搜索结果：Translational and clinical pharmacology

Fibroblast activation protein (FAP) has emerged as a promising target for the development of cancer radiotheranostics due to its selective overexpression in cancer-associated fibroblasts (CAFs) within the tumor stroma. Affinity and selectivity refer to the binding affinities of FAP inhibitors toward FAP and related family members, whereas the accumulation of radiolabeled-FAP inhibitors varies by tumor type. Although monomeric FAP inhibitors (FAPIs) have shown extraordinary utility in diagnostic imaging, their clinical application in radiotherapy has been limited by short tumor retention times and heterogeneous uptake. To address these challenges, homomultimeric FAPI ligands-featuring two or more identical FAP-targeting motifs-have been developed with the aim of enhancing binding avidity and prolonging tumor residence. This review comprehensively examines the evolution of homomultimeric FAPI ligands, from molecular design and preclinical validation to early clinical implementation. We highlight how dimeric and higher-order multimeric constructs improve tumor retention and therapeutic efficacy compared to monomers, while also discussing the impact of linker chemistry, valency, and scaffold architecture on pharmacokinetics and targeting efficiency. Preclinical studies demonstrate that optimized dimers and trimers achieve superior tumor-to-background ratios and sustained tumor uptake, whereas excessive multimerization can lead to steric hindrance and reduced efficacy. Clinical data from pioneering studies using agents such as [177Lu]Lu-DOTAGA.(SA.FAPi)2 and [177Lu]Lu-DOTAGA.Glu.(FAPi)2 confirm prolonged tumor retention, encouraging therapeutic responses and a favorable safety profile in advanced cancers. However, translational challenges remain, including the need for better preclinical models that reflect stromal FAP heterogeneity, optimized radiometal-chelator pairs, and standardized dosing protocols for comparative clinical trials. Overall, homomultimeric FAPI ligands represent a significant advance in FAP-targeted theranostics, offering a robust platform for personalized cancer management.

Sedative-hypnotics, including benzodiazepines (BZDs) and non-benzodiazepine hypnotics (Z-drugs), are widely prescribed for insomnia and anxiety, particularly in older adults. Their long-term cognitive safety and potential association with Alzheimer's disease (AD) remain uncertain. We examined whether use of BZDs and Z-drugs is associated with incident AD and assessed variation by drug class, pharmacokinetics, and methodological factors. PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception to 16 August 2025 without language restrictions. Reference lists of eligible articles and reviews were screened. We included observational cohort and nested case-control studies enrolling adults without dementia at baseline that compared BZD or Z-drug users with non-users and reported incident AD diagnosed using validated clinical or administrative criteria (e.g., ICD-9/10, NINCDS-ADRDA, or NIA-AA). We excluded reviews, case reports, conference abstracts, studies with overlapping populations, and studies without extractable effect estimates. Two reviewers independently screened studies, extracted data, and assessed risk of bias using ROBINS-E. Random-effects meta-analyses were performed separately for odds ratios (ORs) and hazard ratios (HRs). Heterogeneity was quantified with I2. Publication bias was evaluated with funnel plots and Egger test when applicable. Subgroup and meta-regression analyses assessed clinical and methodological modifiers. Certainty of evidence was rated using GRADE. The protocol was prospectively registered (PROSPERO CRD420251141623). Thirteen studies (N = 721,354 subjects) were included. Overall sedative-hypnotic use was associated with higher odds of AD (OR 1.29; 95% CI, 1.10-1.53; I2 = 86.5%). Estimates restricted to HRs were attenuated and not statistically significant (HR 1.17; 95% CI, 0.87-1.58; I2 = 73.1%). In subgroup analyses, BZDs overall (OR 1.21; 95% CI 1.07-1.36), Z-drugs (OR 1.14; 95% CI 1.10-1.18; I2 = 0%), and short-acting agents (OR 1.19; 95% CI 1.04-1.36) were associated with higher odds of AD, whereas broad-acting BZDs were not (OR 1.01; 95% CI 0.98-1.05). Long-acting agents showed a borderline estimate (OR 1.44; 95% CI 0.99-2.09). Age-stratified analyses showed higher odds in individuals aged <75 years (OR 1.36; 95% CI 1.24-1.49), but not in those aged &#x2265;75 years (OR 1.14; 95% CI 0.61-2.11). Estimates were also higher in studies using ICD-based definitions (OR 1.47; 95% CI 1.16-1.86) than in those using clinical criteria (OR 1.13; 95% CI 0.84-1.52). Meta-regression identified drug class and publication year as significant moderators. Risk of bias was rated moderate to serious in several studies, mainly due to residual confounding and exposure misclassification. Certainty of evidence ranged from very low to moderate. Use of BZDs and Z-drugs was associated with increased odds of AD, with variation across drug classes and pharmacokinetic profiles. Short-acting agents, BZDs overall, and Z-drugs were associated with higher risk, whereas broad-acting BZDs were not; this finding should be interpreted with caution given subgroup heterogeneity and limited statistical power. Residual confounding and reverse causation limit causal inference. These results support careful prescribing and the need for prospective studies with detailed characterization of exposure, dose, duration, and clinical indication to clarify whether observed associations reflect drug-related effects or underlying disease processes. PROSPERO protocol number: CRD420251141623.

Cancer represents a major global health threat, and the development of effective anticancer therapies is urgently needed. Sanguisorba officinalis (DY), a traditional Chinese herbal medicine, possesses properties including cooling blood and promoting blood circulation, detoxifying pathogenic toxins, and astringing sores. Increasing evidence suggests that DY and its bioactive constituents exhibit notable anti-tumor effects, with mechanisms that align with traditional Chinese medical principles of enhancing Zhengqi (fuzheng) and removing Xieqi (quxie). However, a comprehensive review that systematically summarizes the antitumor potential of DY and its bioactive constituents is still lacking. In this review, we summarize the anticancer effects of DY extracts and Ziyuglycosides. In vitro studies demonstrate that DY and its active components can inhibit tumor cell proliferation, induce cell cycle arrest, trigger mitochondria-mediated apoptosis, enhance autophagic flux, and suppress invasion and metastasis by regulating Wnt/&#x3b2;-catenin, PI3K/AKT/mTOR, MAPK, and EGFR/NF-&#x3ba;B signaling pathways, as well as downregulating epithelial-mesenchymal transition-related transcription factors and matrix metalloproteinases. In vivo studies confirms DY and its active components inhibit tumor growth and metastasis, regulate the tumor immune microenvironment, modulate Th17/Treg balance, activate CD8+ T cells, and enhance the anti-tumor immune responses. Notably, clinical application evidence indicates that Diyu Shengbai Pian, a preparation derived from DY, have been proven effective in alleviating leukopenia caused by chemotherapy or radiotherapy, highlighting DY's dual therapeutic potential in tumor suppression and mitigating treatment-related adverse reactions. However, current research mainly focuses on in vitro cellular studies and in vivo animal models, lacking large-scale, standardized clinical trials to validate its long-term efficacy and safety in humans. This review systematically summarizes the mechanisms of the anti-tumor and immunomodulatory effects of DY and its active components, and outlines advancements in improving their in vivo delivery efficiency, providing a theoretical basis and research reference for the translational application of DY in cancer therapy.

Strontium (Sr), a trace element with osteogenic, anti-resorptive, immunomodulatory, angiogenic, and antibacterial activities, has become an important functional component in biomaterials for bone regeneration. This review systematically summarizes Sr-functionalized biomaterials, with emphasis on Sr2&#x207a;-mediated molecular mechanisms, concentration-dependent bioactivity, local delivery strategies, fabrication-dependent ion-release behavior, antimicrobial and antioxidant functions, and clinical translational potential. Particular attention is given to the physicochemical regulation of Sr incorporation, therapeutic-ion synergy, fabrication-related release characteristics, and key challenges affecting translational application. In addition, we discuss how Sr cooperates with other therapeutic ions, including Mg, Zn, Cu, Se, and Ga, to coordinate osteogenesis, angiogenesis, immunomodulation, and infection control within the bone-regeneration microenvironment. Current limitations include the lack of unified optimal Sr dosing across different material platforms, insufficient long-term release and biosafety data, limited large-animal and clinical evidence, and an incomplete understanding of Sr-associated antimicrobial mechanisms. Overall, this review provides mechanistic insights and practical guidance for the rational design of next-generation Sr-functionalized bone-repair biomaterials.

Head and neck cancer (HNC), particularly oral squamous cell carcinoma (OSCC), remains a major clinical challenge due to its aggressive behavior, high recurrence rates, and frequent resistance to conventional therapies. Natural compounds, especially curcumin and its derivatives, have gained increasing attention as potential anticancer agents due to their ability to target multiple molecular pathways involved in tumor progression. This review critically evaluates the current preclinical and translational evidence supporting curcumin and its derivatives as monotherapeutic agents in HNC, with particular emphasis on oral cancer. We integrate the available evidence to assess the biological rationale, therapeutic potential, and current limitations of curcumin-based approaches. The molecular mechanisms underlying their antitumor activity are discussed, including modulation of EGFR/ERK and PI3K/Akt signaling pathways, inhibition of NF-&#x3ba;B and STAT3 activation, induction of apoptosis, regulation of oxidative stress, and suppression of epithelial-mesenchymal transition and tumor invasiveness. In addition, we address the impact of curcumin on the tumor microenvironment and its role in overcoming intrinsic cellular resistance mechanisms. The review also highlights advances in drug delivery strategies, such as nanoformulations, that are designed to improve curcumin's bioavailability and therapeutic efficacy. By critically integrating current evidence, this review highlights both the promise and the challenges associated with curcumin-based monotherapy in HNC, emphasizing the need for more robust and clinically relevant studies to support future translation.

Anlotinib, a multi-targeted tyrosine kinase inhibitor, has demonstrated anti-angiogenic and immunomodulatory activity in several solid tumors; however, its efficacy and predictive biomarkers in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) remain unclear. This retrospective, single-center study included 68 patients with histologically confirmed R/M HNSCC who received anlotinib as third-line or later therapy (following failure of at least two prior systemic lines; 12 mg once daily on days 1-14 every 21 days, with dose reductions to 10 or 8 mg as needed) between January 2021 and October 2023. Tumor response was evaluated according to RECIST v1.1 in patients with available radiologic follow-up. Survival outcomes were analyzed in the overall treated population. Archived tumor tissues were subjected to next-generation sequencing (NGS) and multiplex immunofluorescence (mIF) to exploratorily assess genomic alterations and immune microenvironment features. Among 68 treated patients, 14 achieved partial response, and 39&#xa0;had stable disease, yielding an objective response rate (ORR) of 22.1% and a disease control rate (DCR) of 74.6% in treated patients. The median progression-free survival (PFS) and overall survival (OS) in the overall cohort were 6.3 and 8.4 months, respectively. Patients with oropharyngeal carcinoma and ECOG performance status 0-1 demonstrated improved outcomes. NGS analysis identified frequent alterations in TP53, PIK3CA, CDKN2A, PTEN, and FGF/FGFR pathways. PI3K pathway alterations were not associated with prolonged PFS. Tumors with PD-L1 CPS &#x2265; 1 and higher CD8&#x207a; T-cell infiltration exhibited an inflamed phenotype and were associated with improved response. Grade &#x2265;3 adverse events occurred in 25.0% of patients, most commonly hypertension and hand-foot syndrome. Anlotinib demonstrated promising responses with manageable toxicity in a heavily pretreated R/M HNSCC population. Integration of genomic and immune microenvironment features may provide hypothesis-generating insights into patient selection. 1. Why was the study done? Patients with advanced head and neck cancer has returned or spread often have few options after two or more prior treatments. Researchers tested a drug called anlotinib in this difficult-to-treat group. 2. What did the researchers do and find? The study included 68 patients whose cancer had progressed after at least two earlier treatments. Anlotinib stopped tumor growth or shrank tumors in 78 out of 100 patients (disease control rate 78.0%). Tumors shrank significantly in about 20 out of 100 patients (response rate 20.5%). On average, patients lived for 8.4 months, and their cancer did not worsen for 6.3 months. Patients with tumors that had higher levels of a marker called PD-L1 (linked to immunotherapy response) tended to do better. Serious side effects occurred in 25% of patients; the most common were high blood pressure and hand-foot skin reactions. 3. What do these results mean? Anlotinib shows promise as a later-line treatment for advanced head and neck cancer, with manageable side effects. The study also suggests that PD-L1 levels and certain immune features might help predict which patients benefit most.

The exacerbation of chemoresistance and metastasis by synthetic cytotoxic reagents hinders effective cancer therapy, as these events often coincide and lead to poor clinical outcomes, yet are rarely targeted through a shared molecular mechanism. To address this, we established a mechanism-informed natural compound discovery strategy to identify a non-cytotoxic candidate with dual functionality, namely re-sensitizing drug-resistant tumor cells and preventing metastasis. Western blot, RT-qPCR, and flow cytometry were used for evaluating protein and mRNA expression, as well as cell apoptosis, while GC/MS and HPLC analyses for identifying active phytochemicals from extracts of traditional Chinese medicines. Therapeutic potential was validated in multiple mouse cancer models, including K-rasLSL-G12D/+; p53fl/fl mice. Clinical relevance was investigated via meta-analysis of associated gene signatures. Mulberroside A (Mul A) from Cortex Mori Radices was identified as an ideal compound that inhibits P-glycoprotein 1 (Pgp1) in adherent tumor cells and pericellular fibronectin (periFN) assembly on suspended tumor cells (STCs), which drive drug resistance and metastasis, respectively. Using a paclitaxel (PTX)-resistant Lewis lung carcinoma cell line, we demonstrated that ERK-dependent Pgp1 functions as a shared upstream regulator of both chemoresistance and metastatic competence. Accordingly, Mul A inhibited Pgp1 mRNA and protein levels in an ERK-dependent manner, thereby differentially restoring PTX sensitivity both in vitro and in vivo, without intrinsic cytotoxicity, and significantly inhibiting lung metastasis by reducing the Pgp1-XIAP-periFN axis in STCs. Oral administration of Mul A achieved these dual anti-cancer effects in both experimental and spontaneous mouse models. Importantly, meta-analysis of clinical datasets further linked co-elevated FN and Pgp1 expression with poor prognosis and relapse in early-stage cancer patients, underscoring the translational relevance of targeting this shared pathway. These findings identify Mul A as a promising non-cytotoxic therapeutic candidate and elucidate the shared upstream molecular mechanism linking distinct downstream chemoresistance and metastasis.

Acinetobacter baumannii is a globally prevalent Gram-negative pathogen responsible for a substantial proportion of healthcare-associated infections, particularly in intensive care units. Its ability to persist in hospital environments, form biofilms on medical devices, and evade host immune responses has contributed to the rapid emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. This narrative review was conducted through a comprehensive literature search of PubMed, Scopus, Web of Science, and Google Scholar, focusing on studies published primarily over the past two decades. The review summarizes global epidemiology, vulnerable populations, mechanisms of antimicrobial resistance, clinical and economic impacts, and current and emerging therapeutic strategies. The advances in alternative treatments, including antimicrobial peptides, bacteriophage therapy, and vaccine development, are also discussed. In addition to summarizing existing knowledge, this review critically examines the key limitations underlying current therapeutic and vaccine strategies, including rapid resistance evolution, immune evasion, and antigenic variability. It further identifies major translational gaps and proposes future directions integrating systems biology and multitarget approaches. Although preclinical studies demonstrate the promising efficacy of several vaccine candidates, clinical trials in humans remain necessary to confirm their safety and effectiveness.

Rodent models are critical tools in the study of trauma and burn injury, giving mechanistic insights into the unique pathophysiological response and the systemic complications that follow. These models allow researchers to control injury patterns, longitudinally assess immune and metabolic responses, and evaluate therapeutic strategies in ways that are not feasible in human subjects. In this second part of our review, we examine how experimental trauma and burn models have evolved to better replicate the clinical trajectory of critically ill patients, with emphasis on polytrauma, burn injury, and translational relevance. We also highlight the role of the gut microbiome in the pathogenesis of shock within sepsis, trauma, and burn and review how rodent models have been used to investigate dysbiosis and test microbiome-targeted interventions. Although interspecies differences pose translational challenges, ongoing refinements in model selection, injury models, microbiome characterization, and reverse-translational approaches continue to expand the utility of rodent models, allowing researchers to discover vital insights into the complex pathophysiology of these critically ill patients and potential therapeutic targets that guide further investigation.

Takeda G-protein-coupled receptor 5 (TGR5) and farnesoid X receptor (FXR) are bile acid-activated receptors involved in glucose, lipid, and energy homeostasis, making them promising therapeutic targets for type 2 diabetes mellitus (T2DM) and metabolic liver diseases. This review critically analyzes patents published between 2015 and 2025 retrieved from WIPO Patentscope, Espacenet, USPTO, and Google Patents using keyword- and IPC-based strategies. Major patented chemotypes include modified bile acids, benzoic acid-cholane hybrids, heteroaryl scaffolds, and sulfonylurea/sulfonamide derivatives. Several compounds demonstrated sub micromolar (&#xb5;M) to nanomolar (nM) TGR5/FXR agonistic activity, while gut-restricted agonists showed enhanced GLP-1&#xa0;secretion with reduced systemic adverse effects such as gallbladder filling and pruritus. Comparative patent analysis revealed a progressive transition from classical steroidal scaffolds toward tissue-selective and gut-restricted modulators designed to improve receptor selectivity, pharmacokinetics, and translational safety. Despite strong preclinical promise, the clinical translation of TGR5 and FXR agonists remains limited by mechanism-driven toxicities and inadequate long-term tolerability. Future progress will likely depend on tissue-selective, pathway-biased, and gut-restricted modulation rather than further increases in receptor potency.

During pregnancy, noise stress has been associated with the activation of the hypothalamic-pituitary-adrenal axis and increased oxidative stress, which can disrupt hormonal balance and adversely affect pregnancy outcomes. Malondialdehyde (MDA) is a key biomarker of lipid peroxidation, whereas estrogen plays a critical role in maintaining gestational homeostasis. Excess oxidative stress and hormonal imbalance may impair fetal development. Nanocurcumin, a curcumin nanoparticle formulation, exhibits enhanced antioxidant and anti-inflammatory properties compared with conventional curcumin and may offer protective effects against pregnancy-related oxidative damage. This study aimed to evaluate the effects of nanocurcumin on MDA and estrogen levels in pregnant mice exposed to noise-induced stress, contributing to Sustainable Development Goals(SDG) 3 (Good Health and Well-being) through stress mitigation and maternal health protection, and SDG 9 (Industry, Innovation, and Infrastructure) by applying innovative nanotechnology. An experimental study was conducted using 25 pregnant BALB/c mice randomly divided into five groups: K(-): untreated control, K(+): exposed to 135 dB noise for 40 minutes, P1, P2, and P3: exposed to noise and treated with nanocurcumin at 14, 21, and 24.5 mg/kg body weight, respectively. An electric siren was placed inside a soundproof chamber to deliver noise, and the 135 dB intensity was calibrated using a precision digital decibel meter (Benetech GM1356). Oral treatment was administered from gestational day (GD) 6 to gestational day 18. Serum MDA and estrogen levels were measured using an enzyme-linked immunosorbent assay. Data were analyzed using one-way analysis of variance followed by Tukey's honest significant difference post hoc test (p < 0.05). Noise exposure numerically increased both MDA and estrogen levels, although not all differences reached statistical significance. However, nanocurcumin administration significantly reduced both parameters in a dose-dependent manner. The highest dose (24.5 mg/kg BW, P3 group) resulted in a 40.87% reduction in MDA and a 22.88% reduction in estrogen compared to K(+), with values approaching those in the untreated control. Nanocurcumin has potential as a protective agent against noise-induced oxidative stress and hormonal disturbances during pregnancy. To confirm translational relevance, future research should focus on elucidating underlying molecular mechanisms and evaluating fetal outcomes.

Several species of the genus Eryngium are traditionally used for the treatment of diabetes in different regions; however, it is still unclear to what extent these uses are supported by mechanistic pharmacological evidence. This study aims to systematically evaluate and critically synthesize the available evidence on the hypoglycemic mechanisms of Eryngium species, with special emphasis on the agreement between traditional use and experimental models. A systematic literature search was conducted in the PubMed, Scopus, and Web of Science databases up to December 2025, using the terms "Eryngium" and "diabetes." Studies were selected according to predefined inclusion and exclusion criteria. Data were extracted on the plant species, plant part, type of extraction, experimental model, dosage, and proposed mechanisms of action. A total of 13 Eryngium species with reported antidiabetic activity were identified, supported primarily by in vitro and in vivo studies, with limited clinical evidence. The main described mechanisms include modulation of insulin secretion and sensitivity, protection of &#x3b2;-cells, inhibition of hepatic gluconeogenesis, antioxidant and anti-inflammatory effects, modulation of lipid metabolism, and inhibition of carbohydrate-hydrolyzing enzymes. However, substantial heterogeneity was observed in the experimental designs, including variability in the plant parts used, extraction methods, and dosage regimens. Notably, most studies employed extraction procedures and dosages that do not reflect traditional preparations, highlighting a significant gap between ethnopharmacological knowledge and experimental validation. While Eryngium species show promising hypoglycemic mechanisms at the preclinical level, current evidence is limited by methodological heterogeneity and a lack of translational consistency. Future research should prioritize standardization of extracts, their suitability for traditional use, and rigorous evaluation of efficacy and safety to support their clinical applicability.

This study describes the implementation of a mechanistic subcutaneous (SC) injection model for the Open Systems Pharmacology platform. As the SC route of administration is gaining increased popularity, there is a growing need for tools to predict, analyze, and understand the SC absorption process and the mechanisms involved. The interplay between molecular, formulation, administration, and physiological properties influences both the rate and extent of drug appearance in circulation. The primary objective of this study was to provide a structural modeling basis for mechanistic simulations of drug absorption after SC administration, considering fundamental molecular properties and systemic disposition characteristics. A key aspect of the model design was the intention to support generalizability and translational application across drug characteristics and species, providing a consistent structure for both small molecules and biologics. The SC model was implemented leveraging the structure and parameterization of PK-Sim to allow unified integration to the whole-body physiologically based pharmacokinetic model. An input-response analysis and a set of case examples were conducted to visualize model responsiveness and illustrate potential application in drug development. The generic framework may also serve as the backbone for further implementations to describe complex injection and formulation dependencies. Collectively, this framework establishes a mechanistic foundation for the simulation of SC drug absorption of both small molecules and biologics, providing a basis for further development and informed evaluation across preclinical and clinical stages within the Open Systems Pharmacology platform.

Centaurea is a large genus of approximately 700 species, predominantly distributed across the Mediterranean region and Western Asia, that has been empirically used since ancient times for metabolic, inflammatory, hepatic, infectious, and neurological disorders. This systematic review was conducted according to PRISMA 2020 guidelines. A total of 574 eligible studies published between 1955 and 2025 were retrieved from PubMed, SciFinder, and Web of Science. Included studies covered traditional knowledge, phytochemistry, in vitro and in vivo pharmacology, toxicity, and formulation techniques. Centaurea species demonstrate significant phytochemical diversity, especially sesquiterpene lactones, flavonoids, phenolic acids, lignans, and essential oils, which support their antioxidant, antimicrobial, anti-inflammatory, cytotoxic, anticholinesterase, and hepatoprotective properties. Special emphasis-including molecular identification tools, modern extraction technologies, and metabolomics-has enhanced mapping chemical complexity, with modern bioassay platforms revealing its polypharmacology, formulation strategies, and remediation approaches. However, heterogeneity in extraction methods, assay systems, and reporting standards contributes to conflicting findings and limits comparability across studies. Structure-activity relationships indicate that &#x3b1;-methylene-&#x3b3;-lactone moieties, hydroxylated phenolics, and terpenoids are key compounds of bioactivity. Although Centaurea holds strong potential for pharmaceutical development, standardized protocols and rigorous translational research are emerging to address methodological inconsistencies, incomplete toxicological data, and the lack of clinical validation.

Gastrointestinal (GI) cancers are one of the leading causes of cancer death in the world. Since it is often not diagnosed early, it typically becomes resistant to chemotherapy, and genetic alterations in tumors are associated with metabolic remodeling, inflammatory reactions, and immunological evasion. Systemic therapies have improved yet sustained responses in progressive GI disease have not been obtained and require mechanism-directed approaches. Betulinic acid (BA) is an anticancer agent with low normal cell toxicity that exhibits selectivity and is obtained naturally as a pentacyclic triterpenoid. Preclinical results show that BA induces mitochondrial apoptosis, inhibits the PI3K/Akt and NF-&#x3ba;B pathways, inhibits epithelial-mesenchymal transition, and reverses cancer stemness, thereby creating resistance. There are comparative data in favor of pancreatic and colorectal cancers, with strong, validated, and effective data from aggressive disease models; data on gastric cancer accumulate through inflammation and by regulating stemness; esophageal data are preliminary. Nano-delivery is the answer to BA's low solubility and bioavailability, but it still faces challenges related to scale, long-term safety, and regulation. In fact, translational gaps are more about formulation than efficacy, providing a path to optimization, stratification, and clinical progress in GI cancers.

Neurotrophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) exhibit pro-survival and homeostatic properties, but their clinical translation is limited by protein instability and rapid clearance. We evaluated a PEGylated human serum albumin (HSA) nanoparticle system for BDNF/NT3 co-delivery, focusing on physicochemical stability, ocular biodistribution in the rabbit eye, intracellular protein delivery, and protection against oxidative stress-associated cellular damage in human cells. PEGylated HSA-BDNF-NT3 nanoparticles with nominal neurotrophin concentrations of 5&#xa0;&#xb5;g/mL (NeO5) or 10&#xa0;&#xb5;g/mL (NeO10) were generated by spontaneous self-assembly and characterized using multiangle dynamic light scattering, electrophoretic light scattering, and atomic force microscopy. In vivo performance was assessed after intravitreal injection in rabbits by enzyme-linked immunosorbent assay (ELISA)-based protein quantification and exploratory reverse transcription quantitative polymerase chain reaction (RT-qPCR) profiling of survival-, proliferation-, and apoptosis-related genes. Functional delivery was examined in sodium iodate-stressed ARPE-19 and 6-hydroxydopamine-stressed retinoic acid-differentiated SH-SY5Y cells using ELISA assays, JC-1 analysis, Annexin V/ propidium iodide flow cytometry, high-performance liquid chromatography for malondialdehyde quantification, and RT-qPCR. Both formulations formed stable, spherical nanoparticles (5.9-54.2 nm) with low polydispersity index (&#x2248; 0.18) and preserved colloidal integrity over 28 days. In vivo, BDNF was detectable in ocular tissues up to 72&#xa0;h and RT qPCR did not reveal a coordinated pro-apoptotic response under the tested conditions. In vitro, nanoparticle treatment significantly increased intracellular BDNF and NT3 levels, improved viability, reduced apoptotic cell fractions, and markedly decreased lipid peroxidation, particularly for NeO10. Increased tropomyosin receptor kinase B TRKB and cAMP response element-binding protein CREB expression provided supportive molecular evidence consistent with neurotrophin-related cellular responses. PEGylated HSA nanoparticles enable stable neurotrophin loading, efficient intracellular delivery, and attenuation of oxidative stress-induced cytotoxicity. These findings support further development of albumin-based nanocarriers for translational nanomedicine applications.

To evaluate whether cumin (Cuminum cyminum) oil attenuates nandrolone decanoate (ND)-induced hepatic alterations in rats. Eighty male Sprague-Dawley rats were randomized into six groups: control, cumin oil alone, ND low dose (10&#xa0;mg/kg/week), ND high dose (20&#xa0;mg/kg/week), ND low dose&#x2009;+&#x2009;cumin oil, and ND high dose&#x2009;+&#x2009;cumin oil. Cumin oil was administered orally at 400&#xa0;mg/kg/day for 4&#xa0;weeks. Outcomes included relative liver weight index, serum ALT/AST, total bilirubin, lipid profile, and blinded histopathology. Both ND doses increased ALT/AST and bilirubin levels and worsened the lipid profile compared with controls, with more pronounced and significant alterations in the high-dose ND group. Co-administration of cumin oil attenuated ND-associated elevations in liver enzymes and bilirubin, improved lipid parameters, and was associated with reduced histological damage compared with ND alone. Interestingly, cumin oil alone increased ALT/AST and lipid parameters compared with controls, although liver architecture remained unremarkable on H&E. In this rat model, cumin oil co-administration partially attenuated ND-induced hepatic biochemical, lipid, and histological alterations. However, cumin oil alone increased ALT/AST and lipid parameters despite unremarkable H&E morphology. Therefore, the present findings should be interpreted as evidence of context-dependent attenuation during ND exposure, not as proof of an independent hepatoprotective or lipid-lowering effect of cumin oil in healthy rats. Dose-ranging, safety evaluation, batch-specific chemical profiling, preparation standardization, and mechanistic studies incorporating antioxidant/oxidative stress markers such as MDA, GSH, SOD, CAT, GPx, and molecular endpoints are needed to clarify pathways and translational relevance.

Diabetic neuropathy (DN) is a multifactorial complication of diabetes mellitus driven by chronic hyperglycemia, insulin resistance, and disturbed metabolic homeostasis, leading to progressive injury of both the peripheral and central nervous systems. This study investigated whether L-serine supplementation could attenuate DN through dose-dependent metabolic and neuroprotective mechanisms in a high-fat diet (HFD) plus streptozotocin (STZ)-induced diabetic rat model. Male Wistar rats (n = 8 per group) were allocated to five groups: normal control (NC), diabetic control (DC), pioglitazone (PIO; 1.5 mg/kg/day), low-dose L-serine (S1; 200 mg/kg/day), and high-dose L-serine (S2; 400 mg/kg/day). After 60 days of oral gavage, behavioural testing, glucose and insulin profiling, HOMA-IR calculation, brain histopathology, nerve growth factor (NGF) immunohistochemistry, and LC-MS/MS-based proteomic analysis of cerebral tissue were performed. Diabetic rats exhibited marked hyperglycaemia (355.33 &#xb1; 4.72 mg/dL), hyperinsulinaemia, severe insulin resistance (HOMA-IR 16.8 &#xb1; 3.2; a 14-fold increase), impaired thermal nociception, motor dysfunction, and pronounced neuronal degeneration. L-serine supplementation significantly improved metabolic status: S1 reduced HOMA-IR by 77.4% and S2 by 87.5% relative to diabetic controls (p < 0.001). High-dose L-serine produced greater improvements in thermal sensitivity, motor coordination (rotarod latency 26.67 &#xb1; 1.52 s vs. 16.1 &#xb1; 0.85 s in DC; p < 0.05), and NGF expression (8.6-fold increase vs. DC). Histopathology confirmed attenuation of neuronal injury and gliosis in both treatment groups. Exploratory, group-level proteomic profiling identified dose-specific molecular signatures: S1 was predominantly associated with carbohydrate, lipid, and biosynthetic pathways, whereas S2 was associated with synaptic, neurotransmission-related, and proteostasis pathways. Within the constraints of an exploratory design-group-level pooled proteomics, analysis of cerebral rather than peripheral-nerve tissue, and only two doses-these findings indicate that L-serine attenuates the metabolic and behavioural features of experimental diabetic neuropathy and generates the testable hypothesis of dose-dependent neuro-metabolic remodelling. The proteomic signatures are hypothesis-generating and require orthogonal validation before any mechanistic or translational inference can be drawn.

This review explores the mechanistic and translational potential of nanotechnology-based delivery systems for natural compounds in diabetic wound healing. Diabetic wounds present a persistent challenge due to impaired tissue regeneration and chronic inflammation. Phytochemicals such as flavonoids and polyphenols exhibit potent antioxidant, anti-inflammatory, and tissue-regenerative properties but are limited by low bioavailability and stability. Nanoparticle formulations-particularly silver nanoparticles (AgNPs) and chitosan-based nanoparticles (CNPs)-offer innovative solutions by enhancing stability, tissue penetration, and sustained release of these bioactives. Our analysis highlights how these nanocarriers facilitate targeted delivery, thereby amplifying antioxidant activity, antimicrobial effects, and tissue regeneration mechanisms critical for wound healing. The review underscores the mechanistic insights into how nanoparticle systems improve therapeutic efficacy and discusses their translational potential in clinical settings. Notably, AgNPs' antimicrobial properties and green synthesis, along with CNPs' biocompatibility and bioadhesive characteristics, position these nanomaterials as promising candidates for advancing diabetic wound care. This synthesis of current evidence emphasizes nanotechnology's role in overcoming the limitations of natural compounds and advancing sustainable, effective treatments for diabetic wounds.