplatin-induced AKI and to elucidate its underlying mechanisms through integrated multi-omics analyses. Male C57BL/6 mice were randomly divided into five groups: Control group (Control), AKI model group (Model), Rheum-S. miltiorrhiza low-dose group (R-S-low), Rheum-S. miltiorrhiza high-dose group (R-S-high), and curcumin group (Cur). AKI was induced by a single intraperitoneal injection of cisplatin (15 mg/kg). After the experiment, renal function was assessed by measuring serum creatinine (Cr) and blood urea nitrogen (BUN). Inflammatory cytokines and oxidative stress markers were detected using ELISA. Histopathological changes of the kidney tissue were evaluated by H&E staining. Gut microbiota composition, the cecal content metabolome and the renal transcriptome were further analyze. The MAPK signaling pathway in renal tissue was examined via RT-qPCR and Western blot. R-S treatment significantly improved renal function, lowering Cr and BUN, and attenuated renal histopathological injury. It also reduced oxidative stress and inflammation, elevating SOD and GSH, while decreasing IL-1β and TNF-α. Gut microbiota analysis showed that R-S restored microbial diversity, suppressed Escherichia-Shigella, and promoted Lachnospiraceae_NK4A136_group. Metabolomics identified 1237 differential metabolites, with enrichment in linoleic acid metabolism. Transcriptomics revealed 3530 differentially expressed genes, primarily associated with the MAPK signaling pathway. Molecular validation confirmed that R-S downregulated the mRNA expression of IL-1β, IL-6, TNF-α, MAPK 14, MAPK 8, NFKB 1, FOS, and JUN, and suppressed the phosphorylation of p38 MAPK, JNK, and NF-κB p65. The R-S combination alleviates cisplatin-induced AKI by modulating the gut microbiota, regulating metabolic profiles, and suppressing the MAPK signaling axis. This study provides a holistic, multi-omics perspective on the mechanisms of R-S, supporting its potential as a therapeutic agent for AKI.

Sepsis-induced acute lung injury (ALI) is a life-threatening condition with limited therapeutic options. The mitochondrial protein NOD-like receptor X1 (NLRX1) has emerged as a potential immunometabolic modulator, but its functional role and mechanism in septic ALI remain poorly defined. Bioinformatic analysis was performed on the GSE4607 sepsis dataset. A murine model of sepsis-induced ALI was established using cecal ligation and puncture (CLP), with NLRX1 overexpression achieved through adeno-associated virus serotype 9 (AAV9)-mediated gene delivery. Histopathological evaluation, TUNEL staining, and transmission electron microscopy, ELISA were employed to assess lung injury. Mouse lung epithelial cells (MLE-12) were stimulated with lipopolysaccharide (LPS), combined with NLRX1 overexpression and Mdivi-1-mediated mitophagy inhibition to explore the key mechanism by which NLRX1 improves ALI. NLRX1 was significantly downregulated in septic patients and mouse lungs, correlating with mitochondrial damage and NOD-like receptor protein 3 (NLRP3) inflammasome activation. NLRX1 overexpression in CLP mice attenuated pulmonary injury, edema, inflammation, and systemic cytokine release by enhancing mitophagy and suppressing apoptosis. Mechanistically, NLRX1 directly interacted with LC3B to promote mitophagy, thereby preserving mitochondrial membrane potential, reducing superoxide production and mtDNA release, and maintaining ATP levels. By improving mitochondrial homeostasis, NLRX1 overexpression indirectly suppressed NLRP3 inflammasome activation and pyroptosis. Crucially, the mitochondrial fission and mitophagy inhibitor Mdivi-1 abolished all beneficial effects of NLRX1, underscoring the essential role of comprehensive mitochondrial quality control. Our findings identify NLRX1 as a critical protective regulator of mitochondrial integrity that alleviates septic ALI by orchestrating mitophagy and mitochondrial quality control to restrain NLRP3-driven inflammation, presenting a promising therapeutic target.

In humans, empathy is expressed through various prosocial behaviours between individuals that may be enhanced after intake of the synthetic entactogen MDMA (3,4-methylenedioxymethamphetamine, "Ecstasy") as the behavioural expression of the so-called entactogenic syndrome. Rodents may also exhibit empathy-like behaviours, such as social interaction and helping behaviour. In this regard, while social interaction has been reported to be enhanced by MDMA, the effects of this drug on helping behaviour remain unexplored. Nevertheless, because helping behaviour is considered as part of the prosocial repertoire, it may be hypothesised that MDMA should enhance it. In the present study, the evaluation of a subtoxic dose range (0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 5 mg/kg, and 10 mg/kg i.p.) of MDMA on helping behaviour in adult male rats has been conducted using a standardised behavioural setup based on the intrinsic aversion of these animals to water. In addition, as helping behaviour may require a complex interaction between motivational and higher cognitive processes, the neuroplastic effects of MDMA (10 mg/kg i.p.) on cortical and subcortical loci were studied in vivo in anaesthetised rats. Behavioural data indicated that 5 mg/kg and 10 mg/kg of MDMA fully suppressed helping behaviour; 1 mg/kg and 0.5 mg/kg induced partial inhibition only after interchanging roles; and 0.25 mg/kg had no effect. The inhibitions observed at the highest doses (5 mg/kg, and 10 mg/kg) were not reversed after interchanging roles. Electrophysiological data showed that MDMA reinforced long-term depression (LTD) elicited in the nucleus accumbens (NAc) core following stimulation of the dorsal raphe nucleus (DRN). In addition, MDMA increased transcallosal-evoked long-term potentiation (LTP) in the anterior cingulate cortex (ACC) in a serotonin (5-HT)- and oxytocin (OXT)-dependent manner. Taken together, these data support the notion that MDMA disrupts helping behaviour, even though the neuroplastic effects elicited by the drug align with the mechanisms described to promote prosocial/empathic behaviours. The results may suggest a negative modulation of MDMA on neural processes that are essential for the execution of helping behaviour without affecting the willingness to help.

Type 2 asthma is characterized by airway inflammation, mucus hypersecretion, and remodeling, and circadian rhythm dysregulation is implicated in its pathogenesis. Melatonin, a key circadian hormone, modulates inflammatory signaling, but its role in type 2 airway inflammation remains unclear. This study investigated whether melatonin alleviates airway inflammation and epithelial-mesenchymal transition (EMT) through the melatonin receptor 1 (MT1)-Sirtuin 1 (Sirt1) signaling pathway and circadian clock regulation. An ovalbumin (OVA)-induced mouse model of type 2 airway inflammation and cultured airway epithelial cells were used. Lung structural remodeling and mucus production were evaluated using hematoxylin and eosin, Masson's trichrome, and periodic acid-Schiff staining. Airway inflammation was assessed by differential inflammatory cell counts in bronchoalveolar lavage fluid. The mRNA and protein expression of circadian clock genes (CRY1 and PER1) and key components of the MT1-Sirt1 pathway were assessed by quantitative real-time PCR, Western blotting, and immunohistochemistry. EMT-related markers were further examined to explore downstream mechanisms. Melatonin treatment activated MT1-Sirt1 signaling and reduced the expression of circadian clock genes CRY1 and PER1. These effects were accompanied by decreased airway inflammation, reduced mucus production, and attenuation of epithelial-mesenchymal transition (EMT) in airway epithelial cells, all of which reached statistical significance. Our findings identify a novel MT1-Sirt1-circadian gene regulatory axis through which melatonin mitigates type 2 airway inflammation and airway remodeling. These results highlight the therapeutic potential of melatonin for type 2 asthma. Limitations include the use of a single animal model and analysis at a single time point.

While glia-derived exosomes have been extensively studied in heatstroke induced brain injury, the role of exosomal microRNAs (miRNAs) secreted by astrocyte remains underexplored. In this study, the viability of C8-D1A cells decreased after heat stress, apoptosis rate and the expression levels of proinflammatory cytokines such as TNF-α, IL-6, IL-1α and IL-1β increased to different degrees. The extracellular vesicles obtained by ultracentrifugation were identified via transmission electron microscopy (TEM), nanoparticle tracking technology Nanoparticle tracking analysis, and nanoflow cytometry (nanoFCM), which was consistent with the characterization of the exosomes. In the following sections, the collected EVs will be referred to as exosome-enriched preparations. Exosome-enriched preparations's miRNA sequencing identified 23 differentially expressed miRNAs. Further functional analysis via gene ontology enrichment revealed that 46 genes regulated cell death and that 38 genes were involved in neuronal apoptosis. Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis revealed that the main enriched signalling pathways were involved in biological processes such as apoptosis, inflammation, and oxidative stress. Among them, miR-712-3p was the most upregulated miRNA in the heat stress group. MiR-712-3p was overexpressed and inhibited by intranasal administration in vivo and cell transfection in vitro, and it was found that miR-712-3p could reduce brain injury and improve neuronal activity under heat stress. Moreover, RNA sequencing of neurons and transmission electron microscopy revealed that miR-712-3p can affect lysosomal function. Differential expressed genes can be involved in specific lysosome-related processes, and we predicted Atp6v1c1 associated with miR-712-3p as a candidate gene through the miRDB database. Collectively, our findings demonstrate that miR-712-3p ameliorates heat stroke-induced brain injury, with this protective effect being linked to the modulation of neuronal lysosomal function. Furthermore, the study confirms the involvement of astrocyte-derived exosome-enriched preparations in mediating this protective effect in vitro.

Medical aesthetic dermatology is expanding rapidly in response to increasing demand for minimally invasive interventions and advanced topical therapies. The clinical performance of conventional dermatological formulations is frequently limited by inadequate skin penetration, poor stability of active ingredients, rapid degradation, and dose-related adverse effects. Nanotechnology-based drug formulation and delivery systems offer a translational solution to these challenges by enabling targeted, controlled, and sustained delivery of bioactive compounds to specific skin layers and appendages. Nanoscale carriers-including lipid-based systems, polymeric nanoparticles, nanoemulsions, and inorganic or hybrid nanomaterials-enhance dermal and follicular deposition, improve physicochemical stability, and modulate release kinetics of therapeutic and cosmeceutical agents. These mechanisms have facilitated improved outcomes across key aesthetic indications, including skin rejuvenation, pigmentary disorders, acne, hair restoration, and injectable aesthetic interventions. Emerging clinical and preclinical evidence suggests improved local efficacy and potentially reduced irritation and systemic exposure compared with conventional formulations, although further well-controlled clinical studies are required to confirm these benefits. Safety, toxicological behavior, and regulatory considerations remain critical determinants of successful clinical translation, particularly with respect to long-term exposure and nanoparticle-skin interactions. Integration of pharmacological mechanisms with clinical performance highlights the growing role of nanotechnology in redefining therapeutic strategies within medical aesthetic dermatology and supports its continued development within evidence-based translational pharmacology frameworks.

White matter is vulnerable to early ischemic injury. The susceptibility of oligodendrocytes to ischemic damage can lead to demyelination, axonal degeneration, and neurological deficits, making them a key focus for understanding and developing therapies for stroke-related brain injury. In this study, we aimed to investigate how cell metabolism contributes to oligodendrocyte survival and white matter integrity maintenance following ischemia. NCT-503 was injected after inducing transient middle cerebral artery occlusion. After reperfusion, brain infarct volume and neurobehavioral deficits and behaviour performance were assessed. Immunofluorescence staining was performed to evaluate oligodendrocytes death. Cell viability was measured using the CCK8 assay. Flow cytometry analysis was conducted to examine reactive oxygen species (ROS) levels. De novo serine synthesis pathway enzyme phosphoglycerate dehydrogenase (PHGDH) was hardly expressed in neurons, microglia and oligodendrocyte precursor cells (OPCs) but selectively expressed in mature oligodendrocytes and astrocytes. Brain ischemic injury specifically enhanced the expression of PHGDH in oligodendrocytes. PHGDH inhibition with NCT-503 did not affect acute neuronal injury but worsened sensorimotor and cognitive functional outcomes after ischemic stroke. Moreover, white matter integrity and oligodendrocyte survival were specifically reduced after PHGDH inhibition and serine supplementation facilitated oligodendrocyte survival and enhanced white matter integrity, and consequently improved neurological functions. Mechanistically, PHGDH-mediated serine synthesis protected oligodendrocytes from oxidative stress-induced death by promoting glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) production through the one-carbon metabolism pathway. This study reveals the role of PHGDH-mediated de novo serine synthesis in reducing oligodendrocyte death which may provide a potential target for improving neurological function after ischemic stroke.

Neuroimmune interactions serve as a core regulatory node of chronic pain and pruritus and a key target for clinical intervention. Lipocalin-2 (LCN2), a member of the lipocalin superfamily, is a multifunctional protein widely expressed in various tissues and cells. LCN2 exerts diverse biological effects by regulating iron metabolism, mediating inflammatory responses, and participating in signal transduction pathways. In recent years, accumulating evidence has indicated that LCN2 plays a crucial role in the pathogenesis of chronic pain and pruritus through neuroinflammation, neuron-glia interactions, and modulation of neural signaling. In chronic pain, LCN2 contributes to the development and maintenance of inflammatory pain, neuropathic pain, morphine tolerance, and thalamic pain by disrupting iron homeostasis, inducing oxidative stress, and promoting central sensitization. For chronic pruritus, LCN2 modulates the excitability of pruritus-related neurons via pathways such as the IL-6/STAT3 axis, and participates in the pathological processes of pruritus in allergic contact dermatitis, xerosis, atopic dermatitis, and psoriasis. This review summarizes the structural characteristics, physiological functions of LCN2, and its specific mechanisms in regulating chronic pain and pruritus, and further discusses the potential therapeutic value of targeting LCN2, aiming to provide a theoretical basis for the development of novel interventions for chronic pain and pruritus.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a complex pathological process, in which oxidative stress serves as a key pathogenic mechanism. Studies have shown that the anesthetic adjuvant dexmedetomidine (Dex) can improve postoperative cognitive function in AD patients. This study aimed to explore whether dexmedetomidine alleviates AD-associated neuronal apoptosis and cognitive impairment via reducing overproduction of ROS and regulating the XIAP signaling pathway. In vitro experiments were conducted using Aβ1-42-exposed SH-SY5Y cells and primary neurons, employing interventions such as the ROS scavenger NAC, yohimbine pre-treatment, and siRNA-mediated XIAP knockdown. In vivo cognitive deficits and brain pathology were evaluated in AD model mice using Morris water maze tests and immunofluorescence staining. Experimental results demonstrated that Aβ1-42 induced apoptosis in neuronal cells, while dexmedetomidine incubation significantly reduced Aβ1-42 elicited ROS generation, activated XIAP, suppressed MDM2 and ameliorated P53 overactivation, thereby effectively preventing neuronal death. Combined administration of NAC and dexmedetomidine reversed Aβ1-42-induced XIAP inhibition, ROS accumulation, and cell apoptosis. Furthermore, both yohimbine pre-treatment and XIAP knockdown effectively abrogated the ability of Dex to reduce ROS accumulation and mitigate apoptosis. In vivo results indicated that dexmedetomidine improved cognitive deficits and intervened in AD pathology in the hippocampal region of AD model mice. This study reveals that dexmedetomidine inhibits ROS release and activates the XIAP-MDM2-p53 signaling pathway, thereby delaying apoptosis and ameliorating cognitive impairment in AD progression.

Zapnometinib (ATR-002) is a selective MEK inhibitor designed to modulate the MAPK/ERK pathway, which plays a key role in viral infections and inflammatory diseases. Clinical characterization of its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) is essential to support further development. This Phase I clinical trial was registered under EudraCT number 2021-005225-25. This was a Phase I, single-center, randomized, double-blind, placebo-controlled trial conducted in healthy adults. The study included three parts: a single ascending dose (SAD) phase, a multiple ascending dose (MAD) phase, and a drug-drug interaction (DDI) as well as a food-drug interaction (FDI) phase. In the SAD phase, 42 participants received single oral doses of 600, 900, 1,200, or 1,500 mg. In the MAD phase, 29 participants received daily oral doses of 900, 1,200, or 1,500 mg for 7 days. The DDI phase assessed the effect of zapnometinib on CYP2C8 and CYP2C9 activity using repaglinide and celecoxib as probe substrates. Zapnometinib was well tolerated with no serious adverse events reported. Most treatment-emergent adverse events (TEAEs) were mild to moderate, including gastrointestinal symptoms (e.g., diarrhea, nausea) and headache. PK analysis showed dose-proportional increases in Cmax and AUC, with a notable food effect that increases bioavailability. PD evaluation demonstrated significant MEK inhibition, evidenced by reduced ERK phosphorylation. This phase 1 study demonstrates that zapnometinib has a favorable safety and tolerability profile, predictable pharmacokinetics, and potent pharmacodynamic activity. The results support further clinical development of zapnometinib for therapeutic indications involving dysregulated MAPK/ERK signaling.

Traumatic brain injury (TBI) is a major risk factor for major depressive disorder (MDD), yet the underlying mechanisms remain poorly defined. This study demonstrates that toll-like receptor 4 (TLR4) activation drives depressive-like behaviors through dysregulation of the kynurenine pathway (KP) in a murine model of moderate TBI. Using male C57BL/6J mice subjected to controlled cortical impact, we observed depression-like phenotypes (reduced sucrose preference, prolonged immobility in forced swimming tests) specifically at 28 days post-TBI, with an incidence of 28.13%. Proteomics and immunofluorescence analyses revealed significant upregulation of hippocampal TLR4 expression and signaling pathway activation, concomitant with microglial activation. Crucially, the TLR4-specific inhibitor TAK-242 (administered i.p. from days 21-28 post-TBI) ameliorated depressive behaviors and suppressed phosphorylation of NF-κB p65. Mechanistically, TBI induced microglia-dependent upregulation of key KP enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and kynurenine monooxygenase (KMO), leading to accumulation of the neurotoxic metabolite quinolinic acid (QUIN). This TLR4-KP axis was validated in vitro: LPS-stimulated BV2 microglia showed increased IDO1/KMO/QUIN expression, which was abolished by TAK-242 pretreatment. Our findings establish a novel TLR4-KP-QUIN pathway as a critical mediator of post-TBI depression, providing a mechanistic basis for TLR4-targeted therapies. In addition to neuroinflammatory effects, this work mainly mediates dysregulation of TBI-related neuropsychiatric sequelae through metabolism, highlighting TLR4 inhibition as a promising strategy for mitigating chronic depressive outcomes after brain injury.

Polysaccharides comprise a structurally varied class of natural macromolecules found in plants, fungi, animals, marine algae, and microorganisms. Therefore, they have attracted considerable attention over several decades due to numerous anticancer-associated activities indicated by accumulating in vitro and in vivo evidence, along with clinical data of heterogeneous maturity-ranging from well-established adjuvants such as lentinan and PSK, which have demonstrated survival benefits in randomized controlled trials, to early-phase exploratory studies for agents like fucoidan. Traditional chemotherapeutic agents (e.g., alkylating agents, antimetabolites) exert direct cytotoxic effects; however, many contemporary small-molecule drugs-such as kinase inhibitors and hormone receptor modulators-act through targeted inhibition of oncogenic signaling, and immunotherapies (e.g., checkpoint inhibitors) function by enhancing endogenous anti tumor immunity rather than directly damaging tumor cells, as cytotoxic agents do. By contrast, polysaccharides are increasingly recognized as biological response modifiers that exert an impact on cancer development through, for instance, immune system functioning, redox, and/or inflammatory balance, communications between cancer and stromal cells of the tumor microenvironment, and intracellular signaling cascades. This review presents an outline of the structural variability, physiological sources, and functions of polysaccharides relevant to cancer treatment. Based on the present armamentarium of polysaccharides, the main modes of action are summarized in terms of immunomodulation through the engagement of pattern-recognition receptors, oxidative stress and inflammation regulation, quantifiable programmed cell death modes, angiogenesis and metastasis, and indirect regulation of oncogenic signaling pathways. These are first expressed in terms of the target-unrelated context and at the network level. Finally, we briefly discuss recent developments regarding polysaccharides as coadjuvants in chemotherapy, radiotherapy, and immunotherapy, in addition to their status as potential biomaterials in novel drug delivery systems. Critical reviews of relevant issues regarding structural heterogeneity and reproducibility, pharmacokinetics, and clinical translation are given. Indeed, this review presents polysaccharides as multi-functional components in multi-dimensional cancer therapy, paying due attention to appropriate structural elucidation, mechanism validation, and systems-oriented approaches to their rational development and clinical application.